- Email: [email protected]
CIRRHOSIS IN SOUTH LONDON
118 While the plasma-noradrenaline concentration at rest was subnormal in only a minority of low-renin patients, the noradrenaline response to postural stimulation was much diminished, and the blood-pressure rise with the indirectly acting sympathomimetic amine tyramine was clearly attenuated. Tyramine produces raised bloodpressure by releasing the sympathetic neurotransmitter noradrenaline from sympathetic nerve varicosities, and has been used as a pharmacological tool in the study of sympathetic nerve endings.15 The pressor response to tyramine is related to the noradrenaline pool size in the sympathetic nerve ending. 15 Since the blood-pressure response to intravenous administration of noradrenaline in the low-renin hypertensives was normal, the findings with tyramine suggest either diminished accessibility of tyramine to the sympathetic noradrenaline pools, or, more likely, a diminution in noradrenaline pool size. With exogenous adrenergic stimulation of renin release, using isoprenaline, the rise in P.R.A. was subnormal in the low-renin hypertensives. This abnormality was accentuated by dietary sodium restriction. There are other reports also of a diminished renin response to pharmacological stimulation with infusion of noradrenaline 21 and theophylline 20 in low-renin hypertension. Therefore the defective sympathetic nervous stimulation of renin release in low-renin essential hypertension may involve two mechanisms: first, decreased sympathetic nerve traffic to the kidney; and second, a reduction in responsiveness to adrenergic stimulation. Several different mechanisms have been implicated in the pathogenesis of low-renin essential hypertension. Mineralocorticoid excess,3 4 increased central (effective) blood-volume,56 and a reduction in P.R.A. with time in 7 severe or longstanding essential hypertension have all been proposed as explanations of the lower plasmarenin. The haemodynamic findings in low-renin essential hypertension in this study were varied, suggesting such a
pathophysiological heterogeneity.
In
particular,
blood-volume,56 sympathetic nervous underactivity expected to follow from stimulation of cardiopulmonary volume receptors by the higher central blood-volume.2’ 26 It is proposed that the syndrome of low-renin essential hypertension is of diverse setiology, but with secondary sympathetic nervous system underactivity as a feature common to the various forms. The low P.R.A. is probably an expression, at least in part, of defective sympathetic nervous stimulation of renin would be
release. to
M.
E., Hypertension
of Internal
Medicine, University
ot
Michigan
Michigan 48109, U.S.A.
REFRENCE S 1.
Kuchel, O., Fishman, L. M., Liddle, G. W., Michelakis, A. Ann. intern. Med. 1967, 67, 791. 2. Crane, M. G., Harris, J. J., Johns, V. Am. J. Med. 1972, 52, 457. 3. Woods, J. C., Hill, C., Liddle, G. W., Slant, E. G., Michelakis, A. M., Brill, A. B. Archs intern. Med. 1969, 123, 366. 4. Melby, J. C., Dale, S. L., Wilson, T. E. Circulation Res. 1971, 28, suppl. 2, 143. 5. Esler, M., Julius, S., Randall, O. Circulation, 1975, 52, suppl. 2, 55. 6. Esler, M., Julius, S., Randall, O., in The Arterial Hypertensive Disease (edited by G. Rorive and H. van Cauwenberge); p. 231. Paris, 1976. 7. Tuck, M., Williams, G., Cain, J., Sullivan, J., Dluhy, R. Am. J Cardiol. 1973, 32, 637. 8. Esler, M. D., Nestel, P. J. ibid. p. 643. 9. Vander, A. J. Am. J. Physiol. 1965, 209, 659. 10. Collins, R. D., Wemberger, M., Gonzales, C., Nokes, G., Leutscher, J. A. Clin. Res. 1970, 18, 167. 11. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H., Buhler, F. R. New Engl. J. Med 1972, 286, 441.
Haber, E., Koerner, T., Page, L. B., Kliman, B., Purnode, A. J. clin. Endocr. 1969, 29, 1349. 13. Ellis, C. N., Julius, S. Br. Heart J. 1973, 35, 450. 14. Renzini, V., Brunori, C. A., Valori, C. Clinica chim. Acta, 1970, 39, 587 15. Harvey, S. C., Sulkowski, T. S., Weenig, D. J. Archs int. Pharmacodyn. Thér. 1967, 169, 262. 16. Esler, M. D. Clin. Pharmac. Ther. 1974, 15, 484. 17. Dustan, H. P., Tarazi, R. C., Frohhch, E. D. Circulation, 1970, 41, 555. 18. Esler, M. D., Julius, S., Randall, O. S., Ellis, C. N., Kashima, T. Am. J. Cardiol. 1975, 36, 708. 19. Esler, M., Julius, S., Randall, O., DeQuattro, V., Zweifler, A. Clin. Sci molec. Med. (in the press). 20. Lowder, S. C., Hamet, P., Liddle, G. Circulation Res 1976, 38, 105. 21. Jose, A., Crout, J. R., Kaplan, N. M. Ann. intern. Med. 1970, 72, 9. 22. Frohlich, E. D., Tarazi, R. C., Ulrych, M., Dustan, H. P., Page, I. H. Circulation, 1967, 36, 387. 23. Esler, M. D., Nestel, P. J. Clin. Sci. 1973, 44, 213. 24. Biglieri, E. G., Mcllroy, M. B., Naimark, A., Forsham, P H. J. clin. Invest. 1962, 41, 1345. 25. Clement, D. L., Pelletier, C. L., Shepherd, J. T. Circulation Res 1972, 31,
12.
