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ATP-Citrate-Lyase is a key enzyme of cholesterol biosynthesis. Its liver-specific inhibition by the bempedoic acid opens new possibilities to effectively escalate a cholesterol-lowering therapy while avoiding muscle-related side effects. Herein, we present the properties of this new first-in-class pharmaceutical agent and discuss potential consequences for pharmacotherapy., Competing Interests: A. El-Armouche weist auf Forschungs- und/oder Vortragstätigkeiten hin für Boehringer Ingelheim, Novartis, Bayer, Novo Nordisk, Sanofi Aventis, Daiichi Sankyo und Berlin Chemie. Die anderen Autorinnen/Autoren geben keinen Interessenkonflikt an., (Thieme. All rights reserved.)

The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase worldwide, presently affecting 25% of the adult population, and is associated with an elevated risk of total and liver-specific mortality. NAFLD is a chronic disease and results from a combination of genetic, environmental and predominantly lifestyle-related causes. Therefore, NAFLD, similarly to cardiovascular disease, type 2 diabetes and many different types of cancer, can be considered a noncommunicable disease. Consequently, lifestyle intervention, particularly if associated with a large amount of weight loss, is considered highly effective and safe to treat NAFLD. For patients with advanced-stage NAFLD or that cannot lose weight, metabolically-based pharmacotherapy is effective to improve liver histology and cardiometabolic risk profile. If a moderate or advanced stage of liver fibrosis is present, additional antifibrotic therapy is necessary to halt the progression of the disease.

Non-alcoholic fatty liver disease (NAFLD) is of increasing prevalence globally. While lifestyle modifications are recommended, many patients do not succeed to achieve significant and maintained weight loss from lifestyle and as such there is a high unmet need for pharmacotherapy in this group. Comparable to other metabolic diseases including diabetes and dyslipidaemia, a high proportion of patients will likely benefit from permanent pharmacological therapy. Currently there are many compounds with different mechanisms of action in clinical development including metabolic, anti-inflammatory and anti-fibrotic drugs. A number of phase 3 clinical trials are currently ongoing including Elafibranor, a dual PPAR α/δ agonist, Cenicriviroc, a CCR2/CCR5 chemokine antagonist, the nuclear bile acid receptor FXR agonist obeticholic acid, Aramchol, a fatty acid bile acid conjugate that modulates SCD-1, and Resmetrion, a liver-specific THR-β agonist. Further studies with promising pathophysiological mechanisms of action, e. g. the ASK-1 inhibitor Selonsertib or the caspase inhibitor Emricasan have shown negative results. However, some are being further evaluated in combination therapies. The complex pathophysiology of the disease, which combines inflammation, metabolism and fibrosis, has led to the fact that even combinations of several substances are investigated with different modes of action. This review summarizes pivotal clinical trials for patients with NASH in the absence of cirrhosis which are recruiting in the fall of 2019., Competing Interests: (Forschungs-)Unterstützung: Gilead Sciences.Honorar oder Beratungskosten: Allergan, Galmed, Genfit, Gilead Sciences, Intercept Pharmaceuticals, IQVIA, Madrigal, Novartis, Pfizer, Roche, Siemens Healthineers., (© Georg Thieme Verlag KG Stuttgart · New York.)

Synthetic amphetamines such as 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy) have become recreational drugs in German discotheques because of their euphoric and mood-brightening effects. However, their consumption involves considerable risks, which may even be lethal under certain circumstances. A 19-year-old man was taken to a university hospital for suspected intoxication with a narcotic drug, where he died the next day. As cause of death "fulminant liver failure" was diagnosed. In blood from the femoral vein, MDMA was found in a concentration of 4.27 mg/l. Histological examination showed acute necrosis of the liver and parenchymatous bleeding. The second case is that of a 39-year-old man who collapsed at his workplace and died in hospital shortly afterwards. In his rucksack, a small bag with 1.6 g of amphetamine was found. Analysis of blood from the femoral vein showed an amphetamine concentration of 1.08 mg/l.

