Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases.

BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. METHODS: Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.

Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MDR3.

INTRODUCTION: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a severe liver disorder associated with inherited dysfunction of multidrug resistance protein 3 (MDR3/ABCB4), which functions as a phospholipid floppase, translocating phosphatidylcholine from the inner to the outer hemileaflet of the canalicular membrane of hepatocytes. MDR3 deficiency results in a disbalanced bile which may damage the luminal membrane of cells of the hepatobiliary system. We evaluated clinical, biochemical and histological improvement in a genetically proven PFIC-3 patient after long-term ursodeoxycholic acid (UDCA) administration. MATERIAL AND METHODS: A PFIC-3 patient and a relative with cholestatic liver disease were studied. Hepatic MDR3 expression was analyzed by immunohistochemistry and ABCB4 mutations were identified. The effect of the mutations on MDR3 expression and subcellular localization was studied in vitro. RESULTS: A 23-year-old man presented cholestasis with severe fibrosis and incomplete cirrhosis. Canalicular staining for MDR3 was faint. Sequence analysis of ABCB4 revealed two missense mutations that reduce drastically protein expression levels. After 9 years of treatment with UDCA disappearance of fibrosis and cirrhosis was achieved. CONCLUSION: These data indicate that fibrosis associated with MDR3 deficiency can be reversed by long-term treatment with UDCA, at least when there is residual expression of the protein.

[Hydatidosis: Ultrasonographyc screening in the Río Negro Province 25 years after the first screening]. / Hidatidosis: Catastro ecográfico en la Provincia de Río Negro 25 anos después del primer catastro.

INTRODUCTION: Hydatidosis (cystic echinococcosis) is endemic in Rio Negro Province, Argentina. In 1980 started a control program against the disease. In 1984 Frider et al performed the first ultrasound screening in the world at Pilcaniyeu city, later extended to other localities of Rio Negro province. The initial prevalence in asymptomatic people was 7.1% in Pilcaniyeu and 10.1% in Comallo, being all new cases and with surgical indication. OBJECTIVE: The aim of this investigation was to determine the current prevalence and analyze the evolution of the disease across 25 years of the control program. MATERIALS AND METHODS: In 2009 and 2010 ultrasound screening studies were conducted in both locations in all age groups. RESULTS: In 512 ultrasound studies at Pilcaniyeu, the prevalence was 1.5% in children (6 to 14years old) and 4.2% in adults (total 2.5%). In 770 ultrasound studies at Comallo, the prevalence was 1.1 %in children and 6.6% in adults (total 3.0%). The overall reduction in the prevalence reached 67.2%. Regarding the age distribution, rates of 1.6%-1.9% were observed in Pilcaniyeu and of 1.0-1.9% in Comallo between 0 and 30 years old, increasing significantly above 10% after 60 years old in Pilcaniyeu and after 40 years old in Comallo. CONCLUSIONS: The implementation of the program actions reduced the prevalence of the disease but there are still new cases, and that indicates that some bias persists in the control of the epidemiology of the disease and levels of transmission to humans as a consequence of this failures. So the search of asymptomatic cases is still important and also their management based on the follow-up by ultrasound (watch and wait) or in the treatment with albendazol.

[Hydatidosis: Ultrasonographyc screening in the Rio Negro Province 25 years after the first screening]. / Hidatidosis: Catastro ecográfico en la Provincia de Río Negro 25 años después del primer catastro.

