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A prevalence study of primary biliary cirrhosis was carried out in the state of Victoria, Australia, by means of a mail survey of specialist physicians and a review of hospital records. Eighty four cases were identified, giving a prevalence of 19.1 per million population (95% confidence limits (CI) 15.3, 23.7), which is among the lowest in published reports. The prevalence in the Australian born, at risk population (women over the age of 24) was 51 per million (95% CI 37.5, 67.9). Both these figures are considerably lower than those in populations of similar age distribution in the UK and northern Europe. Since most Victorians are descended from British or European settlers, the low prevalence of primary biliary cirrhosis in this study supports the hypothesis that local environmental factors may be important in the pathogenesis of this disease.

Background: Chemoembolization is often used in the treatment of hepatocellular carcinoma; however, there are limited data on its efficacy in an Australian setting. Aims: To review retrospectively the experience of 21 patients with hepatocellular carcinoma who collectively had 36 chemoembolizations performed between October 1995 and February 1999 in a teaching hospital and liver transplant centre in Victoria. Methods: Selective catheterization of the right or left hepatic arteries was performed. A mixture of cis-platin 50 mg, epirubicin 50 mg, mitomycin C 10 mg, Lipiodol and gelfoam was injected. Computed tomography (CT) scans were performed at baseline and at 1–3 months after chemoembolization. Outcome measures included response rates, toxicity, progression-free and overall survival. Results: CT response rates: partial response 19% (n = 7), median duration 11 months (range 2+ to 37+); minor response 17% (n = 6), median duration 7 months (1+ to 12+); stable disease 42% (n = 15), median duration 3 months (1+ to 15 months); and progressive disease 22% (n = 8). Major toxicities included one case each of acute renal failure, contrast encephalopathy, gastric ulceration and hepatorenal failure. Median progression-free survival was 3 months (range 0–37+). Median overall survival was 15 months (range 6–50+). Conclusion: Chemoembolization has a role in the palliative treatment of hepatocellular carcinoma. Our response rates and toxicity data are consistent with those in the published literature. However, new treatments are needed and prevention of disease by reduction in the prevalence of chronic hepatitis B and C will be required to significantly reduce mortality from this tumour. (Intern Med J 2001; 31: 517–522.

SUMMARY 1. A 50 μL bolus dose containing (±)-propranolol hydrochloride (200 μg) and [14C]-sucrose, or antipyrine (2 mg) and [14C]-sucrose, or [14C]-taurocholate sodium was injected into the portal vein of the isolated perfused rat liver preparation and perfusate outflow samples were collected frequently for the next 30min. After a 20 min washout period this procedure was repeated. 2. [14C]-Sucrose, antipyrine and [14C]-taurocholate each eluted as a single peak at 18, 31 and 28 s, respectively, after each dose. In contrast, propranolol eluted with two peaks at approximately 18 and 128 s after dosing. 3. There was no significant difference in dose-corrected area under the outflow curve (AUC) for [14C]-sucrose, antipyrine or [14C]-taurocholate between the first and second doses whereas the mean propranolol AUC for the second dose was only 0.577 ± 0.439 that for the first dose (P

SUMMARY 1. The hepatic reticuloendothelial cell population is generally assumed to increase in size, along with the liver, during ageing in rats. However, this has not been rigorously established. 2. Using electron microscopy and stereological techniques, the present study has shown that the volume densities of hepatocytes and Kupffer cells (and probably also of endothelial cells, fat storing cells and the extracellular space) of the livers of female Sprague-Dawley rats are the same at 2 and 24–25 months of age. 3. This result indicates that the increase in size of the liver during ageing in the rat is associated with an equivalent increase in the volume of each cell population and the extracellular space.

Pulsed Doppler Ultrasound was used to analyze hepatic artery wave forms near the porta hepatis. The Resistive Index (RI) = [peak systolic frequency shift (A)--minimum diastolic frequency shift (B)]/[peak systolic frequency shift (A)] has been calculated from this information. Two populations have been compared; 30 fit hospital staff members, 23 male, 7 female, age mean 37 years and range 19 to 73 years, and 33 cirrhotic potential liver transplant recipients, 16 male, 17 female, age mean 48 years and range 11 to 78 years. The RI was successfully obtained in 94% of the potential transplant patients. There is a significant difference between the RI of the controls (mean = 0.72, SE = 0.2, n = 27) and the cirrhotics (mean = 0.82, SE = 0.2, n = 31), P less than 0.0001. Using a cut off of greater than 0.77 this index has a sensitivity, specificity and overall accuracy of 68%, 70% and 69% respectively.

