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Current Issue

April - June, 2010

Vol. 9 Issue 2

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

  • Prevention of hepatocellular carcinoma Michael C. Kew Page 120-132

    Because of its frequency and grave prognosis, preventing hepatocellular carcinoma is an urgent priority. Prevention should be possible because environmental carcinogens-chronic hepatitis B and C virus infections, dietary exposure to aflatoxins, and iron overload-cause the great majority of these tumors. Chronic hepatitis B virus infection accounts for 55% of global hepatocellular carcinomas and 80% of those in the high-incidence Asia Pacific and sub-Saharan African regions. In these regions the infection that becomes chronic is predominantly acquired very early in life. A safe and effective vaccine against this virus is available and its universal inclusion in the immunization of infants has already resulted in a marked reduction of chronic infection and a 70% decrease in the occurrence of hepatocellular carcinoma in those immunized. Chronic hepatitis C virus infection is the major cause of hepatocellular carcinoma in industrialized countries. The infection is mainly acquired in adulthood and, until a vaccine becomes available, prevention will consist mainly of identifying, counselling, and treating chronically infected individuals, preventing spread of the virus by the use of safe injection practices (particularly in intravenous drug abusers), and screening all donated blood for the presence of the virus. 4.5 billion of the world’s population are exposed to dietary aflatoxins. Prevention involves treating susceptible crops to prevent fungal contamination, and handling the foodstuffs in such a way as to prevent contamination during storage. Iron overload in hereditary hemochromatosis can be prevented by repeated venesection and in African dietary iron overload by fermenting the home-brewed beer in iron-free containers.

  • Effects of systemic chemotherapy on the liver Giuliano Ramadori, Silke Cameron Page 133-143

    The liver is the largest parenchymatous organ of the body and central for intermediate metabolism. Its close contact to the portal blood streaming back from the gut and the systemic circulation is a prerequisite for the various processes ongoing on cellular level. The spatial relationship of the hepatocytes with the different cellular structures of the liver, such as fenestrated sinusoidal endothelial cells, Kupffer cells, and bile canaliculi is important for the organization and performance of the intermediate metabolism of nutrients (proteins, glucose and fatty acids), for the clearance of toxic or infectious agents, for metabolic detoxification and for the excretion of waste products. The administration of chemotherapy is a challenge for the tight regulation and balance of these processes. As most drugs tend to be lipophilic, they are readily taken up by the liver. Under chemotherapy, up to 85% of patients develop liver steatosis. Steatohepatitis is the more serious event, especially if accompanied by an increase in bilirubin levels. Modern understanding of the efficacy, safety and tolerability of combination chemotherapy has to increasingly include the individual context of a patient, such as age, gender, nutritional status, underlying diseases, genetic predisposition, as well as the cross-reactivity of the different drugs. This review tries to capture the various effects of chemotherapy on the liver, with a focus on chemotherapeutical compounds used for the treatment of gastrointestinal cancers.

ORIGINAL ARTICLES

Clinical Studies

  • Nonalcoholic fatty liver disease in asymptomatic obese women(a) Heriberto Rodriguez Hernandez, Miriam Cervantes-Huerta, Jose Luis Gonzalez, María Dolores Marquez-Ramirez, Martha Rodriguez Moran, Fernando Guerrero-Romero Page 144-149

    Objective. To determine the clinical characteristics of NAFLD in asymptomatic obese women. Methods. A total of 457 asymptomatic obese women were enrolled in a cross-sectional study and allocated into groups with and without NAFLD. Irrespective of ALT levels, diagnosis of NAFLD was established by ultrasonographic findings; irrespective of fibrosis, NASH was defined by hepatic histological changes. Results. One hundred ninety five (42.7%) women had elevated ALT levels. Diagnosis of NAFLD was established in 228 (49.9%) women; among women with NAFLD, 34 (14.9%) have ALT levels within the normal range. On the other hand, based on the healthy range for ALT levels (19 UI/L), 336 (73.5%) women had elevated ALT, but only 2 (0.9%) women with NAFLD exhibited ALT levels within normal healthy values. Furthermore, 93 (41%) women who had AST/ALT levels ³ 1 underwent liver biopsy; of these, 90 (96.8%) had diagnosis of NASH and 3 (3.2%) of hepatic cirrhosis. Women with NAFLD were more obese and have higher fasting plasma glucose, triglycerides, ALT, and AST levels than obese women without NAFLD. Seventy six (16.6%) women had diagnosis of diabetes; of these 47 (61.8) in the NAFLD group. Conclusions. Results of this study support the statement that women with NAFLD have an adverse metabolic profile. Furthermore, our results show that hyperglycemia, hypertriglyceridemia and markers of liver injury such as AST/ALT ³ 1 may be useful for early recognition of NAFLD.

