FAMILIAL PSEUDOHYPERKALÆMIA A New Syndrome

175 What is the functional

significance

of

FAMILIAL PSEUDOHYPERKALÆMIA

low-affinity

A New

The likelihood that they include most of the K ref. :;:; 4 and unpublished) suggests that cell-mediated

mechanisms contribute to &bgr;-cell destruction. abnormal effectiveness of lymphoid cells from pawith autoimmune thyroid disease in tests of K-cell is circumstantial evidence supporting the in. cement of cell-mediated cytotoxicity in organ-specific

:atoimmune endocrinopathy. There is increasing evidence that the clinical onset of bears little, if any, relationship to when damage :: the? cells-mediated, perhaps, by pancreatropic vir—first begins. If immune mechanisms contribute to

he continuation of 3-cell destruction, there is likely

to

x evidence of it before diagnosis. ICA exist several months before the onset of clinical disease in genetically ceptible subjects (unpublished) and it is therefore of trzat interest that 5 out of 10 ICA-positive siblings with evidence of hypergiycxmia, but only 1 ICA-negative bling, had raised low-affinity E-RFC levels. This findag, and the association between raised low-affinity E-RFC levels and the occurrence of autoantibodies, suggests that humoral antibody production and cellmzdiated activity might co-exist in autoimmune disease. However, it remains to be shown whether the cytotoxic effect is antibody-dependent or whether the appearance of ICA is simply a marker of &bgr;-cell damage that has already occurred. The in-vitro cytotoxicity for cultured h,uman ?-cells of lymphocytes from newly diagnosed diabetics may help to clarify this issue. The reduction in total T-cell levels with increasing juration of overt diabetes is of interest and perhaps can be explained by alteration in metabolic control, which iepresses lymphocyte function.18 Thus, the apparently normal T-cell percentage at diagnosis is due to the real increase in the proportion of low-affinity E-RFC. This proportion diminishes as the duration of diabetes increases, with a concomitant reduction in the percentage of totalT cells. In conclusion, the measurement of low affinity E-RFC m addition to ICA may be a useful marker of active -cell destruction, particularly in subjects genetically at high risk of diabetes. no

ibis work was supported by grants from the Wellcome Foundation, Mica) Research Council, and the Joint Research Board, St. rtholomew’s Hospital, London, and the C.N.R. (Italy).

Requests for repnnts should be addressed to A. G. C., Department Diabetes, St, Bartholomew’s Hospital Medical College, West SmithLondon EC 17BE. REFERENCES

1. Perlmann P, Perlmann H, Wigzell H. Lymphocyte-mediated cytotoxicity in vitro. Induction and inhibition by humoral antibody and nature of effector

cells, Transplant Rev 1972; 13: 91-114. 2. Nelson DL, Bundy BM, Pitchon NE, Blaese RM, Strober W. The effector cells in human peripheral blood mediating mitogen-induced cellular cytotoxity and antibody-dependent cellular cytotoxicity. J Immunol 1976;

117:1472-81.

3. West WH, Payne SM, Weese JL, Herberman RB. Human lymphocyte subpopulations: correlation between E-rosette-forming affinity and expression

of the receptor. J Immunol 1977; 119: 548-54. WH, Boozer RB, Herberman RB. Low affinity

4. West

E-rosette formation

by

the human K cell. J Immunol 1978; 120: 90-95. JC, Brunner KT. Cell-mediated cytotoxicity, allograft rejection and tumorimmunity. Adv Immunol 1974; 18: 67-132. 6. Calder EA, Irvine WJ, Davidson NMcD, Wu F. T, B and K cells in autoimmune thyroid disease. Clin Exp Immunol 1976; 25:17-22. 7. Feldman JL, Becker MJ, Moutsopoulos H, Fye K, Blackman M, Epstein WV, Talal N. Antibody-dependent cell-mediated cytotoxicity in selected autoimmune diseases. J Clin Invest 1976; 58: 173-79. 8. Cudworth AG Type I diabetes mellitus. Diabetologia 1978: 14: 281-91. 5. Cerottini

G. W. STEWART* J. A. FYFFE†

J. Metabolic Unit,

Syndrome J. M. CORRALL G. STOCKDILL

R. A. STRONG

University Department of Medicine,

Departments of Clinical Chemistry and Clinical and Laboratory Hœmatology, Western General Hospital, Edinburgh EH4 2XU Inherited pseudohyperkalæmia due to an abnormal red-blood-cell potassium leak was discovered in 16 of 28 relatives of a woman with pseudohyperkalæmia. Autosomal dominance seemed to account for inheritance of this abnormality. Affected subjects were not anæmic and had normal in-vivo plasma-potassium concentrations.

