M. L. Clark

BIOLOGICALLY ACTIVE ANDROGENS AND ŒSTRADIOL IN MEN WITH CHRONIC LIVER DISEASE

Abstract Twenty-five men with chronic liver disease were studied. The plasma levels of unbound (biologically active) 17β-hydroxy-androgens (17-OHA), principally testosterone, were significantly lower in them than in controls (means 99 and 160 pg. per ml., respectively). This fall was most striking in the patients with alcoholic cirrhosis (mean 68 pg. per ml.). Serum-luteinising-hormone (L.H.) was high (mean of 2·35 mU. per ml. in controls, 3·7 mU. per ml. in patients). Unbound-plasma-œstradiol levels were normal. Plasma sex-hormone-binding globulin (S.H.B.G.) concentrations were raised twofold although the albumin levels were reduced. It is suggested that in men with chronic liver disease increased hepatic S.H.B.G. production causes the fall in plasma-unbound-17-OHA levels and that the hypothalamus responds to this by stimulating increased L.H. production. Apparently this does not increase Leydig cell production of testosterone enough to return the unbound level to normal. The normal unbound œstradiol levels may be maintained because the effect of the fall in plasma-albumin on œstradiol-binding cancels out the opposite effect of a rise in S.H.B.G. It is suggested that the combination of normal unbound-plasma- œstradiol and reduced unbound androgen levels of hypo- gonadism in chronic liver disease. The greater reduction in unbound-plasma-17–OHA in alcoholic cirrhosis of gynaecomastia and hypogonadism in this form of liver disease.

Nature of the toxicity of cyclosporin A in the rat

Abstract The potent immunosuppressive agent Cyclosporin A (CyA) causes a spectrum of toxicological effects in rats, of which the most striking is weight loss. Pair-feeding experiments have shown that this is caused, in part, by a short period of anorexia. However, even when the food intake has become normal the rats receiving CyA fail to gain weight. That CyA at the doses used causes increased protein catabolism is also indicated by a fall in serum albumin and a marked rise in blood urea unaccompanied by a corresponding rise in creatinine. CyA is mildly and reversibly hepatotoxic and there is slight nephrotoxicity in the rat on the basis of histology and small elevations in creatinine.

Liver disease after bone marrow transplantation.

Liver dysfunction occurs after bone marrow transplantation but the relative importance of graft versus host disease and other factors, such as infection, radiation, and drugs, has not been clearly established. We have studied liver status before and after bone marrow transplantation in 43 consecutive patients and have related this to survival and factors that are recognised to cause liver injury. Minor abnormalities of liver tests occurred in 21% of patients before grafting but this did not influence survival or the development of liver disease after transplantation. During the first 50 days after grafting, 83% of patients had abnormal liver tests which were more severe in patients who subsequently died. Alanine transaminase was significantly higher in non-survivors and appeared to predict survival early after transplantation. Only non-survivors developed clinical signs of liver disease. Severe liver disease was always associated with graft versus host disease and atypia of the small bile ducts was the most useful histological marker of hepatic involvement with this disease. Two of the patients with hepatic graft versus host disease also has hepatic veno-occlusive disease and three fatalities had opportunistic infection of the liver, although, in the latter, death was not due primarily to liver dysfunction. Previous hepatitis and androgen therapy could not be implicated as important causes of hepatic damage but chemotherapy for acute leukaemia and conditioning regimens for bone marrow transplantation appear to be the most important factors in the development of hepatic veno-occlusive disease.

Water and solute absorption from hypotonic glucose-electrolyte solutions in human jejunum.

While oral rehydration therapy with glucose-electrolyte solutions is highly effective, the optimal formulation has not yet been defined. Recent clinical studies suggest that stool volume, and thus water losses, may be reduced if glucose is replaced by a polymeric substrate which reduces osmolality. It is possible that the efficacy of glucose monomer based oral rehydration solutions (ORS) will also improve if osmolality is decreased. Using jejunal triple lumen perfusion in healthy adult volunteers net water and solute absorption were studied from three hypotonic solutions with different sodium concentrations (46, 60, 75 mmol/l) but identical glucose concentrations (90 mmol/l), thus allowing osmolality to rise (210, 240, and 270 mOsm/kg, respectively). Results from these solutions (ORS 45:210, ORS 60:240, and ORS 75:270) were compared with the World Health Organisation oral rehydration solution (WHO-ORS). Greatest water absorption was seen with ORS 60:240 (p less than 0.01). Sodium absorption from ORS 60:240 and WHO-ORS was similar and greater than sodium absorption from ORS 45:210 (p less than 0.05). Potassium and glucose absorption were greater from ORS 60:240 than from any of the other hypotonic solutions (p less than 0.05) and were equal to absorption from WHO-ORS). These results in a short segment of healthy human jejunum suggest that hypotonic ORS containing monomeric glucose may increase water absorption.

Low gluten diet in the treatment of adult coeliac disease: effect on jejunal morphology and serum anti-gluten antibodies.

