Systematic review: hepatitis-associated aplastic anaemia--a syndrome associated with abnormal immunological function.

BACKGROUND: Hepatitis-associated aplastic anaemia is a syndrome in which marrow failure follows the development of hepatitis. AIM: To review systematically the aetiology, immunopathogenesis, clinical presentation, diagnosis and treatment of hepatitis-associated aplastic anaemia. METHODS: Literature searches were undertaken on the MEDLINE electronic database up to December 2008. Twenty-four relevant studies were identified. The clinical and laboratory characteristics of the patients were analysed and reviewed. RESULTS: Hepatitis-associated aplastic anemia is a variant of acquired aplastic anemia in which an episode of hepatitis precedes the onset of aplastic anemia. The hepatitis may be acute and severe, even fulminant; it may be self-limiting or chronic. The pathology is often not attributable to a recognized cause of viral hepatitis. The syndrome occurs in 28 percent of young adults after liver transplantation for non-A, non-B, non-C hepatitis. Several features of the syndrome suggest that the marrow aplasia is mediated by immunological mechanisms, possibly mediated by gamma interferon or the cytokine cascade. Survival of patients treated with hematopoietic cell transplantation has been 82%, and the response rate to immunosuppressive therapy 70%. CONCLUSIONS: Hepatitis-associated bone marrow aplasia is mediated by immunological mechanisms. Treatment options include hematopoietic cell transplantation and immunosuppressive therapy.

Transient elastography to assess hepatic fibrosis in primary biliary cirrhosis.

BACKGROUND: Liver stiffness measurements may have potential for detecting and monitoring hepatic fibrosis in chronic liver disease. AIM: To study the detection, quantification and progression of hepatic fibrosis in primary biliary cirrhosis by liver stiffness measurements. METHODS: Liver stiffness measurements were generated in 80 patients with primary biliary cirrhosis by applying transient elastography; however, as there were 55 with liver biopsy, histological stage (METAVIR) and liver stiffness measurements were compared only in these 55 patients. The efficiency of liver stiffness measurements in predicting stage of fibrosis was determined from the area under receiver operating characteristics curve analysis. RESULTS: Of the 80 patients included, 91, 4% were women and their mean age was 56 +/- 12 (s.d.) years. A significant correlation was found (P < 0.05) between histological fibrosis stage (METAVIR) and liver stiffness measurements. The values obtained from area under receiver operating characteristic curve analysis of liver stiffness measurement data were 0.89 for F > 2 and 0.96 for F = 4. Liver stiffness measurements were 9.0 +/- 5.3 and 7.9 +/- 6.0 kPa for patients followed up more than 5 years and less than 5 years, respectively (P > 0.05). CONCLUSIONS: In patients with primary biliary cirrhosis, median values of liver stiffness measurements correlated with histological severity of hepatic fibrosis. Liver stiffness measurements appear to be promising for liver fibrosis detection and quantification, as well as monitoring its progression, in patients with primary biliary cirrhosis. The progression rate of hepatic fibrosis in our primary biliary cirrhosis patients appears to be slow.

[Utility of analytical parameters in the diagnosis of liver disease]. / Utilidad de los parámetros analíticos en el diagnóstico de las enfermedades hepáticas.

Liver function tests include biochemical parameters (AST, ALT, GGT or Alkaline phosphatase), bilirubin and albumin levels and coagulation tests as prothrombin activity. These tests are commonly used in the routine screening even in symptomatic as in asymptomatic patients, and the right evaluation of the results is of vital importance. Cytolytic elevation in serum aminotransferases: In mild chronic elevation pharmacological toxicity, viral hepatitis, alcoholic and non-alcoholic fatty liver disease and hemochromatosis, should be excluded. Cholestatic elevation os serum enzymes: The first option should be to establish the origin of the alkaline phosphatase elevation, with the evaluation of the GGT levels to confirm the hepatic origin. The next step should be to distinguish the presence of an extrahepatic (biliary obstruction) or intrahepatic (PBC, PSC, drugs, etc) cholestasis, in these cases the most important test should be the abdominal ultrasound, in order to evaluate the biliary system. Hyperbilirubinemia: Non conjugated hyperbilirubinemia (hemolysis, ineffective erythropoiesis, Gilbert or Criggler-Najjar syndromes) and conjugated hyperbilirubinemia, an unusual situation in which Rotor and Dubin-Johnson Syndromes should be considered. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases. At present, there are not prospective studies to evaluate the efficacy of the liver function tests. To carry out a complete medical history, an appropriate physical examination and the appropriate application of non-invasive diagnostic tests (serology, iron levels, autoimmunity or abdominal ultrasound) allow to perform a right diagnosis in most patients, making more complex tests, including liver biopsy, secondary.

