Henry Ford Hospital Medical Journal

Volume 24 | Number 2 Article 4

7-1976 Sideroblastic Louis D. Saravolatz

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Recommended Citation Saravolatz, Louis D. (1976) "Sideroblastic anemias," Henry Ford Hospital Medical Journal : Vol. 24 : No. 2 , 81-86. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol24/iss2/4

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp. Med. Journal Vol. 24, No. 2, 1976

Sideroblastic anemias

Louis D. Saravolatz, M.D.*

J)IDEROBLASTlC anemias are a hetero­ geneous group of disorders that are differen­ tiated on the basis of etiology and clinical and biochemical manifestations. They share the common features of and ringed Sideroblastic anemias are reviewed with sideroblasts in the marrow. emphasis on clinical features, biochemical studies, treatment modalities and prognosis. The ringed sideroblast (Figure 1) is a nor­ A classification of these anemias based on moblast with excessive iron deposited in the etiology is also provided. mitochondria. These deposits have a per­ inuclear arrangement and appear as a ring when stained with . The side- rocyte, a circulating erythrocyte containing excessive stainable iron granules, is not di­ agnostic of sideroblastic anemiasandcan be seen in patients with severe hemolytic ane­ mias or after splenectomy. Sideroachrestic anemia is due to the failure to utilize iron in synthesis and is used syn­ onymously with sideroblastic anemia.

This review summarizes clinical and bio­ chemical features and discusses the patho­ genesis of sideroblastic anemias.

Sideroblastic anemias have been classi­ fied as pyridoxine responsive or resistant, or as hereditary or acquired. There is overlap between these classifications. A better clas­ sification divides these anemias into four *Department of Medicine major groups: (1) hereditary, (2) secondary to Address reprint requeststo Dr. Saravolatz at Henry toxins or drugs, (3) complicating various Ford Hospital, 2799 West Grand Boulevard, De­ disease states, and (4) idiopathic. The salient troit, Ml 48202 laboratory features are shown in Table 1.

81 Saravolatz

Hereditary sideroblastic anemia

The mode of inheritance of the hereditary form of sideroblastic anemia is usually x- Iinked recessive, and therefore most patients are males. The female carriers usually have normal , but some have been reported with abnormal mor­ phology and moderate anem ias.^ There have been reports of hereditary sideroblastic ane­ mia transmitted in an autosomal recessive mode of inheritance.^

The hereditary sideroblastic anemia is usually not recognized until thethird decade of life but may be apparent at birth or infancy. If the patient has had excessive pyridoxine in the diet, the anemia may not occur until the patient has reached 60 years of age. The patient often presents with signs and symptoms of anemia which may be severe (average hemoglobin 6.5 gm%). Most patients show evidence of iron overload with hepatosplenomegaly secondary to iron deposited in the reticuloendothelial system. Figure 1. Up to one third of the patients may have Ringed sideroblast in marrow section x 1100. clinical diabetes or glucose intolerance. Skin Arrow points to higher magnification of the same hyperpigmentation is occasionally ob­ cell (x 2800) to show rod-shaped nature of the served. Patients usually do not show evi­ iron-encrusted perinuclear mitochondria. Prus­ dence of pyridoxine deficiency as sian blue reaction (Courtesy Dr. ).W. Rebuck.) manifested by glossitis, dermatitis, or neuropathy. thesis (Figure 2). The rate limiting reaction in The biochemical defect that has been synthesis is the formation of delta- proposed for hereditary sideroblastic ane­ amino-levulinic acid from succinyl CoA and mia involves the first step in porphyrin syn- glycine and is mediated by A ALA-syn-

Table 1

Laboratory features of sideroblastic anemias

Sideroblastic anemias Normal RBC morphology Hypochromic, microcytic or macrocytic Hemoglobin 6.5-9.0 80-180 ugl 60-140 ugl Tl.B.C. 200-350 ugl 250-400 ugl Reticulocytes 0.5-2.0% 0.5-1.5% Marrow Hemosiderin 3- 64- 1-3 4- Sideroblasts 50-100% (ringed) 20-70% (not ringed) Sideroblastic anemias thetase. This reaction requires the coenzyme been found in hereditary sideroblastic ane­ pyridoxal-5-phosphate which is the active mia and are compatible with a defect in form of pyridoxine. In hereditary sideroblas­ ALA-synthetase. tic anemia a defect in A ALA-synthetase has been proposed.^ This would result in a de­ Since there are various degrees of clinical crease in the amount of free erythrocyte severity and pyridoxine responsiveness in protoporphyrin produced and a pyridoxine hereditary sideroblastic anemia, multiple responsive anemia. ALA-synthetase studies defects in the heme synthetic pathway are have not been done to support this. likely. There have been documented heredi­ However, low protoporphyrin levels have tary cases with high free erythrocyte cor-

