Reverse cascade screening of newborns for hereditary haemochromatosis: a model for other late onset diseases?

BACKGROUND: Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFE haemochromatosis before they developed life threatening complications. METHODS: We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype. FINDINGS: In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.

[Advances in iron metabolism: a transition state]. / Données récentes sur le métabolisme du fer: un état de transition.

PURPOSE: Advances towards the understanding of gene regulation and protein function recently discovered through iron metabolism disorders are the subject of this review. CURRENT KNOWLEDGE AND KEY POINTS: Within a few years the discovery of genes that determine heritable defects of cellular iron uptake or regulation in mice as in humans have provided new insights for investigation into iron metabolism pathways. FUTURE PROSPECTS AND PROJECTS: It is still unclear how connections are made between new proteins in iron uptake, trafficking and regulation of iron homeostasis. Gene expression studies using microarrays technology in different iron conditions should help to explore iron homeostasis further.

[Molecular basis in hereditary haemochromatosis]. / Bases moléculaires des hémochromatoses génétiques.

PURPOSE: Recent discoveries in molecular mechanisms of iron metabolism have changed the classical view of hereditary iron overload conditions. We present natural mutations in newly discovered genes and related phenotypes observed in patients with different form of haemochromatosis. CURRENT KNOWLEDGE AND KEY POINTS: Most haemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Ferroportin, TFR2, hemojuvelin and hepcidin mutations also cause iron overload. Recent data support the hypothesis that haemochromatosis should no longer be considered a monogenic disease but rather an oligogenic disorder. Several results suggest that haemochromatosis could result from digenic inheritance of mutations in HFE and HAMP. FUTURE PROSPECTS AND PROJECTS: Other modifier genes probably influence penetrance in C282Y homozygous patients. Such genes could enhance or reduce the phenotypic expression in various iron overload conditions.

Comparative mutagenicity and genotoxicity of particles and aerosols emitted by the combustion of standard vs. rapeseed methyl ester supplemented bio-diesel fuels: impact of after treatment devices: oxidation catalyst and particulate filter.

Diesel exhausts are partly responsible for the deleterious effects on human health associated with urban pollution, including cardiovascular diseases, asthma, COPD, and possibly lung cancer. Particulate fraction has been incriminated and thus largely investigated for its genotoxic properties, based on exposure conditions that are, however, not relevant for human risk assessment. In this paper, original and more realistic protocols were used to investigate the hazards induced by exhausts emitted by the combustion of standard (DF0) vs. bio-diesel fuels (DF7 and DF30) and to assess the impact of exhaust treatment devices (DOC and DPF). Mutagenicity and genotoxicity were evaluated for (1) resuspended particles ("off line" exposure that takes into account the bioavailability of adsorbed chemicals) and for (2) the whole aerosols (particles+gas phase components) under continuous flow exposure ("on line" exposure). Native particles displayed mutagenic properties associated with nitroaromatic profiles (YG1041), whereas PAHs did not seem to be involved. After DOC treatment, the mutagenicity of particles was fully abolished. In contrast, the level of particle deposition was low under continuous flow exposure, and the observed mutagenicity in TA98 and TA102 was thus attributable to the gas phase. A bactericidal effect was also observed in TA102 after DOC treatment, and a weak but significant mutagenicity persisted after DPF treatment for bio-diesel fuels. No formation of bulky DNA-adducts was observed on A549 cells exposed to diesel exhaust, even in very drastic conditions (organic extracts corresponding to 500 µg equivalent particule/mL, 48 h exposure). Taken together, these data indicate that the exhausts issued from the bio-diesel fuels supplemented with rapseed methyl ester (RME), and generated by current diesel engines equipped with after treatment devices are less mutagenic than older ones. The residual mutagenicity is linked to the gas phase and could be due to pro-oxydants, mainly for RME-supplemented fuels.

Fibrosing alveolitis and hepatitis B surface antigen-associated chronic active hepatitis in a patient with immunoglobulin A deficiency.

Fibrosing alveolitis is described in a 22 year old woman with immunoglobulin A (IgA) deficiency and hepatitis B surface antigen (HBsAg)-associated chronic active hepatitis. At lung biopsy HBsAg was detected by indirect immunofluorescence in the alveolar space but not in the septal fibrosis. We discuss the possible relationships between IgA deficiency on the one hand, and HBsAg-associated lung and liver diseases on the other hand.

Hepatitis C virus infection risk factors in patients admitted in hospital emergency departments in Picardy. Value of oriented screening based on recommendations of the 'Direction Générale de la Santé'.

