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September - October, 2012

Vol. 11 Issue 5

On the cover: A. A computed tomography. B. A right hepatic lobectomy. C and D. Histological studies were performed.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Review of the neurological manifestations of hepatitis E infection Michelle C.M. Cheung, James Maguire, Ivana Carey, Julia Wendon, Kosh Agarwal Page 618-622

    Hepatitis E (HEV) is a common infection worldwide and is an emerging disease in developed countries. The presence of extra-hepatic manifestation of HEV infection is important to bear in mind so that the diagnosis is not missed, since HEV is not routinely tested for in acute hepatitis due to perceived rarity of this infection outside of endemic countries. This article reviews the neurological presentations of acute and chronic HEV, and discusses the viral kinetics against symptomatology, and outcomes of specific treatment. Possible mechanisms of pathogenesis are considered.

  • The epidemiologic burden of hepatitis C virus infection in Latin America Shelagh M. Szabo, Meagan Bibby, Yong Yuan, Bonnie M.K. Donato, R. Jiménez Mendez, G. Castañeda-Hernández, Maribel Rodríguez-Torres, Adrian R. Levy Page 623-635

    Chronic infection with hepatitis C virus (HCV) is a major and growing public health concern worldwide, including in Latin America. With more efficacious therapies becoming available, decision-makers will require accurate estimates of disease prevalence to assess the potential impact of new treatments. However, few estimates of the epidemiologic burden, either overall or by country, are available for Latin America; and the potential impact of currently-available treatments on the epidemiologic burden of HCV in Latin America has not been assessed. To address this, we systematically reviewed twenty-five articles presenting population- based estimates of HCV prevalence from general population or blood donor samples, and supplemented those with publically-available data, to estimate the total number of persons infected with HCV in Latin America at 7.8 million (2010). Of these, over 4.6 million would be expected to have genotype 1 chronic HCV, based on published data on the risk of progression to chronic disease and the HCV genotype distribution of Latin America. Finally, we calculated that between 1.6 and 2.3 million persons with genotype 1 chronic HCV would potentially benefit from current treatments, based on published estimates of genotypespecific treatment responsiveness. In conclusion, these estimates demonstrate the substantial present epidemiologic burden of HCV, and quantify the impending societal and clinical burden from untreated HCV in Latin America.

  • Role of nitric oxide in liver regeneration Cristina E. Carnovale, Maria T. Ronco Page 636-647

    The liver has a remarkable ability to regenerate in response to surgical removal or chemical insult. The mechanisms regulating regenerative processes are complex, and incompletely understood. A large number genes, which are not normally expressed in the quiescent liver, are activated. Immediately after partial hepatectomy (PH) (1-6 h), nitric oxide (NO) is synthesized by liver parenchymal and nonparenchymal cells from L-arginine, via induction of the inducible form of nitric oxide synthase (iNOS). NO is a highly reactive molecule, known to be involved in diverse biological processes in nearly all aspects of life. Liver regeneration is a major area within the field of NO research. Our review describes several processes that have been suggested to be modulated by the NO released following PH, including proliferation, apoptosis and angiogenesis in the remnant tissue. Because iNOS up regulation has such profound physiologic effects, its regulation is strictly controlled. The up regulation of iNOS after PH and the subsequent production of NO induce positive effects on the regulation of early stages of the regenerative process. However, overproduction (> 100%) can have detrimental effects, including apoptosis. Thus, the iNOS induction after PH is necessary, and enough to allow for the normal regenerative process.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Serum cystatin C: a non-invasive marker of liver fibrosis or of current liver fibrogenesis in chronic hepatitis C? José M. Ladero, María C. Cárdenas, Luis Ortega, Andrea González-Pino, Francisca Cuenca, César Morales, Anna Lee-Brunner Page 648-651

