640

increased E.S.R. suggested polymyalgia rheumatica. Wesuggest that these 9 cases demonstrate the transition of

polymyalgia rheumatica into temporal arteritis. Thereverse can also occur, and Ross Russell (1959) noted thatpolymyalgia rheumatica occurred in 3 of his cases of tem-poral arteritis when steroid therapy was discontinued.The exact relation between the two syndromes is

unknown. Since both are associated with the same histo-

logical changes in the arterial wall they presumably repre-sent different clinical manifestations of a single pathologicalentity-giant-cell arteritis. What determines the appear-ance of cranial symptoms, nodular inflammatory changein the temporal vessels and ocular complications in somecases, but not in others, remains a mystery. MacGregor(1961) suggested that involvement of the temporal arterieswould produce headache and visual failure, whilst involve-ment of occipital or other vessels would produce temporalarteritis without headache, free of ocular complications.This hypothesis is negated by the finding of arteritis inthe temporal arteries of cases without cranial symptoms(Alestig and Barr 1963).The pathogenesis of the muscular aches and pains has

been thought to be an arteritis of muscular arteries (RossRussell 1962), but abnormalities in the muscles are rarelydetected (Bruk 1967).

Because corticosteroids have been shown to prevent theloss of sight associated with temporal arteritis (Shick et al.1950, Whitfield et al. 1953, Ross Russell 1959) earlydiagnosis is essential. The existence of pre-headache stagein many cases of temporal arteritis is shown by this series.In half the group (26 out of 50) general symptoms pre-ceded headache-often by many months. The non-specificnature of these early manifestations of temporal arteritisappears to have been responsible for delays in diagnosisand treatment.That temporal arteritis may resemble polymyalgia

rheumatica for 12 to 18 months and then headache andeven ocular involvement develop (cases 4 and 8) is of greatpractical importance. There is still no way of detectingwhich patients with polymyalgia rheumatica will developarteritis (Bruk 1967). It is therefore important to regardsuch patients as being in the pre-headache stage of tem-poral arteritis and to keep them under surveillance. Thereis an argument for treating all such cases with cortico-steroids.

We are grateful to the physicians of the United Oxford Hospitalsfor permission to study the records of patients admitted under theircare.

REFERENCES

Alestig, K., Barr, J. (1963) Lancet, i, 1228.Bagratuni, L. (1956) ibid. ii, 694.Barber, H. S. (1957) Ann. rheum. Dis. 16, 230.Bevan, A. T., Dunnill, M. S., Harrison, M. J. G. (1967) Unpublished.Bruk, M. I. (1967) Ann. Rheum. Dis. 26, 103.Cooke, W. T., Cloake, P. C. P., Govan, A. D. T., Colbeck, J. C. (1946)

Q. Jl Med. 15, 47.Dixon, A. St. J., Beardwell, C., Kay, A., Wanka, J., Wong, Y. T. (1966)

Ann. rheum. Dis. 25, 203.Gordon, I. (1960) Q. Jl Med. 29, 473.Hamrin, B., Jonsson, N., Landberg, T. (1964) Lancet, i, 397.Harrison, C. V. (1948) J. clin. Path. 1, 197.Horton, B. T., Magath, T. B., Brown, G. E. (1932) Proc. Staff Meet. Mayo

Clin. 7, 700.Jennings, G. H. (1938) Lancet, i, 424.Kersley, G. D. (1951) Proceedings of the Second European Congress of

Rheumatology, Barcelona; p. 388.MacGregor, G. A. (1961) Lancet, ii, 1160.Paulley, J. W. (1956) ibid. ii, 946.Ross Russell, R. W. (1959) Q. Jl Med. 28, 471.

— (1962) Ann. rheum. Dis. 21, 171.Shick, R. M., Baggenstoss, A. H., Polley, H. F. (1950) Proc. Staff Meet.

Mayo Clin. 25, 135.Whitfield, A. G. W., Cooke, W. T., Jameson-Evans, P., Rudd, C. (1953)

Lancet, i, 408.

HYPOLIPIDÆMIA IN ANÆMIA

Implications for the Epidemiology of IschaemicHeart-disease

B. M. RIFKINDM.B. Glasg., M.R.C.P.G., M.R.C.P.E.

MORNA GALEB.Sc. Glasg.

