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Multiorgan involvement in thalassaemia major

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Q1: What are the findings on the mri images?

MRI scans of the sella (fig 1 in questions; see p358) show markedly decreased signal intensity in the anterior lobe of the pituitary gland in all the sequences, though best seen on gradient echo images. Hypointense signal is also seen in bilateral basal ganglia.

Q2: What is the diagnosis?

The diagnosis is secondary (erythropoietic) haemochromatosis with hypogonadotropic hypogonadism developing in a patient with β-thalassaemia major.

The child had been diagnosed as having thalassaemia major at the age of 5 months and had received numerous blood transfusions since. She had also been treated with desferrioxamine B. Her serum ferritin level was 8672 μg/l, luteinising hormone was zero, and follicle stimulating hormone level was 0.20 U/l.

MRI the of abdomen and chest (fig 1, next page), done at the same sitting, demonstrates low signal intensity, equal to that of background, in liver, spleen, pancreas and myocardium, indicating iron deposition in these organs also.

Figure 1

(A) Coronal gradient echo image at the level of the heart shows hypointense signal in the myocardium indicating iron deposition and (B) axial gradient echo MRI scan through the upper abdomen showing hypointense signal in the liver, spleen, and the pancreas.

Discussion

Haemochromatosis refers to a group of disorders in which there is a progressive increase in total body iron stores with deposition of iron in the liver, heart, pancreas, and other organs.1

Two generalised categories of iron deposition in iron overload have been described:

(1) Parenchymal cell iron deposition (see box 1)—this is seen in idiopathic (primary haemochromatosis), secondary to anaemia and ineffective erythropoiesis, intravascular haemolysis, cirrhosis, after portocaval anastomoses, and secondary to high intake.

Box 1: Parenchymal cell iron deposition

  • Idiopathic (primary haemochromatosis), secondary to ineffective erythropoiesis, intravascular haemolysis, etc.

  • Organs involved: liver (hepatocytes), pancreas (acinar cells), heart, endocrine glands (anterior pituitary etc).

  • May lead to cellular damage and organ dysfunction.

(2) Reticuloendothelial cell iron deposition (see box 2)—this is seen most commonly in patients who have received multiple transfusions and also in patients with rhabdomyolysis.

Box 2: Reticuloendothelial cell iron deposition

  • Secondary to multiple transfusions, in patients with rhabdomyolysis.

  • Organs involved: liver (Kupffer cells), spleen (reticuloendothelial cells), bone marrow, lymph nodes.

  • No significant organ dysfunction.

Parenchymal cell iron deposition occurs primarily in liver (hepatocytes), pancreas (acinar cells), heart, and other endocrine glands (anterior lobe of pituitary gland). The spleen is usually spared. However, there have been few reports of low signal intensity in the spleen without any history of blood transfusion, the cause of which is unknown.2 Parenchymal cell iron deposition leads to cellular damage and organ dysfunction unless treated.

In transfusional iron overload, haemosiderin is deposited in the reticuloendothelial system, such as the Kupffer cells of the liver and the reticuloendothelial cells of the spleen and bone marrow. This iron is derived from the extravascular haemolysis of intact red blood cells by the reticuloendothelial cells, which occurs during the metabolism of senescent native and transfused erythrocytes. The pancreas is spared because it is not a reticuloendothelial organ. However, pancreatic iron deposition in transfusional iron overload may result from massive transfusion beyond the iron storage capacity of the reticuloendothelial cell system (10 g), which is the amount of iron in 40 units of blood.3 Reticuloendothelial iron deposition does not produce any significant organ dysfunction.

Thalassaemia major, characterised by ineffective erythropoiesis and hypercellular bone marrow, results in secondary erythropoietic haemochromatosis. These patients also absorb iron inappropriately and can develop severe parenchymal cell overload. Also, iron accumulation of the reticuloendothelial system may develop due to repeated transfusions for the anaemia, accounting for the decreased splenic signal intensity. Thus, this group of patients share MRI features of both reticuloendothelial and parenchymal cell iron overload, as seen in our case.

Excess iron deposition in the anterior pituitary leads to degranulation of theadenohypophysis and decreased hormone storage with ensuing hypogonadism due to pituitary hyporesponsiveness to gonadotrophin releasing hormone.4 Iron deposition in the posterior lobe and diabetes insipidus usually do not occur.

Cardiac iron deposition occurs in the ventricular myocardium before atrial myocardium. Furthermore, cardiac iron deposition is exclusively sarcoplasmic and not interstitial; therefore, wall thickness in haemochromatosis is usually normal.5

At MRI, the marked signal intensity reduction is due to decreased T2 relaxation time and magnetic field inhomogeneties created by the excess intracellular iron.

Ferritin and haemosiderin, being para magnetic substances, cause a proton relaxation effect on neighbouring hydrogen nuclei; T1 and T2 relaxation time decreases. Since both T1 and T2 are shortened, intensity may either increase or decrease depending on which relaxation effect, T1 or T2, dominates. For relatively low concentration of iron, as seen in organs like muscle and kidney which do not accumulate iron in high concentration, T1 is considerably shortened and T2 values only slightly shortened leading to increased signal intensity of these tissues. With increasing concentrations of iron, as in liver etc, T2 shortening becomes dominant leading to decreased signal intensity in these organs.6

GRE T2*-weighted sequence is regarded as the most sensitive technique for the detection of parenchymal iron deposition. This is likely due to the lack of a 180° refocusing pulse that partially recovers signal loss from the field in homogeneity in spin echo imaging.4

Final diagnosis

Secondary (erythropoietic) haemochromatosis with hypogonadotropic hypogonadism in a patient with β-thalassaemia major.

References

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