Celiac disease and malignancy.

Fifty-five patients with celiac disease and coexistent malignant disease (27 lymphoma, 28 other malignancies) are described. The important clinical features at presentation of lymphoma were weight loss, abdominal pain, diarrhea, profound weakness and fever, associated with anemia, raised ESR, hypoalbuminemia and steatorrhea. There were no specific features to enable earlier diagnosis. Radiology was unhelpful and in no case were malignant cells seen in the jejunal biopsy. Four of the lymphomas were Hodgkin's disease, none of which involved the bowel; the remainder were reticulum cell sarcoma, 17 of which involved the bowel. Definitive diagnosis prior to death was made in only 18 patients, of whom 16 survived from 2 to 226 days (mean, 76 days). Of the remaining two patients, one is still alive, while the other died 26 years after the original diagnosis of Hodgkin's disease. The possibility of lymphoma should be considered in those who present with celiac disease in middle life and in those who deteriorate for no apparent reason after a period of stability on a gluten-free diet. The index of suspicion for lymphoma in celiac disease should be high and early laparotomy be considered in patients with unexplained deterioration. Twenty-eight patients with 29 carcinomas and 3 other tumors are also described. The presentations of these malignancies were no different from their presentations in non-celiac patients, and their development did not provoke a relapse of celiac disease. Considering the whole series of 55 patients, there was little evidence for the view that malignancy itself was the cause of the flat jejunal mucosal appearances seen in these patients.

Anticonnective tissue and other antitissue 'antibodies' in the sera of patients with coeliac disease compared with the findings in a mixed hospital population.

Serum IgG specificities directed against various components of basement membrane and reticulin have been described, and their incidence in 138 patients with coeliac disease has been compared with that in 110 hospital inpatients, 100 normal blood donors, and 1441 other patients. A wide variety of antitissue specificities were observed but only a few appeared to be of any significance. The 'antireticulin' specificities have been subdivided into different groups according to their distinctive histological staining patterns. Specificity directed primarily against endothelial basement membrane was found most frequently in the sera of patients with hiatus hernia (35%) or coeliac disease (22%). The same specificity was also observed in patients with myasthenia gravis and to a lesser extent in Crohn's disease and in a mixed group of patients with unspecified organic gastrointestinal disease. An epithelial basement membrane reactivity was found in patients with rheumatoid arthritis but only rarely in other conditions. Staining of perivascular connective tissue represented a third type of 'antireticulin' specificity. It was found only rarely, although in coeliac disease this reactivity was found more frequently in combination with other connective tissue specificities.

Serum lysozyme in inflammatory bowel and coeliac disease.

Serum lysozyme levels were determined by a turbidometric method using egg white lysozyme as standard in 100 patients with Crohn's disease, 86 with ulcerative colitis, 31 with coeliac disease, and in 38 normal control subjects. Though the levels in Crohn's disease were significantly higher than those in ulcerative colitis and in coeliac disease, there was marked overlap between the disorders and control subjects, and so they were of no value in differential diagnosis. There was some evidence that serum lysozyme levels reflected disease activity in Crohn's disease but not in ulcerative colitis.

Folates in human serum.

Constituent serum folates have been shown to be altered and in some cases raised in diseases in which total folate levels are known to be frequently decreased. Absorption experiments showed that orally administered folate analogues affect the folate pool in different ways. The stability of the 10-formyltetrahydrofolate level in normal subjects is demonstrated.

Serum folates in man.

In an aseptic microbiological assay of folate compounds and their breakdown compounds, using Lactobacillus casei, Streptococcus faecalis, and Pediococcus cerevisiae, 4a-hydroxy-5methyl-4,5,6,7-tetrahydrofolate and 5-methyl-5,8-dihydrofolate were inactive under all conditions to all three organisms and 5-methyl-5,6-dihydrofolate was inactive unless ascorbate was present in the incubation medium, and then only to L. casei. 5-Methyltetrahydrofolate was active only for L. casei, and activity in purified samples to S. faecalis was due to trace amounts of folic acid. Analysis of S. faecalis values in the serum in normal subjects and in patients with various disorders showed that levels of 10-formyltetrahydrofolate are raised in coeliac disease, leukaemia, rheumatoid arthritis, and schizophrenia. 5-Methyltetrahydrofolate is readily absorbed by normal human subjects and by patients with pernicious anaemia but poorly absorbed by patients with coeliac disease or leukaemia. 5-Methyl-5,6-dihydrofolate was quickly absorbed by normal human subjects, being reflected by a considerably raised level of 5-methyltetrahydrofolate in serum when sodium bicarbonate was given by mouth before the 5-methyl-5,6-dihydrofolate. These higher levels were comparable to those in patients with pernicious anaemia after oral administration of 5-methyl-5,6-dihydrofolate. Oral 5-methyl-5,8-dihydrofolate and 4a-hydroxy-5-methyl-tetrahydrofolate did not appear as microbiologically active folates in the serum. The findings of this study suggest that the availability for biological utilisation of the major dietary folate compounds will depend on the amount of gastric acidity and of ascorbate in the intestinal chyme. Many may be unavailable for metabolic utilization in the body.