    Background. Serum levels of cystatin C, an endogenous inhibitor of cysteine proteases, provide an alternative method to creatinine-based criteria for measuring glomerular filtration rate. Preliminary data suggested that serum cystatin C levels parallel with the stage of liver fibrosis in chronic liver disorders. Our aim has been to evaluate the possible role of serum cystatin C as a marker of liver fibrosis in hepatitis C virus (HCV)-induced chronic liver disease. Material and methods. 100 consecutive patients (56 men, mean age 51.2 ± 9.5 yrs) with HCV-induced chronic liver disease, scheduled for their first liver biopsy and naïve for antiviral therapy were included. Liver fibrosis was evaluated with the METAVIR score. Serum cystatin C and standard laboratory tests were measured simultaneously. Patients with ethanol abuse (> 50 g/day), HBV or HIV coinfection or plasma creatinine ≥ 1.20 mg/dL were excluded. In addition, a second group of 16 patients fulfilling the same requisites and diagnosed with HCV-induced compensated cirrhosis by clinical evidence of portal hypertension was included. Results. Serum cystatin C levels significantly increase from F0 to F2 fibrosis stages, remained stable in F3 and F4 stages and increased again in the group of non-biopsied compensated cirrhosis. Serum cystatin C levels were higher in patients with moderate-advanced necroinflammation in the liver biopsy. Conclusion. Serum cystatin C level may reflect current fibrogenic and necroinflammatory activities in chronic HCV-induced liver disease with normal renal function but can not be considered as a non-invasive marker of liver fibrosis.

  • Clinical course and management of acute hepatitis A infection in adults Ileana MacKinney-Novelo, Josué Barahona-Garrido, Fátima Castillo-Albarran, Jean J. Santiago-Hernández, Nahum Méndez-Sánchez, Misael Uribe, Norberto Chávez-Tapia Page 652-657

    Background. Hepatitis A is the most common type of viral hepatitis in Mexico. The change of hepatitis A epidemiology in Mexico from high to intermediate endemicity leads to increasing susceptible adults for severe illness. Objective. To describe the clinical characteristics and hospital outcome of adult patients with acute hepatitis A infection, and determine risk factor for mortality. Material and methods. This is a retrospective observational, multicentre study in Mexico City and in Guatemala City. All inhospital patients were followed until discharge or death. Risk factors for death/acute liver failure were identified. Results. Forty seven patients were analyzed, sixty percent were male, the prodrome phase was from 3 to 30 days. The three most common symptoms were fever, malaise and jaundice, with 87%, 74% and 62% respectively. The incidence of patients who were treated with antibiotics before hospital admission was up to 34%. Unnecessary imaging studies and out of guidelines drugs were used. Presence of encephalopathy, leukocytes > 19,000/mL, blood urea nitrogen > 36 mg/dL, creatinine > 2 mg/dL, albumin < 2.5 mg/dL and total bilirubin > 9.6 mg/dL, are predictors of mortality. Serum creatinine > 2 mg/dL has the best sensibility and specificity for predicting fulminant hepatitis/death. Conclusion. Acute hepatitis A infection in adults is associated some unnecessary diagnostic and therapeutic approach. Could be associated with fulminant hepatitis, and a creatinine value > 2 mg/dL is the best predictor for fulminant hepatitis and death.

  • Natural history of hepatitis C virus infection in a cohort of asymptomatic post-transfused subjects María Virginia Reggiardo, Fabian Fay, Mario Tanno, Gabriela García Camacho, Oscar Bottaso, Sebastián Ferretti, Alicia Godoy, Claudio Guerrita, Mauro Paez, Federico Tanno, Orlando Ruffinengo, Silvina Benetti, Silvia E. García Borrás, _ Rossi Page 658-666

    Background & aims. Studies about the natural history of hepatitis C virus (HCV) infection report variable progression to cirrhosis depending on study design. Retrospective cross-sectional liver clinic studies overestimate the rate of fibrosis progression due to inclusion of patients with more severe disease leaving mild and asymptomatic patients underrepresented. We evaluated fibrosis progression in a group of "healthy" asymptomatic subjects, attending to a voluntary campaign for the detection of HCV infection. Material and methods. A detection campaign was launched on subjects transfused before 1993. Of 1699 volunteers, 61(3.6%) had HCV infection. A liver biopsy was performed in 40 (65%). Assessed risk factors for liver fibrosis were: sex, body mass index, alcohol consumption (> 20 g/d - >40g/d ), genotype, HLA-DRB1 alleles, present age, age at infection and duration of infection. Results. 25 (62.5%) were women with a median age of 52.5 years. The median duration of infection was 21.5 years with a median age at infection of 27 years. As regards fibrosis, 25 (62.5%) had a Low Stage (F0-F1), 8 patients, 20%, had severe fibrosis, one patient (2.5%) had cirrhosis. Alcohol consumption was the only risk factor associated with fibrosis progression. Conclusions. The low progression to cirrhosis may be explained by the clinical characteristics of our population: asymptomatic middle-aged "healthy" subjects infected at young age. The progression to severe fibrosis was noticeable; hence a longer follow-up might demonstrate changes in this outcome. Significant alcohol consumption clearly worsens the natural history of HCV infection; this is no so evident for occasional or mild alcohol consumers.

