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Journal: Hepatology communications

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Nonalcoholic fatty liver disease (NAFLD) is an emerging entity, becoming the most prevalent pediatric chronic liver disease. Its broad spectrum of histological findings, comorbidities, and complications, including cirrhosis and liver failure, can occur in childhood, emphasizing the severity of pediatric NAFLD. Current lifestyle and diet modifications have been linked to the increasing prevalence of NAFLD, including the rise of fructose consumption, a monosaccharide present in foods that contain added sugar, such as sugar-sweetened beverages. Excessive fructose consumption is believed to cause addiction like alcohol and other drugs. As such, the new term “fructoholism” refers to the consumption of a substance (fructose) that can cause psychological and physical damage and become a major public health concern, highlighting the seriousness of the excessive consumption of fructose in the pediatric age. Hepatic fructose metabolization leads to hepatic steatosis and progression to fibrosis through mechanisms comparable to alcoholic liver disease, hence the term “fructoholic liver disease.” Conclusion: The importance of implementing reliable global strategies, such as education campaigns to promote healthy diet, increasing taxes on foods that contain added sugars, subsidies to promote accessibility to fruit and vegetables, and strict food industry regulation to reduce sugar intake in children and adolescents, cannot be overemphasized.

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Hypogonadism affects hepatic lipid metabolism and is expected to promote nonalcoholic fatty liver disease (NAFLD). The aims of this study were to determine (1) the prevalence of NAFLD in hypogonadal males and (2) the impact of correction of hypogonadism by LPCN 1144 (Lipocine, Inc., Salt Lake City, UT), an oral testosterone prodrug, on NAFLD in this population. Data were derived from a multicenter open-label single-arm trial of LPCN 1144 for hypogonadal males, in which a subset (n = 36) had serial magnetic resonance imaging-proton density fat fraction measurements (National Clinical Trial 03868059). NAFLD prevalence, defined by magnetic resonance imaging-proton density fat fraction ≥5%, was 66%. Eighty-one percent of those with baseline liver fat (BL) ≥5% had improvement in liver fat content, and NAFLD resolved in 33% of subjects at 8 weeks (mean relative reduction: 45%) and 48% (mean relative reduction: 55%) after 16 weeks of LPCN 1144 therapy. The reduction in liver fat was greater in those with higher BL (BL ≥5%: 71%; BL ≥8%: 80%; and BL ≥10%: 75%). Normalization rate of alanine aminotransferase and gamma-glutamyltransferase greater than the upper limit of normal range were 100% and 50% of treated patients, respectively. LPCN 1144 was not associated with major adverse events. Conclusion: Treatment with LPCN 1144 (oral T prodrug) in hypogonadal males with NAFLD resolved NAFLD in approximately half of the affected patients without any safety signals. Further studies are needed to validate its use in hypogonadal males with nonalcoholic steatohepatitis.

20

Probiotics can modulate gut microbiota, intestinal permeability, and immune response and could therefore improve cognitive dysfunction and help avoid potential consequences, such as falls, in patients with cirrhosis. The aim of this study was to evaluate the effect of a multistrain probiotic on cognitive function, risk of falls, and inflammatory response in patients with cirrhosis. Consecutive outpatients with cirrhosis and cognitive dysfunction (defined by a Psychometric Hepatic Encephalopathy Score [PHES] < -4) and/or falls in the previous year were randomized to receive either a sachet of a high-concentration multistrain probiotic containing 450 billion bacteria twice daily for 12 weeks or placebo. We evaluated the changes in cognitive function (PHES); risk of falls (Timed Up and Go [TUG] test, gait speed, and incidence of falls); systemic inflammatory response; neutrophil oxidative burst; intestinal barrier integrity (serum fatty acid-binding protein 6 [FABP-6] and 2 [FABP-2] and zonulin and urinary claudin-3); bacterial translocation (lipopolysaccharide-binding protein [LBP]); and fecal microbiota. Thirty-six patients were included. Patients treated with the probiotic (n = 18) showed an improvement in the PHES (P = 0.006), TUG time (P = 0.015) and gait speed (P = 0.02), and a trend toward a lower incidence of falls during follow-up (0% compared with 22.2% in the placebo group [n = 18]; P = 0.10). In the probiotic group, we observed a decrease in C-reactive protein (P = 0.01), tumor necrosis factor alpha (P = 0.01), FABP-6 (P = 0.009), and claudin-3 (P = 0.002), and an increase in poststimulation neutrophil oxidative burst (P = 0.002). Conclusion: The multistrain probiotic improved cognitive function, risk of falls, and inflammatory response in patients with cirrhosis and cognitive dysfunction and/or previous falls.

18

Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environmentin utero, exerting long-lasting postnatal signatures on the juvenile innate immune system and microbiome that may predispose offspring to development of fatty liver disease. We found that exposure to a maternal Western-style diet (WD) accelerated fibrogenesis in the liver of offspring and was associated with early recruitment of proinflammatory macrophages at 8-12 weeks and microbial dysbiosis as early as 3 weeks of age. We further demonstrated that bone marrow-derived macrophages (BMDMs) were polarized toward an inflammatory state at 8 weeks of age and that a potent antioxidant, pyrroloquinoline quinone (PQQ), reversed BMDM metabolic reprogramming from glycolytic toward oxidative metabolism by restoring trichloroacetic acid cycle function at isocitrate dehydrogenase. This resulted in reduced inflammation and inhibited collagen fibril formation in the liver at 20 weeks of age, even when PQQ was withdrawn at 3 weeks of age. Beginning at 3 weeks of age, WD-fed mice developed a decreased abundance ofParabacteroidesandLactobacillus, together with increasedRuminococcusand decreased tight junction gene expression by 20 weeks, whereas microbiota of mice exposed to PQQ retained compositional stability with age, which was associated with improved liver health.Conclusion: Exposure to a maternal WD induces early gut dysbiosis and disrupts intestinal tight junctions, resulting in BMDM polarization and induction of proinflammatory and profibrotic programs in the offspring that persist into adulthood. Disrupted macrophage and microbiota function can be attenuated by short-term maternal treatment with PQQ prior to weaning, suggesting that reshaping the early gut microbiota in combination with reprogramming macrophages during early weaning may alleviate the sustained proinflammatory environment, preventing the rapid progression of nonalcoholic fatty liver disease to nonalcoholic steatohepatitis in offspring of obese mothers. (Hepatology Communications2018;2:313-328).

Concepts: Immune system, Bacteria, Metabolism, Nutrition, Obesity, Cirrhosis, Non-alcoholic fatty liver disease, Fatty liver

15

Liver disease in pregnancy may present as a disorder that is unique to pregnancy or as an acute or chronic liver disease occurring coincidentally in pregnancy. Hepatic diseases that are unique to pregnancy include hyperemesis gravidarum; preeclampsia/eclampsia; the syndrome of hemolysis, elevated liver enzymes, and low platelets; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Acute and chronic forms of primary hepatic disorders that are seen in pregnancy include viral hepatitis, autoimmune hepatitis, nonalcoholic fatty liver disease, and cirrhosis. Because of the need to consider both maternal and fetal health, there are special considerations for the implementation of diagnostic strategies and pharmacologic therapies for liver disease that occurs in pregnancy. An understanding of the pathogenesis and expression of liver diseases in pregnancy has been evolving, and various diagnostic and prognostic tools have been studied in order to determine noninvasive approaches to identifying and staging of such diseases. Investigations have also been underway to evaluate the safety and utility of existing and new therapeutic agents that previously were thought to not be compatible with pregnancy. This review will explore updates in the epidemiology, diagnosis, and management of various liver diseases seen in pregnancy.

12

The U.S. Drug Induced Liver Injury Network assayed the contents of herbal and dietary supplements collected from patients enrolled into its prospective study. The aim was to determine the accuracy of product labels, and to identify known hepatotoxins. Using high-performance liquid chromatography coupled with mass spectrometry to assay 272 product, 51% were found to be mislabeled; that is, to have chemical contents that did not match the label. Appearance enhancement, sexual performance, and weight loss products were most commonly mislabeled. Whether the mislabeling contributed to liver injury is under study; however, the high mislabeling rate underscores the need for more stringent regulation of supplements.

12

Dipeptidyl peptidase-4 (DPP-4 or clusters of differentiation [CD]26) is a multifunctional molecule with established roles in metabolism. Pharmacologic inhibition of DPP-4 is widely used to improve glycemic control through regulation of the incretin effect. Colaterally, CD26/DPP-4 inhibition appears to be beneficial in many inflammatory conditions, namely in delaying progression of liver pathology. Nevertheless, the exact implications of CD26/DPP-4 enzymatic activity in liver dysfunction remain unclear. In this work, we investigated the involvement of CD26/DPP-4 in experimental mouse models of induced hepatocyte damage that severely impact Kupffer cell (KC) populations. Liver dysfunction was evaluated in CD26 knockout (KO) and B6 wild-type mice during acute liver damage induced by acetaminophen, chronic liver damage induced by carbon tetrachloride, and KC-depleting treatment with clodronate-loaded liposomes. We found that necrosis resolution after hepatotoxic injury was delayed in CD26KO mice and in B6 mice treated with the CD26/DPP-4 inhibitor sitagliptin, suggesting that DPP-4 enzymatic activity plays a role in recovering from acute liver damage. Interestingly, the severe KC population reduction in acute and chronic liver injury was concomitant with increased CD26/DPP-4 serum levels. Remarkably, both chronic liver damage and noninflammatory depletion of KCs by clodronate liposomes were marked by oscillation in CD26/DPP-4 serum activity that mirrored the kinetics of liver KC depletion/recovery. Conclusion:CD26/DPP-4 enzymatic activity contributes to necrosis resolution during recovery from acute liver injury. Serum CD26/DPP-4 is elevated when severe perturbations are imposed on KC populations, regardless of patent liver damage. We propose that serum CD26/DPP-4 is a potential systemic surrogate marker of severe impairments in the KC population imposed by clinical and subclinical liver conditions.