Objective: The effects of rumen-protected choline (RPC) on energy metabolism and milk production in dairy cows were analyzed., Material and Methods: Two hundred and ninety-eight primiparous and multiparous cows of a high producing dairy herd (mean daily milk yield: 32 l) were randomly assigned to control or treatment groups and were fed with 0 or 15 g RPC, respectively, (corresponding to 0 and 60 g/d ReaShure®, respectively) from 21 days before expected calving to 21 days postpartum (p. p.). Blood metabolites were determined for either all cows (glucose, β-hydroxybutyrate [BHB]) or randomly (insulin, insulin-like growth factor-1 [IGF-1], non-esterified fatty acids [NEFA]) during the periparturient period. An index for insulin sensitivity (RQUICKI) was calculated and milk production data (dairy herd improvement tests, 100-days-, 305-days-, milk peak yield, colostrum quality) was analyzed. In the statistical analysis, a distinction was made between the feeding groups and between the parity, and their interactions were analyzed., Results: With the exception of a lower 305-day-milk yield in the treatment group (p < 0.05), the evaluated variables did not show statistically significant differences between the feeding groups and no interactions could be found. In comparison to heifers, multiparous cows had less cases of subclinical ketosis a. p. and p. p. (OR a. p.: 0.178; OR p. p.: 0.310), more of them were above the threshold for somatic cell counts (OR 2.584-3.298), and their milk yields were higher (p < 0.05)., Conclusion and Clinical Relevance: Supplementing RPC did not affect the energy metabolism or the milk production in this herd. Further research in other dairy herds should focus on this topic.

In mammals (e. g. macaques, dogs, cats, rats, sheep) as well as in men (suicides) euthanasia performed by intravenous injection of T 61 leads to serious lesions in lung, kidney or/and liver (endothelial damage, hyperemia, oedema, necrosis). This is caused by the solvent dimethylformamide (DMF). In this study, in contrast, in different species of birds (e. g. blackbird, carrion crow, kestrel, common buzzard, homer pigeon, common wood pigeon, mallard duck) and various modes of applications and dosages T 61, 1.0-3.0 ml/kg body mass, did not induce comparable artefacts in tissues of internal organs in the narcotized animals. Microscopically, only hyperemia and oedema of lung, kidney and/or liver were found. However, milder but similar lesions were detected also in groups of birds euthanized by pentobarbital (200 mg/kg body mass) as well as in control groups (overdosed ketamine intramusculary, 100 mg/kg body mass, and rapid exsanguination). In conclusion, euthanasia of narcotized birds performed by intravenous or intracardial injections ofT 61 seemed to be suitable. The observed lesions could therefore not be interpreted as T61 induced artefacts.

The possibility of liver intoxication at therapeutic doses of paracetamol (maximal dailydose of 4 x 1 g) is supported by retrospective, but not by controlled prospective studies. Intended orsuicidal overdosages are frequently misjudged in retrospektive reports. Malnutrition, ethanol consumption, and drugs inducing hepatic metabolism are no established riskfactors at therapeutic dose levels. Dose adaptation in existing liver disease is recommended for longer-term use.Transient increases in transaminase values (> 3 x upper limits of normal) after regulardoses of paracetamol are not proof of hepatic damage unless associated with corresponding symptoms or laboratory changes indicative of compromised hepatic function (total bilirubin, INR). There is insufficient evidence of liver injury by paracetamol at regular dose levels.

Background: Human tissues or organs vary in the content of long-chain omega-3 fatty acids, in case of diseases the content may even change. These findings cannot be extrapolated from blood lipids., Methods: Overview, Results: By means of liver biopsies it has been shown that eicosapentaenoic acid (EPA) significantly decreases with raising triglyceride accumulation in hepatocytes. This is associated with increased histological signs of inflammation in liver parenchyma. In a study the intake of omega-3 fatty acids (1 g/d) resulted in a rising percentage of EPA in liver triglycerides associated with a reduction of liver fat and inflammation markers., Conclusion: From the results a hitherto widely ignored indication for NAFLD with or without metabolic syndrome can be derived.

