CHAPTER 63 HEREDITARY AND ACQUIRED SIDEROBLASTIC ANEMIAS
CHAPTER 63 HEREDITARY AND ACQUIRED SIDEROBLASTIC ANEMIAS
Definition and History
Etiology and Pathogenesis
Morphologic Aspects. the Sideroblasts
Clinical and Laboratory Features
Primary Acquired Sideroblastic Anemia
Secondary Acquired Sideroblastic Anemia
Hereditary Sideroblastic Anemia
Sideroblastic anemias are characterized by the presence of ring sideroblasts in the marrow. These cells are erythroid precursors that have accumulated abnormal amounts of mitochondrial iron. A variety of abnormalities of porphyrin metabolism have been documented. Hereditary sideroblastic anemias are usually X-linked, the result of mutations in the erythroid form of D-ALA synthase. Inherited autosomal and mitochondrial forms (Pearson syndrome) are also occasionally seen. Acquired sideroblastic anemias can occur as a result of the ingestion of drugs, alcohol, or toxins such as lead or zinc. Ring sideroblasts are also a feature of myelodysplastic states, discussed in Chap. 92. Patients with sideroblastic anemia may respond to pharmacologic doses of pyridoxine, which is often given together with folic acid. Iron loading is common in the sideroblastic anemias, and can be treated by phlebotomy when the anemia is mild or with desferal when it is more severe.
Acronyms and abbreviations that appear in this chapter include: ALA, aminolevulinic acid.
DEFINITION AND HISTORY
Sideroblastic anemias are a heterogeneous group of disorders that have as common features the presence of large numbers of ringed sideroblasts in the marrow (Plate 3), ineffective erythropoiesis, increased levels of tissue iron, and varying proportions of hypochromic erythrocytes in the blood. They may be acquired or hereditary (Table 63-1).
TABLE 63-1 CLASSIFICATION OF SIDEROBLASTIC ANEMIAS
Acquired sideroblastic anemia may be a neoplastic disease, i.e. a clonal disorder that can progress to acute leukemia. This subject is considered in Chap. 92, in which clonal, preleukemic disorders are discussed. Sideroblastic anemia may also develop as a result of the administration of certain drugs, exposure to toxins, or coincident to neoplastic or inflammatory disease. Hereditary sideroblastic anemias include X-chromosome–linked, autosomally linked, and mitochondrial entities. Occasionally a patient with apparently familial disease has developed a myelodysplastic syndrome later,1,2 but with these rare exceptions the disorders are distinct and do not coexist or evolve one from the other.
Although the perinuclear distribution of siderotic granules in the nucleated red cells of patients with various types of anemia was described in 1947,3,4 the concept of sideroblastic anemia as a generic designation was not generally accepted until the publications of Björkman,5 Dacie et al,6 Heilmeyer et al,7,8 Bernard et al,9 and Mollin.10 After description of the primary adult form of refractory sideroblastic anemia,5,6 similarity to the morphologic and erythrokinetic changes in hereditary (sex-linked) hypochromic anemia was recognized. Cooley11 described a patient with an anemia with ovalocytosis, who was shortly thereafter shown to have a hereditary sex-linked disorder12 which we now know to be due to a ALA synthase mutation.13 Autosomally inherited cases were also described,14 and prominent sideroblastic changes of the marrow were found in Pearson’s marrow-pancreas syndrome, a disorder that is associated with mutations of the mitochondrial DNA.15,16,17,18 and 19 Subsequently, it became evident that similar abnormalities were associated with a wide variety of diseases,20 therapy with antituberculosis drugs,21,22 and lead intoxication.23,24,25 and 26 In some patients the anemia responded to large doses of pyridoxine and was designated “pyridoxine-responsive anemia.”10,27,28 and 29 These “secondary” acquired disorders were then incorporated into the classification.
ETIOLOGY AND PATHOGENESIS
MORPHOLOGIC ASPECTS. THE SIDEROBLASTS
Sideroblasts are erythroblasts containing aggregates of nonheme iron appearing as one or more Prussian blue positive granules on light microscopy.30 The morphology of these cells in normal and abnormal states is discussed in detail in Chap. 22. In normal subjects, 30 to 50 percent of marrow erythroblasts contain such granules, which, when viewed by electron microscopy, are seen to be neither within mitochondria nor associated with other cytoplasmic organelles.31 In contrast to the normal cytoplasmic location of siderotic granules, the pathologic sideroblasts in the sideroblastic anemias exhibit large amounts of iron deposited as dust or plaque-like ferruginous micelles between the cristae of mitochondria (Fig. 34-3).32 The iron-loaded mitochondria are distorted and swollen, their cristae are indistinct, and the identification of mitochondria may itself be difficult. In humans, the mitochondria of the erythroblast are distributed perinuclearly,23 and this accounts for the distinctive “ringed” sideroblast identified by Prussian blue staining when mitochondrial iron overload is present (Fig. 33-3 and Plate XVIII-7). The morphologic features that characterize pathologic sideroblasts in various disorders have been summarized.33
The pathogenesis of most of the sideroblastic anemias is not well understood. It is not clear whether the basic mechanism by which abnormal accumulations of intra-mitochondrial iron occur are the same in inherited and acquired forms of the disease. However, it seems appropriate, given the present state of knowledge, to discuss both forms together. The pathogenesis of the disorder may be viewed from two standpoints: the underlying biochemical lesions and the mechanism(s) of the anemia itself.
BIOCHEMICAL LESIONS AND GENETICS
In the search for the biochemical lesions responsible for the development of sideroblastic anemia, attention has been focused upon an intramitochondrial defect in heme synthesis and on possible disturbances in pyridoxine metabolism.
The possible role of defects in heme biosynthesis have occupied center stage since the early studies of Garby et al3434 who postulated that such a defect might exist and demonstrated that the level of free erythrocyte protoporphyrin was decreased and that of coproporphyrin was increased. Subsequently, a variety of abnormalities of the levels of precursors and of their rate of incorporation into heme was documented.35,36,37,38,39 and 40 However, the findings have not all been consistent, since levels of free erythrocyte protoporphyrin have often been increased,41,42 not diminished. The role of mitochondria in the etiology of sideroblastic anemia gained further credence when mutations of the mitochondrial genome were found in patients with Pearson’s syndrome.15,16,17,18 and 19
Sideroblastic anemia with deficiency of ALA synthase of marrow erythroid cells has been documented in subjects both with the congenital disorder and the acquired disease.4344,45 Identification of the defect at the DNA level in the X-linked gene for erythroid-specific ALA synthase (ALAS2) establishes that hereditary X-linked cases are due to structural mutations in this enzyme.45,46,47,48,49,50 and 51 Hereditary sideroblastic anemia with spinocerebellar degeneration is an X-linked syndrome that appears to be distinct from the other forms of sideroblastic anemia.52,53 Although it has been mapped to a region close to the erythroid ALA synthase gene, no changes in the restriction pattern of the ALA synthetase gene was observed,53 as might have been anticipated if the neurologic and hematologic manifestations were due to a small deletion from the X-chromosome. An X-linked ATP-binding cassette has been identified as a candidate gene for this rare disorder.5454 Rare autosomal forms of inherited sideroblastic anemia have been reported.5555
In one or more additional patients with sideroblastic anemia a deficiency of uroporphyrinogen decarboxylase,56,57 and heme synthetase,36,37,58,59 and 60 enzymes also necessary for the synthesis of heme (see Chap. 62), has been identified, but the defect in heme synthetase could simply be due to the inhibitory effect of mitochondrial iron overload on enzyme activity.37 The suggestion34 that a defect in coproporphyrinogen oxidase might be responsible for sideroblast formation could not be confirmed by direct measurement.61 Increased levels of uroporphyrinogen 1 synthase are commonly encountered.40 Alcohol, a common cause of secondary sideroblastic anemia, inhibits heme synthesis at several steps.39 In many instances, no abnormalities in the protoporphyrin synthetic pathway have been demonstrable.62
No single defect in heme synthesis accounts for sideroblast formation in this heterogeneous group of disorders. Moreover, a simple defect in heme synthesis fails to explain certain commonly encountered features such as megaloblastoid and other dyserythropoietic features, the frequently low serum folate levels, and, at times, partial responses to folate administration.
