{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:00:17Z","timestamp":1788973217309,"version":"build-2803163510"},"reference-count":21,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Background: While reducing LDL cholesterol (LDL-C) remains central focuses of conventional preventive cardiology, substantial heterogeneity exists in the cardiovascular risk associated with even extreme LDL-C elevations, likely depending heavily on the broader metabolic context. Specifically, the lean mass hyper-responder (LMHR) phenotype\u2014characterized by markedly elevated LDL-C with elevated high-density lipoprotein cholesterol (HDL-C) and low triglycerides in the setting of a ketogenic diet\u2014has recently been described, though its long-term risk profile remains poorly defined. Case Presentation: We describe a male in his 30s without any congenital dyslipidemia who adopted a ketogenic diet for the management of ulcerative colitis and who subsequently exhibited a sixfold increase in LDL-C from a baseline of 95 mg\/dL to 574 mg\/dL, with total cholesterol of up to 705 mg\/dL, HDL-C at 124 mg\/dL, and triglycerides at 34 mg\/dL. Despite maintaining these extreme lipid levels for nearly seven years, he demonstrated no coronary plaque or stenosis on coronary computed tomography angiography (CCTA; CAD-RADS = 0). Additionally, quantification of coronary plaque as assessed by AI-guided quantified analysis by Heartflow\u00ae identified 0 mm3 plaque in any vessels, placing him in the lowest percentile for atherosclerotic plaque. Conclusions: This case represents an extreme and extensively characterized example of the LMHR phenotype and highlights the limitations of extrapolating cardiovascular risk from LDL-C levels alone without consideration of broader patient context and the etiology of hypercholesterolemia. While a single case cannot redefine clinical practice, this well-characterized case is consistent with emergent literature on LMHR, and careful study of such individuals may provide valuable insights into lipid metabolism, atherosclerosis biology, and precision cardiovascular risk assessment.<\/jats:p>","DOI":"10.3390\/diseases14050168","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Seven Years of 700 Cholesterol Without Coronary Atherosclerosis: A Lean Mass Hyper-Responder Case Report"],"prefix":"10.3390","volume":"14","author":[{"given":"Nicholas G.","family":"Norwitz","sequence":"first","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0288-4458","authenticated-orcid":false,"given":"David","family":"Feldman","sequence":"additional","affiliation":[{"name":"Citizen Science Foundation, Las Vegas, NV 89139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9173-7440","authenticated-orcid":false,"given":"Adrian","family":"Soto-Mota","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Research Unit, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City 14080, Mexico"},{"name":"Tecnologico de Monterrey, School of Medicine, Mexico City 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Norwitz, N.G., and Loh, V. (2020). A standard lipid panel is insufficient for the care of a patient on a high-fat, low-carbohydrate ketogenic diet. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00097"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Norwitz, N.G., Soto-Mota, A., Feldman, D., Parpos, S., and Budoff, M. (2022). Case Report: Hypercholesterolemia \u201cLean Mass Hyper-Responder\u201d Phenotype Presents in the Context of a Low Saturated Fat Carbohydrate-Restricted Diet. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.830325"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Norwitz, N.G., and Cromwell, W.C. (2024). Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment. Metabolites, 14.","DOI":"10.3390\/metabo14010073"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"nzab144","DOI":"10.1093\/cdn\/nzab144","article-title":"Elevated LDL-cholesterol with a carbohydrate-restricted diet: Evidence for a \u2018lean mass hyper-responder\u2019 phenotype","volume":"6","author":"Norwitz","year":"2021","journal-title":"Curr. Dev. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Norwitz, N.G., Soto-Mota, A., Kaplan, B., Ludwig, D.S., Budoff, M., Kontush, A., and Feldman, D. (2022). The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets. Metabolites, 12.","DOI":"10.3390\/metabo12050460"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Budoff, M., Kinninger, A., Manubolu, V.S., Norwitz, N.G., Feldman, D., and Soto-Mota, A. (2026). The Impact of Sustained LDL-C Elevation on Plaque Changes: Primary Coronary plaque progression results from the Keto CTA Study. medRxiv.","DOI":"10.64898\/2026.01.15.26343955"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jacl.2022.10.010","article-title":"Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research","volume":"16","author":"Norwitz","year":"2022","journal-title":"J. Clin. Lipidol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1089\/met.2014.0023","article-title":"Association of adiponectin with serum preheparin lipoprotein lipase mass in women independent of fat mass and distribution, insulin resistance, and inflammation","volume":"12","author":"Tsuboi","year":"2014","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1055\/a-1778-4159","article-title":"FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance","volume":"54","author":"Szczepanska","year":"2022","journal-title":"Horm. Metab. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"901S","DOI":"10.3945\/ajcn.110.001941","article-title":"Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis","volume":"93","author":"Domouzoglou","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.2337\/db10-0193","article-title":"Obesity is a fibroblast growth factor 21 (FGF21)-resistant state","volume":"59","author":"Fisher","year":"2010","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1186\/s12944-016-0337-x","article-title":"Increased ANGPTL3, 4 and ANGPTL8\/betatrophin expression levels in obesity and T2D","volume":"15","author":"Cherian","year":"2016","journal-title":"Lipids Health Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.molmed.2019.05.010","article-title":"ANGPTL4 in Metabolic and Cardiovascular Disease","volume":"25","author":"Aryal","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E1043","DOI":"10.1073\/pnas.1400889111","article-title":"Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise","volume":"111","author":"Catoire","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","first-page":"e48","article-title":"Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association","volume":"42","author":"Ginsberg","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.pcad.2025.03.001","article-title":"Waist to hip ratio modifies the cardiovascular risk of lipoprotein(a): Insights from MESA","volume":"89","author":"Ahmad","year":"2025","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e174125","DOI":"10.1172\/jci.insight.174125","article-title":"High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans","volume":"9","author":"Ryan","year":"2024","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.cmet.2023.12.027","article-title":"Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner","volume":"36","author":"She","year":"2024","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70132","DOI":"10.1002\/jcsm.70132","article-title":"Statin Use Is Associated With a Decline in Muscle Function and Mass Over Time, Irrespective of Statin Pharmacogenomic Score","volume":"16","author":"Gentreau","year":"2025","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.cmet.2025.12.018","article-title":"Bempedoic acid directly binds and activates PPARalpha","volume":"38","author":"Papa","year":"2026","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20240028","DOI":"10.59368\/agingbio.20240028","article-title":"Ezetimibe Lowers Risk of Alzheimer\u2019s and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction","volume":"2","author":"Ganne","year":"2024","journal-title":"Aging Biol."}],"container-title":["Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-9721\/14\/5\/168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:30:59Z","timestamp":1778502659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-9721\/14\/5\/168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,11]]},"references-count":21,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["diseases14050168"],"URL":"https:\/\/doi.org\/10.3390\/diseases14050168","relation":{},"ISSN":["2079-9721"],"issn-type":[{"value":"2079-9721","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,11]]}}}