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Current Issue

January March, 2007

Vol. 6 Issue 1

On the cover: Official Journal of the Mexican Association of Hepatology

EDITORIAL

CONCISE REVIEW

  • Gene therapy of liver cancer Rubén Hernández-Alcoceba, Bruno Sangro, Jesús Prieto Page 5-14

    Gene therapy of liver cancer covers a variety of gene transfer strategies aimed to the treatment of patients with primary and secondary liver tumors, including gene directed enzyme/pro-drug therapy, inhibition of oncogenes and restoration of tumor-suppressor genes, immunotherapy, anti-angiogenesis and virotherapy. Some of these strategies have reached early clinical development with diverse little success.

  • Biliary secretion and excretion in health anddisease: Current concepts Alan F Hofmann Page 15-27

    Biliary secretion in health and disease is reviewed. The powerful techniques of molecular biology have enabled cloning of the transporters involved in biliary secretion and the enterohepatic circulation of bile acids. This, in turn has permitted elucidation of their function as well as their regulation by nuclear receptors. Bile acid secretion is required for efficient lipid absorption, and bile acids also possess powerful direct and indirect antimicrobial functions in the small intestine. The enterohepatic circulation results from efficient ileal absorption, and is highly regulated at two sites. In the hepatocyte, biosynthesis of bile acids is regulated in negative feedback manner by the nuclear receptor FXR as well as by cytokines and by a peptide (FGF-19) liberated by bile acids from the ileal enterocyte. In the ileal enterocyte, bile acid reclamation is regulated in negative feedback manner by FXR and other nuclear receptors. The bile salt export pump (BSEP) mediates uphill canalicular bile acid secretion. Inborn defects in its function cause intrahepatic cholestasis in infants; inhibition of its function by drugs causes hepatotoxicity. Bile acid therapy is based on correction of bile acid deficiency by supplemental bile acids or displacement in which a noncytotoxic bile acid (ursodeoxycholic acid, ursodiol, UDCA) is administered and dilutes out the endogenous cytotoxic bile acids. Administration of primary bile acids may be lifesaving in inborn defects of bile acid biosynthesis. A synthetic bile acid, norUDCA is absorbed by the biliary ductules after secretion and cures the peribiliary fibrosis occurring in the MDR2-/- mouse which lacks biliary phospholipid.

  • Current concepts on the pathophysiology of portal hypertension Aina Rodríguez-Vilarrupla, Mercedes Fernández, Jaume Bosch, Joan Carles García-Pagán Page 28-36

    Cirrhosis of the liver is by far the most common cause of portal hypertension in the western world. Portal hypertension is a frequent clinical syndrome, defined by a pathological increase in the portal venous pressure. When the portal pressure gradient (the difference between pressures in the portal and the inferior vena cava veins: normal value below 6 mmHg) increases above 10-12 mmHg, complications of portal hypertension can occur. Increased resistance to portal blood flow, the primary factor in the pathophysiology of portal hypertension, is in great part due to morphological changes occurring in chronic liver diseases. However, more recently a graded and reversible contraction of different elements of the porto-hepatic bed have been shown to play a role modulating intrahepatic vascular resistance which provides a rationale for the intention to reduce intrahepatic resistance and portal pressure by means of pharmacological agents. The subsequent increase in portal blood flow, as a result of the arteriolar vasodilatation of the splanchnic organs, plays a contributory role maintaining and aggravating the portal hypertensive syndrome. This splanchnic arteriolar vasodilatation is a multifactorial phenomenon, which may involve neurogenic, humoral and local mechanisms.

ORIGINAL ARTICLES

  • Fatty liver: Experience from western India Anjali Amarapurkar, Tanveer Ghansar Page 37-40

    Introduction: Incidence of fatty liver is rising all over the world. Non alcoholic Steatohepatitis which is a subset of fatty liver disease has become a major concern since it is known to progress to liver cirrhosis. Obesity and diabetes mellitus are considered to be the important risk factors for nonalcoholic steatohepatitis. However fatty liver is also seen in non obese and non diabetic individuals. The epidemiology of fatty liver disease slightly differs in different countries, specially where various infections are more prevalent. Aim: To determine various risk factors responsible for steatosis and to assess severity of steatosis with fibrosis amongst various groups. Material and methods: Total 1,230 adult autopsies were screened over the period of 4 years. Amongst them 195 cases showing fatty liver were included in the study. Different risk factors responsible for fatty liver were analyzed from the clinical data and laboratory findings obtained from hospital records. Liver histological sections were studied for the presence of steatosis, inflammation and fibrosis. These 3 histological parameters were compared amongst the risk factors. Results: Alcoholism was found to be the commonest risk factor for staetosis followed by tuberculosis. Other risk factors were cardiac disorders, diabetes, hypertension, Hepatitis B & C infection, HIV and miscellaneous conditions. Overall prevalence of steatosis was found to be 15.8%. Steatosis, inflammation and fibrosis were more common in alcoholics. Tuberculosis was the second commonest risk factor, showed grade 2 to 3 steatosis however inflammation and fibrosis were significantly less in cases of tuberculosis. Findings in other risk factors were variable. Conclusion: Overall prevalence of fatty liver in this autopsy study was found to be 15.8%. Alcoholism was the commonest risk factor followed by tuberculosis. Fibrosis was mainly observed in association with alcoholism as compared to other risk factors.

  • Genistein decreases liver fibrosis and cholestasis induced by prolonged biliary obstruction in the rat Alfonso Leija Salas, Griselda Ocampo, German Garrido Fariña, Jorge Reyes-Esparza, Lourdes Rodríguez-Fragoso Page 41-47

    Fibrosis accompanies most chronic liver disorders and is a major factor contributing to hepatic failure. Therefore, the need for an effective treatment with the aim of modifying the clinical course of this disease is evident. The aim of this work is to determine whether genistein, which has been shown to modulate the physiology and pathophysiology of liver, is able to decrease experimental liver fibrosis and cholestasis. In male Wistar rats, the common bile duct was ligated. Administration of genistein (5 μg rat-1, day-1, p.o.) began four weeks after biliary obstruction and continued for a further four weeks. The liver was used for histological and ultrastructural analysis and for collagen quantification (hydroxyproline content). The degradation of Matrigel® and collagen type I was determined in homogenized liver. Bilirubins and enzyme activities were measured in serum. Genistein was able to improve normal liver histology, ultrastructure, collagen content, and biochemical markers of liver damage. It also increased Matrigel® and collagen type I degradation. In summary, the present report shows that genistein inhibits the fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Genistein has therapeutic potential against liver fibrosis.

  • End-stage renal disease and hepatitis C infection: comparison of alanine aminotransferase levels and liver histology in patients with and without renal damage Ana M. Contreras, Isaac Ruiz, Gisela Polanco-Cruz, Francisco J. Monteón, Alfredo Celis, Gonzalo Vázquez, Efraín Gómez-Herrera, Jesús E. García-Correa, René Male-Velázquez, Sara Ruelas-Hernández Page 48-54

    of alanine aminotransferase (ALT) are related to histological characteristics of liver damage caused by hepatitis C virus (HCV) infection among patients with end-stage renal disease (ESRD) remains unclear. Methods: Patients with a positive anti-HCV antibody titer confirmed by supplemental tests were evaluated by liver biopsy. We compared ALT levels in patients with and without renal damage, with similar histological grades and stages of inflammation and fibrosis. Patients were divided into two groups: patients with ESRD (n = 25) and patients without renal damage (n = 39). Results: The ALT level was 42.1 ± 24.3 IU/L for the ESRD group, compared with 109.9 ± 55.8 IU/L for the non-ESRD group (P < 0.001). Liver inflammation (modified Knodell grade) was 4.0 ± 2.1 in the ESRD group versus 5.2 ± 2.4 in the non-ESRD group; fibrosis (6-point scale) was 1.1 ± 1.2 versus 1.7 ± 1.5, respectively. Conclusions: Despite histological evidence of liver inflammation, ALT levels in the ESRD group were normal, while ALT levels were significantly higher in the non-ESRD group with similar levels of liver inflammation. In conclusion, ALT levels are not a useful indicator of HCV infection in patients with ESRD and liver biopsies should be recommended for kidney transplant candidates.

  • Association of HFE mutations (C282Y and H63D) with iron overload in blood donors from Mexico City Hector A. Baptista-González, Fany Rosenfeld-Mann, Rocío Trueba-Gómez, Luisa Bermejo-Martínez, Nahum Méndez-Sánchez Page 55-60

