Low-Carb Diets and T3: A False Alarm
by Sam Knox
Prologue
Carbohydrate-restricted diets have come under fire recently over concerns that their association with reduced levels of the active thyroid hormone (T3) might cause the symptoms of hypothyroidism. I will argue that those concerns are unfounded.
There’s no shortage of evidence that, when calories are held constant, blood serum levels of T3 fall in concert with decreases in dietary carbohydrate, and zero-carb diets result in levels of T3 similar to fasting.
There is, on the other hand, no evidence that low-carb or ketogenic diets actually cause any symptom of inadequate thyroid hormone. Indeed, the evidence we do have shows that the primary function of T3, regulating basal metabolism, is unaffected by the amount of carbohydrate in a diet, and suggests that lower levels of T3 associated with low-carb diets are the result of a reduced need to metabolise glucose.
A (Very) Brief Introduction to Thyroid Hormones
Thyroid hormone blood serum levels are controlled by the hypothalamic-pituitary-thyroid (HPT) axis. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the pituitary gland to release thyroid stimulating hormone (TSH), which in turn causes the thyroid to release its hormones into the bloodstream.
The thyroid gland produces two hormones, thyroxine (T4) and triiodothyronine (T3), in a ratio of roughly five to one. Both T3 and T4 are either “bound” (in a protein molecule) or “free”, and only the free versions are biologically available. Free T4 is converted to T3 or reverse-T3 (rT3). Free T3 is the active thyroid hormone, while reverse-T3 is either inactive or binds to T3 receptors and inhibits the action of free T3.
Lab tests can measure blood serum levels of TRH, TSH, total T4, total T3, free T4, free T3 and reverse-T3, as well as other markers of thyroid activity.
Hypothyroidism(s)
“Primary” hypothyroidism is caused by the failure of the thyroid gland to produce sufficient thyroid hormones. “Secondary” hypothyroidism is caused by the failure of pituitary or hypothalamus to produce sufficient stimulating hormones.
The symptoms of hypothyroidism include: lowered basal metabolism, fatigue, sluggishness, weakness, cold intolerance, constipation, dry skin, puffy face, hoarse voice, elevated cholesterol, unintentional weight gain, aches and pains, heavier than normal menstrual periods, brittle hair and fingernails, and depression.
In the lab, TSH is elevated and free T4 is low. Levels of free T3 may be normal or low.
“Subclinical” hypothyroidism is characterized by elevated TSH and normal T4, without symptoms.
Low T3 Syndrome
Low T3 syndrome, also known as “euthyroid sick syndrome” (ESS) or “nonthyroidal illness syndrome” (NTIS), is a condition in which thyroid function remains intact but the conversion from T4 to T3 is reduced.
Low T3 syndrome can have other causes, but it is most often found in hospital wards in patients who are ill or recovering from surgery. Whether low T3 syndrome is an adaptive response to stress or a pathology is controversial, as is treatment.
Low T3 syndrome varies in severity depending on the severity of the illness or stress. In “mild” low T3 syndrome, levels of TSH and T4 remain within the normal range, while T3 falls and reverse-T3 rises. In “moderate” low T3 syndrome, TSH is rising and T4 falling, but still within the normal range. In “severe” low T3 syndrome, all thyroid hormones are outside the normal range.
Image: Medscape Reference
Mild low T3 syndrome has no overt symptoms, and any attempt at diagnosis by symptoms that may be associated with the moderate or severe forms is confounded by the underlying illness or stress. The diagnosis of low T3 syndrome is made exclusively in the laboratory, when levels of T3 and reverse-T3 are found to be outside the normal range.
Low T3 syndrome can exacerbate pre-existing thyroid disease (undiagnosed hypothyroidism or subclinical hypothyroidism).
The Argument From Lack of Evidence
Modern versions of low-carb diets have been around since the early 1970′s, and the relationship between dietary carbohydrate and the active thyroid hormone emerged not much later. Nevertheless, in the popular and scientific articles that raised concerns about the safety of low-carb diets, references to the symptoms of hypothyroidism are conspicuous only by their absence.
Ketogenic diets that restrict carbohydrates, calories, and fluid have been used to treat refractory epilepsy, mostly in children, since 1921. Those diets have been studied extensively since that time. The list of possible side effects has grown quite long, but the symptoms of hypothyroidism are not among them.
The relationship between carbohydrate-restriction and reduced levels of T3 was established more than thirty years ago. To this day, there isn’t a single piece of clinical evidence that carbohydrate-restriction alone causes any symptom of hypothyroidism.
The Argument from Basal Metabolism
Low basal metabolism and the symptoms associated with it (cold intolerance, fatigue, sluggishness) can have other causes, but they are the defining features of hypothyroidism.
In weight-maintenance or weight-reduction diets, with one exception, studies in which total calories are held constant have found that basal metabolism was unaffected by the carbohydrate content of the diet. Most importantly, these results suggest that the additional T3 produced by adding carbohydrate to the diet is used primarily, if not exclusively, to metabolize increased levels of blood glucose.
The Argument from Lack of Symptoms
Carbohydrate-restriction results in a hormonal profile that is identical to that of mild low T3 syndrome: TSH and T4 normal, T3 low. (Reverse T3 may be high or normal.)
Mild low T3 syndrome is not associated with any overt symptoms of hypothyroidism. In the words of one researcher, “Patients who have only a drop in serum T3, representing the mildest form of NTIS, do not show clinical signs of hypothyroidism, nor has it been shown that this decrease in serum T3 has an adverse physiological effect on the body …”.
Occam’s Razor
One of the functions of T3 is its role, along with insulin, in lowering blood sugar by transporting glucose from the bloodstream into individual cells.
Other things equal, lower levels of dietary carbohydrate mean lower levels of blood sugar. The simplest and most plausible explanation for the lower levels of T3 that accompany low-carb diets is that the amount of T3 required to perform all of its functions is now less.
Ironically, both T3 and insulin are reduced by a low-carb diet, apparently for the same reason, but you’d be hard-pressed to find someone who referred to this as an “insulin deficiency”.
