The Refeeding Syndrome revisited: you can only diagnose what you know.

BACKGROUND/OBJECTIVES: The Refeeding Syndrome (RFS) is a serious complication in patients receiving nutrition support after a period of severe malnutrition. We frequently recognize and diagnose the RFS due to increased awareness. Thus, we observe that many physicians do not know the RFS and that it is rarely diagnosed. The aim of the study was to determine whether physicians in Germany know the RFS. SUBJECTS/METHODS: A questionnaire with a case vignette about an older person who developed the RFS after initiation of nutritional therapy was submitted to German physicians and fifth year medical students, who were participants of educational lectures. RESULTS: Of the 281 participants who answered the respective question, 40 participants (14%) correctly diagnosed the RFS of the case vignette and 21 participants (8%) gave nearly correct answers. Indeed, the majority of the participants did not diagnose the RFS. CONCLUSIONS: Although the RFS may lead to fatal complications, it is unknown to the majority of the queried physicians. Therefore, there is a call to implement the RFS in respective curricula and increase systematic education on this topic.

Antiarrhythmic drugs impair hepatic uptake and secretory function by different mechanisms in the isolated perfused rat liver.

In the present study the effect of various antiarrhythmic drugs on hepatic perfusion parameters, uptake capacity of organic anions and biliary secretion using the isolated perfused rat liver was examined. Infusion of verapamil (VP), diltiazem, N-propyl-ajmaline (NPAB), and quinidine at pharmacological doses induced consistently a 1.4-1.6-fold increase in portal pressure accompanied by a approximately 60% decrease in bile flow and a approximately 65% inhibition of biliary taurocholate (TC) excretion. Furthermore, hepatic uptake of oxygen, bromosulphthalein (BSP), and TC was significantly reduced. All these effects were dose-dependent and reversible upon withdrawal of the drugs. Studies of the hepatic circulation using a Trypan blue staining technique demonstrated a patchy perfusion pattern during infusion of the antiarrhythmic drugs as compared to the homogenously stained control organ. The hemodynamic alterations and the impairment of the hepatic initial uptake function could be entirely prevented by concomitant administration of the vasodilator papaverine. Bile flow and biliary TC excretion, however, were still inhibited under these conditions. The present results indicate that antiarrhythmic drugs produce cholestasis in the isolated perfused rat liver independently of their adverse effect on hepatic hemodynamics.

Increase in hepatic mixed disulphide and glutathione disulphide levels elicited by paraquat.

Paraquat (1 mM), when added to isolated haemoglobin-free perfused rat liver, leads to an increase of intracellular mixed disulphides from 1.3 mumole GSH equivalents per g wet weight in the controls to 2.5 mumole/g. This raises the proportion of mixed disulphides to total glutathione equivalents from about 0.2 at the beginning of the perfusion to about 0.4. The mixed disulphides are predominantly protein-bound, with low molecular weight compounds being quantitatively negligible. The content of intracellular glutathione disulphide (GSSG) is increased from 17 nmole/g in the controls to 38 nmole/g in the presence of paraquat. In addition, there is an increased rate of release of GSSG into the extracellular (biliary) space, reported previously. It is suggested that, in a reaction catalysed by thioltransferase(s), the rise in GSSG is correlated with the rise in mixed disulphides (reaction 1). Occupancy of potential cellular mixed disulphide sites is about 1/2 in the controls, and rises to about 2/3 in the presence of paraquat. THe ratio of cellular contents, NADPH/NADP+, is decreased from 5.1 in the controls to 2.3 in the presence of paraquat, while the sum of NADPH plus NADP+ remains unaltered. The perturbation in the glutathione status may be related to metabolic effects such as the stimulation of the pentose-phosphate pathway activity, and possibly also to the expression of toxic effects.

Cholestasis and changes in the microcirculation of perfused rat liver caused by the calcium ionophore A23187 and type I antiarrhythmic drugs.

