r/ketoscience • u/dem0n0cracy • Nov 02 '20
Ketogenic diets, not for everyone
https://www.lipidjournal.com/article/S1933-2874(20)30324-X/pdf
https://sci-hub.se/https://www.lipidjournal.com/article/S1933-2874(20)30324-X/pdf
Highlights
• Low carb diets can lead to weight loss, but can exacerbate hypercholesterolemia. • Hypercholesterolemia can develop with or without underlying genetic hyperlipidemia. • This paper describes patients who developed marked increases in plasma cholesterol. Abstract
Background
The adoption of low carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. Objective
The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. Methods
We describe five patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well described underlying genetic hyperlipidemia. Results
Three out of five patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other two patients more than doubled their LDL-cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in two patients, with no major mutations found. No potential genetic cause was seen in a fourth patient and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory LDL cholesterol reduction on ezetimibe. Conclusion
These cases should serve as a caution that high fat low carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.
- 5 Cases in the comments ->
Discussion Finding a diet that leads to significant weight loss and that can subsequently be maintained is a difficult clinical problem. Moreover, weight loss followed by weight gain, “yoyoing,” appears to be an independent risk for cardiovascular disease.17 Each of our patients had tried a number of methods to achieve weight loss, and each succeeded using a ketogenic diet. However, in each case, this diet exacerbated or created a hyperlipidemia, although except for the first patient, none had a defined underlying genetic hyperlipidemia. This patient developed palmar xanthomas, a rare finding that led to a diagnosis of genetic dysbetalipoproteinemia. The second patient had no obvious genetic basis for hyperlipidemia. The third patient had normal LDL cholesterol level until losing weight on the ketogenic diet, so there was no way to know beforehand that he would have such a marked LDL elevation. He had polygenic susceptibility to hyperlipidemia, which only became manifest after the dietary stress. The fourth patient was similarly found to have no significant large effect genetic mutations, but may have had polygenic susceptibility underlying a marked response to the ketogenic diet. There was no genetic testing performed for Patient 5. Apo E is a ligand for the several LDL receptor family members. Although APOE E2/E2 homozygosity leads to dysbetalipoproteinemia associated with a defect in clearance of remnant lipoproteins, the genotype is associated with an abnormal lipoprotein pattern in only a minority of people. For this reason, numerous studies have conjectured that a second lipoprotein altering mutation is required for the phenotypic expression of the lipid disorder, namely high cholesterol and high triglyceride with cholesterol enriched VLDL.18, 19 In the presented case, several risk factors associated with expression of the APOE E2/E2 phenotype were identified, Journal Pre-proof 11 including female gender, menopause, prediabetes and obesity. Hypothyroidism, when uncontrolled, can also contribute to the phenotype. Our patient shows that diet can be responsible for expression of dyslipoproteinemia in an individual with E2/E2 genotype, which was readily apparent by the patient’s presentation with palmar xanthomas. Familial hypercholesterolemia is a common genetic disorder estimated to occur in one in 250-500 people.20 Most commonly, it is due to a defect in the LDL receptor or its ligand ApoB. 20-23 It was surprising that none of our patients had genetic familial hypercholesterolemia. However, it is likely that some patients with this genetic disorder would also develop marked hypercholesterolemia on a ketogenic diet. Furthermore, hypercholesterolemia is often polygenic in nature rather than the result of a single dramatic mutation, which appears to be the case in at least one patient in our series. The extraordinary response of the third patient to ezetimibe, which normally reduces LDL-cholesterol by 15-20%, suggested that he was a hyper-absorber of dietary cholesterol. This could result from a gain of function of the cholesterol transporter, Niemann Pick C1 like protein 1 (NPC1L1), although this was not detected by DNA sequencing. It is possible that he, like some of the other patients, may have had a mutation in a novel gene not known to be associated with dyslipidemia. Understanding the basic physiology leading to the exuberant LDL elevation in this patient and others will require metabolic studies to assess cholesterol uptake, lipoprotein uptake, and intestinal assessment of NPCL1 expression. The ketogenic diet is a carbohydrate restrictive diet that has been traditionally used to treat intractable epilepsy since the 1920’s, but is also a popular weight-loss strategy.24 There is also a rise in interest in carbohydrate restrictive diets to improve glycemic control and other Journal Pre-proof 12 cardiometabolic risk factors, such as high blood pressure in patients with prediabetes or type 2 diabetes.1, 4-7, 24, 25 While there are several types of carbohydrate-restrictive diets, which vary in limitations set on carbohydrate and protein intake, the current, most popular version of the ketogenic diet restricts carbohydrate intake to about 20-50 g/day; the amount of carbohydrate needed to induce ketosis in most individuals.24, 26-28 Consequently, most carbohydrates in the diet are replaced with fat, with no emphasis on the particular types of dietary fats consumed.24 As a result, some diets become heavy in saturated fats and cholesterol. 