Genetic predisposition to development of toxic liver cirrhosis caused by alcohol]

Comprehensive analysis of the contribution of genetic factors into predisposition to alcoholic toxic cirrhosis (TC) was performed. The ABO, RH, HP, TF, GC, PI, ACP1, PGM1, ESD, GLO1, and GST1 genetic polymorphisms were compared in 34- to 59-year-old male TC patients and control donors of the same sex and age. The phenotypic frequencies in the TC group deviated from the theoretically expected values; the main difference was the excess of rare homozygotes for the loci GC, ACP1, ESD, and GLO1. In the TC patients, the observed heterozygosity (Ho) was considerably lower than the theoretically expected value (H(e)). Wright's fixation index (F) in the TC patients was 30 times higher than in the control group (0.0888 and 0.0027, respectively). The frequencies of PI*Z and PI*S, the PI alleles that are responsible for lower concentrations of proteinase inhibitor, were 12 and 6 times higher in the TC than in the control group. The TC patients exhibited a significantly higher frequency of the liver glutathione-S-transferase GST1*0 allele, whereas the GST1*2 frequency was two times higher in the control subjects than in the TC patients (0.2522 and 0.0953, respectively). The TC and control groups showed statistically significant differences in the frequencies of the following alleles of six independent loci: ABO*0, TF*C1, TF*C2, PI*M1, PI*Z, ACP1*C, PGM1*1+, PGM1*1-, PGM1*2-, GST1*0, and GST1*2. The haptoglobin level was significantly higher and the serum transferrin level was drastically lower in all phenotypic groups of TC patients than in control subjects. The concentrations of IgM and IgG depended on the HP, GC, and PI phenotypes. The total and direct reacting bilirubin concentrations depended on the erythrocytic-enzyme phenotypes (ACP1, PGM1, and GLO1) in both TC and control groups.     

The chronic course of spontaneous and experimental hepatitis A in rhesus monkeys with viral persistence]

The prolonged (up to 2 years) complex observation of 11 rhesus macaques (Macaca mulatta) with spontaneous hepatitis A and 14 rhesus macaques with experimental hepatitis A developing after their intravenous and/or oral infection with human hepatitis A virus (HAV). Both natural and experimental infection took a chronic course (15-18 months). In 13 monkeys showing morphological changes in the liver during the whole period of the disease elevated enzyme levels in the blood and virus shedding in feces were periodically observed. Only one monkey had acute hepatitis A which lasted 1.5 months. In 11 monkeys the disease took an undulating course with 1-2 relapses when virological, biochemical and morphological signs of the disease could be detected. Seroconversion was observed in all monkeys. Anti-HAV IgM antibodies were retained for not more than 6-7 months and total anti-HAV antibodies, during the whole period of observation. Relapses were found to induce no antibody formation. Evidence on the prolonged (up to 12-16 months) persistence of HAV in primates was obtained for the first time.     

Liver cirrhosis and liver cancer associated with viral hepatitis B and C in republic of Tatarstan

Clinical and epidemiological data on 93 patients with liver cirrhosis, treated in the Gastroenterological Department of the Republican Clinical Hospital of the of the Republic of Tatarstan MoH in 1998-2000 were analyzed. The retrospective analysis of 856 cases of the liver cancer, diagnosed in the Republic of Tatarstan in 1996-2000, was made. In 20.4% of patients with liver cirrhosis and 16.2% of patients with liver cancer, registered in the Republic of Tatarstan, the serological markers of hepatitis B (HB) and hepatitis C (HC) were detected. The domination of HC markers was observed in the liver cirrhosis and that of HB markers in the cancer of the liver. The liver cirrhosis with HC markers was more often registered in the age group of 45-60 years and with HB markers at the age over 60 years, while the cancer of the liver was more often registered in persons aged 75 years and older. The necessity of introducing the official registration of the liver cirrhosis and cancer associated with chronic infection caused by hepatoviruses B and C is confirmed.     

Subcellular distribution of acid hydrolases in rat liver during toxic hepatitis]

Changes occurring in the lysosome population were assessed by the results of studies of intracellular distribution of the marker lysosome enzymes--acid phosphatase and acid RNAase. An acute (pure CCl4-0.15 ml per 100 g of weight into the stomach) and chronic (inhalation poisoning after Rabinovici and Wiener) toxic hepatitis was accompanied by an increase in the specific activity of the enzymes in the fraction of heavy mitochondria, this pointing to the change in the sedimentation properties of the lysosomes. An increase in "nonprecipitable" activity of the acid RNA-ase in chronic toxic hepatitis served as the sign of injury of the lysosome membranes.     

Alcohol as a pathological factor for patients with acute and chronic viral hepatitis and liver cirrhosis

The investigations have shown presence of HBsAg in the blood sera of 4% of alcohol abusers and in 17.7% of chronic alcoholics. Among 274 patients with acute viral hepatitis A, more than 50% abuse alcohol. The study has revealed that the lipid spectrum has its specific features in hepatitis patients abusing alcohol and chronically addicted to it. Among patients with chronic persistent hepatitis and cirrhosis of the liver, the combined effects of hepatitis B virus and alcohol have been revealed in 50%.     

