Gérard Thiéfin

Prognostic Factors in Patients With Zollinger-Ellison Syndrome and Multiple Endocrine Neoplasia Type 1

Abstract Background & Aims: Risk factors of metachronous liver metastases and death are not well known in patients with the Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. These factors were retrospectively determined in 77 patients. Methods: Data chart review was performed. Results: Median follow-up was 102 months (range, 12–366). Surgery was performed on 48 patients, including 9 of the 10 patients with large pancreatic tumors (≥3 cm). Liver metastases developed in 4 patients (40%) with large pancreatic tumors, in 3 (4.8%) without, and in 1 of the 4 patients with pancreatic tumors of unknown size; all had previously undergone surgery. The only independent factor associated with development of liver metastases identified by multivariate analysis was large pancreatic tumors (risk ratio, 29.0; 95% confidence interval [CI], 3.2–260.7). Surgery was not selected. The probability of being free of liver metastases in the 63 patients without large pancreatic tumors was 96% (95% CI, 88–100) at 10 and 15 years. Thirteen (16.9%) patients died. The only independent factors of death selected by multivariate analysis were Zollinger–Ellison syndrome diagnosis before 1980 (risk ratio, 8.2; 95% CI, 1.7–40.6) and age at diagnosis (risk ratio/year, 1.08; 95% CI, 1.03–1.14). Conclusions: Large pancreatic tumors are predictive of the development of metachronous liver metastases, and surgery does not seem to prevent them. GASTROENTEROLOGY 1999;116:286-293

Immediate Listing for Liver Transplantation Versus Standard Care for Child–Pugh Stage B Alcoholic Cirrhosis: A Randomized Trial

BACKGROUND Liver transplantation improves survival of patients with end-stage (Child-Pugh stage C) alcoholic cirrhosis, but its benefit for patients with stage B disease is uncertain. OBJECTIVE To compare the outcomes of patients with Child-Pugh stage B alcoholic cirrhosis who are immediately listed for liver transplantation with those of patients assigned to standard treatment with delay of transplantation until progression to stage C disease. DESIGN Randomized, controlled trial. SETTING 13 liver transplantation programs in France. PATIENTS 120 patients with Child-Pugh stage B alcoholic cirrhosis and no viral hepatitis, cancer, or contraindication to transplantation. INTERVENTIONS Patients were randomly assigned to immediate listing for liver transplantation (60 patients) or standard care (60 patients). MEASUREMENTS Overall and cancer-free survival over 5 years. RESULTS Sixty-eight percent of patients assigned to immediate listing for liver transplantation and 25% of those assigned to standard care received a liver transplant. All-cause death and cirrhosis-related death did not statistically differ between the 2 groups: 5-year survival was 58% (95% CI, 43% to 70%) for those assigned to immediate listing versus 69% (CI, 54% to 80%) for those assigned to standard care. In multivariate analysis, independent predictors of long-term survival were absence of ongoing alcohol consumption (hazard ratio, 7.604 [CI, 2.395 to 24.154]), recovery from Child-Pugh stage C (hazard ratio, 7.633 [CI, 2.392 to 24.390]), and baseline Child-Pugh score less than 8 (hazard ratio, 2.664 [CI, 1.052 to 6.746]). Immediate listing for transplantation was associated with an increased risk for extrahepatic cancer: The 5-year cancer-free survival rate was 63% (CI, 43% to 77%) for patients who were immediately listed and 94% (CI, 81% to 98%) for those who received standard care. LIMITATION Restriction of the study sample to alcoholic patients may limit the generalizability of results to other settings. CONCLUSION Immediate listing for liver transplantation did not show a survival benefit compared with standard care for Child-Pugh stage B alcoholic cirrhosis. In addition, immediate listing for transplantation increased the risk for extrahepatic cancer. FUNDING The French National Program for Clinical Research.

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease

OBJECTIVE The aim of this retrospective study was to compare clinical, biological, and histological features and treatment response in 115 patients with overlap syndrome (OS), autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC). METHODS Consecutive patients with AIH, PBC or OS followed between 1984 and 2005 in five different centers were included. All data were re-evaluated using current diagnostic criteria of each disease. RESULTS Fifteen patients had OS (13 females), 48 AIH (40 females) and 52 PBC (49 females). Patients with OS were significantly younger than patients with PBC (median age: 44 vs 59 years). Jaundice (20%) and pruritus (20%) were the main initial symptoms in OS. Patients with OS had serum transaminase and gammaglobulin levels significantly higher than patients with PBC; serum alkaline phosphatase, gamma-glutamyl-transpeptidase and IgM levels were significantly higher in OS than in patients with AIH. Histological analysis showed moderate or severe piecemeal necrosis in 86% and destructive cholangitis in 93% in OS group. Among 11 patients with OS treated with ursodeoxycholic acid (UDCA) or immunosuppressors alone, only 6 had a complete biochemical response. In contrast, all patients with OS receiving combined therapy, as first or second line, responded, 5 patients to the combination corticosteroids-azathioprine-UDCA and 2 to the combination cyclosporine-UDCA. CONCLUSION OS is not rare and accounts for 13.9% of patients with autoimmune liver disease in our series. Combination of immunosuppressors and UDCA appears the most efficient treatment in these patients.

