Page 940 - Williams Hematology ( PDFDrive )

915

CHAPTER 59 Myeloid Neoplasms, in which ringed sideroblasts are a common phe-
notypic feature. Acquired polyclonal sideroblastic anemia may also
POLYCLONAL AND develop as a result of the administration of certain drugs, exposure to
toxins, or coincident to neoplastic or inflammatory disease. Hereditary
HEREDITARY SIDEROBLASTIC sideroblastic anemias include X-linked, autosomal, and mitochondrial
entities. Occasionally, a patient with familial disease develops a myelo-
dysplastic syndrome later, but with these rare exceptions, the disor-
1,2
ANEMIAS ders are distinct and do not coexist or evolve one from the other.
Although the perinuclear distribution of siderotic granules
in the erythroblasts of patients with various types of anemia was
described in 1947, the concept of sideroblastic anemia as a generic
3,4
Prem Ponka and Josef T. Prchal designation was not generally accepted until the publications of
9
7,8
10
5
6
Björkman, Dacie, Heilmeyer, Bernard, and Mollin. After these
descriptions of the acquired, “primary adult form of refractory side-
5,6
SUMMARY roblastic anemia,” similarity to the morphologic and erythrokinetic
changes in hereditary (sex-linked) hypochromic anemia was recog-
11
Sideroblastic anemias are characterized by the presence of ring sideroblasts in nized. Cooley described a patient with an anemia with ovalocyto-
the marrow. These cells are erythroid precursors that have accumulated abnor- sis who was shortly thereafter shown to have inherited a hereditary
12
sex-linked disorder that we now know resulted from the mutation
mal amounts of mitochondrial iron. A variety of abnormalities of porphyrin of erythroid-specific aminolevulinic acid (ALA) synthase, ALAS2.
13
metabolism in affected erythroid cells have been documented. Hereditary Autosomally inherited cases were also described, and prominent
14
sideroblastic anemias are usually X linked, as the result of mutations in the sideroblastic changes of the marrow were found in Pearson marrow-
erythroid form of 5-aminolevulinic acid synthase. Inherited autosomal and pancreas syndrome (Chap. 36), a disorder that is caused by mutations
mitochondrial forms are seen, occasionally. Acquired sideroblastic anemias of mitochondrial DNA. 15–19 Sideroblastic anemia can also be associated
20
can occur as a result of the ingestion of drugs, alcohol, or toxins such as lead with a wide variety of diseases, therapy with antituberculosis drugs, 21,22
or zinc, or copper deficiency. Patients with acquired sideroblastic macrocytic and lead intoxication. 23–26 In some patients, the anemia responded to
anemia and variable degrees of thrombocytopenia and leukopenia from large doses of pyridoxine and was designated “pyridoxine-responsive
copper deficiency have been recognized more frequently; the hematologic anemia.” 10,27–29 These “secondary” acquired disorders were then incor-
abnormalities typically resolve after copper replacement. Ring sideroblasts porated into the classification.
are also a feature of myelodysplastic neoplasms, and are discussed in Chap.
87. Some patients with sideroblastic anemia may respond to pharmacologic EPIDEMIOLOGY
doses of pyridoxine. Iron loading is common in the sideroblastic anemias and
can be treated by phlebotomy when the anemia is mild or with iron chelators All of the hereditary forms are rare, and no particular ethnic predilec-
(Chap. 43) when it is more severe. tion is known. Drug-induced forms occur sporadically among subjects
taking the drugs listed in Table 59–1.
ETIOLOGY AND PATHOGENESIS
DEFINITION AND HISTORY
MORPHOLOGIC ASPECTS: THE SIDEROBLASTS
Sideroblastic anemias are a heterogeneous group of disorders that have Sideroblasts are erythroblasts containing aggregates of non–heme iron
as a common feature the presence of: (1) large numbers of pathologic that appear as one or more Prussian blue–positive granules on light
sideroblasts in the marrow, which characteristically display abnormal microscopy. The morphology of these cells in normal and abnormal
30
mitochondrial iron accumulation is in a circumnuclear position in states is discussed in detail in Chap. 31. In normal marrow, virtually
erythroblasts; these are referred to as ringed sideroblasts; (2) ineffec- every erythroblast has siderosomes, iron-containing organelles that are
tive erythropoiesis; (3) increased levels of tissue iron; and (4) varying demonstrable by transmission electron microscopy. Light microscopy of
proportions of hypochromic erythrocytes in the blood. They may be Prussian blue–stained marrow aspirates or biopsy sections is a relatively
acquired or hereditary (Table 59–1). 1,2 insensitive method to identify these structures. One can usually identify
Acquired monoclonal sideroblastic anemia is a neoplastic disease; approximately 25 to 35 percent of erythroblasts with one to three very
that is, a clonal cytopenia or oligoblastic myelogenous leukemia that fine Prussian blue–stained granules in the cytoplasm of a well-prepared
can progress to acute leukemia. This subject is considered in Chap. 87,
marrow sample. Pathologic sideroblasts may be of two types: erythrob-
lasts with a marked increase in the number and size of siderotic granules
in the cytoplasm, compared to normal erythroblasts, or ringed sidero-
blasts. Ringed sideroblasts are the hallmark of the sideroblastic anemias.
Acronyms and Abbreviations: ABCB7, ATP-binding cassette; ALA, 5-aminolevulinic In contrast to the normal cytoplasmic location of siderotic granules, the
acid; ALAS2, gene encoding ALA synthase 2; CPO, coproporphyrinogen oxidase; pathologic sideroblasts in the sideroblastic anemias have large amounts
FECH, ferrochelatase; Fe-S, iron-sulfur; GLRX5, glutaredoxin 5; MLASA, mitochon- of iron deposited as dust- or plaque-like ferruginous micelles between
drial myopathy and sideroblastic anemia; PUS1, pseudouridine synthase 1 gene; the cristae of mitochondria (Fig. 59–1). The iron-loaded mitochondria
31
SLC25A38, mitochondrial carrier family gene; STEAP 3, six-transmembrane epi- are distorted and swollen, their cristae are indistinct, and identification
thelial antigen of prostate 3-ferric reductase; TfR, transferrin receptor; tRNA, transfer of mitochondria may itself be difficult. In humans, the mitochondria
RNA; XLSA/A, X-linked sideroblastic anemia, associated with ataxia. of the erythroblast are distributed perinuclearly, which accounts for
23
the distinctive “ringed” sideroblast identified by Prussian blue staining

Kaushansky_chapter 59_p0915-0922.indd 915 9/17/15 3:17 PM