We report the case of a 53-year-old man with inflammatory pseudotumor (IPT) of the liver and spleen. This concomitant association has rarely been reported. The patient presented with a hypoechoic mass in the liver and a...We report the case of a 53-year-old man with inflammatory pseudotumor (IPT) of the liver and spleen. This concomitant association has rarely been reported. The patient presented with a hypoechoic mass in the liver and a clinical picture of recurrent sepsis; hematochemical exams and imaging data were nonspecific. Antibiotic therapy improved the clinical course, but did not resolve it definitively. After 50 days of therapy, as the hepatic mass decreased a similar lesion appeared in the spleen. The final diagnosis was made on splenectomy and an intra-operative biopsy of the residual liver lesion. The diagnostic problems encountered in this very rare association of IPT of the liver and spleen were similar to those for isolated IPT in the respective single organ sites. After 15 months of follow-up, the patient is in good health and no recurrence of symptoms or masses has been observed.
We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was di...We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.
BACKGROUND/AIMS: In this study the safety and efficacy of a monoclonal anti-HBs, Tuvirumab (Mab), were investigated. Tuvirumab is a human monoclonal antibody recognizing the stable 'a'-determinant of the HBsAg. METHODS:...BACKGROUND/AIMS: In this study the safety and efficacy of a monoclonal anti-HBs, Tuvirumab (Mab), were investigated. Tuvirumab is a human monoclonal antibody recognizing the stable 'a'-determinant of the HBsAg. METHODS: We included ten chronic hepatitis B patients: four received monotherapy, and six combination therapy with interferon alpha 2b. RESULTS: Because the development of insoluble [HBsAg-HBsAb] complexes led to adverse events, the Mab dose had to be reduced in seven patients. In nine patients treatment was stopped prematurely because of lack of efficacy, i.e. neutralization of HBsAg in serum. However, temporary HBsAg levels were reduced by at least 50% in all patients; in three patients receiving combination therapy, background levels of HBsAg in serum were reached. A loss of serum HBV-DNA was seen in three patients in the combination group, followed by HBeAg seroconversion in two patients. CONCLUSIONS: We conclude that Mab was not effective in achieving primary efficacy as assessed by neutralization of circulating HBsAg. Whether a combination of Mab with an antiviral agent that reduces the HBsAg load--and therefore minimizes the risk of adverse events--may result in clinical efficacy should be investigated.
BACKGROUND/AIMS: Nitric oxide is synthesized in diverse mammalian tissues by a family of calmodulin-dependent nitric oxide synthases (NOS). Caveolin, the principal structural protein in caveolae, interacts with endotheli...BACKGROUND/AIMS: Nitric oxide is synthesized in diverse mammalian tissues by a family of calmodulin-dependent nitric oxide synthases (NOS). Caveolin, the principal structural protein in caveolae, interacts with endothelial NOS leading to enzyme inhibition in a reversible process modulated by Ca++-calmodulin. The aim of the present study was to clarify the ultrastructural localization of eNOS and caveolin-1 in hepatic sinusoidal endothelium by an electron immunogold method. METHODS: Male Wistar rats were used. Liver tissues and hepatic sinusoidal endothelial cells isolated from rat livers by collagenase infusion were studied. For immunohistochemistry, liver specimens were reacted with anti-eNOS or anti-caveolin-1 antibody. The ultrastructural localization of eNOS or caveolin-1 was identified by electron microscopy using an immunogold post-embedding method. RESULTS: Immunohistochemical studies using liver tissues localized endothelial NOS in hepatic sinusoidal lining cells, portal veins and hepatic arteries; and caveolin-1 in sinusoidal lining cells, bile canaliculi, portal vein and hepatic arteries. Immunogold particles indicating the presence of eNOS and caveolin-1 were demonstrated on the plasma membrane of sinusoidal endothelial fenestrae in liver tissue and also in isolated sinusoidal endothelial cells. CONCLUSION: Endothelial NOS and caveolin are co-localized on sinusoidal endothelial fenestrae, suggesting that interaction of the two may modulate cellular regulation of NO synthesis.
