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Genetic Haemochromatosis (Iron Overload Disorder).

Genetic haemochromatosis (GH) is a significant cause of arthropathy, particularly in the hands and feet. Patients presenting to a podiatrist with ankle or hind foot pain resembling osteoarthritis, at an unexpected early age and without hind foot deformity or a history of trauma, could be affected. This article explains GH, the relevance to foot pain, and the importance of awareness of the condition.


People with genetic haemochromatosis (GH) --also known as iron overload disorder--are highly likely to develop arthritis, particularly in the hands and feet. This is increasingly referred to as haemochromatosis arthropathy.

In fact, foot and hand arthropathy, in people of a younger age than might be expected, is a key diagnostic marker for haemochromatosis. It is important therefore that podiatrists, chiropodists, physiotherapists, and other healthcare professionals involved in foot care, are aware of the condition and the implications of delayed treatment.

Haemochromatosis arthropathy often manifests itself early on as pain in the hands and feet. Later, haemochromatotics face the prospect of increasing severe and chronic pain, and ultimately fusions and/or multiple joint replacements.

The arthritis recognised as being associated with haemochromatosis most closely resembles osteoarthritis, but is distinctive in occurring at a younger age and involving some joints not usually affected by osteoarthritis; particularly the metacarpophalangeal joints in the hands, and the ankles.

What is genetic haemochromatosis (GH)?

Although even amongst healthcare professionals awareness of it is low, GH is the most common genetic disorder in people of northern European extraction. The mutations involved--usually in a gene called HFE--result in the failure of the body's system for controlling iron absorption from the diet, which takes place in the duodenum and upper small intestine. Excess iron then builds up in various parts of the body to highly toxic and damaging levels. This affects many of the major organs, body functions, and (most significantly in this context) the joints.

Early symptoms of iron overload include fatigue, weakness, joint pains (especially in the hands and feet), abdominal pain, discoloured skin, impotency, loss of libido, shortness of breath, hair loss, forgetfulness, irritability, and menstrual problems.

Left untreated or diagnosed too late, the increasing iron stores go on to cause serious joint damage, chronic fatigue, fibrosis, cirrhosis and cancer ofthe liver, depression and other mental health issues, cardiomyopathy (heart muscle failure), and diabetes. Liver transplant and multiple joint replacements are not unusual, and GH can be fatal.

Unfortunately, iron overload is significantly underreported. When first presenting with symptoms, a patient's diagnosis and treatment is often limited to addressing the results of the toxic levels of iron, rather than the root cause, as illustrated in the table below.
Stored iron in ...    ... can cause ...

The liver            Fibrosis, cirrhosis,

The heart               Cardiomyopathy

The pancreas               Diabetes

Thejoints                 Arthritis

Endocrine               Mental health
system                      issues

Gonads and              Sexual health
endocrine                  problems

Skin                    Hair loss and

The thyroid            Chronic fatigue,

Stored iron in ...   ... which may be wrongly attributed
                                    to ...

The liver                Alcohol and diet, metabolic

The heart                         Lifestyle

The pancreas              Diet and lifestyle, weight

Thejoints                   Ageing, trauma, sports

Endocrine                 Stress, lifestyle, working
system                           environment

Gonads and             Stress, lifestyle, relationship
endocrine                           issues

Skin                      Stress, ageing, lifestyle

The thyroid           Stress, workloads, ageing, anaemia

Stored iron in ...      ... with treatment
                      attempted through ...

The liver            Drugs, lifestyle changes

The heart             Dietary and lifestyle
                         changes, drugs,

The pancreas             Dietary changes,
                        exercise, insulin

Thejoints              Physiotherapy, pain

Endocrine               Stress management,
system               counselling, career and
                        lifestyle changes

Gonads and               Hormone therapy,
endocrine             counselling, lifestyle
system                       changes

Skin                 Drug therapies, dietary

The thyroid            Drug therapies, iron
                         supplements (!)

This demonstrates how diagnosis of underlying iron overload can be missed and treatment significantly delayed, even by an experienced and knowledgeable GP or consultant. Approximately 10,000 haemochromatosis patients have been diagnosed in England, but some research suggest that several hundred thousand may remain undiagnosed.

How is GH treated?

Once correctly identified, treatment for GH is very straightforward in most cases, consisting of the regular removal of blood (venesection), much like a blood donation. The body then uses some of the excess stored iron to make new red blood cells, thus bringing down the amount accumulated in the body. After a programme of de-ironing, a patient may then need a few therapeutic venesections (or to give blood as a donor) each year, to maintain iron stores at a safe level.

In many cases, diagnosis is too late to prevent irreversible damage. Joint damage, for example, cannot be reversed; in fact, joints usually continue to deteriorate even after de-ironing. Cirrhosis ofthe liver cannot be repaired and diabetes may have to be controlled for the long term. Fatigue, mental health, and sexual health problems can sometimes be alleviated, but patients will often continue to struggle.

Why is awareness for foot specialists so important?

Early diagnosis of GH means treatment can start as soon as possible. This can prevent liver and heart damage, pain and other serious complications, and ultimately save lives.

Because hand and foot pain--usually alongside tiredness--is often reported by patients as one of the earliest symptoms, there is the potential for healthcare professionals other than GPs to be able to act on the first clues. Those who should be aware of the condition include pharmacists, podiatrists, chiropodists, physiotherapists, and sports therapists, amongst others. These professionals can draw a patients or clients attention to the possibility of haemochromatosis, and recommend that his or her GP is asked to run the simple blood tests that can show whether iron levels are raised.

