Plasma levels of transforming growth factor beta 1 in chronic liver disease

We describe the case of a 30-year-old female patient with a 7-year history of multiple sclerosis, who presented with an 18-month history of secondary amenorrhoea and vague symptoms which included poor sleep and impaired concentration. Endocrine investigations revealed hypogonadotrophic hypogonadism and GH deficiency, a probable consequence of a hypothalamic plaque. This is the first report of hypogonadotrophic hypogonadism and GH deficiency occurring in conjunction with multiple sclerosis. As such, it should raise suspicion of endocrine dysfunction occurring in a condition with such a vast spectrum of disability as multiple sclerosis.     

Dietary and nutritional abnormalities in alcoholic liver disease: a comparison with chronic alcoholics without liver disease

OBJECTIVE: To document the profile and role of malnutrition in alcoholic hepatitis, compared with chronic alcoholics and nonalcoholic chronic liver disease. METHODS: To this end, we studied 67 patients with alcoholic liver disease (ALD) (group I), 52 chronic alcoholics without histological evidence of liver disease (group II), 44 nonalcoholic cirrhotics (group III), and 52 healthy controls (group IV). Alcoholic and nonalcoholic calories were calculated and percentage dietary and nutritional deficiencies computed. Anthropometric indices, nitrogen balance, and immune status of the patients were assessed. RESULTS: Alcohol constituted about 48% of daily caloric intake in patients with ALD. The percentage mean intake of carbohydrate, protein, and energy was decreased in all three study groups compared with controls. The deficiencies were more pronounced in patients with severe than with moderate ALD. These deficiencies were more severe in the group III patients. Whereas body fat stores were maintained in groups I and II, reduction in lean body mass and serum transferrin was significant in patients in groups I and III. In group II patients compared to group I patients, the body mass index (19.9 +/- 4.0 vs. 22.3 +/- 3.4) and triceps skinfold thickness (6.1 +/- 4.8 vs. 10.2 +/- 5.6 mm) were significantly lower. CONCLUSIONS: 1) protein energy malnutrition is common in both alcoholic and nonalcoholic cirrhotics, but is more pronounced in the latter; 2) the degree and profile of malnutrition in chronic alcoholics and in alcoholic cirrhotics are comparable; 3) based on our results, we hypothesize that malnutrition may not play a primary role in the pathogenesis of ALD.     

Serum IL-8 levels and localization of IL-8 in liver from patients with chronic viral hepatitis

BACKGROUND/AIMS: Interleukin 8 is known as a chemotactic factor for neutrophils and T cells. Such inflammatory cells are observed in the liver tissue in chronic viral hepatitis. However, it is not known whether interleukin 8 relates to hepatic injury in patients with chronic viral hepatitis. Therefore, we determined serum interleukin 8 levels and identified the cells related to interleukin 8 production in liver tissue. METHODOLOGY: Studies were performed on 29 patients with chronic viral hepatitis and 20 normal controls. Serum interleukin 8 levels were assayed using a sandwich ELISA. Immunohistochemical examination was performed to identify the cells related to interleukin 8 production by using a rabbit polyvalent antibody to human interleukin 8. RESULTS: Serum interleukin 8 levels were found to be increased significantly (p<0.05) in patients with chronic viral hepatitis compared with normal controls. They were also increased significantly in patients with chronic active hepatitis compared with chronic persistent hepatitis (p<0.05), and during exacerbation stages compared with remission stages (p<0.05). Out of the 10 patients examined immunohistochemically, interleukin 8 positive cells in the liver tissue were visualized in 7 patients and observed mainly along sinusoids. There was significant correlation between serum interleukin 8 levels and intensity of staining for interleukin 8 in the liver tissue (p<0.05, r=0.869). CONCLUSIONS: Interleukin 8 plays a role in hepatic injury in patients with chronic viral hepatitis, and is mainly produced by nonparenchymal cells in the liver.     

