Ira R. Willner

Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.

OBJECTIVE:Nonalcoholic steatohepatitis (NASH) is a common but poorly understood liver disease. Our aim was to study a large group of patients referred for Hepatology consultation to further characterize this disorder, in particular its demographics and range of severity. We also sought to better understand its etiology and its relationship to the insulin resistance syndrome, known as the metabolic syndrome or syndrome X.METHODS:Retrospective review of 90 patients seen over a 4-yr period.RESULTS:Ninety patients aged 14–70 with NASH seen at the Liver Clinics at either the University of Tennessee or the Medical University of South Carolina. Eleven had complications of portal hypertension and seven of these had undergone or were awaiting transplantation. NASH was seen in nine families either in siblings or in subsequent generations. Diabetes or insulin resistance were present in almost all in this cohort of patients with NASH. Diabetes, hyperlipidemia, hypertension, and atherosclerotic disease, the components of syndrome X, were common in this population.CONCLUSION:NASH affects males and females equally, and presents over a wide age range. Despite its usually benign course, 28% of patients had cirrhosis and almost half of those had complications of portal hypertension, necessitating liver transplantation. Obesity was common in affected patients and cirrhosis was more common in the morbidly obese. Familial clustering was common, with 18% of patients having a similarly affected first degree relative. The clinical features that define syndrome X (diabetes, hypertension, hyperlipidemia, and atherosclerotic disease) are common in affected patients. Studies of glucose tolerance demonstrated unsuspected diabetes in six, and insulin resistance (the hallmark of syndrome X) in 85% of those tested. We hypothesize that NASH is a disorder of genetic etiology and is the hepatic manifestation of syndrome X, the insulin resistance syndrome.

Serious hepatitis A : an analysis of patients hospitalized during an urban epidemic in the United States

