CRISTIANO MARIA FRANCUCCI,*CRISTINA GATTI,* ANDREA CAMILLETTI,*PAOLA FISCALETTI,* RENATA CAUDARELLA,{AND MARCO BOSCARO*From the *Division of Endocrinology, PolytechnicUniversity of Marche, Ancona, Italy; and the Department of Clinical Medicine and AppliedBiotechnology ‘‘D. Campanacci,’’ Alma MaterStudiorum, University of Bologna, Bologna, Italy.Hereditary hemochromatosis (HH) is the mostcommon inherited metabolic disease in the whitepopulation. It is a disorder of iron regulation thatbrings about an excess absorption of dietary iron, whichgradually accumulates in the parenchymal cells of liver,pancreas, heart, anterior pituitary, and gonads. Humaniron homeostasis depends on the coordinated functionsof numerous genes, the precise roles of which are inmany cases still obscure.Classic HH is an autosomal recessive disorderassociated with a mutation of the HFE gene, whichwas discovered in 1996 and is located on chromosome 6.The most common form of HH is related to homozy-gosity for the C282Y mutation of the HFE gene,resulting in a change of tyrosine for cysteine at aminoacid 282 (Feder et al, 1996) This mutation leads toa chain of events that may culminate in severe damageto multiple organs. The C282Y mutation is largelyconfined to whites of north European origin, and thefrequency of homozygosity decreases from the north tothe south of Europe, being lowest in Italy and theMediterranean countries (Carella et al, 1997), wherehemochromatosis is genetically heterogeneous (Pipernoet al, 1998). Another mutation of the HFE gene, termedH63D mutation, results in the substitution of aspartatefor histidine at amino acid 63 and does not appear tohave clinical effects (Gochee et al, 2002). The clinicalsignificance of compound heterozygosity for C282Y andH63D is still controversial (Rochette et al, 1999). It ispossible that several genes, other than HFE, may playa role in the disease in a few patients, presenting similarforms of iron overload which act as modifiers of thephenotype, as seen in HFE knockout mice (Bensaid etal, 2004). Therefore, it is difficult to predict whether andto what extent such a mutation will be phenotypicallyexpressed.The Online Mendelian Inheritance in Man (OMIM)database currently lists 5 types of HH (Bomform, 2002),each caused by mutations involving a different gene, butcases of iron overload have been diagnosed in thosegenes, known to be associated with this disease, thathave a normal sequence, indicating that there are stillother genes to identify.In the most extreme forms of HH, the diseasemanifests itself as cirrhosis, hepatocellular cancer,destructive arthritis, cardiomyopathy, and endocrineproblems such as diabetes mellitus and sexual dysfunc-tion due to hypogonadotropic hypogonadism. Gonadalproblems in hemochromatosis generally result from thedestructive action of hemosiderin in the anteriorpituitary (MacDonald and Mallory, 1959). A reviewby Pedersen-Bjergaard et al. on the pituitary function inhemochromatosis highlighted an insufficiency of pitui-tary gonadotropic secretion with clinical hypogonadismin 46% of the patients, a subclinical insufficiency of thegrowth hormone axis in 15%, of the lactotropic axis in8%, of the thyroid axis in 4%, and of the adrenocorticalaxis in 1.5% of the patients. Moreover, the same authorsunderlined that lactotropic, thyroid, or adrenocorticalinsufficiency was usually associated with hypogonadismor growth hormone insufficiency (Pedersen-Bjergaard etal, 1996). Hypogonadotropic hypogonadism appears tobe unusual in patients with lesser degree of hepaticsiderosis at diagnosis (McDermott and Walsh, 2005).Therefore, partial hypopituitarism alone, in the absenceof any important damage to other main parenchymal