F. W. Schmidt

Glutamate dehydrogenase: biochemical and clinical aspects of an interesting enzyme

The molecular properties and possible metabolic functions of glutamate dehydrogenase (GLDH-EC 1.4.1.3) are described. The distribution of this enzyme in the body and particularly in the liver are outlined. The significance of these properties for GLDH release into the extracellular space, for the distribution and elimination of the enzyme and, foremost, for the assay of GLDH as a diagnostic indicator of hepatic and biliary disease are shown. Analytical methods are reviewed.

Metabolic responses to lipid infusions in patients with liver cirrhosis.

Energy expenditure, whole body substrate oxidation rates and arterial substrate concentrations were measured in 14 patients with liver cirrhosis and 13 control subjects before and during sequential infusions of a long chain (LCT) or a medium chain triglyceride emulsion (MCT) without and with concomitant insulin plus glucose infusions. Resting energy expenditure, basal substrate oxidation rates and the arterial concentrations of glucose, lactate, triglycerides and ketones were normal, whereas plasma free fatty acids and glycerol were both increased in patients with liver cirrhosis. The arterial plasma triglyceride and free fatty acid concentrations as well as whole body lipid oxidation rate rose in response to LCT in both groups and the maximum lipid oxidation rate was 1.1 or 1.3 mg/kg fat free mass x min in controls and in cirrhotics, respectively (n.s.). Concomitantly, glucose oxidation rate fell to 65% of basal values in controls (p < 0.01), but remained nearly unchanged in the cirrhotic group (89% of the basal value; n.s.). The increase in plasma ketones was reduced to 67% of control values in liver cirrhosis (p < 0.01). Only a slight effect on energy expenditure was observed in both groups. When compared to controls, liver cirrhosis impaired insulin-induced increases in glucose disposal (-30%, p < 0.01) and in non oxidative glucose metabolism (-93%, p < 0.01). Concomitantly, normal increases in energy expenditure, glucose oxidation rate and the arterial plasma lactate concentrations and normal decreases in lipolysis, lipid oxidation and ketogenesis were observed in patients with liver cirrhosis. When lipids were given together with glucose, energy expenditure and lipid oxidation increased in controls, but glucose was the preferred fuel oxidised and lipid-induced thermogenesis was reduced in the cirrhotic group. Using a 50% MCT-emulsion, plasma free fatty acid concentrations further increased, but energy expenditure and lipid oxidation remained unchanged in both groups and further increases in plasma ketones were only observed in controls. Infusing glycerol in a subgroup of patients showed no thermogenic effect and a reduced glycerol clearance in liver cirrhosis.

Energy expenditure in children with type I diabetes: evidence for increased thermogenesis.

The aim of the study was to assess whether increased energy expenditure causes the negative energy balance (tissue catabolism) commonly seen in children with insulin dependent (type I) diabetes. Resting metabolic rate and thermogenesis induced by adrenaline were measured in five healthy children and 14 children with type I diabetes who were all free of clinical signs of late complications of diabetes mellitus but differed in their degree of glycaemic control (in eight glycated haemoglobin concentration was less than 10% and in the six others greater than or equal to 10%). When compared with the control subjects children with type I diabetes had normal resting metabolic rates but their urinary nitrogen excretion was significantly raised (11.5 (SD 5.4) mg/min in those with glycated haemoglobin concentration less than 10%, 11.6 (5.2) mg/min in those with concentration greater than or equal to 10% v 5.4 (3.0) mg/min in control subjects). During the infusion of adrenaline the diabetic children showed a threefold and sustained increase in thermogenesis and disproportionate increases in the work done by the heart, in lipid oxidation rate, and in plasma concentrations of glucose, free fatty acids, and ketone bodies. The increased thermogenic effect of adrenaline did not correlate with the degree of glycaemic control. Increased thermogenesis may explain the tissue wasting commonly seen in children with type I diabetes during intercurrent stress.

[Alterations of bile acid metabolism during treatment with chenodeoxycholic acid. Studies of the role of the appearance of ursodeoxycholic acid in the dissolution of gallstones (author's transl)].

