Methionina clearance is a sensitive quantitative test of liver function and improves with SAMe therapy

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Insulin Resistance Metabolic Syndrome in Nonalcoholic SteatohepaUtis Shehan Abeygunasekera,Martin Weltman, Univ of Sydney, Nepnan Hosp, Penrith Australia

Methionine Clearance Is A Sensitive Quantitative Test Of Liver Function And Improves With SAMe Therapy Daniell 6. Hill, Mark D. Prince, Jason Castle, Lisa Gaetke, Rajnnder Chawla, Univ of Kentucky, Lexington, KY; Craig J. McClain, Univ of Louisville, Lexington, KY

Background:Nonalcoholicsteatohepatitis(NASH)is one of the commonest diseasesin Western countries.This condition is frequently associated with Type II diabetes,hyperlipidemia and obesity.Recent studies suggest insulin resistance may be an important feature of NASHAims:The aim was to investigate the relationship between NASH,insulin resistance and body mass index(BMI).Furthermore,to evaluatedisturbances in iron studies in this cohort of patients.Methods:Consecutive patients with liver biopsy proven NASH were recruited from the Liver Clinic.Investigations included standard anthropometric measurements,fasting blood glucose levels,insulin and C-peptide levels as well as iron studies.Results:A total of 26 patients were evaluated of which 65% were male.The mean age was 43 years.The mean body mass index in this cohort was 32.5.Overall 50% of patients were obese(BMI males >31.1;females>32.3).Cpeptide and insulin levels were elevated in 71% and 63% respectively(Referencevalues:cpeptide<1324pmol/L,Insulin<20mlU/ml),while elevated blood glucose levels were observed in 22%(>5.9mmol/L).Elevated ferritin(>250mcg/L)was detected in 58% of patients.Discussion/Conclusions:While blood glucose levels did not fulfill the criteria for diabetes mellitus,there is a strong evidence of insulin resistance as indicated by high insulin/C-peptide levels.This may be related to the fact that the mean age of this cohort is younger than most of the published literature and many may subsequently present with overt hyperglycaemia.Tbern appears to be a significant association between NASH and features of the metabolic syndrome,particularly insulin resistance.Elevatedlevels of ferritin are also observed in patients with NASH,although none of the patients were homozygous for the HFE gone.Iron may be important in the liver injury associated with NASH and this requires further investigation.

Despite extensive investigative efforts, there is no widely accepted test to directly assess liver function available clinically. Aims: To evaluatethe utility of methionine clearanceas a quantitative test of liver function and to determine whether or not improvements in liver function as assessed by methionine clearance could be seen with therapy. Methods: Patients with stable alcoholic cirrhosis and normal control subjects were admitted to the University of Kentucky GCRC. Methionine clearance was assessed by measuring plasma levels of methionine for up to 24 hours following an oral bolus (2-4 gm) of methionine. In one group of patients, a commercially availablebreath test that measureda methionine metabolite was used at the same time that plasma methionine clearance was assessed. Methionine clearance was measured in the patients with stable cirrhosis before and after treatment with S-adenosylmethionine(SAMe) given either IV (2460 mg/d x 17d) or orally (1206-1806 mg bid x 14d). Results: Areas under the curve for methionine clearance in cirrhotic patients vs controls were dichotomous with the normals having distinctly more rapid clearance of methionine from the plasma. There were shifts of methionine clearance curves with more rapid methionine clearance as patients improved clinically. There were decreases in both peak plasma methionine concentrations and area under the curve (by 25-35%) for methionine clearance in 4 of 5 patients receiving IV SAMe and 3 of 3 patients receiving oral SAMe. The breath test for methionine metabolism clearly separated cirrhotic patients from normals. The results of the breath test for methionine clearance correlated with the results from plasma methionine clearance. Conclusion: SAMe, whether given intravenously or orally, improves liver function as measured by methionine clearancein patients having alcoholic cirrhosis. Methionine clearanceis a sensitive quantitative assessment of liver function whether determined by plasma clearanceof methionine or breath test dependent upon methionine metabolism.

277O Relationship ot Carotenoid and Vitamins A and E with the Acute Inflammatory Response in Acute Alcoholic Hepatitis. Ewan H. Forrest, Harry Suzuki, Helen Mackie, D Talwar, Naveed Sattar, John Morris, Glasgow Royal Infirmary, Glasgow United Kingdom

2773 A Single Center's Experience With Acute Alcoholic SteatohepaUUs:Cortioosteroids Compared to Combination UrsodeoxychelicAcid, Vitamin C, and Vitamin E Cheryl A. Cox, Elizabeth E. Respenheide,Stephen H. Caldwell, Univ of Virginia, Charlottesville, VA Background: Acute alcoholic steatobepatitis is a common and serious disease with significant morbidity and mortality. Many different therapeutic strategies have been tried but the results have been generally disappointing and the use of corticosteroids for this problem remains controversial. Purpose: We wanted to review our single center's experience with the use of steroids and the combination of ursodeoxycholic acid, vitamin C and vitamin E (UCE) for treatment of acute alcoholic steatohepatitis over the last five years and compare survival rates in each group. Methods: Using our registry we ascertained patients admitted with acute alcoholic hepatitis from 1995 to 2000. We then did a chart review and identified all patients that were treated with either corticosteroids or UCE combination therapy. The Maddrey discriminant factor and the Child-Pugh score were calculated for each patient. We then looked at survival at 90 days. Treatment was not randomized, but left to the discretion of the attending physician. Results: Over a five-year period, 56 patients were admitted with acute alcoholic hepatitis. 16 of those patients received steroid therapy, 11 received UCE therapy, and all others received another form of treatment, such as supportive care alone. The mean age of the steroid group was 41 + / - 8 years old. The mean age of the UCE group was 45 + / 11 years old. The mean Meddrey score for the steroid group was 52 + / - 23. The mean Maddrey score for the UCE group was 44 + / - 20 (T-test, P ~ 0.3 not significant). The mean Child-Pugh score for the steroid group was 11.7 + / - 1. The mean Child-Pugh score for the UCE combination group was 11.5 + / - 2, which was not significantly different. Threemonth survival in the steroid group was 50% and 20% in the UCE combination group. This yielded a P value of 0.4 (chi square test). Conclusions: Alcoholic steatohepatitis remains a serious disease associated with a high mortality (overall 62% mortality at 3 months in these 21 patients). Becausethe basic mechanism of acute alcoholic steatohepatitis is lipid peroxidation, the use of corticoeteroids would seem counterproductive, as these agents may causefat deposition in the liver. Our experiencesuggests that the use of a membrane stabilizing agent (ursodeoxycholic acid) and antioxidants is as effective as corticosteroids. However, because of the small size of our patient population, it is difficult to draw firm conclusions. Larger controlled studies trials are warranted.

