Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for study of the liver

Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30-45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health-related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party

APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on “APASL consensus statements and recommendations for management of hepatitis C” in March 2015 to revise the “APASL consensus statements and management algorithms for hepatitis C virus infection” (Hepatol Int 6:409–435, 2012). The working party consisted of expert hepatologists from the Asian–Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review

Minimal hepatic encephalopathy in patients with extrahepatic portal vein obstruction

Background Minimal hepatic encephalopathy (MHE) is associated with poor quality of life and increased work And Aims: 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 Thirty-four EHPVO patients with a history of variceal bleed (age 23.2 ± 11.2 yr, M:F 22:12) diagnosed AND METHODS: 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

Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease

Background and Aim: Hepatitis E virus (HEV) has recently been implicated in episodes of acute decompensation in patients having underlying chronic liver disease (CLD) of varying etiology. However, HEV as a cause of acute exacerbation of previously asymptomatic and unrecognized hepatitis B virus (HBV)-infected patients is less well described. The aim of the present study was to investigate the etiology of acute exacerbation of previously asymptomatic and unrecognized HBV-infected patients and to evaluate the relative role of HEV. We also investigated the effect of superinfection on the clinical spectrum of underlying HBV infection. Methods: Forty-three patients presented with the following were retrospectively analyzed: (i) clinical features suggestive of acute hepatitis; (ii) with hepatitis B surface antigen (HBsAg) (+); (iii) IgM hepatitis B core antibody (IgM anti-HBc) (-); (iv) no previous history of liver disease; (v) no features suggestive of CLD at presentation; (vi) HBsAg remaining (+) for at least 12 months on follow up; and (vii) having a follow-up biopsy during the convalescent phase showing evidence of chronic hepatitis B. Results: Of the 43 patients, 21 were hepatitis e antigen (HBeAg) (+) (Gr.1) and 22 HBeAg (-) (Gr.2) at presentation. In Gr.1, only two (9.5%) had superinfection (both with hepatitis A virus), whereas in Gr.2, 11 (50%) had superinfection (27.3% hepatitis E, 13.6% hepatitis A and 9.1% both) (P = 0.007). In Gr.1, the remaining 19 (90.5%) patients had spontaneous exacerbation (immune clearance with spontaneous seroconversion) whereas in Gr.2, the remaining 11 (50%) had spontaneous exacerbation (due to reactivation). Overall, HEV superinfection contributed to 20% of acute exacerbation episodes and, in particular, 36% of episodes in initially HBeAg (-) patients. Time to alanine aminotransferase normalization was longer in patients with superinfection (n = 13) as compared to spontaneous exacerbation (n = 30) (median [range] 36 [8-48]vs 16 [6-36] weeks, P = 0.001). During convalescence, there was no significant difference between histological activity index score (median [range] 8 [4-11]vs 8 [4-16] weeks, P = 0.629) and fibrosis scores (median [range] 3.5 [1-4]vs 2 [1-4] weeks, P = 0.099] on liver biopsy after recovery among patients with acute exacerbation due to superinfection and spontaneous exacerbation. Conclusions: Acute exacerbations in HBeAg (+) patients are most often due to spontaneous viral activation, while in HBeAg (-) patients, superinfection with non-B hepatitis viruses and spontaneous viral activation are equally common. HEV is an important cause of acute exacerbation in previously asymptomatic and unrecognized patients with HBV-related CLD

Endoscopic biliary drainage for severe acute cholangitis in biliary obstruction as a result of malignant and benign diseases

Background and Aims: Endoscopic biliary drainage is an established mode of biliary decompression in patients with acute cholangitis as a result of biliary obstruction secondary to stones and benign strictures. However, there are no reports on endoscopic management of severe acute cholangitis caused by malignant conditions. We prospectively compared the efficacy of the endoscopic drainage for severe acute cholangitis in biliary obstruction as a result of malignant and benign diseases. Methods: Forty-three patients with severe acute cholangitis requiring urgent biliary drainage were included. Sixteen patients (mean age 58.2 ± 9.3 years; seven men, nine women) had biliary obstruction as a result of malignant diseases and 27 had benign biliary diseases (mean age 41.6 ± 14.3 years; nine men, 18 women). Indications for urgent drainage included any one of the following: temperature >38°C (n = 21), septic shock with systolic blood pressure <100 mmHg (n = 9), localized peritonism (n = 21), impaired consciousness (n = 6) and failure to improve within 72 h of conservative management (n = 13). After successful bile duct cannulation, patients received either a nasobiliary catheter (n = 38) or an in-dwelling stent (n = 5) with or without sphincterotomy for biliary drainage. Outcome measures included complications and clinical response. Results: Endoscopic drainage was established successfully in all the patients in both the groups. Clinical improvement after biliary drainage occurred in 94% patients (15/16) in the malignant group compared with 96% patients (26/27) in the benign group (P = not significant [NS]). Fever subsided at a median of 2.2 days in the malignant group and at 1 day in the benign group (P = NS). Normalization of leukocyte count was seen at a median of 6 days (range 1-17) and 2 days (range 1-5) days in the malignant group and the the benign group, respectively (P = NS). There were no endoscopic retrograde cholangiopancreatography-related complications. The mortality rate as a result of cholangitis was 4.6%, that is two of 43 patients (6.2% of the malignant group vs 3.7% of the benign group; P = NS). Conclusions: Endoscopic biliary drainage is equally effective in patients with severe acute cholangitis caused by either malignant or benign biliary diseases

Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis

Background and Aim: Inhibition of tumor necrosis factor (TNF)-α is a logical approach to manage patients with non-alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF-α and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH. Methods: Nine patients (mean age 31.6 ± 7.2 years) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxyfylline at a dosage of 400 mg t.i.d. for 12 months. Besides biochemical assessment, a repeat liver biopsy was performed and the degree of inflammation and fibrosis was compared. Results: After 12 months of therapy a significant reduction in ALT (111 ± 53 IU/L vs 45 ± 19 IU/L, P = 0.003) and aspartate aminotransferase (AST) (61 ± 27 IU/L vs 33 ± 12 IU/L, P = 0.005) levels was observed. Steatosis and lobular inflammation each reduced in 55% and six (67%) patients down-staged on Brunt's staging (P = 0.009). Four out of six patients with baseline fibrosis had reduction in their fibrosis stage. Conclusions: Long-term pentoxyfylline therapy effectively achieves sustained biochemical improvement. This correlates well with histological resolution of the disease

Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding

Background and Aims: The role of propranolol in addition to EVL in the prevention of first variceal bleed has not been evaluated. This prospective randomized controlled trial compared endoscopic variceal ligation (EVL) with propranolol and EVL alone in the prevention of first variceal bleed among patients with high-risk varices. Patients and Methods: One hundred and forty-four consecutive patients with high-risk varices were randomly allocated to EVL plus propranolol (Gr I, n = 72) or EVL alone (Gr II, n = 72). EVL was done at 2-wk interval till obliteration of varices. In Gr I, incremental dosage of propranolol (sufficient to reduce heart rate to 55 beats/min or 25% reduction from baseline) was administered and continued after obliteration of varices. The endpoints of the study were bleeding and death. Results: The two groups of patients had comparable baseline characteristics; follow-up (Gr I: 13.1 ± 11.5 months, Gr II: 11.2 ± 9.9 months), number of cirrhotic and noncirrhotic portal hypertension patients [Gr I 64 (88.6%) and 8 (11.4%), Gr II 63 (87.5%) and 9 (12.5%)], and frequency of Child's A (15 vs 18), B (38 vs 35), and C (19 vs 19). The mean daily propranolol dose achieved in Gr I was 95.6 ± 38.6 mg. Eleven patients had bleeds, 5 in Gr I and 6 in Gr II. All patients bled before the obliteration of varices, the actuarial probability of first bleed at 20 months was 7% in Gr I and 11% in Gr II (p= 0.72). Six patients died in the combination and 8 in EVL group. All deaths in Gr I were due to nonbleed-related causes, while in Gr II, 2 deaths were bleed related, the actuarial probability of death at 20 months was 8% and 15%, respectively (p= 0.37). The probability of bleed-related death was comparable (p= 0.15). At the end of follow-up, 4 patients in Gr I and 11 in Gr II had recurrence of varices (p= 0.03). Side effects on propranolol were seen in 22% patients, in 8% it had to be stopped. There were no serious complications of EVL. Conclusions: Both EVL plus propranolol and EVL alone are effective in primary prophylaxis of bleed from high-risk varices. Addition of propranolol does not decrease the probability of first bleed or death in patients on EVL. However, the recurrence of varices is lower if propranolol is added to EVL

