Marwan Ghabril

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

BACKGROUND & AIMS The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Comparison of Probe-Based Confocal Laser Endomicroscopy With Virtual Chromoendoscopy for Classification of Colon Polyps

BACKGROUND & AIMS Probe-based confocal laser endomicroscopy (pCLE) allows in vivo imaging of tissue at micron resolution. Virtual chromoendoscopy systems, such as Fujinon intelligent color enhancement and narrow band imaging, also have potential to differentiate neoplastic colorectal lesions. The accuracy of these systems in clinical practice is, however, unknown. Our primary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy for classification of colorectal polyps using histopathology as a gold standard. A secondary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy using a modified gold standard that assumed that all polyps >/=10 mm had malignant potential and were considered neoplastic or high risk. METHODS Patients underwent colonoscopy using high-resolution colonoscopes. The surface pit pattern was determined with NBI or FICE in all patients. Confocal images were recorded and subsequently analyzed offline, blinded to the endoscopic characteristics and histopathology. Each polyp was diagnosed as benign or neoplastic based on confocal features according to modified Mainz criteria. RESULTS A total of 119 polyps (81 neoplastic, 38 hyperplastic) from 75 patients was assessed. The pCLE had higher sensitivity compared to virtual chromoendoscopy when considering histopathology as gold standard (91% vs 77%; P = .010) and modified gold standard (88% vs 76%; P = .037). There was no statistically significant difference in specificity between pCLE and virtual chromoendoscopy when considering histopathology or modified gold standard. CONCLUSIONS Confocal endomicroscopy demonstrated higher sensitivity with similar specificity in classification of colorectal polyps. These new methods may replace the need for ex vivo histological confirmation of small polyps, but further studies are warranted.

Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.

OBJECTIVES:The etiology of eosinophilic esophagitis (EoE) is not well understood. It has been proposed that eosinophils migrate to the esophagus in response to various ingested and inhaled allergens. Recent reports in children found an increased proportion of cases of EoE during months with higher outdoor aeroallergens. To our knowledge, this has not been evaluated in adults. We aimed to determine whether there is a seasonal distribution in the number of newly diagnosed cases of EoE in an adult population.METHODS:We conducted a retrospective review of consecutive adult cases newly diagnosed with EoE in 1 year. Cases were grouped based on the index month when the diagnosis was made at endoscopy. To test the consistency of the observations, a second cohort of consecutive cases of similar sample size diagnosed at a different period in time was also analyzed.RESULTS:In total, 41 patients were diagnosed with EoE at our center during the study period, providing an annual prevalence of 0.98%. More cases were diagnosed with EoE during the months of April and May than any other month (P<0.001). When patients were grouped seasonally, there was a significant increase of EoE cases in spring and summer months (n=28) when compared with the fall and winter months (n=13) (P=0.019). Analysis of the second cohort of cases (n=37) from 2002 to 2006 confirmed a similar seasonal diagnostic pattern for EoE during the outdoor seasons.CONCLUSIONS:Our data demonstrate that EoE has a seasonal prevalence in adults. The seasonal variation pattern found in newly diagnosed EoE cases in adults supports the potential role of aeroallergens in the pathogenesis of EoE.

High-Definition Colonoscopy Detects Colorectal Polyps at a Higher Rate Than Standard White-Light Colonoscopy

BACKGROUND & AIMS Adenoma detection rates might be improved through use of high-definition colonoscopy, which can detect subtle mucosal changes. We investigated whether the use of high-definition white-light (HDWL) colonoscopy resulted in a higher rate of adenoma detection than standard-definition white-light (SDWL) colonoscopy in a clinical practice setting. METHODS This retrospective study included 2430 patients who underwent colonoscopies from September 2006 to December 2007; 1226 received SDWL colonoscopy and 1204 received HDWL colonoscopy. We analyzed data from consecutive screening, surveillance, and diagnostic colonoscopies, comparing adenoma and overall polyp detection between procedures. Potentially confounding variables were controlled using multivariable logistic regression analysis. RESULTS The adenoma detection rate was higher among patients who underwent HDWL compared with SDWL colonoscopies (28.8% vs 24.3%; P = .012), as was the polyp detection rate (42.2% vs 37.8%; P = .026). These findings remained after adjustments for potentially confounding variables (P = .018 and .022, respectively). CONCLUSIONS In a general clinical practice setting, HDWL colonoscopy resulted in a higher adenoma detection rate compared with SDWL colonoscopy. The use of SDWL colonoscopy could reduce the number of missed adenomas and the subsequent risk for colorectal cancer.

Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases

BACKGROUND & AIMS Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. METHODS We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. RESULTS The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. CONCLUSIONS Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy

Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double‐blind, placebo‐controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice‐daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P < 0.05), as well as total events (35 versus 57; P = 0.04), and was associated with fewer HE hospitalizations (13 versus 25; P = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P < 0.01), time to first event (HR = 0.29; P < 0.01), and total events (7 versus 31; P < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2014;59:1073‐1083)

Drug-induced liver injury: a clinical update

Purpose of review To gather new and important data published on idiosyncratic drug-induced liver injury (DILI) over the past 2 years in the peer-reviewed literature. Clinical studies focusing on mechanisms of injury, clinical evaluation and prognosis will be reviewed. Recent findings The most common drugs leading to DILI in the United States are antibiotics, central nervous system agents, herbal/dietary supplements and immunomodulatory agents. Hepatocellular type of DILI is more common in younger patients, whereas cholestatic pattern increases with older age. Certain human leukocyte antigen genotype increases the likelihood of flucloxacillin-induced liver injury. Idiosyncratic DILI was shown to have an important dose-dependency and drugs with extensive hepatic metabolism are associated with higher frequency of DILI. Chronic DILI may occur, but development of clinically important liver injury after severe DILI is rare. N-acetylcysteine seems to be beneficial for patients with acute liver failure caused by medications or herbal agents.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL‐40, could be used to predict rapid fibrosis progression (RFP) post‐LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha‐smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 ± 2 (biopsy 1) and 39 ± 6 (biopsy 2) months post‐LT, respectively. RFP was defined as an increase in the fibrosis score ≥ 2 from biopsy 1 to biopsy 2 (a mean interval of 33 ± 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL‐40 performed significantly better than conventional parameters and HSCA in predicting RFP post‐LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA ≥ 90 μg/L and YKL‐40 ≥ 200 μg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL‐40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL‐40 in post‐LT management are warranted. Liver Transpl 14:1294–1302, 2008.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Abstract:  Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Trainee participation is associated with increased small adenoma detection

BACKGROUND Previous studies examining the effect of fellow participation on adenoma detection rate in colonoscopy have yielded conflicting results, and factors such as adenoma size and location have not been rigorously evaluated. OBJECTIVE To examine whether fellow participation during screening, surveillance, or diagnostic colonoscopy affects overall, size-specific, or location-specific adenoma or polyp detection rate. METHODS This was a retrospective study of 2430 colonoscopies performed in our ambulatory surgical center between September 2006 and December 2007, comparing adenoma and polyp detection rates of colonoscopies performed by fellows with supervising staff endoscopists (n = 318) with colonoscopies performed by staff endoscopists without fellow participation (n = 2112). Study participants included patients who underwent screening, surveillance, or diagnostic colonoscopies in our GI suite. Logistic regression analysis was used to evaluate the association of fellow participation with adenoma and polyp detection. RESULTS There was evidence of a higher rate of small (<5 mm) adenoma detection in colonoscopies with a fellow present (25% vs 17%, P = .001). This remained significant after multiple-testing adjustment (P ≤ .003 considered significant). Findings were similar, although not significant for small polyps (36% vs 29%, P = .007). There was a trend toward increased adenoma detection in colonoscopies with a fellow present compared with those without (30% vs 26%, P = .11). Multivariable adjustment for potentially confounding variables did not alter these associations. LIMITATIONS The study had a retrospective design, and information regarding bowel preparation was not available for 37% of patients. CONCLUSION Fellow involvement was associated with increased detection rates of small adenomas, providing evidence that the presence of a fellow during colonoscopy plays a role in enhancing the effectiveness of the examination.