Saturday, December 10, 2011

Evolution and Anorexia Nervosa

There was a bit of a dust-up in the paleo and low carb blogosphere about some comments Gary Taubes apparently made about anorexia and insulin in an interview.  He noted that insulin was used as a therapy for anorexia, thus suggesting that (perhaps) anorexia, like obesity, is a disorder of fat metabolism. My suspicion is that Gary was using those studies as an example of how insulin could cause weight gain.   On the other hand, one doesn't need exogenous insulin to refeed anorexics  - the time-tested method is to keep those far gone enough to have medically dangerous symptoms (unstable blood pressure, dropping electrolytes, or super slow heart rate) under lock and key and get calories in whatever way possible (including via a tube inserted into the stomach.)

One of my attendings in at Children's Hospital characterized anorexia as "a desperate disease."  Often purging and starvation are combined (though this combination would be more correctly called "eating disorder not otherwise specified" or "anorexia nervosa, bingeing-purging subtype" than strict anorexia nervosa), and there were many cases of young teenagers hiding vomit and stool in places in their rooms to conceal purging and to get laxatives (not surprisingly, constipation is a symptom of anorexia).

Cowboy Junkies - Bea's Song (one of the better songs ever written - right click to open in new tab)

My evolutionary psychiatry interest has always been in how psychiatric disorders have changed over the past 100 years of rapidly changing lifestyle and diet.  Anorexia nervosa is one of those illnesses that was exceedingly rare until 50 years ago, then escalated rapidly, then leveled off so far as prevalence, though those who are affected encompass more children and more men now than ever before.  My educated guess is that only a small percentage of us are capable of starving ourselves outright without being under lock and key, and that vulnerable population shows symptoms earlier and earlier in life as societal pressures and the obesogenic environment increases.

A quote from my previous blog post linked above (the medical literature references can be found there):

All eating disorders remain relatively rare [though in total they are more common than schizophrenia and bipolar I disorder]. Anorexia afflicts about 0.5% of women and 0.1% of men. Bulimia around 1-3% of women (also 0.1% of men), and binge eating disorder 3.3% of women and 0.8% of men. Anorexia nervosa remains the most deadly of all psychiatric disorders, with a 5-10% death rate within 10 years of developing the symptoms, and an 18-20% death rate within 20 years. Anorexia is endemic in the fashion industry, to the point where models are now being airbrushed to add curves. Another model, Isabelle Caro, died at age 28 of anorexia, and Ana Reston of Brazil died at age 20, still modeling with a BMI of less than 14.
Photo of Isabelle Caro from Wikipedia
The current state of the art treatment of anorexia begins with refeeding, mostly because we know that semi-starvation itself causes obsessions, depression, and fixation on food.   In the hospital, patients work closely with dietitians, trying to learn how to eat a healthy amount and to establish a better relationship with food.  While medicines that promote weight gain are prescribed, antidepressants and other agents are fairly useless in a starvation situation.

You can imagine the typical well-meaning dietician designed diets for these sick young people.  It's the food pyramid with way too many grains, too little fat, and a focus on "healthy" rather than good old fashioned farm fresh food.  And while I don't really have any objections a food pyramid Mediterranean-style whole foods diet (autoimmune issues with grains notwithstanding), I know that what happens in real life is not skipping breakfast, a light lunch, and a late supper of mussels, olive oil, roasted peppers, tapenade and homemade sourdough bread, but rather three meals and two snacks a day, a version of Weight Watchers™ with Skinny Cow ice cream sandwiches, whole grain Rice o Roni, cans of beans, omega-6 laden commercial salad dressing, boneless skinless chicken breasts,  and "lite" yogurt.

The problem with so many meals a day is that one has to think about food constantly.  I don't think that is the best way to recover from an eating disorder, though one would have to be careful with fasting as well.  I believe intermittent fasting is a valuable practice, a way to lower food reward and to ultimately establish a good relationship with food - I don't have to have it right now, but later would probably be fine too - however, fasting can trigger binges in those who are vulnerable.  It is not verboten in those of normal or excess weight, but should be undertaken with care and support.  In my mind, the healthiest diet is one that you don't have to think about all that much - poached eggs, a beef stew with some liver chunks you cook once and eat all week long.  Cold potatoes and butter.  Forgetting to eat every now and again.

M83  Midnight City (right click to open in new tab)

I believe Jamie sent me this recent paper, Role of the evolutionarily conserved starvation response in anorexia nervosa.  It is a fascinating piece, with an in-depth consideration of biology, evolution, and insulin.