  • Decreased serum total T3 level in hepatitis B and C related cirrhosis by severity of liver damage Fariborz Mansour-Ghanaei, Mojtaba Mehrdad, Sahereh Mortazavi, Farahnaz Joukar, Mohammad Khak, Zahra Atrkar-Roushan Page 667-671

    Objective. Thyroid hormones profile in patients with hepatic cirrhosis due to chronic HBV and HCV infections was evaluated in order to find any relationship between thyroid hormones and severity of liver damage. Material and methods. Patients with the diagnosis of hepatic cirrhosis due to hepatitis B or C were screened for thyroid function status. Child-Pugh and model for end-stage liver disease (MELD) scores were calculated. Considering each thyroid function test, patients were divided into two groups with lower than normal and normal range of thyroid hormones, separately for each (for TSH, normal and upper than normal). The correlation between thyroid function tests and severity of liver disease was taken into account. Results. Number of patients with a T3 level lower than normal range (70-110 ng/dL) significantly increased along with Child-Pugh scores A, B and C. A negative correlation was found between Child-Pugh scores and total serum T3 level (r = -0.453, P < 0.001). Also a reverse correlation was observed between MELD score and T3 levels (r = -0.305, P = 0.14). Conclusion. In conclusion serum T3 concentration is a good index of hepatic function, decreasing by the severity of liver damage.

  • Epidemiologic trends in HBV infections at a reference centre in Turkey: an 11-year retrospective analysis Koray Ergunay, Yasemin Balaban, Erdal Cosgun, Alpaslan Alp, Halis Simsek, Burcin Sener, Gonca Tatar, Gulsen Hascelik Page 672-678

    Objective. To identify changes in hepatitis B epidemiology after the implementation of the nationwide vaccination program in Turkey, hepatitis B virus (HBV) and related tests performed over a period of 11 years (2000-2010) at a reference centre were retrospectively overviewed and statistically analysed for trends. Results. Assay results for Hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), Anti-HBs, Anti-HBe, Anti-HBc immunoglobulins and HBV DNA as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gama-glutamyl transpeptidase (GGT) and alkaline phosphatase (AP) levels, obtained via standardized commercial assays were included in the analysis. Overall, a stable anti-HBs incidence (43.6%) and male predominance in infected individuals were noted. Total Anti-HBc was detected in 43.3% of the Anti-HBs reactive population, demonstrating that the immunity against HBV has still been acquired through virus exposure. An intermediate HBsAg seroprevalence of 6.0% was observed with a significant decrease from 12.3% to 5.0% from 2000 to 2010. Anti-HBe positive infections were more frequent than those with HBe antigenemia (77.1% vs. 18.5%) with a notable increase from 2000 to 2003. HBV DNA was detected in 23.6-25.6% with serological markers of viral replication and was more prevalent in HBeAg positive individuals in parallel with AST, ALT and GGT levels. Evidence for horizontal transfer as the major transmission route was revealed with a reduction of childhood HBV infections, attributable to the ongoing vaccination efforts.

Liver transplantation
  • Liver transplantation in the critically ill: donation after cardiac death compared to donation after brain death grafts C. Burcin Taner, Ilynn G. Bulatao, Lisa C. Arasi, Dana K. Perry, Darrin L. Willingham, Lena Sibulesky, Barry G. Rosser, Juan M. Canabal, Justin H. Nguyen, David J. Kramer Page 679-685

    Patients with end stage liver disease may become critically ill prior to LT requiring admission to the intensive care unit (ICU). The high acuity patients may be thought too ill to transplant; however, often LT is the only therapeutic option. Choosing the correct liver allograft for these patients is often difficult and it is imperative that the allograft work immediately. Donation after cardiac death (DCD) donors provide an important source of livers, however, DCD graft allocation remains a controversial topic, in critically ill patients. Between January 2003-December 2008, 1215 LTs were performed: 85 patients at the time of LT were in the ICU. Twelve patients received DCD grafts and 73 received donation after brain dead (DBD) grafts. After retransplant cases and multiorgan transplants were excluded, 8 recipients of DCD grafts and 42 recipients of DBD grafts were included in this study. Post-transplant outcomes of DCD and DBD liver grafts were compared. While there were differences in graft and survival between DCD and DBD groups at 4 month and 1 year time points, the differences did not reach statistical significance. The graft and patient survival rates were similar among the groups at 3-year time point. There is need for other large liver transplant programs to report their outcomes using liver grafts from DCD and DBD donors. We believe that the experience of the surgical, medical and critical care team is important for successfully using DCD grafts for critically ill patients.

