APASL DEFINITION

2063

Alcohol-related acute on chronic liver failure- compari- son of various prognostic scores in predicting outcome

1111 . Shalimar , Ujjwal Sonika , Saurabh Kedia , Baibaswata Nayak ,

Bhaskar Thakur2, Subrat K. Acharya1; 1Gastroenterology, All India Institute of Medical Sciences, New Delhi, India; 2Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Background and aims: There is no consensus regarding the best available prognostic score in acute on chronic liver failure (ACLF) . We compared all available prognostic models in pre- dicting outcome in alcohol-related ACLF . Methods: All consec- utive patients with alcohol-related ACLF admitted in a tertiary care center in India were included . Admission chronic liver fail- ure (CLIF)- sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE II) score, model for end-stage liver disease (MELD), MELD-Na, Child-Pugh-Turcotte (CTP) score, Maddrey’s discriminant func- tion (DF), ABIC score and CLIF-Consortium (CLIF-C) ACLF score were calculated; receiver operator characteristic (ROC) curves were compared with Hanley and McNeil test . Results: Of the 143 patients with alcohol-related ACLF, 142 (99 .3%) wermales; 90 (62 .9%) died over a median (range) hospital stay of 7 (1-45) days . Grade I ACLF was present in 40 (28%), Grade II in 44 (31%) and Grade III in 59 (41%) patients . The median (IQR) CLIF-SOFA, APACHE II, MELD, CTP score, DF, ABIC score, CLIF C ACLF score were 9 (6-10), 17 (12-22), 24 (17-31), 12 (10-13), 76 .4 (46 .4-101 .1), 17 .9 (12 .3-27 .9), 27 .8 (20 .9-34 .2) and 38 .1 (30 .6-45 .5) respectively . On mul- tivariate cox regression analysis, independent predictors of outcome were hepatic encephalopathy (early: HR 3 .52, 95% CI 1 .51 - 8 .17, P = 0 .003 and advanced: HR 4 .24, 95% CI 1 .48 - 12 .0, P = 0 .007), arterial ammonia (HR 1 .01, 95% CI 1 .00 -1 .02, P < 0 .001) and serum creatinine (HR, 1 .22 95% CI 1 .01-1 .48, P = 0 .033) . The AUROC was highest for CLIF-C ACLF score; with a cut-off score of 44, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 81 .5%, 62 .5%, 77 .9%, 67 .6% and 74 .3% respectively . CLIF-C ACLF was significantly better than MELD, MELD-Na, CTP score, DF, ABIC score and Mad- drey’s DF (P < 0 .05, Hanley and McNeil); however, statistical significance was not seen when compared with APACHE II (P = 0 .118) and CLIF-SOFA score (P = 0 .358) . Conclusions: Alco- hol-related ACLF has a high (62 .9%) mortality over a median hospital stay of 7 days . Among the available prognostic scores, CLIF-C ACLF performs better than other prognostic scores .

 

 

 

2078

Assessment and relevance of coagulation disorders in patients with acute-on-chronic liver failure during Systemic Inflammatory Response (SIRS) and development of sepsis

Madhumita Premkumar, Priyanka Saxena, Roshni Mirza, Sukriti Sukriti, Chhagan Bihari, Ashok Choudhary, Chandan K. Kedarisetty, Shiv K. Sarin; Hepatology, Institute of Liver and Biliary Sciences, Delhi, India

Background: Coagulation system is rebalanced in cirrhosis.The status of baseline coagulation disturbances in ACLF and their alterations with development of sepsis are largely unknown.

Aim: To study the dynamic changes in coagulation profile in ACLF, and their correlation with evolving SIRS and sepsis.

Patients and Methods : Of the 243 consecutive patients withACLF (APASL criteria), 114 with no evidence of sepsis were recruited (mean age 44.3±11.7 yr, males 90%). Predominant etiology for underlying liver disease was ethanol (63.1%). Patients were evaluated by tests like INR and thromboelastography (TEG), Sonoclot, and coagulation factor assays. These results were compared with 25 controls. At presentation 40/114 (35.1%) had SIRS. Twenty eight (24.5%) developed sepsis by day 3 and 52/112 (56.1%) by day 7. Only 11 /74 (14.8%) developed sepsis de novo without prior SIRS. SIRS at presentation posed a mortality risk of 48%. A deranged TEG at presentation was a predictor of bleeding (OR 2.1, p=0.05) and mortality (OR 3.1, p=0.05).Platelet count and functions (as predicted by sonoclot) were significantly lower in ACLF patients with sepsis at day 3 and 7. INR at baseline was associated with a deranged R and K component of TEG (p=0.05) and ACT of Sonoclot (p=0.02). Baseline ACT, CR and PF (sonoclot parameters), were associated with development of SIRS at day 3 (p=0.013) and sepsis at day 7( p=0.012). Likewise R and K of TEG (p=0.064) predicted sepsis. Coagulation assays for protein C,and antithrombin III were lower in all ACLF patients, when compared with controls, but did not change with sepsis. Factor 8 levels were significantly increased in all ACLF subgroups.

Conclusions: Coagulation abnormalities in ACLF are associated and correlate with an increased tendency to bleed, risk of sepsis and mortality. Coagulation parameters such as INR, TEG and Sonoclot are affected by presence of SIRS. Sonoclot parameters at baseline can serve as predictors of development of sepsis and poor outcome

 

316

Predictors of mortality in patients with acute on chronic liver failure: Do we need sub classification?

Shah Vinit, Praveen Sharma, Rinkesh K. Bansal, Tyagi Pankaj, Ashish Kumar, Naresh Bansal, Vikas Singla, Anil Arora; gastroenterology and Hepatology, Sir Gangaram Hospital, New Delhi, India

Background: Acute-on-chronic liver failure (ACLF) is defined as rapid deterioration occurring in a patient with known or unknown chronic liver disease (CLD) due to acute insult. We describe the clinical, biochemical profile of ACLF and the effect of acute insult and associated organ failures on mortality. 

Methods : Patients diagnosed as ACLF as per Asia Pacific Association for study of Liver (APASL) guidelines were prospectively enrolled. Patients evaluated by clinical presentation, etiology of acute insult and underlying CLD, presence of organ failure according to standard guidelines and in hospital mortality. Patients were classified as ACLF-1 when no organ failure except liver, ACLF-2 when had one organ failure along with liver, ACLF-3 when two organ failures along with liver and ACLF-4 with≥ 3 organ failures along with liver.

Results : Three hundred eighteen patients with ACLF (mean age 44.4 ± 11.5 years; M/F 292:26) were included. Median serum bilirubin 15.4 (5-64 mg %), mean CTP score (11 ± 1.9), mean MELD score (26.7 ±7.9) and median hospital stay was 8 (1-82 days). Alcoholic hepatitis (n=185, 58%), hepatitis B virus reactivation (n=32, 10 %) and acute hepatitis E (n=23,7%) were the commonest acute insults . CLD was due to alcohol (n=204,64%),HBV(n=35, 11%) and cryptogenic (n = 67,21%) and others(12,4%).Ascites present in 284 (89%),hepatic encephalopathy(HE) in 152 (48 %),septicaemia 41 (13%),chest infection 62  (20%), spontaneous bacterial peritonitis 30 (9%),acute kidney injury in 143 (45%) at the time of admission . Patients having ACLF-1 were 155 (49%); ACLF-2, 87 (27%); ACLF-3, 39 (12%) and ACLF-4, 37 (12%). Total mortality during hospitalization was (n=161, 51%).Mortality was 50 (32%) in ACLF-1, 47 (54%) in ACLF-2, 28(71%) in ACLF-3 and 36(97%) in ACLF-4. Patients who died had significantly higher CTP score, MELD score, TLC, septicaemia, HE and number of organ failures and significantly lower mean arterial pressure as compared to survivors. There was no significant difference with respect to age, etiology of acute insult, presence of variceal bleed between survivors and non survivors. On multivariate analysis only higher TLC and loss of ≥2 organ failures either at presentation or development during hospital stay were predictors of mortality. Combination of acute kidney injury and high grade HE were associated with highest mortality than other organ failure combinations.

Conclusions: Loss of two or more organ functions either at presentation or during hospital stay and high TLC at baseline are independent predictors of mortality in patients with acute on chronic liver failure.

Acute-on-chronic liver failure in India: The Indian National Association for Study of the Liver consortium experience.

Shalimar¹, Saraswat V², Singh SP³, Duseja A⁴, Shukla A⁵, Eapen CE⁶, Kumar D⁷, Pandey G², Venkataraman J⁸, Puri P⁹, Narayanswami K⁷, Dhiman RK⁴, Thareja S⁷, Nijhawan S¹⁰, Bhatia S⁵, Zachariah U⁶, Sonika U¹, Varghese T¹¹, Acharya SK¹².

Author information

Abstract

BACKGROUND AND AIM:

The aim of this study was to analyze etiologies and frequency of hepatic and extrahepatic organ failures (OFs) and outcome of acute-on-chronic liver failure (ACLF) at 10 tertiary centers in India.

METHODS:

In this retrospective study (2011-2014), patients satisfying Asian Pacific Association for the Study of the Liver definition of ACLF were included. Etiology of acute precipitating insult and chronic liver disease and outcomes were assessed. Occurrence and severity of OF were assessed by chronic liver failure-sequential organ failure assessment score.

RESULTS:

The mean (±SD) age of 1049 consecutive ACLF patients was 44.7 ± 12.2 years; Eighty-two percent were men. Etiology of acute precipitants included alcohol 35.7%, hepatitis viruses (hepatitis A, hepatitis B, and hepatitis E) 21.4%, sepsis 16.6%, variceal bleeding 8.4%, drugs 5.7%, and cryptogenic 9.9%. Among causes of chronic liver disease, alcohol was commonest 56.7%, followed by cryptogenic and hepatitis viruses. Predictors of survival were analyzed for a subset of 381 ACLF patients; OF's liver, renal, coagulation, cerebral, respiratory, and failure were seen in 68%, 32%, 31.5%, 22.6%, 14.5%, and 15%, respectively. Fifty-seven patients had no OF, whereas 1, 2, 3, 4, and 5 OFs were recorded in 126, 86, 72, 28, and 12 patients, respectively. The mortality increased progressively with increasing number of OFs (12.3% with no OF, 83.3% with five OFs). During a median hospital stay of 8 days, 42.6% (447/1049) of patients died. On multivariate analysis by Cox proportional hazard model, elevated serum creatinine (hazard ratio [HR] 1.176), advanced hepatic encephalopathy (HR 2.698), and requirement of ventilator support (HR 2.484) were independent predictors of mortality.

CONCLUSIONS:

Alcohol was the commonest etiology of ACLF. Within a mean hospital stay of 8 days, 42% patients died. OFs independently predicted survival.

 

2054

Etiology of chronic liver disease has no impact on the course and outcome of patients with Acute on Chronic Liver Failure

Yogesh K. Chawla1, Sunil Taneja1, Sahaj Rathi1, Amritangshu Borkakoty1, Ajay K. Duseja1, Shiv K. Sarin2; 1Hepatology, Post- graduate Institute of Medical Education and Research, Chandi- garh, India; 2Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India

Introduction: Acute on Chronic Liver Failure (ACLF) leads to higher mortality . Whether etiology of chronic liver disease influences the course and outcome of these patients is not well understood . Aims: To compare presentation, course and out- come of patients with ACLF with a known etiology of chronic liver disease (KC) to those with cryptogenic chronic liver dis- ease (CC) . Methods: We retrospectively analysed our data- base of 1631 patients of APASL, ACLF Research Consortium (AARC), and included consecutive patients of ACLF according to APASL definition . Patients were divided into 2 groups based on whether etiology of chronic liver disease was known (KC) or cryptogenic (CC) . The clinical and laboratory parameters, organ failures, prognostic models and short term mortality rates were compared . Results: Out of 1631 patients, 1469 patients were eligible for analysis . 1277 (87%) patients were males and 192 (13%) were females . Mean age of the patients was 44 .9 11 .8yrs . The etiology of chronic liver disease was alco- hol in 862 (58 .7%), viral hepatitis in 293 (19 .9%), cryptogenic in 146 (9 .9%), non-alcoholic steatohepatitis in 81 (5 .5%), auto- immune liver disease in 49 (3 .3%) and others in 38 (2 .6%) patients . The most common cause of acute deterioration was alcoholic hepatitis 785 (50 .8%) followed by viral hepatitis in 454 (29%),drug induced in 146 (9 .4%), autoimmune flare in 48 (3 .1%), spontaneous bacterial peritonitis and sepsis in 24 (1 .5%), tropical infections in 6 (0 .4%), variceal bleed in 8 (0 .5%), Wilsons disease in 7 (0 .4%), surgery in 1 (0 .1%) and unknown in 67 (4 .3%) patients . We compared 1323 patients in KC and 146 patients in CC group . The patients were older (49 .2014 .32 vs 44 .3811 .38yrs, p<0 .001) and females were more common in CC group versus KC group (30 .9% vs 6 .5%, p<0 .001) . CC had more severe coagulopathy (INR 2 .87 vs 2 .53, p= 0 .009) . There was no difference in inci- dence of ascites (91 .3 % vs 86 .9%, p=0 .09) or encephalop- athy (49 .6% vs 52 .5%, p=0 .51), severity of encephalopathy (p=0 .88) or the frequency of sepsis (41 .4% vs 44 .1% p=0 .53) . There was no difference in the number of organ failures (1 .49 vs 1 .68,p=0 .06),CTP, (12 vs 11 .8, p=0 .24), MELD scores (29 .9 vs 29 .6, p=0 .39),CLIF-SOFA (11 .7 vs 11 .3, p=0 .20) and APACHE II (14 .92 vs 14 .93, p=0 .64) scores . The 28 day (59% vs 62 .1%, p=0 .50) and 90 day (48 .3 vs 51 .1%, p=0 .51) survival between the two groups was similar . Con- clusion: ACLF is a syndromic entity attributing poor prognosis in patients with chronic liver disease . Our study shows that patients with cryptogenic chronic liver disease with ACLF behave similarly to those with known etiologies in terms of presentation, course and overall outcome

 

 

 

 

 

 

 

 

2059

Natural Course and Outcome in ACLF is Dependent upon the Etiology of Acute Hepatic Insults: Analysis of 368 patients

. Shalimar1, Saurabh Kedia1, Soumya J. Mahapatra1, Baibaswata Nayak1, Deepak Gunjan1, Bhaskar Thakur2, Subrat K. Acharya1; 1Gastroenterology, All India Institute of Medical Sciences, New Delhi, India; 2Biostatisics, All India Institute of Medical Sciences, New Delhi, India

BACKGROUND & AIMS: Acute on chronic liver failure (ACLF) is associated with high short-term mortality . The effect of specific acute hepatic insults on ACLF outcome is not clear . We aimed to compare the natural course and outcomes in ACLF due to acute hepatic insults . METHODS: Consecutive 368 ACLF patients at a tertiary care center in India were included . Etiology of acute hepatic insult and underlying chronic liver disease, and organ failure (OF) data was collected . Model for end-stage liver dis- ease (MELD), chronic liver failure consortium (CLIF)-C ACLF and acute physiology and chronic health evaluation (APACHE) II scores were calculated . Predictors of survival were assessed by Cox-proportional hazard model . RESULTS: Most frequent acute hepatic insult was active alcohol consumption 150 (40 .8%) followed by hepatitis B virus (HBV)- 71 (19 .3%), hepatitis E virus (HEV) superinfection- 45 (12 .2%), autoimmune hepatitis flare-17 (4 .6%), anti-tuberculosis drugs- 16 (4 .3%) and hepati- tis A virus-2 (0 .5%); remaining 67 (18 .2%) were cryptogenic . Patients with active alcohol consumption and cryptogenic acute insults had more severe disease . Median CLIF-C, MELD and APACHE II scores in active alcohol consumers, cryptogenic, HBV and HEV-ACLF were 47 .1, 47 .4, 42 .9, 42 .0 (P = 0 .002); 29, 29 .9, 28 .9, 25 .2 (P = 0 .02); 16 .5, 18 .0, 12 and 14 (P < 0 .001), respectively . Frequencies of kidney and brain failures among above etiologies were also higher- 35 .3%, 34 .3%, 23 .9%, 11 .1% (P = 0 .009); 26 .0%, 22 .4%, 15 .5%, and 4 .4% (P = 0 .01), respectively . Overall mortality rates in the 4 groups were 64 .0%, 62 .7%, 45 .1% and 17 .8% (P < 0 .001), respec- tively . In multivariable model analysis, etiology of the acute hepatic insult- alcohol (HR, 3 .06; 95%CI, 1 .10-8 .49, P = 0 .03) independently predicted mortality . CONCLUSIONS: The pheno- typic presentation of ACLF varies with acute precipitating insult . Active alcohol consumption is associated with higher mortality, whereas HEV superinfection has the best survival .

 

1407

Goal Directed Ammonia Lowering Therapy in Acute on Chronic Liver Failure (ACLF) with Hepatic Encephalopa- thy (HE): A Randomized Trial (ClinicalTrials.gov Identi- fier: NCT02321371)

Tanmay S. Vyas1, Ankur Jindal1, Rakhi Maiwall1, Amrish Sahney1, Chetan Kalal1, Madhumita Premkumar1, Guresh Kumar2, Barjesh C. Sharma1, Shiv K. Sarin1; 1Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India; 2Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India

Background and Aims: HE in ACLF is associated with high mortality . There is limited data on the role of ammonia(NH3) and anti-ammonia measures in treating HE in ACLF . We prospectively studied the NH3 dynamics and effects of goal directed ammonia lowering therapy on short-term disease outcome in ACLF patients with grade III/IV HE . Patients and Methods: Of 276 ACLF patients screened between 11 .2014 and 12 .2015; 86 with grade III/IV HE received aggressive purging with lactulose (100mL followed by 30mL hourly till 4-6 times stool passed) for first 24hr . Patients not achieving NH3 ²70ìg/dL in this period (n=73), were randomized to contin- ued lactulose arm(Gr . A, n=35) or lactulose plus rifaximin arm (Gr . B, n=38) . NH3 level was measured 12 hourly for 72hr . Management of sepsis/coagulopathy/shock/GI-bleeding, was done as per standard protocols . Primary end-point (PEP) was to achieve the target NH3 ²70ìg/dL in 72hr . Patients were followed-up till 30 days to see effect on disease outcome(sec- ondary end point) .Results: Attainment of PEP[21 .1 vs . 22 .9%, p=0 .423], improvement in grade of HE from III/IV to II/I/0 [39 .5 vs . 45 .7%, p=0 .922] & 30 day mortality[34 .2% vs . 42 .9%, p=0 .582] were not different in Gr A vs . B . However, combining the two groups, patients who achieved PEP in 72 hr (responders;n=29, 13 within 24 hr and 16 in next 48 hr), had lower baseline NH3 (169±43 vs . 216±79, p=0 .030), HE grade(grade IV in 0% vs . 26 .3%, p=0 .002), and MELD (25 .7±5 .1 vs . 31 .2±7 .5, p=0 .002) in comparison to non-re- sponders . Responders had greater improvement in HE grade III/ IV to II/I/0 [100 vs . 24 .6%, p<0 .001], and lower frequency of sepsis[10 .3 vs . 64 .9%, p<0 .001] and 30 day mortality[10 .3 vs .82 .5%, p<0 .001;Fig 1, HR=12 .8 for nonresponder; 95% CI 3 .97-41 .49] . NH3 levels correlated with HE grade(R=0 .673, p<0 .0001) . Conclusions: Monitoring and targeting NH3 is important in management of ACLF patients with HE, as patients achieving target NH3 of ²70ìg/dL, have greater likelihood of reversal of HE and improved survival . Additions of rifaximin to lactulose did not help in NH3 reduction or improvement in outcomes/survival . Newer strategies are needed for effective NH3 reduction to reduce mortality in this group .

 

268

Characteristics and outcomes of patients with Hepatitis B virus (HBV) related Acute-on-Chronic Liver Failure (ACLF) by a new classification according to the severity of underlying liver disease

Fangfang Liu1,2, Hong Zang3, Shaoli You1, Bing Zhu1, Yawei Zhang2, Zhihong Wan1, Shaojie Xin1; 1Liver Failure Treatment and Research Center of Beijing 302 Hospital, Beijing, China; 2Yale School of Medicine, New Haven, CT; 3. Liver Transplantation and Research Center of Beijing 302 Hospital, Beijing, China

Background:A new definition and classification for ACLF was proposed including the entire spectrum of chronic liver dis- eases and categorized them as type A(non-cirrhotic), type B(cirrhosis),and type C(decompensated cirrhosis) .We aimed to analyze the characteristics and outcomes of patients with HBV related ACLF according to the new classification . Meth- ods:1,240 patients with HBV related ACLF defined by Asian Pacific Association for the Study of the Liver criteria were ana- lyzed . Precipitants, response, organ failure, and transplant-free survival rates were evaluated and compared between patients with the 3 types . Results:Reactivation of HBV was the most prevalent precipitant in patients with type A (81 .8%) compared to patients with type B (73 .4%) and C(41 .5%)(P<0 .001) .Sep- sis and ischemic were more common precipitants in patients with type C(22 .2% and 24 .4%) compared to patients with type A(6 .0% and 0 .2%) and B(13 .4% and 1 .8%)(P<0 .001) . MELD-Na score and CLIF Consortium ACLF score (CLIF-C ACLFs) were higher in patients with type C in comparison with others (P<0 .001) . The CLIF-C ACLFs showed a higher ability in predicting 90-day transplant-free mortality compared to other scores in patients with Type C (AUROC=0 .7071, P=0 .021) . Infections (including spontaneous bacterial peritonitis and pneumonia) were higher in patients with type C(63 .7%) than in patients with types A (36 .1%) and B (54 .4%)(P<0 .001) . Kidney failure was the most common organ failure, with the higher incidence of 14 .8% in patients with type C compared to patients with type A(1 .4%) and B(5 .8%)(P<0 .001) .The 28-d(72 .2%, 48 .9% and 41 .4% for types A, B and C, respec- tively P <0 .001), 90-d(54 .4%, 27 .3% and 15 .8% for types A, B and C, respectively P <0 .001), and the 1-year transplant-free survival rate(48 .5%, 22 .2% and 7 .5% for types A, B and C, respectively P <0 .001) were different by ACLF subtype . ACLF subtype and CLIF-C ACLFs were both independent risk factors in predicting 28d, 90d, and 1 year transplant-free survival rates in patients with HBV related ACLF(P<0 .001) . Conclu- sion:The new ACLF classification according to the severity of underlying liver disease was clinically useful because different injury, response, and organ failure could be predicted, which also suggests different management strategies and different outcomes .

CLIF-Cs in predicting 90d mortality in typeC and K-M analysis according to ACLF type

 

534

Definition, Characteristics and Prognosis of Hepatitis B Related Pre-Acute-on-Chronic Liver Failure

Tingting Qi1, Congyan Zhu1, Zuxiong Huang2, Zhibin Zhu3, Minghan Tu4, Yongpeng Chen1, Qinjun He1, Fuyuan Zhou1, Xutong Yu1, Guanting Lu1, Jie Gao1, Jinjun Chen1, Jinlin Hou1; 1Hepatology Unit, Nanfang Hospital, Southern Medical Uni- versity, Guangzhou, China; 2Department of Infectious Diseases and Liver Diseases, Infectious Disease Hospital, Mengchao Hepatobiliary Hospital, Fujian Medical University Fuzhou, Fuzhou, China; 3Hepatopathy department 4, The third peo- ple’s hospital of Shenzhen, Shenzhen, China; 4Department of Hepatology, The Ninth Hospital of Nanchang, Nanchang, China

Backgroud Acute-on-chronic liver failure (ACLF) in patients with acute decompensation of cirrhosis has been well established by CANONIC study, characterized by short-term mortality higher than 15% . Whether the EASL-ACLF grading system suits Asia-Pacific Association for the Study of Liver (APASL) defined ACLF, especially in non-cirrhotic patients and how to identify patients who were at higher risk to develop ACLF remained unknown . Methods In this multi-center retrospective study, 329 patients from Nanfang hospital who met APASL defined ACLF at admission were included as derivation cohort, while 302 patients from other three hospitals in main- land China were included as a validation cohort . Pre-ACLF was defined according to the rates of ACLF progression and death within 28 days . A prognostic model for ACLF progression was established through cox-regression and tested by ROC curve analysis . Results Overall, there were 50 .71% and 37 .5% patients were diagnosed with cirrhosis in derivation set and validation set, separately . When stratified according to EASL-CLIF ACLF criteria, the 28-day mortality rates were 10 .0%, 15 .8%, 49 .4%, and 92 .6% for patients with ACLF grade-0 to grade-3 in derivation set and 12 .0%, 16 .7%, 43 .1% and 83 .9% separately in validation set, regardless of the underlying liver disease . However, among patients who met APASL but not EASL ACLF criteria, one third developed EASL-ACLF within 28 days in both derivation and validation set, with 28-day mortality rates of 26 .7% and 37 .0%, separately, indicating the status of “pre-ACLF” . Among such cases, the probabil- ities of EASL-ACLF development and 28-day mortality rates correlated with baseline PT-INR levels, but not total bili- rubin levels . Patients with infection at admission also had a higher probability to develop EASL-ACLF (51 .0% vs . 19 .8%, P<0 .001), but a similar mortality rate compared to those without infection (12 .2% vs . 8 .9%, P=0 .523) in derivation cohort . A prognostic model to predict the progression of EASL-ACLF within 28 days were developed and validated: 0 .033*Age+4 .087*LN_INR+0 .006*NEU%*LN_CRP-6 .237, with AUROCs of 0 .765 (0 .683-0 .846) in derivation set and 0 .751 (0 .662-0 .839) and validation set . Conclusions EASL-CLIF criteria perfectly stratified APASL-ACLF patents with different short-term outcomes . Patients met APASL but not EASL-ACLF criteria can be defined as pre-ACLF, while a prognostic model constituted with age, baseline percentage of neutrophils, C reactive protein and PT-INR can predict the progression of pre-ACLF to ACLF . Disclosures:

Jinlin Hou - Consulting: Gilead, Roche, Novartis, GSK, Abbovir; Grant/ Research Support: Novartis, GSK, BMS, J&J

The following people have nothing to disclose: Tingting Qi, Congyan Zhu, Zuxiong Huang, Zhibin Zhu, Minghan Tu, Yongpeng Chen, Qinjun He, Fuyuan Zhou, Xutong Yu, Guanting Lu, Jie Gao, Jinjun Chen

527

Emerging thrombocytopenia associated with organ failures and short-term mortality of HBV-related Acute on Chronic Liver Failure patients

Tingting Qi1, Congyan Zhu1, Beiling Li1, Zuxiong Huang2, Zhibin Zhu3, Minghan Tu4, Mingxia Zhang1, Guanting Lu1, Xutong Yu1, Jie Gao1, Qinjun He1, Yongpeng Chen1, Fuyuan Zhou1, Hai Li5, Daobing Zeng6, Jun Li7, Jinjun Chen1, Jinlin Hou1; 1Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China; 2Department of Infec- tious Diseases and Liver Diseases, Infectious Disease Hospital, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, China; 3Hepatopathy department 4, The third peo- ple’s hospital of Shenzhen, Shenzhen, China; 4Department of Hepatology, The Ninth Hospital of Nanchang, Nanchang, China; 5Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 6Department of General Surgery, Capital Medical Uni- versity Affiliated Beijing Youan Hospital, Beijing, China; 7State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Background: New onset of thrombocytopenia is common in liver failure patients; however the associations between its detailed kinetics and clinical outcomes and the underlying causality remain unknown . Methods: In a multi-center retrospective study, patients with chronic hepatitis B virus infection and acute-on chronic liver failure (ACLF) patients consistent with Asia-Pacific Association for the Study of Liver (APASL) definition were included . Hepatic platelet accumulation were eveluated in explanted liver tissues . Anti-platelet agents were tested on lipopolysacharide (LPS) plus D-galactosamine (D-GalN) induced mice model of liver failure to elucidate the potential roles platelet play . Results: Of the 582 patients enrolled, a significant decline in platelet counts after admission were observed, which was more severe in patients with higher ACLF grades or those with higher baseline INR levels but unmet EASL criteria (Figure A) . The proportion of platelet decline (%) within the first week correlated with 28-day mortality and new onset of organ failures in EASL-ACLF subjects (Figure B), as well as new onset of coagulatory failure in those who met APASL but unmet EASL criteria . Intra-he- patic platelet accumulation was confirmed in explanted liver tissues in two distinct patterns: aggregated inside the residual hepatocytes or dispersed in necrotic zone(Figure C) . Agkisacucetin, a platelet glycoprotein 1b inhibitor, improved survival rate of LPS/D-GalN induced mice liver failure by 80% (Figure D, P< .001), meanwhile diminished hepatic platelet aggregation and restored declined circula- tory platelet counts (Figure E) . Conclusions: The emerging thrombocytopenia in ACLF was associated with multiple organ system failure (MOSF) and unfavorable short-term outcomes . We speculate that hepatic platelet consump- tion constitute the second hit of liver failure, which lead to MOSF and death . (A)(B) The proportion of platelet decline in HBV-ACLF patients with different baseline characteristics (A) and 28-day outcomes (B) . (C) CD42b expression in explanted liver tissue from ACLF patients . (D)(E) Effect of agkisacucetin on survival rates and circulatory platelet counts in LPS/D-GalN induced mice liver failure .

 

 

 

 

297

Altered hepatic microenvironment governs the nature of hepatic regenerative response to acute hepatic insult

Smriti Shubham1, Jaswinder S. Maras1, Saira Hussain1, Dhananjay Kumar1, Chhagan Bihari3, Hitendra K. Garg2, Rakhi Maiwall1, Viniyendra Pamecha4, Archana Rastogi3, Anupam Kumar1, Shiv K. Sarin2; 1Research, Institute of Liver and Biliary Sciences, New Delhi, India; 2Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India; 3Pathology, Institute of Liver and Biliary Sciences, New Delhi, India; 4HPB Surgery, Institute of Liver and Biliary Sciences, New Delhi, India

Background: Acute hepatic insult triggers hepatic regeneration in both normal and chronic liver disease patient. Hepatic microenvironment plays an important role in both hepatocyte and hepatic progenitor cell (HPC) mediated hepatic regeneration.

Aim: To understand the effect of hepatic microenvironment on the nature of hepatic regeneration in response to acute hepatic insult.

Patients and Methods: Liver biopsy samples from patients with acute-on-chronic liver failure (ACLF, n=31; Gr.1), acute liver failure (ALF, n=10; Gr.2), decompensated liver disease (DLD, n=10; Gr.3) were collected and subjected to immunohistochemical (IHC) staining for Ki67 (hepatocyte self replication) and cytokeratin 7(HPC and intermediate hepatocytes) for characterization of the nature of hepatic regeneration. In the same groups hepatic vein plasma samples were obtained and subjected to cytokine bead array (bioplex-47 cytokines array-Bio-Rad) and the results were correlated with hepatocyte self replication, hepatic progenitor cell activation and maturation.

Results: IHC analysis documented a significant decrease in Ki67+ hepatocytes in Gr.1 as compared to Gr.2 (p=0.003). Further, the number of CK7+ HPC and its maturational lineages was increased in Gr.1 than Gr.2 (p=0.027). The levels of GCSF, GM-CSF, TNF-alpha, IL-2R alpha, beta NGF, HGF, IL-3, SCGF beta, basic FGF were downregulated in Gr.1 than Gr.2 (p<0.05). While the basic FGF, G-CSF, GM-CSF correlated directly to hepatocytes self replication [Ki67(p<0.05,r2>0.3)]; TNF-alpha, G-CSF and GM-CSF documented an inverse correlation with CK7+ HPC and its maturational lineages (p<0.05,r2>-0.3). Multinomial logistic regression analysis documented basic FGF independently correlated with Hepatocytes self replication with a LR=6.3 and HR= 26.4 CI (1.4-495). The G-CSF and TNF-alpha were inversely associated with CK7+ HPC activation and its maturational lineages [HR=7.4(0.9-58), 6.4 (0.9-43)].

Conclusions: Acute hepatic insult in a healthy liver triggers hepatocyte self- replication, but in a chronic liver disease patient triggers HPC mediated hepatic regeneration. Loss of basic FGF in ACLF may be responsible for compromised hepatocyte self replication and loss of G-CSF and TNF alfa may be associated with increased HPC activation and maturation.

 

 

 

 

Chemokine Ligand CXCL-8 mediated Activation and Neutrophil Influx Aggravates Liver Injury and Correlates with Clinical Severity Indices in Acute-on-Chronic Liver Failure (ACLF)

Arshi Khanam1, Peggy Riese2, Nirupma Trehan Pati1, Chandan K. Kedarisetty3, Carlos A. Guzman2, Shiv K. Sarin1,3; 1Research, Institute of Liver and Biliary Sciences, New Delhi, India; 2Vaccinology and Applied Microbiology, Helmohltz Centre for Infection Research (HZI), Braunschweig, Germany; 3Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India

Background:Acute-on-chronic liver failure(ACLF) is a serious and often fatal condition, having very high incidence of infection and mortality. Impaired neutrophil and Th17cell function has been observed in acute liver failure and served as a biomarker involved in organ dysfunction and sepsis.However, its role in ACLF remains unknown.We investigated phenotypic and functional profile of neutrophils and Th17cells associated with disease progression in ACLF.

