Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity, type 2 diabetes mellitus and dyslipidemia, with a global prevalence of 25%. NAFLD arises when the uptake of fatty acids (FA) and triglycerides (TG) from circulation and de novo lipogenesis saturate the rate of FA β-oxidation and very-low density lipoprotein (VLDL)-TG export. Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH, and therefore, alterations in liver and serum lipidomic signatures are good indicators of the disease's development and progression. This review focuses on the importance of the classification of NAFLD patients into different subtypes, corresponding to the main alteration(s) in the major pathways that regulate FA homeostasis leading, in each case, to the initiation and progression of NASH. This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments

Class III obesity is a risk factor for the development of acute on chronic liver failure in patients with decompensated cirrhosis

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes to ACLF development in patients with decompensated cirrhosis. METHODS: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (BMI < 30), obese class I-II (BMI 30-39.9) and obese class III (BMI≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence. RESULTS: Among 387,884 with decompensated cirrhosis, 116,704 patients (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (HR=1.24, 95% CI 1.09-1.41, p<0.001). This finding was confirmed using the NIS (OR=1.30, 95% CI 1.25-1.35, p<0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had greater prevalence of renal failure. CONCLUSION: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly higher prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF. LAY SUMMARY: In this study, we identify that among patients with decompensated cirrhosis, class III obesity is a modifiable risk factor for the development of acute on chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent among obese patients, particularly class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure

Intravitreal triamcinolone acetonide: Pattern of secondary intraocular pressure rise and possible risk factors

Ziad F Bashshur1, Abdallah M Terro1, Christelle P El Haibi1, Akaber M Halawi1, Alexandre Schakal2, Baha&amp;rsquo; N Noureddin11The Department of Ophthalmology, American University of Beirut, Lebanon; 2The Department of Ophthalmology, Hotel Dieu de France (St. Joseph University), LebanonPurpose: To determine the pattern of increase in intraocular pressure (IOP) following intravitreal triamcinolone acetonide (IVTA) and identify possible risk factors associated with this rise in IOP.Methods: We carried out a retrospective review of records for 185 patients (226 eyes) who received 4 mg of IVTA at the American University of Beirut Medical Center and Hotel Dieu de France eye clinics between 2003 and 2005.Results: Mean follow-up was 8.17 months (range 6 to 24 months). The mean number of IVTA injections per eye was 1.31 &amp;plusmn; 0.69. The mean IOP increased after the first IVTA injection from 15.04 &amp;plusmn; 3.18 mmHg at baseline to a mean maximum of 17.20 &amp;plusmn; 5.75 mmHg (p &amp;lt; 0.0001, paired t-test) at month 3 of follow-up with a return to mean baseline IOP (15.49 &amp;plusmn; 4.79 mmHg) at month 12. Fifty nine of 226 eyes showed IOP higher than 21 mmHg during follow-up. Nine eyes started to have IOP greater than 21 mmHg, 6 to 12 months after a single injection. Intraocular pressure lowering medications were started when IOP exceeded 25 mmHg in 15 of the 226 eyes studied. No risk factors have been found to predict this IOP rise.Conclusions: IOP elevation can occur in a significant number of eyes receiving 4 mg of IVTA. This phenomenon seems to be transient and a small number of eyes required treatment during this period. Eyes that received IVTA need to be monitored for IOP changes especially during the first 3 months, but the IOP may still rise 6 months and even 12 months after a single injection. This study did not show any risk factor that may predict this IOP rise.Keywords: intravitreal triamcinolone acetonide, intraocular pressure elevation, diabetic macular edema, choroidal neovascular membrane due to age-related macular degeneration, central retinal vein occlusion, Branch retinal vein occlusion, Uveiti

Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats

Background. This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). Methods. Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham-operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. Results. ACF- induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. Conclusions. This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Background and Aims We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL–apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6, and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Conclusions Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratificatio

Occurrence of liver cirrhosis in England, a cohort study, 1998-2009: a comparison with cancer

OBJECTIVES: There is no routine registration of the occurrence of newly diagnosed cases of cirrhosis in the United Kingdom. This study seeks to determine precise estimates and trends of the incidence of cirrhosis in England, and directly compare these figures with those for the 20 most commonly diagnosed cancers in the United Kingdom. METHODS: We used the Clinical Practice Research Datalink and linked English Hospital Episode Statistics to perform a population-based cohort study. Adult incident cases with a diagnosis of cirrhosis between January 1998 and December 2009 were identified. We described trends in incidence by sex and etiology. We performed a direct standardization to estimate the number of people being newly diagnosed with cirrhosis in 2009, and calculated the change in incidence between 1998 and 2009. RESULTS: A total of 5,118 incident cases of cirrhosis were identified, 57.9% were male. Over the 12-year period, crude incidence increased by 50.6%. Incidence increased for both men and women and all etiology types. We estimated approximately 17,000 people were newly diagnosed with cirrhosis in 2009 in the United Kingdom, greater than that of the fifth most common cancer non-Hodgkin's lymphoma. The percentage change in incidence of cirrhosis between 1998 and 2009 for both men (52.4%) and women (38.3%) was greater than that seen for the top four most commonly diagnosed cancers in the United Kingdom (breast, lung, bowel, and prostate). CONCLUSIONS: The occurrence of cirrhosis increased more than that of the top four cancers during 1998 to 2009 in England. Strategies to monitor and reduce the incidence of this disease are urgently needed

Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats

Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. Sham operated and ACF rats were compared for their morphometric and hemodynamic data, for histopathological and ultrastructural changes in the liver as well as differences in the expression of apoptotic factors. ACF-induced heart failure is associated with light microscopic signs of apparent congestion of blood vessels, increased apoptosis and breakdown of hepatocytes and inflammatory cell inifltration were observed. The glycogen content depletion associated with the increased hepatic fibrosis, lipid globule formation was observed in ACF rats. Moreover, cytoplasmic organelles are no longer distinguishable in many ACF hepatocytes with degenerated fragmented rough endoplasmic reticulum, shrunken mitochondria and heavy cytoplasm vacuolization. ACF is associated with the upregulation of the hepatic TUNEL-positive cells and proapoptotic factor Bax protein concomitant with the mitochondrial leakage of cytochrome C into the cell cytoplasm and the transfer of activated caspase 3 from the cytoplasm into the nucleus indicating intrinsic apoptotic events. Taken together, the results demonstrate that ACF-induced congestive heart failure causes liver injury which results in hepatocellular apoptotic cell death mediated by the intrinsic pathway of mitochondrial cytochrome C leakage and subsequent transfer of activated caspase 3 into to the nucleus to initiate overt DNA fragmentation and cell death