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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. [ABSTRACT FROM AUTHOR]

The well-known normal ranges of laboratory parameters are altered due to the broad spectrum of physiological changes as well as proinflammatory and procoagulant effects of pregnancy. Hepatic disorders of any aetiology can cause potential problems during gravidity. Most frequently toxic-effects, hepatotrop viruses (such as hepatitis B and C), metabolic syndrome and diseases with autoimmune background can be observed. When dealing with "pregnancy-specific hepatic syndromes", it is very important to consider the "timing-factors" of pathologic changes and deterioration of clinical pictures as well. Due to the progress in cholestasis management, early termination of pregnancy can be avoided in many cases. As the overlap is really broad between various hepatic disorders, a multidisciplinary cooperation of different sub-disciplines is emphasized in order to achieve proper diagnosis and curative measures at early phase.

Subsequent studies have implicated the hepatitis C virus (HCV) core protein in the pathogenesis of hepatic steatosis. Chronic HCV infection may also cause steatosis by impairing fatty acid oxidation. There is relationship between accumulation of fat into the liver and overweight and/or obesity. Another unexpected virus-host interaction is the HCV infection and diabetes. HCV encoded proteins might alter insulin signaling thus explaining impaired insulin sensitivity and the occurrence of glycaemic dysregulation. Some pieces of the puzzle are still not well known; e.g. the factors and the spectrum of disorders associated with insulin resistance, and whether the liver is a trigger or target of metabolic syndrome? In this review article clinical consequence of chronic HCV infection, diabetes mellitus and hepatic steatosis are discussed, as well as their possible effects on antiviral therapy.

A twenty year old, foreign-born sportsman visited the Out-patient Clinic of our Hospital with complaints of progressive arthralgia, hepatomegaly and increasingly abnormal liver function tests of six months duration. Tests for virus hepatitis were negative, alcohol abuse or drug addiction could be excluded. An open needle biopsy of the liver was performed and the tissue was examined with the light and electron microscope. On routine light microscopy no abnormality was recognized. Electron microscopic examination revealed changes characteristic of vitamin A toxicity: hyperplasia of the perisinusoidal (Ito) cells with evidence of their activation and transformation, increased storage of lipids and vitamin A, perisinusoidal fibrosis, damage of the sinusoidal wall, partial necrosis in hepatocytes and an increased number of lysosomes, megalysosomes and smooth endoplasmic reticulum (SER), the signs of cholestasis as well as an increased number of Kupffer cells in the lobules etc. Histochemical examination showed a high content of vitamin A in the transitional (Ito) cells and in hepatocytes. These data led to further questioning of the patient who disclosed that he had acne conglobata which had been treated with Isotretionin, 20 mg/day, for more than half a year. After the therapy was stopped, the symptoms of polyarthralgia improved and after a few months they ceased entirely, however, the laboratory data returned to normal only after a long period of time. This case indicates that electron microscopic examination of the liver biopsy may play an important role in the recognition of vitamin A intoxication. It also illustrates that symptoms of joint disease may be caused by long-term retinoid treatment. The authors have presented the latest clinical and experimental data concerning the changes in the liver, joints and skeleton caused by retinoid intoxication.

Previously we observed elevation of the serum concentration of two acute-phase protein (AFP) complement components (C9 and C1-inhibitor) in patients with chronic hepatitis C who responded (R) to IFN-alpha therapy, but not in non-responders (NR). In the present study we investigated the effect of high-dose IFN-alpha therapy on serum concentrations of two positive [orosomucoid (OROSO) and C-reactive protein (CRP)] and two negative [transferrin (TF) and fetuin/alpha2HS-glycoprotein (AHSG)] AFP in an outpatient setting. We investigated blood samples of 40 patients with chronic hepatitis C at the onset and at the end of a 3-month treatment with high-dose IFN-alpha2b (5 MIU/day for 6 weeks, followed by 5 MIU t.i.w.) and of 52 healthy individuals. Serum concentrations of OROSO, TF and AHSG were measured by radial immunodiffusion; CRP levels were determined by immunotubridimetry. Compared to controls, patients with chronic hepatitis C had significantly lower OROSO and CRP, and higher AHSG levels. By the end of treatment, OROSO concentration increased in R (P = 0.0054), but not in NR patients. In contrast, TF levels decreased in R (P = 0.0040), but did not change in NR patients. Similarly, in R patients, AHSG levels tended to decrease (P = 0.0942) following IFN-alpha treatment. We conclude that the acute-phase reaction is suppressed in patients with chronic hepatitis C that may be potentially related to the responsiveness to IFN-alpha therapy.