  • Sustained virological response according to the type of early virological response in HCV and HCV/HIV Paulo R. Lerias de Almeida, Angelo Alves de Mattos, Cristiane Valle Tovo Page 150-155

    Background. The most important factors to predict the sustained virological response (SVR) are the genotype and the fibrosis grade, although there are other predictive factors to be considered, mainly in HCV/ HIV coinfected patients. Aim. To evaluate different prognostic factors to obtain the SVR in HCV monoinfected and HCV/HIV coinfected genotype 1 patients emphasizing the type of early virological response (EVR)-complete or partial. Methods. This is a cohort study, retrospective, where the registers of HCV monoinfected or HCV/HIV coinfected patients, genotype 1, treated with pegylated interferon + ribavirin were reviewed. The prognostic factors: age greater than 40 years, viral load higher than 600,000UI/mL, and fibrosis grade (score METAVIR) were evaluated pre-treatment, and also the EVR considering the reduction of 100 times of the basal viral load (partial EVR) or negative PCR (complete EVR) in the week 12. In the statistical analysis, multivariate analysis was used. The significance level adopted was 5%. Results. There were 323 HCV monoinfected and 59 HCV/HIV coinfected. The SVR was 35.3% in monoinfected and 23% in coinfected patients. The worst results was observed in those with age greater than 40 years, high viral load, pronounced fibrosis (F4) and partial EVR, with an expected probability of 1.9% for SVR in those coinfected and 3.8% in monoinfected. In conclusion, patients with cirrhosis HCV genotype 1, age greater than 40 years, high viral load, coinfected with HIV or not, will present a low SVR if did not obtain negative PCR in week 12, and should be evaluated for discontinuation.

  • Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents Jaber Al-Ali, Salem Owayed, Wafa’a Al Qabandi, Khaled Husain, Fuad Hasan Page 156-160

    Background. Hepatitis C is endemic in the Middle East where genotype 4 accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype 4 is limited. Aim. To evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype 4. Patients and methods. In an open-labeled, uncontrolled pilot study, 12 adolescents (range14-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mg/ kg body weight once per week plus oral ribavirin (15 mg/kg/day) for 48 weeks. Patients were followed for 24 weeks post-treatment. All patients had biopsy proven hepatitis without cirrhosis. Results. One patient withdrew from the study due to developing insulin dependent diabetes mellitus 4 months into treatment. The remaining patients received at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75%). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required adjuvant therapy with hematologic growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism. Conclusion. Combination treatment of peginterferon alfa-2b with ribavirin appears to be efficacious and relatively safe in adolescents with chronic hepatitis C genotype 4.B.

  • Association between elevated aminotransferase levels and the metabolic syndrome in Northern Turkey Beytullah Yildirim, Fikret Ozugurlu, Semsettin Sahin, Huseyin Ozyurt, Omer Atis, Ali Akbas, Yeliz Akturk, Metin Ozdemir, Idris Sahin, Yunus Bulut, Ilker Etikan, M.Murat Firat‡ Page 161-165

    Introduction. Elevated aminotransferase levels(ATLs) are alert the physicians for liver-affecting disease and may reflect liver injury. We aimed to determine the prevalence of elevated ATLs and the association of elevated ATLs with the metabolic syndrome(MetS) in a northern province of Turkey. Materials and methods. Elevated ATLs were evaluated among 1,095 individuals of the Tokat Prevalence Study which have been described in detail elsewhere. 1,095 participants had been selected by a simple random sampling method among 530,000 inhabitants in 70 (12 urban and 58 rural) areas in the province of Tokat which is located in the Black Sea Region of Turkey. Results. The prevalence of elevated serum ALT, AST, and ALT and/ or AST were found as 11%, 7.2%, and 13.3%, respectively. Increased BMI, fatty liver, and MetS were higher in our general population with elevated ATLs. After exclusion of individuals with hepatitis B or hepatitis C infection, 132 individuals with elevated ATLs (91 male and 41 female) were evaluated. MetS was found in 59 participants and its prevalence was markedly higher in females with elevated ATLs (p < 0.0001). When the males with elevated ATLs were evaluated, the ALT levels of the persons who have no risk of MetS (p = 0.007) and the persons who have one risk of MetS (p = 0.001) were lower than the persons with MetS. Conclusions. Elevated ATLs are common and it’s an important cause is MetS in Northern Turkey

