The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Mortality while awaiting liver retransplantation: predictability of MELD scores.

INTRODUCTION: Model for End-stage Liver Disease (MELD) scores at the time of listing on the transplant waiting list have been shown to accurately predict 3-month mortality in adults. There is no data assessing the accuracy of the MELD scores in predicting mortality of patients awaiting liver retransplantation. We sought to determine the outcome of patients listed for retransplantation at a single center and the accuracy of MELD scores in predicting mortality on the transplant waiting list. METHODS: A retrospective review of adult patients at a single center listed for a second liver transplantation during the years 1993 to 2000. MELD scores and a concordance statistic were calculated at the time of initial listing and initial transplant as well as the time of relisting for a second transplant and at 2, 4, 6, 8, 12, and 24 weeks after relisting. RESULTS: Of the 63 patients in the study, 43 (68%) received a second transplant, and 20 (32%) died while awaiting retransplantation. Of the patients receiving a second transplant, 13 (30%) died within 1 year of receiving the transplant. The most common cause of death on the waiting list was sepsis (50%), hepatorenal syndrome (20%), and multiorgan failure (10%), whereas the majority of deaths posttransplantation were sepsis-related (69%). At the time of relisting the c-statistic for MELD scores predicting death after 1 week on the waiting list was 0.78 (P = .007). After 3 months on the waiting list, the c-stat was largely unchanged (0.76, P = .04). CONCLUSIONS: We have shown that MELD scores may predict mortality on the transplant waiting list for patients listed for a second transplant.

Zonal differences in ethanol-induced impairments in hepatic receptor binding.

We have previously shown ethanol-induced defects in receptor-mediated endocytosis of asialoorosomucoid (ASOR), epidermal growth factor (EGF), and insulin in isolated rat hepatocytes. The present study was undertaken to compare the binding of these three ligands in both Zone 1 (periportal [PP] region) and Zone 3 (perivenule [PV] region) of rat liver. Cells from the PV region of ethanol-fed animals bound significantly less EGF (40% decrease) than did cells from the same area in control rats. EGF binding was decreased to a lesser extent (15-25%) in PP cells from ethanol-fed animals compared to controls. When binding of ASOR was examined, ethanol feeding significantly impaired binding in both PP cells (30-35% decrease) and PV cells (50-55% decrease), again showing a greater ethanol-induced impairment in the PV region. Insulin binding in ethanol animals was decreased by 20-25% in both regions compared to controls. In addition, we found that ASOR receptor recycling was impaired to a greater extent in the PV than in the PP region of liver after ethanol feeding, indicating selective impairment of receptor function in the centrilobular region of the liver.

Pegylated interferon for recurrent hepatitis C in liver transplant recipients with renal failure: a prospective cohort study.

BACKGROUND: Hepatitis C (HCV) universally recurs following orthotopic liver transplantation (OLT), representing an important cause for retransplantation. Although it is often treated with interferon and ribavirin, ribavirin is contraindicated in the presence of renal failure. In this setting of renal failure, pegylated-interferon monotherapy may be useful for recurrent HCV in liver transplant patients. METHODS: Between June 2001 and November 2002, patients with recurrent HCV were screened to determine if they were eligible for treatment. Renal failure was defined as serum creatinine greater than 1.8 mg/dL. HCVRNA and liver biopsies were performed prior to treatment, end of treatment (EOT) and 6 months after EOT for those who were HCV-RNA negative at EOT. Patients were followed prospectively after starting weekly pegylated-interferon alpha 2b 1.0 microg/kg (Schering-Plough, Kenilworth, NJ, USA). RESULTS: Among the 45 patients with recurrent HCV screened, 9 were eligible, including 8 men and 1 woman of average age 55 years. Eight patients were intolerant to the treatment requiring discontinuation within the first 3 months. Two patients developed a sustained response to HCV eradication. One patient who completed treatment has normal liver tests but is still viremic. CONCLUSIONS: Pegylated-interferon alpha 2b is poorly tolerated in liver transplant recipients with recurrent HCV and chronic renal failure. Larger, prospective studies are required to determine the optimum duration of treatment and the impact of treatment on histology and quality of life.