The authors speculate that "AN [anorexia nervosa] may be caused by defects in the evolutionarily conserved response to food and nutrient shortage associated with reduced calorie intake."

Some more facts about eating disorders - in 10-20% of patients, the disorder is short-lived.  In 20-30% it is chronic and unremitting.  The most seriously affected are at greatest risk for hypothyroidism, loss of bone density, electrolyte disturbances, low blood cell counts, amenorrhea, suicide, and death.

In anorexia, the physiology of starvation is paramount.  Both brain and peripheral metabolism responses come into play, orchestrated by the brain and the endocrine system (I don't think obesity is far different - I see no reason that obesity would be regulated by fat tissue or the liver when the brain and endocrine system are doing their thing).

The goal of the starvation response is to conserve energy, delay growth, preserve ATP (by increasing efficiency of energy metabolism) and to minimize oxidative damage.  In starvation, changes in the hypothalamus of the brainstem result in a fall in blood insulin levels and a suppression of other anorexogenic factors.  Once ketosis occurs with the depletion of glycogen stores, there is an increase in output from the sympathetic nervous system and stimulation of food-seeking behaviors.  These multiple pathways explain why fasting can be healthy, but also stressful.

One of the major biochemical pathways activated is the IGF-1/FOXO response (an insulin growth factor 1 pathway).  So the authors of this paper postulate something a bit similar to Gary Taubes - anorexia arises when there is defective regulation in the starvation pathway, similar to how insulin deficiency (due to insulin resistance) is a factor in diabetes.  Meaning there is a lot going on with respect to home life, environment, stress, and temperament in eating disorders, but only a select few have the genetic capability to deliberately starve themselves is response to the environment, and those few may have differences in the IGF-1/FOXO pathway.  The researchers were able to find some yeast, fruit flies, worms, and mice with defects in that pathway who tend to restrict food and develop more slowly (or, alternatively, eat more and spontaneously gain weight), and who have genetic differences in the IGF-1/FOXO pathway.

Evidence for genetic vulnerability to anorexia includes the fact that eating disorders are highly heritable. (Uruguayan model Luisel Ramos and her sister both died from anorexia in recent years).   When doing genome-wide linkage analysis of families with eating disorders, many components of the starvation response pathway are located in highly suspect genetic areas.  In practical terms, the increased impetus on thinness and subsequent dieting brings out the reinforcing starvation response as a result of the genetic vulnerability.  A single episode of excessive caloric restriction seems to bring out long-term changes in the neurotransmitter production mediated by FOXO.

Thus caloric restriction and weight loss predispose to additional episodes of dieting, especially in susceptible individuals wih defective regulation of their starvation response, or with perseverative bias in behavior, reflected in obsessive thoughts and compulsivity.

How do these general ideas affect treatment?  Family therapy, distress tolerance, and cognitive behavioral therapy around distorted body image is a cornerstone of therapy for eating disorders, along with the refeeding.

Should we use insulin to treat anorexia?  Well, the reactive hypoglycemia and other risks are problematic.  A more sophisticated approach is to use IGF-1 itself - it can increase appetite and reverse bone loss seen in anorexia.  Long term treatment tends to result in hyperplasia of the lymphatic tissue, tumor promotion, and excess accumulation of body fat.  

Better that we never begin dieting in the first place.  Skipping the processed foods and ensuring there are plenty of healthy fat and nutrients for the brain and muscles seems like the optimal and common sensical approach in that regard.  I'm not sure what to do about the fashion industry...


  1. Interesting post. There has been quite a lot of interest on the cognitive 'phenotype' of AN and other eating disorders particularly overlapping with some of the traits tied into autism:
    The question is what comes first: the mindset (e.g. attention to detail, executive function issues) or the behaviour?
    If there are cognitive 'similarities', the question is whether the two conditions can learn from one and another. Gut permeability issues have been (preliminary) ruled out in AN (see de Magistris et al study: but one does wonder about gut bacterial issues: (whether this is down to the dietary changes or present beforehand is another question).

  2. Good post on a terrible disease. The view of the photo is difficult to tolerate. Also, it surprises me that some european designers chose models that are too thin, not nice or sexy.
    I know there is much controversy among psychologist on how to treat this disorder.