Colorectal cancer (CRC) can only be cured by complete resection of the tumour. Primarily unresectable metastases of the liver are treated by chemotherapy to achieve down-sizing of metastasis and curative resection. Chemotherapy can affect tumour-free healthy liver tissue and lead to histopathological and functional changes summarised as "chemotherapy-associated steatohepatitis" (CASH). We have evaluated a histopathological scoring system for CASH and searched for preoperative risk factors for the development of CASH. Liver alterations such as CASH were more pronounced when patients received chemotherapy, especially when treated with oxaliplatin. A higher BMI, male sex and elevated serum transaminases were risk factors for the development of CASH. Patients with a higher CASH score, reflecting more advanced changes in liver tissue, had a higher serum peak bilirubin level postoperatively. We did not find a higher morbidity or mortality in patients with a more severe liver damage measured by the CASH score., (© Georg Thieme Verlag KG Stuttgart · New York.)

We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors.

The growing number of patients with type 2 diabetes stimulates the development of new antidiabetic drugs. New targets are addressed, as SGLT2 in the kidney or enzymes of glucose metabolism in the liver which might help to lower glucose levels and to overcome insulin resistance. The forthcoming years will show which of the drugs in clinical trials will get marketing authorization.

Chronic liver injury, such as viral hepatitis, alcohol, metabolic syndrome or other toxic damages, leads to an inflammatory response including the infiltration and activation of immune cells and to the proliferation and transdifferentiation of mesenchymal cells within the liver, especially of hepatic stellate cells. These cells produce an excess of extracellular matrix proteins that are deposited in the liver. Hepatic fibrosis may progress to liver cirrhosis and liver failure. This review aims at summarizing the current view on the pathogenic sequence during fibrogenesis highlighting the essential role of cytokines and chemokines. Understanding the complex cellular interactions in liver fibrosis may help to develop novel antifibrotic therapies in the near future.

Non-steroidal, anti-inflammatory drugs are the most widely used remedies worldwide. Drug interactions are frequent, life threatening ones are rare: Bleeds on the basis of inhibition of platelet aggregation and loss of organ protection (GI-tract), thrombotic events due to loss of vasoprotection and increased propensity for blood coagulation (stroke), acute kidney failure on the basis of loss of kidney protection by prostaglandins together with stress to the organ and/or drugs interfering with the renal blood flow. Acute liver toxicity is typical for acetaminophen. Whether the risk is increased by other hepatotoxic drugs, as diclofenac, is uncertain at present. All risks can be reduced considerably by avoiding problematic drug interactions.

Because antidepressants and antipsychotics are commonly described in combination with drugs used to treat comorbid psychiatric or somatic disorders (e.g. anxiolytics, mood stabilizers, cardiovascular drugs, antimicrobial agents), they may be involved in drug interactions. Furthermore, agents such as lithium and atypical antipsychotics may be used to augment the antidepressant response in cases of refractory depression. Based on their mechanisms, drug-drug interactions can be classified either as pharmacokinetic or pharmacodynamic in nature. The well-documented risk of potentially harmful pharmacodynamic drug interactions with first-generation anti-depressants, e.g. monoamine oxidase inhibitors (MAOIs), with regard to the induction of the serotonin syndrome, has contributed to a gradual decline in their use in clinical practise. Second- and third-generation antidepressants have gradually replaced tricyclic antidepressants (TCAs) and MAOIs, mainly because of their improved tolerability and safety profile. The second- and third-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and other compounds with different mechanisms of action. These drugs and also the majority of antipsychotics are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Therefore, the use of these compounds may be associated with clinically relevant pharmacokinetic interactions with other medications. The knowledge about the CYP metabolism of drugs may be used to guide the selection of an antidepressant or an anti-psychotic with a low drug-drug interaction potential for an individual patient. The aim of the present article is to review drug-interaction potentials with specific focus on second-generation antidepressants (SSRIs), newer antidepressants (SNRIs: venlafaxine and duloxetine; bupropion, mirtazapine, trazodone), novel atypical antidepressants (agomelatine), as well as new generation atypical antipsychotics (aripiprazole, paliperidone).

Polyhexamethylene biguanide (PHMB) is considered to be highly histocompatible and is one of the most frequently used wound antiseptics. Only one case of intoxication has been reported so far. The present case of a lethal intoxication is the first fatal incident described where causality is substantiated by a temporal coincidence between application and ascertainable organ damage. The laboratory-chemical and histological investigations verified the toxicity of this substance after intravenous application with the main findings being severe hepatic and pancreatic damage.

