Carnivore Diet --＞ 가족성 고콜레스테롤 혈증 수준의 고지혈증 최신논문...

[문형철]

문형철은 6년동안 케톤생성식단을 했지만

콜레스테롤 수치를 포함한 모든 혈액검사, 소변검사 수치가 정상범위에 있다.

그런데, 야채를 덜 먹는 카니보어 식단은 고콜레스테롤 혈증을 일으킨다.

아래 논문...

https://cafe.daum.net/panicbird/S6LP/243

Re: 최신 논문을 기반으로한 고지혈증 치료법(문치연 발효홍국음)

연구 배경

Carnivore Diet(육식 위주 식단, CD)는

거의 전적으로 동물성 식품만 섭취하는 식단으로,

소셜 미디어에서 큰 인기를 얻고 있습니다.

“Lion Diet” 등으로도 불리며,

체중 감량·염증 감소·대사 개선 등의 주장이 많지만,

표준화된 정의가 없고 장기 효과에 대한 과학적 근거가 부족합니다.

연구 방법

• PRISMA-ScR 지침에 따른 체계적 문헌 검색
• 데이터베이스: PubMed, LIVIVO, Web of Science, Cochrane Library
• 포함 기준: 인간 대상, 동물성 식품 위주(식물성 에너지 섭취 <10%), 영어·독일어 논문
• 최종 포함: 9개의 인간 연구 (2021~2025년 발표, 대부분 사례 보고·소규모 조사)

주요 결과

보고된 긍정적 효과

• 체중 감소
• 포만감 증가
• 일부 염증·대사 지표 개선
• 일부 환자에서 약물 감량 가능

주요 위험

• 영양소 결핍 위험: 비타민 C, 비타민 D, 칼슘, 마그네슘, 요오드, 식이섬유 등
• LDL 콜레스테롤 및 총콜레스테롤 상승
• 건강 상태 악화 사례 1건 보고
• 식물성 파이토케미컬 섭취 감소

근거 질

• 표본 크기가 매우 작고
• 연구 기간이 짧으며
• 대조군이 없는 연구가 대부분 → 근거 수준이 매우 낮음

결론

Carnivore Diet은

단기적으로 일부 이점(체중 감소, 포만감 등)을 줄 수 있으나,

장기적으로는 영양 결핍, 심혈관 질환 위험 증가, 건강에 유익한 식물성 성분 부족 등의 실질적 위험이 크다.

현재로서는 장기 지속을 권장할 수 없다.

한 줄 요약

소셜 미디어에서 유행하는 육식 위주 식단의 현재 과학적 근거를 종합한 결과, 단기 효과는 있을 수 있으나 장기 안전성은 확인되지 않았고 위험이 더 크다는 신중한 결론을 내린 2026년 스코핑 리뷰입니다.

핵심 내용

고지방·저탄수화물 식단(High-Fat, Low-Carbohydrate Diet, 케토제닉·카니보어 유사 식단 포함)이

가족성 고콜레스테롤혈증(Familial Hypercholesterolemia, FH) 수준에 해당하는

심한 고LDL-콜레스테롤혈증을 유발할 수 있다는 점을

비판적으로 검토한 논문입니다.

주요 관찰

• 일부 환자에서 LDL-C가 FH 환자(심지어 동형접합 FH) 수준까지 급격히 상승
• 유전적 돌연변이가 없는 환자에서도 발생
• 저자들의 지질 클리닉에서도 실제 사례 관찰

가능한 기전 (아직 완전히 규명되지 않음)

• LDL 입자 제거(clearance) 감소
• LDL 전구체(VLDL) 생산 증가
• 또는 두 가지의 조합
• 포화지방과 콜레스테롤 섭취 증가 + 탄수화물·식이섬유 섭취 극단적 감소가 주요 특징

임상적 시사점

1. 유전적 돌연변이가 없는 임상적 FH 환자를 볼 때, 반드시 고지방·저탄수화물 식단 여부를 확인해야 함
2. 식단 조절만으로도 LDL-C가 크게 정상화되는 경우가 많음
3. 장기적으로 심혈관 질환 위험 증가 가능성 있음

이전 카니보어 식단 리뷰와의 연결

바로 앞에서 본 2026년 Carnivore Diet 스코핑 리뷰에서 지적된 LDL·총콜레스테롤 상승 위험이,

이 2023년 논문에서는 더 구체적으로 “FH를 모방할 정도로 심각한 수준”까지 도달할 수 있다는 임상 근거를 제시합니다.