BACKGROUND/AIMS: The development of retinal lesions induced by a uniform regimen of interferon-alpha therapy for chronic hepatitis C was prospectively investigated. METHODS: Eighty-one patients received 6 mega units of n...BACKGROUND/AIMS: The development of retinal lesions induced by a uniform regimen of interferon-alpha therapy for chronic hepatitis C was prospectively investigated. METHODS: Eighty-one patients received 6 mega units of natural interferon-alpha intramuscularly daily for 2 weeks and then 3 times a week for 22 weeks. The total dose of interferon-alpha administered was uniformly 478 mega units per patient. Two expert ophthalmologists prospectively examined the patients for retinal lesions before, during and after the therapy. RESULTS: Retinopathy was not found in comparison groups or any of the patients before treatment. In total 34.6% (28/81) of the patients showed cotton-wool spots or minor retinal hemorrhage, or both lesions, during therapy, but these lesions were reversed during or after interferon therapy. The occurrence rates of cotton-wool spots alone, retinal hemorrhage alone and both lesions were 13.6% (11/81), 6.2% (5/81), and 14.8% (12/81), respectively. The appearance of retinopathy did not correlate with patients' background including viral loads and response to the therapy, but was more frequently found in older patients and patients with hypertension and/or diabetes mellitus; disappearance of retinopathy was more prolonged than in patients without these complications. Almost all the lesions appeared 2-4 months after the start of the therapy, and the severity of the lesions did not differ between patients with and without hypertension and/or diabetes mellitus. CONCLUSION: Although it is not clear if interferon-associated retinopathy occurs in a dose-dependent manner, the present study shows a standard pattern of the occurrence of retinopathy in patients with chronic hepatitis C receiving a uniform dosage of natural interferon-alpha.
BACKGROUND/AIMS: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) is a key transcription factor that induces multip...BACKGROUND/AIMS: Idoxifene is a tissue-specific selective estrogen receptor modulator. Estradiol is a potent endogenous antioxidant, and nuclear factor kappaB (NF-kappaB) is a key transcription factor that induces multiple genes in response to inflammation or oxidative stress. The aim of this study was to explore the inhibitory effects of idoxifene and estradiol on NF-kappaB activation in hepatocytes in a state of oxidative stress. METHODS: Lipid peroxidation was induced in cultured rat hepatocytes by incubation with ferric nitrilotriacetate solution. NF-kappaB activity was evaluated by electrophoretic mobility shift assay. RESULTS: The oxidative stress-induced activation of NF-kappaB and degradation of IkappaB-alpha were maximal at 3-5 h, with an increase in lactate dehydrogenase (LDH) and malondialdehyde (MDA) secretion into the culture medium. Treatment with idoxifene and estradiol inhibited IkappaB-alpha degradation and NF-kappaB activation through the attenuation of hepatocyte oxidative bursts and decreased extracellular levels of LDH and MDA. In addition, idoxifene and estradiol inhibited lipid peroxidation in rat liver mitochondria. A potent NF-kappaB inhibitor, pyrrolidine dithiocarbamate, prevented NF-kappaB activation by inhibition of IkappaB-alpha degradation and decreased LDH and MDA levels, suggesting that NF-kappaB might be a regulator in a genetic response to increase oxidative stress-induced hepatic injury. CONCLUSIONS: These findings suggest that idoxifene and estradiol function as antioxidants and protect hepatocytes from inflammatory cell injury.
Although the prognosis of biliary atresia has been improved in recent years, particularly in the era of liver transplantation, hepatic portoenterostomy, e.g., the Kasai operation, is still the first line of surgical trea...Although the prognosis of biliary atresia has been improved in recent years, particularly in the era of liver transplantation, hepatic portoenterostomy, e.g., the Kasai operation, is still the first line of surgical treatment. Successful hepatic portoenterostomy depends on early diagnosis and operation, adequate operative technique, prevention of postoperative cholangitis, and precise postoperative management. The pathophysiology of the liver and of the intrahepatic bile ducts in this disease is still controversial.
