IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. APPROACH AND RESULTS: Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. CONCLUSIONS: A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.

Alcoholic Hepatitis: Risk Factors, Pathogenesis, and Approach to Treatment.

BACKGROUND: Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. METHODS: This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel therapies for AH. RESULTS: The pathogenesis and treatment of AH remain areas of active research. Although abstinence is the cornerstone of therapy for all stages of alcoholic liver disease, corticosteroids have shown modest short-term benefits in treatment of severe AH. CONCLUSIONS: Improved understanding of the pathogenesis of AH has expanded the range of potential treatments for this devastating disease. Several novel therapies are also currently in various stages of testing through clinical trials.

Elevated ammonia concentrations: potential for pre-analytical and analytical contributing factors.

BACKGROUND: No study has explored the separate contributions of pre-analytical and analytical factors to hyperammonemia. METHODS: Laboratory information systems were queried for tests of ammonia concentrations over a 12 month period. Pre-analytic (collection to laboratory receipt) and analytic (laboratory receipt to result) elapsed times were determined. RESULTS: Under routine conditions for 3626 tests, normal and elevated results were similarly distributed if the time from venipuncture to result was <120 min. Delays, during analysis performance and in transportation to the laboratory, potentially contributed to hyperammonemia in a small number of samples (n=96, 2.7%). Similar results were obtained from a second hospital with a separate laboratory. CONCLUSIONS: Delays, in either transportation to the laboratory after collection or before completion of analysis, have the potential to elevate ammonia concentrations and may cause pseudo-hyperammonemia. Unexpectedly elevated ammonia concentrations need to be evaluated for errors in sampling handling.

Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial.

IMPORTANCE: Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades. OBJECTIVE: To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose. DESIGN, SETTING, AND PARTICIPANTS: The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE. INTERVENTIONS: Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization. MAIN OUTCOMES AND MEASURES: The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay. RESULTS: A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related. CONCLUSIONS AND RELEVANCE: PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01283152.

Establishing, harmonizing and analyzing critical values in a large academic health center.

BACKGROUND: No report on establishing critical values (CVs) lists has described a process for harmonizing different lists in a large academic health center or validation on follow-up after 5 years. METHODS: A definition of a critical value was adopted. CVs in use and reporting times for chemistry, hematology and coagulation (CH&C) tests during a 1-week period at one hospital were analyzed prior to the revision and again 5 years later. RESULTS: CVs lists in use by the different campus hospital laboratories were reviewed for compliance with the definition for a critical value. Lists were harmonized with a total of 37 CH&C tests, five of these included adult and either cord blood or neonatal values. Overall, 26 tests were eliminated, 61 individual values were changed and two tests were added. The revised CVs list reduced the number of calls at one primary teaching hospital by 33%. In the next 5-year period, value thresholds changed (n=2) and one value was re-instated (n=1). When retrospectively examined for impact, one value change was considered appropriate. CONCLUSIONS: CVs lists were harmonized among campus hospitals. Tests not considered critical were removed and values adjusted for uniformity. Changes in CVs lists should be evaluated for appropriateness. A process is now in place for periodic review and considerations related to CVs lists.

Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.

BACKGROUND: No study has evaluated current scoring systems for their accuracy in predicting short and long-term outcome of alcoholic hepatitis in a US population. METHODS: We reviewed electronic records for patients with alcoholic liver disease (ALD) admitted to Parkland Memorial Hospital between January 2002 and August 2005. Data and outcomes for 148 of 1,761 admissions meeting pre-defined criteria were collected. The discriminant function (DF) was revised (INRdf) to account for changes in prothrombin time reagents that could potentially affect identification of risk using the previous DF threshold of >32. Admission and theoretical peak scores were calculated by use of the Model for End-stage Liver Disease (MELD). Analysis models compared five different scoring systems. RESULTS: INRdf was closely correlated with the old DF (r (2) = 0.95). Multivariate analysis of the data showed that survival for 28 days was significantly associated with a scoring system using a combination of age, bilirubin, coagulation status, and creatinine (p < 0.001), and an elevated ammonia result within two days of admission (p = 0.012). When peak values for MELD were included, they were the most significant predictor of short-term mortality (p < 0.001), followed by INRdf (p = 0.006). CONCLUSION: On admission, two scoring systems that identify a subset of patients with severe alcoholic liver disease are able to predict >50 % mortality at four weeks and >80 % mortality at six months without specific treatment.

