Effect of alcohol on iron storage diseases of the liver

The consumption of excess alcohol in patients with liver iron storage diseases, in particular the iron-overload disease hereditary haemochromatosis (HH), has important clinical consequences. HH, a common genetic disorder amongst people of European descent, results in a slow, progressive accumulation of excess hepatic iron. If left untreated, the condition may lead to fibrosis, cirrhosis and primary hepatocellular carcinoma. The consumption of excess alcohol remains an important cause of hepatic cirrhosis and alcohol consumption itself may lead to altered iron homeostasis. Both alcohol and iron independently have been shown to result in increased oxidative stress causing lipid peroxidation and tissue damage. Therefore, the added effects of both toxins may exacerbate the pathogenesis of disease and impose an increased risk of cirrhosis. This review discusses the concomitant effects of alcohol and iron on the pathogenesis of liver disease. We also discuss the implications of co-existent alcohol and iron in end-stage liver disease.

Base molecular da hemocromatose hereditária não-clássica em Portugal

A Hemocromatose Hereditária (HH) é uma doença autossómica recessiva caracterizada pela absorção excessiva de ferro a nível intestinal e sua acumulação em órgãos vitais, podendo originar cardiomiopatia, cirrose e carcinoma hepatocelular. O correspondente diagnóstico molecular é obtido pela associação com genótipos específicos no gene HFE (homozigotia para p.Cys282Tyr ou heterozigotia composta p.Cys282Tyr/p.His63Asp). Contudo, nos países do sul da Europa, cerca de um terço dos doentes com diagnóstico clínico de HH não apresenta os referidos genótipos. Para identificar a base molecular da HH não-clássica em Portugal usaram-se metodologias de pesquisa geral de variantes genéticas (SSCP e dHPLC), Next-Generation Sequencing (NGS) e sequenciação de Sanger, cobrindo seis genes relacionados com o metabolismo do ferro em 303 doentes. Identificaram-se 69 variantes diferentes e de vários tipos, por ex. missense, nonsense, de splicing, que perturbam a transcrição do gene ou a regulação da tradução do mRNA. Seguidamente, realizaram-se estudos in silico e in vitro para esclarecer o significado etiológico de algumas das novas variantes. Concluiu-se que a base molecular desta patologia é bastante heterogénea e que a NGS é uma ferramenta adequada para efetuar a análise simultânea dos vários genes num grande número de amostras. Contudo, o estabelecimento da relevância clínica de algumas variantes requer a realização de estudos funcionais.

Cobalt complexes bearing scorpionate ligands: Synthesis, characterization, cytotoxicity and DNA cleavage

A number of novel, water-stable redox-active cobalt complexes of the C-functionalized tripodal ligands tris(pyrazolyl)methane XC(pz)(3) (X = HOCH2, CH2OCH2Py or CH2OSO2Me) are reported along with their effects on DNA. The compounds were isolated as air-stable solids and fully characterized by IR and FIR spectroscopies, ESI-MS(+/-), cyclic voltammetry, controlled potential electrolysis, elemental analysis and, in a number of cases, also by single-crystal X-ray diffraction. They showed moderate cytotoxicity in vitro towards HCT116 colorectal carcinoma and HepG2 hepatocellular carcinoma human cancer cell lines. This viability loss is correlated with an increase of tumour cell lines apoptosis. Reactivity studies with biomolecules, such as reducing agents, H2O2, plasmid DNA and UV-visible titrations were also performed to provide tentative insights into the mode of action of the complexes. Incubation of Co(II) complexes with pDNA induced double strand breaks, without requiring the presence of any activator. This pDNA cleavage appears to be mediated by O-centred radical species.

