Alberto Queiroz Farias

Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2

OBJECTIVES:Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and 2 with HLA-DR and DQ loci.METHODS:We performed HLA-DRB and -DQB1 typing by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) in 139 AIH patients. Most had AIH type 1 associated with circulating anti-smooth muscle antibody with F-actin specificity or antinuclear antibody. Twenty-eight patients presented AIH type 2 with anti-liver/kidney microsome type 1 or anti-liver cytosol type 1 antibodies.RESULTS:We observed a significant increase of DRB1*13 (70%vs 26% of controls, p < 0.00001) and DRB3 (93%vs 69% of controls, p < 0.00001) in AIH type 1 patients. Analysis of patients without DRB1*13 disclosed a secondary association with DRB1*03 (70%vs 30% of controls, p= 0.0001) and either the DRB1*13 or the DRB1*03 alleles were present in the majority of these patients (91%vs 48% of controls, p= 0.001). Comparison of DRB1*13- and DRB1*03-positive subjects revealed that the former alleles conferred susceptibility to younger patients with AIH type 1. DQB1 typing showed a significant increase in DQB1*06 (68%vs 41% of controls, p= 0.00007) in strong linkage disequilibrium with DRB1*13, and a decrease in DQB1*0301 (8%vs 47% of controls, pc= 0.0003). On the other hand, HLA typing of patients with AIH type 2 disclosed a significant increase in the DRB1*07 (68%vs 20% of controls, pc < 0.00014), DRB4 (79%vs 43% of controls, pc= 0.004), and DQB1*02 (86%vs 42%, p= 0.00002) alleles. After exclusion of DRB1*07, a secondary association with HLA-DRB1*03 was further observed in these patients (78%vs 30%, p= 0.007) and most of them had either DRB1*07 or DRB1*03 (93%vs 44% of controls, pc < 0.0001).CONCLUSIONS:Our data indicate that predisposition to AIH types 1 and 2 is associated, respectively, with the DRB1*13 or DRB1*03 and DRB1*07 or DRB1*03 alleles, and suggest that protection against type 1 disease may be conferred by DQB1*0301. In addition, the cluster of DRB1*13 in children with AIH type 1 also supports the concept that different HLA alleles might influence the onset of the disease.

Cardiopulmonary Manifestations of Hepatosplenic Schistosomiasis

Background— Schistosomiasis is a highly prevalent disease with >200 million infected people. Pulmonary hypertension is one of the pulmonary manifestations in this disease, particularly in its hepatosplenic presentation. The aim of this study was to determine the prevalence of pulmonary hypertension in schistosomiasis patients with the hepatosplenic form of the disease. Methods and Results— All patients with hepatosplenic schistosomiasis followed up at the gastroenterology department of our university hospital underwent echocardiographic evaluation to search for pulmonary hypertension. Patients presenting with systolic pulmonary artery pressure >40 mm Hg were further evaluated through right heart catheterization. Our study showed an 18.5% prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography. Invasive hemodynamics confirmed the presence of pulmonary hypertension in 7.7% (95% confidence interval, 3.3 to 16.7) of patients, with a prevalence of precapillary (arterial) pulmonary hypertension of 4.6% (95% confidence interval, 1.5 to 12.7). Conclusions— Our study reinforces the role of echocardiography as a screening tool in the investigation of pulmonary hypertension, together with the need for invasive monitoring for a proper diagnosis. We conclude that hepatosplenic schistosomiasis may account for one of the most prevalent forms of pulmonary hypertension worldwide, justifying the development of further studies to evaluate the effect of specific pulmonary hypertension treatment in this particular form of the disease.

Terlipressin versus Norepinephrine in the Treatment of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis

Background Hepatorenal syndrome (HRS) is a severe and progressive functional renal failure occurring in patients with cirrhosis and ascites. Terlipressin is recognized as an effective treatment of HRS, but it is expensive and not widely available. Norepinephrine could be an effective alternative. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of norepinephrine compared to terlipressin in the management of HRS. Methods We searched the Medline, Embase, Scopus, CENTRAL, Lilacs and Scielo databases for randomized trials of norepinephrine and terlipressin in the treatment of HRS up to January 2014. Two reviewers collected data and assessed the outcomes and risk of bias. The primary outcome was the reversal of HRS. Secondary outcomes were mortality, recurrence of HRS and adverse events. Results Four studies comprising 154 patients were included. All trials were considered to be at overall high risk of bias. There was no difference in the reversal of HRS (RR = 0.97, 95% CI = 0.76 to 1.23), mortality at 30 days (RR = 0.89, 95% CI = 0.68 to 1.17) and recurrence of HRS (RR = 0.72; 95% CI = 0.36 to 1.45) between norepinephrine and terlipressin. Adverse events were less common with norepinephrine (RR = 0.36, 95% CI = 0.15 to 0.83). Conclusions Norepinephrine seems to be an attractive alternative to terlipressin in the treatment of HRS and is associated with less adverse events. However, these findings are based on data extracted from only four small studies.