Treatment of patients with coeliac disease with a low gluten containing diet (LGD) remains controversial. We have studied jejunal morphology and antigluten (AG) antibody titres by ELISA in patients on a LGD of 2.5-5 g/day for three to 14 months (median six months) and compared results with patients on a strict gluten free diet (GFD) for six to 27 months (median 13 months). We found no significant difference in villous height or crypt depth (eight LGD v 10 GFD patients) or serum AG-IgA, -IgG, and IgM titres (13 LGD v 12 GFD patients). there was however, a significant increase (p less than 0.05) in intra-epithelial lymphocytes in those patients on a LGD. We conclude that adult coeliac patients can tolerate a LGD without gross morphological change and without initiating significant AG antibody responses.

Jejunal absorption of an amino acid mixture simulating casein and an enzymic hydrolysate of casein prepared for oral administration to normal adults

1. An intestinal perfusion technique was used in six normal human subjects to study absorption of sixteen individual amino acids from an amino acid mixture simulating casein and from an enzymic hydrolysate of casein, prepared for oral administration to these subjects, which consisted of a mixture of oligopeptides and free amino acids. 2. Total absorption of alpha-amino nitrogen was greater from the casein hydrolysate than from the amino acid mixture, and the considerable variation in percentage absorption of individual amino acids from the amino acid mixture was much reduced when the enzymic hydrolysate solution was perfused, as a number of amino acids which were poorly absorbed from the amino acid mixture were absorbed to a greater extent from the casein hydrolysate. 3. These findings indicate that after extensive intestinal resections or in malabsorption there might be significant nutritional advantages in the administration of protein hydrolysates rather than amino acid mixtures.

L-Arginine, nitric oxide, and intestinal secretion: studies in rat jejunum in vivo.

BACKGROUND: L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginine is thought to have an important role as an intestinal secretagogue. AIM: To determine the effect of L-arginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. METHODS: A 25 cm segment of rat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0.1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mg/kg was examined in rats pretreated with either D-or L-arginine 500 mg/kg. RESULTS: L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7.3 v 17.0 microliters/min/g; p < 0.01). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p < 0.05). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28.4, respectively), which was enhanced by the addition of L-arginine (-30.0 and -41.0, respectively; both p < 0.05). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L- but not D-arginine. CONCLUSIONS: L-arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.

Relative nutritional value of whole protein, hydrolysed protein and free amino acids in man.

To compare their effects on nitrogen balance, diets containing either lactalbumin whole protein, its peptide-rich enzymic hydrolysate or an equivalent mixture of free amino acids as the sole source of dietary nitrogen were fed to two healthy subjects, each studied for 38 days on two separate occasions. The nitrogen intake (47 mg/kg body wt/day) induced a state of negative nitrogen balance, stimulating nitrogen conservation. Net daily nitrogen balance (mean +/- SD) in subject 1 was -0.23 +/- 0.72 g (amino acids) vs + 0.05 +/- 0.52 g (protein) and -0.21 +/- 0.58 g (amino acids) vs -0.05 +/- 0.57 g (hydrolysate), and in subject 2, -0.19 +/- 0.60 g (amino acids) vs -0.16 +/- 0.51 g (protein) and -0.42 +/- 0.35 g (amino acids) vs -0.62 +/- 0.34 g (hydrolysate). Analysis of these results by the cumulative sum technique showed no significant differences in the effect of the three nitrogen sources on nitrogen balance. This study indicates that there is no nutritional evidence to support the current practice of prescribing expensive enteral diets containing peptides or amino acids rather than the much cheaper whole protein to patients with normal gastrointestinal function.

Functional differentiation of human jejunum and ileum: A comparison of the handling of glucose, peptides, and amino acids

The characteristics of glucose, glycine, L-alanine, and glycyl-L-alanine absorption from the jejunum and ileum have been compared in normal human subjects. A perfusion technique has been used, and correct positioning of the perfusion tube has been confirmed by measuring the differential jejunal and ileal handling of bicarbonate. Glucose and glycine were absorbed faster from the jejunum than from the ileum of all subjects studied, and L-alanine was absorbed faster from the jejunum than from the ileum in five out of six subjects studied. In contrast, the dipeptide glycyl-L-alanine was absorbed at comparable rates from the jejunum and ileum. Higher concentrations of free amino acids were detected in the luminal contents aspirated during the ileal dipeptide perfusions. These results emphasize the importance of oligopeptide transport in the absorption of protein digestion products, especially in the human ileum, and the practical implications of these findings are discussed.

Acetate and citrate stimulate water and sodium absorption in the human jejunum.

Using a standard perfusion technique, the organic anions acetate (50 mmol/l) and citrate (5 mmol/l) have been shown to stimulate absorption of water and sodium from the human jejunum. These observations may support further the rationale for including acetate or citrate in oral rehydration solutions for the treatment of acute diarrhoeal disease in humans.