Ana de Lourdes Candolo Martinelli

Frequency, Clinical Characteristics, and Respiratory Parameters of Hepatopulmonary Syndrome

OBJECTIVES To determine the frequency and the clinical characteristics of hepatopulmonary syndrome (HPS) in cirrhotic candidates for orthotopic liver transplantation and to identify the major respiratory parameters predictive of the presence of changes in arterial oxygenation. PATIENTS AND METHODS Patients underwent transthoracic contrast-enhanced echocardiography, pulmonary scintigraphy, pulmonary function test with diffusing capacity of lung for carbon monoxide (DLCO), and measurement of arterial blood gases. RESULTS Fifty-six patients were studied. Twenty-five patients (45%) presented with intrapulmonary vascular dilatations, but only 9 (16%) fulfilled the criteria for HPS. The clinical or demographic characteristics considered did not differ in the patients with and without HPS. The DLCO value was significantly lower in patients with HPS (P=.01). However, 32 (80%) of 40 patients with low DLCO values did not fulfill the criteria for HPS. An alveolar arterial oxygen gradient (AaPO2) of more than 20 mm Hg showed a higher diagnostic accuracy (91%) in the assessment of HPS than did the DLCO of less than 80% predicted (41%) and the AaPO2 of more than 15 mm Hg (71%). CONCLUSIONS The AaPO2 proved to be a more reliable index than PaO2 and DLCO for the determination of changes in arterial oxygenation in HPS. The DLCO does not seem to be a good marker for HPS screening. Intrapulmonary vascular dilatations were frequent, even in patients who did not fulfill the criteria for HPS.

Evolução da ocorrência (1980-1999) da doença de Crohn e da retocolite ulcerativa idiopática e análise das suas características clínicas em um hospital universitário do sudeste do Brasil

Background - Crohns disease and ulcerative colitis are regarded as uncommon in developing countries, but studies on their occurrence in Brazil are scarce. Aims - To determine the occurrence of Crohns disease and ulcerative colitis in a Brazilian university hospital throughout a 20-year period, and analyze the demographical, clinical and evolutive features of these cases. Methods - The frequencies of new cases of Crohns disease and ulcerative colitis admitted from January 1980 up to December 1999 were calculated and a descriptive analysis of the features of all cases seen from January 1990 up to December 1999 was performed. Results - A total of 257 new cases (126 with Crohns disease and 131 with ulcerative colitis) was recorded. The frequencies of admissions for both Crohns disease and ulcerative colitis have increased progressively from 40 up to 61 cases/10.000 new admissions and Crohns disease gradually became more common than ulcerative colitis. For both diseases, there was predominance of women, age at admission in the range of 30-40 years, Caucasian origin, married state and non-smokers. Digestive symptoms presented were similar to those already described for both diseases and there were no differences between Crohns disease and ulcerative colitis regarding the frequencies of general complaints and extra-intestinal manifestations (29.5% vs 23.3%), including thromboembolism (5.9% vs 5.4%). Obstruction and/or perforation were seen in up to 59.2% of Crohns disease cases, whereas 53.7% of all ulcerative colitis cases presented as severe forms. In Crohns disease cases with obstruction, smoking was significantly more common than in non-complicated cases. In ulcerative colitis cases of increased severity, general complaints, extra-intestinal manifestations and pancolitis were significantly more frequent than in less severe forms. Conclusions - For the last 20 years, there have been an increased frequency of admission of inflammatory bowel diseases, and Crohns disease have become more prevalent than ulcerative colitis. Demographical, clinical and evolutive features of these diseases seems to be similar to those already described, but there seems to be a predominance of more severe forms of both diseases.

Are Haemochromatosis Mutations Related to the Severity of Liver Disease in Hepatitis C Virus Infection

It has been proposed that iron overload may adversely affect liver disease outcome. The recent identification of 2 mutations in the HFE gene related to hereditary haemochromatosis (Cys282Tyr and His63Asp) provided an opportunity to test whether they are associated with hepatic iron accumulation and the activity and severity of liver disease in hepatitis C virus (HCV) infection. We investigated the prevalence of HFE mutations in 135 male patients with chronic HCV hepatitis, and correlated genotype distribution with different parameters of iron status and the activity and severity of liver disease. Of these 135 patients, 6 (4.4%) carried Cys282Tyr and 32 (23.7%) carried His63Asp, frequencies which were similar to those observed in healthy controls. Serum iron levels and transferrin saturation (but not ferritin levels or liver iron content) were significantly higher in carriers than in non-carriers of HFE mutations. No difference was observed in serum ALT, AST and GGT levels between carriers and non-carriers. Finally, scores for necroinflammatory activity and fibrosis in the liver were significantly higher in HFE carriers than in non-carriers. Patients with chronic HCV infection carrying HFE mutations tend to present more evident body iron accumulation and a higher degree of necroinflammatory activity and fibrosis in the liver. HFE gene mutations might be an additional factor to be considered among those implicated in the determination of a worse prognosis of the liver disease in chronic HCV infection.