Figure 2

DEFECTS IN THE HEME SYNTHESIS IN SIDEROBLASTIC ANEMIAS

1. A-ALA-S sCoA + glycine ALA P-5-P 3.

Fyridoxine ALA-Dehydrase kinase

Porpliobilinogen Pyridoxine Uroporphyrinogen

Coproporphyrinogen Coproporptiyrinogen Oxidase 1.&3. Fe + Protoporphyrin Heme 3.&4. Heme Syntlietase

1. Defect in Hereditary Sideroblastic Anemia 2. Defect in alcoliol induced Sideroblastic Anemia 3. Defect in lead induced Sideroblastic Anemia 4. Defect in idiopathic refractory Sideroblastic Anemia

8J Saravolatz

proporphyrinogen and low protoporphyrin after ethanol withdrawal.' Alcohol works in with a defect in the enzyme cor- the first step of heme synthesis (Figure 2) and proporphyrinogen oxidase.^ This defect ac­ low levels of pyridoxal-5-phosphate have counts for some of the hereditary patients been found in alcoholics.^ This occurs by who are resistant to pyridoxine since it is not efther decreasing production of pyridoxal-5- a necessary coenzyme in this reaction as it is phosphate by inhibiting pyridoxine kinaseor in the ALA-synthetase mediated reaction. enhancing degradation by stimulating pyridoxal phosphate phosphatase.^ If eth­ anol is not withdrawn, pyridoxine or folate Even though the patient with hereditary will not improve these patients; however, sideroblastic anemia has no evidence for a pyridoxal-5-phosphate will. deficiency of pyridoxine, almost 50% will have an optimal response with the hemo­ globin returning to normal. The minimal can also cause an inhibi­ daily requirement of pyridoxine is 1.5-2.0 tory effect on heme synthesis with a resultant mg/day, however, large doses (50-200 sideroblastic anemia. The principal man­ mg/day) which are used in treatment of ifestations of lead poisoning are abdominal anemias, are free of side effects." The mor­ (pain, constipation, and vomiting) and neu­ phologic abnormalities of the marrow and rologic (paresthesias or psychologic) symp­ peripheral blood do not ever return to nor­ toms. Prominent and an mal. Once a patient is treated with pyridox­ abnormal hemoglobin electrophoresis with ine, treatment must be continued or the increased A2 or E may support the diagnosis. patient will relapse and retreatment may be The diagnosis is established by elevated less successful than previously. Valentine's plasma or urine lead levels. The defects crude liver, androgen, and removal of excess caused by lead poisoning involve multiple body iron have been utilized with usually a steps in the heme synthetic pathway (Figure poor response." 2).' These are associated with elevated A- ALA urinary levels and normal por­ phobilinogen levels, which helps differenti­ ate lead poisoning from porphyrin, where The prognosis in hereditary sideroblastic both ALA and porphobilinogen levels are anemia depends on the response to pyridox­ elevated. This biochemical difference is im­ ine. These patients, unlike those with idi­ portant since, clinically, lead intoxication opathic refractory sideroblastic anemia, do may be indistinguishable from porphyria. not convert to , but succumb to cardiac arrhythmias, liver failure, or failure. Antituberculosis therapy with , , and pyrazinamide have rarely Sideroblastic anemias been associated with sideroblastic anemias. Correction of the anemia can occur with secondary to toxins or drugs either withdrawal of the offending agent Sideroblastic anemias have been associ­ or administration of large doses of ated with various drugs and toxins.^ Ethanol pyridoxine.''" is probably the most common cause of secondary sideroblastic anemias which oc­ cur in nearly one-third of alcoholics who Otherdrugs such as and require hospitalization. Withdrawal of alco­ antineoplastic agents have been reported as hol is accompanied by a reticulocytosis, a causing sideroblastic anemias; however, rise in hemoglobin, and a disappearance of these are very rare complications of these the ringed sideroblasts within 48-72 hours drugs.'-"

