Page 596 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 38 Heme Biosynthesis and Its Disorders 511

deficiency. 234–236 In contrast, binge drinking or chronic alcohol inges- hydrochloride, a copper-chelating agent used in the treatment of
tion in subjects with good nutrition is not associated with sideroblastic Wilson disease. 246,247 Acquired sideroblastic anemia has also been
abnormality. Sideroblastic change is never the sole cause for the anemia precipitated by progesterone given to a patient on two separate occa-
237
of alcoholism. Alcohol has a direct toxic effect on hematopoiesis. An sions 15 years apart, and this anemia promptly reversed on withdrawal
increased or high-normal MCV and vacuolation of red blood cell of the drug. 248
precursors is often seen in addition to the ring sideroblast abnormality.
Red blood cells show dimorphic morphology; evidence in the marrow
237
of folate deficiency is present in half of cases. Transferrin saturation PRESENTATIONS ASSOCIATED WITH SIDEROBLASTIC
and marrow iron stores tend to be increased but may be low if gastro- ANEMIA OR PORPHYRINURIA
intestinal bleeding is present. The ring sideroblasts gradually disappear
234
over 4 to 12 days when alcohol is withdrawn ; during this period, Copper Deficiency or Zinc Overload
there may be a rebound erythroid hyperplasia, reticulocytosis, and
thrombocytosis. Folic acid should be given for the associated megalo- The copper content of a Western diet averages 0.9 to 1.6 mg each
blastic changes after blood is taken for vitamin B 12 and folate assays. day, which is only a few times greater than the amount needed to
249
Alcohol consumption lowers the plasma concentration of pyri- maintain homeostasis of this essential element. Copper deficiency
250
doxal phosphate, a cofactor for ALAS, needed in the first step in heme has been described in malnourished premature infants, in patients
251
238
synthesis. Conversion of ethanol to acetaldehyde is necessary for receiving long-term parenteral or enteral hyperalimentation, after
252
246
this effect, and acetaldehyde acts by accelerating the degradation of gastrectomy, with copper-chelating agents, or on an idiopathic
253
intracellular pyridoxal phosphate in the liver, lowering plasma levels basis. The syndrome of copper deficiency consists of sideroblastic
of this coenzyme. 239 anemia with hypochromic cells in the blood smear, accompanied by
Chronic alcoholics have an altered heme metabolism with increased ring sideroblasts and vacuolated erythroid and myeloid precursors in
urinary excretion of coproporphyrin, mainly isomer III, but normal the marrow, and of neutropenia with an absence of late myeloid forms
urinary excretion of uroporphyrin, ALA, and porphobilinogen. Acute in the marrow (Fig. 38.11). In some reports, patients present with
and chronic ethanol ingestion markedly depresses the activity of ALA neurologic symptoms such as paresthesias, weakness, or ataxia; and
dehydratase in peripheral blood. Ethanol administration to normal demyelination is seen on the magnetic resonance image of the
253
subjects results in increased activity of leukocyte ALAS and erythrocyte brain. In infants, additional features may be seen, such as osteopo-
PBGD, the two rate-controlling enzymes of the pathway. The activities rosis and long bone changes, depigmentation of skin and hair, and
of each of the other four enzymes are depressed. Ferrochelatase, the central nervous system abnormalities. The platelet counts remain
enzyme that inserts iron into protoporphyrin to form heme, shows the normal. Serum copper and ceruloplasmin levels are low, whereas
most marked depression, and in alcoholism there is prolonged depres- serum iron and transferrin saturation levels are normal. The serum
253
sion of uroporphyrinogen decarboxylase, which provides a rationale for zinc concentration may be increased. Prompt reversal of the
the role of ethanol in the etiology of PCT. 240,241 As earlier, ethanol is a hematologic changes follows therapy with 2 to 5 mg/day of copper
major precipitating factor in acute porphyria. 242 sulfate taken orally or 100 to 500 µg/day of copper supplement to
the intravenous alimentation formula.
Large quantities of ingested zinc interfere with copper absorption
Isoniazid and produce the neutropenia and sideroblastic anemia characteristic
254
of copper deficiency. Zinc sulfate is freely available from health
Administration of the antituberculous drug isoniazid has occasionally food stores, and as little as 450 mg/day for 2 years is sufficient for
been associated with development of a sideroblastic anemia after this effect. Sideroblastic anemia has also been ascribed to zinc toxicity
255
1 to 10 months of therapy. The anemia is hypochromic and micro- arising from the ingestion of coins over a period of many years.
cytic, with a dimorphic blood smear and ring sideroblasts in the Serum zinc levels are high, whereas serum copper and ceruloplasmin
marrow. This complication is thought to occur only in slow acetyl- levels are low. Zinc must be discontinued for 9 to 12 weeks for full
ators of isoniazid, allowing this drug to react nonenzymatically with reversal of the anemia and neutropenia.
pyridoxal and to form a hydrazone that is rapidly excreted in the
urine. The anemia can be fully reversed by coadministration of pyri-
243
doxine (25–50 mg/day) with isoniazid or by withdrawing isoniazid. Iron Deficiency Anemia
Another antituberculous drug, pyrazinamide, may also cause a sid-
eroblastic anemia, which is caused by inhibition of ALAS2 and In iron deficiency anemia, there is an accumulation of protoporphyrin
responds to pyridoxine therapy. 244 in erythrocytes that rarely reaches the level found in EPP. The zinc
complex of protoporphyrin is produced because ferrochelatase uses
2+
256
Zn during iron-deficient erythropoiesis. Erythrocyte protopor-
Chloramphenicol phyrin may be raised before changes appear in peripheral blood and
may be helpful in diagnosing iron deficiency when serum iron and
Chloramphenicol is an antibiotic that produces a reversible suppres- ferritin levels are rising as a result of patients having started iron
sion of erythropoiesis after several days of therapy (plasma levels of therapy. In iron-deficient erythropoiesis, erythroid ALAS activity is
10–15 µg/mL). This effect is predictable and separate from the rare reduced below normal. 257
idiosyncratic side effect of aplastic anemia in approximately 1 of
20,000 exposed persons. Nearly all patients given chloramphenicol
(>2 g/day) develop vacuolation of the erythroid precursors and ring Hypothermia
sideroblasts. These effects are thought to arise from suppression of
mitochondrial respiration. Chloramphenicol inhibits mitochondrial Thrombocytopenia, erythroid hypoplasia, and ring sideroblasts have
245
protein synthesis and reduces cytochrome a, a 3 , and b levels. Serum been described in patients with hypothermia associated with neuro-
258
iron concentrations are increased, and reticulocyte numbers are logic disease. These changes reverse slowly as body temperature
subnormal; these changes revert on stopping the antibiotic. returns to normal.
Other Drugs Other Conditions
A reversible acquired sideroblastic anemia has been described with In hereditary tyrosinemia, excess urinary ALA is excreted because
penicillamine, linezolid, and with the use of triethylene tetramine ALA dehydratase is inhibited by succinyl acetone. Like acute