Biomedical subjects
Publications and source records attributed to N McIntyre.
Studies on the isolated perfused rat liver demonstrated that an increase in portal pressure is associated with an increase in the portal blood flow in normal and in cirrhotic livers. In two pigs with portal hypertension mesenteric portal pressure was lowered by mechanically increasing the liver portal blood flow by means of a balloon pump around the portal vein.
Recurrent bleeding after stapled oesophageal transection was studied in 73 patients with cirrhosis transected for acute variceal bleeding. The most frequent source of bleeding was partial or total circumferential oesophageal erosion at the transection: staple-line erosion. This lesion occurred in 36 (49 per cent) patients and was the source of rebleeding in 29 (40 per cent) patients with 54 episodes. Rebleeding in 22 (30 per cent) patients was due to varices in nine (12 per cent), peptic ulcer in six (8 per cent), gastric erosions in two (3 per cent) and unknown sources in five (7 per cent), accounting for 33 episodes. The mean(s.e.m.) blood transfusion requirement for bleeding from staple-line erosions were 1.5 (0.25) units per bleed versus other sources, 6.5(1.0) units per bleed (P less than 0.001). Staple-line erosion was present at the first postoperative endoscopy in 11 (15 per cent) patients but the time to appearance varied widely. The lesion was more common in patients with Pugh's grade A liver disease at the time of transection, reflecting the increased survival rate of these patients. Staple-line erosion is a common source of minor recurrent bleeding following stapled oesophageal transection.
Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (approximately 1.5 mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-3H-glucose turnover were 20-25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41 +/- 4 vs 8 +/- 6 mumol.min-1.kg-1, p less than 0.001) but did not further decrease 3-3H-glucose turnover. Elevated non-esterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability.(ABSTRACT TRUNCATED AT 250 WORDS)
The in vivo dose response curve to insulin were studied, using an euglycemic insulin clamp technique, in 13 cirrhotic patients [8 with "hepatocellular" (HC) (nonalcoholics) and 5 with "cholestatic" (CHOL) cirrhosis] and 12 healthy controls (N). Subjects were studied in the basal state and during infusion of insulin at 3 different rates - 1, 3, 10 mU kg-1 min-1. Insulin responsiveness was similar in N and in HC, but it was 23% greater in CHOL (p less than 0.001). Insulin sensitivity was decreased in cirrhotics as compared with N but this difference was only significant (p less than 0.001) in HC. (ED50:62 + 5, 88 + 13 and 136 + 16 muu ml-1 in N, CHOL and HC respectively). Insulin clearance rate (ICR) was significantly (p less than 0.005) decreased in HC (1060 +/- 80, 996 +/- 95 and 776 +/- 128 ml sq m-1 ml-1 in N, CHOL and HC respectively. Basal hepatic glucose production (BHGP) was 39% lower in HC (p less than 0.005) and 24% lower in CHOL (p less than 0.05) than in N. Erythrocyte cholesterol phospholipid ratio was significantly elevated (p less than 0.001) in both groups of cirrhotic patients but was not correlated to specific metabolic changes described. In summary: i) intervariations in insulin dependent glucose metabolism were described in different cirrhotic groups; ii) basal hepatic glucose production and insulin clearance rate impaired in the different groups of cirrhotics; iii) the role of decreased cholesterol/phospholipid ratio on tissues glucose metabolism in cirrhotic patients should be further studied.
Local skin reactions (chancres) developed at the sites of inoculation with Trypanosoma evansi in rabbits and calves. Trypanosomes multipled in the dermal collagen and, in the rabbit, were present in large numbers by 7 days after infection. Thereafter, however, numbers decreased and few parasites were observed by 11 days after infection. The presence of trypanosomes in the skin caused an extensive inflammatory reaction with disruption of collagen, oedema, necrosis of the skin and increases principally in neutrophils and lymphocytes. In calves, similar changes were observed although there were fewer trypanosomes present in the chancre and the cellular involvement was less extensive than that seen in the rabbit. This early extracellular proliferative phase of development of T. evansi may be of importance in naturally transmitted infections both in the initial establishment of the parasite in the mammalian host and in enabling the parasite to increase the numbers of antigenic variants expressed before the parasites invade the general circulation.
Medical emergencies involving the liver and biliary tract are common clinical problems. If it is already known that the patient has cirrhosis it may be an easy matter to identify the cause of complications such as gastro-intestinal bleeding or coma, but it must be borne in mind that oesophageal varices are not the only cause of such bleeding in cirrhotics and that hepatic encephalopathy is not the only cause of coma. Bacterial infection should always be considered as a possible cause of deterioration in the clinical picture; it may be a complication of pre-existing acute or chronic liver or biliary tract disease or a cause of hepatobiliary disease; prompt administration of appropriate antibiotics may save the patient's life. If there is any suspicion of biliary obstruction in a patient with signs of bacteraemia the biliary tree should be drained without delay. The key to the management of hepatobiliary emergencies lies in prompt and appropriate supportive therapy, and then in a correct diagnosis which may allow specific treatment to be administered. However, it is often difficult to establish the cause, and the resources of a specialist centre may be needed. Prompt referral is indicated when a patient is clearly very ill and shows no signs of rapid improvement.
A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 mu/kg/min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 microU/ml, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes.
Qualitative abnormalities in von Willebrand Factor (vWF) in patients with cirrhosis have been little studied with contrasting results. We used crossed immunoelectrophoresis (2-DIE) and multimeric analysis of vWF in eight patients with stable hepatic cirrhosis to evaluate abnormalities in vWF before and 1 h following intravenous administration of three doses of desmopressin acetate (0.3 micrograms/kg) given at baseline, 4 and 24 h. We thought that qualitative abnormalities might be more easily detected following desmopressin as this is known to release vWF from storage sites. There was an increased electrophoretic mobility on 2-DIE in all patients with no change following desmopressin. The multimeric analysis did not show an increase in lower molecular weight multimers, but showed a statistically significant increase in higher molecular weight multimers following desmopressin (P less than 0.02). These results suggest that the vWF of cirrhotics has an abnormal charge (not altered by release following desmopressin) which would explain the increased electrophoretic mobility on 2-DIE with a normal pattern of lower molecular weight multimers using multimeric analysis.
Congestive gastropathy is a frequent cause of upper gastrointestinal haemorrhage in patients with portal hypertension. The pathogenesis is thought to involve venous congestion with gastric mucosal capillary dilatation. We studied the relation between gastric mucosal capillary dilatation, measured morphometrically, and endoscopic appearances in 74 patients with portal hypertension and 20 control subjects. We also investigated the frequency of gastric colonisation with Helicobacter pylori. Mucosal capillaries in patients were significantly dilated compared with control subjects (p less than 0.001) but the degree of dilatation was not related to the severity of the endoscopic appearances. H pylori was identified in 19 of 74 (26%) patients but was not related to the severity of the endoscopic appearances. These results suggest that other factors in addition to mucosal venous and capillary congestion are important in the pathogenesis of endoscopic congestive gastropathy and that gastric colonisation with H pylori is unlikely to be one of these factors.
Wilson's disease is named after Kinnier Wilson (1878-1937), a famous British neurologist. It is an inherited condition, due to an excess of copper in the liver and brain. The mechanism is unknown, but the gene has been mapped to chromosome 13. The worldwide prevalence is about 30 per million. Patients present with liver disease and/or neuropsychiatric manifestations. Early diagnosis is crucial because there is an effective treatment. This treatment, usually with penicillamine, must be continued for life and without interruption. Liver transplantation may be lifesaving in patients with fulminant hepatitis, or with severe liver disease which is unresponsive to treatment.
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OBJECTIVE: To determine the frequency of an abnormal bleeding time in patients with cirrhosis and to relate this to known factors that affect primary haemostasis and to the severity of liver disease. DESIGN: Prospective clinical and laboratory study in patients admitted for complications or investigations of liver disease. SETTING: Royal Free Hospital hepatobiliary and liver transplantation unit. SUBJECTS: 100 Consecutive inpatients aged 17-74 with various forms of cirrhosis, including alcoholic, biliary, autoimmune, viral, and cryptogenic. At least 10 days had elapsed since any episodes of bleeding, resolution of sepsis, or alcohol intake. No patient was taking any drug known to affect primary haemostasis. MAIN OUTCOME MEASURES: Bleeding time as measured with the Simplate double blade template device. A bleeding time longer than 10 minutes was considered abnormal. Other measures were platelet count, prothrombin time, partial thromboplastin time, packed cell volume, and blood urea, serum bilirubin, and serum albumin concentrations, all measured on each subject at the same time by standard laboratory methods. RESULTS: A weak but significant correlation existed between the bleeding time and the platelet count (rs = 0.483; p less than 0.001). There were significantly lower platelet counts, longer prothrombin times, and higher blood urea and serum bilirubin concentrations in the 42 patients with bleeding times of 10 minutes or more compared with the 58 patients with bleeding times less than 10 minutes. Multiple linear regression analysis showed that the bilirubin concentration as well as the platelet count was independently correlated with the bleeding time. The combination of a platelet count greater than 80 x 10(9)/l and a prothrombin time less than 17 seconds (usually taken as safe limits for performing routine liver biopsy) did not predict a normal bleeding time. Ten of 39 patients fulfilling these criteria had a prolonged bleeding time. CONCLUSIONS: Prolonged bleeding time is common in patients with cirrhosis, even in those with prothrombin times and platelet counts within "safe limits" for invasive procedures. The severity of liver disease as assessed by the bilirubin concentration plays an important part in determining the bleeding time in cirrhosis. The bleeding time should be measured when assessing patients for invasive procedures who have a raised bilirubin concentration or poor hepatic function, even if the platelet count and prothrombin time are considered adequate.
The influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HC1 dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0.5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1.5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.
Fatty acids in cardiac muscle compete with glucose for oxidation, thereby inhibiting glucose utilisation. It is not clear whether a similar mechanism is important in resting skeletal muscle. We used the hyperinsulinaemic euglycaemic clamp technique in conscious rats fasted for 20 h to examine the effects of increased plasma non-esterified fatty acid levels (approximately 1 mmol/l) on glucose metabolism. Insulin was infused at 75 mU/h (plasma insulin, 2.27 +/- 0.21 micrograms/l) or 300 mU/h (16.41 +/- 0.47 micrograms/l). An increase in non-esterified fatty acid levels decreased clamp glucose requirement and 3-3H-glucose turnover by 35% (p less than 0.001) when the higher insulin dose was used but there was no change at the lower dose. At both insulin infusion rates, clamp blood lactate and pyruvate responses suggested inhibition of muscle glycolysis by elevated plasma non-esterified fatty acid concentrations. Quadriceps muscle glycogen deposition during the clamps was enhanced by increased non-esterified fatty acid availability at the lower insulin dose (p less than 0.001) but not at the higher insulin concentration. Activation of pyruvate dehydrogenase during the clamps was partially inhibited by increased plasma non-esterified fatty acid in the heart, adipose tissue and quadriceps muscle. This was evident at both insulin levels in heart but only at the higher insulin concentration in muscle (p less than 0.002). The findings are consistent with an inhibition of glycolysis in skeletal muscle of mixed fibre type as a result of increased fatty acid availability. At low rates of glucose flux glycogen synthesis may compensate for decreased glycolysis so that glucose turnover is not decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
A randomized, double-blind, placebo-controlled trial of somatostatin was conducted among 120 patients admitted for bleeding esophageal varices (59 placebo, 61 somatostatin). An initial 250-micrograms bolus of somatostatin followed by a 5-day continuous infusion of 250 micrograms/h and an identical administration of placebo were evaluated for both the control of bleeding and prevention of early rebleeding from varices. Failure to control bleeding occurred in 22 (36%) somatostatin patients vs. 35 (59%) placebo patients, with time to failure occurring earlier with placebo (P = 0.036). blood and plasma transfused per hour during drug infusion of trial drug was reduced in the somatostatin group: median 0.033 vs. 0.105 unit/h (P = 0.025). Use of balloon tamponade was halved in somatostatin-treated patients. The average effect of somatostatin was a 41% reduction in the hazard of failure (95% confidence interval, -1% to 65%, P = 0.0545) after adjustment for the severity of liver disease, which was the only other variable having a significant influence on time to failure. There was no difference in 30-day mortality per admission (7 placebo, 9 somatostatin) or complications. It is concluded that somatostatin is safe and more effective than placebo for the control of variceal bleeding.
It has been suggested that protein feeding increases portal pressure in cirrhotic patients, but that carbohydrate and fat have little effect. We examined the relationship between feeding and portal pressure, using different liquid test meals (250 or 500 ml non-protein, 250 ml protein-containing, 500 ml water), in 29 alcoholic patients with cirrhosis and portal hypertension. The mean hepatic venous pressure gradient (HVPG) increased significantly 30 min after the protein meal (10% increase; p = 0.009) and returned to basal levels at 60 min. The mean HVPG also increased significantly after the non-protein meal: after 500 ml the increase was 23% at 30 min (p = 0.046) and 17% at 60 min (p = 0.12); and after 250 ml it was 15% at 30 min (p = 0.012) and 7% at 60 min (p = 0.05). Ingestion of 500 ml water caused a small, non-significant, increase in mean HVPG. Plasma glucagon levels increased significantly at 30 and 60 min after the protein meal, but did not change significantly after the non-protein meal or water. Both protein-containing and non-protein meals significantly elevate HVPG in alcoholic patients with cirrhosis and portal hypertension.
Methyl tert butyl ether (MTBE) is a potent cholesterol solvent. We have used MTBE in twelve patients with 19 large radiolucent common bile duct stones which could not be removed endoscopically. MTBE was instilled directly into the common bile duct via a nasobiliary or percutaneous catheter. Successful clearance of the duct was achieved in ten patients. The stones disappeared completely in three patients with MTBE alone; in the remaining seven, it was possible to extract the stones endoscopically after MTBE, even though there was no change in the cholangiographic appearance. MTBE may have a role in the management of large retained common bile duct calculi but, given the practical difficulties of administration, its use should only be considered when other methods have failed and a non-surgical approach is desired.