한 줄 요약

고지방·저탄수화물 식단은

일부 사람에게 유전성 고콜레스테롤혈증과 구별하기 어려운 수준의 심한 이상지질혈증을 유발할 수 있으므로,

관련 환자를 볼 때 반드시 식단을 확인해야 한다는 중요한 임상 경고입니다.

연구 개요

• 독일에서 스스로 카니보어 식단(거의 동물성 식품만 섭취)을 따르는 성인 24명을 대상으로 함
• 중앙 나이 46세, 남성 62.5%
• 67%가 기존에 최소 1개 이상의 질환을 가지고 있었음
• 식단 유지 기간: 중앙값 약 12개월 (1~56개월)

주요 결과

주관적 경험

• 대부분 건강 개선을 위해 시작
• 전반적 건강, 포만감, 수면, 정신적·신체적 상태 개선을 보고한 비율이 높음

혈액 검사 변화

항목                                                   식단 전                             식단 중                             변화

총콜레스테롤	224 mg/dL	305 mg/dL	유의하게 상승 (p < 0.0001)
LDL 콜레스테롤	157 mg/dL	256 mg/dL	유의하게 상승 (p = 0.00024)

• 대부분의 다른 혈액 지표는 정상 범위 내 유지
• 초기에 높았던 HbA1c(당뇨 전단계)와 중성지방은 감소한 사례가 많았음

결론

• 카니보어 식단을 따르는 사람들은 주로 건강 문제로 시작하고, 주관적으로는 호전을 느끼는 경우가 많음
• 대부분의 혈액 지표는 큰 문제가 없었으나, 총콜레스테롤과 LDL이 뚜렷하게 상승하는 현상은 주목할 만하며, 장기적 심혈관 위험에 대한 추가 연구가 필요함

이 연구는 앞서 본 카니보어 관련 리뷰와 사례(황색종 발생, FH 유사 심한 고콜레스테롤혈증)와 일관되게 LDL 상승을 확인한 실제 관찰 연구입니다

환자 및 증상

• 40대 남성
• 손바닥, 발바닥, 팔꿈치에 무증상 황색 결절(yellowish nodules)이 3주간 나타남

관련 병력

• 약 8개월 전부터 Carnivore Diet(육식 위주 식단) 시작
• 하루 섭취량 예시:
  • 치즈 6~9 lb (약 2.7~4 kg)
  • 버터 스틱 다량
  • 햄버거에 추가 지방 다량 포함
• 주관적 효과: 체중 감소, 에너지 증가, 정신 명료함 개선을 보고

검사 소견

• 총콜레스테롤: 1000 mg/dL 초과 (이전 기저치 210~300 mg/dL에서 급격히 상승)
• 진단: 황색종(Xanthoma)

임상적 의미

이 사례는 극단적인 고지방·저탄수화물(카니보어) 식단이

• 총콜레스테롤을 1000 mg/dL 이상으로 올릴 수 있고
• 손바닥·팔꿈치 등에 황색종을 유발할 수 있음을 보여주는 실제 임상 예입니다.

앞서 살펴본 논문들(카니보어 스코핑 리뷰, 고지방 저탄수화물 식단으로 인한 심한 이상지질혈증)에서 경고한 심각한 지질 이상이 실제로 나타난 사례라고 볼 수 있습니다.

Nutrients

. 2023 Feb 15;15(4):962. doi: 10.3390/nu15040962

Severe Dyslipidemia Mimicking Familial Hypercholesterolemia Induced by High-Fat, Low-Carbohydrate Diets: A Critical Review

Veera Houttu 1,2, Aldo Grefhorst 2, Danny M Cohn 1, Johannes H M Levels 2, Jeanine Roeters van Lennep 3, Erik S G Stroes 1, Albert K Groen 2, Tycho R Tromp 1,*

Editor: Frans Stellaard

• Author information
• Article notes
• Copyright and License information

PMCID: PMC9964047  PMID: 36839320

Abstract

Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk.

