Hereditary Hemochromatosis

Hereditary Hemochromatosis

Overview

Hereditary hemochromatosis is the most common autosomal recessive disorder in the white population. It has a prevalence of around 0,3% in Europe. [1]  It develops in people that have a mutation in the HFE gene that leads to increased iron uptake. Typically men develop symptoms sooner than women. Iron deposits in various organs and causes symptoms like liver enlargement, liver damage, dilated cardiomyopathy, arrhythmias, joint problems, or joint pain. Also, people can develop some serious complications that can lower their life expectancy, like heart failure, cirrhosis, liver cancer, and diabetes. Diagnosis is based on genes and blood testing (to assess iron overload). The best treatment option is phlebotomy - the removal of around 500 ml of blood from the body to reduce the amount of circulating iron. The process itself can be compared to blood donations. 

Prevalence & Risk factors

Hereditary hemochromatosis is the most common autosomal recessive disorder in the white population, with a prevalence of 0,2-0,3 %. [1]  It is less common in the African-American and Asian populations. The most important risk factor is genetic predisposition - biallelic HFE gene mutation. Among other risk factors, we can include first-degree relatives with hemochromatosis, age, sex (men develop it sooner than women due to loss of iron with blood during menstruations), and ethnicity.

Genetics

Hereditary hemochromatosis is predominantly referred to as an autosomal recessive disease, however, an autosomal dominant pattern has been described in one form of the disease. Its most prevalent form is caused by homozygous mutations in the HFE gene, specifically the C282Y mutation (both alleles are affected). It is responsible for the production of the protein hepcidin, which is necessary for iron uptake.

Furthermore, this disease can also be caused by mutations in other genes (=non-HFE hemochromatosis), such as HAMP, HJV, TFR2, and SLC40A1.

In spite of the high prevalence of C282Y homozygosity, just a small number of people will accumulate such levels of iron that would cause organ damage. The frequency of C282Y homozygosity is quite the same in both men and women, due to the autosomal recessive manner, but the prevalence of symptoms may vary. Expression in phenotype is visible in about 70% of cases, but on the other hand, less than 10% of individuals struggle with serious iron overload. [2-4]

Signs & Symptoms

Hereditary hemochromatosis is a condition characterized by iron overload and the severity of symptoms depends on the extent of the overload. Most people will not develop any symptoms at all or will present only with mild nonspecific symptoms like fatigue, pain, etc. Presentations associated with significant iron overload are rare in younger individuals. Men typically develop the condition at the age of 40 or older, and women generally develop it after menopause. Iron overload leads to its deposition in various tissues. The most common organ affected is the liver. It manifests with hepatomegaly (enlarged liver), cirrhosis (late-stage liver scarring), and an increased risk of liver cancer. Iron can also deposit in the heart, leading to dilated cardiomyopathy, heart failure, or arrhythmias. Depositions in endocrine organs can cause different hormonal disturbances. In case the pancreas is affected, it can become a cause of diabetes mellitus type 2. Other symptoms may include secondary hypothyroidism or hypogonadism (pituitary gland involvement), arthralgias (pain in joints), skin hyperpigmentation (bronze skin), CNS involvement (cognitive or neurological abnormalities), and susceptibility to infections. 

Diagnosis

To diagnose hereditary hemochromatosis several tests can be performed. Laboratory tests to determine iron overload are serum transferrin saturation and serum ferritin. Additional tests to identify liver damage are liver function tests, MRI, and liver biopsy. Gene testing is also performed to identify the HFE gene mutation. 

Therapy

The most common treatment available is the removal of blood from circulation (phlebotomy). It is similar to the donation of blood. Initially, it has to be done once a week until normal blood iron levels are reached. Then it can be done once every 2-4 months to maintain normal iron levels and prevent its accumulation. 

Prevention

People affected by hemochromatosis don’t need to maintain a special diet. However, avoiding iron and vitamin C supplements is beneficial. Drinking alcohol (1-2 drinks per day) is safe unless the person has liver damage (cirrhosis or hepatitis). It is also recommended to avoid eating raw fish or shellfish. 

Prognosis

Most people with hemochromatosis have a normal life expectancy. Survival may be shortened in people who are not treated and develop serious complications. These include diabetes, cirrhosis, liver cancer, and heart failure. 

Recommendations

  • If you experience any signs or symptoms of iron overload, please contact your doctor. 
  • If you have first-degree relatives affected with hemochromatosis, screening (gene testing) for this disease is recommended. 
  • Improve your health by eliminating raw fish, iron, and vitamin C supplements from your diet and limiting alcohol intake.

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Recommendations

  • If you experience any signs or symptoms of iron overload, please contact your doctor. 
  • If you have first-degree relatives affected with hemochromatosis, screening (gene testing) for this disease is recommended. 
  • Improve your health by eliminating raw fish, iron, and vitamin C supplements from your diet and limiting alcohol intake.

Sources

  1. Adams P. C. (2015). Epidemiology and diagnostic testing for hemochromatosis and iron overload. International journal of laboratory hematology, 37 Suppl 1, 25–30. https://doi.org/10.1111/ijlh.12347
  2. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochrom-atosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108(4):619-623. doi:10.1172/jci200113468
  3. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328-343. doi:10.1002/hep.24330
  4. Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4(1). doi:10.1038/nrdp.2018.16
  5. Bacon B. R. (2021) Management and prognosis of hereditary hemochromatosis, UptoDate https://www-uptodate-com.ezproxy.is.cuni.cz/contents/management-and-prognosis-of-hereditary-hemochromatosis?search=herediatary%20hemochromatosis&source=search_result&selectedTitle=2~119&usage_type=default&display_rank=2#H20
  6. Bacon B. R., Phatak P. (2022) Clinical manifestation and diagnosis of hereditary hemochromatosis, UptoDate https://www-uptodate-com.ezproxy.is.cuni.cz/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemochromatosis?search=hereditary%20hemochromatosis&source=search_result&selectedTitle=1~119&usage_type=default&display_rank=1#H2672738894
  7. Adams P. C. (2015). Epidemiology and diagnostic testing for hemochromatosis and iron overload. International journal of laboratory hematology, 37 Suppl 1, 25–30. https://doi.org/10.1111/ijlh.12347
  8. Hemochromatosis - Diagnosis and treatment - Mayo Clinic. (n.d.). Retrieved April 24, 2022, from https://www.mayoclinic.org/diseases-conditions/hemochromatosis/diagnosis-treatment/drc-20351448

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