Hereditary haemochromatosis.

Hereditary haemochromatosis is a very common genetic defect in the Caucasian population, with an autosomal recessive inheritance. It is characterized by inappropriately increased iron absorption from the duodenum and upper intestine, with consequent deposition in various parenchymal organs, notably the liver, pancreas, joints, heart, pituitary gland and skin, with resultant end-organ damage. Clinical features may be non-specific and include lethargy and malaise, or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation and gonadal failure. Early recognition and treatment (phlebotomy) is essential to prevent irreversible complications such as cirrhosis and hepatocellular carcinoma. The history of this condition dates as far back as 1865, but in the last decade great advances have been made. We discuss the genetics, pathophysiology, clinical features, diagnosis and management of a condition that could easily present to a generalist, and is an important diagnosis not to miss.

Treatment of active Crohn's disease by exclusion diet: East Anglian multicentre controlled trial.

Elemental diet is as effective in producing remission of Crohn's disease (CD) as is corticosteroid treatment, but most patients relapse soon after resumption of a normal diet. We have investigated the efficacies of dietary modification and oral corticosteroids in maintaining remission achieved with elemental diet. In a multicentre trial, 136 patients with active CD were started on elemental diet and other treatment was withdrawn. 43 (31%) declined to continue elemental diet for 14 days, but 78 (84%) of the remaining 93 achieved remission and were randomly assigned corticosteroids (38) or diet (40). Corticosteroid treatment started at 40 mg prednisolone daily, which was tapered and stopped after 12 weeks; that group received dietary advice on healthy eating. The diet group received "tapered" placebo and were instructed to introduce one new food daily, excluding any that precipitated symptoms. Assessment of progress for up to 2 years was made by physicians unaware of group assignment. Intention-to-treat analysis showed median lengths of remission of 3.8 (interquartile range 5.0) months in the corticosteroid group and 7.5 (15.3) months on diet, and relapse rates at 2 years, adjusted for withdrawals, of 79% and 62%, respectively (p = 0.048). Clinical improvement in the diet group was associated with significant changes in plasma albumin and alpha 1-antichymotrypsin concentrations and erythrocyte sedimentation rate. Food intolerances discovered were predominantly to cereals, dairy products, and yeast. Diet provides a further therapeutic strategy in active Crohn's disease.

Helicobacter pylori increases gastric antral juxtamucosal pH.

In order to examine the effect of Helicobacter pylori colonization on the gastric mucus microclimate, antral juxtamucosal pH was measured in 47 patients attending as out patients for upper gastrointestinal endoscopy. The mean pH in 28 patients negative for H. pylori was 6.40 +/- 0.24 compared to 6.88 +/- 0.16 in 19 patients who were positive (P < 0.0001). In six of seven patients who agreed to a second study, H. pylori was eradicated and the mean pH fell from 6.81 +/- 0.17 to 6.08 +/- 0.16 (P < 0.001). The pH remained high in the one patient who remained positive (6.8 and 7.0). This study provides the first in vivo evidence that H. pylori can increase the antral juxtamucosal pH and suggests that ammonia production by the organism is capable of altering gastric mucus microclimate to impair the normal negative feedback controlling gastrin release. This observation may explain the coexistence of relative hypergastrinemia and H. pylori colonization in duodenal ulcer patients.

Effect of bismuth subcitrate and sucralfate on rat duodenal and human gastric bicarbonate secretion in vivo.

Acid and alkali secretion have been examined together with prostaglandin E2 production in response to two mucosal protective drugs, colloidal bismuth subcitrate and sucralfate. Doses of colloidal bismuth subcitrate in the therapeutic range (120 and 1200 mg) had no effect on alkali secretion or luminal PGE2 output when perfused into the stomach of human volunteers. Similarly, in the anaesthetised rat, neither gastric acid nor duodenal alkali secretions were influenced by iv (12 mg/kg) or topical (120 mg/ml) administration of colloidal bismuth subcitrate. In contrast, perfusion of the human stomach with 1 g sucralfate stimulated bicarbonate output by 50%, a response which was unaffected by indomethacin (25 mg/h). A rise of 64% in gastric PGE2 output after sucralfate was, however, prevented by indomethacin pretreatment. Alkali secretion by rat duodenum was also increased by sucralfate but the response depended on the basal secretory rate. Low basal secretors (less than 3 mumol) showed a 75% stimulation whereas rats with high basal secretory rates (greater than 3 mumol) showed no significant response. All duodenal preparations regardless of basal secretory rate showed a stimulation of bicarbonate output with topical PGE2. The results suggest that enhancement of gastroduodenal bicarbonate secretion may play a role in the protective action of sucralfate but is unlikely to explain mucosal protection by colloidal bismuth subcitrate.