High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis.

BACKGROUND: Ursodeoxycholic acid (UDCA) in a dose of 28-30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. AIM: To compare the risk of adverse clinical endpoints in patients with varying disease status. METHODS: We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28-30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. RESULTS: A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P=0.0151) with early histological disease (stage 1-2, n=88) but not with late stage (stage 3-4, n=62) disease (17 vs. 14, P=0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P=0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P=0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints (P=0.073). CONCLUSION: The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin.

Posttransplantation care: role of the primary care physician versus transplant center.

1. Forty percent of transplant centers expect the primary care physician to be the primary physician; 40% have both a primary care physician and a hepatologist manage the patient. 2. Transplant centers expect primary care physicians to provide general preventive medicine, physical examinations, vaccinations, and, rarely, management of hypertension, renal dysfunction, and diabetes. 3. A high percentage of primary care physicians feel comfortable caring and managing the overall health care of a long-term liver transplant patient. 4. Primary care physicians feel at most ease managing preventive care, annual physical examinations, hypertension, diabetes mellitus, hyperlipidemia, bone disease, and vaccinations. 5. Primary care physicians should be aware of the common medical conditions of the liver transplant patient of hypertension, diabetes, obesity, hyperlipidemia, and recurrent disease. 6. Common medical conditions for both the transplant centers and primary care physicians are hypertension, dyslipidemia, diabetes mellitus, malignancy, bone disease, pregnancy, vaccination, infectious prophylaxis, and headaches.

Long-term follow-up of the orthotopic liver transplantation patient.

The primary care gastroenterologist has a crucial role in the long-term management of the patient who has undergone orthotopic liver transplantation. Routine office visits, annual evaluation, and screening and early assessment of complications is crucial to the outcome of the patient. In addition, communication is an important issue for both the transplant center and the primary care physician. This continuing dialog about the patient will enhance his or her care and long-term outcome.

The time and financial impact of training fellows in endoscopy. CORI Research Project. Clinical Outcomes Research Initiative.

OBJECTIVE: To use a national endoscopy database (Clinical Outcomes Research Initiative, CORI) to determine 1) if fellow involvement increases procedure time; and 2) the financial impact of fellow participation for academic centers compared to private practice. METHODS: CORI database from 4/1/97 to 4/1/99 was used to compare endoscopists from private practices, academic medical centers, and Veterans Administration hospitals, with or without fellows-in-training. Data were captured in a computer-generated endoscopy report and transmitted to a central database for analysis. Duration of procedure (minutes) was recorded for diagnostic esophagogastroduodenoscopy (EGD), EGD with biopsy, diagnostic colonoscopy, and colonoscopy with biopsy, in ASA 1 patients. Financial outcomes used 1999 Medicare reimbursement rates for respective procedures and were calculated as procedures per hour on a theoretical practice of 4000 procedures. RESULTS: Teaching fellows endoscopy added 2-5 min for EGD, with or without biopsy, and 3-16 min for colonoscopy, with or without biopsy. Calculating the number of procedures/h of endoscopy, the reimbursement loss resulting from using fellows-in-training in a university setting would be half a procedure/h. In Veterans Administration hospitals, training of fellows would lose a full procedure/h. In a model of 1000 procedures each of EGD, EGD with biopsy, colonoscopy, and colonoscopy with biopsy, the reimbursement difference between private practice physicians or academic attending physicians and procedures involving fellows-in-training would be $500,000 to $1,000,000/yr. CONCLUSIONS: Fellow involvement prolonged procedure time by 10-37%. Thus, per-hour reimbursement is reduced at teaching institutions, causing financial strain related to these time commitments.

The American experience with transplantation for acute liver failure.

Liver transplantation has become the major therapy for acute liver failure (ALF) in the United States. Survival rates range from 46% to 89%. Appropriate patient selection, timely referral, and management of common complications have improved survival. Donor organ shortage may prompt further use of extracorporeal support systems and auxillary transplantation in the future. This article reviews the American experience of liver transplantation in patients with ALF.

Bacterial endocarditis in patients with chronic liver disease.

