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Keywords:

  • haemochromatosis;
  • phlebotomy;
  • desferrioxamine;
  • desferal;
  • SQUID-biosusceptometry

Abstract

  1. Top of page
  2. Abstract
  3. Patients
  4. Results and discussion
  5. References

Summary.  The treatment of iron overload by s.c. desferrioxamine (DFO) was studied in three patients with hereditary haemochromatosis in which phlebotomy treatment was not, or transiently not, possible because of their serious clinical condition or the lack of appropriate peripheral veins. Repeated non-invasive liver iron concentration measurements by superconducting quantum interference device biosusceptometry showed that DFO treatment (2 g/d for 9–11 months) was as effective (liver iron elimination rate: 12 mg/d) as normal phlebotomy treatment (5·9 or 14·3 mg/d respectively) with weekly 500-ml blood removals. This demonstrates that DFO is an effective alternative therapy for haemochromatosis when phlebotomy is not possible.

Hereditary haemochromatosis is a genetic disease in which food iron absorption is inappropriately increased and not balanced to the body iron stores (Feder et al, 1996). Exhaustive phlebotomy is the routine treatment procedure and has clearly proven its effectiveness and safety (Adams et al, 2000). However, some patients cannot be treated with weekly phlebotomy due to a prohibitive clinical situation (severe liver cirrhosis, cardiomyopathy), or due to the lack of appropriate access for the venepuncture. The use of desferrioxamine (DFO) in haemochromatosis was reported in very early studies (Wöhler, 1963; Thompson et al, 1967), but has recently been mentioned only anecdotally in some reviews (Barton et al, 1998; Walker et al, 1998). According to Powell (1994), DFO is a poor substitute for phlebotomy, because it is difficult to achieve a negative iron balance with chelation in haemochromatosis.

The effectiveness of DFO in haemochromatosis in comparison with phlebotomy has not been reported to date. We studied three patients with the typical HFE-haemochromatosis (homozygous C282Y mutation) in which treatment with DFO was monitored by repeated measurements of the liver iron concentration using superconducting quantum interference device (SQUID) biosusceptometry (Nielsen et al, 2002).

Case 1.  A 50-year-old male patient with unclear liver cirrhosis and diabetes was referred to our university hospital because of a severe dilatative cardiomyopathy. A liver biopsy revealed severe iron overload and the diagnosis of hereditary haemochromatosis was made. Phlebotomy had to be stopped after five treatments, because the cardiac situation worsened. The patient also developed (for the first time) severe anxiety, depression and paranoiac symptoms, which disappeared following some weeks of treatment with haloperidol.

Case 2.  A 50-year-old man with haemochromatosis, severe liver cirrhosis and diabetes had his phlebotomy treatment stopped very soon after its commencement due to the development of anaemia and ascites.

Case 3.  A 62-year-old woman with haemochromatosis and diabetes could not undergo phlebotomy treatment due to a lack of the appropriate peripheral veins. The patient refused the implantation of a ‘port-a-cath’.

All three patients were treated by DFO (2 g/d, s.c. infusion >8 h/d).

Results and discussion

  1. Top of page
  2. Abstract
  3. Patients
  4. Results and discussion
  5. References

Desferrioxamine treatment was clearly successful in removing excessive storage iron from the body in all three cases. After 11 months of treatment, cardiomyopathy and the mental situation was greatly improved in case 1 and the liver function was stabilized in case 2. The tolerance to phlebotomy was tested at intervals in both of these patients; both treatment regimes were performed with increasing amounts of blood removal per week, starting with 100 ml. As this was tolerated quite well, DFO injections were stopped and the classical phlebotomy treatment was continued in both patients. The efficacy of iron removal was followed in treatment periods with DFO alone, DFO plus phlebotomy, or phlebotomy alone by repeated measurements of the liver iron concentration by SQUID biosusceptometry (Fig 1).

image

Figure 1. The course of a patient with hereditary haemochromatosis under treatment with desferrioxamine (DFO), DFO plus phlebotomy, or phlebotomy alone (case 1). Crosses indicate liver iron concentration; lines represent a linear regression resulting in the given amounts of daily iron removal from the liver. Serum iron is expressed as μg/l for illustration purposes only [(μg/l)/56 = μmol/l].

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The liver iron elimination rate induced by DFO was similar in case 1 (12·4 mg/d) and case 2 (12·6 mg/d). The amount of iron removed by phlebotomy (250 mg Fe/500 ml blood) was calculated for the periods with exclusive phlebotomy treatment. Corrected for food iron absorption (3 mg/d), and taking also the actual haemoglobin concentration into account, more iron was removed from the whole body (case 1, 19·4 mg/d; case 2, 10·8 mg/d) than from the liver (case 1, 14·3 mg/d; case 2, 5·9 mg/d) in this end phase of exhaustive phlebotomy treatment.

In case 3, the liver iron concentration was reduced from 3·3 mg to 1·1 mg/gliver wet weight (normal 0·1–0·5 mg/g), serum ferritin dropped from 900 to 380 μg/l after 32 weeks of treatment with DFO. The therapy is ongoing in this patient.

It is important that a clear negative iron balance was achieved in all three patients with hereditary haemochromatosis using DFO. Thus, DFO treatment is an effective second line treatment in those patients for whom regular phlebotomy cannot be performed. In the normal haemochromatosis patient, however, phlebotomy treatment is simpler, safer and much more cost-effective compared with DFO.

References

  1. Top of page
  2. Abstract
  3. Patients
  4. Results and discussion
  5. References
  • Adams, P., Brissot, P. & Powell, L.W. (2000) EASL international consensus conference on haemochromatosis. Journal of Hepatology, 33, 485504.
  • Barton, J.C., McDonnell, S.M., Adams, P.C., Brissot, P., Powell, L.W., Edwards C.Q., Cook, J.D. & Kowdley, K.V. (1998) Management of hemochromatosis. Annals of Internal Medicine, 129, 932939.
  • Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.A., Basava, A., Dormishian, F., Domingo, R., Ellis, M.C., Fullan, A., Hinton, L.M., Jones, N.L., Kimmel, B.E., Kronmal, G.S., Lauer, P., Lee, V.K., Loeb, D.B., Mapa, F.A., McClelland, E., Meyer, N.C., Mintier, G.A., Moeller, N., Moore, T., Morikang, E., Prass, C.E., Quintana, L., Starnes, S.M., Schatzman, R.C., Brunke, K.J., Drayna, D.T., Risch, N.J., Bacon, B.R. & Wolff, R.K. (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics, 13, 399408.
  • Nielsen, P., Engelhardt, R., Düllmann, J. & Fischer, R. (2002) Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary haemochromatosis. Blood, Cells, Molecules, and Diseases, 29, 451458.
  • Powell, L.W. (1994) Primary iron overload. In: Iron Metabolism in Health and Disease (ed. by J.H.Brock, J.W.Halliday, M.J.Pippard & L.W.Powell), pp. 227270. Saunders, London.
  • Thompson, R.B., Owen, D.M. & Bell, W.N. (1967) Desferal therapy in iron storage disease. American Journal of Medical Sciences, 253, 453460.
  • Walker, E.M., Wolfe, M.D., Norton, M.L., Walker, S.M. & Jones, M.M. (1998) Hereditary hemochromatosis. Annals of Clinical and Laboratory Science, 28, 300312.
  • Wöhler, F. (1963) The treatment of haemochromatosis with desferrioxamine. Acta Haematologica, 30, 6587.