DISACCHARIDE INTOLERANCE AND MUCOVISCIDOSIS

120

the possibility that the injected cells do not act directly on the tumour but initiate or augment an immune response in the host cannot be excluded.

Summary

primary chemically induced fibrogrowth sarcomata in rats was delayed, and in some instances lengthy regressions were obtained, by treatment with lymphoid cells from other rats that had previously received an implant obtained by biopsy from the tumour to be treated. Repeated injections of cells provided by several donors were necessary. Thoracic-duct lymphocytes were given intravenously, and those from lymph-nodes intraperitoneally. In the majority of studies the tumour-bearing animals were not isogenic with the donor rats. Similar results were obtained, however, where both donor and host were pure-line isogenic rats. A graft-against-host reaction seems not to be involved, and the effect of the treatment appears to depend on the direct or indirect action of lymphocytes which are immunised against specific tumour antigens which were shown to be present in these The

of

tumours. We should like to express our indebtedness to Prof. Alex Haddow, F.R.S., for the help, advice, and encouragement he has given us, and to Mrs. Z. B. Mikulska for making her data on the in-vitro neutralisation of tumour cells by spleen cells available to us. This investigation was supported by grants to the Chester Beatty Research Institute from the Medical Research Council, the British Empire Cancer Campaign, and the National Cancer Institute of the National Institutes of Health, U.S. Public Health Service. REFERENCES

Albright, J. F., Makinodan, T., Mazur, P. (1963) Proc. Soc. exp. Biol., N.Y. 114, 489. Balme, R. H., Dockerty, M. B., Grindley, J. H., Litzow, T. J. (1962) Minn. Med. 45, 892. Boyse, E. A. (1960) Transplant. Bull. 7, 100. Delorme, E. J. (1961) Lancet, ii, 855. Gorer, P. A., Amos, D. B. (1956) Cancer Res. 16, 338. Haddow, A., Alexander, P. (1964) Lancet, i, 452. Klein, G., Klein, E. (1962) Cold Spr. Harb. Symp. quant. Biol. 27, 463. Sjogren, H. O., Klein, E., Hellstrom, K. E. (1960) Cancer Res. 20, —

1561.

Old, L. J., Boyse, E. A. (1964) Annu. Rev. Med. 15, 167. Prehn, R. T. (1963) Proceedings of the Vth Canadian Cancer Conference; p. 387. New York. — Main, J. M. (1957) J. nat. Cancer Inst. 18, 769. Stuart, A. E. (1962), Lancet, ii, 180. Woodruff, M. F. A., Symes, M. O. (1962) Brit. J. Cancer, 16, 707. Anderson, N. F. (1963a) ibid. 17, 482. Stuart, A. E. (1963b) ibid. p. 320. —

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DISACCHARIDE INTOLERANCE AND MUCOVISCIDOSIS R. H. TREFOR JONES M.B. Lpool, D.C.H. ST.

REGISTRAR IN PEDIATRICS, DAVID’S HOSPITAL, BANGOR, NORTH

WALES

THE clinical significance of failure to utilise some disaccharides depends on the importance and the amount of the disaccharide in the diet. Either the enzyme

and one other son were healthy. At the time of the pregnancy the mother was aged 23, and the pregnancy and delivery had been normal. The birthweight of the baby was 6 lb. 3 oz., and feeding was begun on the 2nd day with breast milk. At 5 days the feeding had to be supplemented with fullcream national dried milk because of the child’s failure to regain his birthweight. When he was discharged home on the 8th day, he still weighed only 5 lb. 11 oz. At 6 months the child was referred to the clinic because of recurrent chest infections and a history of occasional pale stools. His weight was then 14 lb. 1 oz., and his diet consisted of fullcream national dried milk, Scott’s oats, Heinz baby foods, and barley rusks. He was pale, with a wheezing chest and a loose cough. No grossly abnormal physical signs were noted, except for scattered expiratory rhonchi. He was given a course of antibiotics by mouth for 2 weeks, after which his respiratory symptoms subsided. At 11 months the child was referred again to the clinic because of failure to gain weight. At this attendance he weighed only 16 lb. 14 1/2 oz., which was the same as 3 months earlier. He now had a history of about five to six bowel movements daily. The stools were loose, frothy, pale, and offensive, and they were accompanied by excessive flatulence. The boy had become irritable, and he screamed or cried most of the time. His mother had noticed a relation between the amount of milk he drank and the frequency and the severity of the diarrhoea. He was now obviously wasted, with very thin limbs and a large protuberant tympanitic abdomen. His buttocks were flattened, and on the inner aspects of both thighs the skin lay loosely in folds. He had a severe napkin rash which was gradually extending down both legs. There was slight dyspnoea with an associated wheeze, and expiratory rhonchi were heard in all areas of his chest. The child was admitted to hospital for investigation and treatment as a case of mucoviscidosis.