Keywords: carnivore diet, ketogenic diet, low-carbohydrate diet, high-fat diet, LDL cholesterol, familial hypercholesterolemia, cardiovascular disease

1. Introduction

The notion that circulating low-density lipoprotein cholesterol (LDL-C) causes atherosclerotic cardiovascular disease (ASCVD) is firmly rooted in evidence from genetic, epidemiological, and clinical studies [1]. Interestingly, some of the earliest lines of evidence were derived from experimental studies involving the modification of plasma cholesterol levels through diet. The pioneering groundwork for cholesterol’s involvement in atherosclerosis can be traced back to St. Petersburg in 1913, when a young experimental pathologist named Anitschkow induced atherosclerosis in rabbits by feeding them purified cholesterol dissolved in sunflower oil. Control animals fed only the sunflower oil showed no lesions [2]. In the following decades, evidence accumulated that unraveled the relationship between (dietary) cholesterol, atherosclerosis, and potential options for treatment [3]. Over a century after Anitchkow’s seminal observations, the interplay between diet and (severe) dyslipidemia is still of special scientific interest, specifically concerning high-fat, low-carbohydrate diets, which is the topic of the narrative review presented here.

Epidemiological observations in large, cross-cultural prospective studies from the general population have been instrumental in linking the intake of fat and cholesterol with plasma cholesterol levels and the incidence of coronary events [4,5]. The first recommendations on dietary intervention to prevent cardiovascular disease were proposed by large professional medical associations in the 1960s [6], and it has now been widely acknowledged that diet has a modest yet meaningful influence on LDL-C levels on a population level [7,8]. The first data to show that cholesterol uptake in the intestine was amenable to a pharmacotherapeutic intervention were derived from the Coronary Primary Prevention Trial, published in 1984. This landmark placebo-controlled randomized clinical trial showed that the bile acid sequestrant cholestyramine, which helps remove cholesterol from the enterohepatic circulation, lowered LDL-C levels and reduced cardiovascular events in 3806 asymptomatic middle-aged men with primary hypercholesterolemia [9].

Bile acid sequestrants have since then been surpassed by statins and other more effective pharmacological lipid-lowering therapies, but dietary modifications continue to be highlighted in the most recent clinical guidelines for the prevention of cardiovascular disease [10,11,12], partly due to their LDL-lowering effect [7,13]. More specifically, guidelines recommend plant-based and Mediterranean-type diets containing vegetables, nuts, whole grains, and fish rich in unsaturated fats and dietary fibers, while the intake of processed meat, deep-fried foods, ice cream, high-fat dairy products, refined carbohydrates, and sweetened beverages high in saturated fatty acids (SFAs), cholesterol, trans-fatty acids (TFAs), sodium, and glucose should be avoided or kept to a minimum.

Besides observational and interventional data on cholesterol intake or reuptake in large study populations, understanding the link between plasma LDL-C, atherosclerosis, and treatment thereof has hugely progressed through the study of patients with extremely elevated plasma LDL-C levels due to genetic causes [3,14]. Patients with familial hypercholesterolemia (FH), an autosomal dominant inherited disorder caused by variants in the genes involved in lipoprotein metabolism [15], have elevated LDL-C levels from birth, which are more than double the LDL-C levels observed in patients from the general population [16,17]. In general, such high LDL-C levels are not observed in healthy individuals who adhere to a dietary pattern rich in fat and cholesterol.

Sparked by striking observations from our own clinical practice, we review the available evidence of high-fat, low-carbohydrate diets linked to severe dyslipidemia that may be mistaken for (clinical) FH. We discuss this phenomenon in light of possible pathophysiological explanations, point out knowledge gaps for future research, and provide practical recommendations to clinicians who encounter such patients.

2. High-Fat, Low-Carbohydrate Diets: Examples from the Lipid Clinic2.1. Carnivorous Diet

Two brothers aged 33 years old (patient 1) and 28 years old (patient 2) were referred by their general practitioner to a university lipid clinic because of severe hypercholesterolemia. Upon referral, the LDL-C levels reported by the general practitioner were 15 and 12 mmol/L, respectively.

Both patients had an unremarkable medical history, used no medication, and had no family history of dyslipidemia or (premature) cardiovascular disease. Patients reported exercising regularly (approximately 4×/week, including resistance training) and had a muscular physique with a body mass index (BMI) of 26.2 and 27.3, respectively.

Physical examination was normal and did not specifically show visible cholesterol depositions in the form of xanthomas, corneal arcus, or xanthelasmata.

A fasting blood sample was obtained, and laboratory eval‎uations showed elevated LDL-C of 15.02 mmol/L and 8.59 mmol/L (patients 1 and 2, respectively, Table 1). We ruled out hypothyroidism and proteinuria as secondary causes of hypercholesterolemia. Liver enzymes were within the upper limits of normal. We suspected familial hypercholesterolemia (FH), possibly even in a homozygous form, as the underlying genetic cause and performed the next-generation sequencing of 27 lipid-related genes [16]. However, no pathogenic variants in any of these genes were found.

