Haemachromatosis

Haemachromatosis

A new female patient presented with a history of recently diagnosed haemachromatosis. She is a 32 year old single woman who had initially presented to a 24 hour medical centre last year for investigation of fatigue. She was confused about venesection and the management of her disease. She did not know what genotype she was and had been told different things by various doctors ranging from advice to have venesection performed every 3 months to only having it done when her "iron levels" were high. Her last venesection was about 3 months earlier.
When I saw her she described 6 weeks of intense fatigue/ asthenia and left knee pain. She wanted to know if she could have a venesection to help with her fatigue and she had been reading about "something else that was given IV after the venesection" and wondered what this was.

PMHx

Bilateral ACL reconstructions following a skiing accident 5 years earlier.
Depression. currently well managed.
Menses age 8. regular but light periods.

Medications

Trifeme

Allergies

NKAD

Clinical questions this case raised for me...

1. What is haemachromatosis?
2. How does haemachromatosis affect women?
3. What is the difference between the gene types?
4. Is iron loading a likely cause for her fatigue?
5. Will venesection alleviate her fatigue?
6. what level of "iron" should we aim for?
7. What physical symptoms should I be looking for?
8. What is the likely course of the disease?
9. What was the "something else given IV" she had been reading about?
10. Can I perform a venesection and how do I do it?
11. What is the pathophysiology/ genetic abnormality that gives rise to HC?

These questions have been answered using Australian Family Physician and doi: 10.1182/asheducation-2006.1.36 ASH Education Book January 1, 2006 vol. 2006 no. 1 36-41                                   

What is haemachromatosis (HC)?

HC is iron overload leading to end organ damage through the interaction of environmental and genetic factors and not the presence of genetic predisposition. Only about 70% of C282Y homozygotes ever develop abnormal iron stores.
Only about 30% of men and less than 1% of women develop significant iron overload related disease (ie actual haemachromatosis).
You can be a C282Y homozygote without having haemachromatosis.

How does haemachromatosis affect women?

Clinically severe disease is less common in females because of menstrual blood loss and blood loss from pregnancy. Women usually present after menopause with symptoms of iron overloading where as men present from their early 30's.

What is the difference between the gene types?

HC is autosomal recessive. Genetic predisposition leads to disease in some but not all cases. More than 90% of hereditary haemachromatosis (HH) are due to homozygosity of C282Y. But not everyone who carries two copies of the C282Y gene will develop significant clinical morbidity. There are actually 4 types of genetic iron overload conditions and HFE haemachromatosis is only one of them.

Is iron loading a likely cause for her fatigue?

One of the main complications of iron overload is severe fatigue.

Will venesection alleviate her fatigue?

Probably...especially if there are no other comorbidities. However in the first 24 hours following venesection, patients can feel worse.

What do the iron studies mean?

• Anyone whom you suspect may have HC should have a fasting serum ferritin (SF) and transferrin saturation (TS).
• Increased transferrin reflects increased absorption and increased serum ferritin reflects increased body iron stores. Serum transferrin is often raised before ferritin becomes raised. Serum ferritin is also an acute phase reactant.
• If SF is high but TS is normal, hereditary haemachromatosis is unlikely...more likely SF is high due to inflammation/ infection.
• If SF is in the normal range in a person with HC, they may have some arthritis but are unlikely to have other symptoms.
• Mild iron excess corresponds to SF values < 500 μg/L, medium to 500–1000, and severe > 1000. This threshold of 1000 should be kept in mind since, beyond this value, severe clinical complications become very likely.
• If serum ferritin is >1000 mcg/ L you must refer to a liver specialist for mx to avoid cirrhosis.

NB there are three main confounding situation situations which make raised plasma ferritin difficult to interpret:

1. Alcholism
2. Metabolic syndrome and NASH
3. Inflammation

If any of these are present then consider MRI Ferrascan to estimate level of iron loading.

What level of "iron" should we aim for?

There are differences in the guidelines but aiming at getting serum ferritin between 50ug/ L to 200ug/ L is reasonable. Patients who present with serum ferritin >1000ug/L are at risk of cirrhosis and so the aim is for a lower serum ferritin to try and deplete the liver. They should see a specialist.

What physical symptoms should I be looking for?

Beware of HC in anyone who presents with marked lethargy and/ or arthralgia and/ or loss of libido. Physical examination may be normal if diagnosed early. If iron loading has progressed you may find liver cirrhosis, testicular atrophy and sore/ tender, swollen joints. (ND common causes of cirrhosis in Australia include NASH, alcoholic cirrhosis and hepatitis...HC is NOT a common cause of liver cirrhosis).

What is the likely course of the disease?

The potential sequaele of untreated iron overload include fatigue, arthritis, impotence, diabetes, fibrosis, cirrhosis and cardiomyopathy. Early diagnosis and Mx prevents complications and results in a normal life expectancy.

What was the "something else given IV" she had been reading about?

An alternative to venesection is desferrioxamine, a chelating agent, but this is expensive and so rarely used.

What do I need to know about venesection?

The Red Cross Blood Bank will do this if you ask them to. Note that the referring doctor remains responsible for the patients overall management.

Hb should be monitored every 2 weeks initially and serum ferritin every month when venesections are first started.

Management of venesections

Venesections should be commenced (even without symptoms) if ferritin > 300 μg/L in men; > 200 μg/L in women.

Induction Phase                          

• The venesections are usually performed on a weekly basis, although their frequency can be adapted to both the initial levels of hyperferritinemia and to the patient’s tolerance. The volume should be adapted to body weight: 7 mL/kg body weight, not exceeding 550 mL per phlebotomy.
• The goal is to obtain ferritinemia ≤ 50-200 μg/L.
• Efficiency is based on serum ferritin, checked on a monthly basis as long as ferritin levels remain above the upper normal limits (300 μg/L in men, 200 μg/L in women). Thereafter, testing should be performed every two venesections.
• Venesections should be held whenever hemoglobin values are < 11 g/dL. 

Maintenance therapy

• Maintenance treatment is based on phlebotomy every 1–4 months, according to the patient’s needs, and aims at maintaining the serum ferritin level ≤ 50 μg/L. The patient should understand that the management is based on ferritin values, which reflect the amount of stored iron, and that transferrin saturation levels can fluctuate and (probably) be acceptable as long as values remain < 75% (when the TS is below this threshold, no potentially toxic iron species are expected to be present in the circulation). This addresses a common misconception that transferrin saturation reflects the degree of saturation of the overall body in iron.
• Serum ferritin levels should be checked at least every two venesections
• hemoglobin monitored within the 8 days preceding each phlebotomy (checking this parameter immediately prior to the venesection may be of course the most simple procedure).

What is the pathophysiology/ genetic abnormality that gives rise to HC?

There is increased iron absorption across the intestinal mucosa. Humans don't have any compensatory mechanisms of iron excretion that can be activated: Normally iron is simply lost when intestinal cells shed away, and through blood loss like menstruation. HFE is the short-hand name for the gene (High Fe) that normally regulates iron uptake in healthy people. The protein encoded by this gene is called the HFE protein. This HFE protein normally forms a complex with beta-2 microglobulin and transferrin receptor 1 (TfR1). The C282Y mutation means that instead of this complex forming on the intestinal cells, the HFE gene gets trapped inside the cell--consequently, no iron is taken up by the TfR1. The body recognises this as a problem and so up regulates the "divalent metal transporter" on the brush border of the intestinal villus cells. The metal transporter then absorbes stacks of iron (way too much). There are other problems that the C282Y mutation cases including messing up the body's ability to monitor and regulate iron.

How is iron overload assessed and managed?

In the past assessment of iron overload was done using a liver biopsy but now there is new non- invasive MRI technology called Ferriscan which does the same job.
An initial course of 1 to 2 venesections per week should be done until excess iron is removed...and then once about 3 to 4 times a year to maintain normal iron stores.

NB 500mls blood contains 250mg iron.

How is the severity of haemachromatosis classified?

• Stage 0 = C282Y homozygosity without biochemical (normal plasma transferrin saturation and ferritin) or clinical symptoms.
• Stage 1 = C282Y homozygosity with increased transferrin saturation (> 45%) but normal serum ferritin values and no clinical symptoms.          
• Stage 2 = C282Y homozygosity with both increased transferrin saturation and ferritin (> 300 μg/L in men; > 200 μg/L in women) but no clinical symptoms. (Start Venesection)
• Stage 3 = C282Y homozygosity with increased transferrin saturation, increased ferritin, and clinical symptoms affecting the quality of life (asthenia, impotence, arthropathies, etc.).  
• Stage 4 = C282Y homozygosity with increased transferrin saturation, increased ferritin, and clinical symptoms manifesting organ damage predisposing to early mortality (cirrhosis with the risk of hepatocellular carcinoma, insulin-dependent diabetes, cardiomyopathy).

Other points:

• This patient had a number of family members who were found to have assymptomatic C282Y homozygotes. To prevent haemachromatosis in these family members, life-long venesection is recommended at 3 x per year.
• Patients should avoid alcohol while serum ferritin is raised
• Patients should avoid vitamin C supplements
• Patients can consider eating less red meat and this might decrease the number of venesections they require.
• Cirrhotic patients should undergo HCC surveillance every six months with hepatic ultrasound and serum alpha-fetoprotein measurement.
• In cirrhotic patients endoscopy should be considered to determine if varices or other evidence of portal hypertension that might require therapy are present.
• Arthralgia can sometimes get worse when venesections are initiated.

Clinical Guidelines

HAEMOCHROMATOSIS (Third edition) 2007

Clinical guidelines for the diagnosis and management of haemochromatosis published by the Digestive Health Foundation (Gastroenterological Society of Australia).

 

 

Hereditary haemochromatosis

Genetics in Family Medicine: The Australian Handbook for General Practitioners (2007)
National Health and Medical Research Council

Fact sheets

Ferriscan and haemochromatosis

Ferriscan is an MRI-based method of measuring liver iron concentration. It provides an accurate, accessible and safe method of assessing the presence and severity of iron overload.

Brochures and Information for Patients

Haemochromatosis (Haemochromatosis Australia)

Brochure published by Haemochromatosis Australia with brief information for patients about haemochromatosis and contact details for Haemochromatosis Australia.

You can order free copies of this brochure at publications@haemochromatosis.org.au.

Haemochromatosis Your Questions Answered

Booklet published by Haemochromatosis Australia with comprehensive consumer focussed information for patients about haemochromatosis. Co-authors include Professor Martin Delatycki, Professor Lawrie Powell, Professor John Olynyk and Dr Barbara Bell (ARCBS). 28 pages A5.

You can order free copies of this brochure at publications@haemochromatosis.org.au .

Hereditary Haemochromatosis

Fact sheet with particular emphasis on genetics of haemochromatosis published by the Centre for Genetics Information (Australia). 2007.

Iron Overload Fact Sheet

Fact sheet published by the Iron Disorders Institute (USA). 2 pages.

Online Training

Hemochromatosis (Iron Storage Disease)

Online training module produced by the Centre for Disease Control and Prevention (USA).