Transient elastography: a valid alternative to biopsy in patients with chronic liver disease.

BACKGROUND: Transient elastography is a novel and non-invasive technique for the evaluation of fibrosis in chronic liver disease. Few studies that exist value the efficacy of transient elastography, mainly in hepatitis C virus-infected patients. AIM: To evaluate the effectiveness, objectivity, reproducibility and safety of this technique. METHODS: We included 103 consecutive patients who underwent a liver biopsy in the last 48 months with a wide spectrum of chronic liver diseases. Median stiffness value (expressed as kilopascals - kPa) was kept as representative of the liver elastic modulus. All biopsy specimens were analysed by the same pathologist according to the METAVIR scoring system. RESULTS: Median value of stiffness in patients with mild or moderate fibrosis (FI and FII), and severe fibrosis or cirrhosis (FIII and FIV) was of 7, 4 +/- 5 and 16, 4 +/- 10 kPa, respectively, with a significant difference between them (P < 0.05). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut-off values for each group. CONCLUSIONS: We found a positive correlation between the liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease aetiology. Transient elastography is an easy, quick to perform and safe non-invasive procedure, reliable for assessing liver fibrosis.

Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients.

OBJECTIVES: Our objectives were to compare angiogenesis soluble factor (ASF) levels in chronic hepatitis C (CHC) patients and healthy individuals, and to investigate potential associations between ASF levels and both histological and biochemical markers of disease progression. METHOD: Thirty-six patients (69% males) positive for HCV-RNA by PCR analysis were included in the study. All patients underwent liver biopsy before treatment. Serum levels of vascular endothelial growth factor (VEGF), soluble Flt-1 and Flk-1 receptors, placental growth factor (PlGF), angiopoietin-2 (Ang-2) and soluble Tie-2 receptor were determined by ELISA. Fifteen healthy subjects were used as controls. RESULTS: In comparison to healthy individuals, CHC patients showed significantly increased serum levels of proangiogenic factors PlGF (22 +/- 5 vs. 18 +/- 8 pg/ml; p < 0.05), Ang-2 (1265 +/- 385 vs. 833 +/- 346 pg/ml; p < 0.005) and sFlt-1 (95 +/- 22 vs. 72 +/- 14 pg/ml; p < 0.0001). Interestingly, in CHC patients serum levels of VEGF and Tie-2 correlated with grade of inflammation, PlGF correlated with stage of fibrosis, and Flt-1 and Flk-1 correlated with serum transaminase levels (p < 0.05 in all cases). CONCLUSIONS: CHC patients showed increased serum levels of ASF, and a significant correlation was shown between serum levels of selected ASFs and grade of inflammation, stage of fibrosis, and transaminase levels.

Rapidly-progressive liver failure secondary to melanoma infiltration.

We describe the case of a 51-year-old man with a history of intraocular melanoma treated with radiotherapy 2 years previously. The patient was diagnosed with mild hypertransaminasemia that progressed to acute liver failure and death in a period of one month. Radiological investigations such as spiral computed tomography and abdominal ultrasonography failed to give an etiologic diagnosis. Autopsy revealed melanoma with diffuse infiltration of the hepatic parenchyma. Because diagnosis is usually delayed, the prognosis of intraocular melanoma is poor. In 40% of cases metastases are present at diagnosis, and the most frequently affected organ is the liver (93-95%). Presentation as acute liver failure can appear after a long disease-free period. For this reason, periodic laboratory tests and hepatic ultrasound examination are recommended in patients diagnosed with this malignancy.

