[Behavioral activation programs: A tool for treating depression efficiently]. / L'activation comportementale : un outil simple et efficace dans le traitement de la dépression.

INTRODUCTION: Major depressive disorder (MDD) is a debilitating disorder, and its treatment often requires complex and costly psychological therapies. Behavioral activation (BA) is a simple, effective and affordable psychotherapy recommended in the treatment of MDD. OBJECTIVES: (i) Explain the theoretical basis of BA and its application in clinical practice. (ii) Review the randomized controlled trials examining BA as a treatment for MDD through a systematic search of the existing literature. METHODS: Medline and ClinicalTrials databases were searched with the following keywords: ("behavioral activation" OR "behavioural activation") AND ("therapy" OR "psychotherapy"). (i) Articles describing BA's theoretical foundations and principles of therapy were selected. (ii) Randomized controlled trials studying BA as a treatment for depression were selected according to the PRISMA criteria. RESULTS: (i) BA is a behavioral therapy that helps patients to increase their behaviors towards rewarding and/or pleasant activities, and to decrease avoidant behaviors maintaining negative affects by negative reinforcement. BA also tends to increase behaviors towards life-goals used as positive reinforcement contingencies. BA is a brief and cost effective therapy, which can be evaluated by specific psychometric scales. (ii) BA has a strong therapeutic effect in MDD as evaluated by several randomized controlled trials of good quality. CONCLUSION: BA is a simple, affordable and effective treatment for MDD. Data is insufficient to provide proof for the interest of using commitment to life-goals as reinforcement contingencies. Behavioral inhibition is encountered amongst several psychiatric disorders and more studies should be conducted to discuss its use for other diseases such as schizophrenia or anxiety disorders.

Venesection therapy of insulin resistance-associated hepatic iron overload.

BACKGROUND/AIMS: The association of hepatic iron overload with metabolic disorders has been coined as the insulin resistance-associated hepatic iron overload syndrome (IR-HIO). METHODS: Fifty-six IR-HIO patients were phlebotomized either weekly (n = 14) or bimonthly (n = 42) and compared with C282Y homozygotes and with ten IR-HIO patients treated by a low calorie diet alone. RESULTS: In venesected patients, the median amount of mobilized iron was 0.6 g in 2.8 months in females and 1.8 g in 5 months in males. Mobilized iron did not differ depending on the frequency of venesections or HFE genotype. When compared with C282Y homozygotes, IR-HIO patients had a similar amount of mobilized iron, but three-fold serum ferritin levels. The presenting symptoms (chronic fatigue and/or polyarthralgias) improved in 6/7 patients. Phlebotomies were well tolerated. In patients treated by a low calorie diet, serum ferritin levels remained stable. CONCLUSIONS: In IR-HIO patients, body iron stores are significantly increased, overestimated by serum ferritin, not modified by a low calorie diet, and safely removed by phlebotomies. Based on these data and on studies indicating that iron excess is associated with increased risk for hepatic fibrosis, cancer and cardiovascular disorders, venesection therapy can be recommended in IR-HIO patients.

Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients.

The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload. We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis. Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.

Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region.

The gene responsible for hemochromatosis (HFE) has been identified on the short arm of chromosome 6, 4.5 Mb telomeric to HLA-A. A major mutation C282Y is closely correlated with the disease, as it accounts for 68 to 100\% of the cases of hemochromatosis. Nevertheless, some C282Y homozygotes subjects have no clinical or biological expression of the disease. Moreover, in Northern European populations a large discrepancy is observed between the number of C282Y homozygotes and the number of diagnosed hemochromatosis patients, suggesting incomplete penetrance of the mutation. To localize and identify the modifying genes, we investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients. Genomic DNA from 20 C282Y homozygotes (10 patients and 10 siblings presenting no or minor biological abnormalities) were studied. Five polymorphisms from the HFE gene were determined by PCR restriction. Extended haplotypes of the 6p21.3 region were constructed with 10 microsatellite markers. All the C282Y homozygotes shared the same HFE polymorphism. The haplotypes presented no significant difference between the probands and their unaffected relatives. These studies suggest that neither HFE polymorphism nor genes surrounding HFE are able to modulate HFE expression.

Clinical aspects of hemochromatosis.

Hemochromatosis is one of the most frequent genetic diseases among the white populations, affecting one in three hundred persons. Its diagnosis has been radically transformed by the discovery of the HFE gene. In a given individual, the diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST. Family screening is mandatory, primarily centered on the siblings. The treatment remains based on venesection therapy which improves many features of the disease (one of the most refractory, however, being the joint signs) and permits normal life expectancy provided the diagnosis is established prior to the development of cirrhosis or of insulin-dependent diabetes. In view of the prevalence, the non-invasive diagnosis, the spontaneous severity and the efficacy of a very simple therapy, hemochromatosis should benefit from population screening. This screening could be based, first, on the assessment of transferrin saturation, followed - when elevated - by the search for the C282Y mutation. The discovery of the HFE gene has also paved the road for the individualization of other types of iron overload syndromes which are not HFE-related.

