A Deeper Look at the Small Bowel: Training Pathways in Video Capsule Endoscopy and Device-Assisted Enteroscopy.

BACKGROUND: Although there are guidelines for video capsule endoscopy (VCE) and device-assisted enteroscopy (DAE), little is known about fellowship training in these technologies. AIMS: The aims were to better characterize current small bowel endoscopy training in 3-year GI fellowship programs and 4th-year advanced endoscopy programs in the U.S. METHODS: We developed an online multiple-choice survey to assess current GI fellowship program training in small bowel endoscopy. The survey was distributed via email to GI fellowship program directors in the U.S. RESULTS: Of the 168 program directors contacted, 59 responded (response rate = 35.1%). There was no statistically significant difference in the availability of VCE or DAE between respondents and non-respondents. VCE training was universally available in 3-year training programs, with 84.8% (50/59) requiring it for fellows. The majority of 3-year GI fellows graduated with independence in VCE: 83.1% (49/59) of programs reported "most" or "all" graduates were able to read independently. DAE techniques were available in 86.4% of training programs (51/59). Training in DAE was more limited and shared between 3-year and 4th-year programs: 12.1% (7/58) of 3-year programs required training in DAE and 22.9% (8/35) of 4th-year programs required training in DAE . CONCLUSIONS: Training in VCE is widely available in U.S. GI fellowship programs, although programs have different ways of incorporating this training into the curriculum and of measuring competency. While DAE technology was available in the majority of programs, training was less frequently available, and training is shared between 3-year fellowship programs and 4th-year advanced endoscopy programs .

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

CD73 (ecto-5'-nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory-denk body formation.

UNLABELLED: Formation of hepatocyte Mallory-Denk bodies (MDBs), which are aggregates of keratins 8 and 18 (K8/K18), ubiquitin, and the ubiquitin-binding protein, p62, has a genetic predisposition component in humans and mice. We tested the hypothesis that metabolomic profiling of MDB-susceptible C57BL and MDB-resistant C3H mouse strains can illuminate MDB-associated pathways. Using both targeted and unbiased metabolomic analyses, we demonstrated significant differences in intermediates of purine metabolism. Further analysis revealed that C3H and C57BL livers differ significantly in messenger RNA (mRNA) level, protein expression, and enzymatic activity of the adenosine-generating enzyme, ecto-5'-nucleotidase (CD73), which was significantly lower in C57BL livers. CD73 mRNA levels were also dramatically decreased in human liver biopsies from hepatitis C and nonalcoholic fatty liver disease patients. Feeding mice with a diet containing the MDB-inducing agent, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), significantly decreased CD73 protein and activity in C57BL livers and resulted in loss of plasma membrane CD73 expression and activity in isolated mouse hepatocytes. To further examine the role of CD73 in MDB formation in vivo, we fed wild-type (WT) and CD73(-/-) mice a DDC-containing diet. Liver enlargement, p62 induction, and disappearance of the K8/K18 cytoskeleton were attenuated in CD73(-/-) , compared to WT livers. MDB formation, as assessed by biochemical and immunofluorescence detection of keratin and ubiquitin complexes, was nearly absent in CD73(-/-) mice. CONCLUSION: Purine metabolism and CD73 expression are linked to susceptibility to MDB formation in livers of different mouse strains. Expression of the adenosine-generating enzyme, CD73, contributes to experimental MDB induction and is highly regulated in MDB-associated liver injury in mice and in chronic human liver disease.

Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is defined based on recent alcohol consumption; however, remote or lifetime alcohol consumption is not taken into account. It is not known whether lifetime alcohol consumption contributes to the severity of disease in patients with NAFLD. To determine the effect of lifetime alcohol consumption on the histological severity in patients with NAFLD. PATIENTS & METHODS: Adults >18 years of age with presumed NAFLD and alcohol consumption <40 g/week were enrolled. Lifetime alcohol consumption was determined using a questionnaire. Patients with a history of long-term alcohol abuse or dependence were excluded. A liver biopsy was reviewed by a single pathologist in a blinded fashion. Demographic, clinical and histological findings were compared in those who had regular alcohol consumption and those who did not. RESULTS: A total of 77 patients had fatty liver on biopsy. Fifty-two patients had a history of regular alcohol consumption. The median lifetime cumulative alcohol intake was 24 gram-years. On multivariable analysis, increasing age (OR 1.07, 95% CI 1.01-1.14) was associated with severe liver disease, whereas alcohol consumption of ≥24 gram-years was associated with less severe disease (OR 0.26, 95% CI 0.07-0.97, P = 0.04). Patients who continued to consume alcohol or had been abstinent for ≤1 year had less severe disease. CONCLUSION: Some degree of regular alcohol consumption over the course of a lifetime compared to minimal intake appears to have a protective effect on the histological severity of liver disease among patients with strictly defined NAFLD.

