MED. THE SIDEROBLASTIC ANAEMIAS · December, 1965 MORROWandGOLDBERG: TheSideroblastic Anaemias 741 Breton-Gorius (1959) demonstrated that the iron in the granules of normalnormoblasts

POSTGRAD. MED. J. (1965), 41, 740

THE SIDEROBLASTIC ANAEMIASJ. J. MORROW, M.B., M.R.C.P.(Glas.), M.R.C.P.

A. GOLDBERG, M.D., M.R.C.P., F.R.C.P. (Glas.), F.R.C.P.Ed.

University Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow, W.1.

THE SIDEROBLASTIC anaemias are a group ofdiseases in which the unique feature is thefinding of 'sideroblasts' or iron-containing redcell precursors in the bone marrow, associatedwith anaemia in the peripheral blood. Theanaemia is usually, but not always hypochromic.Indeed the diagnosis is often first suggestedwhen a hypochromic anaemia has proved re-fractory to treatment with iron; but unlikeiron deficiency anaemia the serum iron is oftenhigh and there are increased tissue iron stores.It is important to make this differentiationearly since excessive iron is almost certainlyharmful. Sideroblastic anaemia may occur asa primary isolated disorder with occasionalevidence of a hereditary predisposition or itmay 'be associated with chronic infections,carcinoma, collagen diseases or ingestion ofcertain drugs. The exact nature of the disease isunknown but in each type there is a disorderof haem biosynthesis in the bone marrow.The Sideroblast

Prussian-blue staining granules were firstrecognised in the red blood cells by Bizzozeroin 1883. Gruneberg (1941) found similargranules in the erythrocytes of normal mice,rats and man and called these cells siderocytes.Such cells were later found in the blood ofpatients who had undergone splenectomy(Doniach, Gruneberg and Pearson, 1943) andsimilar inclusion bodies were observed inhuman marrow normoblasts (Gruneberg, 1941;McFadzean and Davis, 1947; Dacie andDoniach, 1947). ,McFadzean and Davisobserved that they were more numerous inpatients with haemolytic anaemia than innormal subjects, and therefore regarded themas a sign of abnormal haemoglobin synthesis.Douglas and Dacie (1953) found sideroticgranules in the erythroblasts of a large numberof normal subjects and in a wide range ofabnormal blood conditions but not in irondeficiency anaemia. They concluded that theywere normal inclusions of developing erythro-blasts although in cases of congenital

hypochromic anaemia and refractory anaemiathey considered that the abnormally largegranules were caused by defective haemoglobinsynthesis. Kaplan, Zuelzer, and Mouriquand(1954) made similar observations in a largenumber of children; they also noted the returnof granules in the normoblasts of patients withiron deficiency anaemia treated with iron andtheir appearance on addition of iron to culturesof iron deficient normoblasts.The siderotic granules are small in the normal

subject and in conditions such as acquired andcongenital haemolytic anaemia, megaloblasticanaemia, myeloproliferative syndrome, leuk-aemia and related disorders. In these states thegranules are usually not more than 5 or 6 innumber and are distributed in the cytoplasmwith no definite relationship to the nucleus.Morse (1955) drew attention to the correlationof the number of sideroblasts with an elevatedserum iron level and a 'high saturation of theiron binding capacity.

In the group of conditions now referred toas the sideroblastic anaemias there is character-istic erythroid hyperplasia of the marrow oftenwith a preponderance of basophilic cells in-dicating maturation arrest. The proportion ofcells containing siderotic granules is usually,but not always, increased and the granules arelarger, coarser and more numerous in theindividual cells and congregate in the peri-nuclear zone, forming a ring round the nucleus;they are thus referred to as ring sideroblasts.Vacuolation of the cytoplasm of the normo-blasts has also been described (Dacie, Smith,White and Mollin, 1959).Kaplan and others (1954) introduced the

term 'sideroblast' to indicate a normal red cellprecursor with visible iron-containing granules,but Mollin (1965) has applied the term'sideroblast' to the normal cell and 'abnormalsideroblast' where pathological amounts of ironare present.Electron Microscopy

