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British Journal of Haematofogy, 1983, 54, 649-654 Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias MARIO CAZZOLA, GIOVANNI BAROSI,* GAETANO BERGAMASCHI, LAURA DEZZA, PIETRO PALESTRA,* GRAZIA POLINO,* SIMONA RAMELLA,* PAOLO SPRIANO* AND EDOARDO ASCARI Zstitutodi Patologia Medica 1 and *Clinics Medica I ’A. Ferrata’, University of Pavia, Pavia, ftaly Received 14 December 1982; accepted for publication 2 7 February 1 9 8 3 SUMMARY. The relationship between body iron status, degree of anaemia, erythroid expansion, age and sex has been studied in eight patients with congenital dyserythropoietic anaemia (CDA) and two patients with congenital sideroblastic anaemia, who had received no or very few blood transfusions and no medicinal iron during the course of their illness. All patients had increased iron stores. Iron load was mild in three women in the reproductive age and severe in two men, in middle age, who had evidence of parenchymal organ dysfunction. Iron loading, as judged by the plasma ferritin concentration, was independent of the degree of anaemia while it was closely related to the patient’s age and the degree of increase in the total erythropoietic activity. It is concluded that patients with CDA or congenital sideroblastic anaemia are at high risk of developing haemochromatosis in middle age. Prophylactic phlebotomy or iron chelation therapy should be considered for such patients. Iron loading anaemias include various disorders, both congenital and acquired (Bothwell et a], 1979; Jacobs, 1977). While in most of these disorders excess iron stores derive from repeated blood transfusions, certain types of iron loading anaemia are associated with an increase in dietary iron absorption. Within these latter conditions, the risk of secondary haemochromatosis is well defined in thalassaemia intermedia, in which increased iron absorption has been shown to produce parenchymal iron loading which is progressive with increasing age (Pippard et al, 1979, 1982b). In more rare disorders, such as congenital dyserythropoietic anaemias (CDAs) and congenitalsideroblasticanaemias,the risk of iron loading and the factors responsible for it are poorly defined. In 10 such patients we studied the relationship between body iron status, degree of anaemia, erythroid expansion, age and sex. Correspondence: Dr Mario Cazzola, Patologia Medica 1, Policlinco S. Matteo, 27100 Pavia, Italy. 649

Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

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Page 1: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

British Journal of Haematofogy, 1983, 54, 649-654

Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

MARIO CAZZOLA, GIOVANNI BAROSI,* GAETANO BERGAMASCHI, LAURA DEZZA, PIETRO PALESTRA,* GRAZIA POLINO,* SIMONA RAMELLA,* PAOLO SPRIANO* AND EDOARDO ASCARI Zstituto di Patologia Medica 1 and *Clinics Medica I ’A. Ferrata’, University of Pavia, Pavia, ftaly

Received 14 December 1982; accepted for publication 2 7 February 1983

SUMMARY. The relationship between body iron status, degree of anaemia, erythroid expansion, age and sex has been studied in eight patients with congenital dyserythropoietic anaemia (CDA) and two patients with congenital sideroblastic anaemia, who had received no or very few blood transfusions and no medicinal iron during the course of their illness. All patients had increased iron stores. Iron load was mild in three women in the reproductive age and severe in two men, in middle age, who had evidence of parenchymal organ dysfunction. Iron loading, as judged by the plasma ferritin concentration, was independent of the degree of anaemia while it was closely related to the patient’s age and the degree of increase in the total erythropoietic activity. It is concluded that patients with CDA or congenital sideroblastic anaemia are at high risk of developing haemochromatosis in middle age. Prophylactic phlebotomy or iron chelation therapy should be considered for such patients.

Iron loading anaemias include various disorders, both congenital and acquired (Bothwell et a], 1979; Jacobs, 1977). While in most of these disorders excess iron stores derive from repeated blood transfusions, certain types of iron loading anaemia are associated with an increase in dietary iron absorption. Within these latter conditions, the risk of secondary haemochromatosis is well defined in thalassaemia intermedia, in which increased iron absorption has been shown to produce parenchymal iron loading which is progressive with increasing age (Pippard et al, 1979, 1982b).

In more rare disorders, such as congenital dyserythropoietic anaemias (CDAs) and congenital sideroblastic anaemias, the risk of iron loading and the factors responsible for it are poorly defined. In 10 such patients we studied the relationship between body iron status, degree of anaemia, erythroid expansion, age and sex.