Since the correlation between the amount of Ethinylestradiol (EE) and the thromboembolic risk has been recognized, the development of new oral contraceptives (OC) has been characterized by a constant lowering of the EE dosage. The consecutive decrease of ovulation inhibition has been compensated by the introduction of potent progestagens. Therefore, the contraceptive safety has been maintained in presence of less side-effects. The effect of ultra-low-dose OC on acne and seborrhea remains beneficial. The effect of ultra-low-dose OC on bone is contradictory. Because there are fundamental differences between Estradiol and EE, the thromboembolic risk is not decreased by the parenteral administration of EE. In users of the contraceptive patch, it is even increased. EE is not bound at SHBG. Because of its Ethinyl group, the inactivation of EE occurs slowly. Therefore, EE reaches the liver in a low but constant concentration where it modifies many estrogen-dependent hepatic parameters significantly. One of these is hemostasis. It is generally accepted that such changes are responsible for the increased thromboembolic risk of the contraceptive patch and vaginal ring. A reduction of the hormone-free interval of the pill to 5 or 4 days results in a complete suppression of the ovarian function, a reliable ovulation inhibition and an increase of the contraceptive efficacy in spite of a reduction of the EE dosage to 20 microg or 15 microg.

Modern combination chemotherapies, mainly including oxaliplatin or irinotecan, have demonstrated a significant increase in response rates. This led to the concept of down-sizing irresectable liver metastases from colorectal cancer, thereby achieving secondary resectability and possibly cure. However, these benefits of preoperative chemotherapy must be weighed against potential side effects to the surrounding normal liver tissue. In particular, in patients with pre-existing liver disease combination therapy can cause liver damage which may exceed mere steatosis of hepatocytes and lead to inflammation, cholestasis and bleeding. In correspondence to the "non-alcoholic steatohepatitis" (NASH) the term "chemotherapy associated steatohepatitis" (CASH) has been proposed in the literature. Platinum derivatives, in particular, can lead to damage of the hepatic microcirculation and the so-called sinusoidal obstruction syndrome (SOS). Few reports mention an increase in perioperative morbidity after combination chemotherapy. However, there are no comprehensive data on the individual risk of a patient for postoperative complications. If elevated liver enzymes are detected before chemotherapy and cannot readily be explained through liver involvement by the tumor, then close monitoring of enzymes should be performed and a biopsy may be considered in unclear cases. We recommend that the histological changes observed in the liver be quantified and classified by a unifying scoring system and propose, in correspondence to the hepatitis activity scores, a modified scoring system.

The effects of three dietary selenium (Se) levels (0.15, 0.35 and 0.5 mg/kg dry matter (dm) and of two Se-compounds (sodium selenite and Se-yeast) on the Se-status, liver function and claw health were studied using 36 fattening bulls in a two-factorial feeding trial that lasted 16 weeks. The claw health was assessed macroscopically and microscopically. Compared to the two control diets containing 0.15 mg Se/kg dm, the intake of the diets containing 0.35 and 0.50 mg Se/kg dm significantly (P < 0.05) increased the Se-concentration in serum, hair, liver and skeletal muscle. Compared to sodium selenite the intake of Se-yeast resulted in significantly (P < 0.05) higher Se-concentration in serum, liver and hair. Concerning the claw horn quality, there was no significant difference between the different groups; the animals receiving organic Se tended to have a better histological score (P = 0.06) at the coronary band than the groups fed with sodium selenite. The serum vitamin E level decreased significantly (P < 0.05) with increasing Se-intake, which had no influence (P > 0.1) on growth and liver function parameters. With the exception of the decrease of the serum vitamin E level indicating an oxidative stress caused by a high Se-intake, no negative effects of dietary selenium exceeding recommended levels for 4 months were observed.

This article describes the grading and staging systems used in the clinical context for non-neoplastic liver diseases (chronic and autoimmune hepatitis, fatty liver and steatohepatitis, medicinal toxic liver damage, iron storage disease and gall duct diseases). Fibrotic parenchymal alterations can also be assessed as well as livers planned for transplantation, with respect to possible rejection reactions. The basis for the histopathological diagnostic procedure is the liver biopsy. The consistent and correct use of the histological scores is obligatory in the diagnostic assessment of non-neoplastic liver diseases. Different scores are available for the various liver diseases. These are qualitative and quantitative scores based on empiricism and the practical relevance has been effectively proven. Grading describes the inflammatory activity and staging the extent of fibrosis or structural disorders up to liver cirrhosis. In many instances staging is the histopathological criteria for the prognosis assessment and is, therefore, decisive for therapy indications and therapy initiation.

