Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (416 page)

   Studies for diabetes

   Chondrocalcinosis (pseudogout)

   Pituitary dysfunction

   Liver function tests

   Genetic tests for HH. Note: phenotypic analysis should be the first step in screening for HH, with screening strategies including measurement of transferrin saturation and serum ferritin, before resorting to genetic testing.

   HFE genetic hemochromatosis.

   In most patients of European ancestry, HH is the result of mutations in two specific genes known as HFE, found within the major histocompatibility locus on chromosome 6. The HFE gene has two common missense mutations: the C282Y (rare in non-Caucasian populations) and the H63D found in both Caucasians and non-Caucasians) but with a less welldefined role in HH.

   Patients with a C282Y/C282Y genotype are homozygous for HH and are at risk for the phenotypic HH disease. The disease seems to have a low penetrance. The reason for the occurrence of the fully expressed penetrance of these genes remains unknown. The homozygous are generally found to have a higher prevalence of abnormal liver function tests independent of other manifestations of HH. Modifier factors may be genetic, gender, and high iron or alcohol intake.
Genetic population screening for these mutations in individuals with no clinical or biochemical signs of hemochromatosis is not recommended. Screening of families with one proband documented for HH may be helpful for discovering other members affected with the same mutations.

   Patients with a C282Y/wild-type genotype are heterozygous for HH and have less risk of iron overload.

   Patients with a C282Y/H63D genotype (one allele with each mutation) have a 60% chance of intermediate-degree IOD, and 35% have normal iron stores.

   Non-HFE genetic hemochromatosis

   Juvenile hemochromatosis (JH) is the result of a mutation in the gene HJV at chromosome 1q21. This is a rare autosomal recessive disorder similar to HH, but with onset in the second decade of life; a severe form of JH is caused by mutations in HAMP, the gene for hepcidin (in its wild form hepcidin becomes elevated in order to block iron absorption when iron stores become increased).