The treatment of hepatic encephalopathy.

Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

Serum concentrations of sIL-2R, IL-6, TGF-beta1, neopterin, and zinc in chronic hepatitis C patients treated with interferon-alpha.

T lymphocytes and immunoregulatory cytokines play an important role in the host response to hepatitis C virus (HCV) infection. Zinc is required for a wide spectrum of immune functions, including T-cell activity. To determine the clinical significance of the cytokines sIL-2R, IL-6, TGF-beta1, neopterin, and of zinc in chronic heptatitis C virus (HCV) infection, we investigated their concentrations in the serum of 16 patients with chronic HCV infection before, during and at the end of therapy with interferon (IFN) alpha (Roferon A), and after 6 months follow-up. Elevated concentrations of sIL-2R, IL-6, TGF-beta1, and neopterin were found in the serum of all patients prior to therapy, as compared to healthy controls. sIL-2R patterns differed in responders and non-responders. While the mean concentration of sIL-2R (335.75 pg/ml) before therapy was about 40% higher in complete responders (n=4) than in controls (272.20 pg/ml), the mean concentration in non-responders (n=6) was 4-fold higher than in controls (1153.33 pg/ml). During therapy, sIL-2R levels in responders decreased by about 40%. Mean IL-6 concentrations in both complete and partial responders (n=6) decreased continuously during treatment, while mean concentrations in non-responders decreased for only a short time, and increased again after cessation of therapy. Mean levels of TGF-beta1 behaved similarly to those of IL-6. Only negligible differences in mean neopterin levels were found between responders and non-responders over the entire observation time. The mean serum zinc concentrations slightly decreased in all 3 patient groups, the greatest reduction occurring in 3 of the 4 responders. The present findings underscore the importance of the immune system in the pathogenesis of chronic HCV infection. Serum sIL-2R levels may be used as a serological marker of outcome following IFN-alpha treatment.

Adenosine influences the high-affinity uptake of transmitter glutamate and aspartate under conditions of hepatic encephalopathy.

The high-affinity uptake of transmitter glutamate and aspartate in hippocampal slices incubated in sera from patients with hepatic encephalopathy was dramatically reduced in neuropil areas by more than 50% compared with the control level. Adenosine compensates for these reduction in reuptake capacity in a concentration-dependent fashion reaching normal values at 500 microM adenosine. The renormalization of glutamate and aspartate uptake caused by adenosine might reasonably be expected to have potential therapeutic implications for the treatment of hepatic encephalopathy.

[Valine and branched-chain amino acids in the treatment of hepatic encephalopathy]. / Valin und verzweigtkettige Aminosäuren in der Behandlung der hepatischen Enzephalopathie.

We studied the effects of infusion of a liver adapted amino acid solution (Amino-Mel hepa: Group A) versus a liver adapted amino acid solution plus L-valine (Amino-Mel hepa + L-valine: Group B) in 30 patients with decompensated liver cirrhosis with coma. Each 15 patients were randomly allocated to the group A and B, respectively. Both regimens included the infusion of glucose and fat, further supplementation of vitamins and trace elements in addition to the amino acid solution. The results of this study show that in patients with advanced stage of hepatic coma a valine increased supply of branched chain amino acids neither influences the course of the disease nor the death rate. The prognosis of patients with this disease is mainly determined by liver function and accompanying complications.

Hepatic encephalopathy influences high-affinity uptake of transmitter glutamate and aspartate into the hippocampal formation.

The present work was carried out to study the influence of ammonia and factors from sera and cerebrospinal fluid (CSF) from patients with different degrees of chronic liver diseases on [3H]D-aspartate (Asp) and [3H]L-glutamate (Glu) high-affinity uptake into the rat hippocampal formation. For comparison, high-affinity uptake of Glu and Asp was determined in human hippocampal brain tissue obtained at autopsy from cirrhotic patients dying in hepatic coma and from control brains free from neurological, psychiatric, or hepatic diseases. Sera and CSF from patients with chronic liver failure and hepatic encephalopathy (HE) were seen to reduce dramatically Glu and Asp uptake into rat hippocampal dendritic layers. A close inverse relationship was found to exist between the level of ammonia in the sera and the inhibition of uptake, both phenomena correlating highly with the extent of liver failure. The present findings, obtained after dilution of sera from patients with HE while maintaining initial ammonium levels, elucidate, however, that ammonia alone cannot account for the reduction in Glu/Asp uptake capacity. The inhibition of Asp uptake into human hippocampal formation of patients dying in hepatic coma was even more pronounced when compared to that found in rat hippocampus incubated in sera and CSF from patients. Glu/Asp uptake into brain tissue is supposed to be an important factor in the pathogenesis of HE accompanying liver dysfunctions.

[Complications of hepatic coma in liver cirrhosis]. / Komplikationen des Coma hepaticum bei der Leberzirrhose.

59 patients with exogenous liver coma in state III-IV were treated from 1980 to 1989 in our clinic. Incidence and complications in these patients were evaluated retrospectively. The most frequent eliciting factors were gastrointestinal bleeding, infections and acute alcohol excess, more than 2/3 of them having severe portal hypertension with ascites and esophageal varices at the time. Altogether 55 of the 59 liver coma patients died. The most important complications were, beside bleeding and infections, disturbances of the renal function and of the coagulation. Severe acute or chronic liver injury is often associated with multiorgan failure.

Correlations between zinc, amino acids and ammonia in liver cirrhosis.

In view of the universal metabolic importance of zinc in the organism, it was the purpose of the present work to determine the concentrations of zinc in serum, of amino acids and ammonia in plasma of patients with liver cirrhosis, and investigate that correlations might exist between these substances. The study involved 18 patients with decompensated liver cirrhosis without coma and eleven with coma. The subjects with normal livers were used as controls. While confirming known data (reduced zinc levels, imbalance of plasma amino acids, hyperammonaemia in chronic liver diseases) the findings also revealed correlations between the above substances. A negative correlations existed between zinc and ammonia. Decreases in zinc serum levels were accompanied by increases in plasma ammonia concentrations in hepatic coma (p less than 0.05). Plasma levels of amino acids did not correlate with serum zinc concentrations.

[Self-mutilation with a coumarin derivative]. / Selbstbeschädigung durch ein Kumarinderivat.

The experiment of a self-injury by permanent intoxication with the coumarin derivative Warfarin is described. Various isolated haemostatic defects as differential-diagnostically demarcated causes for the leading symptom decrease of the value of the thromboplastin time which concern the effect of coumarin are mentioned. It is referred to the coagulation-analytic and chemical-toxic methods of proof of coumarins.

Clinical studies on zinc in chronic liver diseases.

Zinc is essential to numerous metabolic processes in the organism, multiform symptoms being found especially in deficiencies. In addition to nutritional factors, diseases such as cirrhosis of the liver. Crohn's disease and chronic renal diseases are relevant in this context. In the present work, serum zinc levels were investigated in 109 patients with various chronic liver diseases. The lowest serum zinc concentrations were seen in patients with decompensated hepatic cirrhosis with coma. Patients with decompensated alcoholic cirrhosis had lower zinc levels as subjects with nonalcoholic cirrhosis. None of the groups exhibited a significant change in serum zinc levels during the treatment period. Laboratory data (such as transaminases, thromboplastin time, alkaline phosphatase, total proteins) did not correlate with the serum zinc concentrations. The concentration of plasma ammonia, however, appeared to be inversely related to the serum zinc levels. Thus, patients with coma had maximum ammonia and minimum zinc levels.

[Blood coagulation inhibitors and thrombosis]. / Gerinnungsinhibitoren und Thrombose.

