Suthat Liangpunsakul

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.

Wireless Capsule Endoscopy Detects Small Bowel Ulcers in Patients With Normal Results From State of the Art Enteroclysis

BACKGROUND:Wireless capsule endoscopy (WCE) is a new technology for small bowel imaging.AIM:To report our initial experience with sensitivity of high quality enteroclysis in patients with small bowel ulcers detected by WCE.METHODS:Medical records of all patients referred for WCE from December, 2001 to April, 2002 at our institution were reviewed. All patients had negative upper and lower endoscopies and small bowel barium studies before WCE.RESULTS:There were 40 patients (19 female, mean age 57.3 yr) during this study period. Three patients had multiple small bowel ulcers detected by WCE. One with ileal ulcers and abdominal pain had an enteroclysis at another hospital before WCE. Review of the study at our institution showed that it was of excellent quality and was normal. Two patients with chronic iron deficiency anemia had multiple small bowel ulcers and were referred after WCE for a repeat small bowel barium study by biphasic enteroclysis performed by experienced GI radiologists. The radiologists were told in advance of the WCE findings. Both studies were considered technically to be of perfect quality. Despite this, both studies were negative. All 3 patients improved after therapy for Crohns disease.CONCLUSIONS:Our data indicates that WCE may be more sensitive for small bowel ulcers than the best enteroclysis available.

Propofol versus midazolam/fentanyl for outpatient colonoscopy: administration by nurses supervised by endoscopists

Abstract Background & Aims: Propofol is under evaluation as a sedative for endoscopic procedures. We compared nurse-administered propofol to midazolam plus fentanyl for outpatient colonoscopy. Methods: One hundred outpatients undergoing colonoscopy were randomized to receive propofol or midazolam plus fentanyl, administered by a registered nurse and supervised only by an endoscopist. Endpoints were patient satisfaction, procedure and recovery times, neuropsychologic function, and complications. Results: The mean dose of propofol administered was 277 mg; mean doses of midazolam and fentanyl were 7.2 mg and 117 μg, respectively. Mean time to sedation was faster with propofol (2.1 vs. 6.1 min; P 0.5). Conclusions: Nurse-administered propofol resulted in several advantages for outpatient colonoscopy compared with midazolam plus fentanyl, but did not improve patient satisfaction.

Unexplained Elevations in Alanine Aminotransferase in Individuals with the Metabolic Syndrome: Results from the Third National Health and Nutrition Survey (NHANES III)

BackgroundUnexplained elevations in alanine aminotransferase (ALT) level have been suggested to signify the presence of nonalcoholic fatty liver disease (NAFLD) in adult NHANES III participants. In this study, we examined the relationship between unexplained elevations in ALT level and the metabolic syndrome and the relationship between unexplained elevations in ALT level and microalbuminuria. MethodsWe examined the prevalence and predictors of unexplained elevations in ALT level in 4376 adult NHANES III participants with the metabolic syndrome. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, and the presence of unexplained elevations in ALT level was defined based on the previously published criteria. Prevalence of microalbuminuria was compared between 710 individuals with unexplained elevations in ALT level and 1780 control subjects. ResultsPrevalence of unexplained elevations in ALT level in individuals with the metabolic syndrome was 7% and was significantly higher than in those without the metabolic syndrome (3.5%; OR, 2.07; 95% CI, 1.78–2.41). Younger age, male gender, higher triglycerides or serum iron levels, low levels of certain antioxidants, and insulin resistance (or diabetes) were independently associated with unexplained elevations in ALT level in the metabolic syndrome. Prevalence of microalbuminuria was not different between individuals with unexplained elevations in ALT level and their control subjects (4.8% versus 6.2%, respectively; P = 0.2). ConclusionsIndividuals with the metabolic syndrome have a significantly higher prevalence of unexplained elevations in ALT level. Because unexplained elevations in ALT level may signify the presence of NAFLD, our data support the notion that NAFLD is part of the spectrum of the metabolic syndrome. However, no relationship was demonstrated between unexplained elevations in ALT level and microalbuminuria.

