Haemochromatosis

Introduction

Haemochromatosis refers to iron overload in general and can be have acquired or congenital causes
This topic focuses on hereditary hemochromatosis, which refers to a genetic form of the disease caused by iron dysregulation and absorption
It’s usually an autosomal-recessive disorder that most affects the liver

Iron absorption:

Dietary iron is absorbed in the duodenum. This is done by gut cells called enterocytes. Iron is then exported into the blood through a protein called ferroportin.

The amount of iron absorbed is regulated by hepatocytes from the liver which detect plasma iron levels. It does this using a protein complex which is made up of a couple subunits:

Hemostatic iron regulator
Haemojuvelin
Transferrin receptor 2

Negative Feedback:

When iron levels are too high, these proteins tell hepatocytes to produce more of a protein called hepcidin. This provides negative feedback because hepcidin inhibits ferroportin channels releasing iron into the blood.

Classification:

Type 1 (Hereditary HFE haemochromatosis), which is the main focus of this topic. It’s the most common type accounting for 95% of cases. Its due to a mutation in the HFE gene. This means hepatocytes lose the ability to appropriately increase hepcidin levels and provide negative feedback, resulting in iron overload.

Type 2 (Juvenile haemochromatosis) is a result of a mutation of the haemojuvelin gene. It has an early onset (<30 years) and is characterised by hypogonadism and cardiomyopathy.

Type 3 (Transferrin Receptor 2 Haemochromatosis). This type is due to a mutation in the transferrin receptor 2 gene. It affects middle aged and young adults and resembles type 1.

Type 4 (Ferroportin disease) is distinct from the other types because it’s an Autosomal-dominant disorder which results in issues with the ferroportin protein channel itself – meaning its an issue with the enterocytes not the hepatocytes providing negative feeback.

Consider the following approach to investigating hemochromatosis. If a patient presents with clinically suspicious symptoms, unexplained liver disease or has a first degree relative with HH, then perform iron studies including a transferrin saturation and serum ferritin.

An increased transferrin saturation reflects increased absorption of iron and an increased serum ferritin normally reflects high body iron stores (although please note that is can be high during inflammatory processes as it is an acute phase reactant). If the ferritin is lower than 300 and the transferrin saturation is lower than 45%, reassure the patient and consider retesting later as they are unlikely to have haemochromatosis.

If either are higher than these thresholds and your thinking of HH, progress to HFE genetic testing. If this is negative, consider non-HFE related haemochromatosis.

However, if either are positive, the next step is to consider assessing the degree of iron deposition in the tissues.

Liver involvement can be assessed using blood tests like LFTs.

Imaging via a Liver MRI is a non-invasive way to estimate liver iron content with good sensitivity and specificity.

Finally, a liver biopsy is the most sensitive and specific test for measuring liver iron content with the added benefit of allowing the pathologist to evaluate for injury related to iron overload, like fibrosis or cirrhosis.

Sex hormones should be assessed via testosterone, oestrogen, FSH, and LH assays. Remember hypogonadism is usually secondary, associated with low, rather than high, gonadotrophins.

Finally, cardiac involvement can be investigated with ECGs and echocardiograms.

Management revolves around lifestyle modification, removal of the excess body iron and organ damage monitoring.

Lifestyle modification includes eliminating alcohol consumption because it increases the risk of cirrhosis in hereditary hemochromatosis nearly tenfold. Dietary adjustments are unnecessary.

Removal of excess iron is best done via regular phlebotomy. An initial course of 1–2 venesections per week is performed until the excess iron stores are removed. Once this is achieved, patients usually require one venesection every 3–4 months to keep iron stores at low-normal levels without rendering the patient iron deficient.

An alternative method of treatment is with desferrioxamine, a chelating agent, but this is costly and in practice is rarely needed.

Monitoring for organ damage, especially liver involvement is vital. Patients with cirrhosis have a risk of primary liver cancer even when complete iron depletion is achieved. These patients should be screened every 6 months with hepatic ultrasound and serum alphafetoprotein levels.

Presentation:

The clinical features of the disease is based on how advanced it is. Patients can present in one of four ways:

1. without overload but with a genetic predisposition

2. iron overload without symptoms

3. iron overload with symptoms like arthritis

4. iron overload with organ damage like cirrhosis.

Organs Involved:

Cardiac issues are common because the heart is a major site of iron deposition. It can lead to structural disease like dilated cardiomyopathy and conduction disturbances causing arrhythmias.

Hepatomegaly is present in >95% of symptomatic patients and is usually the first organ involved. Liver damage can result in complications like cirrhosis and hepatocellular carcinoma.

Arthritis occurs in about 25% of people and usually affects the joints in the hands to start. A progressive polyarthritis involving wrists, hips, and knees may also ensue. It can have radiological findings that are indistinguishable from pseudogout, AKA, calcium pyrophosphate crystal deposition disease like chondrocalcinosis.

Diabetes can result from pancreatic iron overload. Interestingly, it appears that iron deposition is relatively selective for beta cells that produce insulin over alpha cells which secrete glucagon.

Gonadal dysfunction results from deposition in the anterior pituitary. This results in a decreased production of gonadotropins, making one sequela secondary hypogonadism. Manifestations include loss of libido, impotence, amenorrhea, and testicular atrophy.

Skin pigmentation is another key feature of advanced haemochromatosis and is a consequence of excess melanin and iron in the dermis. The metallic hue is often described as bronzing and is diffuse.

I remember two mnemonics.

1) Organs impacted: CHAD GonadS

Cardiac
Hepatomegaly
Arthritis
Diabetes
Gonad
Skin

2) Management: TownsendTeaching Rhyme

Abstain, drain the vein, desferrioxamine, retest again.

This reminds me to tell a patient to abstain from alcohol, have regular venesections or removal excess iron with a chelating agent, and continue monitoring organ health again.