A number of mechanisms for sucralfate protection of gastric mucosa during ulcer healing and protection from experimental injury have been proposed. One currently held postulate that sucralfate acts by inhibiting acid/pepsin attack and creating, at acid pH, a barrier to diffusion of hydrogen ions was tested. The experiments took advantage of a cultured rat antral mucosal model in which ethanol injury is assessed by release of radiolabel from 51chromiumloaded mucosa. In this model, with mucosa cultured in the absence of pepsin activity at a neutral pH, sucralfate conferred marked protection; specific 51chromium release fell from 12.4% (s.e.m. = 0.7) in controls to 8.9% (s.e.m. = 0.9) at 0.5 mg/ml (P < 0.05) and 3.4% (s.e.m. = 0.5) at 2.0 mg/ml (P < 0.001) of sucralfate and was abolished at 10 mg/ml and 40 mg/ml (P < 0.001). Pretreatment with sucralfate in vivo also protected the mucosa against subsequent ethanol challenge in the cultured mucosal model, control 12.3% (s.e.m. = 1.9) versus sucralfate pretreatment 6.9% (s.e.m. = 0.7) (P < 0.02). Using computer-assisted macroscopic assessment of mucosal damage after ethanol dosage by gavage, it was further demonstrated that sucralfate protection in vivo is dose-dependent and prolonged, lasting for at least 5 h at a dose of 200 mg/kg. It is concluded that sucralfate-induced protection of the gastric mucosa is long-lasting and can occur via mechanisms other than minimization of acid/peptic attack.

Vasoactive intestinal polypeptide (VIP) is released into the portal circulation by a meal stimulus, but is rapidly cleared from plasma. Although it is known to bind to receptors on liver cells, the role of the liver in the clearance of VIP is not clearly defined. We therefore studied the disappearance of VIP in recirculating and in single pass isolated perfused rat liver (IPRL) preparations. Disappearance of added VIP was rapid in recirculating IPRL experiments with a half life of ca. 30 min. In single-pass steady-state studies in which livers were perfused at 16 ml/min for 30 min, clearance of VIP was complete (16 ml/min) at concentrations of 500 fmol/ml, but clearance fell to 3 and 1 ml/min at perfusate concentrations of 8 and 40 pmol/ml respectively. Further experiments to evaluate whether VIP was disappearing in perfusate itself demonstrated substantial metabolism of VIP in perfusate which had previously been circulated through a liver for 90 min. The products of metabolism were identical to those found in the IPRL. We conclude that VIP is rapidly cleared as it passes through the isolated perfused rat liver model with a significant proportion of clearance attributable to release of a peptidase from the liver into the perfusate.

Lysosomes constitute a small proportion of hepatocyte volume, but they play a key degradative role, particularly during catabolic states such as nutritional deprivation. Our preliminary observations in hepatocytes suggested that fasting may alter the distribution of lysosomes, which are thought to congregate about the biliary canaliculus. The current study aimed to provide, in both fed and fasted rats, a quantitative morphometric analysis of lysosomes in the immediate pericanalicular and successively more distant regions. We selected three regions of radius 0 to 2 (region 1), 2 to 4 (region 2) and 4 to 6 micron (region 3) about the bile canaliculus and compared lysosomal numerical and volume densities. In fed rats, numerical and volume densities of both primary and secondary lysosomes were 5 to 10 times greater in region 1 than in region 3. After a 72-hr fast, this gradient was lost due largely to a reduced number of primary and secondary lysosomes in region 1. Our calculations suggest that during fasting, lysosomes are redistributed away from the bile canaliculus towards the more distant cytoplasm rather than being lost from the cell, for example, into bile. The number of overt macroautophagic vacuoles was not altered by fasting. We estimate that, in fed rats, there are approximately 270 lysosomes per hepatocyte, and that 43% of lysosomes are contained in the immediate pericanalicular region 1, which comprises only 7 to 8% of the cytoplasmic volume. The reason for this pericanalicular concentration of lysosomes and the mechanism of the redistribution with fasting remain to be determined.