The belief in a possible role for pyridoxine has been fostered by the clear demonstration that pyridoxine deficiency in animals is a prototype of sideroblastic anemia.32 blastic anemia can be induced by drugs that reduce the level of pyridoxal phosphate in blood and decrease the d-aminolevulinic acid (ALA) synthetase activity in normoblasts.21,38 Moreover, certain sideroblastic disorders, though clearly not due to pyridoxine deficiency in a conventional sense, are nonetheless responsive to pharmacologic doses of pyridoxine.45,63,64,65 Pyridoxal phosphate is a necessary coenzyme for the initial reaction of protoporphyrin synthesis, the condensation of glycine and succinyl CoA to form ALA, a reaction mediated by ALA synthetase (see Chap. 62). Furthermore, pyridoxal phosphate is a factor in the enzymatic conversion of serine to glycine (see Chap. 25). This reaction generates a form of folate coenzyme necessary for the formation of thymidylate, an important step in DNA synthesis. Pyridoxal 5′-phosphate, the active form of the coenzyme, must itself be enzymatically synthesized from pyridoxine. Deficiencies in its biosynthesis have also been invoked as the possible cause of certain sideroblastic anemias,29,66 but direct measurements of pyridoxal kinase have failed to confirm that the postulated lesion was present.67 There are additional abnormalities that are difficult to rationalize in terms of defects in heme synthesis or abnormalities of pyridoxine metabolism. Sideroblastic anemia has been found in a patient with apparent antibody-mediated red cell aplasia.68 Dramatically altered activity ratios of a wide diversity of enzymes69,70 have been described. There are alterations in red cell antigen patterns frequently with an increase of i and a loss of A1,71 and, in some instances, a variety of metabolic abnormalities. Similar findings occur in certain hereditary and acquired refractory anemias with cellular marrows but without ringed sideroblasts.69 Such dyscrasias are also characterized by ineffective erythropoiesis, and except for the lack of ringed sideroblasts, may in some instances be virtually indistinguishable from their sideroblastic counterparts.72
MECHANISM OF ANEMIA73
The dominant factor producing anemia is ineffective erythropoiesis; the rate of red cell destruction is usually near-normal or only moderately accelerated to levels for which a normally functioning marrow could easily compensate. The half-time of disappearance of intravenously injected tracer doses of radioactive iron may be normal, but it usually is rapid (25 to 50 min; normal mean, 90 to 100 min). The plasma iron turnover tends to be increased (1.5 to 5.9 mg per dl of whole blood per day; normal, approximately 0.6 to 0.2 mg) but incorporation of radioactive iron into heme and its delivery to the blood as newly synthesized hemoglobin are depressed (15 to 30 percent of tracer dose; normal, 70 to 90 percent). Red cell survival, as determined by the 51Cr technique, varies from a half-time of 15 days to normal, corresponding to a mean erythrocyte life-span of approximately 40 to 120 days. As in other kinds of anemia characterized by ineffective erythropoiesis, the total fecal stercobilin excreted per day may be greater than can be accounted for by the daily catabolism of circulating hemoglobin.
CLINICAL AND LABORATORY FEATURES
PRIMARY ACQUIRED SIDEROBLASTIC ANEMIA
The features of primary acquired sideroblastic anemia are described in Chap. 92.
