replacement solutions used in plasma exchange we have not encountered further hypocalcasmic symptoms in paents with a wide variety of diagnoses during 30 sub,,quent plasma exchanges. Because of the low and varied calcium content of P.P.F. we would recommend calcium supplementation during plasma exchange when

:arge volumes of plasma are removed and replaced with

other fetal abnormalities this hypothesis modified, to include three additional mechanisms (see accompanying figure). They have in common the assumption that urination is the principal route by which A.F.P. passes into the amniotic fluid from the normal fetus,12 and that, in common with other amnioticfluid proteins, A.F.P. is mainly degraded by a process of fetal swallowing and digestion.13 According to this hypothesis amniotic-fluid A.F.P. is increased in open N.T.D. because of the partial breakdown of permeability barriers between the fetal c.s.F./serum and the amniotic fluid. Between 15 and 20 weeks’ gestation A.F.P. concentrations in fetal serum 11 and in fetal c.s.F. range from 1000 to 3000 µg/ml14 from 500 to 1000 µg/ml.11 In severe cases of anencephaly with rachischisis the communication between fetal blood and the fluid may be almost complete and fetal erythrocytes have been observed in the .amniotic fluid. 16 In most cases of N.T.D. the lesion is covered by a thin membrane which ensures a gradient between the fetal circulation and the amniotic fluid. I have observed a 16-week fetus with a membrane-covered lumbar spina bifida lesion in which the A.F.P. concentration was 1000 jjLg/ml in the fetal c.s.F. and 100 µg/ml in the surrounding amniotic fluid. Where the lesion is covered by a full thickness of skin, as in the so-called closed N.T.D., amniotic-fluid A.F.P. concentration is not raised. In severe cases of exomphalos (omphalocele) and gastroschisis a similar exposure of the blood-vessels of the extruding viscera will permit easy transudation of fetal serum components into the amniotic fluid.2 17 Where the exomphalos is little more than an umbilical hernia no increase in amniotic-fluid A.F.P. is expected. Both increased A.F.P.2 17 18 and normal A.F.P.19 amniotic-fluid concentrations have been found in exomphalos.

findings must




solutions of low calcium content. Requests for reprints should be addressed to N.A.B., Cancer Con’HUpncv of British Columbia, Vancouver, B.C., Canada V5Z 3J3. REFERENCES

1 Buskard, N. A., Kohner, E. M., Park, D. S., Galton, D. A. G. Proc. int. Soc. Hœmat 1975, 41, 20. 2 Thompson, G. R., Lowenthal, R., Myant, N. B. Lancet, 1975, i, 1208. 3. Lockwood, C. M., Rees, A. J., Pearson, T. A., Evans, D. J., Peters, D. K., Wilson, C. B. ibid. 1976, i, 711. 4. Powles, R., Smith, C., Kohn, J., Hamilton Fairley, G. Br. med. J. 1971, in, 664.

5. Varghese, Z. Ann. clin. Biochem. 1973, 10, 120. 6 Weichselbaum, T. E. Am. J. clin. Path. 1946, 16, 40.



Department of Human Genetics, Western General Hospital, Edinburgh EH4 2XV

Assuming that urination is the principal route by which alpha-fetoprotein (A.F.P.) passes into the amniotic fluid from the normal fetus, and that A.F.P. is mainly degraded by a process of fetal swallowing and digestion, 4 possible mechanisms by which amniotic-fluid A.F.P. is increased by fetal abnormalities are postulated.(1) Amniotic-fluid A.F.P. is increased in open neural-tube defects by leakage of A.F.P. from fetal serum and cerebrospinal fluid.(2) In exomphalos exposure of blood-vessels in the extruding viscera permits transudation of A.F.P. into the amniotic fluid.(3) In nephrosis, fetal proteinuria increases amniotic-fluid A.F.P.(4) Impaired fetal swallowing or digestion would account for increased amniotic-fluid A.F.P. in congenital malformations of the orogastrointestinal tract.


