Adult Primary Sclerosing Cholangitis (PSC) subjects have worse biliary disease at diagnosis compared to pediatric PSC subjects.

INTRODUCTION: Adult Primary Sclerosing Cholangitis (PSC) subjects have worse outcomes compared to pediatric PSC subjects. The reasons for this observation are not completely understood. METHODS: In this single-center, retrospective (2005-17) study we compared clinical information, laboratory data, and previously published MRCP-based scores between 25 pediatric (0-18 years at diagnosis) and 45 adult (19 years and above) subjects with large duct PSC at the time of diagnosis. For each subject, radiologists determined MRCP-based parameters and scores after reviewing the MRCP images. RESULTS: The median age at diagnosis for pediatric subjects was 14 years, while that of adult subjects was 39 years. At the time of diagnosis, adult subjects had a higher incidence of biliary complications like cholangitis and high-grade biliary stricture (27% vs. 6%, p = 0.003) and higher serum bilirubin (0.8 vs. 0.4 mg/dl, p = 0.01). MRCP analysis showed that adult subjects had a higher incidence of hilar lymph node enlargement (24.4% vs. 4%, p = 0.03) at diagnosis. Adult subjects had worse sum-IHD score (p = 0.003) and average-IHD score (p = 0.03). Age at diagnosis correlated with higher average-IHD (p = 0.002) and sum-IHD (p = 0.002) scores. Adult subjects had worse Anali score without contrast (p = 0.01) at diagnosis. MRCP-based extrahepatic duct parameters and scores were similar between groups. DISCUSSION: Adult PSC subjects may have higher severity of disease at diagnosis compared to pediatric subjects. Future prospective cohort studies are required to confirm this hypothesis.

Diagnosis of Primary Sclerosing Cholangitis Beyond Childhood is Associated with Worse Outcomes.

BACKGROUND: The elucidation of differences between adult and pediatric-onset primary sclerosing cholangitis (PSC) may inform clinical decision making, and whether results of adult PSC clinical trials can be extrapolated to pediatric subjects. METHODS: A single-center retrospective analysis of PSC subjects diagnosed during the epoch 2000-13 was conducted. Demographic, clinical, and laboratory data were compared between PSC subjects diagnosed between 0-18 (pediatric) and 19+ (adult) years of age. An adverse outcome was defined as PSC-related death, liver transplant, or malignancy. Survival without any of these was defined as event-free survival. RESULTS: Analyses of 28 pediatric-diagnosed and 59 adult-diagnosed subjects revealed that incidence of early portal hypertension (PHT; P = 0.2), laboratory parameters of liver disease severity, and fibrosis grade at diagnosis were comparable between adult and pediatric PSC subjects. Adult-diagnosed PSC subjects had higher incidences of adverse outcomes compared to pediatric-diagnosed PSC subjects (P = 0.02). The age group 0-18 years (n = 30) had significantly better event-free survival compared to the age group more than 40 years (n = 25; P = 0.03). The prevalence of PHT in adult PSC subjects was 2.6 that of pediatric PSC subjects. PHT adversely affected outcomes in both adult (P < 0.001) and pediatric (P = 0.01) subjects. Adult PSC subjects were more likely to develop biliary complications (BCs; P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult PSC subjects were more likely to have extra-hepatic co-morbidities (P < 0.001). Adult subjects had a longer follow-up duration compared to pediatric subjects (P = 0.06). CONCLUSION: Despite having a comparable clinical, laboratory, and histologic biomarkers of liver disease severity at the time of diagnosis, adult PSC subjects had a worse outcome compared to pediatric PSC subjects. Possible reasons for this finding include higher incidence of PHT, BCs, extra-hepatic co-morbidities, and longer duration of follow-up.

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management.

Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as stillbirth, increase with gestational age, so preterm delivery is generally performed in cases of severe ICP, defined as BA levels above 40 µmol/L. ICP may recur in future pregnancies and is associated with an increased risk for future hepatobiliary, immune mediated, and cardiovascular diseases. Children born of mothers with ICP have normal development but may have a risk for subsequent metabolic disease.

Management of Fontan circulation in pregnancy: a multidisciplinary approach to care.

The Fontan operation was first performed in 1968 and is a palliative procedure for children born with single ventricle forms of congenital heart disease. Today, 70,000 patients worldwide have Fontan circulation today, half of them women, and with an expected 30-year survival of >80%, this population is expected to double in the next 20 years. The Fontan operation surgically redirects systemic venous blood return directly to the pulmonary circulation, bypassing the single ventricle. This abnormal anatomy results in significant challenges for the cardiovascular system and is marked by a sustained, abnormally elevated systemic venous pressure combined with decreased cardiac output. As more women with Fontan circulation reach childbearing age, understanding the unique risks of pregnancy to the mother and fetus and how to best provide clinical care for these women during pregnancy is imperative. However, there are limited clinical data to guide counseling and management in this population. This expert review offers an analysis of the literature about Fontan circulation during pregnancy and describes our center's current multidisciplinary approach to care for these women in the preconception, antepartum, intrapartum, and postpartum periods.

Expanding the Liver Imaging Reporting and Data System (LI-RADS) v2018 diagnostic population: performance and reliability of LI-RADS for distinguishing hepatocellular carcinoma (HCC) from non-HCC primary liver carcinoma in patients who do not meet strict LI-RADS high-risk criteria.

BACKGROUND: Hepatocellular carcinoma (HCC) can be diagnosed using imaging criteria in patients at high-risk for HCC, according to Liver Imaging Reporting and Data System (LI-RADS) guidelines. The aim of this study was to determine the diagnostic performance and inter-rater reliability (IRR) of LI-RADS v2018 for differentiating HCC from non-HCC primary liver carcinoma (PLC), in patients who are at increased risk for HCC but not included in the LI-RADS 'high-risk' population. METHODS: This retrospective HIPAA-compliant study included a 10-year experience of pathologically-proven PLC at two liver transplant centers, and included patients with non-cirrhotic hepatitis C infection, non-cirrhotic non-alcoholic fatty liver disease, and fibrosis. Two readers evaluated each lesion and assigned an overall LI-RADS diagnostic category, additionally scoring all major, LR-M, and ancillary features. RESULTS: The final study cohort consisted of 27 HCCs and 104 non-HCC PLC in 131 patients. The specificity of a 'definite HCC' designation was 97% for reader 1 and 100% for reader 2. The IRR was fair for overall LI-RADS category and substantial for most major features. CONCLUSION: In a population at increased risk for HCC but not currently included in the LI-RADS 'high-risk' population, LI-RADS v2018 demonstrated very high specificity for distinguishing pathologically-proven HCC from non-HCC PLC.

Liver Disease in Pregnancy and Transplant.

PURPOSE OF REVIEW: The purpose of this review is to discuss current and new knowledge regarding liver disease in pregnancy and pregnancy post-liver transplantation. RECENT FINDINGS: Severe liver disease associated with pregnancy is rare. Liver biopsy is rarely needed for diagnosis but is safe in selected cases. Intrahepatic cholestasis of pregnancy (ICP) with serum bile acids level > 40 µmol/L is associated with adverse fetal outcomes. Ursodeoxycholic acid should be initiated at diagnosis. Portal hypertension can worsen during pregnancy and screening endoscopy should be performed in the 2nd trimester. Maternal hepatitis B antiviral therapy can be considered in the 3rd trimester if HVB DNA > 200,000 IU/ml. Tacrolimus is the optimal immunosuppressive therapy during pregnancy post-transplantation. Preconception renal function predicts pregnancy outcome. Overall, the outcome of pregnancy post-transplantation is good but there is an increased risk of preterm delivery, low birth weight, hypertension, and pre-eclampsia. Liver disease of pregnancy can be divided into diseases unique to pregnancy, exacerbated by pregnancy or coexisting with pregnancy. Overall, the outcome of pregnancy post-liver transplantation is good.

An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

The induction of type I interferon production in hepatitis C-infected patients.

Chronic infection with hepatitis C virus (HCV) is a major global health problem. One way HCV may evade the host immune response is by inhibiting the production of type I interferon (IFN). In addition, the standard treatment for chronic HCV infection involves treatment with IFN-alpha (or its pegylated derivative), alone or in combination with ribavirin. Therefore, it is believed that an important reason that most HCV-infected individuals progress from acute to chronic infection is due to a defect in the host response. In this study, we examined the host response to HCV infection in a cohort of patients enrolled in the UTHSC Cooperative HCV Research Center by determining levels of biologically active IFN in the sera of patients. We found that 15 of 35 enrolled HCV-infected patients show serum levels of IFN (ranging from 2 to 40 IU/mL) before initiation of therapy. Uninfected individuals do not have circulating levels of IFN. Basal IFN levels do not correlate with the clinical response to therapy, nor do they reflect the age, sex, or race of patients. These results suggest that the differential response of patients most likely reflects a defect in the later stages of the host innate immune response, such as the cellular response to endogenous or exogenous IFN. In contrast, the early stage of the host immune response in vivo of many HCV-infected patients (approximately 40%) is intact as determined by IFN production.

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

UNLABELLED: Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. CONCLUSION: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Hepatitis C hypervariable region 1: association of reduced selection pressure in african americans with treatment failure.

In a prospective therapeutic trial, features of the hepatitis C quasispecies were investigated as possible markers of therapeutic response. Individuals chronically infected with hepatitis C genotype 1 received antiviral therapy consisting of alpha-interferon plus ribavirin. The study targeted the most rapidly evolving segment of the viral genome, hypervariable region 1 within the envelope-2 gene. Among individuals failing to clear virus in response to therapy, significant differences were observed between quasispecies of African-American and Caucasian subjects. While distance measures for synonymous substitutions were similar between racial subgroups, measures of distance at the amino acid level (nonsynonymous substitutions) varied significantly. Taken together, the observed patterns of variability corresponded to reduced host selection pressure against hypervariable region 1 in African-American nonresponders. Reduced selection pressure was present at baseline and persisted through treatment and follow-up, suggesting population stratification of host factors that influence selection pressure on hepatitis C virus.

Chronic hepatitis C in African Americans and other minority groups.

Chronic hepatitis C virus (HCV) is the most common bloodborne infection in the United States. An estimated 2.7 million Americans are infected, with the greatest prevalence of infection in African Americans at 3.2%. African Americans account for 22% of Americans with HCV. Recent studies have shown that African Americans are less likely to have cirrhosis than similarly infected non-Hispanic white patients and are more likely to have genotype 1 infection and to develop hepatocellular carcinoma. Several studies have shown that the response rates of African Americans to interferon and ribavirin are significantly lower than those for non-Hispanic whites. Despite the relatively low percentage of African-American patients in these early studies, similar preliminary results are being found in larger prospective studies with the newer treatment regimens of pegylated interferon and ribavirin. Differences in immunologic status, viral kinetics, and iron studies have also been found in HCV-infected African-American patients. Less is known about Mexican Americans and other minority groups because they are poorly represented in clinical trials. Efforts at increasing racial diversity in clinical trials are ongoing.