Thomas J. Layden

The Histopathologic Progression of Vitamin A-Induced Hepatic Injury

Abstract The present paper is a follow-up report describing the clinical and hepatic histologic findings of a patient who hod ingested massive doses of vitamin A for many years. Light and electron microscopic features of the patients current liver biopsy specimen demonstrates that cirrhosis may result from prolonged vitamin A ingestion.

Plasma Trace Metals During Total Parenteral Alimentation

The plasma concentrations of the trace metals zinc and copper were studied prospectively in 13 patients with gastrointestinal diseases treated with parenteral alimentation (TPA) for periods of from 8 days to 7 1/2 weeks. Plasma copper levels fell rapidly and consistently in all patients, with an overall rate of - 11 mug per 100 ml per week. Zinc concentrations declined in 10 of 13 patients at a more gradual rate. Analysis of the standard parenteral alimentation fluids revealed zinc content equivalent to 50% of the daily requirement and a negligible content of copper. From combined analysis of plasma zinc, hair zinc, and taste acuity, there is evidence that increased utilization or redistribution within the body may effect plasma concentrations in some patients. Neither an increase in urinary excretion nor a primary decrease in plasma binding proteins appeared to be a major factor in lowering plasma trace metal concentrations. These findings indicate that a marked decrease in plasma copper is regular and a decline in plasma zinc is common during TPA using fluids unsupplemented with trace metals. Supplementation of parenteral alimentation fluids with the trace metals zinc and copper is recommended.

p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients.

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for post-transplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in >10% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53+ (P=0.0007) and Ki-67+ cases (P=0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level ≥100u2009ng/ml at time of diagnosis, compared to those with an AFP level <100u2009ng/ml (P=0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level ≥100u2009ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh

There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis.

M1773 Clinical and Histologic Features Associated with Steatosis in a Cohort of Patients with Chronic Hepatitis C

Steatosis occurs in some patients with chronic hepatitis C and has been associated with fibrosis. Steatosis may result from viral mediated factors such as genotype 3 or coexistant metabolic syndrome. The aim of this study was to evaluate the association of demographic and clinical factors with the presence of steatosis and to evaluate the association between steatosis and histologic features on biopsy and disease progression. Methods: 598 patients underwent biopsy for HCV staging over a 10 year period and were well characterized clinically and histologically. Demographic and clinical data were collected retrospectively. Liver biopsies were read by two clinicians masked to clinical data. Biopsies were systematically evaluated by histology activity index (HAI) [Knodell 1981] and steatosis was graded 0-3. Disease progression was characterized by the fibrosis index (fibrosis stage 0-4/years since first risk factor). Results: The mean age was 49 ± 9 years and the mean BMI was 30 ± 7 kg/m2. The mean duration of infection was 26 ± 9 years. The population was 61% male and was 41% African American, 39% Non-Hispanic White and 20% Hispanic. Diabetes mellitus (DM) was present in 22%, hypertension in 36%, hyperlipidemia in 10% and past alcohol use in 26%. Steatosis (fat >5%) was present in 48% of patients. Those with steatosis had higher mean ALT level (91 ± 81 vs 70 ± 57, p<0.001) and higher mean BMI (30.9 ± 6.9 vs 28.7 ± 6.8, p=0.001). Patients with genotype 3 infection were more likely to have steatosis compared to other genotypes (72% vs 47%, p=0.009). Sixty five percent of Hispanics had steatosis compared to 44% of Non-Hispanic Whites and 43% of African Americans (p<0.001). Steatosis was more common in patients with DM (64% vs 43%, p<0.001). There was no association between steatosis and AST level, duration of infection, gender, hypertension, hyperlipidemia or past alcohol abuse. In multivariate analysis, Hispanic race, BMI and DM remained associated with steatosis. Patients with steatosis on liver biopsy had higher mean levels of portal inflammation (2.3 ± 0.9 vs 2.0 ± 0.8, p<0.001), interface hepatitis (2.9 ± 1.9 vs 2.2 ± 1.8, p<0.001), lobular inflammation (1.3 ± 0.7 vs 0.9 ± 0.9, p<0.001), fibrosis (2.7 ± 1.1 vs 2.4 ± 1.2, p=0.002) and total HAI (9.1 ± 3.8 vs 7.5 ± 3.9, p<0.001). Fibrosis index was higher in those with steatosis (0.12 ± 0.07 vs 0.10 ± 0.07, p=0.021). Conclusion: The presence of steatosis on biopsywas associatedwithmore histologic activity and faster rates of disease progression by fibrosis index. BMI, DM and Hispanic race can help clinicians identify patients at risk for steatosis.

W1815 Elevated ALT Levels Are Common in Chinese Americans Without Hepatitis B

Chronic hepatitis B infection affects approximately 400 million people worldwide, with a disproportionately high prevalence in Asian Pacific Islanders (APIs). HCC is the second leading cause of cancer deaths among APIA men. It is estimated that one in ten APIs is chronically infected with HBV. The guidelines set forth by various organizations lack consistency with regard to HBV screening in APIs. Although screening of all APIs for chronic HBV has been advocated by multiple research groups and mandated by recent legislation in Congress, the Center for Disease Control and Prevention and AASLD each recommend slightly different guidelines. As part of the San Francisco Hep B Free campaign, we offered free serologic screening and vaccination, if appropriate, to over 2000 APIs between January and October 2008. Of the total number of participants screened (2,118), 72 (3.4%) were chronically infected. Of those people who reported previous vaccination, 90 (32.5%) lacked protective antibodies and 3 (1.1%) were actually chronically infected. Among the APIs screened, 64 (3.3%) were chronically infected with HBV. Of those not chronically infected, 993 (51%) lacked protective antibodies and were at risk for future infections. Men were 1.5 times as likely as women to be chronically infected. Adults aged sixty or older were three times more likely to be infected than people under the age of sixty. APIs born in endemic regions were 4.6 times more likely to be chronically infected than U.S.-born APIs. In an earlier study by Hutton et al., a Markov model of different screening strategies suggested that it is cost-effective to screen all APIs, irrespective of birthplace. To date, no studies have examined the rates of chronic infection in secondand third-generation APIs, i.e. U.S.-born APIs whose parents were born in Asia or the U.S. Based on an interim analysis of the San Francisco Hep B Free Campaign, we hypothesize that it is not cost-effective to screen all APIs given the lower prevalence rates in 2nd and 3rd generation U.S.-born APIs. We plan to integrate the data from our screening program with Huttons model to re-evaluate costeffectiveness of HBV screening across different generations of APIs. Clearly, there is a need for identification of hepatitis B cases in the API community and vaccination when appropriate. By identifying non-traditional risk factors such as parental birthplace in U.S.-born APIs, we hope to make screening efforts more targeted, cost-effective, and successful.