Methods:18Alcohol–induced, 17HBV-related ACLF and 18healthy controls(HC) were enrolled. Transjugular liver biopsy was collected from patients. Peripheral blood was taken from patients and HC. Liver infiltrating leukocytes(LILs) and PBMCs were isolated.Percentage of neutrophil, CD16(activation marker), CXCR-1 and 2 (require for neutrophil migration)was observed. Absolute neutrophil, lymphocyte and total leukocyte counts(TLC)was compared in patients with and without sepsis. Neutrophils were stimulated with LPS to detect IL-6, IL-23, CCL-20 and GM-CSF level. Circulating and intrahepatic percentage of Th17cells, IL-23 receptor (require for development of pathogenic Th17)and transcription factor RORγt was investigated.Cells were stimulated in presence and absence of IL-23 and IL-1β. Cytokines IL-17, IL-22, CXCL-8, and IFN-γ were measured.

Results: Significant increase in the percentage of neutrophils,CD16, CXCR-1 and2 was observed in Alcohol(p>0.008, 0.00, 0.00, 0.003) and HBV-inducedACLF(p>0.00, 0.00, 0.00, 0.00) compared to HC. No differences were seen in alcohol vs. HBVinduced ACLF. Absolute neutrophil and lymphocyte count was higher in patients with sepsis than without. Though, TLC was comparable. Inflammatory cytokines(IL-6 p>0.00, GM-CSF- 0.00, IL-23 -0.01, and CCL-20)were significantly high in both groups and positively correlated with INR(p>0.008), MELD(p>0.03) and CTP score.Th17cells(p>0.003), IL-23receptor(p>0.04) and RORγt was significantly higher in peripheral blood of ACLF patients than HC and same was even higher in liver tissue with respect to peripheral blood in ACLF. Increased Th17cells positively correlated with ALT(p>0.00), s bilirubin(p>0.00) and INR value(p>0.00). IL-17(p>0.002), IL- 22(p>0.05), CXCL-8(p>0.03) and IFN-γ produced by Th17cells was highly elevated in ACLF than HC.These cytokines were even higher in liver compared to peripheral blood in ACLF.High CXCL-8 showed strong correlation with increased neutrophil counts(p>0.00).

Conclusion:Increased intrahepatic Th17cells produce CXCL-8 which recruits neutrophils to liver in CXCR- 1/2 dependent manner. Hyper activated neutrophil produces abundant inflammatory cytokines; thus encourages hepatic inflammation and further disease progression.

 

 

 

 

730

Impaired Neutrophil Function Aggravates Liver Injury and Correlates with Clinical Severity Indices in Acute on- Chronic Liver Failure

Arshi Khanam1, Nirupma Trehan Pati1, Peggy Riese2, Archana Rastogi3, Carlos A. Guzman2, Shiv K. Sarin1,4; 1Research, Institute of liver and biliary sciences, Delhi, India; 2Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany; 3Pathology, Institute of Liver and Biliary Sciences, Delhi, India; 4Hepatology, Institute of Liver and Biliary Sciences, Delhi, India

Background: Impaired neutrophil function has been demonstrated in acute liver failure and serves as a biomarker involved in organ dysfunction and increase susceptibility to sepsis. However, its role in acute-on-chronic liver failure (ACLF) remains completely unknown. Patients and methods: We assessed phenotypic and functional alterations of neutrophils and their contribution in hepatic injury in 17 hepatitis B virus-related ACLF (HBV-ACLF), 19 alcohol–related ACLF (alcoholic-ACLF), and 42 chronic hepatitis B (CHB) patients in comparison to 18 healthy controls (HC).Neutrophil phagocytic activity (NPA) was determined by the uptake of opsonized E. coli and reactive oxygen species (ROS) production with or without E. Coli stimulation.CXCR-1 and CXCR-2 expression was analyzed by flowcytometry, immunohistochemistry (IHC) and qRT-PCR.

Results: Percentage of neutrophils was higher in both HBV and alcoholic-ACLF patients than CHB and HC (Table). Contrarily, NPA was significantly impaired in ACLF along with significant increase in ROS. Flowcytometry and IHC showed up-regulated CXCR-1 and 2 in ACLF. In ACLF, intrahepatic CXCR-1 and 2 gene expression was higher more than 6 fold (p<0.00) with a significant increase in pro-inflammatory cytokines (IL-6, IL-17, IL-23, CXCL-8, CCL-20 and GM-CSF). Role of neutrophils in hepatic injury was determined by co-culturing of LPS stimulated neutrophils or their supernatant with HepG2 cells. As compared to controls, activated neutrophils from ACLF significantly induced early apoptosis (p<0.04, 0.05) and necrosis (p<0.00, 0.00) of HepG2 cells by direct contact as well as cytokine/ ROS dependent mechanisms.

Conclusions: ACLF patients have increased frequency of neutrophils, with high expression of migration receptors CXCR1/CXCR2. These activated neutrophils produce high ROS but have impaired phagocytic activity with high pro-inflammatory cytokine propagating hepatic injury and liver failure. Neutrophil functional markers represent a powerful tool for drug targets and clinical management of ACLF patients. Phenotypic and functional characterization of neutrophils in different diseased groups

 

540

Invasive pulmonary aspergillosis in patients with acute-on-chronic liver failure

Jie Gao1, Qing Zhang2, Yuankui Wu3, Tingting Qi1, Jin- jun Chen1; 1Hepatology unit, Nanfang hospital, southern med- ical university, Guangzhou, China; 2Pharmacy Department, Nanfang hospital, southern medical university, Guangzhou, China; 3Department of Medical Image, Nanfang hospital, southern medical university, Guangzhou, China

Background and objectives: Due to delayed diagnosis and non-optimal anti-fungal treatments, invasive pulmonary aspergillosis (IPA) exacerbates the short-term mortality of acute-on-chronic liver failure (ACLF) patients . There was no definition of delayed IPA diagnosis in ACLF patients . We aim to define delayed IPA diagnosis and introduce an optimal voriconazole regimen . Methods: We retrospec- tively analyzed ACLF patients hospitalized in Nanfang Hospital from July 2011 to April 2016 and identified those with IPA . We used the lung score (according to CLIF-SOFA score) and mortality data to define delayed IPA diagnosis . Then we describe the process of establishing an optimal voriconazole regimen with plasma voriconazole moni- toring methods, and validate its superiority by comparing the short-term mortality, resolution of lesions on pulmo- nary CT scanning, and adverse events in different treat- ment groups . Results: The incidence of IPA in ACLF patients was 6 .9% (39/565) . We established a criteria for delayed IPA diagnosis (lung score>1 at the time of IPA diagnosis) based on analysis of the lung score and its association with 28-day mortality . Patients with delayed IPA diagnosis had a greater 90-day mortality than those with prompt diagnosis (11/11 vs 11/28, p<0 .001) . Prompt diagnosed patients treated with echinocandin had a lower 90-day survival rate (1/8 vs 8/10, p=0 .021) than those treated with standard voriconazole . An optimal voriconazole regimen (loading doses: 0 .2 g twice daily; maintenance doses, 0 .1 g once daily) was established, and proved to associate with good clinical outcomes (90-day survival rate of 8/10) and optimal trough blood drug concentrations (1-5 ìg/mL fig.1) . Conclusions: Patients with delayed IPA diagnosis (lung score > 1) had an extremely higher short- term mortality . We validate that an optimal voriconazole regimen was superior to other treatment strategies with respect to efficacy and safety .

Fig 1 . The plasma voriconazole concentrations (A) in patients received standard dosage regimen and underwent dosage adjustments based on the plasma drug levels(n=4), or (B)in patients received optimal dosage from the beginning(n=6)

Disclosures:

The following people have nothing to disclose: Jie Gao, Qing Zhang, Yuankui Wu, Tingting Qi, Jinjun Chen

2061

Monocyte HLA-DR expression, neutrophil oxidative burst capacity and cytokine analysis in patients with decompensated cirrhosis with and without acute-on- chronic liver failure (ACLF).

Sandeep Satsangi1, Ajay K. Duseja1, Meenakshi Sachdeva2, Shallu Tomer2, Sunil Arora2, Sunil Taneja1, Radha K. Dhiman1, Yogesh K. Chawla1; 1Hepatology, Post Graduate Institute of Med- ical Education & Research, Chandigarh, India; 2Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India

Background: Patients with acute-on-chronic liver failure (ACLF) have increased risk of infection due to a dysregulated immune response . Comparative data on the presence of such ‘immune- paresis’ between patients with ACLF and decompensated cir- rhosis without ACLF is not available . Aim of the present study was to compare the immunological functions in patients with decompensated cirrhosis with and without ACLF . Methodology: Ninety six patients with decompensated cirrhosis with (n=38, males=35, mean age=45 .4±12 .9 yrs) and without (n=38, males=29, mean age=48 .2±13 .2 yrs) ACLF were included prospectively . Patients with evidence of current or recent infec- tion (< 1 month) were excluded . ACLF was diagnosed as per the Asian Pacific Association for the Study of the Liver definition and was graded as per the CANONIC study . All patients gave a written informed consent and study had the approval of the institute’s ethics committee . HLA-DR expression was studied by ex vivo mean percentage of monocytes expressing HLA-DR and by the mean fluorescence intensity (MFI) of HLA-DR expression . Neutrophil oxidative burst capacity (NOX) was assessed by in vitro stimulation with phorbol 12-myristate 13-acetate and MFI values of production of reactive oxygen species were analyzed by flow cytometry . Serum levels of cytokines (IL-1â, IL-6, IL-8, IL10, IL-12, and TNFá) were determined by human cytometric bead array kit . Results: Even though the values were lower than the historic controls, there was no difference in mean per- centage of monocytes with HLA-DR expression (42 .6±26 .5% vs . 43 .1±20 .9%) (p=0 .95) and MFI of HLA-DR expression (30 .3±29 .3 vs . 41 .7±52 .1) (p=0 .42) amongst patients with and without ACLF . Both groups of patients had higher NOX and its lower MFI in comparison to historic controls but there was no difference in NOX (149 .9±89 .4 vs . 152 .4±135 .4) (p=0 .29) and its MFI (16 .5±11 .9 vs . 17 .2±16 .1) (p=0 .47) amongst patients with and without ACLF . Patients with ACLF had significantly higher pro-inflammatory cytokines (pg/ml) [IL1â (3 .5±2 .6 vs . 0 .35±1 .12, p<0 .0001), IL-6(220 .9±611 .2 vs . 16 .5±16 .5, p<0 .0001), IL-8 (781 .7±865 .1 vs . 48 .8±62 .0, p<0 .0001), IL-12 (0 .9±1 .1 vs . 0 .1±0 .2, p<0 .0001 ), TNFá (3 .2±2 .9 vs . 0 .35±1 .12, p<0 .0001 ) and anti-inflammatory cytokines (pg/ml) [IL-10(3 .2±3 .6 vs .0 .4±0 .6, p<0 .0001] in comparison to patients with decompensated cirrhosis with- out ACLF . Conclusion: Patients with decompensated cirrhosis with and without ACLF have similar impairment in HLA– DR expression and neutrophil oxidative burst capacity . Both pro-in- flammatory and anti-inflammatory cytokines are increased in patients with ACLF in comparison to decompensated cirrhosis without ACLF .

 

 

TNF-α Induces Receptor Interacting Protein-3 Kinase to Mediate Necrotic Cell Death in Acute-on-Chronic Liver Failure

Arshi Khanam1, Nirupma Trehan Pati1, Archana Rastogi2, Shiv K. Sarin1,3; 1Research, Institute of liver and biliary sciences, New Delhi, India; 2Pathology, Institute of Liver and Biliary Sciences, Delhi, India; 3Hepatology, Institute of Liver and Biliary Sciences, Delhi, India

Background:Molecular mechanism of tumor necrosis factor(TNF-α) and IFN-γ induced necrotic cell death in ACLF remains largely unknown.

Methods:Intrahepatic TNF-α and IFN-γ producing CD8T cells, activation(CD69) and inhibitory marker(PD-1), TNF-α, IFN-γ, CXCL-9,10 and STAT-1 gene expression, plasma TNF-α, IFN-γ levels were analyzed in hepatitis B virus-related ACLF(GroupI,n=14), alcohol–related ACLF(GroupII,n=40), and chronic hepatitis B(GroupIII:n=42) patients. Receptor interacting protein kinase-3(RIP-3) expression was evaluated. Correlations of TNF-α and IFN-γ with clinical parameters of severity was assessed.

Results:Intrahepatic TNF-α producing CD8T cells(p<0.04, 0.05), TNF-α gene (p<0.00,0.00) and plasma TNF-α level(p<0.05, 0.05) were high in Gr.I and II than Gr.III with high CD69 (p<0.05, 0.03) and PD-1(p<0.04, 0.05). Strong CD69 staining to the necrotic vicinity of liver tissue was seen. No change in TNF-α level was seen with PD-1 blockade.Intrahepatic RIP-3 gene expression was higher in Gr.I and II(p<0.00. 0.00), more so in hepatocyte cytoplasm with intense staining towards necrotic areas. Furthermore intracellular(p<0.00, 0.00), plasma(p<0.03, 0.03) and gene expression of IFN-γ(p<0.03, 0.00) was higher in Gr.I and II than III. IFN-γ also induced proinflammatory genes; CXCL-9,10 and downstream signaling molecule STAT-1. TNF-α and IFN-γ were positively correlated with serum ALT(p<0.00, 0.00), INR(p<0.02, 0.00), CTP(p<0.03, 0.02) and SOFA score(p<0.04,0.00).

Conclusions:Increased intrahepatic CD8T cells in ACLF lead to enhanced TNF-α, inducing RIP-3 pathway to mediate hepatocellular necrosis.In addition, IFN-γ promoted proinflammatory pathway induces inflammation and disease progression. High PD-1 expression is not sufficient in controlling TNF-α and IFN-γ induced liver damage.These data could help in developing new single or combined molecular targets to prevent progressive liver injury in ACLF

 

THU-270

 

Hemophagocytic Lymphohistiocytosis (HLH) in patients of acute on chronic liver failure-Results of multination study from APASL-ACLF research consortium (AARC)

H.V. Tevethia¹, A. Choudhury², H.L. Ghazinyan³, C. Eapen⁴, A. Goel⁴,Duan⁵, Y. Chen⁵, D.J. Kim⁶, J.-D. Jia⁶, D. Amarapurkar⁷, S.S. Hamid⁸, W. Jafri⁸, S.-S. Tan⁹, Z. Abbas¹⁰, G.H. Lee¹¹, S.G. Lim¹¹, J.H. Hu¹²,Y. Chawla¹³, S. Taneja¹³, S. Shah¹⁴, C. Kalal¹⁴, H. Deverbhavi¹⁵,O. Yokosuka¹⁶, P. Jain¹⁷, I. Paulson¹⁷, G. Kumar¹⁷, S.K. Sarin². ¹ILBS, Hepatology, New Delhi, India; ²ILBS, Hepatology; ³Nork Clinical Hospital of Infectious Disease Armenia, Hepatology; ⁴CMC, Hepatology, Vellore, India; Beijing You’an Hospital/Translational Hepatology Institute Capital Medical University; ⁶Hallym University College of Medicine, South Korea/Beijing Friendship Hospital, Capital University, Beijing, China; ⁷Bombay Hospital & Medical Research Center, Mumbai, India;⁸Aga Khan University Hospital, Karachi; ⁹Hospital Selayang, Bata Caves, Selangor; ¹⁰Ziauddin University Hospital, Karachi; ¹¹Yong Loo Lin School of Medicine, National University of Singapore; ¹²302 Millitary Hospital Beijing, China; ¹³PGIMER, Chandigarh, India; ¹⁴Global Hospital, Mumbai, India; ¹⁵St John Medical College, Bangalore, India; ¹⁶Chiba University; ¹⁷ILBS

 

Email: hershey4686@gmail.com

 

Background and Aims: Activation of macrophages in response to acute hepatic insult in patients with pre-existing chronic liver disease presenting as ACLF is a new entity, HLH. Considered to be result of a cytokine storm, uncontrolled inflammatory response, HLH has a poor survival. We studied patients of ACLF to investigate the spectrum, presentation and influence of HLH syndrome on organ failure, disease severity and short-term survival.

 

Method: The patients diagnosed to have ACLF (APASL definition) were recruited from 52 centres across Asia Pacific. The data was prospectively collected in this observational study cohort on a

predefined format in the database from October 2012 to September 2017. A total of 615 patients of ACLF with ferritin >500 μg/l, were analyzed among those fulfilling the HLH criteria [5 of 8 criteria i.e. fever, splenomegaly, bicytopenia,hypofibrinogenemia & ferritin >500 μg/l, irrespective of the bone marrow examination).

 

Results: Out of 615 patients with ferritin above >500 μg/l, the HLH was seen in 90 (14.6%) cases i.e. full-filling 5 criteria. Males were 84.1% and with mean age of 43.31 ± 11.69 yrs. Alcohol was the most common acute and chronic etiology followed by Hepatitis B reactivation. The most common presentation was Jaundice (98.5%), hypofibrinogenemia (93.3%), Spleenomegaly (73.1%) and Fever (61%). Organ failures more than 2, Creatinine >1.49 mg/dl, albumin <2.3 gm/l, INR >2.4, Total Bilirubin >22.3 mg/dl and HE at baseline independently predicted 90 day mortality. Presence of HLH increased mortality ( p < 0.001) even though various disease severity scores MELD Na [31.49 ± 7.56 vs 28.05 ± 7.38,* p = 0.27], SOFA [10.69 ± 3.20 vs 8.78 ± 3.09, p = 0.84], AARC Score [10.37 ± 2.15 vs 9.85 ± 2.19, p = 0.79] were not different between those dying versus surviving.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conclusion: Presence of HLH even in absence of bone marrow confirmation is a poor predictor of outcome in patients of ACLF. Diagnosis of HLH predicts worse prognosis. Newer definition and criteria for HLH and its inclusion in liver severity scores is required in ACLF patients.

 

THU-320

 

IRREVERSIBLE MODIFICATION OF CIRCULATING ALBUMIN IN ACUTE ON CHRONIC LIVER FAILURE (ACLF) TRIGGERS NEUTROPHIL BURST VIA INDUCING GENES ASSOCIATED TO CYTOKINE RELEASE AND CELLULAR STRESS

S. Das¹, J.S. Maras¹, S. Hussain¹, P. David¹, S.M. Shasthry²,Trehanpati¹, S.K. Sharma¹, T.P. Singh³, S.K. Sarin⁴. ¹Department of Molecular and Cellular Medicine; ²Department of Hepatology, Institute of Liver and Biliary Sciences; ³Department of Biophysics; ⁴Department of Molecular and Cellular Medicine and Department of Hepatology, All India Institute of Medical Sciences, New Delhi, India

 

E-mail: suri.sukanta@gmail.com

 

Background and Aims: Circulating milieu in ACLF patients is associated with increased systemic oxidative stress and concurrent immune cell activation. Neutrophil respiratory burst results in generation of ROS and RNS. Circulating albumin has ROS and RNS scavenging properties. Modifications in the albumin structure may result in its inability to curb oxidative stress. We examined the contribution of modified circulating albumin in neutrophil activation, production of intracellular stress and associated altered molecular pathways.

 

Methods: Albumin was purified from plasma of alcoholic ACLF (n = 10), cirrhosis (n = 10) and healthy controls (HC, n = 10). Plasma oxidative stress was measured by advanced oxidative protein product (AOPP). Neutrophils from healthy subjects was incubated with albumin purified from study groups and commercially available albumin (5% HSA). Intracellular ROS production was measured by FACS dihydrorhodamine (DHR) test. Cell supernatant was subjected to measurement of neutrophil activation markers; MPO and NGAL. Neutrophils isolated from study groups were subjected to RT-PCR based expression analysis for a panel of 83 genes associated with oxidative stress, neutrophil activation, ER stress, apoptosis, cell adhesion, chemokine and interleukin modules.

 

Results: The purified albumin was 95% pure. Plasma levels of AOPP were found to be significantly higher ( p < 0.05) in ACLF [151.1 μmol/L] as compared to cirrhosis [86.15 μmol/L] or HC [27.40 μmol/L]. Intracellular ROS was found to be highest in healthy neutrophil incubated with ACLF-albumin [MFI = 2,500] as compared to cirrhosis-albumin [MFI = 1,200] or HC-albumin [MFI = 1,000] ( p < 0.01). Commercial albumin did not demonstrate significantly different ROS levels in healthy neutrophils. ACLF-albumin treated cell supernatant had significantly higher ( p < 0.05) MPO and NGAL levels [53.4, 31.4 ng/mL] as compared to that from cirrhotic [45.4, 10.9 ng/mL] or HC [26.9, 5.1 ng/mL]. RT-PCR analysis revealed increased gene expression (>2FC, p < 0.05) in all modules [oxidative stress(79%), neutrophil activation (100%), ER stress (30%), apoptosis (58%), cell adhesion (50%), chemokine and interleukin (57%)] in neutrophils of ACLF as compared to cirrhosis.

 

Conclusions: The present study provides evidence that albumin in ACLF patients is not only oxidatively modified but also acts as a potent mediator for induction of neutrophils during ACLF.

 

 

286

A Dynamic Model for Predicting Outcome in Patients with HBV Related Acute-On-Chronic Liver Failure

Wei Lin1, Chenggang Jin2, Xiaohui Liu1, Jinqiu He3, Ming Li4, Shuqin Zhang5, Yuexin Zhang6, Hong Chen7, Changqing Zhang8  Lixia Ma1, Xinhuan Wei1, Haiqing Guo1, Zhen Li2, Wenfang Wu9, Jinhua Hu10, Qinghua Meng1, Huiguo Ding1, Yu Chen1, Sujun Zheng1, Shuang Liu1, Jing Zhang1, Zhongping Duan1; 1Beijing Youan Hosptial,Capital Medical University, Beijing, China; 2Beijing Normal University, Beijing, China; 3The Ninth Hospital of Nanchang, Nanchang, China; 4The Second People’s Hospital of Fuyang, Fuyang, China; 5Hepatobilary Hospital of Jilin Province, Changchun, China; 6The First Teaching Hospital of Xinjiang Medical University, Wulumuqi, China; 7The First Affiliated Hospital of Lanzhou University, Lanzhou, China; 8The Sixth People’s Hospital of Kaifeng, Kaifeng, China; 9Capital Medical University, Beijing, China; 10302 Military Hospital, Beijing, China

Background: Acute-on-chronic liver failure (ACLF) is a fatal syndrome with rapid progress in months. Most of the existing prediction models were based on static baseline variables from cohort with various etiologies. The aim of the study was to use the 7-day serial serum biomarker to predict outcome of HBV related ACLF.

Design: This was a prospective, multicenter, observational study. The predication model was established based on hospitalized HBV-ACLF patients from 7 hospitals. Thereafter the model was validated in another 74 HBV-ACLF cohorts. All the patients fulfilled the diagnosis criteria of APASAL “ACLF consensus recommendations” (2010). They were all serum HBsAg positive and treated with nucleoside analogs as standard therapy. The primary endpoint was mortality at 12th week. The dynamic model was constructed based on the change of variables over 7 days with logistic regression method by SPSS17.0.

Results: 274 cases were screened and 205 cases were enrolled to the study as derivation cohort. Of the 205 HBV-ACLF patients, 171 (83.4%) were male, median age was 41.2 years. 46.8% was Anti-HBe positive. The median HBV DNA level was 5.7(0~8.9)×log10 IU/ml. 90(43.9%) cases were treated by entecavir(ETV), the others were treated by lamivudine(LAM). The overall 12-week mortality was 23.9% with median survival period 25.9 days. The 12- week mortality in ETV group and LAM group was 25.2% and 22.2% respectively(P=0.742). Four variables were selected as prediction factors: serum total bilirubin (TBil, μmol/L), platelet count (PLT, 109/L), prothrombin activity (PTA, %), Anti-HBe (positive= 1, negative=0). The model was developed with the values on baseline and their evolution on the 7th day. The dynamic HBV-ACLF model was: -1.515+ 0.007× TBil +0.004×evolution in TBil - 0.057× PTA - 0.028×evolution in PTA -0.013× PLT +1.271×Anti-HBe. The model demonstrated improved prediction with an area under the receiver operator characteristic curve (AUC) of 0.856 (cutoff:-0.730; sensitivity:67.3%; specificity: 91.0%), which was superior to the MELD (AUC: 0.579) and the MELD-Na (AUC: 0.624), even when their 7-day serial values were taken into consideration (AUC=0.676 and 0.669 respectively), all p< 0.01. In the validation cohort, the performance of the dynamic HBV-ACLF model (AUC=0.881) also showed superior to MELD (AUC: 0.782) and the MELD-Na (0.761) (all p< 0.01).

Conclusion: The present dynamic prediction model can achieve a better prediction of the 12-week out-come of HBV-ACLF, which may be beneficial for  adjusting therapy strategy on time.

 

 

1263

Validation of TPPM Score in predicting short- term survival in HBV-ACLF patients: a multi- national study from APASL ACLF Research Consortium (AARC)

Tao Chen1, Ke Ma1, Ashok K. Choudhury2, Manoj K. Sharma3, Zhongping Duan4, Shaojie Xin5, Yuemin Nan13, Tao Han6, Soek Siam Tan7, Jinhua Hu8, Saeed S. Hamid9, Amna S. Butt9, Syed M. Jafri9, Guan Huei Lee10, Hasmik Ghazinyan11, Yogesh K. Chawla12, Sunil Taneja12, Akash Shukla14, Man Fung Yuen15, Jidong Jia16, Zaigham Abbas17, Sombat Treepras- ertsuk18, Harshad Devarbhavi19, Abdulkadir Dokmeci21, Deepak N. Amarapurkar20, Manoj K. Sahu22, Laurentius A. Les- mana23, George Lau24, Osamu Yokosuka25, Wei Guo1, Shiv K. Sarin2, Qin Ning1; 1Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology,

2
Wuhan, China; Institute of Liver and Biliary Sciences, New

Delhi, India; 3Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh; 4Youan Hospital, Capital Medical Univer- sity, Beijing, China; 5Youan Hospital, Capital Medical Univer- sity, Beijing, China; 6Third central hospital, Tianjing, China; 7Selayang Hospital, Kepong, Malaysia; 8302 Military Hospital, Peking University Health Science Center, Beijing, China; 9Aga Khan University Hospital, Karachi, Pakistan; 10National Uni- versity of Health System, Singapore, Singapore; 11Nork Clin- ical Hospital of Infectious Diseases, Yerevan, Albania; 12Post Graduate Institute of Medical Education and Research, Chan- digarh, India; 13Department of Traditional and Western Med- ical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China; 14KEM Hospital, Mumbai, India; 15Queen Mary Hospital, Hongkong, Hong Kong; 16Beijing Friendship Hospita, Beijing, China; 17Ziauddin University, Karachi, Paki- stan; 18Chulalongkorn University, Bangkok, Thailand; 19St John Medical College, Banglore, India; 20Bombay Hospital and Medical Research Centre, Mumbai, India; 21Ankara University School of Medicine, Ankara, Turkey; 22IMS &SUM hospital, Odisa, India; 23Digestive Disease & Oncology Centers, Medistra Hospital, Jakarta, Indonesia; 24Humanity and Health Research Centre, Hongkong, Hong Kong; 25Departments of Gastro- enterology and Nephrology, Graduate School of Medicine, Chiba, Japan

Objective: Tongji prognostic predictor model (TPPM)for HBV- ACLF, includes bilirubin (TBIL), INR, number of compli- cations and HBV DNA and has been validated for its predic- tive value from a single center . We aimed to compare TPPM model with model of end-stage liver disease (MELD) and MELD-Na in predicting short term survival in patients with HBV-ACLF from APASL ACLF Research Consortium (AARC) data base, from 26 countries . Patients and Methods: In this prospective-retrospective study, we enrolled 471 (302 males) patients with HBV-ACLF who were hospitalized and treated with anti-HBV nucleot(s)ide analogues (NUCs) and traditional internal medicines . TPPM, MELD and MELD-Na score were measured at hospitalization and 90-day survival was predicted . Results: Among the 471enrolled patients, 302 (64 .1%) survived and 169 (35 .9%) were non-survivors at 90-day . The baseline characters including age (44 .59±13 .62 vs . 45 .73±14 .86yr), gender (male/female, 208/263 vs . 141/161), ALT (491±830vs . 566±773IU/ml), AST (566±723 vs . 602±864, IU/ml), TBIL (18 .2±9 .1 vs . 21 .7±9 .5, mg/dl) and INR (2 .07±0 .69 vs . 2 .65±1 .27)did not show significant difference (p > 0 .05) between survivors and non-survivors . The baseline prognostic scores of TPPM, MELD and MELD-Na between survivors and non-survi- vors were 0 .87±0 .15 vs . 0 .79±0 .22 (p<0 .001), 24 .52±5 .69 vs . 29 .16±6 .57 (p=0 .013) and 27 .27±5 .67vs . 31 .62±5 .37

(p=0 .043) . Using the Hosmer-Lemeshow test, the valida- tion of the TPPM score for HBV-ACLF demonstrated a good degree of fit with prediction of disease prognosis . Based on this large cohort of patients, the TPPM score with an AUC of 0 .732 was found superior to the MELD score and MELD-Na score, which had an AUC of 0 .712 and 0 .714 in predicting 90-day mortality in HBV-ACLF . Conclusion: The TPPM scoring system has been found to be truly predictive and has been validated in the international AARC data- base . It shows its superiority in a disease specific scenario of HBV ACLF compared with MELD and MELD-Na, and is recommended for patient stratification at admission for NUCs and/or liver transplantation .

Disclosures:

Jidong Jia - Consulting: Gilead, Abbvie, BMS, GSK

Osamu Yokosuka - Grant/Research Support: Bayer, Takeda, Tanabe- Mitsubishi, Eizai, Nihonkayaku, Ohtsuka Seiyaku, Bristol Myers, Chugai, Daiichi Sankyo, MSD

Qin Ning - Advisory Committees or Review Panels: ROCHE, NOVARTIS, BMS, MSD, GSK; Consulting: ROCHE, NOVARTIS, BMS, MSD, GSK; Grant/Research Support: ROCHE, NOVARTIS, BMS; Speaking and Teaching: ROCHE, NOVARTIS, BMS, MSD, GSK

The following people have nothing to disclose: Tao Chen, Ke Ma, Ashok k . Choudhury, Manoj K . Sharma, Zhongping Duan, Shaojie Xin, Yuemin Nan, Soek Siam Tan, Jinhua Hu, Saeed S . Hamid, Amna S . Butt, Syed M . Jafri, Guan Huei Lee, Hasmik Ghazinyan, Yogesh K . Chawla, Sunil Taneja, Akash Shukla, Man Fung Yuen, Zaigham Abbas, Sombat Treeprasertsuk, Harshad Devarbhavi, Abdulkadir Dokmeci, Deepak N . Amarapurkar, Manoj K . Sahu, Laurentius A . Lesmana, George Lau, Wei Guo, Shiv K . Sarin

 

THU-319

 

MOLECULAR ELLIPTICITY OF CIRCULATING ALBUMIN-BILIRUBIN COMPLEX IS A RELIABLE PROGNOSTIC MEASURE OF SEVERITY OF ACUTE ON CHRONIC LIVER FAILURE (ACLF)

S. Das¹, J.S. Maras¹, S. Hussain¹, C. Sudarshan², S.M. Shastry³,S.K. Sharma ¹, P. Balaram⁴, S.K. Sarin⁵. ¹Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi;

²Molecular Biophysics Unit, Indian Institute of Science, Bangalore;³Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi; ⁴Molecular Biophysics Unit, Indian Institute of Science, Bangalore; ⁵Department of Molecular and Cellular Medicine and Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India E-mail: suri.sukanta@gmail.com

 

Background and Aims: Interaction of bilirubin with albumin results in an optically active albumin-bilirubin (A-B) complex, measured using circular dichroism (CD) spectroscopy. In liver failure patients, specially ACLF, high bilirubin and low albumin are generally seen and this may affect formation of A-B complexes. We investigated the correlation of variability in A-B complex with the severity and albumin functionality in ACLF patients, in two phases; discovery (DP) and validation phase (VP).

 

Methods: Albumin/bilirubin (A/B) ratio was determined in plasma samples of ACLF [n = 90; 40 enrolled during DP and 50 during VP], cirrhosis [n = 60; 30DP and 30VP], and healthy controls [HC, n = 30; 15DP and 15VP] and CD spectra of A-B complexes were recorded. The optical activity of A-B complex (in term of molecular ellipticity) was estimated from the CD spectra, which was then correlated with the severity and outcome in ACLF patients. Further, the plasma samples were subjected to determination of albumin binding capacity (ABiC) and correlated with molecular ellipticity.

 

Results: The A/B ratio was reduced in ACLF (1.33) as compared to cirrhosis (12.66) and HC (107) ( p < 0.01). Molecular ellipticity of A-B complex was found to be highest in ACLF (2.47 mdeg), compared to cirrhosis (1.1 mdeg) and HC (0.67 mdeg) ( p < 0.01). Molecular elipticity significantly correlated with MELD, CTP and SOFA scores

 

• p < 0.05, r2 > 0.3). ROC analysis showed AUROC of 0.74 ( p < 0.01, 95% CI “0.633–0.856”), cut-off of 1.5 mdeg at “86–87” sensitivity-specificity for molecular ellipticity, which correlated significantly with mortality ( p < 0.05, r2 > 0.3). KM curve analysis elucidated an increase in the overall mortality or 1 month mortality in ACLF patients with molecular elipticity >1.5 medg (log rank <0.01). In addition, binding capacity of circulatory albumin (ABiC) was found to be significantly reduced ( p < 0.001) in ACLF(54.4%) as compared to cirrhosis (74.3%) and HC (96.1%), inversely correlating with molecular ellipticity of A-B complex ( p < 0.05, r2 > 0.3).

 

Conclusions: Molecular ellipticity of A-B complex in plasma correlates with severity and outcome of ACLF patients. Increased interaction between bilirubin and albumin molecules in ACLF patients is an additional mechanism for reduced functionality of albumin and can serve as a reliable marker of outcome in ACLF patients.

