Haemochromatosis is an autosomal recessive gene disorder. The gene that controls haemochromatosis is known as HFE. There are two main mutations that cause hereditary haemochromatosis and are referred to as C282Y and H63D.
What is the difference between heterozygous, homozygous and compound heterozygous?
- Heterozygous: having one copy of the abnormal HFE gene e.g. C282Y or H63D. Also known as a carrier of haemochromatosis. . One in 7 people have one abnormal HFE gene and are referred to as carriers and won't develop haemochromatosis
- Homozygous: Two copies of the same gene abnormality e.g. C282Y/C282Y which is associated with the highest risk of iron overload
- Compound heterozygous: Having one C282Y and one H63D abnormal gene and is associated with less risk of iron overload than the homozygous C282Y
What is the significance of C282Y and H63D?
- The C282Y mutation is associated with the highest risk of iron overload in its homozygous form C282Y/C282Y
- The H63D mutation is associated with a lower risk of iron overload in its Compound heterozygous form C282Y/H63D
- Although the HFE S65C mutation may lead to mild iron overload it is unlikely to be associated with clinically significant haemochromatosis
Hyperferritinaemia:
This condition 90% of diagnoses is not related to iron overload. Elevations of serum ferritin can be seen in the setting of inflammatory conditions such as rheumatoid arthritis, infection, various neoplastic and as a consequence of hepatocyte injury as ferritin is an acute phase reactant.
Metabolic Hyperferritinaemia is the most common cause and is related to glucose and lipid metabolism disorder. NAFL (Non-alcoholic fatty liver disease) involves insulin resistance and metabolic syndrome criteria which includes, Abdominal obesity, High serum TG, Low HDL cholesterol, raised blood pressure, increased fasting BSL and NASH (non-alcoholic steato-hepatitis), liver fibrosis and cirrhosis.
Once diagnosed, haemochromatosis is treated by phlebotomy to rid the body of excess iron and to maintain normal iron stores. Phlebotomy remains the sole recommended treatment for hereditary haemochromatosis and should be undertaken in a case-specific manner.
Dietary Considerations and Prevention:
Dietary factors may influence the phenotypic expression of haemochromatosis. Patients should not consume foods that contain large concentrations of bioavailable iron, such as red meats and organ meats. In addition, iron supplements, including multivitamins with iron and/or vitamin C should be avoided. Substances including tannates (in tea), phytates, oxalates, calcium, and phosphates, can bind iron and inhibit its absorption.
Alcohol abuse may accelerate disease progression and certain alcoholic drinks, especially red wine, contain relatively high concentrations of iron. Ingestion of 30 g or more of ethanol daily potentiates hepatic injury due to iron overload and increases the relative risk for primary liver cancer in persons with cirrhosis.
Long-Term Monitoring:
Physicians should be aware of the possibility of hereditary hemochromatosis, and should perform diagnostic tests when hereditary hemochromatosis is suspected. Regular monitoring of haematocrit, haemoglobin, and serum ferritin levels is necessary in patients undergoing phlebotomy. Genetic testing for hereditary hemochromatosis should also be performed in family members of patients with hereditary hemochromatosis.
Regular follow-up visits should be scheduled with a gastroenterologist, others such as a cardiologist, an endocrinologist, or a haematologist, may be needed for serial diagnostic and therapeutic intervention. Most hepatologists recommend screening for hepatocellular carcinoma with serum alpha-fetoprotein (AFP) every 6 months in patients with cirrhosis.
In the induction phase, weekly phlebotomy is made, with blood removal of 7 mL/kg per phlebotomy (not to exceed 550 mL per phlebotomy). The efficacy of treatment is controlled by ferritin level evaluation in plasma once monthly until the values remain above the upper limits of normal (300 mcg/L in men; 200 mcg/L in women). Haemoglobin level must be checked before each procedure; the reference value is 12-13g/dL (120-130g/L).
In the maintenance phase, the phlebotomy should be performed every 2-4 months. The interval between procedures is determined by the level of ferritin, which should be lower than 50 mcg/mL.[90, 91]
In a retrospective analysis of 12 paired patients from the Netherlands with hereditary hemochromatosis homozygous for the C282Y mutation, those who received proton pump inhibitors (PPIs) had a significant reduction in the frequency of median number of phlebotomies (0.50) compared with before the administration of PPIs (3.17), and those who received PPIs for at least 2 years required significantly fewer phlebotomies (1.25) than those in the paired group before they began taking PPIs (3.17).[92]
Summary
Phlebotomy is generally a safe and efficient method of iron removal. Therapeutic phlebotomy should be performed until iron-limited erythropoiesis develops, identified by failure of the haemoglobin level and/or haematocrit to recover before the next phlebotomy. It should be continued until transferrin saturation is less than 50% and serum ferritin levels are less than 50 ng/mL, preferably 20 mg/mL.
Therapeutic phlebotomy may improve or even cure some of the manifestations and complications of the disease, such as fatigue, elevated liver enzymes, hepatomegaly, abdominal pain, arthralgia’s, and hyperpigmentation.
(With acknowledgment to Australian Red Cross Blood Service)
Further information and useful links available at Haemochromatosis Australia - haemochromatosis.org.au.
References
- 90 Bismuth M, Peynaud-Debayle E, for the Haute Autorite de Sante (HAS) guidelines department. Management of patients with HFE-related haemochromatosis (type 1 haemochromatosis) (July 2005). Available at http://www.has-sante.fr/portail/upload/docs/application/pdf/hemochromatosis_guidelines_2006_09_12__9_10_9_659.pdf. Accessed: June 10, 2011.
- 91 Brissot P, Troadec MB, Bardou-Jacquet E, Le Lan C, Jouanolle AM, Deugnier Y, et al. Current approach to hemochromatosis. Blood Rev. 2008 Jul. 22(4):195-210. [Medline].
- 92 van Aerts RM, van Deursen CT, Koek GH. Proton pump inhibitors reduce the frequency of phlebotomy in patients with hereditary hemochromatosis. Clin Gastroenterol Hepatol. 2016 Jan. 14 (1):147-52.[Medline].
- 93 Falize L, Guillygomarc'h A, Perrin M, Lainé F, Guyader D, Brissot P, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology. 2006 Aug. 44(2):472-7. [Medline].