Nabeen C. Nayak

CYTOPLASMIC COPPER AND ITS TOXIC EFFECTS: STUDIES IN INDIAN CHILDHOOD CIRRHOSIS

Morphological, histochemical, and chemical study of three necropsy specimens of liver in the terminal stage of Indian Childhood Cirrhosis revealed a strikingly high copper content. it is proposed that excess accumulation of copper in the cytoplasm of hepatocytes disturbs the microtubular system, causing hydropic swelling and the formation of Mallorys hyalin. Copper and copper-binding protein showed topographical association with Mallorys hyalin. Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect. The pattern of copper distribution in Indian Childhood Cirrhosis differs from that in Wilsons disease and in prolonged cholestasis with excessive hepatic copper deposition, indicating a different mechanism of the copper accumulation.

Aetiology and outcome of acute viral hepatitis in pregnancy

Abstract The aetiologic types of sporadic acute viral hepatitis in 169 pregnant women were compared with those of 70 non‐pregnant women and 287 adult men. The majority of pregnant women (87.6%) came with acute hepatitis in the last trimester of pregnancy. Non‐A, non‐B (NANB) hepatitis accounted for 81.6% of hepatitis during pregnancy in comparison with 48.6% in non‐pregnant women and 57.1% in adult men. Hepatitis A was extremely uncommon during pregnancy. Hepatitis B infection accounted for 17% of all cases in pregnant women compared with 45% in controls. Acute viral hepatitis in pregnancy had a poor outcome as assessed by maternal and/or fetal mortality (28.5%). The outcome was equally bad in hepatitis NANB and hepatitis B. Pregnant women generally had significantly lower immunoglobulin levels in comparison with non‐pregnant women. In acute NANB hepatitis during pregnancy, serum IgG and IgM levels were lower and higher, respectively, compared with those in non‐pregnant women and pregnant women with acute hepatitis B. It is suggested that an immune suppression during pregnancy might be responsible for increased susceptibility to acute NANB viral hepatitis, which, by itself, seems to induce only a transient acute phase IgM response.

Acute sporadic non‐A, non‐B viral hepatitis of adults in India—Epidemiological and immunological studies

On the basis of tests for specific IgM class antibodies in the serum, infections by hepatitis A virus, hepatitis B virus and hepatitis non‐A, non‐B virus accounted for 7%, 37.8% and 54.2% respectively of 286 cases of acute sporadic viral hepatitis in adults from three different regions of India. Epstein‐Barr virus and cytomegalo virus were insignificant (0.5–1%) aetiological agents. Approximately one‐quarter of all non‐A, non‐B (NANB) cases were additionally HBsAg carriers; there were significant differences in regional frequencies. NANB hepatitis commonly affected individuals in the mid‐fourth decade and occurred throughout the year with small peaks in different seasons. No antigen‐antibody reaction could be demonstrated in various immunological tests including radioimmunobinding using acute and convalescent phase sera. Neither were virus‐like particles visualized in acute phase sera on electron and immuno‐electron microscopy. However, rhesus monkeys inoculated with acute phase serum from a case of NANB hepatitis developed distinct hepatocellular changes at 43–55 days after inoculation, which had some features of similarity with experimental NANB hepatitis of other simian species. Sporadic NANB hepatitis is a major health problem throughout India and intensive study is needed on its epidemiology and aetiology.

Enhancement of aflatoxin B1-induced hepatocarcinogenesis in rats by partial hepatectomy

SummaryThe effect of enhanced cell replication induced by partial hepatectomy (PH) in aflatoxin B1 (AFB1)-induced hepatocarcinogenesis has been studied in rats of the inbred As2 strain. Animals were given 0.25 mg/kg body weight of AFB1 as a single intraperitoneal dose 24 h after PH. Nonhepatectomized animals given the same dose of AFB1 served as controls. Neoplastic nodules and hepatocellular carcinoma (HCC) were detected respectively in 100% and 90% of hepatectomized animals sacrificed between 55 and 65 weeks after AFB1 administration. None of the ten non-hepatectomized rats sacrificed at this time interval showed HCC or neoplastic nodules. On histochemical staining the tumour population was found to be heterogeneous. Thus PH resulted in enhancement of AFB1-induced hepatocarcinogenesis in rats of the AS2 strain.

Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma

Macroautophagy and chaperone-mediated autophagy (CMA) represent two major lysosomal degradation processes and often compensate for one another to facilitate cell survival. The aim of this study was to determine whether these autophagy pathways could compensate for one another to promote HCC cell survival in the cirrhotic liver. Analysis of normal liver tissue showed no expression of glypican-3 or p62 proteins, suggesting that macroautophagy is the major contributor to autophagic flux under non-pathological conditions. Of 46 cirrhotic livers with HCC examined, 39 (84%) of HCCs showed increased expression of p62, and 36 (78%) showed increased expression of glypican-3, while adjacent non-tumorous hepatocytes were negative for expression of p62 and glypican-3, similar to normal liver tissue. These results suggest that macroautophagy flux is impaired in HCC. Furthermore, more than 95% of HCCs showed altered expression of LAMP-2A compared to the surrounding non-tumorous cirrhotic liver, consistent with induction of CMA in HCC. Elevated expression of glucose-regulated protein 78 (GRP78) and heat shock cognate protein (Hsc70) were detected in 100% of HCC and adjacent non-tumorous cirrhotic livers, suggesting that unresolved ER-stress is associated with HCC risk in liver cirrhosis. Interestingly, inhibition of lysosomal degradation using hydroxychloroquine (HCQ) induced expression of the tumor suppressor p53, promoted apoptosis, and inhibited HCC growth, whereas activation of autophagy using an mTOR inhibitor (Torin1) promoted HCC growth. Results of this study suggest that induction of CMA compensates for the impairment of macroautophagy to promote HCC survival in the cirrhotic liver.

Effect of Low Protein Diet on Low Dose Chronic Aflatoxin B1 Induced Hepatic Injury in Rhesus Monkeys

AbstractThe role of dietary protein in low dose chronic alfatoxin B1 (AFB1) liver injury in Rhesus monkeys has been studied using 0.16 and 0.5 ppm of AFB1 in diet. The high and low protein diet contained 20% and 5% casein, respectively. Following 32 weeks of intoxication with 0.16 ppm of AFB1, histological examination revealed mild alterations in low protein group only. However, distinct histochemical and ultra-structural alterations indicative of toxic liver injury are present in both the groups fed AFB1, though more prominent in animals fed a low protein diet. Monkeys on low protein diet surviving for 90 weeks or more show foci of preneoplastic lesions, whereas those on high protein diet reveal no such alterations at the corresponding time interval. With 0.5 ppm of AFB1 in diet, the pattern of toxic liver injury is similar to that of 0.16 ppm of AFB1 in diet. However, the liver damage is more prominent with this dose. The hepatic injury again is more accentuated in the low protein group as compared with...

Hepatitis-B virus and Indian childhood cirrhosis.

The surface and core componenets of hepatitis-B virus have not been detected in livers of patients suffering from Indian childhood cirrhosis using procedures such as immunoperoxidase, immunofluorescence, and orcein staining as well as electronmicroscopy. This finding, together with the other features of the disease, suggests that infection by this virus plays no significant role in the aetiology of Indian childhood cirrhosis.

Effect of low protein diet on chronic aflatoxin B1-induecd liver injury in Rhesus monkeys

Meera Mathur, T.A. Rizvi ~ and N.C. Nayak 2 Department of Pathology, All India Institute of Medcial Sciences, New Delhi; I Present address: Department of Oncology, McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, 450 North Randall A venue, Madison, WI 53 706, USA; 2 Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Saf at, Kuwait 13110

Polymerized albumin binding to serum in various liver diseases: its significance and relation to hepatitis B virus infection.

Sensitive and specific enzyme‐linked immunosorbent assays (ELISA) were developed to detect separately the binding of polymerized human serum albumin (PHSA) to its antibody (A‐PHSA) and to the hepatitis B surface antigen (HBsAg). A‐PHSA was not detected in normal serum, whereas more than one‐third to about half of sera from patients with acute liver cell injury showed this antibody. Frequency of A‐PHSA positivity was low in chronic liver diseases, being relatively higher in those with continuing liver injury. A‐PHSA detection was not related to seropositivity for HBsAg.