PS-073

Albumin decreases the incidence of paracentesis induced circulatory dysfunction with less than 5 litres of ascitic tap in acute on chronic liver failure (ACLF) patients: Randomized controlled trial (NCT02467348)

V. Arora1, R. Maiwall1, S.S. Thomas2, V. Rajan1, R. Ali1, G. Kumar3, P. Jain3, S.K. Sarin4. 1Institute of Liver and Biliary Sciences, Hepatology, Delhi, India; 2Institute of Liverand Biliary Sciences, Clinical Biochemistry, Delhi, India; 3Institute of Liver and Biliary Sciences, Clinical Research and bio statistics, Delhi, India; 4Institute of Liver and Biliary Sciences, Department of Hepatology, Vasant kunj, India

Background and Aims: PICD is diagnosed by increase in plasma renin activity (PRA) (>50% from baseline or >4 ng/ml/hour) on day 6 post large volume paracentesis (>5 L). It is associated with hepatic encephalopathy (HE), hyponatremia and high mortality. Patient  with ACLF have high portal pressure, cardiac output and lower systemic vascular resistance (SVR) compared to decompensatedcirrhosis. There is lack of data on the incidence, diagnosis and

management of PICD in ACLF. We hypothesized an increased predisposition to circulatory dysfunction even with modest volume paracentesis (<5 L) in ACLF patients and aimed to determine the need for albumin infusion.

Method: 59 ACLF patients, undergoing paracentesis of <5 L were randomized to receive albumin (8 g/L of ascitic fluid, Gr A, n = 30) or no albumin (Gr. B, n = 29). Heart rate (HR), systolic BP (SBP), diastolic BP (DBP) were monitored for 6 days. PRA and NTpro-BNP were analysed at baseline, day 3 and 6. Hyponatremiawas defined as Na <130 Meq/l or > 5 Meq ↓, AKI as ICA-AKI criteria & HE ≥ grade 2.

Results: Baseline characteristics were comparable in two groups, including mean volume of tap (4.21 ± .15 vs 4.26 ± .24 L, p = .35), baseline PRA(19.59 ± 7.4 vs 22.52 ± 9.1 ng/ml, p = .18), HVPG (19.1 ±4.6 vs 19.3 ± 5.7 mmHg, p = .18) & SVR 1357 ± 511 vs 1375 ± 419 dynsec/cm5/m2, p = .83). PICD was more frequent in Gr B than A (62% vs. 26%; p = 0.002). ↑ incidence of HE (24% vs 6.7%, p = .06), hyponatremia (62% vs 30%, p = .05), AKI (36% vs 11%, p = .001) and ↓ in DBP (4.37 ± 6.3% vs 9.61 ± 8.4%, p = .009)was more in Gr B than A. ↑ in PRA at day 3 correlated (p < .001, r2 = 0.8) with day 7, indicating reliability of PRA ↑ at day 3. Increase in NTproBNP was noted from baseline to day6 in Gr B (p = .009). Predictors of PICD on day6 on univariate analysis were: baseline HVPG (OR1.19,95% CI1.02–1.39, p = .02), PRA at day3 (OR1.08,95% CI = 1.02–1.15, p = .007) and non-albumin infusion (OR6.11,95%CI = 1.97–18.89, p = .002). On multivariate analysis, only non-albumin infusion (OR11.66, 95% CI 2.43–55.83, p = .002) was significant. Patients who developed PICD had higher mortality (80% vs 20%, p = .001). Gr B had a higher mortality than Gr. A patients (73% vs 26%, p = 0.03).

Conclusion: Even <5 L of ascitic tap without albumin resulted in PICD in 62% ACLF patients with increased incidence of complications &mortality. Albumin reduces the incidence of PICD and mortality to 1/3rd and is recommended as a plasma expander for even modest volume tap in ACLF patients.

2049

Improved short-term survival in patients with Acute-on- Chronic Liver Failure (ACLF) in extremis with a combina- tion therapy approach

Gaurav Pande1, Kamlesh Kumar1, Prabhat Sharma1, Krishna V P1, Amit Goel1, Abhai Verma1, Praveer Rai1, Samir Mohindra1, Uday C. Ghoshal1, Prabhakar Mishra2, Vivek A. Saraswat1; 1gastro- enterology, Sanjay gandhi post graduate institute of medical sci- ences, Lucknow, India; 2Stastistics, SGPGI MS, LUCKNOW, India

Background: ACLF in extremis is a subset with a very high MELD and short-term mortality . Pathophysiology of ACLF is dominated by severe systemic inflammation and aggravated hyperdynamic circulation originating from the gut and lead- ing to multi organ dysfunction .Using a combination of treat- ments that address major pathophysiologic derangements may improve survival . Aim: To study the efficacy of combination medical therapy (CMT) using N-acetylcysteine(NAC), probiot- ics and slow infusion of furosemide, albumin with or without terlipressin [SIFA (T)] in patients with ACLF in extremis with high CVP and compare it with a similar cohort treated with standard medical therapy (SMT). Methods: ACLF according to APASL, OF according to CLIF-SOFA and MELD ³35 were included . After standard blood, urine and ascitic fluid tests a central venous pressure (CVP) catheter was placed .Consecutive patients with CVP ³10 cmH2O received CMT(Arm I) using slow infusion of furosemide (2 mg/ hour),albumin (2 gm/ hour; 20-40g/d;(SIFA), NAC and oral probiotics in addition to SMT for complications of ACLF . Furosemide was stepped up by 2 mg/h every 12 hours for 48 hours based on urinary sodium (UNa+) excretion . If UNa+ still remained <85 mmol/d, terlipres- sin infusion [SIFA (T)] was started at 4mg/24 hrs, (max .up to 8 mg/ 24hr) .Treatment was continued till the patient was clin- ically dry and with UNa+ >85 mmol/L . Similar patients during the same period in other unit of the department received SMT; (Arm II) for ACLF and its complications including lactulose,an- tibiotics,large volume paracentesis terlipressin-albumin therapy for HRS and therapy for other complications as per guidelines . Result:41 patients with ACLF in extremis were included from 2013 to 2015 .20 received CMT (Arm I) and 21 received SMT (Arm II) . Etiology of cirrhosis and of the acute insults did not differ significantly (p>0 .05) . Baseline parameters were also similar (p>0 .05) for serum creatinine (2 .3±1 .67 vs . 2 .4±1 .7); CTP score (12 .8±0 .8 vs . 12 .7±1 .38); number of OF (2 .9±1 .4 vs . 3 .1±1 .5);CLIF-SOFA score (12 .3±1 .9 vs . 12 .2±2 .3) and urine output (523±78 vs . 525±85ml/day) . However, MELD score (39 .50 (36 .25-40 .00) vs37 .00 (35 .5-39 .50; p=0 .03) was higher in group I .Significant improvement (p<0 .05) was seen in urine sodium (27 .6±21 to 202±106 mmol/24hrs),UO (523±78 to 2152±815ml/24hrs) and serum creatinine (2 .3±1 .67 vs . 1 .63±0 .9) after treatment in group I while there was no change in group II [serum creatinine (2 .4±1 .7 to 1 .99±1 .7); UO (525±85ml/day to 810±150ml/d)] .28- day survival in Arm I vs .II was 65% (13/20) vs47% (10/21), (p<0 .05) . Conclusion: Preliminary data suggestCMT in ACLF in extremis may improve survival .

 

1708

Management Of Refractory Variceal Bleed With Dan- nis-Ella Stent In Patients With Acute On Chronic Liver Failure

Rakhi Maiwall, Kapil D. Jamwal, Guresh Kumar, Manoj Sharma, Ashok Choudhary, Ankur Jindal, SM Shashtry, Lovkesh Anand, Amrish Sahney, Shiv K. Sarin; Hepatology, ILBS, New Delhi, India

Background and Aims: Almost, 10% of the bleeding epi- sodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality upto 50% . Severity of liver disease and high portal pressure are mainly responsible for it . TIPS can not be used in these patients due to high MELD score . Self-expandable DE stents could be an effec- tive option for control of refractory variceal bleeds . Patients and Methods: ACLF patients (n=88, mean age 47 .3±10 .9 yr .) with refractory variceal bleeds received either DE stent (Gr . A, n=35) or continued with repeat endotherapy and vasoactive drug (Gr .B, n=55) Matching by propensity risk score (PRS) was done to avoid selection bias . Competing risk Cox regression analysis was done to identify event specific i .e . gastrointestinal bleed-related death . Results: Majority (78 .4%) of the patients were alcoholic with a MELD score of 45 .9±20 . Patients in the two groups had significant differences with respect to base- line MELD and the CTP scores which were not evident in the PRS matched cohort . Control of initial bleeding (89% versus 37%, p<0 .001) and bleed related death (26% versus 64%; p=0 .006) was significantly lower in the DE stent group as com- pared to controls . In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both the pre-match (p=0 .004, HR 0 .24, 95%CI 0 .09-0 .64) and PRS-matched cohorts (p=0 .02, HR 0 .09, 95% CI 0 .01- 0 .74) . Conclusions: Self-expandable DE stents are very effec- tive in control of refractory variceal bleeding and improved mortality in patients with severe liver failure .

 

 

 

 

 

2060

NMR based urinary profiling of Lactulose/Mannitol ratio to compare the intestinal permeability in cirrhosis, acute on chronic liver failure (ACLF) patients and normal controls

Gaurav Pande1, Krishna V P1, Kamlesh Kumar1, Prabhat Sharma1, Dinesh Kumar2, Samir Mohindra1, Deepak Bansal1, Vivek A. Saraswat1; 1gastroenterology, Sanjay gandhi post graduate insti- tute of medical sciences, Lucknow, India; 2Centre of Biomedical Research, CBMR, SGPGI MS, LUCKNOW, India

Background: Increased/altered intestinal permeability is com- mon clinical manifestation in patients with cirrhosis and acute on chronic liver failure (ACLF) . Gut dysbiosis has also been implicated in assessing mortality in patients with ACLF . Aim: The study aims to evaluate the altered intestinal permeability (IP) in healthy controls,cirrhotics and ACLF patients(before and after therapy) Methods: Urinary excretion of lactulose/man- nitol ratio (LMR) is one of the simple and efficient method to assess the intestinal permeability (IP) . Urinary LMR excretion was measured using 1H NMR spectroscopy for 10 healthy controls, cirrhotics and ACLF patients with ascites: ACLF patients were treated with Slow low-dose continuous albumin + Furosemide ± Terlipressin (SAFI± T) and probiotics and after recovery LMR was repeated . Baseline characteristics of ACLF patients were CLIF SOFA score 10 .2±1 .7;CTP-12 .5±1 .4;MELD -29 .5±8 .7 .Mean therapy duration was 14 .3±7 .2 days . Post therapy - Urine sodium had increased from 26 .4±18 mmol/24 hrs to 264±106 mmol/24hrs and Serum Albumin increased to 3 .2±1 .1g/dl from 2 .4±0 .7g/dl (p<0 .05) . Results: The urinary LMR excretion was higher in ACLF patients (untreated) com- pared to compensated cirrhotics(CTP A) and normal controls . In normal controls,median value was 0 .11mmol, range 0 .02 to 0 .3, In cirrhotics median was 0 .26mmol, range 0 .14 to 1 .03) and in ACLF median 0 .61; range0 .12 -1 .93mmol) (p<0 .05) and post therapy ACLF, median 0 .09; range 0 .0 – 0 .43mmol) . However, the urinary LMR excretion in improved ACLF patients was comparable to normal controls indicating restored IP after the treatment . Conclusion:1H-NMR spectroscopy is an efficient analytical tool for the assessment of altered intestinal perme- ability in ACLF and cirrhotic patients with reasonable sensi- tivity and specificity . ACLF patients’ have higher intestinal permeability compared to compensated cirrhotics and controls . Intestinal permeability decreases post therapy suggesting that intestinal decongestion and probiotics may have a role in alter- ing gut permeability

 

2088

Short-term infusion of soyabean oil based intravenous lipid emulsion is safe in patients with acute-on-chronic liver failure (ACLF), improves nitrogen balance and preserves immune functions

Lovkesh Anand, Jaya Benjamin, Avinash Kumar, Paul David, Ashish Vyas, Vanshja Pandit, Nirupma Trehanpati, Vikram Bhatia, Y.K Joshi, Shiv K. Sarin; Institute of liver and biliary sciences, New

Delhi, India BACKGROUND: With preferential oxidation of lipids over glucose

in cirrhosis and intravenous lipid emulsions (ILE) being a concentrated source of energy; ILE should be optimal for nutritional management of patients with cirrhosis. However, such a therapy in the background of progressive liver failure is contentious.

AIM: To assess the metabolic and immune tolerance of ILE in patients with ACLF.

PATIENTS & METHODS: In 30 male patients with ACLF (ethanol related), Soyabean oil (SO) based ILE (20% Intralipid) providing 500 Kcal was administered at a maximum rate of 0.5ml/min for 3 consecutive days over and above oral/enteral diet in a pre-post design. Nutritional effects [nitrogen balance (NB) by 24 hr urinary urea nitrogen excretion], metabolic tolerance [lipid profile, free fatty acids (FFA), serum insulin], oxidative stress [urinary isoprostane], hepatotoxicity [LFT, ammonia] and coagulation profile [TEG & Sonoclot] were studied. Immune modulation was studied using cytokine levels and flowcytometry for monocytes, macrophages, & neutrophils. RESULTS: The baseline characteristics (mean ±SEM) were - BMI : 21.1 ± 4.4 Kg/m2; bilirubin : 22.8 ± 2.2 mg/dl, CTP score :10.4 ± 1.1 and MELD : 26.8 ± 5.2. A two fold increase in NB was seen in 76% of patients, mainly due to decrease in N2 excretion rather than increase in protein intake. Serum bilirubin levels (both direct and indirect) were significantly reduced [p=0.001]. FFA, serum insulin, lipids, ammonia and coagulation parameters remained unchanged. There was an increase in urinary isoprostane (>2 fold), pro-inflammatory and regenerative cytokines IL-6 and TNF-α levels while decrease in IL-10 levels post-lipid infusion. However, no significant increase was seen in the percentage and Median Fluoroscence Intensity (MFI) of monocytes (CD14+ CD16+), macrophages (CD11b+) and neutrophils (CD11b+ CD16+). There was no change in their activation markers like HLA-DR and CD68 expression of TLR on CD14+, CD11b+ cells and CXCR1 and CXCR2 on CD11b+ CD16+ cells.

CONCLUSIONS: SO based ILE is a safe modality of nutritional therapy in ACLF patients as it improves NB without influencing the elimination and hydrolysis of exogenous lipids. The proinflammatory and prooxidative response could be due to the disease per se or the lipid infusion, however, it does not alter the host immune response of severely stressed ACLF patients.

 

SAT-011

 

Terlipressin is superior to Noradrenaline in the management of acute kidney injury (AKI) in patients with ACLF

V. Arora¹, R. Maiwall¹, A. Choudhury¹, P. Jain ², G. Kumar², S.K. Sarin¹. ¹Hepatology; ²Statistics, Institute of Liver and Biliary Sciences,New Delhi, India

 

E-mail: VINOD_UCMS@YAHOO.COM

 

Background and Aims: Hepatorenal syndrome (HRS) carries a high short-term mortality in patients with cirrhosis and ACLF. We have reported a low response to terlipressin in ACLF patients with HRS (Jindal et al., Liv Int 2015). Currently, there are no studies comparing the efficacy of terlipressin(TR) with noradrenaline(NA) in patients with ACLF and HRS, specifically using the revised definitions.

 

Methods: In an open-label randomized controlled trial (GOV: NCT02573727), consecutive patients with ACLF diagnosed with AKI-HRS as per revised international classification of ascites-AKI (ICA-AKI) criteria were randomised to Terlipressin (as continous infusion) plus albumin (1 g/Kg/day for 2 days followed by 25–50 grams/day) (n = 45) versus noradrenaline (0.5–3 mg/hr to achieve target MAP) plus albumin (n = 45). Progression and regression were defined as per ICA-AKI criteria.

 

Results: Baseline characteristics were comparable in both groups. Baseline serum creatinine (S.Cr) (2.01 ± 1.14 vs 2.13 ± 1.40, p = 0.63), AKI stage (2;3) (53% vs 48%, p = 0.67; 47% vs 52%, p = 0.84), peak S.Cr. (2.86 ± 1.36 vs 3.07 ± 1.26, p = 0.47) were comparable in both groups. Sepsis-related HRS was also not significantly different between the two groups (47.8% vs 52%, p = 0.68). A significantly better and early response was achieved in terlipressin group as compared to NA at Day 4 (26.1% vs 11.1%, p = 0.05) and Day 7 (46.6% vs 24.4%, p = 0.04). Overall reversal of HRS was also better with terlipressin as compared to NA (48.9% vs 24.4%, p = 0.02) with a lower requirement of renal replacement therapy (43% vs 56%, p = 0.055) and also improved 28-day mortality (51.1% vs 75%, p = 0.02). On multivariate analysis, sepsis [OR: 3.76, 95 CI (1.36–10.38, p = 0.01], use of terlipressin or NA [OR: 3.23 95 CI(1.18–8.85), p = 0.02], MELD [OR: 1.15, 95 CI (1.04–1.27), p = Gastroscopy (EDS) can be avoided in patients with liver stiffness (LS) < 20 kPa by Transient Elastography (TE) and platelets (PLT) > 150,000/mm³. The aims of this study are to assess the performance of Baveno criteria and to evaluate the ability of RESIST-HCV criteria

 

0.005] were predictors of response. Recurrence of AKI-HRS after discontinuation of therapy was not different between groups (13.6% vs 27.3%; p = .062). Adverse effects limiting use of drugs were higher [6/45, 13.33%] with terlipressin than noradrenaline [1/45, 2.2%, p = 0.11] in noradrenaline group. Using multivariate analysis, presence of HE (HR 8.26,95 CI = 1.28–53.33, p = 0.026), deranged INR (8.40, 95 CI = 1.52–46.39, p = 0.015) were strong predictors of mortality.

 

Conclusions: ACLF-AKI carries a high mortality rate. Terlipressin infusion provided higher response rate and improved survival as compared to noradrenaline infusion in these patients.

566

Acute on chronic liver failure from Wilson disease: Out- come and predictors of mortality in 61 patients

Harshad Devarbhavi1, Chandrashekar Bohra3, Vishnu V. Reddy1, Rajvir Singh Singh2, Tarun S. Joseph1, Mallikarjun Patil1; 1Depart- ment of Gastroenterology, St. John’s Medical College Hospital, Bangalore, India; 2Hamad Medical Center, Doha, Qatar; 3Univer- sity of South Florida, Tampa, FL

Background: Acute on chronic liver failure (ACLF) is an emerg- ing entity with unique pathogenesis and outcome that is differ- ent from decompensated cirrhosis . Patients with Wilson disease (WD) often present acutely with jaundice, ascites, encepha- lopathy or coagulopathy despite underlying cirrhosis . WD is a prototypical example of type B ACLF (Gastroenterology 2014;147:4) There is no study that has analyzed the outcome and predictors of mortality in patients with WD presenting with ACLF . Methods: Sixty-one patients with WD who fulfilled crite- ria for ACLF were identified from a WD registry of 264 patients (1997-2016) . ACLF was defined as per APASL . (Hepatology Int 2009;3:269) . All patients had jaundice (bilirubin>5 mg/dl) and coagulopathy (INR >1 .5) which was complicated by asci- tes and or encephalopathy within 4 weeks . Outcome assessed at 3 months was either death or liver transplantation . Descrip- tive statistics, chi-square test and student t test were carried out to determine differences between survivors and non survivors followed by Cox-regression analysis to determine predictors of mortality . Results: There were 36 males and 25 females with a mean age 14 .4 years . Ascites and encephalopathy were present in 55 (90 .2%) and 29 (47 .5%) patients respectively . Forty-four patients died and two underwent transplantation (75 .4%): 74% with ascites and 96 .5% with encephalopathy . The differences between survivors and non survivors are shown in table . Cox regression analysis identified encephalopathy (Hazards ratio, HR 3 .7), INR (HR 1 .14), serum protein (HR 0 .84), total bilirubin (HR 1) and log WBC (HR 0 .87) as risk fac- tors for mortality . No precipitant could be identified for acute deterioration . Conclusions: Patients with ACLF from Wilson dis- ease have high mortality (75%) and should be expeditiously worked up for liver transplantation . Encephalopathy (not asci- tes alone) is significantly associated with mortality .

 

 

 

 

2045 Does the presence of cirrhosis influence on the mortality rate in patients with acute on chronic liver failure?

Sombat Treeprasertsuk1,2, Kessarin Thanapirom1,2, Roongruedee Chaiteerakij1,2, Ashok Choudhary3, Manoj Sharma3, Rakhi Maiwall4, Viniyendra Pamecha4, Richard Moreau4, Mamun A. Mahtab4, Yogesh K. Chawla4, Soek Siam Tan4, Harshad Devar- bhavi4, Yu Chen4, Zhongping Duan4, Qin Ning4, Deepak N. Amarapurkar4, Saeed Hamid4, Amna S. Butt4, Hasmik Ghazin- yan4, Guan Huei Lee4, Ajit Sood4, Laurentius A. Lesmana4, Gamal Shiha4, Diana A. Payawal4, Abdulkadir Dokmeci4, Shiv K. Sarin4; 1Medicine, Division of Gastroenterology, Chulalongkorn Univer- sity, Patumwan, Thailand; 2Thai Red Cross, King Chulalongkorn Memorial Hospital, PATUMWAN, Thailand; 3Institute of Liver and Biliary Sciences, New Delhi, India; 4APASL ACLF Working Party (AARC)., New Delhi, India

Background: Currently, the APASL Acute-on-chronic liver fail- ure (ACLF) research consortium (AARC) criteria includes non-cir- rhotic chronic liver disease; CLD patients due to the evidence of high mortality rate (Sarin SK, Hepatol Int 2014) . The basal CLD severity may play important role on outcomes . We aim to compare the 28-day and 90-day mortality rate of ACLF patients with and without cirrhosis . Methods: AARC collected data pro- spectively from multicenter of ACLF patients during Oct, 2009 to Apr, 2016 . Of 1621 patients, 637 of them (39%) were diagnosed as cirrhosis which defines as clinical presentations or biochemical or imaging evidence or histopathological con- firmation advanced fibrosis . Baseline characteristics and the 28-day and 90-day mortality were recorded . The Kaplan-Meier ;K-M method was used to compare the mortality rate between two groups . Results: Of a total of 1621 patients, 86 .7% were male with mean age SD of 44 .612 years . The most com- mon acute insult were alcohol (48%), HBV reactivation (16%) and hepatitis E infection (7 .5%) . The baseline MELD score were 29 7 and 52% of patients developed >2 organs failure . The most frequent organs failure were liver (80%), coagulop- athy (35%), and renal failure (23%) . The 28-day and 90-day mortality rate were 39% and 50% respectively . Baseline char- acteristics showed that non-cirrhotic patients had significantly higher MELD score, number of organ failures than those cir- rhotic patients . ACLF patient without cirrhosis had significantly higher 28-day and 90-day mortality rate than cirrhotic patients as shown by the K-M survival curve in figure1 . Conclusion: Our data suggests that the 28-day and 90-day mortality rate of ACLF patient without cirrhosis was significantly higher than those with cirrhotic, thus the presence of underlying cirrhosis at baseline should be evaluated due to its influence on mortality .

THU-107

 

BETTER SURVIVAL IN PATIENTS WITH HEPATITIS E VIRUS C.F. TO OTHER ACUTE INSULTS CAUSING ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) – APASL-ACLF RESEARCH CONSORTIUM (AARC) DATABASE

 

A.Goel¹, C.E. Eapen¹, A. Choudhary², M.K. Sharma², R. Maiwall², M. Al Mahtab³, Y.K. Chawla⁴, S.-S. Tan⁵, Q. Ning⁶, H. Devarbhavi⁷,D.N. Amrapurkar⁸, C.W. Kim⁹, S.S. Hamid¹⁰, A.S. Butt¹⁰,H. Ghazinyan¹¹, Z. Duan¹², C. Yu¹², A. Sood¹³, G.H. Lee¹⁴, Z. Abbas¹⁵, G. Shiha¹⁶, L.A. Lesmana¹⁷, D.A. Payawal¹⁸, A. Kadir Dokmeci¹⁹, M.F. Yuen²⁰, G.K. Lau²¹, Md.F. Karim²², J.D. Sollano²³, S.K. Sarin² and APASL-ACLF working party.

¹Hepatology, Christian Medical College, Vellore; ²Institute of Liver and Biliary Sciences, New Delhi, India;³Bangabandhu Sheikh Mujib Medical university, Dhaka, Bangladesh;⁴PGIMER, Chandigarh, India; ⁵Selayang Hospital University of Malaya, Malaysia, Malaysia; ⁶Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁷St John Medical College, Bangalore;⁸Bombay Hospital & Medical Research Centre, Mumbai, India; ⁹Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, South Korea; ¹⁰Aga Khan University Hospital, Karachi, Pakistan; ¹¹Nork Clinical Hospital of Infectious Diseases, Armenia, Armenia; ¹²Hepatology Institute Capital Medical University, Beijing, China; ¹³Christian Medical College, Ludhiana, India; ¹⁴Department of Gastroenterology & Hepatology, National University Health System, National University of Singapore, Singapore, Singapore; ¹⁵Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan; ¹⁶Egyptian Liver Research Institute And Hospital (ELRIAH), Cairo, Egypt; ¹⁷Disease & Oncology Centers, Medistra Hospital, Jakarta, Indonesia; ¹⁸Fatima Medical University Hospital, Valenzuela MetroManila, Manila, Philippines; ¹⁹Ankara University School of Medicine, Ankara, Turkey; ²⁰Queen Mary Hospital, Hong Kong, Hong Kong; ²¹Institute of Translational Hepatology, Beijing, China; ²²Department of Hepatology, Sir Salimullah Medical College Mitford Hospital, Dhaka, Bangladesh; ²³University of Santo Tomas, España Blvd, Manila, Philippines

 

E-mail: drashishgoel@cmcvellore.ac.in

 

 

 

 

Background and Aims: The current study aims to analyse impact of acute insult on short term mortality in ACLF patients.

 

Methods: AARC, consisting of multiple tertiary centers spread across Asia-Pacific regions, maintains an online database for prospectively accruing data on patients with ACLF, defined as per APASL criteria. The patients were managed as per individual institutional protocols. We compared short term survival in ACLF patients with acute insult caused by alcohol (group 1), Hepatitis E (group 2) and no identifiabe cause (cryptogenic, group 3).

 

Results: From July 2007 to April 2015, ACLF patients with acute

 

insult which was alcohol related (group 1, n = 801, age: 41.9 ± 9.1 years, male: 782, MELD score: 29.4 ± 8.4), Hepatitis E related (group 2, n = 180, age:47.8 ± 13.6 years, male:148, MELD:28.3 ± 7.1) and cryptogenic (group 3, n = 118, age:47.2 ± 14.5; male: 80, MELD: 28.7

 

• 10) were recruited. Short term mortality data was available in 978 (89%) of study patients with follow up duration of 182 (±329) days in group 1, 340 (±514) days in group 2 and 182 (±392) days in group 3. On Kaplan Meier analysis, the median survival in group 1 was 45 days (95% C.I:20–70 days) and group 3 was 47 days (95% C.I:16–78 days). In group 2, 63% survived the follow up period. Overall, group 1 had worse survival as compared to group 2 ( p-value: < 0.001) and similar survival as group 3 ( p-value: 0.4) (see Figure). Cumulative survival at

 

1 week was – group 1: 0.77 (0.018); group 2: 0.88 (0.03) and group 3: 0.7 (0.06).

 

The proportion of patients with decreasing trend of MELD score over 7 days was similar in all groups (224/407 v/s 51/102 v/s 21/41; p-value: 0.6). On Cox proportional hazards model, controlling for baseline MELD score, as compared to group 1, group 2 had significantly lower hazard ratio (0.64, 95% C.I: 0.48–0.86, p-value:0.003); in contrast, group 3 had similar hazard ratio (1.2, 95% C.

 

I: 0.84–1.7, p-value:0. 3) to group 1.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conclusions: In this study conducted in 58 centres, across 18 countires, etiology of acute insult has a significant impact on prognosis of ACLF patients – those with Hepatitis E virus related acute insult tend to have better short term survival compared to those with alcohol related/cryptogenic acute insults. Further studies are needed to analyse the mechanisms of injury by different acute insults in ACLF.

okmeci, George Lau, Shiv K . Sarin, APASL ACLF Working Party

 

 

 

 

 

EASL DEFINITION

 

Indian J Gastroenterol. 2018 Jan;37(1):50-57. doi: 10.1007/s12664-018-0827-z. Epub 2018 Feb 23.

Alcohol-related acute-on-chronic liver failure-Comparison of various prognostic scores in predicting outcome.

Sonika U¹, Jadaun S¹, Ranjan G¹, Rout G¹, Gunjan D¹, Kedia S¹, Nayak B¹, Shalimar².

Author information

Abstract

BACKGROUND AND AIMS:

Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients.

METHODS:

All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronichealth evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey's discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome.

RESULTS:

Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey's score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5-123.0), 33.1 (27.6-40.0), 34.4 (29.5-40.0), 8.5 (7.3-9.6), 15 (12-21), and 51.1 (44.1-56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173-3.682, p = 0.012 and advanced, HR, 2.330; 95% CI, 1.270-4.276, p = 0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023-1.270, p = 0.018), and infection at admission (HR, 1.874; 95% CI, 1.160-23.029, p = 0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD-Na, DF, and ABIC (p < 0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p = 0.660).

CONCLUSIONS:

Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best.

 

 

Am J Med Sci. 2018 Feb;355(2):132-139. doi: 10.1016/j.amjms.2017.08.003. Epub 2017 Aug 3.

Community- or Healthcare-Associated Bacterial Infections Increase Long-Term Mortality in Patients With Acute Decompensation of Cirrhosis.

Zhao H¹, Shi Y¹, Dong H¹, Hu J¹, Zhang X¹, Yang M¹, Fan J¹, Ma W¹, Sheng J¹, Li L².

Author information

Abstract

BACKGROUND:

The aim of the present study was to determine the specific role of different types of bacterial infections (BIs) on the prognosis of cirrhotic patients with acute decompensation (AD).

METHODS:

We performed a prospective, observational cohort study consisting of 492 cirrhotic patients with AD at our center from February 2014 to March 2015. Clinical, laboratory and survival data were collected. The relationship between BIs and mortality was analyzed.

RESULTS:

BIs were identified in 157 of 492 patients at the time of admission or during the hospital stay. Among the patients, 65 had community-acquired (CA) or healthcare-associated (HCA) BIs, 54 developed hospital-acquired (HA) BIs, and 38 had CA/HCA with HA BIs. Patients with CA/HCA BIs had higher 90-day, 1-year and 2-year mortality rates (29.2%, 44.6% and 52.3%, respectively) and CA/HCA BIs remained an independent risk factor for long-term mortality on multivariate analysis (1 year: hazard ratio = 1.60; 95% CI: 1.07-2.41; P = 0.023 and 2 year: hazard ratio = 1.54; 95% CI: 1.05-2.25; P = 0.026). In contrast, patients with HA BIs had a higher 28-day mortality rate than patients with CA/HCA BIs. Logistic regression analysis showed previous ascites and prior BIs within 3 months were independent risk factors for CA/HCA BIs, whereas invasive minor surgical procedures with acute-on-chronic liver failure throughout the hospital stay and high chronicliver failure-sequential organ failure assessment scores were associated with nosocomial BIs.

CONCLUSIONS:

CA/HCA BIs were associated with increased long-term mortality in cirrhotic patients with AD, whereas nosocomial BIs may be related to poor short-term prognosis.

 

 

 

 

Expert Rev Gastroenterol Hepatol. 2018 Mar;12(3):295-302. doi: 10.1080/17474124.2018.1424540. Epub 2018 Jan 12.

Stratified alpha-fetoprotein pattern accurately predicts mortality in patients with acute-on-chronichepatitis B liver failure.

Huang GQ^1,2, Xie YY³, Zhu PW³, Wang XD^1,4, Lin Z^1,4, Wang Y¹, Ye JP¹, Wang YM³, Chen YX¹, Jin XZ¹, Van Poucke S⁵, Chen YP^1,4, Zheng MH^1,4.

Author information

Abstract

BACKGROUND:

Alpha-fetoprotein (AFP) has been shown to predict the prognosis of liver disease in several studies. This study aimed to evaluate the prognostic value of stratified AFP in patients with acute-on-chronic hepatitis B liver failure (ACHBLF).

METHODS:

A total of 192 patients were included and AFP were categorized into quartiles. The prognostic value was determined for overall survival (OS) and assessed by Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazard regression analyses studied the association of all independent parameters with disease prognosis.

RESULTS:

The optimal cut-off points of AFP were: (Q1) 252.3-4800.0 ng/ml, (Q2) 76.0-252.2 ng/ml, (Q3) 18.6-75.9 ng/ml, and (Q4) 0.7-18.5 ng/ml. Based on the Kaplan-Meier analysis of the OS, each AFP quartile revealed a progressively worse OS and apparent separation (log-rank P = 0.006). The second-highest quartiles of AFP (Q2) always demonstrated an extremely favorable short-term survival. Combining the lowest AFP quartiles with a serum sodium < 131mmol/L or an INR ≥ 3.3 showed a poor outcome (90-days survival of 25.0% and 11.9% respectively).

CONCLUSIONS:

Stratified AFP could strengthen the predictive power for short-term survival of patients with ACHBLF. Combining AFP quartiles with low serum sodium and high INR may better predict poor outcome in ACHBLF patients.

