es/iode’s Post

The cardiovascular impact from MASLD/MASH seems to be the outcome rising as the top outcome concern, even over mortality from liver disease itself. Here’s a study that shows the benefits of this NASH/MASH treatment, Resmetirom on CVD driven by dyslipidemia. The study lists limitations, and finds “resmetirom shows promise as a potential treatment for managing dyslipidemia and cardiovascular risk in NASH patients, potentially influencing future treatment guidelines for both liver and cardiovascular health in this population.” “Cardiovascular disease remains one of the leading causes of death in individuals with NASH, underscoring the need for effective treatments that address not only liver health but also the broader metabolic complications of the disease.” “Conclusions: This meta-analysis illustrates that resmetirom profoundly improves lipid profiles in NASH patients, particularly by decreasing LDL-C and TG, without increasing the risk of serious adverse events. These outcomes propose resmetirom's potential as a successful and viable treatment for dyslipidemia in NASH, potentially addressing both liver health and cardiovascular risk.” American Association for the Study of Liver Diseases (AASLD), EASL | The Home of Hepatology, Global NASH Council, The Forum for Collaborative Research: Liver Forum, VCU Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Barcelona Institute for Global Health (ISGlobal), Canadian Association for the Study of the Liver, Global Liver Institute, European Liver Patients' Association - ELPA, LPI LIVER PATIENTS INTERNATIONAL, Christopher Kopka, Paul Brennan, Scott Isaacs, MD, FACP, FACE, Livera Health, Liver Scan Direct, Aegle Medical, Madrigal Pharmaceuticals

📍 Aspirin cuts liver fat in trial 10 percent reduction seen in small study of disease that affects up to a third of U.S. adults Excerpt: The most common chronic liver disease — metabolic dysfunction–associated steatotic liver disease (MASLD) — is characterized by an increased buildup of fat in the liver due to factors such as obesity and Type 2 diabetes. Such elevated fat poses serious health risks, but a recent clinical trial published in JAMA and conducted by investigators from Massachusetts General Hospital points to a possible treatment: aspirin. “Since MASLD is estimated to affect up to a third of U.S. adults, aspirin represents an attractive potential low-cost option to prevent progression to cirrhosis or liver cancer, the most feared complications of MASLD,” said senior author Andrew T. Chan, a gastroenterologist and a professor at Harvard Medical School. Chan and his colleagues tested aspirin’s potential because the drug reduces inflammation and affects fat metabolism. In their Phase 2 trial, 80 adults with MASLD were randomized to receive daily low-dose aspirin or placebo for six months. At the end of the study, the average change in liver fat content was minus 6.6 percent with aspirin versus plus 3.6 percent with placebo, showing that low-dose aspirin reduced the average liver fat content by 10.2 percent compared with placebo. The aspirin was found to be safe and well-tolerated, and also improved various markers of liver health. “Multiple noninvasive blood and imaging-based tests for liver fat, inflammation, and fibrosis all showed a similar direction of benefit that favored aspirin treatment,” said lead author and principal investigator Tracey G. Simon, a hepatologist and an instructor at the Medical School. “Together, these data support the potential for aspirin to provide benefits for patients with MASLD.” Additional studies are needed to determine whether continued aspirin use can reduce individuals’ risk of long-term health complications associated with MASLD, the researchers said. Reference ⬇ Aspirin for Metabolic Dysfunction–Associated Steatotic Liver Disease Without Cirrhosis A Randomized Clinical Trial Tracey G. Simon, MD, MPH1,2,3; Robert M. Wilechansky, MD1,2,4; Stefania Stoyanova, BA4; et al JAMA. 2024;331(11):920-929. doi:10.1001/jama.2024.1215 Read more ➡ https://lnkd.in/eNQhHGsy #aspirin #liver #SteatoticLiverDisease #fattyliver