OBJECTIVE AND DESIGN: Oriented hepatitis C virus (HCV) screening on the basis of transfusion, previous or current parenteral drug addiction, invasive procedures, and in family members of patients with hepatitis C, was recommended in France by the 'Direction Générale de la Santé' (DGS). The aim of this study was to estimate the frequency of these risk factors in patients admitted in hospital emergency departments in Picardy. METHODS: Between 1 June and 31 July 1996, physicians of the emergency units of seven hospitals in Picardy were asked to question admitted patients about risk factors mentioned in the DGS recommendations, and to suggest a screening test when at least one of these risk factors was present. RESULTS: Among 1648 patients, 68.7% had at least one of these risk factors. Screening was accepted by 723 patients, 58.7% of those with at least one risk factor, and more than 70% of those with history of transfusion and/or drug addiction. It was immediately performed in 451, and 2.4% had anti-HCV antibodies. The prevalence of anti-HCV antibodies was 1.5% in patients without history of transfusion or drug addiction and 7.9% in those with at least one of these two risk factors. CONCLUSION: Oriented screening based on transfusion or drug addiction history seems to have better efficiency than the screening policy recommended by the DGS. Poor reliability of answers about medical history was observed probably because of stress related to emergency circumstances. A screening test proposed to patients with these major risk factors by their usual physician would be probably more efficient.

[Effect of acute administration of acamprosate on the risk of encephalopathy and on arterial pressure in patients with alcoholic cirrhosis]. / Effet de l'administration aiguë d'acamprosate sur le risque d'encéphalopathie et sur la pression artérielle chez les malades atteints de cirrhose alcoolique.

To evaluate the risk of hepatic encephalopathy and arterial hypotension in cirrhotic patients after acute administration of acamprosate, a GABA mimetic drug used in the weaned alcoholic, a randomized double-blind trial was conducted in 24 cirrhotic patients with low or moderate hepatic insufficiency (Pugh grade A or B). Twelve patients received 666 mg (2 tablets) of acamprosate and 12 received placebo. The 2 groups were similar before treatment, except for a male predominance in the acamprosate group. Tested parameters were the P100 latency of visual evoked potentials using a checkerboard pattern reversal as stimulus, the number connection test and the arterial blood pressure in upright and recumbent positions. The two first parameters were studied before and 2 hours after treatment. Blood pressure was recorded every half hour during 6 hours. No significant effect on the development of subclinical hepatic encephalopathy was noted. Nevertheless, even if some authors disagree with the GABA hypothesis of hepatic encephalopathy, it is possible that the dose was too low to induce subclinical hepatic encephalopathy. A study with more prolonged treatment could be necessary to be sure of the drug's safety in these patients. On the other hand, a transient decrease of diastolic arterial blood pressure was observed without significant systolic blood pressure modification. These results suggest that a moderate dose of acamprosate does not induce subclinical encephalopathy, but transient diastolic hypotension.

[Ultrasound study of gallbladder motility in healthy subjects. Reproducibility of the method and effect of alcohol]. / Etude échographique de la motricité vésiculaire du sujet sain. Reproductibilité de la méthode et effet de l'alcool.

The protective effect of alcohol against cholesterol cholelithiasis has been established in several epidemiologic studies. An impairment of gallbladder motility in gallstone disease has been demonstrated in animals and in man. At a daily dose of 39 g, alcohol reduces the lithogenic index of bile, but its effect on gallbladder motility is still debated. To test this potential mechanism, the effect of 20 g of alcohol on gallbladder motility was studied, using an ultrasonographic ellipsoid method in 16 healthy male subjects. The stimulus for gallbladder contraction was a Lundh test meal. Using a cross over method, this meal was ingested by each subject once with water and once with alcohol. A third set of measurements was taken in each subject after ingestion of a Lundh meal and water to test the reproducibility of the sonographic method. The gallbladder kinetics were studied for 90 minutes following ingestion of the test meal and beverage. Alcohol stimulated rapid post prandial gallbladder emptying, and accelerated gallbladder filling. This second action could result from sphincter of Oddi pressure enhancement and, perhaps, decrease of gallbladder absorption by Na+ K+ ATPase inhibition. The reproducibility of the method was good. With a decrease of lithogenic bile index, the protective effect of alcohol against biliary cholesterol cholelithiasis could be due either to stimulation of gallbladder emptying and/or acceleration of gallbladder filling.

[The estrogen-androgen profile is unchanged in men with cholelithiasis]. / Le statut estro-androgénique n'est pas modifié chez les hommes atteints de lithiase biliaire.