 

 

 

 

 

Clin Chim Acta. 2018 Mar;478:7-12. doi: 10.1016/j.cca.2017.12.018. Epub 2017 Dec 13.

A nomogram for predicting prognostic value of inflammatory biomarkers in patients with acute-on-chronic liver failure.

Gong J¹, Zhou W¹, Xiao C², Jie Y³, Zhu S⁴, Zheng J⁴, Chong Y⁵, Hu B⁶.

Author information

Abstract

BACKGROUND:

Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) in china is a critical clinical syndrome with a high short-term mortality. This study aimed to construct and validate a model for neutrophil to lymphocyte ratio (NLR)-based nomogram for 3-month mortality estimation for patients with ACLF.

METHODS:

The nomogram was based on a retrospectively study of 96 patients with ACLF. The predictive accuracy and discriminative ability of nomogram were evaluated by a concordance index (C-index), and calibration curve, comparing with model for end-stage liver disease (MELD) score. The results were validated using bootstrap resampling and an external cohort of 88 patients.

RESULTS:

A total of 184 patients with ACLF were enrolled, with 3-month mortality of 40.76%. The cut-off value for NLR was 5.7 using X-tile program. Patients with NLR>5.7 had significantly higher mortality (p<0.001). On multivariate analysis of the training cohort, independent factors for survival were age, NLR and total bilirubin, which were all selected into the nomogram. The calibration curve for probability of survival showed optimal agreement between prediction by nomogram and actual observation. The C-index of nomogram was higher than that of MELD score for predicting survival (0.72 vs 0.56). The results were confirmed in validation cohort.

CONCLUSIONS:

The proposed nomogram with NLR resulted in more accurate prognostic prediction for patients with HBV-related ACLF.

 

 

 

 

 

 

Eur J Gastroenterol Hepatol. 2018 Feb;30(2):130-135. doi: 10.1097/MEG.0000000000001026.

Disruption of the gut-liver axis in the pathogenesis of acute-on-chronic liver failure.

Zhang T^1,2, Sun K¹, Wang Y¹, Huang L³, Lang R⁴, Jiang W^2,5.

Author information

Abstract

Acute-on-chronic liver failure (ACLF) is characterized by organ failure mediated by acute decompensation of cirrhosis. Recent studies have highlighted the importance of the gut-liver axis (GLS) and its association with ACLF pathogenesis. In this review, we discuss the mechanisms related to the alteration of the GLA and their involvement in ACLF pathogenesis and suggest some possible therapeutic options that could modulate the GLA dysfunction. This knowledge may provide information useful for the design of therapeutic strategies for gut dysbiosis and its complications in ACLF.

 

Zhonghua Gan Zang Bing Za Zhi. 2017 Sep 20;25(9):651-654. doi: 10.3760/cma.j.issn.1007-3418.2017.09.003.

[Clinical application of mesenchymal stem cells in treatment of acute-on-chronic liver failure and related research advances].

[Article in Chinese; Abstract available in Chinese from the publisher]

Feng LY¹, Zhang DZ.

Author information

Abstract

in English, Chinese

Acute-on-chronic liver failure is a syndrome characterized by acute exacerbation of chronic hepatitis, organ failure, and high mortality. Clinical treatment of acute-on-chronic liver failure included comprehensive medical treatment, artificial liver support system, and liver transplantation, but such methods have their own shortcomings and patients tend to have a poor prognosis. Mesenchymal stem cells (MSCs), as a new type of cell therapy, have wide sources and are easy to extract and culture. Many studies have shown that MSC treatment not only helps to achieve a high survival rate, but also has good tolerability and safety; therefore, the clinical value of MSCs has become a hot research topic. This article reviews the clinical studies on acute-on-chronic liver failure, related mechanisms, and research advances, in order to provide a reference for future clinical trials and application.

 

Oncotarget. 2017 Aug 4;8(49):84782-84797. doi: 10.18632/oncotarget.19891. eCollection 2017 Oct 17.

SHYCD induces APE1/Ref-1 subcellular localization to regulate the p53-apoptosis signaling pathway in the prevention and treatment of acute on chronic liver failure.

Diao J¹, Li H¹, Huang W¹, Ma W², Dai H¹, Liu Y³, Wang M⁴, Hua HY¹, Ou J¹, Sun X¹, Sun X¹, Yang Y¹.

Author information

Abstract

Background & Aims: San huang yin chi decoction(SHYCD) is derived from the yin chen hao decoction, a well-known and canonical Chinese medicine formula from the "Treatise on Febrile Diseases". Over the past decade, SHYCD has been used to treat and prevent the livercirrhosis and liver failure. In the present study, we investigated the effects of SHYCD for acute on chronic liver failure(ACLF) and explored its potential mechanism. an ACLF rat model, which induced by carbon tetrachloride (CCl4) combined with D-galactosamine (D-GalN) and lipopolysaccharide(LPS), was used and confirmed by B-ultrasound analysis. Rats were randomly divided into control group, model group, SHYCD-H group, SHYCD-M group, SHYCD-L group, AGNHW group. Compared with the ACLF model group, High, medium, and low doses of SHYCD reduced ALT, AST, TBIL, NH3, IL-1β, IL-6, and TNFα expression levels in the serum, Shorten PT and INR time,and increased Fbg content in the whole blood, increased survival rate of the rats, improved liver pathological changes. APE1 / Ref-1 was mainly expressed in the nucleus, but the nucleus and cytoplasm were co-expressed after hepatocyte injury. SHYCD significantly downregulated APE1/Ref-1 expression in the cytoplasm. Increased APE1/Ref-1, Bcl-2, reduced p53, caspase-3, Bax, and Cyt-c in the total protein. Base on the results, we conclused that High, medium, and low doses of SHYCD could be applied in prevention and treatment of ACLF, and dose-dependent. The possible mechanism is to promote the APE1 / Ref-1 from the cytoplasm to the nuclear transfer, regulation of p53 apoptosis signal pathway prevention and treatment of ACLF.

Eur J Gastroenterol Hepatol. 2018 Jan;30(1):33-38. doi: 10.1097/MEG.0000000000000993.

Red blood cell distribution width independently predicts 1-month mortality in acutedecompensation of cirrhotic patients admitted to emergency department.

Turcato G¹, Campagnaro T², Bonora A³, Vignola N³, Salvagno GL⁴, Cervellin G⁵, Ricci G³, Maccagnani A³, Lippi G⁴.

Author information

Abstract

AIM:

The aim of this study was to explore whether red blood cell distribution width (RDW) can help predict the risk of short-term mortality in patients with acute decompensation of cirrhosis.

PATIENTS AND METHODS:

We carried out a retrospective analysis of all patients consecutively admitted to the emergency department (ED) of the University Hospital of Verona (Italy) for acute decompensation of liver cirrhosis, between 1 June 2013 and 31 December 2016. The RDW value was measured at ED admission, along with collection of clinical features and other laboratory data, and was then correlated with severity of disease (Chronic Liver Failure Consortium Acute Decompensation score; CLIF-C AD score) and 1-month mortality.

RESULTS:

The final study population consisted of 542 patients, 80 (14.8%) of whom died within 30 days after ED admission. The median RDW of patients who died was significantly higher than the median RDW of those who survived (17.4 vs. 15.5%; P<0.001). The percentage of patients who died significantly increased across different RDW quartiles (6.8, 9.7, 11.5 and 32.1%, P<0.001). In univariate analysis, significant correlation was observed between RDW and clinical severity of acute decompensate cirrhosis (Child-Pugh score: r=0.198, P<0.001; Model for End-Stage Liver Disease score: r=0.311, P=0.001; CLIF-C AD: 0.127, P=0.005). The combination of RDW and CLIF-C AD score exhibited better performance for predicting 1-month mortality than the CLIF-C AD score alone (area under the curve=0.769 vs. 0.720; P=0.006). In multivariate analysis, RDW was independently associated with a 1.2-2.3 higher risk of 1-month mortality.

CONCLUSION:

The assessment of RDW at ED admission may improve risk stratification of patients with acute decompensation of cirrhosis.

 

 

J Huazhong Univ Sci Technolog Med Sci. 2017 Oct;37(5):755-760. doi: 10.1007/s11596-017-1800-2. Epub 2017 Oct 20.

Association of mRNA expression level of IP-10 in peripheral blood mononuclear cells with HBV-associated acute-on-chronic liver failure and its prognosis.

Wang XL¹, Chen XJ¹, Ye HH², Xing LX¹, Han XY¹, Cheng ZJ², Huang SJ³.

Author information

Abstract

HBV-associated acute-on-chronic liver failure is prevalent in mainland China. The prognosis of HBV-ACLF is poor. The mortality of HBV-ACLF is approximately 80%. Therefore, a prognostic indicator was needed in order to allow us to intervene as soon as possible. The model for end-stage liver disease (MELD) scoring system is widely used to predict the prognosis of liver failure. However, the assessment is too complex to restrict its application. This study aimed to investigate the expression of IP-10 in peripheral blood mononuclear cells (PBMC), in order to explore the relationship between the expression and prognosis of patients with HBV-ACLF. The mRNA level of IP-10 in PBMCs were analyzed in 80 patients with HBV-ACLF, 40 patients with chronic hepatitis B (CHB) and 40 healthy people by fluorescent quantitative PCR. IP-10 mRNA level was significantly higher in the HBV-ACLF group than in the other two groups (P<0.01). Group with MELD score below 30 had lower IP-10 mRNA level than group with MELD score over 30 (P<0.05). The IP-10 mRNA level in PBMCs in positive group was higher than that in negative group (P<0.01). With a threshold of 0.925, the area under the receiver operating characteristic (ROC) curves was 0.815. These findings suggest that assessment of IP-10 mRNA level in the PBMCs would be helpful for evaluating the disease severity and prognosis in patients with HBV-ACLF.

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Hepatol Int. 2017 Nov;11(6):529-539. doi: 10.1007/s12072-017-9822-1. Epub 2017 Oct 5.

AKI persistence at 48 h predicts mortality in patients with acute on chronic liver failure.

Maiwall R¹, Kumar G², Bharadwaj A², Jamwal K¹, Bhadoria AS², Jain P², Sarin SK³.

Author information

Abstract

BACKGROUND AND AIM:

Management of acute kidney injury (AKI) in cirrhotics has undergone a paradigm change. We evaluated the impact of AKI persistence at 48 h on outcome in patients with acute on chronic liver failure (ACLF).

METHODS:

Consecutive patients with ACLF (n = 373) were prospectively followed. AKI was defined as increase in serum creatinine of 0.3 mg/dl or 1.5- to 2-fold from baseline. Persistent AKI was defined as nonresponsive AKI at 48 h with respect to admission serum creatinine.

RESULTS:

AKI at admission was present in 177 (47.5 %) patients. At 48 h, 73 % patients had persistent AKI and 27 % had responsive AKI. High Model for End-Stage Liver Disease (MELD) (≥26) [p, odds ratio (OR), 95 % confidence interval (CI)] [<0.001, 3.65 (2.1-3.67)], systemic inflammatory response syndrome (SIRS) [0.03, 1.6 (1.02-21.6)], and age (≥42 years) [0.03, 1.84 (1.19-2.85)] were significant predictors of AKI persistence. Persistent AKI was associated with significantly higher in-hospital mortality [p < 0.001, hazard ratio (HR) 1.7, 95 % CI 1.32-2.27]. We further found a lower cutoff for serum creatinine of 1.14 mg/dl at 48 h with better sensitivity of 61 %, specificity of 61 %, and likelihood ratio (LR+) of 1.6, correctly classifying 61 %, as against the conventional cutoff of 1.5 mg/dl with sensitivity of 37 %, specificity of 57 %, and LR+ of 3.3, correctly classifying 56 %. This new cutoff also predicted mortality with higher odds (OR 2.4, 95 % CI 1.3-4.8) as compared with the conventional cutoff (OR 2.1, 95 % CI 1.1-4.1).

CONCLUSION:

AKI persistence at 48 h predicts mortality better than serum creatinine of 1.5 mg/dl in patients with ACLF. Serum creatinine value of 1.14 mg/dl and smaller increases in its value should be considered for risk stratification of patients with ACLF for interventional strategies.

 

 

 

 

J Clin Exp Hepatol. 2017 Sep;7(3):247-252. doi: 10.1016/j.jceh.2017.08.001. Epub 2017 Aug 24.

Liver Transplantation for Acute on Chronic Liver Failure.

Choudhary NS¹, Saraf N¹, Saigal S¹, Soin AS¹.

Author information

Abstract

BACKGROUND:

Acute-on chronic liver failure (ACLF) is defined as acute insult on previous liver disease that causes sudden worsening of liver functions.

METHODS:

ACLF is characterized by high incidence of organ failure and prognosis is remarkably worse than patients with cirrhosis. Incidence of organ failures is very high despite best medical care and timely liver transplant before development of multi organ failure is associated with good survival rates.

RESULTS:

At present, there are no reliable score or ways to correctly identify patients who are going to recover from patients who will need transplantation. Organ failures are important part of prognosis and to define need or futility of early liver transplantation.

CONCLUSION:

Asian Pacific Association for the Study of the Liver (APASL) published their recommendations regarding ACLF in 2014. Several important studies regarding course/nature of disease and transplantation for ACLF became available after 2014 APASL recommendations and still there are some unanswered areas. The current review discusses various issues regarding liver transplantation in patients with ACLF.

 

 

 

 

 

 

 

 

 

 

 

J Clin Exp Hepatol. 2017 Sep;7(3):190-197. doi: 10.1016/j.jceh.2017.04.001. Epub 2017 Apr 8.

Characterization of Cerebral Edema in Acute-on-Chronic Liver Failure.

Gupta T¹, Dhiman RK¹, Ahuja CK², Agrawal S¹, Chopra M¹, Kalra N², Duseja A¹, Taneja S¹, Khandelwal N², Chawla Y¹.

Author information

Abstract

BACKGROUND AND AIMS:

The nature of cerebral edema in acute-on-chronic liver failure (ACLF) is not well studied. We aimed to characterize cerebral edema in ACLF using magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI).

METHODS:

Forty-six patients with cirrhosis and acute decompensation were included. Patients were divided into groups A (no cerebral failure, n = 39) and B (cerebral failure, n = 7). Group A was subdivided into no-ACLF (n = 11), grade 1 (n = 10), grade 2 (n = 9) and grade 3 (n = 9) ACLF as per CANONIC study. MRI brain and plasma TNF-alpha, IL-1beta and IL-6 were measured at baseline and 7-10 days after admission. Ten age- and sex-matched healthy controls were also included.

RESULTS:

Mean diffusivity (MD) values, an MRI marker of water content, progressively increased from controls to no-ACLF to ACLF grade 1, 2 and 3 in group A in frontal white matter (FWM) and basal ganglia (P < 0.0001). MD values improved only in survivors on follow-up. MD values correlated with IL-6 levels at baseline. On multivariate analysis MELD score ≥28 and MD values (>8 × 10^-9 M²/s) in FWM were independent predictors of 90-day mortality. There was no significant difference in clinical and MRI parameters between group A and B.

CONCLUSION:

Cerebral edema increases with severity of ACLF. Correlation between MD values and IL-6 levels suggests pathogenic role of inflammation in cerebral edema. Patients with grade 3 ACLF have cerebral edema irrespective of presence of clinically evident cerebral failure. MELD score and cerebral edema have prognostic significance in ACLF.

 

 

 

 

Scand J Gastroenterol. 2017 Dec;52(12):1385-1390. doi: 10.1080/00365521.2017.1369560. Epub 2017 Aug 29.

Single center validation of mortality scores in patients with acute decompensation of cirrhosis with and without acute-on-chronic liver failure.

Alexopoulou A¹, Vasilieva L¹, Mani I¹, Agiasotelli D¹, Pantelidaki H¹, Dourakis SP¹.

Author information

Abstract

OBJECTIVES:

Acute decompensation (AD) of cirrhosis is characterized by high mortality. We aimed to validate the performance in predicting mortality of both the chronic-liver-failure-consortium (CLIF-C) acute-on-chronic liver failure (ACLF) and CLIF-C AD scores in a cohort of patients admitted for AD.

METHODS:

In this prospective cohort study, patients were followed-up during their hospital stay and for 365 days thereafter.

RESULTS:

About 182 patients with AD were enrolled including 78 (42.8%) who met the criteria for ACLF (ACLF-group) while the remaining had AD without ACLF (AD-group). 56.4% and 56.7% of the ACLF- and AD-groups, respectively, had alcoholic cirrhosis and 85.9% of the ACLF-group hepatic encephalopathy. Only few patients were hospitalized in the intensive care unit (ICU) or transplanted. The probabilities of death estimated for both scores were similar to the overall mortality rates observed at all time points. The model had a good fit in the AD-group at 90 days (p = .974) but a worse, yet adequate, in the ACLF-group at 28 days (p = .08). The CLIF-C ACLF or AD scores had an adequate, predictive discrimination ability for mortality at all time points, with Harrel's concordance index-C ranging between 0.64 and 0.65 or 0.64 and 0.68, respectively. Both scores showed a similar predictive accuracy for mortality compared to those of MELD, MELD-Na and Child-Pugh.

CONCLUSIONS:

In this population without access to appropriate ICU treatment, the CLIF-C ACLF and AD performed worse than in studies with patients having ICU access. In addition, the CLIF scores were not superior to classical ones in this setting.

 

 

 

Dig Dis Sci. 2018 Feb;63(2):493-501. doi: 10.1007/s10620-017-4686-8. Epub 2017 Aug 5.

SX-Ella Stent Danis Effectively Controls Refractory Variceal Bleed in Patients with Acute-on-Chronic Liver Failure.

Maiwall R¹, Jamwal KD¹, Bhardwaj A², Bhadoria AS², Maras JS³, Kumar G², Jindal A¹, Choudhury A¹, Anand L¹, Sahney A¹, Kumar A¹, Sharma MK¹, Sharma BC¹, Sarin SK⁴.

Author information

Abstract

BACKGROUND AND AIMS:

Almost 10% of bleeding episodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality up to 50%. Severity of liver disease and high portal pressure are mainly responsible for it. TIPS cannot be used in these patients due to high MELD score. We aimed to evaluate the efficacy of self-expandable DE stents for control of refractory variceal bleeds in patients with ACLF.

METHODS:

Acute-on-chronic liver failure patients (n = 88, mean age 47.3 ± 10.9 years) with refractory variceal bleeds received either DE stent (Gr. A, n = 35) or continued with repeat endotherapy and vasoactive drug (Gr.B, n = 53). Matching by propensity risk score (PRS) was done to avoid selection bias. Competing risk Cox regression analysis was done to identify event-specific, i.e., gastrointestinal bleed-related death.

RESULTS:

Majority (78.4%) of patients were alcoholic with MELD score of 45.9 ± 20.1. Control of initial bleeding was significantly more in the DE stent group as compared to controls in both pre-match (89 vs. 37%; p < 0.001) and PRS-matched cohorts (73 vs. 32%; 0.007). Further, bleed-related death was also significantly lower in DE group as compared to controls in both pre-match (14 vs. 64%; p = 0.001) and PRS-matched cohorts (6 vs. 56%; p = 0.001). In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both pre-match (p = 0.04, HR 0.36, 95% CI 0.13-0.96) and PRS-matched cohorts (p < 0.001, HR 0.21, 95% CI 0.08-0.51).

CONCLUSIONS:

Self-expandable DE stents are very effective in control of refractory variceal bleeding and reduced mortality in patients with severe liver failure.

 

 

Am J Med Sci. 2017 May;353(5):452-458. doi: 10.1016/j.amjms.2017.03.005. Epub 2017 Mar 21.

Risk Factors and Outcomes of Acute Kidney Injury in Patients With Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Yuan W¹, Zhang YY¹, Zhang ZG¹, Zou Y¹, Lu HZ², Qian ZP³.

Author information

Abstract

BACKGROUND:

Acute kidney injury (AKI) is common in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF); however, few studies concerning the risk factors and recovery patterns of renal function have been published.

MATERIALS AND METHODS:

A retrospective analysis of 150 patients with HBV-ACLF was performed. The occurrence, risk factors and functional recovery of AKI among patients with HBV-ACLF were investigated.

RESULTS:

A total of 90 patients (60%) with HBV-ACLF developed AKI. Patients with AKI had higher creatine kinase (P = 0.004), total bilirubin (P = 0.039), HBV viral load (P = 0.044), serum creatine (P < 0.001) and model for end-stage liver disease (MELD) score (P < 0.001) values and a higher proportion of hepatic encephalopathy (P = 0.032) and spontaneous bacterial peritonitis (SBP) (P = 0.042) than patients without AKI. Logistic regression analysis illustrated that SBP (odds ratio = 6.214, P = 0.012) and MELD score (odds ratio = 1.097, P = 0.006) were risk factors for the development of AKI. A subgroup analysis of recovery patterns in renal function showed that patients with a severe AKI stage had worse outcomes (P = 0.007). The proportion of patients who experienced a complete recovery was higher in survivors than in the overall AKI populations (P = 0.004). Follow-up studies showed that the no-AKI group had a higher transplant-free survival rate than the AKI group at day 90 (80.0% versus 26.7%, respectively, P < 0.001). The survival rate among patients with AKI Stage 1 was higher than that of patients with AKI Stage 2 and patients with AKI Stage 3 (P < 0.001).

CONCLUSIONS:

AKI is common in patients with HBV-ACLF. The SBP and MELD score have some prognosis value for patients with AKI. AKI and its stages affect the 90-day transplant-free mortality rate. It is important to focus on exploring the early recognition of AKI and early intervention of those risk factors in individuals with HBV-ACLF.

 

Biomed Pharmacother. 2017 Jul;91:776-787. doi: 10.1016/j.biopha.2017.04.117. Epub 2017 May 10.

Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure.

Gilsanz C¹, Aller MA², Fuentes-Julian S³, Prieto I⁴, Blázquez-Martinez A³, Argudo S², Fernández-Delgado J⁵, Beleña J⁶, Arias J², De Miguel MP⁷.

Author information

Abstract

A serious complication of chronic hepatic insufficiency is acute-on-chronic liver failure, a recognized syndrome characterized by acutedecompensation of cirrhosis and organ/system failure. We investigated the use of adipose-derived mesenchymal stem cells (AD-MSCs) in an experimental model of acute-on-chronic liver failure, developed by microsurgical extrahepatic cholestasis in rats. Rats undergoing microsurgical extrahepatic cholestasis were treated by intraparenchymal liver injection of human or rat AD-MSCs, undifferentiated or previously differentiated in vitro toward the hepatocyte lineage. The groups treated with rat AD-MSCs showed less ascites, lower hepato- and splenomegaly, less testicular atrophy, and an improvement in serum biochemical hepatic parameters. There was also an improvement in histological liver changes, in which the area of fibrosis and bile duct proliferation were significantly decreased in the group treated with predifferentiated rat AD-MSCs. In conclusion, an isograft of hepatocyte-predifferentiated AD-MSCs injected intraparenchymally 2 weeks after microsurgery in extrahepatic cholestatic rats prevents secondary complications of acute-on-chronic hepatic failure. These data support the potential use of autologous AD-MSCs in the treatment of human cholestasis, and specifically of newborn biliary atresia, which could be beneficial for patients awaiting transplant.

 

Alcohol-related acute-on-chronic liver failure-Comparison of various prognostic scores in predicting outcome.

Sonika U¹, Jadaun S¹, Ranjan G¹, Rout G¹, Gunjan D¹, Kedia S¹, Nayak B¹, Shalimar².

 

Abstract

BACKGROUND AND AIMS:

Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients.

METHODS:

All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronic health evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey's discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome.

RESULTS:

Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey's score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5-123.0), 33.1 (27.6-40.0), 34.4 (29.5-40.0), 8.5 (7.3-9.6), 15 (12-21), and 51.1 (44.1-56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173-3.682, p = 0.012 and advanced, HR, 2.330; 95% CI, 1.270-4.276, p = 0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023-1.270, p = 0.018), and infection at admission (HR, 1.874; 95% CI, 1.160-23.029, p = 0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD-Na, DF, and ABIC (p < 0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p = 0.660).

CONCLUSIONS:

Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best.

 

2079

Characteristics and outcome of Severe Alcoholic Hepatitis- related Acute-on-Chronic Liver Failure Syndrome

Alexia Cornillie, Eric Trépo, Delphine Degré, Jonas Schreiber, Antonia Lepida, Christophe Moreno, Thierry Gustot; Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

Background & Aims: Although active alcoholism is known to be a potential trigger for Acute-on-Chronic Liver Failure (ACLF), place of severe alcoholic hepatitis (AH) as precipitating event is currently unknown. We assessed characteristics, outcome and predictive factors for the development of ACLF in patients with severe biopsy-proven alcoholic hepatitis (AH).

Methods: We prospectively followed 145 consecutive biopsy-proven severe AH (mDF≥32) episodes for 6 months. We retrospectively reviewed ACLF diagnosis, grades (based on CANONIC criteria) and prognostic scores, CLIF-C Organ Failure score (OFs) and CLIF-C ACLFs (Jalan et al. J Hepatol 2014;61:1038-47) at the time of liver biopsy (baseline) and at different time pointsduring 3-month follow-up.

Results: At baseline, ACLF was diagnosed among 52% of severe AH episodes (17% of ACLF grade 1 (ACLF-1), 16% of ACLF-2 and 19% of ACLF-3). Compared to AH episodes without ACLF at baseline, AH episodes with ACLF had a higher 28-day and 90-day transplant-free mortality rate (54 vs. 10% and 68% vs. 18% respectively, p<0.001) and a lower probability of Lille model-defined response to corticosteroids (40% vs. 81%, p<0.001). Compared to mDF, MELD and Lille model, baseline CLIF-C Organ Failure score (OFs) was more accurate to predict 28, 90 and 180-day  transplant-free mortality in all AH episodes while CLIF-C ACLFs had a better accuracy in the subgroup of AH episodes with ACLF at baseline. The 28, 90 and 180-day mortality rates of AH episodes with ACLF at baseline did not differ significantly between responders and non-responders to corticosteroids. ACLF occurred during the 3-month follow-up (median of 16 [1-75] days) in 34% of AH episodes without ACLF at baseline and was associated with higher 90-day and 180-day transplant- free mortality compared to those without ACLF during follow-up (55 vs. 3% and 72 vs. 9% respectively, p<0.001). In multivariate analysis, a baseline Child-Pugh score (CPs) ≥11 was the only independent predictor (OR=4.64, 95% CI: 1.42- 15.2, p<0.05) of ACLF development in AH episodes without ACLF at baseline.

Conclusion: ACLF is a prevalent syndrome in severe AH and is associated with a dramatic prognosis. CLIF-C OFs and CLIF-C ACLFs are the most accurate predictors for mortality of patients with AH and patients with AH-related ACLF respectively. Due to the low probability of response to corticosteroids and the absence of survival benefit associated with response in AH-related ACLF, alternative new therapies are rapidly needed in this subgroup of patients.

719

Characterization of Acute-on-Chronic Liver Failure And Prediction of Mortality in Patients with Alcoholic Hepatitis

Hwi Young Kim, Yong Jin Jung, Byeong Gwan Kim, Kook Lae Lee, Won Kim; Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea

BACKGROUND: Alcoholic hepatitis(AH) often evolves to acute on- chronic liver failure(ACLF) which raises the risk of (multi-) organ failure as well as mortality. The aims of the present study were to investigate development and features of ACLF among hospitalized patients with alcoholic hepatitis and to validate a recently developed prognosticator of ACLF.

METHODS: A total of 1191 consecutive patients were evaluated for eligibility, who were hospitalized with AH between 1999 and 2012. Patients with the following conditions were excluded in further analysis: serious cardiovascular diseases (n=13); presence of malignancies (n=5); co-existence of viral hepatitis (n=16); Child-Pugh class A (n=102); use of corticosteroid/pentoxifylline (n=44). Finally, 1011 patients were included for the analysis

CLIF-SOFA scoring system was used as the diagnostic criteria for ACLF(Moreau R, et al. Gastroenterology 2013;144:1426– 1437). CLIF-consortium(CLIF-C) ACLF score was used to predict mortality(Jalan R, et al. J Hepatol 2014;60:s239), and was compared with MELD, MELD-Na, and Child-Pugh score.

RESULTS: Median age was 52 years, and male patients were 88.7%. Median clinical scores at the time of admission were as follows: Maddrey’s discriminant function(MDF), 20.2; model for end-stage liver disease(MELD), 17.1; MELD-Na, 20.7. Systemic inflammatory response syndrome(SIRS) was present in 574(56.8%). A total of 269(26.6%) patients were diagnosed with ACLF: grade 1, 98(36.4%); grade 2, 108(40.1%); grade 3, 63(23.5%). Patients with ACLF had higher clinical scores including MDF, MELD, MELD-Na than those without ACLF. There was no difference in the frequency of ACLF between cirrhotic vs. non-cirrhotic patients (16.7% vs. 27.1%, P=0.088). From multiple logistic regression analysis, predictive factors at admission for the development of ACLF were presence of SIRS(odds ratio(OR), 2.714(95% confidence interval(CI), 1.582-4.657); P<0.001), bacterial infection(OR, 1.698(95% CI, 1.176-2.451); P=0.005), high c-reactive protein(OR, 1.679(95% CI, 1.100-2.561); P=0.016), and low mean arterial pressure(OR, 0.985(95% CI, 0.972-0.999); P=0.032). For prediction of 90-day mortality in patients with ACLF, areas under the receiver-operating curve were 0.731 with CLIF-C ACLF score, 0.688 with Child-Pugh score, 0.634 with MELD, and 0.635 with MELD-Na, respectively.

CONCLUSION: Infection and SIRS may play an important role in the developmentof ACLF in patients with alcoholic hepatitis. CLIF-C ACLF score was shown to be useful in predicting mortality compared with other liver-specific scoring systems in this external validation.

 

1286 w


Impaired TFEB-Mediated Lysosomal Biogenesis Contributes to Acute-on-Chronic Alcohol-In- duced Liver Injury in Mice

Xiaojuan Chao, Shaogui Wang, Yuan Li, Tiangang Li, Hong- Min Ni, Wen-Xing Ding; Pharmacology, Toxicology and Thera- peutics, The University of Kansas Medical Center, Kansas City, KS

Background: Liver cells can adapt and protect themselves in response to stress by activating cellular protective mechanisms such as autophagy and lysosomal biogenesis . However, whether and how these protective mechanisms are impaired after chronic alcohol consumption are largely unknown . Methods: we used GFP-LC3 transgenic mice, liver-specific transcription factor EB (TFEB) and whole body TFE3 knockout (KO) mice as well as TFEB/TFE3 DKO mice . We also used adenovirus-mediated knockdown or overexpression of TFEB in mouse livers . All the mice were subjected to chronic alcohol feeding plus acute binge model . Results: we found that chronic plus acute alcohol binge (acute-on-chronic) inactivates TFEB, a member of the family of helix-loop-helix leucine zipper transcription factors and a master regulator of lysosomal biogenesis, resulting in impaired lysosomal biogenesis and insufficient autophagy in hepatocytes . Mechanistically, acute-on- chronic alcohol increased lysosomal mTOR translocation and activated mTOR in mouse livers resulting in decreased nuclear and total levels of TFEB in hepatocytes . Torin 1, a pharmacological inhibitor of mTOR, improved the impaired TFEB induced by alcohol and protected against alcohol-in- duced steatosis and liver injury . More importantly, overex- pression of TFEB protected against alcohol-induced liver injury by recovering lysosomal biogenesis coupled with increased mitochondrial bioenergetics . In contrast, knock- down of TFEB or deletion of both TFEB and TFE3 (another transcription factor that regulates lysosomal biogenesis) in mice exacerbated alcohol-induced liver injury . Conclu- sions: our findings indicate that impaired TFEB-mediated lysosomal biogenesis contributes to acute-on-chronic alco- hol-induced liver injury .

Disclosures:

The following people have nothing to disclose: Xiaojuan Chao, Shaogui Wang, Yuan Li, Tiangang Li, Hong-Min Ni, Wen-Xing Ding

833 w


Altered Gut Microbiota at Hospitalization are Associated with ACLF, type of Organ Failure, and Death in a Multi-Center North American Cohort

Jasmohan S. Bajaj1, Hugo E. Vargas2, K. Rajender Reddy3, Jennifer C. Lai4, Jacqueline G. O’Leary5, Puneeta Tandon6, Florence Wong7, Dinesh Ganapathy1, Robert Mitrani3, Megan Kelly2, Deanna M. Myer5, Andrew Fagan1, Syl- via Kalainy6, Masoumeh Sikaroodi8, Patrick M. Gillevet8; NACSELD; 1Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, VA; 2Mayo Clinic, Scottsdale, AZ; 3University of Pennsylvania, Philadelphia, PA; 4University of California, San Francisco, CA; 5Baylor University Medical Center, Dallas, TX; 6University of Alberta, Edmonton, AB, Canada; 7University of Toronto, Toronto, ON, Canada; 8George Mason University, Manassas, VA

Altered gut microbiota or dysbiosis is associated with cirrhosis . In single-center studies, they are associated with negative outcomes in cirrhotics but a multi-center evaluation is required . Aim: Determine the alterations in gut microbiota in cirrhotic inpatients that are associated with an increased risk for ACLF, types of organ failure, & mortality . Methods: Non-electively admitted cirrhotic patients underwent stool collection within 48 hours of admission in a multi-center study . Pts were followed until of acute-on-chronic liver failure (ACLF), organ failures &death/discharge to hospice . Microbiota at baseline were studied using 16SrRNA sequencing with LEFSe to deter- mine differences that might predispose to these outcomes . Results: 181 subjects (age 56, MELD 20, 41% infected) were included . 66% were on lactulose/rifaximin & 19% were on SBP prophylaxis on admission . Hospital course: The mean length of stay was 8 days, 17% were transferred to ICU, 14% developed grade 3/4 HE(brain failure), 7% needed ventilation (respiratory failure), 8% developed shock (circulatory failure), 8% required dialysis (renal failure), 8% developed ACLF (↓2 organ failures) &22% died/required hospice . Baseline microbiota were different between infected/uninfected pts, with higher pathogenic taxa Enterococceae, Staphyloccocaceae &lower Bifido- bacteriaceae in infected pts . Hospital course (table): Pts transferred to ICU had lower commensals & higher Proteo- bacteria . Pts who died/went to hospice had higher Entero- cocceae and Proteobacteria . Organ failures: Pts requiring dialysis had higher Proteobacteria constituents & lower Clostridia . HE pts had higher Proteobacteria . Pts needing ventilation and shock had higher taxa from Proteobac- teria, Spirochaetae & Actinobacteria with lower lower Clostridia and Erysipelothriciacae in shock pts . ACLF pts had similar changes as shock pts Conclusion: Alterations in gut microbiota on admission, with higher taxa belonging to the phylum Proteobacteria, are associated with ACLF, organ failures, ICU transfer and death in this multi-center cohort . Future studies with interventions aimed at gut dysbiosis may improve outcomes in admitted cirrhotics at risk of ACLF .

 

THU-246

 

Regional variations in the development of acute-on-chronic liver failure (ACLF) in patients with cirrhosis and bacterial infections

• Wong¹, V. Singh², P. Caraceni³, R. Maiwall⁴, S. Piano⁵, S. Marciano⁶, J. Fernandez⁷, C. Alessandria⁸, E. Soares⁹, D.J. Kim¹⁰, S.E. Kim¹¹,

 

• Marino¹², J. Vorobioff¹³, R. de Cassia Ribeiro Barea¹⁴, M. Merli¹⁵, L. Elkrief¹⁶, V. Manuel, V. Blasco¹⁷, A. Krag¹⁸, S. Singh¹⁹, L.A. Lesmana²⁰, C. Toledo²¹, V. Xavier²², N. Intagliata²³, L. Rabinowich²⁴, T. Bruns²⁵, E.L. Yoon²⁶, M. Girala²⁷, N.T. Pyrsopoulos²⁸, T.H. Kim²⁹, S.Y. Yim³⁰,

F. Durand³¹, A. Gadano⁶, P. Angeli³². ¹University of Toronto, Toronto, Canada; ²Postgraduate Institute of Medical Education and Research, Padova, Italy; ³University of Bologna, Bologna, Italy; ⁴Institute of Liver and Biliary Sciences (ILBS), New Delhi, India; ⁵University of Padova, University and General Hospital of Padova, Padova, Italy; ⁶Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; ⁷Hospital Clinic of Barcelona, Liver Unit, Barcelona, Spain; ⁸University Hospital of Turin, Turin, Italy; ⁹Gastrocenter-Unicamp, Campinas, Brazil; ¹⁰Hallym University College of Medicine, Chuncheon,Republic of South Korea;

 

¹¹Hallym University Sacred Heart Hospital, Republic of South Korea;

¹²Hospital Dr. Carlos B. Udaondo, Buenos Aires, Argentina; ¹³Universidad Nacional de Rosario, Rosario, Argentina; ¹⁴Faculty of Medicine of Bahia, Campo Grande, Brazil; ¹⁵Sapienza University of Rome, Rome, Italy;

 

¹⁶University Hospital of Geneva, Geneva, Italy; ¹⁷Hospital Vall d’Hebron, Liver Unit, Barcelona, Spain; ¹⁸Odense University Hospital, Odense, Denmark; ¹⁹Shri Ramachandra Bhanj Medical College, Orissa, India;

²⁰Digestive Disease and Oncology Centre (DDOC)-Medistra Hospital, Jakarta, Indonesia; ²¹Hospital Valdivia, Universidad Australe de Chile, Valdivia, Chile; ²²Ghent University Hospital, Ghent, Belgium;

 

²³University of Virginia, Charlottesville, United States; ²⁴Tel-Aviv Medical Center, Tel-Aviv, Israel; ²⁵Jena University Hospital, Jena, Germany;²⁶Sanggye Paik Hospital, Inje University Seoul, Seoul, Republic of South Korea; ²⁷Universidad Nacional de Asunciòn, Asunciòn, Paraguay;²⁸Rutgers New Jersey Medical School, Newark, United States; ²⁹Ewha Womens University, Rep. of South Korea; ³⁰Anam Korea University Hospital, Seoul, Rep. of South Korea; ³¹Hospital Beaujon, Clichy, France; ³²University of Padova, Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine, DIMED, Padova, Italy

 

Email: pangeli@unipd.it

Background and Aims: Bacterial infections, by inducing an inflam-matory state and by further perturbing the already abnormal hemodynamics of advanced cirrhosis, can potentially precipitate ACLF. Patterns of bacterial infections and antibiotic resistance vary in different regions of the world. These could possibly contribute to variations in the types of organ failure or severity of ACLF around the world. The aim was to evaluate the regional differences in the development of ACLF as a result of bacterial infections in cirrhosis.

 

Method: The International Club of Ascites (ICA) enrolled 1302 cirrhotic patients admitted for complications of cirrhosis with a concomitant bacterial infection worldwide from Oct 2015 to Sept 2016. All patients had baseline clinical, laboratory and microbio-logical data collected from the time of diagnosis of infection. Information on antibiotic given, antibiotic resistance, further com-plications, patient and infection outcomes were also collected. All patients were followed till liver transplant, or death, or discharge.

 

Results: Patients were divided into 6 regions worldwide (table). Patients were mostly middle aged (57 ± 13 years) men (69%) with alcoholic cirrhosis (52%). ACLF as defined by the EASL-Chronic Liver Failure (CLIF) Consortium was already present in 35% of patients at infection diagnosis, being significantly more prevalent (60%) and more severe in the Indian subcontinent (table) when compared to the rest of the world, possibly related to the high prevalence of multi-drug resistant organisms in India (73% vs. 29%, p < 0.0001). Renal failure was the most common organ failure with ACLF across the world (17–34% of all organ failures). In patients without ACLF at infection diagnosis, further ACLF episodes occurred more frequently in Indian patients than in the other patients (44% vs. 25%, p = 0.0072). The severity of ACLF following treatment of infection was similar across the world ( p = 0.078).

 

South	North	South	North	Indian	Other	P
Europe	Europe	America	America	hospitals	Asian
(n= 428)	(n= 137)	(n = 252)	(n = 69)	(n= 250)	hospitals
					(n= 166)

 

ACLF – n (%)	111	(26)	39 (29)	93 (37)		24	(35)	151	(60)	42	(25)	<0.001
ACLF grade – n (%)
Grade 1	53	(48)	24 (62)	44	(47)	9	(38)	41	(27)	19	(45)	<0.001
Grade 2	42	(38)	8 (21)	35 (38)		6	(25)	59	(39)	14	(33)
Grade 3	16 (14)		7 (18)	14	(15)	9	(38)	51	(34)	9	(21)

 

 

Conclusion: ACLF is common with bacterial infections in cirrhosis, and can occur even after infection is treated. Efforts should be made to prevent infection so to reduce the likelihood of ACLF.

 

577

‘Eastern type’ of Acute-on-chronic Liver Failure (ACLF) is similar in pathophysiologic, diagnostic and prognostic criteria to the ‘Western type’: A comparison of Chinese hospitalized patients with Hepatitis B with CANONIC data

Hai Li1, Marco Pavesi2, Bo Zeng1, Liu-Ying Chen1, Shu-Ting Li1, De-Kai Qiu1, Richard Moreau3, Pere Gines4, Vicente Arroyo5, Rajiv Jalan6; 1Dept. of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China; 2Data Management Center,, EASL-CLIF Consortium, Barcelona, Spain; 3Hopital Beaujon, Clichy, France; 4Hospital Clínic, Barcelona, Spain; 5EASL-CLIF Consortium, Barcelona, Spain; 6Liver Failure Group, Institute for Liver and Digestive Health, UCL, London, United Kingdom

The diagnostic criteria for ACLF were described from data of1353 European patients (CANONIC study;Gastroenterology 2013). Two main observations of the study were that the CLIFSOFA score could be used to diagnose ACLF and classify its severity and, inflammation was important in its pathogenesis. Much debate in the literature has suggested that the ‘Eastern type’ of ACLF, where the main underlying cause of liver disease is Hepatitis B may not have the same pathophysiologic characteristics and therefore requires different diagnostic and prognostic criteria. The aim of this study was to validate the CLIF-SOFA score to diagnose and classify ACLF and, determine whether inflammation played a role in the pathogenesis of ACLF in a population of patients in a single center in Shanghai, China with HBV infection.

METHODS: 890 consecutive hospitalized HBV-related chronic liver disease patients with acute decompensation from 2005-2010 were included. Among them 243 (27%) patients underwent liver transplantation (LT). Predisposition (cirrhosis), acute insult, inflammatory parameters (leukocyte count), CLIF-SOFA score and short-term mortality were used to evaluate the population. RESULTS: According to the CLIF-SOFA score, 24% (211/890) patients had ACLF at enrollment and 7% (62/890) developed ACLF within 28-days. Their 28 and 90-day mortality were 41%, 37% and 46%, 45% respectively. 20%, 53% and 27% patients had ACLF-1, ACLF-2 or ACLF-3. The 28 and 90-day mortality were 24% and 31%; 40% and 44%; 53% and 61% respectively. Non-ACLF patients (69%; 617/890) had a 28 and 90-day mortality of 3% and 6% respectively (P<0.001 vs ACLF). ACLF patients had a significantly higher white cell (10±6*109 vs 5±4*109/L; P<0.001) compared with non-ACLF patients. No precipitating event was identifiable in 62% (130/211) ACLF and 45% (305/679) non-ACLF patients. Both HBV reactivation (30%) and bacterial infection (30%) were the most frequent acute insult for precipitating events identifiable ACLF patients.

CONCLUSION: The results confirm that the clinical characteristics of ACLF patients in China, where the main cause is HBV infection is similar to the clinical characteristics of European patients where the main etiology is alcohol. CLIF-SOFA score allows classification of ACLF into different prognostic groups; precipitating factor is not necessary; infection is an important precipitating factor and systemic inflammation is pathophysiologically important. The data argue strongly that the ‘Eastern’ form of ACLF follows similar diagnostic, prognostic and pathophysiological characteristics to that of the ‘Western’ form suggesting that the definition of ACLF should be harmonized world-wide.

 

Hepatitis E-­induced acute-­on-­chronic liver failure and VI nerve paralysis

Gerhard Jung¹  | Pol Olivas¹ | Alba Díaz² | Sabela Lens¹

¹Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain

 

²Pathology Department, Hospital Clínic, Barcelona, Spain

Correspondence

 

Gerhard Jung, Liver Unit, Hospital Clínic Barcelona, Barcelona, Spain. Email: jung@clinic.cat

A 65-­year-­old patient with long-­term metabolic syndrome and no relevant alcohol consumption was admitted to the hospital due to jaundice. His electronic record revealed a first suspicion of NAFLD 3 months ago because of slight alterations of LFT (AST 80 IU/L). Actual testing showed an important worsening of all LFT (AST 639 IU/L, ALT 456 IU/L, AP 248 IU/L, GGT 293 IU/L) with TB 23 mg/ dL and an INR 1.22. The ultrasound displayed a homogeneous hep-atosplenomegaly, with normal biliary tract. The biopsy showed signs of cirrhosis (Figure 1D), steatosis without steatohepatitis and an overlayed acute hepatitic process (Figure 1A-­C). Testing for hepato-tropic viruses revealed positive HEV IgM and HEV-­RNA (genotype 3). The patient developed grade 2 ACLF (CLIF-­C ACLF Score 49) with de-­novo ascites, grade 2 encephalopathy, bilirubin 50 mg/dL, INR 2.15 and creatinine 3.04 mg/dL. In addition, 2 days after admission the patient presented an acute VI nerve paralysis (Figure 2) with

 

 

 

 

 

 

 

 

 

 

 

 

                                                                                                                                          Figure 2)

 

 

 

 

 

FI G U R E 1   Histological analysis of liver biopsy showed a diffuse lobular hepatitis with mild hepatocellular cholestasis (A; HE 10X) with marked lobular disarray, apoptotic bodies and abundant necroinflammatory foci (B; HE 20X). Areas of confluent hepatocyte necrosis were also noted (C; HE 20X). Masson’s trichrome stain revealed an advanced stage with signs of cirrhosis and focal pericellular fibrosis (D; Masson’s trichrome, 10X)

 

imaging studies discarding an ischaemic origin. Ribavirin was started with good virological response (RNA undetectable), normalization of liver function (AST 39, TB 1.0 mg/dL, INR 1.1), disappearance of as-cites and improvement of diplopia.

Acute hepatitis E can trigger rapid liver impairment and clinical de-compensation in patients with underlying liver disease.^1,2 Associated neurological disorders are not uncommon in HEV infection^3,4 and may warn clinicians to test for HEV serological markers and initiate prompt antiviral therapy in case of diagnosis confirmation.

R E F E R E N C E S

 

1. Donnelly MC, Scobie L, Crossan CL, Dalton H, Hayes PC, Simpson KJ. Review article: hepatitis E-­a concise review of virology, epidemiology, clinical presentation and therapy. Aliment Pharmacol Ther. 2017;46:126‐141.

 

2. Kumar Acharya S, Kumar Sharma P, Singh R, et al. Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid de-compensation and death. J Hepatol. 2007;46:387‐394.

 

3. Mclean BN, Gulliver J, Dalton HR. Hepatitis E virus and neurological disorders. Pract Neurol. 2017;17:282‐288.

 

4. Dalton HR, Kamar N, van Eijk JJ, et al. Hepatitis E virus and neurolog-ical injury. Nat Rev Neurol. 2016;12:77‐85.

 

 

 

530

Invasive Fungal Infections in patients of Acute on Chronic Liver Failure

Nipun Verma1, Shreya Singh2, Sunil Taneja1, Ajay K. Duseja1, Virendra Singh1, Radha K. Dhiman1, Arunaloke Chakarbarti2, Yogesh K. Chawla1; 1Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; 2Medical Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Background: Invasive Fungal Infections (IFI) are an emerging concern in patients with Acute on Chronic Liver Failure (ACLF) . We evaluated the impact of IFI in patients with ACLF and the role of serum biomarkers (1–3)--D glucan (BDG) and galactomannan index (GMI) for early diagnosis . Methods: A retrospective analysis of IFI in patients with ACLF (EASL criteria) admitted in Liver ICU at a tertiary care hospital between January 2016 to December 2016 was conducted . Patients with clinical suspicion of IFI were diagnosed based on criteria adapted from the EORTC/MSG definitions for IFI . Demographic, clinical, laboratory data and the outcomes were analyzed . Results: Out of 264 patients with ACLF, 54 (20 .4%) were evaluated for IFI . Diagnosis of IFI was established in 39 (14 .7%); candidiasis (n=25) and aspergillosis (n=14) . Sites of infection were respiratory (n=13), renal (n=7), fungemia (n=5), spontaneous fungal peritonitis (n=6), renal & respiratory (n=6) and renal & esophageal (n=2) . In patients with IFI versus noIFI there were no differ- ences in age [51 .615 .7 vs . 52 .29 .6; p=0 .886], gender [males 28(71 .8%) vs . 14(93 .3%); p=0 .145], CTP [12(8-15) vs . 11(7-13); p=0 .272] and MELD [30(14-40) vs . 30(15- 40); p=0 .380] . However, prior antibiotic use [37(94 .9%) vs . 4(26 .7%); p0 .001], higher CLIF-OF score [14(8-18) vs . 11(7-14); p0 .001], higher CLIF-C ACLF score [63(39-88) vs . 51(32-67); p=0 .001], higher cerebralOF [26(66 .7%) vs . 2(13 .2%); p=0 .001] and higher respiratoryOF [18(46 .2%) vs . 2(13 .3%); p=0 .031] were observed in IFI versus noIFI . Higher BDG [308(87-500) vs . 74(30- 500); p=0 .002], higher GMI [0 .870 .90 vs . 0 .260 .08;p=0 .019] and lower procalci- tonin (PCT) [0 .8(0 .0-100 .0) vs . 12 .4(0 .5-80)ng/ml; p=0 .001] was observed in patients with IFI versus noIFI . The sensi- tivity, specificity, PPV, NPV and AUROC of BDG (80 pg/ ml) and GMI (0 .5) for diagnosing IFI was 97 .4%, 60%, 86 .4%, 90%, 0 .770 and 43 .6%, 100%, 100%, 40 .5%, 0 .745 respectively . Patients with IFI had a higher mortality compared with noIFI [30(76 .9%) vs . 9(42 .9%); p0 .001] . Non-survivors were more likely to have IFI [30(90 .0%) vs . 6(46%); p=0 .029], higher BDG levels [321(47-500) vs .174(30-500); p=0 .009], higher CLIF-OF score [14(10-18) vs . 11(7-15); p0 .001] and higher CLIF-C ACLF score [68(46- 88) vs . 48(32-67); p0 .001] as compared with survivors . Patients with IFI (n=39), who received antifungals (n=30), 9 survived (treatment duration: 14 days; range 12-14) and 21died (treatment duration: 4 days; range 1-4) . Conclu- sions: IFI constitutes an important cause of mortality in patients with ACLF . BDG and GMI are useful markers to guide timely antifungal therapy in patients with ACLF at high risk for IFI .

Disclosures:

The following people have nothing to disclose: Nipun Verma, Shreya Singh, Sunil Taneja, Ajay K . Duseja, Virendra Singh, Radha K . Dhiman, Arunaloke Chakarbarti, Yogesh K . Chawla

 

1045

IL10 associated downstream signalling pathways play a central role in severe monocyte dysfunction during acute-on-chronic liver failure.

Hannelie Korf2, Johannie du Plessis2, Johannes van Pelt2, Frederik Nevens1,2, Schalk Van Der Merwe1, Elien De Smidt3; 1Hepatology, University of Leuven, Leuven, Belgium; 2Laboratory of Hepatology, University of Leuven, Leuven, Belgium; 3Laboratory of Endocrinol- ogy, University of Leuven, Leuven, Belgium

Objective: Acute-on-chronic liver failure (ACLF) is character- ized by rapid deterioration of liver function in cirrhosis which often precipitates organ failure . ACLF is associated with severe immunodysfunction where immune activation and paresis often co-exist . This dysregulated immune state leads to severe monocyte dysfunction that may precipitate bacterial infections . Although ACLF as disease entity has attracted much attention, little is known about the molecular mechanisms responsible for altered monocyte function in this condition . Design: We studied 64 patients with biopsy proven alcoholic liver disease (n=19 decompensated cirrhosis, n=23 alcoholic hepatitis, n=22 ACLF) and 7 controls . Blood was obtained at admis- sion for biochemical tests, gene expression of PBMC’s, flow cytometry and functional monocyte assays and plasma was used to determine cytokine/chemokine levels . In addition we isolated CD14pos monocytes from 4 donors and 5 well-char- acterized ACLF patients and determined gene expression by NextGen sequencing to characterize key molecular factors associated with monocyte dysfunction using pathway analysis . Additionally functional assays were performed with healthy or ACLF monocytes in the presence or absence of normal or ACLF serum . Results: We observed decreased expression of HLA-DR, TLR2 and TLR4 within the classical monocyte subset and ele- vated numbers of IL10 producing intermediate monocytes in ACLF . Functional analysis of total PBMC and isolated CD14pos monocytes showed severely impaired phagocytosis and oxida- tive burst in ACLF . Increased IL10 gene expression by PBMC’s and elevated IL10 plasma levels in ACLF were associated with decreased survival at 3 and 6 months . Pathway analy- sis revealed significant downregulation of genes associated with immunological processes such as monocyte phagocytosis, cytokine-cytokine interactions and response to bacterial infec- tion . Importantly, culturing healthy monocytes in ACLF serum induced an ACLF dysfunctional phenotype . Conversely, cultur- ing ACLF-monocytes in healthy plasma reversed the ACLF phe- notype and restored phagocytosis . Finally, our data indicated a central role for IL10 in the molecular pathways associated with ACLF . Conclusion: ACLF is associated with severe immune dysfunction . Inducing an ACLF signature in healthy monocytes using ACLF serum-containing media and reversing monocyte dysfunction of ACLF monocytes using normal serum containing medium suggests a circulating factor promotes this syndrome . IL10 associates with more severe immune dysfunction and poor survival in ACLF while expression analysis suggests a crucial role for IL10 as driver of this condition .

 

82

Neutrophil Dysfunction in Acute on chronic liver failure

Radha K. Dhiman1, Dr Kunaal Makkar3, Shallu Tomer2, Sahaj Rathi1, Sunil Arora2, Sunil Taneja1, Ajay K. Duseja1, Yogesh K. Chawla1; 1Hepatology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; 2Immunopathology, Postgraduate Institute of Medical Edu- cation and Research (PGIMER), Chandigarh, India; 3Internal medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

BACKGROUND: Patients with acute on chronic liver failure (ACLF) often have a dysregulated immune response . Dysfunction of the innate immunity is an inte- gral component of this immune failure . In order to better elucidate this pathway, we evaluated neutrophil dysfunc- tion inpatients with ACLF, and its implications on 28- and 90-day mortality . METHODS: Forty-patients with chronic liver disease presenting with an acute decompensation (AD)-10 No-ACLF(ACLF-0), 10 each with grade I, II and III ACLF (CANONIC), and 10 healthy controls were prospec- tively evaluated for presence of neutrophil dysfunction . Neutrophil phenotype (NP) was expressed as percentage of cells positive for antibodies toboth CD16 and CD66b on flow cytometry . Neutrophil Phagocytic Capacity (NPC) was determined using flurorescein isothiocyanatelabelled IgG latex beadsphagocytosed per neutrophil and measured as Mean Fluorescence Intensity (MFI) using flow cytometer . Oxidative burstwas determined as percentage of neutro- phils producing reactive oxygen species (ROS) both at rest and after stimulation with Phobol Myrisate Acetate (PMA) . RESULTS: Neutrophil phenotype (NP)was better in controls compared to AD patients(CD16,66b+85 .211 .3% vs 68 .322 .4%, P=0 .02) . Similarly NPC was higher in controls(98 .3130 .6 vs 22 .518 .9 MFI, P=0 .001) . Oxida- tive burst (OB) at rest was more inAD patients compared to controls (Neutrophils producing ROS- 97 .24 .9% vs 91 .39 .2%, P=0 .006) . However, stimulated OB using PMA was more intensein controls than AD group (Neutro- phils producing ROS -929 .4% vs79 .729 .3%, P=0 .003) . Among patients with AD, both NPand NPCwas better in ACLF-0than ACLF-grades I-III(NP 80 .7 12 .8% vs 63 .822 .9%, P=0 .034; NPC 33 .618 .4 vs 18 .717 .8 MFI, P=0 .029) . However, asignificant difference was not seen among different grades of ACLF .On comparing survi- vors vs non-survivors at 90-days, both NP (78 .211 .9% vs 62 .224 .11%, P=0 .02) and NPC (33 .322 .7 vs 16 .313 .39 MFI, P=0 .004) were higher in survivors . However, such a trend was not noticed at 28-days . NP(CD16,66b+) in 71 .7%neutrophils had 78 .6% sensitivity and 65 .4% specificity in predicting 90-day survival(AUROC 0 .70, 95%CI 0 .55-0 .90, P=0 .017) . NPC MFI17 .3had71 .4 % sensi- tivity and 69 .6 % specificity (AUROC 0 .73, 95%CI 0 .54- 0 .86, P=0 .035) to predict 90-day survival . CONCLUSION: Neutrophil phenotype and phagocytic capacity, and stim- ulated oxidative burst are impaired in patients with ACLF, despite a higher background oxidative burst in these patients . This is consistent with the impaired immune response despite higher background systemic inflamma- tion in these patients . Neutrophil phenotype and phago- cytic capacity may predict survival at 90 days .

Disclosures:

The following people have nothing to disclose: Radha K . Dhiman, Dr Kunaal Makkar, Shallu Tomer, Sahaj Rathi, Sunil Arora, Sunil Taneja, Ajay K . Duseja, Yogesh K . Chawla

544

Predictors of Bacterial Infection in Acute on Chronic Liver Failure

Shekhar S. Jadaun, . Shalimar, Ujjwal Sonika, Baibas- wata Nayak, Gyan Ranjan, Gyanranjan Rout, Saurabh Kedia, Deepak Gunjan; Gastroenterology, All India Institute of Med- ical Sciences, New Delhi, India

Background: Infections are common in patients with cirrhosis, and are associated with increased mortality . Acute on chronic liver failure (ACLF) is associated with high short term mortality . The present study aimed to evaluate the predictors of bacterial infections in patients with ACLF . Methods: Consecutive patients with cirrhosis and acute decompensation(AD)during period January 2011 to March 2017 were included . Data was collected regarding etiol- ogies, onset, organ failure, and site of infections . Predic- tors of survival were assessed by Cox-proportional hazard model . Predictors of infection were assessed by logistic regression model . Results: 597 patients with cirrhosis and AD were classified into groups- no infection (group 1, n=194, 32 .5%), infection at admission or within 48 hours (group 2, 315, 52 .8%) and infection after 48 hours (group 3, n=88, 14 .7%) . Among these patients, no ACLF, ACLF grades 1, 2 and 3 were seen in 26 .5%, 9 .1%, 22 .4% and 40 .4% cases, respectively . Higher frequency of organ fail- ures including kidney, brain, circulation and respiratory failure were seen in groups 2 and 3 as compared with group 1 (P 0 .001 for all) . The frequency of infections increased with increasing grades of ACLF and as compared with no ACLF group . Infection at admission or within 48 hours and infection after 48 hours were seen in 29 .7% and 10 .8% cases with no ACLF; 48 .1% and 24 .1% cases with grade 1; 49 .3% and 11 .9% in grade 2; 69 .7% and 17 .0% in grade 3 (P 0 .001) . The most common site of infection was pneumonia (37 .9%) followed by spontaneous bacte- remia (24 .7%), spontaneous bacterial peritonitis (15 .8%) and urinary tract infection (12 .2%) . On multivariate anal- ysis, presence of infection was associated with significantly higher mortality [group 2 (HR 2 .65; 95% CI, 1 .82-3 .87, P 0 .001) and group 3 (HR 2 .26; 95% CI, 1 .49-3 .42, P0 .001)], as compared with group 1 . On multivariate logistic regres- sion analysis, presence of advanced hepatic encephalop- athy (grades 3 and 4) OR 2 .75 (1 .34-1 .64) and elevated total leucocyte count OR 1 .0 (1 .0-1 .0), P 0 .001 were asso- ciated with infections . Conclusion: Infections are common and are associated with poor outcome in ACLF . Advanced hepatic encephalopathy and increased total leucocyte count are associated with infections .

Disclosures:

The following people have nothing to disclose: Shekhar S . Jadaun, . Shalimar, Ujjwal Sonika, Baibaswata Nayak, Gyan Ranjan, Gyanranjan Rout, Saurabh Kedia, Deepak Gunjan

 

FRI-433

 

The role of bacterial infection (BI) in decompensated cirrhosis patients with or without acute-on-chronic liver failure (ACLF)

Z. Cao¹, X. Lu¹, Z. Li¹, L. Chen², Y. Liu¹, R. Mo¹, P. Ren¹, L. Chen¹, J. Lu¹, X. Wang¹, G. Zhao¹, W. Tang¹, X. Xiang¹, H. Wang¹, W. Cai¹, H. Li², Q. Xie¹. ¹Department of Infectious Disease, Shanghai Ruijin Hospital; ²Department of Gastroenterology, Renji Hospital, Shanghai, China E-mail: estherlucifer@163.com

 

Background and Aims: Bacterial infection (BI) is one of the leading cause of death in cirrhosis. Much of BI is still unknown, especially in decompensated patients. We aimed to characterize BI in chronic HBV infection patients admitted for acute decompensation (AD).

 

Methods: This is a retrospective screen of 5,102 consecutive patients admitted with HBV-related cirrhosis between 2005 and 2010 from two hospitals in Shanghai, China. 1,511 patients admitted for AD were subsequently enrolled under strict exclusion criteria (Fig 1). All patients were followed up until death. Patients who transplanted were censored on the date of transplantation. Patients who survived without transplantation were censored on the date of last follow-up. BI was diagnosed by a standard process, comprehensive evaluation of symptoms, body temperature, routine test of blood/urine/stool/ ascites/hydrothorax, microorganism detection in blood/urine/ sputum/ascites/hydrothorax, immunology and imaging techniques. ACLF and its grades of severity was defined as per CANONIC criteria. The diagnosis of sepsis was based on the updated criteria recently published in JAMA.

 

Results: In the whole cohort, BI was diagnosed in 591 patients (39.11%); of them 358 (23.69%) were confirmed with specific BI sites and 232 (15.35%) were without specific BI sites. There were significant differences between AD patients with (n = 374) and without BI (n = 1,138). BI associated AD had significantly higher rates of admission HE, ACLF and MELD score. The development rate of ACLF within 28 days during hospitalization was significantly higher in BI associated AD patients than those not associated to BI. The mortality probability was significantly higher in patients with BI than in those without BI (Fig. 2a) and markedly increased in sepsis. There were also marked differences between BI patients with (n = 158) and without ACLF (n = 207). BI patients with ACLF were more likely to have HE, ascites and HBV reactivation. The mortality probability of patients with ACLF was much higher than that of patients without ACLF, independently of the presence or absence of BI (Fig. 2b). BI was identified as risk factor of 90-day mortality in AD patients independent of the presence of ACLF or HE. Independent risk factors of 90-day mortality in AD patients with BI were ACLF, sepsis, HE (grade3–4) and previous decompensation.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conclusions: In decompensated cirrhosis, the presence of BI precipitates ACLF and worsens prognosis. The course of ACLF appears to be different according to the presence of BI or sepsis.

 

1392

Impact of Acute-On-Chronic Liver Failure on 90-day Mortality following Liver Transplantation

Eric Levesque2, Audrey Winter4, Zaid Noorah2, Jean-Pierre Daures5, Daniel Azoulay3, Paul Landais4, Cyrille Feray1; 1INSERM 955, Henri MOndor Hospital, Creteil, France; 2Liver ICU, Henri Mondor Hospital, Creteil, France; 3Liver surgery, Henri Mondor Hospital, Creteil, France; 4Clinical Research University Institute, Montpellier University, Montpellier, France; 5Department of Bio- statistics, Epidemiology, Public Health and Medical Information,, CHU NImes, Nîmes, France

Introduction: Acute-On-Chronic Liver Failure (ACLF) is charac- terised by organ failures and is associated with a significant rate of mortality within 28-days (23 to 74%), depending on the number of organ failures . The aim of this study was to assess whether ACLF at the time of liver transplantation (LT) were also a prognostic factor in cirrhotic patients and its impact the early outcome (the 90-day mortality) . Patients and methods: 350 cirrhotic patients admitted to our Liver ICU between January 2008 and December 2013, and who underwent LT, were enrolled in this study . We used ACLF grades based on anal- yses of patients with organ failure and assessed according to ACLF/CANONIC criteria (EASL-CLIF consortium) to categorize the cirrhotic patients . A propensity score was applied with an Inverse Probability Treatment Weighting in a Cox model, and a prognostic score of LT futility (90-day mortality) was generated . Results: The primary indications for liver transplantation were end-stage cirrhosis (n=194; 55%) and cirrhosis with hepatocel- lular carcinoma (n=156; 45%) . 140/350 patients (40%) met the “EASL-CLIF consortium” criteria of ACLF . Overall mortality rate at 90 days post-transplant was 10 .6% (37/350 patients) . In patients with ACLF, the 3-month, 1 year and 5-year rates of patient and graft survival were 79%, 70%, 60% and 77%, 73 and 58%, respectively; in patients without ACLF it was 96%, 91%, 84% and 94%, 88% and 78%, respectively . The 90-day survival rate for ACLF grade 3 was 60% and 83%, 85% and 96% for grades 2, 1 and 0, respectively . ACLF at the time of LT (HR: 5 .78 [3 .42 – 9 .77], p< 0 .001) was an independent pre- dictor of 90-day mortality . Sepsis occurring during the month before LT, high recipient age and male recipient, cause of LT and female donor were also independent risk factors of early mortality . Using the six factors retained in the weighted Cox model, the 90-day mortality risk was calculated according to following equation: Futility Score =1 −0 .9A Where: A = exp (−0.28 (1 if the recipient is male, 0 otherwise) + 0.29 (1 if the donor is male, 0 otherwise) −0.29 (1 if the LT indication is decompensated cirrhosis, 0 if LT is hepatocellular carcinoma on cirrhosis) + 0.44 (1 if the recipient has sepsis, 0 other- wise) + 0.40 (1 if the recipient is older than 57.2 years, 0 otherwise) + 1.75 (1 if the recipient is ACLF, 0 otherwise). Conclusion: LT is feasible in cirrhotic patients with ACLF . How- ever, we showed that ACLF was a significant and independent predictor of 90-day mortality, and thus of futile LT . We propose a score, integrating the concept of ACLF, to identify candidate cirrhotic patients in whom LT might be futile .