Pathological inhibitors of the coagulation which are recognized by characteristic laboratory findings may cause an increased inclination to haemorrhage, may be clinically mute or also may effect an increased inclination to thrombosis (lupus inhibitors). It is reported on patients with rare coagulation inhibitors, a pathologic antithrombin with normal reptilase time and an antithromboplastin with protracted effect, in which thromboses appeared. The occurrence of thromboses in these patients up to now does not allow the assumption of an effect of these inhibitor substances furthering thrombosis, but only the statement that despite coagulation-analytically recognizable inhibition effects the development of a thrombosis is not prevented. A prophylactic factor substitution in operative interventions is not indicated.

[Therapy of hepatic encephalopathy]. / Therapie der hepatischen Enzephalopathie.

The pathogenesis of the hepatic encephalopathy (HE) in spite of substantial progresses in this field still rests unclear. Actually four main hypotheses of the pathogenesis are discussed: the ammonia-hypothesis, the synergism-hypothesis, the hypothesis of the false neurotransmitters and that one of the changes of the normal neurotransmitters and their receptors. A connecting function seems to come up to ammonia. --Reduction of oral protein intake, selection of certain proteins, oral administration of nonabsorbable antibiotics and enemas should be used in order to prevent the intestinal absorption of toxic metabolic products. The parenteral nutrition has the therapy of HE substantially improved. Primarily, the patients receive special amino acid mixtures with a high content of branched chain amino acids and a low content of aromatic acids. The exchange of carbohydrate to some extent through fat improves the parenteral nutrition regime for these patients. The different liver support systems have failed to improve the prognosis of fulminant hepatic failure.

[Acute arterial occlusive syndrome in streptokinase treatment of deep venous thrombosis--successful therapy with urokinase]. / Das akute arterielle Verschlusssyndrom unter der Streptokinasebehandlung einer tiefen Venenthrombose--erfolgreiche Therapie mit Urokinase.

Arterial embolism or thrombosis are very rare complications of the fibrinolytic therapy of deep venous thrombosis. The characteristics symptoms of these illness are the acute arterial failure of the concerned extremity during venous thrombolysis. The diagnosis take place by angiography, by ultrasonics, and in particular cases by the skin thermographic method. If the arterial occlusion is not operable, the thrombolysis by urokinase is discussed. This seems to be the last possible method to support the extremity.

[Behavior of plasma amino acids in alcohol-induced chronic liver diseases]. / Verhalten der Plasmaaminosäuren bei alkoholbedingten chronischen Lebererkrankungen.

In chronic liver diseases of alcoholic and non-alcoholic origin there are strikine differences of aspartate, glutamate and prolin. Where as plasma levels of aspartate and prolin are in most cases higher than in non-alcoholics, glutamate shows a contrary behaviour except in hepatic coma. The plasma ratio of alpha-amino-butyric acid to leucin allows no distinction of alcoholic from non-alcoholic liver lesion.

[Hepatological aspects of surgical interventions in the stomach]. / Hepatologische Aspekte operativer Eingriffe am Magen.

By means of quantitative-biochemical and histomorphological methods after vagotomies changes of the liver could be proved to a smaller extent than after resections of the stomach (Billroth II). Among the bionomic operation methods the supra-selective proximal vagotomy without pylorplastics is superior to other methods under the aspect of the change of the liver.

[The effectivity of long-term treatment of porphyria cutanea tarda from a hepatological viewpoint]. / Untersuchungen zur Effektivität der Langzeitbehandlung der Porphyria cutanea tarda aus hepatologischer Sicht.

34 Patients with an ascertained porphyria cutanea tarda who underwent a long-term therapy a comprehensive internal and hepatological diagnosis was made. In these cases for the first time the estimation of the intrahepatic distribution of enzymes and its comparison with the serum enzymes were also performed. The liver histology allowed a division of our patients into three groups, in which cases the reactive hepatitides prevailed and a conspicuously large proportion of normal histological findings were present. The comparison of all data got with the literature made the conclusion possible that the phlebotomy therapy as well as the care in a special dispensary for years lead to very favourable results on liver and skin.