  3. The adipocytes are controlling the brain, mostly, although it is definitely a two way street.

    Decreased leptin ffa glucose and insulin (all of which are strongly related if not directly caused by small adipocytes - the smaller the adipocyte size, the less leptin, ffa, glucose int he blood, and insulin in the blood there will be) lead to changes in the brain , appetite and food interest... .the changes in the brain are a direct result of changes in the fat tissue. Small adipocytes that easily suppress FFA release and glucose levels that eaisly fall, and very low basal leptin levels, all are a result of fat tissue, and all lead to starvation adaptation, and changes in the brain.

    Starvation adaptation - the changes in endocrine system and the brain - thryoid, adrenal, reproductive - depressive/obsessive/compulsive behaviors of food restricted semistarved people are a direct result not only of energy imbalance but of atrophied adopcytes.

    I see no reason to believe why obesity is different. Hypertrophy/plasia of fat tissue due to chronic hyperinsulism, due to abnormalities in energy use (possibly mitochondrial-level even) should and could lead to similar changes in the brain and endocrine system, so that obesity fuels itself. Step one would be control the abnormal direction of fat tissue growth (abnormally pro weighted toward fat synthesis) and then we find the brain/endocrine normalizes as a result.

    The med diet you suggest for anorexia sounds like a recipe to relapse; from speaking with many eating disordered people, energy imbalance triggers symptoms, which is why many if not most anoretic people develop the illness after going without adequate caloric intake for otherwise normal reasons (e.g. athletic competitions, harmless vanity dieting, an attempt to improve health via fasting, or depression/stress induced loss of appetite).

    Being in ketosis and going without meals, sounds like a terrible idea for a restrictive AN, as this starts the crazy brain cycle... but it is probably quite beneficial for a bulimic/B&P AN, as bulimia , pathological food obsession, is often a direct result of disordered glucose metabolism / reactivity to food in vulnerable individuals. If the bulimic has normal insulin reactions no hypoglycemia and easily uses bodyfat for energy their binge/purge thing gets better. Bulimia and anorexia are very different disorders, even though they are often lumped together, the vulnerabilities are polar opposite. Bulimics have a lack of inhibition/control and very high responsiveness/reward to food with signs of glucose disorders (redundant with the previous). Anorexics are very inhibited by personality, depressive, and have an abnormally low reward response to food and are anhedonic chronically.

    I also agree with Paul... there appears to be evidence that autistic-like brain patterns are a risk for anorexia, probably also modulates defects in pain & reward sensing/responsiveness (no differentiation between pleasure and pain) and other thought patterns like an inability to shift attention, inability to see larger point/picture, tendency to stereotype, poor ability to communicate/express/understand their own emotions and needs in general, similar to autistic children.

  4. Another fascinating post. Through a decade of ironman racing I certainly became a disordered eater with an incredible ability to restrict food intake even during high training loads in order to achieve the 'ultimate' racing body, and to please my coach ... and herein lies another key for me in the whole scenario of eating disorders ... 'to please my coach'.

    As you mention environmental stresses are a big factor alongside genetic predispositions. I have a genetic predisposition to bipolar through my father's mother (also gestational diabetes so an insulin link there too), I can also display some spectacular compulsive obsessive traits (training and racing to the level I did is evidence in itself with obsessive record keeping of hours spent in various training zones, calories burned and consumed etc, etc; training to and beyond exhaustion).

    The first step to recovery for me was reading Taubes and following what turned out to be a Primal/Evolutionary diet - this gave me the mental stability to see how mad my former life had been.

    However, once through a period of stability I was still bouncing up against various issues but with my vastly improved mental state was able to start unravelling why and this has been the crucial breakthrough in understanding for me, and I suspect relates to many other 'suffers' too.

    I have been going back through my life history (in tandem with TCM 5 element acupuncture) and believe I have now found the trigger for a lifetime of dysfunctional behaviours ... the emotional environment of my childhood just wasn't compatible with my natural temperament. I'd clocked up 10 homes by aged 9 and 13 by aged 18, 9 educational establishments. My mother says she did her best to squash any exuberant behaviour she felt might lead me down the path of her manic depressive mother-in-law or that would deem me precocious. Add to that a father who was a high achiever and expected you to perform and who the family followed around the country (and world) following his ambitions. Oh and they argued regularly, without warning, unpredictable angry outbursts that can still leave me feeling like a quivering four year old 40 years on when they occur in my prescence.

    But to the outsider we had an aspiring middle class upbringing, we we envied (apparently) and I've always been told what a happy, non-traumatic childhood I had. That isn't how I experienced it - I can see now I came out of it with many coping strategies that buried who I was in order to please and not to trigger angry outbursts - this leads to self-loathing and beyond.