INTRODUCTION: Hydatidosis (cystic echinococcosis) is endemic in Río Negro Province, Argentina. In 1980 started a control program against the disease. In 1984 Frider et al performed the first ultrasound screening in the world at Pilcaniyeu city, later extended to other localities of Rio Negro province. The initial prevalence in asymptomatic people was 7.1% in Pilcaniyeu and 10.1% in Comallo, being all new cases and with surgical indication. OBJECTIVE: The aim of this investigation was to determine the current prevalence and analyze the evolution of the disease across 25 years of the control program. MATERIALS AND METHODS: In 2009 and 2010 ultrasound screening studies were conducted in both locations in all age groups. RESULTS: In 512 ultrasound studies at Pilcaniyeu, the prevalence was 1.5% in children (6to 14years old) and 4.2% in adults (total 2.5%). In 770 ultrasound studies at Comallo, the prevalence was 1.1% in children and 66% in adults (total 3.0%). The overall reduction in the prevalence reached 67.2%. Regarding the age distribution, rates of 1.6%-1.9% were observed in Pilcaniyeu and of 1.0-1.9% in Comallo between 0 and 30 years old, increasing significantly above 10% after 60 years old in Pilcaniyeu and after 40years old in Comallo. CONCLUSIONS: The implementation of the program actions reduced the prevalence of the disease but there are still new cases, and that indicates that some bias persists in the control of the epidemiology of the disease and levels of transmission to humans as a consequence of this failures. So the search of asymptomatic cases is still important and also their management based on the follow-up by ultrasound (watch and wait) or in the treatment with albendazol.

Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography.

The most serious adverse drug reaction of adalimumab (ADR) is tuberculosis reactivation. We describe a case of a 35-year-old man, with rheumatoid arthritis (RA) and hepatitis C virus genotype 1a with a liver biopsy in 2001 with a METAVIR score pattern A1 F0; he received interferon alpha 2b for six months, but treatment was suspended because of reactivation of RA. Liver function tests after treatment were similar to previous ones showing a minimal cholestatic pattern. In 2008, methotrexate was prescribed, but the drug was withdrawn at the third month because of the appearance of pruritus and Ggt rise. Viral load at that moment was 9300000 UI/mL, log 6,9. The liver biopsy showed a Metavir Score A2 F1. Adalimumab was started in 2010, and at the third month of treatment, Ggt showed a rise of 23 times normal value (NV), alkaline phosphatase 2,5 times NV with AST and ALT with no change. A new liver biopsy showed portal inflammation with eosinophils and a METAVIR A1 F2. We think that adalimumab appears to be responsible for the liver injury, because of temporal relationship, liver biopsy findings, other clinical conditions being discarded, and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended.

Autoimmune cholangitis associated to IgG4 related sclerosing disease.

The IgG4-related sclerosing disease is characterized by the presence of plasmatic IgG4 positive cells and T-lymphocytes infiltration in different organs. We herein report a case of cholestasis due to autoimmune cholangitis associated to IgG4 disease. A 40-year-old woman with a history of pruritus, anosmia, Sjögren's syndrome and diabetes, was referred for a pancreatic tumor. Alkaline phosphatase was 24-fold upper limit of normal (ULN), gamma-glutamyl transpeptidase 21-fold ULN, aspartate aminotransferase 3-fold ULN, alanine aminotransferase 2-fold ULN, cholesterol 408 mg/dL, bilirubin normal, gamma-globulin 3.92 g/dL, IgG4 4.6 g/L, antinuclear antibody positive (1/320), and antimitochondrial antibodies negative. Ultrasound scan (US) showed a mass in the pancreatic head and thickening of the gallbladder and the bile duct walls. Dilation and strictures of the main pancreatic duct and intrahepatic bile ducts were detected by MR cholangiopancreatography. Liver biopsy showed chronic inflammatory lesions, ductal damage (autoimmune cholangitis) (METAVIRA2, F2) and IgG4 bearing plasmatic cells. A cervical lymph node showed IgG4 bearing plasmatic cells. After 2 weeks of treatment with meprednisone, ursodeoxycholic acid and insulin, pruritus and anosmia disappeared. After eleven months of treatment imaging studies showed disappearance of the pancreatic tumor, atrophy of the body and the pancreatic tail and normal biochemical parameters, except for alkaline phosphatase 2-fold ULN. The final diagnosis of our patient was autoimmune hepatitis with cholangitis associated to IgG4 systemic diseases.

Treatment of liver hydatidosis: how to treat an asymptomatic carrier?