  • Efficacy of maintenance subcutaneous hepatitis B immune globulin (HBIG) post-transplant for prophylaxis against hepatitis B recurrence† Janakie Singham, Erica Greanya Pharm, Kirby Lau, Siegfried R. Erb, Nilu Partovi, Eric M. Yoshida Page 166-171

    Background. Patients who receive liver transplantation for chronic hepatitis B infection require long-term combination therapy with hepatitis B immunoglobulin (HBIG) and oral antiviral medication to prophylax against graft re-infection. This study examines the efficacy and patient preference of subcutaneous (SC) administration of HBIG in maintaining anti HBs titres > 100 IU/L. Materials and methods. 12 patients who were stable while receiving our standard IM HBIG protocol received an alternate formulation by SC injection, consisting of 10 mL (3120 IU) HBIG as 4 x 2.5 mL SC injections. SC injection were repeated as soon as titres reached 100-150 IU/mL during the 3 month study period. A questionnaire was administered upon study entry and exit to subjectively assess patient preference. Results. Anti- HBs Cmax after first injection was 441.6 IU/L ± 81.5, and Tmax was 7.1 ± 3.2 days. SC injections were required every 56 days, which compared well to the frequency of required IM injections prior to study enrollment of 45 days. The patients mean ratings of pain on a 0-10 scale were 5 for the IM route and 1.6 for the SC route. All patients preferred the SC injections to the IM. Conclusion. SC administration of HBIG can effectively maintain anti HBs levels above the requisite 100 IU/L while substantially decreasing patient discomfort and improving patient satisfaction, and therefore becomes a very attractive alternative to IM HBIG injections. Further studies and wider use of SC HBIG based on this study may alter the standard practice of transplantation centers.

  • Genotype f prevails in Venezuelan urban patients with chronic hepatitis B Irma V. Machado, María del Pilar Fortes, Berta Vargas-Lovelle, Aleidy C. Trómpiz, Danerys A. López, Roberto V. León, Merita Senior, Lucy Dagher, Carmen E. López, Elena Pestana, Román Bacalao, Miguel E. Garassini Page 172-176

    Hepatitis B virus (HBV) has been classified into 8 genotypes (A-H). Genotypes A, D and F have been identified in some South American countries, but in Venezuela studies have been more restricted to aboriginal communities where genotype F is predominant. The aim of the present study was to identify the prevalence of HBV genotypes among native HBsAg carriers in Venezuelan urban areas. In addition, we correlated the predominant HBV genotype with epidemiological, serological and virological features of the infection. Non-Venezuelan migrant patients were excluded from this study. Serum samples from 90 patients (21 children and 69 adults) with chronic hepatitis B (CHB) were analyzed. Seventy-four patients had CHB e-antigen positive and 16 CHB e-antigen negative. HBV DNA serum levels of the whole group ranged from 4.1 to 8.8 log10 IU/mL. Patients with CHB e-antigen positive showed significantly higher viral loads (P = 0.0001) than the group with CHB e-antigen negative. Eighty-eight patients (97.8%) exhibited HBV genotype F while two non-related patients (2.2%) were infected with A + F genotypes. Genotype F is the main circulating HBV strain among HBsAg carriers from Venezuelan urban areas. This genotype is associated mostly with CHB eantigen positive and high rate of transmission. Progression to cirrhosis and hepatocellular carcinoma could be major clinical events of this patient population independently of age at acquisition or transmission route.