Correspondence: Dr Mario Cazzola, Patologia Medica 1, Policlinco S. Matteo, 27100 Pavia, Italy.

649

Page 2: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

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Page 3: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

Iron Loading Anaemias 65 1

MATERIALS AND METHODS

Patients (Table I). Seven patients had CDA type 11; four of them were reported previously (Barosi et al, 19 79). They had more than 10% binucleated erythroblasts in the bone marrow and evidence of a ‘double membrane’ in most of the erythroblasts examined by electron microscopy. The acidified serum test was positive with some normal sera and negative with patient’s own serum. A 44-year-old man had dyserythropoietic anaemia with evidence of disease from early life but did not fit any of the classical types of CDA (Heimpel, 1975). Two patients had X-linked congenital sideroblastic anaemia.

Seven out of the 10 patients had never been transfused while the other three had received only occasional transfusions (less than 10 in any case). Four subjects were studied at two different times during the course of their illness.

Haematological investigations and evaluation of iron status. Standard haematological methods were used (Dacie & Lewis, 19 75). Ferrokinetic measurements of erythroid activity were performed as previously described (Barosi et al, 19 79). Total erythropoietic activity was evaluated by the marrow iron turnover (MIT) (Stefanelli et al, 1982). The relative rate of erythropoiesis was calculated from the MIT in the patient divided by the mean normal MIT. Plasma ferritin concentration was measured by radioimmunoassay, using antibodies to human liver ferritin. When available, liver biopsy specimens and results of endocrinological investigations were reviewed.

RESULTS

All patients had increased iron stores (Table I) and some of them had evidence of parenchymal organ dysfunction (Table 11). In particular, two male patients aged 44 and 32 years (cases 1 and 4) had hepatic cirrhosis and impaired glucose tolerance, and the older also had hypogonadotropic hypogonadism. In these two patients, liver biopsy showed large amounts of stainable iron in parenchymal cells while serum transaminases were only

Table 11. Parenchymal organ damage and dysfunction in the patients studied (number of subjects with damage with respect to the number of patients eva- luated)

Liver Increased stainable iron 818 Fibrosis 4/8 Cirrhosis 218

Pancreas Impaired glucose tolerance 216

Pituitary gland Hypogonadotropic hypogonadism 116

Page 4: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

652

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Fig 1 . Relationship between the product of the patient's age times the erythroid activity at the time of study and the plasma ferritin concentration. For patients in whom erythroid activity changed following sptenectomy (patients 4. 6, 9 and 10 in Table I) the abscissa was calculated as a sum of two products (one for the period preceding splenectomy. the other for the period following splenectomy). The shaded area represents the normal range for plasma ferritin concentration.

marginally elevated. Thus, the serum ferritin in these patients was more an indication of iron overload than a result of the liver damage per se.

Total erythropoietic activity ranged from 3 to 10.4 times the basal value and was inversely related to the Hb level ( r = -0.58, PcO.05) but with a wide scattering of values. The plasma ferritin concentration was independent of the degree of anaemia. It was closely related to both the patient's age ( r = 0.85, P < O - O l ) and the total erythropoietic activity at the time of study ( r = 0.78, P<0.01). There was an impressive relationship between the plasma ferritin concentration and the product of the above two parameters (Fig 1). It is apparent from Fig 1 that the three women, all in the reproductive age, had lower values for plasma ferritin concentration than the males of the same age.

DISCUSSION

Although secondary haemochromatosis has been reported to be a frequent complication in patients with CDA (Heimpel, 1975) or congenital sideroblastic anaemia (Bothwell et al, 1979). the factors responsible for iron loading in these disorders have not been clearly defined. This study includes only patients who had never been transfused (or had received only occasional transfusions) and had not been erroneously exposed to medicinal iron, in order to evaluate factors that produce iron loading through increased iron absorption from a diet of normal iron content.

Page 5: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

Iron Loading Anaemias 6 5 3

The degree of anaemia was extremely variable in our subjects. Overall, there was an inverse relationship between the Hb level and the total erythropoietic activity, indicating a normal response of the erythroid marrow to the stimulus of anaemia. Nevertheless, there was considerable variation from patient to patient and it was not possible to predict total erythropoietic activity from the Hb level in individual cases.

All the patients studied had increased iron stores and two male subjects over the age of 30 had severe haemochromatosis with clinical evidence of parenchymal organ dysfunction. There was no relationship between iron loading and the degree of anaemia. Such a finding, recently observed also by Pippard et al (1982a) in patients with congenital sideroblastic anaemia, and by Solomon et al (1981) in patients with idiopathic refractory anaemia, indicates that the increased iron stores do not represent a shift of iron from the erythron or an absorption response to anaemia per se.

Sex appeared to be an important factor determining the severity of iron overload, as clearly illustrated by Fig 1. In fact, the three female subjects, all in the reproductive age, had the lowest values for plasma ferritin concentration, suggesting that iron loss through menstruation and pregnancies had partly protected them against iron loading. This does not exclude the possibility of severe iron overload after menopause. In fact, Pippard et al( l982a) have recently reported a 47-year-old woman with congenital sideroblastic anaemia who had massive iron overload and died of intractable heart failure.

The single parameters best related to plasma ferritin concentration were age and total erythropoietic activity. The combination of these two parameters explained 8 8% variation in plasma ferritin (Fig 1). Thus, iron loading was essentialIy related to the duration and the degree of erythroid expansion. A similar conclusion was reached by Solomon et al(1981) in a study of patients with acquired sideroblastic anaemia. This is in keeping with the hypothesis that increased iron absorption in iron loading anaemias is a consequence of the erythropoietic hyperactivity (Cavil1 et al, 1975; Jacobs, 19 77), although the mechanisms mediating such effect are not clear.

The practical conclusion of this study is that patients with CDA or congenital sideroblastic anaemia are at high risk from haemochromatosis in middle age, after menopause in women, independently of the degree of anaemia. Iron loading may continue even after a remarkable improvement in Hb level has been obtained through splenectomy, as erythroid hyperactivity may be still present (subjects 4 , 6 , 9 and 10 in Table I). Therefore, we agree with Pippard et al (1982a) that prophylactic phlebotomy or iron chelation therapy must be considered for these patients.

This work has been supported in part by a grant from the Italian Ministry of Education (Minister0 della Pubblica Istruzione).

ACKNOWLEDGMENT

REFERENCES

BAROSI, G., CAZZOLA, M., STEFANELLI, M. & ASCARI, E. (1979) Studies of ineffective erythropoiesis and peripheral haemolysis in congenital dys-

erythropoietic anaemia type 11. British Journal of Haernatology, 43, 243-250.

BOTHWELL, T.H., CHARLTON, R.W., COOK, J.D. &

Page 6: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias

6 54 Mario Cazzolcl et a1

FINCH, C.A. (1979) Irori Metabolisni in Mar?. Blackwell Scientific Publications, Oxford.

CAVILL. I.. WORWOOD. M. & JACOBS. A. (1975) Internal regulation of iron absorption. Nutitre.

DACIE. J.V. & LEWIS. S.M. (1975) Practical Huerna- tology. 5th edn. Churchill Livingstone. Edin- burgh.

HEIMPEL, H. ( 1 9 7 5 ) Dyserythropoiese und dys- erythropoietische Anamien. Schweizerisclie Medi:inische Wochenschrift. 105, 1562-1 568.

JACOBS, A. (197;) Iron overload-clinical and pathological aspects. Seniinars it? Hmatology.

PIPPARD. M.J.. CALLENDER. S.T.. WARNER. G.T. & WEATHERALL. D.J. (1979) Iron absorption and loading in P-thalassaemia intermedia. Lancet, ii,

256, 328-329.

14,89-113.

8 19-82 1.

PIPPARD. M.J., PETO, T.A. & WEATHERALL, D.J. ( 1982a) Iron overload in non-transfused sidero- blastic anaemias. (Abstract). British Journal of Haernatology. 52, 1 3 7 .

PIPPARD. M.J., RAJAGOPALAN, B., CALLENDER, S.T. & WEATHERALL, D.J. (1982b) Iron loading, chronic anaemia, and erythroid hyperplasia as determinants of the clinical features of p-thalas- saemia intermedia. Advances in Red Cell Biology (ed. by D. J. Weatherall, G. Fiorelli and S. Gorini), p. 103. Academic Press, New York.

SOLOMON. L.R.. HILLMAN, R.S. & FINCH, C.A. I 198 1) Serum ferritin in refractory anemias. Acta Uaematologica (Easel). 66, 1-5.

STEFANELLI, M.. BAROSI, G. & CAZZOLA. M. (1982) Iron kinetics. Quantitative Approaches to Metab- olism (ed. by D. G. Cramp). p. 143. John Wiley. Chichester.