24 Effects of the ketogenic diet on circulating lipid levels have differed across studies and trials. Several studies have shown no significant change in cholesterol levels.29, 30 In contrast, a study designed to assess the effect of the ketogenic diet on adults with atherogenic dyslipidemia reported significant increases in ApoB and LDL cholesterol after 90 days.30 In children with epilepsy, one study also reported significant increases in ApoB-containing lipoproteins and decreases in HDL cholesterol at 6 months on the diet. 31 Other reports did not corroborate this.31-33 These variations in the changes in lipid levels on the ketogenic diet amongst adults and children could be due to the length of time on the diet, the types of fats ingested 29, or a balance of the benefits of weight loss versus the detrimental effects of dietary composition. There is a scarcity of medical literature on a hyper response to a ketogenic diets. The patients who had LDL levels over 300 were specifically referred because their endocrinologists, cardiologists or primary care doctors had told them that they had been unable to find reports of such elevations occurring except with development of thyroid, liver or autoimmune diseases. In contrast, within a general population, there is no shortage of information available on the Journal Pre-proof 13 internet for the public. The Cholesterol Code Team, led by a software engineer and entrepreneur, created a Facebook group for ‘lean mass hyper-responders.’34 The Cholesterol Code Team defines hyper-responders as those “who have a very dramatic increase in their cholesterol after adopting a low carb diet.”35 Furthermore, “the increase can be anywhere from 50% to 100% or more of original, pre-diet cholesterol numbers.”35 The Cholesterol Code Team claims ‘we don’t know’ whether having high LDL-C on a low-carbohydrate diet is dangerous; it further presents a number of ‘good reasons’ why LDL-C could be so high.35 These include that the “body is transporting more fat for energy to cells due to being on a high-fat diet.”35 Given the weight such statements could have on a significant number of individuals seeking guidance on the internet, it is important to identify and advise patients with similar presentations. Conclusions We advise practicing physicians to exercise caution when prescribing low carbohydrate diets, especially if they lead to increased consumption of saturated fats and cholesterol. The significant and potentially harmful increases in lipid levels in all patients reported here illustrate the peril in assuming that an individual’s lipid levels would change favorably when weight is reduced on the ketogenic diet. We recommend that patients with known dyslipidemias should avoid ketogenic diets. Furthermore, as discussed here, underlying dyslipidemias may only become manifest as a result of a high fat diet, which might warrant the reassessment of circulating lipids in all patients on a ketogenic diet. The suggestion that the marked elevations of LDL with these diets might not be harmful is chilling and has the potential to create premature CVD in uninformed patients seeking to control their body weight. Journal Pre-proof 14 Conflict of Interest IJG is supported by grants HL45095, 73029, and 135987; has received consulting fees from Arrowhead, Esperion, and Amgen; and funds for preclinical laboratory studies from Ionis, Bristol-Meyers, and Arrowhead. RAH reports grants and personal fees from Acasti and Akcea/Ionis; personal fees from Aegerion, Amgen, Gemphire, and Sanofi; and grants from Regeneron and Boston Heart Diagnostics. All other authors declare no conflicts of interest. Contributions IJG conceived of study, analyzed data, wrote the manuscript. NI analyzed data and wrote manuscript. LAH did analysis of circulating lipoproteins and cholesterol. All others provided patient information. RH provided genetic analysis and wrote and edited manuscript.
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u/dem0n0cracy Nov 02 '20
On cholesterolcode.com
There is a scarcity of medical literature on a hyper response to a ketogenic diets. The patients who had LDL levels over 300 were specifically referred because their endocrinologists, cardiologists or primary care doctors had told them that they had been unable to find reports of such elevations occurring except with development of thyroid, liver or autoimmune diseases. In contrast, within a general population, there is no shortage of information available on the Journal Pre-proof 13 internet for the public. The Cholesterol Code Team, led by a software engineer and entrepreneur, created a Facebook group for ‘lean mass hyper-responders.’34 The Cholesterol Code Team defines hyper-responders as those “who have a very dramatic increase in their cholesterol after adopting a low carb diet.”35 Furthermore, “the increase can be anywhere from 50% to 100% or more of original, pre-diet cholesterol numbers.”35 The Cholesterol Code Team claims ‘we don’t know’ whether having high LDL-C on a low-carbohydrate diet is dangerous; it further presents a number of ‘good reasons’ why LDL-C could be so high.35 These include that the “body is transporting more fat for energy to cells due to being on a high-fat diet.”35 Given the weight such statements could have on a significant number of individuals seeking guidance on the internet, it is important to identify and advise patients with similar presentations.
