If you’d like to learn more about lipoprotein(a), you can watch Siobhan’s presentation on it here
Lastly — you can always just ask us anything our Questions Page. (Just be aware our site does not constitute medical advice and we always recommend consulting with your doctor.)
In our recent Lean Mass Hyper-Responder (LMHR) case report, we performed extensive genetic testing on the subject, LM, and activity sought input from clinicians and geneticists outside the research team. Because of the broad nature of our testing and absence of notable findings, as determined by expert consultants, and manuscript length limitations, we stated in our publication: “Whole exome sequencing performed by Veritas Genetics, and independent dyslipidemia and ASCVD genetic risk testing by GB Healthwatch, revealed no pathogenic or likely pathogenic variants that could account for LM’s phenotype.”
As part of our continued commitment to open and transparent science, we are happy to disclose what results we can. But before doing so below, it is important to highlight two caveats:
1. While a whole exome sequence was ordered, it would obviously be inappropriate to release the entire Variant Call Format file. This represents the subject’s actual genetic code and to disclose the code would be a serious infringement on the subject’s privacy, and one that could potentially be used to his disadvantage in future. Thus, calls for access to the complete raw exome sequence by individuals not part of the patient’s care team will not be entertained.
2. Given the scope of the genetic testing performed, it is inevitable variants will be found. Every person carries risk variants. The important question is whether variant can explain the clinical and metabolic (LMHR) phenotype at hand. By way of example, a risk variant for elevated triglycerides is not clinically relevant if the subject’s triglycerides are 40 mg/dl.
Moving onto the genetic findings: In addition to the exome sequence with professional geneticist interpretation, we also ordered a Dyslipidemia and ASCVD comprehensive risk panel — the same one that is being ordered for the LMHR prospective trial (recruitment underway) and that includes the following targets: LDLR, APOB, PCSK9, LDLRAP1, LPL, CETP, LCAT, LIPC, LIPE, LIPG, LPA, PPARG, STAP1, ABCA5, ABCA6, ABCG5, APOC2, LMF1, GBIHBP1, CREB3L3, GCKR, SCARB1, ABCA1, APOA1, APOA5, BHMT, CBS, MTHR, MTR, MTRR, PEMT, SHMT1, GUCY1A1, ITGB3, MEF2A, NOS3, PLA2G7.
As shown below, and consistent with the published text, testing by GB Healthwatch, “revealed no [0] pathogenic or likely pathogenic variants that could account for LM’s phenotype.”
In terms of variants not classed as pathogenic/likely pathogenic, there were no variants in genes classically associated with familial hypercholesterolemia at levels seen in this patient: LDLR, APOB, LDLRAP1, or PCSK9. Overall, six potentially notable variants were identified, as follows:
Pathogenic and Likely Pathogenic Variants (0) and Variants of Uncertain Significance (VUS) and High-Risk Variants, provided by GB Healthwatch
ABCG8 521G>A, heterozygous VUS for sitosterolemia. Sitosterolemia is a condition in which plant sterols and other sterols can be hyperabsorbed. Given that this is a hyperabsorption disorder, the mainstay of therapy is dietary restriction of both cholesterol and plant sterols. Of note: (i) testing performed on LM on October 20, 2021 confirmed normal campesterol levels at 8.2 mg/L. (ii) Most importantly, a hyperabsorption phenotype is inconsistent with the clinical presentation. As reported in the manuscript, when hyperabsorption was considered in the case of LM, “LM was recommended to reduce dietary cholesterol intake, eliminating liver, shellfish, and egg yolks from his diet (in substitution for lean chicken, fish, and egg whites). One month later, in September 2020, his LDL-C was remeasured at 545 mg/dl (HDL-C 94 mg/dl, TG 58 mg/dl).” Thus, LM’s dietary cholesterol intake was lowest when his LDL-C was at its peak, and hyperabsorption cannot account for his LDL-C phenotype on a carbohydrate restricted diet.
APOA5 3’UTR, heterozygous variant and risk factor for hypertriglyceridemia. The patient’s triglycerides ranged from 39 – 58 mg/dL. Again, the risk variant is inconsistent with the metabolic phenotype.
CBS 133C>T missense heterozygous VUS for homocystinuria. LM has no clinical signs of this disorder and homocysteine last measured January 3rd 2020 normal at 9.7 umol/L.
