N. D. Gallagher

Long-term survival with tumor regression in androgen-induced liver tumors.

Two patients with androgen‐induced liver tumors, one of whom had been partially treated by a liver resection, are reported. Hepatocellular carcinoma was diagnosed on histologic grounds. The patients had been receiving androgen therapy for primary diagnoses of either hypopituitarism or paroxysmal nocturnal hemoglobinuria. After androgen withdrawal, both are alive and well with no evidence of residual tumor 10 and 14 years after diagnosis, respectively.

Thrombocytopenia post liver transplantation: Correlations with pre-operative platelet count, blood transfusion requirements, allograft function and outcome

This study reports that thrombocytopenia is a universal phenomenon post hepatic transplantation. In 53 consecutive adult patients undergoing liver transplantation the platelet count fell by a mean of 63% (157 x 10(9)/l to 50 x 10(9)/l). The platelet count reached a nadir at Day 5 post-transplant but returned to pre-operative levels by Day 14. Non-parametric regression analysis found that pre-operative platelet count, blood transfusion requirements and maximum post-operative ALT values were independent predictors of the percentage fall in platelet count. No correlation was seen with length of graft cold ischaemic time or the use of University of Wisconsin (UW) solution. The nadir day correlated with maximum post-operative bilirubin and ALT, graft ischaemic time and use of UW solution. Maximum post-operative ALT was also an independent predictor of nadir platelet count. It was observed that patients who did not survive the hospital admission had lower post-operative platelet counts and these did not return to pre-operative levels by Day 14. The percentage fall in platelet count was an independent predictor of survival. Severe thrombocytopenia was associated with cerebral haemorrhage in 3 patients. This report provides evidence that allograft dysfunction (maximum post-operative bilirubin and/or AST/ALT) was the most consistent independent predictor of the nadir platelet count, nadir day and percentage fall in platelet count post liver transplantation although the exact mechanism(s) of the platelet changes remain uncertain.

A specific gastrin receptor site in the rat stomach

A specific receptor for gastrin I has been demonstrated in the rat stomach fundus. Specific binding of 125I-labelled gastrin I was localised to particles sedimenting between 250--20 000 X g. Saturation of binding sites occurred with a gastrin concentration of 10(-11) M in an assay system containing 0.6--1.7 mg/ml of homogenate protein. Gastrin binding was shown to be reversible, temperature- and pH-dependent, and susceptible to tryptic digestion. Electron microscopic and enzymatic studies showed the binding fraction to contain predominantly mitochondria. Preincubation of the homogenate with 10(-8) M cholecystokinin or secretin inhibited gastrin binding to a greater extent than an equimolar concentration of pentagastrin. Cimetidine, a histamine receptor antagonist, did not affect binding of gastrin to the receptor.

Mortality and rebleeding following Transjugular Intrahepatic Portosystemic Stnt Shunt for variceal haemorrhage

The present study investigates clinical factors associated with decreased survival following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS). Sixty‐seven patients underwent TIPSS for bleeding related to portal hypertension, 42 (63%) on an urgent basis. TIPSS was successfully placed in 65 (97%) patients with no fatal procedural complications. Thirty day mortality was 21%, there being several predictive factors: transfer from another institution, urgency of procedure, sepsis, encephalopathy, higher mean serum bilirubin and low serum albumin. However, using regression analysis, 30 day mortality was predicted independently only by severe liver disease (Child‐Pugh C, P= 0.003) and older age (P= 0.003). When stratified by Child‐Pugh class, cumulative survival rates at 1 year for class A, B and C were 100, 90 and 34%, respectively. Only three of 25 patient deaths were due to variceal rebleeding. Thirty (46%) patients had a total of 41 rebleeding episodes, with mean time to first rebleed of 4.8 months (range, 3 days‐38 months). Cumulative rebleeding rate at 1 year was 25%. Log‐rank analysis did not reveal a significant difference in overall survival between rebleeders and non‐rebleeders (P= 0.125). When investigated, shunt abnormalities (stenosis, occlusion) were identified in all cases of rebleeding. Our findings confirm TIPSS can be safe and effective in the control of refractory variceal haemorrhage. However, prognosis remains poor for patients with advanced liver disease, particularly if older and in the emergency setting. Vigilant surveillance and high rate of intervention is necessary to maintain shunt patency. Consideration could be given to elective shunt surgery instead of TIPSS for patients with recurrent bleeding and good prognosis liver disease.

Striking variability of hepatic copper levels in fulminant hepatic failure

Two cases of acute hepatic failure are reported in which the diagnosis of Wilsons disease was considered because of low serum ceruloplasmin, low serum copper levels and high 24 h urinary copper. Case 1 had Kayser‐Fleischer rings, haemolysis and a high 24 h urinary copper, and so Wilsons disease was confidently diagnosed. Case 2 had high urinary copper excretion, but [64Cu] study indicated a 24: 2 h ratio of 0.7 and made the diagnosis of Wilsons disease uncertain. Both patients underwent orthotopic hepatic transplantation, and multiple biopsies were taken from the resected specimen in order to estimate hepatic copper levels. In both cases, hepatic copper levels revealed considerable variation: 0.8–5.2 μmol/g dry wt (case 1) vs 0.02–12.65 μmol/g dry wt (case 2). In case 1, only two of 14 levels were within the diagnostic range for Wilsons disease (> 4 μmol/g dry wt), whereas hepatic copper levels in case 2 were in the Wilsonian disease range in three of 16 specimens. These results were in contrast to uniformly high hepatic copper levels in one patient with established cirrhosis secondary to Wilsons disease and two cases of primary biliary cirrhosis. This report indicates that hepatic copper levels vary greatly in acute liver failure, and that estimates from a single biopsy specimen may be misleading as to the cause of the underlying liver disease.

Liver transplantation for primary sclerosing cholangitis versus primary biliary cirrhosis: A comparison of complications and outcome

Abstract Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are the most common cholestatic disorders in adulthood requiring hepatic transplantation. Although they run similar courses, they may have different problems before and after transplantation. The aim of this study was to compare pre‐ and post‐transplant complications and outcomes in these two similar but distinct patient groups. One hundred and seventeen adult patients underwent liver transplantation at our institution over a 6 year period, including 19 with PSC and 20 with PBC. Pre‐transplant there were no significant differences in age, liver biochemistry, haematology or Child‐Pugh scores between the two groups. The mean duration of disease before transplant was longer in PSC patients (11.7 vs 6.5 years; P < 0.05). The prevalence of septic cholangitis was greater in PSC (58 vs 5%; P < 0.01) as was the requirement for surgical or radiological interventional procedures, excluding cholecystectomy (53 vs 0%; P < 0.01). At transplantation, four patients with PSC had previously unrecognized cholangiocarcinoma. In the pre‐transplant period these four patients had uncontrolled biliary sepsis at the time of transplant vs five of 15 PSC patients without cholangiocarcinoma. Postoperatively, PSC patients had a greater prevalence of intra‐abdominal sepsis requiring surgical or radiological intervention (42 vs 5%; P < 0.05). In comparison, patients with PBC had a high prevalence of skeletal complications (30 vs 10%; P < 0.05) particularly avascular necrosis (15 vs 0%). The prevalence of chronic rejection was similar in both groups (15%). Overall survival was higher in PBC patients (85 vs 63%; P < 0.05). The prevalence of postoperative intra‐abdominal sepsis requiring surgical or radiological intervention was higher in those patients with PSC who died (six of seven) compared to survivors (two of 12), (P < 0.001). Postoperative uncontrolled intra‐abdominal sepsis directly contributed to more deaths in PSC patients (four of seven vs 0%). In conclusion, despite many similarities with PBC, PSC patients have higher prevalence of pre‐ and postoperative intra‐abdominal sepsis that may contribute to poorer survival. In contrast PBC patients have excellent survival rates after a liver transplant, although bony complications are increased.