High dose vitamin K3 infusion in advanced hepatocellular carcinoma

Background and Aim: The survival of patients with unresectable advanced hepatocellular carcinoma (HCC) with portal vein thrombosis is dismal. Current therapeutic options have limited efficacy. Vitamin K has been shown to have antitumor effect on HCC cells both in cell lines and patients with advanced HCC. The aim of this study was to assess the clinical efficacy of high dose vitamin K3 in the treatment of advanced HCC with portal vein thrombosis. Methods: Forty-two consecutive patients with advanced HCC (Stage C according to BCLC staging system) with portal vein thrombosis were randomized into two groups: (i) high dose vitamin K3 (n = 23); and (ii) placebo (n = 19). The vitamin K3 was administered by i.v. infusion of 50 mg/day with daily increase of dose by 50 mg for 6 days, followed by 20 mg i.m. twice daily for 2 weeks. Results: Of the 23 patients treated with vitamin K, one (4.3%) achieved complete response and three (13%) partial response, for a total of four (17.4%) objective responders overall. The overall mean survival was 8.9 ± 8.8 months (median: 6; range 1-37 months) in the vitamin K group and 6.8 ± 5.3 months (median: 5; range 1.5-21 months) in the placebo group (P = 0.552). The mean duration of survival was longer in patients in the vitamin K group who achieved objective response (22.5 ± 12.2; median: 21; range 11-37 months) as compared to patients not achieving objective response (6.1 ± 4.6; median: 5; range 1-16 months) (P = 0.0.002). Portal vein thrombosis resolved with complete patency in one (4.35%) patient. Conclusions: Treatment with high dose vitamin K produces objective response in 17% patients with improved survival in patients achieving objective response; however, it does not affect the overall survival

Antiviral therapy in advanced chronic liver disease due to hepatitis C virus infection: pilot study

Background: Antiviral therapy has not been adequately evaluated in patients with hepatitis C virus (HCV)-related advanced liver disease due to apprehensions of adverse events and intolerance. The titrable dose of interferon (IFN)-α and ribavirin was evaluated in a flexible regimen in a pilot study. Methods: Twenty-five patients with HCV-related advanced chronic liver disease received IFN-α 1-3 MIU daily with ribavirin 200-600 mg daily for 9 months-3 years. Careful assessment of safety, tolerability and efficacy was made. Results: Improvement in Child-Pugh score (8.4 ± 1.2 to 7.4 ± 2.0; P = 0.010) and serum albumin (3.0 ± 0.5 g/dL to 3.6 ± 0.5 g/dL; P = 0.007) occurred at follow up after antiviral therapy (median dose and duration: IFN-α 1.5 MIU/day for 12 months and ribavirin 400 mg/day for 7.5 months) as compared to baseline. Ascites regressed in 53% of patients (11/21). Thirteen patients (52%) lost HCV-RNA on therapy and eight (32%) achieved sustained virological response (SVR). Death occurred in three patients (12%) while on therapy, in two due to infection. No patient died in the responder group compared to five deaths (29%) in the non-responder group. However, there was no difference in the cumulative probability of survival in the sustained virological responder versus non-responder (P = 0.09). Adverse events were common (92%), but permanent withdrawal was required in only five patients (20%). Conclusions: Low and titrable dose IFN-α and ribavirin therapy in patients with HCV-related advanced chronic liver disease achieves improvement in hepatic synthetic function, Child-Pugh score and ascites. However, close monitoring for serious adverse events is warranted

Beneficial effects of tumor necrosis factor-α inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis

Background: Tumor necrosis factor-&#945; (TNF- &#945;) has been incriminated to play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Pentoxifylline, a TNF-&#945; inhibitor could prove useful in treating patients with NASH. Methods: Eighteen patients (mean age, 34 &#177; 7.8 yr) with histologically proven NASH and with persistently elevated ALT (&gt;1.5 times) were given pentoxifylline at a dosage of 400 mg t.i.d. for 6 months. No lipid-lowering agent or antioxidants were concurrently advised. Results: Impaired fasting glycemia, impaired glucose tolerance, diabetes mellitus, and hypertriglyceridemia were noted in 6, 35, 17, and 53% of the patients, respectively. After 6 months of therapy, fatigue improved (55.6 vs 20%, P = 0.016), but serum triglyceride (182 &#177; 66 vs 160 &#177; 55 mg/dl, P = 0.397), cholesterol (173 &#177; 46 vs 162 &#177; 40 mg/dl, P = 0.440), and body mass index (BMI) (27.3 &#177; 3.1 vs 26 &#177;3.1 kg/m<SUP>2</SUP>, P = 0.087) remained unchanged. Mean AST (66 &#177; 29 vs 33 &#177; 11 IU/l, p &lt; 0.0001) and ALT (109 &#177; 44 vs 47 &#177; 20 IU/l, p &lt; 0.0001) reduced significantly. ALT normalized in 23% at month 1 (P = 0.125), 35% at month 2 (P = 0.125), and 60% at month 6 (P = 0.008) of treatment. The insulin resistance index assessed by homeostatic metabolic assessment (HOMA<SUB>IR</SUB>) improved (5.1 &#177; 3.4 vs 2.6 &#177; 2, p = 0.046) and the serum TNF-&#945;reduced significantly after therapy (22.15 &#177; 2.49 vs 17 &#177; 2.58 pg/ml, p = 0.011). The drug was well tolerated. Conclusion: In patients with NASH, pentoxifylline therapy effectively achieved significant clinical and biochemical improvement with reduction in HOMA<SUB>IR</SUB>. These benefits are possibly mediated through suppression of TNF- &#945;