    The perfect storm arises (in terms of developing mental dysfunction) when this kind of stressful background (which was actually quite hidden under the RADAR with a veneer of happy go-get-it family life) for my kind of character is COMBINED with a genetic predisposition.

    Again, it's never just one thing, its the whole scenario that needs to be looked at. We are so advanced with the biochemical science we can now perform that we are in danger, in my opinion, of missing the whole picture. That's what I find so satisfying about Chinese medicine take it looks at the whole energetic entity and treats every person on an individual basis.

  5. My latest hobby is coming up with ways to describe my way of eating that are succinct, non-confrontational and low on the food freak scale. Thanks for the great new addition of "good old fashioned farm fresh food"!

  6. I find the perfect mental balance and energy level that I achieve in a fasted state to be a very desirable condition. I am not in a danger to be anorexic, being a middle-aged women with BMI 27, with no coach to please. I changed my diet on LC after 45 for several reasons, when, together with other health problems, horrible moods started to torture me. Normally my fast don't last longer than 24 hours. It is easy to imagine that somebody with the same appreciation for fasting as me could be carried out of balance without desire to be very thin, but for the reason of seeking for balanced mental state.

  7. Thanks for this fascinating post, Emily.

    "Caloric restriction and weight loss predispose to additional episodes of dieting, especially in susceptible individuals wih defective regulation of their starvation response, or...obsessive thoughts and compulsivity."

    My experience is 100% in line with this, as well as your assertion that "a single episode of excessive caloric restriction" can be all it takes. For me, it began with overzealously losing the freshman 15 (which had brought me up to a non-underweight BMI for the first time in my life)--and being so relieved that I'd ridden myself of this overnight ballooning that I decided to keep going, and going, and going....

    My concern is whether it's desirable to use IGF-1 (or any other substance) to increase appetite. I'm sure anorexics do have a certain 'cognitive phenotype' one that is prone to environmental stressors causing a 'starve to live' (cf.: fight or flight) response. So I'm positing (again, I have not had extensive interaction with other crazies) that lack of appetite is *learned* to enable starvation as a coping mechanism. And because anorexics are predisposed to a 'crazy brain cycle', wouldn't eliminating lack of appetite just make for more craziness? Because you would be removing a major outlet for dealing with things that she doesn't have the resources/skills to deal with.

    I was never in in-patient treatment because I told some fantastically tall tales to wriggle out of it, but I would be reassured if increasing appetite via a drug/exogenous hormone is a last resort. With the perverse notions of 'being [mentally] strong' that an anorexic harbors, it seems that acquiring a foreign uncontrollable appetite (where one is actively 'losing control') would in some sense be worse than being fed through a tube (where clearly someone else is in control, and one is just a rag doll)....

    "Better that we never begin dieting in the first place. [Skip] the processed foods...." Let's shout it from the rooftops; that's a crystal-clear gem if there ever was one!

  8. Paul - there is a certain sort of stereotypical obsessive anorexic patient - (a generalization, of course!) typically high functioning, formerly very good at school, with an emotionally distant father or mother… in some respects similar to the obsessive, repetitive high functioning autistic, but seems to experience pain on an emotional level that is more approachable. Anorexia overlaps so many disorders- delusions, depression, anxiety, addiction, obsessions.

    Woo - I would say there are as many different ways to design an ultimate diet for anorexics as there are those who suffer. Some have significant food phobia and do much, much better if they don't have to eat all the time. Others prefer controlled, small portion meals - but they can be so very ritualized and take so much time - ever watch someone on an eating disordered unit eat a yogurt? It can take 30 minutes, with delicate sweeps of the top creating a small bead on the spoon to be carefully tested with the tongue, then consumed… as with everything by the time we get down to the individual level it has to be very personalized, though I can't help but think nutrient-rich calories in any form would be helpful. I really don't see how the adipocytes would hold sway when the hormonal regulation is masterminded by the brain, but I suppose we all pick which chicken and egg we want to see.

    Cavegirl - yes, the major flaw of "evidenced-based" medicine is that the evidence base is for the statistical average, the prototype patient, not the individual.