Background: Increased sympathetic nervous activity which induces vasoconstriction and decreases perfusion may be an underlying mechanism behind the development of perioperative liver damage. This animal study was designed to assess how clonidine-induced systemic sympathicolysis affects liver oxygenation with respect to induced hypotension and vasodilatation under physiological conditions., Methods: Following ethical approval 17 anesthetized and acutely instrumented pigs were randomly assigned to 2 groups. Group 1 consisted of 8 animals receiving intravenous clonidine (2 microg x kg(-1) bolus and 2 microg x kg(-1) x h(-1) for induction of sympathicolysis and group 2 consisted of 9 animals serving as controls. After obtaining baseline values, measurements were repeated 90 and 250 min after starting to reduce systemic sympathetic nervous activity., Results: Clonidine-induced systemic sympathicolysis was associated with decreased mean arterial blood pressure, cardiac output and heart rate. Portal venous and hepatic arterial blood flow, oxygen delivery to the liver, oxygen uptake and liver tissue oxygen partial pressure remained unchanged. The plasma indocyanine green disappearance rate increased., Conclusion: We concluded that despite decreased mean arterial pressure and cardiac output, clonidine-induced systemic sympathicolysis did not affect liver oxygenation or perfusion.

Hepatotoxicity is a significant complication of therapeutic drug use. As ist can imitate nearly all hepatopathies, the diagnosis of drug-induced liver disease is difficult. Most often, it is a diagnosis of exclusion. The following morphological changes are known, dependent on the target cell type: acute and chronic hepatitis, granuloma formation, and fatty liver disease, cholestatic type acute and chronic liver damage with or without inflammation,or mixed forms of liver injury. Portal or perisinusoidal fibrosis can occur following each type of liver damage. Vascular changes or neoplasms are rare. Drug induced liver injuries are more likely induced by type B damage, which is not expected and cannot be reproduced in animal testing. Type A damage, which is known from toxicity assays, is less likely. A specific therapeutic regime is not available. Therefore, early recognition and cessation of the use of the drug is necessary.

A 22-year-old female with a history of developmental delay and seizures successfully treated with carbamazepine and levetiracetam developed fulminant hepatic failure and subsequently died. She had been admitted to the hospital following secondary generalized seizures of 35 min duration. A circulatory shock as well as intoxication was taken into consideration during the clinical course. Autopsy failed to reveal a macroscopically discernible cause of death. Significant findings on microscopic examination included acute tubular necrosis in the kidneys, pre-existing marked accumulation of neutral lipid within the hepatocytes as well as hyperacute liver damage with evidence of almost complete hepatocyte necrosis. Carbamazepine and levetiracetam were simultaneously determined from blood and tissues such as liver, lungs, muscle and kidneys by LC-MS/MS following addition of lamotrigine as an internal standard and liquid-liquid extraction. Validation data are given for levetiracetam. Both carbamazepine and levetiracetam were present in blood at concentrations within or below the therapeutic range, respectively. Moreover, tissue concentrations suggested long-term administration of anticonvulsant drugs, which is in accordance with the medical history. After excessive drug concentrations could be ruled out, the metabolic consequences of a prolonged carbamazepine therapy to cause severe hepatic injury in the present case are discussed. A mechanism of injury to the hepatocytes may be membrane damage by either an increased production of free radicals and/or a decreased free radical scavenging capacity. Following ischemia with reperfusion and during hyperthermia, large amounts of free radicals are formed. Induction of the mixed oxidase activity during longterm administration of carbamazepine may also increase production of free radicals, leaving the hepatic cell more vulnerable to oxidative injury.