Dietary anamnesis revealed that both patients had started a carnivorous diet approximately one year prior to presentation to the lipid clinic. This diet consists solely of meat (mostly red) and high-fat dairy products. The calculated energy intake from carbohydrates on a typical day was <3 E-% (6 g/d), meaning that this diet was strongly ketogenic. The intake from protein and fat was 37 E-% and 61 E-%, respectively (see Appendix A).

Although no lipid profiles were available prior to the initiation of the carnivore diet, we suspected this diet to cause an abnormal lipid profile. We strongly advised the patients to adopt a regular, balanced dietary pattern (including carbohydrates and vegetables) and explained the risks of prolonged exposure to such elevated LDL-C levels. However, both decided to continue the carnivore diet and decided against starting lipid-lowering therapy as an alternative way to reduce the elevated LDL-C levels.

We performed fast protein liquid chromatography (FPLC) using stored plasma. This showed disproportionately elevated very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) fractions, which suggested that the overproduction of VLDL contributed to hypercholesterolemia (Figure 1).

Figure 1.

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Results of the total cholesterol distribution in plasma after fast protein liquid chromatography (FPLC) profiling from patient 1 and patient 2 compared with that of pooled plasma from healthy subjects. The elution of the main lipoprotein classes is indicated for very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), respectively.

To better understand the effect of this diet on glucose metabolism, we measured fasting levels of glucose, insulin, and c-peptide and calculated the HOMA-IR to gauge the level of insulin sensitivity. Insulin and c-peptide were close to the lower limit of normal, and HOMA-IR was found to approximate >95th percentile, compared with a relevant reference population [18], which suggested good to very good insulin sensitivity.

We investigated whether a copious intake of dietary fatty acids and cholesterol would overwhelm the hepatic triglyceride and cholesterol pools and manifest as hepatic steatosis. We performed vibration-controlled transient elastography (VCTE) using FibroScan® 530 Compact (Echosens, France) estimated liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) in the right liver lobe of both patients but found no signs of liver fibrosis or steatosis. Liver MR spectroscopy subsequently confirmed the near absence of liver fat in both patients.

We performed a carotid ultrasound, which revealed intima–media thickening suggestive of the early development of atherosclerosis.

Table 1.

Summary of laboratory and imaging results derived from patients 1 and 2 adhering to a carnivore diet.

Patient 1Patient 2Reference Range

BMI (kg/m2)	26.2	27.3	18.5–25
Total cholesterol (mmol/L)	16.81	10.88
HDL cholesterol (mmol/L)	1.53	2.00
LDL cholesterol (mmol/L)	15.02	8.59
Triglycerides (mmol/L)	0.57	0.65	<1.80
ApoB (mg/dL)	321	186	<120
ApoA1 (mg/dL)	156	188
Lp(a) (nmol/L)	18	7	<105
Glucose (mmol/L)	4.3	5.0	<6.0
Insulin (pmol/L)	16.4	17.5	12–96
C-peptide (nmol/L)	0.19	0.19	0.2–0.8
HOMA-IR	0.5	0.6	<2.0
FibroScan CAP (dB/m)	185	185	156–288
FibroScan LSM (kPa)	6.2	6.2	<7
Liver fat content (%)	<2	2.7	<5
Carotid IMT thickness (percentile)	>97th	90th	Based on age and sex, according to [19]

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2.2. Journey from Zero-Carb to Raw-Food Diet

Patient 3 was a 23-year-old male referred to the academic hospital lipid clinic for the analysis of severe hypercholesterolemia, with an LDL-C level of 12.2 mmol/L reported by his general practitioner.

The patient had no relevant medical history and used no medication. Besides his maternal grandmother, who had started statin therapy at an elderly age, it was unknown if family members had hypercholesterolemia. The family history of cardiovascular disease was negative. The patient told us he had specially requested a lipid panel measurement from his general practitioner because he was interested to learn his blood cholesterol levels after having recently adopted a new diet. The patient reported that, since his youth, he had struggled to maintain a healthy and balanced diet and that he had experienced that his dietary pattern was closely linked to his psychological well-being. The patient had, therefore, experimented with progressively eliminating food products from his diet. This led to the point that, at the time of referral, the patient was on a zero-carb diet rich in animal proteins and fats in the form of eggs and bacon, supplemented with raw minced meat, raw liver, and a limited amount of vegetables.