Metabolic dysfunction-associated steatotic liver disease (aka MASLD, formerly NAFLD) is one of the leading causes of liver disease in the U.S. and for some can progress to liver failure requiring transplantation. In this phase 2 study, for patients treated with retratrutide (a "triple G" agonist- GLP-1/GIP/glucagon- that is also being studied as an anti-obesity medication) at the highest dose, by 48 weeks 93% achieved RESOLUTION of steatosis (defined as liver fat <5%). As access to anti-obesity medications is extremely limited, it's important that we have these studies measuring improvement in obesity-related comorbidities which may help expand coverage (as was the case for Wegovy and cardiovascular disease). https://lnkd.in/gH-A9b-S

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as NAFLD, significantly raises cardiovascular disease (CVD) risk due to shared metabolic disorders like obesity, type 2 diabetes, and hypertension. New research emphasizes the need for early CVD risk assessment using noninvasive tools like transient elastography and the FIB-4 index. Lifestyle changes and pharmacological interventions, such as statins and GLP-1 receptor agonists, can effectively manage MASLD and reduce cardiovascular risk. Future studies aim to uncover new biomarkers and therapeutic targets to further mitigate this risk. “Patients with MASLD have a significantly increased risk of cardiovascular events. Therefore, early assessment of CV risk, noninvasive screening and management of these patients are crucial. Treatment of MASLD focuses on lifestyle.” Original paper: Henry Z., Sechi, L.A., Eliano Pio Navarese, MD, PhD, FESC, FACC. et al. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: a comprehensive review. Cardiovasc Diabetol 23, 346 (2024). https://lnkd.in/g_2Dgnu6 American Association for the Study of Liver Diseases (AASLD), EASL | The Home of Hepatology, Canadian Association for the Study of the Liver, Global NASH Council, Global Liver Institute, European Liver Patients' Association - ELPA, LPI LIVER PATIENTS INTERNATIONAL, Aegle Medical. Written in collaboration with CHATGPT4o.

Spotlight on MASLD and Cardiovascular Risk Recent research highlights the link between Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD, and an increased risk of cardiovascular disease (CVD). With shared risk factors like obesity, type 2 diabetes, and hypertension, it's essential to prioritize early CVD risk assessment using noninvasive tools like #FibroScan and the FIB-4 index. Key Takeaways: - Lifestyle modifications and pharmacological options, including statins and GLP-1 receptor agonists, can effectively manage MASLD and lower cardiovascular risks. - Future studies are set to explore new biomarkers and therapeutic targets to enhance patient outcomes. Let’s drive awareness and promote proactive measures for better health outcomes! #MASLD #CVD #FibroScan #HealthcareInnovation #PatientCare #LiverHealthMatters

All indications are that all the described alterations were triggered by increased hepatic levels of transforming growth factor-beta 1 (TGF-β1) and an SMAD3mediator protein, which are the main inducers of liver fibrosis. Thus, treatment with recombinant CDF15 can activate AMPK and decrease levels of active SMAD3 in mouse liver and in primary hepatocyte cultures. “In conclusion, the results indicate that GDF15 activates AMPK protein and inhibits hepatic gluconeogenesis and fibrosis through the reduction of the TGF-β1/SMAD3 pathway,” says Vázquez-Carrera. “These results suggest that modulation of GDF15 levels could be useful to improve the effectiveness of current anti-diabetic treatments, as hepatic gluconeogenesis is key in hyperglycaemia in patients with type 2 diabetes mellitus, and serum TGF-β1 levels are also increased in these patients,” concludes the researcher. #diabetes #therapy

