[Drug-induced liver injury-significance of pathology]. / Drug-Induced Liver Injury ­ Stellenwert der Pathologie.

Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.

Metaproteomics of fecal samples of Crohn's disease and Ulcerative Colitis.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic inflammatory bowel diseases (IBD) of the gastrointestinal tract. This study used non-invasive LC-MS/MS to find disease specific microbial and human proteins which might be used later for an easier diagnosis. Therefore, 17 healthy controls, 11 CD patients and 14 UC patients but also 13 Irritable Bowel Disease (IBS) patients, 8 Colon Adenoma (CA) patients, and 8 Gastric Carcinoma (GCA) patients were investigated. The proteins were extracted from the fecal samples with liquid phenol in a ball mill. Subsequently, the proteins were digested tryptically to peptides and analyzed by an Orbitrap LC-MS/MS. For protein identification and interpretation of taxonomic and functional results, the MetaProteomeAnalyzer software was used. Cluster analysis and non-parametric test (analysis of similarities) separated healthy controls from patients with CD and UC as well as from patients with GCA. Among others, CD and UC correlated with an increase of neutrophil extracellular traps and immune globulins G (IgG). In addition, a decrease of human IgA and the transcriptional regulatory protein RprY from Bacillus fragilis was found for CD and UC. A specific marker in feces for CD was an increased amount of the human enzyme sucrose-isomaltase. SIGNIFICANCE: Crohn's Disease and Ulcerative Colitis are chronic inflammatory diseases of the gastrointestinal tract, whose diagnosis required comprehensive medical examinations including colonoscopy. The impact of the microbial communities in the gut on the pathogenesis of these diseases is poorly understood. Therefore, this study investigated the impact of gut microbiome on these diseases by a metaproteome approach, revealing several disease specific marker proteins. Overall, this indicated that fecal metaproteomics has the potential to be useful as non-invasive tool for a better and easier diagnosis of both diseases.

Patients with ultrasound diagnosis of hepatic steatosis are at high metabolic risk.

Background and aims: Hepatic steatosis is the basis of non-alcoholic fatty liver disease (NALFD). Mere fat accumulation within hepatocytes is considered the mild form of NAFLD, but can progress in some patients to advanced steatohepatitis (NASH), which may lead to fibrosis, cirrhosis or hepatocellular carcinoma. However, even hepatic steatosis alone may be a risk factor for cardiovascular disease (CVD). Patients and methods: In the present real life study 106 patients from the outpatient clinic of the Department for Gastroenterology and Hepatology with either NAFLD (n = 60) or other typical diagnoses (n = 46) were included. Ultrasound examination identified 77 patients with hepatic steatosis. Liver enzymes, lipid profile, surrogate cell death markers, and adiponectin were determined. Transient elastography (Fibroscan®) and bioelectrical impedance analysis (BIA) were performed. Results: Mean patient age was 46 years (23 - 62) for non-NAFLD and 53 years (18 - 71) for the NAFLD group. ALT and AST did not differ significantly between the two groups. Adiponectin and HDL were significantly lower in NAFLD (p < 0.05) and BIA profiles showed higher fat and fat free mass. Non-NAFLD patients with steatosis also exhibited an adverse metabolic profile. Overall steatosis was associated with factors of metabolic syndrome (MS) and CVD. Prevalence of CVD and factors of MS hint to steatosis as an early event for these conditions. Conclusion: Patients with steatosis are at higher cardiovascular and metabolic risk without differences in transaminases levels compared to those without steatosis. Steatosis diagnosed by ultrasound needs to rise attention for further metabolic alterations including CVD.

Multimodal therapy of recurrent and refractory bleeding from esophageal varices - case report and review of the literature.

Bleeding from esophageal varices is a major cause of mortality in patients with advanced liver disease. Although standard treatment and secondary prophylaxis are effective, in some patients sustained hemostasis cannot be achieved. We report the case of a woman with alcoholic liver disease in whom pharmacological, endoscopic, and intravascular therapies failed to control variceal bleeding. Only a combination of (repeated) band ligation, insertion of a self-expanding metal stent, TIPS implantation and redilatation, transjugular variceal embolization, and finally implantation of a portocaval shunt proved to be successful. We discuss the stepwise approach to this situation and the challenges encountered in the process.

[Hepatic steatosis : Differential diagnostics and current aspects]. / Hepatische Steatosen : Differenzialdiagnostik und aktuelle Aspekte.

The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed.

The diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and frequently accompanied with obesity, insulin resistance, hyperlipidemia and hypertension. NAFLD comprises a variety of clinical conditions ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), with significant hepatic injury and possible progression to cirrhosis and hepatocellular carcinoma. The traditional "second hit" and the recent "multiple parallel hit" theories are the most popular explanations for the pathogenesis of NASH. NAFLD is usually diagnosed by ultrasonographic examination of the liver. For specific diagnosis of the extent and severity of NAFLD, in particular to determine NASH, the gold standard is still liver biopsy. Though, there are some promising non-invasive markers emerging for NAFLD diagnosis and assessment. Currently there is no specific therapy for NAFLD or NASH itself. Thus management of NAFLD mainly relies on initiating weight loss and on treatment of accompanying factors e.g. insulin resistance, hypertension or hyperlipidemia. In the present overview we aimed to summarize options for diagnosis and treatment of NAFLD and NASH based on the current literature.

[Cytokeratin 18 as marker for non-invasive diagnosis and prognosis of acute and chronic liver diseases]. / Zytokeratin-18 als Marker zur nichtinvasiven Diagnostik und Prognose akuter und chronischer Lebererkrankungen.

INTRODUCTION: Currently liver biopsy represents the gold standard to assess severity and fibrosis grade in liver diseases. Since this laborious, costly, and invasive procedure is associated with possible complications, non-invasive methods and biomarkers, which allow for an easy, reliable, and repeatable assessment of liver disease are warranted. Cytokeratin (CK) 18 is an intermediary filament protein, expressed in hepatocytes, which is proteolytically cleaved during liver damage. The resultant CK-18 fragments are released by hepatocytes and can be detected in serum. METHODS: A selective literature search in PubMed for original publications about the detection of CK-18 cell death markers in liver diseases was undertaken. RESULTS: Assessment of CK-18 cell death biomarkers allows for the early detection of liver damage in acute and chronic liver diseases. This is even feasible when transaminases are in the normal ranges. Detection of CK-18 biomarkers can also hint at disease activity and severity. For example, patients with non-alcoholic steatohepatitis exhibit elevated serum cell-death markers compared to those with simple steatosis. Furthermore, in patients with relevant fibrosis higher CK-18 values are found as compared to those with low fibrosis. In acute liver failure, cell death biomarkers may assist decision finding for the necessity of liver transplantation. DISCUSSION: Due to promising results of various studies, CK-18 cell death markers could be applied in clinical routine soon.

Adiponectin attenuates osteolysis in aseptic loosening of total hip replacements.

Joint replacements have a longer durability in patients with high serum levels of adiponectin (APN) than in patients with low levels. We aimed to characterize the unknown pathophysiological effects of APN on wear particle-induced inflammation, apoptosis and osteolysis. Immunohistochemistry was performed to detect APN, its receptors and apoptosis in patients with and without aseptic loosening. Additionally, APN knockout mouse studies and pharmacological intervention of APN were performed in an established calvarial mouse model. Osteolysis and inflammation were quantified by histomorphometry and microcomputed tomography, apoptosis by immunohistochemistry and TUNEL assay. In a cell culture model, human monocyte-derived macrophages were incubated with or without metal wear debris particles and partially treated with APN. Expression of APN, AdipoR1 and calreticulin in specimens from patients with aseptic loosening were significantly higher than in patients without aseptic loosening. Administration of APN in mice significantly reduced wear particle-induced inflammation, osteolysis and the number of caspase-3-positive macrophages. The cell culture model showed that APN leads to significantly lower values of TNF-α. These findings support a prominent role of APN in the development of particle-induced osteolysis and APN may be therapeutically useful in patients with aseptic loosening.

[Liver parameters in intensive care medicine]. / Leberparameter in der Intensivmedizin.

Elevated liver function tests in ICU-bound patients are associated with a greater risk of mor-tality. Chronic liver diseases as well as acute events and complications of therapy are among the causes. The disorder could further be investigated by assessment of liver cell integrity markers (AST, ALT and GLDH), cholestasis parameters -(bilirubin, GGT, ALP) and liver synthethic function (albumin, coagulation profile). Ultrasound and elastography are cheap and mobile options to evaluate chronic liver disease, cholestasis or perfusion of the liver. The interpretation of the results should include the medical history on the ICU. Liver injury could be due to septic or isch-aemic complications as well as toxic side effects or parenteral nutrition. The main therapeutic option is to identify the cause of the liver dysfuntion and to eliminate it as far as possible.

Acute management of refractory variceal bleeding in liver cirrhosis by self-expanding metal stents.

BACKGROUND AND AIMS: Current treatment strategies of variceal bleeding (VB) include banding and sclerotherapy. However, up to 10% of bleeding events remain refractory to standard therapy with high mortality. With this study, we aimed to evaluate the implantation of self-expanding metal stents (SEMS) for the management of therapy-refractory variceal bleeding. PATIENTS AND METHODS: Eight cirrhotic patients who presented to our unit with a total of 9 refractory bleeding events were treated by SEMS placement. RESULTS: Stenting resulted in immediate hemostasis in all cases without recurrent bleeding with SEMS in situ. After stabilization, 1 patient was treated by transjugular intrahepatic portosystemic shunt (TIPS) and after the second bleeding episode by TIPS dilation. One patient underwent orthotopic liver transplantation (OLT). The remaining patients were treated with standard drug regimens to reduce portal pressure. The SEMS were removed after a median of 11 days. No acute hemorrhage was noted on stent retrieval. While no early rebleeding occurred in the patients after TIPS implant, TIPS dilation or OLT, 3 out of 5 patients on conservative treatment experienced recurrence of VB within 9 days after SEMS removal. CONCLUSIONS: SEMS placement sufficiently stops hemorrhage in refractory VB. Due to the high rebleeding rate after conservative treatment alone following SEMS removal, this procedure may be utilized as a mere bridging method. Additional interventional and/or surgical methods to effectively reduce portal pressure (i.e. TIPS, OLT) should be considered. Further studies to evaluate the optimum treatment algorithm of refractory esophageal VB are warranted.

Excessive bilirubin elevation in a patient with hereditary spherocytosis and intrahepatic cholestasis.

Hereditary spherocytosis is a common hemolytic anemia with an estimated incidence of 1 / 2500 births. It is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton. Mutations in the ABCB11 gene, encoding the bile salt export pump, can entail progressive familial intrahepatic cholestasis and benign recurred intrahepatic cholestasis. A 18 year old Turkish patient with hereditary spherocytosis was admitted to hospital with pruritus and severe jaundice. Ultrasound examination presented stones in gallbladder and bile duct. After endoscopic retrograde cholangiography with extraction of small bile duct stones abdominal pain resolved and liver enzymes normalized within a few days, but bilirubin and bile acids remained highly elevated. Liver biopsy revealed a severe canalicular cholestasis. Genetic analysis showed the compound heterozygous variants ABCB11 A 444V and 3084A > G. Treatment with ursodesoxycholic acid and intermittent therapy with prednisone reduced pruritus and jaundice with concomitant improvement of blood test. Here we report the first case of a patient with combined hereditary spherocytosis and compound heterozygous ABCB11 gene variants predisposing to intrahepatic cholestasis. Therefore, patients with hemolytic disorders should be investigated for bile acid transporter diseases in case of hyperbilirubinemia and severe cholestasis.

Glutathione-S-transferase subtypes α and π as a tool to predict and monitor graft failure or regeneration in a pilot study of living donor liver transplantation.

OBJECTIVE: Glutathione-S-transferase (GST) subtype α and π are differentially expressed in adult liver tissue. Objective of the study was if GST α and π may serve as predictive markers for liver surgery, especially transplantations. METHODS: 13 patients receiving living donor liver transplantation (LDLT) and their corresponding donors were analyzed for standard serum parameters (ALT, AST, γGT, bilirubin) as well as GST-α and -π before LDLT and daily for 10 days after LDLT. Patients (R) and donors (D) were grouped according to graft loss (R1/D1) or positive outcome (R2/D2) and above named serum parameters were compared between the groups. RESULTS: R1 showed significantly increased GST-α and significantly lower GST-π levels than R2 patients or the donors. There was a positive correlation between GST-α and ALT, AST as well as bilirubin and a negative correlation to γGT. However, γGT correlated positively with GST-π. Graft failure was associated with combined low GST-π levels in donors and their recipients before living donor liver transplantation. CONCLUSION: Our data suggest that high GST-α serum levels reflect ongoing liver damage while GST-π indicates the capacity and process of liver regeneration. Additionally, GST-π may be useful as marker for optimizing donor and recipient pairs in living donor liver transplantation.

Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C.

Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.

A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review.

The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter ß-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure.

Crohn's disease-induced non-alcoholic fatty liver disease (NAFLD) sensitizes for severe acute hepatitis B infection and liver failure.

Non-alcoholic fatty liver disease (NAFLD) commonly is associated with chronic inflammatory bowel disease (CIBD) and usually is considered to be stable and benign. However, NAFLD -- and in particular its subset, non-alcoholic steatohepatitis (NASH) -- may lead to progressive liver disease. Moreover, NAFLD sensitizes the liver to injury and increases the risk of developing acute-on-chronic liver failure following a "third hit". We here present one patient with NASH, as probably induced by long-standing Crohn's disease in the absence of ethanol consumption or abuse. The patient acquired an acute HBV infection and died from complications. As based on the clinical and histological findings, Crohn's disease appears to be a risk factor for developing NAFLD and thus to contribute to the progression into NASH. In conclusion, we suggest that Crohn's disease-related NAFLD may increase the vulnerability of the liver, which indicates that patients with a known history of CIBD merit special attention.

The relationship between apoptosis and non-alcoholic fatty liver disease: an evolutionary cornerstone turned pathogenic.

The data currently available favor a model for the pathogenesis of non-alcoholic fatty liver disease that is based on an apparent sequential relationship of intrahepatic apoptosis, inflammation and fibrogenesis. Based on both hepatic and peripheral insulin resistance, the hepatocellular accumulation of triglycerides, termed steatosis, initially leads to an altered metabolism of glucose and free fatty acids in the liver. In response, increased expression of death receptors in simple steatosis enhances the hepatocytes' susceptibility for pro-apoptotic stimuli, thus eliciting excessive hepatocyte apoptosis and inflammation. Evidence indicates that these processes, if prolonged, activate both hepatic stellate and Kupffer cells, thus leading to a vicious circle in which apoptosis, inflammation, cellular activation, and collagen deposition are upregulated even further.

Persistently altered visceral perception after resection of an esophageal granular cell myoblastoma: a therapeutic concept revisited.

Granular cell tumors (GCTs) are rare and usually benign gastrointestinal tumors. Their most frequent symptoms are dysphagia and epigastric or retrosternal discomfort. We here report a case of esophageal GCT with continued symptoms of retrosternal discomfort, postprandial feeling of fullness, and early satiety despite complete thoracoscopic resection of the tumor. In contrast, all functional tests were in the normal range. We thus suggest that, due to their neuroectodermal origin, GCTs may affect neuronal alterations leading to a persistently disturbed visceral mechanosensory perception. Consequently, this case also cautions the therapeutic concept to solely relieve GCT symptoms by resection if the tumor is less than 20 mm in diameter.

[Sonography and scintigraphy in the diagnosis of cystadenolymphomas (warthin tumor)]. / Wertigkeit der Szintigraphie und der Sonographie in der Diagnostik der Zystadenolymphome der Glandula parotis.

BACKGROUND: Is scintigraphy in the preoperative diagnosis of cystadenolymphomas dispensable? PATIENTS AND METHODS: In this prospective study 35 patients with tumors of the parotid gland were examined sonographically and scintigraphycally and the results were compared with the histological findings. RESULTS: By means of sonography 88 % (22/25) of the cystadenolymphomas were correctly diagnosed and by means of scintigraphy 80 % (20/25). CONCLUSIONS: Sonography is recommendable as the first-line diagnostic procedure in cystadenolymphomas because it is without radiation load, the free choice of the echographic plane, and it can be repeated as often as desired. Scintigraphy adds in selected cases, as in elder patients, additional informations. The combination of sonography and scintigraphy confirms the presence of cystadenolymphoma and allows the surgeon to make a decision and to avoid surgery especially in high-risk patients.

[Generalized pustulous psoriasis: A novel extraintestinal manifestation of Crohn's disease?]. / Psoriasis pustulosa generalisata: neue extraintestinale Manifestation des Morbus Crohn?

A 66-year-old female patient suffering for 10 years from Crohn's disease firstly presented with a parallel outbreak of generalized pustulous psoriasis and Crohn's disease. A second synchronous exacerbation of both disorders occurred after discontinuation of treatment with prednisolone, methotrexate, and mesalazine. As to their pathogenetic concepts, both disease entities reveal similar immunologic alterations, i. e. comparable patterns of cytokines, chemokines, and inflammatory cells (T cells and neutrophils). Generalized pustulous psoriasis, therefore, might develop as hitherto undescribed, more rare extraintestinal manifestation of Crohn's disease.