Infliximab-induced hepatitis: absence of cross-toxicity with etanercept

We describe a patient presenting with acute hepatitis while receiving infliximab for ankylosing spondylitis. A slight increase in serum aminotransferases was first observed in this patient after 4 infusions of infliximab. The treatment was stopped after the 6th infusion when laboratory work-up revealed a 10-fold increase in serum levels of aminotransferases. A liver biopsy showed interportovenular bridging necrosis with macrophage accumulation consistent with the diagnosis of acute toxic hepatitis. After infliximab discontinuation, hepatic abnormalities resolved and the patient was treated with etanercept for more than 2 years without recurrence of hepatitis. This case underlines the lack of hepatic cross-toxicity between infliximab and etanercept making possible the continuation of anti-TNF-alpha therapy with etanercept in patients who have presented infliximab-related hepatic dysfunction.

Virological and histological responses to one year alpha-interferon-2a in hemodialyzed patients with chronic hepatitis C

Background: α-Interferon-2a (IFNα) alone is a therapy of limited proven benefit for non-uremic patients with chronic hepatitis C virus (HCV) infection. In dialyzed patients, such an effect is suggested on small short-term studies without sufficient clinical and virologic follow-up to document any sustained effect. Protocol: Twelve chronically hemodialyzed patients with chronic hepatitis C and waiting for renal transplantation were included in a prospective open study of treatment with IFNα. We used, as did others, doses of 3 million units (MU), three times a week, but for a longer period of treatment of 12 months. Follow-up was continued for 6 months after the end of IFNα in order to document any sustained biochemical, virological and histological responses. Results: Aminotransferase levels returned to the normal range within 1–2 months of treatment in all patients in whom they had been elevated at baseline. At 1 month of treatment, serum HCV-RNA was not detected in 5 (41%) patients and in 9 (75%) at 12 months. A sustained virological response was documented in 4 (33%) patients 6 months after the end of treatment. Relapse occurred in 5 patients within 2 months after IFNα withdrawal. HCV genotype was not predictive of any sustained response. At inclusion, using the histologic Metavir scoring system, half of the patients had low-grade cytolytic activity and none had cirrhosis. After IFNα, liver biopsy specimens were available from 9 patients and showed histologic improvement in 3. IFNα tolerance was poor, inducing a 5% mean weight loss and the acute rejection of two nonfunctioning kidney grafts. Conclusion: This study documents that administration of IFNα at 3 MU three times a week, for 12 months, in hemodialysis patients with chronic hepatitis C was efficient for clearing the serum of HCV-RNA in 75% of the patients. A sustained response was maintained in one third of these patients after cessation of IFNα, and was predicted by the early serum clearance of the virus within the first 2 months of treatment. We confirm that a 12-month treatment period carries a higher sustained response rate than shorter treatment periods. These encouraging results call for larger studies in uremic patients, using IFNα alone or in association with new antiviral drugs.

Risk factors and long-term course of thyroid dysfunction during antiviral treatments in 221 patients with chronic hepatitis C.

AIM To identify the predictive factors of dysthyroidism during treatment for chronic viral hepatitis C and to evaluate the long-term outcome of these patients. METHODS Patients treated for chronic viral hepatitis C between 1990 and 2001 were analyzed retrospectively. Patients with dysthyroidism before treatment and patients positive for hepatitis B surface antigen or human immunodeficiency virus antibodies were excluded. Dysthyroidism was defined by an abnormal serum TSH level on two separate occasions. RESULTS 221 consecutive patients were included. Among them, a hundred were treated twice by interferon alpha, 21 had 3 treatments and 3 had 4 treatments. Fifteen of these patients (7%) had dysthyroidism during antiviral therapy. There was no significant difference in the frequency of dysthyroidism during the first and the second treatment [respectively 4,1% (N = 9) and 6% (N = 6)]. Female gender and the presence of antimicrosome or antithyroperoxydase (anti-TPO) antibodies before antiviral treatment were predictive factors of dysthyroidism. Treatment by interferon and ribavirin did not increase the risk of dysthyroidism compared to monotherapy with interferon. Pegylated interferon (N = 49) was not a risk factor compared to standard interferon. Thirteen patients had hypothyroidism (2 of them as a result of biphasic thyroiditis) and 2 had hyperthyroidism. The antiviral treatment was continued in 11 patients. Seven out of 13 patients with hypothyroidism required an indefinite treatment (follow-up: 15 to 90 months). CONCLUSIONS In our series, 7% of patients with chronic viral hepatitis C had a dysthyroidism during antiviral therapy. Predictive factors were female gender and positive antimicrosome or anti-TPO antibodies before treatment. Absence of dysthyroidism during a first antiviral treatment did not preclude from the risk of dysthyroidism during a second treatment.