Summary

Introduction IN

pseudohyperkalxmia, misleadingly high plasmapotassium concentrations are measured in normokalaemic subjects because of in-vitro potassium loss from blood cells. The phenomenon is recognised in leukaemia and thrombocythxmia.1-1 We describe a family in which some members had pseudohyperkalaemia due to an abnormal leak of potassium from erythrocytes. First Case The proband, a 34-year-old white woman with variable hyperkalaemia was referred by her family doctor. She had been prescribed diuretics for chronic ankle swelling. She had a history of Bell’s palsy and probable benign positional vertigo. The only abnormal physical signs were moderate obesity, perforation of the right tympanic membrane, and left-facial-nerve palsy, all of long standing. Repeated assays of urea and electrolytes (on no medication) on blood-samples centrifuged and separated immediately were normal. Routine urinalysis, fasting serum lipids, plasma haptoglobin, urinary electrolytes, and assessment of hepatic, renal, and adrenal function were normal. Electrocardiogram, chest X-ray, electroencephalogram, and other relevant neurological investigations were normal. *Present address: Physiological Laboratory, Cambridge CB2 3EG. address: University Department of Medicine, Castle Street, G4 0SF.

†Present

Glasgow

9. Cudworth AG, Bottazzo GF, Doniach D. Genetic and immunological factors in Type I diabetes. In: Immunology of diabetes. W. J. Irvine ed. Edinburgh: Teviot Publications, 1979. 10. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965; 14: 613-39. 11. Junker K, Egeberg J, Kromann H. An autopsy study of the islets of Langerhans in acute-onset juvenile diabetes mellitus. Acta Path Microbiol Scand 1977; 85(A): 699-706. 12. Huang SW, Maclaren NK. Insulin-dependent diabetes: a disease of autoaggression. Science 1976; 192: 64-96. 13. Buschard K, Madsbad S, Rygaard J. Passive transfer of diabetes mellitus from man to mouse. Lancet 1978; i: 908-10. 14. Lipsick J, Beattie G, Osler AG, Kaplan NO. Passive transfer of lymphocytes from diabetic man to athymic mouse. Lancet 1979; i: 1290-91. 15. Thurneyssen FK, Bialettes B, Vague PH, Selam JL, Mirouze J. Passive transfer of lymphocytes from diabetic man to mouse. Lancet 1979; i: 1291-92. 16. Bottazzo GF, Cudworth AG, Moul DJ, Doniach D, Festenstein H. Evidence for a primary autoimmune type of diabetes mellitus. Br Med J 1978; ii: 1253-55. 17. Joysey VC, Wolf E. HLA-A, -B and -C antigens, their serology and cross reaction Brit Med Bull 1978; 34:217-22. 18. MacCuish A, In: International symposium on immunological aspects of diabetes mellitus. Acta Endocrinol (Suppl) 1976; 205: 49-52.

176 Blood from the proband was added to 4 standard lithium tubes (Stayne LH10). These were allowed to stand at room temperature and were centrifuged and separated at 0, 2, 4 and 6 hours, respectively after venepuncture. The in-vitro change in plasma-potassium in the proband and mean values (±2 SEM) for sixteen affected family members, twelve nonaffected family members, and twenty-two controls aged 21-37 years (eight men and fourteen women) are shown in fig. 1. Plasma-potassium increased with standing-time in the proband and affected family members but not in the controls. Lactatedehydrogenase activities in centrifuged plasma remained constant and within the normal range in all samples. In the -proband, there was no significant rise in plasma potassium concentrations in blood maintained at 37°C in vitro. Standard techniques were used for hamiatological measurements.4 Haemoglobin (Hb) was 15.3 g/dl, white-blood-cell count 7 - 2 x 109/1, mean cell volume 89 fl, mean cell Hb concentration 38-3 g/dl, mean cell Hb 33-9 pg, haematocrit 0.402, platelets 178x109/1, and reticulocytes 1-0-3.5%. The blood film was slightly abnormal, with anisopoikilocytosis, slight polychromasia, a few target cells and stomatocytes, occasional ovalocytes with double central pallor (similar to those seen in much greater proportion in Malayan ovalocytosis5), and occa-