Investigations The haemoglobin was 66% and the blood-count was normal; urine examination was negative. The faecal fat content was 24% of the dry weight. On stool analysis no pathogen was isolated, and no exudate, cyst, or ovum was seen. There was no tryptic activity of the duodenal juice (two estimations) or of the fxces (three estimations). The sweat test, carried out on two occasions, gave values for sodium of 27 and 10 mEq. per litre, and the chloride was 8 mEq. per litre (as estimated by pilocarpine iontophoresis). There was insufficient sweat for a second chloride estimation. Chest X-ray revealed no evidence of pulmonary disorder. Course In view of the clinical picture of malabsorption with recurrent respiratory infection and foul-smelling stools, together with the laboratory evidence (except for sodium and chloride levels in the sweat), mucoviscidosis seemed the obvious diagnosis. Treatment was therefore given with 1 tablet of pancreatin (’Pancrex V ’) four times daily, and a normal diet. After a week or more there was no improvement nor had the weight increased. His stools continued to be frothy, frequent, and offerrsive. In consequence, the child’s

for hydrolysis of the disaccharide may be congenitally absent or there may be a transient deficiency or inhibition of the enzyme. The symptoms of this lack of hydrolysis are due to the failure of absorption of the disaccharide, and the consequences of its increased accumulation in the small intestine. The clinical disturbance is cus-

(disaccharidase) responsible

tomarily referred intolerance.

to as

disaccharide

Case-report patient, boy, was born at St. David’s Hospital in September, 1962. Both parents The

a

Disaccharide-tolerance

curves

(d) glucose-galactose. M:R.

=

for (a) lactose, with (b) sucrose, (c) maltose, and maximum rise.

121 SUCROSE CONTENT OF CERTAIN

FOODS*

*

According to Winton and Winton, 1946. disaccharide tolerance was tested, and the results are shown in the accompanying figure. A rise of less than 25 mg. per 100 ml. in blood-glucose after the ingestion of a loading dose of disaccharide has been said to indicate a failure in absorption. The finding of an abnormally low disaccharide-tolerance curve for lactose as well as for sucrose suggested that the child was unable to hydrolyse these sugars. Treatment was therefore begun with a diet containing very little lactose (’ Low-Lactose’, Cow and Gate) and as free as possible from sucrose (see table). To this diet was added pancreatin tablets and supplementary iron and vitamins. For 2 weeks there was very little change in the infant’s weight, though his general condition was very much improved. The number of bowel movements had decreased appreciably, as well as the accompanying frothiness and excessive flatulence. At this stage a severe chest infection developed, accompanied by a paroxysmal productive cough, and with signs confined mainly to both lung bases. A chest X-ray showed the increased density of simple inflammation at the right base. Gastric contents were cultured, and they twice grew Staphylococcus pyogenes, which was sensitive to methicillin. A course of methicillin for 10 days brought remission of the signs and symptoms. The child has since continued to take cloxacillin 125 mg. twice daily, and he has been relatively free from respiratory infection. There has been a steady gain in weight, and his general condition has continued to improve. The diarrhoea has not recurred, and his protuberant abdomen and flattened buttocks are slowly reverting to normal.