 

A Case of Live Donor Liver Transplantation in Acute-on-Chronic Liver Failure with Budd - Chiari Syndrome: Donor and Recipient with Antiphospholipid Antibody Syndrome

Aiman Obed Abdalla Bashir Anwar Jarrad

1 Department of Hepatobiliary and Transplant Surgery, Jordan Hospital, Amman, Jordan 2 Department of General and Transplant Surgery, Jordan Hospital, Amman, Jordan 3 Department of Hepatology, Gastroenterology and Hepatobiliary/Transplant Unit, Jordan Hospital, Amman, Jordan

Objective:

Rare co-existance of disease or pathology

Background:

Acute-on-chronic liver failure was first defined within the last 10 years as acute decompensation of chronic liv-

er disease accompanied by multiorgan failure and poor outcome. Budd-Chiari syndrome is a rare and poten-

tially deadly hepatic condition. To the best of our knowledge, this is the first case report of a live liver donor

recipient with antiphospholipid antibody syndrome.

Case Report:

A 47-year-old woman from Sudan with acute-on-chronic liver failure and subacute Budd-Chiari syndrome trig-

gered by active pneumonia was evacuated to Amman, Jordan. In Amman, she was transferred to our hospital

for liver transplant evaluation.

She presented with progressive liver failure, acute kidney failure, acute respiratory failure, and encephalop-

athy stage IV. Multidisciplinary therapy was initiated with IV anti-infective drugs and optimizing mechanical

ventilation.

Clinically, we stopped her progressive deterioration after 48 h and she improved slightly in our ICU. Accelerated

work-up for donors and recipient was completed and her daughter was selected as a medically appropriate do-

nor despite the fact that she was found to have heterozygote factor V Leiden mutation and antiphospholipid

antibody syndrome, similar to her mother.

A lifesaving live-donor liver transplantation was carried out after 72 h. Donor and recipient were discharged in

good condition with normal liver function and both were discharged on anticoagulant Rivaroxaban 20 mg.

Conclusions:

We present the first case of a patient with acute-on-chronic liver failure with subacute Budd-Chiari syndrome,

which was triggered by bacterial pneumonia and was successfully treated by live-donor liver transplantation

from a donor with antiphospholipid antibody syndrome.

MeSH Keywords:

Budd-Chiari Syndrome • Liver Failure, Acute • Liver Transplantation • Pneumonia, Bacterial

Abbreviations:

BCS – Budd-Chiari syndrome; APS – antiphospholipid antibody syndrome; MPD – primary myeloprolifera-

tive disorders; FVLM – factor V leiden mutation; ACLF – acute-on-chronic liver failure; LDLT – living donor

liver transplantation; GRWR – graft-to-recipient weight ratio

 

 

 

2069

Impact of genetic variation of the AVP1a receptor on the presence of circulatory failure in patients with acute decompensation of liver cirrhosis or acute-on-chronic liver failure

Annarein J. Kerbert1, Jelte Schaapman1, Johan van der Reijden1, Amorós Àlex2, Aiden McCormick3, Bart van Hoek1, Vicente Arroyo4, Pere Gines4, Rajiv Jalan5, Victor Vargas6, Rudolf E. Stauber7, Hein W. Verspaget1, Minneke Coenraad1; 1Gastroenterology- Hepatology, Leiden University Medical Center, Leiden, Netherlands; 2Data Management Center, CLIF consortium, Barcelona, Spain; 3Gastroenterology-Hepatology, St Vincent’s University Hospital, Dublin, Ireland; 4Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; 5Gastroenterology-Hepatology, University College London, London, United Kingdom; 6Liver Unit, Hospital Vall d’Hebron, CIBERehd, Barcelona, Spain; 7Internal Medicine, Medical University of Graz, Graz, Austria

Background & aims: Acute-on-chronic liver failure (ACLF) is defined as an acute decompensation of former stable chronic liver disease (AD) accompanied by the presence of organ failure and a high risk of short-term mortality. Systemic hemodynamic derangement and activation of endogenous vasoconstrictor systems are thought to contribute to the pathogenesis. Arginine vasopressin is a key-regulator in hemodynamic homeostasis and mediates splanchnic vasoconstriction through the arginine vasopressin 1a receptor (AVP1aR). Aim of the present study was to assess whether genetic variation of AVP1aR is associated with the presence of circulatory failure in patients with AD or ACLF.

Methods: Eight single nucleotide polymorphisms (SNPs) of AVP1aR with possible clinical relevance were identified. From 824 cirrhotic patients admitted for AD, clinical, laboratory and survival data were retrieved from the CANONIC database. Presence of circulatory failure was defined as a mean arterial blood pressure (MAP) < 70 mmHg or the use of vasopressors. ACLF was defined according to the CLIF Consortium Organ Failure score. All patients were genotyped for all eight SNPs using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism or PCR allele-specific amplification primers. Fisher’s exact test and linear regression analysis were used to test for association between allele frequencies and dichotomous and continuous variables respectively. Results are shown as mean ± SD. P< 0.05 was considered statistically significant.

Results: Patients with ACLF (n=184) had a significantly lower MAP as compared to patients without ACLF (80 ± 13 vs. 84 ± 12 mmHg, p< 0.001). The use of vasopressors was also significantly more frequent in patients with ACLF as compared to those without ACLF (19.0% vs. 2.9%, p< 0.001). Circulatory failure was present in 61 out of 824 patients, of whom 44 fulfilled the criteria of ACLF. A C>T mutation in SNP rs7308855 showed a significant association with the presence of circulatory failure in patients with AD (p= 0.025) and a clear trend towards the presence of circulatory failure in patients with ACLF (p= 0.085). A trend was also found for a T>A mutation in SNP rs7298346 to be associated with the presence of circulatory failure in patients with AD (p= 0.062). In addition, this mutation showed a significant association with the presence of circulatory failure in the subgroup of patients with ACLF (p= 0.046).

Conclusions: Single nucleotide polymorphisms in the AVP1a receptor are associated with the presence of circulatory failure in patients with acute decompensation of liver disease and ACLF.

 

 

673

Extracellular vesicles induce renal tubular cells apoptosis, oxidative stress and func- tional abnormalities in patients with an acute decompensation of cirrhosis

Alessandra Brocca1, Davide Medica2, Salvatore Piano1, Antonietta Romano1, Marta Tonon1, Antonietta Sticca1, Vin- cenzo Cantaluppi3, Paolo Angeli1; 1Department of Medicine DIMED, Unit of Medical Emergencies in Liver Transplantation, University of Padova, Padova, Italy; 2Department of Medi- cal Sciences, University of Torino, Torino, Italy; 3Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy

Introduction: Acute decompensation (AD) of cirrhosis is the main cause of hospitalization in patients with cirrhosis and patients with AD may develop acute-on-chronic liver failure (ACLF) . Acute kidney injury is common in these patients . Recent findings suggests that splanchnic arte- rial vasodilation cannot fully explain organ dysfunction in these patients . Extracellular vesicles (EVs) are involved in many important biological processes as well as in disease pathogenesis . The origin and the role of EVs in the pathogenesis of liver disease is poorly recognized . Aims: The aims of this study were: a) to characterize plasma EVs isolated from patients with compensated cirrhosis (CC), AD, ACLF and healthy subjects, b) to study the in vitro effects of isolated EVs on renal tubular cells (RTCs) . Material and Methods: Demographic, clinical and labora- tory features of 12 CC patients, 13 AD patients, 11 ACLF patients and 12 healthy subjects were collected . Plasma EVs were extracted by ultracentrifugation and characterized in size and concentration by nanoparticle tracking analysis (NTA) . Detection of EVs surface proteins, ROS productions in RTCs, protein expression in RTCs was performed by FACS analysis . Cytotoxic effects of plasma EVs on RTCs were assayed by XTT assay and TUNEL assay . Results: Plasma EVs isolated from ACLF patients were more concentrated and bigger in size compared to healthy subjects (p=0 .002) . Plasma EVs were mainly derived from platelets activated endothelium, as shown by the expression of (CD62E) . The levels of CD62E were significantly higher in ACLF patients compare to CC patients and healthy subjects (p=0 .011 and p=0 .004, respectively) . Platelet derived and monocytes derived EVs, as assessed by CD41, CD42b and CD14, were not found . CD40L levels, a receptor involved in lympho- cytes T activation, were significantly higher in CC, AD and ACLF groups than in healthy subjects (p0 .02) . Plasma EVs from patients with AD and ACLF exerted a higher cytotoxic effects than EVs from healthy subjects and CC patients on RTCs (p0 .001) . Cells incubated with EVs from AD and ACLF patients showed an increase in apoptosis (p0 .001) and ROS production (p0 .001), loss of albumin intake capabilities (p0 .001) and reduction of ZO-1 expression (p=0 .017) compared to healthy subjects and CC patients . Conclusions: EVs derived from activated endothelium may exerts an important role in the pathogenesis of acute kidney injury in patients with AD of cirrhosis and ACLF . Disclosures:

Antonietta Romano - Grant/Research Support: GILEAD; Speaking and Teaching: GILIEAD, ABBVIE, BRISTOL MYERS SQUIBB

Paolo Angeli - Advisory Committees or Review Panels: Sequana Medical, NanoAntibiotics; Grant/Research Support: Mallinckrodt Pharmaceuticals

The following people have nothing to disclose: Alessandra Brocca, Salvatore Piano, Marta Tonon, Antonietta Sticca

 

Regional variations in the development of acute-on-chronic liver failure (ACLF) in patients with cirrhosis and bacterial infections

F. Wong1, V. Singh2, P. Caraceni3, R. Maiwall4, S. Piano5, S. Marciano6, J. Fernandez7, C. Alessandria8, E. Soares9, D.J. Kim10, S.E. Kim11, M. Marino12, J. Vorobioff13, R. de Cassia Ribeiro Barea14, M. Merli15, L. Elkrief16, V. Manuel, V. Blasco17, A. Krag18, S. Singh19, L.A. Lesmana20, C. Toledo21, V. Xavier22, N. Intagliata23, L. Rabinowich24, T. Bruns25, E.L. Yoon26, M. Girala27, N.T. Pyrsopoulos28, T.H. Kim29, S.Y. Yim30, F. Durand31, A. Gadano6, P. Angeli32. 1University of Toronto, Toronto, Canada; 2Postgraduate Institute of Medical Education and Research, Padova, Italy; 3University of Bologna, Bologna, Italy; 4Institute of Liver and Biliary Sciences (ILBS), New Delhi, India; 5University of Padova, University and General Hospital of Padova, Padova, Italy; 6Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 7Hospital Clinic of Barcelona, Liver Unit, Barcelona, Spain; 8University Hospital of Turin, Turin, Italy; 9Gastrocenter-Unicamp, Campinas, Brazil; 10Hallym University College of Medicine, Chuncheon,Republic of South Korea; 11Hallym University Sacred Heart Hospital, Republic of South Korea; 12Hospital Dr. Carlos B. Udaondo, Buenos Aires, Argentina; 13Universidad Nacional de Rosario, Rosario, Argentina; 14Faculty of Medicine of Bahia, Campo Grande, Brazil; 15Sapienza University of Rome, Rome, Italy; 16University Hospital of Geneva, Geneva, Italy; 17Hospital Vall d’Hebron, Liver Unit, Barcelona, Spain; 18Odense University Hospital, Odense, Denmark; 19Shri Ramachandra Bhanj Medical College, Orissa, India; 20Digestive Disease and Oncology Centre (DDOC)-Medistra Hospital, Jakarta, Indonesia; 21Hospital Valdivia, Universidad Australe de Chile, Valdivia, Chile; 22Ghent University Hospital, Ghent, Belgium; 23University of Virginia, Charlottesville, United States; 24Tel-Aviv Medical Center, Tel-Aviv, Israel; 25Jena University Hospital, Jena, Germany; 26Sanggye Paik Hospital, Inje University Seoul, Seoul, Republic of South Korea; 27Universidad Nacional de Asunciòn, Asunciòn, Paraguay; 28Rutgers New Jersey Medical School, Newark, United States; 29Ewha Womens University, Rep. of South Korea; 30Anam Korea University Hospital, Seoul, Rep. of South Korea; 31Hospital Beaujon, Clichy, France; 32University of Padova, Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine, DIMED, Padova, Italy

Background and Aims: Bacterial infections, by inducing an inflammatory state and by further perturbing the already abnormal hemodynamics of advanced cirrhosis, can potentially precipitate ACLF. Patterns of bacterial infections and antibiotic resistance vary in different regions of the world. These could possibly contribute to variations in the types of organ failure or severity of ACLF around the world. The aim was to evaluate the regional differences in the development of ACLF as a result of bacterial infections in cirrhosis.

Method: The International Club of Ascites (ICA) enrolled 1302 cirrhotic patients admitted for complications of cirrhosis with a concomitant bacterial infection worldwide from Oct 2015 to Sept 2016. All patients had baseline clinical, laboratory and microbiological data collected from the time of diagnosis of infection. Information on antibiotic given, antibiotic resistance, further complications, patient and infection outcomes were also collected. All patients were followed till liver transplant, or death, or discharge.

Results: Patients were divided into 6 regions worldwide (table). Patients were mostly middle aged (57 } 13 years) men (69%) with alcoholic cirrhosis (52%). ACLF as defined by the EASL-Chronic Liver Failure (CLIF) Consortium was already present in 35% of patients at infection diagnosis, being significantly more prevalent (60%) and more severe in the Indian subcontinent (table) when compared to the rest of the world, possibly related to the high prevalence of multidrug resistant organisms in India (73% vs. 29%, p < 0.0001). Renal failure was the most common organ failure with ACLF across the world (17–34% of all organ failures). In patients without ACLF at infection diagnosis, further ACLF episodes occurred more frequently in Indian patients than in the other patients (44% vs. 25%, p = 0.0072). The severity of ACLF following treatment of infection was similar across the world (p = 0.078).

Conclusion: ACLF is common with bacterial infections in cirrhosis, and can occur even after infection is treated. Efforts should be made to prevent infection so to reduce the likelihood of ACLF.

Sequential assessment of Acute-on-Chronic Liver Failure and Hyponatremia in cirrhotic patients: correlation of reversibility and evolution with short term survival

Livia B. Victor, Caroline B. Souza, Camila M. Alcântara, Tatiana Valdeolivas, Vanessa L. Zenatti, Zulane D. Veiga, Daniela M. Mariz, Emilia Ahmed, Flavia F. Fernandes, Gustavo Pereira; Hospital Geral de Bonsucesso, Rio de Janeiro, Brazil

Acute-on-Chronic Liver Failure (ACLF) is a syndrome characterized by organ failure and high mortality. Hyponatremia conveys poor prognosis in cirrhosis and is not part of CLIF C-OF, a score used for diagnosis of ACLF. Few studies have evaluated the prognostic capability of sequential assessment of ACLF and Hyponatremia. Objective: evaluate changes in ACLF and hyponatremia and their interaction in predicting survival.

Methods: prospective study with consecutive hospitalized cirrhotic patients. Presence and grading of ACLF and Hyponatremia were evaluated at day 1 (D1) and 7 (D7). Both were classified as persistent, transient, de novo or absent.

Results:272 patients (56±14 years, 56% male) were included. Ascites and hepatic encephalopathy were present at admission in 68% and 34% of patients. Child and MELD were 9±2 and 17±7. At inclusion, ACLF was diagnosed in 64 patients, and was most commonly classified as grade I (86%). Mean CLIF C-OF was 7.6±1.3 (vs. 5.5±0.8 for patients without ACLF, P<0.001). Throughout the first week, ACLF was reversed in 28 and persisted in 36 patients and de novo ACLF was diagnosed in 9 patients. ACLF at day 7 was more severe, as evidenced by higher prevalence of grade II/III ACLF (37% vs. 14% at D1) and high CLIF C-OF (mean values for persistent, de novo, transient and no ACLF 10±3, 11±3, 7±1 and 6±1 respectively, p<0.001). Hyponatremia was present at inclusion in 42 patients and was classified as persistent in 20 and transient in 22. Serum sodium values for these groups were 123±6 and 126±3. In addition, 23 patients developed de novo hyponatremia. Mean serum sodium changes from D1 to D7 for persistent, transient, de novo, and no hyponatremia was 2±6, 9±6, -7±4 and 0.6±5 mEq/L (p<0.001). Severe hyponatremia (Na+ <125mEq/L) was less frequent at D7 (21% vs. 38%. at D1, p<0.01). 3-month survival was 69%. On multivariate analysis, ACLF at D7 and Hyponatremia at D1 as well as ascites and leucocyte count, were independent predictors of survival. Survival for patients with D7 ACLF was 23% (versus 59% for transient and 82% for no ACLF, p<0.001). Patients with persistent and transient hyponatremia had similar survival (27 and 36% respectively), which was significantly lower than for de novo or no hyponatremia (74 and 76%, p<0.001).

Conclusion: ACLF and Hyponatremia are frequent and associated with poor survival in cirrhosis. ACLF at D7 is strongly correlated with mortality, independently of being persistent or having developed during hospitalization. Hyponatremia retains most of this prognostic capability at hospital admission. Combination of hyponatremia at D1 and ACLF at D7 identify patients at higher risk of shortterm mortality.

LBP-028

The kynurenine pathway in cirrhosis. Relationship with the development of acute decompensation and acute-on-chronic liver failure, clinical course and mortality

J. Claria1,2, R. Moreau1,3, F. Fenaille4, A. Amoros5, C. Junot4, H. Gronbaek6, M. Coenraad7, K. Oettl8, P. Caraceni9, C. Alessandria10, J. Trebicka5,11, M. Pavesi5, C.D. Gomez5, A. Albillos12, T. Gustot13, T. Welzel14, J. Fernandez2,5, R.E. Stauber8, F. Saliba15, N. Butin4, B. Colsch16, C. Moreno13, F. Durand17, F. Nevens18, R. Banares19, D. Benten20, P. Ginès2, A. Gerbes21, R. Jalan22, P. Angeli23,M. Bernardi9, V. Arroyo1. 1European Foundation for the study of chronic liver failure, Grifols Chair, Barcelona, Spain; 2Hospital Clínic, Barcelona, Spain; 3Inserm U1149, Centre de Recherche sur l’Inflammation, Paris, France; 4CEA, iBiTec-S; 5European Foundation for the study of chronic liver failure, Barcelona, Spain; 6Aarhus University Hospital, Aarhus, Denmark; 7Leiden University Medical Center, Leiden, Netherlands; 8Medical University of Graz, Graz, Austria; 9Università di Bologna, Bologna, Italy; 10San Giovanni Battista Hospital, Torino, Italy; 11UKB University of Bonn, Bonn, Germany; 12Hospital Ramón y Cajal, Madrid, Spain; 13Hospital Erasme, Bruxelles, Belgium; 14J.W. Goethe University Hospital, Frankfurt am Main, Germany; 15Paul-Brousse Hospital (AP-HP), Villejuif, France; 16CEA, iBiTec-S; 17Beaujon Hospital (AP-HP), Clichy, France; 18Hospital Gasthuisberg Leuven, Leuven, Belgium; 19Complutense University of Madrid, Madrid, Spain; 20University Hospital Hamburg-Eppendorf, Hamburg, Germany; 21Ludwig-Maximilians-Universität Hospital München, München, Germany; 22University College London, Royal Free Hospital, United Kingdom; 23University of Padova, Padova, Italy

Background and Aims: Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases (i.e. severe sepsis or pancreatitis) SI activates tryptophan (Trp) degradation via the kynurenine pathway (KP), giving rise to toxic metabolites that cause tissue/organ damage and immunosuppression. We aimed to

characterize the poorly known KP in patients with cirrhosis.

Methods: The circulating levels of Trp, metabolic markers of KP activity (kynurenine, kynurenic acid and quinolinic acid), SI (cytokines, sCD163 and sCD206) and oxidative stress (irreversible oxidized albumin) were measured at enrolment in 40 healthy subjects, 39 patients with compensated cirrhosis (no history of AD), 342 patients hospitalized with AD (no ACLF) and 180 patients with ACLF, and repeated in 258 patients during 28-day follow-up.

Results: First: among the whole group of patients, KP activity at enrolment was found to be normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI and oxidative stress; it was significantly higher in ACLF with kidney failure than in ACLF without kidney failure (Figure 1, values represented in quadratic scale). Second: among the patients with AD at enrolment, baseline KP overactivity was significantly higher in patients who did (n = 56) than in those who did not (n = 286) develop ACLF during hospitalization, suggesting that overactivation of the KP precedes ACLF development. Third: among “uninfected” patients with ACLF at enrolment (n = 108), those who developed nosocomial infections (n = 61; 56.4%) showed higher baseline KP activity and immune suppression (significantly higher levels of sCD206 and IL-10) than those without nosocomial infections, suggesting a relationship between KP overactivity, immunosuppression and nosocomial infections in ACLF. Fourth: among patients with follow-up samples, the 28- day course of AD or ACLF (worsening, improvement, stable) closely correlated with parallel changes in KP activity. Fifth: higher baseline KP activity at enrolment independently predicted mortality in patients with AD and in those with ACLF.

Conclusions: This study shows that features of KP activation appear in patients with AD and culminate in those with ACLF. Moreover, it suggests a role for KP overactivity in the pathogenesis of AD and ACLF, clinical course and mortality.

 

2075

Circulating interleukin 6, 10 and 17 as prognostic markers in patients with liver cirrhosis

Josiane Fischer1, Telma E. Silva1, Pedro E. Soares e Silva1, Bruno S. Colombo1, Letícia M. Wildner2, Maria Luiza Bazzo2, Tania S. Frode2, Silvana Vigil de Melo2, Julia S. Rosa2, Esther B. Dantas- Correa1, Janaína L. Narciso-Schiavon1, Leonardo L. Schiavon1; 1Internal Medicine, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Brazil; 2Department of Clinical Analysis, Federal University of Santa Catarina, Florianopolis,

Brazil

Introduction: Activation of inflammatory system is present from the early stages of cirrhosis and it is associated with elevated levels of cytokines. However, data about the prognostic significance of circulating cytokines in liver cirrhosis is still lacking. We sought to investigate the prognostic significance of IL-6, IL-10 and IL-17 in patients with stable cirrhosis and in subjects admitted for acute decompensation (AD) of cirrhosis.

Methods: This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n = 118), and (2) subjects hospitalized for AD (n = 130). Thirty healthy subjects served as control group. The acute-on-chronic liver failure (ACLF) criteria were applied according to the EASL-CLIF Consortium.

Results: IL-6 and IL-10 levels were higher in both groups of patients with cirrhosis as compared to control group and also in patients with AD in relation to stable cirrhosis (P < 0.05). In stable cirrhosis, during a median follow-up of 17 months, an event (hospitalization, death or liver transplantation) occurred in 26 patients and was associated with higher IL-6 (3.56 pg/mL vs. 2.13 pg/mL, P = 0.013) and IL-10 (0.54 pg/mL vs. 0.22 pg/ mL, P = 0.021), but not IL-17 levels. In the hospitalized cohort, 39 patients died after 90 days of follow-up. Logistic regression analysis showed that death in AD cohort was independently associated with ascites (OR 6.286, 95% CI 1.826 – 21.635; P = 0.004), MELD (OR 1.300, 95% CI 1.175 – 1.439; P< 0.001) and IL-6 (OR 1.002, 95% CI 1.000 – 1.004, P =0.029). The AUROC of IL-6 to predict 90-day mortality was 0.779 ± 0.046 and the Kaplan–Meier survival probability was 90.0% for IL-6 < 21 pg/mL and 46.7% for IL-6 ≥ 21 pg/mL (P < 0.001). Cytokine levels were evaluated for the prediction of bacterial infection. Regression analysis showed that bacterial infection diagnosed during the first 48 hours after admission was associated with IL-6, CRP and ascites. IL-6 exhibited higher AUROC than CRP for predicting bacterial infection (0.831 ± 0.043 vs. 0.763 ± 0.048, respectively). Higher IL-6 levels were observed in ACLF patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Cytokines levels were reassessed at the third day of hospitalization in 74 subjects. No differences between admission and third-day levels were noted for IL-6. Lower IL-10 levels were observed at third day regardless of the presence of ACLF or death during follow-up. However, IL-17 levels dropped significantly only in those who died during follow-up.

Conclusion: Circulating IL-6, IL-10 and IL-17 are of prognostic value in patients with cirrhosis.

549

Decrease of platelet count is a negative indicator of acute-on-chronic liver failure outcome

Shanshan xu1, Yali chen2, Xinhuan Wei1, Wei Lin1, Jing zhang1; Beijing You'an Hospital, Capital Medical University, Beijing Lu'he Hospital, Capital Medical University; 1Beijing You’an Hospital, Capital Medical University, Being, China; 2Beijing Lu’he Hospital, Capital Medical University, Being, China

Background and aim: Thrombocytopenia (platelet count125x109/L) was often seen in serious disease . In some acute-on-chronic liver failure (ACLF) patients platelet count decrease significantly . We deduced that platelet decrease might correlated with prognosis of ACLF . Methods: ACLF patients were recruited from September 2014 to September 2016 prospectively . All the patients were followed up until discharge . The diagnostic criteria is based on diagnostic criteria for ACLF developed by the European Association for the Study of the Liver . Serum thrombopoeitin was detected by ELISA . Results: Fifty four ACLF patients were recruited and the mortality rate was 33 .3% . The average age was 46 .111 .7, male patients accountedfor 85 .2% . 72 .2% was HBV related ACLF and the others were alcoholic . The average baseline platelet counts was 80 .0(36 .0,334 .0)109/L . Platelet count decreased more in dead group than survivors ((-43 .458 .9) 109/L vs (-11 .529 .1) 109/L, P=0 .041) . The cutoff value of difference of platelet count between discharge and base- line were set as -27 .5109/L . The fatality rate was signifi- cantly higher in those platelet count decreased more than 27 .5109/L (72 .2% vs 22 .2%, P=0 .000) . Univariate analysis showed that platelet count, prothrombin time activity, activated partial thromboplastin time and serum glucose were independent factors of the prognosis . Multivariate analysis showed that platelet count change was the only independent factor of the prognosis . Area under receiver operating curve was 0 .743(0 .962~0 .998) . The level of serum thrombopoeitin were not significantly different between survival group and death group (P0 .05) . Conclu- sions: The baseline platelet count in ACLF patients was significantly lower . Platelet count decreased more in death patients than in survivors and was the only indicator for in-hospital death . Platelet decrease may not due to bone marrow suppression . Consumption or redistribution of platelet should be considered .

Disclosures:
The following people have nothing to disclose: Yali chen, Jing zhang

 

Dynamic assessment is superior to baseline assessment in prognostication of patients with acute on chronic liver failure

S. Rathi1, S. Taneja1, A. Duseja1, V. Gautam2, Y. Chawla1, R.K. Dhiman1. 1PGIMER, Hepatology, Chandigarh, India; 2PGIMER, Microbiology, Chandigarh

Background and Aims: Acute on Chronic Liver Failure (ACLF) is a dynamic syndrome that leads to high risk of mortality in patients with cirrhosis. While the definitions of both acute events and underlying chronic liver disease are debated by different groups, the prognostic scoring models in all definitions are based on variables at presentation. We studied a dynamic model of prognosis assessment and compared it with the static models.

Method: We prospectively evaluated 160 patients who presented with acute decompensation of cirrhosis, which included development of ascites, hepatic encephalopathy, variceal bleeding or sepsis. These patients were assessed at baseline and at day 5–6 of admission in terms of prognostic scores like Model for End stage Liver Disease (MELD), Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), ACLF Grade, and Simple Organ Failure Count (SOFC), and followed up till 90 days or until death.

Results: Of the total, 126 patients were analysed. The mean age was 47.8 } 12.4 yrs, and 104(82%) were males. Alcohol was the most common etiology of cirrhosis (52%), followed by non-alcoholic steatohepatitis/cryptogenic. Ascites was the most common acute decompensation (81%), and infections were the most common acute precipitating event. A total of 70 (55.6%) survived at 4 weeks, and 32 (25.4%) at 3 months. The prognostic scores at day 5–6 fared better than baseline scores in predicting 28-day mortality. SOFC and CLIFSOFA score at day 5–6 were the best predictors of mortality with an AUROC of 0.88 and 0.87 respectively. For 90-day mortality, CLIF-C ACLF at day 5–6 fared the best (AUROC 0.79). Patients who showed worsening of organ failurewere less likely to survive as compared to those who either remained stable or improved (28-day survival OR- 0.36, 95% CI 0.16–0.79, P= 0.017; 90-day -day survival OR-0.34, 95% CI 0.13–0.87, P = 0.03). Moreover, patients with 3 or more organ failures at day 5–6 had a uniformly poor survival irrespective of the severity at presentation.

Conclusion: ACLF is a dynamic process with a potential for reversibility. However, most prognostic models based on a single baseline assessment, which may not be adequate. A dynamic assessment at day 4–5 after initial stabilization in-hospital gives a much better measure of the severity of the disease and risk-stratification. Moreover, patients who fail to improve or deteriorate at day 4–5 have a uniformly poor prognosis, and an argument may be made for futility of care.

538

Evaluation of CLIF Consortium Acute Decom- pensation score (CLIF-C ADs) as a predictor of short-term acute-on-chronic liver failure (ACLF) development and mortality in patients with decompensated cirrhosis (DC).

Caroline B. Souza, Juliana Piedade, Lívia Guimarães, Livia B. Victor, Camila M. Alcântara, Bárbara Rodrigues, Raquel Loyola, Flavia F. Fernandes, Gustavo Pereira; Liver Unit, Hospital Geral de Bonsucesso, Rio de Janeiro, Brazil

Background: prognosis of patients with DC is not homog- enous, as some of them are at increased risk of ACLF development and short term mortality . Identification of this high-risk group is crucial . CLIF-C ADs was proposed as a prognostic tool for patients with DC . However, this score was neither validated outside Europe nor as a predictor of ACLF development . Objectives: evaluate the prognostic capability of CLIF-C ADs to predict ACLF and survival . Methods: prospective study with inclusion of consecutive hospitalized patients . Patients with ACLF at admission were excluded . According to CLIF-C ADs, patients were classified in low (45), intermediate (46-59) and high (60) value groups . Development of ACLF was evaluated within 7 days and survival at 3 months . Results: 227 patients (5614 years, 51% male) were included . At admission, ascites and hepatic encephalopathy were present in 63% and 26%, Child and MELD was 92 and 145 . Mean CLIF C-ADs was 509 and patients were clas- sified as low, intermediate and high CLIF C-ADs in 27, 60 and 13%, respectively . Patients with high CLIF-C ADs had more frequently alcohol cirrhosis, ascites, hepatic enceph- alopathy, SBP and SIRS, higher WBC and CRP, lower MAP and albumin, as well as higher frequency of kidney and cerebral dysfunction and coagulation failure . Within the first week, 20 patients (9%) developed ACLF . At admis- sion, these patients were older, had lower albumin, higher creatinine, MELD, Child and CLIF-C ADs (p0 .05) . On multivariate analysis, albumin (HR:0 .90, 95%CI 0 .81- 0 .99, p=0,027) and CLIF-C ADs (HR:1 .13,95%CI 1 .06-1 .21, p 0 .001) were predictors of ACLF . Frequency of ACLF in low, intermediate and high CLIF-C ADs was 1, 7 and 30% (p0 .001) . ACLF was associated with lower survival (18vs .82%, p0 .001) . Among patients without ACLF at D7, sodium, MELD, CHILD and CLIF-C ADs correlated with survival . There was a small decrease in CLIF-C ADs from D1 to 7 (499 vs . 479, p=0 .01) . Nevertheless, 72% of patients remained within the initial CLIF-C ADs groups and only 10% progressed to a higher score group . On multivariate analysis, ascites (HR:2 .32,95%CI 0 .94-5 .71, p=0 .07) and CLIF-C ADs (HR:1 .07,95%CI 1 .03-1 .12, p=0 .01) at admission were predictors of mortality . Corresponding survival for patients with low, intermediate and high CLIF-C ADs was 93%, 80% and 50% (p0 .0001) . Conclusion: CLIF-C ADs predicts survival and ACLF development at short term . Assessment of ascites and albumin at admission may add further prognostic information . Among patients with DC, those with CLIF-C ADs 60 have more severe systemic inflammation and worst extra-hepatic organ function and should be considered at a pre-ACLF state .

Disclosures:

The following people have nothing to disclose: Caroline B . Souza, Juliana Piedade, Lívia Guimarães, Livia B . Victor, Flavia F . Fernandes, Gustavo Pereira

 

2080

MELD score and liver stiffness are predictive for the development of acute decompensation that induce acute-on chronic liver failure

Moon Young Kim, Yoo Li Lim, Soon Koo Baik, Sang Ok Kwon; Internal medicine, Yonsei University Wonju college of medicine, Wonju, Korea (the Republic of)

Background and Aim: The risk estimation for the future development of AD that causes ACLF (AD-ACLF) is essential for the management strategies of cirrhotic patients. In recent reports, non-hemorrhagic AD is increasing and has more roles in the development of ACLF. The aim of this study is evaluation about the prognostic factors in the prediction of future AD-ACLF development.

Methods: For 25.1 months of median follow up, 379 cirrhotic patients(male 317, 83.6%/alcohol related patients 295(77.8%)) who performed baseline hepatic venous pressure gradient(HVPG), serologic tests and liver stiffness(LS) measurement using transient elastography(Fibroscan) have been prospectively followed for the development events including AD-ACLF. The first episode of AD-ACLF was decided as an events. Through binary logistic regression analysis, parameters that showed P < 0.1 were selected and Cox proportional hazard model.

Results: 63 patients developed AD-ACLF (16.6%) during the follow up period. Among AD-ACLF, non-hemorrhagic events (ascites, encephalopathy, infection includes SBP, jaundice) were more common (39 patients) than hemorrhagic events (GI bleeding)(24 patients). In the univariate analysis, Child-Pugh score (CP score), MELD score, HVPG, LS showedsignificant relation with the development of AD-ACLF. In Cox proportional hazard model analysis (adjusted by age, sex, alcohol drinking state) for the AD-ACLF development using CP, MELD score and HVPG, only MELD score showed significant hazard ratio (HR) 1.100 (1.010 – 1.197, P = 0.028). HVPG showed borderline value (HR 1.048, 0.999-1.099, P = 0.56) and CP score was not significant (HR 1.154, 0.975-1.367, P = 0.95). When LS was added in this model, MELD (HR 1.122, 1.027-1.225, P = 0.01) and LS (HR 1.023, 1.008 – 1.038, P = 0.003) showed significant predictive value but HVPG and CP score did not. Especially, for the non-hemorrhagic events, MELD (HR 1.215, 1.063-1.358, P = 0.001) and LS (HR 1.034, 1.014 – 1.054, P = 0.001) showed powerful predictive value. In contrast HVPG and CP score was not significant (P = 0.447 and 0.499 respectively).

Conclusion: High MELD and LS were significant risk factors for the development of ACLF inducing AD. Moreover contrary to HVPG, MELD and LS showed high risk in the development of non-hemorrhagic AD. These findings are relevant to recent increase of clinical significance of non-hemorrhagic AD in ACLF and cirrhosis.

2055

Plasma markers of liver cell death Keratin 18 (K18) and its caspase-cleaved fragment (cK18) are novel biomark- ers to define progression of cirrhotic patients with acute decompensation to acute on chronic liver failure (ACLF) and mortality

Stewart Macdonald1, Fausto Andreola1, Patrik Bachtiger1, Alex Amoros3, Marco Pavesi3, Rajeshwar Mookerjee1, Alexander L. Gerbes5, Elsa Solà4, Paolo Caraceni6, Richard Moreau2, Pere Gines4, Vicente Arroyo3, Rajiv Jalan1; 1Institute for Liver and Diges- tive Health, University College London, London, United Kingdom; 2Service d’Hepatologie, Hopital Beaujon, Assistance Publique-Ho- pitaux de Paris, Clichy, France; 3European Foundation for the study of Chronic Liver Failure (EF-CLIF)., Barcelona, Spain; 4Liver Unit, Hospital Clinic University of Barcelona, Barcelona, Spain; 5Liver Center Munich, Department of Medicine 2, klinikum der LMU Munchen-Grosshadem, Munich, Germany; 6Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy

Acute on chronic liver failure (ACLF) is a devastating clinical syndrome that develops in cirrhotic patients suffering acute decompensation (AD) . About 20% will progress to ACLF during hospitalisation . The CLIF-AD score has limited accuracy and new biomarkers are needed . Intermediate filament K18 is present in hepatocytes and during apoptosis undergoes frag- mentation (cK18); both are detectable in the plasma . The aim of this study was to evaluate their potential as biomarkers . Materials and Methods 376 patients from the CANONIC study cohort with acute decompensation of cirrhosis were included . 82 presented with ACLF and 294 with AD, of whom 70 pro- gressed to ACLF . Additionally 44 patients with stable cirrhosis (SC) and 34 healthy volunteers (HV) were included . Baseline Serum K18 and cK18 were measured by ELISA [M65 EpiDeath (Peviva) and M30 Apoptosense (Peviva) respectively] . Results A stepwise increase in K18 and cK18 level was demonstrated with increasing clinical severity (p<0 .001) (see table 1 .) and between different severities of ACLF grades (p=0 .009) . Mortal- ity: Both K18 and cK18 were independent predictors of 28-day and 90-day mortality [K18:HR 1 .36 (95%CI 1 .03-1 .81) (p=0 .03), cK18:HR 1 .46 (95%CI 1 .06-2 .01)(p=0 .02)] and 90-day survival [(K18:HR 1 .26 (95%CI 1 .01-1 .56)(p=0 .038), cK18:HR 1 .32 (95%CI 0 .99-1 .75)(p=0 .06)] . The addition of K18 to the CLIF-C AD score improved the C-index for predic- tion of 28 day mortality [CLIF-C AD 0 .788 (95%CI 0 .688- 0 .888), CLIF-C AD+K18 0 .816 (95%CI 0 .718- 0 .825)] and 90 day mortality [CLIF-C AD 0 .725 (95%CI 0 .653-0 .797), CLIF-C AD+K18 0 .75 (95%CI 0 .675-0 .913-0 .825)] . Predic- tion of Progression from AD to ACLF: Both K18 and cK18 were significantly higher in the patients that progressed compared with those who did not (both p<0 .001) . Their inclusion sig- nificantly improved the predictive ability of CLIF-C AD score (AUROC 0 .696 (0 .626-0 .765) to 0 .742 (0 .673-0 .811) . Con- clusion These data clearly demonstrates a statistically signifi- cant stepwise increase in serum K18 and cK18 with clinical severity of patients with acute decompensation . Inclusion of K18 values into the CLIF-AD score improves predictive value for progression to ACLF and 28-day and 90-day mortality in patients with AD .

 

1908

Prediction model of the progression of patients with acute deterioration of hepatitis B virus related chronic liver disease to acute-on- chronic liver failure

Chen Li, Bing Zhu, Sa Lv, ShaoLi You, Shaojie Xin; 302 Military Hospital, Beijing, China

Background and research objective: Hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) is a type of high-mortality disease based on acute deteriora- tion (AD) of HBV related chronic liver disease (CLD) . This study aimed to establish a new model for the prediction of the ACLF occurrence risk among patients with AD of HBV related CLD . Methods: A total of 754 patients with AD of HBV related CLD (TBIL 51 .3 mol/L and PTA 60%, 40% PTA 60% when TBIL 171 .1 mol/L) hospitalized in Beijing 302 Military Hospital of China from October in 2014 to October in 2016 were retrospectively analyzed and divided into a training cohort (580 cases) and a valida- tion cohort (174 cases) . The ACLF occurrence probability of these patients was statistically analyzed within 4 weeks, and the duration to progress to ACLF was identified . In the training cohort, multivariate logistic regression anal- ysis (LRA) was performed to determine the indepen- dent predictors on ACLF occurrence from patients with AD of HBV related CLD and to develop a new prediction model . The validation cohort was utilized to verify the new prediction model, and the receiver operating charac- teristic (ROC) curve was drawn to evaluate the prediction value of the new model . Results: 88 .9% of the patients initially suffered from liver cirrhosis, the baseline Model for End-Stage Liver Disease (MELD) score was 16 .9 . 9 .9% of the patients progressed to ACLF within 4 weeks, the time for them to progress to ACLF was 12 .0 6 .7 days . Multivariate LRA showed that age, PTA, TBIL, D/T, Na, and spontaneous reactivation of HBV were independent predictors of the ACLF occurrence from patients with AD of HBV related CLD within 4 weeks . The new prediction model was characterized by R = 3 .090 + 0 .035 Age (years) −0 .050 PTA (%) + 0 .005 TBIL (mol/L) + 0 .044 D / T (%) −0 .072 Na (mmol/L) + 0 .180 HBV DNA (log10) . The areas under the ROC curves (AUCs) of the training cohort and the validation cohort in the new model were 0 .820 and 0 .852, respectively, and their AUCs were higher than MELD . The cut-off value of the new model was −2 .12, based on this cut-off value, the patients were divided into two groups both in the training cohort and the validation cohort . The mortality in high scores group (−2 .12) were higher than in low scores group (−2 .12) . Conclusion: A new prediction model of ACLF occurrence was established from patients with AD of HBV related CLD within 4 weeks . The new model could be used by clinicians to recognize patients with AD of HBV related CLD with high risks of progressing to ACLF .

Disclosures:

The following people have nothing to disclose: Chen Li, ShaoLi You, Shaojie Xin

 

50

Predictive factors for the development of acute-on-chronic liver failure in hospitalized decompensated cir-rhotic patients

Florence Wong1, K. Rajender Reddy2, Jacqueline G. O’Leary3, Puneeta Tandon4, Guadalupe Garcia-Tsao5, Patrick S. Kamath6, Scott W. Biggins7, Benedict Maliakkal8, Michael B. Fallon9, Jen-nifer C. Lai10, Paul J. Thuluvath 11, Ram M. Subramanian12, Hugo E. Vargas13, Leroy Thacker15, Jasmohan S. Bajaj14; 1Medicine, Gastroenterology, University of Toronto, Toronto, ON, Canada; 2Medicine, Gastroenterology & Hepatology, University of Pennsyl-vania, Philadelphia, PA; 3Medicine, Hepatology, Baylor University Medical Centre, Dallas, TX; 4Medicine, Gastroenterology, Uni-versity of Alberta, Edmonton, AB, Canada; 5Medicine, Digestive Diseases, Yale University School of Medicine, New Haven, CT; 6Gastroenterology, Hepatology & Internal Medicine, Mayo Clinic, Rochester, MN; 7Medicine, Gastroenterology, University of Col-orado, Denver, CO; 8Medicine, Gastroenterology, University of Rochester, Rochester, NY; 9Medicine, Gastroenterology & Hepa-tology, Texas Liver Center, Houston, TX; 10Medicine, Gastroenter-ology & Hepatology, University of California/San Francisco, San Francisco, CA; 11Institute for Digestive Health & Liver Diseases, Mercy Medical Centre, Baltimore, MD; 12Medicine, Gastroenter-ology, Emory University Medical Centre, Atlanta, AL; 13Medicine, Gastroenterology, Mayo Clinic Arizona, Phoenix, AZ; 14Gas-troenterology, Hepatology & Nutrition, Virginia Commonwealth University, Richmond, VA; 15Biostatistics, Virginia Commonwealth University, Richmond, VA

Acute-on-chronic liver failure (ACLF) is often precipitated by an event that disturbs systemic or regional hemodynamics, lead-ing to significant deterioration of liver function with one or more extra-hepatic organ failures, associated with high mor-bidity and mortality.. Identifying predictors of ACLF is critical to develop preventive strategies. . Aim: To identify predictors for ACLF development in hospitalized cirrhotic patients.. Meth-ods: We compared cirrhotic inpatients who developed ACLF >48 hours after admission (ACLF+) with those who did not (ACLD-) from the North American Consortium for the Study of End-Stage Liver Disease, consisting of 16 tertiary-care hepatol-ogy centers that prospectively enrolled non-elective admitted cirrhotic patients . . Those admitted with ACLF were excluded. . ACLF is defined by the presence of ≥2 organ failures: 1) cir-culatory- need for vasopressor support; 2) renal- initiation of dialysis; 3) cerebral- Grade III or IV hepatic encephalopathy; 4) respiratory- need for ventilation. . Results: Inpatients with ACLF+ vs. . ACLF- were similar (mean± SD) in age (55. .7±8..3 vs.. 57..6±10..5 years), male sex (65 vs.. 63%) alcoholic (30 vs.. 30%) and diabetes (37 vs.. 34%).. The ACLF+ group was more likely to be admitted with infections, hence their higher white cell count, and was more likely to have systemic inflamma-tory response syndrome (SIRS) when compared to ACLF- group (Table 1).. Amongst the ACLF+ group, 51, 23 and 7 patients had 2, 3 and 4 organ failures respectively, with no signifi-cant differences between the ACLF subgroups. . Independent predictors for ACLF development included a high admission MELD, presence of SIRS, and hospitalization in <6 months (all p<0. .05). . In-hospital and 30-day mortality were significantly higher in the ACLF+ vs.. ACLF- patients (41% vs.. 3%, and 53% vs.. 7% respectively) (p<0..0001).. Conclusions: Sicker admitted cirrhotic patients with a previous admission in < 6 months are more likely to develop ACLF, especially when inflammation is present, likely related to infections. . Hospitalized cirrhotic patients with high MELD need to be monitored closely for the development of ACLF, especially if infection is present..

 

*meanSD

Disclosures:

Florence Wong - Consulting: Gore Inc; Grant/Research Support: Mallinckrodt

K. . Rajender Reddy - Advisory Committees or Review Panels: Merck, Janssen, BMS, Abbvie, Gilead; Grant/Research Support: Merck, BMS, Gilead, Janssen, Abbvie

Jacqueline G.. O’Leary - Advisory Committees or Review Panels: Gilead, Inter-cept, Novartis; Consulting: Abbvie, Fish & Richarson PC; Grant/Research Sup-port: Fisher Scientific; Speaking and Teaching: Gilead, Abbvie, Merck, Astellas; Stock Shareholder: Medfusion

Guadalupe Garcia-Tsao - Advisory Committees or Review Panels: Abbvie, Fibro-gen, Intercept, Exalenz, Conatus, LAT Pharma; Consulting: Galectin

Patrick S.. Kamath - Advisory Committees or Review Panels: Sequana Medical

Benedict Maliakkal - Speaking and Teaching: Valeant Pharma (Salix), Merck, AbbVie, Bristol Myers Squibb, Intercept, Grifols

Michael B.. Fallon - Advisory Committees or Review Panels: American Gastroen-terology Assocation: Clinical Gastroenterology and Hepatology Associate Edi-tor; Board Membership: ABIM Transplant Hepatology Test Writing COmmittee, Memorial hermann Health System: Physician Advisory Council; Grant/Research Support: Grifolis, Eisai, Inc, Conatus Pharmaceuticals, Intercept Pharmaceuticals, Tobira Therapeutics

Paul J. . Thuluvath - Advisory Committees or Review Panels: Abbvie, Gilead; Grant/Research Support: Gilead, AbbVie, BMS, Isai, Salix; Speaking and Teaching: AbbVie, Bayer/Onyx, Gilead

Jasmohan S.. Bajaj - Consulting: Valeant, Norgine, Intercept, and Abbott; Grant/ Research Support: His institution has received grant funding from Salix and Grifols

The following people have nothing to disclose: Puneeta Tandon, Scott W.. Big-gins, Jennifer C.. Lai, Ram M.. Subramanian, Hugo E.. Vargas, Leroy Thacker

 

 

1802

Sequential CLIF-SOFA (C-S) scores decrease with terlipressin therapy and correlate more strongly with survival than baseline scores, in subjects with acute-on-chronic-liver failure (ACLF) and hepatorenal syndrome Type 1 (HRS-1)

Florence Wong2, Stephen Chris Pappas1, Arun J. Sanyal3, Khu- rram Jamil4; REVERSE, OT-0401 Investigators; 1Orphan Thera- peutics, The Woodlands, TX; 2Medicine, University of Toronto, Toronto, ON, Canada; 3Medicine, Virginia Commonwealth University, Richmond, VA; 4Medical Sciences, Mallinckrodt, Hampton, NJ

BACKGROUND: Changes in C-S scores and ACLF grade have been shown to be strong predictors of survival in patients with ACLF . The utility of these parameters to predict short- and medium term survival has not been clearly studied in a rigorously defined subgroup of patients with ACLF and HRS-1 . The purpose of our study was to evaluate changes in C-S scores and ACLF grades in patients with HRS-1 being treated with albumin in addition to terlipressin (terli) or placebo (PBO) . METHODS: Pooled data from the 2 largest randomized trials of terli versus PBO in HRS-1 were used to determine BL, and change from BL to the earlier of study Day 7 or end of treatment (EOT) . The correlation between BL or change from BL C-S scores and ACLF grade and survival (percent alive at Day 90) was evaluated with standard correlation curves . RESULTS: Data were available for 308 subjects (153 terli, 155 PBO); mean C-S score (SD) was 10 .0 (2 .3) terli, and 9 .8 (2 .2) PBO . ACLF grade 1,2 or 3, occurred in 44 .5%, 34 .4% and 20 .5% of subjects respec- tively . Change in C-S score from BL to earlier of study Day 7 or EOT was greater in the terli group, -0 .40 (1 .67), versus PBO, 0 .00 (1 .54), p=0 .025; ACLF grade also tended to improve: terli, -0 .4(0 .78) vs . PBO, -0 .2(0 .70), p=0 .079 . There was a significant but poor correlation between BL C-S score and survival: terli r2=0 .588, p= .0035, PBO r2=0 .345, p=0 .035 . In contrast, there was a highly significant and strong negative correlation between change in C-S and survival in the terli group, r2=0 .936, p0 .0001, but not in the PBO group, r2=0 .119, p=0 .364 (Figure) . CONCLUSION: Terli treatment in patients with HRS-1 is associated with a decrease in CLIF-SOFA scores and ACLF grade . There is a strong correlation between change in C-S score and survival in these patients . Sequential CLIF-SOFA scores may be particularly useful to predict survival in patients with ACLF and HRS-1 receiving terlipressin .

 

539

The bilirubin/prothrombin crossing rule improves the prognostic accuracy of CLIF-C ACLF score in patients with acute-on-chronic liver failure

Adria Carpio, Enric Reverter, Adria Juanola, Gerhard Jung, Gabriel Mezzano, Karina Botana, Julieta Santillan, Maria Hernandez-Tejero, Angels Escorsell, Javier Fernandez; Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain

Background: Acute-on-chronic liver failure (ACLF) associ- ates a high mortality and a specific prognostic score has been developed (CLIF-C ACLF) . In the setting of ACLF many clinicians believe that a bilirubin value (in mg/dL) exceeding prothrombin index (%) could associate a 100% short-term mortality but this hypothesis has never been challenged . We aimed at assessing the prognostic accuracy of this potential futility rule in a contemporary cohort of ACLF patients . Methods: We retrospectively collected 348 patients admitted to our ICU (2008-16) who fulfilled ACLF criteria at admission . They were followed-up until day 90 for transplant-free mortality . Patients in whom bilirubin values (mg/dL) exceeded prothrombin index (%) at any time were identified . Prognostic accuracy of CLIF-C ACLF at day 3 and at bilirubin/prothrombin crossing were assessed, both for discrimination (ROC curves) and calibration (Hosmer-Lemeshow test) . The crossing variable was added to CLIF-C ACLF to assess prognostic refinement at days 28 and 90 (logistic regression, AUC changes by DeLong test) . In patients with bilirubin/prothrombin crossing we collected days between this event and the decision of ther- apeutic limitation . Results: We included 348 patients with ACLF grade 1 (25%), 2 (41%) and 3 (34%) . Cirrhosis etiol- ogies were alcohol (54%), HCV (30%) and others (16%), and causes of admission were sepsis (34%), bleeding (20%) encephalopathy (18%) and others (28%) . 48 patients presented bilirubin/prothrombin crossing, and mortality was 44 (92%; 1 transplant) and 47 patients (98%) at days 28 and 90, respectively . Median time from admission to crossing event was 4 days (IQR 13 .5), and median time from this event until therapy limitation (30/48 patients) was 4 days (IQR 10 .3) . CLIF-C ACLF score at day 3 (n=264) performed well in our cohort for 28 and 90 days mortality: AUROC 0 .83 (0 .78-0 .89) and 0 .82 (0 .77-0 .87), respectively . Calibration was good for both 28 and 90 days (H-L test non significant) . The crossing variable was associated with 28 and 90 days mortality independently of CLIF-C ACLF score: OR 16 .3 (5-53) and 38 .3 (5-300), respectively . Addi- tion of the crossing variable improved AUROC for 28 and 90 days mortality (0 .88 and 0 .85 respectively, both with p0 .05 at DeLong test) . In patients with the crossing event, CLIF-C ACLF score calculated at day of crossing did not change overall performance . Conclusion: Patients with ACLF admitted to the ICU who present a crossing of bili- rubin and prothrombin values associate an extremely high mortality rate . This variable improved the prognostic performance of CLIFC-ACLF score and might be a useful tool to limit standard critical care .

Disclosures:

The following people have nothing to disclose: Adria Carpio, Enric Reverter, Adria Juanola, Gerhard Jung, Gabriel Mezzano, Karina Botana, Julieta Santillan, Maria Hernandez-Tejero, Angels Escorsell, Javier Fernandez

 

2051

The combined of Urine Neutrophil Gelatinase-associated Lipocalin and the CLIF-SOFA score in prediction of mor- tality of patients with acute-on-chronic liver failure

Tongluk Teerasarntipan1, Khajohn Tiranathanagul3,2, Kessarin Thanapirom1,2, Roongruedee Chaiteerakij1,2, Piyawat Komol- mit1,2, Pisit Tangkijvanich4, Sombat Treeprasertsuk1,2; 1Medicine, Division of Gastroenterology, Bangkok, Thailand; 2King Chu- lalongkorn Memorial Hospital, Thai Red Cross society, Bangkok, Thailand; 3Medicine, Division of Nephrology, Bangkok, Thailand; 4Biochemistry, Liver research Unit, Bangkok, Thailand

Background: Acute-on-chronic liver failure (ACLF) causes organ(s) failure with high short term mortality . CLIF-SOFA score is the proposed scoring system for ACLF diagnosis, which composed of six organs failure criteria, including renal failure which is the major organ that related to short term death . We aimed to study the clinical significance of urine Neutrophil Gelatinase-associated Lipocalin (uNGAL), a new biomarker for early detection acute kidney injury (AKI), in combination with CLIF-SOFA score for mortality prediction in ACLF patients . Methods: We enrolled prospectively Thai cirrhotic patients with acute decompensation who were admitted at the King Chulalongkorn Memorial Hospital, Bangkok, during August 1, 2014 to November 30, 2015 . The CLIF-SOFA score, clinical history, laboratory profiles and uNGAL were collected within 48 hours . The modified CLIF/uNGAL-56 was developed with using the standard CLIF and/or urine Neutrophil Gelatinase-as- sociated Lipocalin (uNGAL) >56 ng/mL as an additional cri- terion of acute kidney injury (Treeprasertsuk S, et al . BMC Gastroenterol 2015 Oct 16;15:140 .) . The 30-day mortality and clinical outcomes were recorded . Results: There were 77 acute decompensated cirrhotic patients enrolled . According to the CLIF-SOFA score, 32 patients (42 .6%) had ACLF . Accord- ing to their baseline characteristics; there was no significant difference in mean age, gender, etiology of cirrhosis, precipi- tating causes of acute decompensation between both groups . Patients with ACLF had higher MELD score than those without ACLF (26 .9 VS 16 .6; P<0 .001) . The 30-day mortality rate of ACLF patients was 43 .7% which was significantly higher than those without ACLF (13 .3%) . By using the CLIF-SOFA, it can predict the 30-day mortality with relative risk (RR) of 3 .3 (95%CI 1 .4-7 .6) . With the modified CLIF/uNGAL-56, the 30-day mortality rate was 38 .6% and this new score can pre- dict the 30-day mortality with RR of 4 .2 (95%CI 1 .4-13 .3) as shown in table 1 . Conclusion: The combined of urine Neutro- phil Gelatinase-associated Lipocalin and the CLIF-SOFA score increase the prediction value of mortality compared to CLIF- SOFA score alone in patients with acute-on-chronic liver failure .

 

The outcome of acute-on-chronic liver failure in the intensive care is similar to a propensity matched ICU population without liver disease

S. van der Merwe1, P. Meersseman2, L. Langouche3, H. Korf4, J.D. Plessis5, M. Mekeirele2, D. Cassiman6,W. Laleman5,7, F. Nevens5,7, A. Wilmer2, G. Van den Berghe2,3. 1UZ Leuven, Department of Gastroenterology and Hepatology, Belgium; 2UZ Leuven, Department of Internal Medicine, Leuven, Belgium; 3KU Leuven, Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, Leuven, Belgium; 4KULeuven, Laboratory of  Hepatology, Leuven, Belgium; 5KU Leuven, Laboratory of Hepatology, Leuven, Belgium; 6University hospitals leuven, Gastroenterology and Hepatology, Leuven, Belgium; 7UZ Leuven, Gastroenterology and Hepatology, Leuven, Belgium

Background and Aims: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis, development of organ failure and high short-term mortality. It is unclear whether the ICU outcome in ACLF is different from other ICU populations. We compared the clinical course and host response in critically ill ICU patients with or without ACLF matched for baseline severity of illness scores.

Method: A post-hoc analysis was performed of the large EPaNic ICU study (n = 4640): 133 patientswere identified with cirrhosis of whom 71 patients fulfilled the Canonic criteria for ACLF. These patients were matched for type and severity of illness and demographics to 71 septic and 71 medical ICU patients without liver disease. The clinical, biochemical and outcome parameters were compared and, in a subset of 100 patients, day 1 serum cytokines were quantified.

Results: The outcome of ACLF when compared to septic or medical ICU patients, matched for baseline parameters of illness severity, was similar regarding length of ICU stay, development of new infections, organ failure and septic shock, ICU hospital and 90 day mortality. CRP and platelets levels were lower in ACLF patients throughout the first week in ICU. Baseline cytokines IL-10, IL-1β, IL-6, and IL-8 were similarly elevated in ACLF and septic ICU patients, whereas serum TNF-α was higher and CCL13 lower in ACLF.

Conclusion: ACLF patients admitted to the ICU showed comparable clinical and ICU outcomes compared to non-ACLF patients without liver disease with similar baseline severity of illness characteristics. This suggest that admission criteria to the ICU should not be different in ACLF compared to other populations. Furthermore, ACLF patients that are liver transplant candidates should be identified early in their ICU course.

 

THU-044

 

Evaluation of the CLIF-C ACLF score in critically ill cirrhotic patients in intensive care units in Europe and North America: a multicenter cohort study

C.J. Karvellas^1,2, E. Garcia-Lopez³, J. Fernandez⁴, F. Saliba⁵, E. Sy⁶,Jalan⁷, M. Pavesi³, T. Gustot⁸, G. Mezzano⁹, J.J. Ronco⁶, V. Arroyo⁹ and CLIF Consortium (EF CLIF). ¹Critical Care Medicine; ²Hepatology, University of Alberta, Edmonton, Canada; ³Department of Statistics, Barcelona Clinic/EF CLIF; ⁴Critical Care Medicine, University of Barcelona, Barcelona, Spain; ⁵Centre Hépato-Biliaire, Hôpital Paul Brousse, Paris, France; ⁶Critical Care Medicine, University of British Columbia, Vancouver, Canada; ⁷Hepatology, University College London, London, United Kingdom; ⁸Hepatology, Hospital Erasme, Brussels, Belgium; ⁹Hepatology, University of Barcelona, Barcelona, Spain E-mail: cjk2@ualberta.ca

 

Background and Aims: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality. Critical care physicians are often faced with difficult decisions regarding ongoing life support or palliation. This study aimed to evaluate the CLIF-C ACLF score in ACLF patients admitted to intensive care units (ICU) from different global regions and compare discrimination ability with previously published scores.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Methods: Cohort analysis of data from 593 ACLF patients from ICUs in Canada (Alberta, British Columbia), Europe (Paris, Barcelona) and those enrolled in the CANONIC study who on ICU admission met criteria for ACLF. Cumulative Incidence Functions (CIF) of mortality

were estimated by ACLF grade at admission and at day 3. A concordance index (C-index) was used to compare the survival discrimination abilities of CLIF-C ACLF, MELD, APACHEII, and Child-Pugh (CTP) scores.

 

Results: In this pooled sample (n = 593; mean age 55 years, 31% female), the most common etiology was alcohol (55%) and the most common reason for ICU admission was infection (30%). Of 593 ICU ACLF patients, on admission 109 (18%) had ACLF-1, 178 (30%) ACLF-2 and 306 (52%) had ACLF-3 with corresponding 90-mortality rates of 39%, 43% and 80% respectively ( p < 0.001). In a subgroup of the sample (223/593) where data on day 3 were also available, 90-day mortality rates were as follows: NO ACLF on Day 3 = 18%, ACLF-1 22%, ACLF-2 59%, ACLF-3 80%; ( p < 0.001). Plots of CIF for mortality based on ACLF grade on admission and day 3 are shown in Figure 1 ( panel A and B). Differences among strata (ACLF grades) were statistically significant (Gray’s test p < 0.001 for both). In evaluating admission prognostic scores in pooled ICU patients (n = 593), CLIF-C ACLF demonstrated superior discrimination between survivors and non survivors at 90 days (c-statistic 0.68 (95% CI 0.65, 0.71)) compared with MELD (0.65 (0.62, 0.68), p = 0.024) and Child Pugh (0.64 (0.60, 0.67), p = 0.012) but not APACHEII (0.65 (0.61, 0.69), p = 0.13). A CLIF-C ACLF score >70 were associated with mortality rates of 88% at 28 days and 93% at 90 days.

 

Conclusions: In ACLF patients admitted to ICUs in different regions (Europe, North America) and units (Specialty Liver and General ICUs), the CLIF-C ACLF demonstrated better discrimination at day 28 and day 90 compared to MELD and CTP. In high risk ICU patients (CLIF-C ACLF >70), decisions regarding transition to palliation should be explored between patient families and the ICU providers.

 

THU-261

 

Hyperkalemia influences the outcome of patients with cirrhosis with acute decompensation (AD) and acute on chronic liver failure (ACLF)

 

G. Mezzano¹, A. Cardenas^1,2, F. Aguilar³, M. Pavesi³, C. Sole¹, E. Solà¹, L. Napoleone¹, I. Graupera¹, A. Juanola¹, M. Carol¹, G. De Prada¹,Fabrellas¹, J. Martinez⁴, F. Saliba⁵, T. Welzel⁶, V. Arroyo³, P. Ginès⁷. ¹Hospital Clinic, Liver Unit, Barcelona, Spain; ²Institut d’Investigacions Biomediques August Pi i Sunyer y Centro de Investigaciones en Red Hepaticas y Digestivas (CIBERehd), Barcelona, Spain; ³EASL CLIF Consortium, European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; ⁴Hospital Universitario Ramón y Cajal, Department of Gastroenterology and Hepatology, Spain; ⁵Hôpital Paul Brousse, Hepatology, Spain; ⁶JW Goethe Universität, Hepatology, Germany; ⁷Liver Unit, Barcelona, Spain

 

Email: acardena@clinic.cat

 

Background and Aims: Hyperkalemia is considered a risk factor of mortality in different clinical scenarios such as heart failure, chronic kidney disease and diabetes mellitus. The aim of this study was to investigate whether hyperkalemia is a risk factor for mortality in patients with cirrhosis and acute decompensation (AD) with and without ACLF

 

Method: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,314 consecutive patients admit-ted to 29 European centers with AD both with and without associated ACLF (294 and 1,020 respectively). Hyperkalemia was defined as serum potassium above 5.0 mEq/L. For the analysis, we considered all patients with presence of at least one valid measure of serum potassium from admission through hospitalization.

 

Results: Of the 1314 patients admitted with AD, 294 presented ACLF at admission. Prevalence of hyperkalemia in the whole cohort was 11.7% with a mean serum potassium of 5.47 mEq/L. The prevalence of hyperkalemia was significantly higher in patients with ACLF versus those with AD (22.4% and 8.6% respectively, p < 0.001). Presence of hyperkalemia was associated with an increased 90, 180 and 360-day mortality risk with higher hazard ratio (HR) in ACLF than in acute decompensation (10 vs 2.3 at 90-day p < 0.001, 8.9 vs 3.1 at 180-day,

p < 0.001 and 5.8 vs 3.8 at 360-day, p < 0.001). In a multivariate analysis development of hyperkalemia during admission was independently associated with 90-day mortality [HR 2.4 (1.7–3.4)]. To assess further the prognostic value in the whole cohort, we compared the ROC curves of the MELD score with and without hyperkalemia during admission; this showed an increase of the AUC for MELD score from 0.74 to 0.76 p < 0.001. This MELD-K model resulted in a higher diagnostic accuracy to predict 90-day mortality on the whole cohort.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conclusion: The presence of hyperkalemia is an independent predictive factor of survival in patients with cirrhosis AD and ACLF. The addition of hyperkalemia to the MELD score improves the diagnostic accuracy to predict 90-day mortality in patients with AD and ACLF.

 

 

 

 

THU-382

 

LECITHIN-CHOLESTEROL ACYLTRANSFERASE ACTIVITY AND APOLIPOPROTEIN A1 LEVELS PREDICT PROGRESSION TO ORGAN FAILURE IN ACLF PATIENTS AND 3 MONTH MORTALITY FOLLOWING ACUTE CIRRHOSIS DECOMPENSATION

3. Samra¹, K.L. Thomsen^1,2, A.F.B. DaSilva¹, R. Sawhney¹, H. Jones¹,J. Owen¹, R.P. Mookerjee¹. ¹UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom; ²Department Of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark

 

E-mail: karethom@rm.dk

 

Background and Aims: Lecithin cholesterol acyltransferase (LCAT) is secreted by the liver and esterifies plasma cholesterol, a vital step regulating HDL levels and cell membrane cholesterol. LCAT activity is thought to decrease with increasing liver disease severity and similar data exists for HDL levels but this has not been evaluated in acute-on-chronic liver failure (ACLF). The aim of this study was to determine LCAT activity and HDL levels in acute cirrhosis decompensation (AD) and determine their prognostic utility and relationship with progression of organ failure.

 

Methods: Patients admitted to Royal Free London with acute cirrhosis decompensation were included and characterised by clinical disease severity scores (including ACLF) and standard biochemistry. Admission plasma was assessed for LCAT activitypercent cholesterol esterification (%CE)], apolipoprotein A1 (ApoA1) and HDL and their relationship with subsequent clinical outcomes.

 

Results: 72 acute decompensated cirrhosis patients were included: age 50 (24–75) yrs; 46 male; 55-alcohol; 9-viral; 2-PBC; 4-NASH; 2-AIH. 43 patients fulfilled ACLF criteria (grades 1–3) at baseline or within 72 hours of inclusion (mean MELD 27.5 ± 1.1); the remainder (AD: n = 29) had no organ failure (mean MELD 15.4 ± 0.8). 24 patients died within 3 months of admission; encephalopathy was the most common organ failure. %CE was reduced in ACLF patients and was lowest in ACLF 2–3 cf. ACLF 1 (1.7 ± 0.5 vs 3.8 ± 0.8 p < 0.02) and correlated with MELD (spearman rank: r = −0.5; p < 0.0001). This was mirrored by significantly lower ApoA1 levels in ACLF patients cf. AD patients (0.41 ± 0.04 vs. 0.6 ± 0.06, p < 0.001) which progressed from grade 1 to 2/3 (0.5 ± 0.2 vs 0.34 ± 0.2 g/L; p < 0.001). Similarly, HDL levels were significantly lower in ACLF vs AD patients ( p < 0.01). ROC curve analysis showed ApoA1 as a good predictor of 3 month mortality (AUC 0.82; C.I. 0.72–0.91), highest in patients with values <0.5 cf. values ≥0.5 g/L (54 vs. 6%; p < 0.001). %CE also had predictive utility for mortality with AUROC 0.74 (C.I. 0.59–0.89).