Drug induced hepatotoxicity is clinically important for several reasons. These forms of liver injury can mimic almost all other liver diseases, making it necessary to include them into the differential diagnosis in patients with unclear liver damage. The diagnosis must be made indirectly, by judging the temporal relationship with therapy and by exclusion of other liver diseases. Re-exposure is dangerous should be avoided. Knowledge of the most important risk factors is important for avoiding drug-induced liver injury. Since there is no specific therapy for most drug-induced liver injuries, early stopping of the administration of suspected drugs is very important.

Flutamide is an antiandrogen and frequently used for the treatment of prostatic cancer. Severe hepatotoxicity occurs in few patients but may be fatal. We report on two patients with prostatic cancer who received a therapy with flutamide. They showed different degrees of liver damage. One patient recovered completely after withdrawal of Flutamide under medication with steroids. Clinical symptoms and laboratory findings returned to normal within four weeks. Despite immediate withdrawal of Flutamide, the other patient showed a severe course with progressive liver dysfunction and hepatorenal syndrome. He finally died under the clinical picture of fulminant hepatic coma. This case represents the first death associated with flutamide in Germany. The literature concerning the metabolism of flutamide and the published cases of hepatotoxicity of this drug are reviewed.

The rapid development of molecular toxicology is providing innovative approaches to an improved investigation and recognition of toxic substances. Proteome analysis offers, with 2DE/MS (two-dimensional gel electrophoresis and mass spectrometry) and SELDI (surface enhanced laser desorption/ionisation), a promising discipline to classify molecular changes caused by toxic exposure. The Rat Liver Foci Bioassay (RLFB) is a detailed, well-described model for the investigation of liver carcinogenesis induced by chemical substances. Based on this model, we examined whether proteomic methods of molecular toxicology can be used for the early recognition of toxic and/or carcinogenic characteristics of toxic substances. In addition, identification and subsequent prevalidation of new hepatocellular biomarkers was performed, enabling better prediction of toxic and/or carcinogenic effects. This could lead to a more meaningful RLFB and thus to an improved risk assessment of chemicals. 2DE analysis in this study showed that deregulated proteins are assigned to mainly anabolic and catabolic metabolism pathways in the cell. Beyond this, individual proteins were identified which play a key role in the carcinogenic process. A comparison of the differentially expressed proteins in tissue from tumour-bearing animals and tissue derived from the start of the study revealed that protein expression changes (biomarkers) were already detectable shortly after exposure. In addition, analysis by SELDI clearly showed several differentially expressed proteins and/or derived masses. The spectra represented specific differences in tissues, which could be assigned to the same histopathological endpoints. With bioinformatics analysis it was possible to identify individual discriminating mass peaks, which were indicative of tumour formation. Group specific changes can be illustrated and/or represented in more detail with further cluster analysis methods. These results give hope for an improved prediction of hepatotoxicity and carcinogenicity by means of protein markers, which could in the future lead to a shortening of carcinogenicity studies and to a reduction in the use of experimental animals.

Background: Controlled hypotension (CH) is an established method to reduce intraoperative bleeding. The aim of the study was to investigate the influence of CH induced by sodium nitroprusside (SN) or esmolol on hepatocellular integrity., Methods: Prospective, randomized, controlled study. 45 patients scheduled for elective endonasal sinus surgery were allocated to one of the following three groups: 1. SN-group (n = 15): CH induced by SN. 2. Esmolol-group: CH induced by esmolol. In both groups mean arterial pressure was kept between 50-55 mmHg. 3. Control group (n = 15): no hypotension was performed (MAP > 70 mmHg). The cytosolic liver enzyme alpha-glutathione S-transferase (alpha-GST) and standard liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) were measured at the following timepoints: preoperative (T0), at the end of surgery (T1), 2 h (T2), 24 h (T3) and 48 h (T4) postoperatively., Results: alpha-GST concentrations were significantly higher in patients receiving CH (SN: 5.9 +/- 3.4; Esmolol: 6.5 +/- 2.8 microg/L) in comparison with controls (2.5 +/- 1.4 microg/L) at T1. Already at T2 there were no significant differences between the three groups. Standard liver enzymes showed a similar course in all groups., Conclusion: The small but significant increase of alpha-GST in both hypotension groups suggests that hypotension induces a mild damage of hepatocellular integrity.

