Adrian P. Douglas

Response of the jejunal mucosa in adult coeliac disease to oral prednisolone

Five patients with adult coeliac disease were treated with prednisolone for four to five weeks while continuing a normal gluten-containing diet. A prompt histological, ultrastructural and enzymic recovery of the jejunal mucosa in all five was accompanied by an incomplete metabolic response in three of four patients tested. These findings are discussed in relation to the possible immunological pathogenesis of coeliac disease.

Fulminant Wilson's disease with haemolysis and renal failure: copper studies and assessment of dialysis regimens.

Two girls, aged 12 and 17 years, presented with hepatocellular dysfunction and severe haemolysis due to Wilsons disease (hepatolenticular degeneration). This was accompanied by acute renal failure. In the absence of renal function sufficient for the urinary excretion of penicillamine, studies were performed to assess the potential of peritoneal dialysis, ascites removal by ultrafiltration-reinfusion, and haemodialysis as alternative excretory pathways for copper. The greatest amount of copper, as judged by rising bath concentrations, seemed to be eliminated with haemodialysis. But this was accompanied by a progressive increase in serum copper concentrations with rapid clinical and biochemical deterioration leading to death within 48 hours. A small amount of copper was lost with ascites removal. Significant amounts of copper were removed during peritoneal dialysis (36 mumol/day (2287 microgram/day)), although a clinical response was not evident before haemodialysis was introduced. The administration of penicillamine orally, intravenously, or intraperitoneally produced no measurable increase in copper excretion into the peritoneal dialysate. Hence peritoneal dialysis alone appears to offer the greatest potential benefit with regard to both eliminating copper and altering the course of this fulminant form of Wilsons disease.

The cell cycle time in the flat (avillous) mucosa of the human small intestine

A hyperproductive mucosal state in gluten-sensitive enteropathy has been proposed on the basis of an elevated mitotic index, but this parameter is dependent on the mitotic duration when used as an index of proliferative status. The mitotic duration was therefore measured in two control patients with normal villous mucosae and in two patients with the flat avillous mucosa of untreated gluten-sensitive enteropathy, using two different stathmokinetic techniques with vincristine. No significant difference in mitotic duration was found but values obtained for cell cycle time showed a halving in the flat mucosae. An increased rate of cell production in the small bowel mucosa of untreated gluten-sensitive enteropathy is thus confirmed.

The Distribution and Enteric Loss of 51Cr-Labelled Lymphocytes in Normal Subjects and in Patients with Coeliac Disease and Other Disorders of the Small Intestine

Peripherally harvested lymphocytes have been labelled with 51Cr, reinjected into human subjects and their distribution then studied. Evidence is presented which suggests faecal loss of 51Cr represents loss of T lymphocytes and that there is normally a pathway of lymphocyte removal into the gut of probable importance in lymphocyte migration streams. In 9 normal subjects, without structural intestinal disease, faecal loss of lymphocytes over 5 days was 0.20% (SEM +/- 0.06) whereas in 5 patients with untreated coeliac disease faecal loss was 1.13 +/- 0.34%, in 7 with Crohns disease it was 1.01 +/- 0.21% and in 5 with intestinal lymphangiectasia loss was 0.61 +/- 0.10%. In 1 patient with acute tropical sprue, enteric loss was 0.97%. By contrast, faecal loss was normal in 3 coeliac patients in remission on a gluten-free diet. Measurements were also made using an external counter. In contrast to the normals, where count rates steadily diminished, an increasing activity was recorded over the umbilicus over 7 days after dose administration in all the disease categories studied with the exception of the treated coeliacs. The finding of an increased enteric loss of lymphocytes may explain many of the immunological abnormalities in the conditions studied.

The measurement of cell production rates in the crypts of lieberkuhn

A method is described of assessing the proliferative state in the small bowel mucosa employing the metaphase-arresting (stathmokinetic) properties of vincristine, applicable to both animals and man. In the rat a value for the migration rate of 1.78 cell positions per hour was obtained by the stathmokinetic method, in agreement with a further measurement of the migration rate made using tritiated thymidine. Values for the transit time through the crypt (34 hours) and for the cell production rate (39 cells per crypt per hour), are in good agreement with previously published values. A control patient and a patient with the flat mucosa of gluten-sensitive enteropathy were also studied by the vincristine technique. The migration and cell production rates were markedly increased in the flat mucosae. A hyperproductive proliferative state is therefore confirmed in the flat mucosa of untreated gluten-sensitive enteropathy. The results show the vincristine technique to be eminently applicable to problems involving intestinal cell kinetics.

Peptide hydrolase activity of human intestinal mucosa in adult coeliac disease.

The levels of two peptide hydrolases were studied in intestinal mucosa from normal subjects, patients with untreated coeliac disease, and treated patients. The mucosa from the untreated patients had significantly reduced activity against glycyl-glycine and leucylleucine. No such difference was found for the treated patients and it was concluded that the reduction in peptidase activity was secondary to the mucosal damage.

Measurement of cell production rate in the human small bowel.

The assumption that an elevated mitotic index occurs in the small bowel mucosa of coeliac disease was checked by an in vivo method using metaphase arrest with vincristine. No change