Physical examination showed a lean young male (BMI 21 kg/m2) without signs of xanthoma, xanthelasmata, or corneal arcus, and was otherwise unremarkable.

A repeat lipid profile was obtained, which showed somewhat lower, albeit still severely elevated, levels of LDL-C at 7.9 mmol/L, which could well be consistent with heterozygous FH. However, genetic analysis using next-generation sequencing showed no FH-causing variant. It was suspected that the patient’s diet contributed to the elevated LDL-C levels. Dietary changes as well as the lowering of LDL-C by starting statin therapy were discussed, and the patient opted to modify his diet first.

Three months later, the patient had significantly reduced his intake of animal fats (mostly cut his intake of eggs and bacon), and a repeat lipid panel showed a near normalization of LDL-C levels (Table 2), after which he was referred back to the care of the general practitioner. The most recent lipid panel was completely normal for age and gender. At this time, the patient reported being on a balanced raw food diet with approximately 400 g of raw meat or fish daily, supplemented with leafy vegetables, nuts, and fruit (usually 2 or 3 mangos daily). The patient reported no intake of starchy carbohydrates.

Table 2.

Lipid panels of patient 3.

ReferralLipid Clinic, First VisitLipid Clinic, Second VisitStudy VisitTimepointT = 0+3 Months+6 Months+4 Years

Total cholesterol (mmol/L)	15.0	10.07	5.11	3.79
HDL cholesterol (mmol/L)	2.22	1.76	1.55	1.17
LDL cholesterol (mmol/L)	12.15	7.93	3.40	2.29
Triglycerides (mmol/L)	1.40	0.85	0.35	0.74
ApoB (mg/dL)	N.A.	N.A.	N.A.	64

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2.3. Heterozygous Familial Hypercholesterolemia Derailed

Patient 4 was a male diagnosed with FH (variant p.R3500Q in APOB) at the age of 31 years old, with no relevant medical history. Following the diagnosis of FH, a statin combined with ezetimibe had been prescribed as lipid-lowering therapy, and the patient was regularly followed up by his internist at the lipid clinic.

At the age of 41 years old, the patient started a low-carb high-fat diet along with his spouse, who intended to lose weight. At the latest lipid panel obtained before the patient had started this diet, LDL-C levels were relatively well controlled at 2.9 mmol/L, with the patient taking rosuvastatin 40 mg and ezetimibe 10 mg daily. However, when the patient presented for his next yearly follow-up visit after having adopted his new diet, LDL-C levels were severely elevated at 8.39 mmol/L (Table 3). Adherence to lipid-lowering medication was unchanged, and secondary causes of hypercholesterolemia (hypothyroidism and proteinuria) were ruled out. The estimated untreated LDL-C levels would well be within the range observed in patients with homozygous FH.

Table 3.

Lipid panels of patient 4.

Pre-DietOn DietModified DietTimepointT = 0+6 Months+9 Months

Total cholesterol (mmol/L)	4.7	10.8	5.1
HDL cholesterol (mmol/L)	1.4	2.15	1.4
LDL cholesterol (mmol/L)	2.9	8.39	2.8
Triglycerides (mmol/L)	0.9	1.78	0.8
ApoB (mg/dL)	79	194	79

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The patient was referred to a dietician for dietary assessment and counseling. His diet was shown to be low in carbohydrates and high in dairy fats (Appendix B), and recommendations were made for a more balanced diet. His BMI dropped from 23.4 to 21.4 kg/m2 with diet. With the help of his dietician, the patient modified his diet by, amongst others, reducing his intake of dairy fat. At the next follow-up visit, LDL-C had completely normalized to pre-diet levels (Table 3), with unchanged adherence to lipid-lowering therapy.

3. Mechanism of Dietary Induced Hypercholesterolemia

Recent observations from our clinical practice add to the emerging literature describing the association between high-fat, low-carbohydrate diets and severe hypercholesterolemia. We reviewed these findings and possible pathophysiological explanations for this phenomenon as well as opportunities for future research. We argue that clinicians should rule out adherence to a high-fat, low-carbohydrate diet in patients presenting with clinical FH.