Diagnosis, staging and treatment of hepatocellular carcinoma

Hepatocellular carcinomas are aggressive tumors with a high dissemination power. An early diagnosis of these tumors is of great importance in order to offer the possibility of curative treatment. For an early diagnosis, abdominal ultrasound and serum alpha-fetoprotein determinations at 6-month intervals are suggested for all patients with cirrhosis of the liver, since this disease is considered to be the main risk factor for the development of the neoplasia. Helicoidal computed tomography, magnetic resonance and/or hepatic arteriography are suggested for diagnostic confirmation and tumor staging. The need to obtain a fragment of the focal lesion for cytology and/or histology for a diagnosis of hepatocellular carcinoma depends on the inability of imaging methods to diagnose the lesion. Several classifications are currently available for tumor staging in order to determine patient prognosis. All take into consideration not only the stage of the tumor but also the degree of hepatocellular dysfunction, which is known to be the main factor related to patient survival. Classifications, however, fail to correlate treatment with prognosis and cannot suggest the ideal treatment for each tumor stage. The Barcelona Classification (BCLC) attempts to correlate tumor stage with treatment but requires prospective studies for validation. For single tumors smaller than 5 cm or up to three nodules smaller than 3 cm, surgical resection, liver transplantation and percutaneous treatment may offer good anti-tumoral results, as well as improved patient survival. Embolization or chemoembolization are therapeutic alternatives for patients who do not benefit from curative therapies.

Liver iron concentration evaluated by two magnetic methods: Magnetic resonance imaging and magnetic susceptometry

Quantification of liver iron concentration (LIC) is crucial in the management of patients suffering from certain pathologies that can produce iron overload, such as Cooleys anemia and hemochromatosis. All of these patients must control the level of iron deposits in their organs to avoid the toxicity of high LIC, which is potentially lethal. This paper describes experimental protocols for LIC measurement using two magnetic techniques: magnetic resonance imaging (MRI) and biomagnetic liver susceptometry (BLS). MRI proton transverse relaxation rate (R2) and image intensity, evaluated pixel by pixel, were used as indicators of iron load in the tissue. LIC measurement by BLS was performed using an AC superconducting susceptometer system. A group of 23 patients with a large range of iron overload (0.9 to 34.5 mgFe/gdry tissue) was evaluated with both techniques (MRI × BLS). A significant linear correlation (r = 0.89–0.95) was found between the LIC by MRI and by BLS. These results show the feasibility of using two noninvasive methodologies to evaluate liver iron store in a large concentration range. Both methodologies represent an equivalent precision. Magn Reson Med 54:122–128, 2005.

Hepatic stellate cells in hepatitis C patients: Relationship with liver iron deposits and severity of liver disease

Background and Aim:  To determine the relationship between hepatic stellate cell (HSC) populations and severity of liver disease and liver iron deposits in patients with chronic hepatitis C virus (HCV). We also studied the relationship between iron cellular distribution and HSC population and the role of HFE mutations in the determination of iron deposits.

Porphyria cutanea tarda in Brazilian patients: association with hemochromatosis C282Y mutation and hepatitis C virus infection

OBJECTIVE:Porphyria cutanea tarda (PCT) is commonly associated with iron overload and hepatitis C virus (HCV) infection. Association between hemochromatosis C282Y or H63D mutations and PCT has been observed, although not uniformly, and iron overload is also commonly found in chronic HCV hepatitis. The aim of the present study was to investigate the frequency of C282Y and H63D mutations and HCV infection in Brazilian patients with PCT and their relationship with iron overload.METHODS:Twenty-three patients (19 men) aged 39.6 ± 11.1 yr were studied. All had dermatological lesions of PCT and high levels of urinary uroporphyrin. HCV infection and iron overload were investigated. DNA samples were analyzed for the presence of HFE mutations.RESULTS:The frequency of C282Y was significantly higher in PCT patients than in 278 healthy individuals (17.4% vs 4%, odds ratio = 5.1, 95% confidence interval 1.5–17.6, p= 0.02), whereas no difference was observed regarding the H63D mutation (30.4% vs 31%, odds ratio = 1, 95% confidence interval 0.4–2.4, p= 1). Biochemical tests in PCT patients showed iron overload with transferrin saturation = 47.3 ± 20.7% and ferritin = 566.8 ± 425 ng/ml. Fifteen of 23 (65.2%) patients had HCV infection and alcohol ingestion was observed in 17 of 23 (73.9%).CONCLUSIONS:PCT patients exhibited evidence of iron overload, a high frequency of HCV, and an association with C282Y mutation. These data further support the notion that both acquired and inherited factors contribute to the occurrence of PCT, and indicate that screening for C282Y may be justified in PCT patients.

Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection

Summary.  As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)‐G is well described as a tolerogenic molecule, we evaluated HLA‐G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA‐G expression was assessed by immunohistochemistry. No HLA‐G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane‐bound HLA‐G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA‐G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA‐G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA‐G (103.7 copies/mL). These results indicate that HLA‐G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

Effect of a thrombin receptor (protease-activated receptor 1, PAR-1) gene polymorphism in chronic hepatitis C liver fibrosis.

Background and Aim:  Tissue injury leads to activation of coagulation and generation of thrombin. Inhibition of thrombin receptor protease‐activated receptor 1 (PAR‐1) has been shown to reduce liver fibrosis in animals. This study aimed to evaluate the effect of PAR‐1 gene polymorphism on rate of liver fibrosis (RF) in chronic hepatitis C.

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy

Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a (40KD) plus ribavirin has given an overall sustained virological response of 18% in F3/F4 previous nonresponder US patients. We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.