824. 26. Pelletier, C. L.,
Shepherd, J. T.
ibid.
1973, 33, 131.
CIRRHOSIS IN SOUTH LONDON
cen-
tral blood-volume was increased, without an increase in total blood-volume, in six patients, while four patients had severe longstanding hypertension. Adrenal steroid metabolism was not studied by us, so the existence of non-aldosterone mineralocorticoid hypertension in some of these patients is possible.4 These different pathophysiological patterns may all be associated with sympathetic nervous underactivity. Reduced sympathetic responsiveness has been described in severe, longstanding essential hypertension 22 23 although the mechanism is uncertain. Primary aldosteronism, which may be considered as the prototype of human mineralocorticoid hypertension, is also associated with diminished sympathetic nervous responsiveness. 24 In hypertensives with an increase in central
Requests for reprints should be addressed
Section, Department
Medical Center, Ann Arbor,
H.
J.
F. HODGSON*
R. P. H. THOMPSON
St. Thomas’ Hospital, London SE1
Alcoholism was the major ætiological factor in 65% of 78 patients presenting with cirrhosis to a hospital in Central London during 1968-74. It is suggested that in the U.K. the importance of alcoholism in patients with cirrhosis has been underestimated.
Summary
Introduction THERE is little agreement on the relative importance of alcohol in the aetiology of cirrhosis of the liver in the U.K. Surveys in 1966 and 1973 of patients with cirrhosis implicated alcoholism as the primary factor in from 24%’ to 51 %2 of cases. This may be partly because the relative importance of alcohol will vary between surveys carried out in specialised centres and those in less specialised district general hospital. Furthermore, the consumption of alcohol in the U.K. has been steadily increasing over the past 20 years,3 and so the contribution made by alcohol to liver disease may be expected to rise. "Present address:
Department of Medicine, Royal Free Hospital, London NW1
119
surveyed all cases of cirrhosis diagnosed histological grounds between 1968 and 1974 in a London teaching hospital (St. Thomas’) which did not We therefore
on
act as a
referral
centre
for liver disease.
Patients and Methods
During the 6-year period (1968-74) cirrhosis of the liver was diagnosed on histological grounds in 78 patients. The criteria were liver-cell damage, regeneration, and fibrosis4 in all except those patients in the early stages of primary biliary cirrhosis. The patients’ case-histories and biopsy reports were reviewed retrospectively. In 3 patients in whom cirrhosis was an incidental finding at necropsy there was inadequate clinical and laboratory evidence to determine the aetiology of the cirrhosis, and these cases were excluded from the study. Patients were assigned to the following ætiological groups: (1) Alcohol-associated cirrhosis-patients with a history of heavy alcohol intake, estimated at over 120g of alcohol per day for more than 5 years, and a compatible liver biopsy specimen. (2) Active chronic hepatitis with cirrhosis-patients with histological criteria for active chronic hepatitis5 with smooth-muscle or antinuclear antibodies, or hepatitis-B surface antigen present in their sera. (3) Cryptogenic cirrhosis patients in whom the histological appearances of the liver biopsy specimens were those of an inactive, or minimally active, cirrhosis, and who denied heavy alcohol intake. (4) Primary biliary cirrhosis-patients whose liver biopsy specimens fulfilled the criteria of Scheuer and Sherlock,6 and in whose detected.
sera
antimitochondrial antibodies
were
(5) Secondary biliary cirrhosis-patients whose liver biopsy specimens showed the histological appearances of a biliary cirrhosis associated with longstanding extrahepatic biliary
Fig. 1-Etiology of liver disease in 75 patients with cirrhosis.
’
Presenting features.-The single main presenting features in the 49 patients with alcohol-associated cirrhosis are
shown below:
obstruction. Results
All but 7 patients in the survey were resident in London (57 patients) or the south-east (11 patients) at the time of referral. 2 patients were of no fixed abode. No patients resided abroad.
Ætiology Fig. 1
shows the presumed aetiologies of cirrhosis the 75 patients. In 65% of the cases the ciramongst rhosis was alcohol-associated.
Sex incidence.-29 (59%) of the alcoholic patients were women. All those with primen, and 20 and 8 of the 9 patients with active cirrhosis, mary biliary chronic hepatitis, were female. 4 men and 4 women had were
(41%)
cryptogenic cirrhosis. Clinical Features in Patients with Alcoholic Cirrhosis
Age.—The male alcoholic patients were aged 28-75 at presentation, with three-quarters of them presenting between ages 40 and 60. The female alcoholic patients were aged from 38 to 64, over half presenting between ages 50 and 60. Alcohol consumed.-12 patients (10 male, 2 female) said they drank mainly beer, 14 (8 male, 6 female) mainly spirits, and 3 (1 male, 2 female) mainly cider. The remaining patients gave no particular preference. 12 of the 49 (24%) were in occupations directly connected with alcohol (bar staff, publicans, wine waiters, or
brewery staff).