An effective vaccine for the hepatitis A virus (HAV) is now available, but the recommended indications for its use remain limited [1]. The Memphis, Tennessee, metropolitan area is experiencing an epidemic of hepatitis A. Memphis and Shelby County have a population of approximately 830 000 persons, 50% of whom are African American. For each year from 1989 to 1993, an average of 57 cases of hepatitis A were reported, but 210 cases were reported in 1994 and 1538 cases were reported in 1995 [2]. Neighboring counties in Mississippi and Arkansas noted similar increases [3]. This epidemic has not been associated with a common food source or a breakdown in public sanitation. Few recent urban epidemics of hepatitis A in industrialized countries have not been traced to a common source [4]. We present an analysis of the clinical features of patients hospitalized during this epidemic. Methods The computerized medical records of the 15 acute care hospitals (2 of which are pediatric hospitals) in Shelby County were queried for the discharge diagnosis of acute hepatitis A (International Classification of Diseases, Ninth Revision [ICD-9] codes 070.1 [acute hepatitis A without coma] and 070.0 [acute hepatitis A with coma]) for the study period of 1 January 1994 through 31 December 1995. The paper charts for the retrieved patient names were reviewed by five of the authors, who used a standardized form to record demographic data, epidemiologic risk factors, reasons for hospitalization, underlying medical conditions, and serious complications. A diagnosis of acute hepatitis A required positivity for HAV IgM antibody in conjunction with compatible symptoms and laboratory findings. We sought information on the following risk factors for transmission of HAV: exposure to day care, household contact, association with a restaurant, being a homosexual man, occupational exposure, hemophilia, active use of injection drugs, travel to areas in which hepatitis A is endemic, consumption of raw shellfish, and unknown. We also sought information on underlying medical conditions, including chronic liver disease, significant alcohol consumption (>50 g/d for >5 years), HIV infection, cardiovascular disease, underlying cancer, chronic immunosuppression, and diabetes. Complications sought included acalculous cholecystitis, hemolysis, autoimmune hepatitis (antinuclear antibody titer > 1:160 or positive smooth-muscle antibody titer > 1:80 and compatible liver biopsy findings), pancreatitis, prolonged cholestasis (serum bilirubin level > 136 mol/L [8 mg/dL] for >12 weeks), and relapsing hepatitis. If two or more unrelated complications were present, they were all recorded. If a complication was caused by an underlying condition (for example, acute renal failure in a patient with fulminant hepatitis), only the underlying complication was recorded. Any unanticipated complication that was encountered during chart review was recorded. This study was approved by the institutional review board of the University of Tennessee. The Fisher exact test was used to analyze the data. Statistical significance was defined as a P value less than 0.05. Results We identified 313 patients and reviewed their charts. Fifty charts were excluded because patients lacked documented HAV IgM antibody. Four charts could not be retrieved. Three patients who were seen in two hospitals were not counted twice. The remaining 256 charts belonged to patients who met the criteria for hepatitis A. Demographic data for the study patients are shown in Table 1. Two hundred thirty-one patients were residents of Shelby County, and 25 were from surrounding communities. Table 1. Characteristics of Hospitalized Patients with Hepatitis A* The source of hepatitis A was identified in only 21% of patients (Table 1). The two restaurant-associated cases were from a large outbreak in Arkansas. On admission, 89% of patients had prolonged nausea or vomiting, or both; 26% had coagulopathy (prothrombin time 3 seconds prolonged); 21% had marked jaundice (bilirubin level > 170 mol/L [10 mg/dL]); and 18% had abdominal pain. Preexisting underlying disease alone or in combination was present in 17% of patients; this was alcoholism in 24 patients (9%), diabetes in 16 (6%), chronic hepatitis B or C in 10 (4%), and HIV infection in 4 (2%). No association was seen between the presence of underlying disease and the occurrence of a serious complication (P > 0.2). The clinical complications encountered are shown in Table 2. Thirty-five patients (14%) had 39 serious complications; 20 of these complications were extra-hepatic and 19 were hepatobiliary. Most were present on admission or were evident within 2 days after admission. Twenty-five percent of patients 40 years of age or older and 11% of patients younger than 40 years of age had at least one complication (P = 0.014). Of the 35 patients with serious complications, only 2 (5.7%) would have been advised to receive vaccine under current guidelines (1 had chronic hepatitis C and 1 was an active user of injection drugs) [1]. Table 2. Complications of Hepatitis A by Age Ten patients had findings consistent with acalculous cholecystitis, but none required cholecystectomy. Three patients had prolonged cholestasis with jaundice lasting up to 20 weeks. A 3-year-old child presented with hypoglycemia, hyperammonemia, and mental status changes that resolved with supportive treatment. Ten patients had evidence of hemolysis and 3 patients had acute renal failure; 2 of the 3 required hemodialysis but recovered. Four patients were known to be pregnant. Two of the 4 presented in the first trimester, and the other 2 presented in the third trimester and had preterm labor with premature delivery. Both mothers and babies recovered. Two patients presented with new-onset diabetes with ketoacidosis. A 14-year-old girl developed pericardial and pleural effusions that required pericardiocentesis for cardiac tamponade. Five patients died (Table 2). Two of the five died of complications of fulminant hepatic failure; one was awaiting liver transplantation at the time of death. This 28-year-old man developed hepatic coma within 72 hours and herniated from refractory increased intracranial pressure. The other patient who died of complications of fulminant hepatic failure was a 23-year-old man who developed the adult respiratory distress syndrome and died of cardiac arrest. Two patients had prolonged illness with antinuclear antibody titers greater than 1:640 and liver biopsy results consistent with autoimmune hepatitis. Neither of these patients was known to have previous liver disease. One improved clinically while receiving prednisone and azathioprine but died of infectious complications. The other died of gastrointestinal hemorrhage, liver failure, and increased intracranial pressure before immunosuppressive therapy was started. One patient with chronic hepatitis C and a history of ethanol abuse died of progressive liver failure. Three of the 53 patients (5.7%) 40 years of age and older and 2 of the 203 patients (1%) younger than 40 years of age died (P = 0.062). Discussion Hepatitis A is usually self-limited, and full recovery is seen by 3 months in 85% of cases [5]. Previous reports have shown a case-fatality rate of only 0.01% to 0.03% [6] but an increased risk for death with age [7]. Risk for death is also increased in patients with chronic liver diseases [8]. The financial burden of hepatitis A on the U.S. health care system is substantial [9]; the estimated cost of a recent outbreak of 43 cases was