CDKN2B-AS1 22124478A>G homozygous variant that codes for an altered form of a long non-coding RNA that is associated with increased risk of myocardial infarction in some studies. While this variant does associate with increased risk of myocardial infarction, the increased risk does not appear to be driven by alternations in blood lipids, including LDL-C and there is no reason to believe it contributed to the patient’s phenotype on a carbohydrate restricted diet.
LPL 953A>G heterozygous variant that has been linked to increased risk for hypertriglyceridemia. As noted, the patient’s triglycerides ranged from 39 – 58 mg/dL. Again, the risk variant is inconsistent with the metabolic phenotype.
SLC22A1 1022C>T heterozygous variant and risk factor for elevated Lp(a). As stated in the report, Lp(a) was high in the subject prior to adopting a ketogenic diet and is elevated in the patient’s father. This allele is presumably paternally inherited and there is no reason to believe it contributed to the patient’s LMHR phenotype.
In addition to the targeted genetic risk panel, a 144-page report corresponding to the exome sequence also revealed no known pathogenic or likely pathogenic variants for heart disease. Under “important” risk variants, the patient was noted to be a carrier for HFE 845G>A for hereditary hemochromatosis, MEFV 442G>C for Familial Mediterranean Fever, and MMP2 524G>A for multicentric osteolysis, nodulosis, and anthropopathy. These are all autosomal recessive conditions, and the patient does not present with signs or symptoms of any of these disorders. Homozygosity for lactose intolerance was also noted.
Under “noteworthy” variants, 7 variants were identified for cancer risk, 3 for clotting disorders, 4 for neurological disorders, 4 for other organ health, and only one for cardiovascular disease. This variant was in KCNE1 with classification of “no known risk” (VUS), for long QT syndrome, as detailed below. Taken together, the exome sequence revealed no notable findings that could explain the patient’s LMHR phenotype.
Thus, these genetic data provide no means by which to explain the patients presentation, defined by a shift from normal LDL-C of 95 mg/dl while on a mixed macronutrient diet to an LMHR triad of LDL-C 393 – 545 mg/dl, HDL-C ~115 mg/dl, triglycerides ~40 mg/dl. In fact, several of the identified variants were associated with increased risk for hypertriglyceridemia, which is in obvious contrast to the patient’s presentation.
In summary, our interpretation is that, while one cannot rule out genetic contribution or modification, the evidence at hand is most consistent with the hypothesis that the LMHR phenotype is driven by non-genetic factors including leanness and dietary macronutrient composition. More details on the Lipid Energy Model will be forthcoming shortly.
We’re happy to announce the release of our new LMHR Case Study this week in Frontiers in Endocrinology. Feel free to download the PDF and share the page link if you find the paper compelling. (The more our work is shared, the more it supports our efforts, of course.)
Highlights of the new paper:
LDL-C increased from 95 to 545 mg/dL at its peek
Keto diet is “Mediterranean” style with >4:1 unsaturated to saturated fat ratio
No genetic abnormalities found to explain phenotype
No detectable plaque in CT Angiogram after 2.5 years of followup
Recently, Mark Lightell, a 29-year-old endurance athlete, took it upon himself to try to convert to the LMHR phenotype with a two-week n=1 experiment. You can find Mark’s post about this experience here. Mark and Dave invited me to do a little commentary on Mark’s experiment. Here it goes…
First, I want to reinforce my respect for Mark’s scientific curiosity. As I wrote in my closing note to Mark’s post, “[T]he fact that Mark’s personal hypothesis leans towards isolated high LDL-C being sufficient to drive atherosclerosis (and, thus, less in line so with some in the LMHR community) does not preclude him from sharing a genuinely scientific interest in the LMHR phenomenon, nor should it. This n =1 experience is a testament to how those with different hypotheses can share scientific curiosity and collaborate in genuine attempts at pursuing scientific truth.” In fewer words, “GO Mark!”
With that, some thoughts…
Study Duration
Mark’s hypothesis was that “adherence to a very low carb ketogenic diet will produce a LMHR profile within a timespan of 2 weeks.” While the half-life of LDL particles would suggest a full conversion to the LMHR phenotype (LDL-C ≥ 200, HDL-C ≥ 80, and TG ≤ 70 mg/dL) could be possible in two weeks, I think it’s first important to consider the impact and timeframe of fat-adaptation.
The Lipid Energy Model (manuscript for publication in production) proposes that the high LDL-C observed in LMHR is driven by dependence on fat as fuel and on the LPL-mediated turnover of hepatically secreted VLDL. That’s a jargony way of stating that the LMHR phenotype is most likely to be exhibited in those who are fully fat adapted.
While Mark’s endurance exercise regimen suggests that his body should be good at oxidizing fat at baseline, the fact that his body was completely naive to carbohydrate restriction also means he probably did not achieve full fat adaptation within 14 days of starting a ketogenic diet. Of course, he did see a trend towards the LMHR phenotype (a doubling of LDL-C from 68 to 139 mg/dL) consistent with what the LEM would predict in an individual who is in the process of fat adapting, and upregulating VLDL secretion and peripheral turnover.
There are, of course, other explanations. For instance, synthesis of ApoB could have been rate-limiting, creating a metabolic bottle neck for the repackaging and export of non-esterified fatty acids upon VLDL, to be converted into LDL by LPL. Again, this is a jargony way of stating, metabolic change takes time, and I’m not sure one should expect full conversion to LMHR in two weeks.
Vegan Diet Baseline
The choice of both the baseline diet and the ketogenic diet were interesting. With respect to the baseline diet, it was Mark’s choice to consume a vegan diet to lower his LDL-C as much as possible as a run-in phase, although he doesn’t regularly consume a vegan diet. As he has disclosed, his normal resting LDL-C on a mixed macronutrient diet rests at ~130 mg/dL. Thus, the transformation observed in his experiment could be interpreted as a reversion to his personal baseline.
It is pertinent to contrast this scenario (vegan diet to keto-carnivore diet) against much of the current LMHR community who have converted to the phenotype from a standard mixed diet after changing to many forms of ketogenic diets (standard to ketogenic). In other words, in this case, we can’t distinguish between the putative contributions of the ketogenic diet raising the LDL-C or the vegan diet lowering it. That evidently creates a major confound in data interpretation that is important to highlight.
Keto-carnivore Diet
As I was not consulted on the formulation of the baseline diet, neither was I consulted on the formulation of the on the ketogenic diet. Mark’s ketogenic diet reflected Dave’s standard diet and included Colby Jack Cheese, Beef Franks, Hard boiled eggs, Diet Coke, with the addition of uncured bacon… for variety (that’s a laugh line folks). Mark explains that he “found the diet intolerable” and “had a miserable time.” All I have to say to that is, I probably would have reacted the same way.
Quickly, for those of you who don’t know, Dave and I are quite close and I love him like a brother. So, what I say next is written with a comedic tone (but with honesty): Dave’s diet makes me sad. Sometimes, after a nice dinner of smoked salmon with capers, roasted garlic, buffalo mozzarella and extra virgin olive oil, and dark chocolate with coconut manna for dessert, Dave and I will get on a Zoom call and I’ll see him munching on a piece of string cheese with a Diet Coke and my tongue will cry a little for him.
Point being, I don’t blame Mark for quitting the Dave diet after two weeks, especially when his gut had recently been adapting to veganism. (Talk about a shock to the microbiome! – It’s like tossing a giraffe into the arctic). The fact that he lasted two weeks is a testament to his strength. But the more serious point I want to make is that Dave’s diet is not necessary or typical of LMHR. You can be an LMHR while eating vegetables or without eating meat or eggs.
So, to Mark: I’m sorry.
To Dave: You and I need to have a little chat about both your diet and – more pressingly – sleeping habits.
And to readers: We will shortly have for you a rather striking demonstration of how the LMHR phenotype can occur in the context of a low-saturated fat ketogenic diet. Let’s put a pin in that…
“Picking up the torch”
In his post, Mark expresses a desire for someone to “pick up the torch” and replicate his attempt to prospectively convert to LMHR, albeit over a greater time frame. I can here confirm that is being done. We have another community member who has self-selected to attempt to convert to LMHR over the next couple of months. Like Mark, she’s young, athletic, and by all measures metabolically fit with a baseline LDL-C on a mixed diet (not vegan) of 50 – 79 mg/dL. (Some other markers: HDL-C 73 mg/dL, TG 50 mg/dL, HbA1c 4.8%, insulin 4.9 uIU/L, BMI 24 kg/m2.) I think we will all be interested to see what happens.