A Prospective Study of Conventional and Expanded Coagulation Indices in Predicting Ulcer Bleeding After Variceal Band Ligation

BACKGROUND & AIMS There is controversy over whether coagulation status predicts bleeding caused by ulceration after esophageal varices band ligation (EVL). METHODS EVL was performed for primary (n = 45) or secondary (n = 105) prophylaxis in 150 patients with cirrhosis (Child A, n = 74, 49%; Child B, n = 42, 28%; Child C, n = 34, 23%). International normalized ratio (INR) and platelet counts were assessed in all. In 92 patients, levels of factor V, fibrinogen, D-dimer, protein C and protein S, von Willebrand factor, and thromboelastography (TEG) were assessed. Platelet count <50 x 10(3)/mm(3) and INR >1.5 were considered high-risk cutoff for bleeding. Conversely, platelet count >or=50 x 10(3)/mm(3) with INR <or=1.5 were safe cutoffs. RESULTS Overall, 11 patients (7.3%) had post-EVL ulcer bleeding. Bleeding occurred in 5 patients with Child A/B (4.3%) and 6 patients with Child C (17%) (P = .0174 for Child A/B versus Child C). Eight patients with bleeding were among the 110 below the cutoff for INR and platelet count, whereas only 3 of the patients with bleeding were among the 40 patients with purported high-risk values (P = 1.0). Among the 92 patients with expanded coagulation tests, bleeding occurred in 5. There was no difference in any of the coagulation parameters, including overall TEG patterns, between patients who did and did not bleed. CONCLUSIONS Post-EVL ulcer bleeding was associated with Child C status but not with conventional or expanded coagulation indices in cirrhotic patients without renal failure or infection undergoing elective EVL. These results call into question the common use of prophylactic procoagulants in the elective setting.

FREQUENCY OF CONCURRENT AUTOIMMUNE DISORDERS IN PATIENTS WITH AUTOIMMUNE HEPATITIS: EFFECT OF AGE, GENDER, AND GENETIC BACKGROUND

Background Concurrent autoimmune disorders (CAIDs) have been shown to occur in 22% to 34% of the patients with autoimmune hepatitis (AIH). Their presence has been linked to female gender, older age, and to certain HLA antigens, namely HLA-A11, DRB1*04, and DRB4*01. Aims To assess the frequency and nature of CAID in Brazilian patients with AIH types 1 (AIH-1) and 2 (AIH-2) and to investigate the influence of age, gender, and genetic background in their occurrence. Patients and Methods The presence and nature of CAID was studied in 143 patients [117 females, median age 11 (1.3 to 69)] with AIH-1 (n=125) and AIH-2 (n=28). HLA typing and tumor necrosis factor α gene promoter and exon 1 cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms were determined by polymerase chain reaction-based techniques. Results The frequency of CAID was similar in patients with AIH-1 (14%) and AIH-2 (18%), but their nature was shown to vary. Arthritis was seen in half of the patients (n=8) with CAID and AIH-1 and in none of those with AIH-2. Subjects with AIH-1 and CAID were shown to be older [24 (1.3 to 61) vs. 11 (1.3 to 69) y, P=0.02] and to have more often circulating antinuclear antibody (76% vs. 40%, P=0.008) and less frequently antiactin antibodies (33% vs. 75%, P=0.008) when compared with their counterparts without CAID. No particular HLA-DR and DQ alleles, as well as tumor necrosis factor α and CTLA-4 genotypes, were associated with CAID. Conclusions The nature, but not the frequency, of CAID was shown to vary in AIH-1 and AIH-2. In subjects with AIH-1, CAID was linked to older subjects and to the presence of antinuclear antibody. No predisposition to CAID was associated to HLA-DRB1*04 or DDB4*01 alleles. The observed lower frequency of CAID could be attributed to the lower age of disease onset in Brazilians and to differences in HLA-encoded susceptibility to AIH-1 observed in South America.

Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis

Background and Aims:  Predisposition to primary biliary cirrhosis (PBC) has been classically linked to HLA‐DRB1 locus. However, the presence of the HLA‐DRB1*08 antigen has been reported in less than one‐third of PBC patients from Northern Europe and Japan. Recently, polymorphisms in the tumor necrosis factor alpha (TNFA) gene promoter at position −308 and in exon 1 of the cytotoxic T lymphocyte antigen‐4 (CTLA‐4) gene at position 49 have been associated with susceptibility to PBC in Caucasians. In addition, the presence of HLA‐DRB1*08 and the TNFA*1 allele was also linked to progression to end‐stage liver disease. The aims of the present study were to investigate the frequencies of HLA‐DR and DQ antigens and TNFA and CTLA‐4 alleles in PBC patients from a different genetic background, as well as to assess the role of TNFA alleles and HLA‐DR antigens in disease progression.

Nodules less than 20 mm and vascular invasion are predictors of survival in small hepatocellular carcinoma.

Background The aims of this study were to analyze the overall survival of patients with cirrhosis and small hepatocellular carcinoma (HCC) and identify independent pretreatment predictors of survival in Brazil. Methods Between 1998 and 2003, 74 patients with cirrhosis and small HCC were evaluated. Predictors of survival were identified using the Kaplan-Meier survival curves and the Cox model. Results The overall survival rates were 80%, 41%, and 17% at 12, 36, and 60 months, respectively. The mean length of follow-up after HCC diagnosis was 23 months (median 22 mo, range: 1 to 86 mo) for the entire group. Univariate analysis showed that model for endstage liver disease (MELD) score (P=0.016), Child-Pugh classification (P=0.007), α-fetoprotein level (P=0.006), number of nodules (P=0.041), tumor diameter (P=0.009), and vascular invasion (P<0.0001) were significant predictors of survival. Cox regression analysis identified vascular invasion (relative risk=14.60, confidence interval 95%=3.3-64.56, P<0.001) and tumor size >20 mm (relative risk=2.14, confidence interval 95%=1.07-4.2, P=0.030) as independent predictors of decreased survival. Treatment of HCC was related to increased overall survival. Conclusions Identification of HCC smaller than 20 mm is associated with longer survival. Presence of vascular invasion, even in small tumors, maybe associated with poor prognosis. Treatment of small tumors of up to 20 mm diameter is related to increased survival.

Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti‐M2 seropositive variant form of autoimmune hepatitis

Background and Aims:  According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH.

Familial amyloidotic polyneuropathy type 1 in Brazil is associated with the transthyretin Val30Met variant

UNLABELLED Familial amyloidotic polyneuropathy type 1 (FAP1) is an inherited systemic amyloidosis that is secondary to the deposition of transthyretin (TTR) variants in peripheral nerves and in certain visceral organs. More than 50 distinct mutations have already been described in the TTR gene. Yet, the most common mutation found worldwide is a substitution of valine for methionine in position 30 (Val30Met). Currently, the variants of TTR in Brazilian FAP1 patients remain largely unknown and the aim of this study was to analyze the frequency of the TTR Val30Met mutation in such Brazilian subjects. METHODS Thirty-two FAP1 patients belonging to 24 different families were studied for the presence of Val30Met variant by PCR-RFLP. RESULTS All Brazilian FAP1 subjects studied were positive for the TTR Val30Met variant. As expected, all of them were heterozygous for the mutation. CONCLUSION TTR Val30Met mutation was the sole TTR variant found in Brazilian FAP1 patients in this cohort, and it was present even in those subjects without a clear history of Portuguese ancestry.

No evidence of de novo amyloidosis in recipients of domino liver transplantation: 12 to 40 (mean 24) month follow-up.

UNLABELLED Domino liver transplantation (DLT) has been performed for selected recipients at several centers, but de novo amyloidosis in recipients of livers from patients with familial amyloid polyneuropathy (FAP) remains a serious concern. AIM To evaluate the occurrence of de novo amyloidosis in recipients of DLT. PATIENTS AND METHODS Seven recipients of FAP livers were followed for clinical and electroneuromyographic signs of FAP and also for de novo amyloid deposition in the gut. RESULTS No signs and symptoms of de novo FAP nor any evidence of amyloid deposits in the gut were observed in recipients of DLT after a mean follow-up of 24 [12-40] months. CONCLUSIONS Signs and symptoms of FAP do not occur early in recipients of DLT. These livers could therefore be offered to patients suitable for conventional LT, particularly older subjects in whom the event of de novo amyloidosis would seem improbable.