The epidemiological differential diagnostic signs of viral hepatitis A and viral hepatitis E]

A retrospective epidemiologic analysis of cases diagnosed as hepatitis A (HA) has been made in territories characterized by high intensity (4 towns in Central Asia) and low intensity (Novomoskovsk, Tula Province) of the epidemic process development. Morbidity structures for different age and social groups of the population, as well as the morbidity time course, both annual and over many years, were analyzed over 1973-1986. Specific features in the development of the epidemic process in HA and hepatitis E (HE), formerly called hepatitis non-A, non-B with the fecal/oral mechanism of the infection transmission, were studied. Twelve epidemiological differential diagnostic signs of these two infections were formulated, classified, and validated. Contribution of centralized water supply and sewage systems to the development of HE epidemic process and the regulating role of infectious immunological mechanisms in the development of HA epidemic process were demonstrated.     

Changes in the liver lysosomes of the rat in chronic toxic hepatitis]

A study was made of permeability of the lysosome membranes and subcellular distribution of acid hydrolases in chronic hepatitis caused by CCl4 inhalation and during the restoration of the liver after injury. No normalization of the indices under study occurred during the period of up to 14 days after the last CCl4 inhalation: changes in the stability of the lysosome membran persisted and redistribution of acid hydrolases was noted. This redistribution was associated with both the processes of injury and restoration of the liver.     

Synthesis of nitric oxide in patients with viral hepatitis]

The end products of nitric oxide (NO) metabolism in human organism, i.e. anions, nitrites (NO2) and nitrates (NO3), are excreted predominantly (95%) via urine. The quantity of these products in urine is an adequate index of NO synthesis in human organism. We measured the quantities of of NO2 and NO3 excreted during of monoviral hepatitis A, B, C, D and in the course of mixed viral hepatic infections, which were caused by the above mentioned viruses. The hyperexcretion of NO2 and NO3 was higher and longer during hepatitis C and D versus hepatitis B, and during the latter versus hepatitis A. The inability of NO to stop the infection may be caused by low sensitivity of the viruses to NO and/or by local low concentration of NO in the site of inflammation.     

State of liver mitochondrial respiratory chain in rats with experimental toxic hepatitis

Polarographical determination of oxygen concentration has shown that in rats with experimental hepatitis induced by combined ethanol and CCl₄ administration for 4 weeks, the functioning of the hepatocyte mitochondrial respiratory chain is impaired. Development of liver pathology was accompanied by adipose dystrophy, fibrosis, and an increase of triglycerides and lipid peroxidation products in the liver tissue. The endogenous respiration rate in hepatocytes isolated from the pathologically altered liver was 34% higher than in the control. Cell respiration was not stimulated by the addition of the substrates malate and pyruvate with digitonine. An uncoupler of oxidation and phosphorylation, 2,4-dinitrophenol, increased the hepatocyte oxygen consumption rate by 37%, while addition of the inhibitor of the I complex, rotenone, decreased cell respiration in pathologically altered hepatocytes by 27%. The states 3 (V₃) and 4 (V₄) of mitochondrial respiration with malate + glutamate as substrates were found to be higher by 70% and 56%, respectively, as compared with the control level. When using malate + glutamate or succinate as substrates, V₃ and Vd (dinitrophenol respiration) in the toxic hepatitis hepatocyte mitochondria did not differ from the control, which indicates no uncoupling occurred of the oxidation and phosphorylation processes. Cytochrome c oxidase activity was elevated (+80%) as compared with the control. Administration of the hypolipidemic agent symvastatin simultaneously with ethanol and CCl₄ resulted in a reduction of the degree of liver adipose dystrophy, prevented activation of lipid peroxidation, and decreased the hepatocyte endogenous respiration rate. Addition of malate + pyruvate, dinitrophenol or rotenone produced oxygen consumption changes similar to those in the control. However, in mitochondria isolated from the pathologically altered liver, symvastatin induced an uncoupling effect on the respiratory chain in the presence of the substrates malate + glutamate, but did not change the cytochrome c oxidase activity. We suggest that functioning of the NCCR complex in the hepatocyte mitochondria of animals with experimental toxic hepatitis is impaired, which leads to an intensive superoxide anion production at the level of this complex. Under these conditions, the defect of the NADH-coenzyme Q-oxidoreductase is compensated by functioning of other complexes of the respiratory chain (SCCR, coenzyme Q-cytochrome c-reductase, cytochrome c oxidase, and ATP-synthase activities).     

Role of vacuolar apparatus overload in lysosomal changes in liver cells in acute toxic hepatitis]

Physical and chemical properties of the rat liver lysosomes with single Triton WR 1339 overloading were studied during the administration of a detergent to intact rats and those with acute toxic hepatitis. Administration of the latter to intact animals was accompanied by a reduction of the floating density of the particles, solubilization of the lysosome enzymes and by increased fragility of the particles in the hypotonic medium. Lysosomes of the hepatocytes in rats with toxic hepatitis also displayed signs of overloading of the vacuolar apparatus with the preparation administered. The most pronounced solubilization of the lysosomal enzymes beta-galactosidase, acid RNA-ase, cathepsin D--was noted in case of combined action of CCl4 and Triton WR 1339 24, 48, 72 hours and 7 days after the CCl4 poisoning. Possible consequences of overloading of the vacuolar apparatus of the rat hepatocytes are discussed.