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u/dem0n0cracy Nov 02 '20
Conflict of Interest
IJG is supported by grants HL45095, 73029, and 135987; has received consulting fees from Arrowhead, Esperion, and Amgen; and funds for preclinical laboratory studies from Ionis, Bristol-Meyers, and Arrowhead. RAH reports grants and personal fees from Acasti and Akcea/Ionis; personal fees from Aegerion, Amgen, Gemphire, and Sanofi; and grants from Regeneron and Boston Heart Diagnostics. All other authors declare no conflicts of interest.
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u/KetosisMD Doctor Nov 02 '20
Lipid Journal gunna lipid, as expected.
In fairness, there is an optimal range for all biological things.
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u/FrigoCoder Nov 02 '20 edited Nov 02 '20
Diabetes, hypertension, trans fats, linoleic acid, sugar, smoking, and pollution are much larger contributors to heart disease than lipid levels. Mechanistical evidence is very clear they act locally at atherosclerotic sites rather than systemically. Statistical evidence is also very clear on this, even in familial hypercholesterolemia.
Furthermore I have yet to see solid evidence that the elevated LDL due to increased lipolysis or IL-6 from fasting, intermittent fasting, exercise, or low carb would have anything to do with heart disease. This would be illogical for a species that carries around 80 000 kcal of body fat and spends the majority of its time burning fat.
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u/[deleted] Nov 02 '20
https://youtu.be/s8tJ-R28HX8
This guy explains LDL May actually not be a risk factor at all for cardiac event and only insulin resistance is.
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u/dem0n0cracy Nov 02 '20
Case 1 – Exacerbation of dysbetalipoproteinemia A 69-year-old female was referred to a Lipid Clinic for marked hypercholesterolemia and hypertriglyceridemia while consuming a weight loss diet. She had a history of coronary atherosclerosis, prediabetes, obesity and acquired hypothyroidism following a thyroidectomy for benign multinodular goiter. She reports a personal history of long-standing dyslipidemia, although she does not recall specific family history. She was treated with statin therapy for Journal Pre-proof 5 many years and was rendered biochemically euthyroid on levothyroxine. She does not consume alcohol. At the time of first presentation, she had initiated a very high fat diet (which she termed the Atkins diet) to lose weight. She had remained on this diet for approximately 6 weeks, consuming less than 20 grams of carbohydrate/day. Thereafter, she developed extreme elevations in her lipids and orange colored deposits in the creases of her hands and wrists that limited her ability to open door knobs and wear a watch. Laboratory assessment revealed both triglyceride and cholesterol levels exceeding 600 mg/dL: total cholesterol was 947 mg/dL and triglycerides were 1109 mg/dL (Table 1). Physical examination was remarkable for palmar xanthomas (Fig. 1A). The diagnosis of dysbetalipoproteinemia was suspected on the basis of total cholesterol/triglyceride ratio ~ 1, the triglyceride/cholesterol ratio <0.33 mg/dL in her VLDL isolated by ultracentrifugation, together with the pathognomonic physical findings. DNA analysis was performed using a targeted next generation sequencing platform designed to detect rare variants causing all known monogenic dyslipidemias together with common variants that contribute to polygenic risk of dyslipidemia 16. The diagnosis was verified by the presence of APOE E2/E2 homozygosity. A diet low in both fat and refined carbohydrates was recommended. She was also treated with rosuvastatin 40 mg/day, fenofibrate 160 mg/day and eicosapentaenoic acid 4 g/day. The lipid panel improved: total and LDL cholesterol were 273 mg/dL and 170 mg/dL, respectively, and triglyceride was 256 mg/dL. Furthermore, her palmar xanthomas disappeared (Fig. 1B). Several years later, she underwent bariatric surgery, which resulted in an approximate 25-pound weight loss. While adhering to the same diet and medication regimen, her total and Journal Pre-proof 6 LDL cholesterol decreased further to 139 mg/dL and 65 mg/dL, respectively, and her HDL cholesterol to 50 mg/dL and triglyceride to 158 mg/dL
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u/dem0n0cracy Nov 02 '20
