Radiological and surgical differences between congenital end-to-side (Abernethy malformation) and side-to-side portocaval shunts.

OBJECTIVE: Distinguishing retrohepatic end-to-side portocaval shunts (ES-PCS) and side-to-side portocaval shunts (SS-PCS) can be difficult, but it is essential for determining the treatment strategy. Our experience with retrohepatic PCS is analyzed. METHODS: Since 2007, 9 children (5/9 ES-PCS and 4/9 SS-PCS) were surgically treated. Radiology studies included Doppler-ultrasound, CT/MRI and angiography/occlusion test (8/9). RESULTS: CT in 5/5 ES-PCS revealed the portal vein (PV) entering the left side of the vena cava with a uniform shape. 4/4 SS-PCS showed aneurysmal PV containing the origin of the main intrahepatic portal branches (IHPB) entering the cava anterior aspect or slightly to the right with a variable length (from long to short/wide). ES-PCS anatomy showed caudate lobe absence with the fistula entering the left cava aspect free of parenchyma, but anterior through the caudate lobe in SS-PCS. With the angiography/occlusion test, the IHPB was undeveloped in ES-PCS (portal pressure > 38 mmHg) and hypoplasic in SS-PCS (portal pressure < 25 mmHg). ES-PCS treatment included: 1/5 hepatectomy and 4/5 definitive banding (one by laparoscopy); while in SS-PCS: 1/4 liver transplantation, 2/4 1-step closure (one by laparoscopy), and 1/4 definitive banding. CONCLUSION: Fistula shape, cava relationship, IHPB and portal pressures differ between the two shunt types. A question arises regarding the need for secondary complete closure after banding. LEVEL OF EVIDENCE: Level IV.

Relevance of activated hepatic stellate cells in predicting the development of pediatric liver allograft fibrosis.

Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P < 0.001) and by LAFSc (P < 0.001). The ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P < 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P < 0.01, respectively), but not at 3 years (P = 0.8). ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P < 0.01) and by LAFSc (r(2) = 0.3; P = 0.03). Furthermore, ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD.

Long-term outcome of hepatitis C virus infections acquired after pediatric liver transplantation.

The outcomes and characterization of hepatitis C virus (HCV) infections after pediatric liver transplantation (LT) have rarely been reported. We describe our experience with HCV infections after pediatric LT. Ten of 207 children (4.8%) who underwent LT at our institution (1985-2010) developed previously undiagnosed HCV disease. Eight received a liver graft before blood product and donor screening for HCV became available. The mean age at transplantation was 8.9 ± 4.3 years, and the median time from transplantation to the diagnosis of HCV was 15.1 years (range = 0.2-19.7 years). The genotypes were 1 (n = 8), 3 (n = 1), and undetermined (n = 1). At the time of this writing, all the patients were still alive with a mean follow-up of 7.3 ± 5.5 years after the diagnosis of HCV. Five patients did not receive treatment; 2 of these patients achieved spontaneous viral clearance (SVC). Four of the 5 treated patients achieved a sustained virological response, and 3 had an early virological response (EVR). Two of these 4 patients developed chronic rejection while they were on treatment, but this was resolved with a conversion from cyclosporine A to tacrolimus. The remaining patient was continuing treatment and had achieved EVR. In conclusion, despite the limitations of our series, de novo HCV infections after pediatric LT seem to have a slow histological progression. Even with genotype 1, the patients have a good long-term prognosis and respond well to treatment. Nevertheless, chronic rejection during antiviral therapy may develop. In addition, SVC may occur in this population.

Cytotoxic T-lymphocyte-associated antigen-4 single nucleotide polymorphisms and haplotypes in primary biliary cirrhosis.

BACKGROUND & AIMS: Twin and family studies suggest that there is a significant heritable component to primary biliary cirrhosis (PBC). Selected cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) gene polymorphisms have been proposed as nonspecific determinants of disease risk in a variety of autoimmune diseases, including PBC. However, there has been considerable debate over the validity of these associations and the precise location of the disease-promoting polymorphism. METHODS: We investigated 6 single-nucleotide polymorphisms in the CTLA4 gene in a total of 327 PBC patients and 391 healthy controls: 247 patients and 292 controls from the United Kingdom and a further 80 patients and 99 controls from northern Italy. RESULTS: The previously reported association with CTLA4 A+49G was not replicated in the Italian series, and there were no significant differences in the distribution of any of the 6 polymorphisms comparing allele, genotype, or haplotype distribution in patients vs healthy controls in the UK series. Furthermore, there were no significant associations with the clinical variables of histologic stage, portal hypertension, or Mayo score. However, when PBC-40 Fatigue Domain scores were considered, a number of significant trends were noted, but none were significant after correction for multiple testing. Thus, fatigue scores were higher in those with the CTLA4 -319 T allele (P < .05, p corrected not significant) and in those with the CTLA4 +49 AA genotype (P < .05, pc not significant). CONCLUSIONS: Contrary to previous reports the CTLA4 gene is not a major risk factor for PBC, nor is it a major determinant of disease progression.

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study.

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA-DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well-characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA-DRB1*0801 in both groups of patients compared to population-specific healthy controls (12% versus 4% in the UK patients, P=.00087, OR=3.05; and 18% versus 6% in the Italian patients, P=.021, OR=3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P=.0071, OR=0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P=.042, OR=0.65 in the UK patients; and 10% versus 31%, P=.00092, OR=0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific.

Lack of higher frequency of the chemokine receptor 5-delta32/delta32 genotype in hepatitis C.

PURPOSE: An elevated frequency of the CCR5-Delta32 mutation in German patients with hepatitis C with viremia has been reported. The aim of the present study was to verify whether this mutation occurs in an Italian population with hepatitis C and whether it is an adverse host factor indicative of severity of liver disease and response to antiviral therapy. STUDY: The authors amplified 189-bp (wild-type) and 157-bp (Delta32 deletion) fragments of the CCR5 gene by polymerase chain reaction in 130 patients with chronic hepatitis C. Comparisons were drawn with 110 blood donors and 135 patients with primary biliary cirrhosis. RESULTS: Four (3.1%) patients with chronic hepatitis C and 1 blood donor (0.9%) were CCR5-Delta32 homozygous, whereas there was no CCR5-Delta32 homozygosity among primary biliary cirrhosis patients; the wild-type gene was present in a similar percentage in the 3 groups of patients without any significant difference (83.1% vs 90.4% vs 83.6%, respectively). Among the patients with chronic hepatitis C, no significant correlation was found between CCR5-Delta32 homozygosity and the following parameters: histologic grade/stage, hepatitis C virus genotype, viral load, serum aspartate aminotransferase, serum alanine aminotransferase, and serum gamma-glutamyltransferase. Ninety-five patients received a standard antiviral protocol with pegylated interferon (PEG Intron)+ribavirin; a sustained response was achieved in 59 patients (62.1%), and the remainder did not respond or experienced a relapse. Response to treatment was not influenced by CCR5-Delta32 deletion. CONCLUSION: No greater frequency of CCR5-Delta32 homozygosity was seen in an Italian population of patients with chronic hepatitis C. This mutation does not seem to influence either the overall severity of liver disease or the response to viral therapy.

Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea.

OBJECTIVES: Diagnosis in chronic diarrhea in the absence of a distinctive clinical pattern is often challenging, as biochemical tests prescribed at the first evaluation do not show enough sensitivity and specificity to tailor further investigation. Intestinal permeability to sugars is an accurate test for detecting intestinal damage. The aim of this study was to evaluate the diagnostic value of the lactulose/mannitol (L/M) test in patients with chronic diarrhea. METHODS: We conducted a prospective cohort study to evaluate the diagnostic value of the L/M test in chronic diarrhea. The test was administered to 261 consecutive patients presenting with three or more bowel movements daily for at least 3 wk. Biochemical tests including complete blood cell count, acute phase reactive proteins, serum albumin and iron, and stool cultures for bacteria, ova, and parasites were assessed at the same time. Additional diagnostic investigations were directed by clinical features as well as first-line test results. RESULTS: Over 3 yr, 120 (46%) of our patients were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed. Multivariate logistic regression analysis revealed that the L/M test and C-reactive protein were independent predictors for the final diagnosis of organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI = 1.29-1.78) and 5.2 (95% CI = 1.90-14.12), respectively. The area under the receiver operating characteristic (ROC) curve of the adjusted model was 0.82, with positive predictive value of 80.4% and negative predictive value of 77.7%. CONCLUSIONS: The L/M test is a powerful tool for workup in patients with chronic diarrhea. Introducing the L/M test as first-level test effectively improves the selection of patients who need further evaluation.

Gastroduodenal and intestinal permeability in primary biliary cirrhosis.

OBJECTIVES: To evaluate gastrointestinal permeability in primary biliary cirrhosis (PBC), using a sensitive method to detect epithelial damage, and to correlate it with the Mayo score, histological stage, ascites, spontaneous bacterial peritonitis, endoscopic signs of portal hypertension and Helicobacter pylori infection. METHODS: Fifty consecutive patients with PBC and 39 patients with cirrhosis of other aetiologies (non-PBC) were enrolled in the study. Coeliac disease was initially ruled out in all participants. Permeability was assessed using sucrose (gastro-duodenum) and lactulose-mannitol (intestine). RESULTS: Sucrose excretion was above the limit in both PBC and non-PBC patients. Twenty-two per cent of PBC patients had an increased result for the lactulose-mannitol test compared to 12.8% of non-PBC cirrhotic patients. PBC patients had high sucrose excretion levels irrespective of the presence of any oesophageal varices, which significantly increased the gastroduodenal permeability in non-PBC patients only when associated with hypertensive gastropathy. Sucrose excretion was significantly enhanced by hypertensive gastropathy in non-PBC patients (P < 0.001) but not in PBC patients. No significant correlation was found in either group between gastrointestinal permeability and the other parameters. CONCLUSIONS: Gastrointestinal permeability is increased in PBC. Portal hypertension contributes to altered gastric mucosal permeability in non-PBC cirrhosis, whereas different epithelial dysfunction can be hypothesized in PBC.