From a medical unit and the Department of Medicine,Royal Infirmary, Glasgow

Summary Hypocholesterolæmia and hypophospho-lipidæmia are present in most subjects with

chronic anaemia due to a variety of causes. Ultra-

centrifugal analysis showed a proportionate decrease ofcholesterol and phospholipid in all three main plasma-lipoprotein fractions. 2 siblings with congenital micro-spherocytosis, in whom hæmolysis was compensated, werealso hypocholesterolæmic and hypophospholipidæmic.7 patients with congenital microspherocytosis treated10 months to 32 years ago by splenectomy tended to havelow cholesterol and phospholipid levels, but not to thesame extent as the anæmic subjects. In a patient withcongenital microspherocytosis, splenectomy was associatedwith doubling of the cholesterol value. Vitamin-B12therapy produced a rise in the serum-cholesterol level ofa patient with pernicious anæmia. Serum-triglyceridelevels were not reduced either in 6 anæmic patientsstudied or in patients with congenital microspherocytosis.The hypolipidæmia of anæmia is probably due to more

than one factor. The findings may explain the differencesin the incidence of ischæmic heart-disease between the

sexes, between premenopausal and postmenopausalwomen, and between developed and underdevelopedcountries.

Introduction

SIXTY-FIVE years ago Erben (1902) reported lowcholesterol levels in chlorosis. Hypocholesterolasmia andhypophospholipidsemia were, thereafter, described bymany workers as a feature of a variety ofansemias. In 1931Peters and Van Slyke were able to say that a generalreaction to anaemia was an excess in the plasma of fat(neutral fat) and fatty acids, and a deficiency of phospho-lipids and cholesterol. These observations seem to haveexcited little attention. Yet the association of hypo-lipidasmia with such a common state as anxmia mighthave an important bearing on the epidemiology of athero-sclerosis and ischaemic heart-disease., as well as beingimportant in its own right. We report here a confirmatorystudy of this association.

Subjects and MethodsThe patients studied were: (1) 26 with chronic anamlia due

to a variety of causes (table I); (2) 2 siblings with congenitalmicrospherocytosis without anaemia, (3) 7 patients with con-genital microspherocytosis treated by splenectomy 10 monthsto 32 years previously; (4) 1 with congenital microspherocytosisstudied before and shortly after splenectomy; (5) 1 with

pernicious anaemia studied before and shortly after treatmentwith vitamin Bu.

Serum-lipid levels were estimated by the following methods:cholesterol, Henly’s (1957) modification of the method ofZlatkis et al. (1953); triglyceride, Van Handel and Zilversmit(1957); phospholipid, Bartlett (1959). Ultracentrifugal analysisof the plasma-lipoproteins of an anaemic subject was performedby the method of Havel et al. (1955).

Results

The serum-cholesterol level was low in almost all the

641

TABLE I-SERUM CHOLESTEROL AND PHOSPHOLIPID LEVELS (mg. per100 ml.) IN ANEMIC PATIENTS

* Where more than one estimation was made, the number is given inparentheses; and the mean result is shown.

26 anaemic patients (table i); in 2 it was less than 100 mg.per 100 ml., in 11 it lay between 100 and 150 mg. per100 ml., and in only 1 was it above 250 mg. per 100 ml.Such levels are well below those encountered in thegeneral population (for example, Adlersberg et al. 1956).The results in some of the patients we studied may also becompared with those obtained by us in a group of healthymales (table 11). Of the 9 male anxmic subjects, whoseages allowed comparison, 5 (nos. 2-4, 7, 9) had a

cholesterol level which fell on or beyond the lower 95% or99% confidence limits of the corresponding subjects.

Serum-phospholipid levels were measured in 10 of theanxmic patients (table i). When compared with the

generally accepted levels for phospholipids (for example,Adlersberg et al. 1956) almost every patient showed a

TABLE II-LOWER CONFIDENCE LIMITS OF SERUM-CHOLESTEROL LEVELS

(mg. per 100 ml.) OF HEALTHY MEN

considerable reduction. Half the patients had levels below200 mg. per 100 ml., and the highest value was 233 mg.per 100 ml.The triglyceride levels of 6 fasting ansemic patients are

shown in table ill. The results are within normal limits

(for example, see Fredrickson et al. 1967).The lipid composition of the three major plasma-

lipoprotein fractions of an anaemic patient (no. 2), as

obtained by ultracentrifugal analysis, is shown in table iv,together with the results for the cholesterol and phospho-lipid composition of these fractions found by Havel et al.(1955) in males of corresponding age. Each of thefractions of the anxmic patient showed a proportionatereduction in its cholesterol and phospholipid content.The 2 siblings with congenital microspherocytosis with-

out anaemia had much-reduced cholesterol and moderatelyTABLE IV-LIPID COMPOSITION (mg. per 100 ml.) OF LIPOPROTEIN

FRACTIONS IN A FASTING ANEMIC PATIENT (no. 2)

* Figures in parentheses refer to results of Havel et al. (1955) for 10 malesubjects, mean age 26 years.