Reliability of the Roussel Uclaf Causality Assessment Method for Assessing Causality in Drug-Induced Liver Injury

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test‐retest and interrater reliabilities of RUCAM in retrospectively‐identified cases of drug induced liver injury. The Drug‐Induced Liver Injury Network is enrolling well‐defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug‐induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol‐defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test‐retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test‐retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five‐category scale improved these reliabilities but only marginally. Conclusion: The mediocre reliability of the RUCAM is problematic for future studies of drug‐induced liver injury. Alternative methods, including modifying the RUCAM, developing drug‐specific instruments, or causality assessment based on expert opinion, may be more appropriate. (HEPATOLOGY 2008.)

The Role of Lipid Metabolism in the Pathogenesis of Alcoholic and Nonalcoholic Hepatic Steatosis

Hepatic steatosis is now understood to play an important role in the development of advanced liver disease. Alcoholic and nonalcoholic fatty liver each begin with the accumulation of lipids in the liver. Lipid accumulation in the liver can occur through maladaptations of fatty acid uptake (either through dietary sources or from fat tissue), fatty acid synthesis, fatty acid oxidation, or export of lipids from the liver. Alterations in mechanisms of fatty acid uptake through both dietary uptake and lipolysis in adipose tissue can contribute to the pathogenesis of both disorders, as can effects on fatty acid transporters. Effects on lipid synthesis in alcoholic and nonalcoholic fatty liver involve the endoplasmic reticulum (ER) stress response, homocysteine metabolism pathway, and different transcription factors regulating genes in the lipid synthesis pathway. Fatty acid oxidation, through effects on AMP-activated protein kinase (AMPK), adiponectin, peroxisome proliferator-activated receptors (PPARs), and mitochondrial function is predominantly altered in alcoholic liver disease, although studies suggest that activation of this pathway may improve nonalcoholic fatty liver disease. Finally, changes in fatty acid export, through effects on apolipoprotein B and microsomal transport protein are seen in both diseases. Thus, the similarities and differences in the mechanism of fat accumulation in the liver in nonalcoholic and alcoholic liver disease are explored in detail.

Is hypothyroidism a risk factor for non-alcoholic steatohepatitis?

Purpose Thyroid hormones play an important role in the regulation of lipid and carbohydrate metabolism, both of which are affected in patients with non-alcoholic steatohepatitis (NASH). Anecdotally, we have observed that a number of patients with NASH carried a diagnosis of hypothyroidism. However, it is unknown if thyroid dysfunction plays any role in the pathogenesis of NASH. To further investigate this observation, we conducted a case-control study to determine the association between hypothyroidism and NASH. Subjects and Methods Cases were defined as patients with well-documented NASH attending hepatology clinics at Indiana University Hospital from January 1, 1995 to December 31, 2000. Age, gender, race, and body-weight matched individuals seen during the same period in the general medical clinics served as controls. Patients with a previous diagnosis of hypothyroidism who are currently on synthetic T4 replacement were considered to be “hypothyroid”. The strength of association was assessed by logistic regression analysis after controlling for the frequency of diabetes mellitus, hyperlipidemia, and hypertension. Results One hundred seventy-four patients with NASH (cases) and 442 controls were included. The mean age of cohort was 49 ± 13 years, 59% were female, and 98% were white. The prevalence of hypothyroidism in patients with NASH was 15% was significantly higher than in the controls (7.2%, P < 0.001). By multivariate analysis, the prevalence of hypothyroidism in the NASH group was significantly higher than in control group (OR: 2.3, 95% CI: 1.2–4.2, P = 0.008). Conclusion These data suggest that hypothyroidism is associated with human NASH. Further research is needed to confirm this finding and to understand its implications.

Etiology of new-onset jaundice: How often is it caused by idiosyncratic drug-induced liver injury in the United States?