Gastrointestinal hcemorrhage.-During the 6 years of (28%) of the alcoholic patients had gastrointestinal haemorrhage; 8 bled from oesophageal varices, 3 from erosive gastritis, 1 from a gastric ulcer, and 1 from a duodenal ulcer. In 1 patient the source of bleeding was not identified. 3 patients died after episodes of bleeding (2 from varices, 1 from a duodenal ulcer); in all 3 patients there was evidence of severe liver failure (encephalopathy, fetor, and jaundice). Other clinical features.-Ascites developed in 19 the survey, 14
(38%) of the alcoholic patients. Hepatic encephalopathy developed in 11 of whom 6 died shortly afterwards. Associated diseases.-17 of the 49 patients with alcoholic cirrhosis had other chronic medical conditions, namely: duodenal ulcer (4 patients); neoplasms other than primary liver-cell carcinoma (3); acute relapsing pancreatitis (2); diabetes (2); pulmonary tuberculosis (2); hypertension (2); porphyria cutanea tarda (1); chronic bronchitis and emphysema (1). Routine Liver Function Tests Serum
concentrations, where available, of bilirubin,
alkaline phosphatase, glutamic oxaloacetic transaminase (s.G.o.T.), albumin, and globulin at presentation are
120
Fig. 2-Results of tests of liver function at admission in patients with cirrhosis. Those in 3 patients with hepatoma are shown by triangles.
shown in fig. 2. Only 7 of the 49 patients (14%) had abnormalities in any of these standard tests.
no
-
Prognosis Because the
study period extended from 1968 to final survival 1974, figures cannot be given. 10 men and 3 women died during the period of study, 5 within a year of diagnosis. The mean age at death of the 10 men was 56 years, and of the 3 women, 48 years. The causes of death are given below:
Discussion In this unselected retrospective series of patients with cirrhosis of the liver, alcohol was the most important oetiological factor. Although some patients with cryptogenic cirrhosis may have been wrongly included, it is likely, in view of the known difficulty of eliciting a history of alcoholism, that our results underestimate the importance of alcohol. The frequency of alcoholism in our patients (65%) is similar to that of American and European series (Boston, U.S.A. 83%;’ Rochester, U.S.A. 64%;" Chile 78%;9 Vienna 76%10 and is notably higher than most English series. In 1966 a specialist referral centre in London reported that 24% of cirrhosis was due to alcoholism,1 and a district hospital in Birmingham reported figures of 33% in 1959-1964," and 51% in 1964—1969 .2 Our results, however, are more in accord with the frequency of 64% briefly reported from Liverpool in 1972,12 and the 56% reported in London in the late nineteenth century.13 The figures from Birmingham2 11 have shown an in-
a decade in the frequency of alcoholism among patients with cirrhosis, and our experience confirms this. The annual consumption of alcohol has increased over the past two decades and the incidence of alcoholism is increasing,3 so this trend may be expected to continue. 41% of our patients with alcoholic cirrhosis were female, compared with 30% in London in 1966,’ 20% in Birmingham in 1968,11 and 36% in Liverpool in 1972,12 The higher proportion in more recent surveys may be due to the increase in alcoholism amongst women.’4 It is unlikely, however, that 40% of alcoholics are female, and indeed, a survey in Camberwell, an area of London in which many of our patients live, showed that during the same years as our study, alcoholism was six times more common amongst men than women in that area.15 Whilst the high proportion of females with cirrhosis in our series suggests that women who drink alcohol to excess may be more likely to develop cirrhosis than men, further evidence is required. The clinical features in our patients with alcoholic cirrhosis conform to the recognised pattern. Ascites, oedema, and jaundice were common presenting features; gastrointestinal bleeding was often from causes other than oesophageal varices.12 The liver function tests showed no specific abnormalities, and any or all of them were often normal. At the end of this survey primary liver-cell carcinoma had developed in 3 patients, but the final frequency will almost certainly be greater. Serumalkaline-phosphatase was markedly elevated at presentation in all 3 carcinoma cases, but this feature was also found in patients in whom no tumour has yet been diagnosed (fig. 2). This survey suggests that alcohol is the major cause of hepatic cirrhosis in London, as it appears to be in other cities of the western world. With increasing con-
crease over
121
sumption of alcohol the incidence of cirrhosis will rise, and so the early diagnosis of alcoholism is a priority in health care. Recognition that liver damage is due to alcohol is worthwhile, because there is evidence that even when cirrhosis is established the prognosis can be improved by abstinence,’6 although not all studies accord with this view. 17 A careful history from the patient and his relatives and the examination of the histological appearances of a liver biopsy specimen are often required to establish the aetiology. Requests for reprints should be addressed
to
intermittent swelling of the bitten limb.’Zagreb antivenom became available in Britain in 1969. Experimentally, it is very effective in neutralising Vipera berus venom and it is highly purified. Because of a death due to Pasteur antivenom in 1957 and other factors, many clinicians in Britain are reluctant to use antivenom. We have therefore assessed the effectiveness of Zagreb antivenom in monkeys, simulating so far as is practicable the clinical problem of adder-bite poisoning in man. Methods
