The low carbohydrate diet (LCD) is a medical nutrition therapy (MNT) that is being used for increasing number of conditions. There are many variations of the LCD including the Zone diet, the Atkins diet, the ketogenic diet (KD), the carnivore diet (CD). There are growing data to support the efficacy of an LCD to treat diabetes [1,2], obesity [3], MASLD [4], hypertension [5], epilepsy [6], mental health disorders [7,8], and arthritis [9]. The more refractory or severe the condition is, the more strict carbohydrate restriction is necessary. Epilepsy refractory to medications, for example, requires some form of KD [6]. A CD is defined by intake of meat as a primary source of nutrition and a total or near total exclusion of plants from the diet. There can be some variation in approaching a CD, which ultimately is a form of LCD itself. Some individuals do better entirely excluding plants along with the natural defense chemicals and pesticides they contain, while others eat primarily meat and incorporate as tolerated certain types of plants. Safety concerns regarding long-term continuation of a CD have been raised, mostly in regard to the saturated fat content. The US Department of Agriculture (USDA) recommends that saturated fat should make up <10% of the total caloric intake of anyone 2 years of age or older [10]. The idea is that lowering saturated fat intake could lower the levels of certain lipid carrying molecules circulating in the blood.

How one responds to an LCD is highly variable. It has been known for some time that a portion of individuals following an LCD will experience LDL-C elevation [11]. A randomized controlled clinical trial (N=120) of overweight, hyperlipidemic volunteers showed an increase in LDL-C was seen in 30% of those that started an LCD compared to only 16% of those that started a low-fat high-carbohydrate semi-starvation diet [3]. Lean mass hyper-responder (LMHR) is a term used to refer to an individual that has a marked increase in serum low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol after initiating LCD. The LMHR phenotype is defined by LDL-cholesterol (LDL-C) ≥200 mg/dL, HDL-cholesterol (HDL-C) ≥80 mg/dL, and TG ≤70 mg/dL [12]. Baseline lipid panel values are in normal ranges and there genetic testing for familial hypercholesterolemia are normal in LMHR subjects. Norwitz and colleagues proposed the lipid energy model (LEM) [13] to explain the sudden elevation in LDL-C experienced by LMHR subjects. As glycogen stores decrease and an increased fatty acid liberalization occurs after initiating a KD, hepatic uptake of fatty acids leads to hepatic very low-density lipoprotein (VLDL) production. The rate at which lipoprotein lipase (LPL) mediates transfer of triglyceride (TG) molecules to adipocytes from VLDL increases. Surface transfer of TG from VLDL to HDL also increases. The result is higher blood LDL-C and HDL-C cholesterol.

MW is a 42-year-old male with a prior medical history of anxiety, depression, GERD, and hypertension that were all put into remission 10 years ago with a ketogenic diet (KD). His family history is positive for paternal obesity and hypertension, maternal dyslipidemia, and diabetes in his paternal and maternal grandparents. He consumed a strict KD for 3 years that included meat, dairy products, non-starchy vegetables, low-glycemic berries, and non-nutritive sweeteners. The macronutrient composition of the KD varied daily but was kept at approximately 65-80%, 20-30%, and <5% of fat, protein, and carbohydrate, respectively. Most energy was taken ad libitum in the form of fatty cuts of beef, hamburger, cheese, and cream. Considerable effort was made to only consume small quantities of nuts (mostly macadamia nuts), berries, and cocoa powder. Artificial sweeteners and erythritol were consumed nearly daily as desired.

MW subsequently consumed to satiety a pure carnivore diet (PCD) for a 14-week period in the fall of 2017. More than 80% of the caloric intake was from beef, mostly in the form of fatty cuts of beef steak, hamburger, and beef fat trimmings purchased from the local butcher [Table 1]. The KD was resumed following the 14-week PCD for an additional 7 years.

Table 1: Gross Intake of Animal Products Over 14-Week Period.

None of the conditions put into remission by the initial KD returned during the 14 weeks of the PCD. No adverse effects or signs of vitamin deficiency were experienced by MW. No signs of scurvy such as gum disease, easy bleeding, petechiae, fatigue, weakness, or fatigue occurred. Rapid weight loss did occur for 42 days before leveling off despite an increase in caloric intake. MW had an initial body weight of 88.5 kg (195.2 lbs, BMI 25.6 kg/ m²), technically in the overweight category. Body weight down trended to 77.7 kg (71.2 lbs, BMI 22.5 kg/m²) over the first 42 days. Daily caloric intake was 1,651 kcal over this period. Weight stabilized at 76.1 kg (167.8 lbs) to 78.4 kg (172.8 lbs) over the remaining 56 days despite increasing mean daily intake by 753 kcal/d during this period (mean of 2404 kcal/d) [Diagram 1, 2, 3]. The highest energy intake was during the third 32 days (2,663 kcal/d).

Diagram 1: Body Weight Over the 98-day Trial.

Body weight decreased daily for 42 days where it leveled off and remained stable despite increase in caloric intake.

Diagram 2: Daily Energy Intake.

Energy intake increases were due to increase in appetite and added beef fat trimmings from the local butcher.

Diagram 3: Macronutrient Intake.

Fat was the macronutrient that was consumed in the largest quantity. 83.3% of caloric intake was accounted for by fat.

Diagram 4: Random Blood Glucose over the Trial.

Blood glucose remained stable throughout the 14 weeks.

Diagram 5: Blood β-HB.

β-HB indicates that MW was in physiologic ketosis.

A baseline fasting laboratory test was done one day prior to starting the PCD. The LDL-C remained stable at 186 mg/dL initially, increasing to only 190 mg/dL on day 39 of the experiment. After an increase in dietary fat from beef fat trimmings of various beef cuts, the LDL-C dropped to 150 mg/dL on day 98. Other laboratory markers were relatively stable [Table 2]. Blood glucose (BG), taken using ACCU-CHEK® Compact Plus glucometer, ranged from 66-105 mg/dL. A Nova Max® Plus ketometer was used to measure blood ketone bodies [Diagram 4]. Beta-hydroxybutyrate (β-HB) ranged from 1.1 to 4.0 mmol/L, indicating mild to moderate ketosis throughout [Diagram 5].

After discontinuing the PCD and re-initiating the KD, MW regained much of the lost weight to return to a baseline of 80-82 kg (176-181 lbs) for 7 years. Increase in weight could be correlated with increase in dietary intake. Mean caloric intake during the PCD 2,081 kcal/d. It trended up from 1,653 kcal/d over the first 32 days to 2,403 kcal/d over the last 56 days. The 7 years following the PCD, daily intake on the KD has been approximately 2,800-3,200 kcal/d. Percentage of energy intake by macronutrients is currently approximately 65-80%, 20-30%, and <5% of fat, protein, and carbohydrate, respectively.

Table 2: Labs Over Time Spanning Three Different Eating Patterns.

The relationship between dietary patterns to LDL-C changes, weight changes, and comorbidity remission will be discussed below.

• LMHR could manifest in more mild forms.
• LMHRs do not respond to dietary saturated fat like the general population.
• The clinical implications of long-term KD on an LMRH phenotype are unknown, but a recent study suggests no significant atherosclerosis developed over a year in LMRH individuals.
• Some part of a more balanced diet might contribute to weight gain.
• Comorbidities put into a remission by a KD remain in remission with a PCD.

1) The LMHR phenotype is defined by LDL-cholesterol (LDL-C) ≥200 mg/dL, HDL-cholesterol (HDL-C) ≥80 mg/dL, and TG ≤70 mg/dL [12]. We have a case report of an individual that experienced a significant increase in LDL-C, increase in HDL, and decrease in TG that does not meet the definition of LMHR. This does not negate the relevance of the LEM on certain individuals. It could be that because the initial BMI was 25.6 kg/m² rather than the typical BMI of around 22 kg/m², MW experienced an attenuation of the effects of the LEM. Body weight is known to be an important contributor to the LMHR phenotype. It is unclear how much body weight plays a role in LMHR versus insulin sensitivity.

