Stage Of Acute Hepatitis Research Articles

Acute hepatitis C – from the time of diagnosis up to six months of follow-up: a cohort retrospective study

Background Worldwide, the hepatitis C virus (HCV) infection is a common cause of chronic liver disease, but it is rarely diagnosed in the stage of acute hepatitis. Although hepatitis C was the most important hepatitis related to blood products transfusion, since 1992 the overall epidemiology of HCV infection has changed dramatically, many newly diagnosed cases of HCV infection being related to the intravenous drugs use.

Hepatitis C Virus Proteins Activate NRF2/ARE Pathway by Distinct ROS-Dependent and Independent Mechanisms in HUH7 Cells

Hepatitis C virus (HCV) is a highly pathogenic human virus associated with liver fibrosis, steatosis, and cancer. In infected cells HCV induces oxidative stress. Here, we show that HCV proteins core, E1, E2, NS4B, and NS5A activate antioxidant defense Nrf2/ARE pathway via several independent mechanisms. This was demonstrated by the analysis of transient co-expression in Huh7 cells of HCV proteins and luciferase reporters. Expression, controlled by the promoters of stress-response genes or their minimal Nrf2-responsive elements, was studied using luminescence assay, RT-qPCR and/or Western-blot analysis. All five proteins induced Nrf2 activation by protein kinase C in response to accumulation of reactive oxygen species (ROS). In addition, expression of core, E1, E2, NS4B, and NS5A proteins resulted in the activation of Nrf2 in a ROS-independent manner. The effect of core and NS5A was mediated through casein kinase 2 and phosphoinositide-3 kinase, whereas those of NS4B, E1, and E2, were not mediated by either PKC, CK2, PI3K, p38, or ERK. Altogether, on the earliest stage of expression HCV proteins induced a strong up-regulation of the antioxidant defense system. These events may underlie the harmful effects of HCV-induced oxidative stress during acute stage of hepatitis C.

Sexual dimorphism in LEC rat liver: Suppression of carbonic anhydrase III by copper accumulation during hepatocarcinogenesis

We examined age-related changes in the protein expression of carbonic anhydrase III (CAIII) in livers of Long-Evans with a cinnamon-like color (LEC) rats using an agouti color (LEA) rats as controls. The levels of the protein of CAIII in the liver of LEC male rats increased before 20 weeks of age, at the stage of acute hepatitis, and were decreased at 54 weeks of age, while those of CAIII in the liver of LEA male rats were highly expressed at all ages. In the normal LEA rats, CAIII showed sexual dimorphism. The level of CAIII in LEA male rat liver relative to female was four times higher. On the other hand, young LEC rat (at 4-12 weeks) showed a higher protein level of CAIII than LEA rats, and then decreased during development of hepatitis. CAIII mRNA also decreased in the LEC rat liver during hepatocarcinogenesis. The level of CAIII in the tumor region was lower than that in the tumor-free region. Immunohistochemical analysis showed that glutathione S-transferase P (GST-P) was positive and CAIII was negative in the precancerous region. The expression of CAIII was suppressed in cancerous lesions in hepatoma-bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that suppression of CAIII accompanied hepatocarcinogenesis and it is a secondary consequence of the high copper levels in the liver.

A Marked Increase in Free Copper Levels in the Plasma and Liver of LEC Rats: An Animal Model for Wilson Disease and Liver Cancer

Most of copper present in rat plasma and liver binds to caeruloplasmin and metallothionein, respectively, and is not redox active. However, free forms of copper including loosely bound forms to other molecules are redox active. We assessed the free copper in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease and liver cancer. Compared to those of control rats, the liver and plasma of LEC rats showed a marked elevation of free copper, especially at the stage of acute hepatitis, in parallel with an increase of total copper levels in the livers and a decrease of plasma caeruloplasmin (ferroxidase I) activity. At the onset of jaundice, the total copper levels, however, decreased in liver, but increased in plasma, while free copper levels in both liver and plasma remained higher. Free iron levels in both liver and plasma were also determined and did not change significantly, except for the case of plasma in jaundiced rats. The data are consistent with a proposal in which increased levels of redox active free copper in the liver of LEC rats catalyze Fenton-type reactions, producing a large flux of hydroxyl radicals that would play an important role in the observed liver dysfunction, leading to acute hepatitis, and, finally, hepatocarcinoma. This is the first demonstration that the free copper may participate in the pathophysiology of the LEC rats and Wilson disease.

A High Expression of Heme Oxygenase-1 in the Liver of LEC Rats at the Stage of Hepatoma: The Possible Implication of Induction in Uninvolved Tissue

We have examined changes in the expression of heme oxygenase-1 (HO-1), an inducible isoform and HO-2, a constitutive isoform, in the liver of Long-Evans with a Cinnamon-like color (LEC) rat, a mutant strain which spontaneously develops acute hepatitis and hepatoma. HO-1 expression was highly enhanced in the LEC rat livers with jaundice, and then decreased slightly, but overall remained at a higher level than in the Long-Evans with Agouti color (LEA) control rats, as judged by Northern blotting analysis of the whole liver extract. The high expression of HO-1 in the LEC rat liver was, however, not due to the actual cancer lesion but, rather, due to the surrounding uninvolved tissues including hepatocytes. Immunohistochemical analysis also supported this conclusion. Among normal tissues, the expression of HO-1 but not HO-2 was high in only the spleen of both LEC and LEA rats.The high expression observed in the stage of acute hepatitis and hepatoma stages in the LEC rat is probably due to the oxidative stress caused by the accumulation of free copper and free iron levels which has been reported earlier by our group (Suzuki et al., Carcinogenesis, 1993,14, 1881–1884 and Koizumi et al., Free Radical Research, in press) as well as by free heme levels. The inflammatory cytokines produced by the surrounding tissue at the hepatoma stage would also be expected to play a role in the induction mechanism. The physiological relevance of HO-1 induction might be an adaptive response to oxidative stress and vasodilatory effect of carbon monoxide on sinusoidal circulation.

Induction of aldose reductase gene expression in LEC rats during the development of the hereditary hepatitis and hepatoma.

We examined age‐related changes in the protein and the mRNA expression of aldose reductase in livers of Long‐Evans with a cinnamon‐like color (LEC) rats, which develop hereditary hepatitis and hepatoma with aging, using Long‐Evans with an agouti color rats as controls. The levels of the protein and mRNA of aldose reductase increased after 20 weeks, at the stage of acute hepatitis, and were maintained at 60 weeks of age, while those of aldehyde reductase seemed to be constant at all ages. The expression of aldose reductase was marked in cancerous lesions in hepatoma‐bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that elevation of aldose reductase accompanied hepatocarcinogenesis and may be related to the acquisition of immortality of the cancer cells through detoxifying cytotoxic aldehyde compounds.

Interferon gamma production in whole peripheral blood culture in acute hepatitis B

Interferon gamma (IFNg) production in whole peripheral blood (WPB) and mononuclear (MN) cell culture in acute hepatitis B (AHB) was compared. IFNg production was induced by phytogem agglutinin and measured in the cell supernatants of 14 AHB patients in the course of the disease. There were some up-regulating factors of IFNg production that probably operated in WPB culture: the presence of autoerythrocytes as well as the low content of monocytes. Autoserum regulated IFNg production in a stage-dependent way: it decreased IFNg activity at the bilirubin peak in hepatitis B infection, but not in convalescence. In contrast, we did not find a serum blocking effect in the corresponding stage of acute hepatitis A. The nature of this serum blocking factor in AHB is unclear.

Elevated Level of 8‐Hydroxydeoxyguanosine in DNA of Liver, Kidneys, and Brain of Long‐Evans Cinnamon Rats

Long‐Evans Cinnamon (LEG) rats, a mutant strain originating from Long‐Evans rats, spontaneously develop hereditary hepatitis followed by hepatocellular carcinoma. The hepatic disorder in LEC rats is associated with their abnormal copper metabolism; metal‐catalyzed reactions often give rise to oxygen radicals, which may be related to the carcinogenesis. By means of high‐pressure liquid chromatography with electrochemical detection, cellular DNA damage caused by oxygen radicals can be assessed in terms of the amount of 8‐hydroxydeoxyguanosine (oh8dG). We assayed the amount of oh8dG in DNA of liver, kidneys, and brain of LEC and Long‐Evans Agouti (LEA) control rats in seven groups (n=3 to 6) aged from 5 weeks to 24 months. Control rats, a healthy sibling line, were age‐matched. The amount of oh8dG was correlated with the severity of the age‐related clinical symptoms in LEC rats. The amount was higher in LEC rats than in the controls, especially in the liver at the acute stage of hepatitis. These findings suggest that oxygen radicals may be important in the carcinogenesis that occurs in LEC rats.

Isoniazid-rifampin-induced hepatitis in hepatitis B carriers

From January 1984–December 1987, 1783 patients received combination therapy of isoniazid, rifampin, and ethambutol for the control of tuberculosis. Forty-two developed symptomatic hepatitis during the period of treatment. Fifteen were hepatitis B virus carriers, and the remaining 27 were noncarriers. The peak serum transaminase and bilirubin levels were higher in carriers. Seven carriers died of fulminant or subacute hepatic failure, and only 1 noncarrier died. Eleven carriers had detectable serum hepatitis B virus deoxyribonucleic acid during the acute stage of hepatitis. The roles of isoniazid-rifampin combination therapy and hepatitis B virus in the adverse outcomes of carriers were discussed.

β-Hexosaminidase Level in Serum from Patients with Viral Hepatitis as a Measure of Reticuloendothelial Function

The lysosomal enzyme beta-hexosaminidase was elevated in different forms of hepatitis. The enzyme level was correlated to the aminotransferases in the acute stage of hepatitis A and B. In hepatitis B there was also a correlation to ALP and bilirubin. In chronic hepatitis B a significant correlation was found only to ALAT. The elevated beta-hexosaminidase levels are attributed to defective non-parenchymal liver cell function in hepatitis.

Paradoxical urinary excretion of D-glucaric acid in acute viral hepatitis.

The urinary excretion of D-glucaric acid and the plasma clearance of antipyrine were estimated during the acute phase of viral hepatitis and again during recovery. The plasma clearance of antipyrine was impaired during the acute stage of hepatitis, while the urinary excretion of D-glucaric acid was paradoxically high. Both parameters returned to normal during recovery. These findings suggest that the use of urinary D-glucaric acid excretion as an index of microsomal enzyme induction is unreliable when there is liver injury.

Histopathology of liver biopsy specimens.

Histologic features characteristic for vorious diffuse and localized liver diseases were outlined and the diagnostic criteria for those lesions were described. A case, in which development of early cirrhosis from a stage of acute hepatitis was followed, was briefly described and histologically illustrated. Correlation of clinical and histological diagnosis was tabulated, frequency of diagnostic accordance was calculated and difficulty of diagnosis of chronic hepatitis was emphasized.

Effect of Infectious Hepatitis on the Immunoglobulins in Mentally Retarded Children

In this study, the humoral immunologic status of 60 institutionalized children with infectious hepatitis was evaluated during the acute or icteric stage and followed one, four, and seven months after the sudden onset of the disease. The determination of the humoral immunologic status consisted of the following: (1) the study of serum protein distribution by acetate electrophoresis mobility; (2) quantitative evaluation of serum by immunochemical analysis for immunoglobulins (Ig), 1 IgA (7S γ1 , βA), IgM (19S γ1 , βM), and IgG (7S γ2 ); and (3) qualitative evaluation of serum IgG for virus neutralizing antibody response on 8 to 12 standard enteric viruses as well as viruses isolated from patients during the acute stage of hepatitis. These data are correlated for the 60 patients who had either clinical jaundice or an increase in serum glutamic pyruvic transaminase (SGPT) levels, or both. It was not surprising to find varying increases in immunoglobulin levels

Role of rest and ambulation in liver disease; management of acute infectious hepatitis.

The current use of bed rest in the treatment of diseases of the liver is admittedly empiric. All observers have agreed that bed rest during the acute stage of hepatitis generally improves the immediate symptoms. Hepatic tenderness is less under conditions of rest, while increase in size and tenderness of the liver frequently occurs with ambulation. Laboratory evidence of worsening hepatic function often parallels the change in liver size and tenderness. When the resistance of the host is high, and possibly when the virus is of a low degree of virulence, no permanent deleterious effects result from relapses due to early ambulation. Recovery progresses satisfactorily despite lack of rest. However, these clinical and laboratory signs of relapse may be the first indications of a more serious progressive hepatitis. The role of bed rest has not been tested by controlled observations under such circumstances. Until studies of this nature have been made, the judicious use of bed rest in the treatment of the acute stages of hepatic disease is recommended.