Liver hydatidosis is the most common clinical presentation of cystic echinococcosis (CE). Ultrasonographic mass surveys have demonstrated the true prevalence, including the asymptomatic characteristic of the majority of cases, providing new insight into the natural history of the disease. This raises the question of whether to treat or not to treat these patients, due to the high and unsuspected prevalence of CE. The high rate of liver/lung frequencies of cyst localization, the autopsy findings, and the involution of cysts demonstrated in long time follow-up of asymptomatic carriers contribute to this discussion. The decision to treat an asymptomatic patient by surgery, albendazole, or puncture aspiration injection and re-aspiration or to wait and watch, is based on conflicting reports in the literature, the lack of complications in untreated patients over time, and the spontaneous disappearance and involution of cysts. All these points contribute to difficulties of individual clinical decisions. The patients should be informed of the reasons and the risks of watchful/waiting without treatment, the possibility of complications, and the risks of the other options. As more information on the natural history of liver hydatidosis is acquired, selection of the best treatment will be come easier. Without this knowledge it would be very difficult to establish definitive rules of treatment. At present, it is possible to manage these patients over time and to wait for the best moment for treatment. Follow-up studies must be conducted to achieve this objective.

Naturally occurring hepatitis B virus (HBV) variants with primary resistance to antiviral therapy and S-mutants with potential primary resistance to adefovir in Argentina.

Hepatitis B virus (HBV) variants may either emerge in patients with chronic hepatitis B (CHB) as a result of positive selection pressure exerted by their own immune response, or during therapy with nucleos(t)ide analogues (NAs). Naturally occurring HBV variants with primary antiviral resistance are rarely observed. The aim of this study was to retrospectively analyze the (eventual) circulation of HBV variants with natural resistance to NAs currently used as therapy for CHB in Argentina. This study reports 13 cases of CHB-infected patients with natural antiviral resistance to at least one NA. Five of them were also carriers of S-variants that might escape the humoral immune system recognition with potential resistance to adefovir. In addition to the already reported A2 HBV subgenotype association to NAs natural resistance, E and F genotypes association to such resistance is described for the first time. These findings suggest that sequence analysis of the HBV reverse transcriptase might be an essential tool before starting antiviral therapy, in order to choose the proper NAs for optimizing the therapeutic management of chronically infected patients. Moreover, the circulation and transmission of S-mutants with resistance to such antiviral drugs should be of public health concern as they may represent an additional risk for the community.

[Twenty-four weeks therapy with peginterferon alfa-2a could be similar to 48 weeks therapy in patients with HBeAg positive chronic hepatitis B and good predictors of response: results of a pilot study]. / El tratamiento de 24 semanas con PEG interferón alfa 2a podría ser similar al de 48 semanas en pacientes con hepatitis B crónica HBeAg positivo y buenos predictores de respuesta: resultados de un estudio piloto.

BACKGROUND: 48 week therapy with peginterferon alfa-2a has demonstrated to be effective in about one third of patients with HBeAg-positive chronic hepatitis B. Although the recommended treatment duration for these patients is 48 weeks, there are no enough data supporting 48 weeks of therapy over 24 weeks of therapy. Treatment might be shortened particularly in patients with good predictors of response. AIM: To compare the efficacy of 48 weeks vs 24 weeks of therapy with peginterferon alfa-2a, in patients with chronic hepatitis B who had good predictors of response. PATIENTS AND METHODS: Nineteen patients with high baseline ALT levels (> 3 ULN) and low viral load (HBV DNA < 10(9) copies/ml) were treated with peginterferon alfa-2a 180 mcg/week, during 48 weeks. Virological, biochemical and serological responses were compared with those obtained in 16 patients with similar baseline characteristics treated with peginterferon alfa-2a for 24 weeks. All patients had a followup period of 24 weeks after the end of therapy. RESULTS: At end of follow-up, HBeAg seroconversion was observed in 7/19 (36.8%) of patients treated for 48 weeks and in 6/16 (37.5%) of patients treated for 24 weeks (NS). Patients treated for 48 weeks evidenced a significantly higher decrease in HBV DNA at the end of therapy than patients treated for 24 weeks (-4.8 logs vs -3.6 logs respectively, p < 0.05). However, the percentage of patients with HBV DNA < 100.000 copies/ml was similar in both groups at the end of follow up (42.1% vs 43.7%, NS). No significant differences between both groups were observed regarding ALT normalization, HBsAg loss or seroconversion. The incidence of aderse events was similar in both groups. CONCLUSION: The results from this pilot study indicate that 24 weeks of therapy with peginterferon alfa-2a could be similar to 48 weeks therapy in patients with HBeAg positive chronic hepatitis B who have good predictors of response.