Review article: angiogenesis soluble factors as liver disease markers.

Angiogenesis is the formation of new blood vessels from pre-existing ones; it has been studied at the molecular level in different pathologies and is currently considered a promising novel therapeutic target in cancer. Recently, the use of angiogenesis soluble factors as markers of tumour growth has been investigated. The knowledge gained has led to test their use as therapeutic agents. Additionally, angiogenesis soluble factors could be used for the follow-up of pathologies that currently require monitoring with invasive techniques, like chronic viral hepatitis or renal and haematological diseases. The different factors have been described in multiple studies. In some cases, such as hepatocellular carcinoma, a potential use as prognostic markers has been suggested.

Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection.

AIM: To systematically review the experience of therapeutic studies where alpha-interferon with or without ribavirin was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus may induce regression of lymphoproliferative disorders. METHODS: We used bibliographical searches in electronic databases and in the Cochrane Library to determine our results. RESULTS: Sixteen studies where an anti-viral regimen was administered to 65 hepatitis C virus-infected patients with lymphoproliferative disorders were identified. Complete remission of the lymphoproliferative disorder was achieved in 75% of the cases. In contrast, hepatitis C virus-negative subjects did not respond to interferon, indicating that the response in the hepatitis C virus-infected patients is not merely due to the antiproliferative effect of interferon. Remission after HCV eradication was maintained, provided that infection did not reappear. In hepatitis C virus-infected patients with non-Hodgkin's lymphoma treated with corticosteroids/chemotherapy liver function tests deterioration did not occur. The addition of interferon to standard chemotherapy may decrease hepatic side-effects of chemotherapy. CONCLUSIONS: Although it is evident that larger therapeutical trials of anti-viral therapy are needed to determine the role of this strategy in hepatitis C virus-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that interferon (plus ribavirin) is an attractive therapeutic option for some hepatitis C virus-related low-grade lymphomas.

Hepatitis C virus-related extra-hepatic disease--aetiopathogenesis and management.

Summary Hepatitis C virus infection is often associated with extra-hepatic manifestations, secondary to the elicitation of autoimmune reactions, generalized deposition of immune complexes and lymphoproliferative disorders. The most clearly established associations are those linking chronic hepatitis C with mixed cryoglobulinaemia (and the related glomerulonephritis and cutaneous vasculitis), as well as with the presence of autoantibodies. Less well-documented disorders include non-Hodgkin's lymphoma, thrombocytopenia, sialadenitis, thyroid disease, lichen planus, porphyria cutanea tarda, rheumatoid disorders and neurological disorders. Extra-hepatic manifestations are most frequent in patients of female sex, advanced age, long-lasting infection and cirrhosis. Optimal treatment strategies should be based on the predominant manifestation of the disease. In the case of autoimmune disorders not clearly attributable to the viral infection, corticosteroids may be the most effective option. Interferon-alpha alone or in combination with ribavirin may be indicated for those disorders related to immune complex deposition, such as mixed cryoglobulinaemia, although relapses of extra-hepatic signs often occur on discontinuation of treatment. In some cases, interferon-alpha may induce or exacerbate some extra-hepatic manifestations.

[Bile duct obstruction due to non-Hodkin's lymphoma in patients with HIV infection]. / Ictericia obstructiva por linfoma no hodgkiniano en pacientes con infección por el VIH.

Acquired immune deficiency syndrome increases the risk of developing non-Hodgkin's B-cell lymphoma (NHL) (relative risk over 100). NHL tend to be high-grade and to affect the central nervous system and digestive tract. Biliary tract compression is usually due to external compression from enlarged lymph nodes, but is not usually the first manifestation.We describe 2 cases of bile duct obstruction secondary to NHL in patients diagnosed with HIV infection. Histological diagnosis of the lymphoma can be difficult but is necessary so that these patients do not undergo highly aggressive surgical treatment instead of chemotherapy, which currently produces the best results. Therefore, we emphasize the importance of including lymphomas in the differential diagnosis of bile duct obstruction in patients with HIV infection.

Review article: immunopathogenetic and therapeutic aspects of autoimmune hepatitis.