It is well established that cholelithiasis is more frequent in women than in men. This difference is usually explained by the effects of estrogens and progesterone on the metabolism of bile acids, biliary cholesterol secretion and saturation, and gallbladder motility. Another explanation could be a protective effect of androgens against cholelithiasis in men. To test this hypothesis, we determined the hormonal, androgenic and estrogenic, status of 15 male patients with asymptomatic gallstone disease and in 15 control patients with normal gallbladder matched for age and body weight. No significant difference in the plasma concentrations and the urinary excretion rate of sex hormones (testosterone, dihydrotestosterone, androstenedione, testosterone and androstanediol glucuronides, estradiol, estrone, total estrogens), as well as in the plasma sex hormone binding globulin, was found between the 2 groups of patients. The development of cholelithiasis in men, therefore, does not appear to be related to modification of sex steroids.

[Increased fasting gallbladder volume: a new ultrasonic sign of cirrhosis?]. / L'augmentation du volume vésiculaire à jeun: un nouveau signe échographique de cirrhose?

Ultrasound was used to calculate fasting gallbladder volume in three groups of patients: 90 with cirrhosis (alcoholic in 75 cases), 41 with non cirrhotic liver disease (alcoholic in 14 cases), and 38 controls. Gallbladder volume was evaluated according to sex, age, alcoholism, presence of gallstones, time of diagnosis, and biological tests of hepatocellular function. Mean fasting gallbladder volume was significantly higher in cirrhotic patients (45.89 +/- 32.65 ml, m +/- 1 SD) than in patients with non cirrhotic liver disease (25.31 +/- 14.08 ml) and in control subjects (21.28 +/- 10.30 ml) (P less than 0.001), but there was a great overlap between individual results in each group. No relationship was found between gallbladder volume and all clinical and biological tested parameters, except for decreased prothrombin time (P less than 0.02). Further studies are necessary to consider this ultrasound sign as an useful diagnostic tool in cirrhosis.

[Adult idiopathic ductopenia. 1 case]. / Ductopénie idiopathique de l'adulte. Un cas.

Idiopathic adult ductopenia is very rare. We report one case in a 30-year-old man, whose clinical course was characterized by jaundice and pruritus. Laboratory investigations revealed cholestasis and polyclonal hypergammaglobulinemia. Serum antinuclear, antimitochondrial, and anti-smooth muscle antibodies and serological markers for viral hepatitis were negative. Endoscopic retrograde cholangiography showed no liver or biliary tract abnormalities. Histological examination of a liver specimen showed a vanishing bile duct syndrome and moderate portal infiltration with lympho-histiocytic cells; there were no granulomas. Liver transplantation was performed due to rapid development of cirrhosis. The differential diagnosis of idiopathic adult ductopenia with small duct primary sclerosing cholangitis, auto-immune cholangiopathy, and non syndromic paucity of intrahepatic bile ducts is unclear.

[Helicobacter pylori and gastroduodenal lesions in 547 symptomatic young adults]. / Helicobacter pylori et lésions gastro-duodénales chez 547 jeunes adultes symptomatiques.

OBJECTIVES: Helicobacter pylori (H. pylori) is involved in the pathogenesis of gastric inflammatory disorders. Both antral chronic gastritis and H. pylori infection prevalence increase with age. The aim of the study was to assess the prevalence of H. pylori infection in young adults and to study the relationship between endoscopical and histological features and H. pylori infection. METHODS: The study concerned 547 young patients (age: 18-25 years), undergoing endoscopy for upper gastrointestinal symptoms. The severity and the activity of chronic gastritis was graded by histological examination of antral biopsies. The diagnosis of H. pylori infection was based on histology and culture or urease test. RESULTS: Fifty-three percent of the patients had a normal endoscopy; 44 ulcers were found: 34 duodenal ulcers and 10 gastric ulcers. H. pylori infection was detected in 34% of cases. The prevalence of H. pylori infection was 29.8% in non-ulcer patients, 50% in gastric ulcers and 91% in duodenal ulcers (P < 0.01). Duodenal ulcer, aspect of antral mosaic mucosa and nodular gastritis, were closely related to the presence of H. pylori. There was a significant relationship between H. pylori infection and both the severity (P < 0.01) and the activity (P < 0.01) of the antral chronic gastritis. The prevalence of follicular gastritis was 22% : it was present in 60% of H. pylori positive patients and 2.4% of H. pylori negative patients. H. pylori infection was more frequent in patients from Africa than in Europeans (P < 0.01). There was no significant association between H. pylori infection and different types of diets, settlements (rural vs urban) or symptoms. CONCLUSION: These results show that in the young population studied, duodenal ulcer, nodular gastritis, antral mosaic mucosa, active chronic gastric and follicular gastritis are closely related to H. pylori infection. They suggest that in the subgroup of non ulcer symptomatic patients, H. pylori prevalence is higher than in the general population.