Characteristics of serum hyaluronate concentrations in patients with alcoholic liver disease

It has been reported that serum hyaluronate [hyaluronic acid (HA)] concentrations are increased in liver diseases, especially in alcoholic liver disease (ALD). However, the characteristics of serum HA concentration in patients with ALD have not been studied. In this study, first, we measured serum HA concentrations in patients with different stages of both ALD and non-ALD to clarify the characteristics of serum HA concentration in patients with ALD. Second, we measured serum HA concentrations in patients with ALD sequentially after abstinence. We also measured serum HA concentrations in patients with chronic type C hepatitis before and after treatment with interferon. Finally, we analyzed the relationship between serum HA concentrations and the contents of type IV collagen and laminin in the livers of both ALD and non-ALD patients. Serum HA concentrations in liver disease were higher than the cut-off value, and increased significantly (p < 0.001) in parallel with the progression of hepatic fibrosis in both ALD and non-ALD patients. Serum HA concentrations in patients actively drinking with ALD were significantly higher (p < 0.001) than those in non-ALD. After 4 weeks of abstinence, these concentrations fell to the levels of non-ALD. Although serum ALT levels were decreased in 80% of patients treated with interferon, serum HA concentrations were not changed or increased. A significant correlation between serum HA concentrations and hepatic type IV collagen and laminin content was present in ALD, but not in non-ALD. These results clearly suggest that the increase of serum HA concentrations in ALD may be associated with not only hepatic fibrosis, but also alcohol drinking.     

Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease

Formalin-fixed sections from the brains of 36 patients (30 alcoholic and 6 nonalcoholic) with autopsy-proven cirrhosis who died while in a hepatic coma were stained with hematoxylin and eosin, and examined for the presence of diencephalic, cerebellar, pontine, and basal ganglia lesions. Significant neuropathology was identified in 23 of 36 cases consisting of mammillary body and thalamic lesions characteristic of Wernicke encephalopathy (WE) (9 cases, all alcoholic patients) and cerebellar degeneration (20 cases, 17 alcoholic and 3 nonalcoholic patients). Clinical diagnosis of WE had been entertained during life in only 2 of these patients. All cases, alcoholic and nonalcoholic, manifested mild to severe Alzheimer's type II astrocytosis. No cases of central pontine myelinolysis nor acquired (non-Wilsonian) hepatocerebral degeneration were found. These findings show that the brains of a high proportion of cirrhotic patients with end-stage liver disease manifest concomitant unsuspected diencephalic and cerebellar pathology. The high incidence of WE underscores the need for early sustained treatment of alcoholic cirrhotic patients with vitamin B1. Evaluation of the neurological sequelae of liver transplantation, particularly of alcoholic patients with end-stage liver disease, may require a careful neurological and radiological assessment both before and after surgery.     

The correction of the immune and microcirculatory disorders in patients with chronic hepatitis of alcoholic and viral etiologies

A simple, rapid and sensitive method for the clean-up and analysis of cefoxitin in serum and tissue is described. Serum (0.5 ml) and tissue (100 mg) samples after homogenization underwent high speed centrifugation. Chromatography was performed on a muBondapak C18 cartridge using a mobile phase of 0.005 M potassium dihydrogen phosphate-acetonitrile-glacial acetic acid (77.5:22:0.5, v/v/v) with a flow-rate of 2.0 ml/min. Ultraviolet detection occurred at 235 nm. The procedure produced a linear curve for the concentration range 100-5000 ng/ml. The assay produced accurate, repeatable and rapid results for both tissue and serum samples without the need for chemical extraction.     

A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease

To clarify the relationship between hepatitis C virus infection and excessive alcohol intake, we carried out histological examination of the liver in 46 alcoholics with chronic hepatitis C virus infection and compared the findings in 55 patients with chronic hepatitis C, 38 with alcoholic liver disease, and 27 with chronic hepatitis B. The majority of alcoholics with chronic hepatitis C virus infection displayed virus-related histological changes very similar to those in chronic hepatitis C, including frequent lymphoid follicles (34.7%) or aggregates (93.3%) in the portal tracts, mild necroinflammatory change (76.1%) in the parenchyma, and lymphocytosis in sinusoids (83.7%). Liver cell dysplasia and irregular regenerative activity of hepatocytes were rarely observed. The effects of alcohol on the liver were found to be minimal in the majority. These findings could suggest that the hepatic injury in the majority of alcoholics with chronic hepatitis C virus infection in Japan is due to persistent hepatitis C virus infection rather than to alcoholic injury. In addition, our study disclosed that the perivenular fibrosis which is designated as a histological characteristic of alcoholic liver disease is frequently observed in chronic hepatitis C. These similarities suggest that a similar fibrogenesis is present in chronic hepatitis C and alcoholic liver disease.     

Post-prandial serum hyaluronan concentration in patients with chronic liver disease

Serum hyaluronan measurement is an option for diagnosing cirrhosis and assessing liver fibrosis, but it is of little use in the diagnosis of chronic hepatitis and compensated liver cirrhosis. It is generally known that intake of food results in elevation of the serum hyaluronan concentration. This work was designed to determine whether a change in the serum hyaluronan concentration after eating might reflect the hepatic sinusoidal endothelial cell impairment in chronic liver diseases. The chronological measurement of serum hyaluronan concentration after eating was performed after an overnight fast in 31 patients with chronic hepatitis, 31 cirrhotic patients, and 8 healthy subjects. The hyaluronan concentration in the loading test increased with the severity of the liver disease in the patients with chronic hepatitis, being significantly higher in the patients with moderate or a higher grade of necroinflammation than in those with a minimal grade, and also significantly higher in patients with stage 3 fibrosis than in those with stage 2 or less. The elevation of the concentration after eating in patients with liver cirrhosis was marked and the range did not overlap with that in patients with chronic hepatitis. Even in 14 patients with compensated liver cirrhosis whose hyaluronan concentration pre-prandially was less than 200 ng/ml, the range of the post-prandial peak concentration did not overlap with that in the chronic hepatitis patients. These results suggest that the evaluation of post-prandial serum hyaluronan concentration is potentially useful for assessing the grading of necroinflammation and staging of fibrosis in patients with chronic hepatitis, as well as for diagnosing compensated liver cirrhosis.     

Aetiology and pathogenesis of alcoholic liver disease

Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.     

Recurrence of alcoholic liver disease after liver transplantation

The acute toxicity of six metals [Hg, Cd, Cu, Zn, Cr(II), and Cr(VI)] to Daphnia magna neonates was evaluated using three different test media (Elendt M7, a complex medium containing EDTA; ASTM hard water and EEC, two simple media free of chelators). The EC50 values, at both 24 and 48 h, obtained for Zn, Cr(II), and Cr(VI) were similar in all of the media tested. Hg was more toxic in ASTM than in M7 and in EEC media. The toxicity of Cd and Cu was similar in ASTM and EEC media and higher when evaluated in M7 medium. Thus, M7 should be used only carefully for the toxicity evaluation of mixtures and effluents containing metals. It is recommended, however, that it be excluded from use in tests evaluating samples of unknown composition, or those known to contain Cu and Cd. For the metals tested in this study, a factor of five applied to each 48-h EC50 would be sufficient in order to attain the respective acute NOECs for immobility.     

The pathogenesis of alcoholic liver disease

The immunoglobulin (Ig) isotype (IgG, IgA, IgM) production of peripheral blood mononuclear cells from 28 patients having multiple myeloma (MM) was analyzed. The total Ig secreting capacity of the cells, as measured by ELISA from the cell culture medium, was not found to be significantly reduced in MM (1,118 +/- 1,394 micrograms/l) as compared to the values of 9 controls (898 +/- 520 micrograms/l), but a significant isotype switching towards the tumor paraprotein type was observed in the patients with active MM (p < 0.001). The percentage of IgG in the active IgG-MM was 88 +/- 11% and that of IgA in the active IgA-MM 83 +/- 13%, the control values being 44 +/- 11% for IgG and 44 +/- 13% for IgA. The proportions of isotypes resembled those of the controls in the inactive phase of the disease. Despite this dominating paraprotein class isotype production, no evidence of Ig gene clonal rearrangements was found in cells studied by either Southern blotting or the more sensitive polymerase chain reaction method, which suggests that polyclonal rather than monoclonal PB B cells are responsible for the Ig production observed.