Autoimmune hepatitis is a chronic, progressive liver disease that responds well to immunosuppressive therapy, but has a poor prognosis if untreated. Possible triggering factors include viruses, other autoimmune disorders and drugs. The molecular mechanisms contributing to the pathogenesis include: reactions of autoantibodies against their corresponding autoantigens; aberrant expression of histocompatibility antigen class I and II molecules, cell adhesion molecules and cytokines; increased oxidative stress; and the occurrence of angiogenesis. The prevalence of the disease is highest in Caucasians, Europeans and women. The natural history of autoimmune hepatitis shows a poor prognosis, with frequent progression to cirrhosis and hepatic insufficiency in untreated patients. The occurrence of hepatocellular carcinoma is rare and is found only in long-standing cirrhosis. Corticosteroids as monotherapy or in combination with azathioprine are the treatments of choice; different therapeutic schedules and particularities of treatment for pregnant women and children have been established. To avoid treatment-associated adverse effects, alternative therapies have been proposed, including ciclosporin, budesonide, tacrolimus, mycophenolate mofetil, ursodeoxycholic acid, methotrexate, cyclophosphamide, mercaptopurine and free radical scavengers. Liver transplantation is indicated for patients refractory to or intolerant of immunosuppressive therapy.

[Mesenteric fibromatosis as the cause of a single abdominal mass]. / Fibromatosis mesentérica como causa de masa abdominal única.

We present a mesenteric desmoid tumor in a man without associated diseases. Characteristics of this tumor are reviewed and the need to perform total exeresis of the mass for diagnosis is emphasized. Although surgery is the treatment of choice, alternative treatments are recommended when surgery cannot be performed, has been incomplete, or in cases of repeated recurrence.

[Changes in iron metabolism in chronic hepatitis C]. / Alteraciones del metabolismo del hierro en la hepatitis crónica C.

Serum iron studies have high values in 30% of patients with virus C (HCV) chronic hepatitis even in hemochromatosis range. These indices do not represent hepatic iron storage which has a low to moderate intensity. Heterozygosity for hereditary hemochromatosis could be responsible of the iron liver storage in some patients. Nowadays the relationship between hepatic iron loading and HCV infection is unknown. It has been suggested that iron storage could allow HCV infection or, by other way, it may be caused by the infection. Iron, per se, has hepatolesive effect and acts synergistically with HCV worsening liver injury. Also, iron storage reduces the interferon response rate, and iron depletion with phlebotomies improves transaminases level. However, it is discussed if the association: iron removal-interferon treatment improves interferon alone treatment response. In this work all these points are reviewed.

S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.

BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

Immunohistochemical evidence of immunopathogenetic mechanisms in chronic hepatitis C recurrence after liver transplantation.

Viremia and genotype are implicated in a rapid course of posttransplant hepatitis C virus (HCV) infection recurrence, but the role played by host immune reactions has not yet been evaluated. We correlated the degree of liver injury with the intrahepatic expression of molecules involved in immune response. The study included 32 biopsies of 30 liver transplant recipients. Recurrence of viremia was detected by Amplicor assay. Genotype was tested by Inno-Lipa. Cryostat sections were assessed by immunohistochemistry, using a wide panel of monoclonal antibodies. Correlations between histological-immunohistochemical semiquantitative evaluation and levels of viremia were performed. In severe hepatic inflammation, high numbers of activated cytotoxic T cells were found, along with marked hepatocellular expression of beta 2-microglobulin (beta 2-MG) and intercellular adhesion molecules. Likewise, a strong vascular adhesion molecule expression was observed mainly in those areas that were more inflamed. A striking endoglin reactivity was detected in enlarged portal tracts, and the presence of neoformed microvessels was also noteworthy. By contrast, in mild hepatic inflammation only a few activated T cells were detected, together with a weaker reactivity for all molecules studied. The level of viremia did not correlate with the degree of liver damage. The severe forms of post-transplant HCV infection recurrence are associated with a marked and aberrant intrahepatic expression of molecules involved in antigen recognition, and intercellular and vascular adhesion, decisive in regulating the recruitment and activation of cytotoxic T lymphocytes.