Awareness of GH amongst health care professionals is also important when considering treatment options for conditions within their own specific field. Podiatrists in particular may find that the pharmaceuticals usually prescribed for conditions such as onychomycosis, are unsuitable for patients with a depressed liver function, as can be the case with haemochromatotics. Medications such as Terbinafine and Itraconazole should not be prescribed until satisfactory liver function has been established by a blood test. Similarly, in cases of cardiomyopathy, which can be caused by GH, slightly more cardiotoxic local anaesthetics such as Marcaine should be used with prudence and in some cases avoided altogether in favour of alternative agents such as Scandonest or Lidocaine.

Howard Don, Chairman of The Haemochromatosis Society, says,

"It is clear that a combination of fatigue and foot/hand arthritic pain are highly indicative of iron loading. It is equally clear that earlier diagnosis than is currently achieved on average would prevent a lot of pain and suffering, and save lives. Improved awareness and understanding of the condition is therefore paramount."

Testing for iron overload

GPs and consultants--including rheumatologists--can readily check for iron overload. The tests involved are not particularly expensive and in the case of blood tests can provide evidence to confirm diagnosis within a few days. The usual tests are:

Serum Ferritin; a proxy indicator of the level of stored iron. However, serum ferritin levels are also impacted by factors such as medication, inflammation, alcohol, and metabolic syndrome and is therefore not a definitive test when considered alone.

Transferrin Saturation; a measure of the capacity of the body's system for transporting iron. A highly loaded "transport system" (above 50%) is a diagnostic marker for iron overload. In combination with a high serum ferritin level, this is a conclusive test.

Liver Function Tests (LFT panel) are often carried out as part of investigations into iron overload because excess iron is stored initially in, and impacts quickly on, the liver. Identification of liver problems is a diagnostic marker, an indicator of the urgency of venesection, and of course, essential in its own right.

The HFE genetic test; a check for mutations that are known to cause the vast majority of cases of genetic haemochromatosis; these are known as mutations C282Y and H63D. Other mutations may also be checked, though these are much rarer. A genetic predisposition to iron overload does not always mean that it will occur, but the test is very important both as a diagnostic confirmation and to inform discussions with family members.

A rheumatologist's perspective

Dr Patrick Kiely, Consultant Rheumatologist at St Georges Hospital, London, writes,

"The majority of (patients) describe widespread joint pain. This can be associated with early morning stiffness as well as pain throughout the day ... The delay from first symptoms to diagnosis of iron overload is approximately 7 years, with 77% of people reporting joint pain, predating diagnosis by more than 5 years in 40%.

The joints most frequently affected are the metacarpophalangeal (MCPs), proximal interphalangeal, 1st carpometacarpal and distal interphalangeal joints in the hands, and also the ankles, hips, and knees. The clinical appearances are those of osteoarthritis (OA), with bony swelling and loss of range of movement The discriminatory features are onset of pain before age 60, which is early for osteoarthritis, and involvement of the MCPs and ankles, especially in the absence of trauma.

In established cases X-rays show characteristic features of OA, including chondrocalcinosis. Osteophytes are potentially discriminatory, as although a common feature of OA, they are abundant in haemochromatosis, and described as 'hooks' at the MCP joints. On MRI, bone marrow lesions and cysts are very frequently seen, and whilst these are also features of OA, their prevalence and extent are high in haemochromatosis. In conclusion, be suspicious of iron overload if you find a patient before the age of 60 with OA that has no explanation (i.e. without physical trauma, congenital abnormality, family history or other reason) and be especially alert to involvement of the MCPs and ankle/ hindfoot joints."

A genetic condition

Because haemochromatosis is a genetic condition, discussions with a patient about the family medical history may also provide evidence of iron overload. For example, if a patients parents have experienced any of the symptoms of iron overload outlined above this would strengthen suspicion.

It is also worth noting that the mutations that cause iron overload are particularly prevalent in people with Celtic roots, especially in Irish families where up to l in 8 people may be carriers. The origin of the mutations is believed to stem back to the Viking invasion of Ireland and iron overload is definitely more prevalent amongst the Irish diaspora around the world.

Key summary points for a podiatrist

Genetic haemochromatosis (iron overload) is a potentially fatal condition that is all too often undiagnosed or diagnosed after significant damage to the joints and organs. Earlier diagnosis is essential and a key marker is arthritis of the hands and feet. Joint pain in the ankle/hindfoot in patients under 60 should prompt suspicion of GH, especially if combined with knuckle pains, fatigue, and/or Celtic ancestry.

More Information

The Haemochromatosis Society


Additional resources

The Haemochromatosis Society website www.ironoverload. and The Haemochromatosis Handbook (available to purchase from the society)

Advice for Patients from Haemochromatosis Arthropathy Research Initiative (HARI)

Haemochromatosis: unexplained metacarpophalangeal or ankle arthropathy should prompt diagnostic tests: findings from two UK observational cohort studies A Richardson, A Prideaux, P Kiely Scand J Rheumatol 2016;00:1-6

( uploads/2016/06/SJR-manuscript.pdf)

The Heamochromatosis Society Conference 31 March 2017 New Understanding of Genetic Haemochromatosis Video 4: The Fernau Lecture

Arthropathy as a Marker for Genetic Haemochromatosis Dr P Kiely, Consultant Rheumatologist, St George's Hospital, London

David Head Chief Executive The Haemochromatosis Society
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Author:Head, David
Publication:Podiatry Review
Date:Oct 1, 2017
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