Effect of bismuth subcitrate on amphibian gastroduodenal bicarbonate secretion.

The ulcer healing and cytoprotective properties of colloidal bismuth (De-Nol) are well established although its mode of action is unclear. We have examined the action of bismuth subcitrate, the active ingredient of De-Nol, on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Addition of bismuth subcitrate (10(-6) to 10(-4) M) to the luminal solution produced a dose dependent increase in bicarbonate secretion from both gastric and duodenal mucosae without a change in transmucosal potential difference. The magnitude of this stimulation was greater for gastric than duodenal mucosae at all dose ranges. A second bismuth salt, bismuth oxynitrate, produced similar increases in bicarbonate secretion from gastric mucosae. Pretreatment of gastric mucosa with the cyclooxygenase inhibitor, indomethacin (10(-5) and 10(-4) M), did not abolish the secretory response to bismuth subcitrate. Similar treatment with the chloride transport inhibitor, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) (10(-3) M) prevented the secretory response to bismuth subcitrate.

Stimulation of amphibian gastroduodenal bicarbonate secretion by sucralfate and aluminium: role of local prostaglandin metabolism.

The present studies were designed to explore the possible mode of protective and ulcer healing actions of sucralfate by examining its effect on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Luminal sucralfate (0.5 g/l) significantly increased bicarbonate secretion by fundic and antral mucosa without influencing transmucosal potential difference. Significant stimulation of duodenal bicarbonate secretion occurred only at 1.0 g/l without change in potential difference. Aluminium, a component of sucralfate, produced similar increases in bicarbonate secretion, while the sucrose and sulphate components were without effect. Pretreatment of mucosae with the cyclooxygenase inhibitor, indomethacin (10 5M) did not abolish the secretory response to sucralfate or aluminium. The results suggest that stimulation of gastroduodenal bicarbonate secretion, possibly by the aluminium moiety of sucralfate, may play a role in its protective and ulcer healing actions.

Neural regulation of duodenal alkali secretion: effects of electrical field stimulation.

The role of transmitters released from enteric neurons in regulating bicarbonate secretion by the proximal duodenum has been studied using electrical field stimulation (EFS). Stripped duodenal mucosa from Rana catesbeiana was mounted as an intact tube over circular platinum electrodes, and luminal alkalinization was measured by pH stat titration before, during, and after EFS. Transmucosal potential difference (PD) was simultaneously measured before and after EFS by paired electrodes. Square-wave pulses 50 V, 2 ms in duration, at 10 Hz were delivered in trains of 0.5 s at 1 Hz for periods of 15 min after stable basal secretion. This resulted in a 63 +/- 27% increase in alkalinization that returned to basal values after cessation of the stimulus, without change in transmucosal PD. Serosal-to-lumen [3H]mannitol flux was not affected. Repetition of the stimulus resulted in similar responses for as long as the tissue remained viable. The response to EFS was abolished by tetrodotoxin (10(-6) M) and veratrine (0.1 mg/ml), indicating that intrinsic neurons were responsible for mediating the effect. In addition, the effect was blocked by serosal dinitrophenol (10(-4) M), indicating that the secretory response occurred by a metabolically dependent process. These results indicate that alkalinization by proximal duodenum may be controlled by neurotransmitter release from local enteric neurons.

Effect of luminal pH on the output of bicarbonate and PGE2 by the normal human stomach.

The gastric output of bicarbonate and prostaglandin E2 has been calculated using a perfusion technique before and after instillation of 100 mM hydrochloric acid into the stomach of seven healthy volunteers. A significant increase in bicarbonate output occurred from 258 +/- 38 mumol/30 min during the basal period to 531 +/- 86 mumol/30 min after return of the intragastric pH to neutral (p less than 0.05). Prostaglandin E2 output also increased significantly from 410 +/- 136 pmol/30 min to 1002 +/- 194 pmol/30 min (p less than 0.05). The changes were caused mainly by an increase in gastric secretory volume with only non-significant increases in concentrations of bicarbonate and prostaglandin E2. The results suggest that mechanisms exist to adjust the rate of gastric bicarbonate secretion to the prevailing intraluminal pH and that this may occur through the release of prostaglandin E2.

Effects of sucralfate on gastroduodenal bicarbonate secretion and prostaglandin E2 metabolism.

The mechanism of action of sucralfate has been investigated. Using homogenized rabbit mucosa, the drug increased arachidonic acid conversion to prostaglandin E2 without affecting catabolism. Luminal administration of sucralfate (0.5 g/liter) caused marked stimulation of bicarbonate secretion by isolated amphibian gastric mucosa but not duodenal mucosa. In a higher dose (1 g/liter), duodenal bicarbonate secretion was also stimulated. These effects are likely to be due to endogenous prostaglandin formation since they are inhibited by indomethacin. The results suggest that the cytoprotective action of sucralfate is due to stimulation of endogenous prostaglandin formation and may involve various mucosal defensive factors.

Pseudopolycythaemia and coeliac disease.

We report two patients in whom introduction of a gluten free diet for coeliac disease was associated with the development of pseudopolycythaemia.

Simultaneous measurement of in vitro gastroduodenal prostaglandin E2 synthesis and degradation in peptic ulcer disease.

The ability of mucosal specimens from the stomach and duodenum to synthesize and degrade prostaglandin E2 has been determined in normal subjects and peptic ulcer patients. Significant reduction in fundic PGE2 synthesis capacity was observed in gastric ulcer patients. There was also significant reduction in the PGE2 degradation capacity of antral, fundic, and duodenal mucosal specimens in gastric ulcer patients. Patients with gastritis showed significant elevation of both antral and fundic PGE2 synthesis capacity compared with normal but no alteration in PGE2 degradation. No differences were observed in PGE2 synthesis and degradation rates in patients with duodenal ulcer. The results argue in favour of an association between impairment of PGE2 metabolism in the mucosa of patients with gastric but not duodenal ulceration.

ERCP in late post-traumatic biliary fistula.

A case is described in which a huge subcapsular bile collection due to biliary fistula presented late after hepatic trauma and in which ERCP indicated the diagnosis.

Effect of sucralfate on gastroduodenal bicarbonate secretion and mucosal prostaglandin E2 metabolism.

The effect of sucralfate on gastroduodenal bicarbonate secretion has been examined using isolated amphibian mucosa. Significant increases in gastric bicarbonate secretory rate were seen following addition of 0.5 milligram sucralfate to the luminal solution. Duodenal alkali secretion was stimulated only by a higher concentration of 1 milligram. Pretreatment with indomethacin prevented the increases in gastric and duodenal bicarbonate secretion observed after sucralfate. Other experiments indicated that sucralfate caused stimulation of prostaglandin E2 formation by mucosal homogenates. These studies demonstrate that sucralfate is a potent stimulant of gastroduodenal bicarbonate secretion and that the action is dependent on mucosal prostaglandin formation. These effects are likely to play an important role in the mode of action of the drug.

Effect of certain ulcer-healing agents on amphibian gastroduodenal bicarbonate secretion.

The effect of luminal application of aluminum sulphate, sucralfate, and bismuth subcitrate on gastroduodenal alkali secretion has been studied with isolated amphibian mucosa. The mucosa, stripped of its external muscle layer, was mounted in chambers that allowed titration of alkali secretion and measurement of transmucosal potential difference and electrical resistance. Neutral aluminum sulphate (3 X 10(-3) M) increased bicarbonate secretion by fundic (mean +/- SEM = 144 +/- 48%, n = 5, P less than 0.05), antral (mean +/- SEM = 214 +/- 63%, n = 4, P less than 0.05), and duodenal (mean +/- SEM = 133 +/- 44%, n = 6, P less than 0.005) mucosa. Sucralfate (0.5 g/l) stimulated fundic (mean +/- SEM = 183 +/- 87%, n = 4, P less than 0.05) and antral (mean +/- SEM = 156 +/- 58%, n = 5, P less than 0.005) alkali secretion and, at a concentration of 1 g/l, duodenal output (mean +/- SEM = 42 +/- 15%, n = 6, P less than 0.05). Bismuth subcitrate (10(-4) M) produced a significant rise in fundic (mean +/- SEM = 80 +/- 21%, n = 5, P less than 0.05) and duodenal (mean +/- SEM = 62 +/- 7%, n = 6, P less than 0.05) alkali secretion. None of these agents altered transmucosal potential difference or electrical resistance. The actions of these agents on gastroduodenal bicarbonate secretion may be important in their ulcer healing effects.