1137

THE LANCET

ErythropoietinTHERE is overwhelming evidence that the glyco-

protein erythropoietin is essential to the main-tenance of the body’s red-cell mass at an optimalphysiological level,’2but how hypoxia, of whatevertype, is translated by the body into augmentederythropoietin production is still far from clear.The kidney is intimately involved in the erythro-poietic response of normal adult man-but a pa-tient without kidneys is still capable of mounting areticulocytosis in the face of blood-loss or anoxia.’ 4Moreover, there is now evidence that, in the fetalrat, and probably in the human fetus, the liver isan important source of erythropoietin.s,6 Attemptsto extract an active erythropoietic substance fromnormal human kidney have often been disappoint-ing (though it has occasionally been demonstratedin the fluid of kidney cysts in patients believed tohave renal polycythoemia 7); one possibility is that thekidney secretes, not erythropoietin itself, but anenzyme ("renal erythropoietic factor") which actson a plasma substrate ("erythropoietinogen") toproduce the hormone.8 Another theory is that thekidney does produce erythropoietin, but that thehormone is then inhibited by a lipid present in kid-ney tissue until activated by a factor in normal ser-um : there is some evidence that serum from

hypoxic animals is more potent in this respect thannormal serum.9 To complicate matters further,

1 Erslev, A. J. in Hematology (edited by W. J. Williams, E. Beutler, A. J. Ers-lev, and R. W. Rundles). New York, 1972.

2. Krantz, S. B. J. Lab. clin. Med. 1973, 82, 847.3. Nathan, D. G., Schupack, E., Stohlman, F., Merrill, J. P. J. clin. Invest.

1964, 43, 2158.4. Erslev, A. J., McKenna, P. J., Capelli, J. P., Hamburger, R. J., Cohen,

H. E., Clark, J. E. Archs. intern. Med. 1968, 122, 230.5 Schooley, J. C., Mahlmann, L. J. Proc. Soc. exp. Biol. Med. 1974, 145,

1081.6. Finne, P. H., Halvorsen, S. Archs. Dis. Child. 1972, 47, 683.7. Rosse, W. F., Waldmann, T. A. Blood, 1964, 24, 739.8. Gordon, A. S., Cooper, G. W., Zanjami, E. D. Semin. Hœmat. 1967, 4, 337.9 Erslev, A. J., Kazal, L. A., Miller, O. P. Proc. Soc. exp. Biol. Med. 1971,

138, 1025.

erythropoietic activity has been ascribed to sub-stances such as red-cell haemolysates, bilirubin, andcyclic A.M.P., although conceivably their action ismediated through erythropoietin itself. Neverthe-

less, it may be better to refer to the "humoral

erythropoietic regulating activity" rather than tosingle factors such as erythropoietin. The bulk ofclinical and experimental evidence suggests that, inthe adult, the kidney is the organ which "senses"anoxia, although it may not play a solo role; more-over, we do not know the precise identity of thekidney cells which trigger erythropoietin produc-tion.

There have been many attempts to correlate

erythropoietin levels, in blood or urine, with thehsematocrit. ADAMSON et al.10 showed such a corre-lation in volunteers who were venesected, and pa-tients with aplastic anaemia usually have high levelsof erythropoietin. In many chronic ansemias, how-ever, the correlation is less good. This maymean-as in renal disease, in certain chronic sys-temic disorders, and in starvation-that there is a ‘

defect in the erythropoietin system, but it mightsimply reflect difficulties in the assay, or in equat-ing an assay result with daily hormone production:thus, there is evidence that erythropoietin is meta-bolised in the body and perhaps utilised in the mar-row itself.11,12 In this event, even a 24-hour urinecollection may not accurately measure total hor-mone production.

Another difficulty is that, although tissue anoxiais the ultimate stimulus to erythropoietin produc-tion, hæmatocrit and oxygen tension do not alwaysreflect the oxygen-delivering capacity of theblood." The position of the oxygen-haemoglobindissociation curve also plays a part in regulatingthe red-cell mass.14 Individuals with haemoglobinmutants that possess an increased affinity foroxygen and a relatively low P50 have erythrocy-tosis, whereas those who have abnormal hoemoglo-bins with a reduced affinity for oxygen, and a highP 50’ seem to tolerate a surprisingly low hsematocritwithout increasing erythropoietin production or

marrow erythropoiesis. A similar mechanism mayhelp to explain why some patients with cor pul-monale are less polycythaemic than might be expec-ted : respiratory acidosis decreases oxygen affinityand therefore tends to improve oxygen deliveringcapacity.The regulation of erythropoiesis in the newborn

is especially complex. After birth erythropoiesis vir-tually ceases:’s the haemoglobin falls and plasma-

10. Adamson, J. W., Alexanian, R., Martinez, C., Finch, C. A. Blood, 1966, 28,354.

11. Alexanian, R. J. Lab. clin. Med. 1969, 74, 614.12. Stohlman, F., Brecker, G. Proc. Soc. exp. Biol. Med. 1959, 100, 40.13. Rørth, M. Clin. Hœmat. 1974, 3, 595.14. Bellingham, A. J., Huehns, E. R. Nature, 1968, 218, 924.15. Gairdner, D., Marks, J., Roscoe, J. D. Archs. Dis. Childh. 1952, 27, 128.

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erythropoietin is often not detectable until about 3months of age; but the anaemia of erythroblastosisfetalis and the hypoxia of cyanotic heart-disease areassociated with persistently high plasma-erythro-poietin levels, suggesting a normal regulatory mech-anism for erythropoiesis. 16 STOCKMAN and hiscolleagues17 have investigated the more profound"physiological" ansemia seen in premature infantsand variously ascribed to an increased plasmavolume, haemolysis, bone-marrow depression, andfailure to elaborate erythropoietin. They foundthat, in 45 premature infants, there was a signifi-cant, though not very close, inverse correlationbetween haemoglobin and plasma-erythropoietinlevels: there was a better inverse correlation between

plasma-erythropoietin levels and the "oxygen-unloading" capacity of the infant’s blood. One in-teresting feature was that in those babies with lessthan 30% fetal haemoglobin, and whose oxygen-dis-sociation curves were shifted to the right, the

haemoglobin levels fell much lower than those withmore than 60% fetal haemoglobin before a compar-able erythropoietin response occurred. The impli-cation is that premature infants do respond appro-priately to alterations in the oxygen-unloadingcapacity of the blood, and that the position of thedissociation curve, not the haemoglobin concentra-tion alone, is critical in determining the rate oferythropoiesis. As is true in patients with heemoglo-bin variants, the definition of anaemia in the new-born is imprecise, and must take account of factorsregulating the affinity of haemoglobin for oxygenand tissue requirements for oxygen as reflected inthe metabolic rate and body’s oxygen consumption,which may be much reduced in the premature in-fant. Such considerations must influence decisionsabout the need for transfusions in these babies. AsNATHAN points out,18 throughout the animal king-dom oxygen requirement by the tissues is the fun-damental stimulus of erythropoiesis. We still havemuch to learn about the way in which this stimulus

leads, eventually, to the appearance of erythro-blasts in the marrow.

Briquet’s Syndrome or Hysteria?HYSTERIA continues to be recognised as a formal

psychiatric diagnosis and is accorded a category informal psychiatric classification systems. 1,2Nevertheless there are many who believe that hys-teria no longer merits a diagnostic label. Twenty-

16. Halvorsen, S. Acta pœdiat. scand. 1963, 52, 425.17. Stockman, J. A., Garcia, J. F., Oki, F. A. New Engl. J. Med. 1977, 296, 647.18. Nathan, D. G. ibid. 1977, 296, 685.1. General Register Office. A Glossary of Mental Disorders. London, 1968.2. American Psychiatric Association: Diagnostic and Statistical Manual of

Mental Disorders. Washington, 1968.

six years ago ELIOT SLATER could find no reasonfor the continued use of hysteria as a diagnosis,since he claimed that assessment was unreliable,that the condition showed no evidence of constitu-tional or genetic factors, and that hysterical symp-toms could be found in epilepsy and a large numberof psychiatric conditions including schizophrenia,depression, and personality disorders. He con-

cluded that hysteria merely described a symptommechanism and that, if a patient showed "signs ofhysteria and no more, then these are signs that wehave not looked deeply enough". He gave furthersubstance to this argument in a later paper whichdescribed the follow-up of patients diagnosed ashysterical several years earlier. Very few of thesepatients had retained their original diagnosis andabout a third of them had been found to have anew organic diagnosis which was presumed to havebeen present but undetected at the time of the orig-inal diagnosis. Yet others had acquired psychoticillnesses.4 It could also be argued that, since a diag-nosis carries with it the status of a disease, hysteriacannot be regarded as a diagnosis: it does not

satisfy ScADDiNG’s criteria of an abnormal phe-nomenon which differs from the norm "in such away as to set the patient at a biological disadvan-tage".5 There is no evidence that the symptoms ofhysteria are biologically unhelpful, and indeed theopposite is frequently the case-hence the

emphasis on secondary gain as an important partof the condition. No-one could argue that the self-

preserving hysterical fugue of the front-line soldier,in taking him away from the battlefield, is detri-mental in any biological sense.

Despite these many criticisms hysteria continuesto be diagnosed, though perhaps with more cautionthan previously. Attempts have been made at

redefining the diagnosis. In the United Statesworkers at St. Louis have replaced the diagnosis ofhysteria with that of Briquet’s syndrome. BRIQUETwas -a French physician who in 1859 described thesyndrome of symptoms presumed to be hysterical innature sincethey were medically unexplained andtended to affect several organ systems at differenttimes.6 Further description and refinement’-" havedefined a syndrome which omits reference to moti-vation and dynamic mechanisms. The St. Louisgroup, going by their own diagnostic criteria, rec-kon that Briquet’s syndrome is common in women,occurring in 1-2%,12 but they seem to have a sur-

3. Slater, E. J. ment. Sci. 1961, 107, 359.4. Slater, E., Glithero, E. psychosom. Res. 1965, 9, 9.5. Scadding, J. G. Lancet, 1967, ii, 877.6. Briquet, P. Traité clinique et thérapeutique de l’hystérie. Paris, 1859.7. Perley, M. J., Guze, S. B. New Engl. J. Med. 1962, 266, 421.8. Guze, S. B. Am. J. Psychiat. 1967, 124, 491.9. Woodruff, R. A. Jr. Br. J. Psychiat. 1967, 114, 1115.

10. Guze, S. B. Sem. Psychiat. 1970, 2, 392.11. Guze, S. B., Woodruff, R. A., Jr., Clayton, P. J. Am. J. Psychiat. 1971, 128,

643.12. Woodruff, R. A., Jr., Clayton, P. J., Guze, S. B. J. Am med. Ass. 1971, 215,

425.