84 Sideroblastic anemias

Sideroblastic anemias phyrin.* However, Kuchner et al reviewed complicating various disease states 17 patients with IRSA and found only one patient with a low heme synthetase level.' Sideroblastic anemias have been associ­ Amino acid incorporation studies have ated with many illnesses (Table 2). The shown that there is normal globin synthesis clinical features, course, treatment and prog­ and abnormal heme synthesis in IRSA, nosis are related to the nature of the associ­ however, the exact location of the defect is ated disease rather than the sideroblastic unknown.' If heme synthetase was the site of anemia. If the underlying illness is improved, the defect in IRSA, this would explain the the hemoglobin rises and the sideroblasts low heme and the elevated free erythrocyte may disappear. Some investigators have protoporphyrin levels. found that 50% of these patients will res­ pond to pyridoxine with a rise in hemo­ globin of 2-5 gm %.' This may be beneficial When pyridoxine is used in IRSA there is if the underlying illness is incurable, an increase in free erythrocyte pro­ however, treatment should always be di­ toporphyrin but no change in hemoglobin. rected at the underlying illness first. IRSA is refractory to almost all forms of treatment Iron, pyridoxine, folic acid, B12, vitamin C, splenectomy, cobalt, and both Table 2 oral and parenteral liver extract have been used unsuccessfully. There have been a few Diseases associated with sideroblastic anemias reports of IRSA patients having minimal responses to pyridoxine. Also, four patients Leukemia Carcinomas have been reported who responded to an­ vera Cirrhosis drogen therapy with an increase in hemo­ Myelofibrosis Rheumatoid arthritis globin of 3-6 gms." Hemolytic anemias Chronic infections Lymphomas Uremia Multiple myeloma Polyarteritis nodosa The prognosis for IRSA is quite good with a median survival of 10 years. Since these patients present in the seventh decade of life, Idiopathic refractory their survival approaches that of the normal sideroblastic anemia population. The requirement of transfusions to minimize symptoms of anemia is the most Idiopathic refractory sideroblastic anemia important factor in reducing survival in (IRSA) is a disease of unknown etiology IRSA. The average survival for IRSA is 8.4 which has distinct features and is not associ­ years when transfusions are required as ated with drugs, toxins or any underlying compared to 15 years in the patients not illness. This is a disease of older adults with needing transfusions." the average of presentation being 66. These patients are often asymptomatic and have physical examinations that are unremarka­ Patients with IRSA die of the usual dis­ ble except for mild pallor. Iron is desposited eases ofthe aged which are unrelated to their in the reticuloendothelial system but few sideroblastic anemia. The incidence of acute patients have evidence of hepatic or pan­ myelogenous leukemia is, however, in­ creatic insufficiency. creased in IRSA, and Dameshak' has advo­ cated that IRSA is a premalignant condition It has been postulated that the defect in which eventually develops into leukemia in IRSA is in the heme synthetase mediated nearly 50% of patients. The actual incidence reaction (Figure 2) since these patients have of acute myelogenous leukemia is probably an elevated free erythrocyte protopor­ closer to 7% .'

85 Saravolatz

References

1. Hines JD, Grasso JA: The sideroblastic ane­ 6. Cartwright CE, Deiss A: Sideroblasts, side- mias. Semin Hematol 7:86, 1970 rocytes, and sideroblastic anemia. N £ng/ / Med 292:185, 1975 2. Cotton HB, Harris JW: Familial pyridoxine responsive anemia. yC/Zn/nvest 41:1352,1962 7. Chisholm JJ: Disturbances in the biosynthesis of heme in lead intoxication. / f^diatr 64:174, 3. HeilmeyerL: Disturbances in Heme Synthesis. 1964 Springfield, IL. Charles C. Thomas, ppl03-178, 1966 8. Kushner JP, et al: Idiopathic refractory side­ roblastic anemia. Medicine 50:139, 1971 4. Wintrobe: Clinical , seventh edi­ tion, 1974 9. Dameshek W: The Diguglielmo syndrome re­ visited. Blood 34:567, 1969 5. Pierce HI, McGuffin RG, Hillman RS: Clinical studies in alcoholic sideroblastosis. Arch/ntem Med 136:283,1976