Clinical presentation

A 55-year-old woman presented to our hepatology outpatient clinic with symptoms of anaemia. Her medical history included hereditary haemochromatosis type 1, psoriatic arthropathy and bilateral cataracts since early adulthood. There was a family history of early-onset cataracts. Haemochromatosis was treated by frequent phlebotomies (2–4 per month) since diagnosis 2.5 years earlier, limited by several episodes of severe symptomatic anaemia (minimal haemoglobin: 7.0 g/dL). Despite anaemia, she presented with constantly high levels of ferritin (>1000 ng/mL) throughout the period of phlebotomies so that she was referred to our clinic for further diagnostics and therapy. At presentation, physical examination showed signs of anaemia but no signs of liver cirrhosis. The levels for γ-glutamyltransferase, alanine transaminase, bilirubin, international normalised ratio (INR) and thrombocytes were within the normal range. Notably hypochromic, microcytic anaemia (haemoglobin 9.8 g/dL) with high levels of ferritin (1346 ng/mL), distinctly decreased transferrin saturation (2.9%) and normal levels of vitamin B12 and folic acid were observed. Homozygosity of the human haemochromatosis protein (HFE) C282Y polymorphism was confirmed by genetic testing. Abdominal ultrasound and chest x-ray showed normal results. Ophthalmologic examination revealed a noticeable form of bilateral cataract consisting of scattered punctate with nuclear opacities (figure 1A,B).

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Figure 1

(A) Retroillumination photograph and (B) Scheimpflug tomography of the patient illustrate the typical finding of a star-shaped cataract and peripheral flecks.

Question

See page 698 for answer

What unifying diagnosis explains haemochromatosis, high levels of ferritin, hypochromic microcytic anaemia and very low transferrin saturation?

Answer

From question on page 686 Medical history, laboratory findings and pathognomonic cataract morphology indicated simultaneous presence of hereditary hyperferritinaemia cataract syndrome (HHCS) and haemochromatosis (figure 1A,B). HHCS is a very rare autosomal dominant disorder caused by disruption of posttranscriptional regulation control of the L ferritin gene.1 Mutations in the iron-responsive element of the L ferritin mRNA impair the affinity for binding to iron regulatory proteins (IRPs) causing unregulated synthesis of L ferritin (figure 2). Resulting high serum ferritin levels are no longer indicative of body iron stores and accumulate in the lenses triggering bilateral early onset cataracts.2 The heterozygous C33T mutation was detected in our patient by genetic testing. High ferritin levels in HHCS fail to indicate iron loss during phlebotomies. In our case, phlebotomies were carried out excessively leading to severe iron deficiency anaemia. Interruption of phlebotomies increased haemoglobin levels and led to an improved general state. Guidance of further phlebotomies is difficult as ferritin levels cannot be used. As for potential surrogate markers of cellular iron content (transferrin saturation, serum transferrin receptor, MRI) no formal validation data are available in patients with haemochromatosis and liver puncture remains the only reliable alternative.3 Her son, also receiving frequent phlebotomies, was tested positive for the indicated gene mutation.

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Figure 2

Post-transcriptional L-Ferritin gene regulation and pathophysiology of hereditary hyperferritinaemia cataract syndrome (HHCS): Binding of iron regulatory proteins 1 (IRPs) to iron response element (IRE), regulated by iron concentrations, blocks translation of L ferritin mRNA. In case of HHCS, mutations in the IRE reduce affinity for IRPs, resulting in unregulated L ferritin synthesis.