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Idiopathic adulthood ductopenia (IAD) is a chronic small duct cholestatic biliary disease that is characterized by the loss of interlobular bile ducts. It is diagnosed when there is biochemical evidence of cholestatic liver disease, ductopenia on liver biopsy, and no other identifiable cause of cholestasis. We present a patient with 10 days of progressive abdominal pain, jaundice, and worsening liver function tests who advanced to fulminant liver failure with no apparent underlying cause. He was found to have cirrhosis, with biopsy demonstrative of ductopenia, consistent with idiopathic adulthood ductopenia, which is a rare etiology of cirrhosis but should be considered when the typical workup yields no answer.

Right heart catheterizations (RHC) are often performed prior to liver transplantation (LT) to rule out significant portopulmonary hypertension. Many times, elevated left heart filling pressures are found consistent with Heart Failure with Preserved Ejection Fraction (HFpEF). Pre-transplant HFpEF has

Background & Aims Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. Methods We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. Results Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. Conclusions In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov , Number: NCT03092375 .

Context Little systematic research has been conducted to understand pain among persons with end-stage liver disease, especially among liver transplant candidates. Appropriate pain assessment and management are important areas of consideration as treatment options are limited. Objective To describe the nature of chronic pain in patients with end-stage liver disease, the extent to which pain affects daily level of functioning, and the variety and effectiveness of current treatments. Design Retrospective chart review. Setting Academic medical center in the Southeastern United States. Patients Data were collected from 108 consecutive adult liver transplant candidates. Results Most (77%) reported having experienced moderate levels of bodily pain within the past 24 hours. Patients with only alcoholic cirrhosis reported less pain than patients with cirrhosis due to other causes (alcoholism and hepatitis C, nonalcoholic steatohepatitis, only hepatitis C). Pain interfered significantly across all 10 functional domains assessed. Although 90% reported being prescribed a variety of analgesic agents (most commonly short-acting opioids), patients reported experiencing only 33% pain relief. Conclusions Pain is a significant problem among liver transplant candidates, and current pain treatments are perceived to be relatively ineffective. Increased understanding is needed to safely and effectively evaluate and treat such medically complicated patients.

Standard esophagogastroduodenoscopy (EGD) is costly and uses conscious sedation that cirrhotic patients may tolerate poorly. This study aimed to determine the feasibility and acceptance of unsedated esophagoscopy with an ultrathin battery-powered endoscope (BPE) in cirrhotic patients for diagnosing esophageal varices (EV).We first studied the prevalence of significant gastroduodenal pathology that could be missed if only esophagoscopy were performed in cirrhotic patients undergoing liver transplant evaluation. A prospective study was then done to evaluate a BPE in EV screening. Unsedated per-oral endoscopy was first done by a single endoscopist using a BPE, followed by EGD by a second endoscopist who was masked to the BPE result. A visual analog score was used to determine patient tolerance. Patients were asked about their preference for endoscopy in the future. A paired Student t test and the kappa statistic were used in the statistical analysis.In the retrospective study, 199 patients were reviewed; three patients (1.5%) had gastric ulcers, and two patients (1%) had duodenal ulcers. In the prospective study, 28 cirrhotic patients (16 women) were evaluated. EV were diagnosed in 14 patients with a BPE, and 13 were confirmed by standard EGD (sensitivity and negative predictive value 100%, specificity and positive predictive value 93%, kappa = 0.93). EV were graded as large in one and small in 13 patients with a BPE, but small varices diagnosed in one patient were not confirmed on EGD. Both procedures were well tolerated by all patients. Twenty-seven of 28 patients preferred unsedated endoscopy with a BPE over EGD.Unsedated endoscopy with a BPE is safe and well tolerated. The diagnostic accuracy of a BPE for diagnosing EV is the same as by EGD. Esophagoscopy with a BPE is a potential alternative to EGD for EV screening.

Therapy for veno-occlusive disease of the liver (VOD) occurring after bone marrow transplantation should be directed at those with moderate or severe disease who will not recover on their own. Thrombolytic therapy may have a role in severe VOD as long as there is no renal or lung impairment. However, the risk of bleeding complications, including the risk of cerebral hemorrhage, must be considered in these patients. Defibrotide has shown promise for treatment of severe VOD but is not yet widely available in the United States. Therapy directed at reducing portal hypertension such as transjugular intrahepatic portosystemic shunts helps reduce ascites but has no effect on mortality. Liver transplantation has been reported but should be considered only in patients with severe liver failure who would have a good outcome in the absence of liver disease or have undergone bone marrow transplantation for benign disease. The most important advances in VOD has been in the prevention of this syndrome by recognizing the risk factors for it and changes in conditioning regimens before bone marrow transplantation.

OBJECTIVE: The aim of this study is to report the clinical response observed in a U.S. veteran population with hepatitis C to combination therapy with Rebetron (interferon/ribavirin) outside of a controlled study environment. METHODS: Ninety-nine consecutive patients with hepatitis C who met the approved guidelines for treatment were offered treatment with Rebetron. Ninety-four patients initiated therapy. All patients received formal instruction on the use of the drug, as well as the side effects and were instructed to report any side effects. Follow-up was scheduled twice a month for the first month, then monthly unless adverse events were observed. RESULTS: Ninety-four of 99 patients initiated therapy. Thirty-two patients were lost to follow-up or did not tolerate therapy. Ethnic distribution comprised 56 whites, 42 African Americans, one Hispanic. Of the 56 whites who started therapy, 39 completed treatment. Sustained viral response (SVR) for all genotypes was observed in 10 of 39 (26%). In the African American patients, 22 of 42 (52%) completed therapy, but a SVR was noted in none. The only Hispanic patient did not respond to therapy. In the veteran population, favorable factors associated with achieving SVR included having genotype other than 1, absence of cirrhosis, and ethnicity. Factors contributing to the low response rates were difficulty in adhering to therapy as well as a predominance of genotype 1. CONCLUSIONS: Using an intention-to-treat analysis, only 10% of veterans achieved SVR. These findings highlight the need to develop a multidisciplinary team to address the complexity of treating the veteran patient with hepatitis C.

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.

Hepatic Splenosis Masquerading as Hepatocellular Carcinoma in a Chronic Hepatitis C Patient

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.

Immunodeficiency-associated lymphoproliferative disorders (ILDs) are well-described entities that occur in the setting of organ transplant, bone marrow transplant, and congenital or acquired immunodeficiency [1,2]. The latest World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues [3] defines a subset of "other iatrogenic ILDs", composed mostly of lymphoproliferations occurring in the setting of patients receiving immunosuppressive therapy (particularly methotrexate or anti-TNF (tumor necrosis factor) agents) for autoimmune diseases or conditions other than in the transplant setting such as rheumatoid arthritis [4―9] or inflammatory bowel disease [10]. The role of Epstein-Barr virus (EBV) in ILDs is well characterized and the EBV-positive ILDs have a better prognosis than their EBV negative counterparts [9]. Among the morphologic variants of iatrogenic ILDs are classical Hodgkin lymphoma (cHL) and Hodgkin-like lymphoproliferations resembling cHL. These are rare entities with very few cases reported in the medical literature [4,8,11,12]. We report a case of EBV-positive ILD of the Hodgkin-like variant in a patient on long-term mycophenolate mofetil (MMF) for autoimmune hepatitis. Our patient had a complete response after withdrawal of immunosuppression and treatment with rituximab. As many of these cases will resolve without cytotoxic chemotherapy, this case highlights the importance of recognizing this clinical entity [4] and distinguishing it from de novo lymphomas.

Mesenteric vein thrombosis is an uncommon manifestation of hypercoagulable states. A case is reported of superior mesenteric vein (SMV) thrombosis in a patient with pancreatitis and protein C deficiency. A discussion of SMV thrombosis identification, management, and outcomes is included. The patient presented with a significant history of alcohol abuse and constant, midepigastric abdominal pain associated with nausea and vomiting. Amylase and lipase were elevated, and the patient was treated for pancreatitis. His symptoms initially responded to intravenous fluid hydration, but soon his clinical picture worsened, with increased nausea and vomiting, abdominal pain, and distension. Contrasted computed tomography of the abdomen revealed SMV thrombosis. A hypercoagulable workup revealed protein C deficiency. After a 3-month course of oral anticoagulant therapy, the SMV thrombosis resolved.

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.

