20

CONCLUSIONS

1. The pattern of postsynaptic neuronal activity in hepaticencephalopathy is similar to that induced by drugs whichcause GABA-ergic neural inhibition.

2. Outside the central nervous system a major source ofGABA is the enteric bacterial flora.

3. When the liver fails plasma GABA levels rise and theblood-brain barrier becomes permeable to an isomer ofGABA, both phenomena occurring before the onset of

encephalopathy.4. Hepatic encephalopathy is associated with increased

numbers of binding-sites for GABA and for benzodiazepineson postsynaptic neural membranes.

HYPOTHESES

On the basis of experimental findings three hypotheses areproposed:

1. In liver failure gut-derived GABA passes through apermeable blood-brain barrier and induces its own receptorson postsynaptic neural membranes, possibly increasing thesensitivity of the brain to GABA-ergic neural inhibition.

2. Gut-derived GABA contributes to the neural inhibitionof hepatic encephalopathy.

3. An increased number of drug-binding sites mediates theincreased sensitivity to barbiturates and benzodiazepinesobserved in liver failure by permitting increased drug effect.The validity of these hypotheses is experimentally

approachable in man..

REFERENCES

1. Schenker S, Breen KJ, Hoyumpa AM. Hepatic encephalopathy-current status.Gastroenterology 1974; 66: 121-51.

2. Fisher JE, Baldessarini RJ. Pathogenesis and therapy of hepatic coma. In: Popper H,Schaffner F, eds. Progress in liver diseases, vol. V. New York: Grune and Stratton,1975: 363-97.

3. Conn HO, Lieberthal MM. The hepatic coma syndromes Baltimore- Williams and

Wilkins, 1978.4. Zieve L. Hepatic encephalopathy: summary of present knowledge with an elaboration

on recent developments. In: Popper H, Schaffner F, eds. Progress in liver diseases,vol VI New York: Grune and Stratton, 1979: 327-41

5. Zieve L. The mechanism of hepatic coma Hepatology 1981; 1: 360-65.6. Tallman JF, Paul SM, Skolmck P, et al. Receptors for the age of anxiety: pharmacology

of the benzodiazepines. Science 1980, 207: 274-78.7. Skolmck P, Moncada V, Barker JL, et al Phenobarbital: dual actions to increase brain

benzodiazepine receptor affinity. Science 1981; 211: 1448-50.8. Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore

receptor complex common site of minor tranquiliser action. Biol Psychol 1981, 16:213-29.

9. Costa E, DiChiara G, Gessa GL, eds. GABA and benzodiazepine receptors NewYork: Raven Press, 1981

10. Roberts E, Case TN, Tower DB, eds. GABA in nervous system function New YorkRaven Press, 1976.

11. Krogsgaard-Larsen P, Scheel-Kruger J, Kofod H, eds GABA neurotransmitters NewYork: Academic Press, 1979.

12. Mandel P, DeFendis FV, eds. GABA-biochemistry and CNS functions. New York:Plenum Press, 1979.

13. Krnjevic K, Phillis JW. Iontophoretic studies of neurones in the mammalian cerebralcortex J Physiol 1963; 165: 274-304.

14. Smialowski A. The effect of intrahippocampal administration of &ggr;-aminobutyric acid(GABA). In: Fonnum F, ed. Ammo acids as chemical transmitters New York.Plenum Press, 1978: 1977-80

15. Trewby PN, Casemore C, Williams R. Continuous bipolar recording of the EEG mpatients with fulminant hepatic failure. Electroenceph Clin Neurophysiol 1978; 45:107-20.

16. Blitzer BL, Waggoner JG, Jones EA, et al. A model of fulminant hepatic failure in therabbit. Gastroenterology 1978, 74: 664-71.

17. Purpura DP. Intracellular studies of synaptic organisations in the mammalian brain.In: Pappas GD, Purpura DP, eds. Structure and function of synapses. New YorkRaven Press, 1972 257-302.

18. Schafer DF, Brody LE, Jones EA. Visual evoked potentials: an objective measurementof hepatic encephalopathy in the rabbit. Gastroenterology 1979; 77: A38.

19. Schafer DF, Fowler JM, Brody LE, et al. Hepatic coma and inhibitoryneurotransmission: the enteric bacterial flora as a source of &ggr;-aminobutyric acid.Gastroenterology 1980; 79: 1052

20. Schafer DF, Waggoner JG, Jones EA. Sera from rabbits in acute hepatic coma inhibitthe binding of [3H]&ggr;-aminobutyric acid to neural membranes. Gastroenterology1980; 78: 1320

21. Schafer DF, Thakur AK, Jones EA. Acute hepatic coma and inhibitoryneurotransmission increase in &ggr;-aminobutyric acid levels in plasma and receptors inbrain. Gastroenterology 1980; 79: 1123.

22. Schafer DF, Fowler JM, Jones EA Colonic bacteria: a source of &ggr;-aminobutyric acid inblood. Proc Soc Exp Biol Med 1981, 167: 301-03.

23 White HL, Sata TL. GABA-transaminases of human brain and peripheraltissues-kinetic and molecular properties. J Neurochem 1978; 31: 41-47.

24. Ferenci P, Schafer DF, Shrager R, et al. Metabolism of the inhibitory neurotransmitter&ggr;-aminobutyric acid in a rabbit model of acute hepatic failure. Hepatology 1981; 1:509.

25 Blasberg RG, Gasendam J, Patlak CS, et al. Changes in blood-brain transfer

parameters induced by hyperosmolar intracarotid infusion and by metastatic tumorgrowth In: Eisenberg HM, Suddith RL, eds. The cerebral microvasculature. NewYork Plenum Press, 1980: 307-19

26 Horowitz M, Schafer DF, Molnar P, et al. Blood-brain barrier changes in acute hepaticencephalopathy Pediatr Res 1981, 15: 706.

27. Krnjevic K. Chemical nature of synaptic transmission in vertebrates. Physiol Rev1974; 54: 418-540

28. Schafer DF, Thakur AK, Jones EA. Increased &ggr;-aminobutyric acid receptorsassociated with acute hepatic encephalopathy in rabbits. Clin Res 1980; 28: 485A

29. Baxter JD, Funder JW. Hormone receptors. N Engl J Med 1979; 301: 1149-60.30. Schenker S. Hepatic coma current concepts of pathogenesis. Dig Dis 1970; 2: 1-4.31. Fessel JM, Conn HO An analysis of the causes and prevention of hepatic coma.

Castroenterology 1972; 62: 191.32. Fowler JM, Schafer DF. A mechanism for the increased sensitivity to benzodiazepines

in hepatocellular failure evidence from an animal model. Gastroenterology 1981, 80:1359.

Reviews of Books

PathophysiologyThe Biological Pnnczples of Disease. Irzternatzonal Textbook of Medicine,vol. 1. Edited by Lloyd H. Smith, University of California, San Francisco,and Samuel O. Thier, Yale University School of Medicine. Philadelphiaand Eastbourne: W. B. Saunders. 1981. Pp. 1918. £42.50.

THE Cecil Textbook of Medicine has rightly claimed an enthusiasticinternational readership for over 50 years. This new InternationalTextbook of Medicine-perhaps taking a leaf out of Passmore andRobson’s Companion to Medical Studies-has been designed to

"articulate with" Cecil. Volume I (under review) deals with

pathophysiology or the biological principles of disease and volumeII (see below) with medical microbiology and infectious disease;volume III is the regular classic Cecil, a new edition of which isexpected in 1983.

I endorse most strongly the principles encompassed in this firstvolume. Whenever possible, disease should be explained and taughtthrough an understanding of basic biology. This requires that thestudy of anatomy, physiology, biochemistry, pharmacology, andpathology should not consist merely of the accumulation of

seemingly irrelevant and dissociated information that most medicalstudents find hard to absorb or retain but should include the study ofdisease. It is this sort of integration that many clinical teachers havetried (with only limited success) to introduce into their curricula, butwhich is so often resented by preclinical teachers who see the discip-linary content of their courses as more important than its applicationto clinical medicine. In a recent article (Lancet Sept. 5, p. 513)Professor Dornhorst expressed the view that "The science teacherneeds to accept that medical practitioners are technologists ratherthan scientists. They are science users who need to know enough ofthe main ideas and results of the basic sciences to be able to assim-ilate relevant new information in their chosen fields ...". By pro-viding an outline of the main ideas of the relevant basic sciences, thistextbook goes a long way towards meeting what, to me, is a

deficiency in our medical teaching.The distinguished authorship is mostly American, but there are

important chapters by three of the most accomplished Britishphysicians (D. J. Weatherall and colleagues on the blood and blood-forming organs, J. N. Walton on neurology, and C.T. Dollery onclinical pharmacology). Quite logically, chapter I is on cell biology,and the senior author, Palade, is a Nobel laureate. An understandingof modern biology rests on knowledge of cell structure and function,and the descriptive parts of this chapter are backed up by beautifullucid reproductions of electron microscopy and freeze-fracture

21

preparations. Each element of the cell is dealt with in terms of

morphology and function, and an important section on proteinsynthesis leads naturally on to chapter II (David W. Martin), ongenetics. A detailed consideration of gene expression and thegenetic apparatus (again well-illustrated, mostly by simple line-diagrams) precedes an account of mendelian inheritance and asection on human chromosome disorders, which contains the book’sfirst reference to a clinical application of basic knowledge. Otherexamples of genetic disorder are discussed in detail, with generalcomments on prenatal diagnosis, the genetics of twinning, aging,and cancer and a largely speculative discussion of the treatment ofgenetic disease. The chapter ends with a section on counselling.This chapter on genetics seems to exemplify the principles of thebook-an excellent survey of the basic science of genetics inter-spersed with important practical clinical considerations, a patternwhich is repeated in chapter III, on immunology, and chapter IV, onneoplasia.From this point the emphasis changes. Chapter V, on the blood

and blood-forming organs, provides a link between the earlier

chapters on genetics, immunology, and neoplasia and spills liberallyover into organ pathophysiology, which forms the basis of the rest ofthe book. Each of the major organs of the body is discussed in turnand the same emphasis is placed on basic understanding. There arealso chapters on metabolism, nutrition, and clinical pharmacology.When reviewing a general textbook, it is tempting to look most

critically at the chapters one knows best, in my case that on

endocrinology, written by Grant and Rodger Liddle (a father andson team?). Grant Liddle (senior?) is a most distinguished endocrin-ologist and this contribution bears the stamp of distinction. Thegeneral principles of endocrinology are covered in a masterlyfashion. Mechanisms of hormone action are dealt with concisely in 3pages. An important section on the coordinating role of the nervoussystem is followed by a consideration of individual hormones, whichare described so lucidly that the picture of clinical deficiency oroverproduction of each hormone is built up quite logically. In this,as in other chapters there is a valuable selection of references. I

enjoyed reading this chapter but, because of less familiarity with theother subjects, I found the rest of the book more instructive. It

seems, therefore, that depth and comprehension have beencombined with clarity and readability.

I recommend this book enthusiastically. It meets what I regard asthe essential of undergraduate teaching by providing a solid base ofunderstanding on which clinical knowledge can be built. If volumeII deals as effectively and thoroughly with microbiology and infec-tious diseases and volume III lives up to the standards of earliereditions of Cecil, we will have gained a major textbook of medicinethat will prove valuable to preclinical and clinical students as well asto postgraduates.

Department ofmedicine,lJDIversIt)’ofBlrmlOgham R. HOFFENBERG

Medical Microbiology and Infectious Diseases

International Textbook of lvledzclI1e, vol. II. Edited by Abraham I Braude,Umversny of Cali forma, San Diego. Philadelphia and Eastbourne: W. B.Saunders. 1981. Pp. 1935. 48 50.

IT is remarkable that two huge books on infectious diseases havebeen published within two years of each other, one having 172contributors (Principles and Practice of Infectious Diseases, edited byMandell, Douglas, and Bennett), and this one 192. What is perhapseven more surprising is that the authors should, to some extent,overlap.This book is the second volume of the International Textbook of

Medicine, and it will come as a culture shock to some physicians thatCecil’s Textbook of Medicine is only one of the three volumes.Nevertheless, the international situation is such that a book on

microbiology and infectious diseases should be given as much spaceas general medicine since, worldwide, infectious diseases are

present on an enormous scale. The international flavour of the bookis reflected by the fact that 63 of the contributors work outside theUnited States. However, despite the title, some of the contributionsreflect a parochial point of view, and some of the reference lists show

few or any publications outside the country where the writer works.It must be said at once that this is a textbook which covers a widearea and which contains much valuable information. There are,however, problems posed by the somewhat restricted outlook ofsome of the writers and also by the almost impossible task ofmaintaining a firm editorial hand on such a large amount ofcontributed material. Hence, we read that Haemophilus influenzae isthe commonest cause of bacterial meningitis. This may be so for theUnited States, but it is certainly untrue on a worldwide scale. Thereis sometimes a discrepancy between the microbiological section andthe clinical section-for example, the biochemical reactions forsalmonellas given in the section of microbiology are different fromthose given in one of the tables in the clinical section. Unbelievably,within 11 pages of each other, there are two articles on Clostridiumperfringens food poisoning which are virtually identical in content,the only difference being that one is in the section on food poisoningand the other in the section on enteritis.There are many useful line-drawings and several photographs are

of acceptable quality. However, many have suffered in reproductionand there are some which would have been much better left out.There are some points of view expressed which conflict. For

example, we are told that intravenous chloramphenicol is thetreatment of choice for systemic salmonella infections, because oralchloramphenicol is associated with marrow dysplasia, whereas inthe section on the treatment of typhoid fever, oral chloramphenicoltherapy is recommended. Since the classification of salmonellas intothree biotypes bears no relationship to the view of the subject held inthe United Kingdom, it would mislead unsuspecting trainee

bacteriologists and clinicians; and, surprisingly, there is no mentionof the phage typing of salmonellas, which is such a valuable epi-demiological tool.This, then, is a textbook which will be of value as a reference

volume, but could, in some instances, mislead the beginner.Prospective purchasers would be well advised to shop around beforedeciding whether this text fulfils their needs, and they must decidewhether the convenience of having infectious diseases and micro-biology in one volume outweighs the advantages of having perhapsmore carefully edited information in separate volumes of micro-biology and infectious and tropical diseases.

Department of Laboratory Medteme,Ruchill Hospital,Glasgow R. J. FALLON

Perinatal Diseases

InternatIOnal Academy of Pathology, Monograph No. 22. Edited by RichardL. Naeye, Hershey Medical Center, Pennsylvania, John M. Kissare,Washington University School of Medicine, St Louis, Missouri, andNathan Kaufman, International Academy of Pathology, Augusta,Georgia. Baltimore and London: Williams and Wilkms. 1981. Pp. 425.$52,75; 31.65.

ADDED to the shortage of pathologists with interest and expertisein the perinatal field is a lack of good reviews which generalpathologists can consult on pathological conditions affecting theplacenta, fetus, and neonate. This deficiency is partly rectified by abook based on a course organised by the United States-CanadianDivision of the International Academy of Pathology in February,1980. The contributors comprise many of the most distinguishedNorth American paediatric pathologists. The work is in no sense acomprehensive treatise on perinatal pathology but deals withseveral general aspects of perinatal disease and a number of specificareas of the subject which may present diagnostic problems.Many of the chapters are well-written major reviews of their

subjects which are not readily available elsewhere. The pathology ofinfection in the perinatal period is discussed in several importantcontributions. Suspicion of an infection may be one of the mainreasons for submitting the placenta to special examination.

Techniques which can be used to confirm the diagnosis, and whichrange from amniotic and chorionic smears to fluorescent antibodyprocedures and electron microscopy, are described and referenced.Fetal and placental lesions characteristic of a wide spectrum of viralinfections are discussed and illustrated. The chapter on the

influence of maternal diabetes on the fetus and placenta highlights

22

the continuing difficulty in explaining the high incidence of severecongenital malformations and occasional unexplained fetal deaths.Congenital neoplasms, although rare, will be encountered by mosthistopathologists; Louis Dehner’s critical review of these lesionsshould prove of widespread practical value.The paediatric pathologists are on less sure ground when

discussing the general aspects of their subject. Not everyone wouldagree with Richard Naeye that the three environmental factors thatmost often influence the fetus are maternal nutrition, cigarettesmoking, and coitus. The standard of illustration throughout thebook is excellent and the photomicrographs are reproduced to agenerous scale. Any paediatric pathologist should seriouslyconsider adding this book to his personal library, while the generalhistopathologist will find it a useful source of reference for several ofthe problem areas of perinatal pathology.Department of Paediatricsand Neonatal Medicine,

Hammersmith Hospital, London J. S. WIGGLESWORTH

Thrombosis

Clinics in Haematology, vol. X, no. 2. Edited by C. R M. Prentice, RoyalInfirmary, Glasgow. Philadelphia and Eastbourne: W. B. Saunders. 1981.Pp. 437.10.75.

THE structure of this issue follows that of the basic Clinics pattern,with contributions by several authors under the guidance of a guesteditor. In his foreword Dr Prentice explains that since it would bealmost impossible to provide an exhaustive coverage of all that isknown of thrombosis, topics have been selected so as to highlightrecent advances in knowledge.

. The three areas covered are basic mechanisms of thrombosis and

atherogenesis, clinical pharmacology of antithrombotic drugs, andselected clinical topics. The only area not included that might berelevant to haematologists is laboratory techniques involved inassessing the "hypercoaguable state"; an outline of these tech-niques, with some comments on their indications, suitability, andinterpretation, would have been useful.There is a certain amount of repetition, but this allows each

chapter to be read in isolation, which is an advantage in this sort ofbook. In general, there is a good balance between basic mechanismsand clinical application. The results and interpretation of clinicaltrials of antithrombotic drugs and treatment regimens are particu-larly well set out and evaluated.The book best serves the person to whom it is presumably

directed-namely, the general haematologist. In that aim itmaintains the general high standard of this series.