Successful interferon treatment in a patient chronically infected with hepatitis B virus carrying unusual S- (and P-) mutants in the presence of anti-HBs antibodies.

BACKGROUND: Hepatitis B virus (HBV) immune escape mutants with point mutations within the S gene may arise during the natural course of HBV infection, due to a positive selection pressure exerted by the host immune response. Mutations within the immunodominant B and T cell epitopes of hepatitis B surface antigen (HBsAg) allow the resulting S-mutants to propagate even in the presence of neutralizing anti-HBs antibodies and the HBV-specific T-cell immune response. AIM: To study the antiviral effect of Pegylated-interferon (Peg-IFN) in a patient with chronic hepatitis B carrying unusual S-(and P-) mutants in the presence of anti-HBs antibodies. PATIENTS, METHODS AND RESULTS: We report on a 43-year-old male chronically infected with a genotype A HBV strain, with cocirculation of both HBsAg and anti-HBs antibodies, who received treatment with 120 mug of Peg-IFN for 24 weeks. HBeAg seroconversion and clearance of both HBV DNA by polymerase chain reaction and HBsAg were successfully achieved. Improved histology was observed in a biopsy performed 44 weeks after Peg-IFN therapy was completed. It seems plausible that the ascribed genotype A could have contributed to the effective response to Peg-IFN, even though the treatment was provided only throughout a 24-week period. CONCLUSION: To our knowledge, this is the first report regarding the successful result obtained by using Peg-IFN as a treatment for a chronically HBV-infected patient carrying HBsAg immune escape mutants.

[Obstructive jaundice associated Burkitt's lymphoma mimicking pancreatic carcinoma]. / Ictericia obstructiva asociada a linfoma de Burkitt en un adulto inmunocompetente.

The primary compromise of the pancreas in lymphomas is uncommon. However, in advanced stages of Non-Hodgkin's lymphomas (LNH) the secondary invasion of the pancreas is observed more frequently. Jaundice due to extrahepatic cholestasis as a presentation form is extremely rare, with only few cases described in the literature. The aim is to present a case of an obstructive jaundice as an expression of Burkitt's lymphoma probably due to a diffuse pancreatic infiltration in an adult without immunodeficiency with a rapid response of cholestasis to low dose of hydrocortisone. Skin tumor simultaneously present with jaundice allowed the histologic diagnosis with skin biopsies. After a unique dose of 100 mg hydrocortisone, jaundice improved and cholestatic enzymes decreased, pancreas became smaller and common bile duct diameter became normal at ultrasound and CT scan, also skin tumors turn pale and diminished in size. There are isolated reports of Burkitt's lymphoma cases with associated obstructive jaundice due to pancreatic infiltration or by compression by lymph nodes of the bile ducts, many of them are pediatric cases or immunodepressed HIV patients. In the case presented, surgical resection of the pancreatic infiltration and biliary drainage, either surgical or endoscopic during the same procedure was not necessary for the histopathologic diagnosis of the illness like is described in the literature. The diagnosis was suspected by the rapid decrease of cholestatic features after a single dose of hydrocortisone and the histology was easy done by a skin biopsy. We think the interest in this case is the quick response to low doses of corticoids, which avoided the necessity of surgical procedure for the diagnosis of the biliary tree obstruction, allowing a quick implementation of the specific chemotherapeutic treatment of the lymphoma without any surgical or endoscopic procedures to heal the jaundice.

Ictericia obstructiva asociada a linfoma de Burkitt en un adulto inmunocompetente / Obstructive jaundice associated Burkitt's lymphoma mimicking pancreatic carcinoma

