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Current Issue

July - September, 2009

Vol. 8 Issue 3

On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Methodology of Diagnostic Tests in Hepatology Erik Christensen Page 177-183

    The performance of diagnostic tests can be assessed by a number of methods. These include sensitivity, specificity, positive and negative predictive values, likelihood ratios and receiver operating characteristic (ROC) curves. This paper describes the methods and explains which information they provide. Sensitivity and specificity provides measures of the diagnostic accuracy of a test in diagnosing the condition. The positive and negative predictive values estimate the probability of the condition from the test-outcome and the condition’s prevalence. The likelihood ratios bring together sensitivity and specificity and can be combined with the condition’s pre-test prevalence to estimate the posttest probability of the condition. The ROC curve is obtained by calculating the sensitivity and specificity of a quantitative test at every possible cut-off point between ‘normal’ and ‘abnormal’ and plotting sensitivity as a function of 1–specificity. The ROC-curve can be used to define optimal cut-off values for a test, to assess the diagnostic accuracy of the test, and to compare the usefulness of different tests in the same patients. Under certain conditions it may be possible to utilize a test’s quantitative information as such (without dichotomization) to yield diagnostic evidence in proportion to the actual test value. By combining more diagnostic tests in multivariate models the diagnostic accuracy may be markedly improved.

  • Hepatotoxicity by drugs and dietary supplements: safety perspectives on clinical and regulatory issues Rolf Teschke Page 184-195

    Hepatotoxicity by drugs and dietary supplements (DDS) is a rare and unpredictable event but with the risk of a life-threatening clinical course when it occurs. It may emerge despite intensive chemical, toxicological and observational studies that indicate no hepatotoxic signals. This suggests major clinical and regulatory issues that must be addressed in the area of accurate testing, reporting, and accessibility of reliable data. Consequently, in a clinical setting, safety concerns are key elements in the treatment of patients, and require that the diagnosis of DDS hepatotoxicity clearly be established. Causality of DDS hepatotoxicity may be pursued using a diagnostic algorithm consisting of a pre-test, a main-test as the scale of the updated CIOMS (Council for International Organizations of Medical Sciences), and a post-test. The results of these tests are then sent item by item to the National Health Agency, where the case will undergo further evaluation for pharmacovigilance, strategic aspects and safety issues. After this analysis, all items of the tests are included in the regulatory database freely accessible to the health and scientific community. With this diagnostic and regulatory algorithm the risk of misdiagnoses and inappropriate regulatory measures may be minimized and the safety improved. In conclusion, DDS hepatotoxicity is a rare but is a potentially life-threatening entity requiring a reliable diagnosis with the aid of a diagnostic algorithm, and a thorough pharmacovigilance evaluation by national and international health agencies. Safety aspects in DDS hepatotoxicity represent a major clinical and regulatory issue and should consequently be addressed.

ORIGINAL ARTICLES

Clinical Studies

  • Evaluation of liver diseases in Iranian patients with primary antibody deficiencies Farzaneh Motamed, Asghar Aghamohammadi, Soltani Asghar, Mahmoud Soltani, Mahboubeh Mansouri, Nima Rezaei, Shahram Teimourian, Nima Pouladi, Sina Abdollahzadeh, Nima Parvaneh Page 196-202

    Introduction. Patients with primary antibody deficiency (PAD) can complicate with liver disease. This study was performed in order to study the prevalence and causes of hepatobiliary diseases in Iranian patients with PAD. Material and methods. Sixty-two patients with PAD were followed-up and signs and symptoms of liver disease were recorded. All patients were screened for hepatitis C virus (HCV-RNA) and those patients with any sign of liver disease or gastrointestinal complaints were tested for Cryptosporidium parvum. Results. Clinical evidences of liver disease, including hepatomegaly, were documented in 22 patients (35.5%). Eight patients (13%) had clinical and/or laboratory criteria of chronic liver disease. Only one patient was HCV-RNA positive; he had stigmata of chronic liver disease and pathologic evidence of chronic active hepatitis with cirrhosis. Cryptosporidium parvum test was positive for one patient with hyper-IgM syndrome. In liver biopsy of patients with liver involvement, one had histological findings related to sclerosing cholangitis, and five had mild to moderate chronic active hepatitis with unknown reason. Conclusions. Chronic active hepatitis is the most common pathologic feature of liver injury in Iranian patients with PAD. Liver disease in PAD usually accompanies with other organ involvements and could increase the mortality of PAD. Whether this high rate of liver disease with unknown origin (75%) is the result of an unidentified hepatotropic virus or other mechanisms such as autoimmunity, is currently difficult to understand.

