LKM3 autoantibodies in hepatitis C cirrhosis: a further phenomenon of the HCV-induced autoimmunity.

Chronic hepatitis C is frequently associated with laboratory markers-including LKM1 autoantibodies--of autoimmunity. A 62-yr-old woman with hepatitis C cirrhosis presented autoantibodies against liver and kidney microsomal proteins. By further evaluation of autoantibodies using ELISA and immunoblotting LKM1 and LKM3 autoantibodies could be revealed. The target antigen of LKM3 autoantibodies proved to be UGT-1.1 isoenzyme. In the absence of chronic hepatitis D infection or autoimmune hepatitis type 2, this is the first case that reports the occurrence of LKM3 autoantibodies in HCV-induced chronic liver disease.

[The role of perisinusoidal (Ito) cells in the course of hepatocellular carcinoma: light and electron microscopic data to the pathogenesis of hepatocellular carcinoma]. / A perisinusoidalis (Ito-) sejtek szerepe a hepatocellularis carcinoma kórlefolyásában: fény- és elektronmikroszkópos adatok a hepatocellularis carcinoma patogeneziséhez.

The clinical history of a 49 year old female patient suggested a multifocal, rapidly progressive liver disease of one month duration, apparently due to metastatic tumour. An open needle biopsy of the liver revealed a primary hepatocellular carcinoma of low grade malignancy; the diagnosis was confirmed by histological, immunohistochemical and electron microscopic studies. Besides the ultrastructural examination of the liver biopsy disclosed an unusually marked proliferation of perisinusoidal (Ito)-cells. The authors assume that the myofibroblast proliferation and transformation of Ito-cells in the noncirrhotic liver led to the formation of multifocal areas. The perisinusoidal cell proliferation was presumably due to vitamin A intoxication caused by an extreme vegetarian diet (daily consumption of large amounts of carrot juice for years, as disclosed by a retrospectively obtained history). It is assumed that the vitamin A abuse, and perisinusoidal cell proliferation may have promoted the unusually rapid progression of the multifocal, but histologically low grade hepatocellular tumour. Spectacular clinical improvement could be observed after chemotherapy, combined with local hyperthermic treatment. Presumably, the change in diet (cessation of excessive retinol and carotene intake) also may have had a beneficial effect. After one year the clinical course suggests a slower progression of tumour growth which would be more in keeping with the prognosis based on the histologic appearance of the low grade hepatocellular carcinoma. This patient's case illustrates the importance of electron microscopy supplementing diagnostic histological and immunohistochemical examinations.

C5b-9 and interleukin-6 in chronic hepatitis C. Surrogate markers predicting short-term response to interferon alpha-2b.

BACKGROUND: Available data and our observations suggest that elevated levels of interleukin (IL)-6 and -10 and some complement parameters may be associated with a poor response to IFN alpha. We evaluated how baseline levels of C5b-9, IL-6, and IL-10 influence the outcome of IFN alpha treatment. METHODS: Fifty-one patients with established chronic hepatitis C were enrolled and treated with IFN alpha-2b. Before and after a 12-week-IFN-treatment (3 MU or 5 MU tiw) serum levels of IL-6, IL-10, C5b-9 and RNA of hepatitis C virus (HCV) were assessed. Sera of 46 sex- and age-matched, healthy blood donors served as control. RESULTS: While two-thirds of patients was considered 'responder', 14 patients had no significant decrease either in HCV RNA or in ALT levels. In the responder's group lower baseline levels of IL-6 and C5b-9 were found than those in the 'non-responder' group. As a result of IFN therapy HCV RNA and C5b-9 levels significantly decreased. While the serum concentration of IL-6 increased during the follow-up period, regarding IL-10, no change was observed. In patients with 'low' baseline levels of C5b-9 (<2053 ng/ml) IFN alpha resulted in a significantly (P = 0.0005) higher decrease in HCV RNA level. Regarding 'low' IL-6 values (< 1.47 pg/ml) similar but somewhat less significant (P = 0.0039) difference was found if the change of HCV RNA was investigated. The odds ratio of patients with low IL-6 and/or C5b-9 to responding to IFN alpha treatment was almost 10 times (CI: 9.1 (1.8-50.9)) higher as compared with patients without 'low' levels of these parameters. CONCLUSION: Our data suggest that serum level(s) of IL-6 and/or C5b-9 taken prior to the initiation of IFN treatment may serve as surrogate marker(s) in evaluating patients with chronic hepatitis C whether to get IFN alpha in monotherapy or to consider having combination therapy in the form of IFN alpha-ribavirin.

Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population.

We sought to determine the distribution of vitamin D receptor genotypes defined by the BsmI polymorphism and to investigate their association with bone mineral density in patients with primary biliary cirrhosis. Vitamin D receptor genotype and bone mineral density at the lumbar spine was determined in 31 female Hungarian patients with primary biliary cirrhosis and 51 age-matched healthy female controls. The genotype frequency (BB: 45%, Bb: 32%, bb: 22%) of the patients was significantly different from the control group (P = 0.01) due to an overrepresentation of the BB genotype. There was an apparent trend, not reaching statistical significance, for a lower bone mineral density in both the patient and control groups carrying a B allele. In conclusion, we found a strikingly high frequency of the BB genotype in patients with primary biliary cirrhosis, which raises questions about hormonal influences on the development of primary biliary cirrhosis.

[Activity of neutral endopeptidase in serum of patients with primary biliary cirrhosis]. / Neutrális endopeptidáz-aktivitás primer biliaris cirrhosisos betegek szérumában.

Neutral endopeptidase (neprilysin; EC 3.4.24.11) is present in the brush border membrane, for example in the bile ducts. We investigated serum neprilysin activity and its correlation with cholestatic markers in patients with primary biliary cirrhosis. Sera of 39 patients with primary biliary cirrhosis (37 females, 2 males, mean age 45 years, range 24-71 years) were investigated. Twenty-seven healthy volunteer subjects served as control. Serum neprilysin activity was measured by a sensitive microplate-based continuous monitoring kinetic assay. Succinyl-alanyl-alanyl-phenyl-alanyl-4- nitroanilide was used as substrate. For statistical analysis Kruskal-Wallis ANOVA by ranks and Mann-Whitney U test were used. The neprilysin activities were significantly higher in stages III (mean 13.2 +/- SD 10.8 U/l) and IV (21.8 +/- 17.5) than in the control subjects (2.4 +/- 2.9, p < 0.01). There was no significant difference in neprilysin activity between the patients with stages I and II, or between stage I + II (2.88 +/- 3.0) and the control. Positive correlation was found between the activity of neprilysin and serum bilirubin, alkaline-phosphatase and gamma-glutamyl-transferase (p < 0.005 for each). In this study we confirmed that serum neprilysin activity is elevated in patients with primary biliary cirrhosis at advanced stages and the elevation correlated with the cholestatic markers. The increased neprilysin activity seems to be an indicator for the severity and progression of the disease.

Changes in the acute phase complement component and IL-6 levels in patients with chronic hepatitis C receiving interferon alpha-2b.

In order to study the effect of interferon alpha on the levels of acute phase complement proteins in vivo, serum concentrations of C9 and C1-inhibitor (C1-INH) were measured in patients with chronic hepatitis C before and 3 months after the beginning of interferon alpha2b therapy. Serum levels of the activation product of terminal complement pathway, C5b-9, HCV RNA and IL-6 were also determined. IFN alpha treatment significantly (P<0.0001) increased the serum concentrations of both complement proteins. C5b-9 levels were found to significantly decrease during the same period of time. When the patients were divided into responders or non-responders (more or less than 50% decrease in plasma HCV RNA concentrations) C9 and C1-INH levels were elevated only in the responder patients. There was no correlation between the changes of IL-6 levels or the amounts of IFN alpha administrated on one hand, and the changes in the complement protein levels on the other. These findings suggest that the marked increase in the serum concentrations of the acute phase complement proteins is a secondary phenomenon due to the IFN alpha-caused diminution of the viral load and the resulting immune complex-induced complement activation.