OBJECTIVE: Although patients with cirrhosis have an increased susceptibility for bacterial infections, endocarditis complicating cirrhosis has been reported only infrequently. In this study, our objective was to determine whether, bacterial endocarditis is, in fact, a complicating factor in cirrhosis. METHODS: We retrospectively studied all cases of bacterial endocarditis that occurred over the last 15 yr in patients with known cirrhosis. RESULTS: Ten patients (three males, seven females) were identified, whose mean age was 55 yr (range 29-65 yr). Bacterial organisms included Staphylococcus aureus, coagulase-positive (eight patients), Peptostreptococcus (one patient), and Enterococcus (one patient). Underlying liver disease consisted of alcoholism (five patients), autoimmune chronic active hepatitis (two), cryptogenic cirrhosis (two), and primary biliary cirrhosis (one). Distribution of heart valves affected were mitral valve (six), aorta (two), and there were two involving both mitral and aortic valves. Echocardiograms revealed vegetation in 50% of the patients. Laboratory studies were markedly abnormal, with mean values of albumin 2.4 mg/dl, creatinine 2.5 mg/dl, BUN 76.5 mg/dl, and total bilirubin 8.2 mg/dl. Potential associated sources of infection were upper gastrointestinal bleeding (four), pneumonia (two), and one each of spontaneous bacterial peritonitis, hip replacement, heart catheterization, and abdominal abscess. The outcome was poor, with death in eight of 10 patients. CONCLUSIONS: Bacterial endocarditis may complicate cirrhosis, may be more frequent in females, typically involves the mitral valve, and probably is due to Staphylococcus aureus.

Pneumococcal vaccine response in cirrhosis and liver transplantation.

Cirrhosis is a major risk factor for severe pneumococcal infection, and patients evaluated for liver transplantation routinely receive pneumococcal vaccine. This study followed serologic antibody levels of 45 adults evaluated for transplantation and 13 age-matched control subjects. All received 23-valent pneumococcal polysaccharide vaccine (PPS). Serum anti-PPS levels and antibodies specific for capsular types 3 and 23 were measured by ELISA before and 1 and 6 months after vaccination. Antibody levels for the 25 patients who received transplants also were measured immediately before and 3 months after transplantation. Control subjects had higher IgG responses to the whole vaccine, whereas patients appeared to produce more IgM and IgA. IgA, and possibly IgM levels, also declined faster in patients than in control subjects. All anti-PPS levels were at or below prevaccination baselines by 3 months after transplantation. These data suggest that vaccination with PPS may not be effective for patients during and after liver transplantation.

Collagenous enterocolitis: a manifestation of gluten-sensitive enteropathy.

We report coexistent collagenous colitis and collagenous sprue in a 62-year-old woman with diarrhea. Investigations suggested malabsorption, and small intestinal biopsies demonstrated a flattened mucosa with subepithelial collagen deposition. Colonic biopsies also showed a thickened subepithelial collagen band as well as a striking lamina propria inflammatory cell infiltrate. Symptomatic remission was induced with a gluten/lactose-free diet, oral prednisone, and sulfasalazine and has been maintained with gluten restriction alone. Repeat biopsies after 2 months demonstrated restoration of normal small intestinal and colonic collagen bands; only a chronic inflammatory cell infiltrate (consistent with microscopic/lymphocytic colitis) persisted in colonic biopsies. We propose that, in this instance, collagenous enterocolitis represented a diffuse manifestation of gluten sensitivity.

Gender differences in colorectal polyps and tumors.