Prevalence and clinical impact of Upper Gastrointestinal Symptoms in subjects treated with Low Dose Aspirin: The UGLA survey

BACKGROUND Upper Gastrointestinal Symtoms (UGS) is a reason for discontinuation in patients treated by Low Dose Aspirin (LDA). The nationwide UGLA survey was designed to evaluate the prevalence and the pattern of UGS in patients on LDA, to assess the independent correlates of UGS and finally to determine their impact on treatment compliance. METHODS The UGLA survey was carried out on a representative sample of 10,000 subjects aged 50 or over. Prevalence and clinical impact of UGS related to LDA was appraised by standardised multi-choice questions. RESULTS A total of 8106 propositus (8106/10,000) accepted to participate in the survey. Among them, 986 (12.2%) were treated with LDA. The prevalence of UGS was 15.4% in subjects on chronic LDA (152/986), 70% being gastroesophageal reflux (GER) (heartburn and/or regurgitation). UGS was reported to occur at least once a week in 60% of propositus (91/152) and daily life was reported to be moderately and severely impaired in 53% (81/152) and 20% (30/152) of them, respectively. UGS impacted compliance to treatment in 12% of propositus with UGS. A prior history of dyspeptic symptoms was predictive of LDA-related UGS (OR: 17.60; CI 95%: 11.52-26.88) whereas neither, gender nor aspirin dosage (ranging from 75 and 325 mg) predicted the occurrence of UGS. CONCLUSIONS Fifteen percent of patients treated with LDA suffered UGS, mostly GER symptoms which had a negative impact on daily life in 3 out of 4 patients and on treatment compliance in 1 out of 8 patients.

Diagnosis of hepatocellular carcinoma in cirrhotic patients: a proof-of-concept study using serum micro-Raman spectroscopy

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. The development of novel diagnostic methods is needed to detect tumours at an early stage when patients are eligible for curative treatments. The purpose of this proof-of-concept study was to determine if micro-Raman spectroscopy applied to the sera of cirrhotic patients may be an alternative method for rapidly discriminating patients with and without HCC. Serum samples were collected from 2 groups of patients: cirrhotic patients with HCC (n = 37) and without HCC (n = 34). Two different approaches were used, dried serum drops and freeze-dried serum, and micro-Raman spectra were acquired in the point-mode with a 785 nm laser excitation in the spectral range of 600-1800 cm(-1). Spectra were quality-tested and pre-processed (smoothing, baseline subtraction, vector normalization). Using principal component analysis, the 2 classes, corresponding to cirrhotic patients with and without HCC, could not be differentiated. In contrast, the support vector machine method using the leave-one-out cross validation procedure was able to correctly classify the two groups of patients with an overall rate of accuracy of 84.5% to 90.2% for dried serum drops and 86% to 91.5% for freeze-dried serum. These results are promising and support the concept that serum micro-Raman spectroscopy may become a useful diagnostic tool to detect biomarkers in the field of cancer, as described here for distinguishing between cirrhotic patients with and without HCC.

Ischaemic colitis in a patient taking meloxicam

The safety of cyclo-oxygenase 2 (COX-2) preferential inhibitors such as meloxicam is debated. We describe a patient who presented with bloody diarrhoea after 15 mg meloxicam daily for 10 days for osteoarthritis. The endoscopic and histological features were consistent with the diagnosis of ischaemic colitis. Symptoms and endoscopic lesions quickly regressed within 1 week of meloxicam withdrawal. There was no evidence of another cause of colonic ischaemia. We suggest that meloxicam might have intestinal toxic effects when taken in high doses, because of reduced COX-2 selectivity.

Colonic Flat Neoplasia: Frequency and Concordance Between Endoscopic Appearance and Histological Diagnosis in a French Prospective Series

Colonic Flat Neoplasia: Frequency and Concordance Between Endoscopic Appearance and Histological Diagnosis in a French Prospective Series