The neurological manifestations of malabsorption.

The clinical and pathological findings in patients with neurological disorders in association with disordered function of the small intestine, in particular coeliac disease, are outlined. The possible significance of the abnormalities of pyridoxine, tyrosine and tryptophan metabolism are considered in relation to biopterin derivatives and their relevance to neurological dysfunction.

Finger clubbing and regional enteritis.

Finger clubbing was present in 105 of 181 (58%) patients. It was related to the activity but not to the site of the disease and disappeared two to three months after the disease became quiescent.

Pregnancy and Crohn's disease.

Of 77 married women with Crohn's disease, 25 were sterile. In the remaining 52 (98 pregnancies) the risks of prematurity, stillbirth, abortion, or congenital abnormality were not increased. There was no evidence that pregnancy exerted adverse effects on the course of the disease or increased the mortality rate. Sterility was the main problem encountered.

Peptic ulceration in Crohn's disease (reional enteritis).

The incidence of peptic ulceration in a personal series of 300 patients with Crohn's disease was 8%. Resection of 60 or more centimetres of the small intestine was associated with significantly increased acid output, both basally and following pentagastrin stimulation. Only five (4%) of the 124 patients who received steroid steroid therapy developed peptic ulceration. It is suggested that resection of the distal small bowel may be a factor in the probable increase of peptic ulceration in Crohn's disease.

Corticosteroid or corticotrophin therapy in Crohn's disease (regional enteritis).

Amongst 300 patients with Crohn's disease followed between 1944 and 1968, corticosteroids or corticotrophin was given to 124 patients, to 87 of them for more than 12 months. In the short-term assessment of 89 of these patients, 76% improved clinically within six months, but within 12 months 29% of these had relapsed. In the long term, the risk of operation each year for the patients treated with steroids was twice that of those not treated. There was a significantly increased mortality rate in the patients treated with steroids which in part was due to complications induced by this therapy for which no evidence of long-term benefit emerged from this study.

Serum concentrations of 25-hydroxy vitamin D in Europeans and Asians after oral vitamin D3.

Serum concentrations of 25-hydroxy vitamin D (25-OHD3) were measured in seven Asians of Indian extraction and eight Europeans before and at intervals after taking 1 mg vitamin D3 by mouth. In all subjects the concentrations rose in the 24 hours after ingestion. There was little change over the next nine days in the concentrations in the Europeans but those in the Asians continued to rise until about day 10. Subsequent rates of fall in 25-OHD3 were similar in the two groups. Our observations suggest that the low serum concentrations of 25-OHD3 found in Asians are not caused by either impaired intestinal absorption of vitamin D or rapid clearance of 25-ODH3 from the plasma.

Determining disease activity in inflammatory bowel disease.

To provide a stronger relationship between clinical assessment of disease activity and laboratory measurements, we studied hemoglobin concentrations, sedimentation rates, and the serum levels of albumin and of seromucoids in 86 patients; first when seriously ill with either ulcerative colitis or Crohn's disease, and then again when they were well. Only albumin and seromucoids were separated clearly in the two states: hemoglobin and sedimentation rates showed significant overlap. Paired correlation tests between 10 laboratory variables in 149 patients with Crohn's disease of varying severity revealed a highly significant correlation between seromucoids and albumin (r = 0.71). Both variables correlated with six others, but at lower levels. Processing the correlation matrix by factor analysis suggested that the serum levels of albumin and seromucoid are indicators of the same effect--disease activity. A simple index using only hemoglobin, albumin, and seromucoid values, was derived from this analysis, positive values indicating health and negative ill health. Serum levels of albumin and seromucoids provide the essential data to determine disease activity at routine follow-up of inflammatory bowel disease or to indicate the success or failure of therapeutic regimens, overriding any arbitrary clinical assessment.

Coeliac disease and immunological disorders.

Out of 314 patients with coeliac disease, 63 had associated disorders of known or suspected immunological cause (excluding aphthous stomatitis and dermatitis herpetiformis). Autoimmune diseases appeared to occur more often in patients with coeliac disease than in the normal population, 52 such diseases being found in 45 patients. Of individual disorders, diabetes mellitus, thyroid diseases, and ulcerative colitis seemed to be more common than expected. Atopy (asthma and eczema) occurred in 7% of the patients. Most of these immunological disorders developed when the patients were on normal diet. A gluten-free diet and virtually normal jejunum did not prevent their development, and the diet had little ameliorating effect on their course apart from an occasional dramatic improvement in atopic patients.