OBJECTIVES: To use a national endoscopy database (CORI) to determine 1) whether gender differences are noted in the prevalence and location of polyps and tumors; 2) whether women have a higher rate of right-sided polyps or tumors; and 3) whether age influences these results. METHODS: CORI database from April 1, 1997 to February 19, 1999, captured in a computer-generated report, was analyzed. Polyps for this study were defined as sessile or pedunculated and as >9 mm. Tumors were defined as lesions characteristic of adenocarcinoma (mass, apple-core). Pure right-sided colon (PRS) was defined as cecum, ascending, hepatic flexure; right-sided as PRS plus the transverse colon; and left-sided as the splenic flexure, descending, sigmoid and rectum. RESULTS: Men have a greater risk of polyps [odds ratio (OR), 1.5] and tumors (OR, 1.4) than women. The risk of finding polyps and tumors at colonoscopy increases with age, with the highest risk noted in those >69 yr of age relative to patients <50 yr of age (polyps, OR = 2.7; tumors, OR = 4.0). Right-side polyps and pure right-sided polyps as defined by the study design were noted to be more frequent than left-sided polyps in patients >60 yr of age. Women have a greater risk of developing pure right-sided polyps (OR, 1.2), tumors (OR, 1.6) and right-sided tumors (OR, 1.5) than men. CONCLUSIONS: Men have a higher prevalence of colon polyps and tumors than women. A progressive risk of polyp or tumor formation is noted with aging. Women had a greater number of pure right-sided polyps and tumor development. Colonoscopy is needed to correctly diagnose an increasing prevalence of right-sided pathology in the elderly.

Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease.

OBJECTIVE: The objective of the study was to determine the prevalence and associations of abnormal alpha1-antitrypsin phenotypes in Caucasian adults with end stage liver disease with particular emphasis on heterozygous phenotypes and disease from hepatitis C virus. METHODS: All patients (788) with end stage liver disease considered for liver transplantation from July 1990 to June 1996 in a referral-based university hospital transplant center (University of Nebraska Medical Center, Omaha, NE) comprised the study population. Data for the study population was determined by retrospective review of the transplantation database at the transplant center. Hepatitis C virus infection was determined by a second generation ELISA method, and alpha1-antitrypsin phenotyping was performed on agarose gel with serum quantitation using a Behring Nephelometer. RESULTS: Among 683 Caucasian patients with severe liver disease, the prevalences of Pi ZZ, Pi MZ, and Pi MS were 0.4, 7.3, and 8.2%, respectively, compared with 0, 2.8, and 4.2% in the control population. The odds of having a heterozygous Z phenotype were significantly increased in Caucasian patients with hepatitis C virus (odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.1-9.0), alcoholic liver disease (OR = 5.0, 95% CI = 2.6-9.6), primary hepatic malignancy (OR = 7.4, 95% CI = 2.9-19.0), and cryptogenic cirrhosis (OR = 2.6, 95% CI = 1.1-6.3) compared with the control population. Caucasian patients with hepatitis C or B virus were 3.6 times more likely to have a heterozygous Z phenotype than a normal phenotype compared with patients with diseases of autoimmune etiology. CONCLUSION: This study provides evidence of an association of heterozygous Z alpha1-antitrypsin phenotype with end stage liver disease of several etiologies, not hepatitis C virus alone.

Attitudes and expectations of 1995 gastroenterology graduates about gastroenterology.

OBJECTIVE: To learn more about current attitudes and expectations of recent (June 1995) graduates of gastroenterology fellowship programs, why they chose either a private practice or academic career, and what impact managed care or health care reform had in their decision. METHODS: Between April and June 1995, and 8-page, 35-question survey questionnaire was mailed to graduating fellows and returned for evaluation. RESULTS: Graduates believed managed care had an impact on job availability, but it was not a factor in their job choice. Forty percent of the respondents reported that finding a job was either difficult or very difficult. The majority of respondents (67%) are pursuing a career in private practice. Most private practice physicians (PP) trained in 2-yr programs whereas academic physicians (AC) trained for the most part in 3-yr programs. The principal criteria on which decisions regarding job selection were based were similar between the two groups: co-workers, geographic location, access to patient care, and ability to perform endoscopy. Respondents in PP and AC expected to work 50-70 h/wk, care for patients with similar diseases, and have ample time for family. They would choose GI again as a career and believed that there is a future in GI. Salary expectations varied markedly between the two groups, and AC physicians were more concerned about their future financial needs. Twenty percent of PP physicians and 71% of AC physicians plan to participate in clinical research. CONCLUSIONS: Recent graduates of gastroenterology fellowship programs continue to have high expectations of their future careers. Although some had difficulty finding a job and stated that, although managed care had an impact on the job market, it had not yet become a major factor in their job selection.