In Vivo Evidence That Cobalamin Is Absorbed by Receptor-Mediated Endocytosis in the Mouse

This study examines the mechanism of cobalamin absorption in the context of receptor-mediated endocytosis. Uptake, the amount of cobalamin that left the intestinal lumen, and transport, the component that was located in organs beyond the intestine, were measured after feeding saturating doses of [57Co]cobalamin to mice. Uptake from a 40-ng dose of [57Co]cobalamin at 1 h was 18.6 +/- 6.3 ng (mean +/- SD; n = 6). When the dose was given 1 h after 40 ng of unlabeled cobalamin, uptake was 18.5 +/- 1.5 ng, n = 6, indicating rapid clearance of the surface receptors. Transport of the initial and of a subsequent dose of cobalamin could not be detected for 2 h but the amounts and rates of transport were similar. Oral chloroquine and intraperitoneal cycloheximide reduced transport at 4 h to 4.3 +/- 1.6 ng, n = 8 and 5.6 +/- 2.4 ng, n = 7, respectively. Control values were 14.3 +/- 1.3 ng, n = 8. These results indicate that the transport of cobalamin involves a series of compartments, one of which may be lysosomal, and that there is a requirement for new protein synthesis.

Humoral Regulation of Vitamin B12 Absorption by Pregnant Mouse Small Intestine

In vivo experiments in which pregnant mice were fed an oral dose of 40 ng of [57Co]B12 demonstrated that there was a progressive increase in B12 absorption in the 3rd week of pregnancy. The absorptive mechanism resembled that in nonpregnant animals on the grounds that the mechanism was saturable, and presumably intrinsic factor (IF) dependent, and that it was localized to the ileum. In vitro studies of IF-57Co B12 binding to ileal homogenates confirmed the requirement for IF. Studies in late pregnancy showed that IF-[57Co]B12 binding to ileal homogenates, expressed as nanograms of IF-[57Co]B12 bound per milligram of protein, was twice that of nonpregnant animals. When ileal homogenates were prepared from mice on days 20 to 21 of gestation, IF-[57Co]B12 binding fell to nonpregnant levels within 2 to 4 hr of hysterectomy. Hourly injections of serum from mice in late pregnancy, or from a female at the 37th week of gestation, maintained IF-B12 binding at levels reached during pregnancy, whereas nonpregnant serum was ineffective.

Intrinsic factor-cobalamin accumulates in the ilea of mice treated with chloroquine

Chloroquine, which interferes with the degradation of a number of transport proteins, impedes the exit of cobalamin from the small intestine of the mouse. This study was designed to determine if treatment with the drug led to the retention of cobalamin in the form of intrinsic factor-cobalamin in the ileal mucosa. Solubilized homogenates were prepared 2-4 h after an oral dose of [57Co]cobalamin and were examined by gel chromatography. There was a progressive transfer of [57Co]cobalamin from a protein identified as intrinsic factor to transcobalamin II in control mice. In chloroquine-treated mice, the major radioactive protein peak 2-4 h after an oral dose corresponded with the position of intrinsic factor. Only a small amount of the radioactivity was associated with transcobalamin. Cobalamin binding proteins were also identified by polyacrylamide gel electrophoresis and by their reaction with specific antibodies. It is concluded that chloroquine interferes with the release of cobalamin from intrinsic factor and thus slows the release of cobalamin from the intestine.

Increased intestinal uptake of cobalamin in pregnancy does not require synthesis of new receptors

Increased intrinsic factor cobalamin binding to receptors present in ileal mucosa from mice in the late stages of pregnancy is regulated by placental lactogen. In mice at day 18-20 of pregnancy given an intraperitoneal injection of cycloheximide, 0.5 mg/kg, receptor binding was reduced from 0.42 ng/mg protein to 0.18 ng/mg protein 4 h later. Intestinal mucosal protein synthesis was less than 20% of control values after this dose of cycloheximide. Although this result could be interpreted to mean that the increase in receptors in pregnancy was due to new protein synthesis, cycloheximide-treated mice also had reduced concentrations of placental lactogen in serum. Supplementation with the hormone in cycloheximide-treated mice maintained receptor binding at pregnant levels. Analysis of binding data showed receptor number to be 3.1 X 10(11)/mg protein and the binding constant (Ka) to be 0.5 X 10(12) M-1, which were similar to values found in untreated pregnant mice. It is concluded that, because the increase in receptors cannot be explained on the grounds of new protein synthesis, placental lactogen may recruit cryptic intrinsic factor cobalamin receptors.