[Genetic hemochromatosis and the HFE gene]. / Hémochromatose génétique et gène HFE.

The discovery of the HFE gene has lead to considerable improvement in the understanding and the management of genetic hemochromatosis. More than 90% of well-defined patients are homozygous for the C282Y mutation, and genetic testing has become an important diagnostic tool. The significance of the other mutations in the HFE gene remain controversial: only C282Y/H63D compound heterozygotes could present with a phenotype compatible with hemochromatosis, but with a mild expression and a low penetrance. The link between iron overload and HFE mutation is explained by the interaction between HFE protein, beta-2-microglobulin and transferrin receptor, which is abolished by the C282Y mutation, but is not yet fully understood.

[Iron overload and public health]. / Surcharges en fer et santé publique.

Genetic hemochromatosis, due to its frequency (about 300,000 cases in France) and to its severity, must be considered as a public health burden. Its curability--insofar as its diagnosis has been made early--and the disposal of non invasive and reliable phenotypic (transferrin saturation) and genotypic (HFE C282Y mutation) tests make its diagnosis easy. Thus, diagnosis faced with early clinical and biological symptoms must be promulgated as screening in probant families. General screening is still hampered by ethical and socio-economic obstacles, but should be evaluated in large prospective studies. Otherwise, the recently described insulin resistance-associated liver iron overload syndrome might account for epidemiological associations that have been reported between increased body iron stores and cancerous, cardio-vascular and hepatic disorders. This might extend markedly the impact of iron overload in public health and lead to broaden screening and prevention to all iron overload conditions.

[Genetics and physiopathology of hemochromatosis]. / Génétique et physiopathologie de l'hémochromatose.

Thanks to the discovery of the HFE gene and of its mutations, it is now established that the most frequent form of hemochromatosis is related to homozygosity for the mutation C282Y, and that other types of hemochromatosis, unrelated to HFE mutations, do exist such as the juvenile hemochromatosis. From a pathophysiological standpoint, the C282Y mutation impairs HFE protein expression at the surface of the membrane and disturbs the cellular entry of iron (carried by circulating transferrin) into the cryptic duodenal cell. This, in turn, is likely to lead to an aberrant programmation of the degree of iron influx from the digestive lumen into the apical duodenal cells. The resulting hyperabsorption, which forms the basis of iron overload in hemochromatosis, is likely to implicate an overexpression of the transmembrane iron carrier DMT1. It is remarkable to observe that these major improvements in the knowledge of hemochomatosis have been accompanied by similar improvements in the understanding of normal iron metabolism.

[Diagnosis and treatment of genetic hemochromatosis]. / Diagnostic et traitement des hémochromatoses génétiques.

Genetic hemochromatosis is an autosomal recessive disease, characterized by an increased iron absorption, leading to progressive iron overload. The fully expressed phenotype comprises fatigue, skin pigmentation, liver disease with hepatomegaly, cirrhosis and hepatocellular carcinoma, and diabetes. Arthralgias are frequent, cardiopathy or impotence may occur. This presentation is now unfrequent with earlier diagnosis, and patients are often asymptomatic--with only biochemical expression--or pauci-symptomatic (mild fatigue, arthralgias or increased transaminases). Transferrin saturation is always increased. Serum ferritin is proportional to iron burden. Diagnosis is now easy, since most patients are homozygote for the C282Y mutation of the HFE gene. Liver biopsy can be useful to quantify iron overload and assess liver fibrosis. The disease can be lethal due to liver disease, carcinoma or heart disease, but life expectancy goes to normal if patients are treated before the occurrence of cirrhosis. Treatment relies on regular venesections. Familial screening is essential.

[Iron in the era of molecular biology]. / Le fer à l'âge de la biologie moléculaire.

Identification of the HFE gene and its C282Y and H63D mutations has improved the classification of iron overload disorders. Inherited hemochromatosis is due mainly, or perhaps only, to C282Y homozygosity, whereas nonhemochromatosis forms of iron overload are due to other HFE mutations and are usually responsible for mild overload precipitated by another factor such as cirrhosis or insulin-resistance. In practice, the diagnosis of inherited hemochromatosis rests on demonstration of homozygosity for the C282Y mutation; in this setting, the role of liver biopsy is to evaluate the prognosis by looking for fibrosis. In patients who are not homozygous for the C282Y mutation but have severe iron overload, causes other than hemochromatosis should be looked for before the extremely remote possibility of nonC282Y-related hemochromatosis is considered; here, liver biopsy remains of considerable diagnostic usefulness.