In recent years, the role of nitric oxide (NO) in the pathogenesis of liver disease and its complications has been extensively studied. There remain, however, many areas of controversy. In particular, the effect of NO on...In recent years, the role of nitric oxide (NO) in the pathogenesis of liver disease and its complications has been extensively studied. There remain, however, many areas of controversy. In particular, the effect of NO on vascular function in the systemic circulation and the hepatic microcirculation has received the greatest attention. It has been proposed on the one hand that increased NO synthesis is responsible for the development of the hyperdynamic circulation in cirrhosis, while decreased production of NO within the hepatic microcirculation may be important in the development of parenchymal tissue damage and the onset of portal hypertension. The purpose of this review is to examine the available data concerning the role of NO in liver disease and to discuss some of the controversies and contradictions that surround it.
BACKGROUND/AIMS: Growth hormone (GH), when overexpressed in male and female GH-transgenic mice, is known to induce liver tumours within 1 year. This study aimed to gain a clearer understanding of the interaction between...BACKGROUND/AIMS: Growth hormone (GH), when overexpressed in male and female GH-transgenic mice, is known to induce liver tumours within 1 year. This study aimed to gain a clearer understanding of the interaction between GH and tumour cells in vivo. METHODS/RESULTS: The carcinogen diethylnitrosomine (DEN) was administered to neo-natal transgenic and non-transgenic mice maintained in a "hepatocarcinogenesis resistant" genetic background (C57BL/6J). Macroscopic, microscopic and liver weight/body weight ratio analyses revealed that carcinogen-induced hepatocarcinogenesis was dramatically accelerated in young GH-transgenic mice compared to non-transgenic counterparts. Image analysis of microscopic hepatocellular neoplasms showed rapidly increasing tumour burdens, and neoplastic foci size over time in young adult GH-transgenic mice. The magnitude of enhanced tumour growth was equivalent in both male and female transgenic mice, whereas much lower and sexually dimorphic tumour growth rates (males>females) were observed in non-transgenic mice treated with DEN. BrdU labelling experiments demonstrated that rapid tumour growth in carcinogen-treated GH-transgenic mice was due to the promotion of cell proliferation in emerging lesions. Tumour cell proliferation in young GH-transgenic mice was 2.6- and 4-fold higher, respectively, than that observed in similar age male and female non-transgenic mice. Interestingly, both GH-transgenic and non-transgenic mice displayed progressively slower tumour growth rates in older animals. CONCLUSION: Overall, GH synergistically promotes carcinogen-induced hepatocarcinogenesis in both sexes of GH-transgenic mice by stimulating tumour cell proliferation.
BACKGROUND/AIMS: Recent reports of an association between human leucocyte antigens (HLA) and persistence of hepatitis B virus infection, and the familial clustering of hepatocellular carcinoma raise the question of genet...BACKGROUND/AIMS: Recent reports of an association between human leucocyte antigens (HLA) and persistence of hepatitis B virus infection, and the familial clustering of hepatocellular carcinoma raise the question of genetic susceptibility. Previous studies have been limited to serological phenotyping of HLA B and DR antigens. The aim of this study was to use molecular genotyping to investigate HLA class II as a risk factor for the development of hepatocellular carcinoma in Hong Kong Chinese. METHODS: We determined HLA DRB1, DQA1, DQB1 and DPB1 alleles in 123 hepatitis B surface antigen positive patients (84 with hepatocellular carcinoma and 39 without) and 124 matched controls. RESULTS: The alleles DRB1*1501 (36% of HCC patients versus 19% of controls, odds ratio=2.44), DQA1*0102 (42% versus 26%, odds ratio=2.07), and DPB1*0501 (80% versus 63%, odds ratio=2.35) were significantly more common in patients with hepatocellular carcinoma, and DQA1*03 (36% versus 56%, odds ratio=0.53), DQB1*0302 (4.% versus 13%, odds ratio=0.25) and DPB1*0201 (14% versus 29%, odds ratio=0.4) were found at significantly lower frequencies. CONCLUSIONS: Although none of these associations was significant after correction for multiple testing, this report suggests that further investigations are warranted.
AIMS/BACKGROUND: The hepatitis C virus (HCV) core protein is known to play an important role in hepatocarcinogenesis. Recent studies have suggested that the increased proliferation rate of hepatocytes is a major risk fac...AIMS/BACKGROUND: The hepatitis C virus (HCV) core protein is known to play an important role in hepatocarcinogenesis. Recent studies have suggested that the increased proliferation rate of hepatocytes is a major risk factor for the development of hepatocellular carcinoma. In this study, we investigated whether the HCV core protein promotes the cell growth rate through the modulation of cyclin E expression levels. METHODS/RESULTS: HCV core stable transfectant Rat-1 cell lines showed a markedly increased proliferation rate compared to mock cells. Cyclin E expression and its associated kinase activities were remarkably increased in HCV core stable transfectants. Cyclin E mRNA levels were also upregulated in these cell lines. CONCLUSIONS: Our data suggest that the HCV core protein promotes cell proliferation through upregulation of the cyclin E expression levels, implying this property of HCV core protein plays an important role in hepatocarcinogenesis.
AIMS/BACKGROUND: Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alc...AIMS/BACKGROUND: Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non-alcoholic fibrosis or cirrhosis. METHODS: Interventions encompassed peroral colchicine at any dose versus placebo or no intervention. The trials could be double-blind, single-blind or unblinded. The trials could be unpublished or published as an article, an abstract, or a letter, and no language limitations were applied. All analyses were performed according to the intention-to-treat METHOD: MEDLINE, The Cochrane Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled Trials Register and full text searches were combined. RESULTS: Combining the results of 14 randomized clinical trials including 1138 patients demonstrated no significant effects of colchicine on mortality (odds ratio (OR): 0.91; 95% confidence interval (CI) 0.64, 1.31), liver related mortality (OR: 0.98; CI 0.56, 1.74), complications (OR: 1.06; CI 0.65, 1.73), and the other outcomes. Colchicine was associated with a significantly increased risk of adverse events (OR: 4.41; CI 2.24, 8.70; p< 0.001). CONCLUSIONS: Colchicine should not be used for liver fibrosis or liver cirrhosis irrespective of etiology. Future trials on colchicine for liver diseases ought to be large.
BACKGROUND/AIMS: Insulin-like growth factor-I (IGF-I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhos...BACKGROUND/AIMS: Insulin-like growth factor-I (IGF-I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF-I levels and BMD in patients with CLD of other causes. METHODS: Fifty-eight patients with CLD were included. Age- and sex-matched normal individuals served as controls. Serum levels of IGF-I and IGF-II and their binding proteins (IGFBP-1-3) were measured by radioimmunoassay. BMD was measured by dual energy X-ray absorptiometry. RESULTS: IGF-I levels were 57+/-33 and 136+/-48 ng/ml; p<0.0001 in patients and controls, respectively. IGF-II and IGFBP-3 levels were lower (p<0.0001) and IGFBP-1 and IGFBP-2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP-2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF-I, IGF-II, IGFBP-1-3 and BMD in either patients or controls. CONCLUSION: Patients with CLD have low levels of IGF-I, IGF-II and IGFBP-3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.