The calcium-ionophore A23187 causes a reversible increase of the hydrostatic pressure in the portal vein of perfused rat liver. Concomitantly, hepatic functions like the production of bile and the transhepatic movement of the bile acid taurocholate are diminished, mainly due to decreased uptake. These phenomena are partly explained by changes in the microcirculation of the liver, visualized by Trypan blue staining. Both the increase in portal pressure and the major part of the decrease of biliary excretion of taurocholate and bile flow are prevented by the addition of the vasodilator papaverine. The type I antiarrhythmic drugs quinidine and N-propylajmaline bitartrate (NPA), at high concentrations, also induce a rise in portal pressure and act as a cholestatic agent. The rise in portal pressure caused by NPA requires the presence of extracellular calcium and is counteracted by papaverine. In contrast to A23187, the cholestasis caused by NPA is not influenced by papaverine. While NPA decreases the hepatic uptake and biliary excretion of taurocholate, papavarine is able to restore only the uptake and not the excretion. The concentration of taurocholate in the bile is not significantly changed by NPA.

Do doctors know how much nutrition patients need--a survey from Germany?

For the diagnosis, prevention and therapy of malnutrition, it is important to estimate the energy and fluid requirements of an individual patient. To our knowledge, it is unknown how accurately medical doctors can estimate the energy and fluid requirements of patients in a clinical routine situation. Hence, we conducted the following survey. A written face-to-face survey about the energy and fluid requirements of and tube feeding and fluid recommendations for a typical patient was performed with 179 medical doctors. An estimation error of >15% was defined as relevant. The results revealed substantial variations in estimating the energy and fluid needs of the patient. A total of 25% of the participants underestimated the energy requirements, and 47% of the participants underestimated the fluid requirements. In addition, 68% of the participants recommended a daily dose of tube feeding that was <85% of the reference value. A substantial proportion of medical doctors show a lack of knowledge concerning energy and fluid requirements, which demonstrates a need for better medical education with regard to nutrition.

Glucagon induces biliary protein excretion in guinea pigs.

This study was done to determine glucagon's effect on protein biliary excretion in anesthetized, bile duct-cannulated guinea pigs. Glucagon (1.4 nmol.min-1.kg-1) induced choleresis and increased protein biliary concentration from 0.12 +/- 0.04 to 0.20 +/- 0.6 mg/ml and protein output from 22.8 +/- 3.8 to 54.5 +/- 16.1 micrograms.kg-1.min-1. Protein biliary excretion increased during the first 10 min of glucagon infusion and progressively declined thereafter. Biochemical analysis of biliary protein revealed that the increase could be accounted for primarily by an increase in the lysosomal enzymes acid phosphatase and beta-glucuronidase. Biliary excretion of the canalicular membrane enzymes 5'-nucleotidase and alkaline phosphatase only modestly increased, whereas that of [14C]sucrose, a marker of paracellular fluid transport, was unaffected. On the other hand, glucagon enhanced biliary entry of horseradish peroxidase in a fashion similar to that observed with total endogenous protein. These effects were mediated by the adenosine 3',5'-cyclic monophosphate (cAMP) system, since infusion of dibutyryl-cAMP at 0.5 mumol.kg-1.min-1 increased bile flow and biliary protein excretion in a time-dependent manner, as observed with glucagon. Glucagon's failure to sustain enhanced protein biliary output was not due to declining hepatic concentrations of cAMP or to depletion of hepatocellular lysosomal enzymes. These studies provide evidence that glucagon stimulates biliary excretion of protein in guinea pigs that can be accounted for by biliary discharge of enzyme originating from the canalicular membrane and, primarily, from the lysosomal compartment. Although the precise mechanism(s) underlying these effects remains to be elucidated, it is suggested that the increase in canalicular membrane enzyme excretion is due to glucagon's effect on exocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Conservative therapy of liver failure]. / Konservative Therapie der Leberinsuffizienz.

Hepatic failure is characterized by decreasing liver function involving synthesis, regulation and detoxification. In most cases, acute liver failure results from acute viral hepatitis. Furthermore, intoxications or metabolic decompensation can cause fulminant hepatic failure. Chronic liver failure is defined as progressive decline in liver function in previously existing liver disease, mostly liver cirrhosis. Clinical manifestation of both acute and chronic hepatic failure is determined by hepatic encephalopathy and severe disturbance of the hemostatic system. Causal therapy does not exist; the inducing agent or reason should be eliminated. The major supportive strategy comprises removal of toxic metabolites from the intestine and stabilization of the hemostatic system. As prognosis of both acute and chronic liver failure is very poor, orthotopic liver transplantation represents the ultima ratio therapy.