SECONDARY ACQUIRED SIDEROBLASTIC ANEMIA
The administration of certain drugs and the ingestion of alcohol may cause sideroblastic anemia. The drugs that are most commonly associated with this type of anemia are isonicotinic acid hydrazide,74 pyrazinamide,21,22,75 and cycloserine,21,22,75 all pyridoxine antagonists. Although plasma pyridoxal phosphate levels are often low in alcoholic patients, there is no correlation between these levels and the appearance of ringed sideroblasts in the marrow.76
Anemia secondary to drugs may be quite severe, even necessitating transfusion,21 but characteristically the anemia improves rapidly when the patient is given pyridoxine and/or when administration of the offending drug is discontinued. The red cells are hypochromic and commonly there is a dimorphic appearance of the erythrocytes in the blood film, i.e. two populations of red cells can be distinguished. The reticulocyte count is low or normal.77 In rare instances a sideroblastic anemia first observed during the course of drug administration has progressed in the face of discontinuing the putative offending drug. In such cases the patient presumably was suffering from an underlying myelodysplastic disorder.
Heteroplasmic point mutations in subunit 1 of the mitochondrial cytochrome oxidase have been documented in two patients with sideroblastic anemia.78
HEREDITARY SIDEROBLASTIC ANEMIA
Hereditary sideroblastic anemia is very uncommon. More instances of the X-chromosome–linked varieties than of apparently autosomally inherited cases have been documented.79 The disorder is heterogeneous. In some of the cases of hereditary iron loading anemia that are cited below either the presence of the sideroblasts in the marrow or the hereditary nature of the disorder is presumed; it has not been clearly documented in each case.
Anemia is usually apparent during the first few months80 or years34,35 of life; it may even occur prenatally.81 However, two remarkable patients, in whom microcytic anemia first became evident in the eighth and ninth decade of life, were found to have a microcytic, pyridoxine-responsive anemia apparently related to inherited mutations of the ALAS2 gene.82
Pallor is the most prominent physical finding; splenomegaly may be present44 but not universally so.34,80 The anemia is characteristically microcytic and hypochromic and prominent dimorphism of the red cell population has been noted in carrier females of the sex-linked form of the anemia.12,80,83 This has been regarded as evidence of X-inactivation affecting the locus responsible for this disorder,35,80,83,84 but it is notable that marked dimorphism sometimes is seen in the red cells of affected males as well,12,34 and in autosomal forms of the disease.85 The degree of aniso- and poikilocytosis is usually striking. Sometimes the anemia can be macrocytic,1,86 especially in mitochondrial forms of the disease. The red cells show marked heterogeneity with respect to resistance to osmotic lysis: a flattened curve indicates that cells with both increased and decreased resistance to lysis are present.34,87 The white cell count is usually normal or slightly decreased, unless splenectomy has been performed. Then it may be greatly elevated.88 Splenomegaly is present in most cases.88 In one family a platelet function abnormality resembling a storage pool defect was noted,89 but this could have been an independently inherited disorder.
Pearson marrow-pancreas syndrome is a refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction occurring during infancy.90,91 Most patients die in infancy, although there is considerable phenotypic variation, presumably depending upon the number of mitochondria affected and their tissue distribution.
Most patients with hereditary sideroblastic anemia appear to have some response to treatment with pyridoxine in doses of 50 to 200 mg per day,12,80,83,88,92,93,94 but failures have also been observed.7,34,42 Some patients have responded to doses as low as 2.5 mg/day.88 An additional effect may be achieved by the administration of folic acid.80 Very rarely patients have been reported to respond to a crude liver extract, and it has been suggested that tryptophane may be an active principle, enhancing the effect of pyridoxine.95,96 Responses to pyridoxine may result in an increase in the steady-state hemoglobin level of the blood or a decrease in the transfusion requirement, but normalization of the hemoglobin level does not usually occur, and the anemia relapses when pyridoxine administration is discontinued.
Iron overloading regularly accompanies this disorder and may be the cause of death42,37 (Chap. 42). Iron storage may be enhanced when the mutations of hereditary hemochromatosis are co-inherited.97 If the anemia is not too severe, or if it can be partially corrected by the administration of pyridoxine, phlebotomy may be used to diminish the iron burden.98,99 Otherwise it may be advisable to attempt to decrease the amount of body iron by the use of desferrioxamine (Chap. 42).
One child with a hereditary form of the disease has been treated successfully by marrow transplantation.100
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn