Hemochromatosis

Hereditary hemochromatosis (HH) is a genetic disease caused by abnormal levels of iron. It is regarded as more common than most people think or is underdiagnosed. It can cause liver disease, arthritis, pituitary disease and abnormal skin color.

HH is a term generally used to define a group of autosomal recessive genetic disorders characterized by iron accumulation in parenchymal organs, primarily the liver, which can potentially result in impaired organ structure and function. In recent years, hepcidin has been identified as the key hormone that controls the saturation of plasma transferrin with iron (transferrin saturation). Hepcidin deficiency causes increased transferrin saturation, which is the unifying feature and principal biochemical finding of all forms of HH. [2]

Genes that stimulate hepcidin production such as HFE, HJV and TFR2 are therefore associated with hemochromatosis. [2]

IRON PANEL TESTS

The following make up the Iron Panel Test. These tests look at serum ferritin, total-iron-binding-capacity, transferrin, hemoglobin, and serum iron. These tests need to be taken as a panel, not independently, to receive a comprehensive and accurate assessment of a potential hemochromatosis diagnosis. [1]

SERUM IRON (SI)

This test is best conducted after fasting for at least three hours. Also, iron or vitamin C supplements should be discontinued at least three days before taking the test. Do not discontinue other medication unless your doctor tells you to. [1]

SERUM FERRITIN (SF)

This test measures the amount of iron contained or stored in the body. Serum ferritin reference ranges are different for adults and children. For adults, the ideal range is 50-150 ng/ml. [1]

TOTAL IRON BINDING CAPACITY (TIBC)

This test tells how well your body can bind to iron. Serum iron divided by TIBC x 100% gives you important information about the transferrin-iron saturation percentage (TS%). TS% is usually 25-35%; in some people with iron overload, the TS% is very high. There are other types of iron overload where the TS% is normal. [1]

HEMOGLOBIN (Hgb)

Hemoglobin value determines the absence or presence of anemia. It does not quantify iron but hemoglobin levels are vital to determining the therapy for iron reduction (or replenishment.)  In the case of iron reduction Hgb needs to be sufficient for blood removal otherwise, iron chelation might be considered.  [1]

TRANSFERRIN (TF)

Transferrin is sometimes included in an iron panel: transferrin is a protein that transports iron from the intestine into the blood. [1]

Gene testing

Example of results from a patient: 

HEREDITARY HEMOCHROMATOSIS DNA MUT

RESULT: POSITIVE FOR ONE HFE GENE PATHOGENIC VARIANT: C282Y

(HETEROZYGOTE)

Interpretation: One copy of the C282Y pathogenic variant in the HFE gene was detected. This patient is negative for the H63D pathogenic variant. Individuals with this genotype may have elevated serum transferrin iron saturation levels. This result reduces the likelihood of hereditary hemochromatosis (HH). However, it does not rule out the presence of other pathogenic variants within the HFE gene or a diagnosis of HH. The risk of this individual to carry an HFE pathogenic variant other than those tested in this assay depends greatly on family and clinical history as well as ethnicity. This assay does not test for other primary or secondary iron overload disorders. Consider genetic counseling and DNA testing for at-risk family members.

HFE-related HH

The vast majority (typically >90%) of patients with clinically characterized hereditary hemochromatosis (HH) are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. By far the most common, well-defined and prevalent form of HH is HFE-related HH, associated with homozygosity for the A allele in the single nucleotide variant rs1800562, NG_008720.2:g.10633G>A; NM_000410.3:c.845G>A; NP_000401.1:p.Cys282Tyr), most commonly referred in the literature as C282Y (p.C282Y according to the recommended nomenclature). This form of HH is particularly common in Caucasians where 1 in 200–300 individuals are homozygous for p.C282Y. [2]

Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. [2]

LIVER BIOPSY

In the past, liver biopsy was widely used to diagnose hemochromatosis. Today, liver biopsy is not necessary to diagnose the inherited form; DNA tests are available to determine if a person has genetic hemochromatosis. Liver biopsy remains the gold standard for assessing liver health. Other less invasive diagnostic aids are available; these should be discussed with a medical specialist such as a gastroenterologist.