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Detection of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is essential for stratifying patients according to the risk of liver-related morbidity. Noninvasive methods such as vibration-controlled transient elastography (VCTE) and Fibrosis-4 index (FIB-4) have been recommended to identify patients for further assessment. The aim of this study was to assess the potential impact of implementing a “FIB-4 First” strategy to triage patients entering a NAFLD assessment pathway. The pathway for patients with suspected NAFLD was piloted at a tertiary liver center. Referral criteria were 16-65 years old, elevated alanine aminotransferase and/or steatosis on imaging, and absence of a previous liver diagnosis. A registered nurse risk-stratified all patients based on VCTE and FIB-4 was calculated. Potential alternative diagnoses were excluded with bloodwork. A total of 565 patients underwent risk stratification with VCTE with a 97% success rate. Ten percent had VCTE of at least 8 kPa; 560 patients had FIB-4 available for analysis and 87% had values less than 1.3. Of those with a FIB-4 of at least 1.3, 69% had a VCTE less than 8 kPa. Further modeling showed that the presence of diabetes, age, and body mass index had only a moderate impact on the association between FIB-4 and elastography values if using a FIB-4 threshold of 1.3. Conclusion: A FIB-4 threshold of 1.3 was acceptable for excluding the presence of advanced fibrosis (assessed by VCTE). A staged risk-stratification model using FIB-4 and VCTE could save up to 87% of further assessments. This model could improve accessibility by moving the initial fibrosis evaluation to the medical home and helping to prioritize patients for further specialized care.

8

Hepatitis C virus (HCV) infection is a leading cause of liver-related morbidity and mortality, and more than 2 million adults in the United States are estimated to be currently infected. Reducing HCV burden will require an understanding of demographic disparities and targeted efforts to reduce prevalence in populations with disproportionate disease rates. We modeled state-level estimates of hepatitis C prevalence among U.S. adults by sex, birth cohort, and race during 2013-2016. National Health and Nutrition Examination Survey data were used in combination with state-level HCV-related and narcotic overdose-related mortality data from the National Vital Statistics System and estimates from external literature review on populations not sampled in the National Health and Nutrition Examination Survey. Nationally, estimated hepatitis C prevalence was 1.3% among males and 0.6% among females (prevalence ratio [PR] = 2.3). Among persons born during 1945 to 1969, prevalence was 1.6% compared with 0.5% among persons born after 1969 (PR = 3.2). Among persons born during 1945 to 1969, prevalence ranged from 0.7% in North Dakota to 3.6% in Oklahoma and 6.8% in the District of Columbia. Among persons born after 1969, prevalence was more than twice as high in Kentucky, New Mexico, Oklahoma, and West Virginia compared with the national average. Hepatitis C prevalence was 1.8% among non-Hispanic black persons and 0.8% among persons of other races (PR = 2.2), and the magnitude of this disparity varied widely across jurisdictions (PR range: 1.3-7.8). Overall, 23% of prevalent HCV infections occurred among non-Hispanic black persons, whereas 12% of the population was represented by this racial group. These estimates provide information on prevalent HCV infections that jurisdictions can use for understanding and monitoring local disease patterns and racial disparities in burden of disease.

7

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Although hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham National Health Service Foundation Trust. The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry. Seventy-two human liver specimens were analyzed, including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two-way analysis of variance [ANOVA], P = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 μM vs. 616 μM in normal liver) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA, P = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean, 462 μM vs. 322 μM; P < 0.01 in nonsevere vs. severe alcoholic steatohepatitis, respectively). NAD+ concentration was inversely related to serum bilirubin concentration (r2 = -0.127; P = 0.04) and positively correlated with myeloperoxidase activity (r2 = 0.31; P = 0.003). The concentration of NAD+ and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+ and precursor levels as well as depressed myeloperoxidase activity.