2002 Blackwell Science Ltd.

Volume 116(4-II) March 2002 pp 733-743

Sideroblastic anaemias
[Review] Alcindor, Thierry; Bridges, Kenneth R.
Division of Haematology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Correspondence: Kenneth R. Bridges, Brigham and Women's Hospital, 75 Francis Street, Midcampus 3, Boston, MA 02115, USA. E-mail: kbridges@rics.bwh.harvard.edu

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Hereditary sideroblastic anaemias

X-linked sideroblastic anaemia Other hereditary forms of sideroblastic anaemia Mitochondrial cytopathies Myelodysplastic syndromes Drug- and toxin-induced sideroblastic anaemias Nutritional factors Treatment

Acquired sideroblastic anaemias

Clinical manifestations and diagnosis Conclusion References

Graphics

Figure 1 Table I. Categories ...

The sideroblastic anaemias are a heterogeneous group of disorders whose two distinctive features are ring sideroblasts in the bone marrow (abnormal erythroblasts with excessive iron accumulation in the mitochondria) and impaired haem biosynthesis (Bottomley, 1982; May & Fitzsimons, 1994). The aetiology, epidemiology, pathophysiology and treatment of these conditions differ vastly. The mitochondrion is the nexus of sideroblastic anaemia, however. Disturbed mitochondrial metabolism characterizes all sideroblastic anaemias in which a cause has been determined. is a simplified schema of haem biosynthesis. The process begins in the mitochondrion with the condensation of glycine and succinyl-CoA to form delta-amino levulinic acid (ALA) with pyridoxal phosphate as a cofactor (Bottomley & Muller-Eberhard, 1988). ALA then moves to the cytoplasm where several additional enzymatic transformations produce coproporphyrinogen III. This molecule enters the mitochondrion where additional modifications, including the insertion of iron into the protoporphyrin IX ring by ferrochelatase, produce haem.
Figure 1

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Figure 1. Simplified schema of haem biosynthesis. Haem biosynthesis begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid (delta-aminolevulinic acid). Biosynthesis moves to the cytosol where multiple enzymatic steps produce coproporphyrinogen III. This molecule enters the mitochondrion for the final steps of haem biosynthesis.

Numerous studies of various subtypes of sideroblastic anaemias demonstrate impaired haem production (Vogler & Mingioli, 1968; Konopka & Hoffbrand, 1979; Pasanen et al, 1985). Most commonly, the sideroblastic anaemias are classified as hereditary or acquired conditions (Table I). The hereditary forms are primarily X-linked, although some families display autosomal dominant or autosomal recessive modes of transmission (Amos et al, 1988). Isolated cases of congenital sideroblastic anaemia often defy classification as they lack the well-documented pedigrees needed to firmly establish modes of transmission (Dolan & Reid, 1991).

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Table I. Categories of sideroblastic anaemia.

The acquired sideroblastic anaemias are far more common than the hereditary varieties. Drugs and toxins lead this category, propelled largely by the high frequency of alcohol abuse in many societies (Pierce et al, 1976; Larkin & Watson-Williams, 1984). The next largest subgroup, refractory anaemia with ring sideroblasts, is itself a subset of the myelodysplastic syndromes (MDS) (Hast, 1986). Hypothermia is a rare antecedent of sideroblastic anaemia (O'Brien et al, 1982). The exact mechanism by which disturbed haem metabolism produces sideroblastic anaemias remains elusive. Haem is an essential component of many mitochondrial enzymes (e.g. cytochromes b, c1, c, a, a3) as well as cytosolic enzymes such as catalase (Verkhovsky et al, 1996; Barros et al, 2001; Matsuno-Yagi & Hatefi, 2001). The molecule is also an integral component of haemoglobin in which it has both structural and functional roles. Haem modulates translation of globin mRNA, stabilizes the globin protein chains and mediates reversible oxygen binding. 5-aminolevulinic acid synthase (ALAS) is both the first and rate-limiting enzyme in haem biosynthesis (Bottomley & Muller-Eberhard, 1988). Haem modulates its activity through feedback inhibition. The gene that encodes ALAS-1 (also called ALAS-n) resides on chromosome 3 (3p21) (Bishop et al, 1990). This ubiquitous enzyme is particularly abundant in the liver. ALAS-1 provides the basal haem production needed by all cells and maintains a relatively stable level. The enzyme directly relevant to sideroblastic anaemia is ALAS-2 or ALAS-e (erythroid). The gene encoding this enzyme exists on the X chromosome (Xp11.21), with expression restricted to the erythroid lineage (Cox et al, 1990; Cotter et al, 1992a). ALAS-2 activity lacks known feedback regulation by haem. The enzyme is, however, a member of a small family of genes whose expression is modulated by iron (Cox et al, 1991; Bhasker et al, 1993; Melefors et al, 1993). The best-characterized genes of this family are those encoding ferritin and the transferrin receptor (Klausner & Harford, 1989). Ferritin mRNA contains a conserved stem-loop sequence in the 5'-untranslated region called the iron response element (IRE). A homologous sequence exists in the 5'-untranslated region of the ALAS-2 message (Dandekar et al, 1991). In contrast, transferrin receptor mRNA has five IRE elements all in the 3'-untranslated region. Two cytoplasmic proteins called the iron regulatory proteins 1 and 2 (IRP1 and IRP2) bind to the IRE regions of the messenger RNA. In the absence of iron, IRP1 binds to the IRE elements in the 5'-untranslated regions of the messages encoding ferritin and ALAS2 (Melefors et al, 1993). The IRE/IRP complex blocks message translation, dampening the biosynthesis of ferritin and ALAS-2. This response makes teleological sense. In the absence of iron, the cell does not need the iron storage protein, ferritin. Similarly, in the absence of iron, erythroid precursors need not produce protoporphyrin IX as this molecule cannot be converted to haem. The signal feature of sideroblastic anaemia is mitochondrial iron deposition (Koc & Harris, 1998). Erythroid precursors stained for iron with Perl's Prussian blue often show two or

three bluish green inclusions called siderosomes. The cells that contain these iron granules are called sideroblasts. In sideroblastic anaemia, the iron-containing particles are larger and more numerous. Many erythroblasts contain six or more blue-green particles that ring the nucleus creating the pathognomonic ring sideroblast. Ring sideroblasts comprise between 15% and 50% of the erythroblasts in most patients while some display only ring sideroblasts on bone marrow examination. Electron microscopy shows crystalline iron deposits between cristae in the matrix of the mitochondrion (Grasso & Hines, 1969). The basis of this phenomenon is unknown. Simple cellular iron overload is not the answer. Massive cellular iron overload occurs in both hereditary and transfusional haemochromatosis. Neither disorder manifests iron laden mitochondria. Sideroblasts show normal iron uptake, but subsequent poor incorporation into haem (May et al, 1982). Mishandling of iron by mitochondria could be the basis of the iron deposits. Production of protoporphyrin in quantities insufficient to accept mitochondrial iron would theoretically create a scenario conducive to mitochondrial iron accumulation. Our limited understanding of mitochondrial iron metabolism has, however, precluded testable hypotheses. Mitochondrial iron deposits could be more than morphological curiosities. Iron catalyses the formation of reactive oxygen species through Fenton chemistry (Liochev & Fridovich, 1994). Molecules such as the hydroxyl radical (OH) arise in settings in which oxidation reactions occur in proximity to iron (Gutteridge et al, 1981). The oxidative metabolic machinery of the mitochondrion creates an ideal environment for the generation of reactive oxygen species. The primary damage in sideroblastic anaemia that produces ironladen mitochondria could create a feedback loop with escalating mitochondrial injury. The hydroxyl radical, for instance, promotes lipid and protein peroxidation as well as cross-links in DNA strands (Park & Floyd, 1992; Thomas et al, 1993). The latter phenomenon could be particularly injurious given the dearth of DNA repair enzymes in mitochondria (Boore, 1999). Reports exist of patients whose sideroblastic anaemia improved when their iron overload was reduced through phlebotomy (French et al, 1976; Cotter et al, 1999). Phlebotomy could have reduced iron-mediated injury to erythroblasts in these patients. Patients with sideroblastic anaemia show enhanced apoptosis of bone marrow cells relative to normal (Fontenay-Roupie et al, 1999; Matthes et al, 2000). When measured, however, the level of marrow reactive oxygen species was similar in the two groups, raising questions about their role in the process of apotosis (Matthes et al, 2000). Short half-life makes reactive oxygen species notoriously difficult to assess. Further investigation should shed new light on the issues of bone marrow injury and ineffective erythropoiesis in sideroblastic anaemia.

Hereditary sideroblastic anaemias

X-linked sideroblastic anaemia
In 1945, Thomas Cooley described the first cases of X-linked sideroblastic anaemia in two brothers from a large family in which the inheritance of the disease was documented through six generations (Cooley, 1945). Although rare, the disorder nonetheless is the most common of the hereditary sideroblastic anaemias. Defects involving two independent genes on the X-chromosome produce X-linked sideroblastic anaemia. The more common form results from mutations of the gene encoding ALAS-2 (Bottomley et al, 1995).

Missense mutations of the ALAS-2 gene produce most cases of X-linked sideroblastic anaemia (Bottomley et al, 1992; Cotter et al, 1992b; Cox et al, 1992, 1994; Edgar et al, 1997). Years after their initial evaluation, investigators located several members of the pedigree originally described by Cooley and analysed their DNA using current techniques in molecular biology (Cotter et al, 1994). These family members did indeed have missense mutations involving the ALAS-2 gene. Rarely has anyone correctly described two major disorders that withstood the rigours of subsequent scientific investigation by more powerful analytical tools. The other disorder in this instance is, of course, Cooley's anaemia, now known as [beta]-thalassaemia major (Cooley et al, 1927). The mutations of the ALAS-2 gene can be classified according to their effects on the enzyme product: low affinity for pyridoxal phosphate, structural instability, abnormal catalytic site, or increased susceptibility to mitochondrial proteases. Any of these abnormalities decrease the biosynthesis and/or steady-state level of ALAS and consequently lower production of protoporphyrin and haem. The degree of anaemia improves with pyridoxine supplementation when the mutation disrupts the catalytic association between ALAS-2 and pyridoxal phosphate (Cox et al, 1994). Improvement in the anaemia could reflect enhanced protoporphyrin and haem synthesis with reduced mitochondrial iron deposition and dampened generation of reactive oxygen species. The bone marrow of many patients with sideroblastic anaemia displays erythroid hyperplasia, consistent with the concept of ineffective erythropoiesis in this condition. The bone marrow's plethora of erythroid precursors fails to supply the peripheral blood with mature erythrocytes, making erythropoiesis by definition ineffective. Ineffective erythropoiesis increases iron absorption from the gastrointestinal tract. Therefore, patients with even mild sideroblastic anaemia can develop substantial iron overload (Fitzcharles et al, 1982; Peto et al, 1983). Hereditary x-linked sideroblastic anaemia usually occurs in males, of course. Cases involving females in a family derive most commonly from skewed lyonization patterns in the affected girls (Seip et al, 1971; Buchanan et al, 1980; Seto et al, 1982; Dolan & Reid, 1991). Some women in affected families have developed sideroblastic anaemia later in life owing to progressive stochastic inactivation over time of the X-chromosome bearing the normal ALAS-2 gene (Cazzola et al, 2000). A second group of hereditary X-linked sideroblastic anaemias result from defects involving a different gene on the X-chromosome and manifest a strikingly different phenotype. The syndrome produces a severe congenital ataxia, in addition to sideroblastic anaemia. The causal gene encodes an ATP-binding cassette (ABC) protein now designated as hABC7 (Shimada et al, 1998). The gene localizes to chromosome Xq13.1q13.3 (Raskind et al, 1991). ABC proteins generally mediate transmembrane transport of various small molecules. hABC7 is an orthologue of the yeast ATMl gene whose product localizes to the inner mitochondrial membrane (Shimada et al, 1998). A family with X-linked sideroblastic anaemia and ataxia displayed a mutation in the hABC7 gene that segregated with the affected males in the kindred and was absent in controls (Allikmets et al, 1999). The hABC7 gene in another family contained a single missense mutation that reduced the protein's functional activity by half, as assessed by complementation studies using yeast in which the ATMl gene was deleted (Bekri et al, 2000). The complementation assay involved maturation of proteins containing an

iron/sulphur (Fe/S) cluster. The investigators hypothesized that impaired production of Fe/S cluster proteins in erythroid precursors, such as IRP1, could produce sideroblastic anaemia. The ataxia could reflect dysfunction of cytoplasmic proteins crucial to spinocerebellar development.

Other hereditary forms of sideroblastic anaemia

Reports exist of both autosomal dominant and autosomal recessive modes of transmission for hereditary sideroblastic anaemia (Kasturi et al, 1982; Van Waveren et al, 1987; Jardine et al, 1994; Kardos et al, 1996). The genes involved in these cases remain elusive. Some investigators postulate that the products of the affected genes somehow dampen the biosynthesis or the activity of ALAS with a consequent diminution of haem production. ALAS is synthesized on cytoplasmic ribosomes as a 65-kDa proenzyme whose leader mediates entry into the mitochondrion (Ferreira & Gong, 1995). The pro-sequence is clipped, producing a 595-kDa active enzyme. Scission of the pro-sequence in the cytoplasm could produce sideroblastic anaemia. The enzymatically active ALAS in this scenario could not enter the mitochondria. Furthermore, ALAS in the cytoplasm would be a target for many proteases. Hypercatabolism of ALAS appears to cause some cases of pyridoxine-response anaemia (Aoki et al, 1979). More information on the interplay between ALAS subcellular localization and sideroblastic anaemia would broaden our understanding of this area.