Effects of interferon treatment on the glucose metabolism of patients with chronic hepatitis C.

Background: The authors report on changes in carbohydrate metabolism observed in 32 patients undergoing therapy with interferon-alpha for chronic hepatitis C. Methods: Diabetes had been diagnosed in three patients and impaired glucose tolerance ascertained in one patient before interferon therapy was started. The remaining 28 patients were non-diabetic. Interferon-alpha was administered in 3-MU doses three times per week. Results: Glucose tolerance deteriorated in two of the three diabetics, and eventually these patients had to be switched from oral hypoglycemic agents to insulin. The patient with impaired glucose tolerance at baseline progressed gradually to overt diabetes. Nine of the 28 previously non-diabetic patients developed impaired glucose tolerance during interferon therapy. Conclusion: The deleterious effects of interferon-alpha on carbohydrate metabolism proved to be reversible. Regular monitoring of the glucose level of patients during and after interferon therapy is mandatory.

[Effect of interferon therapy on carbohydrate metabolism in chronic hepatitis C patients]. / Interferon kezelés hatása a hepatitis C vírus indukálta krónikus májbetegek szénhidrát-metabolizmusára.

Reversible impact of alpha-interferon on carbohydrate (CH) metabolism was observed in patients with hepatitis C treated with interferon between 1993 and 1997. Of the 32 patients 3 individuals had known to have diabetes mellitus before the treatment and 1 had impaired glucose tolerance (IGT). 28 patients proved to have normal CH metabolism before the interferon treatment. To each patients was interferon alpha was administrated in a dose 3 MU TIW. During the 6 months interferon therapy of the 3 patients treated with oral antidiabetic drug one's diabetes mellitus did not deteriorated, but 2 patients required insulin therapy. In the patient with known IGT a manifested diabetes mellitus has gradually developed. Out of the 28 patients with normal CH metabolism in 9 cases developed IGT, 19 patient's CH metabolism did not change significantly. All of the changes induced by interferon proved to be reversible.

Coincidence of hereditary angioedema (HAE) with Crohn's disease.

A patient with two diseases, based presumably on different immunopathological mechanisms, hereditary angioedema (HAE) and Crohn's disease, was followed for 8 years. For more than three years of this observation period, detailed laboratory data were also available and could be analyzed. Both diseases had severe courses requiring chronic treatment with danazol and sulfasalazine, respectively. During exacerbation of Crohn's disease, the levels of C4 was found to be significantly lower than during the periods free of symptoms of both diseases. This drop was probably due to an impaired C1-inhibitor activity. HAE attacks and acute exacerbation of Crohn's disease never occurred simultaneously. This finding may be a mere chance but may also indicate that the different immunopathological processes underlying HAE and Crohn's disease influence each other.

[Practical considerations of immunoprophylaxis in viral hepatitis]. / Hepatitis vírusfertözések immunprofilaxisának gyakorlati vonatkozásai.

Hepatitis virus infections belong to the major etiological factors of both acute and chronic liver diseases. During the last years--apart from the passive immunoprophylaxis through the administration of immunoglobulin--safe and efficacious hepatitis vaccines (against hepatitis A and B viruses) has also became available in Hungary. In this review the authors focus on the practical considerations of the immunoprophylaxis of hepatitis viruses. General consensus concerning the clinical use of hepatitis A vaccine has not been accepted, and human immunoglobulin is the only acceptable measure to prevent postexposure hepatitis A virus infection. Hepatitis B immunoglobulin (HBIG) is administered to prevent hepatitis B infection after exposure of HBV-contaminated body fluids and in infants born to HbsAg-positive mothers. Recombinant hepatitis B vaccine has the crucial note in the WHO's program for eradication of hepatitis B. While in the areas of high endemicity the implementation of universal hepatitis B vaccination is recommended, in the countries with low HbsAg-carrier prevalence infants' and/or adolescents' vaccination can offer alternative choices. Prevention of health-care workers against hepatitis virus infection and the vaccination of patients with chronic liver disease are also of great importance. There is also an urgent need to establish multidisciplinary professional cooperation to be able to carry out effectively the WHO's recommendations for prevention of hepatitis B infection.

[Cryoglobulinemia and chronic liver diseases]. / Kryoglobulinämie und chronische Lebererkrankungen.

Cryoglobulinemia can be associated with several infections, immunoproliferative tumors, chronic liver, renal and systemic autoimmune diseases. In the first part of the publication the authors give a review of the main clinical and laboratory properties of cryoglobulins. In essential mixed cryoglobulinemia syndrome (purpura, arthralgia, weakness) clinical and laboratory signs of damaged liver function can often be seen. However, there are mixed cryoglobulins in chronic liver disease of different etiologies as well. In 30-94% of patients with hepatitis C virus infection and hepatitis C virus-induced chronic liver diseases laboratory signs (occasionally clinical symptoms as well) or mixed cryoglobulinemia can be diagnosed. Serological markers of hepatitis C virus infection have been found in the cryoprecipitates of patients with mixed cryoglobulinemia. A high prevalence of mixed cryoglobulins in serum of patients with chronic hepatitis C virus infection and hepatitis C virus-induced chronic liver disease suggests that this virus has a significant role in the pathogenesis of mixed cryoglobulins. Also, an impaired clearance function of the liver in the uptake of cryo(immuno)complexes may be an important causative factor in the production of cryoglobulins in chronic liver diseases of different etiologies.

[Simultaneous occurrence of hereditary angioneurotic edema and Crohn disease]. / Hereditaer angioneuroticus oedema és Crohn-betegség együttes elöfordulása.

Hereditary C1 esterase inhibitor deficiency is often associated with immunpathologic disorders. The authors present a case of the rare coincidence of hereditary angioedema (HAE) and Crohn's disease. The history of the patient is analysed along with the familial occurrence of the disease. Characteristic abdominal manifestations of C1 esterase inhibitor deficiency are compared to the clinical signs of Crohn's disease. Differential diagnostic pitfalls are described along with efficatious therapeutic options.

[Cryoglobulinemia in chronic liver diseases: cause or consequence?]. / Cryoglobulinaemia krónikus májbetegségekben: ok, vagy következmény?

Cryoglobulinemia occurs in a wide spectrum of infectious, autoimmune, neoplastic, renal and liver diseases. In the first part of the publication the authors give a review about laboratory and clinical features of cryoglobulinemia and its associated syndromes. In essential mixed cryoglobulinemia (arthralgia-purpura-weakness) clinical and laboratory evidence of liver involvement are frequently found. In chronic liver diseases of different etiologies mixed cryoglobulins can be detected. In 30-94% of cases of chronic hepatitis C virus infection and chronic liver diseases related to hepatitis C virus laboratory signs (and occasionally clinical symptoms as well) of mixed cryoglobulins have recently been reported. In the cryoprecipitates of these cryoglobulins positive patients markers of hepatitis C virus have been detected. The presence of high prevalence of cryoglobulins in chronic hepatitis C virus infection and chronic liver diseases related to hepatitis C virus suggests a significant role for this hepatotropic virus in the pathogenesis of mixed cryoglobulins. On the other side, the impact of impaired liver function in the clearance of (cryo)immunocomplexes from the serum can be a causative factor in the production of cryoproteins in chronic liver disease of different etiologies.