[The diagnosis of hemochromatosis in the era of the gene]. / Le diagnostic de l'hémochromatose à l'heure du gène.

The discovery of the hemochromatosis gene has deeply changed and simplified the diagnosis of the disease. In a given individual, establishing the diagnosis relies, from now on, on a simple blood sample showing the couple: elevated transferrin saturation and homozygous C282Y mutation (= C282Y +/+). Liver biopsy should only be performed when iron overload is massive in order to detect cirrhosis (or bridging fibrosis), i.e. in a prognostic view. Practically, liver biopsy is confined to the following two situations: when the C282Y +/+ patient exhibits hepatomegaly and/or an increase in serum transaminases and/or a serum ferritin level above 1,000 micrograms/L; whenever, despite a strong bio-clinical suspicion of iron overload, genetic testing does not show the expected homozygosity for C282Y. At the family level, evaluating the risk for hemochromatosis is now "instantaneous" thanks to genetic testing. One must, however, keep in mind in interpreting the data of the family members that: clinical expression of the homozygous status is not constant; heterozygosity for C282Y does not per se lead to significant iron overload, but may constitute a co-factor exacerbating (or increasing the risk of) other hepatic or non hepatic diseases. Heterozygosity exposes also to the risk of homozygosity among the offspring; this knowledge of C282Y status must be balanced by the negative impact from the standpoint of possible societal genetic discrimination.

Insulin resistance-associated hepatic iron overload.

BACKGROUND & AIMS: Hepatic iron overload has been reported in various metabolic conditions, including the insulin-resistance syndrome (IRS) and nonalcoholic steatohepatitis (NASH). The aim of this study was to show that such hepatic iron overload is part of a unique and unrecognized entity. METHODS: A total of 161 non-C282Y-homozygous patients with unexplained hepatic iron overload were included. We determined the age; sex; presence of IRS (1 or more of the following: body mass index of >25, diabetes, or hyperlipidemia); serum iron tests and liver iron concentration (LIC; reference value, <36 micromol/g); liver function test results; C282Y and H63D HFE mutations; and liver histological status. RESULTS: Patients were predominantly male and middle-aged. Most (94%) had IRS. Transferrin saturation was increased in 35% (median, 42%; range, 13%-94%). LIC ranged from 38 to 332 micromol/g (median, 90 micromol/g), and LIC/age ratio ranged from 0.5 to 4.8 (median, 1.8). Allelic frequencies of both HFE mutations were significantly increased compared with values in normal controls (C282Y, 20% vs. 9%; H63D, 30% vs. 17%), only because of a higher prevalence of compound heterozygotes. Patients with no HFE mutations had similar degrees of iron overload as those with other genotypes, except for compound heterozygotes, who had slightly more iron burden. Steatosis was present in 25% of patients and NASH in 27%. Portal fibrosis (grades 0-3) was present in 62% of patients (grade 2 or 3 in 12%) in association with steatosis, inflammation, and increased age. Sex ratio, IRS, transferrin saturation, and LIC did not vary with liver damage. Serum ferritin concentration, liver function test results, and fibrosis grade were more elevated in patients with steatosis and NASH than in others, but LIC and allelic frequencies of HFE mutations were similar. CONCLUSIONS: This study shows that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an IRS irrespective of liver damage.

A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria.

BACKGROUND/AIMS: The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings. METHODS: In 217 patients, the phenotypic diagnosis of hemochromatosis was based on strict bioclinical and/or histological criteria, and their genotypic profile (C282Y and H63D mutations) was determined. RESULTS: 1) 209 of the 217 probands were C282Y +/+. In 33 cases, an HFE-identical sibling was identified. Two of them had neither a clinical nor a biochemical phenotypic profile of hemochromatosis in the absence of any external factor which might have attenuated this expression. 2) Eight patients (seven males) were not C282Y +/+. Their genotypic profiles were: (C282Y +/-): six cases (four were H63D +/- and two H63D -/-); (C282Y -/-): two cases (one was H63D +/+, one H63D +/-). Phenotypic expression consisted of six cases of mild liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload (one with alcoholic cirrhosis). Three HFE-identical siblings were identified, none of them presenting with iron excess. CONCLUSIONS: In our population: 1) The classical phenotypic criteria fitted, in 96.3% of cases, with a homogeneous genotypic entity defined by homozygosity for the C282Y mutation. Incomplete penetrance of the homozygous status was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might present with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.