Of course, these n = 1, while prospective, are not properly designed clinical trials. Hopefully, we will acquire the partnerships and resources to conduct these after publication of the Lipid Energy Model manuscript. Already, I’m noting more serious researchers within academia approaching us about this work. The ball is starting to pick up steam…
But, circling back to the point I made above, the most notable thing to me about individuals like Mark and our anonymous second subject is that their self-directed efforts represent an interest in a scientific curiosity (the LMHR phenotype) sufficient in magnitude to compel them to put their tongues, guts, and bodies on the line to pursue science. If that’s not being a citizen scientist, I don’t know what is.
Other Lab Abnormalities
As a final comment, Marks labs were also notable for several abnormalities, including but limited to leukopenia (WBC 2.2 – 3.0 x10e3/uL) and elevated bilirubin throughout the vegan and keto-carnivore stages, and thrombocytopenia while vegan (PLT 127 x10e3/uL). These abnormalities were largely pre-existing and we have reinforced his doctor position that he pursue a hematology consult. It’s important to acknowledge these other abnormalities, not only for their potential interaction with the results, but also to strongly caution others against embarking on dramatic lifestyle changes without professional consultation when one is aware of pre-existing conditions, especially dietary changes that may exacerbate pre-existing nutrient deficiencies.
Note from Dave: I laughed out loud when I read Nick’s comment above, “Dave’s diet makes me sad.” To be sure, Nick, that’s not actually my normal diet at all. The “baseline diet” is strictly for experiments and doesn’t include Diet Coke and bacon. But the three baseline components (+ vitamins & electrolytes) were selected against many criteria that includes availability and consistency when traveling, avoidance of preparation and/or cooking oils that could be confounding, and zero fiber – to name just a few. I wanted to get as few components as possible to achieve this baseline, and that’s where I landed. In short, it’s my version of a “ketovore chow” that has been very successful for replication of baseline bloodwork as well (such as with OxLDL Replication Experiment). We can discuss more in depth when we do a podcast on this experiment — should be fun! 😉
Note from Dave: Mark Lightell is actually a frequent commenter at the LMHR Facebook group, but he is notably an advocate for reduction of LDL cholesterol and ApoB, and a firm believer in the Lipid Heart Hypothesis. However, he’s also interested in our work and saw a clear opportunity to make a contribution with this experiment. I think you’ll find this guest post on his experiment very interesting. Also, see Nick’s companion analysis for this experiment, and our added note at the end.
Vegan Diet vs Keto/Carnivore Diet – My Attempt to Create a LMHR
The LMHR phenotype paper by Nick Norwitz, Dave Feldman, and colleagues suggests that LMHRs, rather than being a genetic anomaly, may be a reproducible metabolic phenomenon. If this is true, it should be possible to recreate this LMHR lipid profile in most people who are metabolically healthy (low TG/HDL ratio) and lean, and in whom dietary energy is derived primarily from fat with minimal carbohydrate intake. Due to LDL particles having a half-life of 3 days, I further expect the LMHR phenotype could be seen over the course of 2 weeks.
My Hypothesis
In people who are lean, metabolically healthy (exhibiting a low TG/HDL-C ratio), and with lower BMI, adherence to a very low carb ketogenic dietwill produce a LMHR lipid profile within a timespan of 2 weeks.
I fit these criteria, with the added benefit of having a high energy demand due to my daily exercise (50+ miles of running per week). According to the Lipid Energy Model, proposed to mechanistically explain the phenotype, this should amplify the effect due to my body requiring a greater volume of lipoproteins (LDL) to traffic triglycerides for energy. I’ve never done a low carb diet, but given that I should be the ideal candidate for this effect, I decided to give it my best shot.
Dec 2020 – 15k
General Health and Physical Fitness
I’m a 29 year old endurance athlete, 5′ 9″ with lifelong weight around 130-135 lbs. I’m in good health with no known medical conditions. I take no medications or supplements. My most recent race (January 2022) was a 10k in 40:11 (~6:28 min/mile pace).
Experiment Design
Step 1: Reduce LDL-C as low as possible with a carb-based Vegan diet.
Step 2: Immediately switch to a 2 week Keto-carnivore diet to maximally increase LDL-C.
3 weekly lab draws as follows: March 3 (Vegan), March 10 (Keto), March 17 (Keto).
Lab draws will be ~14 hours water fasted.
All food weighed via food scale.
Maintain aerobic training (50+ miles per week).
In case you’re pressed for time, here’s the summary:
Over the two week experiment my LDL-C increased over 2-fold, albeit not quite to the LMHR LDL-C threshold of 200. Specifically, my LDL-C increased from 68 to 139, which suggests to me that it is very much possible to induce the LMHR metabolic phenomenon, but that 2 weeks is not a sufficient time frame. I suspect 3-4 weeks would have shown LDL-C of 200 or more.
Main Lab Results
Lab changes greater than 20% are shaded gray
Sample Meals & Daily Routine
Weight
The Start
I wanted to begin the experiment by establishing a low baseline LDL-C. After the conclusion of my December 2021 Vegetarian experiment (where I brought LDL-C down to 64) I was enjoying the freedom of “no diet,” eating frequently at restaurants. I’ve always been weight stable so it wasn’t that I had gained weight, but rather that it was extremely likely my LDL-C was far above the 64 I got in December.
So starting February 5, 2022 I began the work to reduce my LDL-C. I went back to my proven Vegetarian diet, but was tempted with ideas to achieve an even lower LDL-C than last time, so I changed it to a Vegan diet. I removed animal products, got dietary cholesterol down to 0mg, reduced saturated fat as much as possible, while maximizing PUFA intake via walnuts, and increasing fiber.
At the time, I thought the PUFA-to-saturated fat ratio was key to getting my LDL-C even lower, ideally to 50s. I had promising results going from a 3:1 to a 6:1 PUFA-to-saturated fat ratio during my December 2021 Vegetarian experiment, so naturally I thought increasing the ratio to 9:1 would produce an even greater effect.
Week 1 – Vegan Routine
Two meals a day
Wake up at 11am
Breakfast of ~2800 calories. Finish breakfast by ~1pm
Go to work at 2pm
Lunch at 7pm, just Diet Coke or water
Get off work at 11pm
Run after work at ~11:30pm
After run, Dinner at ~1am, ~400 calories
I found this diet easily tolerable and enjoyable, even if fairly restrictive and mundane. I ended up running 52 miles this week, with total carbs averaging 418g/day.
So March 3, 2022 arrives and I have labs drawn.
Results: Week 1 – Vegan
HDL: 80
Trig: 48
LDL: 68
Pft, 68?? Where’s my 50? I found this result disappointing, as I really thought my “improvements” would beat my last result of 64 from December 2021 to give me my lowest LDL-C yet. From this result I’ve concluded that the PUFA-to-saturated fat ratio is not as powerful as I thought for reducing LDL-C. While LDL-C did not behave as I predicted, it was not the goal of this experiment (just an “along the way” project).
It was time for the Keto/Carnivore arm of the experiment.
I tried Dave Feldman’s baseline diet of Colby jack cheese, beef franks, and hard boiled eggs but found the diet intolerable after 2 days, primarily due to the hard boiled eggs. So I switched to uncured bacon, Colby jack cheese, and diet coke for the remaining 5 days.
Week 2 – Keto/Carnivore Foods
Day 1 & 2: Colby Jack Cheese, Beef Franks, Hard boiled eggs, Diet Coke
Day 3 – 7: Uncured Bacon, Colby Jack Cheese, Diet Coke
Week 2 – Keto/Carnivore Routine
3 Meals a Day
Wake up at 11am
Breakfast of ~2000 calories. Finish breakfast by ~1pm
Go to work at 2pm
Lunch at 7pm, ~800 calories
Get off work at 11pm
Run after work at ~11:30pm
After run, Dinner at ~1am, ~600 calories
The switch to bacon had a promising start but eventually became difficult to tolerate, which is to be expected after consuming 12 packs of bacon in 5 days. I managed to stick with it until the first Keto lab draw. I ended up running 74 miles this week, with total carbs averaging 5g/day.
Not quite what I expected. I was hopeful for something in the 130s range, so I found this a bit disappointing.
At this point I was quite sick of bacon and Colby Jack cheese, so I adopted a slightly more flexible Keto/Carnivore diet while maintaining the supreme directive of minimal carbohydrates.
Week 3 – Keto/Carnivore Foods
Grilled Chicken, Scrambled Eggs, Butter, Pork Sausage, Pepper Jack Cheese, Mozzarella, Cream Cheese, Pepperoni, Heavy Whipping Cream, Diet Coke
Week 3 – Keto/Carnivore Routine
3 Meals a Day
Wake up at 11am
Breakfast of ~2200 calories. Finish breakfast by ~1pm
Go to work at 2pm
Lunch at 7pm, ~800 calories
Get off work at 11pm
Run after work at ~11:30pm
After run, Dinner at ~1am, ~400 calories
I ended up running 52 miles this week, with total carbs averaging 12g/day.
LDL-C increased an additional 54% in 7 days.(104% increase over 2 weeks.)
Better, but at the start of this I fully believed it was going to be a slam dunk of an experiment with LDL 200+. Instead, what I feared most ended up happening: A middling result that effectively demands a longer experiment. What would have happened in just one more week? I was this close to finding out, but wow was this diet difficult and absolutely unenjoyable. Maximal carb elimination made the diet so restrictive to the point that I could not continue it past 2 weeks. I had so much drive and motivation at the start, but that was largely sapped from me on this diet. Food became a chore that gave me no enjoyment, I was not hungry most of the time, and generally did not feel great. It was made worse by the fact that, given my activity levels, I needed to consume ~3400+ calories per day of food that I did not care for just to maintain my weight.
All that to say: Yes I had a miserable time, and yes I fell short of my goal to create LMHR lipids at will, but I’m still glad I did it. Now hopefully someone else can take the torch and try for 3-4 weeks to see what would have happened.
Why did you do this experiment in the first place?
I find lipids and biomarkers pretty fascinating. Especially the nature of LDL and its function in the body. I know it’s a controversial topic, so to clarify my position I will say that I’m convinced of LDL/apoB being causal in cardiovascular disease. My main interest is the quantification of that risk.
If LDL/apoB is the only risk factor, what is the risk forsomeone like me? An athlete with high HDL, low triglycerides, and low body fat, but on an “anything goes” diet of restaurant food my LDL-C will rest at around ~130. How much risk do I have between 68 and 130? I don’t think anyone has an answer to that, other than the basic binary answer of “yes it’s more atherogenic”. I think it matters if we’re talking months to a year vs years to a decade+ in life expectancy. Some people may be willing to make that trade of not having to limit their food choices for a lifetime if the cost is “minimal” with regard to elevated LDL/apoB.
That’s why I find Dave Feldman’s research into this topic interesting, because he is essentially exploring a niche where increases in LDL may not be a pathological response, but rather a benign adaptive one. While I would like for that to be the case, I’m also aware that the preponderance of evidence we currently have is stacked against that idea, but that doesn’t mean it’s not an idea worth exploring. If it did end up being true, it would be a fascinating discovery if only because literally, “how does that work?”. And for those of us in good health with high HDL and low triglycerides, where elevated LDL/apoB is our only risk factor, we would no longer have to limit food choices to keep this marker within range.
In summary, I think there is something interesting happening here with this massive increase in LDL, and this was my attempt at adding my piece to the puzzle.
Miscellaneous Results
hsCRP – Increased to 1.45 on Keto/Carnivore, compared to my baseline in the 0.17-0.39 range. I think it’s interesting how my hsCRP perfectly matches how unwell I felt without carbs.
Platelets – Arguably the most unusual result. Platelets were below ref range (common for me) in Week 1 – Vegan and Week 2 – Keto. Only Week 3 – Keto showed normal platelets.
HDL-P – Increased to the 35.9umol/L on Week 3 – Keto/Carnivore, which is the highest it’s ever been. I’m usually quite low in HDL-P, even when I’ve had 92 HDL-C.
Bilirubin – Decreased linearly with the duration of the keto diet. Bilirubin went from my normal of 3.2 down to 1.7 by Week 3 – Keto, which is the lowest I’ve ever seen it.
Resting HR – The Keto/Carnivore diet resulted in a higher resting HR. At first I thought it was because I went from 50 to 70 miles in one week, but my HR was at its highest after reducing my mileage down to 50 in the final week of the experiment, so this is clearly an effect from diet and not training load.
Insulin – This behaved as expected. Insulin was already low on a carb-based diet, and went even lower on a Keto diet.
Note from Nick: I want to begin my concluding remark by repeating two quotes from Mark: (i) “I find lipids and biomarkers pretty fascinating,” and (ii) “If LDL/apoB is the only risk factor, what is the risk for someone like me?” These quotes represent questions I and other LMHR ask themselves every day. Notably, the fact that Mark’s personal hypothesis leans towards isolated high LDL-C being sufficient to drive atherosclerosis (and, thus, less in line so with some in the LMHR community) does not preclude him from sharing a genuinely scientific interest in the LMHR phenomenon, nor should it. This n=1 experience is a testament to how those with different hypotheses can share scientific curiosity and collaborate in genuine attempts at pursuing scientific truth. For more thoughts, read my commentary here.