  • Acute hepatitis E in Montenegro: Epidemiology, clinical and laboratory features Dragica Terzic, Brankica Dupanovic, Boban Mugosa, Nenad Draskovic, Neda Svirtlih Page 203-206

    Objective. To evaluate the incidence, demographic, clinical and laboratory characteristics of patients with acute viral hepatitis E in Montenegro. Material and methods. A total of 400 patients with acute viral hepatitis from January 1st, 2000 to December 31st, 2007 were enrolled in the study. Serological tests for hepatitis A, B, C, D, and E viruses, Epstein-Barr virus, cytomegalovirus, and herpes simplex viruses were performed. Standard laboratory tests for liver function were analyzed. The results are presented as absolute numbers, mean ± SD, range of values, and percent. A P value < 0.05 was considered significant. Results. Twenty-four (6%) patients had clinically and/or serologically confirmed acute hepatitis E. The mean age of the patients was 25 ± 6 years; 62.5% were males. The majority of the patients (66%) belonged to the 20 to 40 yrs age group (P < 0.05). Seven patients were asymptomatic. Foremost symptoms were loss of appetite (100%), fatigue (94%) and vomiting (75%). The most frequent clinical sign was mild to moderate liver enlargement (94%). Jaundice had 12/17 symptomatic patients. Elevation of alanine aminotransferase was found in 19 patients including two patients without symptoms. The enzyme, gamma glutamyltranspeptidase was increased in all patients. Conclusion. Acute hepatitis E in Montenegro emerges as an autochthonous infection with a low incidence. Sub-clinical and anicteric infections may occur. Elevation of gamma glutamyltranspeptidase is an important parameter of the biochemical profile of the disease.

  • Reversal of hepatorenal syndrome in cirrhotic patients with terlipressin plus albumin. First experience in Mexico Linda E. Muñoz, Eliud G. Alcalá, Paula Cordero, Manuel A. Martínez, Nathalie Y. Vázquez, Susana Galindo, Eduardo Mendoza, José J. Segura Page 207-211

    Introduction. Type 1 hepatorenal syndrome (HRS) is a functional renal failure that complicates end-stage cirrhosis. The vasopressin analogue terlipressin has been associated with improved renal function in patients with type 1 HRS. Aim. To evaluate the effectiveness of an infusion of terlipressin plus albumin in reversing type 1 HRS, its tolerability, and its adverse effects. Methods. Thirteen consecutive patients with cirrhosis and type 1 HRS were included in the study. All patients received terlipressin plus albumin as treatment for HRS. The patients were divided in two groups. Group 1 contained eight patients in whom HRS was reversed with treatment, who were classified as responders. Group 2 contained five patients who were nonresponders. Results. Sixty-one percent of the patients who received terlipressin plus albumin responded to therapy and underwent HRS reversal. In two patients, treatment with terlipressin was stopped because of adverse events. No relapse of HRS after terlipressin withdrawal was observed in this study. Conclusion. The rate of successful treatment with terlipressin plus albumin was 61%, similar to that in previously reported controlled trials. However, this is the first experience reported in Mexico. A cardiovascular evaluation is required before the start of treatment with terlipressin. This treatment appears to be an effective therapy for improving renal function in patients with type 1 HRS.