TABLE V-SERUM-LIPID LEVELS (mg. per 100 ml.) (MEAN OF TWOOBSERVATIONS) IN FASTING SIBLINGS WITH CONGENITAL MICRO-

SPHEROCYTOSIS WITHOUT ANEMIA

* From "Cr studies.

TABLE VI-SERUM-LIPID LEVELS (mg. per 100 ml.) IN FASTING PATIENTSWITH CONGENITAL MICROSPHEROCYTOSIS TREATED BY SPLENECTOMY

reduced phospholipid levels, but unremarkable tri-

glyceride levels (table v).The 7 patients with congenital microspherocytosis,

treated at a variable time previously by splenectomy, hadcholesterol and phospholipid levels which were lower thannormal but not to the same extent as in the anaemic

patients (table vi). 3 of them had a cholesterol level above200 mg. per 100 ml. and in only 1 was it below 150 mg.per 100 ml.; this woman (patient c), although clinicallywell and non-anxmic, had a slight reticulocytosis anda raised indirect bilirubin level, suggesting the possibilityof some persistent hxmolysis. These 7 patients hadnormal triglyceride levels. Patient f is a sibling of the2 non-anaemic siblings with congenital microspherocytosisdescribed above. Her lipid levels were well above those ofher siblinss.

642

TABLE VII-EFFECT OF RECENT SPLENECTOMY ON SERUM-LIPID LEVELS

(mg. per 100 mi.) IN FASTING PATIENT WITH CONGENITAL MICRO-SPHEROCYTOSIS

* Splenectomy.

TABLE VIII-EFFECT OF VITAMIN-B12 ADMINISTRATION ON SERUM-

CHOLESTEROL LEVELS (mg. per 100 ml.) IN PATIENT (no. 6) WITHPERNICIOUS ANlEMIA

* 1000 tLg. vitamin Eu administered.

The rise in serum-cholesterol levels following splenec-tomy in a patient with congenital microspherocytosis isshown in table vn, no consistent changes were observedin the triglyceride and phospholipid levels. Similarlyserum-cholesterol levels rose progressively after the initialdose of vitamin B12 in a patient (no. 6) with perniciousanaemia (table vm).

Discussion

The occurrence of hypolipidxmia in chronic anaemiamay be insufficiently appreciated. If the present figuresare representative, then it may be by far the commonesttype of hypolipidxmia. The present study shows that thelarge majority of anaemic patients have reduced-and oftenmuch-reduced-lipid levels, and ultracentrifugal analysisshows that the fall in cholesterol and phospholipid levelsis shared proportionately by the three major lipoproteinfractions.

Nevertheless the association is not straightforward. Forexample, the 2 siblings with congenital microspherocytosisand evidence of haemolysis but without clinical anxmiahad low cholesterol and phospholipid levels; their siblingwho had been treated previously by splenectomy hadconsiderably higher cholesterol and phospholipid levels.The possibilities are that: (1) these patients had a co-incidental hypolipidaemia, which seems most unlikely; or(2) they had been intermittently anaemic in the past andwere, fortuitously, in a non-anaemic phase at the time ofsampling; or (3) haemolysis itself, insufficient to produceclinical anaemia, may lead to hypolipidxmia. The thirdpossibility is supported by the findings in patient c withcongenital microspherocytosis treated by splenectomy(table vi), who was no longer anxmic but in whom theevidence suggested mild haemolysis. She had the lowestcholesterol and phospholipid levels of her group.The findings in the splenectomised subjects also suggest

that the relation between anaemic disorders and hypo-lipidaemia is not simple. Several reports show that

splenectomy, when performed to correct a haemolyticanaemia, results in a rise in the plasma cholesterol andphospholipid levels (King 1914, Bloor and MacPherson1917, MacAdam and Shiskin 1922-23). The presentfindings agree with these observations; the patient studiedbefore and after splenectomy showed a steep rise in hercholesterol level; and the group of subjects in whom