  • Serum concentrations of substance P in cholestasis Mayur Trivedi, Nora V. Bergasa Page 177-180

    Substance P (SP) is an excitatory neuropeptide that acts via the neurokinin-1 receptor (NK-1) in the nervous system. Pruritus, a complication of cholestasis, is a nociceptive stimulus; thus, we hypothesized that cholestasis would be associated with increased neurotransmission via SP as evidenced, in part, by increased serum concentrations of this neuropeptide. Accordingly, the aim of this study was to determine the serum concentration of SP in patients with pruritus secondary to cholestasis and in the serum of rats with cholestasis secondary to bile duct resection (BDR). The mean serum SP concentration of patients with chronic liver disease (CLD) and pruritus was 9.09 pg/mL SD ± 6.5, significantly higher than 0.74 pg/mL SD ± 0.77, the mean serum concentration of SP from patients with CLD without pruritus (p = 0.0001), and from that of the control group, which was 0.65 pg/mL SD ± 0.37 (p = 0.0001). The mean serum SP concentration from six rats with cholestasis secondary to BDR six and fourteen days after surgery was 57.9 pg/mL, SD ± 17.3, and 56.3 pg/mL, SD ± 21.4, respectively, as compared to the concentration from the sham resected control group, which was 3.5 pg/mL SD ± 0.59 (p = 0.002) at six days post surgery. In conclusion, in cholestasis, there is increased availability of SP. These data provide a rationale for the study of SP release and metabolism in cholestasis, and in the mediation of the pruritus.

  • Anti-parietal cell autoantibodies (PCA) in primary biliary cirrhosis: a putative marker for recurrence after orthotopic liver transplantation? Sandra Ciesek, Thomas Becker, Michael P. Manns, Christian P. Strassburg Page 181-185

    Introduction. Liver transplantation (OLT) for primary biliary cirrhosis (PBC) is characterized by disease recurrence of up to one third of patients. The diagnosis of recurrence requires a cholestatic profile and a typical histology representing a challenge for transplant hepatologists. Antimitochondrial antibodies (AMA) establish the initial diagnosis, persist after OLT, and are thus of limited value for the diagnosis of recurrence. Aim of this analysis was to identify serological parameters associated with recurrent PBC. Patients and methods. OLT performed between 1992 and 2006 at Hannover Medical School were evaluated retrospectively including histology before and after OLT, autoimmune serological parameters and clinical characteristics. Results. Between 1992 and 2006 72 patients underwent OLT with histologically confirmed PBC. Median follow up was 123 months. AMA persisted in 55 (76%) patients. Anti-parietal cell antibodies (PCA) were detectable in 41% of the patients before and 47% after OLT. Liver biopsies were obtained in 34 patients post OLT upon clinical suspicion, and recurrent PBC diagnosed in 28% after a mean of 71 months (range 13-161). Anti-PCA were detected in 100% of patients with recurrence before and following transplantation, 54% of patients with anti-PCA before OLT developed recurrence during follow-up. There were no differences in immunosuppressive regimen. Discussion. Although unspecific for the diagnosis of PBC, anti-PCA prevalence increased after OLT, and was 100% in patients with recurrent PBC. Recurrent PBC developed in 54% of patients with anti-PCA before OLT suggesting a diagnostic role of anti-PCA as a simple and cost effective marker of recurrence.

  • Neuroendocrine metastatic tumors of the liver resembling hepatocellular carcinoma Julián Arista-Nasr, Jose Antonio Fernández-Amador, Braulio Martinez-Benítez, Jazmín de Anda-González, Leticia Bornstein-Quevedo Page 186-191