SummaryNine patients with radiolucent stones in the gallbladder were investigated before and during treatment with chenodeoxycholic acid (CDC). During treatment the biliary composition of bile acids changed considerably. Before the ingestion of CDC, bile acids consisted predominantly of cholic acid, deoxycholic acid and CDC; lithocholic acid was present in small amounts only. In the course of treatment CDC or this bile acid together with ursodeoxycholic acid (UDC) became the major biliary bile acid. The content of CDC increased from 47.6±4.21 to 79.2±6.37 SEM %, whereas that of UDC increased from 2.7±1.15 to 13.4±6.47%. The unsulfated lithocholic acid increased slightly from 0.7±0.22 to 2.7±0.41%. The bile acid pool expanded by an average of 130%. The degree of expansion of the pool varied considerably among the different patients. The largest increase in the pool size, however, occurred in the patients with the largest content of UDC in bile. Gallstone dissolution was observed in five patients. Among these five were those patients with the highest content of UDC, Corresponding 8.6, to 29.4 and 51.7%, respectively. These findings suggest that, in addition to CDC, UDC has a cholelitholytic effect in vivo. Of interest also was the observation that the patients in whom the size of the bile acid pool increased only very little showed no dissolution of gallstones. Both the stool weight and the fecal excretion of the isotopes, after the administration of radioactively labeled bile acids, increased only slightly during the treatment with CDC. The cholelitholytically efficacious dose of 20 mg/kg/day of CDC applied in this study appears to be useful in that 94% of it was absorbed.ZusammenfassungNeun Patienten mit nichtschattengebenden Konkrementen in der Gallenblase wurden vor und während einer Langzeitbehandlung mit Chenodesoxycholsäure (CDC) untersucht. Die CDC-The-rapie führte zu einer grundlegenden Änderung der biliären Gallensäurenzusammensetzung. Während sich die Gallensäuren vor der Behandlung vorwiegend aus Cholsäure, Desoxycholsäure und CDC und zu einem geringen Teil auch aus Lithocholsäure zusammensetzten, war unter der Behandlung fast ausschließlich nur noch CDC oder diese Gallensäure zusammen mit ihrem Epimer Ursodesoxycholsäure (UDC) nachweisbar. Der CDC-Gehalt stieg von 47,5±4,21 auf 79,2±6,37 SEM% an, während UDC durchschnittlich von 2,7±1,15 auf 13,4±6,47% zunahm. Die nicht sulfatierte Lithocholsäure vermehrte sich geringfügig von 0,7±0,22 auf 2,7·0,41%. Der Gallensäurenpool vergrößerte sich unter der Behandlung durchschnittlich um 130%. Die Größenveränderungen des Pools schwankten jedoch erheblich zwischen den einzelnen Patienten. Am weitaus stärksten ausgeprägt war die Poolvergrößerung bei den Patienten mit dem höchsten UDC-Gehalt in der Galle. Eine Gallensteinauflösung wurde bei fünf Patienten beobachtet. Unter diesen fünf befanden sich die drei Patienten mit dem höchsten UDC-Gehalt, der bei 8,6, 29,4 bzw. 51,7% lag. Es kann damit als gesichert gelten, daß UDC ähnlich wie CDC einen cholelitholytischen Effekt in vivo hat. Interessant ist auch die Beobachtung, daß die Patienten, deren Gallensäurenpool sich unter der Behandlung nur geringfügig vergrößerte, keine Gallensteinauflösung zeigten.Die Isotopenausscheidung im Stuhl nach Gabe radioaktiv markierter Gallensäuren und das Stuhlgewicht stiegen unter der Behandlung mit CDC nur geringfügig an. Die verwendete therapeutisch wirksame Dosis von 20 mg/kg/ die erscheint zweckmäßig, da sie von unseren Patienten durchschnittlich zu 94% absorbiert wurde.Nine patients with radiolucent stones in the gallbladder were investigated before and during treatment with chenodeoxycholic acid (CDC). During treatment the biliary composition of bile acids changed considerably. Before the ingestion of CDC,bile acids consisted predominantly of cholic acid, deoxycholic acid and CDC; lithocholic acid was present in small amounts only. In the course of treatment CDC or this bile acid together with ursodeoxycholic acid (UDC) became the major biliary bile acid. The content of CDC increased from 47.5 +/- 4.21 to 79.2 +/- 6.37 SEM %, whereas that of UDC increased from 2.7 +/- 1.15 to 13.4 +/- 6.4%. The unsulfated lithocholic acid increased slightly from 0.7 +/- 0.22 to 2.7 +/- 0.41%. The bile acid pool expanded by an average of 130%. The degree of expansion of the pool varied considerably among the different patients. The largest increase in the pool size, however, occurred in the patients with the largest content of UDC in bile. Gallstone dissolution was observed in five patients. Among these five were those patients with the highest content of UDC, Corresponding 8.6, to 29.4 and 51.7%, respectively. These findings suggest that, in addition to CDC, UDC has a cholelitholytic effect in vivo. Of interest also was the observation that the patients in whom the size of the bile acid pool increased only very little showed no dissolution of gallstones. Both the stool weight and the fecal excretion of the isotopes, after the administration of radioactively labeled bile acids, increased only slightly during the treatment with CDC. The cholelitholytically efficacious dose of 20 mg/kg/day of CDC applied in this study appears to be useful in that 94% of it was abosrbed.

Sensitivity of bile acid breath test in the diagnosis of bacterial overgrowth in the small intestine with and without the stagnant (blind) loop syndrome.

The bile acid breath test was studied to examine its sensitivity for establishing the diagnosis of bacterial overgrowth in comparison to that of the Schilling test and small-intestinal cultures in 12 patients with a stagnant (blind) loop syndrome, as well as in 38 patients who had other conditions with suspected bacterial contamination of the small intestine. The presence of bile acid malabsorption was excluded in all 50 patients by studies of fecal excretion of radioactively labeled bile acids. The bile acid breath test was positive in 100% (12/12) of the patients with a stagnant (blind) loop syndrome, whereas 92% (11/12) had a positive Schilling test and 75% (9/12) a positive small-intestinal culture. The abnormal tests improved only in 2 of 4 patients treated with tetracycline. In the group of 38 patients without demonstrable dilated or blind loops of small bowel who were suspected of having bacterial contamination of small bowel, the bile acid breath test was positive in 53% (20/38), the Schilling test in 39% (15/38), and the small-intestinal culture in 45% (17/38). The difference in the incidence of positive results between the tests in the two patient groups was statistically not significant. The findings of these studies have the following diagnostic implications: (1) Bile acid breath test, Schilling test, and cultures of aspirates from the upper small bowel are of comparable sensitivity in the detection of bacterial overgrowth in the small intestine. (2) A negative bile acid breath test makes the diagnosis of a stagnant (blind) loop syndrome very unlikely.

Gabexate mesilate and camostate: New inhibitors of phospholipase A2 and their influence on the alpha-amylase activity in serum of patients with acute pancreatitis

The new synthetic polyvalent protease inhibitors gabexate mesilate (ethyl-p[6-guanidinohexanoyloxy]-benzoate methansulfonate) and camostate (N,N-dimethylcarbamoylmethyl-4-[4-guanidinobenzoyloxy]-phenylacetate methansulfonate) were tested for possible inhibition of phospholipase A2 activity. In a pilot study, we treated 17 patients suffering from acute pancreatitis with continuous intravenous administration of gabexate mesilate, 450 mg/d. The results were compared with a placebo group (same standard therapy) of 21 patients suffering from acute pancreatitis. In vitro experiments showed that, at concentrations between 10(-4) and 5 X 10(-4) mol/L (depending on the enzyme assay employed) for gabexate mesilate and between 10(-3) and 5 X 10(-4) mol/L for camostate, a 50% reduction in phospholipase A2 activity was effected. Comparing the two groups of acute pancreatitis patients after 6 days of treatment with gabexate mesilate, we observed a statistically significantly lower alpha-amylase activity in the serum of treated patients compared with the placebo group.

Total body water, extracellular water, plasma volume, and total body potassium in cirrhosis of the liver