Secretin stimulates bile ductular secretory activity through the cAMP system.

Although convincing evidence has been obtained to support a ductular origin of secretin choleresis, the precise mechanism of the choleretic effect of the hormone is poorly understood. The present studies were carried out to 1) further clarify the anatomic site at which secretin stimulates bile flow and 2) establish the signal transduction system underlying this effect. To this end, parenchymal and nonparenchymal liver cells, the latter enriched in bile duct cells, were isolated from rats with ductular cell hyperplasia, and the effect of secretin on intracellular formation of both adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (IPs) was compared with that observed with glucagon and [Tyr10,13,Phe22,Trp25]secretin (SG-secretin). In the pancreas, secretin stimulates both messenger systems, while SG-secretin activates only the cAMP cascade. In isolated hepatocytes, both secretin and SG-secretin failed to increase formation of cAMP and IPs, which were instead activated by glucagon. In isolated bile duct cells, secretin induced formation of both cAMP and IPs, while SG-secretin stimulated solely the cAMP system, as in the pancreas. Glucagon did not stimulate either messenger system in this cell preparation. In vivo, both secretin and SG-secretin stimulated a bicarbonate-rich fluid in rats with bile ductular cell hyperplasia and in normal guinea pigs, which was demonstrated to originate at the distal biliary epithelium. These findings support the existing view that glucagon stimulates canalicular bile flow, while secretin increases secretory activity at the bile ductules and/or ducts. More importantly, they indicate that stimulation of ductular secretory activity by secretin is mediated by the cAMP system and does not involve the IP signal transduction pathway.

Colitis ulcerosa complicated by malignant lymphoma: case report and analysis of published works.

A 51 year old woman with a two year history of ulcerative colitis developed a wide spread gastrointestinal non-Hodgkin's lymphoma of low grade malignancy (MALT-lymphoma) involving upper and lower gastrointestinal tract, spleen, and bone marrow. After chemotherapy, clinical symptoms improved and lymphocytic infiltrates disappeared. Thirty nine cases of ulcerative colitis and 22 cases of Crohn's disease complicated by gastrointestinal lymphomas reported in published works are reviewed. In inflammatory bowel diseases any dense lymphocytic infiltrates seen in biopsy specimens obtained from ulcerative colitis or Crohn's disease should be assessed to exclude gastrointestinal lymphoma.

Glucagon effect on intracellular proteolysis and pericanalicular location of hepatocyte lysosomes in isolated perfused guinea pig livers.

In guinea pigs, glucagon choleresis is accompanied by a significant, but transient, stimulation of biliary protein secretion, which can be accounted for mainly by biliary discharge of lysosomal enzymes. To clarify whether intracellular proteolysis--a process regulated by glucagon and taking place predominantly in the lysosomes--may interact with biliary protein secretion, we determined hepatic proteolytic activity and bile secretory function during substrate deprivation, amino acid supplementation, and glucagon administration in isolated perfused guinea pig livers. To further elucidate the nature of transient lysosomal enzyme release into bile during glucagon infusion, we analyzed pericanalicular distribution of lysosomes by quantitative electron microscopy. The results demonstrate that intracellular proteolysis is accompanied by biliary excretion of lysosomal enzymes. Glucagon-induced secretion of these enzymes as well as labeled proteins into bile occurs independent of protein breakdown and cannot be modulated by addition of amino acids as potent inhibitors of intracellular proteolysis. During glucagon administration, bile canalicular area and pericanalicular distribution of secondary lysosomes show a rapid increase, which persists during the entire infusion period and thus does not explain the transient biliary release of lysosomal enzymes. We therefore postulate that regulation of this process must be located beyond the lysosomal compartment, either involving transport processes or intracellular kinetics of lysosome formation or altered fusion kinetics at the bile canalicular membrane compartment. Metabolic and biliary effects of glucagon seem to occur independent of each other and to underly different regulatory mechanisms.

Norepinephrine-induced cholestasis in the isolated perfused rat liver is secondary to its hemodynamic effects.