Epilogue
There are anecdotal reports of symptoms of hypothyroidism in those following a low-carb diet that were improved by the isocaloric addition of dietary carbohydrate.
The preponderance of clinical evidence suggests that their symptoms were caused by too few calories or a pre-existing thyroid condition. Attempting to treat the symptoms of hypothyroidism by adding carbohydrate to the diet might offer some improvement via the placebo effect, but it will not address the underlying cause and, more importantly, will delay treatment.
Notes
“There’s no shortage of evidence …”: Refs. 1-12.
“A (Very) Brief Introduction to Thyroid Hormones”: Ref. 13.
“Hypthyroidism(s)”: Ref. 14, 15.
“Low T3 syndrome, also known as…”: Ref. 16.
“Whether low T3 syndrome is adaptive…”: Ref. 17.
“Low T3 syndrome varies in severity…”: Ref. 18.
“Mild low T3 syndrome has no overt symptoms…”: Ref. 17.
“Low T3 syndrome can exacerbate…”: Ref. 19.
“Ketogenic diets that restrict …”: Ref. 23.
“… are not among them …”: Ref. 24.
“In weight-maintenance or weight-reduction diets …”: Refs. 7, 11, 25-30.
“… with one exception…”: Ref. 8. Hendler, et al, found that adding table sugar to a weight-reducing diet increased basal metabolism, and suggested that weight-loss might be enhanced in this way. Given the known effect of refined carbohydrate on norepinephrine, and the effect of norepinephrine on basal metabolism, however, it’s impossible to conclude from this study that the elevated metabolism was caused by the increase in T3.
“Carbohydrate-restriction results in …”: Refs. 3, 5-7, 10-12.
“Mild low T3 syndrome is not associated with …”: Ref 17:
“One of the functions of T3 …”: Refs. 2, 31.
References
(Abstracts and links to free full text are included where available.)
1. Danforth, et al: Dietary-induced Alterations in Thyroid Hormone Metabolism during Overnutrition, Clin Invest. 1979 November; 64(5): 1336–1347
Abstract: Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine [T4] production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.
2. Spaulding, et al: Effect of caloric restriction and dietary composition of serum T3 and reverse T3 in man, Journal of Clinical Endocrinology & Metabolism, Jan, 1976; 42 (1): 197–200
Abstract: To evaluate the effect of caloric restriction and dietary composition on circulating T3 and rT3 obese subjects were studied after 7-18 days of total fasting and while on randomized hypocaloric diets (800 kcal) in which carbohydrate content was varied to provide from 0 to 100% calories. As anticipated, total fasting resulted in a 53% reduction in serum T3 in association with reciprocal 58% increase in rT3. Subjects receiving the no-carbohydrate hypocaloric diets for two weeks demonstrated a similar 47% decline in serum T3 but there was no significant change in rT3 with time. In contrast, the same subjects receiving isocaloric diets containing at least 50 g of carbohydrate showed no significant changes in either T3 or rT3 concentration. The decline in serum T3 during the no-carbohydrate diet correlated significantly with blood glucose and ketones but there was no correlation with insulin or glucagon. We conclude that dietary carbohydrate is an important regulatory factor in T3 production in man. In contrast, rT3 concentration is not significantly affected by changes in dietary carbohydrate. Our data suggest that the rise in serum rT3 during starvation may be related to more severe caloric restriction than that caused by the 800 kcal diet.
3. Davidson, et al: Effect of carbohydrate and noncarbohydrate sources of calories on plasma 3,5,3′-triiodothyronine concentrations in man, Journal of Clinical Endocrinology & Metabolism, Apr, 1979; 48 (4): 577–581.
Abstract: To evaluate the effect of changes in dietary carbohydrate (CHO) and excessive caloric consumption on circulating thyroid hormone levels, six normal weight subjects were fed five separate diets: three isocaloric diets with 20%, 40%, or 80% CHO and two hypercaloric (+2000 calories) diets with 20% or 40% CHO for 5 days each as outpatients. T4, T3, and rT3 concentrations were measured in plasma samples collected on the morning of the sixth day. At least 1 week of the subjects’ usual diets intervened between each experimental diet.
Mean T4 and rT3 levels were similar after all diets. Pair-wise comparisons among all five diets revealed significantly (P <;;;;;;;;;;;;;;;;;;;; 0.005) increased T3 concentrations after both hypercaloric diets compared to the iso-20 and iso-40 diets, and after the iso-80 compared to the iso-20 diet. A multiple regression analysis of the data revealed the highest correlation of T3 levels with total calories (r = 0.68; P <;;;;;;;;;;;;;;;;;;;; 0.001) rather than with the intake of CHO (r = 0.46; P <;;;;;;;;;;;;;;;;;;;; 0.025), fat (r = 0.49; P <;;;;;;;;;;;;;;;;;;;; 0.02), or protein (r = 0.30; P = NS). A repeated measures analysis of variance of the data revealed that over a daily caloric range of 2100-4100 calories, increasing CHO intake between 204-408 g did not influence T:t levels. However, over this same range of CHO intake, increasing calories between 2100-4100 was associated with increased T3 concentrations. Furthermore, this caloric effect on T3 levels was independent of CHO intake.
These data suggest that: 1) non-CHO as well as CHO sources are important modulators of plasma T3 concentrations in man; and 2) the influence of non-CHO calories may actually be more pronounced than that of CHO when at least a normal amount (-200 g) of CHO is ingested.
4. Azizi F.: Effect of dietary composition on fasting induced changes in serum thyroid hormones and thyrotropin.Metabolism, 1978; 27: 935-942.
“Azizi (17) using a 800 kcal mixed or exclusively carbohydrate refeeding diet over a 4-day period reported that T3 returned to baseline, while it continued to decrease when the diet contained only protein or fat.” (Cited in Serog, et al, 1982.)
