Research Blog

October 5, 2022

Hemochromatosis: An Iron Overload Disorder



Hemochromatosis is a disorder of iron metabolism characterized by increased absorption and storage of iron that can damage the liver, pancreas, heart, reproductive organs, endocrine glands, and joints.

 Hemochromatosis affects 1 in 500 individuals and is the most common inherited disorder in Caucasians. It may be inherited or secondary to other conditions (Pagana 2021).

Restriction of iron intake and removal through phlebotomy are primary interventions for this potentially debilitating disease although chelation therapy may be appropriate for some individuals. Iron studies and genetic testing assist in the diagnosis. However, additional biomarkers that address inflammation, oxidative stress, liver function, thyroid function, and glucose regulation can help assess organ status and future disease risk.

Hemochromatosis may be associated with (Al-Chalabi 2021, Barton 2000, Ellervic 2011, Girelli 2022, Golfeyz 2018, Pagana 2021, Palmer 2018, Piperino 2020, Porter 2022, Raymond 2021):

  • Elevated ferritin, serum iron, transferrin saturation, ALT, MCV, and MCH
    • A transferrin saturation of at least 45% and elevation of ferritin at least two times the normal value is characteristic of hemochromatosis.
  • Decreased unsaturated iron binding capacity, hepcidin, and prolactin
  • Damage to the liver, pancreas, pituitary, and thyroid as well as other organs
  • Diabetes, arthritis, heart failure, cirrhosis, fibrosis, and liver cancer
  • Abdominal pain, fatigue, arthralgia, impotence, heart failure, cirrhosis, hepatomegaly, ascites, and skin hyperpigmentation.

Pathophysiology of Hemochromatosis (Porter 2021)

Organs affected by hemochromatosis include the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol intake and viral hepatitis accelerate the pathology associated with hemochromatosis, especially with respect to the liver and pancreatic toxicity.

  • Cirrhosis is present in 70% of patients with hemochromatosis. In these patients, there is a marked increased incidence of hepatocellular carcinoma, which is a significant cause of death.
  • Diabetes is the primary manifestation of pancreatic iron deposition. The incidence of diabetes is approximately 50% in symptomatic patients, and the risk is increased in heterozygotes for hereditary hemochromatosis.
  • Arthropathy manifests as joint pain without joint destruction. Although the presentation is identical to that of degenerative joint diseases, calcium pyrophosphate crystals can be found in the synovial fluid. It can still progress after the normalization of iron stores.
  • Cardiac symptoms result from iron deposition in the cardiac muscle fibers and cells of the conduction system. Electrocardiac abnormalities can be present before true cardiac dysfunction occurs. Symptoms are due to congestive heart failure as a result of dilated cardiomyopathy and cardiac arrhythmias. Left ventricular failure can sometimes be reversed with the removal of iron stores.
  • Hypogonadism, with resultant impotence, is due to iron-induced hypothalamic or pituitary failure, resulting in impairment of gonadotropin hormone release.
  • Skin hyperpigmentation is a result of both iron and melanin deposition. It does not usually occur before the iron stores exceed five times the normal levels.
  • Iron overload of macrophages can cause impaired phagocytosis and lead to decreased immunity, resulting in an increased risk of infection from Listeria, Yersinia enterocolitica, and Vibrio vulnificus. Patients with hemochromatosis should not handle or eat raw shellfish due to the increased risk of sepsis from Vibrio vulnificus.
  • Iron deposition in the thyroid gland causes hypothyroidism. The risk of hypothyroidism is 80 times greater than normal for men with hemochromatosis.
  • Iron deposition in the adrenal and parathyroid glands rarely results in clinical manifestations.
  • Liver biopsy is the test that is most sensitive and specific for measuring liver iron content and can also assess liver damage. On histopathological analysis with Perls Prussian blue staining, there is a classic pattern in which iron deposits primarily in hepatocytes and biliary epithelial cells, with slight involvement of Kupffer cells. A liver biopsy is indicated in the following situations:
  • Elevated liver enzymes in a diagnosed case of hemochromatosis
  • Serum ferritin levels more than 1000 mcg/L
  • Liver enzymes are usually elevated, with most patients having elevated aminotransferase levels, but the liver enzymes are usually not higher than twice the normal levels.
  • Fasting blood glucose levels need to be checked for diabetes. Glycosylated hemoglobin levels might not be reliable in patients with high red cell turnover.
  • Other tests that need to be done in patients with high ferritin levels are echocardiogram for cardiomyopathy, hormone levels to evaluate hypogonadism, and bone densitometry to evaluate for osteoporosis.
  • First-degree relatives of patients with hemochromatosis should undergo screening with genetic testing

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Adams, Paul C et al. “Serum ferritin is a biomarker for liver mortality in the Hemochromatosis and Iron Overload Screening Study.” Annals of hepatology vol. 14,3 (2015): 348-53.

Al-Chalabi, Mustafa, et al. “Physiology, Prolactin.” StatPearls, StatPearls Publishing, 29 July 2021.

Bacon, Bruce R et al. “Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.” Hepatology (Baltimore, Md.) vol. 54,1 (2011): 328-43. doi:10.1002/hep.24330

Barton, J C et al. “Screening for hemochromatosis in routine medical care: an evaluation of mean corpuscular volume and mean corpuscular hemoglobin.” Genetic testing vol. 4,2 (2000): 103-10. doi:10.1089/10906570050114786

Beutler, Ernest et al. “Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease.” Acta haematologica vol. 107,3 (2002): 145-9. doi:10.1159/000057632

Ellervik, Christina et al. “Elevated transferrin saturation and risk of diabetes: three population-based studies.” Diabetes care vol. 34,10 (2011): 2256-8. doi:10.2337/dc11-0416

Girelli, Domenico et al. “Hemochromatosis classification: update and recommendations by the BIOIRON Society.” Blood vol. 139,20 (2022): 3018-3029. doi:10.1182/blood.2021011338

Golfeyz, Shmuel et al. “Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI.” Expert review of gastroenterology & hepatology vol. 12,8 (2018): 767-778. doi:10.1080/17474124.2018.1496016

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021

Palmer, William C et al. “Diagnosis and Management of Genetic Iron Overload Disorders.” Journal of general internal medicine vol. 33,12 (2018): 2230-2236. doi:10.1007/s11606-018-4669-2

Piperno, Alberto et al. “Inherited iron overload disorders.” Translational gastroenterology and hepatology vol. 5 25. 5 Apr. 2020, doi:10.21037/tgh.2019.11.15

Porter, Joann L. and Prashanth Rawla. “Hemochromatosis.” StatPearls, StatPearls Publishing, 11 June 2022. 

Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021

Tag(s): Conditions

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