Long-term benefit of hepatitis C therapy in a safety net hospital system: a cross-sectional study with median 5-year follow-up.

OBJECTIVES: To demonstrate the survival benefit from sustained virological response (SVR) in a safety net hospital population with limited resources for hepatitis C virus (HCV) therapy. DESIGN AND SETTING: We conducted a retrospective study at an urban safety net hospital in the USA. PARTICIPANTS AND INTERVENTION: 242 patients receiving standard HCV therapy between 2001 and 2006. PRIMARY AND SECONDARY OUTCOME MEASURES: Response rates, including SVR, were recorded for each patient. Univariate and multivariate analyses were performed to identify predictors of SVR and 5-year survival. RESULTS: A total of 242 eligible patients were treated. Treatment was completed in 197 (81%) patients, with 43 patients discontinuing therapy early-32 due to adverse events and 11 due to non-compliance. Complications on treatment were frequent, including three deaths. SVR was achieved in 83 patients (34%). On multivariate analysis, independent predictors of a decreased likelihood of achieving SVR included African-American race (OR 0.20, 95% CI 0.07 to 0.54), genotype 1 HCV infection (OR 0.25, 95% CI 0.13 to 0.50) and the presence of cirrhosis (OR 0.26, 95% CI 0.12 to 0.58). Survival was 98% in those achieving SVR (median follow-up 72 months) and 71% in non-responders and those discontinuing therapy (n=91, median known follow-up 65 and 36 months, respectively). On multivariate analysis, the only independent predictor of improved survival was SVR (HR 0.12, 95% CI 0.03 to 0.52). Both cirrhosis and hypoalbuminaemia were independent predictors of increased mortality. CONCLUSIONS: Treatment before histological cirrhosis develops, in combination with careful selection, may improve long-term outcomes without compromising other healthcare endeavours in safety net hospitals and areas with financial limitations.

An automated model using electronic medical record data identifies patients with cirrhosis at high risk for readmission.

BACKGROUND & AIMS: Patients with cirrhosis have 1-month rates of readmission as high as 35%. Early identification of high-risk patients could permit interventions to reduce readmission. The aim of our study was to construct an automated 30-day readmission risk model for cirrhotic patients using electronic medical record (EMR) data available early during hospitalization. METHODS: We identified patients with cirrhosis admitted to a large safety-net hospital from January 2008 through December 2009. A multiple logistic regression model for 30-day rehospitalization was developed using medical and socioeconomic factors available within 48 hours of admission and tested on a validation cohort. Discrimination was assessed using receiver operator characteristic curve analysis. RESULTS: We identified 836 cirrhotic patients with 1291 unique admission encounters. Rehospitalization occurred within 30 days for 27% of patients. Significant predictors of 30-day readmission included the number of address changes in the prior year (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.05-1.21), number of admissions in the prior year (OR, 1.14; 95% CI, 1.05-1.24), Medicaid insurance (OR, 1.53; 95% CI, 1.10-2.13), thrombocytopenia (OR, 0.50; 95% CI, 0.35-0.72), low level of alanine aminotransferase (OR, 2.56; 95% CI, 1.09-6.00), anemia (OR, 1.63; 95% CI, 1.17-2.27), hyponatremia (OR, 1.78; 95% CI, 1.14-2.80), and Model for End-stage Liver Disease score (OR, 1.04; 95% CI, 1.01-1.06). The risk model predicted 30-day readmission, with c-statistics of 0.68 (95% CI, 0.64-0.72) and 0.66 (95% CI, 0.59-0.73) in the derivation and validation cohorts, respectively. CONCLUSIONS: Clinical and social factors available early during admission and extractable from an EMR predicted 30-day readmission in cirrhotic patients with moderate accuracy. Decision support tools that use EMR-automated data are useful for risk stratification of patients with cirrhosis early during hospitalization.