Tyrosinemia Type I (TT1) is a rare inherited metabolic disease of tyrosine metabolism caused by autosomal recessive fumarylacetoacetate hydrolase deficiency. Because of the enzyme defect, toxic metabolites such as fumaryl-, maleyl- and succinylacetoacetate and succinylacetone accumulate. Untreated, TT1 can cause liver pathology including acute liver failure, liver fibrosis, cirrhosis, hepatocellular carcinoma or hepatoblastoma, as well as renal tubular dysfunction, episodes of porphyria crises with neuropathy, and suboptimal neurocognitive outcomes. Patients are diagnosed either via newborn screening or after clinical presentation with elevated tyrosine and succinylacetone in dried blood spots (DBS), plasma or urine. Currently, TT1 patients are receiving treatment with Nitisinone (NTBC), a medication that effectively blocks the formation of toxic metabolites by inhibiting an upstream enzyme. Coupled with a tyrosine-restricted diet, this approach has significantly improved clinical outcome. 10 years ago, the laboratory of metabolic diseases introduced a home monitoring system for patients with TT1, analyzing succinylacetone, NTBC, tyrosine and phenylalanine in DBS. Recently, the method for succinylacetone was transferred to an Ultra High-Performance Liquid Chromatography (UHPLC) system coupled to a SCIEX triple quad 6500+ mass spectrometer (SCIEX), resulting in a 10-fold increase in analytical sensitivity. The detection limit of our method has now improved from 0.05 to 0.004 µmol/L, and the limit of quantification from 0.17 to 0.013 µmol/L. In addition, the reference values were reevaluated and changed from <0.30 to <0.18 µmol/L. The modification of the method may be a promising step in enhancing the metabolic control of individuals with TT1. If you have an interest in obtaining measurements for DBS succinylacetone, NTBC, tyrosine and phenylalanine for your TT1 patients, we can provide packages for home blood spot sampling and transport. Please contact us at lmzg@umcg.nl. Rebecca Heiner-Fokkema, Joost Groen, Ronald Maatman #metabolicdiseases, #tyrosinemiatypeI, #succinylacetone, #homemonitoring

Fatty liver disease happens when a person’s body begins to store fat in the liver, which can damage the organ. Some forms of fatty liver disease are caused by excessive alcohol use. However, one in three Americans develop fatty liver from metabolic dysfunction-associated steatotic liver disease (MASLD), which is often correlated with obesity and diabetes. #MASLD is now the most common liver disease worldwide. One severe form of MASLD is called metabolic dysfunction-associated steatohepatitis (MASH). It is estimated that up to 250 million people worldwide have some form of #MASH. If left untreated, many of these patients will develop #cirrhosis, where healthy cells are replaced by scar tissue. Damage done by cirrhosis is irreversible, and the only treatment is liver transplantation. Previously, the only treatment plan for MASH was diet and exercise, but in March 2024, the U.S Food and Drug Administration approved the use of #Resmetirom, a thyroid hormone-like drug for MASH. The laboratory of Paul M Yen, MD, FACP, professor in the Cardiovascular and Metabolic Disorders Program at Duke-NUS Medical School and the Duke Department of Medicine provided much of the preclinical and clinical evidence for this therapy based upon its studies of thyroid hormones and MASH. This drug goes to the liver selectively and acts on specific thyroid hormone receptors to reduce side effects on the heart and bone. https://lnkd.in/ei_5T7kk

Building a better rat Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus Gregory M T Hare 1 2 3, Yanling Zhang 3, Kyle Chin 1 2, Kerri Thai 3, Evelyn Jacobs 1, Melina P Cazorla-Bak 1 2, Linda Nghiem 3, David F Wilson 4, Sergei A Vinogradov 4, Kim A Connelly 2 3 5, C David Mazer 1 2 3 6, Roger G Evans 7, Richard E Gilbert 3 8 Affiliations expand PMID: 34184431 PMCID: PMC8239445 DOI: 10.14814/phy2.14890 Free PMC article Abstract Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (Pk O2 ), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on Pk O2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary Pk O2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in Pk O2 . By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in Pk O2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper Pk O2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.

Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point Eric Bachman 1, Thomas G Travison 2, Shehzad Basaria 3, Maithili N Davda 2, Wen Guo 2, Michelle Li 2, John Connor Westfall 3, Harold Bae 3, Victor Gordeuk 2, Shalender Bhasin 4 Affiliations expand PMID: 24158761 PMCID: PMC4022090 DOI: 10.1093/gerona/glt154 Abstract Background: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. Methods: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. Results: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. Conclusions: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis. Keywords: Erythropoietin; Ferritin.; Hepcidin; Testosterone.