Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.

Impact of High Glucose Exposure on Induction of Apoptosis and Its Implication on Developing Retina of Zebrafish Embryos.

The objective was to study the effects of high glucose on the morphological changes and to observe the expression of apoptosis regulatory proteins in the developing retina in vivo using zebrafish embryos. Wild-type male and female zebrafish were allowed for normal mating and the fertilized eggs were collected and exposed to hyperglycemic conditions (25 mM D-glucose) for 96 h. The embryos were subjected to various morphological and histological analyses in a time-dependent manner. The embryos showed morphological defects such as body curvature, abnormal eye shape, and low pigmentation of the eye in the high glucose-induced embryos compared to the control. Histomorphometry studies using H&E-stained slides showed increased thickness of GCL and INL and thinning of the IPL in the retina of high glucose-exposed embryos when compared to its time-matched control. Furthermore, the TUNEL assay and modified trichrome staining indicated apoptosis of many cells in the high glucose-induced group compared to the control. Immunohistochemistry findings revealed that expression of BAX, caspase 3, and caspase 9 was increased with decreased expression of Bcl-2 in the high glucose-treated group compared to control. From the present data, it is concluded that gestational exposure to high glucose stimulates apoptotic cell in the developing retinal layers via activating the pro-apoptotic and repressing the anti-apoptotic proteins.

Effects of social determinants of health on mortality and incident liver-related events and cardiovascular disease in steatotic liver disease.

BACKGROUND: Social determinants of health (SDOH) are becoming increasingly recognised as mediators of human health. In the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), most of the literature on SDOH relates to individual-level risk factors. However, there are very limited data on neighbourhood-level SDOH in MASLD. AIM: To assess whether SDOH impact fibrosis progression in patients who already have MASLD. METHODS: This was a retrospective cohort study of patients with MASLD seen at Michigan Medicine. The primary predictors were two neighbourhood-level SDOH, 'disadvantage' and 'affluence'. The primary outcomes were mortality, incident liver-related events (LREs) and incident cardiovascular disease (CVD). We modelled these outcomes using Kaplan-Meier statistics for mortality and competing risk analyses for LREs and CVD, using a 1-year landmark. RESULTS: We included 15,904 patients with MASLD with median follow-up of 63 months. Higher affluence was associated with lower risk of overall mortality (hazard ratio 0.49 [0.37-0.66], p < 0.0001 for higher vs. lower quartile), LREs (subhazard ratio 0.60 [0.39-0.91], p = 0.02) and CVD (subhazard ratio 0.71 [0.57-0.88], p = 0.0018). Disadvantage was associated with higher mortality (hazard ratio 2.08 [95% confidence interval 1.54-2.81], p < 0.0001 for the highest vs. lowest quartile) and incident CVD (subhazard ratio 1.36 [95% confidence interval 1.10-1.68], p < 0.0001). These findings were robust across several sensitivity analyses. DISCUSSION: Neighbourhood-level SDOH are associated with mortality, incidence of LREs and incident CVD in patients with steatotic liver disease. Interventions aimed at disadvantaged neighbourhoods may improve clinical outcomes.

Higher mortality among lean patients with non-alcoholic fatty liver disease despite fewer metabolic comorbidities.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD. METHODS: This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis. RESULTS: A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2-3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3 months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2-3 groups respectively. CONCLUSIONS: Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.

Providing Compassionate Care: The Role of Medical Students and Videoconference Technology in the COVID-19 Pandemic.

Patient and family communication is a well-known factor associated with improved patient outcomes. During the COVID-19 pandemic, visitation restrictions meant communication with patients and their families became a challenge, particularly with intubated patients in the intensive care unit. As the hospital filled with COVID-19 patients, medical students and physicians at Albany Medical Center identified the urgent need for a better communication method with families. In response, the COVID-19 Compassion Coalition (CCC) was formed. The CCC's goal was to decrease the distress felt by families unable to visit their hospitalized loved ones. They developed a streamlined process for videoconferencing between patients on COVID-19 units and their families by using tablets. Having medical students take responsibility for this process allowed nurses and physicians to focus on patient care. Incorporating videoconferencing technology can allow physicians and nurses to better connect with families, especially during unprecedented times like a pandemic.

Generation and characterization of three clones (NCCSi007A, NCCSi007B and NCCSi007C) of an integration free induced Pluripotent Stem Cell line from a patient with alcoholic liver cirrhosis of Indian ethnicity.

Three induced pluripotent stem cells (iPSC) clones NCCSi007-A, NCCSi007-B and NCCSi007-C were generated from CD4+T cells of a 38 years old male patient suffering from liver cirrhosis- alcoholic and minimal hepatic encephalopathy of Indian origin. The CD4+T cells of the patient were reprogrammed using integration free, Sendai viral vector system. Each of the three iPSC clones showed high alkaline phosphatase (ALP) activity, expressed pluripotency markers OCT4, SOX2, NANOG, KLF4, SSEA-4, TRA-1-60, showed normal male karyotype (46, XY) and exhibited multi-lineage differentiation.