Hemorrhagic ascites. Clinical presentation and outcomes in patients with cirrhosis.

BACKGROUND & AIMS: Hemorrhagic ascites can pose diagnostic and therapeutic dilemmas in patients with cirrhosis. We aimed at exploring the characteristics and outcomes of patients with cirrhosis and hemorrhagic ascites. METHODS: The records of all patients with cirrhosis and ascites, who underwent paracentesis between 2003 and 2010 at Parkland Memorial Hospital, were retrospectively reviewed. Hemorrhagic ascites was defined as an ascitic fluid red blood cell (RBC) count ≥ 10,000/µl. We compared each patient with 3 age- and gender-matched controls (cirrhotic patients with ascites and an ascitic RBC count <10,000/µl). Survival curves were generated using Kaplan-Meier plots and compared using the log rank test. RESULTS: 1113 cirrhotic patients underwent paracentesis; 214 (19%) had hemorrhagic ascites. Patients with hemorrhagic ascites had higher rates of spontaneous bacterial peritonitis (p <0.001), acute kidney injury (AKI, p <0.001), and were more likely to require intensive care unit (ICU)-level care (p=0.01) compared to patients without hemorrhagic ascites. Patients with hemorrhagic ascites had a higher mortality than controls at one month (87% vs. 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%). Using multivariate regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 1.34, 95% CI 1.07-1.68) after adjusting for the model for end-stage liver disease score (HR 1.04, 1.03-1.05), ICU-level care (HR 2.02, 1.63-2.51) and presence of hepatocellular carcinoma (HR 2.27, 1.61-3.19). CONCLUSIONS: Patients with hemorrhagic ascites had a significantly higher rate of ICU care, AKI, and mortality than patients with portal hypertension and ascites but without hemorrhagic ascites. We conclude that hemorrhagic ascites is a marker of advanced liver disease and poor outcome.

Multiple factors contribute to positive results for hepatitis A virus immunoglobulin M antibody.

CONTEXT: In the United States, a successful vaccination program for hepatitis A virus (HAV) infection has decreased both its incidence and the true positive rate for diagnostic immunoglobulin M (IgM) antibody to HAV in acute hepatitis. OBJECTIVE: To survey positive results of HAV IgM tests and determine the effect of changing ordering options. DESIGN: We reviewed all positive results for IgM antibody to HAV between January 2007 and December 2010. Patient demographics, clinical history, and laboratory data were recorded and the encounter, order, and reason for test reviewed. Each result was categorized as indicating acute, recent, resolved, or indeterminate HAV infection. RESULTS: A total of 10,735 tests were performed; 35 patients had 49 positive results. Most positive test results were associated with outpatient visits and were ordered in the assessment of patients with liver disease, but not clinical acute hepatitis. In the final analysis, 4 patients had acute hepatitis A and 20 individual patients had recent and/or resolved hepatitis. All but 1 of the remaining 11 patients had another established cause of liver disease with a positive IgM HAV antibody test result; data to determine causality were insufficient. The total number of tests requested annually decreased more than 35% with the introduction of computerized physician order entry. CONCLUSIONS: Current assays for IgM HAV antibodies are overused in the absence of clinical acute hepatitis; future clinical decision support may improve patterns of order entry. Most patients have findings consistent with HAV exposure but not acute hepatitis; dormant viral infection may be a continuing source of antigen.

Continuous furosemide infusion in the management of ascites.

