Haemochromatosis is an iron overload disorder characterised by a progressive increase in total body iron stores and deposition of iron in some non-reticuloendothelial system (RES) body organs which results in some instances in organ dysfunction.
This article focus on the general principles of haemochromatosis, as well as effects of iron accumulation in the liver, the most frequently affected organ. Clinical and imaging changes in other organ systems are discussed separately:
- haemochromatosis: cardiac manifestations
- haemochromatosis: skeletal manifestations
- haemochromatosis: pancreatic manifestations
- haemochromatosis: CNS manifestations
Haemochromatosis may be primary which is a genetic disorder or secondary which can result from a variety of diseases.
Primary haemochromatosis is an autosomal recessive condition due to an abnormal HFE gene, the protein product of which regulates iron absorption from the gastrointestinal tract.
Approximately 2-5% of the population are heterozygous carriers (Caucasian population), resulting in 0.2-0.5% prevalence of homozygous individuals 6. This makes haemochromatosis one of the most common genetic disorders in Caucasians of Northern European ancestry.
Although the genetic defect is distributed equally among men and women, the iron loss as a result of menstruation is protective, resulting in a clinical male predilection (M:F ~ 2:1).
In men, the diagnosis usually becomes evident in middle age (30-40 years of age) whereas in women, clinical manifestation is delayed until the post-menopausal period.
Secondary haemochromatosis is rare and is usually seen in association with diseases that chiefly cause haemosiderosis. The distribution of iron in both RES and non-RES tissues can thus assist in the imaging differentiation between primary and secondary disease 6.
- frequent transfusion
- mainly depositional siderosis in the reticuloendothelial system (RES)
- if > 40 units transfused: then may cause haemochromatosis (non-RES iron deposition)
- high erythrogenic requirements (haemolytic anaemia, myelodysplasia)
- mainly depositional siderosis in RES from transfusion
- increased duodenal iron absorption may lead to haemochromatosis (non-RES iron deposition)
- bantau siderosis: rare cause in Africa due to iron-laden locally-brewed beer
As haemochromatosis may affect a number of organ systems, patients not surprisingly may present with a variety of signs and symptoms. These are most pronounced in primary haemochromatosis and include 4:
- hyperpigmented skin "bronze": 90%
- hepatomegaly: 90%
- arthralgia: 50% (see skeletal manifestations of haemochromatosis)
- diabetes: 30% (see pancreatic manifestations of haemochromatosis)
- heart failure/arrhythmia: 15% (see cardiac manifestations of haemochromatosis)
- hypogonadotropic hypogonadism (see CNS manifestations of haemochromatosis)
The fundamental pathology that underlies haemochromatosis is the accumulation of iron and increase in total body iron stores (as high as 50-60g) and abnormal non-reticuloendothelial deposition, which in turn leads to organ dysfunction.
Haemochromatosis is distinct from, and should not be confused with, haemosiderosis which refers to reticuloendothelial system (RES) iron deposition and does not cause organ damage.
Eventual organ dysfunction is the final step in a cascading sequence of events 5:
- increased gastrointestinal absorption of iron
- increased cellular uptake of iron into non-RES
- liver is the primary organ of deposition
- pancreatic, cardiac, skeletal, and CNS deposition can occur once hepatic deposition is extensive
- iron gets deposited in periportal hepatocytes (ferritin and haemosiderin)
- perilobular fibrosis ensues with fibrous septa
- can progress to cirrhosis with broad fibrous septa surrounding large areas of relatively normal liver parenchyma
General visceral features of haemochromatosis are increased organ density (CT) and reduced organ signal intensity (MRI). Secondary imaging features include hepatomegaly, cirrhosis and signs of heart failure.
The pattern of iron deposition is important. Predominant involvement of the liver, without deposition in spleen or bone marrow, is consistent with non-RES iron deposition and is characteristic of primary haemochromatosis. Iron deposition in the spleen and bone marrow, but to a lesser degree in the liver is consistent with RES deposition and is most likely due to haemosiderosis, which may or may not be associated with secondary haemochromatosis.
CT, although readily available, is not very sensitive for the diagnosis of haemochromatosis 6. In positive cases, marked homogenous increase in liver density (75-130 HU) is demonstrated, making the portal vessels and hepatic veins appear of low attenuation relative to the liver on non-contrast CT.
Dual-energy CT can be used to quantitate iron deposition.
See the subarticle on MRI liver iron quantification.
MRI is not only the most sensitive imaging modality for the diagnosis of haemochromatosis but is also able to estimate iron concentration within the liver, thus forestalling the need for repeated biopsies 6.
Visceral iron results in susceptibility artefact which leads to T2* signal loss. The result is low signal that is seen on all sequences, but particularly gradient echo and T2. It is useful to compare organ signal to that of skeletal muscle, with lower organ signal than muscle indicating the presence of iron.
Gradient in-phase and out-of-phase sequences are particularly useful, demonstrating changes that are the opposite of those seen in hepatic steatosis. In haemochromatosis, the liver on in-phase sequence (which is usually obtained second, and thus more susceptible to T2* effects) demonstrates low signal, whereas the out-of-phase sequence demonstrates higher signal 6.
In primary haemochromatosis, spleen and bone marrow signal are typically normal and low pancreatic signal is usually only seen if there is cirrhosis.
Quantitative MR techniques for measuring iron deposition have been developed, consisting of multiple gradient-echo sequences with progressively increasing TEs. The degree to which signal drops can then be plotted and an estimate of iron concentration generated. In cases with very high concentration, the method is unreliable as too little signal is returned from the liver 6.
Treatment and prognosis
Treatment in primary disease involves frequent phlebotomy which improves symptoms such as hepatomegaly, skin pigmentation, lethargy, and abdominal pain. However, arthritis is not affected by therapy. This also improves mild abnormalities of glucose metabolism. However, if type I diabetes mellitus has developed, insulin replacement will still be required. Some improvement in hepatic fibrosis and cardiac dysfunction can also be expected.
Secondary haemochromatosis and haemosiderosis may require iron chelation therapy, depending on the underlying cause.
Poor prognostic factors include the development of:
General imaging differential considerations for hepatic appearances include:
- 1. Bonkovsky HL, Rubin RB, Cable EE et-al. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. 1999;212 (1): 227-34. Radiology (full text) - Pubmed citation
- 2. Siegelman ES, Mitchell DG, Semelka RC. Abdominal iron deposition: metabolism, MR findings, and clinical importance. Radiology. 1996;199 (1): 13-22. Radiology (citation) - Pubmed citation
- 3. Kawamoto S, Soyer PA, Fishman EK et-al. Nonneoplastic liver disease: evaluation with CT and MR imaging. Radiographics. 18 (4): 827-48. Radiographics (abstract) - Pubmed citation
- 4. Dähnert W. Radiology Review Manual. Lippincott Williams & Wilkins. (2007) ISBN:0781766206. Read it at Google Books - Find it at Amazon
- 5. Guyader D, Gandon Y, Deugnier Y et-al. Evaluation of computed tomography in the assessment of liver iron overload. A study of 46 cases of idiopathic hemochromatosis. Gastroenterology. 1989;97 (3): 737-43. Pubmed citation
- 6. Queiroz-andrade M, Blasbalg R, Ortega CD et-al. MR imaging findings of iron overload. Radiographics. 2009;29 (6): 1575-89. doi:10.1148/rg.296095511 - Pubmed citation