heparin

sional macroplatelets. The following investigations were normal: serum vitamin B12 and folate; plasma iron and iron binding capacity; direct Coombs’ tests; Ham’s test for acid hsemolysis; Hb electrophoresis ; heat stability test; hypotonic blood film for stomatocytes ;6 red-blood-cell pyruvate kinase, hexokinase, and glucose-6-phosphatase; Jacob and Jandl ascorbate-cyanide screen; osmotic fragility test on fresh blood and on blood incubated for 24 h at 37°C, and red-cell glutathione concentration. Red-cell adenosine triphosphate (ATP)7 was 712 µmol/l cells

(normal 700-900). Autohaemolysis showed a mild type-II abnormality -without glucose, 3-9% (normal 0.2-2.0), with glucose, 3-7% (normal 0.0-0-9). Red-blood-cell survival (51Cr) was 16.5 days (normal 22-27 days). The blood-group was A, rhesus-positive.- Red-blood-cell potassium6 was 80 mmol/l cells (normal 88-6-109-4) and sodium was normal at 8-0 mmol/l cells (reference range 4.9-10.9). Red-blood-cell ATPase

activity8 was normal.

Family Studies The family was screened for pseudohyperkalæmia and routine hæmatology was performed on all living members (fig. 2). 3 dead members had died of unrelated causes; the

cause of death was not known in the other 2. 16 of the 28 members studied had pseudohyperkalae- t mia. Mean plasma-potassium concentrations (±2 SEM) are plotted in fig. 1. One affected member had been admitted to hospital ten years before with suspected psit-

Fig. 1-Plasma-potassium of proband and mean values (t2 SEM) of affected family members, non-affected family members, and controls in relation to standing-time at room temperature before centrifugation.

Hyperkalaemia was detected and the test was repeated. The repeat result was normal and the problem tacosis.

dismissed. All family members had normal Hb and haptoglobin levels. 14 out of 16 blood-films of affected family members showed the mild morphological changes (barely distinguishable from normal) as described in the proband. The mean reticulocyte-count was 2.63±0.28% (±2 SEM) in affected subjects 1.0±0.15% in nonaffected members.

was

Discussion

Pseudohyperkalxmia due to an in vitro red-blood-cell leak was found in many members of a family. The distribution of affected members is consistent with an autosomal dominant mode of inheritance. The proband showed a mild compensated hsemolytic state with a slight reticulocytosis and a reduced red-blood-cell survival. The blood film showed minor morphological changes, presumably related to in-vivo erythrocyte potassium deficiency. We did not find any other published reports of familial pseudohyperkalaemia or of this phenomenon unrelated to white-blood-cell or platelet lysis. Abnormal redblood-cell cation transport has been reported in various

conditions,9.1O

including hereditary stomatocytosis,

and sickle-cell disease. However, all of these conditions have been excluded by appropriate test5 and in none has pseudohyperkalaemia been observed. Measurement of cation fluxes are proposed to determine whether the leak, which is exacerbated by maintaining the cells at a subphysiological temperature, is primarily due to altered membrane permeability or to a cation

spherocytosis,

Fig. 2-Family tree. Arrow indicates proband.

pumping defect. Affected subjects

are not

expectancy. The in vivo

anaemic and have normal life

plasma-potassium

is normal

177

i,,4, from affected subjects taken for plasma potassium 6LÌmation must be centrifuged and separated immedifor accurate determination of in vivo concentra-

:B’Q5.Digoxin, which inhibits the red-blood-cell sodiumpotassium pump, could exacerbate erythrocyte ’potassium depletion and frank haemolysis could be proJuKd. In the presence of impaired renal or adrenal function, dangerous hyperkalxmia could ensue. lIe thank the following for helpful advice and valuable assistance: 1rS.Allan, Dr D. B. Horn, Dr G. Blundell, and Mr R. Webber ,1[’rhe Bï’estem General Hospital, Dr V. L. Lew and Dr J. C. Ellory the Physiological Laboratory, Cambridge, Prof.D. L. Mollin of the - Matotogy department, St. Bartholomew’s Hospital, Prof. Sir John Daaz of the hsmatology department, Hammersmith Hospital, and Dr 0,Pretsell.

