Page 944 - Williams Hematology ( PDFDrive )

918 Part VI: The Erythrocyte Chapter 59: Polyclonal and Hereditary Sideroblastic Anemias 919

in the formation protoporphyrin IX levels; instead, the amount of pro- usually is rapid (25 to 50 minutes; normal mean: 90 to 100 minutes) but
toporphyrin IX is moderately increased. Impaired iron reduction in some patients may be normal. The plasma iron turnover tends to be
43
could cause intramitochondrial iron accumulation in patients with increased (1.5 to 5.9 mg/dL of blood per day; normal: approximately
myelodysplastic syndromes. The ferric reductase, STEAP 3 (six-trans- 0.30 to 0.70 mg/dL per day), but incorporation of radioactive iron into
membrane epithelial antigen of prostate 3-ferric reductase), is involved heme and its delivery to the blood as newly synthesized hemoglobin are
3+
100
in the reduction of Fe to Fe in endosomes. Based on the model depressed (15 to 30 percent of tracer dose; normal: 70 to 90 percent).
2+
of the direct interorganellar transfer of iron (see Fig. 59–2), it can be Red cell survival ranges between 40 and 120 days, indicating some cases
assumed that there is only one reduction step during the path of iron have moderate or only very slightly shortened red cell life-span, whereas
from endosomes to FECH. However, the efficient insertion of ferrous in other cases red cell survival is normal. As in other kinds of anemia
ions into protoporphyrin IX may still require a reducing environment characterized by ineffective erythropoiesis, the fecal stercobilin excreted
in mitochondria that would be provided by an uninterrupted respira- per day may be greater than can be accounted for by the daily catabo-
tory chain. This proposal is compatible with the fact that sideroblas- lism of circulating hemoglobin.
101
tic anemia accompanying Pearson marrow-pancreas syndrome is
caused by deletions of mitochondrial DNA genes, products of these are
102
involved in electron transport. Indeed, there are at least some myelo- CLINICAL AND LABORATORY
dysplasia-associated sideroblastic anemia patients described caused by FEATURES
acquired mutations in cytochrome oxidase, encoded by mitochondrial
DNA. 54,55,103–105 However, a rigorous study failed to find cytochrome oxi- PRIMARY ACQUIRED (CLONAL)
dase mutations in 10 patients with myelodysplasia-associated siderob- SIDEROBLASTIC ANEMIA
lastic anemia. Alternatively, these is some evidence that ABCB7 (see
106
the above discussion on XLSA/A) could be a possible candidate gene The primary acquired sideroblastic anemia is described in Chap. 87.
for the formation of ringed sideroblasts in refractory anemia with ring Anemia is present in more than 90 percent of patients. Patients may be
sideroblasts. 107 asymptomatic or, if anemia is more severe, have the nonspecific symp-
toms of anemia including pallor, weakness, loss of a sense of well-being,
and exertional dyspnea. A small proportion of patients have infections
Mitochondrial Myopathy and Sideroblastic Anemia related to severe granulocytopenia or hemorrhage related to severe
There are some similarities and some dissimilarities between Pearson thrombocytopenia at the time of diagnosis; however, this variant of
marrow-pancreas syndrome and patients with mitochondrial myop- myelodysplastic syndrome has the lowest probability of symptomatic
athy and sideroblastic anemia (MLASA). 57,108,109 In both cases, there neutropenia, thrombocytopenia, and acute leukemic transformation
are defects in the mitochondrial electron transport chain, likely creat- among all myelodysplastic syndromes (Chap. 87). Hepatomegaly or
ing an environment that retards iron access to FECH in the reduced splenomegaly occurs also rarely in this type of myelodysplastic syn-
form. Both disorders are hereditary, but Pearson syndrome is caused by drome. Iron overloading regularly accompanies this disorder, usually
large deletions of mitochondrial DNA, whereas MLASA results from a in those who have a large requirement for transfusion, and may be the
homozygous missense mutation in the genomic DNA of pseudouridine cause of death (Chap. 87).
108
synthase 1, encoded by PUS1 gene. It has been proposed that deficient
pseudouridylation of mitochondrial transfer RNAs (tRNAs) explains
the pathogenesis of MLASA type of sideroblastic anemia. 108 SECONDARY ACQUIRED SIDEROBLASTIC
Mitochondrial Ferritin Mitochondrial ferritin is a ferritin iso- ANEMIA
form with ferroxidase activity that is expressed only in mitochondria Drugs and Alcohol
(Chap. 42). This protein is encoded by an intronless nuclear gene and The administration of certain drugs and the ingestion of alcohol may
can store iron within a shell of homopolymers. 110–112 Although the func- cause sideroblastic anemia (see Table 59–1). The drugs that are most
tion and regulation of expression of this protein is not fully understood, commonly associated with this type of anemia are isonicotinic acid
the induction of mitochondrial ferritin causes the transfer of iron from hydrazide, pyrazinamide, 21,22,117 and cycloserine, 21,22,117 all pyridoxine
116
113
cytosolic ferritin to mitochondrial ferritin. The mitochondrial fer- antagonists. Although plasma pyridoxal phosphate levels are often low
ritin has a very low expression in all tissues except testis. 110,112 Although in alcoholic patients, there is no correlation between these levels and the
mitochondrial ferritin is not expressed in normal erythroblasts, it is appearance of ringed sideroblasts in the marrow. 118
expressed in ring sideroblasts of patients with sideroblastic anemias, Anemia secondary to drugs may be quite severe, even necessi-
114
caused by ALAS2 defects, as well as those associated with myelodys- tating transfusion, but characteristically the anemia improves rap-
22
plastic syndromes. In both, iron is sequestered within mitochondrial idly when the patient is given pyridoxine and/or when administration
ferritin. Because mitochondrial ferritin has ferroxidase activity, it of the offending drug is discontinued. The red cells are hypochromic,
114
likely protects mitochondria by converting the toxic ferrous iron to fer- and a dimorphic appearance of the erythrocytes in the blood film may
ric iron that is stored. Further research is needed to explain the mech- be notable, that is, two populations of red cells can be distinguished;
anism of mitochondrial ferritin induction in erythroblasts of patients hypochromic and anisocytic, along with normochromic and normo-
with sideroblastic anemias, both hereditary and acquired. Whether cytic. The reticulocyte count is low or normal. In rare instances, a
119
the mitochondrial ferritin also accumulates iron in ring sideroblasts of sideroblastic anemia first observed during the course of drug adminis-
patients with XLSA/A has not yet been studied. tration has progressed in the face of discontinuing the putative offend-
ing drug. In such cases, the patient presumably was suffering from an
Mechanism of Anemia unmasked underlying myelodysplastic neoplasm.
The dominant factor that determines anemia is ineffective erythropoiesis
(intramedullary apoptosis); the rate of red cell destruction is usually Copper Deficiency
near-normal or only moderately accelerated to levels for which a nor- In 1974, two patients with sideroblastic anemia, one also with neu-
mally functioning marrow can compensate. The half-time of disap- tropenia, following extensive bowel surgery and long-term parenteral
115
pearance of intravenously injected tracer doses of radioactive iron is nutrition were described. In 2002, another patient was described who
120

Kaushansky_chapter 59_p0915-0922.indd 919 9/17/15 3:17 PM