2) This report is contrary to the conventional conception that increases in saturated fat intake increase LDL-C [14,15]. As MW lost weight on a PCD, the lipid panel remained relatively static. LDL-C remained stable at 186 mg/dL at baseline and then 190 mg/dL at follow-up after 38 days of continued weight loss. Over the next 60 days, energy intake increasing by 688 kcal/d in large part due to an increase in beef fat. Despite saturated fat intake increasing from 50 g to 88 g daily, the LDL-C actually decreased to 150 mg/dL in the 12/19/2017 lab report. It was previously reported that an LCD lower in saturated fat resulted in the LMHR phenotype [16] and that concurrent increase in total saturated fat and carbohydrate actually lowered LDL-C [17]. An additional report suggests that LDL-C elevates during times of energy deficiency and depresses during energy excess in LMHRs [18]. These findings are consistent with the LDL-C drop that MW experienced following an increase in total caloric and saturated fat intake.

 3) The clinical implications of long-term continuation of a KD on an LMHR are unclear and more data are needed. However, a recent study showed that carbohydrate restriction for a mean of 4.7 years in 80 metabolically healthy LMHR individuals with a mean LDL-C of 272 mg/dL did not result in a greater atherosclerotic plaque burden (measured with coronary artery calcium and coronary computed tomography angiography) than controls with markedly lower LDL-C [19].

4) A well-formulated PCD could be superior to a less strict KD in maintaining optimal body weight. MW had a borderline overweight BMI of 25.6 kg/ m² at the start that decreased to 22.5 kg/m² and then stabilized through the finish of the PCD trial. Increase in appetite and intake increased accordingly thereafter perhaps as a compensatory mechanism to help stabilize body weight. The BMI stayed roughly the same until the KD was re-introduced and MW began consuming even more. Increased carbohydrate content, decreased fat intake, artificial sweeteners, dairy products, and/or non-starchy plants may have contributed to an increase in nutrient intake. Changes in macronutrient composition from the PCD to the type of KD that MW follows could theoretically cause an increased endogenous insulin secretion and weight gain. However, insulin levels were not measured. Artificial sweeteners have the potential to stimulate weight gain due to changes in behavior [20] or perhaps as a result of an increase in pro-inflammatory processes in the gut [21].

5) Red meat is frequently vilified for causing gastrointestinal disorders. Counter to conventional wisdom, which was based on conjecture, MW put GERD into remission for 10 years by following a diet very high in red meat and dietary fat. Data regarding GERD are conflicting, however it a review article suggests that carbohydrate intake is more likely to play the greatest role in exacerbation of subjective symptoms and objective metrics [22]. More recent data suggest simple sugars exacerbate both [23]. GERD not caused by defects in anatomical structure could theoretically be caused by any various etiology or combination of etiologies. While more research certainly needs to be done, this would explain the ambiguity in currently available GERD studies.

The anxiety and treatment-resistant depression have been put into remission for the 3 years on a KD leading up to the PCD. Symptoms did not return during any of the transition periods to or from the PCD, or thereafter. More severe psychological conditions have been put into remission with an LCD [7], although the mechanisms to explain the benefits of the LCD are unclear.