Using the electron microscope Bessis and

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December, 1965 MORROW and GOLDBERG: The Sideroblastic Anaemias 741

Breton-Gorius (1959) demonstrated that theiron in the granules of normal normoblasts andreticulocytes is in ferritin, scattered throughoutthe cytoplasm either as single ferritin moleculesor as clusters. In the abnormal sideroblasts ofsideroblastic anaemia they found a markedincrease in non-haem iron which appeared intwo forms; ferritin indistinguishable fromnormal and an abnormal form, amorphous anddustlike, to which they applied the term'ferruginous micelles'. They located ferritin inthe mitochondria as well as in the cytoplasmand ferruginous micelles only in mitochondriaespecially in the perinuclear zone. Thesemitochondria were disrupted and abnormal instructure. It has been suggested that theappearance of the ring sideroblast is due to thepersistence of large numbers of viable andnon-viable iron-laden mitochondria in theirprimitive perinuclear situation.

Tissue Iron Stores in Sideroblastic AnaemiaTissue iron stores, mainly in the bone marrow

and liver, are increased in sideroblastic anaemia.In the more severe cases, fully developedchanges of haemochromatosis may develop(Losowsky and Hall, 1965; Verloop, Bierenegaand Diezeraad-Njoo, 1962). Where largeamounts of parenchymal iron are 'laid downin the liver no perinuclear distribution is found(Bessis and Caroli, 1959). Excess iron has alsobeen found in pancreas, spleen, kidneys andgastric mucosa. Brain and Herdan (1965) foundthat the concentration of liver iron, but notmarrow iron, was related to the amount oftherapeutic iron or blood transfusion given;there was little hepatic iron in patients not sotreated.

Definition and ClassificationThe sideroblastic anaemias may be defined

as a group of diseases of multifactorial aetiologyin each of which there is derangement in thefinal pathway of haem biosynthesis in theerythrocyte precursors giving rise to anaemiaand characteristic ring sideroblasts in the bonemarrow.They may be divided into primary and

secondary groups depending on whether theanaemia is the sole abnormality present orwhether it occurs in the presence of anotherdisease. Such a classification '(Table 1) doesnot imply any morphological difference in theform of the sideroblasts present or the presenceof any other haematological differentiatingfeatures.

TABLE 1

CLASSIFICATION OF SIDEROBLASTIC ANAEMIASPrimary(a) Congenital

1. Hereditary sex-linked anaemia t(Rundles andFalls (1946)).

2. Familial Ihypochromic anaemia (Mills andLucia (1949)).

3. Anaemia hypochromia, sideroachrestica heredi-taria (Heilmeyer (1958)).

4. Hereditary sideroblastic anaemia (Lukl andothers (1958); Losowsky and Hall (1965)).

(b) Acquired1. Chronic refractory anaemia with sideroblastic

bone marrow (Bjorkman (1956)).2. Refractory normoblastic anaemia (Dacie and

others '(1959)).Secondary

1. Anaemia associated with lead poisoning.2. Anaemia associated with antituberculous drugs

INAH, cycloserine, pyrazinamide.3. Sideroblastic anaemia associated with:

CarcinomaRheumatoid arthritisMyeloproliferative diseasesPolyarteritis nodosaMultiple myelomaHereditary and acquired haemolytic anaemiaLeukaemiaAddisonian pernicious anaemia

Primary (Idiopathic) Sideroblastic Anaemia(1) Congenital Sideroblastic Anaemia

Genetic Transmission. The number of casesof familial sideroblastic anaemia repcrted issmall and in only two families have studies beenextensive enough to reliably indicate the modeof inheritance. Losowsky and Hall (1965)studied 110 members of a family in fourgenerations and found a varying degree ofanaemia, peripheral hypochromia and abnormalring sideroblasts in 10. The pattern of in-heritance showed a sex-linked partiallyrecessive character; all but one of the anaemicsubjects were males. Some female carriersshowed typical red cell changes but in only oneof these was anaemia present. The familystudied by Lukl, Weiderman and Barborik(1958) showed a similar mode of inheritance.Dacie (1954), Byrd and Cooper (1961), Verloop,Bierenga and Diezeraad-Njoo (1962) andRedmond, Robertson and Nelson (1963) alsoreported family studies in which the affectedmembers were predominantly male.Many cases of hereditary hypochromic

anaemia have been reported which are probablyexamples of hereditary sideroblastic anaemiaalthough sideroblasts in these cases were notspecifically sought. Large familial studies byCooley (1945) and Rundles and Falls (1946)indicate a sex linked inheritance. Several other

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742 POSTGRADUATE MEDICAL JOURNAL December, 1965

studies (Mills and Lucia, 1949; Gelpi and Ende,1958; and Ludin, 1957) report familial hypo-chromic anaemia but the genetic pattern isnot clear although again there is a markedpreponderance of males.Age of Onset. The congenital type of sidero-

blastic anaemia usually appears in adolescenceor early manhood, but the range is wide.

Clinical and Haematological Findings. Apartfrom pallor, clinical examination is usuallyuninformative. The spleen is seldom palpablebut the liver may be palpable if there is markedhaemosiderosis. Anaemia is usually of moder-ate degree with a low mean corpuscularhaemoglobin concentration and normal meancorpuscular volume. There is marked hypo-chromia and a variable degree of dimorphism.Osmotic fragility of the red cells is diminishedand by separating the two types of cell bycentrifugation, it can be shown that the increasedresistance lies in the apparently abnormal cells.The reticulocyte count is normal. The bonemarrow shows marked erythroblastic hyper-plasia usually but not always with largenumbers of abnormal ring sideroblasts. Erythro-poiesis is normoblastic in most cases buttransitional megaloblastic changes have beendescribed. The serum iron is usually raisedand the iron binding capacity saturated.Female carriers seldom show any haemato-

logical abnormality and when changes occurthey are minimal, usually some degree ofdimorphism and hypochromia with or withoutmild anaemia. Increased siderotic granulationof the normoblasts may be present but ringforms are scanty. The serum iron and per-centage saturation of transferrin are usuallynormal.(2) Acquired Sideroblastic Anaemia

Several cases of refractory anaemia havebeen described in patients without a hereditarybackground and some of these can probablybe included in this group. In twelve cases ofBomford and Rhoads (1941) the marrow wastermed as 'immature hypercellular' and in someof these iron was conspicuous. Bjorkman (1956)described four cases of refractory anaemia andhyperplasia of the marrow which containednormoblasts with siderotic granules andvacuoles. The serum iron was raised at somestage of the illness. One case died of acutemyeloblastic leukaemia. Other cases ofrefractory anaemia with marrow sideroblastshave been reported by Heilmeyer, Keiderling,Belger and Bernauer (1958) and Dacie andothers (1959).Age and Sex Incidence. The anaemia usually

appears in later life but the range is wide. Bothsexes are affected with some preponderance offemales.

Haematological Findings. The anaemia isusually of moderate severity and is normo-chromic and normocytic although a variablenumber of hypochromic microcytic cells arepresent. The reticulocyte count is normal.There may be leukopenia and occasionallythrombocytopenia. The erythrocyte osmoticfragility is normal. The bone marrow displaysintense normoblastic hyperplasia and largenumbers of abnormal sideroblasts: megalo-blastic change has been found in a few cases.There is evidence of maturation arrest in theincreased numbers of basophilic normoblastspresent and defective haemoglobinisation isapparent in many cells. Many nuclei appearpyknotic and vacuolation of the cytoplasm ofthe normoblasts is conspicuous.Serum iron and percentage saturation are

usually normal but high iron levels and asaturated iron binding capacity may occur.