MEASUREMENT of amniotic-fluid alpha-fetoprotein

A.F.P.) is now widely used as a test for the early prenatal diagnosis of anencephaly and spina bifida.1 Greatly increased A.F.P, values have also been observed early in pregnancy in other fetal abnormalities-e.g., exomphalos,2 congenital nephrosis,3 sacrococcygeal tera:oma,4 duodenal atresia,5 and intrauterine death.6 The auses

of abnormal amniotic-fluid

mester are

less easy to

esophageal atresia,’


in the third tri-

determine, but have included


tetralogy,S hydrocephaly,9

and severe Rh isoimmunisation. 10 Originally it was suggested that the origin of the in:reased amniotic-fluid A.F.P. in fetal neural-tube defects .D.) lay in leakage of the protein from fetal serum :.^,;; cerebrospinal fluid (C.S.F.).11 In the light of new

Possible mechanisms


by which anmiotic-fluid A.F.P. is increased by fetal

346 Increased amniotic-fluid A.F.P. concentrations have been reported in congenital nephrosis of the Finnish It is claimed that the characteristic proteinuria of neonatal life manifests itself in the fetus before 20 weeks’ gestation. Because of the very high concentration of A.F.P. in fetal serum at this stage of gestation a fetal proteinuria would give a large relative increase in amniotic-fluid A.F.P. Other renal syndromes associated with a congenital proteinura-such as familial nephrosis with urinary-tract anomalies, finger defects, and split uvula or congenital nephrosis with pulmonary stenosis20—may also occur with raised amniotic-fluid A.F.P. Conversely in disorders associated with renal agenesis, such as Potter syndrome, the absence of a fetal urinary contribution to the amniotic-fluid should be marked by a very low A.F.P. concentration. The fourth mechanism for increasing A.F.P. in amniotic fluid is through disturbed or absent fetal swallowing or digestion. About two-thirds of anencephalics have impaired swallowing mechanisms2’and this is equivalent to the proportion in which amniotic-fluid A.F.P. remains very high throughout pregnancy, 22 rather than falling in parallel with fetal serum concentrations. In congenital malformations of the orogastrointestinal tract similar interference with the normal turnover of amniotic-fluid protein is to be expected. Raised amniotic-fluid A.F.P. was reported in two cases of cesophageal atresia 7 23 during the third trimester of pregnancy. A case of duodenal atresia, associated with Down syndrome, was diagnosed at 17 weeks’ gestation on the basis of very high amniotic-fluid A.F.P. Down syndrome per se does not lead to high amniotic-fluid A.F.P. concentration and it seems that in this case the duodenal atresia interfered with absorption of the proteins of the amniotic fluid. It thus seems probable that at least some though not necessarily all19 tracheal, gastric, and intestinal atresia should be diagnosable in this way. A possible additional mechanism for increasing A.F.P. has been proposed by Seller et al.24 They suggested that A.F.P. could leak from the fluid-filled pouches of skin in the cervical region of fetuses with Turner syndrome. The original observation was made in amniotic fluids aspirated from the sacs of spontaneous-abortion meterial, where A.F.P. is often increased even with a normal fetus. It now seems that some 25 but not all26 cases of Turner syndrome will have increased amniotic-fluid A.F.P. early in pregnancy, and that the distinction depends on the presence or absence of cystic hygroma or fluid pouches from which A.F.P. can leak.




Brock, D. J. H. Br. med. Bull. 1976, 32, 16. Nevin, N. C., Armstrong, M. J. Br. J. Obstet. Gynœc. 1975, 82, 826. Kjessler, B., Johansson, S. G. O., Sherman, M., Gustavson, K. H., Hultquist, G. Lancet, 1975, i, 423. 4. Schmid, W., Muhlethaler, J. P. Humangenetik, 1975, 26, 353. 5. Weinberg, A. G., Milunsky, A., Harrod, M. J. Lancet, 1975, ii, 496. 6. Wismewski, L., Skrzydlewski, Z., Orciuch, J. Br. med. J. 1974, iii, 742. 7. Seppala, M. Obstet. Gynec., N.Y. 1973, 42, 613. 8. Seppala, M. Ann. N.Y. Acad. Sci. 1975, 259, 59. 9. Seppala, M., Unnerus, H. A. Am. J. Obstet. Gynec. 1974, 119, 270. 10. Seppala, M., Rusolahti, E. Obstet. Gynec. 1973, 421, 701. 11. Brock, D. J. H., Sutchffe, R. G. Lancet, 1972, ii, 197. 12. Seppala, M., Rusolahti, E. Am. J. Obstet. Gynec. 1972, 114, 595. 13. Pritchard, J. A. Obstet. Gynec., N.Y. 1965, 25, 289. 14 Gitlin, D., Boesman, M. J. clin. Invest. 1966, 45, 1826. 1. 2. 3.