BACKGROUND AND AIM:The epidemiology of acute drug-induced liver injury (DILI) in the United States has not been well studied. We conducted a study of adults with new-onset jaundice at a nonreferral community hospital to better understand the epidemiology of acute DILI.METHODS:This is a retrospective study of adult outpatients and inpatients (≥18 yr) with new-onset jaundice over a 5-yr period (1999–2003) at Wishard Memorial Hospital, Indiana. Patients with new-onset jaundice were identified using our electronic medical record system and individual medical records were reviewed to extract the required clinical data. New-onset jaundice was defined as the presence of total serum bilirubin >3 mg/dL in patients without a prior total bilirubin >3 mg/dL.RESULTS:A total of 732 eligible adults constituted our study cohort. Sepsis or altered hemodynamic state resulting in presumed ischemic liver injury is the single most common cause of jaundice (22%). Acute liver disease as a result of nonalcoholic etiologies caused new-onset jaundice in 97 patients (13%), with acute viral hepatitis in 66 patients (9%) and DILI in 29 patients (4%). Most cases of DILI were as a result of acetaminophen toxicity with idiosyncratic DILI occurring in only five patients (0.7%). No mortality was observed at 6 wk in patients who developed idiosyncratic DILI.CONCLUSION:Idiosyncratic DILI appears to be a rare cause of new-onset jaundice in a community hospital setting.

Performance of given suspected blood indicator

OBJECTIVES:Given Imaging (Yoqneam, Israel) has developed a suspected blood indicator (SBI) function for its wireless capsule endoscopy (WCE) software. The SBI detects blood and marks appropriate images for interrogation. The sensitivity and accuracy of SBI and its role in examining WCE studies is unknown. Our aim was to evaluate the accuracy of this new software in detecting small bowel lesions.METHODS:WCE reports of all patients referred for WCE in October and November, 2002, were reviewed. The images from each patient were reviewed by experienced gastroenterologists at 15 frames/s. The findings detected by gastroenterologists were compared to those recognized by SBI. Arteriovenous malformations (AVMs), ulcers, erosions, and sites of active bleeding were considered significant lesions.RESULTS:A total of 24 patients (16 women and eight men, mean age 59 yr) were studied during this period. The indications for the study were iron deficiency anemia in 18 patients and abdominal pain in six patients. A total of 109 lesions were identified by gastroenterologists (47 AVMs, 18 active bleeding ulcers, 18 ulcers without bleeding, and 26 erosions). Active bleeding seen by gastroenterologists was secondary to AVMs (five cases), jejunal ulcers (11 cases, all in the same patient), and gastric ulcers (two cases). A total of 31 potential areas of blood were identified by SBI. When compared to those findings recognized by gastroenterologists, 28 lesions were correctly identified (six AVMs, 13 active bleeding ulcers, (three AVMs and 10 jejunal ulcers), seven nonbleeding ulcers, and two nonbleeding erosions. The overall sensitivity, positive predictive value, and accuracy of SBI to detect significant small bowel lesions were 25.7%, 90%, and 34.8%, respectively. If only actively bleeding lesions in the small bowel were considered, SBI had sensitivity, positive predictive value, and accuracy of 81.2%, 81.3%, and 83.3%, respectively.CONCLUSIONS:SBI has good sensitivity and positive predictive value for actively bleeding lesions in the small bowel. Complete review of the study by the physician is still needed. SBI should be considered as a complementary and rapid screening tool for gastroenterologists to identify actively bleeding lesions.

Alcohol and lipid metabolism

Hepatic lipid metabolism is controlled by several master transcription factors, in particular peroxisome proliferator‐activated receptor‐α (PPAR‐α) and sterol response element binding protein‐1 (SREBP‐1). Peroxisome proliferator‐activated receptor‐α is a receptor for free fatty acids (FFA), and can activate genes involved in transport, oxidation, and export of FFA. Sterol response element binding protein‐1 is a sensor for the level of cholesterol in the liver, and is able to activate genes involved in synthesis of cholesterol and FFA. Chronic ethanol treatment of cells or animals inhibited PPAR‐α function and activated SREBP. In addition, ethanol inhibited adenosine monophosphate‐dependent protein kinase (AMPK). The AMPK controls fatty acid metabolism by inhibiting acetyl‐coenzyme A carboxylase, reducing malonyl‐coenzyme A, and thereby permitting fatty acid transport into and oxidation in the mitochondrion. Adenosine monophosphate‐dependent protein kinase was inhibited in alcohol‐treated animals and cells. The mechanisms by which ethanol affects AMPK and the transcription factors are as yet incompletely understood.