The Bronze Killer: Haemochromatosis and Diabetes Jenny E
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Peer Review Australian Diabetes Educator, Volume 17 Number 2, June 2014 The Bronze Killer: Haemochromatosis and Diabetes Jenny E. Gunton, Amit Lalwani Introduction commonly inherited disorders. overload often goes undetected There is abnormally increased for years, until the damage is Haemochromatosis is one of absorption of iron from the done. Haemochromatosis has the causes of diabetes. It leads intestine, leading to deposition been called the ‘Celtic curse’ to excess iron in the blood and of excess iron in a wide range of based on its higher prevalence more importantly in the tissues organs. It is sometimes referred in people from Ireland, Wales, of the body. It is one of the most to as a ‘silent killer’ because iron Scotland, and Great Britain. Types of Haemochromatosis An overview of iron trafficking is shown below in Figure 1 Figure 1 - Overview of iron trafficking and metabolism: Hepcidin is a regulator of iron trafficking. In normal individuals, circulatory iron received from daily food intake sets hepcidin synthesis by hepatocytes at a basal level. The amount of iron released from macrophages and intestine (enterocytes) is modified by serum hepcidin that contributes to the pool of circulatory iron in a regulatory feedback loop to keep the hepatic production of hepcidin under control. Hepcidin blocks ferroportin activity, which inhibits iron absorption from the intestine (duodenum) and iron recycling from macrophages. Hepcidin is synthesized in the liver, and its decreased production leads to excess accumulation of iron in enterocytes and macrophages. HFE, the product of the haemochromatosis gene, is required for hepcidin activation in response to the circulatory iron signal. Hence mutations in this gene (or in hepcidin) disrupt iron homeostasis and cause haemochromatosis. Corresponding author: Jenny E. Gunton References and M.B.B.S, FRACP, PhD Acknowledgements: Diabetes and Transcription Factors Lab Head Garvan Institute of Medical Research [email protected] 34 Australian Diabetes Educator, Volume 17 Number 2, June 2014 There are a number of genes arthropathy affecting the 1st, 2nd Diagnosis that when mutated lead to and/or 3rd metacarpophalangeal haemochromatosis. These joints may develop, which is a The first step in diagnosing an genes include HAMP (hepcidin classic sign3,4. People with this iron-overload disorder is to assess antimicrobial peptide), HFE pattern of arthritis, which spares iron status. If the probability of (haemochromatosis), HFE2 other joints, who also have diabetes, haemochromatosis is thought to (haemochromatosis type 2 should always be screened for be low, a simple measurement (juvenile)), SLC40A1 (solute haemochromatosis. Images of of ferritin alone could be carrier family 40 (iron-regulated the hands of 2 normal individuals undertaken. However, ferritin transporter), member 1), and (Austrian origin) indicating is an acute phase reactant, so it TFR2 (transferrin receptor 2). the relevant joints is shown goes up with any acute illness, A mutation in each type of in Figure 2. A diagrammatic including viruses, so it may be gene causes a specific type illustration of course of more useful to request “iron of haemochromatosis1. The progression of haemochromatosis studies”. These will include commonest by far is HFE, which is shown in Figure 3. The classic serum iron, transferrin, ferritin is responsible for classic, or type 1 bronze skin colour is usually a and either TIBC (total iron haemochromatosis. The different late symptom, as in the case of binding capacity) or transferrin types of haemochromatosis and ‘bronze diabetes’. saturation. Iron studies therefore the gene mutation(s) responsible allow assessment of iron status are listed in Table 1 below. so long as there is not a severe illness at the time. If the iron Table 1 – Different types of haemochromatosis studies suggest that the person has excess iron, with high transferrin saturation (or low Haemochromatosis Type Gene involved TIBC) and high ferritin, then Type 1 haemochromatosis or HFE (haemochromatosis) proceeding to genetic testing is Classic haemochromatosis indicated. Normal ranges vary HAMP (hepcidin antimicrobial between laboratories, but the Type 2 haemochromatosis peptide) or HFE2 (hemochromatosis ‘normal’ for ferritin in males is type 2 (juvenile)) approximately 30-300 µg/L and 6,7 Type 3 haemochromatosis TFR2 (transferrin receptor 2) for females is 10-200 µg/L . Type 4 haemochromatosis or SLC40A1 (solute carrier family 40 Mutations in the HFE gene are Ferroportin disease (iron-regulated transporter), member 1) identified by genetic testing (i.e. sequencing the gene). This is somewhat expensive, but more Prevalence importantly, identifying genetic In very