Excess zinc and progressive cholestasis: a new disease?
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Animals↗
Biomedical subjects
S K Acharya
Publications and source records attributed to S K Acharya.
Genotype determination of hepatitis C virus from northern India: identification of a new subtype.
Hepatitis C virus (HCV) shows substantial nucleotide sequence diversity distributed throughout the viral genome, with many variants showing only 68-79% overall sequence homology. This has led to problems in diagnosis of HCV using commercial immunoassays. Based on clustering of homologous sequences, various genotypes and subtypes of HCV have been described from different geographical regions. In the present study, 11 isolates from India were genotyped using sequence comparison for part of the non-structural (NS5) and structural (core) regions. Parts of the genome covering 451 bp (nt 9-459) of the core gene and a 249 bp fragment (nt 7959-8207) of the NS5 gene were reverse transcribed and amplified using nested polymerase chain reaction (RT-PCR). The amplified fragments were cloned and sequenced. The classification into genotypes was done on the basis of phylogenetic analysis. Four isolates showed sequence homology to type 1b. Two of the isolates were classified as type 3a. One isolate was classified as type 3b and the remaining four isolates were found to be variants of type 3 but did not belong to any designated subtype. On the basis of phylogenetic analysis two of the unclassified isolates were put into a new subtype of 3 named as 3g. In one of these variants, parts of a 5'-noncoding (5' NCR; 204 bp), envelope-E1 (435 bp), and NS3 (502 bp) regions were also amplified, cloned, and sequenced. This study demonstrates the type 3 variants including a new subtype (3g) to be the major cause of HCV infection in India.
Amino Acid Sequence↗
Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome.
The profiles of patients with fulminant hepatic failure (FHF) from developing countries have not been reported earlier. The current study was conducted prospectively, at a single tertiary care center in India, to document the demographic and clinical characteristics, natural course, and causative profile of patients with FHF as well as to define simple prognostic markers in these patients. Four hundred twenty-three consecutive patients with FHF admitted from January 1987 to June 1993 were included in the study. Each patient's serum was tested for various hepatotropic viruses. Univariate Cox's regression for 28 variables, multivariate Cox's proportional hazard regression, stepwise logistic regression, and Kaplan-Meier survival analysis were done to identify independent predictors of outcome at admission. All patients presented with encephalopathy within 4 weeks of onset of symptoms. Hepatotropic viruses were the likely cause in most of these patients. Hepatitis A (HAV), hepatitis B (HBV), hepatitis D (HDV) viruses, and antitubercular drugs could be implicated as the cause of FHF in 1.7% (n= 7), 28% (n= 117), 3.8% (n= 16), and 4.5% (n= 19) patients, respectively. In the remaining 62% (n= 264) of patients the serological evidence of HAV, HBV, or HDV infection was lacking, and none of them had ingested hepatotoxins. FHF was presumed to be caused by non-A, non-B virus(es) infection. Sera of 50 patients from the latter group were tested for hepatitis E virus (HEV) RNA and HCV RNA. In 31 (62%), HEV could be implicated as the causative agent, and isolated HCV RNA could be detected in 7 (19%). Two hundred eighty eight (66%) patients died. Approximately 75% of those who died did so within 72 hours of hospitalisation. One quarter of the female patients with FHF were pregnant. Mortality among pregnant females, nonpregnant females, and male patients with FHF was similar (P > .1). Univariate analysis showed that age, size of the liver assessed by percussion, grade of coma, presence of clinical features of cerebral edema, presence of infection, serum bilirubin, and prothrombin time prolongation over controls at admission were related to survival (P < .01). The rapidity of onset of encephalopathy and cause of FHF did not influence the outcome. Cox's proportional hazard regression showed age > or = 40 years, presence of cerebral edema, serum bilirubin > or = 15 mg/dL, and prothrombin time prolongation of 25 seconds or more over controls were independent predictors of outcome. Ninety-three percent of the patients with three or more of the above prognostic markers died. The sensitivity, specificity, positive predictive value, and the negative predictive value of the presence of three or more of these prognostic factors for mortality was 93%, 80%, 86%, and 89.5%, respectively, with a diagnostic accuracy of 87.3%. We conclude that most of our patients with FHF might have been caused by hepatotropic viral infection, and non-A, non-B virus(es) seems to be the dominant hepatotropic viral infection among these patients. They presented with encephalopathy within 4 weeks of the onset of symptoms. Pregnancy, cause, and rapidity of onset of encephalopathy did not influence survival. The prognostic model developed in the current study is simple and can be performed at admission.
Adolescent↗
Polycythemia vera: overt to latent form in a patient with Budd-Chiari syndrome.
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Adult↗
Hepatitis D virus (HDV) infection in severe forms of liver diseases in north India.
BACKGROUND: Preliminary reports indicate that hepatitis D virus (HDV) infection exists in India. However, its prevalence in patients with different types of liver diseases has not been studied in detail. The aim of this study was to evaluate the status of HDV infection in severe types of liver disease in India. METHODS: Using commercial kits for various hepatitis viral markers, the present study was undertaken to determine the serological status of hepatitis B virus (HBV) and hepatitis D virus (HDV) markers in 208 patients with severe liver diseases. This total included 110 cases with fulminant hepatic failure (FHF), 65 cases with subacute hepatic failure (SHF) and 33 cases with chronic active hepatitis (CAH). RESULTS: The hepatitis B surface antigen (HBsAg) carrier population, indicated by the presence of HBsAg without IgM anti-HBc (hepatitis B core) in serum, was recorded in 23.6%, 24.6% and 60.6% cases of FHF, SHF and CAH groups, respectively. HBV infection, as indicated by serum positivity of IgM anti-HBc in the FHF and SHF groups and HBsAg and/or IgM anti-HBc in the CAH group, was detected in 19.1%, 23.1% and 69.7% of cases from these three groups, respectively. IgM anti-HDV, demonstrating active/recent HDV infection, was found in 8.1% cases of FHF and 9.2% cases of SHF patients. HDV as a superinfection in HBsAg carriers was noted in 4.5% and 4.6% cases, respectively of FHF and SHF groups. Similarly, HDV-HBV coinfection, diagnosed by simultaneous presence of IgM anti-HBc and IgM anti-HDV in the FHF and SHF groups, was recorded in 3.6% and 4.6% of cases from these two groups, respectively. In the CAH group, HDV infection was observed in 9.2% cases. CONCLUSION: HDV infection, recorded in less than 10% of patients with different liver diseases in India, seems to be an unimportant factor in inducing severe liver diseases in this country.
Hepatitis D↗
Epidemiology of hepatitis B virus infection in India.
The average estimated carrier rate of hepatitis B virus (HBV) in India is 4%, with a total pool of approximately 36 million carriers. Wide variations in social, economic, and health factors in different regions may explain variations in carrier rates from one part of the country to another. Professional blood donors constitute the major high risk group for HBV infection in India, with a hepatitis B surface antigen positivity rate of 14%. Blood transfusions represent the most important route of HBV transmission among adults. However, most of India's carrier pool is established in early childhood, predominantly by horizontal spread due to crowded living conditions and poor hygiene. Acute and subacute liver failure are common complications of viral hepatitis in India and HBV is reckoned to be the aetiological agent in 42% and 45% of adult cases, respectively. HBV is reported to be responsible for 70% of cases of chronic hepatitis and 80% of cases of cirrhosis of the liver. About 60% of patients with hepatocellular carcinoma are HBV marker positive. Small numbers of patients have been reported to be infected with the pre-core mutant virus but none with the S mutant. Coinfection with hepatitis C virus or hepatitis delta virus is comparatively uncommon. In conclusion, hepatitis B is a major public health problem in India and will continue to be until appropriate nationwide vaccination programmes and other control measures are established.
Hepatitis B↗
Protracted viremia during acute sporadic hepatitis E virus infection.