Requests for reprints should be addressed Laborators5 Cambridge CB2 3EG.

to

G.W.S., Physiological

Preliminary Communication CENTRAL-NERVOUS-SYSTEM DEFECTS IN CHILDREN BORN TO MOTHERS EXPOSED TO ORGANIC SOLVENTS DURING PREGNANCY PETER C. HOLMBERG Institute of Occupational Health, Haartmaninkatu 1, 00290 Helsinki 29, Finland

REFERENCES 1. Bronson WR, DeVita VT, Carbone PP, Cotlove E. Pseudohyperkalæmia due to release of potassium from white blood cells during clotting. N Eng J

Med 1966; 274: 369-75.

Chumbley LC. Pseudohyperkalæmia in acute myelocytic leukæmia. JAMA 1970; 211: 1007-09. 3. Bellevue R, Dosik H, Spergel G, Gussoff BD. Pseudohyperkalæima in extreme leukocytosis. J Lab Clin Med 1975; 85: 660-64. 4. Dacie JV, Lewis SM. Practical hæmatology. 5th ed. Edinburgh: Churchill, 2.

1975.

5. Lie-Injo LE. Hereditary ovalocytosis and hæmoglobin-E ovalocytosis in Malayan aborigines. Nature 1965; 208: 1329. 6. Wiley JS, Ellory JC, Shuman MA, Shaller CC, Cooper RA. Characteristics of the membrane defect in hereditary stomatocytosis. Blood 1975; 46: 337-56. 7. Beutler E. Red cell metabolism: a manual of biochemical methods. 2nd ed. New York: Grune and Stratton, 1975. 8. Ellory JC, Maher P. A change in the internal affinity of LK goat red cell sodium pumps induced by high pH. Biochim Biophys Acta 1977; 471:

320-32. 9. Parker JC, Welt LG. Pathological alterations of cation movements in human red blood cells. Arch Intern Med 1972; 129: 111-117. 10. Wiley JS. Genetic abnormalities of cation transport in the human erythrocyte. In: Ellory JC, Lew VL, eds. Membrane transport in red cells. London: Academic Press, 1977: 337-61.

through the skin, lungs, and digestive tract and they can cross the placenta. Kucera’ has linked the syndrome of caudal regression in man with exposure to organic fat solvents during pregnancy. Volatile anaesthetics are also suspected of embryotoxicity in man.2,3 I present here a study of mothers of children with congenital central-nervous-system (CNS) defects and matched-pair controls in which exposure to organic solvents was defined as.far as possible. MATERIAL AND METHODS

two-year study of mothers of children with congenital central-nervous-system defects and their matched-pair controls, exposure to noxious influences during pregnancy was analysed. Information on exposure was gained by interviews with all the mothers, sometimes supplemented by visits to their places of work. Significantly more casemothers than control-mothers had been exposed to organic solvents during the first trimester of pregnancy

Summary

In

a

p<0&mid ot;01). INTRODUCTION

ORGANIC solvents have received much attention in the Dast decade as possible factors or cofactors in the causation of embryotoxic effects in man. They are absorbed TABLE

1-14CASES

The basic information about the mothers of children with congenital CNS defects and their matched-pair controls was attained from the Finnish Register of Congenital Malformations.’ This register was established in 1963 as a monitoring system and has been expanded by the addition of information on matched-pair controls. The matched control-mother is the mother whose delivery immediately preceded that of the casemother in the same maternity welfare district. In addition to the information obtained through the register-family history of the mother; her previous diseases; her previous pregnancies, abortions, and obstetric complications; results of physical and laboratory examinations and diagnostic procedures; and drugs prescribed during pregnancy-information on exposure was collected by a single interviewer who visited each case and control-mother. A specially designed

OF CNS DEFECTS IN WHICH THE MOTHER HAD BEEN EXPOSED TO ORGANIC SOLVENTS