Radha K. Dhiman

Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis

Background and Aims: The natural history of subclinical hepatic encephalopathy (SHE) is unknown. The present study was conducted to study the prevalence and the natural history of SHE in patients with cirrhosis of the liver.

Herbal Medicines for Liver Diseases

Herbal medicines have been used in the treatment of liver diseases for a long time. A number of herbal preparations are available in the market. This article reviews four commonly used herbal preparations: (1) Phyllanthus, (2) Silybum marianum (milk thistle), (3) glycyrrhizin (licorice root extract), and (4) Liv 52 (mixture of herbs). Phyllanthus has a positive effect on clearance of HBV markers and there are no major adverse effects; there are no data from randomized controlled trials on clinically relevant outcomes, such as progression of chronic hepatitis to cirrhosis and/or liver cancer, and on survival. Silymarin does not reduce mortality and does not improve biochemistry and histology among patients with chronic liver disease; however, it appears to be safe and well tolerated. Stronger neominophagen C (SNMC) is a Japanese preparation that contains 0.2% glycyrrhizin, 0.1% cysteine, and 2% glyceine. SNMC does not have antiviral properties; it primarily acts as an anti-inflammatory or cytoprotective drug. It improves mortality in patients with subacute liver failure and improves liver functions in patients with subacute hepatic failure, chronic hepatitis, and cirrhosis with activity. SNMC does not reduce mortality among patients with cirrhosis with activity. SNMC may prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C, however, prospective data are lacking. Liv 52, an Ayurvedic hepatoprotective agent, is not useful in the management of alcohol-induced liver disease. Standardization of herbal medicines has been a problem and prospective, randomized, placebo-controlled clinical trials are lacking to support their efficacy. The methodological qualities of clinical trials of treatment with herbal preparations are poor. The efficacy of these herbal preparations need to be evaluated in rigorously designed, larger randomized, double-blind, placebo-controlled multicenter trials.

Diagnosis and Prognostic Significance of Minimal Hepatic Encephalopathy in Patients with Cirrhosis of Liver

Background and AimsMinimal hepatic encephalopathy is the mildest form of the spectrum of hepatic encephalopathy (HE) that impairs health-related quality of life. We assessed (1) the usefulness of psychometric hepatic encephalopathy score and critical flicker frequency for the diagnosis of minimal hepatic encephalopathy, and (2) prognostic significance of minimal hepatic encephalopathy.MethodsOne hundred patients with liver cirrhosis without overt HE were subjected to psychometric hepatic encephalopathy score and critical flicker frequency evaluation. Eighty-three age- and sex-matched healthy volunteers served as controls. Minimal hepatic encephalopathy was diagnosed when the psychometric hepatic encephalopathy score was ≤−5. An age-adjusted Z score <−2 on the critical flicker frequency was considered abnormal.ResultsForty-eight (48%) patients had minimal hepatic encephalopathy as indicated by altered psychometric hepatic encephalopathy score. Critical flicker frequency was altered in 21 patients; 17 also showed impaired psychometric hepatic encephalopathy score thus providing additional information in only 4 patients. Forty-six of 48 patients with minimal hepatic encephalopathy and 48 of 52 patients without minimal hepatic encephalopathy completed the follow-up. Eighteen (39.1%) patients died among those who had minimal hepatic encephalopathy compared to 11 (22.9%) patients who did not have minimal hepatic encephalopathy. Among the several variables analyzed in this study, univariate analyses showed that age, serum bilirubin level, Child-Turcotte-Pugh score and psychometric hepatic encephalopathy score were associated with a poor prognosis. The multivariate analysis identified two variables as significant independent prognostic factors; psychometric hepatic encephalopathy score ≤−6 [hazard ratio 2.419 (95% CI, 1.014–5.769)] and Child-Turcotte-Pugh score ≥8 [hazard ratio 2.466 (95% CI, 1.010–6.023)] predicted poor survival.ConclusionsPsychometric hepatic encephalopathy score is a useful tool for the diagnosis of minimal hepatic encephalopathy in an outpatient setting. Both psychometric hepatic encephalopathy score and Child-Turcotte-Pugh score have prognostic value on survival.

Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy

BACKGROUND & AIMS Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy. This cross-sectional study was carried out to elucidate the role of bacterial overgrowth of the small intestine and delayed intestinal transit among patients with MHE. METHODS Two-hundred-thirty patients with cirrhosis were screened; 102 patients (44.4%) who met the eligibility criteria were included in the study. MHE was diagnosed when the psychometric hepatic encephalopathy score was ≤-5. All patients underwent a glucose breath test for small intestinal bacterial overgrowth (SIBO) and lactulose breath test for oro-cecal transit time (OCTT). RESULTS Fifty-seven (55.9%) patients with cirrhosis had MHE. Among these patients with MHE, 22 (38.6%) had SIBO, while 4 (8.9%) without MHE had SIBO (p = 0.001). The prevalence of SIBO was higher in patients with CTP classes B and C (69.2%) compared to those in CTP class A (30.8%); p = 0.054. OCTT was significantly prolonged in patients who had SIBO than in those who did not have SIBO (p<0.0001). Univariate analysis demonstrated that increased age, female gender, low educational status, low albumin, presence of SIBO, and prolonged OCTT were associated with the presence of MHE. Multivariate analysis demonstrated SIBO as the only factor associated with MHE. CONCLUSIONS Our study conclusively demonstrates high prevalence of SIBO in patients with cirrhosis with MHE. This study gives the rationale of treatment directed against SIBO and gut dysmotility, which may include non-absorbable antibiotics such as rifaximin, probiotics, and prokinetics.

Portal hypertensive biliopathy

Extrahepatic portal venous obstruction (EHPVO) is a common cause of portal hypertension in the developing countries, and constitutes up to 40% of all patients with portal hypertension.1,2 EHPVO is a common cause of major upper-gastrointestinal bleeding among children.2–4 The most common presentation in children is well-tolerated variceal bleeding and splenomegaly. In adults, EHPVO is often recognised when evaluating for other disorders or with uncommon presentations such as jaundice, pruritus, acute cholecystitis-like syndrome, ascites and so on, resulting from prolonged portal hypertension.5–7 The portal vein in EHPVO is transformed into a cavernoma, which is a bunch of multiple collateral veins around the obstructed portion of portal vein (fig 1). Marked improvements in the management of variceal bleeding in patients with EHPVO have resulted in an improved survival, thus presenting with unusual symptoms in adulthood. Figure 1  Splenoportovenogram showing multiple collaterals (portal cavernoma) replacing the portal vein (arrows) in a patient with extrahepatic portal venous obstruction. The splenic vein is normal (arrowheads). The reasons for EHPVO are obscure in approximately half of the patients. Omphalitis and intra-abdominal sepsis are the common causes in neonates and children. Adults develop EHPVO due to increased blood coagulability, local inflammation, intra-abdominal sepsis, myeloproliferative disorders, underlying cirrhosis, or tumours in the liver, bile ducts or pancreas.7,8,9,10 Gibson et al 11 first reported the relationship between EHPVO and jaundice in 1965. Since then, several cases of obstructive jaundice due to common bile duct (CBD) obstruction caused by cavernomatous transformation of portal vein (portal cavernoma) have been described. Williams et al 12 were the first to report cholangiographic changes caused by choledochal varices. We, for the first time, describe abnormalities on endoscopic retrograde cholangiography (ERC) in a prospective study.13 These abnormalities were similar to those of primary sclerosing cholangitis and …

Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End‐Stage Liver Disease (MELD) and King's College Hospital Criteria

While Kings Hospital Criteria (KCH) criteria are used worldwide, the Model for End‐Stage Liver Disease (MELD) is a more recently developed scoring system that has been validated as an independent predictor of patient survival in conditions for liver transplantation (LT). The aim of the present study was to compare MELD and KCH criteria with other early clinical prognostic indicators (CPI) in a cohort of patients with fulminant hepatic failure (FHF). A total of 144 patients (mean age 31.7 ± 14.7 yr; range 12–82 yr; 62 males) with FHF due to acute viral hepatitis were included into the study. Variables found significant on univariate analysis were entered into a multivariate logistic regression analysis. A total of 52 (36.1%) patients survived, the remaining 92 (63.9%) died. Univariate analysis showed that age, duration of jaundice, jaundice‐encephalopathy interval (JEI), grade of encephalopathy, presence of cerebral edema, bilirubin, prothrombin time, creatinine, and MELD score were significantly different between survivors and nonsurvivors. Multivariate logistic regression identified 6 independent CPI of adverse outcome on admission: age ≥50 yr, JEI >7 days, grade 3 or 4 encephalopathy, presence of cerebral edema, prothrombin time ≥35 seconds, and creatinine ≥1.5 mg/dL. Presence of any 3 of 6 CPI was optimum in identifying survivors and nonsurvivors. A MELD score of ≥33 was found to be best discriminant between survivors and nonsurvivors by the construction of receiver operating characteristic (ROC) curves. Any 3 CPI were superior to MELD and KCH criteria in predicting the outcome (c‐statistic [95% confidence interval]: CPI 0.802 [0.726–0.878], MELD 0.717 [0.636–0.789], and KCH criteria 0.676 (0.588–0.764); P values: CPI vs. MELD 0.045, CPI vs. KCH criteria 0.019, and MELD vs. KCH criteria 0.472). In conclusion, MELD and KCH criteria are not as useful as a combination of other early CPI in predicting adverse outcome in patients with FHF due to acute viral hepatitis. Liver Transpl, 2007.