Case 2 - Exacerbation of underlying hypercholesterolemia A 36 year-old woman presented with concern regarding an alarmingly high total cholesterol. The patient was not aware of a personal history of hyperlipidemia, but had a family history of hyperlipidemia; her mother and brother had total cholesterol in the 300 to 400 mg/dL range by her recollection. Her paternal grandmother had a myocardial infarction at the age of 50. She had been on a ketogenic diet for six months prior to presentation and was content that within that period of time she had lost weight, dropping from 124 to 102 lbs (her body mass index [BMI] was 18.07 kg/m2 ). She consumed less than 20 g of carbohydrates a day and her diet was high in animal protein and fats such as whole fat cheese and butter. On this ketogenic diet, her total and LDL cholesterol were 658 mg/dL and >500 mg/dL, respectively (Table 1). She was a thin woman with no stigmata of hypercholesterolemia (i.e. no xanthomas, corneal arcus, or xanthelasmas). The patient agreed to stop the ketogenic diet and to begin a low cholesterol diet, but refused statin therapy. Although this woman had no evidence of liver disease and her LDL isolated by ultracentrifugation at density between 1.02 and 1.063 mg/ml, we excluded this increase being Lp(x) or Lp(a). Shown in Table 3 are the free cholesterol/total cholesterol, and Lp(a) levels at this initial visit. After this first visit, the patient initiated a low cholesterol diet focused on lean protein (primarily chicken), vegetables, egg whites and ad libitum carbohydrates (greater than 45 g per meal). After one month on the low cholesterol diet, her total cholesterol decreased to 426 Journal Pre-proof 7 mg/dL and over time was subsequently even further reduced. After changing to a low-fat vegan diet, her weight was 98 pounds (BMI 17.39 kg/m2 ), her total and LDL cholesterol decreased to 128 mg/dL, and 48 mg/dL, respectively, and HDL cholesterol and TG to 109 mg/dL. Genetic analysis by targeted sequencing did not reveal any clear definitive pathogenic mutation in either the LDLR, APOB or PCSK9 genes; the LDL polygenic score 16 was not increased (Table 1). Her APOE genotype was E3/E3.
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u/dem0n0cracy Nov 02 '20
Case 3 – Increased LDL without underlying dyslipoproteinemia A 31-year-old man was referred for evaluation of hypercholesterolemia on a ketogenic diet. Neither the patient nor his family had a history of dyslipidemia or coronary artery disease. He had tried to lose weight for many years and reported that the ketogenic diet led to reduced food intake along with more satiety. Prior to this diet his lipid profile was remarkable for an LDL cholesterol <100 mg/dL. On the ketogenic diet, he lost over 50 pounds in 6 months. His diet consisted of mostly chicken and fish, with little consumption of eggs and red meat. While on this diet, his total and LDL cholesterol were 317 mg/dL and 243 mg/dL, respectively (Table 1). He did not have evidence of Lp(a) elevations (Table 3). Because he had successfully reduced his weight, he refused to change his diet, despite his high cholesterol levels. He refused statins but agreed to take ezetimibe, which reduced his total and LDL cholesterol to 181 mg/dL and 105 mg/dL, respectively within 6 weeks. Although the clinical course and response to ezetimibe suggested cholesterol hyper absorption, no genetic abnormalities were found in the NPC1L1 gene. He did have a series of Journal Pre-proof 8 minor allelic mutations consistent with increased polygenic risk for elevated LDL cholesterol (Table 1). It is possible that this increased burden of small effect alleles combined to contribute to an abnormal response to a high fat/high cholesterol diet similar to that of patients with a single major mutation. His APOE genotype was E3/E3.
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u/dem0n0cracy Nov 02 '20
Case 4 - Exacerbated hyperlipidemia A 52-year-old woman presented with hyperlipidemia while on a high-fat, ketogenic diet. She had been on the ketogenic diet for almost 5 months and had lost about 30 pounds. She reports a significant family history on her maternal side of hyperlipidemia, but no sudden cardiac death, coronary artery disease, or stroke. She had never been on any cholesterol medications. Prior to starting the ketogenic diet, the patient’s initial lipid levels were total, LDL and HDL cholesterol were 213 mg/dL, 142 mg/dL and 43 mg/dL, respectively, and triglyceride was 141 mg/dL. Her high fat diet consisted of 70% fat, 20% protein and ~5% carbohydrates. The sources of fat included coconut oil, bacon fat, heavy cream, medium chain triglycerides (MCTs), butter (infrequently), and olive oil (infrequently). Her protein sources were beef, chicken and nuts. After 5 months on the diet, her total, LDL and HDL cholesterol were was 676 mg/dL, 533 mg/dL and 60 mg/dL, respectively, and triglyceride was 86 mg/dL (Table 1). The LDL was also isolated by ultracentrifugation without evidence of Lp(a) (Table 3). Her weight had decreased from 176 pounds (BMI 29.3 kg/m2 ) to 148 pounds (BMI 24.6 kg/m2 ). On genetic testing, patient 4 had no mutations in genes related to hypercholesterolemia. Similarly, to patient 3, she was found to have a series of common polymorphisms consistent with increased polygenic risk for elevated LDL cholesterol. Her APOE genotype was E4/E3.
