Amal Santra

Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.

There is a paucity of community‐based epidemiological data on nonalcoholic fatty liver (NAFL) among nonaffluent populations in developing countries. Available studies are radiological and/or biochemical and lack histological assessment, limiting their strength. We conducted a prospective epidemiological study comprising a 1:3 subsample of all adult (>18 years) inhabitants of a rural administrative unit of West Bengal, India. Subjects positive for hepatitis B virus and/or hepatitis C virus infection and consuming any amount of alcohol were excluded. Diagnosis of NAFL was by dual radiological screening protocol consisting of ultrasonographic and computed tomographic examination of the liver. Transient elastographic examination and liver biopsy were performed in a subset to identify significant liver disease. The risk factors of having NAFL were analyzed. A total of 1,911 individuals were analyzed, 7% of whom were overweight and 11% of whom had abdominal obesity. The prevalence of NAFL, NAFL with elevated alanine aminotransferase, and cryptogenic cirrhosis was 8.7%, 2.3%, and 0.2%, respectively. Seventy‐five percent of NAFL subjects had a body mass index (BMI) <25 kg/m2, and 54% were neither overweight nor had abdominal obesity. The subjects with the highest risk of having NAFL were those with a BMI >25 kg/m2 (odds ratio 4.3, 95% confidence interval 1.6‐11.5). Abdominal obesity, dysglycemia (fasting plasma glucose >100 mg/dL or elevated homeostatic model assessment of insulin resistance), and higher income were the other risk factors. Even having a normal BMI (18.5‐24.9 kg/m2) was associated with a 2‐fold increased risk of NAFL versus those with a BMI <18.5 kg/m2. Conclusion: There is a significant prevalence of NAFL and potentially significant liver disease, including cryptogenic cirrhosis, in this predominantly nonobese, nonaffluent population in a developing country. NAFL will be a major determinant of future liver disease burden in countries of the developing world. (HEPATOLOGY 2010)

Distinctiveness of genotypes of Helicobacter pylori in Calcutta, India.

The genotypes of 78 strains of Helicobacter pylori from Calcutta, India (55 from ulcer patients and 23 from more-benign infections), were studied, with a focus on putative virulence genes and neutral DNA markers that were likely to be phylogenetically informative. PCR tests indicated that 80 to 90% of Calcutta strains carried the cag pathogenicity island (PAI) and potentially toxigenic vacAs1 alleles of the vacuolating cytotoxin gene (vacA), independent of disease status. This was higher than in the West (where cag PAI(+) vacAs1 genotypes are disease associated) but lower than in east Asia. The iceA2 gene was weakly disease associated in Calcutta, whereas in the West the alternative but unrelated iceA1 gene at the same locus is weakly disease associated. DNA sequence motifs of vacAm1 (middle region) alleles formed a cluster that was distinct from those of east Asia and the West, whereas the cagA sequences of Calcutta and Western strains were closely related. An internal deletion found in 20% of Calcutta iceA1 genes was not seen in any of approximately 200 strains studied from other geographic regions and thus seemed to be unique to this H. pylori population. Two mobile DNAs that were rare in east Asian strains were also common in Calcutta. About 90% of Calcutta strains were metronidazole resistant. These findings support the idea that H. pylori gene pools differ regionally and emphasize the potential importance of studies of Indian and other non-Western H. pylori populations in developing a global understanding of this gastric pathogen and associated disease.

Arsenic in Drinking Water and Skin Lesions: Dose-Response Data from West Bengal, India

Background. Over 6 million people live in areas of West Bengal, India, where groundwater sources are contaminated with naturally occurring arsenic. The key objective of this nested case-control study was to characterize the dose-response relation between low arsenic concentrations in drinking water and arsenic-induced skin keratoses and hyperpigmentation. Methods. We selected cases (persons with arsenic-induced skin lesions) and age- and sex-matched controls from participants in a 1995–1996 cross-sectional survey in West Bengal. We used a detailed assessment of arsenic exposure that covered at least 20 years. Participants were reexamined between 1998 and 2000. Consensus agreement by four physicians reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases clinically diagnosed in the field. Results. The average peak arsenic concentration in drinking water was 325 &mgr;g/liter for cases and 180 &mgr;g/liter for controls. The average latency for skin lesions was 23 years from first exposure. We found strong dose-response gradients with both peak and average arsenic water concentrations. Conclusions. The lowest peak arsenic ingested by a confirmed case was 115 &mgr;g/liter. Confirmation of case diagnosis and intensive longitudinal exposure assessment provide the basis for a detailed dose-response evaluation of arsenic-caused skin lesions.

Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation

Background: Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)‐induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N‐acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S‐transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD‐induced hepatotoxicity.