Chronic Liver Disease in Patients with Prolidase Deficiency: A Case Series.

Introduction: Prolidase deficiency is a rare autosomal recessive disorder caused by variants in the PEPD gene. Patients usually have multi-organ involvement and a wide range of clinical features including recurrent skin ulcers, dysmorphic facial features, recurrent infections, intellectual disability, and splenomegaly. Studies have shown that patients with prolidase deficiency may have hepatic manifestations including hepatomegaly and abnormal liver enzymes. However, there is no detailed description of liver disease in this patient population. Case Presentation: Here, we present 3 patients with prolidase deficiency with varying extents of hepatic involvement. Conclusion: Prolidase deficiency patients with liver disease should be followed up long term to understand more about the pathophysiology and the impact of liver disease on long-term outcomes.

A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.

UNLABELLED: In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. CONCLUSION: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.

Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C.

BACKGROUND & AIMS: Chronic hepatitis C is associated with an increased prevalence of insulin resistance, which might result from liver disease, metabolic factors, or the hepatitis C virus (HCV) itself. The effect of antiviral treatment on insulin sensitivity is not well-known. We evaluated changes in insulin resistance and weight in patients with hepatitis C during and after peginterferon and ribavirin therapy. METHODS: Virahep-C was a prospective, multicenter study of a 48-week course of combination antiviral therapy in patients infected with HCV genotype 1. Insulin resistance (IR) was estimated by the homeostasis model assessment index (HOMA2-IR) based on fasting glucose and insulin levels. RESULTS: Among 341 patients, 40% had insulin resistance (HOMA2-IR > 2.0). The presence of insulin resistance was associated with increasing age, body mass index (BMI), and fibrosis stage. Among patients with insulin resistance at the start of the trial, median decreases in HOMA2-IR values during treatment were 0.74 at 24 weeks and 0.89 at 48 weeks, whereas BMI decreased by 1.2 and 2.2 at the same time points (P < .001 for all). At follow-up, HOMA2-IR and BMI levels returned toward baseline values in patients who did not respond or relapsed, but HOMA2-IR values remained significantly lower in patients with sustained virologic response (SVR) (P < .001), despite increases in BMI. CONCLUSIONS: In patients with HCV genotype 1 infections, therapy with peginterferon and ribavirin is associated with decreases in body weight and insulin resistance. Among patients with insulin resistance before treatment, resolution of HCV infection results in sustained improvements in the HOMA-IR index, suggesting that HCV could have a direct role in the pathogenesis of insulin resistance.

Clinical and histopathologic features of fluoroquinolone-induced liver injury.

BACKGROUND & AIMS: Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS: We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS: Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS: Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Editorial: Exercise for NAFLD: does intensity matter?

Currently, there are no established means for the prevention or treatment of non-alcoholic steatohepatitis (NASH) despite our increasing understanding of nonalcoholic fatty liver disease (NAFLD) pathogenesis implicating insulin resistance (IR) as a key factor and highlighting the central role of lipotoxic liver injury in the development of NASH. Lifestyle interventions aiming at decreasing IR and preventing lipotoxicity, including weight loss, diet, and physical exercise, are in the frontline for NASH patient management. Physical activity may ameliorate IR, maintain weight loss, and improve liver histology in NASH patients. However, there are no recognized criteria for the optimal intensity, duration, or total volume of exercise needed to obtain these beneficial effects. In this issue of the American Journal of Gastroenterology, Kistler and colleagues show that vigorous, but not moderate exercise, nor total duration or volume of physical activity, is related to decreased odds of having NASH or advanced fibrosis. Prospective studies using the objective criteria of physical activity, addressing the role of concurrent weight loss, and assessing individual histological features are needed to further clarify the effects of exercise intensity on NAFLD histology.

Associations between serum lipids and hepatitis C antiviral treatment efficacy.

UNLABELLED: Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep-C, a prospective study of treatment-naïve patients with genotype 1 HCV infection who received peginterferon (PEG-IN) alfa-2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG-IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low-density lipoprotein cholesterol, with an interaction between high-density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR. CONCLUSION: Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication.

Non-alcoholic fatty liver disease in diabetes: When to refer to the hepatologist?

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. A strong relationship exists between NAFLD and diabetes mellitus. There is growing evidence of a mechanistically complex and strong association between the two diseases. Current data also shows that one disease actually leads to worsening of the other and vice versa. Understanding of the various pathophysiological mechanisms involved, natural history and spectrum of these two diseases is essential not only for early diagnosis and management but also for prevention of severe disease forms. Despite the tremendous progress made in recent times in acquiring knowledge about these highly prevalent diseases, the guidelines and recommendations for screening and management of diabetics with NAFLD remain ambiguous. An interdisciplinary approach is required to not only raise awareness of the prevalence of NAFLD in diabetics but also for better patient management. This can help attenuate the development of significant complications, such as cirrhosis, decompensation and hepatocellular carcinoma in these patients, thereby halting NAFLD in its tracks. This review focuses on the pivotal role of primary care physicians and endocrinologists in identification of NAFLD in diabetics in early stages and the role of proactive screening for prompt referral to hepatologist.