 

Conclusions: Our data show for the first time that reduced LCAT activity and corresponding ApoA1 levels (reflecting mature HDL) define progression to organ failure following acute cirrhosis decompensation and predict 3 month mortality. This provides a potential mechanistic insight into organ failure in ACLF and justifies a rationale for intervention given current trials of recombinant therapy for primary LCAT deficiency.

 

FRI-022

 

NACSELD acute-on-chronic liver failure (NACSELD-ACLF) predicts 30-day mortality in admitted cirrhotic patients

J.G. O’leary¹, K.R. Reddy², P. Tanson³, P.S. Kamath⁴, F. Wong⁵,Garcia-Tsao⁶, J. Lai⁷, S. Biggins⁸, M.B. Fallon⁹, R. Subramanian¹⁰,Thuluvath¹¹, B. Maliakkal¹², L. Thacker¹³, J.S. Bajaj¹³ and NACSELD. ¹Simmons Transplant Institute, Baylor University Medical Center, Dallas; ²Internal Medicine, University of Pennsylvania, Philadelphia, United States; ³Internal Medicine, University of Alberta, Alberta, Canada;

⁴Internal Medicine, Mayo Clinic, Rochester, United States; ⁵Internal Medicine, University of Toronto, Toronto, Canada; ⁶Internal Medicine, Yale University, New Haven; ⁷Internal Medicine, UCSF, San Francisco;

 

⁸Internal Medicine, University of Colorado, Denver; ⁹Internal Medicine, University of Texas, Houston; ¹⁰Internal Medicine, Emory University, Atlanta; ¹¹Internal Medicine, Mercy Medical Center, Baltimore;

 

¹²Internal Medicine, University of Rochester, Rochester; ¹³Internal Medicine, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, United States

 

E-mail: dr_jackieo@yahoo.com

 

Background and Aims: NACSELD (North American Consortium for the Study of End-Stage Liver Disease) acute-on-chronic liver failure (NACSELD-ACLF), defined as ≥2 extra-hepatic organ failures, has previously been proposed as a simple bedside tool to assess risk of mortality in admitted infected cirrhotic patients. Aim: We validated NACSELD-ACLF’s ability to predict 30-day mortality (defined as in-hospital death or discharge to hospice) in a separate multicenter prospectively enrolled cohort of both infected and uninfected admitted cirrhotic patients.

 

Methods: We utilized the NACSELD database of 16 tertiary care hepatology centers that prospectively enroll admitted cirrhotic patients (N = 2,675). For this validation the cohort was randomly split 60%/40% into training (N = 1,605) and testing (N = 1,070) groups. Organ failures assessed were: (1) shock, (2) hepatic encephalopathy (grade III/IV; HE), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation).

 

Results: Admitted cirrhotic patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 and alcohol-induced cirrhosis

 

(45%). 1,079 patients in total had an infection during hospitalization. Because of random splitting of the cohort no demographic differ-ences were present between the 2 groups. Overall the mean MELD was 19, serum creatinine was 1.43, serum albumin was 2.8, and median Child score was 10. Multivariable modeling revealed NACSELD-ACLF as the strongest predictor of mortality after control-ling for admission age, WBC, serum albumin, MELD score, and infection status (Figure). The training set AUC was 0.8073 and the testing set AUC improved to 0.8433.

 

 

 

 

 

 

 

 

 

Conclusions: Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple reliable bed-side tool to predictor 30-day mortality in both infected and uninfected admitted cirrhotic patients.

 

FRI-038

 

Presence of ACLF is the best predictor of mortality in patients with decompensated chronic liver disease managed in a non-specialist environment

 

L. Burke¹, C. Lane¹, Y. Gao-Du¹, R. Driver¹, L. Corless¹. ¹Hull and East Yorkshire NHS Trust, Hull, United Kingdom

E-mail: l.burke@doctors.org.uk

 

Background and Aims: Acute on chronic liver failure (ACLF) is a severe complication of decompensated chronic liver disease (DCLD) characterized by organ failure and high short-term mortality. The significance of ACLF was originally proven in a cohort of patients across European liver units but the concept remains poorly recognised in non-specialist areas, potentially impacting ability to identify at-risk patients and modify treatment accordingly.

 

In our centre – typical of United Kingdom practice - people with DCLD are admitted via a general medical admissions unit under the care of acute physicians, gastroenterologists or hepatologists, and Child-Pugh (CP) score may be the only prognostic tool used. We sought to establish the relative value of ACLF in this context.

 

Methods: A retrospective cohort study was conducted of all DCLD admissions from April 2014 – June 2015. Records were reviewed to determine presence/absence of ACLF according to EASL-CLIF consor-tium definition alongside clinical parameters including CP, model for end stage liver disease (MELD) score and presence of sepsis. Data were analysed to identify statistically significant predictors of 30-day and overall mortality

 

Results: 117 DCLD patients (median age 56 [30–88]) were included, with alcohol the predominant aetiology (n = 79 [67%]). 45 patients (38%) met ACLF criteria of any grade at presentation or during admission. ACLF correlated with MELD, CP and sepsis (all p < 0.001), but not age, aetiology or first presentation. 30-day mortality was significantly greater in those with ACLF than without (71 vs 12% p < 0.001), and exceeded overall mortality in previously published series. ACLF – but not MELD or sepsis – remained independently associated with 30-day mortality after multivariate analysis (OR 8.2 95% CI 2.8–p < 0.001). Overall median survival was significantly worse in ACLF (18 vs 455 days; p < 0.001) (Fig 1), and Cox proportional hazards analysis confirmed ACLF was the only parameter independently associated with overall survival (HR 3.12 95% CI 1.4–6.9 p = 0.005)

 

 

 

 

 

 

 

 

 

 

 

 

 

           

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Conclusions: The study confirms that in a non-specialist area, ACLF is the best predictor of mortality in DCLD. Poor awareness of ACLF by non-specialists may have contributed to the high mortality observed compared to previously published data. Presence/absence of ACLF can be readily assessed on the ward and we propose that it becomes the primary tool employed by all physicians to identify those at high-risk of short-term mortality and to prompt specialist input.

 

THU-267

 

Analyzing the Duration Between Acute Insult and ACLF in a Chinese 14 centers, prospective study for natural course of ACLF

 

17. Wenyi^1,2, B.-Y. Xu³, X. Zheng⁴, J. Chen⁵, X.-B. Wang⁶, Y. Huang⁷, Y. Gao⁸, Z.-J. Meng⁹, Z.-P. Qian¹⁰, F. Liu¹¹, X.-B. Lu¹², J. Shang¹³, H. Li¹⁴, S. Wang¹⁵, H. Li^2,16. ¹Shanghai Jiao Tong University, Shanghai Institute of

 

Digestive Disease, Department of Gastroenterology, Shanghai, China; ²Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Department of Gastroenterology, Shanghai, China; ³Southwest Hospital, Third Military Medical University, Department of Infectious Diseases, Chongqing, China; ⁴Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Department of Infectious Diseases, Wuhan, China; ⁵Nanfang Hospital, Southern Medical University, Department of Infectious Diseases, Guangzhou, China; ⁶Beijing Ditan Hospital, Capital Medical University, Department of Infectious Diseases, Beijing, China; ⁷Xiangya Hospital, Central South University, Department of Infectious Diseases, Hunan, China; ⁸The First Hospital of Jilin University, Department of Infectious Diseases, Jilin, China; ⁹Taihe Hospital, Hubei University of Medicine, Department of Infectious Diseases, Hubei, China; ¹⁰Shanghai Public Health Clinical Centre, Fudan University, Department of Infectious Diseases, Shanghai, China; ¹¹The Second Hospital of Shandong University, Department of Infectious Diseases, Shandong, China; ¹²The first Affiliated Hospital of Xinjiang Medical University, Department of Infectious Diseases, Xinjiang, China; ¹³Henan Provincial People’s Hospital, Department of Infectious Diseases, Henan, China; ¹⁴Affiliated Hospital of Logistics University of People’s Armed Police Force, Department of Infectious Diseases, Tianjin, China; ¹⁵Fuzhou General Hospital of Nanjing Military Command, Department of Infectious Diseases, Fujian, China; ¹⁶Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Chinese Ministry of Health, Shanghai, China

 

Email: haili_17@126.com

 

Background and Aims: Patients with chronic liver disease who are at high Acute-on-Chronic liver failure (ACLF) risk are characterized by

precipitating events (PE), intra- and extrahepatic organ failure(OF) and rapid deterioration to death. Although the time interval between PE and single liver failure(LF) as four weeks has been defined in APASL consensus, however studies on such interval and clinical course of ACLF are scarce. Whether intra- and extrahepatic PE lead to distinct durations remains uncertain. Hereby we analyzed the intervals of PE-to-single LF and PE-to-ACLF in Chinese CANONIC study patients.

 

Method: A Chinese nationally 14 liver centers representative cohort comprising 2600 chronic liver disease patients (including 70% cirrhotic and 30% non-cirrhotic) with acute decompensation or acute liver injury(defined as ALT > 3NL or TB > 2NL) was recruited. single LF (TB > 12 mg/dl) and ACLF were diagnosed using CLIF-OF score. We evaluated PE-to-single LF interval among cirrhotic patients who developed single LF at admission or within 28-days hospital-ization after admission. Next, PE-to-ACLF interval was studied among patients who had defined PE and developed ACLF during hospitalization. The two intervals were then compared in patients with isolated defined intrahepatic PEs (including HBV reacti-vation, active alcohol intaking, superimposed hepatic virus and drug-induced hepatic injury)and those with infections as only existing extrahepatic PE.

 

Results: Among 1833 cirrhotic patients, 1070(58.4%) had explicit PE. Among those PE defined patients, 205 patients had single LF, and 76% patients develop single within 4 weeks when PE occurred. 71.5% etiology are HBV related and 20.6% developed ACLF. PE-to-single LF intervals for patients with intra-(n = 94) and extrahepatic PE (n = 111) were 19(7–42) (median and interquartile range) and 4(1–11) days, respectively ( p < 0.0001). There was a significant PE-to-ACLF interval difference between intra- (n = 41) and extrahepatic (n = 55) PE(21(8–

 

4. vs 15(9–24) days, p = 0.02). Comparing with bacterial infection as an only existing extrahepatic PE (n = 84), those with intrahepatic PEs (n = 51) had significant longer PE-to-single LF interval (intra:16(7–

 

• vs extra: 2(1–7) days, p < 0.0001), when PE-to-ACLF interval reached borderline significance(intra:16.5(7–44) days, n = 16 vs extra 15(9–24) days, n = 36; p = 0.05).

Conclusion: Our multicenter, prospective study showed both single LF and extrahepatic OF were most likely to occur within less than 4 weeks after PE presence among eastern type cirrhotic patients. Additionally, Both single LF and ACLF developed more rapidly with the presence of extrahepatic insult, especially in patients with bacterial infection. Exploring the interval from both PE-to-single LF and PE-to-ACLF interval will help to understand the natural course evolution about HBV dominated Eastern type ACLF.

 

 

Oral 2017

35. Molecular Adsorbent Recirculating System (MARS) Can Reduce Short-term Mortality among Patients with Acute-on-chronic Liver Failure

Hans U. Gerth1, Michele Pohlen2, Gerold Thoelking1, Her- mann Pavenstädt1, Anna Hüsing3, Iyad Kabar3, Marco Pavesi4, Vicente Arroyo5, Rafael Banares4, Hartmut H. Schmidt3; 1Nephrology, University Hospital, Muenster, Germany; 2Oncol- ogy, University Hospital, Münster, Germany; 3Hepatology, University Hospital, Münster, Germany; 4Liver Unit, Madrid, Spain; 5Liver Unit, Barcelona, Spain

Background: Acute-on-chronic liver failure (ACLF) is asso- ciated with numerous consecutive organ failures and a high short-term mortality rate . Molecular adsorbent recir- culating system (MARS) therapy has demonstrated bene- ficial effects on the distinct symptoms, but the associated mortality data remain controversial . We intended to generate new hypotheses that would form the basis for better management strategies and interventions to reduce the high mortality rate associated with ACLF . Methods: This analysis was conducted in two parts: First, 101 patients with ACLF grade 1-3 and CLIF-C-OF liver subscore=3 but stable pulmonary function were identified and received either standard medical treatment (SMT, n=54) or SMT and MARS (n=47) at the University Hospital Muenster . Second, the results of this retrospective analysis were tested against the data from the prospective randomized RELIEF trial by applying the recently introduced CLIF-cri- teria . Results: Additionally to improved laboratory param- eters (bilirubin and creatinine), the short-term mortality (up to day 14) of the MARS group was significantly reduced compared with SMT . A reduced 14-day mortality rate was observed in the MARS group (9 .5% vs . 50 .0% with SMT, p=0 .004), especially in patients with multi-organ failure (ACLF grade 2-3) . Concerning the affected organ system, this effect of MARS on mortality was particularly evident among patients with increased kidney, brain or coagulation CLIF-C-OF subscores . Subsequent reanalysis of the RELIEF dataset with adoption of the CLIF-classification resulted in similar findings . Conclusion: MARS treatment was associated with an improved short-term survival of patients with ACLF and multi-organ failure . Among these high-risk patients, MARS treatment might bridge to liver recovery or liver transplantation .

Disclosures:

Vicente Arroyo - Advisory Committees or Review Panels: Baxter TheraMARS; Speaking and Teaching: GRIFOLS

Rafael Banares - Advisory Committees or Review Panels: abbvie, gilead, baxter, janssen; Grant/Research Support: gambro; Speaking and Teaching: gilead, bms, janssen

The following people have nothing to disclose: Hans U . Gerth, Michele Pohlen, Gerold Thoelking, Iyad Kabar, Hartmut H . Schmidt

 

548

Prospective evaluation of the Thromboelas- trography (ROTEM®) profile in patients with Acute-on-Chronic Liver Failure (ACLF) and decompensated cirrhosis.

Background & Aims: Thromboelastography (TE) is a useful tool for monitoring coagulation in patients with compen- sated and decompensated cirrhosis (DC) . The TE profile in compensated cirrhosis is usually normal, whereas in decompensated cirrhosis it can be hypo or hypercoagu- lable . TE has not been adequately studied in patients with ACLF . Our aim was to assess the TE profile in patients with ACLF (grades 1-3) and in patients with DC . Methods: We evaluated patients with ACLF and DC at Hospital Clinic in Barcelona, Spain from August/2015 to December/2016 . Blood samples for TE (ROTEM®) were obtained at admis- sion and at 48-72 hr . Patients were followed for 3 months . We excluded patients with prior transfusions other than red blood cells within one week of inclusion . Sample size was calculated by estimating TE profiles in patients with DC available in the literature . A hypo-coagulable profile was defined by the presence of 3 or parame- ters under the reference range . Results: 34 patients with ACLF and 28 with DC were included . Patients with ACLF displayed a more intense hypo-coagulable profile (56% vs 29% in patients with DC; p=0 .04) . Time to initial fibrin formation was delayed in patients with ACLF compared to those with DC . In patients with ACLF, clot formation time (CFT) was delayed [CFTINTEM 132(79-182) vs . 161(79- 259) p=0 .009] compared to its baseline value 48h later . Maximum clot firmness (MCF) was also reduced [MCFINTEM [51(44-61) vs 47(39-56) p= 0 .007] compared to the base- line value 48h later . In contrast, both parameters (base- line and 48h later) improved in patients with DC; CFTINTEM [110(86-160) vs . 100(63-141), p=0 .005] and MCFINTEM [55(48-60) vs . 57(49-65, p=0 .02)] . Bleeding events at admis- sion and during hospitalization were similar among both groups . Blood product requirements (red blood cells, fresh frozen plasma, platelet, and fibrinogen) during hospital- ization were higher in patients with ACLF compared to those with DC (44% vs . 18%, p=0 .02) . CFT at admission was similar among ACLF grades 1,2,3 but more prolonged in ACLF 3 vs . ACLF 1&2 at 72h (192(123-339)& 188(107- 219) vs .318(149-773) p=0 .02 . CLIF-SOFA score (10 (10-13) vs . 7 (7-8), hospital stay (18 (11-26) vs . 8 (5-13) days), and 28 and 3-month mortality (50 vs . 7%) and (66 vs . 11%) were higher in patients with ACLF . Conclusion Patients with ACLF display a more hypo-coagulable profile than patients with DC . Clot formation time and maximum clot firmness progressively worsen 48 hours after admission in patients with ACLF but in contrast, improve in those with DC . Bleeding events among both groups were similar however patients with ACLF required more transfusions . Disclosures:

The following people have nothing to disclose: Annabel Blasi, Andrea Calvo, Maria Hernandez, Juan Carlos Reverter, Javier Fernandez, Andres Cardenas

 

2053                                      

Protective effects of beta-blockers in patients with acute- on-chronic liver failure including circulatory failure requiring vasopressors

Mohammed A. Medhat1,2, Olivier Roux1, Valerio Giannelli1, Clem- ent Lejealle1, Emmanuel Weiss3, Catherine Paugam3,4, Richard Moreau1,4, Claire Francoz1,4, Francois Durand1,4; 1Hepatology & Liver Intensive Care, Hopital Beaujon, Paris, France; 2Tropical Medicine & Gastroenterology, Al-Rajhy liver hospital, Assiut univer- sity hospitals, Assiut, Egypt; 3Anesthesiology and Intensive Care, Hopital Beaujon, Paris, France; 4INSERM U1149, University Did- erot Paris 7, Paris, France

Background & aims: Recently, several studies have suggested that non selective beta-blockers (NSBB) may have beneficial effects in patients with acute on chronic liver failure (ACLF) through reducing the severity of inflammatory response . On the other hand, the use of beta blockers remains controver- sial in non-cirrhotic patients with septic shock . The aim of this study was to explore the impact of NSBB in patients with ACLF and distributive shock requiring vasopressors (norepinephrine) . Patients and methods: Eighty consecutive patients with ACLF admitted from June 2010 to Sept 2015 in a specialized ICU and were retrospectively studied . All patients had distributive circulatory failure defined by the need for norepinephrine to achieve a target mean arterial pressure of 65mmHg after ade- quate fluid resuscitation . The study subjects were classified into NSBB+ (receiving NSSB) and NSBB- (not receiving NSBB) groups . Patients were followed up from admission in the ICU to death, transplantation or last follow-up visit for patients alive without transplant at the end of the study . Results: The study population included 58 males and 22 females . The mean age of the study participants was 54 9 years . Causes of cirrhosis were alcohol in 62%, HCV in 19%, HBV in 6% and others in 16% . Mechanical ventilation (MV) and renal replacement therapy (RRT) were used in 72% and 49% patients, respectively (including 40% with both MV and RRT in addition to vasopres- sors) . Forty patients out of eighty (50%) were receiving NSBB at admission (NSBB+) . The mean of the MELD score at admission was not significantly different in NSBB+ (29) and NSBB- (32) patients . No significant difference was found between the 2 groups (NSBB+ vs NSBB-) regarding age (56 vs 52-y), gender (72 % vs 72% males), rate of MV (69% vs 75%), rate of RRT (41% vs 57%), rate of empirical antibiotics before admission (65% vs 52%), and rate of documented infection after admis- sion (85% vs 78%) . The proportion of patients who were trans- planted was not significantly different in the 2 groups (20% vs 7%, p=0 .1) . Transplant free-survival (Kaplan-Meier) was signifi- cantly better in NSBB+ as compared to NSBB- patients (48% vs . 15% at 28-day, respectively, p=0 .007) . On multivariate analysis (Cox model including NSBB and MV), only NSBB was significantly and independently predictive of survival (p=0 .02) . Conclusion: The results of this series suggest that NSBB intake at admission of patients with ACLF and circulatory failure requiring administration of vasopressors is associated with better outcome, irrespective of the presence or absence of bacterial infection .

 

 

 

SAT-004

 

Prolonged intensive care support of patients with acute on chronic liver failure and CLIF-C ACLF score greater than 70 may be futile

N. Zakeri¹, K.L. Thomsen^1,2, B. Agarwal³, R. Jalan¹, R.P. Mookerjee¹.

¹Institute for Liver and Digestive Health, University College London and Royal Free Hospital, London, United Kingdom; ²Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; ³Department of Intensive Care Medicine, Royal Free Hospital, London, United Kingdom

 

E-mail: nzakeri@doctors.org.uk

 

Background and Aims: ACLF (Acute on chronic liver failure) is a syndrome characterised by high short-term mortality, especially with ≥3 organ failures (ACLF grade 3). The CLIF-C ACLF score was developed to stratify mortality risk but data on thresholds to triage therapy in ACLF 3 is limited. We evaluated short-term outcomes for ACLF 3, compared the predictive value of the CLIF-C ACLF score against other prognostic scores and determined if there is a potential threshold suggesting futility.

Methods: Data analysed from 2005 to 2012 in a single tertiary centre from 278 ACLF patients, based on ACLF grade on day of intensive care unit (ICU) admission. Data was collected on demographic and biological variables, precipitants for cirrhosis decompensation, presence of infection and number of organ failures and used to calculate MELD-Na, Child-Pugh, CLIF-organ failure (CLIF-OF), and CLIF-C ACLF scores. Survival data included 28 day and 3 month transplant-free survival.

Results: 210 patients had ACLF Grade 1 and 2; of these 10 were transplanted; 32% died within 28 days, and 41% by 3 months. The remaining 68 patients (mean age 52 years; range 25 to 77) met ACLF 3 criteria upon ICU admission and none were transplanted. The predominant aetiology was alcohol (54%) and bacterial infection the precipitating event in 50% of cases. 28-day mortality was 72% (n = 49), 45% with ≥ 4 organ failures. 3-month survival was 13% (n = 9). 28-day mortality was not associated with age, bilirubin, INR, leukocyte count or creatinine but was significantly associated with the number of organ failures ( p = 0.008), the CLIF-OF score ( p = 0.001) and CLIF-C ACLF score ( p = 0.0001). 3-month survival was significantly associated with CLIF-OF score (p = 0.005) and CLIF-C ACLF score ( p = 0.002).

In ACLF 3, CLIF-C ACLF score was a good predictor of 28-day mortality with AUROC 0.80 (CI 0.69–0.91) compared with MELD-Na (AUROC 0.66; CI 0.51–0.81). A CLIF-C ACLF score <70 (n = 53) had a 28-day mortality of 64% compared to 100% ( p = 0.006) for patients with a score ≥70 (n = 15; see Kaplan-Meier figure). The positive predictive value for a score of ≥70 was 100% (CI 78–100%).

 

Conclusions: Patients with ACLF 3 have very high short-term mortality. Our data suggests CLIF-C ACLF score at ICU admission provides a robust predictor of 28-day and 3-month mortality in this group, whilst bilirubin does not help prognosticate. A CLIF-C ACLF score ≥70 provides a potential threshold to set limits when treatment appears futile without liver transplantation.

 

 

 

 

 

 

 

 

 

 

FRI-004

 

Slow infusion of furosemide and albumin with or without terlipressin safely mobilizes ascites and impacts hemodynamics and intestinal permeability in ACLF patients with organ failure(s) and improves 28-day survival

 

G. Pande¹, S. Shalimar², K. Kumar¹, P.N. Sharma¹, V.P. Krishna¹,

S. Mohindra¹, V.A. Saraswat¹ and Sanjay Gandhi Institute of Medical Sciences.Lucknow.INDIA. ¹Gastroenterology, SGPGI MS, Lucknow;

 

²Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

 

E-mail: drgauravpandey@yahoo.com

Background and Aims: ACLF mortality increases with extra-hepatic organ failure(s) (OF). Ascites mobilisation is challenging with OFs. To study the efficacy of Slow infusion of furosemide and albumin with or without terlipressin SIFA (T) as per response-guided protocol to achieve complete ascites mobilization.

 

Methods: Patients hospitalized at 2 government tertiary centres in India,between December 2012 to July 2016 with >Gr 2 ascites and ACLF ≥ Grade I as per CLIF-SOFA and CVP >10 cmH₂O were included. Baseline chemistry and Echocardiography and Intestinal permeabil-ity(IP) assessment with urinary lactulose/mannitol ratio (LMR) were done. Consecutive patients in Arm I received SIFA (T); Arm I; furosemide 2 mg/h, albumin 2 gm/h; 20–40 g/d] in addition to standard medical therapy(SMT) for ACLF complications. Furosemide was stepped up by 2 mg/h every 12 hours if UNa < 85 mmol/d. After 48 hrs, terlipressin was started at 4 mg/24 hrs,(max. 8 mg/24 hr) and alternately stepped up if UNa <85 mmol/d till complete ascites mobilisation. Arm II received SMT for ACLF complications as per guidelines including oral dirutics, terlipressin-albumin therapy for HRS Results: 230 patients (143 Arm I; 87 in Arm II) The etiology of cirrhosis and acute insult didnot differ significantly ( p = NS). Baseline parameters including Serum(S) creatinine (1.6 ± 1.01 vs. 1.38 ± 1.14), S. bilirubin (16.4 ± 10.2 vs. 19.4 ± 9.8 mg/dl), CTP (11.4 ± 1.3 vs. 11.6 ± 1.73); MELD (30.3 ± 8.1 vs. 30.2 ± 7.5); number of OF (2 ± 1.2 vs. 2 ± 1.8) and CLIF-SOFA (10.9 ± 1.7 vs. 10.3 ± 1.5) were similar ( p = NS). All patients in Arm I and 28/87 in Arm II mobilised ascites competely in 15.2 ± 4 vs 6.4 ± 3.1days. Post therapy Arm I significant increase in urine sodium (34.8 ± 24 to 267 ± 142 mmol/24 hrs), urine output (503 ± 102 to 3,531 ± 1,508 mL/24 hrs). Survival for ACLF-1/2/3 in ArmI vs II was 87%/90/86.7# vs. 70%/66/52%(p < 0.05). Echo para-meters pre-therapy improved significantly post therapy( p < 0.05) in Arm I including:Heart rate-94.5 ± 7.74 to 80 ± 8.35, Mean arterial pressure 78.27 ± 6.47 to 86.37 ± 6.05 mmHg, Stroke volume 90.1 ± 20.67 to 73.1 ± 25.13, Cardiac output 8.6 ± 2.1 to 5.93 ± 2.42 L/min, Cardiac Index 4.62 ± 1.21 to 3.53 ± 1.49 L/min/m², Systemic vascular resistance 720.73 ± 238.18 to 1,341.38 ± 608.37 dyn·s/cm⁵,with sig-nificant reduction in renal artery resistive index (0.82–0.70) Significant improvment in IP and weight loss (10.2 ± 2.3 kg vs 2.4 ± 1.2 kg) and 28-day survival (88.4% vs. 66.4%) was seen in Arm I ( p = 0.001)

 

 

Conclusions: SIFA(T) in ACLF with OF may modify deranged systemic hemodynamics, IP and improve survival

 

 

THU-331

 

USE OF NON-SELECTIVE BETA BLOCKERS (NSBB) IN CIRRHOTIC PATIENTS WITH BACTERIAL INFECTIONS IS ASSOCIATED WITH LOWER FREQUENCY OF SEPSIS, BUT NOT OF ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) OR SURVIVAL. RESULTS OF A PROSPECTIVE STUDY

G.H. Pereira¹, C. Baldin¹, L. Victor¹, J. Piedade¹, L. Guimarães ¹, T. Rocha¹, Z. Veiga¹, F. Fernandes¹, E. Ahmed¹, J.L. Pereira¹. ¹Liver Unit, Bonsucesso General Hospital, Rio de Janeiro, Brazil

 

E-mail: ghspereira@gmail.com

 

Background and Aims: Use of NSBB has deleterious effects in decompensated cirrhosis. Bacterial infections are associated with Sepsis and ACLF, and NSBB trough reduction in systemic inflammatory response, could have beneficial effects. There are few data respect use of NSBB in patients with bacterial infections and their correlation with SIRS and ACLF. Our objective was to evaluate the frequency of complications of cirrhosis, incidence and clinical course of ACLF and SIRS in patients with and without NSSB use.

 

Methods: Cirrhotic patients prospectively included in a large database were analyzed. Bacterial infections and sepsis were diagnosed at hospitalization. ACLF was diagnosed and staged according to CLIF C OF score. Dose and type of NSSBB used within last 3 months was recorded. Frequency of complications of cirrhosis, sepsis and ACLF were compared between groups.

 

Results: 163 patients were included (57 ± 12 years, 64% male, MELD 18 ± 6, child C 54%). The most common type of infection was SBP and skin infections (37 and 38 patients). One hundred four patients were currently using NSSB. Patients taking NSBB more commonly had previous variceal bleeding, ascites and hepatic encephalopathy. At study inclusion, prevalence of complications of cirrhosis, liver and kidney function parameters were similar between patients taking NSBB or not. However, the frequency of ascites and hepatic encephalopathy throughout hospital stay was higher in patients taking NSBB (90 vs. 79%, 60 vs. 43%, p < 0.05). Use of NSBB was associated with lower heart rate (76 ± 12 vs.85 ± 15, p < 0.001), leukocyte count (7.5 ± 4.5 vs. 9.7 ± 7.6, p = 0.04) and frequency of sepsis (21 vs. 42%, p = 0.03). Frequency of ACLF was similar between groups (38 vs. 27%, p = 0.2), as well as CLIF-CF OF score and frequency of grade 2–3 ACLF. Patients taking NSBB had lower frequency of liver and coagulation failure, but higher frequency of kidney and cerebral failure. In –hospital and 3-month survival for patients taking NSBB and not was 67 and 59% versus 69 and 63% ( p = ns).

 

Conclusions: In patients hospitalized with bacterial infections, NSBB use is associated with higher frequency of complications of cirrhosis. Patients with NSBB had a blunted inflammatory response, as evidenced by lower frequency of sepsis. NSBB does not reduce ACLF frequency or severity, but their use correlates with distinct types of organ failure. Use of NSBB in cirrhotic patients with bacterial infections does not modify prognosis.

PS-015

Gut microbiome is profoundly altered in acute-on-chronic liver failure as evaluated by quantitative metagenomics. Relationship with liver cirrhosis severity

C. Sole1,2,3, M. Llopis2, E. Sola2,4,5, K. Da Silva6, S. Guilly7, E. Le-Chatelier6, P. Huelin2,5,8, R. Moreira2,M. Carol2,9, G. De Prada2,10, S. Ehrlich6, I. Graupera2,5,10, L. Napoleone10,11,12,13, E. Pose2,5,10, A. Juanola10, N. Fabrellas2,5,9, J. Dore7, D. Ehrlich7, P. Ginès2,10,14. 1Hospital Clinic Barcelona, Liver Unit; 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona; 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Spain; 4hospital Clinic Barcelona, Liver Unit, Barcelona; 5centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Spain; 6INRA (Institut national de la recherché agronomique), Unité MetaGenoPolis (MGP), Centre de recherche de Jouy-en-Josas, France; 7iNRA (Institut national de la recherché agronomique), Unité MetaGenoPolis (MGP), Centre de recherche de Jouy-en-Josas, France; 8Hospital Clinic Barcelona, Liver Unit; 9Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona; 10Hospital Clinic Barcelona, Liver Unit, Barcelona; 11IDIBAPS, Barcelona, Spain; 12University of Barcelona, Faculty of Medicine and Health Sciences, Barcelona, Spain; 13CIBEReHD, Barcelona, Spain; 14Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain

Email: csolem@clinic.ub.es

Background: Alterations in gut microbiome are common in human chronic diseases. Previous studies in patients with cirrhosis have shown a decreased gut microbial richness compared to healthy subjects. ACLF is the most severe clinical form of cirrhosis and is frequently associated with bacterial infections arising from endogenous flora. There is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics.

Aims: To investigate the alterations in gut microbiome in a large series of patients with cirrhosis encompassing the whole spectrum of disease, from compensated (C), to acutely decompensated (AD) without ACLF, and ACLF.

Method: Stool samples were collected prospectively from 200 patients with cirrhosis: 35 C, 89 AD, and 76 ACLF. DNA extraction was performed using the Ion Proton sequencer for metagenomics characterization of complex microbial communities’ composition. Microbial geneswere grouped into clusters, denoted as metagenomics species (MGS), on the basis of their abundance profiles. Data was analyzed using non-parametric tests (Kruskal Wallis test or Dunn test), and Spearmans’ correlations (p < 0.01).

Results: Overall, there was a significant loss of gene richness that correlated with disease stages. Gene richness was particularly low in patients with ACLF, independently of whether ACLF was present at hospital admission or developed during hospitalization. Reduced gene richness in ACLF appeared to be unrelated to antibiotic therapy. Two-hundred-and-ninety of the 1158 MGS detected contrasted between at least one disease stage. Interestingly, 44 MGS contrasted between AD and ACLF. The number of organ failures and MELD and Child-Pugh scores correlated positively with 3 MGS, basically from taxa that belong to Enterococcus. Unexpectedly, disease severity and organ failure also correlated with the finding of human DNA in stools.

Conclusion: Cirrhosis is characterized by marked alterations in gut microbiome that correlate with disease stage. Gene richness is strikingly reduced in the setting of ACLF. Enterococcus species correlate with disease severity, particularly with ACLF. The significance of the finding of homo sapiens DNA in stool samples of patients with cirrhosis, is uncertain but could be a marker of gut inflammation associated with disease severity, as shown by findings in inflammatory bowel disease.