Department of Haematology,St Thomas’ Hospital, London T. C. PEARSON

The Clay Pedestal- A Re-exammation of the Doctor-Pallem Relattonslaip. Thomas Preston,

University of Washington. Seattle: Madrona Publishers. 1981. Pp. 226.$12.95. _

-

THE opening chapters of this lucidly written book may berecommended to students eager to engage with topics such as "whypeople go to doctors", "physicians, quacks and healers", "thedoctor-patient contract", and "science versus clinical judgement".Some criticism is due, however, because these complex mattersrequire more than presenting only one side of the argument. That,complains the author, is what physicians do when talking to

patients, and that is just what he himself does here. Since he is aphysician (and professor of medicine), and since he writes here forpatients, the fault is understandable. He also earns his own criticismof doctors for not being scientific; his material is exceedingly partialand his assertions are dogmatic. Still, the message is clear: doctorsdo not deserve their high status. Dr Preston does not think well ofhis colleagues.

In later chapters such as those on "overtreatment and the capacityto harm" and "the fundamental deception of medicine", polemicsabound. Patients are advised: "Call your doctor ’Mr’, ’Mrs’, ’Ms’.

Why do you call the physician ’Dr?’ ... Why do you accord thisspecial status?". They are told that "deception of the patient issystematically if unconsciously taught to the medical student fromthe beginning of his clinical experience". He offers the nice

concept: "the waitress-in-training is judged by how well she servesthe customer; the physician-in-training is judged by how well heserves the profession"; but the comparison is not apt. Diners are tobe given what they order, not what is good for them. What willreaders make of "the heart surgeon... doesn’t have any special skillsor knowledge that the average person couldn’t learn with training"or "most doctors, who are as honest as any other professional group,indulge in unconscionable self-enrichment"? The author has

perhaps chosen to write in this unbalanced way in the mistakenbelief that this will set right a perceived opposite imbalance inpresent views held by patients about doctors. By so doing he hasforfeited credibility.Books of this kind seek to shift the doctor-patient relationship

from autocratic, if benevolent, paternalism facing ignorantdependence towards a sharing of information and decision-makingbetween adult equals. The change, which accords with anti-elitistfashion, is generally urged because of greater public education.Preston calls to his aid only the badness of physicians in rousing"medical consumer groups" to abandon trust in their doctors. Whobenefits from that?

Department of Psychiatry,University Hospital of South Manchester NEIL KESSEL

Seizure Disorders

A Pharmacological Approach to Treatment. B. J. Wilder, University ofFlorida College of Medicine, Gamesville, Florida, and J. Bruni, WellesleyHospital, Toronto, Ontario. New York: Raven Press. 1981. Pp. 256$33.32.

THE authors’ stated aim is to synthesise clinical information andscientific data on the pharmacological and physiological aspects ofantiepileptic drugs, with a view to proper medical management ofconvulsive disorders.Three introductory chapters on seizure classification, pharma-

cological principles, and medical management precede individualsections on each of the major groups of drugs. Three more chapters,on drug monitoring and seizure control, drug interaction, and drugtoxicity, and one on quantitative analysis of antiepileptic drugscomplete the text. Much of the information given in the introduc-tory chapters is repeated without amplification in the sections onindividual drugs, and again in the chapters on monitoring,interaction, and toxicity. In some instances, contradictorystatements appear in different sections of the book. The generalrecommendations for the uses of individual drugs would not alwaysfind universal acceptance, nor is the principle that a good trial ofmonotherapy must precede polytherapy adhered to throughout. Ina book purporting to approach a disorder pharmacologically, Iwould not expect to find suggestions, on at least two occasions, thatphenobarbitone and primidone should not be used concurrentlybecause of the risk of sedation. Reference to the illogicality of thiscombination is eventually made in the chapter on primidone, but isincorrectly described as potentiation of phenobarbitone byprimidone in a later section on drug interactions. Optimum rangesfor the serum level of antiepileptic drugs vary from chapter tochapter, as do the toxic effects. Although there are references to 922works, the choice of references is uneven, with some well-accepteddata heavily alluded to, while the origins of more controversialstatements are left obscure. References are not always accuratelyinterpreted, and in some instances bear no relationship to theinformation in the text. It might have been hoped that the indexwould enable the scattered pieces of information to be collated, butit often points to only one of multiple sources in the text.

It is difficult to know for whom this book was written. It has notfulfilled the authors’ aspiration and is unlikely to satisfy the needs ofeither the pharmacologist or the physician involved in the treatmentof seizure disorders.

Department ofPaediatnc Neurology,University Hospital of Wales SHEILA J. WALLACE