Diabetic fatty liver disease is associated with specific changes in blood-borne markers.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) can lead to cirrhosis and hepatocellular carcinoma and is strongly associated with obesity and insulin resistance. The aim of this study was to assess if plasma markers associated with NAFLD are increased in people with concomitant diabetes compared with those without. METHODS: A total of 68 participants were recruited from diabetes and liver clinics. Fatty liver disease was indicated by routine blood tests and ultrasonography. Forty-seven participants had type 2 diabetes; of them, 18 had no fatty liver disease as defined previously (DNoFLD) and 29 had fatty liver disease (DFLD); the remaining 21 had fatty liver disease but no diabetes (NonDFLD). Serum samples were analyzed for adiponectin (APN), alanine and aspartate aminotransferases and plasma for cholesterol, triglyceride, hyaluronic acid (HA), procollagen peptide III, alkaline phosphatase and fibrinogen. RESULTS: Hyaluronic acid and procollagen peptide III were significantly higher and adiponectin significantly lower in DFLD than NonDFLD and DNoFLD, the difference being particularly marked for hyaluronic acid and APN. There was no difference in these markers between NonDFLD and DNoFLD and no association between any plasma or serum marker and ultrasound grade of steatosis. CONCLUSION: We have identified markers of hepatic steatosis that appear to be specific for people with type 2 diabetes. A further longitudinal study is merited to assess the role of these markers in understanding the progression of hepatic steatosis and fibrosis in people with and without diabetes.

Increased intragastric acid-resistant lipase activity and lipolysis in pancreatic steatorrhoea due to cystic fibrosis.

We measured gastric lipase activity and lipolysis in postprandial gastric samples from 10 adults with steatorrhoea due to cystic fibrosis (CF) and from 10 healthy volunteers of similar age and sex. Gastric samples were aspirated for 2 h following a meal consisting of emulsified long-chain triglyceride. Mean acid-resistant lipase activity was twice as high in CF patients as in controls (596 vs. 299 nmol/ml/min fatty acid released; p = 0.028 for area under the curve). Lipolysis rose from 5 to 10% during the postprandial period in CF patients, compared with a constant 5% in controls (p = 0.036 for area under the curve). We conclude that, in healthy adults, lipolysis of long-chain triglyceride starts in the stomach, while in adults with pancreatic steatorrhoea due to CF, gastric lipase activity and intragastric lipolysis are increased, perhaps in compensation for pancreatic insufficiency.

Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhoea due to cystic fibrosis.

We investigated the therapeutic potential of an acid-resistant fungal lipase prepared from Aspergillus niger. We first demonstrated in vitro that it had a wide pH optimum of 2.5-5.5 and was resistant to pepsin and trypsin. We gave the enzyme or matching placebo in random order by mouth with a fatty meal to 10 adult patients with pancreatic steatorrhoea due to cystic fibrosis (CF) and sampled gastric contents for the following 2 h. Mean acid-resistant lipase activity was 330 nmol/ml/min free fatty acid released on placebo, compared with 896 nmol/ml/min on fungal lipase (p = 0.006 for area under the curve). We compared this lipase's clinical efficacy with that of two conventional pancreatin microsphere formulations in an open randomised crossover fat-balance study in 10 similar patients. Each preparation was given for 2 weeks, and a fat-balance study, using a faecal recovery marker, was performed on the final 3 days; a period without treatment was also included. The fungal lipase had no effect on faecal wet weight or on the coefficient of fat absorption (59.0% vs. 52.3%; NS) in comparison with placebo. The established enteric-coated microsphere preparation (Creon) produced a significant reduction in faecal wet weight and improvement in coefficient of fat absorption (81.4% vs. 52.3%; p less than 0.01) in comparison with placebo. The newer microsphere preparation (Pancrex M) was also effective, but perhaps less so than Creon; there were no significant differences between the two preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Three different methods of inhibiting lipolysis in human chyme in vitro: efficiency and effect on phase distribution of lipids.