Miscellaneous
  • A clinical survey of bleeding, thrombosis, and blood product use in decompensated cirrhosis patients Neeral L. Shah, Patrick G. Northup, Stephen H. Caldwell Page 686-690

    Background. The relative incidence of bleeding and thrombotic events and the use of blood products in hospitalized cirrhosis patients have not been widely reported. We aimed to estimate the magnitude of bleeding events and venous thrombosis in consecutive hospitalized cirrhotic patients over a finite time period and to examine the amount and indications for blood product use in cirrhosis patients admitted to a tertiary care center. Results. Among patients admitted with decompensated liver disease, 34 (40%) suffered bleeding events (about one-half non-variceal) and 6 patients (7%) suffered deep venous thrombosis. In the blood product survey, 168 patients were transfused with plasma or platelets during the survey intervals. Liver disease patients accounted for 7.7% of the total but disproportionately consumed 32.4% (46 of 142) of the units of plasma mostly administered as prophylaxis. In contrast, cirrhosis patients received only 7 of the 53 units of platelets transfused (13.2%) during the survey intervals. Conclusions. Coagulation issues constitute a common problem in patients with liver disease. Recent advances in laboratory testing have shown that stable cirrhosis patients are relatively hypercoagulable. The result of this prospective survey among decompensated (unstable) cirrhosis patients shows that, while DVT is not uncommon, bleeding (non-variceal in one half) remains the dominant clinical problem. This situation likely sustains the common practice of plasma infusion in these patients although its use is of unproven and questionable benefit. Better clinical tools are needed to refine clinical practice in this setting.

  • Does the size of the needle influence the number of portal tracts obtained through percutaneous liver biopsy? Ioan Sporea, Diana Gherhardt, Alina Popescu, Roxana Sirli, Maria Cornianu, Diana Herman, Simona Bota Page 691-695

    Aim. Liver biopsy (LB) is often essential for the diagnosis and staging of chronic viral hepatitis. The aim of our paper was to establish if the size of the biopsy needle influences the number of portal tracts obtained through LB. Material and methods. We conducted a retrospective study on 596 echoassisted percutaneous LBs performed in the Department of Gastroenterology and Hepatology Timisoara during a 4 years period. We included only those biopsy results that had mentioned both the type of needle and the number of portal tracts. All LBs were echoassisted and performed with Menghini modified needles 1.4 and 1.6 mm in diameter (technique with two passages into the liver). The liver fragments were analyzed by a senior pathologist and Knodell score was used to describe necroinflammatory activity as well as fibrosis. We compared the number of portal tracts obtained with 1.4 vs. 1.6 Menghini needles. Results. Type 1.4 mm Menghini needles were used for 80 LBs, while 1.6 mm type were used in 516 LBs. Liver fragments obtained with 1.6 mm Menghini needles had a significantly higher mean number of portal tracts as compared to those obtained with 1.4 needles (24.5 ± 10.6 vs. 20.8 ± 8.6, p = 0.003). Conclusion. The 1.6 mm Menghini needles provide better liver biopsy specimens, with higher number of portal tracts, as compared to 1.4 mm Menghini needles.

  • Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in Emergency Department: Uri-Quick Clini-10SG® vs. Multistix 10SG® Félix I. Téllez-Ávila, Norberto C. Chávez-Tapia, Ada M. Franco-Guzmán, Misael Uribe, Florencia Vargas Vorackova Page 696-699

    Background and aim. Bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis causing significant mortality. Delay in SBP diagnosis is a serious problem. The aim of this study was to evaluate the diagnostic yield of Uri-Quick Clini-10SG® vs. Multistix 10SG® reagent strips in an Emergency Department. Material and methods. A prospective study of consecutive patients with ascites and paracentesis attending to Emergency Department from March 2005 to February 2007 was made. SBP was defined by ≥ 250 neutrophiles /mm3. The ascites obtained at bedside was immediately tested in a dry test tube with both the Uri-Quick Clini 10SG® and MultistixSG10®. The Uri-Quick Clini 10SG® and Multistix SG10®. Strips were considered positive at grade ≥ 3 (≥125 leukocytes/mL). Results. A total of 223 ascitic fluid samples were obtained. There were 49 episodes of SBP. Median age was 54 (range 18-87 year) years; 62.3% were female. The sensitivity, specificity, PPV, NPV, and 95% CI for Uri-Quick Clini 10SG® were 79.6 (64-87), 98.2 (94-99), 90.5 (78-96) and 93.9 (89-96), respectively. For MultistixSG10® the values were 77.5 (64- 88), 97.7 (93-98), 90 (77.9-96.2), and 94 (89.4-96.6), respectively. Conclusion. The use of reagent strip is useful for SBP diagnosis in an emergency setting. The high PPV allow start antibiotic treatment. In areas without the resources to perform conventional ascites fluid analyses, these strips could be presently used.

  • NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population Xiaozhen Lv, Shaowen Tang, Yinyin Xia, Yuan Zhang, Shanshan Wu, Zhirong Yang, Xiaoting Li, Dehua Tu, Yixin Chen, Peiyuan Deng, Yu Ma, Dafang Chen, Ru Chen, _ Zhan Page 700-707

    Background. Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. Aim. To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. Material and methods. A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results. A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. Conclusions. In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Prolonged cholestasis triggered by hepatitis A virus infection and variants of the hepatocanalicular phospholipid and bile salt transporters Marcin Krawczyk, Frank Grünhage, Miriam Langhirt, Rainer M. Bohle, Frank Lammert Page 710-714

    Hepatitis A virus (HAV) infection resolves in most patients uneventfully within weeks from the onset of the disease. In rare cases, however, it may relapse or cause prolonged cholestasis. Here we present a case of a 36-year-old female patient who developed severe pruritus and jaundice three weeks after initially uncomplicated hepatitis A. A relapse of the infection was excluded. Since therapy with colestyramin, antihistaminics, naloxon and ursodeoxycholic acid (UDCA) did not improve symptoms, we decided to perform plasma absorption and to start rifampicin therapy. Under these measures, pruritus and jaundice, as well as serum bilirubin levels improved gradually and after four plasmapheresis sessions we were able to discharge the patient. Genetic testing showed the presence of two procholestatic polymorphisms, the c.3084 [GG] variant within the gene encoding the hepatocanalicular bile salt transporter ABCB11 and the c.711 [AT] variant of the phosphatidylcholine floppase ABCB4. We speculate that this compound ABCB4- ABCB11 genotype led to a severe intrahepatic cholestasis in the setting of HAV infection. In conclusion, our case suggests that polymorphisms within the hepatocanalicular transporters may contribute to a more pronounced course of HAV infection. Although dedicated studies in large cohorts of patients are needed to confirm this observation, we speculate that patients carrying procholestatic hepatobiliary transporter variants may benefit from vaccination against hepatitis A.

  • Primary hepatic neuroendocrine tumour requiring live donor liver transplantation: case report and concise review Ananta Gurung, Eric M. Yoshida, Charles H. Scudamore, Almoutaz Hashim, Siegfried R. Erb, Douglas L. Webber Page 715-720

    Primary hepatic neuroendocrine tumours are rare tumours effecting relatively young patients. As metastatic neuroendocrine tumours to the liver are much more common, extensive investigations are crucial to exclude a primary tumour elsewhere. We report a case of a 27 year old woman who presented with fatigue, increased abdominal girth and feeling of early satiety and bloating. Extensive work up failed to show tumour at another primary site. Hepatic artery embolization showed no effect, so the patient underwent total hepatectomy and live-donor liver transplant. Grossly the tumour measured 27 cm. Microscopic examination showed bland, monomorphic cells growing in tubuloglandular and trabecular growth patterns. Cells were positive for neuroendocrine (synaptophysin, chromogranin, CD56) and epithelial markers (MOC31, CK7, CK19). Cytoplasmic dense neurosecretory vesicles were seen on ultrastructural examination. Based on the Ki-67 rate, mitotic count, lack of marked nuclear atypia and absence of necrosis, a diagnosis of primary neuroendocrine grade 2 was conferred.

  • Primary hepatic amyloidosis: a mini literature review and five cases report Ya Dong Wang, Cai-Yan Zhao, Hong Zhu Yin Page 721-227

    Primary hepatic amyloidosis (PHA) is characterized by abnormal deposition of monoclonal immunoglobulin light chains (AL) in the liver. This rare condition is frequently undiagnosed or misdiagnosed and can be associated with poor prognosis. At present, the precise pathogenesis is not fully understood. Despite that hepatomegaly and elevated alkaline phosphatase (ALP) are present in most patients with PHA, no specific clinical markers have been identified. Staining of hepatic tissues with Congo Red is often regarded as the "gold standard". Pharmacological therapy should aim to rapidly reduce the supply of misfolded amyloidogenic AL. High-dose intravenous melphalan (HDM) and autologous stem cell transplantation (ASCT) appear to be the most appropriate therapy but controversies still exist.

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