Conflict of Interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

1. Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015; 31: 1-13.
2. Lennerz BS, Barton A, Bernstein RK, Dikeman RD, Diulus C, Hallberg S, et al. Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics. 2018; 141: e20173349.
3. Yancy WS Jr, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med. 2004; 140: 769-77.
4. Vilar-Gomez E, Athinarayanan SJ, Adams RN, Hallberg SJ, Bhanpuri NH, McKenzie AL, et al. Post hoc analyses of surrogate markers of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis in patients with type 2 diabetes in a digitally supported continuous care intervention: an open-label, non-randomised controlled study. BMJ Open. 2019; 9: e023597.
5. Saslow LR, Jones LM, Sen A, Wolfson JA, Diez HL, O'Brien A, et al. Comparing Very Low-Carbohydrate vs DASH Diets for Overweight or Obese Adults with Hypertension and Prediabetes or Type 2 Diabetes: A Randomized Trial. Ann Fam Med. 2023; 21: 256-263.
6. D'Andrea Meira I, Romão TT, Pires do Prado HJ, Krüger LT, Pires MEP, da Conceição PO. Ketogenic Diet and Epilepsy: What We Know So Far. Front Neurosci. 2019; 13: 5.
7. Danan A, Westman EC, Saslow LR, Ede G. The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients. Front Psychiatry. 2022; 13: 951376.
8. Adams RN, Athinarayanan SJ, McKenzie AL, Hallberg SJ, McCarter JP, Phinney SD, et al. Depressive symptoms improve over 2 years of type 2 diabetes treatment via a digital continuous remote care intervention focused on carbohydrate restriction. J Behav Med. 2022; 45: 416-427.
9. Ciaffi J, Mitselman D, Mancarella L, Brusi V, Lisi L, Ruscitti P, et al. The Effect of Ketogenic Diet on Inflammatory Arthritis and Cardiovascular Health in Rheumatic Conditions: A Mini Review. Front Med (Lausanne). 2021; 8: 792846.
10. Dietary guidelines for Americans, 2020-2025. Available at: https://www.dietaryguidelines.gov/sites/default/files/2021-03/Dietary_Guidelines_for_Americans-2020-2025.pdf (Accessed: 29 December 2024).
11. Creighton BC, Hyde PN, Maresh CM, Kraemer WJ, Phinney SD, Volek JS. Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes. BMJ Open Sport Exerc Med. 2018; 4: e000429.
12. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a "Lean Mass Hyper-Responder" Phenotype. Curr Dev Nutr. 2021; 6: nzab144.
13. Norwitz NG, Soto-Mota A, Kaplan B, Ludwig DS, Budoff M, Kontush A, Feldman D. The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets. Metabolites. 2022; 12: 460.
14. KINSELL LW, PARTRIDGE J, BOLING L, MARGEN S, MICHAELS G. Dietary modification of serum cholesterol and phospholipid levels. J Clin Endocrinol Metab. 1952;12: 909-913.
15. AHRENS EH Jr, BLANKENHORN DH, TSALTAS TT. Effect on human serum lipids of substituting plant for animal fat in diet. Proc Soc Exp Biol Med. 1954; 86: 872-8.
16. Norwitz NG, Soto-Mota A, Feldman D, Parpos S, Budoff M. Case Report: Hypercholesterolemia "Lean Mass Hyper-Responder" Phenotype Presents in the Context of a Low Saturated Fat Carbohydrate-Restricted Diet. Front Endocrinol (Lausanne). 2022; 13: 830325.
17. Norwitz NG, Cromwell WC. 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. 2024; 14: 73.
18. Feldman D, Huggins S, Norwitz NG. Short-term hyper-caloric high-fat feeding on a ketogenic diet can lower low-density lipoprotein cholesterol: the cholesterol drop experiment. Curr Opin Endocrinol Diabetes Obes. 2022; 29: 434-439.
19. Budoff M, Manubolu VS, Kinninger A, Norwitz NG, Feldman D, Wood TR, et al. Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial. JACC Adv. 2024; 3: 101109.
20. Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013; 24: 431-41.
21. Antasouras G, Dakanalis A, Chrysafi M, Papadopoulou SK, Trifonidi I, Spanoudaki M, et al. Could Insulin Be a Better Regulator of Appetite/Satiety Balance and Body Weight Maintenance in Response to Glucose Exposure Compared to Sucrose Substitutes? Unraveling Current Knowledge and Searching for More Appropriate Choices. Med Sci (Basel). 2024; 12: 29.
22. Lakananurak N, Pitisuttithum P, Susantitaphong P, Patcharatrakul T, Gonlachanvit S. The Efficacy of Dietary Interventions in Patients with Gastroesophageal Reflux Disease: A Systematic Review and Meta-Analysis of Intervention Studies. Nutrients. 2024; 16: 464.
23. Gu C, Olszewski T, King KL, Vaezi MF, Niswender KD, Silver HJ. The Effects of Modifying Amount and Type of Dietary Carbohydrate on Esophageal Acid Exposure Time and Esophageal Reflux Symptoms: A Randomized Controlled Trial. Am J Gastroenterol. 2022; 117: 1655-1667.