Praveen Sharma

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

Secondary Prophylaxis of Hepatic Encephalopathy: An Open-Label Randomized Controlled Trial of Lactulose Versus Placebo

BACKGROUND & AIMSnHepatic encephalopathy (HE) is associated with a poor prognosis. Lactulose is used for the treatment of HE. There is no study on the prevention of recurrence of HE using lactulose.nnnMETHODSnConsecutive cirrhotic patients who recovered from HE were randomized to receive lactulose (HE-L group) or placebo (HE-NL group). All patients were assessed by psychometry (number connection test [NCT-A and B], figure connection test if illiterate [FCT-A and B], digit symbol test [DST], and object assembly test [OAT]), critical flicker frequency test, and blood ammonia at inclusion. Primary end point was development of overt HE.nnnRESULTSnOf 300 patients with HE who recovered, 140 (46.6%) met the inclusion criteria and were included. There was a high prevalence of abnormal psychometry test results (NCT-A, 67.5%; NCT-B, 62.5%; DST, 70%; and OAT, 80%), and FCT-A and B were abnormal in 10 of 14 patients. Critical flicker frequency was <38 Hz in 77 patients (55%). Twelve (19.6%) of 61 patients in the HE-L group and 30 (46.8%) of 64 in the HE-NL group (P = .001) developed HE over a median follow-up of 14 months (range, 1-20 months). Readmission rate due to causes other than HE (HE-L vs HE-NL, 9:6; P = NS) and deaths (HE-L vs HE-NL, 5:11; P = .18) in 2 groups were similar. Recurrence of overt HE was significantly associated with 2 or more abnormal psychometric tests after the recovery of an episode of HE (r = 0.369, P = .02).nnnCONCLUSIONSnLactulose is effective for prevention of recurrence of HE in patients with cirrhosis.

Noncirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and treatment

The Asian Pacific Association for the Study of the Liver (APASL) Working Party on Portal Hypertension has developed consensus guidelines on the disease profile, diagnosis, and management of noncirrhotic portal fibrosis and idiopathic portal hypertension. The consensus statements, prepared and deliberated at length by the experts in this field, were presented at the annual meeting of the APASL at Kyoto in March 2007. This article includes the statements approved by the APASL along with brief backgrounds of various aspects of the disease.

Addition of Propranolol and Isosorbide Mononitrate to Endoscopic Variceal Ligation Does Not Reduce Variceal Rebleeding Incidence

BACKGROUND & AIMSnEndoscopic variceal ligation (EVL) and propranolol are standard secondary prophylaxis therapies for variceal bleeding. Addition of isosorbide mononitrate (ISMN) to propranolol improves its hemodynamic efficacy; we investigated whether a combination of EVL and propranolol/ISMN was more effective than EVL alone for secondary prophylaxis.nnnMETHODSnPatients with a prior variceal bleed were randomly assigned to groups given a combination (n = 88) of EVL, propranolol (dose titrated to reduce heart rate to 55 beats per minute), and ISMN (40 mg/day) or EVL alone (n = 89). Primary end points were rebleeding or death; secondary end points were new complications of portal hypertension or serious adverse effects.nnnRESULTSnThe actuarial probabilities of rebleeding 2 years after therapy were 27% in the combination group and 31% in the EVL alone group (P = .822). Two patients in the combination group and 3 patients in the EVL alone group died during the study period (P = .682); no deaths were caused by variceal hemorrhage. In cirrhotic patients, the actuarial probabilities of rebleeding were 24% and 30%, respectively (P = .720). Secondary end points were comparable between groups. In multivariate analyses, presence of ascites (P = .003), serum albumin < 3.3 g/dL (P = .008), and hepatic venous pressure gradients > or = 18 mm Hg (P = .009) were independent risk factors for variceal rebleeding.nnnCONCLUSIONSnEVL alone is sufficient to prevent variceal rebleeding in cirrhotic and noncirrhotic patients with history of variceal bleeding. Addition of propranolol and ISMN to EVL does not reduce the incidence of variceal rebleeding but increases severe adverse effects. Risk factors for rebleeding include ascites, low serum albumin, and high hepatic venous pressure gradients.

Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: An open label trial

BACKGROUND/AIMSnSevere alcoholic hepatitis (AH) is associated with very high mortality. Tumor necrosis factor-alpha (TNF-alpha) contributes to the progression of AH and TNF-alpha antagonists like infliximab may help in ameliorating the severity and complications of AH. There is a scarcity of data regarding the safety and efficacy of infliximab monotherapy in the treatment of AH. We evaluated infliximab monotherapy in patients with severe AH.nnnMETHODSnPatients with severe AH (Maddreys score>32) received a single dose of infliximab 5 mg/kg IV. The primary endpoint was survival assessed at one and two months. The secondary endpoints were reduction of the Maddreys DF and development of any bacterial infections. Predictors of survival were assessed at admission and at day 7.nnnRESULTSnNineteen patients were enrolled in the study and received infliximab. By the end of one month two patients died resulting in 1-month survival of 17/19 (89%). By the end of two months four additional patients died resulting in 2-month survival of 68%. At the end of one and two months, compared to baseline, there was significant improvement in median values of Maddreys DF (p<0.05). Median serum TNF-alpha levels decreased from 45 (range 11-19,880) at baseline to 20 (range 4-8600) pg/mL at 4 weeks (p=0.001). CRP levels, MELD score, and absolute neutrophil count decreased significantly. Five patients (26%) developed infection: three of them had pneumonia, while two developed a flare of pulmonary tuberculosis. Three patients recovered with treatment but two patients (10%) died (one with pneumonia leading to sepsis and the other of disseminated tuberculosis). Absence of hepatic encephalopathy at admission significantly predicted survival. Among patients who survived only 1/13 (8%) had hepatic encephalopathy at admission while among patients who died 4/6 (67%) had hepatic encephalopathy (p=0.017). Lille score and delta bilirubin at day 7 (DBD7) (defined as [baseline serum bilirubin minus serum bilirubin at day 7] x 100/baseline serum bilirubin), also predicted 2-month mortality. The area under ROC curve of DBD7 values for predicting survival was 0.77 (95% CI 0.55-0.99). DBD7 of >7.5% best predicted survival in the patients (sensitivity 85%, specificity 67%, PPV 85%, NPV 67%, and overall accuracy 79%).nnnCONCLUSIONSnIn severe AH, single dose infliximab is associated with improvement in parameters of severity and survival. However, infection remains a concern. Hepatic encephalopathy at admission, Lille score and DBD7 predicted 2-month mortality. Large randomized controlled trials are needed before infliximab can be recommended for AH.

Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis.

Background/Aims: Minimal hepatic encephalopathy (MHE) impairs health‐related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. However, not all patients respond to lactulose. We evaluated predictors of nonresponse to lactulose.

Minimal Hepatic Encephalopathy in Patients With Extrahepatic Portal Vein Obstruction

BACKGROUND AND AIMS:Minimal hepatic encephalopathy (MHE) is associated with poor quality of life and increased work disability in cirrhotic patients. Its prevalence in extrahepatic portal vein obstruction (EHPVO) is not known. We studied the prevalence of MHE in EHPVO patients and utility of critical flicker frequency (CFF) for diagnosing MHE.PATIENTS AND METHODS: Thirty-four EHPVO patients with a history of variceal bleed (age 23.2 ± 11.2 yr, M:F 22:12) diagnosed by either Doppler US or MR angiography, which demonstrated portal vein obstruction and/or portal vein cavernoma, were evaluated by psychometry (number connection tests A, B or figure connection tests A, B) and P300 auditory event-related potential (P300ERP). CFF was also evaluated. MHE was diagnosed by abnormal psychometry (>2 standard deviation [SD]) and/or P300ERP (>2.5 SD).RESULTS:Prevalence of MHE (N = 12) was 35.3%. Of 34 patients, P300ERP was abnormal (380.0 ± 28.9 msec) in 11 (32%), psychometry in 9 (26.4%), both P300ERP and psychometry in 8 (23.5%), and CFF <38 Hz in 7 (21%) patients. Six (67%) patients with abnormal psychometry and 7 (64%) with abnormal P300ERP had CFF below 38 Hz. CFF had sensitivity (75%), specificity (96%), positive predictive value (86%), negative predictive value (93%), and diagnosis accuracy of 91% when compared to patients with both abnormal psychometry and P300ERP. The venous ammonia level was higher in patients with MHE (83.1 ± 29.7 vs 44.7 ± 16.1 μmol/L, P < 0.001) compared to patients without MHE. Spontaneous shunts were present in 67% of patients with MHE compared to 14% of non-MHE patients. MHE was more common in patients with spontaneous shunts (72.7% vs 17.4%, P= 0.001) than without spontaneous shunts.CONCLUSIONS:Prevalence of MHE in EHPVO patients is 35.3%, and CFF alone can reliably diagnose 88% of MHE patients with both abnormal psychometry and P300ERP. However, in view of the relatively low number of patients with MHE, the usefulness of CFF in this setting awaits confirmatory studies.

Hemodynamic studies in acute-on-chronic liver failure.

Background Patients with decompensated cirrhosis and acute liver failure have circulatory dysfunctions leading to high portal pressure and cardiac output (CO) and low systemic vascular resistance (SVR). Circulatory changes in acute-on-chronic liver failure (ACLF) patients have not been studied. We studied the portal, systemic, and pulmonary hemodynamics in patients with ACLF and compared them with compensated and decompensated cirrhotics. Patients and Methods Clinical features and hemodynamic profile were studied in patients with ACLF and compared with age- and sex-matched compensated and decompensated cirrhotics with portal hypertension. Results The study cohort comprised 144 patients categorized into one of three groups (ACLF, compensated cirrhosis, and decompensated cirrhosis), with 48 (33%) patients in each group. All values are given as the mean ± standard deviation, except for frequencies (%). The mean arterial pressure (MAP) and SVR were lower in the ACLF than the compensated group and were similar to those of the decompensated group (MAP 90 ± 16 vs. 99 ± 15 vs. 96 ± 16xa0mmHg; SVR 912 ± 435 vs. 1350 ± 449 vs. 891 ± 333xa0dynxa0s/cm5). The mean CO of the ACLF patients was higher than that of the compensated group and similar to that of the decompensated group (CO 8.9 ± 3.5 vs. 6.1 ± 1.7 vs. 9.0 ± 3.0 l/min). The pulmonary vascular resistance (PVR) and pulmonary capillary wedge pressures (PCWP) were similar in all the three groups (PVR 78 ± 48 vs. 109 ± 70 vs. 61 ± 47xa0dynxa0s/cm5; PCWP 8 ± 4 vs. 8 ± 4 vs. 10 ± 5xa0mmHg). The mean hepatic venous pressure gradient (HVPG) in the ACLF group was 15.1 ± 6.3xa0mmHg, which was significantly higher than that of the compensated group (11.7 ± 6.3xa0mmHg), but lower than that of the decompensated cirrhosis group (20.2 ± 6.0xa0mmHg). When patients of ACLF were categorized on the basis of their variceal size, the mean HVPG in ACLF patients with small varices was similar to that of compensated cirrhotics (13.7 ± 5.7 vs. 11.7 ± 6.3xa0mmHg; Pxa0=xa00.146), while in the ACLF patients with large varices, the HVPG was comparable to that of the decompensated cirrhotics (18.7 ± 6.6 vs. 20.2 ± 6.0xa0mmHg; Pxa0=xa00.442). Conclusions The systemic hemodynamics in patients with ACLF is similar to that in decompensated cirrhotics. The portal pressure in these patients is higher than that in the compensated cirrhotics, and in the subgroup with large varices, it becomes similar to that of decompensated cirrhotics.

Natural History of Minimal Hepatic Encephalopathy in Patients With Extrahepatic Portal Vein Obstruction

OBJECTIVES:Minimal hepatic encephalopathy (MHE) leads to deterioration in patient quality of life and could be a marker for future episodes of clinical hepatic encephalopathy (HE) in liver cirrhosis. Whether MHE predicts HE in extrahepatic portal vein obstruction (EHPVO) is not known. We studied the incidence of overt HE in EHPVO patients with MHE.METHODS:Consecutive patients (from October 2006 to July 2007) with a diagnosis of EHPVO were followed up at 3-month intervals. MHE was diagnosed by abnormal psychometry (>2 s.d.) and/or P300 auditory event-related potential (P300 ERP) (>2.5 s.d.), and HE was diagnosed as per West-Heaven criteria. Critical flicker frequency (CFF) was also measured at baseline and after 1 year.RESULTS:Thirty-two EHPVO patients (age, 23.2±10.8 years; M/F 22:10) were followed up for 1 year. Of 32 patients, P300 ERP was prolonged in 8 (25%) (371.8±13.9u2009ms), 9 (28%) had abnormal psychometric tests, and CFF was <38u2009Hz in 8 (25%) patients after a follow-up of 13.5±2.4 months. Of 12 patients who had MHE at baseline, 9 (75%) patients continued to have MHE, and in 3 (25%) patients it disappeared. One (5%) of the remaining 20 patients developed MHE during the follow-up. Venous ammonia level was higher in patients with MHE (79.7±17.0u2009μmol/l; range 33–124) compared with patients without MHE (46.6±19.8u2009μmol/l; range 24–78, P<0.001) on follow-up. Similarly, patients who had spontaneous shunts (n=10) had significantly higher venous ammonia levels (82.4±20.3 vs. 47.1±16.7u2009μmol/l; P=0.001) than those who had no shunt (n=22). Neither patients who had MHE nor those who did not have MHE at baseline developed HE.CONCLUSIONS:Seventy-five percent of extrahepatic portal vein obstruction patients with MHE continued to have MHE, and new-onset MHE developed in 5% over 1 year. In this small sample, patients with EHPVO and MHE did not progress to overt encephalopathy within the relatively short time frame studied.

Predictors of nonresponse to lactulose in patients with cirrhosis and hepatic encephalopathy.

Background and aims Lactulose is commonly used in the treatment of hepatic encephalopathy (HE). However, all patients do not respond to lactulose. We evaluated predictors of nonresponse to lactulose in patients with cirrhosis and HE. Patients and methods Consecutive cirrhotic patients with HE were enrolled. HE was diagnosed by West Haven criteria. Patients were treated with lactulose and correction of any associated precipitating factors. Nonresponse was defined if patient remained in HE even after 10 days of treatment or died while in HE. Results Of 300 patients with cirrhosis and HE, 231 (77%) patients met the inclusion criteria. The majority (95%) of the patients had Grade 2 or 3 HE. Of 231 patients, 180 (78%) responded to lactulose. Fifty-one (22%) did not respond to lactulose, 34 (15%) died without any improvement in HE and HE did not improve in 17 (7%) patients after 10 days of therapy. On comparing baseline parameters between nonresponders versus responders there was significant difference between baseline age (42.0±11.9 vs. 46.6±12.7 year, P=0.02), total leukocyte count (median, 9300 vs. 7300u2009cells/mm3, P=0.001), serum sodium level (129.9±6.2 vs. 133.7±7.1u2009mmol/l, P=0.001), model for end stage liver disease (MELD) score (22.9±3.8 vs. 19.9±4.2, P=0.001), mean arterial pressure (MAP, 77.9±10.0 vs. 86.3±8.7u2009mmHg, P=0.001), serum AST (median, 114 vs. 76u2009IU/l, P=0.01), serum ALT (median, 84 vs. 48.5u2009IU/l, P=0.001), spontaneous bacterial peritonitis [18 (35%) vs. 37 (21%), P=0.02] and hepatocellular carcinoma [HCC, 17 (33%) vs. 14 (7%), P=0.001]. On multivariate analysis baseline total leukocyte count, MELD, MAP, and HCC were independent predictors of nonresponse to lactulose (P=0.001). Combination of low MAP, high MELD, and presence of HCC had diagnostic accuracy of 81% in predicting nonresponse to lactulose. Conclusion Of 78% patients with chronic liver disease with HE (majority with Grade 2 and 3) responded to lactulose. High baseline MELD, high total leukocyte count, low serum sodium, low MAP, and presence of hepatocellular carcinoma were predictors of nonresponse to lactulose.