Hemochromatosis – Morning Report March 8th

In this blog post, you will find a summary of hemochromatosis including a brief discussion epidemiology, pathophysiology, investigations, extrahepatic manifestations, and pearls on management.

1. Epidemiology of Hemochromatosis

Hereditary hemochromatosis is one of the frequent autosomal recessive hereditary diseases in European Caucasians. Its geographic distribution is worldwide however it is most commonly seen in those of northern European origin, particularly Nordic or Celtic ancestry, in which its prevalence is 1 per 220-250 people.

The prevalence of hereditary hemochromatosis related to the HFE-gene mutation is similar in the USA, Europe, and Australia, and it is approximately 1 in 200–400 people.

2. Pathophysiology of Hemochromatosis

Some terms that are important for understanding iron metabolism are included here:

  • Ferritin: Protein inside cells that stores and releases iron
  • Transferrin: Glycoprotein produced by the liver that carries iron in the circulation
  • Total iron binding capacity (TIBC): BOTH the serum iron and the iron-binding sites on transferrin that are not bound to iron (also known as the unsaturated iron-binding capacity)
  • Transferrin-iron saturation: amount of iron bound to transferrin; percentage is calculated by dividing serum iron/TIBC
  • Hepcidin: Hormone produced and released by the liver in response to serum iron levels, which blocks absorption of iron from the intestinal mucosa by breaking down ferroportin-1
  • Ferroportin-1: Transmembrane protein intestinal epithelial cells, hepatocytes, macrophages which allows iron to be exported from cells

Iron is absorbed by enterocytes in the proximal small intestine; there is heme iron and non-heme iron which is mainly ferric iron. To allow absorption and transport across the membrane of enterocytes, Fe3+ (or ferric iron) is reduced by ferric reductase duodenal cytochrome B to Fe2+ (ferrous iron). Ferrous iron is transported across divalent metal transporter 1 then when inside the cell, iron is either stored bound to ferritin or can be transported across basolateral membrane via ferroportin. As a part of this, ferrous iron gets converted back to ferric iron.

Hepcidin controls the extracellular iron concentrations by binding to and inducing the degradation of cellular iron exporter ferroportin. Therefore concentrations of hepcidin are inversely proportional to iron absorption.

Synthesis of hepcidin is regulated by a number of factors including hypoxia, iron concentrations, anemia, inflammatory cytokines, as well as other bone morphogenic proteins (BMPs) that seem to bind haemojuvelin (HFE2, also known as HJV) as a co-receptor and signal through SMAD family member 4 (SMAD4), a protein of the transforming growth factor β superfamily.

Though the exact mechanism by which the C282Y HFE protein, ferroportin and hepcidin interact is not known.

Reference – Adams, P. C., and J. C. Barton. (2007). Hemochromatosis. Seminar. Lancet. 370: 1855-60.

Deregulation of their iron metabolism with elevated transferrin saturation and high ferritin levels –> then can lead to iron overload in internal organs.

There are four types of HH based on proteins involved. Type 1a HH is the most common inherited type; the most common mutation responsible for hereditary hemochromatosis (HHC) is based on a G to A transition at 845 nucleotide of the HFE gene, which leads to a cys282tyr substitution. This is known as type 1a.

Genetic mutation in H63D doesn’t cause significant iron overload but assist in phenotypic expression of iron overload so when in combination with C282Y (ie compound heterozygote C282Y/H63D) this is Type 1b HH. Homozygous H63D are not at increased risk of iron overload. Type 1c related to mutation S65C may lead to increased iron and ferritin levels but is not associated with iron overload.

Types 2-4 HH are not associated with HFE gene. Type 2 is juvenile hemochromatosis (mutation in HJV gene in Type 2a and HAMP gene in Type 2b) which can lead to severe iron overload related to hepcidin deficiency. Type 3 HH is associated with transferrin receptor 2 gene mutations and therefore diminished hepcidin. Type 4 is the only autosomal dominant form of hemochromatosis (FPN1 gene mutation and iron retention inside cells). See ACG article below on the manifestations in these other forms of HH.

3. Investigations for Hemochromatosis

See algorithm below from the ACG guidelines on who to screen for HH. Tests to send in this setting include:

  • Serum ferritin
  • Transferrin saturation
  • Serum iron level

As per Choosing Wisely, HFE genotyping should only be done in patients with an elevated serum ferritin AND fasting transferrin saturation > 45%. Of note, there is a very small subset of patients that could be missed i.e. some non-HFE forms of primary iron overload. For example, in Type 4A HH, there is low plasma iron, normal or low transferrin saturation but high serum ferritin.

See the American guidelines below which say transferrin saturation > 45% AND/OR elevated serum ferritin.

Reference – Kowdley, Kris V. MD, FACG; Brown, Kyle E. MD, MSc; Ahn, Joseph MD, MS, MBA, FACG (GRADE Methodologist); Sundaram, Vinay MD, MSc ACG Clinical Guideline: Hereditary Hemochromatosis, The American Journal of Gastroenterology: August 2019 – Volume 114 – Issue 8 – p 1202-1218 doi: 10.14309/ajg.0000000000000315

There are secondary causes of iron overload to be considered, including iron-loading anemias (ex. RBC transfusions, sickle cell anemia, thalassemia major), chronic liver disease (non-alcoholic fatty liver disease, hepatitis B, C, porphyria cutanea tarda), other systemic inflammatory diseases and malignancies such as HCC.

The guidelines suggest a non–contrast-enhanced MRI (MRI T2*) be used to noninvasively measure liver iron concentration, in the non-C282Y homozygote with suspected HH. If there is a concomitant need to stage hepatic fibrosis or evaluate for alternate liver
diseases, then liver biopsy is the preferred method to determine hepatic iron concentration.

4. Extrahepatic Manifestations of Hemochromatosis

Hepatic maninfestations include transaminitis, hepatomegaly, cirrhosis, fibrosis, and hepatocellular carcinoma. Extraheptic manifestations of hemochromatosis include:

  • Hypothyroidism
  • Arthritis (2nd/3rd MCP or wrist joints “hook-shaped osteophytes” on X-ray, chondrocalcinosis)
  • Hypogonadism
  • Hypopituitarism
  • Restrictive/dilated cardiomyopathy, heart failure, arrhythmias
  • Diabetes
  • Bronzing of the skin
  • Osteoporosis
  • Porphyria cutanea tarda
    • Onycholysis and blistering of the skin in areas that receive higher levels of exposure to sunlight
    • Primary cause is a deficiency of uroporphyrinogen deoxycarboxylase (UROD) a cytosolic enzyme that is the step in the enzymatic pathway that leads to synthesis of heme
    • Development of photo-sensitivities causing blisters and erosions on sun-exposed skin
  • Amenorrhea
  • Infections at risk of: Yersinia, Pasturella, Vibrio vulnificus, Listeria

5. Management of Hemochromatosis

  • Phlebotomy to target ferritin 50-100 ug/dL (micrograms per decilitre) in C282Y homozygote or C282Y/H63D compound heterozygote
  • Avoid vitamin C supplementation, avoid raw shellfish (risk of Vibrio vulnificus, Listeria, Yersinia, E coli)
  • Screen 1st degree relatives as above
  • Liver transplant should be considered in patients with HH who have decompensated cirrhosis or HCC
  • Iron chelation for treatment of HH in those who are intolerant/refractory to phlebotomy, or when phlebotomy has potential for harm (severe anemia, CHF)
  • Hepatocellular carcinoma screening recommendations the same as those with cirrhosis from other etiologies


  • Adams, P. C., and J. C. Barton. (2007). Hemochromatosis. Seminar. Lancet. 370: 1855-60.
  • Kowdley, Kris V. MD, FACG; Brown, Kyle E. MD, MSc; Ahn, Joseph MD, MS, MBA, FACG (GRADE Methodologist); Sundaram, Vinay MD, MSc ACG Clinical Guideline: Hereditary Hemochromatosis, The American Journal of Gastroenterology: August 2019 – Volume 114 – Issue 8 – p 1202-1218 doi: 10.14309/ajg.0000000000000315
  • Canadian Association for the Study of Liver Disease. (2020). Five Tests and Treatments to Question. Accessed at https://choosingwiselycanada.org/recommendation/hepatology/ Accessed on March 12, 2022
  • Bacon, B.R., Adams, P.C., Kowdley, K.V., Powell, L.W. and Tavill, A.S. (2011), Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology, 54: 328-343. https://doi.org/10.1002/hep.24330

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