R. P. H. T.
REFERENCES 1. Sherlock, S. Acta med. scand. 1966, suppl. 445. p. 426. 2. Jain, S., Paton, A., Wansbrough-Jones, M. H. Midland med. Rev. 1973, 9, 13. 3. Br. med. J. 1972, iv, 625. 4. Gastroenterology, 1956, 31, 213. 5. de Groote, J., Desmet, V. J., Gedigk, P., Korb, G., Popper, H., Poulsen, H., Scheuer, P. J., Schmid, M., Thaler, H., Uehlinger, E., Wepler, W. Lancet, 1968, ii, 626. 6. Sherlock, S., Scheuer, P. J. New Engl. J. Med. 1973, 289, 674. 7. Garceau, A. J., Chalmers, T. C. ibid. 1963, 268, 469. 8. Douglass, B. E., Snell, A. M. Gastroenterology, 1950, 15, 407. 9. Armas-Cruz, R., Yazigi, R., Lopez, O., Montero, E., Cabello, J., Lobo, G. ibid. 1951, 17, 327. 10. Schneiderbaur, A. Wien. med. Wschr. 1964, 114, 738. 11. Stone, W. D., Islam, N. R. K., Paton, A. Q. Jl Med. 1968, 37, 119. 12. Forshaw, J. Br. med. J. 1972, iv, 608. 13. Rolleston, H. D., Fenton, W. J. Birmingham med. Rev. 1896, 40, 193.
14. Glatt, M. M. Br. J. Hosp. Med. 1974, 11, 111. Edwards, G., Hawker, A., Hensman, C., Peto, J., Williamson, V. Br. J. Psychiat. 1973, 123, 169. 16. Brunt, P. W., Kew, M. C., Scheuer, P. J., Sherlock, S. Gut, 1974, 15, 52. 17. Soterakis, J., Resnick, R. H., Iber, F. L. Lancet, 1973, ii, 65. 15.
Thirteen male rhesus monkeys (Macaca mulatta) weighing 4-8-8-0kg were studied. Before each injection and venepu ncture the monkeys were sedated with intramuscular ketamine hydrochloride 10-17 mg/kg. Three control monkeys received intravenous Zagreb antivenom (from Regent Laboratories Ltd., Cunard Road, London NW10 6PN) or subcutaneous adrenaline but no venom. Ten monkeys received V. berus venom (from Czechoslovakia, kindly donated by F. Kornalik), in amounts detailed in the accompanying table. The venom in 0.25 ml saline, was injected subcutaneously into the back of the right hand. Five of these ten monkeys received no antivenom, in order to determine the approximate lethal dose for rhesus monkeys and to assess the natural history of non-lethal poisoning. The other five monkeys received Zagreb antivenom by slow injection into the femoral or subclavian vein 1-4 hours after venom injection. At this stage all monkeys were in shock and, although the antivenom did not seem to cause any adverse effect on the monkeys, 0.5 ml 1/1000 adrenaline was injected subcutaneously 5 minutes after the antivenom injection was completed.
Investigations
EFFECTIVENESS OF ZAGREB ANTIVENOM AGAINST ENVENOMING BY THE ADDER, VIPERA BERUS R. D. G. THEAKSTON
H. A. REID
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA Rhesus monkeys injected subcutaneously with 2, 3, or 4 mg Vipera berus venom per kg body-weight all died in shock. With 1 mg/kg the monkey had severe systemic and local effects taking 12 days to resolve. Five monkeys each received 4 mg/kg (a triple-lethal dose) and Zagreb antivenom was injected intravenously 1-4 hours after venom injection. The contents of 2 ampoules (10.8 ml) up to 3 hours later saved the monkeys; at 4 hours later the monkey died. But when the antivenom dose was raised to 16.2 ml 4 hours after venom, it saved the monkey. In addition to saving life, the antivenom greatly reduced the local venom effects. It is suggested that the results justify giving Zagreb antivenom to patients with severe adder-bite poisoning; and it should also be considered in adults to minimise morbidity from local effects.
Summary
Introduction ALTHOUGH adder bites in Britain are uncommon and when they do occur poisoning is often trivial, nevertheless severe poisoning sometimes results and on rare occasions it is fatal. Adults may take weeks or months to recover and can be unpleasantly troubled by pain and
Shock was deemed present when the monkey was cold and cyanosed, peripheral pulses were impalpable, and ear-prick blood was no longer obtainable. Monitoring the blood-pressure was attempted with a Roche ultrasonic ’Arteriosonde’ but proved unsatisfactory; invasive methods of monitoring the blood-pressure were considered unsuitable. Local swelling, assessed by circumference measurements to the nearest 0.5cm at the same marked level of both hands, wrists (thinnest part), forearms (fattest part), and arms (middle) is expressed as percentage increase (total of all 4 measurement sites) compared with those before venom injection. Electrocardiogram (E.C.G.) recordings and blood-samples were taken before venom injection and at various intervals up to and including terminal stages or complete recovery. On the blood-samples the following studies were performed by methods previously recorded:2 leucocyte-count, plateletcount, haemoglobin, hacmatocrit, thrombin-clotting time, assay of factors v, vn, vin, tx, and x, plasma-fibrinogen, levels of serum-fibrinogen/fibrin-degradation products, lysis of fibrin plates by plasma, and euglobulin fractions. Plasma urea, proteins, and potassium, sodium, bicarbonate, creatine phosphokinase, aspartate, and alanine aminotransferases were assayed by routine procedures. Details of E.C.G. changes, hsematology including coagulation tests, complement profiles, biochemistry, and morbid pathology will be published elsewhere.