Background and Aim: Hepatocellular damage in acute alcoholic hepatitis (AAH) is thought to be mediated in part by oxidative stress. Vitamins A and E, and the carotenoids are important plant derived antioxidants. Low concentrations of these might potentiate alcoholic liver damage. The aim of this study was to determine the concentration of these antioxidants and relate these levels to the acute inflammatory response in AAH. Methods: Eleven patients with AAH diagnosed on clinical criteria were studied. Five patients had paired samples (day 1-3 and day 7-9 after admission). The concentration of vitamins A and E, and the carotenoids were measured by high-performance liquid chromatography. C-reactiveprotein (CRP)was measured by polarisation immunnassay. Results: Plasma concentrations are shown in the table. The levels of these antioxidants were all lower than those of historical controls (p<0.095). The IogCRP correlated with lycopene (r-0.559; p
Lycopene aCarotene pCarotene Vit A

CRP

Vit E

30.5-+9.8

18.9_+1.7 45.4_+7.4 40.4+7.4

11.2~1.0 23.2-+4.1 0.27-+0103

2771 Risk Factors for NASH in Patients with CryptogenicCirrhosis Aristotle Eusebio Mendiola, Robert G. Gish, CA Pacific Medical Ctr, San Francisco, CA Background: The relationship between non-alcoholic steatohepatitis(NASH) and cryptogenic cirrhosis(CC) remains unclear. To determine the prevalenceof risk factors for NASH in patients with CC, we conducted a retrospective chart review of our transplant database. Methods: Patients with CC from 1988-2000 were selected based on the following criteria: negative hepatitis viral serologies, specifically for HBV(HBsAgnegativeor HBsAgnegativeand undntectable HBV DNA) and HCV(anti-HCVnegative or anti-HCV negative and undetectable HCV RNA by PCR); normal iron studies, alpha-1 antitrypsin levels, ceruloplasmin and/or 24Hr. urinary Cu; negativeautoimmune serologies including ANAand/or ASMA or gamma globulins; negative drug history including alcohol; and a diagnosis of cirrhosis by liver biopsy or clinically with imaging studies(U/S or CT). Patients with confirmed HCV cirrhosis were used as controls. Both arms were evaluatedfor previous exposure to blood products, needlestick injury, tattoos, high risk sexual activity, a history of diabetes mellitus and/or hypertriglyceridemia(TG>20O). Individual weights and heights were obtained to calculate body mass index(BMI). Results: We analyzed51 patients in each arm. There were no significant differences in the percentages of females in the study and control groups. The CC group had a mean BMI of 29.6 with controls having a mean BMI of 30.4(p=0.57). Twenty-four percent of the liver biopsies in the CC group and 23% in the control group demonstrated steatosis(p=O.84). A history of diabetes was found in 43% of patients in the CCgroup compared to 27% of controls(p = 0.10). There were significantly more patients with hypertriglyceridemia in our CC group(41%) compared to only 4% of the control group(p
2774 First Results of Tissue Doppler Index (TDI) Measurements in the Classification of Diffuse Liver Diseases Joerg Siegfried Bleck, Stephan Ziegenhom, Bita Boozari, Michael Gebel, Mechthild Westhoff-Bleck, Michael Goeke, Michael Manns, Dept Gastroenterology and Hepatology, Hannover Germany Problem: Until now the tissue doppler index TO/was successfully used in cardiological and angiological applications by quantifying and visualisating of tissue movement of the heart and the vessel walls.The wall movement correlates with tissue elasticity. The finger palpation is the only noninvasive clinical method to test liver elasticity. This is the first study to prove TDI in the abdomen by investigating the influence of several liver diseases on the elasticity of the organ. Methods: In 65 patients (30 healthy N, 6 with cirrhosis Ci, 8 with chronic hepatitis Ch, 2 with acute hepatitis H and 19 with fatty liver E histological proved) TDI was measured in a area of the right hepatic vein and portal vein (2x2cm region of interest ROI). RO/were acquired in inspiration for 10 cardiac cycles at the time point of P,QRS and T of the ECG. TO/sequences(Toshiba SSA-380A) were digitized and stored on an image server using DICOM interface. The colored pixel of the TO~-ROI were analyzed using the relative velocity histogram (first order statistic). Results: The effect of hepatic vein and portal vein wall movement on the surrounding tissue was only small. In contrast the measurement at the T- time of the ECG (ventricle contraction) allows a vessel independent differentiation of

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