    Sarah - the medical approach and the refeeding is based on the principal that no therapy will work while a person is actively starving - there is a lot of evidence proving this fact. Thus the faster one is able to refeed, the faster other therapies will work - this will presumably decrease costs of hospital admission and make outpatient treatment feasible at an earlier date. Sometimes those sorts of practicalities outweigh the traumatic option (though increasing appetite via a pill is less traumatic than the nasogastric tube feeding)

  9. Well, thanks. Thanks a lot. Now how am I supposed to get back to work after sampling a dose of Margo in the morning!

  10. Hmm, that makes sense. I guess I just really wanted to believe that a better environment, good people, and enough hard work can get 99.99% of sufferers to the safety of shore, without such traumatic interventions. Thank you for prescribing prudently, and for presiding over the exquisitely tortured yoghurt rituals :)

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  12. Kurt Harris - that will accomplish next to nothing. Do you honestly think some random teenagers working in a gym are going to convince this mentally ill woman that she needs to stop starving herself? Sometimes people with AN are very very aware of how thin they are and how they are going to die, they can't stop. It's like telling someone with OCD "you know, if you wash your hands 20 times, you aren't making them clean, you are just wasting your time and damaging your skin". They know this. They are crazy and can't help it.

    As a physician you should be more aware of the mental state of patients; a bunch of 21 year old kids at the gym are not going to be able to help this person.

    IF it distresses you that much, you should try to contact her family and have a proper intervention, give them contact numbers of good eating disorder resources.

    Sounds to me like you don't want to look at the scary woman at the gym, and this begins and ends your problem. As long as she is no longer in your presence, then you are cool about it. If she leaves the gym, she'll just find another. Or alternatively she will eat even less, because she was not able to burn off her 300 calories, or whatever.

    And why are you putting the onus on some random workers at a gym? They have zero medical education, training, and no idea how to help this person. AGain, as a physician, you have far more power to help than they do.

  13. Great post - again. I'm wondering if you'd consider doing a post sometime on the high overlap and migration of eating disorders? Nothing like making a complex topic even more so. If anyone can make sense of it, though, it's you.

    And, KGH.... thank you for taking a stand on this. Another reason you rock.

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  15. Woo - would it help for a strange, older man to come up to a young, eating-disordered woman in the gym, identify himself as a doctor, and tell her she needs to stop her behavior? Who knows? Eating disorders are such a conglomeration of disorders - delusions, obsessions, depression, anxiety, addiction… who knows what will cause someone to "hit bottom" so to speak. Sometimes there is no "bottom." From the gym's perspective, often there is a medical clearance before returning to workout after surgery or hospitalization. Uncontrolled eating disorders would be no different, and it would be in the gym's interest not to permit people who are not medically safe working out (uncontrolled, severely underweight anorexia would certainly qualify). I can't see what is controversial or wrong about that.

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  17. Woo - I'm not going to post your next comment in reply to Kurt. I rather regret posting the first. In a year and a half and nearly 3000 comments I've only every moderated spam and one exceptionally verbose tumeric enthusiast. Commenters have been exceptionally respectful, and I do appreciate the questions, the concerns, and the alternative viewpoints.

    But I don't want the comments here to descend into anarchy as they have on some other very good blogs, nor do I think passing vitriol back and forth is a useful contribution to the discussion of eating disorders. I posted Kurt's reply as you dropped the first salvo, and it only seemed fair to allow him his response. But that's the end of it. This blog is my totalitarian regime.

  18. If I may contribute, not knowing as much as you all about AN, I believe Kurt's actions are analogous to picking up trash off the street in the hopes of improving the environment, i.e. the effort, although seemingly benevolent, may be utterly meaningless in the grander scheme of things.

    There is a woman like this in my gym as well, 70yrs old, cardio junkie, wishing to stay "skinny and cut," and having no interest in training strength for her brittle frame (I work as a personal trainer in a medium sized facility), and there is probably one or two in the gym two blocks down, and two blocks down from that etc. etc. So if Kurt really wishes to help ANs, he would need to work on a much larger scale, perhaps creating an AN awareness month that goes global, not bringing awareness to a single individual in one gym.

    I think Kurt's behavior certainly does raise the question, was he trying to remove her from his sight or really trying to help? Tolerance is very important but I'd say if you really wanted to help her then you would go and speak with her as a physician with plenty of experience.

  19. "You can imagine the typical well-meaning dietician designed diets for these sick young people. It's the food pyramid with way too many grains, too little fat, and a focus on "healthy" rather than good old fashioned farm fresh food."

    I hear you. For the last few weeks I've been working on a one-page diet-and-supplement handout for recovering meth addicts for the local health board. Because I have had the experience and known enough other users to know what works.
    You can imagine the feedback from dieticians, the official websites
    , the over-promotion of grains and sidelining of fats. It's as if everyone is already obese, even some starving (literally) tweaker.
    I managed to get in the line "favour energy and nutrient dense meals". You don't hear that often these days.


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