  • Hepatocellular carcinoma: Epidemiological profile from a cohort of federal employees in Mexico Laura Ladrón de Guevara, Paulo Rojas-Macuil, Xochiquetzal Sánchez-Chávez, Alejandro Rossano-García, Ma. Teresa Gorraez-de-la-Mora, Guadalupe Cervantes-Sánchez, Julita Orozco-Vázquez, Mario Lemus- Velázquez, Leticia Rosas-Zúñiga, Aura Erazo-Valle, Mauricio Di-Silvio Page 212-219

    Introduction. Hepatocellular carcinoma (HCC) has become a frequent type of cancer in Mexico. At the present time it represents the 19th cause of death in the population. Objective. To recognize the epidemiological profile and the treatment results in a cohort of federal employees with HCC. Material and methods. We analyzed 47 consecutive cases with HCC diagnosis from January 2004 till December 2007. Twenty four demographic data, tumor staging, clinical, and biochemical variables were analyzed to identify parameters predicting survival by computing Kaplan-Mier and Mantel-Cox survival curves. Results. Patient reference increased 5% each year. The mean age was 60.4 years, 63.8% female sex, and 72.3% had cirrhosis, 44.7% had Hepatitis C infection. Most patients presented with advanced disease: 55.3% were AJCC stage 3 and 21.3% stage 4, 51.1% were BCLC class D. Mean tumor size was 8.09 cm. Median survival time from diagnosis was 122 days. Patients that did not receive treatment had a median survival of 70 days; the longest survival of patients was of those that received transarterial chemoembolization with a median of 707 days, followed by surgery with 683 days. Univariate analysis showed survival was associated to MELD score, AJCC and BCLC staging, creatinine level and ascites. Multivariate analysis showed tumor differentiation, AJCC staging and the choice of treatment to be related to the risk of death. Conclusion. An increase in the referral of HCC was demonstrated. Most patients had cirrhosis and HCV infection. Due to advance disease staging, TACE was the treatment that offered longest survival.

  • Percutaneous ethanol injection before liver transplantation in the hepatocellular carcinoma Fernanda Branco, Concepción Brú, Ramon Vilana, Luis Bianchi, Angelo Alves de Mattos Page 220-227

    Background/objectives. The study evaluates the outcome of patients who performed orthotopic liver transplantation (LT) as treatment for hepatocellular carcinoma (HCC), with percutaneous ethanol injection (PEI) while on the waiting list, verifying the effectiveness of this treatment in producing tumor necrosis and avoiding dropout and identifying treatment-related complications. Material and methods. Medical records of 97 patients on the waiting list for LT at Hospital Clinic of Barcelona were examined. Sixty-two (56.3%) patients had been treated with PEI (group 1); 35 (31.8%) had not received any anti-tumor therapy before LT (group 2). Results. Complete necrosis of the tumor was observed in 38/59 (64.3%) patients. The presence of additional nodules in the explant and the diameter of the main tumor of group 1 was significantly lower than in group 2 (p = 0.002). Dropout related to tumor progression occurred in 4.8% and 8.5%, and tumor recurrence in 5% and 6.2% for groups 1 and 2, respectively. Major complications were not evidenced after 421 PEI sessions and there was no tumor implant in the needle traject. Conclusions. In conclusion, the percutaneous treatment of HCC with PEI is a safe and effective method before the LT.

ORIGINAL ARTICLES

Basic studies

  • Effects of Japanese herbal medicine inchin-ko-to on endotoxin-induced cholestasis in the rat Juan Pablo Arab, Carolina Ramírez, Pablo Muñoz, Margarita Pizarro, Nancy Solís, Arnoldo Riquelme, Marco Arrese Page 228-233