[Seroprevalence of viral hepatitis A in at the Amiens University Hospital]. / Séroprévalence de l'hépatite virale A au CHU d'Amiens.

OBJECTIVES AND METHODS: The epidemiology of viral hepatitis A has been evolved in the past few years, resulting in an increasing number of people without immunity to this virus. Health care workers are usually considered to be a group at risk of contamination by hepatitis A. A sero-epidemiologic study was performed in 525 members of the Pediatry, Gastroenterology, Internal medicine, Digestive radiology, kitchen and maintenance department staffs in the Amiens University Hospital. The aim of this study was to describe the epidemiology of hepatitis A and to estimate the level of occupational hazard it represents in the hospital. RESULTS: Age, low education level, country of origin in an endemic region and more than 2 siblings or children were significantly associated with the presence of anti-HAV antibodies. The prevalence of 50% was similar to that observed in other hospitals, but lower than that found in the general population. Seroprevalence was not higher in departments exposed to stools (Pediatry, Digestive endoscopy and laboratories) than in others. A higher rate of seroprevalence was observed in kitchen and maintenance staffs than in medical, laboratory and Radiology staffs, in Internal medicine than in the Gastroenterology Department, and in the laboratory than in Radiology Department. These differences disappeared after adjustment for extraprofessional parameters which appeared to be most important for hepatitis A epidemiology. CONCLUSIONS: The hospital occupational hazard for hepatitis A virus did not seem higher than that observed in the general population.

[Endoscopic sclerotherapy of hemorrhagic esophageal varices. 86 cases]. / Sclérose endoscopique des varices oesophagiennes hémorragiques. 86 observations.

OBJECTIVES: Haemorrhage due to rupture of oesophageal varices is a major cause of death in patients with cirrhosis. We evaluated retrospectively our results with endoscopic sclerosis in order to evaluate recurrence, compliance and long-term survival. METHODS: Endoscopic sclerosis was performed with a flexible endoscope in 86 patients from 1986 to 1989. Ninety-nine percent of the patients had cirrhosis; they were equally distributed in the 3 Child-Pugh classes. Sclerosis was performed once a week for three weeks then once every 3 weeks until eradication. Sessions was performed during an episode of haemorrhage in 17 patients and begun after bleeding had stopped in 69 others. Mean clinical follow-up was 24 +/- 14 months and mean endoscopic follow-up, 19 +/- 15 months. RESULTS: The mean number of sessions was 5.3 +/- 3.5 (range 1-17) per patient. Haemostasis was obtained in 4 out of 17 patients treated in emergency situations. Eradication was attained in 50 patients (58%). Recurrent varices were observed in 28 of these 50 and recurrent bleeding in 13, leading to 2 deaths. Global mortality over the period studied was 36%: 24 patients died before eradication, 7 after and 2 due to extra-hepatic causes. More than two-thirds of the deaths occurred during the first 2 months, mainly after recurrent bleeding. Global actuarial survival was 70% at 12 months, 62% at 24 months and 56% at 36 months. There was a significant difference in actuarial survival between Child-Pugh classes A and B patients and Child-Pugh class C patients. CONCLUSION: Our experience and the data in the literature indicate that sclerosis can be beneficial in patients with haemorrhagic oesophageal varices, but must be carried out within the framework of comprehensive care and follow-up.

[HBsAg screening during pregnancy in the French province Picardy]. / Grossesse et hépatite B en Picardie: traçabililité du dépistage et prévalence.

OBJECTIVE: Screening for maternal hepatitis B surface antigen (HBsAg) is mandatory in France since 1992, however, no evaluation is available. We studied the traceability of HBsAg screening and its prevalence in pregnant women in Picardy for year 2006. PATIENTS AND METHODS: Traceability of HBsAg screening was studied in a sample of 1198 hospital case files, which were randomized and stratified for all the 20 clinics of the region (22,114 deliveries), both public and private. HBsAg prevalence was also studied using various registries (PMSI national database of medical acts performed during hospitalization, central pharmacies and obstetric theatres). RESULTS: The traceability of the screening was lacking in 9.9% (range: 0-34.7%, depending on the maternity clinic). The prevalence of HBsAg during pregnancy was 1.8 per 1000 women (upper limit: 4.3 per 1000) from the case files sample. Registries examination showed large variations of HBsAg's prevalence from 0 to 12.0 per 1000 (mean: 2.9; CI 95%: 7 to 17) among the region. DISCUSSION AND CONCLUSION: HBsAg traceability during pregnancy must be improved. HBsAg prevalence largely varies among maternity clinics and is a significant issue which is underestimated in France.