Introduction: In addition to interferon, lamivudine is the other widely used antiviral agent in the therapy of chronic hepatitis B. This nucleoside analogue inhibits the RNA-dependent DNA polimerase and the reverse transcription by integrating in the viral DNA, which results in the secondary suppression of viral protein synthesis and replication of HBV. It has numerous advantages such as effective viral inhibition, mild side effects and the possibility of oral administration; on the other hand it poses the problem of time-correlated appearance of lamivudine resistant mutants during therapy., Aims: In the Virusserology Laboratory of the Department I. Internal Medicine, Szent György Hospital, Székesfehérvár, detection and type determination of the therapy resistant mutants in the C and B domains of HBV DNA polimerase gene has been carried out the for one year. In this paper, the authors review the molecular biological background of lamivudine resistance and summarise the applied test methodologies and the early results., Patients: Six-month and/or 12-, 18-month samples of 18 chronic hepatitis B patients (4 women/14 men) treated in seven Hepatology Centres in Hungary were analysed., Methodology: Mutants of codons 528, 552, and 555 in the HBV polimerase gene were determined by nested polimerase chain reaction and reverse hybridisation., Results: M528, V552, I552 and I555 mutants in different variations could be detected in ten out of 18 patients., Conclusions: Nowadays, drug therapy is the only treatment option used for the therapy of early and progressed chronic hepatitis B in Hungary. This new diagnostic technique was introduced to clarify the background of ineffective lamivudine therapy. Therapy resistance can occur due to the lack of reaction or the appearance of the special, therapy resistant mutants of the virus. Detection of these YMDD mutants together with the clinical picture and the biochemical and virological parameters can help in forming a decision about cessation of lamivudine therapy or application of a new drug.

Background and Aims: Antimitochondrial antibodies (AMA) which recognize pyruvate acetyltransferase (PDC-E2) represent a highly diagnostic feature of primary biliary cirrhosis (PBC). The analysis of immunofluorescence (IF)-AMA-positive sera in PBC patients indicates a conformational epitope located within the lipoyl binding domain of bovine branched-chain acyltransferase (BCKADC-E2) alone or in combination with AMA directed against PDC-E2 the significance of which is presently unclear. In the present study, immunoreactivities and disease associations of AMA against BCKADC-E2 were analyzed. B-cell autoepitopes on BCKADC-E2 were mapped by immunoprecipitation assay., Methods: Sera of 96 IF-AMA-positive patients with serological evidence of anti-BCKADC-E2 alone (n = 26), anti-PDC-E2 alone (n = 15), and both anti-BCKADC-E2 and anti-PDC-E2 (n = 55) were analyzed by Western blot and ELISA in addition to an analysis of B cell autoepitopes on BCKADC-E2 by immunoprecipitation using in vitro translated, unmodified human proteins. Ninety-four patients without IF-AMA [blood donors (n = 30), rheumatoid arthritis (n = 40), autoimmune hepatitis (AIH)(n = 10) and primary sclerosing cholangitis (PSC) (n = 14) served as controls., Results: Eighty of 81 (99%) sera positive for BCKADC-E2 recognized the full length, mature protein, while only 2/10 AIH sera and none of the other controls showed reactivity. Of the 68 PBC sera 58 (85%) recognized the N-terminus consisting of aa 1-144 representing the lipoyl domain. Surprisingly, C-terminal sequences (aa 143-421) were recognized by 46 out of 68 sera (68%). Three PBC sera reacted with the C-terminus only. Only 1/7 serum from patients with an "overlap syndrome of PBC and AIH" was reactive with C-terminal sequences., Conclusions: Our analysis of BCKADC-E2-positive PBC sera identified a novel B cell epitope on the C-terminal part of the human protein. Our data indicate that a distinct subset of AMA recognize sequence(s) on BCKADC-E2 which located outside of the lipoyl binding domain. The absence of immunoreactivity against C-terminal sequences may serve as a marker differentiating patients with PBC and overlap syndrome of PBC with AIH.