Secondary Sideroblastic AnaemiaThe diagnosis of secondary sideroblastic

anaemia depends on the coexistence of anotherdisease along with the characteristic anaemia.No morphological difference is apparent be-tween the sideroblasts seen in the primary andsecondary types. MacGibbon and Mollin (1965)studied 35 cases of secondary sideroblasticanaemia associated with a wide range ofdiseases and in 75%/ of cases found the severityof the abnormalities to be as great as those seenin a group of primary sideroblastic anaemias.Differences between the two groups are mainlyof degree but in secondary sideroblastic anaemiahypochromia is relatively uncommon, megalo-blastic change more frequent and the serumiron level and percentage saturation of the ironbinding capacity more variable.Sideroblastic Anaemia and other Diseases

Sideroblastic anaemia has been found inassociation with chronic infections, neoplasticand collagen diseases and in a number of otherconditions summarised in Table 1. In manycases the anaemia was an unexpected findingin the general investigation of the patient. Thediagnosis of secondary sideroblastic anaemiaoffers no difficulties where the associateddisease is overt but where no such conditionis obvious, a thorough search for latentneoplastic or collagen disease must be made.Drugs

Sideroblastic anaemia has been found in asmall number of tuberculous patients under

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TABLE 2COMPARISON OF CONGENITAL AND ACQUIRED PRIMARY SIDEROBLASTIC ANAEMIA

Congenital AcquiredAge Mainly young Later lifeSex Male Male and FemaleFamily History Present AbsentAnaemia Hypoohromic mainly Dimorphic: variable

slight dimorphism hypochromiaMCHC Low NormalMCV Normal Normal/highReticulocytes Normal Normal and occasionally raisedMarrow Hyperplastic normoblastic Normoblastic or megaloblasticSideroblasts very numerous Sideroblasts numerous

Normoblasts vacuolated andpyknoticAbnormal Hb Absent Absent

Osmotic fragility Decreased Slightly decreasedSerum iron High VariableTIBC (Total Iron-binding Saturated VariableCapacity)5'Cr survival Normal or slightly reduced Normal or slightly reduced59Fe studies Ineffectual erythropoiesis Ineffectual erythropoiesisErythrocyte porphyrins Protoporphyrin normal or Protoporphyrin normal orand precursors decreased increased

Coproporphyrin increased Coproporphyrin increasedDelta amino laevulic acid Delta amino laevulic acidincreased increased

treatment with isoniazid and the newer anti-tuberculous drugs cycloserine and pyrazinamide.Verwilghen, Reybrouk, Callens and Cosemans(1965), reported five such cases where with-drawal of either cycloserine or pyrazinamideresulted in cure of the anaemia. Isoniazid-induced anaemia has responded to pyridoxine(Redleaf, 1962; MoCurdy, 1963), although inthese cases sideroblasts were not specificallysought.Lead PoisoningThe anaemia of lead poisoning is partly

haemolytic but there is also evidence of grossdisturbance of haem synthesis (Dagg, Goldberg,Lochhead and Smith, 1965) and abnormal ringsideroblasts have been found in the bonemarrow (Bessis and Jensen, 1965).Radioisotope Findings in Sideroblastic Anaemia

In both the congenital and acquired formsof sideroblastic anaemia red cell survivalmeasured by the radiochromium technique hasbeen normal or only slightly reduced. Thedaily output of faecal urobilinogen and thedecrease in free plasma haptoglobin (Verloopand others, 1962) are greater than can beaccounted for by the minor degree of peripheralhaemolysis. There is presumably a state ofineffectual erythropoiesis, that is, many of thered cells or their precursors are destroyed whilestill in the bone marrow or shortly after their

release into the peripheral circulation.Ferrokinetic studies have shown a rapidplasma iron clearance and increased plasmairon turnover, but gross impairment of iron

utilisation. Losowsky and Hall (1965) foundincreased absorption of radioiron with increasediron storage in the liver and spleen in thehereditary form. Increased absorption of ironwas not, however, found by Brain and Herdan(1965).

In the anaemia of lead poisoning, red cellsurvival is moderately reduced and radioironstudies reveal normal iron turnover and markedreduction of iron utilisation. These abnor-malities resolve with treatment (Dagg, Goldberg,Lochhead and Smith, 1965).Differential Diagnosis

1. Other refractory anaemias, e.g. theanaemia of chronic infection, uraemia andhaemoglobinopathies can be differentiated fromsideroblastic anaemia by marrow examination,biochemical investigations and by a search forabnormal haemoglobins.

2. Iron deficiency anaemia. Hypochromiais present in both iron deficiency anaemia andin sideroblastic anaemia particularly of thehereditary type. These can be easily differen-tiated by measurement of serum iron and ironbinding capacity in addition to estimation ofthe iron content of the bone marrow. Thissimple differentiation is important in order to

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avoid the needless and potentially harmfuladministration of iron.

3. Erythraemic myelosis. The most difficultdifferential diagnosis is that from chronicerythraemic myelosis (Di Guglielmo's Disease).In this condition erythroblasts usually occurin the peripheral blood and multinucleated redcell precursors and myeloblasts are prominentin the bone marrow. Furthermore, the periodicacid Schiff reaction of the erythroblasts isusually more strongly positive than in sidero-blastic anaemia (Verloop and others, 1962).Dameshek (1965) has drawn attention to themany morphological, histochemical, enzymicand radioisotopic similarities between the twoconditions and has suggested that many casesof acquired sideroblastic anaemia are examplesof early Di Guglielmo's Disease. The relation-ship of 'the two conditions, however, must awaita clearer understanding of the fundamentalabnormalities present.TreatmentThe management of primary sideroblastic

anaemia is aimed at the effective treatment ofthe anaemia itself and the avoidance of tissueiron overload or its reduction if it is alreadypresent.

Fortunately, many. cases do not requiretreatment because the haemoglobin is spon-taneously maintained at a reasonable level.In the more severe primary sideroblasticanaemias the most satisfactory response topyridoxine is usually found in the hereditarygroup where a reticulocytosis and a rise ofhaemoglobin to normal levels may occasionallybe attained. Satisfactory remission of theacquired anaemia may also occur with pyri-doxine. Complete haematological remission isunlikely in either group. The dose of pyridoxinerequired varies widely. In the hereditaryanaemia as little as 2 mg. daily may suffice.In general large doses ranging from 100-1,000mg. daily are necessary to maintain improve-ment. Further improvement may occur withthe administration of folic acid, especiallywhere megaloblastic change has occurred, butmay also be seen in cases where such changesare not evident. Deficiencies of vitamin B12and ascorbic acid may aggravate the anaemiaand partial improvement will occur with theiradministration.Where treatment with these agents has failed

blood transfusion may become necessary, butbecause of the danger of haemosiderosis andof aggravating the fundamental defect in theseanaemias, it should only be used whenabsolutely necessary.

Where anaemia is not severe excess iron maybe removed by small frequent venesections andthis may in addition result in improvement ofthe anaemia (Verloop and others, 1962). Whereanaemia is severe the only available means ofremoving iron is by using chelating agents.Desferrioxamine is the most effective of theseat present but since the maximum daily lossis unlikely to exceed 20 mg. it is of limitedvalue.

Secondary sideroblastic anaemia may resolvewith effective treatment of the primary diseaseand complete haematological remission can beexpected. Other cases may respond completelyto combined pyridoxine and folic acid treatment(McGibbon and Mollin, 1965).Nature of the DiseaseThe sideroblastic anaemias form such a

heterogeneous group and their aetiologicalassociations are so diverse, that the questionmust be asked-what is the nature of theseconditions? Are they primarily disorders ofcellular growth of the marrow or dyscrasias ofmarrow porphyrin metabolism or inborn errorsof metabolism or marrow defects induced bydrugs or primary diseases? Or are theyseparate conditions, each with the commonpathological finding-the marrow sideroblast?Disturbance of Cell Growth in Marrow

There are, of course, gross morphologicalchanges in the bone marrow and often in theperipheral blood. In addition to a failure ofhaemoglobin synthesis, there is a state ofineffectual erythropoiesis. Dameshek (1965) hasdrawn attention to the similarities-clinical,haematological and possibly enzymic-betweenacquired sideroblastic anaemia and the chronicform of erythraemic myelosis (Di Guglielmo'sdisease); furthermore some cases of acquiredsideroblastic anaemia have terminated asleukaemias (Bjorkman, 1956; Heilmeyer, 1964).These points underline the association ofneoplastic processes with sideroblastic anaemia.Disorder of Porphyrin MetabolismOne of the final steps in the formation of

haemoglobin is the incorporation of iron intoprotoporphyrin by the enzyme haemsynthetase.In the sideroblastic anaemias there is not onlyevidence of accumulation of iron, but also ofabnormalities in porphyrin metabolism in thered cells or their precursors. In hereditarysideroblastic anaemia erythrocyte proto-porphyrin is normal or reduced and erythrocytecoproporphyrin and 8-amino laevulic acid levelsare raised, while in the acquired form there is

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an increase in coproporphyrin and 8-aminolaevulic acid but the protoporphyrin remainsnormal or is slightly raised (Garby, Sjolin andVahlquist, 1957; Dacie and others, 1959;Heilmeyer, 1960; Heilmeyer and Clotten, 1961).There are thus enzymic defects early in theformation of porphyrin as well as at the finalphase of iron incorporation into protoporphyrin.It is of interest that in the hereditary type thereis not only an accumulation of 8-amino laevulicacid and coproporphyrin, but also a morefrequent response to pyridoxine therapy. Inthe family of Losowsky and Hall (1965) allaffected members responded to pyridoxine, butthere was no evidence of an abnormality inthe enzyme which incorporates iron intoprotoporphyrin (haemsynthetase). Pyridoxalphosphate is responsible for the combinationof glycine and succinyl CoA to form 8-aminolaevulic acid, and in addition it has been shownto be necessary for the mobilisation of ironfrom mitochondria (Cooper, Webster andHarris, 1963).Lead causes a secondary sideroblastic

anaemia and it mainly affects the phases ofhaem synthesis prior to 8-amino laevulic acidformation and also the incorporation of ironinto protoporphyrin (Goldberg, Ashenbrucker,Cartwright and Wintrobe, 1956; Lichtman andFeldman, 1963), but it probably also affectsother intermediate phases of porphyrinsynthesis. The direct measurement of haem-enzymes in these diseases has so far provedinconclusive, mainly because of the technicalproblem of enzyme measurement in humanmarrow. Losowsky and Hall (1965) used aperipheral blood reticulocyte preparation intheir studies which showed no abnormality ofhaemsynthetase activity, but Steiner, Baldiniand Dameshek !(1963) found a decrease inhaemsynthetase and 8-amino laevulic aciddehydrase in bone marrow aspirates, whileVavra (1964) using blood haemolysates foundno evidence of impairment of porphyrin-forming enzymes.There are some findings which suggest that

the intracellular accumulation of iron inhibitsseveral stages of haem synthesis. Bishop andBethel (1959) have suggested that the stage inhaem synthesis where glycine is combined withsuccinyl CoA, may be blocked by excessiveiron forming an inactive complex with pyri-doxine, which can only be overcome by largeamounts of pyridoxine; drug-induced sidero-blastic anaemia in guinea-pigs was aggravatedby large doses of parenteral iron (Harriss,MacGibbon and Mollin, 1965).