BACKGROUND/AIMS: A number of vasoactive substances have been implicated as potential mediators of intrahepatic portal hypertension. Endothelin (ET)-1 has been suggested to be involved in the regulation of hepatic microci...BACKGROUND/AIMS: A number of vasoactive substances have been implicated as potential mediators of intrahepatic portal hypertension. Endothelin (ET)-1 has been suggested to be involved in the regulation of hepatic microcirculation and development of portal hypertension. The aim of this study was to clarify the localization of two subtypes of ET receptors, ET A (ETAR) and B receptors (ETBR), in normal rat liver, and how the receptor expressions are altered in CCl4-induced cirrhotic rat liver. METHODS: Liver specimens were examined immunohistochemically after reacting with anti-ETAR and anti-ETBR rabbit polyclonal antibodies. Immunogold staining was also performed using the same antibodies, and examined under light and electron microscopy. RESULTS: In normal rat liver, immunohistochemistry revealed expression of ETAR and ETBR on the hepatic sinusoidal lining cells. By immunogold electron microscopy, electron-dense gold particles indicating the presence of ETARs were localized mainly on hepatic stellate cells (HSCs) and to a lesser extent on sinusoidal endothelial cells (SECs), while ETBRs were expressed equally intensely on HSCs and SECs. In cirrhotic animals, both ETAR and ETBR increased significantly on HSCs, while there were no significant increases in either receptor on SECs. CONCLUSIONS: In the normal state, HSCs possess both ETARs and ETBRs, while SECs mainly possess ETBRs. In cirrhosis, endothelins may exert more intense effects on HSCs via the enhanced ETARs and ETBRs, causing an increase in hepatic sinusoidal microvascular tone.
BACKGROUND/AIMS: The activation of hepatic stellate cells (HSC) to extracellular matrix (ECM) producing myofibroblasts (MFB) is the key pathogenetic event in human liver fibrogenesis. Latent transforming growth factor be...BACKGROUND/AIMS: The activation of hepatic stellate cells (HSC) to extracellular matrix (ECM) producing myofibroblasts (MFB) is the key pathogenetic event in human liver fibrogenesis. Latent transforming growth factor beta binding protein (LTBP), a component of the profibrogenic large latent transforming growth factor (TGF)-beta complex, is suggested to be important for secretion, latency, storage and activation of TGF-beta in the ECM. This study was performed to identify the expression profile of all hitherto known LTBP isoforms and LTBP splice variants in conjunction with that of TGF-beta isoforms in cultured human liver MFB. METHODS: Cultured human MFB were analyzed for TGF-beta and LTBP using reverse-transcription polymerase chain reaction (RT-PCR), sequence analysis, immunofluorescence staining, metabolic labeling, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Transcripts of all three TGF-beta isoforms, of all four LTBP isoforms and of nearly all splice variants of LTBP-1 and LTBP-4 so far known were detected. Metabolic labeling followed by immunoprecipitation with anti-LTBP-1 antibody revealed the synthesis of LTBP proteins. Secretion of free LTBP and LTBP integrated into the large latent TGF-beta complex was demonstrated by size-exclusion chromatography. Co-localization of LTBP-1 and -2 with fibronectin and collagen type I was observed by double immunofluorescence staining. CONCLUSION: The expression of a complete profile of hitherto known LTBP proteins by cultured human MFB suggests a role in modulating the bioactivity of TGF-beta in the diseased liver.
BACKGROUND/AIMS: Hepatocellular carcinoma is a common malignancy and a major complication of untreated haemochromatosis. Encapsulation of liver tumours has been associated with a better prognosis and longer disease-free...BACKGROUND/AIMS: Hepatocellular carcinoma is a common malignancy and a major complication of untreated haemochromatosis. Encapsulation of liver tumours has been associated with a better prognosis and longer disease-free periods following resection. This study investigated the source of the tumour capsule in patients with haemochromatosis and coexisting hepatocellular carcinoma and examined potential factors influencing development. METHODS: Five haemochromatosis patients with encapsulated hepatocellular carcinoma were studied. Myofibroblasts were identified using combined immunohistochemistry and in situ hybridisation for alpha-smooth muscle actin and procollagen alpha1(I) mRNA, respectively. Immunohistochemistry was also performed for transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-beta receptor and malondialdehyde. RESULTS: Procollagen alpha1(I) mRNA co-localised to alpha-smooth muscle actin positive myofibroblasts. The number of myofibroblasts was maximal within the capsule and decreased away from the tumour. TGF-beta1 protein was expressed in iron-loaded cells in non-tumour liver at the interface of tumour capsule. PDGF-beta receptor expression was observed in mesenchymal cells in the tumour capsule and in portal tracts. Malondialdehyde adducts were observed in the tumour, non-tumour tissue and in the capsule. CONCLUSIONS: This study provides evidence that myofibroblasts are the cell type responsible for collagen production within the tumour capsule surrounding hepatocellular carcinoma in haemochromatosis. The production of TGF-beta1 by iron-loaded hepatic cells at the tumour capsule interface may perpetuate the myofibroblastic phenotype, resulting in the formation of the tumour capsule.
