Haemochromatosis

Haemochromatosis is an iron overload disorder characterized by a progressive increase in total body iron stores and deposition of iron in a number of non-reticuloendothelial system (RES) body organs resulting in some instances in organ dysfunction. 

This article focus on general principles of hemochromatosis, 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:

• cardiac manifestations of haemochromatosis
• skeletal manifestations of haemochromatosis
• pancreatic manifestations of haemochromatosis

Epidemiology

Haemochromatosis may be primary which is a genetic disorder or secondary which can result from a variety of disorders.

Primary haemochromatosis

Primary haemochromatosis is an autosomal recessive condition due to 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

Secondary haemochromatosis (non-reticuloendothelial system (RES) iron deposition) 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.

Causes

• frequent transfusion 
  • mainly depositional siderosis in 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 

Clinical presentation

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

• hyper-pigmented 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)

Pathology

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 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 and cardiac deposition can occur once hepatic deposition is extensive
• iron gets deposited in periportal hepatocytes (ferritin & haemosiderin)
• perilobular fibrosis ensues with fibrous septa
• can progress to cirrhosis with broad fibrous septa surrounding large areas of relatively normal liver parenchyma

Radiographic features

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.

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

CT, although readily available, is not very sensitive for the diagnosis of haemochromatosis ⁶. In positive cases, marked homogenous increase in liver density (approximately HU 75 - 130) is demonstrated, making the portal vessels and hepatic veins appear of low attenuation relative to liver on non-contrast CT. 

Dual energy CT can be used to quantitate iron deposition.

MRI

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. 

Diagnosis

Visceral iron results in susceptibility artifact which leads to T2* signal loss. The result is low signal 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 is typically normal and low pancreatic signal is usually only seen if there is cirrhosis. 

Quantification

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 improve 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 haemosdierosis may require iron chelation therapy, depending on the underlying cause. 

Poor prognostic factors include the development of

• cirrhosis
• hepatocellular carcinoma (HCC)
• diabetes 
• cardiomyopathy

Differential diagnosis

Generla imaging differential considerations include

• haemosiderosis - eg. thalassaemia: iron deposition mainly in spleen / bone marrow compared with primary haemochromatosis where iron is mainly in liver.
• other causes of a hyperdense liver on CT ⁶
  • amiodarone
  • Wilson disease
  • colloidal gold treatment