    Background/Objective. Inchin-ko-to (ICKT) is an herbal medicine used in Japan to treat jaundice and liver fibrosis. We investigated the effect of oral ICKT supplementation on endotoxin-induced cholestasis in the rat. Material and methods. Lipopolysaccharide (LPS) injection (1 mg/kg body weight i.p.) was used as a model of sepsis-induced cholestasis. Bile flow, biliary bile salt secretion, biliary glutathione secretion and protein expression of the main hepatobiliary transporters Na(+)-taurocholate-cotransporting peptide (Ntcp), multidrug resistance protein 2 (Mrp2) and bile salt export pump (Bsep) were analyzed by conventional techniques in ICKT treated and non-treated animals. Results. Injection of LPS induced a significant decrease of bile flow (-24%), biliary bile salts (-40%) and glutathione excretion (-70%) as well as a significant decrease in Ntcp (-90%) and Mrp2 (-80%) protein levels. ICKT supplementation partially prevented the effects of LPS determining a less intense reduction in bile flow (-10%), a normalization of glutathione excretion as well as a significant increase in Mrp2 protein levels to 60% of the levels observed in control animals. ICKT administration did not modify the effects of LPS on BS secretion or Ntcp protein levels. Conclusion. Our data show that oral supplementation of ICKT partially prevents LPS-induced cholestasis by increasing Mrp2 protein levels and biliary glutathione excretion thus increasing bile salt-independent flow.

  • The effects of pegylated interferon alpha 2b on bile-duct ligation induced liver fibrosis in rats Billur Canbakan, Hakan Akin, Gulgun Tahan, Orhan Tarcin, Fatih Eren, Ozlen Atug, Veysel Tahan, Nese Imeryuz, Ozlem Yapicier, Erol Avsar, Nurdan Tozun Page 234-240

    Objective. To test the effects of peginterferon in an unrecoverable model of bile-duct ligation (BDL) induced liver fibrosis. Material and methods. Thirty-seven Wistar rats were divided into five groups: group 1, BDL + peginterferon (n = 8); group 2, BDL (n = 8); group 3, sham + peginterferon (n = 7); group 4, sham (n = 7); and group 5, control group (n = 7). Peginterferon-alpha 2b (50 μgr/kg) or saline (1 mL/kg) was administered intraperitonealy every week for four weeks. Serum biochemical markers, liver tissue oxidative stress, collagen and transforming growth factor- (TGF-) levels were examined after four weeks. Liver slides were stained by hematoxylin and eosin and Masson trichrome\Gomory reticulum staining. Results. The levels of tissue collagen, TGF-, biochemical markers (AST, ALT, bilirubins, alkaline phosphates, gamma-glutamyl transpeptidase) and oxidative stress markers (Malondialdehyde, luminal, lucigenin) of the BDL group were higher than the sham operated and control groups (all-p < 0.001). Peginterferon improved malondialdehyde, luminal and glutathione levels in the BDL + peginterferon group (p < 0.05). Histopathological examination of the BDL groups showed stage-3 fibrosis, while all the control groups were normal. Peginterferon showed no improvement in fibrosis either histologically, or biochemically. Conclusions. Peginterferon improved levels of malondialdehyde, glutathione and luminal in the rat model of BDL induced liver fibrosis. Peginterferon however, showed no anti-fibrotic effects in this model and therefore may not be a useful treatment for liver fibrosis.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Unusual case of plasmablastic Non-Hodgkin’s lymphoma located in the liver. First case reported in an AIDS patient Humberto Metta, Marcelo Corti, Aldo Maranzana, Ricardo Schtirbu, Marina Narbaitz, Marcela De Dios Soler Page 242-245

    Plasmablastic lymphoma is a rare and a relatively new entity that was first described in the jaws and the oral cavity of HIV-AIDS patients. We report a case of plasmablastic lymphoma involving the liver in an AIDS patient. Plasmablastic lymphoma is considered a diffuse large B-cell lymphoma with a unique phenotype and predilection for the oral cavity. The case presented had a unique hepatic lesion, localized in the left lobe of the liver. Diagnosis was confirmed by hepatic biopsy guided by Computerized Tomography scan and histopathology. The smears showed a dense infiltrate composed by atypical lymphocytes with numerous plasmocytes expressing the plasma cell markers MUM-1 and CD138 and negative for the B-cell markers CD3, CD20 and CD45. Immunohistochemical and in situ hibridization revealed the Epstein-Barr virus genome in the atypical cells. Polymerase chain reaction was negative for HHV-8 RNA.