    Background and objective: Iron overload has been associated with HFE mutations (C282Y and H63D). We investigated the association between these mutations and high serum ferritin in a sample of healthy adult men. Design and methods: We enrolled unrelated blood donors from three hospitals in Mexico City in a crosssectional study. Serum ferritin (SF) was determined to define iron overload, and HFE gene mutations were identified by PCR–RFLP. Results: We evaluated 2524 male blood donors and included 246 individuals for each group. We identified 108 individuals with HFE gene mutation, 20.5 % were heterozygote (wt/H63D or wt/C282Y) and the remaining homozygote (H63D/ H63D). The genotype wt/C282Y was observed in two cases, none cases with C282Y/C282Y. The allelic frequency of H63D and C282Y was 0.115 and 0.002, respectively. We observed different association for H63D allele with iron overload (OR 1.54, CI 95 %1.16-2.03) and none in allele C282Y. Although values averages were different, the extreme dispersion of serum ferritin not showed statistically significant differences between H63D and C282Y alleles and ferritin concentrations. Conclusions: The male unrelated blood donors from Mexico City with iron overload prevalence of 13.8% hold similarities with other populations from Europe o America continent, respecting the allele frequency H63D. Nevertheless, allele frequency C282Y is lower than that observed in descendents from northern Europe. We have not observed statistic difference of SF or iron overload frequency by effect of both alleles.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Cholestatic hepatitis with severe systemic reactions induced by trimethoprim-sulfamethoxazole G Kouklakis, A Mpoumponaris, P Zezos, J Moschos, A Koulaouzidis, A Nakos, A Pehlivanidis, M Iosiphidis, E Molyvas, N Nikolaidis Page 63-65

    Trimethoprim-Sulfomethoxazole (TMP-SMX) related hepatotoxicity and associated severe systemic reaction are not frequent and documented only in case reports. We report a case of a 30-year-old man, who underwent a 15-day therapy with TMP-SMX for urinary tract infection and two weeks later developed acute cholestatic hepatitis, fever and a skin rash followed by severe systemic reaction. He was admitted in Intensive Care unit and with supportive therapy and prednisolone administration, he showed subsequent improvement over a period of few days. He had fully recovered months later. All tests for other causes of liver disease were negative and his liver biopsy showed evidence of drug-induced hepatic injury.

  • Spontaneous partial regression of hepatocellular carcinoma in a cirrhotic patient Judith Meza-Junco, Aldo J. Montaño-Loza, Braulio Martinez-Benítez, Tatiana Cabrera-Aleksandrova Page 66-69

    Spontaneous regression of a malignant tumor is an exceptional phenomenon. A 56-year-old woman with liver cirrhosis related to chronic hepatitis C presented with a liver tumor. Partial regression of a hepatocellular carcinoma was diagnosed by imaging studies that showed progressive diminution of the size of the tumor and changes in the tumor markers. However, because of the persistence of the tumor and uncertainty in the diagnosis we recommended surgery. A hepatectomy was performed and a hepatocellular carcinoma moderately differentiated was found. The patient is now doing well and without any evidence of recurrence at 25 months after surgery. We found 61 case reports that have been published from 1982 to September 2006, with apparently spontaneous regression of hepatocellular carcinoma. The precise mechanism regarding the spontaneous regression of this tumor is not fully understood, either ischemia due to rapid growth of the neoplasia or particular inflammatory and immunologic mechanisms may be involved in the regression of the hepatocellular carcinoma.

  • Drug-related hepatotoxicity in a renal transplant recipient with long-term survival and hepatitis C Ana M. Contreras, Francisco J. Monteón, María Rosa Flores, Federico Mendoza-Sánchez, Isaac Ruiz Page 70-73

    Drug-related hepatotoxicity is more common in renal transplant (RT) recipients with chronic liver disease because drug metabolism is not as efficient in these individuals. We describe a long-term survivor (30 years) of renal transplantation with hepatitis C virus (HCV) and drug-related hepatotoxicity. Our patient, a 26-year-old male, developed uremic syndrome in May 1976 and received a renal allograft from a related, living donor with an identical human leukocyte antigen genotype in August 1976. Maintenance immunosuppression treatment consisted of azathioprine (AZA) and prednisone. In 1993, the patient tested negative for HCV antibody v1.0 (anti-HCV). In 2000, the patient had elevated aminotransferases, which was attributed to pravastatin treatment. Remission of this abnormality was achieved once pravastatin was discontinued. In 2003, the patient again exhibited elevated levels of aminotransferases and AZA-related hepatotoxicity was suspected; therefore, AZA was discontinued and treatment with mycophenolate mofetil was initiated, which led to normal aminotransferase levels. The patient tested positive for anti-HCV v3.0 and HCV RNA and a liver biopsy showed chronic hepatitis with moderate activity. Currently, the patient’s renal transplant and liver are functional. In conclusion, hepatotoxic drugs should be used with caution in renal transplant recipients and close monitoring of liver function in patients with chronic viral hepatitis is crucial.

The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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