Liver injury associated with kratom, a popular opioid-like product: Experience from the U.S. drug induced liver injury network and a review of the literature.

BACKGROUND: Kratom is a botanical product used as an opium substitute with abuse potential. METHODS: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. RESULTS: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. CONCLUSION: Kratom can cause severe liver injury with jaundice.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.

Hepatic steatosis is the accumulation of fat in liver cells. Insulin resistance (IR) occurs when normal amounts of insulin do not stimulate insulin activity in cells. Both conditions have been described in hepatitis C virus (HCV) infection and are thought to be biologically related. This study examined the association of genetic variants with steatosis and IR among 167 African Americans and 184 Caucasian Americans with HCV genotype-1. Steatosis was defined as at least 5% of fat in cells on liver biopsy. IR was quantified as a score greater than 2 from the Homeostasis Model Assessment, version 2.2 (HOMA2-IR). Associations were investigated by estimating odds ratios separately by race. Statistically significant associations (p < 0.05) were observed for variants in interleukin-10 (IL10), leptin receptor (LEPR), interleukin-6 (IL6) and transforming growth factor beta-1 (TGF-beta1) for both outcomes. Some significant interactions were observed between IL10,LEPR and TGF-beta1 polymorphisms and HOMA2-IR scores when examining steatosis. The interaction of HOMA2-IR and IL10 was consistent in both races whereas for LEPR and TGF-beta1 the interactions were statistically significant in only one of the racial groups.These results could imply that some IL10,LEPR and TGF-beta1 polymorphisms may modify an association between steatosis and IR.

Gastric and duodenal ischaemia after transarterial chemoembolisation for hepatocellular carcinoma: an unexpected but significant complication.

Transarterial chemoembolisation (TACE) is commonly used for unresectable intermediate-stage hepatocellular carcinoma (HCC). TACE is usually well-tolerated. We report a case of a patient who presented with a gastrointestinal bleed from TACE. A 64-year-old man presented with chronic hepatitis C cirrhosis and multifocal bilobar HCC. He had previously undergone multiple TACE sessions, radiofrequency ablation and stereotactic body radiation therapy. In the evening of his TACE procedure, he developed abdominal pain and haematemesis. An oesophagogastroduodenoscopy (OGD) showed non-bleeding oesophageal varices and ulcerations in the stomach and duodenum, with pathology demonstrating mucosal necrosis. The patient recovered and was discharged on omeprazole. While TACE is considered safe with most patients only experiencing postembolisation syndrome, vascular complications have been reported. In our patient, OGD revealed ulcerations, with biopsies confirming ischaemic ulceration. The likely aetiology was seepage of the embolic particles into neighbouring arteries. Patients should be carefully selected for TACE and monitored post procedure.

Assessing the validity of self-reported medication adherence in hepatitis C treatment.

OBJECTIVE: To assess the validity of self-reported medication adherence provided by individuals in treatment for hepatitis C virus (HCV) infection with a regimen of peginterferon and ribavirin. METHODS: Adherence was evaluated prospectively among 196 African American and 205 white subjects enrolled in Virahep-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C), a treatment study for genotype 1 HCV infection. Adherence to the prescribed dose was measured by 2 methods: self-report questions administered during multiple clinic visits, using a touch screen computer; and recordings of bottle openings, using an electronic monitor placed inside the cap of prescription containers. Self-reported responses were compared with the electronic monitor data. Nonparametric tests were used to test the association between adherence measures at 4, 12, 24, 36, and 48 weeks of treatment. RESULTS: The estimated proportion of participants who were adherent prior to a given visit ranged from 85% to 97% (ribavirin) and 97% to 100% (peginterferon) by self report and from 69% to 90% (ribavirin) and 84% to 100% (peginterferon) by electronic monitors. For ribavirin, the percentage of cases in which the 2 measurement methods agreed varied from 68% to 90%; peginterferon agreement was from 84% to 100%. Overall, adherence was higher for peginterferon than for ribavirin but decreased over time for both medications. Self-reported adherence was usually higher than that assessed by electronic measures, and the level of discrepancy increased during the course of treatment. CONCLUSIONS: Adherence to peginterferon and ribavirin decreased gradually during therapy but remained relatively high. Simple self-reported measures can be used to screen for nonadherence to HCV drug therapy, but should be considered as overestimation of the actual amounts taken.