Hemochromatosis: Clinical sciences

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Introduction0:00–1:05

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.

Focused H&P1:05–2:52

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.

Suscept hemochromatosis2:52–3:28

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.

Alternative diagnosis3:28–4:19

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.

Hemochromatosis4:19–4:43

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.

Primary hemochromatosis4:43–6:17

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.And here’s a high-yield fact!
Biopsy with Prussian blue staining shows a characteristic pattern of hepatic accumulation of iron with sparing of Kupffer cells until later in the disease.
By contrast, iron accumulation in parenteral iron overload occurs predominantly in Kupffer cells, which remove foreign debris and particles that have come from the hepatic portal system when passing through the liver.After diagnosing primary hemochromatosis, proceed with management.

Management of primary hemochromatosis6:17–8:41

This primarily relies on therapeutic phlebotomy, which involves the removal of a certain amount of blood to help reduce iron levels via hemoglobin loss.
Keep in mind that therapeutic phlebotomy can improve fatigue, skin pigmentation, as well as liver and cardiac function. However, blood removal will not improve arthralgia and endocrine complications, like diabetes and hypogonadism.
In addition to phlebotomy, counsel your patient on lifestyle modifications. These patients should avoid alcohol, as it increases the risk of cirrhosis in the already susceptible liver.
Next, encourage your patient to avoid iron supplements and vitamin C, because vitamin C enhances iron absorption! An alternative treatment option to phlebotomy is erythrocytapheresis, which involves the selective removal of red blood cells while the remaining blood components, such as proteins and thrombocytes, are saved!
Consider erythrocytapheresis in individuals with thrombocytopenia and hypoproteinemia. Finally, if there’s end-stage liver failure, consult your surgery team for liver transplantation!
Here’s another clinical pearl! Patients with hemochromatosis have an increased risk of cirrhosis and hepatocellular carcinoma, therefore, they require a thorough liver assessment.
You should suspect liver fibrosis in patients with persistently elevated liver function tests, or serum ferritin levels greater than 1000 nanograms per milliliter.
In this case, order an abdominal ultrasound with elastography, an MRI of the liver, or a liver biopsy. These tests determine fibrosis presence and degree, which can help you predict progression to cirrhosis and hepatocellular carcinoma.
Finally, you should offer genetic screening to all adult first-degree relatives, along with genetic counseling, if they have HFE gene mutations.Now that we’re done with hereditary hemochromatosis, let’s go back and take a look at individuals who have no HFE gene mutations.
In this case, diagnose secondary hemochromatosis, which is also known as secondary iron overload!Once you diagnose secondary hemochromatosis, your next step is to determine the underlying cause of iron overload.

Secondary hemochromatosis8:41–8:44

Secondary hemochromatosis causes8:44–9:33

If the patient’s history reveals alcoholic liver disease, non-alcoholic fatty liver disease, or HCV infection, diagnose secondary iron overload due to chronic liver disease!
On the flip side, if your patient has thalassemia or sickle cell disease, diagnose iron overload due to iron-loading anemia.
Sometimes your patient might report a history of multiple blood transfusions. In this case, diagnose transfusional iron overload!
Finally, if history reveals parenteral or oral iron supplementation, diagnose secondary iron overload due to excessive iron supplementation!

Management of secondary hemochromatosis9:33–10:01

Finally, let’s go over management for secondary hemochromatosis. This primarily relies on chelating agents, such as deferoxamine, deferiprone, and deferasirox.
Chelating agents bind excess iron and form complexes, which are then excreted through bile or urine. Lastly, in some cases, you can consider therapeutic phlebotomy.Alright, as a quick recap… Hemochromatosis is a condition associated with excess iron deposition throughout the body.

Review10:01–10:57

It is characterized by serum ferritin of 300 micrograms per liter or higher, and TSAT of 45% or more. Once you diagnose hemochromatosis, order HFE genetic testing.
If HFE genetic testing reveals positive HFE mutations, diagnose primary hemochromatosis. Management primarily relies on therapeutic phlebotomy, lifestyle modifications, as well as considering erythrocytapheresis.
In severe cases, consider liver transplantation. On the flip side, if no HFE mutation is present, diagnose secondary hemochromatosis, assess the underlying cause, and proceed with management.
This primarily relies on chelating agents,