Note from Dave: this guest post from Nick Norwitz discusses our #LMHRpaper, which as of today, is now finalized. Thanks again to the many wonderful readers who contributed their efforts in our final edit.
The final version of the Lean Mass Hyper-Responder (LMHR) paper was just released!
I’m pleased to report that, even in the early days since the initial release of the unedited accepted manuscript (on November 30, 2021), this paper has stimulated vigorous discussion, risen to the top of its journal for all time reads, and is among the top 15 trending papers across all American Society of Nutrition associated journals for the year 2021. So, what’s all the fuss about? This blog is intended to get you up to speed so you can be part of the discussion and follow this exciting line of biomedical research as the conversation continues to heat up.
But the elevations in LDL exhibited by these lean persons on low-carb diets had two peculiar features that set it apart from other forms of high LDL.
Extreme LDL Increases
First, the LDL increases were much larger than those typically associated with living an unhealthy lifestyle. When most doctors think about high LDL related to being unhealthy and eating a poor diet, they think about levels in the high 100s. But lean people on carbohydrate-restricted diets were anecdotally observing LDL levels of 200, 300, 400, and even 500 mg/dL or more.
In fact, some LMHRs exhibit LDL levels as high as persons with homozygous familial hypercholesterolemia, a rare and devastating genetic condition (1 in 1,000,000) that likewise associates with very early heart disease.
Very High HDL and Very Low Triglycerides
Second, when lean people do see increases in LDL on a carbohydrate-restricted diets, they tend to be accompanied by high HDL (so-called “good cholesterol”) and low triglycerides (TG), fat in the blood. This pattern of high HDL and low TG is exactly opposite the profile of “atherogenic dyslipidemia,” which is defined by low HDL and high TG, and is, at present, the predominant risk factor for cardiovascular disease (Libby, 2021).
Simply put, when lean people on low-carbohydrate diets saw increases in LDL they were quite often in the context of otherwise excellent metabolic health markers. Therefore, Dave created a set of three cut points that combine to define what would become the LMHR phenotype:
LDL cholesterol ≥ 200 mg/dL
HDL cholesterol ≥ 80 mg/dL
TG cholesterol ≤ 70 mg/dL
Now for a couple comments on the definition of LMHR. First, why these cut points? Well, in addition to approximating threshold levels Dave Feldman was empirically observing in the world around him for lean athletic people who went low-carb, these triad of cut-points were chosen for just how extreme they are.
To meet someone with LDL ≥ 200 is rare. To meet someone with HDL ≥ 80 is rare, and to meet someone with TG ≤ 70 is rare. Thus, the probability of meeting someone who meets all the cut points by chance is highly unlikely. Otherwise put, if someone presents with this triad, it seems reasonable to hypothesize that the markers are associated with each other.
Other important point is that LMHR are only defined by this triad, and NOT by any measure of leanness. This is confusing because “lean” is in the name of the phenotype, but that’s only because the triad – at least in Dave’s point of view in 2017 – tended to occur in people who were lean and athletic. In other words, the name LMHR is the hypothesis – that this triad present in lean people who go low-carb.
Study Suggests that LMHR Exist!
Being Leaner & Having Lower TG/HDL Predicts Larger LDL Increases on a Low-Carb Diet
It was a long time coming, but we finally put that hypothesis to the test in a scientific study.
In this new study, published in Current Developments in Nutrition, we collected survey data from people who were low-carb, who were not on statins, and who had lipid data from before they started their low-carb diet as well as recent lipid data from on their lowcarb diet.
Then, rather than massaging the numbers to conform to our hypothesis, we engaged in a “hypothesis-naïve exploratory analysis” in which we took all the data we had on respondents — including age, sex, BMI, and current and pre-low carb LDL, HDL, and TG levels — and asked a computer to tell us which factors were most strongly and reliably associated with increases in LDL after starting a low-carb diet.
The results were clear. No matter how we approached the question (be it multivariate linear regressions or hypothesis-naïve computer-generated decision trees [Supplemental Figure 3]) we found that having lower BMI and a lower TG/HDL ratio associated with larger increases in LDL.
The relationship can be clearly seen in the bar graph below. The further you go to the left, the lower the BMI. The further you go to the back, the lower the pre-diet TG/HDL ratio. And the height of the bar is the median increase in LDL.