BACKGROUND/AIMS: Hepatitis E virus (HEV) is associated with epidemic and sporadic hepatitis in developing countries. The disease is largely self-limited with no long-term sequelae. The source of HEV for maintenance of the disease in an endemic area is unknown. This study investigated the occurrence and duration of viremia in patients with acute sporadic HEV infection. METHODS: In 26 of 37 patients with sporadic acute non-A, non-B viral hepatitis, HEV infection was diagnosed based on positivity for immunoglobulin M anti-HEV and/or presence of viremia as shown by reverse-transcription polymerase chain reaction. In 4 patients, fecal samples were analyzed for presence of virus using polymerase chain reaction. Multiple samples were studied at varying times in 20 patients. RESULTS: Viremia was detected in 19 of 26 patients. Two patients had viremia in the absence of immunoglobulin M anti-HEV. Four patients had protracted viremia of 45-112 days' duration. One patient showed fecal virus shedding up to the 52nd day of illness. CONCLUSIONS: Protracted viremia and prolonged fecal shedding of HEV were shown in a small group of patients. These patients may serve as temporary virus carriers responsible for continuous contamination of the sewage water.
Acute Disease↗
Prospective study of plasma fibronectin in fulminant hepatitis: association with infection and mortality.
BACKGROUND/AIMS: Plasma fibronectin is an opsonic glycoprotein, normally synthesized by the liver, which decreases subsequent to severe liver damage and low levels of which may contribute to reticuloendothelial system dysfunction by compromising opsonic activity. This may result in an increased frequency of infection and death. The present study was conducted to evaluate the association of plasma fibronectin activity with infection and mortality in patients with fulminant hepatic failure. METHODS: Plasma fibronectin was estimated serially in 69 consecutive patients with fulminant hepatic failure, nine patients with uncomplicated acute viral hepatitis and 32 normal volunteers. RESULTS: Plasma fibronectin levels in patients with fulminant hepatic failure (85.6 +/- 75.8 micrograms/ml) were significantly lower than in patients with uncomplicated acute viral hepatitis (295.5 +/- 88.5 micrograms/ml) and healthy volunteers (362.6 +/- 69.2 micrograms/ml). Forty-nine (72%) patients with fulminant hepatic failure died. The initial values of fibronectin in fulminant hepatic failure did not correlate with mortality. Patients with fulminant hepatic failure who survived showed a progressive rise in the fibronectin levels compared to the absence of an increase in fibronectin levels in the non-survivors. The mortality in patients with fulminant hepatic failure with infection (24/27) was significantly higher (p < 0.05) compared to those without infection (25/42). Initial fibronectin levels in patients with infection (70.3 +/- 54.2 micrograms/ml) were significantly lower (p < 0.05) than in those without infection (92.3 +/- 64.4 micrograms/ml). We conclude that plasma fibronectin levels in patients with fulminant hepatic failure are decreased compared to healthy subjects and the absence of an increase in levels indicates a poor prognosis. Low levels of fibronectin are associated with an increased incidence of infection, which increases the mortality in these patients.
Adolescent↗
Prevalence of hepatitis C virus antibodies in the general population & in selected groups of patients in Delhi.
We report on the prevalence of anti-HCV antibodies in healthy individuals and patient groups with different liver diseases. The healthy population comprising 234 voluntary blood donors and 65 pregnant women with no history of liver diseases, had a per cent positivity of 1.5 anti-HCV in each group. The patients groups comprising 32 with acute viral hepatitis, 110 with fulminant hepatic failure, 65 with subacute hepatic failure, 33 with chronic active hepatitis, 45 with cirrhosis and 10 with hepatocellular carcinoma, had anti-HCV per cent positivity of 12.5, 43.6, 41.5, 48.5, 8.8 and 0 respectively. Anti-HCV was also tested in sera from 9 patients who had developed post-transfusion hepatitis and was recorded in 2 (22.2%) within one year of transfusion.
Blood Donors↗
Etiological role of hepatitis E virus in sporadic fulminant hepatitis.
Non-A, non-B hepatitis viruses have been implicated as the etiological agent(s) in up to 60% of patients with fulminant hepatitis. These agents are reported to induce a higher mortality than other causes of fulminant hepatitis. Hepatitis E virus (HEV) and hepatitis C virus (HCV) at present constitute the major identifiable non-A, non-B hepatitis agents. Of these, HEV has been established as the sole cause of epidemic hepatitis in Afro-Asian countries, and fulminant hepatitis has been recorded during such epidemics. However, in sporadic cases, the etiological role of HEV in fulminant hepatitis has remained uncertain. The role of HCV in acute liver disease and fulminant hepatitis remains unclear. The present study was undertaken to investigate the association of HEV and HCV in patients with fulminant hepatitis by direct detection of the viral genome using reverse transcription-polymerase chain reaction (RT-PCR). Serum samples from 50 serologically identified non-A, non-B fulminant hepatitis cases negative for cryptic hepatitis B virus (HBV) infection examined via PCR were tested for HEV and HCV RNA using RT-PCR. For HEV primers from the nonstructural region (ORF-1) were used, and for HCV primers from the highly conserved 5' untranslated regions were used. The products were analysed using agarose gel electrophoresis and confirmed by hybridisation with radiolabelled internal oligonucleotide probes. HEV was detected in 31 (62%) of the 50 fulminant non-A, non-B hepatitis cases. In 18 (36%) cases, HCV RNA was detected. In 11 (22%) of the HCV cases, the HEV genome was also amplified. In 20 (40%) cases, HEV was detected alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Diagnosis of hepatitis C virus-associated chronic liver disease in India: comparison of HCV antibody assay with a polymerase chain reaction for the 5' noncoding region.
The relative value of an anti-hepatitis C virus (HCV) serological assay and reverse transcriptase-nested polymerase chain reaction assays (RT-PCR) were investigated for the constant 5' putative noncoding region of HCV for the diagnosis of HCV-associated chronic liver diseases in India. One hundred fifteen patients with biopsy proven chronic active hepatitis and 140 cases of cirrhosis of the liver were investigated for anti-HCV antibody using a second generation commercial enzyme-linked immunosorbent assay (ELISA). A proportion of these patients: 42 with chronic hepatitis and 27 with cirrhosis of the liver were analysed further for HCV RNA in the serum using RT-nested PCR assay. Thirty-three (12.9%) of the 255 patients were positive for anti-HCV antibody and 23 of 69 (33.3%) patients were positive for HCV RNA in serum. Fifteen of the 33 (45.5%) anti-HCV positive patients had HCV RNA in the serum. Eight of 36 (22.2%) HCV seronegative patients tested were found with HCV RNA. This indicates that the diagnosis of HCV infection is not possible if it is based solely on the available serodiagnostic tests. Inclusion of both assays improved the diagnostic efficiency, 18.8% (13/69) were negative for all virological markers associated with HBV and HCV infection. Since a majority of the chronic liver disease patients (143/255 [56%]) were seronegative for either HBV or HCV infection, it is significant that HCV RNA was detected in 38% (8/21) of a randomly selected group from these patients. The antibody assay and PCR were compared using interclass correlation (kappa statistics).(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?
Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy.
Acetaminophen↗
Status of hepatitis viral markers in patients with acute and chronic liver diseases in northern India.
The present study describes the frequency of hepatitis viral markers in patients with uncomplicated acute viral hepatitis (AVH; n = 32) and in patients with severe liver diseases, including those with fulminant hepatic failure (FHF; n = 110), subacute hepatic failure (SAHF; n = 65), and chronic active hepatitis (CAH; n = 33). The results indicate that hepatitis A virus infection is quite rare, whereas hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the predominant causes of acute and chronic liver failure in India. The incidence of HBV infection in AVH, FHF, SAHF, and CAH groups was recorded in 3.7, 19.1, 23.1, and 69.7% of the cases, respectively. Similarly, HCV infection in these four groups was noted in 12.5, 45, 44.6, and 48.5% of the cases, respectively. Further analysis of HCV infection demonstrated that it was as frequent as single infection in acute cases, but more commonly found in association with HBV infection in chronic liver failure cases. Hepatitis D virus (HDV) infection, as indicated by the presence of IgM anti-HDV antibodies, was recorded in 7.3% of the cases with AVH, in 7.3% of the cases with FHF, in 9.2% of the cases with SAHF, and in 6.1% of the cases with CAH. HDV was associated with HBV both as superinfection as well as coinfection. Interestingly, nearly 2-6% of the cases in each group showed the presence of simultaneous HBV, HCV, and HDV infection. 83.3% of the AVH, 42.1% of the FHF, 37.0% of the SAHF, and 15.1% of the CAH patients had unknown viral markers.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Biliary strictures on ERCP: a study in northern India.
Case records of 82 patients with biliary stricture diagnosed on endoscopic retrograde cholangiopancreatography (ERCP) during a 7-years period (1983-89) were analysed for its aetiology, clinical presentation, laboratory abnormalities and radiological characteristics. The aetiology was found to be benign in 59 and malignant in 23 patients. Forty seven percent of all strictures were post cholecystectomy strictures (PCS). Presence of mucosal irregularity and incomplete stricture were commoner with malignancy. Malignant biliary strictures (MBS) were commonly seen in males, occurred at older age, had short history, had higher alkaline phosphtase and serum bilirubin values when compared to patients with benign biliary strictures (BBS).
Adult↗
Should we redefine acute liver failure?
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Acute Disease↗
Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP4A cDNAs.
PCR was used to demonstrate the presence of a conserved region and to clone novel members of the cytochrome P-450 4A gene family from guinea pig, human and mouse cDNAs. This strategy is based on the sequences at nucleotides 925-959 and at the haem binding domain (nucleotides 1381-1410) of the rat CYP4A1 gene. Murine Cyp4a clones showed high sequence identity with members of the rat gene family, but CYP4A clones from human and guinea pig were equally similar to the rat/mouse genes, suggesting that the rat/mouse line had undergone gene duplication events after divergence from human and guinea-pig lines. The mouse Cyp4a-12 clone was localized to chromosome 4 using interspecific backcross mapping, in a region of synteny with human chromosome 1. The assignment of the human CYP4A11 gene to chromosome 1 was confirmed by somatic cell hybridization. An RNAase protection assay was shown to discriminate between the murine Cyp4a-10 and Cyp4a-12 cDNAs. Treatment of mice with the potent peroxisome proliferator methylclofenapate (25 mg/kg) induced Cyp4a-10 RNA in liver, and to a lesser extent in kidney; there was no sex difference in this response. Cyp4a-12 RNA was present at high levels in male control liver and kidney samples, and was not induced by treatment with methylclofenapate. However, Cyp4a-12 RNA was present at low levels in control female liver and kidney RNA, and was greatly induced in both organs by methylclofenapate. Guinea pigs were exposed to methylclofenapate (50 mg/kg), but there was no significant induction of the guinea-pig CYP4A13 RNA. These findings are consistent with a species difference in response to peroxisome proliferators between the rat/mouse and the guinea pig.
Amino Acid Sequence↗
A prospective randomized study to evaluate propranolol in patients undergoing long-term endoscopic sclerotherapy.
A prospective randomized double-blind study was conducted to evaluate the efficacy of propranolol in patients with portal hypertension undergoing long-term endoscopic sclerotherapy (EST) for recurrent variceal bleeding. Consecutive patients with portal hypertension (Child's class A or B) due to cirrhosis (n = 72), non-cirrhotic portal fibrosis (n = 29) and extrahepatic portal venous obstruction (n = 13) attending the liver clinic of a tertiary care center were included in the study. All patients had had at least one documented episode of variceal bleed in the previous 4 weeks. Fifty-eight patients received propranolol and 56 received placebo in addition to weekly EST. Rebleeding occurred in 12 (21%) patients in the placebo group and 10 (17%) patients in the propranolol group during a mean follow-up period of 24.4 +/- 10.4 months in the former and 23.8 +/- 9.2 months in the latter group (P > 0.1). The number of episodes of rebleeding (14 in the placebo and 12 in the propranolol group) were also similar (P > 0.1). The median bleeding-free period was more than 40 months in both treatment groups (P > 0.1). The mean transfusion requirements and the number of hospital admissions for rebleeding were also similar in the two treatment groups (P > 0.1). Complete obliteration of varices was achieved in 44 (78.9%) patients in the placebo group and 43 (75.5%) patients in the propranolol group (P > 0.1). Recurrence of new varices was seen in two patients in the placebo and in three of those in the propranolol group. Seven patients in the placebo group and five in the propranolol group died (P > 0.1). Complications related to EST were similar in the two treatment groups but additional adverse effects were observed in the propranolol group. The cumulative incidence of rebleeding in the placebo group was 12.7 and in the propranolol group it was 11.2 per 100 patient years of follow-up. It is concluded that the addition of propranolol in patients with portal hypertension and fair hepatic function on long-term EST does not confer any additional benefit.
Administration, Oral↗
Pathology of subacute hepatic failure.
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Adult↗