TRIMETHYLAMINE METABOLISM IN LIVER DISEASE

1106 The two samples of lactoferrin (Dr Masson and Dr Baudner) were immunologically identical on testing by doublediffusion technique, and the precipitating lines between each immune serum and each lactoferrin fused completely. The immunoplates contained twelve wells. Three were filled with 2 x 20 A of standard lactoferrin diluted 1/2 (20 g/ml), 1/4, and 1/6. The other wells contained 2 x 20 .1 of the different pancreatic juices, concentrated by lyophilisation or alcoholic precipitation. The protein content (measured by optical density at 280 nm with an extinction coefficient of Efïfi 20) ranged from 9 to 47 mg/ml juice. The plates were allowed to diffuse 48 h at 20 °C and then washed with isotonic saline for 3 days. The plates were stained for 1 min in 0-1% amidoschwarz (Merck) and then destained in 10% acetic acid. A standard curve was constructed by plotting the square of the diameter of the rings of precipitation against the lactoferrin concentration, and lactoferrin concentrations of samples of pancreatic juice were read off from this standard curve. By this method it is possible to visualise a lactoferrin concentration of about 2 Lg/ml to 25 fLg/ml. These results are shown in the figure, expressed as a percentage of total protein. The data obtained by radial immunodiffusion and those given by radioimmunoassay were in good agreement. The two assays confirm the increased lactoferrin concentration in juice from men with chronic pancreatitis. In six normal juices the range is from 0.002 to 0-02% with a mean of 0.013%, and in six juices from men with chronic calcifying pancreatitis from 0.033 to 0.92% with a mean of 0-23%. The assay of lactoferrin on immunoplates may be as accurate as radioimmunoassay, and can be easily set up in the

The crucial question is-how do the minor hazards of interrupting whole-body irradiation compare with anaesthetic complications in a patient who will often already have received considerable cytotoxic chemotherapy? Cape Town Leukæmia Centre and Departments of Hæmatology and Radiotherapy,

PETER JACOBS HELEN S. KING

Groote Schuur Hospital, Observatory, Cape Town, South Africa

=

laboratory. Unité de Recherches de

Pathologie Digestive

(INSERM U31),

C. FIGARELLA

TRIMETHYLAMINE METABOLISM IN LIVER DISEASE

SiR,—Trimethylamine (T.M.A.), a highly volatile amine, is responsible for the odour of rotting cartilaginous marine fish. The major source of T.M.A. in man is the metabolism of dietary choline by intestinal bacteria. T.M.A. formed in this way is normally absorbed into the splanchnic venous system and is converted to the stable non-volatile T.M.A.-N-oxide by the hepatic enzyme amine oxidase.2.3 Any T.M.A. not oxidised enters the systemic circulation where it is excreted in urine, breath, and sweat, normally in minute quantities. Interference with the hepatic metabolism of T.M.A. could be expected in patients with cirrhosis of the liver, because of impaired hepatocellular function or because of the presence of portasystemic venous shunts. This would result in increased levels of T.M.A. entering the systemic vascular system to be excreted in increased amounts in both breath and urine. In a pilot study to investigate this possibility, urinary trimethylamine excretion was measured in patients with liver disease.

J. P. ESTEVENON

46 chemin de la Gaye, 13009 Marseille, France

H. SARLES

1. Gruger, E. H. J. agric. Food Chem. 1972, 20, 781. 2. Lintzel, W. Biochem. Z. 1934, 273, 244. 3. de la Huerga, J., Popper, H. J. clin. Invest. 1951, 30,

GENERAL ANÆSTHESIA FOR HIGH-DOSE TOTAL-BODY IRRADIATION

SIR,-Dr Whitwam and his colleagues (Jan. 21,

p. 128) deof general anaesthesia for patients undergoing whole-body irradiation. In the light of our experience with this form of radiotherapy we are concerned that our British colleagues should have found it necessary to resort to general anaesthesia. In our bone-marrow transplantation programme the patients with refractory or relapsed acute leukaemia are irradiated over a 2 h period from alternate sides of the body to a dose of 1000 rad determined in the midplane at the level of the pelvis, and special attention is given to protection of the ,hands from undue exposure. We can appreciate that there are benefits of general anaesthesia in this setting, but do not think that it is routinely necessary. We find premedication with metoclopramide for 48 h before irradiation and chlorpromazine immediately before exposure is remarkably effective. We cannot claim that our patients do not become nauseous, but we have never had to discontinue irradiation for this reason, although further anti-emetics may occasionally be required after the first hour; we have certainly not encountered the situation where therapy needed to be interrupted twenty times. On the day of radiotherapy the patients receive diphenoxylate and codeine phosphate as prophylaxis against the diarrhoea that may follow from radiation sickness. The doses are adjusted to meet individual requirements. Our greater concern, however, is the effect that anaesthetic agents may have on the liver; for example, cytotoxic drugs are hepatotoxic’ and, particularly when combined with radiation (unpublished) may result in hepatitis.

scribe the

1.

use

Penta, J. S., 247.

von

Hoff, D. D., Muggia,

F. M. Ann.

intern.

Med.

1977, 87,

T.M.A. responses to choline

463.

