Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients.

BACKGROUND: Minimal hepatic encephalopathy (HE) and HE grade 1 (HE1) according to the West Haven criteria have recently been grouped as one entity named-covert HE- (CHE). Data regarding the impact of CHE on health-related quality of life (HRQoL) and sleep quality are controversial. AIM: First, to determine whether CHE affects HRQoL and sleep quality of cirrhotic patients and second, whether minimal HE (MHE) and HE1 affect HRQoL and sleep quality to a comparable extent. METHODS: A total of 145 consecutive cirrhotic patients were enrolled. HE1 was diagnosed clinically according to the West Haven criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to detect MHE. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL and Pittsburgh Sleep Quality Index (PSQI) was applied to assess sleep quality. RESULTS: Covert HE was detected in 59 (40.7%) patients (MHE: n = 40; HE1: n = 19). Multivariate analysis identified CHE (P < 0.001) and female gender (P = 0.006) as independent predictors of reduced HRQoL (CLDQ total score). CHE (P = 0.021), low haemoglobin (P = 0.024) and female gender (P = 0.003) were identified as independent predictors of poor sleep quality (PSQI total score). Results of CLDQ and PSQI were comparable in patients with HE1 and MHE (CLDQ: 4.6 ± 0.9 vs 4.5 ± 1.2, P = 0.907; PSQI: 11.3 ± 3.8 vs 9.9 ± 5.0, P = 0.3). CONCLUSION: Covert HE was associated with impaired HRQoL and sleep quality. MHE and HE1 affected both outcomes to a comparable extent supporting the use of CHE as a clinically useful term for patients with both entities of HE in clinical practice.

[Hepatocellular carcinoma]. / Das hepatozelluläre Karzinom.

Hepatocellular carcinoma (HCC) is a highly malignant tumor and is the most common cause of death in patients with underlying liver cirrhosis. The main risk factor for development of HCC is liver cirrhosis. Because of the increasing frequency of nonalcoholic steatohepatitis, the incidence of HCC is also expected to considerably rise in Western countries in upcoming years. Identification and surveillance of patients at risk is crucial because curative treatment approaches can only be applied at early stages of the disease. Due to underlying liver cirrhosis, therapeutic strategies are limited and require intense interdisciplinary cooperation and multimodal approaches. However, a strong morphological and genetic heterogeneity of HCC remains a major challenge for development of new treatment modalities and demands personalized precision medicine approaches in order to improve patient outcome.

[Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure]. / Kosteneffiziente medikamentöse Therapie der Hepatitis C durch neue Vergütungsmodelle - pay for cure.

Direct acting antivirals (DAAs) have increased cure rates for chronic hepatitis C infection up to nearly 100 %. At the same time treatment costs have risen significantly. Treating all HCV infected patients in Germany with DAAs would generate medication costs ranging between 19 and 37 billion EUR depending on the drug regimen used. Expenses in patients who fail to respond to treatment would amount to approximately 0.9 to 2.15 billion EUR. In difficult to treat patient populations that are characterized by prior failure to treatment or advanced liver disease, lost drug expenses are particularly high due to lower cure rates and longer treatment duration. Outcome-based reimbursement schemes are used to improve the quality of care and to reduce costs in the health care system. In Germany, disease management programs have been implemented for defined chronic diseases. However, drug reimbursement is still based on packages sold (pay for pill). In this context, it would be appealing to link reimbursement and treatment success (pay for cure) in order to reward successful treatment, limit lost drug spending and develop a shared risk environment that would involve all concerned parties. Under the assumption that 20,000 patients with HCV are treated each year in Germany and that cure rates are 95.4 %, the saved treatment costs would amount up to 45 and 107 million EUR per year. By this approach, economic incentives to withhold therapy from difficult to treat patients could be avoided.

New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor.

BACKGROUND: The influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients. METHODS: Data from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included. RESULTS: NODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(±1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (±2.67) years). CONCLUSION: NODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor.

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors.

Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.

[Etiology and complications of liver cirrhosis: data from a German centre]. / Ätiologie und Komplikationen der Leberzirrhose: Daten eines deutschen Zentrums.

BACKGROUND: Liver cirrhosis develops as a terminal complication of chronic liver disease. The clinical course is determined by the underlying etiology and the accompanying risk factors, which are influenced by the geographic and cultural background. METHODS: A total of 236 patients (159 men, 77 women, median age 57 [22-81] years) were included for retrospective analysis between July 2012 and February 2014 using standardized questionnaires during an outpatient visit at a hepatology clinic. RESULTS: The most common etiologies of liver cirrhosis were related to alcohol consumption (52 %), chronic hepatitis C (28 %) or hepatitis B (14 %) infection and NASH (nonalcoholic steatohepatitis, 6 %). At the time of presentation 55 % patients had compensated cirrhosis corresponding to Child-Turcotte-Pugh (CTP) stage A, while 45 % were in a decompensated stage (30 % CTP B and 15 % CTP C). Subgroups were analyzed for the incidence of complications and the emergence of infections. Most frequently esophageal varices (60 %) and ascites (49 %) were observed, followed by pleural effusion (14 %), hepatic encephalopathy (25 %) or hepatorenal syndrome (18 %). 16 % of patients exhibited infection based on clinical criteria. An infective agent was isolated in 38 % of all cases with infection and of those 50 % were gram positive bacteria. In multivariate analysis only the presence of ascites was an independent risk factor for infection. CONCLUSION: Despite improved medical therapies for viral hepatitis, these were the most frequent causes of liver cirrhosis, closely followed by alcoholic cirrhosis. The observed complications included bacterial infection and complication related to portal hypertension.

