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Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice
(2016)
Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.
Objectives
Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers.
Methods
Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH.
Results
The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91%) and specificity (83%).
Conclusions
Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.
Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment
(2014)
Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14% to 27% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD).
Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013.
Results: The term “non-alcoholic fatty liver disease” covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steatohepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5% to 20% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10% to 20% of cases. In fewer than 5% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05% to 0.3% for the prevalence of cirrhosis in the general population. About 2% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82% to 90% and a negative predictive value of 88% to 93%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition.
Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3% to 5%.
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.
Background:
Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed. DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades, ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic anemia (IHA) has especially been reported to cause severe complications and fatal outcomes.
Case Presentation:
A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks. Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune hemolytic (DIIHA) anemia to ceftriaxone could be confirmed.
Conclusions:
The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for this complication must be raised among treating physicians.
Background
Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients.
Methods
The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores.
Results
At the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m\(^{2}\)) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT.
Conclusion
Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.
Objective
At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by \(^{13}\)C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate.
Methods
A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. Statistical analysis: variance analyses, bivariate correlation, and multilinear regression analysis.
Results
After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). \(^{13}\)CO\(_{2}\) exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated \(^{13}\)CO\(_{2}\)-generation under these conditions.
Conclusion
Quantification of \(^{13}\)C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. \(^{13}\)C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance
(2016)
Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.
Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 % of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 % in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.