Haemochromatosis

Haemochromatosis is a disorder affecting iron storage in which we have excessive iron levels in the body resulting in iron deposition in tissues.

Pathophysiology

Haemochromatosis is an autosomal-recessive disorder affecting the haemochromatosis gene (HFE) on chromosome 6 which encodes for the human homeostatic iron regulator protein.

It senses and regulates the iron stores through modulation of the expression of the iron-regulatory hormone hepcidin. Hepcidin works by binding to ferroportin which is the iron export channel that transports iron out of the cells and into the bloodstream. When hepcidin binds to these channels, it breaks it down and we do not receive more iron in the blood. However, when there are issues with sensing iron stores, hepcidin is underexpressed and we get haemochromatosis as a result.

Most common mutations are:

1. C282Y - homozygotes have low hepatic hepcidin expression meaning duodenal absorption of iron continues even when there is sufficient iron storage. Macrophages also continually release iron from erythrophagocytosis.
2. H63D

There may be mutations of hepcidin, ferroportin (causing ferroportin disease), transferrin receptor 2 (causing transferrin receptor 2 haemochromatosis) or haemojuvelin (which causes juvenile haemochromatosis).

Once there is an iron overload, eventually iron will begin to deposit in organs such as the liver, heart, anterior pituitary, pancreas, joints. This causes pro-oxidant effects which damage these organs. It may lead to fibrosis of organs (however, removal of the iron will also lead to reversal of the excessive iron).

Iron physiology and interpreting iron studies:

Iron is absorbed from the duodenum. It is converted from ferric (Fe3+) → ferrous (Fe2+) iron. It is then absorbed through DMT1 channels into the enterocytes and then from the enterocytes into the circulation through ferroportin 1.

When iron is in the plasma it is then oxidised by haephestin and bound to transferrin.

Transferrin (transporter of ferric iron) transports iron in the blood and is also able to enter cells (mainly RBCs, hepatocytes and immune cells) by binding to the transferrin receptor (TfR).

Most serum iron is converted into haem in erythroid cells (precursor erythrocytes) which then combines with globin to form haemoglobin. When the RBC dies, the iron is saved by macrophages with erythrophagocytosis and the iron re-enters circulation

Iron is mainly stored as ferritin and a small portion is stored as haemosiderin.

Now let’s look at the different iron studies and what they are actually measuring:

• Serum iron - measures the ferric iron (Fe3+) that is bound to transferrin. It is a poor marker of iron levels as this level can vary greatly with many factors.
• Ferritin - as mentioned this is an intracellular storage protein of iron that indicates the total iron stores in the body.
• Elevated ferritin - is a marker of iron overload but as mentioned before, ferritin is also an acute phase reactant and can be elevated with liver disease and inflammation.
• Reduced ferritin is the most specific measure of IDA as nothing else will cause low ferritin levels. How
• Transferrin/total iron binding capacity (TIBC) - transferrin is the transporter protein of iron in the blood. The TIBC is proportionate to this. It is essentially the reverse of ferritin.
• Elevated transferrin/TIBC - marker of IDA.
• Reduced transferrin/TIBC - may indicate an acute phase reaction, liver disease or iron overload.
• Transferrin saturation - the percentage of transferrin bound to iron. It is more accurate at determining the total body iron than measuring serum iron.
• Elevated transferrin saturation - iron overload (haemochromatosis, multiple transfusions, iron-loading anaemias).
• Reduced transferrin saturation - IDA or chronic disease.

🔢 Classification

The American College of Gastroenterology has classified haemochromatosis into 4 types based on its aetiology:

⚠️ Risk factors

• Family history - screening is recommended for siblings and children of the affected patients.
• Middle age - symptoms tend to present in 40s and 50s.
• Male gender - men present at a younger age as women are “protected” from iron overload due to natural iron loss with menses and parturition.
• White ancestry
• Supplemental iron - will not cause haemochromatosis but can increase or accelerate its clinical manifestations.
• Vitamin C - large amounts of vitamin C increases iron absorption. Patients with haemochromatosis should be advised against having large amounts of vitamin C.

😷 Presentation

• Fatigue, weakness, lethargy
• Arthralgia - often affecting the 2nd and 3rd MCP joints and PIP joints, and sometimes the wrist, knee, hip and shoulder joints. X-rays of the hand may show squared-off bone ends with osteophytes, joint space narrowing, cyst formation, sclerosis, chondrocalcinosis. This is similar to osteoarthritic changes,
• Hepatomegaly - often associated with fibrosis and cirrhosis of the liver.
• Diabetes
• Hypogonadism
• In males: impotence and and loss of libido.
• In females: amenorrhoea.
• Bronzing of the skin → grey/brown skin with grey patches in the mouth most commonly occurring on the face, neck, extensor surface of forearms and dorsum of the hand, genitals and lower legs.
• Hair loss
• Memory and mood disturbances

Less common symptoms include:

• Heart failure
• Arrhythmias
• Porphyria cutanea tarda - fragile skin with bullae and blisters + liver dysfunction.

🔍 Investigations

Other investigations that may be done include:

💯 Criteria

We can divide it into 5 stages of disease according to the French Haute Autorite de Sante:

1. Stage 0: C282Y homozygosity with normal transferrin and normal ferritin and no clinical symptoms.
2. Stage 1: C282Y homozygosity with raised transferrin saturation (>45%) but normal ferritin and no clinical symptoms.
3. Stage 2: C282Y homozygosity with raised transferrin saturation (>45%) and raised ferritin (>300ng/mL in men and >200ng/mL in women) and no clinical symptoms.
4. Stage 3: C282Y homozygosity with raised transferrin saturation (>45%) and raised ferritin (>300ng/mL in men and >200ng/mL in women) and presence of symptoms that affect their quality of life.
5. Stage 4: C282Y homozygosity with raised transferrin saturation (>45%) and raised ferritin (>300ng/mL in men and >200ng/mL in women) and presence of symptoms that cause organ damage and predispose to early death.

🧰 Management

🚨 Complications

• Diabetes mellitus
• Liver cirrhosis
• Hypogonadism
• Cardiomyopathy - improves with venesection.

• HCC
• Hypothyroidism
• Chondrocalcinosis (pseudogout)