15. Brock, D. J. H. Clinica chim. Acta, 1974, 57, 315.


Johannesburg, South Africa

proposed that analgesic-induced papillary necrosis is due to a progressive blood-vessels of the renal papilla and of small narrowing renal pelvis.


It is

papillary necrosis is the hallmark of analgesicinduced kidney disease. This has been known for more than 25 years, yet despite extensive experimental investigation of the condition and the examination of human material, the cause of the papillary necrosis is unknown. The microscopic appearance of the necrotic papilla, namely the gradual loss of tubular elements progressing to total necrosis and with little inflammatory response, RENAL

a slow ischaemic process or "slow infarction" of the medullary structures. We observed12 an unusual microangiopathy in patients suffering from the effects of analgesic abuse. This change which was found in the vessels of the renal pelvis, ureter, and bladder consisted of a pronounced thickening of the walls of the capillaries and larger arterioles and venules with resultant almost total obliteration of these vessels. The affected capillaries lay just beneath the mucosa, although at times the change was seen in deeper and somewhat larger vessels. Examination of the necrotic papillae of kidneys with analgesic nephritis revealed vessels with similar abnormalities lying between the thickened, degenerating tubules. Many workers have suggested that analgesics exert their harmful effect on the kidney by interfering with the blood-vessels of the renal papilla.34 However, the microangiopathy described above has not been reported pre-


viously. The renal papilla has 2 sources of blood-supply. The of the juxta medullary glomeruli are responsible for the major blood-supply to the medulla. However, Fourman and Moffat5 demonstrated that the mucosal lining of the renal pelvis has its own system of blood-vessels which have important connections with the vessels of the renal medulla. These connections are closely associated with ectopic glomeruli which are found in the pelvic mucosal tissue. The efferents curve over the calyceal recesses to enter the medulla, where they form vasa recta. Thus it is proposed that the microangiopathy with resultant narrowing that has been observed in these pelvic and papillary vessels in the presence of analgesic abuse is of paramount importance in the development of analgesic-induced papillary necrosis of the kidney.

vasa recta

16. Milunsky, A., Alpert, E. Lancet, 1976, i, 1015. 17. De Bruijn, H. W. A., Huisjes, H. J. ibid. 1975, i, 525. 18. Ambender, E., Hirschhorn, K. ibid. 1976, i, 597. 19. Brock, D. J. H., Sutcliffe, R. G. Trans. biochem. Soc. 1973, i, 149. 20. McKusick, V. A. Mendelian Inheritance in Man, Baltimore, Maryland. 1975. 21. Abramovitch, D. R. J. Obstet. Gynœc. Br. Commonw. 1970, 77, 865. 22. Brock, D. J. H., Nelson, M. M. ibid, 1974, 81, 177. 23. Seppala, M., Laes, E., Harvo-Noponen. ibid. p. 827. 24. Seller, M. J., Creasy, M. R., Alberman, E. D. Br. med. J. 1974, ii, 524 25. Hunter, A., Hammerton, J. L., Baskett, T., Lyons, E. Lancet, 1976, i,598. 26. Milunsky, A., Alpert, E. J. Pediat. 1974, 84, 889.

Mechanisms by which amniotic-fluid alpha-fetoprotein may be increased in fetal abnormalities.

345 replacement solutions used in plasma exchange we have not encountered further hypocalcasmic symptoms in paents with a wide variety of diagnoses d...
273KB Sizes 0 Downloads 0 Views