Publications

Of the clinical complications of cirrhosis, hepatic encephalopathy (HE) is the most devastating. HE is a spectrum of reversible cognitive changes ranging from minimal HE (MHE) (mild inattention and deficits of executive function) to overt HE (disorientation to coma). More than 40% of patients with cirrhosis develop HE, which increases mortality, falls, motor vehicle accidents, and has a significant psychosocial impact.1 Early recognition is crucial. Patients with cirrhosis are recommended to receive an assessment for MHE.2.

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.

Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy-proven NAFLD were enrolled in this cross-sectional study. PNPLA3 I148M and TM6SF2 E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP-IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP-IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (P < 0.001 to 0.02) after adjustment for potential confounders. PNPLA3 148M and TM6SF2 E167K genotypes were significantly associated with steatosis (P = 0.003 and P = 0.02, respectively). A combination of the eLP-IR and genetic score was able to predict the presence of NAS ≥3 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3-4 liver fibrosis with an AUROC of 0.82. Conclusion: This proof-of-concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors.

OBJECTIVES: Our current understanding of normal bowel patterns in the United States (US) is limited. Available studies have included individuals with both normal and abnormal bowel patterns, making it difficult to characterize normal bowel patterns in the US. The current study aims to (1) examine frequency and consistency in individuals with self-reported normal bowel habits and (2) determine demographic factors associated with self-reported normalcy.

METHODS: This study used data from adult participants who completed bowel health questions as part of the National Health and Nutrition Examination Survey (NHANES) in 2009-2010 and who reported normal bowel patterns (N=4,775). Data regarding self-perceived bowel health; stool frequency; stool consistency (using the Bristol Stool Form Scale (BSFS)); and demographic factors were analyzed.

RESULTS: 95.9% of the sample reported between 3 and 21 BMs per week. Among men, 90% reported a BSFS between 3 and 5, while for women it was 2-6. After controlling for age, the following demographic variables were associated with normalcy: male sex, higher education, higher income, <2 daily medications, and high daily fiber intake. Hispanic ethnicity was significantly associated with abnormal self-reported bowel habits.

CONCLUSIONS: This is the first study to evaluate normal bowel frequency and consistency in a representative sample of adults in the US. The current findings bolster the common "3 and 3" metric of normal frequency (3 BMs/day to 3 BMs/week) while also suggesting different criteria for normal consistency for men and women. Finally, this study provides novel information about demographic factors associated with normal frequency and consistency.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication that accounts for up to 20% of malignancies after solid organ transplantation. We describe a rare case of isolated PTLD in the adrenal gland occurring 7 months after liver transplant in a patient who developed a primary Epstein-Barr virus infection. He was treated with rituximab and his immunosuppression regimen was minimized. We review the incidence, pathogenesis, presentation, and management of PTLD in the liver-transplant population. Our case highlights the variation in the presentation of PTLD and the importance of a high index of suspicion among the at-risk group.

Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) are cell surface-located transmembrane ecto-enzymes of the CD39 superfamily which regulate inflammation and tissue repair by catalyzing the phosphohydrolysis of extracellular nucleotides and modulating purinergic signaling. In the liver, NTPDase2 is reportedly expressed on portal fibroblasts, but its functional role in regulating tissue regeneration and fibrosis is incompletely understood. Here, we studied the role of NTPDase2 in several models of liver injury using global knockout mice. Liver regeneration and severity of fibrosis were analyzed at different time points after exposure to carbon tetrachloride (CCl4) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or partial hepatectomy in C57BL/6 wild-type and globally NTPDase2-deficient (Entpd2 null) mice. After chronic CCl4 intoxication, Entpd2 null mice exhibit significantly more severe liver fibrosis, as assessed by collagen content and histology. In contrast, deletion of NTPDase2 does not have a substantial effect on biliary-type fibrosis in the setting of DDC feeding. In injured livers, NTPDase2 expression extends from the portal areas to fibrotic septae in pan-lobular (CCl4-induced) liver fibrosis; the same pattern was observed, albeit to a lesser extent in biliary-type (DDC-induced) fibrosis. Liver regeneration after partial hepatectomy is not substantively impaired in global Entpd2 null mice. NTPDase2 protects from liver fibrosis resulting from hepatocellular injury induced by CCl4. In contrast, Entpd2 deletion does not significantly impact fibrosis secondary to DDC injury or liver regeneration after partial hepatectomy. Our observations highlight mechanisms relating to purinergic signaling in the liver and indicate possible therapeutic avenues and new cellular targets to test in the management of hepatic fibrosis.

BACKGROUND: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized.

MATERIALS AND METHODS: We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes.

RESULTS: In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype.

CONCLUSIONS: PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.

BACKGROUND & AIMS: Treatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy.

METHODS: We performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A.

RESULTS: The presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m2 were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the "BE3A score." For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7).

CONCLUSIONS: We identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis.