Clinical History
A 48 year old white Northern European woman had been suffering from right upper quadrant abdominal pain for almost a year. Liver enzymes were slightly elevated and US of the liver had shown slight acoustic shadowing. She was referred for an abdominal MRI to rule out pathology other than steatosis.
Imaging Findings
Apart from a dull right upper abdominal pain, the patient’s history was uneventful. US performed externally ruled out focal liver lesions or bile calculi and showed enhanced echogenicity with slight acoustic shadowing of the liver parenchyma, which was attributed to steatosis. ALT was 60 U/l, AST 42 U/l, other parameters were not reported. Constant or excessive alcohol consumption was denied by the patient. Our MRI protocol included T1-weighted in-phase and opposed-phase double gradient echo sequences (Fig 1a), T2-weighted FSE sequences with and without fat saturation (Fig 2), and a 3D gradient echo pre- and post-contrast series (not shown). The liver tissue exhibited a marked signal loss on the FSE sequences with a long TE and on the in-phase images of the double gradient echo series. Iron overload was suspected and primary haemochromatosis was confirmed by laboratory tests and subsequent genetic testing.
Discussion
Hereditary haemochromatosis (HHC) comprises several genetic subtypes, but only type 1 with a homozygous C282Y mutation of the HFE gene on chromosome 6 is of clinical importance. It accounts for 90% of cases in the Caucasian subpopulation in Europe. In Europeans of Mediterranean origin, there is a much less frequent mutation in the transferrin receptor 2 gene, that causes type 3 HHC. Both are autosomal-recessive traits. The pathogenic mechanism consists in an inadequately high intestinal iron absorption that after decades may cause iron overload and damage to various organs. Only homocygotes are at a risk; their prevalence is approximately 0.5% in Central Europe. The manifestation also depends on non-genetic factors such as iron intake and blood loss. Females develop clinical symptoms 5-8 times less frequently and 10-20 years later than males. HHC must also be differentiated from secondary haemochromatosis (SHC), which may result from repeated blood transfusions in anaemic disorders, e.g. thallasaemia, sickle cell anaemia or myelodysplastic syndrome. In SHC, iron first accumulates in RES macrophages, whereas in HHC, it is stored primarily in parenchymal cells. Therapy of HHC consists of iron depletion by means of phlebotomy. In SHC, by contrast, phlebotomies are contraindicated because of the anaemia. Iron chelators must be administered. Diagnosis of haemochromatosis is made by elevated transferrin saturation. Serum ferritin is also an indicator, but lacks specificity if performed alone. The diagnosis is confirmed by a genetic test. Liver biopsy is necessary only in patients without the typical gene mutation or ferritin values > 1000 ng/ml, leading to an increased risk of cirrhosis and hepatocellular carcinoma [1]. This is where MRI screening for liver cancer normally starts. However, MRI can detect haemochromatosis at an earlier stage, before permanent organ damage will occur. Several studies have shown significant correlations between T1 and T2 relaxation rates and the liver iron content (LIC) yielded by biopsy [2]. Due to the absence of radiofrequency refocussing, gradient echo sequences are the most sensitive in detecting small amounts of iron [3]. The double gradient echo signal characteristics in the present case appear to be the opposite of those normally observed in hepatic steatosis (Fig. 1b). However, the phenomenon is not based on chemical shift, which causes signal cancellation in opposed-phase images of fatty tissues. In fact, it occurs due to susceptibility effects, for the opposed-phase echo is the first echo acquired and the second in-phase echo is acquired at a longer TE. This allows more time for dephasing due to field inhomogenities. An understanding of both effects is important for correct interpretation of hepatic MR images [4].
Quantitative measurement of LIC by MRI is possible within a certain range. Depending on the pulse sequence, the minimum TE and the field strength, there is a maximum measurable LIC, beyond which there is total signal loss. For this to occur, the normal value of 36 mmol/kg must be increased at least five-fold [3]. Reliable data are obtained, only if the equipment is calibrated for such measurement. Most scanners however, do not fulfil this criterion.
Differential Diagnosis List
Hereditary (primary) haemochromatosis type I
Final Diagnosis
Hereditary (primary) haemochromatosis type I