Mitochondrial cytopathies
Oxidative phosphorylation within mitochondria generates most of the ATP used by eukaryotic cells. The mature erythrocyte is the sole mammalian cell devoid of mitochondria, relying totally on glycolysis as an energy source. Most cells contain between 100 and 300 mitochondria (Jaussi, 1995). These semiautonomous organelles probably began as freestanding prokaryotes that invaded eukaryotic cells more than a billion years ago (Jansen, 2000). They eventually evolved a symbiotic relationship with their eukaryotic hosts. The former prokaryotes lost the capacity for independent existence but became indispensable to the eukaryotic cells. Mitochondria retain vestiges of their former independent life. Most importantly, the organelles have a small DNA genome (about 16 kb) and replicate independently within their host cells. Mitochondrial DNA retains many features of prokaryotic genomes, including a circular structure lacking introns (Boore, 1999). The mitochondrial genome encodes a small number of proteins as well as several transfer RNA molecules. Mitochondrial DNA lacks chromatin and the organelles have limited DNA repair capacity (Higuchi & Linn, 1995). Consequently, mutations in the mitochondrial genome that produce sideroblastic anaemia probably remain uncorrected. Mitochondria replicate independently of the nuclear genome (Kuroiwa, 2000). When cells undergo mitosis, the organelles distribute stochastically to the daughter cells. Acquired mitochondrial defects therefore pass unevenly to the daughter cells. This property is important to some of the hereditary mitochondrial disorders that produce sideroblastic anaemia. This characteristic also poses a conundrum with respect to the acquired sideroblastic anaemias. A few cases of sideroblastic anaemia associated with myelodysplasia have acquired mutations that impair function of some cytochromes (see below). The mutation presumably began as an alteration in a single mitochondrion. The mystery is how mitochondria with impaired enzymatic function come to predominate in

the cells. Each mitochondrion has several genomes (i.e. several circular DNA molecules) and each cell has several hundred mitochondria. Logically, a defective mitochondrion should be at a survival disadvantage. The acquired sideroblastic anaemias remind us that much remains to be learned about the physiology of these fascinating organelles. The mitochondrial cytopathies are a heterogeneous group of disorders produced by deletions in the mitochondrial genome (Egger et al, 1981; Kitano et al, 1986; Runge et al, 1986). Some deletions encompass as much as 30% of the 16-kb mitochondrial genome. Two factors contribute to the peculiar inheritance patterns in these disorders. First, independent mitochondrial replication combined with random segregation into the daughter cells at mitosis means that, by pure chance, newly replicated cells can have more or fewer defective mitochondria. Second, mitochondrial cytopathies are maternally transmitted because ova are the sole source of an embryo's mitochondria. A mother with mild manifestations of a syndrome can thus have one child who is unaffected and another who has extremely severe disease (mitochondrial heteroplasmy).
Pearson et al (1979) described

children from several unrelated families who manifested sideroblastic anaemia and exocrine pancreatic dysfunction. Subsequent cases of what is now called Pearson's syndrome also had varying degrees of lactic acidosis, hepatic and renal failure. Bone marrow examination showed, in addition to prominent ring sideroblasts, large vacuoles in the erythroid and myeloid precursors. Few of the probands survived past early childhood. The disorder results from mitochondrial DNA deletions that often are as large as 4 kb (Cormier et al, 1990). Southern blots of mitochondrial DNA show genomes of normal size along with the truncated DNA. Variation in the intensity of the two bands reflects mitochondrial heteroplasmy in the mother and offspring (Bernes et al, 1993). These deletions impair the biosynthesis of various components of the mitochondrial respiratory chain critical to mitochondrial function. Other disorders result from deletions of different portions of the mitochondrial genome [e.g. myopathy, encephalopathy, ragged red fibres (in muscles) and lactic acidosis, or MERRL] (Egger et al, 1981). Although sideroblastic anaemia is not in the clinical spectrum of most such syndromes, exceptions exist (Inbal et al, 1995). Wolfram syndrome is an instructive condition that could shed additional light on the interplay between nuclear genes and mitochondria (Borgna-Pignatti et al, 1989). The condition results from large deletions of the mitochondrial genome. The heteroplasmic nature of the mitochondrial defect in Wolfram syndrome is typical of a mitochondrial cytopathy. The defining characteristics of the disorder are diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD). Sideroblastic anaemia in association with mitochondrial deletions occurs in a subset of these patients (Rotig et al, 1993). Wolfram syndrome differs from other mitochondrial cytopathies by way of its autosomal inheritance pattern (Barrientos et al, 1996). Mutations in the gene designated WFS1/wolframin produce the DIDMOAD constellation of defects (Inoue et al, 1998; Strom et al, 1998). The gene product is a transmembrane protein of undetermined function (Takeda et al, 2001). Patients with defects in the WFS1/wolframin gene do not necessarily develop sideroblastic anaemia in addition to the DIDMOAD anomalies (Hardy et al, 1999). Mutations in WSF1/wolframin could be necessary, but not

