A M Dawson

Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease

51 patients with Crohns disease who were in good health while taking azathiprine, 2 mg/kg body-weight/day, for at least six months were allocated either to a group in which azathioprine was continued or to one in which a control tablet was substituted. The trial lasted one year unless relapse recurred earlier. The cumulative probability of relapse was nil at six months and 5% (+/-5 S.D.) at a year among those on azathioprine, compared with 25% (+/-9 S.D.) at six months and 41% (+/-11 S.D.) at a year among those in the control group (P less than 0.01). 1 patient in whom azathioprine was continued died of pancytopenia in the fourth month of the trial. Azathioprine is potentially toxic but appears to reduce the relapse-rate in Crohns disease.

SITE OF PAIN FROM THE IRRITABLE BOWEL

The distribution of pain from the colon was examined in normal subjects and in patients with irritable bowel syndrome (IBS). Colonic pain was induced by inflating a balloon (introduced during colonoscopy) at several sites throughout the colon. The pain was felt predominantly in the central, lower, and left abdomen in nine patients presenting with rectal bleeding and no spontaneous pain. Pain was felt in any part of the abdomen in 48 patients with painful IBS. Distension of the ascending and transverse colon often produced right-sided or upper abdominal pain in patients with IBS and in 29 of the 48 the pain induced was the same in quality and site as their presenting complaint. In addition pain was referred to several, previously undescribed, extra-abdominal sites. Wider recognition of the distribution of colonic pain could prevent unnecessary investigations including laparotomy.

Male gonadal function in coeliac disease: 1. Sexual dysfunction, infertility, and semen quality

The prevalence of hypogonadism, sexual dysfunction and abnormalities of semen quality was determined in 28 consecutive males with coeliac disease. These observations were related to jejunal morphology and nutritional status, and were compared with findings in 19 men with Crohns disease of similar age and nutritional status. Two of the 28 coeliacs (7%) had clinical evidence of hypogonadism but impotence and decreased sexual activity occurred more commonly, the latter apparently improving after gluten withdrawal. Of the married coeliacs, 19% had infertile marriages, a value greater than expected in the general population. Hypogonadism and sexual dysfunction were not detected in our patients with Crohns disease. Seminal analysis in coeliacs revealed marked abnormalities of sperm morphology and motility, but only the former appeared to improve after gluten withdrawal. Similar abnormalities, however, were also detected in patients with Crohns disease, although, unlike the coeliacs, 46% also had reduced concentrations of spermatozoa. Semen quality in coeliac disease could not be clearly related to general or specific (serum vitamin B12 and red cell folate) nutritional deficiencies or to fertility, although sperm motility was markedly reduced in two of the three coeliacs with infertile marriages. The presence of antisperm antibodies did not appear to be an important aetiological factor in male infertility in coeliac disease. The pathogenesis of infertility and sexual dysfunction in coeliac disease remains unclear, suggesting that factors such as endocrine dysfunction or other specific nutritional deficiency may be involved.

COLONOSCOPIC DIAGNOSIS OF MINIMAL CHANGE COLITIS IN PATIENTS WITH A NORMAL SIGMOIDOSCOPY AND NORMAL AIR-CONTRAST BARIUM ENEMA

8 patients with normal sigmoidoscopic appearances and normal results by high-quality air contrast barium enema had substantial or total colitis diagnosed for the first time at colonoscopy performed within a month of the radiological examination. Colitis was confirmed in all 8 patients by histological examination of biopsy specimens. Barium enema radiographs were independently reviewed by three experienced observers who also reviewed other normal and abnormal radiographs. One observer regarded all 8 sets of radiographs from the patients with colitis as being of normal appearance, and 4 patients were reported as having normal radiographs by all three observers. All 7 of the rectal biopsy specimens taken showed histological features of inflammatory bowel disease. This emphasises the importance of performing a rectal biopsy in patients with gastrointestinal symptoms of unknown cause.

Male gonadal function in coeliac disease: 2. Sex hormones.

Hypogonadism, infertility, and sexual dysfunction occur in some men with coeliac disease. We have measured plasma testosterone, dihydrotestosterone, sex-hormone binding globulin, oestradiol, and serum luteinising hormone in 41 men with coeliac disease and have related these findings to jejunal morphology, fertility, semen quality, and sexual function. To determine the specificity of these observations in coeliacs we also studied 19 nutritionally-matched men with Crohns disease, and men with chronic ill-health due to rheumatoid arthritis and Hodgkins disease. The most striking endocrine findings in untreated coeliacs were increased plasma testosterone and free testosterone index, reduced dihydrotestosterone (testosterones potent peripheral metabolite), and raised serum luteinising hormone, a pattern of abnormalities indicative of androgen resistance. As jejunal morphology improved hormone levels appeared to return to normal. This specific combination of abnormalities was not present in any of the disease control groups and, to our knowledge, androgen resistance has not been described previously in any other non-endocrine disorder. Plasma oestradiol concentration was modestly raised in 10% of coeliacs and 11% of patients with Crohns disease. Unlike plasma androgens and serum luteinising hormone in coeliacs, plasma oestradiol was not clearly related to jejunal morphology. Androgen resistance and associated hypothalamic-pituitary dysfunction appear to be relatively specific to coeliac disease and cannot be explained merely in terms of malnutrition or chronic ill-health. In addition, our findings suggest that this endocrine disturbance may be related to sexual dysfunction in coeliac disease but its relationship to disordered spermatogenesis in this condition has not been clearly established.