Prediction of esophageal varices in Patients with cirrhosis

809 706 [10]. The median age of the patients who died in our series was 40 years. Of the five patients who died, only one had evidence of chronic liver disease. Complications were more common in patients 40 years of age and older, and mortality rates also seemed to be higher in this group. However, two patients younger than 30 years of age died. Some patients with hepatitis A had unexpected clinical manifestations. Extrahepatic complications occurred in 8% of our patients. Acalculous cholecystitis, hemolysis, acute renal failure, and reactive arthritis have been reported [11-13]. Unusual extrahepatic manifestations included new-onset diabetes, preterm labor, and pericardial and pleural effusions. We identified two cases of autoimmune hepatitis associated with acute hepatitis A, and at least four similar cases have been reported [14]. The hepatitis A virus may serve as a trigger for autoimmune hepatitis in genetically susceptible persons, a phenomenon that has been reported after rubeola and Epstein-Barr virus infection [15, 16]. Between 1983 and 1992, the Viral Hepatitis Surveillance Program did not identify risk factors for HAV transmission in 40% of cases [17, 18]. We were unable to identify risk factors for transmission in 79% of patients; this points out a limitation of retrospective studies. In addition, study patients were hospitalized at 15 institutions and were cared for by multiple physicians, and the admission history was not uniform. For example, patients who had exposure to asymptomatic children with hepatitis A would not have been documented. The studies performed during hospitalization were not standardized, and some complications may have been overlooked, making our estimates imprecise. Biases related to which patients sought medical care and which physicians chose to hospitalize them may limit the generalizability of our findings. We were unable to assess patients who were not hospitalized. Immunity to hepatitis A approaches 100% in young adults in developing countries. In contrast, immunity in the United States is low: 38% overall, 11% in persons younger than 5 years of age, and 74% in persons older than 50 years of age [19, 20]. A substantial segment of the U.S. adult population is therefore susceptible to HAV infection, setting the stage for large-scale urban outbreaks. This is exemplified by a recent epidemic in Shanghai that affected more than 300 000 persons and caused

Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency

Goals To identify predictors of esophageal varices (EV) using available clinical, laboratory, and diagnostic imaging variables. Background Patients with cirrhosis frequently undergo screening endoscopy for varices so that prophylactic therapy and/or follow up can be planned. It is unclear how often patients should be screened endoscopically for varices, and there are few data on the relationship of varices to nonendoscopic variables. Study Charts were reviewed for 247 consecutive patients with cirrhosis who underwent screening esophagogastroduodenoscopy for varices. Results A total of 184 patients (68 women) were studied. Ninety-four patients (51%) had varices; of whom, 90 had only EV (small, n = 66; large, n = 24), 13 had EV and gastric varices, and 4 had isolated gastric varices. The distribution of EV according to the Child–Turcotte–Pugh class was as follows: A, 35%; B, 60%; and C, 69%, with roughly equal prevalence of large varices (29%, 24%, and 24%, respectively) in each class. Independent predictors of large varices were thrombocytopenia (p = 0.02) and splenomegaly (p = 0.04) seen using imaging. A platelet count of less than 68,000/mm 3 had the highest discriminative value for large EV with a sensitivity of 71% and a specificity of 73%. Splenomegaly had sensitivity and specificity of 75% and 58%, respectively. Using these two variables, we placed patients into one of four groups, with a risk for large varices ranging from 4% to 34%. Conclusions The prevalence of EV in cirrhosis increases with the severity of liver disease, as expected. Thrombocytopenia and splenomegaly are independent predictors of large EV in cirrhosis. Further prospective studies might result in a discriminating algorithm to predict which patients with cirrhosis would benefit from early or regular endoscopy to detect clinically significant varices.

