Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites

Intestinal stenosis in Crohn's disease shows a generalized upregulation of genes involved in collagen metabolism and recognition that could serve as novel anti-fibrotic drug targets

Background and Aims: Crohn's disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. Methods: Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. Results: mRNA expression of collagen type I (COL1A1, 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III (COL3A1, 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. Conclusion: Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen

Cytoplasmic cleavage of IMPA1 3' UTR is necessary for maintaining axon integrity

The 3′ untranslated regions (3′ UTRs) of messenger RNAs (mRNAs) are non-coding sequences involved in many aspects of mRNA metabolism, including intracellular localization and translation. Incorrect processing and delivery of mRNA cause severe developmental defects and have been implicated in many neurological disorders. Here, we use deep sequencing to show that in sympathetic neuron axons, the 3′ UTRs of many transcripts undergo cleavage, generating isoforms that express the coding sequence with a short 3′ UTR and stable 3′ UTR-derived fragments of unknown function. Cleavage of the long 3′ UTR of Inositol Monophosphatase 1 (IMPA1) mediated by a protein complex containing the endonuclease argonaute 2 (Ago2) generates a translatable isoform that is necessary for maintaining the integrity of sympathetic neuron axons. Thus, our study provides a mechanism of mRNA metabolism that simultaneously regulates local protein synthesis and generates an additional class of 3′ UTR-derived RNAs

Barriers That Obstruct Return to Work After Coronary Bypass Surgery:A Qualitative Study

Coronary artery bypass grafting is the most frequently performed cardiac surgical procedure. Despite its benefits on survival and quality of life, it is associated with a considerable financial burden on society including sick leave. Our study aimed to explore the barriers that obstruct return to work after coronary artery bypass grafting. We performed a qualitative study with in-depth interviewing of patients 6 months after their surgery. We included ten working patients and interviewed them and their spouses at home. The interviews were transcribed and two investigators independently searched the transcriptions for barriers that had obstructed return to work. Based on the interviews we were able to distinguish four main groups of barriers: 'personal', 'healthcare', 'work' and 'law & regulation.' The personal barriers were subgrouped in affective, physical, cognitive, social and individually determined factors. Conclusion In a qualitative study we showed that personal barriers as well as barriers regarding healthcare, work and law & regulation, were perceived by patients as important factors obstructing return to work after coronary artery bypass grafting. To overcome the identified barriers, the process of return to work could preferably be initiated during the hospital phase, started during cardiac rehabilitation, and coordinated by a case-managing professional

Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis

AIM: To review the current literature for the specific clinical characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC). METHODS: A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for "primary sclerosing cholangitis" in Pubmed. "Clinical characteristics" were specified into five predefined subthemes: epidemiology of IBD in PSC, characteristics of IBD in PSC (i.e., location, disease behavior), risk of colorectal cancer development, IBD recurrence and de novo disease after liver transplantation for PSC, and safety and complications after proctocolectomy with ileal pouchanal anastomosis. Papers were selected for inclusion based on their relevance to the subthemes, and were reviewed by two independent reviewers. Only full papers relevant to PSC-IBD were included. Additionally the references of recent reviews for PSC (<5 years old) were scrutinized for relevant articles. RESULTS: Initial literature search for PSC yielded 4704 results. After careful review 65 papers, comprising a total of 11406 PSC-IBD patients, were selected and divided according to subtheme. Four manuscripts overlapped and were included in two subthemes. Prevalence of IBD in PSC shows a large variance, ranging from 46.5% to 98.7% with ulcerative colitis (UC) being the most common type (> 75%). The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis. Although IBD in PSC is found to be a quiescent disease, pancolitis occurs often, with rates varying from 35% to 95%. Both backwash ileitis and rectal sparing are observed infrequently. The development of dysplasia or colorectal carcinoma is increased in PSC-IBD; the cumulative 10 years risk varying between 0% and 11%. Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in 1.3% to 31.3% of PSC-IBD patients. The risk for development of pouchitis in PSC-IBD is found to be significant, affecting 13.8% to 90% of the patients after proctocolectomy with ileo anal-pouch anastomosis. CONCLUSION: IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn's disease and therefore requires specialized management

Does postoperative cognitive decline after coronary bypass affect quality of life?

OBJECTIVE: This study aimed to explore the influence of coronary artery bypass grafting (CABG) on both postoperative cognitive dysfunction and quality of life (QoL) and the association between the two patient-related outcomes. METHODS: In a prospective, observational cohort study, patients with elective, isolated CABG were included. Cognitive function was assessed using the Cogstate computerised cognitive test battery preoperatively, 3 days and 6 months after surgery. QoL was measured preoperatively and at 6 months using the RAND-36 questionnaire including the Physical Component Score (PCS) and the Mental Component Score (MCS). Regression analysis, with adjustment for confounders, was used to evaluate the association between postoperative cognitive dysfunction and QoL. RESULTS: A total of 142 patients were included in the study. Evidence of persistent cognitive dysfunction was observed in 33% of patients after 6 months. At 6 months, the PCS had improved in 59% and decreased in 21% of patients, and the MCS increased in 49% and decreased in 29%. Postoperative cognitive changes were not associated with QoL scores. CONCLUSIONS: Postoperative cognitive dysfunction and decreased QoL are common 6 months after surgery, although cognitive function and QoL were found to have improved in many patients at 6 months of follow-up. Impaired cognitive function is not associated with impaired QoL at 6 months. TRIAL REGISTRATION NUMBER: NCT03774342

Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation:study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial

INTRODUCTION: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally. METHODS AND ANALYSIS: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00–3:59 hour) or to the control arm (4:00–15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation. TRIAL REGISTRATION NUMBER: NL8740

Branched chain amino acids are associated with metabolic complications in liver transplant recipients

Background: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. Methods: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. Results: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P &lt; 0.001) and T2D (P = 0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18–2.20, P = 0.003) for MetS and 1.60 (95%CI: 1.14–2.23, P = 0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P = 0.002). Conclusion: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx.</p

Branched Chain Amino Acids are associated with Metabolic Complications in Liver Transplant Recipients

BACKGROUND: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. METHODS: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. RESULTS: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P<0.001) and T2D (P=0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18-2.20, P=0.003) for MetS and 1.60 (95%CI: 1.14-2.23, P=0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P=0.002). CONCLUSION: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx