Incidence of cancer in primary biliary cirrhosis: The mayo experience

A1312 AASLDABSTRACTS • L0463 VITAMIN E IN TREATMENT OF HEPATITIS C RESISTANT TO ALPHA INTERFERON: A RANDOMIZED, DOUBLE-BLINDED, PLAC'F~OCONTROLLED PILOT STUDY. MT Nguyen, RA Rubin, MA Zern. Division of Gastroenterology and Hepatology, Allegheny University Hospitals at Graduate, and Thomas Jefferson University Hospital, Philadelphia, PA. Background: Lipid peroxidation associated with free radical production has been implicated as one of the hepatotoxic mechanisms of hepatitis C. Antioxidants such as vitamin E have been known to protect liver tissue against oxidative stress and injury in animal models. Hepatic vitamin E depletion has been detected in patients with chronic hepatitis C infection. The main objective of our pilot study is to demonstrate whether or not vitamin E monotherapy would be effective in treatment of hepatitis C resistant to standard alpha interferon therapy. Methods: We used d-alpha-tocopheryl-polyethylene-glycol-1000 succinate (TPGS), a water-soluble form of vitamin E, which is well-absorbed even in patients with cholestasis. Thirteen patients, seven women and six men, with mean age of 42 years (range of 19 to 62 years), with compensated liver disease, were randomized to two arms: seven to one arm with TPGS, 25-50 mg/kg/day, and six to the placebo arm, for 6 months. All were off over-thecounter vitamin supplements for at least one month. Liver function tests were followed at monthly intervals. Liver biopsy was performed prior to and after the study period. All 13 patients completed the study trial with no significant side effects observed. Results: No ALT normalization was seen in either group. Mean pretreatment ALT levels in the study and placebo groups were 119 IU/L and 120 lUlL respectively. Mean post-treatment ALT levels in the study and placebo groups were 109 IU/L and 107 IU/L respectively (p-not significant). No significant changes were seen in liver histology before and after treatment in either group. All patients continued to demonstrate the presence of HCV, which was measured by PCR and/or bDNA HCV, at the end of the study period. Conclusions: The results of this small pilot study suggest that vitamin E monotherapy in treatment of hepatitis C resistant to alpha interferon is not an effective alternative. Combination therapy with other antiviral therapies such as alpha interferon and/or ribavirin may offer a better outcome. • L0464

INCIDENCE OF CANCER IN PRIMARY BILIARY CIRRHOSIS: THE MAYO EXPERIENCE. Pardeen K Niihawan, Terry M Therneau, E Rolland Dickson, Keith D Lindor; Division of Gastroenterology and Hepatology and Department of Biostatistics at the Mayo Medical Foundation, Rochester, MN. Patients with primary biliary cirrhosis (PBC) may be at increased risk for malignancies, although this is controversial. Furthermore, most studies have looked at specific malignancies; however, there is little information about overall risk for cancer. METHOD: We performed a retrospective review of the records of patients with the diagnosis of PBC and of malignancies. We reviewed records of patients with PBC presenting to the Mayo Clinic between 1976 and 1985. This allowed for a follow-up period of UP to 20 years; thereby providing sufficient time to estimate the incidence of cancer in these patients. The diagnosis of PBC was based on cholestatic liver tests, positive antimitochondrial antibody and liver biopsy findings. We excluded patients who were diagnosed with malignancies prior to or at the same time the diagnosis of PBC was made. The incidence of malignancies was compared to published data by the Surveillance, Epidemiology and End Results (SEER) program. RESULTS: Of the 1004 patients with PBC in the Mayo Clinic data base, we had to exclude 58 patients due to diagnosis of malignancies made earlier or at the same time the PBC diagnosis was confirmed. We found 76 patients with PBC who had malignancies; of these 9 had two primary malignancies, 4 had three primary sites and the remaining 63 had only one primary site. This amounted to a total of 93 cancer events occurring in 76 females and 17 males. For females, the predicted cancer events according to the SEER data was 46.8 for our population. Our observed value of 76 was significantly different with a relative risk (RR) of 1.62 (p=0.0001). Similar results were seen in males with the predicted value being 9.1 and the observed value of 17, with an RR of 1.88 (p=0.0095). The only malignancy that was significantly more common in patients with PBC was liver cancer with an RR of 47 for women and 60 f o r men. The most common malignancies in decreasing order of frequency were breast in 15 patients, gastrointestinal in 11 females and 4 males, hepatocellular in 10 females and 5 males, gynecological in 13 females, lung cancer in 8 females and only 1 male, and the remaining 26 patients were grouped as miscellaneous. CONCLUSIONS: Patients with PBC are at an increased risk of developing malignancies. Females, who are predominantly at risk for PBC, have a 1.62 (p=0.0001) RR, and the male population has a 1.88 (p=0.0095) RR. Therefore, PBC patients may benefit from more aggressive surveillance for malignancies during their lifespans.