1107 Twelve patients with established chronic liver disease were studied and the results compared with those obtained in nine apparently healthy controls. Subjects were studied while on a normal diet containing 500-900 mg choline/24 h and also after a 5 g oral choline load given in divided doses over 24 h. T.M.A. in a 5 ml sample of freshly voided early morning urine was immediately converted to the more stable T.M.A.-hydro-

0-1 Bool/I hydrochloric acid. T.M.A. in 5 µl aliquots of urine was measured by gas chromatography.4.s Each urine sample was also analysed for creatinine. Results are expressed as a T.M.A./creatinine ratio (flmol T.M.A./mmol chloride by adding

Commentary from Westminster From Our

Parliamentary Correspondent

The Review Body’s Report

creatinine). In the nine normal subjects, the T.M.A./creatinine ratio rose from a mean basal or precholine level of 2.2 (s.D.1-4) to a mean postcholine level of 3.4 (1-3). In the twelve patients with liver disease, the T.M.A./creatinine ratio rose from a mean basal level of 15.5(10-3) to a postcholine mean of 103.3(102.3). The basal urinary T.M.A./creatinine ratio of normal subjects was significantly greater than that of the patients with liver disease (P<0.005) and the increase in urinary T.M.A./creatinine ratio after choline loading was significantly greater (p<0.005) im the patients with liver disease than normal. Choline loading produced an absolitte separation in the ratio between the patients and the normal controls (figure). This preliminary study suggests that T.M.A. metabolism is disturbed in liver disease, and that measurement of urinary T.M.A. after a choline load could prove a sensitive index of this

hepatocellular dysfunction. Impaired hepatic metabolism of T.M.A. could be of potential significance in the pathogenesis of both hepatic fetor and encephalopathy. In renal failure, urinary excretion of T.M.A. is impaired and excess T.M.A. is excreted by the lungs, contributing to the odour of urasmic breath.6 In our study the odour of T.M.A. was clinically detectable in the basal urine samples of two of the patients with liver disease and was evident in eight others after the choline load. Since T.M.A. is highly volatile it will also be excreted in increased amounts in the sweat and breath of these patients, and could contribute to the odour of fetor hepaticus. An unusual encephalopathy manifested by lethargy and personality change which progressed to convulsions and stupor has been described in a patient with trimethylaminuria,7 a metabolic disorder associated with a decrease in hepatic amine oxidase activity. Preliminary studies in rats have demonstrated that T.M.A. in very high doses can induce encephalopathy and coma.9 Ammonia, free fatty acids, and mercaptans act synergistically to produce encephalopathy in animals.10.1l If T.M.A. acts synergistically with these compounds, the high levels of T.M.A. in liver disease could also contribute to the pathogenesis of hepatic encephalopathy.

study was supported in part by the Alfred Hospital Dr Henry scholarship and the George Adams dermatology research fellowship. This Laurie

of Medicine, Monash University, and Gastroenterology Service and

Department

ROBIN MARKS FRANK DUDLEY ABRAHAM WAN

Biochemistry Department, Alfred Hospital

Prahran, Melbourne, Australia

4.

Marks, R., Greaves,

M.

W., Danks, D., Plummer, V. Br. J. Derm. 1976, 95,

Suppl. 14, 11. 5. 6.

Marks, R., Greaves, M. W., Prottey, C., Hartop, P. J. ibid. 1977, 96, 399. Simenhoff, M. L., Burke, J. F., Saukkonen, J. J., Ordinario, A. T., Doty,

7.

Danks,

R. New Engl. J.Med. 1977, 297, 133. D. M., Hammond, J., Schlesinger, P., Faull, K., Burke, D., Halpern,

B. ibid. 1976, 295, 962. 8. Higgins, T., Chaykins, S.,

Hammond, K. B., Humbert, J. R. Biochem. Med.

1972, 6, 392. 9. Marks, R., Dudley, F. J. Unpublished.

10. Zieve, F. J., Zieve, L., Doizaki, W. M., Gilsdorf, R. B. J. Pharmac. exp. Ther. 1974, 1911, 10. 11. Zieve, L., Doizaki, W. M., Zieve, F. J.

J. Lab. clin. Med. 1974, 83, 16.

AN air of

very enthusiastic acceptance was the of doctors and dentists to last reaction predominant Review week’s Body report on their pay. The document, the recommendations of which the Government has accepted, fell well short of convincing most of the beneficiaries that they were likely to be justly treated in the years ahead, but it appeared to have done just enough to prevent any widespread industrial action this summer. That at least was the initial response. This week and in the days ahead the report will be considered in detail by all the groups concerned. The general sentiments in the document will find total support in the profession. The Review Body has done exactly what the British Medical Association and others asked of it. It has assessed precisely what doctors and dentists ought to get to bring them back into line with other professional groups. It says that years of pay restraint, tailored in the main for the industrial shop floor, have distorted incomes. The concept of self-financing productivity schemes simply does not fit in with a profession whose concern is preventing and controlling disease. If the present serious decline in morale is not reversed, says the report, the consequence for the National Health Service and for the community as a whole will become increasingly serious. It adds: "The community can ill afford to prolong indefinitely a situation in which the rewards of those whose responsibility it is to provide care for the health of the community are left to lag substantially behind rewards in other fields, some of which may not be as essential to the general needs of the community". The report is rich in facts and figures to support its general theme. The standard of living of a general practitioner or a consultant with a few years’ seniority, married with two children under 11, is estimated to have fallen by 18-19% between April, 1975, and April, 1977, and that of a junior hospital doctor by between 6% and 9%. In contrast the fall for the average wage or salary earner has been less than 5%. So the report recommends, and the Government has accepted, a staged deal offering 10% now and a further 18-5% by 1980 at a cost of (66 million now and (135 million later. But despite the profession’s own wish for an across the board increase of 10% now, the Board decided on increases ranging from 4.4% for junior doctors to 19% for consultants. The plight of consultants is given great emphasis in the report. It points to a significantly smaller increase in numbers last year attributed to the reluctance of some doctors, notably senior registrars, to accept promotion that would involve a reduction in their income. Consequently the number of vacant consultant posts increased considerably last year from 686 to 819, as did the number of posts unfilled for more than a year. Referring to the implementation of the second stage of the April, not