Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland.

Paracetamol overdose is the commonest cause of acute liver failure in the UK, which has led to measures to restrict its sale. We aimed to establish whether changes in the referral of patients with paracetamol-induced acute liver failure have occurred since the introduction of legislation. We compared data from patients admitted to the Scottish Liver Transplantation Unit in 1992-98 with those admitted in 1998-2001. The incidence of paracetamol-induced liver failure, severity of patients' illness, and outcome did not differ between the groups. Patients with paracetamol-induced acute liver failure had higher Carstairs scores (1.99 [95% CI 1.33-2.65]; n=190) than patients with non-paracetamol acute liver failure (0.02 [-0.79 to 0.84]; n=68). We have shown an association between paracetamol-induced acute liver failure and social deprivation.

The outcome of the first 165 orthotopic liver transplants in Scotland.

The Scottish Liver Transplant Unit is now in its sixth year of existence. We present the outcome of the first 165 transplants which have at least 12 months follow up. The overall patient (n = 143) survival rates at 1, 3 and 5 years were 86.6%, 79.3% and 74.7% and the graft survival rates were 76.9%, 69.1% and 64.8%. The one year survival rate for patients with chronic liver disease (n = 113) was 89.2% compared with 76.6% for acute liver failure (Breslow = 0.05). The one year survival rate for the first 71 patients receiving their primary graft was 81.7% compared with 91.5% for the subsequent 71 patients (Breslow = 0.09). The majority of deaths (n = 29) were due to sepsis (n = 7), at operation (n = 6) or due to graft vascular insufficiency (n = 4). There were two cases of de novo haematological malignancy. The outcome of the first 165 transplants in Scotland compares very well with other countries throughout the world.

Comparison between theophylline and spironolactone in the management of cirrhotic ascites: a randomized controlled study.

BACKGROUND: It has been suggested that adenosine is involved in the renal haemodynamic and tubular abnormalities observed in cirrhosis. Low-dose theophylline is an adenosine antagonist and recent studies have shown that this drug can improve renal blood flow and sodium excretion in cirrhotic patients. METHODS: Fifteen patients with newly diagnosed cirrhotic ascites were randomized to receive either 100 mg spironolactone daily for 7 days or 250 mg theophylline on days 1, 2, 4 and 6. Baseline clinical and urinary and serum biochemical data were collected and compared following therapy. RESULTS: After 7 days of spironolactone there were increases in urinary sodium excretion (43.5 +/- 15.6 vs. 106.8 +/- 34.7 mmol/day; P < 0.05) and urine volume (769.1 +/- 206.5 vs. 1541.6 +/- 342.6 mL/day; P < 0.05). No changes in the patients' weight, creatinine clearance or serum electrolytes were observed. No change was detected in any of these parameters following theophylline therapy. CONCLUSION: Adenosine antagonism in the form of low-dose theophylline is less efficacious than spironolactone in the management of cirrhotic ascites.

A randomized trial comparing transjugular intrahepatic portosystemic stent-shunt with variceal band ligation in the prevention of rebleeding from esophageal varices.

The aim of this study was to compare transjugular intrahepatic portosystemic stent-shunt (TIPSS) with variceal band ligation (VBL) in the secondary prophylaxis of esophageal variceal hemorrhage in patients with cirrhosis. Fifty-eight patients with cirrhosis who presented with the first episode of esophageal variceal hemorrhage were randomized to TIPSS (31) or VBL (27), 24 hours after control of bleeding. Shunt function was assessed after 1 month and then at 6 monthly intervals thereafter. VBL was performed weekly until variceal eradication, and then at 3 months, 6 months, and yearly thereafter. Mean follow-up in the TIPSS group was 15.7 (+/-10.2) months; in the VBL group, it was 16.8 (+/-10.9) months. Results for rebleeding and mortality were analyzed on an intention-to-treat basis and using the Kaplan-Meier method. The frequency and the severity of variceal rebleeding was significantly lower in the TIPSS group (9.8%), compared with the VBL group (51.9%) (P < .0006). Although mortality rates were not significantly different, 8 of the patients who rebled in the VBL group required TIPSS therapy for uncontrolled bleeding. No significant differences were found in the frequency of other complications such as encephalopathy and sepsis. Patients in the VBL group required significantly greater time in the intensive care unit during the period of this study (<0.03). The total direct cost of treatment incurred was pound sterling 1,373 ($2,200) per patient, the cost being less in the patients treated with TIPSS compared with VBL. The results of this study show that TIPSS is superior to VBL for the secondary prophylaxis of variceal hemorrhage in patients with cirrhosis.

Colonic stricture in cystic fibrosis unmasked by successful transjugular intrahepatic portosystemic stent shunt (TIPSS).

TIPSS was successfully performed in a 10-year-old female cystic fibrosis (CF) patient with bleeding gastric varices due to portal hypertension; precipitation of portosystemic encephalopathy later unveiled the presence of a latent colonic stricture associated with high potency pancreatic enzymes. The unusual sequence of events resulting from the co-existence of two CF pathologies are described, and the implications of treatment discussed.

The distribution of myelinated nerve fibers in the mature opossum esophagus.

Myelination of nerve fibers could be important in establishing normal esophageal peristalsis. We therefore examined the general distribution and the age of appearance of myelinated nerve fibers in the smooth-muscle part of the esophagus of the American opossum. Tissues stained with thionein and Sudan black B were examined by light microscopy. Other tissues were prepared for electron microscopy and examined in the light microscope in Toluidine blue stained sections as well as at electron microscopy. In mature animals (weight greater than 2.0 kg, age greater than or equal to 1 year), myelinated nerve fibers, oriented mainly craniocaudally, were most abundant at the striated muscle-smooth muscle junction, and declined in density distally along the organ. They were nearly absent at the esophagogastric junction. They were more abundant in the stomach just below the esophagogastric junction. The myelinated nerve fibers commonly lay within sheathed fascicles that had the appearance of peripheral nerves, like the shunt fascicles of the stomach and colon. In immature animals myelinated fibers did not appear until a weight of about 1 kg was reached, 50 days after weaning and about 150 days after birth. Since the younger animals are presumably swallowing normally, myelination of the extrinsic nerves is not essential for esophageal motor function.

Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation.

The kinetics of plasma noradrenaline (NA) were studied in 14 patients with cirrhosis and ascites and 13 normal subjects. [3H]noradrenaline ([3H] NA) was infused intravenously to steady state and the spillover of NA into plasma and its clearance from plasma calculated. The increase in plasma NA in the cirrhotic patients was due to an increase in NA spillover (14.5 vs 3.9 nmol min-1m-2; P less than 0.001). NA plasma clearance was also increased in the cirrhotic patients (3.5 vs 2.11 min-1m-2; P less than 0.01). Plasma NA and dihydroxyphenylglycol (DHPG), a metabolite of NA of which a portion is formed after re-uptake of NA into sympathetic nerve endings, were then measured in 23 patients with cirrhosis and ascites, 17 patients with cirrhosis who had never had ascites, and 34 normal subjects. Both plasma NA and DHPG were significantly increased in the patients with ascites (NA 4.7, DHPG 14.7 nmol l-1 and in the patients with cirrhosis but no ascites (NA 3.8, DHPG 12.0 nmol l-1) compared with normal subjects (NA 1.9, DHPG 8.8 nmol 1-1). Therefore, the increase in plasma NA in cirrhosis is due to increased activity of the sympathetic nervous system rather than interference with the metabolism of NA or impaired neuronal uptake of NA. This increase appears to precede the development of ascites.

Impaired pressor reactivity in cirrhosis: evidence for a peripheral vascular defect.

The blood pressure responses to intravenous infusions of norepinephrine and angiotensin II, sympathetic and nonsympathetic vasoconstricting agents, respectively, were measured in 20 patients with cirrhosis (10 Child-Pugh grade A and 10 Child-Pugh grades B or C) and in 20 healthy subjects. The log PD20 (dose of agonist required to raise blood pressure by 20 mm Hg) for norepinephrine was 4.78 +/- 0.36 (mean +/- S.D.) in patients with severe cirrhosis and 4.36 +/- 0.37 in controls, p less than 0.01. Log PD20 for angiotensin II was 3.16 +/- 1.06 in patients with severe cirrhosis and 1.97 +/- 0.74 in controls, p less than 0.01. Cardiovascular responses to selective sympathetic agonists were measured in 10 other cirrhotic patients (all Child-Pugh grades B or C) and in 10 healthy controls. Log PD20s for phenylephrine, an alpha-1 adrenoceptor agonist, and for alphamethylnorepinephrine; an alpha-2 adrenoceptor agonist, were increased in cirrhosis (phenylephrine = 5.35 +/- 0.49 vs. 4.95 +/- 0.35, p less than 0.05; alphamethylnorepinephrine = 4.05 +/- 0.26 vs. 3.44 +/- 0.55, p less than 0.001). In contrast, log CD20 (dose of agonist required to raise the heart rate by 20 beats/min) for isoproterenol, a beta-adrenoceptor agonist, was similar in cirrhotic patients and controls (2.81 +/- 0.38 vs. 2.94 +/- 0.45, p = 0.49). These studies demonstrate that pressor reactivity to both sympathetic and nonsympathetic agonists is impaired in severe cirrhosis, that the impaired sympathetic responses are not caused by generalized sympathetic desensitization and that the site common to the four agonists with impaired responses is the peripheral vascular smooth muscle.

Binding studies of platelet alpha 2- and lymphocyte beta 2-adrenoceptors in patients with cirrhosis.

Radioligand binding studies were performed on 10 patients with cirrhosis and 10 healthy subjects. Bmax and KD of platelet alpha 2-adrenoceptors, studied using [3H]-yohimbine, were similar in both groups (Bmax 24.9 vs 22.1 fmol/10(9) platelets, P = 0.47; KD 4.6 vs 5.5 nmol 1-1, P = 0.56). Bmax and KD of lymphocyte beta 2-adrenoceptors, studied using [125I]-iodocyanopindolol, were also similar in both groups (Bmax 24.0 vs 27.2 fmol mg-1 protein, P = 0.55; KD 49.6 vs 55.3 pmol 1-1, P = 0.65). In this model there is no evidence of adrenoceptor down-regulation in cirrhosis despite the increased sympathetic activity in this condition.

Impairment of autonomic reflexes in cirrhosis.

Autonomic dysfunction may contribute to the hemodynamic disturbances in cirrhosis. Tests of autonomic function were performed in 20 patients with cirrhosis and 20 healthy subjects. The patients with severe cirrhosis (Child's grade B or C) had significant reductions in the Valsalva ratio, the heart rate variation during both facial immersion in water and deep breathing, the pressor response to forearm isometric exercise, and the heart rate response to dynamic exercise. The cold pressor test and the heart rate response to lying down were unaffected. These results indicate impairment of both sympathetic and parasympathetic reflexes in severe cirrhosis which may contribute to the hemodynamic disturbances of cirrhosis. Further studies are required to define the site of these defects.

Rise in plasma noradrenaline with age results from an increase in spillover rate.

Venous plasma noradrenaline (NA) kinetics, determined using steady-state intravenous infusions of subpressor doses of [3H] NA, were measured in 8 young, 13 middle-aged and 8 elderly subjects. Plasma NA concentrations were 0.71 nmol/l (0.25-0.98) in the young, 1.90 nmol/l (0.98-3.65) in the middle-aged and 3.03 nmol/l (1.15-3.85) in the elderly (young vs. elderly, p less than 0.001). NA spillover rates were 2.07 nmol/l/m2 (1.05-4.91) in the young, 3.91 nmol/l/m2 (1.62-9.44) in the middle-aged and 7.57 nmol/l/m2 (4.38-24.0) in the elderly (young vs. elderly, p less than 0.001). Plasma NA clearance was similar in young and elderly subjects. NA spillover was positively correlated with age (r = 0.58; p less than 0.01) and was not independently related to blood pressure. The rise in plasma NA with age results from an increase in spillover rate rather than any alteration in clearance.

The anti-secretory effect and pharmacokinetics of omeprazole in chronic liver disease.

The anti-secretory effects and pharmacokinetics of omeprazole were investigated in ten patients with chronic liver disease. Plasma omeprazole concentrations were measured after a 10-mg intravenous dose of omeprazole and on the first and seventh days of a 7-day course of 10 mg oral omeprazole daily. Pentagastrin tests were performed on the day before oral omeprazole was commenced and 24 h after the last oral dose. The pre-treatment basal and peak gastric acid outputs were low (mean rates of 1.44 mmol/h and 9.26 mmol/h, respectively) and following 7 days of oral 10 mg omeprazole daily, were lowered by 95% and 90% respectively. Following 10 mg intravenous omeprazole, plasma clearance was reduced, and plasma half-life and area under the concentration curve were increased, in comparison with previous studies in healthy subjects. The plasma concentration curves for oral and intravenous doses were very similar. After both the first and seventh oral doses, maximum plasma concentration and area under the curve were higher than in healthy subjects. No accumulation of omeprazole was demonstrated. The pharmacokinetics of omeprazole in chronic liver disease could be influenced by low gastric acidity, poor liver function and/or portasystemic shunting. A dose of 10 mg omeprazole daily has been shown to be an effective anti-secretory agent in chronic liver disease.

In vivo and in vitro studies of the site of inhibitory action of omeprazole on adrenocortical steroidogenesis.

The site of omeprazole inhibition of adrenal steroidogenesis has been sought in vivo by analyzing the patterns of urinary steroid metabolite excretion after 6 days of treatment with placebo/omeprazole. Excretion rates of androsterone, aetiocholanolone, dehydroepiandrosterone, 11 beta hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol and alpha cortolone were reduced, indicating a block at an early step in steroidogenesis, possibly cholesterol side-chain cleavage. In vitro studies have confirmed this finding by measuring conversion of added precursors to cortisol in isolated bovine adrenocortical cells. Cortisol synthesis from added 20 alpha hydroxycholesterol was inhibited by 83% in the presence of 100 micrograms omeprazole/ml. Conversion from pregnenolone and progesterone and their 17 alpha hydroxylated derivatives was inhibited by 20-40% whereas cortisol production from added 11 deoxycortisol was not affected. These data suggest that omeprazole primarily inhibits cholesterol cleavage and does not inhibit 3 beta hydroxysteroid dehydrogenase, 17 alpha hydroxylase or 11 beta hydroxylation; 21 hydroxylase activity may be marginally attenuated.

Abetalipoproteinaemia in adults: role of vitamin therapy.

The retinal and neurological complications of abetalipoproteinaemia may be preventable by replacing vitamins A and E from an early age, but their role in adult presentations is less clear. Two adult females with abetalipoproteinaemia have received 8 and 10 years respectively of replacement therapy with vitamins A, E and linoleic acid. In Case 1, visual function improved objectively on commencing therapy but has subsequently deteriorated and her neuropathy has slowly progressed. The rate of progression of neurological impairment in Case 2 was slowed but not halted by therapy, and her severe visual disturbance was unaffected. Replacement by fat soluble vitamins has only a limited role in the management of abetalipoproteinaemia once irreversible neurological/retinal damage has occurred.

The effects of omeprazole on endocrine function in man.

We have assessed the effect of omeprazole on various endocrine functions in man. Eight healthy subjects took 60 mg omeprazole or placebo daily for 1 week in a double-blind, randomized, cross-over study. On Day 7 basal concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, testosterone, thyroid-stimulating hormone (TSH), and serum thyroxine (T4) and tri-iodothyronine (T3) were measured, followed by the gonadotrophin response to luteinising hormone releasing hormone (LHRH) and the prolactin and TSH responses to thyrotrophin releasing hormone (TRH). There were no differences in basal or stimulated values between omeprazole and placebo. In a second study, a further 8 subjects were similarly treated, and on Day 7 serial measurements of cortisol and 11-deoxycortisol were made before and for 2.5 h after intravenous adrenocorticotrophin (ACTH). There were no differences in basal values or pattern of response to ACTH for either hormone. Omeprazole in clinical practice is unlikely to cause any significant interference in endocrine function.

Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.

Midazolam kinetics and psychomotor function were studied after an intravenous dose of 0.075 mg/kg body weight in seven patients with alcoholic cirrhosis and eight control patients. Four of the seven cirrhotics died of complications of their liver disease within six months of the study. The metabolism of midazolam was significantly impaired in the cirrhotic patients (p less than 0.025). These patients also had evidence of greater sedation than the control group for up to six hours after the dose was administered (p less than 0.05). The clearance of midazolam did not correlate significantly with the serum albumin, or bilirubin, or with the kinetics of antipyrine, or indocyanine green. This study shows significant delay in the elimination of midazolam and decreased psychomotor function in patients with severe alcoholic liver disease. Caution is needed in using this drug for premedication in such patients before endoscopy.