Treatment of severe Crohn's disease with anti-CD4 monoclonal antibody.

BACKGROUND: Monoclonal CD4 antibodies have been proposed as a new immunosuppressant drug in the treatment of inflammatory bowel disease. We report our experience of treatment with a monoclonal anti-CD4 (B-F5) antibody in severe refractory Crohn's disease. METHODS: Twelve patients with severe refractory Crohn's disease were treated in an open clinical trial. B-F5 was given intravenously at a dose of 0.5 mg. day/kg for 7 consecutive days (patients 1-8). For patients 9-12, B-F5 was given at a dose of 0.5 mg. day/kg on the first day (day 0) and of 1 mg.day/kg on days 1-6. Follow-up examinations were carried out at days 8, 15, 22 and 30. Endoscopic evaluation was performed on days 0 and 30 in eight of 12 patients. RESULTS: Immediately after the first infusion, one patient had dyspnoea and tachycardia requiring cessation of the treatment. Among the 11 patients who received the complete course of treatment, two had prolonged clinical improvement and two had partial clinical improvement. Significant endoscopic improvement was observed in only one patient. No sustained depletion of CD4+ cells could be observed. CONCLUSION: In this uncontrolled open trial, monoclonal anti-CD4 B-F5 antibody was not successful in severe Crohn's disease.

Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. French-Speaking Club for the Study of Portal Hypertension.

OBJECTIVE: Beta-blockers have been shown to reduce portal pressure in patients with cirrhosis and limit the development of portosystemic shunts in portal hypertensive animals. Thus, a randomized double-blind trial was conducted to evaluate propranolol in the prevention of the development of large oesophageal varices in patients with cirrhosis without varices or with small varices. METHODS: One hundred and two patients received long-acting propranolol (160 mg/day) and 104 patients received a placebo. At inclusion, there was no significant difference between the two groups in terms of clinical characteristics or biochemical tests. At 2 years, the size of varices was estimated on video recordings. RESULTS: One-third of the patients were lost to follow-up, and 95%/97% of the remaining patients were compliant in the propranolol and placebo groups, respectively. At 2 years, the proportion of patients with large varices was 31% in the propranolol group and 14% in the placebo group (P< 0.05). Three and four patients bled in the propranolol and placebo groups, respectively, and nine and ten died, respectively. CONCLUSION: This trial suggests that propranolol administration cannot be recommended for the prevention of the development of large oesophageal varices in patients with cirrhosis; thus other studies are needed in selected subgroups of patients.

[Decrease of fecal beta-galactosidase activity in Crohn disease]. / L'activité bêta-galactosidasique fécale est diminuée au cours de la maladie de Crohn.

An increased degradation of colonic mucus by bacterial enzymes might participate in the development of mucosal lesions in inflammatory bowel disease. The biodisponibility of drugs used in the treatment of such disease relies upon the metabolic activity of colonic bacterial flora. This activity can be indirectly assessed by measuring fecal enzymatic activities. The aim of this study was to compare fecal beta-galactosidase (beta-gal) activity in controls, in patients suffering from extradigestive inflammatory disease and in patients with Crohn's disease (CD). Three groups were studied including 11 healthy volunteers (6 F, 5 M) mean age 29 years (21-37), 20 patients with rheumatoid arthritis (RA) (17 F, 3 M), mean age 61.5 years, and 34 patients with non operated CD (21 F, 13 M) mean age: 27 years (13-50). The Crohn disease activity index (CDAI) was > 150 in 24 and < 150 in 10. beta-gal activity was measured in fecal extracts by its ability to hydrolyze paranitrophenyl beta-D-galactopyranoside and expressed as units of enzymatic activity/gram of fecal proteins. beta-gal activity was significantly decreased in patients with CD (16 +/- 4.5 U/g) (m +/- sem) as compared with patients with RA (353 +/- 64 U/g) (P < 0.0001) and to controls (263 +/- 40 U/g) (P = 0.002). beta-gal activity was not significantly different in controls and in patients with RA. Patients with active CD had a significantly lower beta-gal activity than patients with quiescent CD (9.5 +/- 3.7 U/g vs 31.4 +/- 11.5 U/g) (P = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

[Importance of liver puncture biopsy and endoscopic retrograde cholangiography in patients with chronic anicteric unexplained cholestasis. A retrospective study in 79 patients]. / Intérêt de la ponction-biopsie hépatique et de la cholangiographie rétrograde endoscopique chez les malades ayant une cholestase chronique anictérique inexpliquée. Etude rétrospective chez 79 malades.

AIM: To determine the diagnostic value of systematic liver needle biopsy and endoscopic retrograde cholangiography in patients with unexplained chronic anicteric cholestasis. METHODS: Seventy nine patients presented with anicteric cholestasis for over 6 months as defined by: a concomitant increase in at least 2 of 3 cholestatic enzymes (GGT, alkaline phosphatase, 5'nucleotidase); a low cytolytic ratio (ALT/AP (xN/xN) < or = 5); and negative test results (normal ultrasound scan; no antimitochondrial antibodies, viral, drug-induced, or toxic hepatitis, or known ulcerative cholitis). Based on liver biopsy and endoscopic retrograde cholangiography, 5 groups were determined; group A: normal liver biopsy and endoscopic retrograde cholangiography; group B: primary sclerosing cholangitis with histological biliary lesions; group C: primary sclerosing cholangitis with normal histology; group D: histologic biliary lesions alone; group E: other (aspecific histologic lesions, isolated anomalies of intrahepatic bile ducts on endoscopic retrograde cholangiography). RESULTS: Diagnosis of cholestasis was fortuitous in 43% of cases. Group A: 5 patients had normal liver biopsy and endoscopic retrograde cholangiography; group B (10 patients): 5 with destructive cholangitis, 5 with degenerative cholangitis, associated with portal fibrosis in 90%; group C: none of the patients had primary sclerosing cholangitis with normal histology; group D: 39 patients {idiopathic ductopenia (1), Caroli's disease (1), benign recurrent cholestasis (1), regenerative nodular hyperplasia (4), destructive cholangitis without ductopenia (7), degenerative cholangitis (15), ductular proliferation (10)}; group E: 24 patients with aspecific histologic lesions, and one patient with isolated anomalies of the intrahepatic bile ducts on endoscopic retrograde cholangiography. CONCLUSIONS: In the present population: a) 13% presented with intense cholangitis and primary sclerosing cholangitis on endoscopic retrograde cholangiography; b) 49% presented with various histologic biliary lesions without primary sclerosing cholangitis. We conclude that in chronic anicteric cholestasis of unexplained origin, first choice work-up should include liver biopsy, and endoscopic retrograde cholangiography should only be performed when intense histologic cholangitis is observed.

[Pregnancy after hepatic transplantation: what is the maternal risk?]. / Grossesse après transplantation hépatique: quel est le risque maternel?

OBJECTIVES AND METHODS: We report 7 pregnancies which occurred from 1988 to 1995 in 5 women who underwent liver transplantation. The immunosuppression regimen associated cyclosporine, azathioprine and prednisone. RESULTS: Mean age at conception was 25. During pregnancy, cholestasis occurred in 2 women. None of the patients experienced rejection. An increase in serum creatinine was observed in 3 cases. Serum uric acid increased in the third trimester of pregnancy in 6 cases, associated with arterial hypertension in 3 cases. In 4 cases, toxemia led to premature delivery. Seven childbirths occurred between the 34th and 38th week of gestation, by vaginal delivery (n = 3) or caesarean section (n = 4). Newborn weights ranged from 1,350 g to 3,100 g. A favorable outcome was observed in all mothers, with a follow-up ranging from 2 months to 7 years after delivery. CONCLUSION: These results suggest that a successful pregnancy is possible after liver transplantation in young women with normal hepatic function and treated with cyclosporine. The risk of toxemia is mainly related to renal function before pregnancy.

[Sicca syndrome and hepatitis C virus infection: a Gougerot-Sjögren pseudo-syndrome?]. / Syndrome sec et infection par le virus C de l'hépatite: un pseudosyndrome de Gougerot-Sjögren?

These last years, different virus have been incriminated in the etiopathogeny of the primary-Sjögren's syndrome and more particularly the hepatitis C virus. We have led a prospective study over 23 patients presenting a primary Sjögren's syndrome, searching for a sign of infection by the hepatitis C virus and over 23 patients presenting an active chronic hepatitis C virus searching for a Gougerot-Sjögren syndrome. The overcoming of the hepatitis C virus in the Sjögren group was 4.7% which was not significatively higher than in our sample of population. Parallelly, the search of the Sjögren's syndrome, in the hepatitis C virus group, found 4 patients (feminine, average age 48.5 years old) whose clinical board was compatible with this diagnostic. Antinuclear antibodies have not been found in any of the 23 patients. The lymphocytic typing of the infiltrate in the minor salivary glands biopsies showed a predominance of the CD8 lymphocytes in a proportion of 2/1, contrasting with what is observed in primary Sjögren's syndrome. We concluded that hepatitis C virus may be more associated with a chronic lymphocytic sialadenitis than an authentic primary Sjögren's syndrome.

[Glycoforms of alpha-1 antichymotrypsin in infectious process. Diagnostic value and follow-up]. / Etude des glycoformes de alpha 1-antichymotrypsine au cours des processus infectieux. Valeur diagnostique et suivi évolutif.

OBJECTIVES: Three alpha 1-antichymotrypsin (alpha 1-ACT) glycans have been identified. We followed their levels during the septic processes in 24 patients in order to determine their diagnostic value in correlation with C-reactive peptide in patients with infection. METHODS: Sera were collected for assay on days 0, 3 and 6 after starting antibiotics. Erythrocyte sedimentation rate, alpha 1-ACT and C-reactive protein were determined. RESULTS: Erythrocyte sedimentation rate changed little while C-reactive protein fell sharply as in other inflammatory processes. Crossed immunoaffinoelectrophoresis showed a decreased formation of the Con-A non reactive fraction which disappeared rapidly after initiating antibiotics. Glycan microheterogeneity returned to normal at 6 days while C-reactive protein and alpha 1-ACT were still elevated. CONCLUSION: Synthesis and glycosylation of alpha 1-ACT are independent. Study of alpha 1-ACT glycan microheterogeneity may provide a useful test in the diagnosis of inflammatory processes of unknown origin and may be helpful in following-up patients with sepsis.

Autoimmune hepatitis and multiple sclerosis: a coincidental association?

In the present study we report, as part of a large multiple sclerosis (MS) cohort (1800 patients), three cases of untreated patients who developed autoimmune hepatitis (AIH). The prevalence of AIH in the general population is about 0.0169% and seems to be higher in our MS cohort (0.17%). We suggest that a liver biopsy should systematically be performed in untreated MS patients with a sustained increase of liver enzyme.

Impaired secretion and mRNA expression of monokines by alveolar macrophages from nonsmoking patients with alcoholic liver cirrhosis.

Alveolar macrophages (AM) exposed to microorganisms secrete cytokines that are important to lung defense. Since alcoholic liver cirrhosis (ALC) patients are susceptible to lung infections, the ability of AM in such patients to produce the cytokines tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 was evaluated by mRNA expression and protein secretion. Adherent AM from ALC and alcoholic patients and controls were cultured with and without lipopolysaccharide (LPS): Mean cytokine levels in ALC and alcoholic subjects were not significantly different than in controls. However, LPS-stimulated AM from 13 of 29 ALC patients exhibited a reduced ability, compared with that from controls, to secrete the cytokines (P < .05 for all 3). Specific mRNA expression was also impaired in the 13 patients, and their liver diseases were more severe than those of other patients. Impaired cytokine production by AM in ALC patients with severe cirrhosis may account for their increased susceptibility to lung infections.

Hepatic iron overload: diagnosis and quantification with MR imaging.

OBJECTIVE: The aim of this study was to assess the sensitivity of MR imaging in the diagnosis of liver hemochromatosis and its ability to quantify hepatic iron concentration (HIC). SUBJECTS AND METHODS: MR images were prospectively obtained in 58 patients suspected to have hemochromatosis. We used a scanner with a 0.5-T magnet and two sequences: gradient-echo T1-weighted (400/12 [TR/TE], 90 degrees flip angle) and gradient-echo T2*-weighted (700/30, 30 degrees flip angle) sequences. Measurement of the liver-to-muscle signal-intensity ratio was compared with the HIC value measured at biopsy for each patient. RESULTS: Both MR sequences showed significant correlation between decreased signal-intensity ratios and increased HIC (r = -.87 for T1-weighted sequences and r = -.74 for T2*-weighted sequences). The sensitivity and specificity of the T2*-weighted sequence (signal-intensity ratio < 0.8) to detect iron overload (HIC > 36 mumol/g) were 91% and 88%, respectively. The best correlation was obtained with T2*-weighted sequences, when patients had an HIC less than 100 mumol/g (r = -.71); with T1-weighted sequences, the best correlation was obtained when patients had an HIC of 100-324 mumol/g (r = -.67). We found a significant correlation between the HIC revealed on MR images, calculated from both sequences, and that measured at biopsy when patients had an HIC of less than 300 mumol/g (r = -.93, p < .01). CONCLUSION: MR imaging shows promise in differentiating normal from abnormal hepatic iron concentration and in grossly quantifying moderate degrees of hepatic iron overload.

Simultaneous determination of pulmonary and intestinal permeability in patients with alcoholic liver cirrhosis.

The aim of this prospective study was to assess pulmonary and intestinal permeability (PP and IP, respectively) in patients with alcoholic liver cirrhosis (ALC). Thirty-five non-smoking patients with biopsy-proven ALC were included (mean grade B in Child's classification). None had a previous history of pulmonary disease and all had a normal chest radiograph and computed tomography scan. Lung function tests and bronchoalveolar lavage (BAL) were also performed. The PP was studied by measuring the lung to blood clearance of inhaled 99mTc-DTPA aerosol. Clearance half-time (T 1/2, in minutes) and residual activity (RA in %) were obtained from exponential fitting of the right pulmonary clearance curve. IP was concurrently evaluated by measuring the urinary recovery of ingested 51Cr-EDTA, according to Bjarnason's technique and expressed as a percentage of the total oral dose. Results were compared with those obtained in non-smoking healthy control subjects. PP was significantly (P<0.05) increased in patients with ALC (T 1/2 65.9 +/- 32.2 min, RA 87.1% +/- 6.7%) versus control subjects (T 1/2 85.2 +/- 20.8 min, RA 92.8% +/- 2.6%). IP was not significantly different between patients and controls (2.39% +/- 2.20% vs 1.74% +/- 0.81%). A significant correlation (P<0.05) was found between PP and total cell number in BAL and total lymphocyte number in BAL. In conclusion, in patients with ALC, PP is increased without any association with IP, the severity of cirrhosis according to Child's classification or the results of pulmonary function tests. These findings may reflect primary involvement of the alveolar epithelium. In patients with ALC, PP is correlated with total cell number and total lymphocyte number. Increased PP may be due to activated cytotoxic lymphocytes and/or abnormal macrophage activity.