Hepatic Damage Caused by Chronic Arsenic Toxicity in Experimental Animals

Objective: Noncirrhotic fibrosis of the liver is common in subjects chronically consuming ground water geologically contaminated with arsenic, but the mechanism of the hepatic fibrosis is not known. Because lipid peroxidation has been implicated in the development of several other forms of hepatic fibrosis, including iron and copper overload, we have explored the roles of oxidative stress and lipid peroxidation in the causation of hepatic fibrosis in a murine model of chronic arsenic toxicity. Methods: Male BALB/c mice were given drinking water contaminated with arsenic (3.2 mg/L) or arsenic-free (<0.01 mg/L, control) ad libitum. Mice were sacrificed at 3, 6, 9, 12, and 15 months for examination of hepatic histology and assays of hepatic reduced glutathione content, lipid peroxidation, enzymes of the antioxidant defense system, and membrane-bound sodium/potassium ATPase (Na+/K+ ATPase). Results: After 12 months of arsenic feeding, the liver weights increased significantly as did serum aspartate aminotransferase and alanine aminotransferase. After 6 months of arsenic feeding, hepatic glutathione and the enzymes glucose-6-phosphate dehydrogenase and glutathione peroxidase were significantly lower than those of the control group. Hepatic catalase activity was significantly reduced at 9 months in the arsenic-fed group, while glutathione-S-transferase and glutathione reductase activities were also significantly reduced at 12 and 15 months. Plasma membrane Na+/K+ ATPase activity was reduced after 6 months while lipid peroxidation increased significantly after 6 months of arsenic feeding. Liver histology remained normal for the first 9 months, but showed fatty infiltration after 12 months of arsenic feeding. Histologic evidence of fibrosis was observed after 15 months. Conclusion: We have demonstrated hepatic fibrosis due to long-term arsenic toxicity in an animal model. Initial biochemical evidence of hepatic membrane damage, probably due to reduction of glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic feeding resulted in fatty liver with serum aminotransferase and alanine aminotransferase elevated at 12 months and hepatic fibrosis at 15 months. The murine model is proposed as relevant to epidemic human toxicity in areas of arsenic contamination.

Endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleed: Preliminary report of a randomized controlled trial

Background: Prevention of variceal bleeding, a major cause of morbidity and mortality, is an important goal in the management of patients with portal hypertension (PHT). Although propranolol has been found useful in preventing the first episode of variceal bleeding (primary prophylaxis) in cirrhotic PHT, it has limitations which include side effects, contraindications, non‐compliance and failure in some patients. Endoscopic variceal ligation (EVL) has not been used for primary prophylaxis.

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.

Randomized Placebo-Controlled Trial of 2,3-Dimercaptosuccinic Acid in Therapy of Chronic Arsenicosis Due to Drinking Arsenic-Contaminated Subsoil Water

INTRODUCTION Chronic arsenic toxicity producing various clinical manifestations is currently epidemic in West Bengal, India, Bangladesh, and other regions of the world. Animal studies have indicated that 2,3-dimercaptosuccinic acid can be used as an oral chelating agent. A prospective, double-blind, randomized controlled trial was carried out to evaluate the efficacy and safety of 2,3-dimercaptosuccinic acid for chronic arsenicosis due to drinking arsenic-contaminated (> or = 50 micrograms/L) subsoil water in West Bengal. METHOD Twenty-one consecutive patients with chronic arsenicosis were individually randomized (random number; assignment made by individual not evaluating patients) into 2 groups: 11 patients (10 male, age 25.5 +/- 8 years) received 2,3-dimercaptosuccinic acid 1400 mg/d (1000 mg/m2) in the first week and 1050 mg/d (750 mg/m2) during the next 2 weeks with a repeat course 3 weeks later. The other 10 patients (all male, age 32.2 +/- 9.7 years) were given placebo capsules for the same schedule. The clinical features were evaluated by an objective scoring system before and after treatment. Routine investigations including liver function tests, arsenic concentrations in urine, hair, and nails, and skin biopsy evaluations were also completed. RESULTS Though there was improvement in the clinical score of 2,3-dimercaptosuccinic acid-treated patients, similar improvement was observed in the placebo-treated group. There were no statistical differences in the clinical scores between the 2 groups at the beginning and at the end of treatment. Similarly, no differences were found for the other investigated parameters. CONCLUSION Under the conditions of this study, 2,3-dimercaptosuccinic acid was not effective in producing any clinical or biochemical benefit or any histopathological improvement of skin lesions in patients with chronic arsenicosis.

Non-cancer effects of chronic arsenicosis with special reference to liver damage

Patients from the affected area in West Bengal, India, have been treated at our institute since 1983. This chapter presents data on the basis of studies on 156 patients. Eleven patients who stopped drinking arsenic-contaminated water for 12 years were re-examined and the results are also presented.

Multiplex PCR Assay for Rapid Detection and Genotyping of Helicobacter pylori Directly from Biopsy Specimens

ABSTRACT We developed and evaluated a simple, novel multiplex PCR assay for rapid detection of Helicobacter pylori infection and for the determination of vacA and cagA genotypes directly from gastric biopsy specimens. This assay did not require culturing of strains or extraction of DNA from biopsy samples. This multiplex PCR assay would be of particularly great value for laboratories in developing countries.