The liver is essential for metabolism of drugs and exogenous toxins. Therefore, liver toxicity due to natural, domestic and industrial toxins or drugs is common but rarely recognised. Although thorough epidemiological data are missing, the number of cases with drug-induced liver toxicity is increasing, parallel to the growing number of drugs. Adverse hepatic reactions may present as acute or chronic liver damage. Independent from the cause and mechanism of liver damage, the clinical presentation may be either cytolytic or cholestatic. In addition, liver damage may be accompanied by a systemic hypersensitivity reaction against the applied agent. Drug- or toxin-induced liver damage includes vascular damage, induction of liver tumours and development of liver cirrhosis. The prerequisite for specialised treatment of drug-induced adverse hepatic reactions is establishing the diagnosis which is obtained by a thorough medical history taken by an experienced physician with a special emphasis on drug or toxin exposure. The diagnosis may be confirmed by additional diagnostic measures (e. g. liver biopsy) or the clinical course after exposure to the causing agent has been stopped. Only in a minority of cases a definite treatment may be available. Therefore, the main aim is to prevent chronic liver damage through early and correct diagnosis. Due to the extensive variety of possibly liver toxic drugs and chemical agents this aspect is a major challenge to physicians.

Purpose: Development and evaluation of a new photodynamic treatment technique for the laser therapy of liver malignancies, Material and Methods: The combination with new catheter systems enables the use of the photodynamic therapy (PDT) to treat also tumors in parenchymal organs. So far it is mainly used to treat superficial or endoluminal tumors. The presented study is part of a multicenter phase I-study. We treated 5 patients with colorectal liver metastases with the new photosensitizer SQN 400 and following interstitial photodynamic laser treatment. Evaluation of tumors were performed by contrast-enhanced CT scans., Results: In the contrast enhanced CT scans the development of a complete necrosis within a radius of 1 cm around every single fibre could be shown. Additional the ablation of tumors with the combined use of several fibres is possible. Severe complications or toxicities were not observed., Conclusion: The photodynamic laser therapy of liver malignancies is a minimal invasive procedure with little side effects which produces sharply defined yet small volumes of necrosis.

Pancreatectomy for pancreatic carcinoma makes high demands on the perioperative anesthesiologic management of these patients. This survey is centered on pathophysiological reflections related to the choice of the anesthesia and accompanying therapy, concerning the pathological mechanisms of intra- and postoperative complications. The influences of the surgical as well as the anesthesiological procedure on the autonomous nervous system and splanchnic blood flow, the organo-specific consequences of the resection and the possible influences on the immune system are discussed. Recommendations for perioperative medical care of these patients are derived from it. Central points are an anesthesiologic management adapted to the patient with regard to pathophysiological changes caused by surgery, monitoring and therapy of the disturbed fluid balance, postoperative intensive care as well as an optimal pain treatment.

Glucocorticoids are known to increase blood glucose levels, and an impairment of glucose tolerance is a common side effect of glucocorticoid therapy and a central feature of Cushing's disease. A major pathophysiological event in this process is an increased glucose production of the liver on the basis of glucocorticoid-induced insulin resistance resulting in an increment in hepatic gluconeogenesis. Both, glucocorticoids and insulin are known to affect the expression of the two gluconeogenic key enzymes, phosphoenolpyruvate-carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). While glucocorticoids are known to stimulate the expression of the PEPCK- and G6Pase gene, insulin decreases hepatic glucose production through an inhibition of PEPCK- and G6Pase gene expression. Recently, considerable progress has been made in the understanding of the signal transduction involved in the glucocorticoid- and insulin-dependent regulation of hepatic gluconeogenesis. In this article, we will review the most recent advances and assemble the current knowledge into a clinically relevant pathophysiological model.