Several other studies have reported patients consuming a high-fat ketogenic diet who present with high LDL-C levels consistent with FH, which was shown to be reversible with the normalization of the diet. Goldberg and colleagues reported five cases of LDL-C levels ranging from 6.3 to as high as 17.7 mmol/L. Genetic analysis revealed no pathogenic FH variants in any of the patients, although the patient with the highest cholesterol levels was found to have dysbetalipoproteinemia (confirmed by identification of APOE E2/E2 genotype) [20]. Schaffer et al. reported three patients with severe hypercholesterolemia (LDL-C levels of 8.9, 11.5, and 15.5 mmol/L), whose LDL-C levels decreased after making dietary modifications [21]. Norwitz and colleagues reported a series of five patients on a ketogenic diet whose LDL-C levels ranged from 6.2 to up to 17.2 mmol/L. All tested negative for an FH-causing variant and after the reported moderate reintroduction of carbohydrates (50–100 g/day), hypercholesterolemia attenuated and even normalized in one patient [22]. The same authors also recently described a 26-year-old male with ulcerative colitis who, in an attempt to relieve its symptoms, initiated a ketogenic diet on which LDL-C levels peaked at 14.1 mmol/L [23]. Interestingly, a coronary CT angiography did not show (non)calcified plaque after two years of exposure to LDL-C levels in a similar range, as seen in patients with homozygous FH [23,24].

The fact that this phenomenon is more widespread than the subject of academic curiosity, only described in rare case descriptions, is exemplified by a recent online survey that collected patient-reported data, including lipid panels, from several hundred adults following a carbohydrate-restricted diet [22]. Of all the 903 participants who participated in the survey, 42% and 22% reported having LDL-C levels higher than 6.5 mmol/L and 8.5 mmol/L, respectively. These values are thresholds in the Dutch Lipid Clinic Network (DLCN) criteria used in the (clinical) diagnosis of FH. Notably, 5% of the respondents entered LDLC levels > 13 mmol/L, which is considered to be consistent with homozygous FH, the most severe form of inherited dyslipidemia, which can cause cardiovascular mortality as early as in childhood if left untreated [24,25].

These observations, combined with the cases we described, are examples that both individuals adhering to these diets as well as their clinicians, should be cautious of their potential to cause or exacerbate severe hypercholesterolemia. High-fat, low-carbohydrate (‘keto’) diets may be considered in a line of fad diets known for exaggerated health claims and are frequently propagated through social media, where health misinformation is widespread, and the quality is difficult to assess [26]. Support for these diets is often provided in the form of opinionated, absolute statements that lack the backing of good-quality evidence highlighting harms and benefits [27,28]. Nevertheless, the number of individuals who follow a high-fat, low-carbohydrate diet is considerable and increasing. This diet is reported among the most frequently followed dietary patterns in the United States, with comparable preval‎ence to the commonly recommended Mediterranean and dietary approaches to stopping hypertension (DASH) diet [29,30]. There is currently no evidence to support that prolonged exposure to high levels of LDL-C in the context of high-fat, low-carbohydrate diets is not atherogenic (and therefore ‘safe’), which should be balanced against the totality of evidence on atherogenic lipoproteins and their causal role in the development of ASCVD [1].

The observations of extreme hypercholesterolemia described here and by others beg a discussion of possible pathophysiological explanations for this phenomenon. High levels of LDL-C may result from the reduced clearance of LDL particles from the circulation, the increased production of their VLDL precursor, or a combination of both. The increased intake of dietary fat and cholesterol, combined with limited to no intake of carbohydrates, are salient features of the diets consumed by the patients we described. In the following sections, we discuss these factors and their potential roles in the pathophysiology of hypercholesterolemia individually, but it is likely that these factors act in concert.

3.1. Increased Intake of Dietary Cholesterol

Cholesterol stores in the human body are in a constant state of flux. Cholesterol in LDL particles either originates from intestinal absorption or de novo synthesis in the liver. After an LDL particle is taken up by the liver, its cholesterol content enters the hepatic cholesterol pool and may either be secreted back into the bloodstream packed in lipoproteins or be excreted in bile directly or after conversion to bile acid. Combined with the intake from diet, this cholesterol is partly taken up by the intestine and transported back to the liver and partly exits the body through feces [31]. It could be hypothesized that the hypercholesterolemia observed in our patients is partly due to their cholesterol-rich diet.

However, cholesterol absorption, synthesis, and biliary excretion appear to be balanced in a way that the dietary intake of cholesterol, under normal circumstances, only modestly translates into the cholesterol levels found in the circulation. For example, vegans consuming 90% less dietary cholesterol than omnivores were found to have plasma LDL-C levels that were only 13% lower [32]. A meta-analysis of intervention studies that supplemented cholesterol through diet showed only moderate increases in LDL-C levels (up to 0.22 mmol/L) [33]. The apparent ‘resilience’ of the plasma cholesterol to high dietary cholesterol intake is exemplified by a case report of an 88-year-old male who ate 25 eggs per day but had a normal plasma LDL-C level of 3.68 mmol/L and no clinically important atherosclerosis. Isotope studies revealed that, compared with 10 healthy controls, the subject had a markedly reduced rate of cholesterol absorption and hepatic cholesterol synthesis but greatly increased synthesis of bile acids [34].

