Hemochromatosis: Clinical sciences

Hemochromatosis, or simply iron overload, is a condition associated with excess iron deposition throughout the body.

In the early stage, hemochromatosis is usually asymptomatic, but over time, accumulated iron leads to long-term oxidative stress and eventual tissue fibrosis and organ dysfunction. The most commonly affected organs include the liver, heart, joints, endocrine organs, and the skin.

Now, based on the underlying cause, hemochromatosis can be classified as primary and secondary. Primary hemochromatosis, also known as hereditary hemochromatosis, is an autosomal recessive disorder caused by mutations in genes that control iron absorption; while secondary hemochromatosis is associated with underlying causes of iron overload, such as chronic liver disease, anemia, or excessive iron supplementation.

If your patient presents with a chief concern suggesting hemochromatosis, your first step is to perform a focused history and physical examination. Typically, your patient will report fatigue in combination with symptoms based on the organ that’s affected. In most cases, your patient will also report skin changes like bronzing!

As iron accumulates in the skin, it stimulates melanocytes to produce melanin, which eventually results in slate gray pigmentation that primarily affects the face, neck, genital region, and extensor surfaces of forearms and lower legs.

Next, iron deposition in joints can result in joint pain, especially in the digits at the second and third metacarpophalangeal joints and in the knees. Additionally, it can affect the heart, causing cardiomyopathy and symptoms such as chest pain, shortness of breath, and dyspnea on exertion.

Additionally, there might be a history of alcohol use, liver disease, diabetes mellitus, or a family history of hemochromatosis. The physical examination could reveal bronze skin discoloration, joint swelling, as well as signs of cardiomegaly and hepatomegaly!

Now, here’s our first clinical pearl! In some individuals, iron accumulation can affect the pituitary gland and lead to hypogonadotropic hypogonadism. In such cases, patients will report decreased libido, impotence, or amenorrhea. Additionally, the physical exam may reveal small testicular size, gynecomastia, and reduced body hair.

Now, with these findings, you should suspect hemochromatosis. Your next step is to order labs including serum ferritin, iron, and total iron-binding capacity, or TIBC. Next, calculate a transferrin saturation, or TSAT, which estimates the degree to which iron-transport protein transferrin is saturated with iron! Calculate TSAT by dividing the serum iron by TIBC and multiplying the quotient by 100.

Let’s take a look when the serum ferritin level is less than 300 micrograms per liter. Now, if the serum ferritin level is less than 300 micrograms per liter, and the TSAT is less than 45%, there’s no iron overload so you should consider alternative diagnoses.

Here’s a high-yield fact! In addition to being an iron transport protein, ferritin is also an acute phase reactant, meaning it might be elevated in acute inflammatory conditions, such as infection; or chronic inflammation like rheumatoid arthritis. So, if the serum ferritin level is elevated, but the TSAT is normal or low, you should consider inflammation as a possibility. However, if the serum ferritin is normal and the TSAT is elevated, this points to an early stage of hemochromatosis.

Let’s take a look when the serum ferritin is 300 micrograms per liter or higher. If the serum ferritin is 300 micrograms per liter or higher, and the TSAT is 45% or more, you should diagnose hemochromatosis. Next, order HFE genetic testing to determine whether your patient has primary or secondary hemochromatosis.

Let’s take a look at HFE gene mutation. Keep in mind that hereditary hemochromatosis is most commonly diagnosed early in biological males at around the age of 40, or biological females at the age of 60. This is because, in biological females, some iron is lost during menstruation and pregnancy, which helps eliminate excess iron until they enter menopause.

Now, here’s a clinical pearl to keep in mind! The absence of the HFE gene mutation doesn't always rule out hereditary hemochromatosis. While uncommon, your patient might have hereditary hemochromatosis due to mutations in other gene loci involved in iron metabolism. This condition is known as non-HFE hereditary hemochromatosis. If you suspect it, obtain an MRI of the liver or liver biopsy to evaluate if there are increased iron deposits, and you can order non-HFE genetic testing.