    Certain neuroendocrine tumors (NET) metastasized to the liver can resemble hepatocellular carcinoma (HCC) in cytological needle biopsy. Experience concerning the histologic characteristics of metastatic NET resembling HCC in core needle hepatic biopsies has been scarce. The aim of this study is to describe the histological criteria in seven metastatic NET that resembled HCC in core needle hepatic biopsy. From a total of 285 needle biopsies with primary or metastasized hepatic neoplasms, seven cases were selected originally diagnosed as HCC or HCC vs. NET metastasized to the liver. Fourteen needle biopsies of hepatocellular carcinomas were also studied for comparative purposes. In all of these neoplasms the diagnosis of endocrine tumor was confirmed by immunohistochemical studies and the following information was recorded: age, sex, radiological alterations, primary site of the NET, and follow-up. The following histological data were also recorded: fibrotic stroma associated or not with the neoplastic cells, growth pattern, form of the cells, cellular size, mitotic figures, nucleomegaly, apparent nucleoli, chromatin in salt and pepper, plasmacytoid cells, intranuclear inclusions, and biliary pigment. In conclusion, these characteristics were common in metastasized neuroendocrine tumors: extensive stromal fibrosis, slight to moderate atypia, hyperchromatic nuclei, plasmacytoid cells, and thin delicate strands of fibrovascular tissue supporting larger acinar groups of net cells. HCC had a more infrequent fibrotic stroma, moderate to marked atypia, and in some biopsies biliary pigment, intranuclear inclusions, and clear cells.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Spontaneous HBsAg seroconversion after severe flare of chronic hepatitis B infection Akif Altinbaþ, Ilhami Yüksel, Melih Pamukcu, Fuat Ekiz, Ömer Baþar, Osman Yüksel Page 194-197

    The results of the acute exacerbations of hepatitis B virus are varied from silent to severe acute hepatitis. HBsAg seroconversion induced by either antiviral drugs or occurred spontaneously, as a targeted end point of HBV infection management is infreaquent. The affect of the severe hepatitic flare on HBsAg seroconversion was reported before, however the predictive markers of HBsAg seroconversion are not clear yet. The reasons of the spontaneously HBV re-activations, or its usual results are not known well. We, herein reported a case, with the high serum HBV DNA titer during an acute spontaneously induced severe exacerbation of HBV infection which spontaneously resulted in total HBV recovery.

  • Severe acute hepatitis in the dress syndrome: Report of two cases Sabela Lens, Gonzalo Crespo, Jose A. Carrión, Rosa Miquel, Miquel Navasa Page 198-201

    The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, also known as DIHS (drug-induced hypersensitivity syndrome), is a severe idiosyncratic reaction to several drugs, mainly antiepileptics and antibiotics, which can occasionally produce acute liver failure. In this article we present two cases of the DRESS syndrome presenting with severe acute hepatitis, including the first case of DRESS associated with levetiracetam. Although both cases finally resolved with good outcomes, DRESS can lead to acute liver failure and has a bad prognosis when liver damage is present. Rapid diagnosis is crucial since withdrawal of the offending drug is the key of treatment, while the potential role of corticosteroids is discussed.

  • Spontaneous clearance of hepatitis C infection post-liver transplant:A rare but real phenomenon? A case report and review of the literature Mazhar Haque, Almoutaz Hashim, Erica D. Greanya Pharm, Urs P Steinbrecher, Siegfried R Er, Eric M. Yoshida Page 202-206

    Recurrent hepatitis C virus (HCV) infection after liver transplantation is a significant cause of morbidity, mortality and graft loss. Spontaneous clearance of recurrent HCV after liver transplant is a rarely reported phenomenon. We report a case of a 66-year-old woman who underwent liver transplantation for HCV cirrhosis (treatment- naive genotype 2) under immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and short-term corticosteroids. The patient developed histologically proved severe cholestatic recurrence of HCV hepatitis. Immunosuppression was reduced to tacrolimus monotherapy because of cytopenia. She subsequently became RNA negative at week 44 post- transplant while on tacrolimus and MMF despite no antiviral therapy. A spontaneous sustained virologic clearance was confirmed with subsequent HCV nucleotide testing. Only a few similar cases have been reported in the literature with uninterrupted immunosuppression and subsequent spontaneous clearance. Our experience, and the few other published cases in the literature, suggests that spontaneous clearance of HCV after liver transplantation is a rare but real phenomenon. Better understanding of this phenomenon may help to manage recurrent HCV disease after transplantation.

  • Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood Fatih Ermis, Kemal Oncu, Melih Ozel, Yusuf Yazgan, Ahmet Kemal Gurbuz, Levent Demirturk, Hakan Demirci, Taner Akyol, Aptullah Hahoglu Page 207-210

    Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder, characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The attacks can start at any age, but the first attack is usually seen before the second decade of life. We report the case of a young adult male patient with BRIC who presented with recurrent cholestatic jaundice and pruritus with negative work up for all possible etiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with rifampicin and has not suffered another attack on follow up. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.

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