[Abnormal hepatic function tests in pregnancy: causes and consequences]. / Kóros májlelet áldott állapotban: okok és teendok.

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.

[Clinical correlations of chronic hepatitis C, diabetes mellitus and steatohepatitis]. / A hepatitis C, a diabetes mellitus és a steatosis hepatis kapcsolatának néhány klinikai vonatkozása.

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.

Serum anti-cholesterol antibodies in chronic hepatitis-C patients during IFN-alpha-2b treatment.

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.

[Relationship of the clinician and the pathologist at the turn of the millennium]. / A klinikus és a patológus kapcsolata az ezredfordulón.

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 future of pathology--from the viewpoint of clinical pathology]. / A patológia jövóje--a klinikai patológia oldaláról.

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.

[Ultrastructural findings in the liver due to long-term retinol (isotretinoin) treatment. Significance of the perisinusoidal (Ito) cells]. / Retinoid (isotretionin) tartós kezelés mellékhatásait feltáró ultrastrukturális elváltozások a májban.

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.

[Determination of the lamivudine-resistant mutants of hepatitis B virus]. / A hepatitis B-vírus lamivudinrezisztens mutánsainak meghatározása.

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.

Characterization of a lipoyl domain-independent B-cell autoepitope on the human branched-chain acyltransferase in primary biliary cirrhosis and overlap syndrome with autoimmune hepatitis.

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.

Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-alpha2b.

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.