Bessis and Jensen have demonstrated thatit is the accumulation of ferritin in themitochondria which is responsible for theappearance of 'ringed sideroblasts'. It has beenshown that the mitochondria contain about80% of the haemsynthetase activity in thefractionated hepatic cell of man and the rat(Lochhead and Goldberg, 1961) and that thisintracellular constituent also plays an importantpart in other phases of haem synthesis such asthe transformation of coproporphyrinogen toprotoporphyrin. Ribosomes, which may alsoaccumulate ferritin, play a notable part inglobin synthesis. It is likely that any depressionin globin synthesis in the sideroblastic anaemiasis associated with, or possibly caused byabnormal haem synthesis, since the synthesis ofhaem and globin are closely linked (Rimington,1958).Inborn Error of MetabolismThere are thus enzymic defects early in the

formation of porphyrins as well as at the finalphase of iron incorporation into protoporphyrin.Although most of the cases of sideroblasticanaemia have failed to show a genetic back-ground, in the rare hereditary form a sex-linkedrecessive type of inheritance has been demon-strated. This small group may, in the futureconform to the definition of an inborn errorof metabolism, but more definitive enzymestudies are required.Marrow Dyscrasia Induced byDiseases or DrugsMany of the examples of sideroblastic

anaemia have been associated with primarydiseases, such as neoplastic or collagen diseases,or with drug ingestion particularly the anti-tuberculous drugs, especially INAH. Anexperimental sideroblastic anaemia has beendescribed in guinea-pigs, intoxicated withINAH and cycloserine (Harriss and others,1965). The mode of action of these drugs isuncertain, but it may be related to an inter-ference with pyridoxine metabolism. Carlson(1956) found an increased urinary excretion ofpyridoxine during INAH therapy and hesuggested that the drug complexed withpyridoxine which was then excreted in theurine. It is unlikely, however, that pyridoxinedeficiency alone causes sideroblastic anaemia,since Harriss and others (1965) failed toproduce a characteristic sideroblastic anaemiain mice either by a pyridoxine free-diet or bythe pyridoxine-inhibitor, deoxypyridoxine.

There is probably a more subtle association

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between the primary collagen and neoplasticdiseases and sideroblastic anaemia. Anaemiaitself is a usual complication of these diseases,and it is most unusual for this to take theform of a sideroblastic anaemia. Some patientsafflicted with these conditions may have alatent hereditary defect predisposing them todevelop sideroblastic anaemia. In others theineffectual hyperplastic marrow, associated withthe primary disease, may be profligate of itspyridoxine stores, causing a deficiency whichwould contribute to the development ofsideroblastic anaemia.

It would seem therefore that the sideroblasticanaemias are a group of diseases multifactorialin pathogenesis, but each with the final commonpathway of deranged haem synthesis in thebone marrow which results in the formation ofthe sideroblast. From this definition the sidero-blastic anaemias bear some resemblance to thehepatic porphyrias, which are a group ofdiseases also multifactorial in pathogenesis,each with a final pathway of deranged haemsynthesis in the liver. Thus in both the sidero-blastic anaemias and in the hepatic porphyriasa disease exists which is caused by an inbornerror of metabolism-hereditary sideroblasticanaemia and acute intermittent porphyriarespectively; in both there is also a type causedby neoplasm-Di Guglielmo's disease and theporphyrin-producing hepatic adenoma (Tio,Leijnse, Jarrett and Rimington, 1957) res-pectively; in both there is a type caused bydrugs: isoniazid-induced sidero!blastic anaemiaand hexachlorobenzene - induced cutaneoushepatic porphyria (Cetingil and Ozen, 1960).

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MED. THE SIDEROBLASTIC ANAEMIAS · December, 1965 MORROWandGOLDBERG: TheSideroblastic Anaemias 741 Breton-Gorius (1959) demonstrated that the iron in the granules of normalnormoblasts