Liver morphology with emphasis on bile ducts changes and survival analysis in mice submitted to multiple Schistosoma mansoni infections and chemotherapy

In an attempt to be as close as possible to the infected and treated patients of the endemic areas of schistosomiasis (S. mansoni) and in order to achieve a long period of follow-up, mice were repeatedly infected with a low number of cercariae. Survival data and histological variables such as schistosomal granuloma, portal changes, hepatocellular necrosis, hepatocellular regeneration, schistosomotic pigment, periductal fibrosis and chiefly bile ducts changes were analysed in the infected treated and non treated mice. Oxamniquine chemotherapy in repeatedly infected mice prolonged survival significantly when compared to non-treated animals (chi-square 9.24, p = 0.0024), thus confirming previous results with a similar experimental model but with a shorter term follow-up. Furthermore, mortality decreased rapidly after treatment suggesting an abrupt reduction in the severity of hepatic lesions. A morphological and immunohistochemical study of the liver was carried out. Portal fibrosis, with a pattern resembling human Symmers fibrosis was present at a late phase in the infected animals. Bile duct lesions were quite close to those described in human Mansonian schistosomiasis. Schistosomal antigen was observed in one isolated altered bile duct cell. The pathogenesis of the bile duct changes and its relation to the parasite infection and/or their antigens are discussed.

Molecular aspects of hepatic carcinogenesis

Exogenous agents correlated with hepatocellular carcinoma (HCC) have been identified and well characterized. These agents, including the different viruses that cause chronic hepatitis and cirrhosis, can lead to regenerative nodules and dysplastic nodules/adenomatous hyperplasia. These conditions associated with several molecular alterations of hepatocyte ultimately culminate in hepatocellular carcinoma. Recently, there has been a great progress in the identification of somatic and germinative mutations that may be correlated with the development of HCC, justifying a review on the subject. Hence, the factors involved in the process of hepatic carcinogenesis, such as infection by the hepatitis B and C viruses, with a special focus in the molecular alterations described in recent years are discussed herein, pointing out areas potentially relevant for clinical development.

The influence of the human genome on chronic viral hepatitis outcome

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.

Dapsone hypersensitivity syndrome in an adolescent during treatment during of leprosy

A 12 y old girl was admitted 24 days after start a WHO multidrug therapy scheme for multibacillary leprosy (dapsone, clofazimine and rifampicin) with intense jaundice, generalized lymphadenopathy, hepatoesplenomegaly, oral erosions, conjunctivitis, morbiliform rash and edema of face, ankles and hands. The main laboratory data on admission included: hemoglobin, 8.4 g/dL; WBC, 15,710 cells/mm³; platelet count, 100,000 cells/mm³; INR = 1.49; increased serum levels of aspartate and alanine aminotransferases, gamma-glutamyl transpeptidase, alkaline phosphatase, direct and indirect bilirubin. Following, the clinical conditions had deteriorated, developing exfoliative dermatitis, shock, generalized edema, acute renal and hepatic failure, pancytopenia, intestinal bleeding, pneumonia, urinary tract infection and bacteremia, needing adrenergic drugs, replacement of fluids and blood product components, and antibiotics. Ten days after admission she started to improve, and was discharged to home at day 39th, after start new supervised treatment for leprosy with clofazimine and rifampicin, without adverse effects. This presentation fulfils the criteria for the diagnosis of dapsone hypersensitivity syndrome (fever, generalized lymphadenopathy, exfoliative rash, anemia and liver involvement with mixed hepatocellular and cholestatic features). Physicians, mainly in geographical areas with high prevalence rates of leprosy, should be aware to this severe, and probably not so rare, hypersensitivity reaction to dapsone.

Carcinoma Hepatocelular Metastático: Massa Auricular Direita como Manifestação Clínica Primária. Caso Clínico

Nos doentes com carcinoma hepatocelular a incidência de metástases cardíacas é de 0.67-3%. Mesmo na ressecção com intuito curativo, o prognóstico é reservado, sendo a sobrevida aos 5 anos de 12-39%. Descrevemos um caso clínico, pouco habitual, de um indivíduo do sexo masculino, de 51 anos de idade, que apresentava uma massa localizada à aurícula direita, diagnosticada por exame histopatológico, como sendo metástase de um carcinoma hepatocelular, tendo sido necessária a ressecção cirúrgica urgente, devido a instabilidade cardiovascular.