sufficient to produce sideroblastic anaemia. The low incidence of both Wolfram syndrome and mitochondrial cytopathy makes coincidence unlikely in the subset of Wolfram patients who develop sideroblastic anaemia. Clearly, Wolfram syndrome is fertile ground in the search for links between the function of nuclear genes and the mitochondrion.

Acquired sideroblastic anaemias

Acquired sideroblastic anaemias substantially exceed hereditary forms in frequency. The disorder sometimes surfaces in the context of a myelodysplastic syndrome. Other instances of acquired sideroblastic anaemias reflect exposure to toxins or deficiencies of nutritional factors. The heterogeneity of the hereditary sideroblastic anaemias can produce cases with mild or moderate anaemia and varying degrees of iron overload (French & Jacobs, 1976; Fitzcharles et al, 1982; Peto et al, 1983). Some of these cases evade detection until adulthood. Hereditary sideroblastic anaemias most often have striking phenotypes that manifest in childhood or infancy, however. In contrast, the acquired sideroblastic anaemias, particularly those associated with myelodysplasia, nearly always occur in older adults.

Myelodysplastic syndromes
The myelodysplasias are a group of disorders whose emblematic feature is haematopoietic stem cell dysfunction (Basa, 1992). Chromosomal abnormalities, such as the 5q- anomaly, often accompany the condition (Sole et al, 2000). All three haematopoietic cell lines display dysplastic features. Common characteristics include prominent nucleoli, abnormal granulation of myeloid precursors, multinucleated erythroid precursors and small megakaryocytes that often contain a single nucleus. Ineffective erythropoiesis is frequent (Matthes et al, 2000). Deteriorating bone marrow function manifests as peripheral blood cytopenias of the three haematopoietic cell lines. Myelodysplasia has 1- and 5-year cumulative risks of acute leukaemia of 20% and 38% respectively (Sole et al, 2000). The abnormal stem cells can evolve a number of metabolic disturbances, including defective anchoring of phosphotidylinositol-linked membrane proteins (i.e. paroxysmal nocturnal haemoglobinuria, PNH), haemoglobin H production and ring sideroblasts (Yoo et al, 1980; Peters et al, 1983; Hillmen & Richards, 2000). Investigators often viewed the acquired sideroblastic anaemia associated with myelodysplasia as a monolithic entity, dubbed refractory anaemia with ring sideroblasts (RARS). Closer inspection revealed that certain morphological and chromosomal features predict significant differences in the clinical course of patients with sideroblastic anaemia (Gattermann et al, 1990). One subset of patients has dysplastic features confined to the erythroid series. Chromosomal abnormalities occur, but usually are relatively selective with defects such as the 5q- anomaly. This condition is designated pure sideroblastic anaemia (PSA). In the absence of myeloid or platelet abnormalities, anaemia dominates the clinical course. The need for frequent transfusion produces iron overload that can impair cardiac function and injure the liver. With adequate chelation therapy, these patients can survive and even thrive for many years. Most importantly, acute leukaemia occurs rarely (Germing et al, 2000). The second group of patients has abnormalities in all three cell lines in addition to ring sideroblasts (Balduini et al, 1999). Conspicuous chromosomal abnormalities often include

multiple deletions, trisomy or inversions. Although the anaemia is troublesome, neutrophil and platelet anomalies are the cardinal clinical problems. Infection is the most common cause of death, reflecting both neutropenia and neutrophil dysfunction. Bleeding owing to thrombocytopenia and/or platelet dysfunction is common. Nearly 40% of patients who survive these problems develop an acute leukaemia that often is refractory to treatment (Sole et al, 2000). The prognostic implications of these two forms of sideroblastic anaemia associated with myelodysplasia require mandatory detailed morphological and cytogenetic evaluation at the time of diagnosis (Yunis et al, 1988). The ring sideroblasts associated with myelodysplastic syndromes manifest in both the early and late erythroid precursors. This contrasts with the hereditary X-linked conditions in which prominent sideroblastic rings generally appear in the more differentiated normoblasts. Only recently have investigators pinpointed some of the abnormalities that might explain the ring sideroblasts associated with myelodysplasia. The greatest likelihood is that multiple defects exist, reflecting the heterogeneous nature of myelodysplasia and its associated sideroblastic anaemia (Gattermann, 2000).
Gattermann et al (1997)