rare cases, iron overload disorders in people comes with accumulates before birth. Haemochromatosis is more the crucial need for pre-test and These cases are called neonatal post-test genetic counselling, so haemochromatosis. It progresses common in people of Northern European backgrounds with it must not be undertaken lightly. rapidly and is characterized by Since it is a genetic disease, if liver damage that is apparent approximately 1 in 11 persons being heterozygous carriers and identified, it also has implications at birth or on the first day of for testing of parents, siblings life. The gene or genes causing 1 in 200 being homozygous for C282Y mutations. The and children. These are the neonatal haemochromatosis are reasons why assessing iron status not known2. expression of the disease is affected by factors that include should be done as the first step Clinical Presentation/ alcohol consumption, dietary except in the case of screening Features/Expression/ iron intake, blood loss due to relatives of people with known Manifestations menstruation and pregnancy, haemochromatosis. and blood donation. Other There are no symptoms specific to contributing factors include blood In patients who are positive haemochromatosis. Diagnosis can transfusions, oral iron pills or for mutations, usually MRI be missed even in advanced stages iron injections, with or without (magnetic resonance imaging) unless looked for specifically. Early supplemental vitamin C intake of the liver is undertaken to diagnosis is difficult. Symptoms (vitamin C helps your body to assess hepatic iron loading, and usually start between ages 30-50 absorb iron), hepatitis, or non- a liver fibroscan (a special kind in men, but may begin earlier in alcoholic steatohepatitis5. of ultrasound) is often done some patients and are usually later to assess fibrosis. These tests in women. Initial symptoms are Haemochromatosis is much less together assess liver risk and will non-specific and include fatigue, common in Asia, the Middle East usually, in combination with the weakness, nonspecific abdominal and most of Africa because of a serum iron studies, decide the problems and pseudogout. Later, lower prevalence of the genetic mutations in non-Caucasians. CONTINUED ON PAGE 36 › 35 Peer Review › FROM PAGE 35 Australian Diabetes Educator, Volume 17 Number 2, June 2014 Table 2 – Complications of haemochromatosis Sign/Disease Symptoms Occurs in about 35-75% of the patients. Hepatomegaly. Liver disease Chronic liver disease signs, such as cutaneous stigmata of liver disease (palmar erythema, spider angioma, or jaundice). Liver failure. Cirrhosis. Hepatocellular carcinoma develops in 30% of patients with cirrhosis (risk > 200-fold). Up to 65% of patients. More likely to develop in those with a family history of diabetes. Prevented by early treatment. Diabetes Early alteration of glucose intolerance and insulin resistance may partially be improved by phlebotomy treatment. Treatment after long-term diabetes is unlikely to reverse glucose intolerance. Bronzing or metallic or slate grey skin coloration. Hyper-pigmentation Results from a combination of iron deposition and melanin in the dermis. or skin bronzing Pigmentation is usually diffused and generalized, but may be more prominent on the face, neck, lower forearms, lower legs and genital regions. Arthropathy (abnormality of joints) develops in 25-50% of patients More commonly occurs after age 50. Non-inflammatory. Arthropathy Particularly involves the small joints of the hands, especially the first, second and/or third metacarpophalangeal joints (CLASSIC SIGN). Usually no warmth, redness, or deformity. Congestive heart failure Abnormal heart rhythms (arrhythmias), which can cause symptoms of palpitations, Heart disease chest pain and lightheadedness. Cardiomyopathy (enlarged heart muscle). Pituitary dysfunction produces a plethora of endocrine disturbances. Reduced gonadotropin levels are seen commonly. Can also cause reductions in Pituitary disease gonadal synthesis of sex steroids, which in turn delays sexual maturation in some children with transfusional iron overload. Infertility is also seen quite commonly. Can occur in both males and females. Loss of libido, impotency, amenorrhea, testicular atrophy, sparse body hair. The production of gonadotropins is decreased due to impairment of hypothalamic- Hypogonadism/ pituitary function by excess iron deposition. Infertility Adrenal insufficiency, hypothyroidism and hypoparathyroidism is seen in rare cases. Excess iron deposition in the hypothalamus and/or pituitary can affect production of hormones that are critical for reproductive function. treatment offered. Treatment of they would be given dietary These tests have largely removed Haemochromatosis recommendations alone and be the need for liver biopsy, except followed