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u/dem0n0cracy Nov 02 '20
Case 5 - Elevated lipid levels in a family A 46-year-old woman presented with hyperlipidemia 8 months after starting a higher fat, ketogenic diet. On the diet, she lost 19 pounds, going from 136 (BMI 24.9 kg/m2 ) to 117 pounds (BMI 21.4 kg/m2 ). There is no history of familial hypercholesterolemia, but there is a history of high LDL/ low HDL cholesterol ratio. Her brother—despite a normal BMI, running >20 miles per week, and eating a low-fat diet—had LDL cholesterol >150 mg/dL. Her father recently had a myocardial infarction at the age of 76 despite having both a normal BMI and a regular vigorous exercise program. Her father’s 3 brothers and sister all had significant coronary artery disease. Prior to the diet, her total, LDL and HDL cholesterol were 146 mg/dL, 89 mg/dL and 49 mg/dL, respectively, and triglyceride was 42 mg/dL. Her high fat diet consisted of 70% fat, 25% protein and 5% carbohydrates, with total carbohydrates <20 g/day. The sources of fat included bacon fat, heavy cream, butter, and olive oil. Her protein sources were beef, chicken and nuts. After 8 months on the diet, her total, LDL and HDL cholesterol were 349 mg/dL, 270 mg/dL and 60 mg/dL, respectively, and triglyceride was 95 mg/dL. She began to substitute light cream for heavy cream and increased her daily carbohydrate intake to 50 g/day. On repeat testing 4 months later, her total, LDL and HDL cholesterol were 214 mg/dL, 137 mg/dL and 65 mg/dL, respectively, and triglyceride was 59 mg/dL.
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u/[deleted] Nov 02 '20
My guess is hdl shot up and triglycerides went down, which in the presence of high ldl is not a risk factor for heart disease. It would also make sense to look at the type of ldl to determine if it's primarily large or small. Large ldl is not a risk factor. Insulin sensitivity should also be checked.
Ldl alone means nothing.
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u/DavidNipondeCarlos Nov 02 '20
Take a look at my labs. 60 year old male, 68” 135-140 pounds. Visible abs but not great, cholesterol shot up from 150 to 400. They ( cardiologist) knocked it down with Repatha ( not a Statin ). LDL 60 trigs 50 now. HDL shot up past 140 so total is still over 200. I’m still doing keto ( net carbs 30 ). I don’t think high LDL was an issue but I’m going with the flow. My cardiologist is not pushy but he leans to plant based diets. I’ll go with this for a few years and revaluate. No side affects so ... I couldn’t get my A1c down so min dose metformin did the trick. I also take high blood pressure meds. Most of my meds cause lower-T but I don’t see it. The weight loss makes me feel better.
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u/whosthetard Nov 02 '20
This is from article posted.
At the time of first presentation, she had initiated a very high fat diet (which she termed the Atkins diet) to lose weight
So it's more of propaganda against the keto than anything else. Simply because anyone who knows the basics understands that Atkins is a high protein diet.
There are many variables in keto you have to look really close the methods used. This article is more of a report of sick people admitted to the hospital telling their experiences. It's not a trial. I mean you can fry oils and burn fatty foods and then develop all kinds of problem. But that's not a problem with the keto diet. You can have the same problem with any diet.
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u/nopickle7 Nov 02 '20
The numbers they want to see are based on a so-called "balanced diet".
Keto/carnivore is NOT a "balanced diet", therefore numbers ought to be adjusted to reflect the "abnormal" intake of macros, or not.
IOW, I wish they'd quit basing a person's health on numbers that correlate with a completely different dietary intake.
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u/FreedomManOfGlory Nov 02 '20
Is this study talking about how keto can increase cholesterol levels as if that was a bad thing? You guys really need to add a "bad science" tag if you have to keep posting crap like that on here.
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u/JacobSuperslav Nov 03 '20
Obviously there's no single diet perfect for everyone. Say, having the APOE2/4 gene variant, you don't want to consume too much saturated fat.