Association of GST null genotypes with anti-tuberculosis drug induced hepatotoxicity in Western Indian population.

BACKGROUND: The first line anti-tubercular (anti-TB) treatment normally involves isoniazid, rifampicin, pyrazinamide, and ethambutol. Clearance of these drugs depends on the activity of several enzymes such as N-acetyl transferase 2, cytochrome P450 oxidase and glutathione S-transferase (GST). Some of these enzymes are highly polymorphic leading to significant inter-individual variation in their activity thereby increasing the risk of drug induced hepatotoxicity (DIH). AIM: To investigate the possible association of anti-TB DIH with genetic polymorphism of GST genes in Western Indian population. MATERIAL AND METHODS: A prospective case-control study was undertaken on patients who received anti-TB treatment. Cases (n = 50) were distinguished from controls (n = 246) based on occurrence of DIH during anti-tubercular treatment. A multiplex polymerase chain reaction was employed to identify homozygous null mutation at GSTM1 and GSTT1 loci. Results. Homozygous null mutation in GSTM1 gene alone or in both GSTM1 and T1 genes was found to be significantly associated with anti-TB DIH at p < 0.02 and p < 0.007, respectively, in our study population. CONCLUSIONS: This is the first study to report GSTM1 null and combined GSTM1 and T1 null genotypes to be risk factors of anti-TB DIH in Western Indian population. Screening of patients for these genotypes prior to anti-TB regimen would provide better control of hepatotoxicity.

Angiogenesis in chronic liver disease.

BACKGROUND: Chronic liver disease is characterized by inflammation and fibrosis. As a consequence angiogenesis leading to new vasculature may have prognostic value in disease progression. Interfering with angiogenesis may be a potential target to avoid progression of liver disease. Hence we planned to evaluate the CD34 and vascular endothelial growth factor (VEGF), the markers for angiogenesis in chronic liver disease. METHOD: Liver biopsies from 79 patients of chronic liver disease and 21 cases of HCC (M: F = 4:1, age range 22 to 80) were stained for routine HE, CD 34 and VEGF immunostaining (Dako Corp & Santa Cruz respectively). Etiologies of chronic liver disease were alcoholic liver disease, HBV, HCV infection, NAFLD, autoimmune liver disease, and cryptogenic liver disease. Thirty biopsies from normal liver obtained at autopsy were taken as controls. Expressions of CD 34 and VEGF were compared with the stage of fibrosis. RESULTS: Out of 79 patients, angiogenesis was seen in 45.5% cases of chronic liver disease. None of the case with normal liver histology was CD 34 or VEGF positive. No significant correlation of angiogenesis was found between any etiologies of chronic liver disease. CD 34 was positive in 18/21 (85.7%) cases of hepatocellular carcinoma. CD 34 and VEGF positivity was 20.9% and 46.5% in stage 1 and 2 fibrosis while it was 75% and 80% in stage 3 and 4 fibrosis respectively. VEGF appeared more common as compared to CD 34 in early fibrosis. CONCLUSION: Angiogenesis was present in 45.5% cases of chronic liver disease. It was proportional to the increase in stage of fibrosis. Expression of VEGF was commonly found in early stages of fibrosis. Hence, therapeutic strategies of inhibiting VEGF expression may be of importance in preventing the progression of chronic liver disease in its early stage.

Histological spectrum of liver in HIV - autopsy study.

INTRODUCTION: Liver abnormalities are common in HIV positive patients. They are usually part of generalized process and rarely produce significant liver failure. AIM: To evaluate histological spectrum of liver disease in HIV positive patients and to ascertain if any pathologic features are widespread among HIV infection. MATERIAL & METHODS: Autopsy data from year 1991 to 2003 consisting of 60 HIV positive patients were evaluated. Demographic profile, clinical and laboratory data were obtained from hospital records. Macroscopic findings of all organs at autopsy were noted. Histological features of liver were studied in detail using routine H & E., Ziehl-Neelson stain for acid fast bacilli and other special stains such as PAS and GMS for fungal infection were done whenever indicated. RESULTS: Patients were in age group 19 to 55 years with mean age of 32.1 year; male to female ratio was 4:1. Evidence of tuberculosis either pulmonary or extrapulmonary was found in 35 (58.3%) cases. On histological examination of liver, tubercular granulomas were seen in 19 (31.6%) cases of disseminated tuberculosis. Granulomas were typical caseating epitheloid cell type in 14 (73.6%) and in 5 cases granulomas were not typical. Acid fast bacilli were demonstrated in 4 (6.6%) cases, all of which showed presence of granulomas. Other histological findings were sinusoidal and centrivenular congestion in 14 (23.3%), extensive fatty change 6 (10%), portal inflammation resembling chronic hepatitis 5 (8.3%), focal necrosis 2 (3.3%), Kupffer cell hyperplasia 1 (1.6%) and metastasis from known case of adenocarcinoma of pancreas 1 (1.6%). Associated hepatitis C and B infections were seen in 4 (6.6%) and 1 (1.6%) respectively. Opportunistic infection was seen in only 1 (1.6%) case with disseminated cryptococcosis involving liver. In remaining 6 (10%) liver histology was normal. Considering cause of death, 58.3% patients died due to disseminated tuberculosis. Patients with associated hepatitis B & C infection died due to liver cirrhosis and the remaining died of miscellaneous conditions, which were not related to HIV infection. CONCLUSION: Histopathological findings of the liver in HIV positive patients were mainly non specific. Tuberculosis was the commonest infection noted. There was no significant mortality observed specifically related to liver involvement in these patients.