splenectomy had been performed some time previouslyhad cholesterol and phospholipid levels which were higherthan in the anaemic subjects. Nevertheless, their levelstended to be lower than in normal subjects. Williams et al.(1937) suggested that, although plasma-lipid levels roseafter the treatment of pernicious anxmia, they were stilllower than in normal plasma. Longstanding anaemia mayprevent restoration of plasma-lipid levels to normal evenwhen the anxmia is corrected. The rapid rise incholesterol levels following treatment of the patient withpernicious anxmia with vitamin B12, before there wasa noteworthy change in the hxmoglobin level (table vm),is further evidence against the hypolipidxmia being dueto the anaemia itself.The frequent occurrence of hypolipidaemia in chronic

anaemia has important implications for the aetiology ofischaemic heart-disease. Anxmia is common in Westernwomen; for example, it was found in nearly 50% ofwomen aged 18-55 years from the poorer areas ofAberdeen (Davidson and Fullerton 1938), in 25-30% ofwomen aged 15-34 years over a 5-year period in a generalpractice (Fry 1961), and in 15% of a combined sample ofmen and women in an agricultural community (Kilpatrick1961). Over the long period during which atherosclerosisdevelops many women, perhaps a majority, will be overtlyanxmic. The present findings suggest that in the ansemicphase they will have reduced lipid levels. Correction ofthe anxmia may not completely restore the lipid levels.Since serum-cholesterol levels in women under the age of50 are directly related to the risk of ischaemic heart-disease(Kannel et al. 1966), anaemia may account for the relativefreedom from ischaemic heart-disease of premenopausalwomen compared with men of corresponding age, ratherthan hormonal differences (Lancet 1961, British MedicalJournal1963). The cessation of iron loss due to menstrualbleeding and childbearing with the consequent fall in theincidence of anxmia following the menopause (Fry 1961)might account for the higher lipid levels of post-meno-pausal women (Oliver and Boyd 1959) and their higherincidence of ischaemic heart-disease (Oliver and Boyd1959). Similarly, in underdeveloped countries a highincidence of anaemia may also be related to a low incidenceof ischxmic heart-disease.We thank Prof. E. M. McGirr for laboratory facilities and the

various physicians of Glasgow Western and Royal Infirmaries whopermitted us to study their patients. We acknowledge the financialassistance of Imperial Chemical Industries.

Requests for reprints should be addressed to B. M. R., Laboratoryof Molecular Diseases, National Heart Institute, National Institutesof Health, Bethesda, Maryland 20014, U.S.A.

REFERENCES

Adlersberg, D., Schaefer, L. E., Steinberg, A. G., Wang, C-I. (1956)J. Am. med. Ass. 162, 619.

Bartlett, G. R. (1959) J. biol. Chem. 234, 466.Bloor, W. R., MacPherson, D. J. (1917) J. biol. Chem. 16, 193.British Medical Journal (1963) ii, 1487.Davidson, L. S. P., Fullerton, H. W. (1938) Edinb. med. J. 45, 1.Erben, F. (1902) Z. klin. Med. 47, 302.Fredrickson, D. S., Levy, R. I., Lees, R. S. (1967) New Engl. J. Med. 276, 148.Fry, J. (1961) Br. med. J. ii, 1732.Havel, R. J., Eder, H. A., Bragdon, J. H. (1955) J. clin. Invest. 34, 1345.Henly, A. A. (1957) Analyst, Lond. 82, 286.Kannel, W. B., Dawber, T. R., McNamara, P. (1966) J. Iowa med. Soe.

56, 26.Kilpatrick, G. S. (1961) Br. med. J. ii, 1736.King (1914) Archs intern. Med. 14, 145.Lancet (1961) i, 269.MacAdam, W., Shiskin, C. (1922-23) Q. Jl Med. 16, 193.Oliver, M., Boyd, G. S. (1959) Lancet, ii, 690.Peters, J. P., Van Slyke, D. D. (1931) Quantitative Clinical Chemistry;

vol. I. London.Van Handel, E., Zilversmit, D. B. (1957) J. Lab. clin. med. 50, 152.Williams, H. H., Erickson, B. N., Bernstein, S. S., Macy, I. G. (1937)

Proc. Soc. exp. Biol. Med. 45, 151.Zlatkis, A., Zak, B., Boyle, A. J. (1953) J. Lab. clin. Med. 41, 486.