5. Serog, et al: Effects of slimming and composition of diets on V02 and thyroid hormones in healthy subjects, American Journal of Clinical Nutrition, Jan 1982; 35: 24-35
Abstract: Oxygen consumption and plasma thyroid hormone concentrations are modified by both low- and high-calorie diets. It has been suggested that the trigger may be changes in weight (“adipostatic” hypothesis involving the difference between the actual weight and the “set point”) or changes in amount of carbohydrate in the diet (“carbohydrate” hypothesis”). Two experiments were performed in order to test both hypotheses. Fourteen young healthy volunteers were studied: I) at their spontaneous stable weight; 2) while losing weight rapidly on a calorically restricted diet; 3) and then at their stable new weight when consuming a refeeding diet. The calorie restricted diet resulted in decrease of c’O2, and T3, and an increase of rT3; the refeeding diet resulted in values of ı‘O2, T3, and rT3 intermediate between those of the spontaneous diet and those ıf the restricted diet. Another group of nine subjects were studied at their spontaneous caloric and proteic levels, comparing a diet containing only protein and carbohydrate with a diet containing only protein and fat. During the low carbohydrate diet rT3 increased and T3 decreased but they remained unchanged during the carbohydrate-rich diet. Thus neither the adipostatic hypothesis nor the carbohydrate hypothesis is sufficient alone to explain the observed changes in serum T3 and rT3.
From the full text: ” …VO2 [oxygen consumption] does not vary significantly even when T3 and rT3 vary.”
6. Fery F, et al.: Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects. Diabetes & Metabolism, Dec 1982; 8 (4): 299-305
The effects of a 4-day isocaloric isoprotenic dietary replacement of carbohydrate by fats were studied in six healthy subjects, the experimental diet being preceded and followed by a 3-day period of balanced diet. During the ketogenic regimen, the concentrations of fat derived substrates (free fatty acids, glycerol and 3-hydroxybutyrate) rose significantly and glucose levels decreased by 16.5 +/- 3.2% (mean +/- SEM). The hormonal pattern switched towards a catabolic mode with a fall in insulin levels (-44.0 +/- 6.3%) and a rise in glucagon concentration (+39.0 +/- 10.4%). A significant fall in triiodothyronine and rise in reverse triiodothyronine were observed, while thyroxine levels remained unchanged. The average levels of the most important gluconeogenic amino acids (alanine, glutamine, glycine, serine and threonine) were reduced by 8-34% while those of the branched chain amino acids increased by more than 50%. Since these changes reproduce those observed after a few days of total fasting, we suggest that it is the carbohydrate restriction itself which is responsible for the metabolic and hormonal adaptations of brief fasting.
7. Mathieson RA, et al. The effect of varying carbohydrate content of a very-low-caloric diet on resting metabolic rate and thyroid hormones. Metabolism, May, 1986; 35 (5): 394-398
Twelve obese women were studied to determine the effects of the combination of an aerobic exercise program with either a high carbohydrate (HC) very-low-caloric diet (VLCD) or a low carbohydrate (LC) VLCD diet on resting metabolic rate (RMR), serum thyroxine (T4), 3,5,3′-triiodothyronine (T3), and 3,5,3′-triiodothyronine (rT3). The response of these parameters was also examined when subjects switched from the VLCD to a mixed hypocaloric diet. Following a maintenance period, subjects consumed one of the two VLCDs for 28 days. In addition, all subjects participated in thrice weekly submaximal exercise sessions at 60% of maximal aerobic capacity. Following VLCD treatments, participants consumed a 1,000 kcal mixed diet while continuing the exercise program for one week. Measurements of RMR, T4, T3, and rT3 were made weekly. Weight decreased significantly more for LC than HC. Serum T4 was not significantly affected during the VLCD. Although serum T3 decreased during the VLCD for both groups, the decrease occurred faster and to a greater magnitude in LC (34.6% mean decrease) than HC (17.9% mean decrease). Serum rT3 increased similarly for each treatment by the first week of the VLCD. Serum T3 and rT3 of both groups returned to baseline concentrations following one week of the 1,000 kcal diet. Both groups exhibited similar progressive decreases in RMR during treatment (12.4% for LC and 20.8% for HC), but values were not significantly lower than baseline until week 3 of the VLCD. Thus, although dietary carbohydrate content had an influence on the magnitude of fall in serum T3, RMR declined similarly for both dietary treatments.
8. Hendler, et al: Sucrose substitution in prevention and reversal of the fall in metabolic rate accompanying hypocaloric diets. American Journal of Medicine, 1986; 81 (2): 280-284
Hypocaloric diets cause a fall in resting metabolic rate that interferes with weight loss. To evaluate the mechanisms underlying this phenomenon, resting metabolic rate was measured sequentially in six healthy obese women on a weight maintenance diet (more than 2,300 kilocalories), after 15 days of an 800 kilocalories carbohydrate-free diet, and after isocaloric sucrose replacement for an additional 15 days. The carbohydrate-free diet produced a 21 percent decline in resting metabolic rate (p less than 0.005) as well as a decrease in circulating triiodothyronine (41 percent, p less than 0.02) and insulin (38 percent, p less than 0.005) concentrations. Plasma norepinephrine levels also tended to decline (10 percent, 0.05 greater than p less than 0.1). However, when sucrose was substituted, resting metabolic rate rose toward baseline values even though total caloric intake was unchanged and weight loss continued. The sucrose-induced rise in resting metabolic rate was accompanied by a rise in serum triiodothyronine values, but not plasma insulin or norepinephrine concentrations. Throughout, changes in resting metabolic rate correlated with changes in serum triiodothyronine levels (r = 0.701, p less than 0.01). In four obese women, a hypocaloric sucrose diet was given at the outset for 15 days. The fall in both resting metabolic rate and triiodothyronine concentration was markedly reduced as compared with values during the carbohydrate-free diet. It is concluded that carbohydrate restriction plays an important role in mediating the fall in resting metabolic rate during hypocaloric feeding. This effect may, at least in part, be related to changes in circulating triiodothyronine levels. Incorporation of carbohydrate in diet regimens may, therefore, minimize the thermic adaptation to weight loss.
9. Burman KD, et al. Glucose modulation of alterations in serum iodothyronine concentrations induced by fasting. Metabolism, Apr, 1979; 28 (4): 291–299
10. Volek JS, et al. Body composition and hormonal responses to a carbohydrate-restricted diet. Metabolism. 2002 Jul; 51 (7): 864-870
The few studies that have examined body composition after a carbohydrate-restricted diet have reported enhanced fat loss and preservation of lean body mass in obese individuals. The role of hormones in mediating this response is unclear. We examined the effects of a 6-week carbohydrate-restricted diet on total and regional body composition and the relationships with fasting hormone concentrations. Twelve healthy normal-weight men switched from their habitual diet (48% carbohydrate) to a carbohydrate-restricted diet (8% carbohydrate) for 6 weeks and 8 men served as controls, consuming their normal diet. Subjects were encouraged to consume adequate dietary energy to maintain body mass during the intervention. Total and regional body composition and fasting blood samples were assessed at weeks 0, 3, and 6 of the experimental period. Fat mass was significantly (P <;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;or=.05) decreased (-3.4 kg) and lean body mass significantly increased (+1.1 kg) at week 6. There was a significant decrease in serum insulin (-34%), and an increase in total thyroxine (T(4)) (+11%) and the free T(4) index (+13%). Approximately 70% of the variability in fat loss on the carbohydrate-restricted diet was accounted for by the decrease in serum insulin concentrations. There were no significant changes in glucagon, total or free testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-I (IGF-I), cortisol, or triiodothyronine (T(3)) uptake, nor were there significant changes in body composition or hormones in the control group. Thus, we conclude that a carbohydrate-restricted diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men, which may be partially mediated by the reduction in circulating insulin concentrations.
11. Bisschop PH, et al. Isocaloric carbohydrate deprivation induces protein catabolism despite a low T3-syndrome in healthy men. Clinical Endocrinology, 2001; 54: 75-80
Dietary carbohydrate content is a major factor determining endocrine and metabolic regulation. The aim of this study was to evaluate the relation between thyroid hormone levels and metabolic parameters during eucaloric carbohydrate deprivation. We measured thyroid hormone levels, resting energy expenditure (by indirect calorimetry) and urinary nitrogen excretion in six healthy males after 11 days of three isocaloric diets containing 15% of energy equivalents as protein and 85%, 44% and 2% as carbohydrates. In contrast to the high and intermediate carbohydrate diets, carbohydrate deprivation decreased plasma T3 values (1.78 +/- 0.09 and 1.71 +/- 0.07 vs. 1.33 +/- 0.05 nmol/l, respectively, P <;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; 0.01), whereas reverse T3, T3 uptake and free T4 levels increased simultaneously compared to the other two diets. TSH values were not different among the three diets. Although dietary carbohydrate content did not influence resting energy expenditure, carbohydrate deprivation increased urinary nitrogen excretion (10.91 +/- 0.67 and 12.79 +/- 1.14 vs. 15.89 +/- 1.10 g/24 h, respectively, P = 0.03). Eucaloric carbohydrate deprivation increases protein catabolism despite decreased plasma T3 levels. Because it has previously been shown that starvation decreases plasma T3 levels, resting energy expenditure and nitrogen excretion, these discordant endocrine and metabolic changes following carbohydrate deprivation indicate that the effects of starvation on endocrine and metabolic regulation are not merely the result of carbohydrate deprivation.
12. Otten MH, et al. The Role of Dietary Fat in Peripheral Thyroid Hormone Metabolism. Metabolism, Oct, 1980; 29 (10): 930-935 Arzneimittelforschung, 1986 Feb;36(2):262-5
Short term changes in serum 3,3′,5-triiodothyronine (T3) and 3,3’5-triiodothyronine (reverse T3, rT3) were studied in four healthy nonobese male subjects under varying but isocaloric and weight maintaining conditions. The four 1500 kcal diets tested during 72 hr, consisted of: I, 100% fat; II, 50% fat, 50% protein; III, 50% fat, 50% carbohydrate (CHO), and IV, a mixed control diet. The decrease of T3 (50%) and increase of rT3 (123%) in the all-fat diet equalled changes noted in total starvation. In diet III (750 kcal fat, 750 kcal CHO) serum T3 decreased 24% (NS) and serum rT3 rose significantly 34% (p <;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; 0.01). This change occurred in spite of the 750 kcal CHO. This amount of CHO by itself does not introduce changes in thyroid hormone levels and completely restores in refeeding models the alterations of T3 and rT3 after total starvation. The conclusion is drawn that under isocaloric conditions in man fat in high concentration itself may play an active role in inducing changes in peripheral thyroid hormone metabolism.
13. The Merck Manual for Healthcare Professionals: Overview of Thyroid Function
14. The Merck Manual for Healthcare Professionals: Hypothyroidism
15. The Mayo Clinic: Hypothyroidism Symptoms
16. The Merck Manual for Healthcare Professionals: Euthyroid Sick Syndrome
17. DeGroot, Leslie: Dangerous Dogmas in Medicine: The Nonthyroidal Illness Syndrome. Journal of Clinical Endocrinology & Metabolism January 1, 1999 vol. 84 no. 1 151-164
18. Medscape Reference: Euthyroid Sick Syndrome
19. Medscape Reference: Euthyroid Sick Syndrome, Clinical Presentation
20. Mastorakos, et al: Exercise and the stress system. Hormones (Athens). 2005 Apr-June; 4(2): 73-89
21. O’Connell, et al: Changes in serum concentrations of 3,3′,5′-triiodothyronine and 3,5,3′-triiodothyronine during prolonged moderate exercise. J Clin Endocrinol Metab. 1979 Aug;49(2):242-6.
The effect of moderate bicycle exercise (3.5 h) on peripheral thyroid hormone metabolism was studied under two conditions (with and without glucose infusion) in four normal males. Serum T3, rT3, total protein, plasma glucose, and FFA were determined. Exercise induced an increase in rT3 from 29 to 40 ng/dl (P less than 0.01), a decrease in T3 from 154 to 147 ng/dl (P less than 0.01), and an increase in T4 from 7.1 to 7.5 micrograms/dl (P less than 0.05). When glucose was infused during exercise, the changes in rT3 were blunted (P less than 0.01) and the changes in T3 and T4 were diminished. During exercise, rT3 correlated with FFA (r = 0.95) and plasma glucose (r = -0.87). When glucose was infused during exercise, these correlations decreased (r = 0.81 and -0.56, respectively). Since moderate, prolonged exercise induces a state of early or acute starvation it is concluded that the changes in peripheral thyroid hormone metabolism reported here are similar to those found in starvation. The temporal changes of rT3, FFA, and plasma glucose during exercise suggest a relationship between thyroid hormone metabolism and the uptake and utilization of FFA and glucose or the mixture of these body fuels.
22. Phinney, et al: Capacity for Moderate Exercise in Obese Subjects after Adaptation to a Hypocaloric, Ketogenic Diet. J Clin Invest. 1980 November; 66(5): 1152–1161.
23. Wirrell, Elaine: Ketogenic Ratio, Calories and Fluids: Do They Matter? Epilepsia. 2008 November; 49(Suppl 8): 17–19
24. Kang, et al: Early- and Late-Onset Complications of the Ketogenic Diet for Intractable Epilepsy Epilepsia 2004;45:1116–1123.
The most common early-onset complication was dehydration, especially in patients who started the KD with initial fasting. Gastrointestinal disturbances, such as nausea/vomiting, diarrhea, and constipation, also were frequently noted, sometimes associated with gastritis and fat intolerance. Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia. Most early- and late-onset complications were transient and successfully managed by careful follow-up and conservative strategies. However, 22 (17.1%) patients ceased the KD because of various kinds of serious complications, and 4 (3.1%) patients died during the KD, two of sepsis, one of cardiomyopathy, and one of lipoid pneumonia.
25. Leibel, et al: Energy intake required to maintain body weight is not affected by wide variation in diet composition. Am J Clin Nutr. 1992 Feb;55(2):350-5.
“Other investigators, studying subjects over shorter time periods than we used here, reported no effect on various aspects of energy expenditure (24-h expenditure, resting metabolic rate) of high- vs low-CHO diets. (See refs. 26-30)
26. Lean, et al: Metabolic effects of isoenergetic nutrient exchange over 24 hours in relation to obesity in women. Int J Obes 1988;12: 15-27.
27. Hurni, et al: Metabolic effects of a mixed and a high-carbohydrate diet in man, measured over 24 hours in a respiration chamber. Br J Nutr 1982;47:33-43.
28. McNeill, et al: Inter-individual differences in fasting nutrient oxidation and the influence ofdiet composition. Int J Obes 1988;12:455-63.
29. Abbott, et al: Energy expenditure in humans: effects of dietary fat and carbohydrate. Am JPhysiol 1990;258:E347-5 1.
30. Hill, et al: Nutrient balance in humans: effects of diet composition. Am J Clin Nutr 1991;54:lO-7.
31. Colorado State Online Textbooks: Mechanism of Action and Physiologic Effects of Thyroid Hormones
” Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells …”
32. Loucks AB, Callister R.: Induction and prevention of low-T3 syndrome in exercising women. Am J Physiol. 1993 May;264(5 Pt 2):R924-30.
I’m inclined to agree with your major points.
Thanks for reading, Steve.
I was mostly making a common-sense argument that thyroid hormones are “too low” only when they cause symptoms, not when they are just lower than some baseline.
That was an excellent article, right on target.
I watched the “low carb causes hypothyroidism” meme take off in Paleo and now many of them consider it fact. Then I switched off Paleo forums! Sheesh!
Thanks for stopping by.
Speaking of Paleo, this article (abstract) suggests that excess carbs, by raising T3, is the cause of iodine deficiency diseases:
http://www.medical-hypotheses.com/article/S0306-9877(04)00169-0/abstract
Very nicely done, Sam. I, too, think this is one of the new anti-ketogenic myths that have come along to replace the old ones. Ketoacidosis, Kidneys, Osteoporosis — safely in their graves. Now they’re going after hormones.
Hey Amber,
After I wrote this article, I saw that you had covered some of the same ground in a thread at Paleohacks. I just wanted to acknowledge that in some way. Thanks for stopping by.
Sam
Hi Sam,
You’ve gathered a very nice collection of papers, but the papers clearly show that carb (or carb+protein) intake are important factors in T3/rT3 levels; glucose scarcity clearly depresses T3 production in the liver and peripherally and can generate hypothyroid symptoms.
The papers don’t support your main conclusions:
1) Yes, underfeeding lowers T3, but some people want to be on calorie-restricted diets for weight loss. Shouldn’t we show them how to minimize the drop in T3 and any hypothyroid symptoms that result?
2) Yes, exercise, especially endurance exercise, increases glucose requirements and can induce the low-T3 glucose conservation mechanism. But in what sense does that prove that the exercise is “too much exercise” and not that the carb intake was too little? Some people want to be athletes. If they can be successful endurance athletes on higher-carb but not lower-carb diets, that would seem to indicate they should eat more carbs.
3) Yes, underlying hypothyroid conditions do contribute to the issue. But your conclusion — “Attempting to treat the symptoms of hypothyroidism by adding carbohydrate to the diet might offer some improvement, either because the symptoms were not caused by impaired thyroid function or via the placebo effect, but it will not address the underlying cause and will delay treatment.” – misses the point of debate. No one ever said that low carb damages the thyroid gland, or that additional carbs would heal the thyroid; what people do say is that hypothyroid symptoms brought on by reduced T4 to T3 conversion in the liver (a glucose conservation measure) can be relieved by adding carbs to the diet. In what sense then is the higher T3 and relief from symptoms that come with carb consumption a “placebo effect”? It’s clearly physiological. There seems to be some play with word meanings here. “Hypothyroid” does not imply a pathology of the thyroid; there is central hypothyroidism due to pituitary issues, and secondary hypothyroidism due to reduced T3 generation peripherally or in the liver. By the way, did I miss when doctors became effective at treating “the underlying cause” of hypothyroidism? The usual treatments, thyroid hormone replacement, provide symptomatic relief and do not address the underlying cause of hypothyroidism. This sort of “treatment” can be damaging to health in the case of low-T3 due to glucose scarcity, as it defeats the body’s evolved mechanisms for allocating what glucose is available to their most valuable uses.
In other places you set up straw men, eg “The belief that, in healthy individuals, carbohydrate restriction can consistently cause the symptoms of hypothyroidism” – no one has asserted this. The problem of high LDL on low-carb diets, which is one of the low T3 effects, seems to occur in maybe 2% of low-carb dieters. We are dealing with a minority population. However, if protein were restricted alongside carbohydrate, the problem could probably be induced in close to 100% of people. One of your cites (Otten MH, et al. The Role of Dietary Fat in Peripheral Thyroid Hormone Metabolism.) notes: “The decrease of T3 (50%) and increase of rT3 (123%) in the all-fat diet equalled changes noted in total starvation.” This clearly ties the low T3 problem to a carb+protein deficiency, which makes sense since protein can compensate for missing glucose by mechanisms such as gluconeogenesis.
I think you’ve done a good job refuting certain misconceptions of the issue – eg, that there is thyroid dysfunction occurring – but you certainly haven’t refuted the idea that low-T3 induced by glucose scarcity can be beneficially relieved by eating more carbohydrate.
Best, Paul
Hey Paul,
Thanks for reading and commenting.
“You’ve gathered a very nice collection of papers, but the papers clearly show that carb (or carb+protein) intake are important factors in T3/rT3 levels; glucose scarcity clearly depresses T3 production in the liver and peripherally and can generate hypothyroid symptoms.”
I stated clearly that reducing dietary carbohydrate also reduces serum levels of T3, but none of the papers I cited show a connection between lower levels of T3 from carbohydrate restriction and any symptom of hypothyroidism and, as far as I know, there’s no clinical evidence that such a connection exists. The evidence we do have from hospital evaluations of euthyroid sick syndrome suggest that as long as TSH and T4 remain stable, lower levels of T3 alone do not produce any overt symptoms of hypothyroidism.
“The papers don’t support your main conclusions:
1) Yes, underfeeding lowers T3, but some people want to be on calorie-restricted diets for weight loss. Shouldn’t we show them how to minimize the drop in T3 and any hypothyroid symptoms that result?”
The evidence from studies that measured dietary carbohydrate, total calories, and basal metabolism suggest that basal metabolism is a function of total calories, not dietary carbohydrate. Adding carbs without increasing calories will raise T3 levels but will not elevate metabolism. Anyone who exhibits metabolic symptoms of hypothyroidism (cold intolerance, fatigue) is suffering from a lack of calories, not a lack of carbohydrate.
“2) Yes, exercise, especially endurance exercise, increases glucose requirements and can induce the low-T3 glucose conservation mechanism. But in what sense does that prove that the exercise is “too much exercise” and not that the carb intake was too little? Some people want to be athletes. If they can be successful endurance athletes on higher-carb but not lower-carb diets, that would seem to indicate they should eat more carbs.”
Low T3 levels associated with exercise appear to be the result of a calorie deficit, not the exercise itself. If dietary carbohydrate makes the difference between success or failure as an endurance athlete, I would submit it’s the effect on glycogen stores, not the effect on T3.
“3) Yes, underlying hypothyroid conditions do contribute to the issue. But your conclusion — “Attempting to treat the symptoms of hypothyroidism by adding carbohydrate to the diet might offer some improvement, either because the symptoms were not caused by impaired thyroid function or via the placebo effect, but it will not address the underlying cause and will delay treatment.” – misses the point of debate. No one ever said that low carb damages the thyroid gland, or that additional carbs would heal the thyroid; what people do say is that hypothyroid symptoms brought on by reduced T4 to T3 conversion in the liver (a glucose conservation measure) can be relieved by adding carbs to the diet. In what sense then is the higher T3 and relief from symptoms that come with carb consumption a “placebo effect”? It’s clearly physiological. There seems to be some play with word meanings here. “Hypothyroid” does not imply a pathology of the thyroid; there is central hypothyroidism due to pituitary issues, and secondary hypothyroidism due to reduced T3 generation peripherally or in the liver. By the way, did I miss when doctors became effective at treating “the underlying cause” of hypothyroidism? The usual treatments, thyroid hormone replacement, provide symptomatic relief and do not address the underlying cause of hypothyroidism. This sort of “treatment” can be damaging to health in the case of low-T3 due to glucose scarcity, as it defeats the body’s evolved mechanisms for allocating what glucose is available to their most valuable uses.”
The point of the debate is whether or not reduced peripheral conversion to T3 from reduced carbohydrate results in symptoms of hypothyroidism. I think the evidence shows that it does not, and if lowering carbohydrate does not cause the symptoms of hypothyroidism it follows that adding carbohydrate will not alleviate them.
“In other places you set up straw men, eg “The belief that, in healthy individuals, carbohydrate restriction can consistently cause the symptoms of hypothyroidism” – no one has asserted this. The problem of high LDL on low-carb diets, which is one of the low T3 effects, seems to occur in maybe 2% of low-carb dieters. We are dealing with a minority population. However, if protein were restricted alongside carbohydrate, the problem could probably be induced in close to 100% of people. One of your cites (Otten MH, et al. The Role of Dietary Fat in Peripheral Thyroid Hormone Metabolism.) notes: “The decrease of T3 (50%) and increase of rT3 (123%) in the all-fat diet equalled changes noted in total starvation.” This clearly ties the low T3 problem to a carb+protein deficiency, which makes sense since protein can compensate for missing glucose by mechanisms such as gluconeogenesis.”
My experience is that authoritative statements about low-carb diets and hypothyroid symptoms tend not to be qualified in this way.
“I think you’ve done a good job refuting certain misconceptions of the issue – eg, that there is thyroid dysfunction occurring – but you certainly haven’t refuted the idea that low-T3 induced by glucose scarcity can be beneficially relieved by eating more carbohydrate.”
I never intended to refute the idea that reducing levels of carbohydrate also reduces T3 or that adding carbohydrate elevates T3. I intended to refute the idea that low T3 from carbohydrate restriction causes the symptoms of hypothyroidism, and I think that both empirical evidence and physiology support me.
The underlying assumption of the proponents of the idea that low-carb diets cause symptoms of hypothyroidism, and the underlying assumption of your arguments here, is that evidence of reduced T3 from low-carb diets is sufficient to make your case. If the only function of T3 was regulating basal metabolism, you’d all be right, but T3 has other functions, the most pertinent being its role in glucose metabolism. I think the evidence shows that lowered T3 alone is insufficient to produce hypothyroid symptoms and that lower levels of T3 associated with low-carb diets are a function of the reduced need to metabolize blood sugar.
Sam
Hi Sam,
No, my point was that people on very low-carb diets sometimes develop some negative symptoms, such as elevated LDL or low body temperature, that these are associated with low T3 levels, that there are plausible biological mechanisms connecting these symptoms to low T3, and that both the low T3 and the symptoms go away when carb intake is increased.
If the definition of hypothyroidism is specifically under-production of hormone by the thyroid gland, then it’s not hypothyroidism. In the clinical literature this collection of symptoms is more commonly called “euthyroid sick syndrome” or some such term, or are un-named as a syndrome. (I’ve called them “zero-carb dangers”). But their name is a semantic issue.
More substantive would be the issue your last sentence raises: Are low T3 levels on low-carb diets a function of “a reduced need to metabolize blood sugar”, as you say, or “an enhanced need to suppress utilization of blood sugar,” as I say?
How reduced carb intake could reduce the benefits the body would obtain from glucose is a mystery to me, so I think it’s more likely that the benefits are the same and it’s the lack of glucose that is forcing the body to forego those benefits.
Best, Paul
Paul,
Respectfully, anecdotes are not evidence.
There is simply no clinical evidence that reduced peripheral conversion of T4 to T3 associated with an otherwise adequate low-carb diet causes lower body temperature or lower basal metabolism. Indeed, the evidence we do have shows that, other things equal, basal metabolism is a function of calories, not carbohydrate.
The bottom line, for me, is this: Hypothyroidism is a serious and depressingly common medical condition, one from which I suffer myself. It is irresponsible, at best, to base a medical treatment on what is little more than conjecture, especially conjecture that has so little empirical or theoretical support.
Sam
“No, my point was that people on very low-carb diets sometimes develop some negative symptoms, such as elevated LDL or low body temperature, that these are associated with low T3 levels, that there are plausible biological mechanisms connecting these symptoms to low T3, and that both the low T3 and the symptoms go away when carb intake is increased.’
“Elevated” LDL or “low” body temperature aren’t “symptoms.” They’re just measured changes in the body that might be healthy or unhealthy or inconsequential to overall health. No one really knows which of these is the case, or if any of them is the case in general. As you know, there is wide disagreement about such things.
Making any sort of change (e.g., diet, supplements, medication) specifically to address an LDL or body temperature measurement is a classic case of treating a number rather than treating a person. At the pretty primitive current state of our understanding, there’s no way to know if such interventions will be good or harm.
Now if someone actually feels sick, or is sick, on a low-carb diet that’s a different story. But as you know, the experienced low-carb docs have an excellent track record of troubleshooting such problems, which usually resolve over time anyway. Adding carbs back instead of troubleshooting may make a person feel better, but attributing that to improved thyroid metabolism is a pretty big leap.
It is probably the case that some people, at least, do better long term if they eat at least a little carb. Even Gary Taubes says this of himself. But to argue for carb consumption based on LDL or body temp measurements or any other test, rather than real symptoms, is to me no different in principle than taking statins to “treat” an LDL measurement in an otherwise healthy person. The wisdom of this is unclear at best to me.
By the way, my own endocrinologist (I have Hashimoto’s) stopped even measuring T3 and rT3 years ago. “Treating” these values never helped the patients. Treating actual hypothyroid symptoms (and following TSH and T4 to avoid any gross mis-dosing) works like a charm. He has concluded that he has absolutely no idea what any particular person’s thyroid lab values should be, as long as they’re not at obviously pathological extremes. That humility is one of the things that makes him a truly great doc.
Hi, Paul.
I disagree that we would want to minimize the drop in T3 that results from caloric restriction, because it’s very likely that the lowered T3 prevents muscle loss in the calorie restricted condition. Likewise, it does not seem desirable to add carbohydrate to a low calorie condition, because comparisons of lower and higher carbohydrate levels in calorie restriction show more muscle retention with lower carbohydrate levels.
As to the hypothesis that the more extreme elevation of LDL seen rarely in low carb dieters is caused by low T3, you are right in emphasizing that this is a matter of “plausible biological mechanism”. Since this hypothesis — that low T3 occasionally causes very high LDL — hasn’t yet been tested, we can’t be sure it is the cause in these cases.
Reasoning about mechanisms can be valuable for developing hypotheses, but I wouldn’t forgo a clinically validated therapy based only on reasoning of that type.
I am not a doctor, or a biologist, or a “scientist” of any kind, just a reasonably experienced (35 years) attorney on a low carb diet for three years. The idea of evidence in these discussions is an interesting one, and I would have to end up on the side of studies and experiments, trying even then to consider the underlying purpose and the various other considerations that usually result in the entire affair being unreproducible. Whatever issues may exist, it is an entirely different category from anecdotes. Lab test and symptoms are even better.
But these ideas of various individuals (Who? When? How documented?) complaining of “thyroid” issues seem entirely untrustworthy and pointless.
The most likely explanation of the drop in the active hormone is the reduced need or purpose for the hormone “caused” by the reduced need metabolize glucose. This is not only observed, apparently, but reasonable, as fewer carbohydrates result in a reduced need to metabolize the reduced glucose.
I do not see how any of that is subject to much argument.