ZusammenfassungUntersucht wurden die Flüssigkeitsräume Extrazellulärwasser (82-Bromid; ECW), Ganzkörperwasser (3-THO; TBW), Intrazellulärwasser (ICW=TBW-ECW) und Plasmavolumen (51-Chrom; PV), sowie das Ganzkörperkalium (40-K; TBK) bei Lebercirrhotikern (n=12) im Vergleich zu einer Kontrollgruppe (n=12). Die auf das Körpergewicht bezogenen Größen ECW (39%), TBW (28%), ICW (19%) und PV (24%) fanden wir bei den an Lebercirrhose Erkrankten vergrößert, das Ganzkörperkalium (% des Sollwertes) um 28% erniedrigt. Diese Ergebnisse weisen darauf hin, daß bei der Lebercirrhose weniger die sogenannte fettfreie Substanz (lean body mass; LBM) als vielmehr die intrazelluläre Kaliumkonzentration verringert ist. (Cirrhose: 84±21 mol/l ICW; Kontrolle: 115±23 mmol/l ICW). Als Ursachen werden ein vermindertes Kalium (mmol) pro Zelle und eine vergrößerte intrazelluläre Wasserkonzentration (ml/kg) diskutiert. Die Korrelation zwischen dem TBK (%) und dem Serum-Kalium (mmol/l) beträgtr=0,56 (p<0,002). Die klinisch chemischen Parameter γ-Globuline, Cholinesterase, Serumnatrium und Albumine (g/l PV) korrelieren signifikant mit den charakteristischen Veränderungen der Flüssigkeitsräume und des Ganzkörperkaliums. Hierbei ist das auf das Körpergewicht bezogene Gesamtalbumin trotz der relativen Hypoalbuminämie nicht erniedrigt. Unsere Ergebnisse sprechen für die ‘overflow theory’ der Ascites-Pathogenese (Lieberman et al., 1970).SummaryExtracellular water (EWC; 82-bromide), total body water (TBW; 3-THO), intracellular water (ICW=TBW-ECW), plasma volume (PV; 51-Cr), and total body potassium (TBK; 40-K) were studied in patients with cirrhosis of the liver (n=12) and in controls (n=12). ECW (39%), TBW (28%), ICW (19%), and PV (24%) increased, TBK (28%) however, decreased in cirrhosis. The results indicate that it is less the lean body mass, but rather the intracellular potassium concentration that is lowered (cirrhosis: 84±21 mmol/l ICW; controls: 115±23 mmol/l ICW). Decreased potassium per cell (mmol) and increased intracellular water are discussed as possible reasons for this. The correlation between TBK (%) and serum potassium (mmol/l) was found to ber=0.56 (p<0.002). Correlations between the biochemical parameters gamma-globulins, cholin esterase, serum sodium and serum albumin (g/l PV) and characteristic fluid disturbances in cirrhosis are highly significant whereas albumin (g/kg bodyweight) was the same in both groups. We can support the ‘overflow theory’ of ascites formation [19].

Sex differences of plasma cholinesterase in the rat.

Plasma cholinesterase activity of adult female HAN-Wistar rats was found to be 5.5-fold higher than that of adult male rats kept under constant specified pathogen-free (SPF) conditions up to their 870th day of life.

Reduced metabolic efficiency in patients with Crohn's disease

Malnutrition is frequently seen in patients with inflammatory bowel disease, and parenteral or enteral nutrition is considered essential in this patient group. However, many patients with Crohns disease have difficulties in gaining weight in response to overfeeding, suggesting reduced energy retention. Substrate utilization and nutrient balances as well as changes in body composition were followed in 10 patients with Crohns disease immediately in the course of remission on low-dose steroid treatment, during an eight-day period of continuous enteral nutrition at constant (protocol 1:1.5-fold basal energy expenditure) and increasing (protocol 2:0.5- to 2.0-fold basal energy expenditure) nutrient supply. Energy, substrate, and nitrogen balances all became positive in response to overfeeding. However, fat was predominantly oxidized at an infusion rate of 1.2 g/kg body wt/day, whereas carbohydrates and proteins were effectively stored. A positive energy balance was reached at an energy infusion rate exceeding 31 kcal/kg body wt/day and corresponding substrate supplies of 1.6, 1.7, and 1.1 g/kg body wt/day for carbohydrates, fat, and protein, respectively. Nitrogen balance normalized at a supply of 0.14 g/kg body wt/day, which also reduced myofibrillar protein breakdown. Considering the relative contributions made by these nutrients in the diets, an accumulation of carbohydrates and protein but a depletion in fat became evident from nutrient balances. In fact, body weight increased by 0.12 kg/day, which was explained by an increased extracellular (+0.18 kg/day) and body cell mass (+0.04 kg/day) at reduced fat mass (−0.10 kg/day). Concomitantly, plasma T3 and insulin secretion both increased, whereas sympathetic nervous system activity decreased with overfeeding. This is contrary to data observed in healthy subjects. Fat instead of glucose is the major energy substrate during the clinical course of treatment in patients with Crohns disease. These patients therefore store less of surplus fuels as fat explaining their difficulties in gaining weight.

Effekte einer Captopriltherapie auf die Natrium- und Wasserausscheidung bei Patienten mit Leberzirrhose und Aszites

SummaryAscites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium,-potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 × 6.25 mg/d captopril for 5 days and 4 × 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril.PRA increased significantly after 2 days of captopril treatment. 2 × 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 × 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again. Conclusion: In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.UNLABELLED Ascites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium, -potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 x 6.25 mg/d captopril for 5 days and 4 x 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril. PRA increased significantly after 2 days of captopril treatment. 2 x 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 x 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again. CONCLUSION In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.