Hepatic Artery Thrombosis in Live Liver Donor Transplantation: How to Solve - a Case Report

The decrease in the number of cadaveric donors has proved a limiting factor in the number of liver transplants, leading to the death of many patients on the waiting list. The living donor liver transplantation is an option that allows, in selected cases, increase the number of donors. One of the most serious complications in liver transplantation is hepatic artery thrombosis, in the past considered potentially fatal without urgent re-transplantation. A white male patient, 48 years old, diagnosed with hepatocellular carcinoma in chronic liver failure caused by hepatitis B virus, underwent living donor liver transplantation (right lobe). Doppler echocardiography performed in the immediate postoperative period did not identify arterial flow in the right branch, having been confirmed thrombosis of the right hepatic artery in CT angiography. Urgent re-laparotomy was performed, which consisted of thrombectomy and re-anastomosis of the hepatic artery with segmental splenic artery allograft interposition. The patient started anticoagulation and antiplatelet therapy with acetylsalicylic acid. Serial evaluation with Doppler echocardiography showed hepatic artery patency. At present, the patient is asymptomatic. One of the most devastating complications in liver transplantation, and particularly in living liver donor, is thrombosis of the hepatic artery; thus, early diagnosis and treatment is vital. The rapid intervention for revascularization of the graft avoids irreversible ischemia of the bile ducts and hepatic parenchyma, thus avoiding the need for re-transplantation.

Yellow fever virus isolated from a fatal post vaccination event: an experimental comparative study with the 17DD vaccine strain in the Syrian hamster (Mesocricetus auratus)

In order to investigate the pathogenicity of the virus strain GOI 4191 that was isolated from a fatal adverse event after yellow fever virus (YFV) vaccination, an experimental assay using hamsters (Mesocricetus auratus) as animal model and YFV 17DD vaccine strain as virus reference was accomplished. The two virus strains were inoculated by intracerebral, intrahepatic and subcutaneous routes. The levels of viremia, antibody response, and aminotransferases were determined in sera; while virus, antigen and histopathological changes were determined in the viscera. No viremia was detected for either strain following infection; the immune response was demonstrated to be more effective to strain GOI 4191; and no significant aminotransferase levels alterations were detected. Strain GOI 4191 was recovered only from the brain of animals inoculated by the IC route. Viral antigens were detected in liver and brain by immunohistochemical assay. Histothological changes in the viscera were characterized by inflammatory infiltrate, hepatocellular necrosis, and viral encephalitis. Histological alterations and detection of viral antigen were observed in the liver of animals inoculated by the intrahepatic route. These findings were similar for both strains used in the experiment; however, significant differences were observed from those results previously reported for wild type YFV strains.

Tendències temporals de la mortalitat per càncer de fetge a Catalunya: periode 1983-2002 i projeccions pel 2005

Estudi elaborat a partir d’una estada al Finnish Cancer Registry a Helsinki, Finlandia entre setembre i novembre del 2006. Davant l’increment dels tumors hepàtics en països industrialitzats, s’avaluen les tendències temporals de la malaltia hepàtica a Catalunya durant el període 1983-2002 i s’estima la tendència futura a partir de l’any 2005. L’estudi s’ha basat en dades del Registre de Mortalitat de Catalunya i de l’Institut d’Estadística de Catalunya. La malaltia hepàtica inclou diverses tipologies de tumors hepàtics i la cirrosi hepàtica. Els models edad-període-cohort s’han emprat per estimar els efectes període de mortalitat i cohort de naixement. Els resultats han mostrat que les taxes de mortalitat per cirrosi han disminuït en ambdós sexes, exceptuant els homes d’entre els 35-50 anys, pels quals la mortalitat es mantingué estable. S’han observat increments en la mortalitat per carcinoma hepatocel•lular i en els tumors de vies biliars intrahepàtiques, mentre que les projeccions mostren estabilitat en la tendència d’aquestes malalties durant el període 2005-2009. Les tendències de la mortalitat per malaltia hepàtica constatades poden ser degudes a la implementació de teràpies noves, nous mètodes de diagnòstic, infecció pel virus de l’hepatitis C d’altres factors desconeguts.

Portal vein embolization before right hepatectomy: prospective clinical trial.

OBJECTIVE: To assess the impact of liver hypertrophy of the future liver remnant volume (FLR) induced by preoperative portal vein embolization (PVE) on the immediate postoperative complications after a standardized major liver resection. SUMMARY BACKGROUND DATA: PVE is usually indicated when FLR is estimated to be too small for major liver resection. However, few data exist regarding the exact quantification of sufficient minimal functional hepatic volume required to avoid postoperative complications in both patients with or without chronic liver disease. METHODS: All consecutive patients in whom an elective right hepatectomy was feasible and who fulfilled the inclusion and exclusion criteria between 1998 and 2000 were assigned to have alternatively either immediate surgery or surgery after PVE. Among 55 patients (25 liver metastases, 2 cholangiocarcinoma, and 28 hepatocellular carcinoma), 28 underwent right hepatectomy after PVE and 27 underwent immediate surgery. Twenty-eight patients had chronic liver disease. FLR and estimated rate of functional future liver remnant (%FFLR) volumes were assessed by computed tomography. RESULTS: The mean increase of FLR and %FFLR 4 to 8 weeks after PVE were respectively 44 +/- 19% and 16 +/- 7% for patients with normal liver and 35 +/- 28% and 9 +/- 3% for those with chronic liver disease. All patients with normal liver and 86% with chronic liver disease experienced hypertrophy after PVE. The postoperative course of patients with normal liver who underwent PVE before right hepatectomy was similar to those with immediate surgery. In contrast, PVE in patients with chronic liver disease significantly decreased the incidence of postoperative complications as well as the intensive care unit stay and total hospital stay after right hepatectomy. CONCLUSIONS: Before elective right hepatectomy, the hypertrophy of FLR induced by PVE had no beneficial effect on the postoperative course in patients with normal liver. In contrast, in patients with chronic liver disease, the hypertrophy of the FLR induced by PVE decreased significantly the rate of postoperative complications.

Actualités en hépatologie [Highlights in hepatology]

This review highlights recent advances in hepatology, including new insights into the clinical penetrance of hereditary hemochromatosis, the development of non-immunosuppressive cyclosporin A analogs for the treatment of chronic hepatitis C, thrombopoietin receptor agonists for thrombocytopenia in cirrhosis, the development of vasopressin V2 receptor antagonists (vaptans) for the management of ascites and hyponatremia in portal hypertension, the description of chronic hepatitis E in immunosuppressed patients, and the development of sorafenib as the first molecularly targeted therapy with a demonstrated benefit in the treatment of advanced hepatocellular carcinoma. These new developments will be summarized and discussed critically, with a particular emphasis on their potential implications for current and future clinical practice.

The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver.

BACKGROUND/AIMS: The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPARalpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating pro-inflammatory genes. The objective of this study was to further characterize the role of PPARalpha in inflammatory gene regulation in liver. RESULTS: According to Affymetrix micro-array analysis, the expression of various inflammatory genes in liver was decreased by treatment of mice with the synthetic PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. In contrast, expression of Interleukin-1 receptor antagonist (IL-1ra), which was acutely stimulated by LPS treatment, was induced by PPARalpha. Up-regulation of IL-1ra by LPS was lower in PPARalpha -/- mice compared to Wt mice. Transactivation and chromatin immunoprecipitation studies identified IL-1ra as a direct positive target gene of PPARalpha with a functional PPRE present in the promoter. Up-regulation of IL-1ra by PPARalpha was conserved in human HepG2 hepatoma cells and the human monocyte/macrophage THP-1 cell line. CONCLUSIONS: In addition to down-regulating expression of pro-inflammatory genes, PPARalpha suppresses the inflammatory response by direct up-regulation of genes with anti-inflammatory properties.

Factores de recidiva del carcinoma hepatocelular tras resección quirúrgica con intención curativa

El carcinoma hepatocel•lular representa del 70-80% dels tumors hepàtics primaris. És la sisena neoplàsia més freqüent i la tercera causa més freqüent per càncer. Els factors de risc més importants són l'hepatitis B i C. La resecció quirúrgica és la primera opció terapèutica. La causa de la mort dels pacients sotmesos a resecció hepàtica amb intenció curativa és la recidiva. Les taxes de recidiva global arriben al 70-100% als 5 anys. Identificar els factors de risc de recidiva és important per augmentar la supervivència, aplicant teràpies preventives o incloent en llista d'espera de trasplantament.