[Drug-induced liver injury with an autoimmune phenotype following anti-TNF Therapy - presentation of cases and review of literature]. / Medikamentöse Schädigung der Leber mit autoimmunem Phänotyp durch TNF-Blockade - Fallvorstellung und Review der Literatur.

Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-α) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation.

[Therapy of hepatocellular carcinoma]. / Therapie des hepatozellulären Karzinoms.

Today, hepatocellular carcinoma (HCC) represents the leading cause of death in patients with liver cirrhosis; in most western countries the incidence is also expected to increase further. Due to insufficient surveillance of patients at risk, most cases are diagnosed in an intermediate to advanced stage, leading-together with the underlying liver cirrhosis-to limited therapeutic options and a dismal prognosis. Therefore, classification according to stage and interdisciplinary treatment decisions in experienced centers are of paramount importance to provide an individualized treatment plan when considering potentially curative (resection, liver transplantation, local ablation) and palliative (transarterial approaches, sorafenib) treatment options. There is hope that the prognosis of patients with HCC can be improved in the near future by better prevention, stringent surveillance, multimodality treatment approaches, and an expansion of personalized medicine.

Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells.

The endemic occurrence of obesity and the associated risk factors that constitute the metabolic syndrome have been predicted to lead to a dramatic increase in chronic liver disease. Non-alcoholic steatohepatitis (NASH) has become the most frequent liver disease in countries with a high prevalence of obesity. In addition, hepatic steatosis and insulin resistance have been implicated in disease progression of other liver diseases, including chronic viral hepatitis and hepatocellular carcinoma. The molecular mechanisms underlying the link between insulin signaling and hepatocellular injury are only partly understood. We have explored the role of the antiapoptotic caspase-8 homolog cellular FLICE-inhibitory protein (cFLIP) on liver cell survival in a diabetic model with hypoinsulinemic diabetes in order to delineate the role of insulin signaling on hepatocellular survival. cFLIP regulates cellular injury from apoptosis signaling pathways, and loss of cFLIP was previously shown to promote injury from activated TNF and CD95/Apo-1 receptors. In mice lacking cFLIP in hepatocytes (flip(-/-)), loss of insulin following streptozotocin treatment resulted in caspase- and c-Jun N-terminal kinase (JNK)-dependent liver injury after 21 days. Substitution of insulin, inhibition of JNK using the SP600125 compound in vivo or genetic deletion of the mitogen-activated protein kinase (MAPK)9 (JNK2) in all tissues abolished the injurious effect. Strikingly, the difference in injury between wild-type and cFLIP-deficient mice occurred only in vivo and was accompanied by liver-infiltrating inflammatory cells with a trend toward increased amounts of NK1.1-positive cells and secretion of proinflammatory cytokines. Transfer of bone marrow from rag-1-deficient mice that are depleted from B and T lymphocytes prevented liver injury in flip(-/-) mice. These findings support a direct role of insulin on cellular survival by alternating the activation of injurious MAPK, caspases and the recruitment of inflammatory cells to the liver. Thus, increasing resistance to insulin signaling pathways in hepatocytes appears to be an important factor in the initiation and progression of chronic liver disease.

IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma.

IgG4-related disease has gained increased attention worldwide. While the initial focus was on autoimmune pancreatitis which was first described in Asian populations and turned out to be of relevance in Western populations too, the scope has recently broadened towards a notion of a multi-systemic disease with very diverse manifestations such as autoimmune pancreatitis, IgG4-related sclerosing cholangitis (IgG4-SC), retroperitoneal fibrosis and tubulointerstitial nephritis. IgG4-SC (also known as IgG4-associated cholangitis, IAC) represents a rare but clinically challenging differential diagnosis in patients with obstructive jaundice and proximal extra- or intrahepatic biliary strictures which can be mistaken for cholangiocarcinoma (CC). We present the case of a 79-year-old male patient who presented with obstructive jaundice and biliary strictures at the hepatic duct bifurcation without any evidence for autoimmune pancreatitis and without elevation of serum IgG4-concentrations who underwent hemihepatectomy for suspected CC. However, on histological examination of the resection specimen CC could not be confirmed. It was only after several episodes of obstructive jaundice had reoccurred that the diagnosis of IgG4-SC could be established by reexamination of the surgical specimen which showed extensive infiltration with IgG4-positive plasma cells. Appropriate medical treatment with steroids and azathioprine led to complete remission of the disease. Early recognition of IgG4-SC can save patients from potential harmful and unnecessary surgical interventions. Here we describe the clinical features of this rare case of IgG4-SC with extensive liver tissue infiltration with IgG4-positive cells but without elevated serum IgG4 concentration or evidence of autoimmune pancreatitis. We describe diagnostic criteria for IgG4-SC and review recent insights in pathophysiology and treatment options.

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels--a study in twins.

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD.