Prenatal Diagnosis of Anencephaly

Human serum normally contains only the conjugated bile salts, glycocholate, glycochenodeoxycholate, taurocholate and taurochenodeoxycholate (Sandberg et al., 1965 ; Panveliwalla et al., 1970), with a total concentration below 5pmol/l. In serum from jaundiced patients the total bile salt concentration may rise to values exceeding 250pmol/l (Panveliwalla et al., 1970). The conjugated chenodeoxycholates and free acids that we have now shown to inhibit brain respiration in vitro often account for more than half of the total bile salts and may perhaps exert an inhibitor action in vivo. These observations may be relevant to the genesis of coma during hepatic failure, for it is known that during hepatic coma the O2 uptake of human brain is below that of normal subjects (Wechsler et al., 1954; Fazekas et al., 1956). Although several of the metabolites that are retained in extracellular fluid during hepatic coma may inhibit respiration by rat brain slices in vitro (Walshe et al., 1958; Lascelles & Taylor, 1968), only bile salts do so at concentrations close to those found pathologically. Ammonia, for example, will inhibit respiration by rat brain slices only when in a concentration of approx. 1000 times that of plasma, even though the plasma ammonia concentration in hepatic coma often parallels the degree of coma. Three difficulties stand in the way of accepting a role for bile salts in causing hepatic coma. First, it is not known whether bile salts pass into cerebrospinal fluid; secondly, many jaundiced patients have raised plasma concentrations of bile salts without coma supervening; thirdly, the correction of hepatic coma by treatment with high-carbohydrate regimes cannot be easily explained if bile salts are solelyresponsible for the fall of O2 uptake. For these reasons we are increasingly attracted to the possibility that more than one factor is involved. The inhibition of respiration achieved by the conjugated bile salts parallels their detergent properties. Thus Hofmann (1963) has shown that for representative polar and non-polar compounds the conjugated deoxycholates and chenodeoxycholates have a lower critical micellar concentration and higher saturation ratio than the cholate conjugates. It is possible that the bile salts in hepatic coma permit relatively easy access to the brain of other respiratory toxins that would not themselves inhibit brain respiration in so low a concentration. In this context it is noteworthy that Lascelles &Taylor (1968) were able to show, with brain slices, potentiation of inhibition of O2 uptake by combinations of metabolites each of which was present in a concentration known not to be inhibitory. Finally, hepatic coma is often accompanied by acute renal failure. There can be no doubt that bile salts can penetrate the glomeruli and be reabsorbed by the renal tubules. If free chenodeoxycholate were formed in hepatic disease it might perhaps inhibit renal O2 uptake and contribute to the development of acute renal failure.