Aims: Hair ethyl glucuronide (EtG) is a promising biomarker of moderate-to-heavy alcohol consumption and may have utility in detecting and monitoring alcohol use in clinical populations where alcohol use is of particular importance. This study evaluated the relationship between hair EtG and drinking in patients with liver disease. Methods: The subjects (n = 200) were patients with liver disease who presented for care at a university medical center. Alcohol use during the 3 months preceding participation in the study was assessed, and a sample of hair was obtained for EtG testing. Classification of drinking status (any drinking or averaging at least 28 g per day) by hair EtG was evaluated, as well as the effects of liver disease severity and demographic and hair care factors. Results: The area under the receiver operating characteristic curve for detecting an average of 28 g or more per day during the prior 90 days was 0.93. The corresponding sensitivity and specificity of hair EtG ≥8 pg/mg for averaging at least 28 g of ethanol per day were 92 and 87%, respectively. Cirrhosis and gender may have a modest influence on the relationship between drinking and hair EtG. Conclusion: Hair EtG was highly accurate in differentiating subjects with liver disease averaging at least 28 g of ethanol per day from abstainers and lighter drinkers.

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.

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.

Background & Aims: Alpha1-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.

Introduction: Biliary tract leaks occur in up to 26% of patients undergoing choledocho-choledochostomy (CDCD) during lever transplantation (OLT), but there is no consensus on optimum treatment. Surgical repair, radiological drainage, endoscopic biliary sphincterotomy, nasobiliary drain placement and trans-papillary stenting have been used with success, but the role of ERCP with placement of a "leak bridging" stent has not been well examined. Aim: To assess biliary stent placement across the leak site as a primary treatment for post OLT biliary disruption. Methods: 292 OLT's were performed between Oct 1990 and Oct 1999, 215 with CDCD anastomosis. 32 CDCD cases (15%) were complicated by biliary leaks, of which 6 underwent primary surgical repair. The remaining 26 patients (median age 47; range 29-69; 19 male) were treated endoscopically. Results: The median time from OLT to ERCP was 43 days (range 10-193). 11 patients had related symptoms (fever, abdominal pain, clinically evident jaundice) and 19 had abnormal liver biochemistry. Endoscopic retrograde cholangiography was successfully performed in all cases. The leak was situated at the anastomosis in 11 cases, T-tube site in 11, donor cystic duct in 2 and at both anastomosis and cystic duct in 2 cases. 6 patients had had a T-tube removed within the previous 48 hours. Primary treatment was with stenting (7fr-11.5fr) to bridge the leak in 24 cases (92%), papillary stenting alone in 1 and nasobiliary tube placement in 1. Initial treatment was successful in 23 cases (91%), but unsucessful in 3 cases (2 cases with leak-bridging stents and the single patient with a transpapillary stent). 4 patients died during follow-up, all from unrelated causes. Conclusion. ERCP with placement of a leak bridging stent has a high success rate in the treatment of post OLT cystic duct, T-tube and anastomotic biliary leaks.

TO THE EDITOR: Sensorimotor demyelinating polyradiculoneuropathy is a rare complication in liver transplant (LT) patients taking tacrolimus (1, 2). The following case illustrates that cyclosporin neurotoxicity may also present as sensorimotor demyelinating polyradiculoneuropathy despite therapeutic blood levels, and masquerade as diabetic polyneuropathy.

Memphis and Shelby County, Tennessee, experienced an epidemic of hepatitis A in 1994 and 1995. More than 1700 cases were reported.To characterize the clinical features of patients hospitalized during a large urban epidemic of hepatitis A.Retrospective chart review.15 acute care hospitals in Shelby County, Tennessee.256 patients hospitalized with acute hepatitis A.Laboratory findings (such as prothrombin time and bilirubin level), complications, and mortality.The median patient age was 26 years. Thirty-nine complications occurred in 35 patients. Twenty patients (8%) had extrahepatic complications, and 5 (2%) died. Patients 40 years of age and older were more likely to have serious complications, including death (P = 0.014). Sixty-seven patients (26%) presented with coagulopathy (prothrombin timeor = 3 seconds prolonged). Fifty-four patients (21%) had a bilirubin level greater than 170 micromol/L (10 mg/dL).During this epidemic, hepatitis A caused serious illness and death. Complications were more frequent in patients 40 years of age and older, but young, healthy persons were also at risk for severe complications.