In healthy adults, the average fractional absorption rate of cholesterol in the intestine is approximately 50% but with great inter-individual variation ranging from 20% to 80% [35,36]. Although stable isotope studies were beyond the scope of our study, it is possible that the increased dietary intake of cholesterol exceeded the relative capacity to downregulate its intestinal absorption in our patients. The overload of dietary cholesterol delivered to hepatocytes may contribute to the downregulation of the LDL receptor (LDLR) and thus increase the circulating LDL-C levels [37,38,39].

The influence of gut microbiota on bile acid metabolism is another factor influencing cholesterol absorption [40]. Gut microbiota influence the circulating LDL-C levels via the conjugation of primary bile acids to secondary bile acids [41] and by facilitating bile acid excretion into feces [40]. Specific bacterial phyla, such as Lactobacillus and Clostridium, can prevent the reabsorption of bile acids into the enterohepatic circulation through the deconjugation of bile acids. Since most bile acids are taken up in a conjugated form, deconjugation by gut microbes may be an important factor in mediating cholesterol levels. It is possible that a high-fat, low-carbohydrate diet alters gut microbiota composition in an unfavorable way so that the intestinal reabsorption of bile acids and cholesterol is enhanced, and hence, cholesterol accumulates more quickly in the circulation. Unfortunately, fecal samples were unavailable from the cases we described.

3.2. Increased Intake of Dietary Fatty Acids

In the second half of the 20th century, large epidemiological studies linked the composition of dietary fat with plasma LDL-C levels and cardiovascular outcomes [42]. It is now clearly established that the intake of saturated fatty acids (SFAs) increases the circulating LDL-C levels, although the overall effect of limiting SFA intake on cardiovascular health remains controversial [43,44]. Meta-regression analysis of 84 feeding studies showed that replacing the daily energy intake from SFAs with carbohydrates or unsaturated fatty acids considerably lowers LDL-C levels [45]. The LDL-increasing mechanism of SFAs was investigated in various in vitro and in vivo models [46] and likely involves decreased mRNA and protein expression‎ of LDLR, as well as decreased LDLR activity [47]. It has to be noted that this effect depends on SFA type: 12–16 carbon fatty acids, found in dairy and red meat, have the largest effect to raise LDL-C [43,44]. This notion is supported by feeding trials in which increased SFA intake in the form of red meat resulted in higher LDL-C levels than the same SFA intake through nonmeat protein sources [48]. High SFA intake by our patients likely contributed to their hypercholesterolemia, and the fact that LDL-C levels dropped when patient 4 exchanged his intake of butter, meat, and dairy products for more vegetables and vegetable oils supports this notion.

Furthermore, an increased flux of fatty acids to the liver stimulates the assembly and secretion of VLDL particles [49], which would be in line with the abundance of VLDL-C observed with FPLC analysis in patients 1 and 2. However, the absence of triglycerides suggests other factors are also at play, such as extremely efficient lipolytic activity or the active exchange of cholesteryl esters.

3.3. Decreased Intake of Carbohydrates

Diets are generally considered very low in carbohydrates when the energy intake from carbohydrates is <10% of the total energy intake or <50 g per day [50]. These diets have been recommended as a treatment for patients with specific medical conditions, such as rare metabolic diseases or epilepsy, where hyperlipidemia is a well-known side effect of the ketogenic diet [51,52]. The ketogenic diet is gaining increasing scientific attention in the field of sports medicine, where multiple feeding trials have been conducted in healthy athletes that consistently show increases in LDL-C levels [53,54,55,56,57]. However, individual responses are variable, and LDL-C levels do not reach the levels consistent with homozygous FH, as observed in the extreme cases we presented. Carbohydrate-restricted diets have further gained attention through popular scientific news outlets and social media channels to reduce weight, as was the case for patient 4.