1. The efficiencies of three different methods of inhibiting fatty acid production in chyme have been evaluated. The effects of each method on the phase distribution of fatty acids after ultracentrifugation have been studied. 2. Chyme fatty acid concentrations were measured during a 4 h incubation (a) without an inhibitor, (b) after acid treatment, (c) after addition of p-bromophenylboronic acid and (d) after heating. 3. In a separate experiment, fresh chyme was incubated to allow equilibration of lipolysis. Aliquots were treated by each inactivation method and ultracentrifuged overnight to separate the phases. Total and micellar fatty acids and glycerides were measured. 4. In the first experiment, acid treatment completely inhibited fatty acid generation producing 4 h concentrations which were 93.4 +/- 5.6% (mean +/- SEM) of initial values compared with 398.0 +/- 54.0% (P less than 0.05) for uninhibited samples. p-Bromophenylboronic acid and heating gave significant but incomplete inhibition (132.9 +/- 6.6% and 166.1 +/- 15.2% of initial concentrations, respectively). 5. Ultracentrifugation disclosed five phases in all except the acid-treated samples, which had four. Micellar phase fatty acid concentrations were significantly higher in the acid-treated than in the untreated samples (2.6 +/- 0.7 versus 1.7 +/- 0.5 mmol/l, P = 0.05), as were glyceride concentrations (1.5 +/- 0.4 vs 0.6 +/- 0.3 mmol/l, P = 0.05). 6. It was concluded that acid treatment was the most efficient inhibitor of fatty acid production, but it disrupted the phases. p-Bromophenylboronic acid gave significant inhibition without causing phase disruption and was therefore the most useful inhibitor overall.

Variceal haemorrhage in hereditary haemorrhagic telangiectasia.

Hepatic in involvement in hereditary haemorrhagic telangiectasia can lead to cirrhosis and occasionally to portal hypertension and variceal haemorrhage. The ultrasonographic, arteriographic and histological findings are described in a patient with this complication. Hepatic artery embolisation proved unsuccessful in arresting repeated haemorrhage which was eventually controlled by hepatic artery ligation. Porto-systemic venous shunting, an apparently logical approach to management, would probably have aggravated the problem.

Review: pancreatic enzyme replacement--applied physiology and pharmacology.

The treatment of pancreatic steatorrhoea can often be improved by attention to the pathophysiological and pharmacological principles involved. Factors influencing the efficacy of pancreatic enzyme replacement include physiological characteristics of the individual patient and pharmaceutical characteristics of the supplement. Different patients may be best suited by different preparations and there is no overall 'best buy'. The new enteric-coated microsphere formulations are often most effective, but also more expensive than conventional preparations. Adjunctive H2-blockade can help appropriately selected patients with resistant steatorrhoea. Knowledge of the underlying cause may guide the choice of supplement and its dose, but trials of different regimens may prove necessary. Successful management, particularly of malnourished patients, involves optimization of dietary fat intake in addition to enzyme replacement.

Medical management of radiation enteritis--an algorithmic guide.

An algorithmic guide to the differential diagnosis and management of late radiation enteritis is proposed. The proposition is based on physiological principles and clinical experience rather than on published reports. Too few patients with late radiation enteritis are seen in most oncology centres for a large prospective trial of the algorithm to be set up, but we hope it will stimulate further investigation.

Ileal resection: effect of cimetidine and taurine on intrajejunal bile acid precipitation and lipid solubilisation.

We have investigated whether pH-dependent bile acid precipitation limits lipid solubilisation after ileal resection, and whether treatment with cimetidine, or taurine improves solubilisation. Nine ileal resection patients were treated with placebo, cimetidine and taurine in random order for two weeks each. Upper jejunal content was aspirated and pooled according to pH for three hours after a standard Lundh test meal. On placebo, 50% of the bile acids were precipitated at pH less than 5, compared with only 26% at pH greater than 6, whilst aqueous-phase lipid concentration tended to be lower at pH less than 5 than at pH greater than 6 (5.1 vs 8.2 mmol/l). On cimetidine mean pH rose, particularly during the third hour (6.6 vs 5.8, p less than 0.05), associated with a reduction in bile acid precipitation (13.9 vs 33.1%, p less than 0.05), and an increase in aqueous-phase lipid concentration (10.4 vs 6.6 mmol/l, p less than 0.05). On taurine, the proportion of taurine conjugated bile acids increased (67 vs 22%, p less than 0.01), but there was no significant change in bile acid precipitation or lipid solubilisation. Lower jejunal samples were aspirated similarly from five of these patients on no treatment, and all were at pH greater than 6; apparent 'precipitation' was reduced (16.4 vs 28.1%), but lipid solubilisation did not improve. These findings suggest that pH dependent bile acid precipitation can limit lipid solubilisation within the jejunum after ileal resection, and that these effects can be reduced by cimetidine but not by taurine. Cimetidine may have a role in ileal resection patients with severe steatorrhoea unresponsive to dietary fat restriction.

Effect of cimetidine on enzyme inactivation, bile acid precipitation, and lipid solubilisation in pancreatic steatorrhoea due to cystic fibrosis.

In pancreatic steatorrhoea, both pH-dependent bile acid precipitation and enzyme inactivation may limit the efficacy of pancreatic enzyme supplements and both may be preventable by addition of cimetidine. To separate these effects we compared postprandial jejunal aspirate from eight adults with steatorrhoea due to cystic fibrosis on three randomised treatment regimens (pancreatin, cimetidine, and both together). We also compared the results with those of previous studies of patients on no treatment, and of healthy subjects. On pancreatin 60% of the test meal entered the jejunum at pH less than 5 compared with 17% in health. Lipase concentration and lipolysis increased over the values on no treatment (14.2 vs 4.4 U/l, p less than 0.01; 16% vs 11%, p less than 0.02) but bile acid precipitation was not reduced (38% vs 27%, NS), and aqueous-phase lipid concentration decreased (6.7 vs 8.6 mM/l, p less than 0.05). On cimetidine, bile acid precipitation fell (19% vs 38%, p less than 0.05); although lipase concentration and lipolysis were lower than on pancreatin (4.8 U/l vs 14.2 U/l, p less than 0.01; 9% vs 16%, p less than 0.01) lipid solubilisation increased (8.8 vs 6.7 mM/l, p less than 0.05). On the combination, there was a marked improvement (p less than 0.02) in lipid solubilisation (18.3 mM/l), reflecting the improvement both in lipase (38.4 U/l) and lipolysis (24%), and in bile acid precipitation (5.6%). We conclude that the efficacy of pancreatin is limited by pH-dependent bile acid precipitation in addition to enzyme inactivation. The action of cimetidine in improving the efficacy of pancreatin depends on prevention of both these effects.

Effect of intrajejunal acidity on lipid digestion and aqueous solubilisation of bile acids and lipids in health, using a new simple method of lipase inactivation.

We have investigated whether acid-mediated bile acid precipitation, pancreatic enzyme inactivation, and fatty acid partitioning occur in health when intraluminal pH falls below 5. In order to assess lipolysis and aqueous solubilisation of lipid, we first developed a new technique for inactivating lipase in jejunal aspirate (acid inactivation), and showed it to be more effective and simpler than the established technique (heat inactivation). We then studied 14 healthy subjects, aspirating jejunal content for three hours after a liquid meal, and pooling according to pH. Eighteen per cent of the total aspirate was collected at pH less than 5 compared with 56% at pH greater than 6 (p less than 0.01). Forty eight per cent of the bile acids were precipitated at pH less than 5 compared with 18% at pH greater than 6 (p less than 0.01), leading to a reduction in aqueous phase bile acid concentration at low pH (2.1 mmol/l at pH less than 5 vs 5.8 mmol/l at pH greater than 6, p less than 0.01). Lipase activity was reduced at low pH (133 IU/l at pH less than 5 vs 182 IU/l at pH greater than 6, p less than 0.01), leading to reduced lipolysis at low pH (14% at pH less than 5 vs 32% at pH greater than 6, p less than 0.01). Aqueous phase lipid concentration was reduced at low pH (3.5 mmol/l at pH less than 5 vs 12.5 mmol/l at pH greater than 6, p less than 0.01). This reduction was less dependent on bile acid precipitation than on lipase inactivation and fatty acid partitioning. We conclude that intraluminal acidity influences aqueous solubilisation of bile acids and lipid in health.

Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentrations in pancreatic steatorrhoea due to cystic fibrosis.

We have investigated whether jejunal hyperacidity leads to bile acid precipitation and thus limits lipid solubilisation in patients with pancreatic steatorrhoea. Jejunal contents from 12 adults with steatorrhoea due to cystic fibrosis were aspirated for three hours after a liquid test meal, and pooled according to their pH. Thirty eight per cent of the total aspirate was collected at pH less than 5 in cystic fibrosis, compared with 18% in healthy controls (p less than 0.05). Forty six per cent of the bile acids were precipitated at pH less than 5, compared with 15% at pH greater than 6 (p less than 0.01), leading to reduced aqueous phase bile acid concentration at low pH (4.7 mmol/l at pH less than 5 vs 12.5 mmol/l at pH greater than 6, p less than 0.01). Aqueous phase lipid concentrations were reduced at low pH (5.6 mmol/l at pH less than 5 vs 10.2 mmol/l at pH greater than 6, p less than 0.01). Lipolysis and total fatty acid concentrations were greatly reduced and did not vary with pH. We therefore conclude that jejunal hyperacidity leads to bile acid precipitation in pancreatic steatorrhoea due to cystic fibrosis, and imposes a further limitation on lipid solubilisation over that of lipase deficiency.

Radiographic abnormalities of the duodenum in cystic fibrosis.

Radiologically demonstrable abnormalities of the duodenum are common in cystic fibrosis and are most prevalent in the second part of the duodenum. Out of 14 upper gastrointestinal barium studies performed on patients with cystic fibrosis over a period of 10 years, radiographic abnormalities of the duodenum were found in 12, an incidence of 86%. The abnormalities consisted of thickened mucosal folds, nodular indentations and effacement of the normal mucosal pattern. A duodenal stricture that was radiologically similar to a carcinoma presented as pyloric obstruction in one patient and this resolved on medical treatment. We conclude that barium studies in patients with cystic fibrosis may uncover unsuspected abnormalities of the duodenum, that these form part of the syndrome and that invasive treatment is not indicated.

Pancreatic Society of Great Britain and Ireland: Annual Meeting, 1980: Role of pH-dependent bile acid precipitation in fat maldigestion due to pancreatic steatorrhoea. Preliminary communication.

In pancreatic steatorrhoea due to cystic fibrosis (CF) a major proportion of the meal enters the jejunum below the critical pH of 5, causing bile acid (BA) precipitation and limiting aqueous solubilisation of lipid. Treatment with pancreatin alone results only in a small increase in lipolysis as the lipase is largely inactivated; aqueous lipid solubilisation is not improved as BA precipitation remains a limiting factor. Treatment with cimetidine alone, by reducing BA precipitation, improves lipid solubilisation without improving lipolysis. Treatment with cimetidine and pancreatin reduces pancreatic lipase inactivation and BA precipitation leading to the greatest improvement in lipid solubilisation.

Postprandial gall-bladder emptying in patients with gall stones.

Gall-bladder emptying in response to a standard meal was assessed in 34 patients with radiolucent gall stones and 34 matched controls. Percentage gall-bladder emptying, derived from volume measurements made on standardised oral cholecystography, was significantly higher at 15 minutes in the patients than the controls (mean +/- SE of mean 38.0 +/- 3.7% v 28.0 +/- 3.8%). This difference was maintained at 30 and 60 minutes. It is concluded that postprandial gall-bladder emptying is increased in patients with cholesterol gall stones, and that this may be the cause of the small bile-acid pool found in these patients.

Gall-bladder sensitivity to cholecystokinin in patients with gall stones.

Gall-bladder sensitivity to cholecystokinin (CCK) was determined by dynamic cholescintigraphy in 18 patients with radiolucent gall stones and 18 matched controls during an infusion of CCK in which the rate of infusion was increased. In 10 of the matched pairs the patient was more sensitive than the control, in one the control was more sensitive, and in seven no difference was detected (p = 0.012). It is concluded that patients with cholesterol gall stones have increased gall-bladder sensitivity to CCK, and that this may be important in the pathogenesis of this disease.