GASTROENTEROLOGY Vol. 114, No. 4

• L0465 PARTIAL REPLACEMENT OF BILE SALTS CAUSES DRASTIC ALTERATION IN BILE METASTABILITY IN SUPERSATURATED MODEL BILE SYSTEMS: RELATION TO BILE SALT MICELLEFORMING CAPACITY. T. Nishioka, S. Tazuma, Y. Sunami, S. Yasumiba, H. Hyogo, H. Miyake, Y. Hattori, H. Miura, G. Yamashita, G. Kajiyama, The First Dept. of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan. Backzround/Aims: Cholesterol crystallization is a key step in the gallstone pathogenesis and is affected by various factors including cholesterol saturation index which is calculated using classical determinants of simple aqueous systems. In contrast, human native bile contains a mixture of bile salts having different micelle-forming capacity, and therefore, the relevancy of the importance of lipid composition to physiological bile metastability is yet to be established. Thus, the present study was performed to evaluate the thermodynamic effect of bile salt molecular species on cholesterol nucleation process in model systems. Methods: Supersaturated model biles were prepared with an identical composition on a molar basis (taurocholate /lecithin /cholesterol, 71:18:11; TLC, 12 g/dl), except for replacing taurocholate (10, 20 and 30%) with various taurine-conjugated bile salts; deoxycholate (TDC), chenodeoxycholate (TCDC), [3-muricholate (TI3MC), ursodeoxycholate (TUDC), ursocholate (TUC), followed by time-sequential scanning for cholesterol crystallization; 1) in quantity by spectrophotometrically, 2) in dimension by the laserscattering diffraction analyzer, and 3) in morphology by video-enhanced microscopy. Results: were as follows (%control values, 30% replacement bile salt respectively);

TDC TCDC TC (cont) TUDC TUC TflMC

CGR 158" 178" 100 10.6t 11.8 t 12.2t

Crystal FCM 174" 158" 100 8.24t lO.Ot 15.0t

Crystal habits plate & arch plate & arch plate & arch liquid & needle liquid & needle liquid & arch

Vesicles Vmax 94.3 95.0 100 203* 231 * 227*

DM 108 113 100 97 93 98

(CGR: Crystal Growth Rate, FCM: Final Crystal Mass, Vmax: maximum vesicle turbidity, DM: dimension of vesicles). Each bile salt affected values of CGR, FCM and Vmax in a dose-depend. Summary_ and conclusions: Drastic alteration in cholesterol crystallization process was evident by partial replacement with bile salts having different hydrophobicity, and the acceleration potency correlated with their micelle-forming capacity. Hydrophilic bile salts (TUDC, TUC, TI3MC) inhibit cholesterol precipitation through the formation of a stabilized liquid-crystalline phase, whereas hydrophnbic bile salts (TDC, TCDC) shifted vesicular lipids into micelles, resulting in destabilizing vesicles. Thus, minimal changes in bile salt composition may lead to drastic alteration in bile lipid metastability. This study was supported, in part, by the Ministry of Education of the Japanese Government, awarded to Dr. Tazuma (No. 06670557). • L0466 INCREASE OF ANDROSTENEDIONE AND ESTRADIOL IN CIRRHOTIC MEN TREATED BY TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC STENT-SHUNT (TIPS). Nolte W, Schindler C, Wuttke W*, Hartmann H, Htifner M and Ramadori G. Division of Gastroenterology and Endocrinology; *Division of clinical and experimental Endocrinology, University of G~ttingen, Germany. Liver cirrhosis can be associated with alterations of sex steroid metabolism and transport, especially noted in patients with poor liver function. Hypogonadism, feminization, and impotency in men as well as oligomenorrhea in women evolves from these changes. To evaluate the effect of shunting on sex steroid serum concentrations, we performed a controlled and prospective study in cirrhotic patients having received a transjugular portosystemic stent shunt (TIPS) due to complications of portal hypertension. We measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroxyepiandrosteronesulfate (DHEAS), androstenedione (A), estradiol (E2), 17-OH-progesterone (17-OH-P) and the T/SHBG ratio before and 3 months after TIPS in a group of 27 patients (17 men, 10 women; mean age 57, range 34-73 years) and in a non-shunted group of 20 age and sex matched cirrhotic patients at baseline and three months later. Etiology of cirrhosis was alcohol toxic in 67%. In men of both groups, mean baseline values within normal range were found for T, SHBG, LH, FSH, 17-OH-P and E2, whereas DHEAS was reduced (TIPS mean: 361 ng/ml, normal range: 690-5000 ng/ml) and A was elevated (TIPS mean: 4.4 ng/ml, normal range: 0.8-2.5 ng/ml). Three months after TIPS a significant increase for T from 4.2 to 6.0 ng/ml and for SHBG from 66 to 89 nmol/1 was observed but the ratio T/SHBG remained stable. A and E2 significantly increased, mean serum levels rising from 4.4 to 5.6 ng/ml and from 26.6 to 40.3 pg/ml respectively. In women of both groups E2 was low (TIPS mean: 27 pg/ml), whereas DHEAS and A were deranged at baseline like in men. Three months after TIPS only T showed a significant increase but the ratio T/SHBG did not change. In the non-shunted group no