Relationship between plasma testosterone and dihydrotestosterone concentrations and male facial hair growth

Linear facial hair growth and the density of facial hair were measured by a photographic method and their relationship to plasma testosterone (T) and dihydrotestosterone (DHT) concentra tions was examined in twelve healthy men. In addition, we investigated eight men with coeliac disease in whom we had previously demonstrated reversible androgen resistance. The divergence of plasma T (increased) and DHT (decreased) concentrations in this condition enabled examination of possible independent actions of these androgens on facial hair growth.

Amino acid and peptide absorption in patients with coeliac disease and dermatitis herpetiformis

A double-lumen perfusion technique has been used to study amino acid and peptide absorption in eight normal control subjects, 13 patients with untreated adult coeliac disease, and 16 patients with dermatitis herpetiformis who had varying morphological abnormalities of the small bowel. All subjects were perfused with isotonic solutions containing 10 mM glycyl-L-alanine and 10 mM glycine + 10 mM L-alanine. Patients with adult coeliac disease had impaired absorption of glycine (p < 0·01) and L-alanine (p < 0·05) from the amino acid solution compared with the control subjects. Amino acid uptake from the dipeptide solution was not significantly impaired, although four individual patients had impaired uptake of both amino acids. In contrast to these findings, very few patients with dermatitis herpetiformis had impaired amino acid absorption from either solution. Sodium absorption was impaired from both solutions when the groups of patients with adult coeliac disease and dermatitis herpetiformis with subtotal villous atrophy and partial villous atrophy were studied, and there were patients in each group who secreted sodium and water. The results suggest that malabsorption of dietary protein is unlikely to occur in dermatitis herpetiformis but may occur and contribute to protein deficiency seen in some severe cases of adult coeliac disease. The impairment of sodium and water absorption provides evidence that there may be functional impairment of the jejunal mucosa in dermatitis herpetiformis as well as in adult coeliac disease.

Relative nutritional value of whole protein, hydrolysed protein and free amino acids in man.

To compare their effects on nitrogen balance, diets containing either lactalbumin whole protein, its peptide-rich enzymic hydrolysate or an equivalent mixture of free amino acids as the sole source of dietary nitrogen were fed to two healthy subjects, each studied for 38 days on two separate occasions. The nitrogen intake (47 mg/kg body wt/day) induced a state of negative nitrogen balance, stimulating nitrogen conservation. Net daily nitrogen balance (mean +/- SD) in subject 1 was -0.23 +/- 0.72 g (amino acids) vs + 0.05 +/- 0.52 g (protein) and -0.21 +/- 0.58 g (amino acids) vs -0.05 +/- 0.57 g (hydrolysate), and in subject 2, -0.19 +/- 0.60 g (amino acids) vs -0.16 +/- 0.51 g (protein) and -0.42 +/- 0.35 g (amino acids) vs -0.62 +/- 0.34 g (hydrolysate). Analysis of these results by the cumulative sum technique showed no significant differences in the effect of the three nitrogen sources on nitrogen balance. This study indicates that there is no nutritional evidence to support the current practice of prescribing expensive enteral diets containing peptides or amino acids rather than the much cheaper whole protein to patients with normal gastrointestinal function.

REVERSIBLE INSENSITIVITY TO ANDROGENS IN MEN WITH UNTREATED GLUTEN ENTEROPATHY

Plasma androgen and gonadotrophin concentrations have been measured before and during treatment of 23 men with gluten enteropathy. Before treatment, there was marked rise in total plasma-testosterone, free testosterone concentration (as assessed by the free testosterone index), and plasma-luteinising-hormone concentration. In contrast, 5 alpha-dihydrotestosterone concentrations were lower than normal. All these abnormalities reverted towards normal with successful treatment of the jejunal mucosal lesion. These data are consistent with a reversible tissue resistance to circulating plasma-testosterone in men with gluten enteropathy and subtotal villous atrophy.

Reintroduction of gluten in adults and children with treated coeliac disease.

Twenty-eight patients, thought to have coeliac disease and on gluten free diets, were put on a normal diet to confirm their diagnoses. Nineteen had been diagnosed in adult life (ACD) and nine in childhood (CCD). Patients were assessed on jejunal, morphological, and symptomatic parameters. Eighteen patients with ACD relapsed within seven weeks. Nine patients with CCD relapsed at variable times but five took longer than seven weeks, the longest period beint 10 months. Seven patients had no symptoms despite morphological deterioration during challenge and one patient, with ACD, did not relapse and was HLA B8 negative. This patient with ACD had subtotal villous atrophy on two jejunal biopsies and later showed morphological improvement on a gluten free diet. There was no correlation between the relapse time and time spent on a gluten free diet.