Results Untreated Monkeys
Monkeys receiving 2-4 mg/kg venom died (see table). Shock and E.C.G. changes started within 20 minutes with 4 mg/kg and in all fatal cases persisted till death (see table). Vomiting and diarrhoea, which are common in human poisoning, did not occur. Local swelling and hæmorrhagic discoloration were mild in fatal cases as the monkeys did not live long enough for them to fully
pathophysiological heterogeneity.
In
particular,
blood-volume,56 sympathetic nervous underactivity expected to follow from stimulation of cardiopulmonary volume receptors by the higher central blood-volume.2’ 26 It is proposed that the syndrome of low-renin essential hypertension is of diverse setiology, but with secondary sympathetic nervous system underactivity as a feature common to the various forms. The low P.R.A. is probably an expression, at least in part, of defective sympathetic nervous stimulation of renin would be
release. to
M.
E., Hypertension
of Internal
Medicine, University
ot
Michigan
Michigan 48109, U.S.A.
REFRENCE S 1.
Kuchel, O., Fishman, L. M., Liddle, G. W., Michelakis, A. Ann. intern. Med. 1967, 67, 791. 2. Crane, M. G., Harris, J. J., Johns, V. Am. J. Med. 1972, 52, 457. 3. Woods, J. C., Hill, C., Liddle, G. W., Slant, E. G., Michelakis, A. M., Brill, A. B. Archs intern. Med. 1969, 123, 366. 4. Melby, J. C., Dale, S. L., Wilson, T. E. Circulation Res. 1971, 28, suppl. 2, 143. 5. Esler, M., Julius, S., Randall, O. Circulation, 1975, 52, suppl. 2, 55. 6. Esler, M., Julius, S., Randall, O., in The Arterial Hypertensive Disease (edited by G. Rorive and H. van Cauwenberge); p. 231. Paris, 1976. 7. Tuck, M., Williams, G., Cain, J., Sullivan, J., Dluhy, R. Am. J Cardiol. 1973, 32, 637. 8. Esler, M. D., Nestel, P. J. ibid. p. 643. 9. Vander, A. J. Am. J. Physiol. 1965, 209, 659. 10. Collins, R. D., Wemberger, M., Gonzales, C., Nokes, G., Leutscher, J. A. Clin. Res. 1970, 18, 167. 11. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H., Buhler, F. R. New Engl. J. Med 1972, 286, 441.
Haber, E., Koerner, T., Page, L. B., Kliman, B., Purnode, A. J. clin. Endocr. 1969, 29, 1349. 13. Ellis, C. N., Julius, S. Br. Heart J. 1973, 35, 450. 14. Renzini, V., Brunori, C. A., Valori, C. Clinica chim. Acta, 1970, 39, 587 15. Harvey, S. C., Sulkowski, T. S., Weenig, D. J. Archs int. Pharmacodyn. Thér. 1967, 169, 262. 16. Esler, M. D. Clin. Pharmac. Ther. 1974, 15, 484. 17. Dustan, H. P., Tarazi, R. C., Frohhch, E. D. Circulation, 1970, 41, 555. 18. Esler, M. D., Julius, S., Randall, O. S., Ellis, C. N., Kashima, T. Am. J. Cardiol. 1975, 36, 708. 19. Esler, M., Julius, S., Randall, O., DeQuattro, V., Zweifler, A. Clin. Sci molec. Med. (in the press). 20. Lowder, S. C., Hamet, P., Liddle, G. Circulation Res 1976, 38, 105. 21. Jose, A., Crout, J. R., Kaplan, N. M. Ann. intern. Med. 1970, 72, 9. 22. Frohlich, E. D., Tarazi, R. C., Ulrych, M., Dustan, H. P., Page, I. H. Circulation, 1967, 36, 387. 23. Esler, M. D., Nestel, P. J. Clin. Sci. 1973, 44, 213. 24. Biglieri, E. G., Mcllroy, M. B., Naimark, A., Forsham, P H. J. clin. Invest. 1962, 41, 1345. 25. Clement, D. L., Pelletier, C. L., Shepherd, J. T. Circulation Res 1972, 31,
12.
824. 26. Pelletier, C. L.,
Shepherd, J. T.
ibid.
1973, 33, 131.
CIRRHOSIS IN SOUTH LONDON
cen-
tral blood-volume was increased, without an increase in total blood-volume, in six patients, while four patients had severe longstanding hypertension. Adrenal steroid metabolism was not studied by us, so the existence of non-aldosterone mineralocorticoid hypertension in some of these patients is possible.4 These different pathophysiological patterns may all be associated with sympathetic nervous underactivity. Reduced sympathetic responsiveness has been described in severe, longstanding essential hypertension 22 23 although the mechanism is uncertain. Primary aldosteronism, which may be considered as the prototype of human mineralocorticoid hypertension, is also associated with diminished sympathetic nervous responsiveness. 24 In hypertensives with an increase in central
Requests for reprints should be addressed
Section, Department
Medical Center, Ann Arbor,
H.
J.
F. HODGSON*
R. P. H. THOMPSON
St. Thomas’ Hospital, London SE1
Alcoholism was the major ætiological factor in 65% of 78 patients presenting with cirrhosis to a hospital in Central London during 1968-74. It is suggested that in the U.K. the importance of alcoholism in patients with cirrhosis has been underestimated.
Summary
Introduction THERE is little agreement on the relative importance of alcohol in the aetiology of cirrhosis of the liver in the U.K. Surveys in 1966 and 1973 of patients with cirrhosis implicated alcoholism as the primary factor in from 24%’ to 51 %2 of cases. This may be partly because the relative importance of alcohol will vary between surveys carried out in specialised centres and those in less specialised district general hospital. Furthermore, the consumption of alcohol in the U.K. has been steadily increasing over the past 20 years,3 and so the contribution made by alcohol to liver disease may be expected to rise. "Present address:
Department of Medicine, Royal Free Hospital, London NW1
119
surveyed all cases of cirrhosis diagnosed histological grounds between 1968 and 1974 in a London teaching hospital (St. Thomas’) which did not We therefore
on
act as a
referral
centre
for liver disease.
Patients and Methods
During the 6-year period (1968-74) cirrhosis of the liver was diagnosed on histological grounds in 78 patients. The criteria were liver-cell damage, regeneration, and fibrosis4 in all except those patients in the early stages of primary biliary cirrhosis. The patients’ case-histories and biopsy reports were reviewed retrospectively. In 3 patients in whom cirrhosis was an incidental finding at necropsy there was inadequate clinical and laboratory evidence to determine the aetiology of the cirrhosis, and these cases were excluded from the study. Patients were assigned to the following ætiological groups: (1) Alcohol-associated cirrhosis-patients with a history of heavy alcohol intake, estimated at over 120g of alcohol per day for more than 5 years, and a compatible liver biopsy specimen. (2) Active chronic hepatitis with cirrhosis-patients with histological criteria for active chronic hepatitis5 with smooth-muscle or antinuclear antibodies, or hepatitis-B surface antigen present in their sera. (3) Cryptogenic cirrhosis patients in whom the histological appearances of the liver biopsy specimens were those of an inactive, or minimally active, cirrhosis, and who denied heavy alcohol intake. (4) Primary biliary cirrhosis-patients whose liver biopsy specimens fulfilled the criteria of Scheuer and Sherlock,6 and in whose detected.
sera
antimitochondrial antibodies
were
(5) Secondary biliary cirrhosis-patients whose liver biopsy specimens showed the histological appearances of a biliary cirrhosis associated with longstanding extrahepatic biliary
Fig. 1-Etiology of liver disease in 75 patients with cirrhosis.
’
Presenting features.-The single main presenting features in the 49 patients with alcohol-associated cirrhosis are
shown below:
obstruction. Results
All but 7 patients in the survey were resident in London (57 patients) or the south-east (11 patients) at the time of referral. 2 patients were of no fixed abode. No patients resided abroad.
Ætiology Fig. 1
shows the presumed aetiologies of cirrhosis the 75 patients. In 65% of the cases the ciramongst rhosis was alcohol-associated.
Sex incidence.-29 (59%) of the alcoholic patients were women. All those with primen, and 20 and 8 of the 9 patients with active cirrhosis, mary biliary chronic hepatitis, were female. 4 men and 4 women had were
(41%)
cryptogenic cirrhosis. Clinical Features in Patients with Alcoholic Cirrhosis
Age.—The male alcoholic patients were aged 28-75 at presentation, with three-quarters of them presenting between ages 40 and 60. The female alcoholic patients were aged from 38 to 64, over half presenting between ages 50 and 60. Alcohol consumed.-12 patients (10 male, 2 female) said they drank mainly beer, 14 (8 male, 6 female) mainly spirits, and 3 (1 male, 2 female) mainly cider. The remaining patients gave no particular preference. 12 of the 49 (24%) were in occupations directly connected with alcohol (bar staff, publicans, wine waiters, or
brewery staff).
Gastrointestinal hcemorrhage.-During the 6 years of (28%) of the alcoholic patients had gastrointestinal haemorrhage; 8 bled from oesophageal varices, 3 from erosive gastritis, 1 from a gastric ulcer, and 1 from a duodenal ulcer. In 1 patient the source of bleeding was not identified. 3 patients died after episodes of bleeding (2 from varices, 1 from a duodenal ulcer); in all 3 patients there was evidence of severe liver failure (encephalopathy, fetor, and jaundice). Other clinical features.-Ascites developed in 19 the survey, 14
(38%) of the alcoholic patients. Hepatic encephalopathy developed in 11 of whom 6 died shortly afterwards. Associated diseases.-17 of the 49 patients with alcoholic cirrhosis had other chronic medical conditions, namely: duodenal ulcer (4 patients); neoplasms other than primary liver-cell carcinoma (3); acute relapsing pancreatitis (2); diabetes (2); pulmonary tuberculosis (2); hypertension (2); porphyria cutanea tarda (1); chronic bronchitis and emphysema (1). Routine Liver Function Tests Serum
concentrations, where available, of bilirubin,
alkaline phosphatase, glutamic oxaloacetic transaminase (s.G.o.T.), albumin, and globulin at presentation are
120
Fig. 2-Results of tests of liver function at admission in patients with cirrhosis. Those in 3 patients with hepatoma are shown by triangles.
shown in fig. 2. Only 7 of the 49 patients (14%) had abnormalities in any of these standard tests.
no
-
Prognosis Because the
study period extended from 1968 to final survival 1974, figures cannot be given. 10 men and 3 women died during the period of study, 5 within a year of diagnosis. The mean age at death of the 10 men was 56 years, and of the 3 women, 48 years. The causes of death are given below:
Discussion In this unselected retrospective series of patients with cirrhosis of the liver, alcohol was the most important oetiological factor. Although some patients with cryptogenic cirrhosis may have been wrongly included, it is likely, in view of the known difficulty of eliciting a history of alcoholism, that our results underestimate the importance of alcohol. The frequency of alcoholism in our patients (65%) is similar to that of American and European series (Boston, U.S.A. 83%;’ Rochester, U.S.A. 64%;" Chile 78%;9 Vienna 76%10 and is notably higher than most English series. In 1966 a specialist referral centre in London reported that 24% of cirrhosis was due to alcoholism,1 and a district hospital in Birmingham reported figures of 33% in 1959-1964," and 51% in 1964—1969 .2 Our results, however, are more in accord with the frequency of 64% briefly reported from Liverpool in 1972,12 and the 56% reported in London in the late nineteenth century.13 The figures from Birmingham2 11 have shown an in-
a decade in the frequency of alcoholism among patients with cirrhosis, and our experience confirms this. The annual consumption of alcohol has increased over the past two decades and the incidence of alcoholism is increasing,3 so this trend may be expected to continue. 41% of our patients with alcoholic cirrhosis were female, compared with 30% in London in 1966,’ 20% in Birmingham in 1968,11 and 36% in Liverpool in 1972,12 The higher proportion in more recent surveys may be due to the increase in alcoholism amongst women.’4 It is unlikely, however, that 40% of alcoholics are female, and indeed, a survey in Camberwell, an area of London in which many of our patients live, showed that during the same years as our study, alcoholism was six times more common amongst men than women in that area.15 Whilst the high proportion of females with cirrhosis in our series suggests that women who drink alcohol to excess may be more likely to develop cirrhosis than men, further evidence is required. The clinical features in our patients with alcoholic cirrhosis conform to the recognised pattern. Ascites, oedema, and jaundice were common presenting features; gastrointestinal bleeding was often from causes other than oesophageal varices.12 The liver function tests showed no specific abnormalities, and any or all of them were often normal. At the end of this survey primary liver-cell carcinoma had developed in 3 patients, but the final frequency will almost certainly be greater. Serumalkaline-phosphatase was markedly elevated at presentation in all 3 carcinoma cases, but this feature was also found in patients in whom no tumour has yet been diagnosed (fig. 2). This survey suggests that alcohol is the major cause of hepatic cirrhosis in London, as it appears to be in other cities of the western world. With increasing con-
crease over
121
sumption of alcohol the incidence of cirrhosis will rise, and so the early diagnosis of alcoholism is a priority in health care. Recognition that liver damage is due to alcohol is worthwhile, because there is evidence that even when cirrhosis is established the prognosis can be improved by abstinence,’6 although not all studies accord with this view. 17 A careful history from the patient and his relatives and the examination of the histological appearances of a liver biopsy specimen are often required to establish the aetiology. Requests for reprints should be addressed
to
intermittent swelling of the bitten limb.’Zagreb antivenom became available in Britain in 1969. Experimentally, it is very effective in neutralising Vipera berus venom and it is highly purified. Because of a death due to Pasteur antivenom in 1957 and other factors, many clinicians in Britain are reluctant to use antivenom. We have therefore assessed the effectiveness of Zagreb antivenom in monkeys, simulating so far as is practicable the clinical problem of adder-bite poisoning in man. Methods
R. P. H. T.
REFERENCES 1. Sherlock, S. Acta med. scand. 1966, suppl. 445. p. 426. 2. Jain, S., Paton, A., Wansbrough-Jones, M. H. Midland med. Rev. 1973, 9, 13. 3. Br. med. J. 1972, iv, 625. 4. Gastroenterology, 1956, 31, 213. 5. de Groote, J., Desmet, V. J., Gedigk, P., Korb, G., Popper, H., Poulsen, H., Scheuer, P. J., Schmid, M., Thaler, H., Uehlinger, E., Wepler, W. Lancet, 1968, ii, 626. 6. Sherlock, S., Scheuer, P. J. New Engl. J. Med. 1973, 289, 674. 7. Garceau, A. J., Chalmers, T. C. ibid. 1963, 268, 469. 8. Douglass, B. E., Snell, A. M. Gastroenterology, 1950, 15, 407. 9. Armas-Cruz, R., Yazigi, R., Lopez, O., Montero, E., Cabello, J., Lobo, G. ibid. 1951, 17, 327. 10. Schneiderbaur, A. Wien. med. Wschr. 1964, 114, 738. 11. Stone, W. D., Islam, N. R. K., Paton, A. Q. Jl Med. 1968, 37, 119. 12. Forshaw, J. Br. med. J. 1972, iv, 608. 13. Rolleston, H. D., Fenton, W. J. Birmingham med. Rev. 1896, 40, 193.
14. Glatt, M. M. Br. J. Hosp. Med. 1974, 11, 111. Edwards, G., Hawker, A., Hensman, C., Peto, J., Williamson, V. Br. J. Psychiat. 1973, 123, 169. 16. Brunt, P. W., Kew, M. C., Scheuer, P. J., Sherlock, S. Gut, 1974, 15, 52. 17. Soterakis, J., Resnick, R. H., Iber, F. L. Lancet, 1973, ii, 65. 15.
Thirteen male rhesus monkeys (Macaca mulatta) weighing 4-8-8-0kg were studied. Before each injection and venepu ncture the monkeys were sedated with intramuscular ketamine hydrochloride 10-17 mg/kg. Three control monkeys received intravenous Zagreb antivenom (from Regent Laboratories Ltd., Cunard Road, London NW10 6PN) or subcutaneous adrenaline but no venom. Ten monkeys received V. berus venom (from Czechoslovakia, kindly donated by F. Kornalik), in amounts detailed in the accompanying table. The venom in 0.25 ml saline, was injected subcutaneously into the back of the right hand. Five of these ten monkeys received no antivenom, in order to determine the approximate lethal dose for rhesus monkeys and to assess the natural history of non-lethal poisoning. The other five monkeys received Zagreb antivenom by slow injection into the femoral or subclavian vein 1-4 hours after venom injection. At this stage all monkeys were in shock and, although the antivenom did not seem to cause any adverse effect on the monkeys, 0.5 ml 1/1000 adrenaline was injected subcutaneously 5 minutes after the antivenom injection was completed.
Investigations
EFFECTIVENESS OF ZAGREB ANTIVENOM AGAINST ENVENOMING BY THE ADDER, VIPERA BERUS R. D. G. THEAKSTON
H. A. REID
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA Rhesus monkeys injected subcutaneously with 2, 3, or 4 mg Vipera berus venom per kg body-weight all died in shock. With 1 mg/kg the monkey had severe systemic and local effects taking 12 days to resolve. Five monkeys each received 4 mg/kg (a triple-lethal dose) and Zagreb antivenom was injected intravenously 1-4 hours after venom injection. The contents of 2 ampoules (10.8 ml) up to 3 hours later saved the monkeys; at 4 hours later the monkey died. But when the antivenom dose was raised to 16.2 ml 4 hours after venom, it saved the monkey. In addition to saving life, the antivenom greatly reduced the local venom effects. It is suggested that the results justify giving Zagreb antivenom to patients with severe adder-bite poisoning; and it should also be considered in adults to minimise morbidity from local effects.
Summary
Introduction ALTHOUGH adder bites in Britain are uncommon and when they do occur poisoning is often trivial, nevertheless severe poisoning sometimes results and on rare occasions it is fatal. Adults may take weeks or months to recover and can be unpleasantly troubled by pain and
Shock was deemed present when the monkey was cold and cyanosed, peripheral pulses were impalpable, and ear-prick blood was no longer obtainable. Monitoring the blood-pressure was attempted with a Roche ultrasonic ’Arteriosonde’ but proved unsatisfactory; invasive methods of monitoring the blood-pressure were considered unsuitable. Local swelling, assessed by circumference measurements to the nearest 0.5cm at the same marked level of both hands, wrists (thinnest part), forearms (fattest part), and arms (middle) is expressed as percentage increase (total of all 4 measurement sites) compared with those before venom injection. Electrocardiogram (E.C.G.) recordings and blood-samples were taken before venom injection and at various intervals up to and including terminal stages or complete recovery. On the blood-samples the following studies were performed by methods previously recorded:2 leucocyte-count, plateletcount, haemoglobin, hacmatocrit, thrombin-clotting time, assay of factors v, vn, vin, tx, and x, plasma-fibrinogen, levels of serum-fibrinogen/fibrin-degradation products, lysis of fibrin plates by plasma, and euglobulin fractions. Plasma urea, proteins, and potassium, sodium, bicarbonate, creatine phosphokinase, aspartate, and alanine aminotransferases were assayed by routine procedures. Details of E.C.G. changes, hsematology including coagulation tests, complement profiles, biochemistry, and morbid pathology will be published elsewhere.
Results Untreated Monkeys
Monkeys receiving 2-4 mg/kg venom died (see table). Shock and E.C.G. changes started within 20 minutes with 4 mg/kg and in all fatal cases persisted till death (see table). Vomiting and diarrhoea, which are common in human poisoning, did not occur. Local swelling and hæmorrhagic discoloration were mild in fatal cases as the monkeys did not live long enough for them to fully