VALIDATION OF BLOOD PHOSPHATIDYLETHANOL AS AN ALCOHOL CONSUMPTION BIOMARKER IN PATIENTS WITH CHRONIC LIVER DISEASE

BACKGROUND & AIMS Alpha 1 -antitrypsin deficiency (AAT) is an autosomal recessive disease that affects 1 in 2500 persons and might lead to cirrhosis. Our study aim was to characterize the liver disease in AAT and identify factors associated with advanced liver disease. METHODS A cohort of the Alpha-1 Foundation Registry who reported liver disease was surveyed with a liver disease questionnaire to obtain information related to liver disease, liver transplantation, and AAT phenotype. RESULTS One hundred sixty-five of the 2175 participants in the registry reported a history of jaundice or liver disease, and 139 (84.2%) completed the questionnaire. Of these, 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% did not know their phenotype. Analysis of 104 participants with a known age of diagnosis included 30 participants diagnosed with liver disease before 18 years, of whom 15 had advanced liver disease defined as liver transplantation or listed for liver transplantation. No differences in age, age at diagnosis, gender, race, phenotype, or infant jaundice were identified. Seventy-four participants were diagnosed after age 18 years, of whom 25 had advanced liver disease. In this group, advanced liver disease was associated with male gender ( P = .006) and a greater mean body mass index ( P = .01), but not with race, Pi phenotype, infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequently reported in the nontransplant group (34.7% vs 8.0%, P = .01), and the mean daily alcohol use was significantly greater in this group ( P = .04). CONCLUSIONS Our results suggest that male gender and obesity but not alcohol or viral hepatitis predispose to advanced liver disease in adults with AAT.

Posttransplantation Lymphoproliferative Disorder—The Great Mimic in Liver Transplantation: Appraisal of the Clinicopathologic Spectrum and the Role of Epstein-Barr Virus

BACKGROUND Blood phosphatidylethanol (PEth) is a promising biomarker of alcohol consumption. This study was conducted to evaluate its performance in patients with liver disease. METHODS This study included 222 patients with liver disease. Patient-reported alcohol use was obtained as a reference standard, and PEth was measured by tandem mass spectrometry. Receiver operating characteristic (ROC) and contingency table analyses were used to assess the performance of PEth in detecting any drinking and averaging 4 or more drinks daily in the past 30 days. RESULTS At the limit of quantitation (20 ng/ml), PEth was 73% sensitive (95% confidence interval [CI] 65 to 80) and 96% specific (95% CI 92 to 100) for any drinking in the past month. Subjects who drank but had a negative PEth result were mainly light drinkers. Subjects who reported 30-day abstinence but with quantifiable PEth either reported heavy drinking within the past 6 weeks or had data that suggested underreported drinking. At the optimal cutoff concentration of 80 ng/ml, PEth was 91% sensitive (95% CI 82 to 100) and 77% specific (95% CI 70 to 83) for averaging at least 4 drinks daily. CONCLUSIONS PEth is a useful test for detecting alcohol use in patients with liver disease, but cutoff concentrations for heavy drinking will result in misclassification of some moderate to heavy drinkers.

The decision-making value of magnetic resonance cholangiopancreatography in patients seen in a referral center for suspected biliary and pancreatic disease

Case series describing posttransplantation lymphoproliferative disorder (PTLD) after liver transplantation (LTx) have been limited in number because of the rarity of the disorder. The prevalence of Epstein‐Barr virus (EBV) infection and its detection, the clinical and histological diversity of disease, and survival have varied. The aim of this study is to define the clinical and pathological spectrum of PTLD after LTx, and evaluate EBV prevalence, impact of infection, and patient survival. A retrospective analysis of all LTx recipients at our institution diagnosed with PTLD from January 1990 until May 2005, recording clinical presentations, times of presentation after transplantation, histological findings, results of EBV assessment, and survival, as well as the interrelationship of these variables. Among 621 LTx recipients were 22 cases of PTLD in 21 patients, of whom 5 were children and 16 were adults. Extranodal disease was present in 17 of 22 cases (77%) involving a wide variety of organ systems, while 5/22 (23%) had lymphadenopathy. The spectrum of PTLD histopathology was equally varied. In situ hybridization for EBV showed negativity in 8 of 13 (62%) and positivity in 5 of 13 (38%) cases tested. Neither time interval from transplantation to presentation (median 33 months) nor mortality (average 32%) was influenced by EBV status. In conclusion, PTLD in LTx recipients is predominantly extranodal and can involve a wide variety of organ systems, which may confound initial diagnosis. The lymphoproliferative histological spectrum is also diverse. Nowadays, PTLD is frequently EBV‐negative, and EBV status does not appear to influence clinical or pathological presentation, or survival. Liver Transpl 13:904–912, 2007.