A decreased intake of carbohydrates inadvertently means that the relative intake of protein and/or fat is increased, but the relative importance of ‘low-carbohydrate’ vs. ‘high-fat’ diet intake in causing hypercholesterolemia remains to be established. It has been hypothesized that carbohydrate restriction leads to increased dependence on fat as a metabolic substrate, which drives the increased hepatic secretion of triglyceride rich VLDL. It is thought that triglycerides are taken up very rapidly by peripheral tissues, which have come to rely heavily on fats as their metabolic substrate. The resulting lipid profile is characterized by markedly elevated levels of LDL-C and HDL-C, yet low triglycerides [58]. Our observation of elevated VLDL-C, LDL-C, and HDL-C, combined with relatively low levels of triglycerides found in patients 1 and 2, are in support of this ‘lipid energy model’. The authors further hypothesize that low levels of insulin, as we observed in patients 1 and 2, in combination with low hepatic glycogen stores (not measured by us), contribute to increased VLDL secretion rates. There is anecdotal evidence that the reintroduction of carbohydrates reverses the hypercholesterolemia seen in these subjects [22,23], but this could not be accurately assessed in our patients. Future studies, such as stable isotope studies under controlled feeding conditions, are required to unravel the relative importance of carbohydrate restriction on the observed increases in LDL-C levels. Such studies can also be used to determine both the excretion and absorption rates of cholesterol in the gut, as well as the production and uptake of lipoproteins by the liver in the context of high-fat, low-carbohydrate diets.

4. Conclusions and Future Research

In conclusion, mounting evidence describes the relationship between high-fat, low-carbohydrate diets and severely elevated plasma LDL-C levels generally considered to be consistent with (homozygous) FH. This phenomenon provides unique opportunities to study the fundamental (patho)physiological mechanisms involving cholesterol and lipoprotein homeostasis. Clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and ASCVD risk.

Acknowledgments

The authors thank the participants for their contribution to this research.

Appendix ADietary Pattern of Patient 1 on an Example Day

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Table A1.

Calculated energy (kcal) and macronutrient (g and E-%), fiber (g), salt (g), and sodium (mg) intake on an example day of case 1 on a carnivore diet.

Patient 1

Energy (kcal/d)	3275
Fat (g/d)	220.5
Fat (E-%)	60.6
Saturated fat (g/d)	99.0
Saturated fat (E-%)	27.2
Protein (g/d)	304.1
Protein E-%	37.1
Carbohydrate (g/d)	5.5
Carbohydrate (E-%)	0.7
Alcohol (g/d)	6
Fiber (g/d)	0.4
Salt (g/d)	12.8
Sodium (mg/d)	5097

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E-%, percentage of energy intake; g/d, grams per day; kcal/d, kilocalories per day; mg/d, milligrams per day.

Appendix BDietary Pattern of Patient 4 on Example Days

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Table A2.

Calculated energy (kcal) and macronutrient (g and E-%), fiber (g), salt (g), and sodium (mg) intake on an example day of case 4 on a low-carbohydrate, high-fat diet.

Patient 4

Energy (kcal/d)	1912
Fat (g/d)	147.2
Fat (E-%)	69.3
Saturated fat (g/d)	74.1
Saturated fat (E-%)	34.9
Protein (g/d)	85.2
Protein (E-%)	17.8
Carbohydrate (g/d)	55.3
Carbohydrate (E-%)	11.6
Alcohol (g/d)	0.0
Fiber (g/d)	17.2
Salt (g/d)	3.9
Sodium (mg/d)	1558

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E-%, percentage of energy intake; g/d, grams per day; kcal/d, kilocalories per day; mg/d, milligrams per day.

Author Contributions

Conceptualization, T.R.T., V.H. and A.K.G.; resources, E.S.G.S.; data curation, T.R.T., J.H.M.L. and J.R.v.L.; writing—original draft preparation, T.R.T. and V.H.; writing—review and editing, A.G., D.M.C., J.R.v.L., A.K.G. and E.S.G.S.; visualization, T.R.T. and V.H.; supervision, A.K.G. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Amsterdam UMC, location AMC (protocol code NL62407.018.17) for studies involving humans.

Informed Consent Statement

Written informed consent has been obtained from the patient(s) to publish this paper.

Data Availability Statement

Not applicable.

Conflicts of Interest

V.H., A.G., D.M.C., J.H.M.L., A.K.G. and T.R.T. declare no conflict of interest. J.R.v.L. reports research grants from Amryt and Novartis (all paid to the institution). E.S.G.S. reports consulting fees from Amgen, Sanofi, Regeneron, Esperion, Novartis, and Ionis/Akcea (all paid to the institution).

Funding Statement

This research was funded by research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445) and Klinkerpad funds. VH is appointed by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 813781 ITN BestTreat.

Footnotes

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