described at least two point mutations in mitochondrial DNA of patients with acquired sideroblastic anaemia. One mutation was a T->C change at nucleotide 6742 of the mitochondrial genome. The affected gene encodes cytochrome c oxidase subunit 1. The mutation produced an aberrant protein in which a threonine residue replaced isoleucine at position 280. The other mutation also involved a T->C transition, this time at nucleotide 6721 of the mitochondrial genome. The defect again altered cytochrome c oxidase subunit 1, resulting in a change from methionine to threonine at residue 273. Mitochondria from other tissues of these patients showed no abnormality, consistent with an acquired defect solely involving the haematopoietic stem cells. Further investigation proved these mutations to be heteroplasmic, i.e. the affected cells have a mixture of normal and mutant mitochondria. These investigators reported another mitochondrial DNA mutation involving one of the mitochondrial transfer RNAs (Gattermann et al, 1996). The functional consequence, if any, of the mutation is unknown.

Drug- and toxin-induced sideroblastic anaemias

Drugs and toxins are important causes of sideroblastic anaemias and Table I lists some of the causal agents. The compounds most commonly implicated inhibit steps in the haem biosynthetic pathway. Eliminating the offending agent usually corrects the sideroblastic anaemia. Ethanol is the most frequent cause of toxin-induced sideroblastic anaemia (Lindenbaum & Roman, 1980; Larkin & Watson-Williams, 1984). The complication is uncommon, but the use (and misuse) of the agent is widespread. Ethanol probably causes sideroblastic anaemia by two mechanisms: direct antagonism to pyridoxal phosphate and/or associated dietary deficiency of this compound (McColl et al, 1980; Middleton, III, 1986; Leibman et al, 1990). The bone marrow changes associated with ethanol toxicity include vacuoles in the normoblasts in addition to sideroblasts. Interestingly, chloramphenicol commonly produces vacuoles in the normoblasts and likewise can induce sideroblastic anaemia (Beck et al, 1967). Chloramphenicol inhibits mRNA translation by the 70S ribosomes of prokaryotes. The drug does not affect 80S eukaryotic ribosomes. Most mitochondrial proteins are encoded

by nuclear DNA and are imported into the organelles from the cytosol where they are synthesized. Mitochondria retain the capacity to translate, on their own ribosomes, a few proteins encoded by the mitochondrial genome. True to its prokaryotic heritage, mitochondrial ribosomes are similar to those of bacteria, meaning that chloramphenicol inhibits protein synthesis by these ribosomes. Chloramphenicol-induced sideroblastic anaemia is believed to result from this inhibition. Animal studies have documented diminished ALAS and ferrochelatase activity in cases of sideroblastic anaemia secondary to chloramphenicol intoxication (Rosenberg & Marcus, 1974). More recently, Leiter et al (1999) examined the effects of chloramphenicol on cellular iron metabolism using the human erythroleukaemia cell line, K562 as a model system. As expected, chloramphenicol inhibited oxidative metabolism, reduced the activity of cytochrome c oxidase and lowered the ATP content of the cells. Chloramphenicol also markedly reduced the production of ferritin and the transferrin receptor by the cells. This effect was surprising as the two iron-related proteins are synthesized on eukaryotic ribosomes in the cytosol. Chloramphenicol did not inhibit the synthesis of other cytoplasmic or membrane proteins of the cell. The investigators concluded that the previously unsuspected link between mitochondrial function and cellular iron metabolism might contribute to the microcytic, hypochromic anaemia that often develops with chloramphenicol therapy even in the absence of sideroblastic changes in the bone marrow. Isoniazid frequently causes sideroblastic anaemia (Sharp et al, 1990). Pyridoxine prophylaxis is part of treatment regimens involving the drug in order to prevent this complication. Isoniazid-induced sideroblastic probably reflects inhibition of ALAS activity (Haden, 1967; Yunis & Salem, 1980). Lead intoxication is a particularly insidious cause of anaemia (Goyer, 1993). Although lead toxicity is commonly mentioned as a cause of sideroblastic anaemia, no well-documented case exists in the literature. The assertion that lead produces sideroblastic anaemia appears to be preserved in the literature by reference to indirect sources. Finally, overdose of chelators such as penicillamine or triethylene tetramine dihydrochloride (Trientene or TTH) used to treat Wilson's disease can produce sideroblastic anaemia. Excessive chelation produces a relative copper deficiency (Perry et al, 1996). Wilson's disease is uncommon, so the use and availability of these copper chelators is low.

Nutritional factors
Nutrients involved in haem biosynthesis include pyridoxine and copper, among others. The role of pyridoxal phosphate, a metabolite of pyridoxine, has been mentioned. Primary pyridoxine deficiency, usually secondary to malnutrition, is occasionally associated with sideroblastic anaemia. However, other manifestations, such as peripheral neuropathy and dermatitis, dominate the clinical picture. Pyridoxine deficiency frequently co-exists with alcoholism in cases of sideroblastic anaemia (Hines & Cowan, 1970; Pierce et al, 1976). Although sideroblastic anaemia solely as a result of pyridoxine deficiency occurs in animals, the phenomenon is undocumented in humans.

The role of copper in human iron metabolism is extremely complex (Danks, 1986). Copper enhances intestinal iron absorption, modulates reticuloendothelial activity, facilitates cellular iron uptake from transferrin and promotes iron incorporation into haem. Copper deficiency of all causes (malnutrition, prolonged total parenteral nutrition, gastric surgery, prematurity, zinc supplementation, excessive chelation) can produce acquired sideroblastic anaemia (Ashkenazi et al, 1973; Zidar et al, 1977; Broun et al, 1991; Perry et al, 1996.)

Clinical manifestations and diagnosis

Sideroblastic anaemias tend to be moderate to severe conditions with haemoglobin levels ranging usually from 4 to 10 g/dl. Patients have the usual symptoms of anaemia including fatigue, dizziness and decreased tolerance to physical activity. Other symptoms and signs not related to anaemia can point to a cause of the condition (e.g. alcoholism). The history should include detailed questions concerning possible toxin or drug exposures, as these conditions are reversible. A thorough family history looking for anaemia, particularly in male relatives, is important. Severe hereditary sideroblastic anaemias present in childhood. However, milder cases of hereditary sideroblastic anaemia whose symptoms do not draw attention can elude detection until adulthood (Fitzcharles et al, 1982). Severe forms of most diseases are usually described first. Over time, a broader clinical spectrum with mild or formes frustes of the conditions becomes apparent. No pathognomonic physical finding exists for sideroblastic anaemia. The bone marrow picture in sideroblastic anaemia was described earlier. The blood smear sometimes reveals basophilic stippling, hypochromia and microcytosis, although normocytosis and macrocytosis are possible, particularly in myelodysplastic syndromes. Pappenheimer bodies are atypical except with absent splenic function. A dimorphic red cell population is characteristic of female carriers of the hereditary conditions. Patients with pure sideroblastic anaemia or refractory anaemia with ring sideroblasts can also manifest a dimorphic red cell population (Harris et al, 1993). Co-existence of normal and sideroblastic erythroid maturation is the probable basis of this phenomenon. Electronic blood analysers display this anomaly as an elevated RDW. Iron deficiency and sideroblastic anaemia can co-exist. This scenario is particularly common in patients with myelodysplasia who can have chronic gastrointestinal bleeding owing to platelet problems. Iron deficiency can mask the characteristic bone marrow findings of sideroblastic anaemia. Sideroblastic anaemia remains in the differential diagnosis of patients with iron deficiency and anaemia that is refractory to iron replacement. A repeat bone marrow following iron replacement can show ring sideroblasts not seen in the initial sample. Iron overload occurs far more frequently than does iron deficiency, even in the absence of transfusions. Tissue damage from the iron overload is an important cause of morbidity and mortality in these patients (Schafer et al, 1985). Treatment with the iron chelator, desferrioxamine, can be life saving in patients who develop iron overload. Close monitoring of the indirect indicators of tissue iron content is key to the management of these patients (see below). Co-existing mutations in the gene responsible for hereditary haemochromatosis (HFE) appear not to be the basis of iron overload in sideroblastic anaemia (Beris et al, 1999).

Ineffective erythropoiesis with enhanced gastrointestinal iron absorption probably contributes to iron overload in many patients (Peto et al, 1983). The marked variability in the aetiology and bone marrow manifestations of sideroblastic anaemia could explain much of the heterogeneous iron loading in this syndrome. The clinical picture parallels that seen with congenital dyserythropoietic anaemias in which iron overload also correlates with ineffective erythropoiesis and is not associated with the haemochromatosis gene mutation (Wickramasinghe et al, 1999). Levels of the soluble transferrin receptor correlate positively with iron overload in patients with congenital anaemias (Cazzola et al, 1999). However, routine clinical assays such as serum ferritin levels and transferrin saturation usually suffice to detect iron overload in patients with sideroblastic anaemia.

Treatment
Treatment of sideroblastic anaemia begins with ruling out reversible problems including alcohol or other drug toxicity, as well as exposure to toxins. Treatments are largely supportive, consisting primarily of blood transfusions to maintain an acceptable haemoglobin level. A trial of pyridoxine (100 mg/d orally) is reasonable as the drug has few drawbacks and is an enormous benefit in responsive cases (Murakami et al, 1991). With the exception of some patients taking 1000 mg or more of pyridoxine daily, few sideeffects have been reported. A complete response to pyridoxine generally occurs in cases resulting from ethanol abuse or the use of pyridoxine antagonists. Discontinuation of the offending agent hastens recovery. Some patients with hereditary, X-linked sideroblastic anaemia also respond to pyridoxine (Edgar et al, 1997). Improvement with pyridoxine is rare for sideroblastic anaemias of other aetiologies. After obtaining baseline parameters (red cell indices, iron studies), the initial dose of pyridoxine should be 50100 mg/d by mouth. Folic acid supplementation compensates for possible increased erythropoiesis, should the pyridoxine prove effective. A reticulocytosis occurs within 2 weeks in responsive cases, followed by a progressive increase in the haemoglobin level over the next several months. The maintenance dose of pyridoxine is that which holds the haemoglobin level at a steady state. Microcytosis often persists, but is clinically insignificant. Large doses of pyridoxine presumably overcome the defect in ALA production in patients with low-activity mutant ALAS-2 enzymes. Investigation of one patient with pyridoxineresistant X-linked sideroblastic anaemia showed that the mutant ALAS-2 protein was unable to bind the beta subunit of ATP-specific succinyl CoA to form a functional enzyme (Furuyama & Sassa, 2000). Pyridoxine cannot compensate for an ALAS-2 mutant with such extremely low activity. Correction of iron overload improves the response to pyridoxine in some patients with X-linked sideroblastic anaemia (Cotter et al, 1999). More recently, cytokine therapy with erythropoietin and granulocyte colony-stimulating factor (G-CSF) has been added to the treatment armamentarium for acquired sideroblastic anaemia. Combination therapy appears more effective than single-agent treatment (Negrin et al, 1996). A large Scandinavian study with long-term follow-up showed a response rate in excess of 40% in patients with refractory anaemia and ring sideroblasts (HellstromLindberg et al, 1998). Combination therapy with erythropoietin and G-CSF is particularly appealing as side-effects are largely mild and other treatments are largely effete.

Transfusion is the kernel of care with sideroblastic anaemias. Symptoms rather than an absolute haemoglobin level or haematocrit should guide transfusion therapy. This limits the adverse consequences of transfusion, which include transmission of infections, alloimmunization and secondary iron overload. Even in patients with no meaningful transfusion history, yearly monitoring of the ferritin level and transferrin saturation can unveil progressive iron loading. Iron chelation with desferrioxamine is the standard treatment for iron overload, whether transfusional in origin or the result of excessive iron absorption. Occasionally, patients with modest anaemia (e.g. haemoglobin = 10 g/dl) who are not transfusion dependent will tolerate small-volume phlebotomies to remove iron. In some cases, the anaemia improves with removal of excess iron (French & Jacobs, 1976; Hines, 1976). This could reflect a reduction in mitochondrial injury by iron-mediated reactive oxygen species. This is speculation, however, and the scenario is distinctly unusual. Case reports exist of allogeneic bone marrow or stem cell transplantation for inherited sideroblastic anaemia (Urban et al, 1992; Gonzalez et al, 2000). The obvious advantage is possible cure, as has occurred in patients with [beta]-thalassaemia. Possible cure must be balanced against transplant complications, particularly in older people. Families with severe forms of hereditary sideroblastic anaemia should receive genetic counselling.

Conclusion
Sideroblastic anaemias vary in aetiology and pathophysiology. The common thread in these disorders is distinct biochemical abnormalities affecting the mitochondrion and haem biosynthesis. Recent discoveries have improved our understanding of the interplay between mitochondrial function, haem biosynthesis and cellular iron metabolism. This new knowledge will probably point the way to improved therapies.

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Keywords: anaemia; sideroblastic; mitochondria; haem

Accession Number: 00002328-200203040-00003

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