For hundreds of years butterbur (Petasites hybridus) has been used against many diseases. Modern indications are the prophylaxis of migraine, tension headache, spasms of the urogenital tract, gastro-intestinal tract and bile duct and hopefully hay fever and asthma in the near future. The petasines, the main components of butterbur, inhibit the synthesis of leucotrienes and decrease the intracellular concentration of calcium which explains the anti-inflammatory and spasmolytic properties of extracts of butterbur. Thanks to extraction with supercritical CO(2) the concentrations of the potentially hepatotoxic and carcinogenic pyrrolizidine alkaloids lie below the detection limits. Until now four cases of a reversible cholestatic hepatitis have been probably associated with long-term administration of butterbur (incidence of 1:175.000). It is unknown which components of butterbur are responsible for the long-term hepatotoxicity. Further side effects involve the gastrointestinal tract and are usually mild., (Copyright 2003 S. Karger GmbH, Freiburg)

History: A 46-year-old woman presented for an emergency admission because of colic-like upper abdominal pain and markedly impaired general condition. Eight days before admission she had started and continued to take pantoprazole because of symptoms of gastroesophageal reflux., Investigations: Clinical examination and laboratory tests indicated abnormal liver functions suggesting hepatitis. Serology largely excluded an infectious, autoimmunological or metabolic cause. Duplex sonography gave no evidence of bile obstruction or Budd-Chiari syndrome., Diagnosis and Course: The patient's condition and laboratory tests after the drug had been discontinued gradually improved on symptomatic treatment, indicating pantoprazole-induced hepatitis., Conclusion: Intake of proton pump inhibitors is a rare cause but should be considered in the differential diagnosis of hepatitis of uncertain etiology.

A 71-year-old man with chronic atrial fibrillation was treated with aspirin because of a right cerebral infarction. Oral anticoagulation was not initiated because of a secondary hemorrhagic transformation. Six years later after a left cerebral transient ischemic attack aspirin was replaced by ticlopidine. Two weeks after starting ticlopidine he experienced abdominal cramps and diarrhea. Also dark urine and gray-colored stools were noticed, so that the patient stopped taking ticlopidine. 40 days after starting ticlopidine he was admitted to our hospital because of cholestatic jaundice. Serum alkaline phosphatase (305 U/l) and gamma GT (143 U/l) were elevated, the total bilirubin was 18.6 mg/dl at peak. GOT and GPT were 2.7 fold increased. After exclusion of a viral infection and autoimmune disease liver biopsy was performed, which showed a centroacinar cholestasis compatible with a drug-induced liver damage. 79 days after discontinuation of the drug laboratory signs of cholestasis had disappeared. In patients in whom long-term therapy with ticlopidine is indicated regularly laboratory tests and clinical examinations should be done to recognize infrequent side effects such as the cholestatic hepatitis in time.

History and Admission Findings: After removal of an herniated intervertebral disc a 49-year-old man had recurrent pain in the lumbar region, treated with diclofenac and flupirtine. 4 months postoperatively he was referred to the author's hospital because of progressive rise in transaminase levels and in cholestasis parameters. Physical examination on admissions was unremarkable, except for jaundice., Investigations: Laboratory tests showed an increases in transaminases (GPT 769 U/l [normal: < 23 U/l], GOT 285 U/l [normal: < 19 U/l]) and in cholestasis-related values (gamma-GT 172 U/l [Norm 6-28 U/l], alkaline phosphatase 207 U/l [normal < 175 U/l], total bilirubin: 2.5 mg/dl [Norm < 1.1 mg/dl]). This corresponded to the histological finding of toxic damage to the liver parenchyma. Viral, autoimmune and metabolic causes had been excluded. DIAGNOSES, TREATMENT AND COURSE: The history as well as laboratory and histological findings indicated diclofenac-induced toxic hepatitis. The drug was discontinued and without any treatment all laboratory values returned to normal within 9 weeks., Conclusion: Diclofenac, a frequently prescribed non-steroid anti-inflammatory drug, is generally thought to be relatively safe. But it can produce toxic hepatitis which may be asymptomatic (but this patient was jaundiced) and may take an unforeseeable course. This should be taken account of by regularly monitoring liver functions.

We report the case of a severe relapsing phenprocoumon-induced hepatitis. The first episode of hepatitis was thought to be caused by another drug (Verapamil). The anticoagulation with Phenprocoumon was therefore continued after healing of liver inflammation. The relapse typically developed after a shorter exposition-time supporting the hypothesis of an allergic etiology. Fortunately we didn't find any cross-reaction between Phenprocoumon and Acenocoumarol. The patient could thus be anticoagulated orally without complications. If long term anticoagulation is absolutely essential, it is reasonable to prescribe a different Coumarin-derivate. In the case of a cross-reaction, the therapy should be continued with low-molecular weight heparin.