Previously we detected more than 3 times higher anti-cholesterol antibody (ACHA) levels in HIV positive patients compared to healthy individuals, however, this level significantly decreased during highly active anti-retroviral therapy (HAART). In our present study we examined whether these findings could also be detected in patients with chronic hepatitis C (CHC). We calculated the correlation between the ACHA levels and the C5b-9 complement activation product. 39 patients with CHC were treated with IFN-alpha-2b (Schering-Plough) 5 MU daily for 6 weeks, followed by 5 MU TIW. Serum levels of ACHA and complement activation products were measured with ELISA. Serum HCV RNA was measured by a highly sensitive branched DNA technique before and 3, 6 and 12 months after the beginning of IFN-alpha-2b therapy. 52 healthy persons served as controls. At the onset of treatment ACHA level was significantly (p = 0.0062) higher in patients (40 (24-69) AU/ml) (median (interquartile range)) than in control sera (26 (20-35) AU/ml). In the 26 responder patients ACHA levels decreased to the normal level during the therapy, but no change was observed in the 13 non-responders. In patients with a sustained response ACHA levels remained low till the end of the 12 months IFN treatment. ACHA levels were significantly (p = 0.0422) higher in the patients with low (< 4.0 mmol/l) than in those with normal (> or = 4.0 mmol/l) cholesterol concentrations. The ACHA level before the therapy strongly correlated (r = 0.5499, p = 0.0014) with C5b-9 serum levels. ACHA levels are elevated in CHC, but this elevation is not as high as in HIV. Decrease of viral load by IFN-alpha-2b treatment in the responders results in normalization of ACHA concentration. High ACHA levels in patients with low serum cholesterol concentration suggest that high ACHA levels may contribute to the decrease in cholesterol levels. The correlation between the ACHA and C5b-9 levels indicate, that the ACHA may play a role in the complement activation in CHC.

Pathology is one of the fundamental diagnostic fields of medicine, its position has changed and will undergo transformation in the 21st century due to the introduction of new methods. Theoretically, pathology was based upon 3 pillars: 1. the autopsies, 2. the surgical pathology, i.e. the processing and evaluation of different biopsies and surgically resected specimens and 3. the cytological investigations. The autopsy was the dominant field till the end of the seventies of the 20th century but about the turn of the 20th and 21st century the cytology, first of all the fine needle aspiration cytology took over the leading role in the pathologic diagnostic activity. This displacement resulted in such a high decrease in the number of autopsies that it is impossible to conclude appreciable epidemiological statements. Meanwhile the role and position of the pathologist has changed also substantially. Previously he was regarded often as a prosecuting attorney. At present time this opinion is transformed into clinical pathologist. Errors in the histopathological diagnosis and reporting can occur in the surgical pathology but its number is not high. To detect and to avoid them is attainable by composition of an adequate audit-system. The number of the new investigatory methods is increasing nowadays wide-spreadingly in the medicine and so in the pathology too. The immunocytochemistry is regarded already as a conventional method but the PCR and FISH-technique are applied also on a large scale. At the same time, new tools such as the cDNA microarray technology, the micro-chip based analytical chemistry, the laser capture microdissection and the wireless medical information appear also in the pathology. The modern information technology is impacted more intensively into the day-to-day pathological work. This method enables to develop worldwide communicating systems which can make perfect the diagnostic work. The pathologist has traditionally functioned as a medical consultant to the clinician. The predominant function of the pathologist has to be evolved from that of medical consultant to that of information specialist.

The autopsy, once a fundamental and familiar component of medical practice based on the good cooperation of clinicians and pathologist, is now infrequently used. Recent data indicate that autopsies are performed only about one third of the cases in Hungary and less that 1 of 10 inpatients death in the united States. Explanation for this decrease is multifactorial, involving changing professional and patients attitudes, the advent of sophisticated antemortem diagnostic methods, socioeconomic factors, and medicolegal concerns as well. Teaching institutions need to reevaluate concerning the need and practice of the autopsy. "The final audit" not always reflect well on clinical diagnoses and management of patients. Many facts proves that our modern tools still not enough to reach always a correct and safe diagnoses. Errors are still common in medicine. About 10% of necropsies indicate a clinical managements different from what the patients received, 20% reveal additional diagnoses, and 60% of cases have teaching point. Though autopsy is expensive and time consuming, moreover the shortage of pathologist is evident, necropsy should remain the cornerstone of medicine in the new millennium as well. There are a broad range of different fields where pathologist and clinicians should work together in an everyday--setting--e.g. evaluate biopsy- or cytology-samples. Clinicopathological conferences are also important to discuss cases mainly for teaching purposes. Without maintaining the traditionally good cooperation neither clinicians nor pathologists will be able to give proper answers to the challenges and professional questions of the new era.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.