What is intriguing to me is the idea that glucose has to be kept in a very tight range within the body and blood, which suggests a very active mechanism to use glucose first, not out of preference for glucose as a fuel, but the body treating it (in excess) as a poison to be removed until proper levels are achieved.
Finally, the discussion has to be somewhat consistent with proper levels of thyroid hormone…. But the entire discussion on that topic can be pointless because in general the samples and discussion are based on a modern diet for the population that is relatively high in carbs, as opposed to fats, resulting in a higher need for thyroid hormone, as is entirely reasonable. Thus “normal” thyroid levels are probably about right, for a carb based diet.
This discussion sounds too much like the one regarding cholesterol, when the focus became the numbers, rather than the individual, and rather than the problem, and people were cured of high cholesterol. Not with good results. No one even fully or truly understands the various cholesterol and CHD issues (at least no one with any modesty), but there is no lack of pronouncements.
Richard,
Thanks for reading and commenting.
Yours is a very astute analysis. I’ve been reading the full-text of this study … http://www.ncbi.nlm.nih.gov/pubmed/15142639 … which suggests that modern levels of T3 are 1.5 times higher than they were before the advent of agricultural carbohydrates, and that iodine deficiency diseases are more likely the result of excess dietary carbohydrate than lack of iodine.
What follows from this is that levels of T3 associated with low-carb diets are more likely to represent what is healthy or natural rather than “normal” levels taken from a population with unnaturally high levels of carbohydrates from food.
I think most of the motivation for these controversies has more to do with market forces than science. Some people have carved out a niche by being critical of, or opposed to, low-carb diets, and they are eager to bring to light any evidence that they might be harmful.
Richard, that’s my interpretation of the phrase “preferred fuel” as well. It’s an unfortunate choice of words, although just about any word that means “first” is probably going to have a positive implication. Even saying the body uses glucose if it is “available” sounds like a “preference”.
Something like “the body temporarily stops metabolizing all other fuels, to prioritize getting rid of excess glucose”, would be just as true to the observations, but with quite a different underlying set of assumptions.
Richard,
Great comments. I often think about lab values as the normals are set for 95% of the population (of which a vast amount eat a poor diet) and are irrelevant. They are great though if a doc is trying to push meds on someone… Your comparison to cholesterol is spot-on – It’s all about symptoms.
Also, it is quite interesting when one applies the view of carbohydrates as poison and not preferred – even with insulin, our “save me” hormone when blood sugar gets too high.
I go around in circles whether the thyroid issue is a serious problem in the low-carb world, or just another attack by the anti-LCers. The other issue is we can clearly raise carbs and remain low-carb by definition. I go by Volek and Westman’s 150 a day or less is low carb, though I rarely if ever break 100. I think very often people (including myself at times) think low-carb has to be ketotic less than 50. Some may function better at a slightly higher level of carbs (especially if consumed before and after exercise) and some ride in ketosis level. Like many things, there is no right answer. Regardless, I (and I am assuming many of you all) believe the best level of carb intake, regardless of the exact amount, is still low-carb.
Sam – great thought-provoking article that has created dialogue that we desperately need on the topic.
Amber – spot on. It is amazing how any one issue on a low-carb diet turns into the Apocalypse. This is standard though and why as low-carb followers, we must have thick skin!
“Respectfully, anecdotes are not evidence.”
Sam, where have we read that before? Ignoring anecdotal evidence is the problem. You may say that you have no explanation for them, but ignoring it is not science. It is done by the people who don’t care about science. You do I believe so don’t do that.
You can’t be blind to so many people on very low carb diets complaining about cold extremities. What would you say to that? They were eating too less. Could it be that they feel nauseous eating the food, and the feeling doesn’t go away even after a couple of weeks. Could it be that they are not able to digest the food, which is giving them that reaction.
Don’t blame those people that they are not eating enough. They probably cannot eat enough on the very low carb diet. Remember everybody is different so your experience may not agree with others.
anand,
It’s too difficult to know what these people are actually doing. Anecdotes everywhere vary widely, and it’s not easy to even know who speaks accurately. Maybe their calorie intake is very low. Maybe they consume very little salt or vitamin A. Lots of low carb dieters have claimed great “devotion” on “meat and water,” but anyone knowledgeable would know that is a bad idea, as is living on grilled chicken and lettuce.
Other fanatical groups like “Peatatarians” are similarly questionable. I like Danny Roddy, but he went from like vegan, to zero carb, to Ray Peat. It’s hard to trust personal anecdotal evidence from someone like that. Many “paleos” also come from veg*n backgrounds. I think people like Art Ayers, Peter Dobromylskyj, Ray Peat (though like I said, he gets a cult-like following), etc are the best nutrition writers because they have no monetary conflict of interest or any group association. They are curious and investigative, not preachy.
Saying “everybody is different” is the salesman’s tactic to appear authoritative yet open-minded. Of course everyone is different, but it is also possible to understand differences. I think the low carb critics have provided some interesting ideas and encouraged new learning, but Sam makes a good bottom line argument in that hypothyroid symptoms are probably the result of low calorie leading to low metabolic rate symptoms, not low carbohydrate per se leading to lower t3.
There are too many dietary factors that influence thyroid hormones and health in general; it would take an impossibly large number of studies to look at the effects of salt, vitamin D, liver intake, Mg supplements, fiber intake, PUFA, etc in different contexts.
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[...] believes that low T3 on low-carb diets is healthy, and other low-carb advocates, such as Sam Knox, have made similar [...]
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This is so helpful and informative. Especially the graph showing the range of the normal levels of serum hormone concentration
[...] This thought is actually another one of the diet-health controversies. Others are claiming ESS cannot be produced by a low carb diet. [...]
Wow, what a great, lively and intellectual discussion! I’m impressed with the level of dialogue and the conclusions that came out of it. I follow the “type o” blood type diet which is very similar to paleo and have come across the same struggles. I think the take-away is we can throw away the thyroid meds, and eat enough calories to fuel us with the level of energy we want to have (while balancing with lifespan goals). Thanks to Sam and everyone else who shared their thoughts.