BACKGROUND: The current therapy for patients hospitalized with ascites requires titration of oral diuretics and often needs several days. A faster method for predicting the response to a given dose of diuretic may allow this process to be completed more rapidly. AIM: The objective of this study was to describe the short-term safety and efficacy of a diuretic infusion to predict net sodium excretion in patients with cirrhosis, ascites, and edema using a fractional excretion of sodium (FENa) of 1% or greater as the target. METHODS: We conducted a retrospective case series of patients admitted for management of ascites who received intravenous furosemide by continuous infusion in ascites management. Patients were stratified depending on whether they had edema or received an intravenous bolus of furosemide or a large-volume paracentesis. The primary outcome was the proportion of patients achieving a FENa of 1% or greater during the infusion. Secondary outcomes included development of electrolyte abnormalities or acute kidney injury during or immediately following the infusion and natriuresis on titrated oral furosemide. RESULTS: Forty-seven patients meeting criteria were identified from 721 patients seen in consultation. Ten of the patients had edema and received neither bolus intravenous diuretic therapy nor therapeutic paracentesis; all 10 achieved a FENa of 1% or greater. One patient had transient hypokalemia. Of 37 patients who either had no edema or received additional treatment options, all but 6 patients achieved a FENa of 1% or greater. Transient complications in 31 patients with natriuresis included hyponatremia (n = 1), hypokalemia (n = 5), and acute kidney injury (n = 3). Twenty-four-hour urine sodium averaged more than 4 g/d on the titrated oral furosemide regimen in 19 patients completing the collection. CONCLUSIONS: Use of a short continuous furosemide infusion can achieve a FENa of 1% or greater in patients with cirrhotic ascites and may be safe and efficacious for diuresis, meriting further study.

Predictors of liver transplant eligibility for patients with hepatocellular carcinoma in a safety net hospital.

BACKGROUND: Liver transplantation for patients with hepatocellular carcinoma (HCC) affords excellent long-term survival but is limited to patients with early stage tumors. Predictors for orthotopic liver transplantation eligibility are not well defined for patients in a safety-net hospital system. AIMS: To clarify the clinical presentation of HCC and define predictors for early stage disease in a racially diverse safety-net hospital system. METHODS: We retrospectively reviewed records of patients with HCC presenting to a large urban county hospital between January 1998 and October 2007. Logistic regression analysis was used to find predictors of OLT eligibility. RESULTS: Of the 266 patients with HCC, 62% had multiple tumors, 47% had portal vein thrombosis and only 22% were potential liver transplant candidates based on Milan criteria. Male gender (OR 0.33; 95% CI 0.17-0.65) and AFP levels > 20 ng/mL (OR 0.22; 95% CI 0.11-0.45) were negative predictors of liver transplant eligibility. Age, race, and underlying viral liver disease were not significant predictors of early tumor stage. CONCLUSIONS: A minority of HCC patients in a safety-net hospital are eligible for liver transplant at the time of diagnosis. Men have more advanced tumors at presentation, which may be related to more aggressive tumor biology or differential rates of HCC surveillance.

Acute kidney injury and chronic kidney disease in hospitalized patients with cirrhosis.

BACKGROUND: Renal dysfunction is a common and potentially life-threatening complication in hospitalized patients with cirrhosis. AIMS: To determine the prevalence, cause, and outcome of patients with cirrhosis and acute kidney injury (AKI) and/or chronic kidney disease (CKD). METHODS: This retrospective analysis examined hospital records of 152 consecutive patients with cirrhosis and creatinine levels of 1.5 mg/dL or greater. Multiple clinical and laboratory variables were abstracted for each subject. Precise definitions were used to define cirrhosis and etiologies of renal dysfunction. Univariate and multivariable logistic regression analyses were performed to identify features with prognostic value for hospital mortality. RESULTS: The most common type of renal dysfunction was AKI, present in 107 patients (70%). Acute kidney injury plus CKD was found in 26 patients (17%), and CKD alone was present in 19 patients (13%). Prerenal azotemia was the most common cause of AKI (69%), often occurring secondary to gastrointestinal hemorrhage. The overall mortality for the cohort was 31%, with the highest mortality occurring in patients with type 1 hepatorenal syndrome (HRS) (11/14, 79%). We were unable to identify any patient meeting diagnostic criteria for type 2 HRS. The development of AKI on preexisting CKD did not infer worse prognosis than AKI alone. The presence of upper gastrointestinal bleeding, bacteremia, and HRS-1 predicted mortality. CONCLUSIONS: Both AKI and CKD are common in hospitalized patients with cirrhosis, often occurring simultaneously. Type 2 HRS was not identified, suggesting that its diagnostic criteria may need reevaluation or that this syndrome may not represent a unique functional kidney disorder.