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.

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.

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 .

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.

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.

Cryptic but Deadly: A Serious Killer in Patients with Advanced Liver Disease that Should Not Be Missed.

Cryptococcal peritonitis is an under-recognized disease that is an important cause of mortality in end-stage liver disease. We report a 43-year old male with decompensated cirrhosis secondary to refractory autoimmune hepatitis on immunosuppression with hepatocellular carcinoma who developed cryptococcal peritonitis. The patient subsequently developed ischemic bowel and multisystem organ failure secondary to abdominal compartment syndrome, leading to rapid deterioration and death. Frequently, these patients experience delays in diagnosis and treatment, which leads to a rapid and high mortality. This case report synthesizes data regarding the optimal approach for screening and managing patients with cryptococcal peritonitis and proposes a pathogenic mechanism of mortality with implications for improved treatment in the future.

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.

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.

A new era in the treatment of chronic hepatitis C infection.

Treatment of chronic hepatitis C virus (HCV) infection has evolved over the past three decades. At the start, treatment involved interferon monotherapy followed by combination therapy using interferon and ribavirin, and subsequently evolved to pegylated interferon (Peg-IFN) and ribavirin. In genotype 1 infection, rates of sustained virological response (SVR) are approximately 45 % with Peg-IFN and ribavirin, whereas SVR rates in genotypes 2 and 3 infections are as high as 70 % to 80 %. Side effects and cost related to these drugs are important concerns, particularly in countries like India where patients have to bear their health expenses. In the recent past, there has been a significant change in course with the on-going search and the development of more effective drugs in the management of HCV infection. Telaprevir and Boceprevir are two new potent protease inhibitors (direct acting antiviral or DAA agents) which, when administered with Peg-IFN and ribavirin, have shown to result significantly higher SVR rates in phase 3 studies in patients with genotype 1 infection, both in treatment naïve patients (up to 75 %) and those with previously failed therapy. Several other new antiviral agents some in combination with Peg-IFN and ribavirin and some in combination without Peg-IFN (IFN-free regimens) are currently being tested in patients with genotype 1, 2 and 3 infections and are expected to dramatically change the armamentarium of HCV therapy in the coming years.

Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis.

BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. AIMS: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. METHODS: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. RESULTS: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. CONCLUSIONS: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. IMPACT: Our results differ from the guidelines of the AASLD.

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.

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.