  • Gilbert’s syndrome and antiviral therapy of hepatitis C Katja Deterding, Kurt Grüngreiff, Tim O. Lankisch, Andrej Potthoff, Matthias J. Bahr, Michael P. Manns, Heiner Wedemeyer, Christian P. Strassburg Page 246-250

    Treatment of chronic hepatitis C with type I interferons and ribavirin can be associated with exacerbation of hepatitis and sometimes liver decompensation. We report two patients with chronic hepatitis C virus infection who experienced a severe increase of bilirubin levels of up to 17 times upper the limit of normal value in the absence of deterioration of hepatic function during therapy with pegylated-interferon and ribavirin. A genetic disposition for Gilbert’s syndrome explained the adverse events and permitted a continuation of therapy leading to a sustained clearance of chronic hepatitis C infection. Since one patient jaundiced already during a lead-in treatment period with ribavirin monotherapy we suggest that hyperbilirubinaemia during combination therapy is primarily caused by ribavirin rather than by effects of interferon alpha on UDP-glucuronosyltransferase activities. Of note, both patients recovered from their initial unconjugated hyperbilirubinemia despite continuation of ribavirin therapy, which indicates that compensatory mechanisms leading to a normalization of UGT1A1 activity are likely.

  • Mexican-native human echinococcosis: Case report of an underestimated disease Juan Steta, Aldo Torre Page 251-254

    Mexico is considered a virtually free region of cystic echinococcosis. Almost all case reports within the country involve immigrants or traveling patients. This manuscript presents a Mexican-native human echinococcosis that developed in the setting described below. Review of current evidence suggests that this infection has been underestimated.

  • Multiple pyogenic liver abscesses caused by Streptococcus constellatus in the Amazon region. Case report André Luiz Santos Rodrigues, Manoel C. P. Soares, Francisco L. P. Ramos, Lucas Crociati Meguins Page 255-257

    There are few studies reporting pyogenic liver abscess (PLA) caused by Streptococcus constellatus in the medical literature. S. constellatus is a comensal microorganism that belongs to the Streptococcus milleri’s bacteria group and is not considered to be pathogenic for humans. We report the case of a 23-year-old man with a 15-days history of abdominal pain in the right flank followed by daily fever, chills, nausea, vomits, sialism and jaundice. Physical examination revealed moderate jaundice (2+/4+), abdominal distention, generalized pain and tender over the right flank with positive Blumberg’s sign. Additionally, the liver was palpable 5 cm below the costal margin in the right midclavicular line. Abdominal Computerized Tomography showed multiple hypodense hepatic images suggestive of liver abscesses. The patient underwent surgical exploration of the abdomen through a sub-costal incision and, during operation ruptured abscess localized on the hepatic segment III was drained. Culture of the purulent material obtained at surgery yielded Streptococcus constellatus as the causative agent. Liver abscess is a potential life-threatening disease that must be treated as soon as possible with invasive approaches, if necessary, and bacteriological studies performed when possible, allowing isolation of causative agents and specific antibiotic therapy.

  • Severe hepatotoxicity by Indian Ayurvedic herbal products: A structured causality assessment Rolf Teschke, Ruediger Bahre Page 258-266

    The case of a 64 year old female patient is presented who has treated herself for 9 months with various Indian Ayurvedic herbal products for her vitiligo and experienced a causally related severe hepatotoxicity (ALT, 601 U/L; AST, 663 U/L; Bilirubin, 5.0 mg/dL). After discontinuation, a rapid improvement was observed. Causality assessment with the updated CIOMS (Council for International Organizations of Medical Sciences) scale showed a probable causality (+8 points) for Bakuchi tablets containing extracts from Psoralea corylifolia leaves with psoralens as ingredients, as the primary candidate causing the hepatotoxic reaction. The degree of probability was lower with +6 points for other used herbs: Khadin tablets containing extracts from Acacia catechu leaves; Brahmi tablets containing Eclipta alba or Bacopa monnieri; and Usheer tea prepared from Vetivexia zizaniodis. The case is the first report of Indian Ayurvedic herbal products being potentially hepatotoxic in analogy to some other herbs.

LETTER TO EDITOR

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