BACKGROUND/AIMS: Cyclin D1 gene amplification and cyclin D1 protein overexpression have been reported in various human tumors, including hepatocellular carcinoma (HCC). However, their significance is still controversial....BACKGROUND/AIMS: Cyclin D1 gene amplification and cyclin D1 protein overexpression have been reported in various human tumors, including hepatocellular carcinoma (HCC). However, their significance is still controversial. In the present study, we examined the expression of cyclin D1 and its relationships to p53 and Ki-67 in HCCs. METHODS: The expression and topological distribution of cyclin D1, p53 and Ki-67 in 50 cases of HCC were examined immunohistochemically, and the relationship between the expression of these proteins and their pathologic features was investigated. RESULTS: Overexpression of cyclin D1 was noted in 58% of the HCC cases, and significantly associated with a well-differentiated histology and a low Ki-67 labeling index (LI). Cyclin D1 overexpression was also observed in all (7 of 7) dysplastic nodules and in non-neoplastic hepatocytes. On the other hand, aberrant p53 expression was detected in 36% of the cases, which showed positive relationships with poor differentiation, portal vein invasion, and KI-67 LI. Only eight of the 50 cases examined (16%) were positive for both cyclin D1 and p53, which showed only a small number of cyclin D1-positive cells. There was no significant relationship between the expressions of cyclin D1 and p53. CONCLUSIONS: Our results suggest that cyclin D1 overexpression may be an early event in hepatocarcinogenesis and that it plays a role in tumor differentiation. In addition, cyclin D1 expression is not correlated with tumor cell proliferation in HCCs.
BACKGROUND/AIMS: Bile duct cells are known to be susceptible to hepatitis B and C virus, while it has been recently suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may have a direct role in t...BACKGROUND/AIMS: Bile duct cells are known to be susceptible to hepatitis B and C virus, while it has been recently suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may have a direct role in the pathogenesis of vanishing bile duct syndrome (VBDS) after liver transplantation. We report the development of a cholestatic syndrome associated with bile duct damage and loss in four HCV-infected renal transplant recipients. METHODS: All four patients were followed up biochemically, serologically and with consecutive liver biopsies. Serum HCV RNA was quantitatively assessed and genotyping was performed. RESULTS: Three patients were anti-HCV negative and one was anti-HCV/HBsAg positive at the time of transplantation and received the combination of methylprednisolone, azathioprine and cyclosporine A. Two patients became anti-HCV positive 1 year and one patient 3 years post-transplantation. Elevation of the cholestatic enzymes appeared simultaneously with seroconversion, or 2-4 years later, and was related to lesions of the small-sized interlobular bile ducts. Early bile duct lesions were characterized by degenerative changes of the epithelium. Late and more severe bile duct damage was associated with bile duct loss. The progression of the cholestatic syndrome coincided with high HCV RNA serum levels, while HCV genotype was 1a and 1b. Two patients (one with HBV co-infection) developed progressive VBDS and died of liver failure 2 and 3 years after biochemical onset. One patient, despite developing VBDS within a 10-month period, showed marked improvement of liver function after cessation of immunosuppression because of graft loss. The fourth patient, who had mild biochemical and histological bile duct changes, almost normalized liver function tests after withdrawal of azathioprine. CONCLUSION: A progressive cholestatic syndrome due to bile duct damage and loss may develop in renal transplant patients with HCV infection. The occurrence of the lesions after the appearance of anti-HCV antibodies and the high HCV RNA levels are indicative of viral involvement in the pathogenesis. Withdrawal of immunosuppressive therapy may have a beneficial effect on the outcome of the disease.