Hepatocyte lysosomes disassemble materials derived from intracellular sources, including lipid-containing membranes, by a process called autophagy. In addition, hepatocyte lysosomes can release their contents into bile by exocytosis. Therefore, using both in vivo and in vitro models, we tested the hypothesis that acute pharmacologic induction of autophagy would modify the biliary excretion of lysosomal protein and of lipids. We treated rats with a single dose of chloroquine (10 mg/kg), glucagon (1 mg/kg), or control solutions and collected bile via bile fistulas. Both chloroquine and glucagon immediately caused a marked and parallel decrease in biliary excretion of three lysosomal enzymes, N-acetyl-beta-glucosaminidase, beta-glucuronidase, and beta-galactosidase, to 25%-30% of baseline values (p less than 0.01). This decrease was sustained for 2 h after glucagon and 4 h after chloroquine administration. In contrast, biliary lipid changes were minor: a slight lowering of biliary cholesterol secretion after chloroquine (p less than 0.05), but no change in biliary bile acids, cholesterol, and phospholipid secretion after glucagon. Changes in biliary excretion of lysosomal enzymes accompanying chloroquine and glucagon administration were associated with morphologic evidence of autophagy as assessed by electron microscopy and by increased fragility of hepatic lysosomes as assessed by latency of N-acetyl-beta-glucosaminidase. These in vivo changes in biliary lysosomal enzyme excretion induced by chloroquine and glucagon were confirmed in vitro using the isolated perfused rat liver. Thus, acute induction of autophagy results in conservation of hepatic lysosomal protein and has virtually no effect on biliary lipid excretion.

The substituted benzimidazole, omeprazole, is a potent inhibitor of the ATP-dependent proton pump of the parietal cell. Since there is accumulating evidence that hepatic lysosomes also possess an ATP-dependent proton pump system to maintain internal acidification, and since antibodies to the putative lysosomal proton pump protein are immunologically similar to the parietal cell (H+ + K+) ATPase, we studied the effects in rats of six days of omeprazole treatment on hepatic lysosomal function. Omeprazole, 5 mg kg−1, a dose five times the ED50 for gastric acid secretion inhibition in rats, did not alter the activity of three representative lysosomal enzymes in liver (acid phosphatase, β-galactosidase and N-acetyl-β-glucosaminidase) nor did it alter lysosomal enzyme latency, a measure of the integrity of the lysosomal membrane. Furthermore, bile flow and the secretion of lysosomal enzymes into bile were also unaffected by omeprazole. These data indicate that in rats short-term treatment with omeprazole, in doses that markedly inhibit gastric acid secretion, has no major biological effect on liver lysosomal integrity and lysosomal enzyme activity.

:Zinc is an important trace metal and, in liver disease, abnormal zinc metabolism has been reported. In this study of patients with fulminant hepatic failure progressing to grade IV encephalopathy, plasma zinc concentrations fell during the illness to reach levels significantly below normal; during this time urinary zinc excretion was markedly elevated.

Fourteen patients with ileal dysfunction due to resection or bypass were encountered over an 18-month period. Symptoms had been present for a mean period of 1.8 years. Diarrhoea was a universal symptom, and varied from mild to incapacitating. Weight loss, due in part to malabsorption and in part to the patients' fear of eating, occurred in 10 of 14 patients. The chief metabolic abnormalities were steatorrhoea and hypokalaemia. Vitamin B12 deficiency, folate deficiency, anaemia, hypoalbuminaemia, hypocalcaemia, hypomagnesaemia, hyperoxaluria, and an abnormal prothrombin ratio were less frequently seen. Treatment with cholestyramine and/or long-chain fat restriction effectively reduced diarrhoea in every case, and this was supplemented by replacement of specific deficiencies. There was little added benefit from non-specific antidiarrhoeal agents. It was found that the major symptoms of ileal dysfunction are readily treated, but that attention should also be given to a number of nutritional deficiencies.

Neurotensin is released from the intestinal mucosa into the portal circulation and, to exert a systemic effect, it must traverse the liver intact. We examined the potential role of the liver in neurotensin clearance using the isolated perfused rat liver model. With N-terminal and C-terminal directed RIAs and HPLC, we demonstrated rapid metabolism of intact neurotensin to inactive N-terminal fragments in the isolated rat liver system. The disappearance half-lives of C-terminal and N-terminal immunoreactivity were 20.4 +/- 6.0 min and 82.7 +/- 7.7 min, respectively, (P less than 0.002). To assess whether this neurotensin disappearance might be due to metabolism within the perfusate itself by a peptidase released from liver, we further incubated neurotensin in perfusate previously circulated through liver. A rapid and progressive breakdown of intact neurotensin to N-terminal fragments was again shown. These data demonstrate that a substantial proportion of the hepatic clearance of neurotensin is attributable to release of a peptidase by the liver into the circulation.

Summary 1. The biliary excretion of a tracer pulse of sodium [14C] taurocholate injected into the portal vein was compared in adult and near-term foetal sheep. 2. Biliary excretion was virtually complete in both adult and foetus, although appreciably faster in the adult. 3. These results indicate that at birth the mechanisms for bile salt uptake and excretion in the sheep liver are well established.

Summary: The plasma disappearance of an intravenously injected tracer dose of glycocholic acid (glycine-1-14Cy was compared in patients with and without diffuse hepatocellular disease. No difference was found between the two groups of patients. We conclude that this test is not a sensitive index of the presence of significant liver disease.

SUMMARY 1. Neurotensin is released from the intestine into the portal circulation and to exert a systemic effect it must traverse the liver intact. 2. The role of the liver in neurotensin clearance was examined using the isolated perfused rat liver preparation. Two concentrations of neurotensin were used to determine the extraction capacity of the liver. 3. Approximately 10% of the added neurotensin (with either dose) was extracted in a single pass through the liver. This extraction rate was low when compared to previous studies with cholecystokinin (60% extraction in a single pass) and vasoactive intestinal peptide (100%). 4. It is concluded that there is a small but high capacity for direct extraction of neurotensin. This low direct extraction percentage supports our previous contention that the major influence of the liver on the metabolism of neurotensin is by the release of neurotensin degrading peptidases into the circulation.

During injury to the gastric mucosa, lysosomes become more fragile and lysosomal enzymes, which are activated at acid pH, leak into the surrounding environment. It is not clear whether these changes contribute to the mechanism of damage or are merely a secondary result of it. To test whether lysosomes modulate gastric mucosal damage, we pretreated rats with a lysosomal labilizing agent, Triton WR 1339 (1.5 g/kg) and histologically assessed mucosal damage in vivo after challenge with 30% ethanol. No significant differences were found in the length or depth of eroded mucosa: mean erosion length, Triton 23.9 +/- 6.6% vs. control 19.7 +/- 5.2%; mean depth (micron), Triton 19 +/- 4 vs. control 20 +/- 7. After a similar pretreatment regimen, rat antral mucosa was cultured, challenged with ethanol and damage assessed by release into media of previously incorporated mucosal 51chromium. With 15% ethanol challenge, no change in 51chromium release was seen: after Triton, 9.8 +/- 1.4% vs. control 10.3 +/- 1.0%. Triton pretreatment perturbed gastric lysosomes as shown in organ culture by significantly raised tissue lysosomal enzyme activities and increased lysosomal enzyme release into culture media after ethanol challenge. The lack of effect of this pretreatment regimen suggests that lysosomes do not have a major pathogenetic role in ethanol-induced gastric damage.

We tested the hypothesis that hepatocyte microtubules modulate the biliary excretion of endogenous and exogenous constituents of hepatocyte lysosomes. We collected bile via bile fistulas from male rats before and after acute administration of colchicine and vinblastine, agents known to bind to hepatocyte microtubules; rats were then killed and livers were homogenized for biochemical analyses or processed for electron microscopy. Colchicine caused biphasic, parallel alterations in the biliary excretion of three lysosomal enzymes compared with control rats given saline or lumicolchicine; a peak rise in enzyme outputs of approximately 175% at 45-60 min after colchicine administration was followed by a sustained fall to approximately 25% of control values, which persisted for 2-4 h. When hepatocyte lysosomes were prelabeled in vivo by administration of [3H]Triton WR-1339, a nonionic detergent that is sequestered in hepatic lysosomes, the biliary excretion of radiolabel in response to colchicine paralleled the biliary excretion of the three lysosomal enzymes. Vinblastine also induced a biphasic response in biliary lysosomal enzyme output that was similar to that produced by colchicine administration. Morphometric analysis of electron micrographs of rat livers demonstrated changes in the number of lysosomelike vesicles in the vicinity of bile canaliculi after colchicine and vinblastine administration; the initial increase in lysosomal enzyme secretion was associated with a significant decrease in the number of pericanalicular lysosomes after both agents, while the subsequent decrease in enzyme secretion coincided with an increase in the number of pericanalicular lysosomes after vinblastine.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Perhexilene, a long-acting anti-anginal drug, can induce adverse effects on the liver which may be dose-dependent. At high concentrations, perhexilene causes marked morphological changes in hepatocyte lysosomes. The current study examined the effect of 'therapeutic' doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model. 2. Pharmacokinetic studies demonstrated that clearance of single doses of perhexilene by the perfused rat liver was dose-dependent and established a 'therapeutic' dose of 0.6 mg using the IPRL. A 5 day pretreatment regimen of 20 mg/kg per day was shown to produce 'therapeutic' perhexilene concentrations of 150-210 ng/ml. 3. At perhexilene concentrations equating the 'therapeutic' range in man, the major effect of perhexilene was at the biliary pole of the hepatocyte. In 5 day pretreatment dose studies, lysosomal enzyme excretion into bile was markedly increased. In single dose studies, the increase in biliary lysosomal enzyme output partially reflected an increase in bile water production which was not seen with the 5 day pretreatment regimen. Hepatic and perfusate lysosomal enzyme activities were not affected. 4. This selective effect of perhexilene on hepatocyte-to-bile lysosomal excretion may reflect intracellular lysosomal drug localization.