Sex hormones and chronic liver disease.
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Biomedical subjects
Publications and source records attributed to M S Losowsky.
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1. The measurement of the intestinal metabolism of the nitrogen moiety of glutamic acid has been investigated by oral ingestion of l-[15N]glutamic acid and sampling of arterialized blood. 2. Measurements have been made in six normal adults weighing an average of 72.8 kg ingesting 100 mg of l-[15N]glutamic acid after an overnight fast. 3. Measurement of the enrichment of arterial glutamic acid, glutamine and alanine was by gas chromatography-mass spectrometry. Isotopic enrichment of the amino acids was followed for 150 min after the ingestion of the amino acid. 4. Arterialized venous blood amino acid concentrations, measured by h.p.l.c., demonstrated no significant changes during the course of the experiment. 5. From the observed appearance of label in arterialized glutamic acid, alanine and glutamine, little luminal glutamic acid reaches the extracellular pool. The majority of the administered nitrogen label appears in the arterial alanine and glutamine components.
Nutritional assessments were performed in three groups of hospitalized elderly women comparable in age and mobility: a group with Alzheimer's disease (ALZ), a multi-infarct dementia group (MID) and a nondemented group (ND). We have shown that: ALZ patients lose weight and on average weigh 21% less than ND patients and 14% less than MID patients. This weight loss is not accounted for by any obvious deficit in food intake, or by malabsorption. Biochemical indices of nutrition are little different in the three groups. The reason for weight loss in ALZ remains uncertain.
Dynamic hepatic scintigraphy was performed in 49 patients with established cirrhosis, using intravenous 99Tcm-pertechnetate and 99Tcm-sulphur colloid in a prospective study of its predictive value. There was a close correlation between the hepatic perfusion index (reflecting the ratio of arterial to total hepatic blood flow) obtained with pertechnetate (HPI-P) and with sulphur colloid (HPI-C) (r = 0.775; p less than 0.0001), and both indices correlated with disease severity (HPI-P p less than 0.0001; HPI-C p less than 0.01). HPI-P was significantly increased in patients who died, in patients with varices and in those with hepatic encephalopathy. HPI-C was significantly increased in patients with varices, in patients with hepatic encephalopathy and in those who had bled from varices. Neither HPI-P nor HPI-C was able accurately to predict the development of complications during the follow-up period. The trapping index (TI), reflecting a combination of hepatic extraction efficiency, degree of intrahepatic shunting and extrahepatic extraction of colloid, was significantly impaired in patients who died and in those with ascites, varices and/or variceal bleeding, but not in patients with hepatic encephalopathy. The trapping index correlated with disease severity, as did the computer-derived spleen-liver ratio (S-L ratio). Neither TI nor S-L ratio was able to predict the development of complications. The clearance rate constant of colloid from peripheral blood, the uptake rate constants for liver and spleen, and splenic volume were all found to be unhelpful as indicators of disease severity or as predictors of complications. While perfusion indices derived by dynamic hepatic scintigraphy reflect the severity of the underlying liver disease, their determination on a single occasion appears to offer no benefit in predicting the likelihood of major complications.
The liver is a steroid-responsive organ and contains high levels of androgen receptors (AR). The present study investigated cytosolic AR concentrations in diseased human liver obtained by needle biopsy. Insufficient tissue was available for full Scatchard analysis. Previous studies have shown the binding affinity of the liver AR to be sufficiently constant to allow the use of a single saturating dose analysis, using 3H-mibolerone as the active ligand, for the estimation of binding sites. Thirteen samples were studied and compared to normal liver. AR was identified in all samples and the level negatively correlated to the degree of liver damage. A role for AR in hepatocellular carcinoma has been postulated and anti-androgens used in treatment. This study shows AR can be measured in needle-biopsy specimens and, if hepatocellular carcinoma is proven to be hormone sensitive, then this technique may help in the assessment of such tumours.
Budd-Chiari syndrome was diagnosed in a 13 year old boy who presented with ascites. Angiographic studies showed occlusion at the ostia of the hepatic veins. This was treated surgically by the Senning operation of transcaval dorsocranial resection of the liver and hepatocaval anastomosis. The patient's ascites cleared and he remains well 10 months after surgery.
To investigate local humoral immunity in ulcerative colitis (UC), immunoglobulin (Ig) contents and net Ig production in vitro was assessed using organ cultures of colonic biopsies from 21 patients with quiescent disease and 11 controls. Ig was estimated by enzyme linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and IgG. In parallel, numbers of IgA plasma cells were estimated by indirect immunoperoxidase staining of tissue sections for IgA. IgA was the dominant Ig isotype found pre-existing in colonic mucosae, and secreted in vitro. In UC patients, preformed tissue IgA and IgA produced in vitro were significantly increased compared with controls. There was no concomitant increase in amounts of sIgA synthesised in culture, however, although numbers of IgA plasma cells were increased in UC patients by an amount comparable with the increased in vitro IgA production. These results directly show a dysfunction of transepithelial IgA secretion in quiescent ulcerative colitis. Despite a significantly raised concentration of tissue IgG in UC patients, little was produced in vitro in patient and control groups alike, suggesting that mucosal IgG was serum derived, and not linked to local IgA production.
Methionine enkephalin and catecholamines were measured in carefully collected plasma samples from 25 patients with cirrhosis and ascites, and 25 with cirrhosis without ascites, 15 disease and 15 healthy controls. Methionine enkephalin was invariably raised in the ascites group, the median value being 4.6-6.9 times that of the other three groups. Similarly, in the ascites group, median noradrenaline was increased 2.5-4.2 and median adrenaline 1.8-2.5 times that of the other groups. Plasma methionine enkephalin is considerably raised in patients with cirrhotic ascites and has actions which could enable it to be an initiating factor of ascites formation.
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Increased sympathetic tone and adrenal medullary activity in hepatic cirrhosis may promote portal hypertension. We suggest that they may be imperfect homeostatic mechanisms attempting to maintain systemic arterial pressure in response to chronic vasodilatation and that small, endogenous opioid peptides may play a part in this vasodilatation. As initial investigation of this hypothesis, we measured noradrenaline (an indicator of sympathetic tone), adrenaline and methionine enkephalin in the plasma of patients with cirrhosis with oesophageal varices which had or had not bled previously, patients with cirrhosis without varices, patients with acute liver disease and controls. In patients with cirrhosis, noradrenaline, adrenaline and methionine enkephalin were all greatest in those with oesophageal varices which had previously bled. In this group, noradrenaline correlated strongly with the widely used prognostic guide, Pugh's modification of Child's classification. In patients with acute liver disease, methionine enkephalin and adrenaline were increased six- and four-fold respectively. However, noradrenaline was normal, suggesting that increased sympathetic tone in cirrhosis may develop gradually. The use of opioid antagonists may enable determination of whether elevated plasma opioid peptides in cirrhosis stimulate the increase in sympathetic tone and plasma adrenaline, and promote bleeding oesophageal varices.
The effect of acute ethanol ingestion on plasma gamma aminobutyric acid (GABA) levels was investigated in eight volunteers. Subjects were studied on two days: a control during which light activity and non-alcoholic fluid intake was allowed and a study day during which ethanol was ingested to maintain blood alcohol levels at a mean of 130 mg%. Plasma GABA levels were estimated at 1, 4 and 8 hr. GABA levels were raised at 1 and 4 hr on the study day compared to the control day. GABA levels at 8 hr were not significantly different on the two days. Acute alcohol ingestion raised plasma GABA in healthy male volunteers.
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A micro enzyme-linked immunoassay (ELISA) is described for the quantitation of secretory IgA as distinct from monomeric IgA. The assay is sensitive (linear down to 30 ng/ml) and reproducible (inter-assay variation: 17.0%; intra-assay variation: 11.5%). The assay has the further advantages of rapidity, the ability to handle large numbers of samples, and uses commercially available reagents throughout. Minimal interference from a large (greater than 25-fold) excess of monomeric IgA was observed. The results obtained for serum secretory IgA concentrations by this method correlated well with those reported by other workers for normal control patients, patients with IgA deficiency and patients with liver disease.
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We tested the hypothesis that super-efficient starch absorption, by reducing the supply of carbohydrate to the colon, may be associated with and possibly promote colonic neoplasia. By means of breath hydrogen measurements following a potato meal and comparison with the hydrogen response to lactulose, the amount of starch escaping small bowel absorption was measured in 10 patients who had a colonic adenoma removed endoscopically and in 10 controls. The subjects' consumption of starch and fiber was assessed. Percentage unabsorbed starch was approximately half as much in the patients (5.3%) compared with the controls (10.9%, P less than 0.05). Consumption of starch and dietary fiber, and mouth-to-cecum transit times were not significantly different. Unabsorbed starch was calculated to contribute to 6.0 g/day colonic carbohydrate in the patients and 10.9 g/day in the controls (P less than 0.05). This study confirms that unabsorbed starch provides an important quantity of colonic carbohydrate and suggests that super-efficient starch absorption, by reducing this provision, may promote colonic neoplasia.