Discussion

utilise lactose when it forms the main carbohydrate in the diet and when it constitutes about half the total daily calorific requirement naturally has a profound effect on nutrition. Ordinarily, lactose is hydrolysed into glucose and galactose by the action of lactase, and the galactose thus formed is converted into glucose; hence all hydrolysed lactose is eventually converted into glucose. Excessive lactose in the small intestine increases bacterial breakdown. In consequence, the stools become frequent (often as many as ten a day), foul-smelling, and frothy. The increase in gaseous byproducts gives rise to excessive flatulence, increased peristalsis, and colicky abdominal pain. The raised content of lactic acid in the stools causes an excoriating rash of the buttocks. The laboratory findings reflect a sluggish rise in blood-glucose after the ingestion of lactose or other disaccharide. Giving a diet free of lactose or the offending disaccharide results in remission of the symptoms and eventual return to normal weight and health. Sucrose intolerance was described by Prader et al. (1961) in five children. Each had normal lactose and maltose tolerance curves, but a low response to sucrose. Weijers (1960) described three cases of the same condition; two had normal lactose and maltose tolerance curves, and the third showed intolerance to both sucrose and maltose. Holzel et al. (1959) reported the case of two siblings who showed a normal disaccharide tolerance to all but lactose. Its occurrence in two siblings suggested that the Failure

to

condition was inherited. A further case was later described by Holzel et al. (1962) and also by Durand (1958). Recently Cozzetto (1963) has described a case of concurrent lactose intolerance and mucoviscidosis. In this patient, as in others, there was an abnormal lactosetolerance curve but normal responses to sucrose, maltose, and glucose-galactose; and the sodium and chloride levels of sweat were raised. Tryptic activity was absent in the duodenal juice and in the faeces. Enzyme assay of a biopsy specimen of jejunal mucosa revealed reduced lactase activity but normal sucrase activity. Dahlqvist (1962) and others have shown that the small intestine contains at least six different enzymes which are concerned with hydrolysis of disaccharides. Disaccharide intolerance may be either a primary or a secondary disorder. The primary disorder, is a congenital inborn error of metabolism owing to the absence of a particular disaccharidase. This is the condition which Holzel et al. (1959) describe as alactasia. The secondary type is found in association with acute or chronic diarrhoea of other origin, and this is transient. Frothy stools were not present in our patient until about the age of 9 months, though pale stools were recorded at 6 months. The probability, therefore, is that this child’s primary disease was mucoviscidosis, and that the chronic diarrhoea resulting from the lack of trypsin eventually inhibited the action of invertase and lactase, causing transient disaccharide intolerance. The patient has continued on a low lactose and sucrose diet with added pancreatin; his bowel now acts once daily, and the fxces are normal in colour and consistence. The lactose and sucrose tolerance curves have not been

repeated.

Summary

Intolerance to lactose and sucrose in an infant was probably the result of chronic diarrhoea due to mucoviscidosis. I should like to thank Dr. Gwyn Griffith, consultant paediatrician, for his permission to publish the case-report; Dr. H. Edwards for photographs; and Mr. R. A. Evans of the department of agricultural biochemistry, University College of North Wales, for his help with the sucrose-free diet. REFERENCES

Cozzetto, F. J. (1963) Pediatrics, 32, 228. Dahlqvist, A. (1962) J. clin. Invest. 41, 463. Durand, P. (1958) Minerva pediat. 10, 706. Holzel, A., Schwarz, V., Sutcliffe, K. W. (1959 Lancet, i, 1126. Mereu, T., Thompson, M. L. (1962) ibid. ii, 1346. Prader, A., Auricchio, S., Mürset, G. (1961) Schweiz. med. Wschr. 91, 465. Volwiler, W. (1957) Amer. J. Med. 23, 250. Weijers, H. A., van de Kamer, J. H., Mossel, D. A. A., Dicke, W. K. (1960) Lancet, ii, 296. Winton, A. L., Winton, K. B. (1946) Structure and Composition of Foods. —

PHENACETIN AND THE KIDNEY A. K. BROWN LATE MEDICAL

M.B. Manc., M.R.C.P. REGISTRAR, ANCOATS HOSPITAL,

M.B.

MANCHESTER *

R. PELL-ILDERTON Manc., M.C.Path., Dip.Path.

CONSULTANT PATHOLOGIST, ANCOATS HOSPITAL, MANCHESTER "

single typical case of phenacetin nephropathy " reported in the United Kingdom (Sanerkin and Weaver 1964) contrasts sharply with the numerous reports of the condition from other countries (Moolten and Smith 1960, Hultengren 1961, Nordenfelt and Ringertz 1961, McCutcheon 1962, Harvald 1963). As this may be owing to failure to recognise the condition, we here describe the history and postmortem findings in a further case. THE

* Present address:

Liverpool.

Cardiology Department,

Sefton General

Hospital,