In this study we examined the effect of pharmacological doses of various alpha-adrenergic agents on hepatic portal perfusion, organic anion uptake and bile secretion using the isolated perfused rat liver. Addition of norepinephrine at portal perfusate concentrations ranging from 0.01 to 100 mumol/L induced a dose-related increase in portal pressure with a twofold increment at the highest concentration. This was accompanied by an inhibition of hepatocellular uptake of taurocholate by 16.8% +/- 1.8% and of sulfobromophthalein (BSP) by 32.9% +/- 3.0% compared with controls. Moreover, a 22.5% +/- 3% decrease in bile flow rate and a 22.8% +/- 4% inhibition of biliary excretion of taurocholate were observed. Addition of other alpha-adrenergic agonist (epinephrine, dopamine and phenylephrine) at similar concentrations produced the same hepatic effects as observed with norepinephrine. During infusion of these alpha-adrenergic agents, trypan blue infusion revealed a patchy perfusion pattern of the liver surface compared with the homogeneously stained organs in controls. The hemodynamic alterations could be confirmed by electron microscopy examination that demonstrated that increased portal pressure produced by norepinephrine was associated with sinusoidal shunting. All hemodynamic, metabolic and biliary changes induced by norepinephrine could be entirely prevented by concomitant infusion of the alpha-antagonist phentolamine, thus indicating that norepinephrine-induced hepatic effects were mediated by alpha-receptors. In contrast, simultaneous addition of papaverine, an unspecific vasodilator, prevented the hemodynamic and the biliary changes of norepinephrine, but failed to modify the metabolic effects of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Properties of a transmission grating behind a grazing incidence telescope for cosmic x-ray spectroscopy.

Third-order aberrations are discussed of a transmission grating positioned behind a Wolter type I telescope, using Fermat's principle. We describe the conditions required to obtain a coma-free grating. The performance of a grating spectrometer for cosmic x-ray spectroscopy is discussed in some detail.

mechanism of glucagon choleresis in guinea pigs.

The present studies were carried out to clarify the mechanism of glucagon choleresis in guinea pigs. At the infusion rate of 1.4 nmol.min-1.kg-1, glucagon increased bile flow from 206.6 +/- 14.3 to 302.6 +/- 35.0 microliters.min-1.kg-1 and bicarbonate biliary concentration from 63.7 +/- 4.2 to 75.5 +/- 5.9 meq/l. Measurements of bile acid excretion in bile, the biliary tree volume, and of the hormone choleretic effect in guinea pigs with proliferated bile ductules/ducts induced by alpha-naphthylisothiocyanate feeding indicated that glucagon, unlike secretin, stimulated canalicular bile flow. Inhibition of prostaglandin synthesis by indomethacin administration (5 mg.kg-1.h-1) did not modify the choleretic effect of glucagon, and infusion of a glucagon analogue (TH-glucagon, 1.4 nmol.min-1.kg-1), which did not increase hepatic formation of adenosine 3'5'-cyclic monophosphate (cAMP), failed to stimulate bile flow. Like the parent hormone, however, TH-glucagon augmented plasma glucose levels and stimulated formation of inositol phosphates. Colchicine pretreatment (0.5 mg/kg ip) almost entirely prevented the choleretic effect of glucagon but did not modify spontaneous and bile acid-induced bile flow and the stimulatory effect of the hormone on glucose release and on hepatic formation of cAMP and inositol phosphates. Finally, glucagon produced a large increase in the biliary entry of horseradish peroxidase, even though this effect was transient and was not coupled to the increase in bile flow. These results indicate that glucagon choleresis in the guinea pig is not secondary to prostaglandin release, is canalicular in origin, involves bicarbonate secretion, is mediated by cAMP, and requires an intact microtubular system.

Liver carcinogenesis associated with feeding of ethionine in a choline-free diet: evidence against a role of oval cells in the emergence of hepatocellular carcinoma.

In an attempt to clarify the role of oval cells in the emergence of hepatocellular carcinoma, we fed rats a choline-free diet containing 0%, 0.05% or 0.1% ethionine. The incidence and nature of premalignant and malignant hepatic lesions were then related to the degree of oval cell proliferation. Intake of choline-free diet alone for up to 12 mo was associated with minimal oval cell proliferation; cholangiofibrosis, hepatocellular nodules and hepatocellular carcinoma were observed in 55%, 23% and 14% of the animals, respectively. When rats were given the choline-free diet with 0.05% ethionine, proliferation of oval cells was more pronounced; after a 6- to 12 mo feeding period, cholangiofibrosis (57%) was again observed. However, hepatocellular nodules (91%) and hepatocellular carcinoma (74%) were the most common lesions seen with this feeding regimen. Finally, rats fed the choline-free diet with 0.1% ethionine had massive oval cell proliferation and progressive loss of parenchymal liver tissue. Most of these animals died before they had consumed the choline-free diet with 0.1% ethionine for 12 mo. Rats in this group (96%) exhibited large and numerous cholangiofibrotic lesions, but hepatocellular nodules and carcinoma were not detected. In all animals of each experimental group, hyperplastic bile duct cells in areas of cholangiofibrosis and oval cells were positive for cytokeratin 19, an intermediate filament protein present only in bile duct cells in normal liver. Hepatocellular nodules and hepatocellular carcinoma were invariably negative for cytokeratin 19. We interpret these findings to suggest that oval cells are not involved in the histogenesis of hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

[Intrahepatic cholestasis and aplastic anemia following administration of prajmaline]. / Intrahepatische Cholestase und aplastische Anämie nach Prajmalin-Einnahme.

Intrahepatic cholestasis and aplastic anemia after N-propylajmaline. A 43 year old female patient taking oral contraceptives for more than five years received the antiarrhythmic drug N-propylajmaline for treatment of ventricular arrhythmia. After twelve days (total dosage 510 mg N-propyl-ajmaline) acute severe intrahepatic cholestasis and aplastic anemia developed. The erythropoeisis improved after three weeks of treatment with corticosteroids. However, despite treatment with phenobarbital the jaundice receded very slowly. Even after nine years of follow-up cholestatic enzymes are still significantly elevated although serum bilirubin levels are in the normal range. This case report demonstrates that antiarrhythmic drugs may induce nearly irreversible intrahepatic cholestasis and severe hematological disturbances.

In liver transplantation, T tube bile represents total bile flow: physiological and scintigraphic studies on biliary secretion of organic anions.

The present study was performed to clarify the recovery of hepatocellular uptake and the biliary secretion of bile acids during the first 14 days after orthotopic liver transplantation (OLT) and to determine the fraction of bile flow appearing outside through the T tube and entering the duodenum. Therefore, we determined primary and secondary bile acids in bile samples obtained from the T tube at day 5 after OLT, while the T tube was permanently open, and at days 10 and 14 after OLT, i.e., 4 and 9 days after closure of the T tube, respectively, thus restoring enterohepatic bile acid circulation. In addition, we performed hepatobiliary scintigraphy using technetium 99m-labeled [2,4,6 trimethyl-3-bromo]imino-diacetic acid (technetium 99m-BRIDA) in 12 patients between days 4 and 17 after OLT. Chromatographic analyses of biliary bile acids showed no secondary bile acids during the first 5 days after OLT, as opposed to 10 and 14 days after OLT when enterohepatic circulation was restored. Eleven patients with an uncomplicated postoperative course after OLT showed a significantly reduced hepatic uptake and biliary secretion of 99mTc-BRIDA during the first days after OLT with progressive recovery. One patient with an acute allograft rejection episode showed almost no uptake and only minimal secretion. The bile fraction appearing outside through the inserted T tube represented 94.6% +/- 6.2% of the injected 99mTc-BRIDA. We conclude that OLT results in markedly impaired hepatocellular uptake and biliary secretion of organic anions. Simultaneously, bile acid synthesis is significantly reduced, which, in addition, diminishes bile secretion of the graft. We show that T tube bile is a valid tool for bile physiological studies in patients in whom transplantation was successfully performed.

Distribution of glucose-6-phosphatase activity in normal, hyperplastic, and preneoplastic rat liver.

The significance of glucose-6-phosphatase (G6P) expression by bile duct-like cells proliferating during hepatocarcinogenesis in the histogenesis of hepatocellular carcinoma is not clear. To this end, we measured the histochemical and biochemical activity of G6P in normal rat liver, and in rat livers in which bile duct-like proliferation was induced by either hyperplastic (bile duct ligation for 14 days or feeding alpha-naphthylisothiocyanate for 28 days) or neoplastic (feeding a choline-devoid diet containing 0.1% ethionine for 60 days) regimens. In normal, hyperplastic, and preneoplastic livers, G6P histochemical activity was confined to the hepatocytes; proliferated bile duct-like cells, like normal bile ducts, did not display visible G6P staining. When the enzyme activity was determined biochemically, however, hydrolysis of glucose-6-phosphate was observed in both parenchymal and nonparenchymal liver cells isolated from all experimental animals. In elutriated nonparenchymal fractions, G6P activity was directly proportional to the number of cells positive for gamma-glutamyl transpeptidase and cytokeratin no. 19 (markers of bile duct cells) and inversely proportional to the number of cells positive for vimentin (marker of mesenchymal cells). These results indicate that, while by light microscopy hepatic G6P histochemical activity is detectable only in the hepatocytes, the biochemical activity is also expressed in proliferating bile duct-like cells. However, the nonparenchymal activity is observed during both neoplastic and hyperplastic liver growth, thus indicating that the presence of this enzyme in bile duct-like cells proliferating during hepatocarcinogenesis should not necessarily be construed as supporting their stem cell nature nor their neoplastic commitment.

[The aorto-enteric fistula--a rare, but important cause of upper gastrointestinal hemorrhage]. / Die aortoenterische Fistel--eine seltene, aber wichtige Ursache oberer gastrointestinaler Blutungen.

During the last two years two patients with upper gastrointestinal bleeding caused by an aortoenteric fistula were admitted to the hospital. The first patient had a primary fistula between an arteriosclerotic aneurysm of the abdominal aorta and the duodenum. The second patient had an infected aortobifemoral graft which had penetrated into the upper jejunum. The aortoenteric fistula is one of the very rare causes of upper gastrointestinal bleeding. Referring to previous surgery at the aorta a primary and secondary type of fistula are differentiated. The primary fistula often induces a small initial bleeding followed by a severe hemorrhage with hematemesis and melaena. The secondary form is mostly caused by bacterial infection of the graft. Recurrent fever attacks are a common clinical symptom without any evidence of the origin of the bacteriemia. Principally the combination of upper gastrointestinal bleeding and aortic graft is always suspicious of an aortoenteric fistula. The most important preoperative examinations are endoscopy, computed tomography scan, and arteriography. The treatment must be surgical. Either a synthetic graft surrounded by omentum is implanted or an axillobifemoral or aortobifemoral bypass is constructed. Even if the diagnosis is made early mortality of the disease is about 20-30%.

Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation.

The present study characterizes recovery of bile secretion after orthotopic liver transplantation (OLT) in humans with special regard to hormonal regulation of bile acid-independent bile flow by glucagon and secretin. Sixty-seven patients with an uncomplicated postoperative course were studied during the first 3 weeks after OLT to determine normalization of bile flow. A group of 7 and 10 patients, respectively, underwent a biliary stimulation test by either glucagon at days 7, 14, and 21 after OLT or by secretin at days 2, 10, and 21 after OLT. Secretin tests were similarly performed in patients with acute severe rejection during the first 10 days after OLT, while glucagon tests were performed in patients with acute allograft rejection occurring 2 weeks after OLT. Furthermore, hormone effects were studied in nontransplanted patients after cholecystectomy with indwelling biliary T tube. After OLT, bile secretory function recovered and stabilized within 14 days after surgery by reconstitution of both bile acid-dependent and -independent bile flow. Two weeks after OLT, bile secretion was comparable with nontransplanted patients after cholecystectomy. Glucagon and secretin stimulated bile acid-independent bile flow in transplanted and nontransplanted patients significantly, yet secretin choleresis, unlike glucagon choleresis, had already occurred during the first days after OLT and was unaffected by acute allograft rejection. These results allow the speculation that, in humans, glucagon and secretin exert their choleretic activity by different mechanisms and/or at different anatomical sites in the liver. Assuming that secretin acts at the bile duct cells, its secretory capacity was not altered by the transplantation procedure and during moderate or severe rejection episodes, as opposed to glucagon choleresis, which most likely originates in the hepatocytes and requires an entirely reconstituted canalicular transport system after OLT.