SENSITIVITY AND SPECIFICITY OF URINARY ETHYL GLUCURONIDE AND ETHYL SULFATE IN LIVER DISEASE PATIENTS

Abstract OBJECTIVE: To assess the ability of MRCP to alter the differential diagnosis and to prevent diagnostic and/or therapeutic ERCP. The diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) for biliary and pancreatic disease is well documented. Some believe MRCP may prevent diagnostic ERCP or add useful information, however there are no reports of its impact on clinical management. METHODS: Consecutive patients referred for ERCP underwent clinic evaluation, then MRCP, and then ERCP. In Phase 1, the number of differential diagnoses and the perceived need for diagnostic ERCP were evaluated after each step by the endoscopist who performed the ERCP. In Phase 2, the process was repeated after presenting clinical information and MRCP results to different individual physicians: another endoscopist, a hepatologist, a radiologist, and a surgeon (all were blinded to ERCP results). RESULTS: Forty patients were enrolled. Clinical contexts were jaundice (19.7%), abnormal liver enzymes (42.6%), abdominal pain (11.5%), recurrent acute pancreatitis (11.5%), and suspected complications of chronic pancreatitis (14.7%). In Phase 1, adding MRCP information to diagnostic ERCP information did not change the mean number of differential diagnoses significantly and prevented no therapeutic ERCP. In Phase 2, adding MRCP to clinical information only (without ERCP) reduced the differential diagnosis significantly for the radiologist and the surgeon only and would have prevented ≤3% of diagnostic and therapeutic ERCP for all physicians. CONCLUSION: The value of MRCP information may be limited if patient selection is inappropriate and may differ in physicians depending on their speciality.

A fistula from the portal vein to the bile duct: an unusual complication of transjugular intrahepatic portosystemic shunt

BACKGROUND It is important to monitor alcohol use in the care of patients with liver disease, but patient self-report can be unreliable. We therefore evaluated the performance of urine ethyl glucuronide (EtG) and ethyl sulfate (EtS) in detecting alcohol use in the days preceding a clinical encounter. METHODS Subjects (n = 120) were recruited at a university-based hepatology clinic or during hospitalization. Alcohol consumption was ascertained by validated self-report measures. Urine EtG (cutoff 100 ng/ml) and EtS (cutoff 25 ng/ml) concentrations were assayed by a contracted laboratory using tandem mass spectrometry. The sensitivity and specificity of each biomarker in the detection of drinking during the 3 and 7 days preceding the clinic visit were determined, as well as the influence of liver disease severity on these results. RESULTS Urine EtG (sensitivity 76%, specificity 93%) and urine EtS (sensitivity 82%, specificity 86%) performed well in identifying recent drinking, and liver disease severity does not affect biomarker performance. After elimination of 1 false-negative self-report, urine EtG > 100 ng/ml was 100% specific for drinking within the past week, whereas 9% of the subjects without evidence of alcohol drinking for at least 1 week had EtS > 25 ng/ml. CONCLUSIONS Urine EtG and EtS can objectively supplement the detection of recent alcohol use in patients with liver disease. Additional research may determine optimal methods for integrating these tests into clinical care.

Prospective evaluation of a 3.1-mm battery-powered esophagoscope in screening for esophageal varices in cirrhotic patients.

We describe a case of a portal vein bile duct fistula as a complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. The patients course was complicated by endocarditis, hemobilia, recurrent episodes of fever, and bacteremia, followed by liver transplant. The findings of fever, bacteremia (especially with Gram-negative organisms), and a decreased hematocrit after shunt placement should raise the suspicion of an infected shunt with a possible fistula.