Picking out the LMHR
After establishing that those who are leaner with lower TG/HDL ratios exhibited larger increases in LDL with carbohydrate restriction, it made sense to try to separate the true LMHR (those who met all three cut-points) from the larger cohort and see how different they really were…
Of the 548 participants that met the inclusion criteria, 100 were bona fide LMHR (which is a lot, considering many people don’t believe LMHR exist). And, true to their name, they were Lean!
The average BMI of a LMHR was 22.0, as compared to 24.6 for the rest of the low-carb sample in this study (between group p = 1.2×10-11). Furthermore, LMHR exhibited higher LDL, higher HDL, and lower TG, with mean values of 320, 99, and 47 mg/dL respectively.
And, importantly, LMHR did not differ in terms of their pre-diet LDL when compared to the non-LMHR population. In fact, median pre-diet LDL was 135 mg/dL in non-LMHR and 133 mg/dL in LMHR. No difference!
A LMHR Case Report Shows the Phenotype is Reversible
Now, you’ve probably sensed a lot of enthusiasm from me, but don’t mistake intellectual excitement about a fascinating observation for a suggestion that high LDL levels in LMHR are benign.
Setting my own hypotheses aside, we do not yet know if the risk associated with high LDL is any different in the context of LMHR as compared to any other context. And most experts would agree that high LDL is dangerous, regardless of cause.
This very question — is high LDL harmful in LMHR? — is currently being assessed in a prospective study (data from which are expected to drop in 2023). And I will be vocal about the data when they emerge, whatever they say.
Nevertheless, for the time being, many or most LMHR patients and their doctors are concerned about their high LDL. That said, many of those same people find a low-carb way of life to be tremendously beneficial for their various metabolic disorders. This begs the question, can you “fix” the LDL problem (perceived or true) through lifestyle? The answer, yes — at least partially.
As part of this study, we also wrote up a case series of five patients who were LMHR or borderline LMHR. These patients all exhibited extraordinary increases in LDL upon starting a ketogenic diet. And, importantly, all were tested for genetic mutations associated with high LDL and all tested negative, supporting the notion that being a LMHR is not a genetic condition but a metabolic phenomenon.
One patient saw his LDL increase from 116 to 665 mg/dL (no surprise, he was the leanest).
All of the patients refused, or were intolerant of, statins and instead opted to reintroduce a moderate amount of carbohydrate, ~50 – 100 grams, in order to transition from a very low-carb ketogenic diet to a diet that was still low-carb (<130 grams net carbs per day).
Impressively, all participants saw their LDL drop by at least 100 mg/dL, with larger drops occurring on those with high levels. The patient who saw his LDL increase to 665 mg/dL exhibited a 480 mg/dL drop in LDL by doing nothing more than adding about a small, sweet potato’s worth of carbs per day.
Stop and think about that for a second. In this context, a sweet potato per day could drop LDL by almost 500 mg/dL!
Future Directions
This is only step one, putting the LMHR phenomenon on the map. This paper suggests that LMHR are real and, if I do say so myself, really interesting!
In my opinion, no true student of health and/or medicine can observe this phenomenon and not be intrigued.
But what this paper does not do is explain the “how.” It likewise can’t evaluate the risk. Those are the subjects of upcoming projects.
We are working on formulating an official “Lipid Energy Model” manuscript, explaining the potential mechanisms at work behind the findings of this paper. And, a LMHR study also recently launched out of ULCA, courtesy of Dave’s efforts, that will track plaque progression in the coronary arteries of 100 LMHRs. This paper was just the first domino…
Additional Notes
This paper describes a phenomenon. It does not explain the mechanism nor comment on risk.
Saturated fat intake was not measured; however, it seems highly unlikely variations in saturated fat intake can explain the findings as this would assume that, across the study sample of 548 people, lean people and those with good metabolic health preferentially and reliably consumed more saturated fat.
The phenomenon is likely metabolic, not genetic. This is supported by at least three lines of evidence in this study:
LMHR have normal pre-low carb LDL levels. In fact, in the study, pre-diet LDL levels were the same between LMHR and non-LMHR.
It’s been anecdotally observed that LMHR who gain weight exhibit drops in LDL, despite no change in their genetics.
Most importantly, genetic testing in the five patients in the case series were negative. Genetic testing performed on other subjects not reported in this study have also been negative.
Media and Podcasts Around the Paper
For a list of selected podcasts, videos, and media releases that cover this paper, please see the links below (Updated January 28, 2022):
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