El compromiso primario del páncreas en los linfomas es muy poco frecuente, sin embargo, en los estadios avanzados de los linfomas no Hodgkin la invasión secundaria de la glándula es observada con mayor frecuencia. El objetivo de esta presentación es describir un caso de linfoma de Burkitt en un adulto inmunocompetente que presentó como manifestación relevante colestasis extrahepática secundaria probablemente a infiltración pancreática difusa y tumores cutáneos cuya histología permitió hacer el diagnóstico. Luego de una dosis única de hidrocortisona de 100mg, mejoró la ictericia, disminuyeron las enzimas de colestasis, las lesiones cutáneas y disminuyó el tamaño del páncreas en la ecografía y en la tomografía computada. Existen en la literatura reportes aislados de casos de linfoma tipo Burkitt que se asocian a ictericia obstructiva secundaria y a infiltración pancreática o del hilio hepático, tratándose en su mayoría de casos pediátricos o de individuos afectados por el virus de la inmunodeficiencia humana (VIH). Creemos que el interés de este caso radica en la rápida respuesta a dosis bajas de corticoides de la colestasis, lo que evitó la necesidad de un procedimiento quirúrgico tanto diagnóstico como terapéutico de la obstrucción biliar, como está referido en la literatura, permitiendo instaurar rápidamente el tratamiento quimioterapéutico específico de esta entidad sin maniobras quirúrgicas o endoscópicas.

The primary compromise of the pancreas in lymphomas is uncommon. However, in advanced stages of Non- Hodgkin’s lymphomas (LNH) the secondary invasion of the pancreas is observed more frequently. Jaundice due to extrahepatic cholestasis as a presentation form is extremely rare, with only few cases described in the literature. The aim is to present a case of an obstructive jaundice as an expression of Burkitt’s lymphoma probably due to a diffuse pancreatic infiltration in an adult without immunodeficiency with a rapid response of cholestasis to low dose of hydrocortisone. Skin tumor simultaneously present with jaundice allowed the histologic diagnosis with skin biopsies. After a unique dose of 100 mg hydrocortisone, jaundice improved and cholestatic enzymes decreased, pancreas became smaller and common bile duct diameter became normal at ultrasound and CT scan, also skin tumors turn pale and diminished in size. There are isolated reports of Burkitt’s lymphoma cases with associated obstructive jaundice due to pancreatic infiltration or by compression by lymph nodes of the bile ducts, many of them are pediatric cases or immunodepressed HIV patients. In the case presented, surgical resection of the pancreatic infiltration and biliary drainage, either surgical or endoscopic during the same procedure was not necessary for the histopathologic diagnosis of the illness like is described in the literature. The diagnosis was suspected by the rapid decrease of cholestatic features after a single dose of hydrocortisone and the histology was easy done by a skin biopsy. We think the interest in this case is the quick response to low doses of corticoids, which avoided the necessity of surgical procedure for the diagnosis of the biliary tree obstruction, allowing a quick implementation of the specific chemotherapeutic treatment of the lymphoma without any surgical or endoscopic procedures to heal the jaundice.

Unusual naturally occurring humoral and cellular mutated epitopes of hepatitis B virus in a chronically infected argentine patient with anti-HBs antibodies.

Serum hepatitis B virus (HBV) DNA was extracted from a chronically infected patient with cocirculation of hepatitis B surface antigen (HBsAg) and anti-HBs antibodies. Direct PCR and clone-derived sequences of the S and overlapped P genes were obtained. DNA sequences and phylogenetic analysis ascribed this isolate to genotype A (serotype adw2). Five of six HBV DNA clones exhibited point mutations inside and outside the major hydrophilic region, while the sixth clone exhibited a genotype A "wild-type" amino acid sequence. Observed replacements included both humoral and/or cellular (major histocompatibility complex class I [MHC-I] and MHC-II) HBV mutated epitopes, such as S45A, P46H, L49H, C107R, T125A, M133K, I152F, P153T, T161S, G185E, A194T, G202R, and I213L. None of these mutants were individually present within a given clone. The I213L replacement was the only one observed in the five clones carrying nonsynonymous mutations in the S gene. Some of the amino acid substitutions are reportedly known to be responsible for the emergence of immune escape mutants. C107R replacement prevents disulfide bonding, thus disrupting the first loop of the HBsAg. Circulation of some of these mutants may represent a potential risk for the community, since neither current hepatitis B vaccines nor hyperimmune hepatitis B immune globulin are effectively prevent the liver disease thereto associated. Moreover, some of the recorded HBsAg variants may influence the accuracy of the results obtained with currently used diagnostic tests.