Probiotic VSL#3 Reduces Liver Disease Severity and Hospitalization in Patients With Cirrhosis: A Randomized, Controlled Trial

BACKGROUND & AIMS Little is known about whether probiotics can affect outcomes of patients with cirrhosis and hepatic encephalopathy (HE). We assessed the efficacy of a probiotic preparation in preventing the recurrence of HE (primary outcome) and reducing the number of hospitalizations and severity of liver disease in patients with cirrhosis. METHODS We performed a double-blind trial at a tertiary care hospital in India. Patients with cirrhosis who had recovered from an episode of HE during the previous month were assigned randomly (using computer-generated allocation) to groups given a probiotic preparation (VSL#3, 9 × 10(11) bacteria; CD Pharma India Private Limited, New Delhi, India) (n = 66) or placebo (n = 64) daily for 6 months. RESULTS There was a trend toward a reduction in the development of breakthrough HE among patients receiving the probiotic (34.8% in the probiotic group vs 51.6% in the placebo group; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.38-1.11; P = .12). Fewer patients in the probiotic group were hospitalized for HE (19.7% vs 42.2%, respectively; HR, 0.45; 95% CI, 0.23-0.87; P = .02) or for complications of cirrhosis (24.2%) than in the placebo group (45.3%) (HR, 0.52; 95% CI, 0.28-0.95; P = .034). Child-Turcotte-Pugh and model for end-stage liver disease scores improved significantly from baseline to 6 months in the probiotic group, but not in the placebo group. There were no adverse events related to VSL#3. CONCLUSIONS Over a 6-month period, daily intake of VSL#3 significantly reduced the risk of hospitalization for HE, as well as Child-Turcotte-Pugh and model for end-stage liver disease scores, in patients with cirrhosis. ClinicalTrials.gov number: NCT01110447.

Biliary changes in extrahepatic portal venous obstruction: Compression by collaterals or ischemic?

BACKGROUND The postulated mechanisms of biliary abnormalities in extrahepatic portal venous obstruction (EHPVO) are either extrinsic compression by collaterals or ischemic injury due to venous thrombosis. If the former hypothesis is correct, then biliary changes should revert to normal after portasystemic shunt surgery. METHODS Five patients with EHPVO who underwent portasystemic shunt surgery were studied. One of these patients had obstructive jaundice due to portal cavernoma. Endoscopic retrograde cholangiography (ERC) was performed before as well as after the shunt surgery. Doppler ultrasound and splenoportovenography were obtained to confirm the diagnosis of EHPVO as well as shunt patency. RESULTS All patients had biliary abnormalities on pre-shunt ERC. The post-shunt ERC showed partial reversal of biliary abnormalities in 3 patients, complete reversal in 1 patient, and no reversal in 1 patient. Smooth strictures opened after shunt surgery and proximal dilatation disappeared in most patients. The indentations and caliber irregularities disappeared after shunt surgery, whereas angulations and ectasias of biliary ducts persisted. CONCLUSION Shunt surgery results in regression of some of the biliary abnormalities and relieves biliary obstruction, suggesting that mechanical compression by collaterals is the mechanism behind biliary abnormalities in EHPVO. However, some biliary changes persist after shunt surgery signifying fixed obstruction due to ischemia or fibrous scarring. Thus, the two theories are not mutually exclusive.

Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy.

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the mildest form of spectrum of hepatic encephalopathy (HE). Patients with MHE have no recognizable clinical symptoms of HE but have mild cognitive and psychomotor deficits. The prevalence of MHE is high in patients with cirrhosis of liver and varies between 30% and 84%; it is higher in patients with poor liver function. The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests, and treatment of those patients diagnosed to have MHE has been recommended. Ammonia plays a key role in the pathogenesis of MHE, which is thought to be similar to that of overt HE. Thus, ammonia-lowering agents such as lactulose and probiotics have been tried. These agents have been shown to improve cognitive and psychometric deficits, and have good safety profile. Future studies will better define the role of other drugs, such as rifaximin, acetyl L-carnitine and L-ornithine L-aspartate.