Dr. Holtorf has been working with a number of his patients -- many of whom have an underactive thyroid -- who have found it difficult or seemingly impossible to lose weight. What he discovered is that while there are many factors involved in the inability to lose weight, almost all the overweight and obese patients he treats have demonstrable metabolic and endocrinological dysfunctions that are major contributors to the weight challenges of these patients. In particular, Dr. Holtorf has, based on some of the latest research, focused on evaluating two key hormones -- leptin and reverse T3 (rT3)-- and treating any identified irregularities to help his patients lose weight.
I'm pleased to be able to bring you this interview with Dr. Kent Holtorf, discussing his approaches to help thyroid patients achieve long-term weight loss.
Mary Shomon: You have said that you feel that two key hormones -- leptin and reverse T3 -- are playing a key role in regulating weight and metabolism. Can you tell us a bit about leptin, first, and what it has to do with weight loss challenges?
Kent Holtorf, MD: The hormone leptin has been found to be a major regulator of body weight and metabolism. Leptin is secreted by fat cells and the levels of leptin increase with the accumulation of fat. The increased leptin secretion that occurs with increased weight normally feeds-back to the hypothalamus as a signal that there are adequate energy (fat) stores. This stimulates the body to burn fat rather than continue to store excess fat, and stimulates thyroid releasing hormone (TRH) to increase thyroid stimulating hormone (TSH) and thyroid production.
Studies are finding, however, that the majority of overweight individuals who are having difficulty losing weight have varying degrees of leptin resistance, where leptin has a diminished ability to affect the hypothalamus and regulate metabolism. This leptin resistance results in the hypothalamus sensing starvation, so multiple mechanisms are activated to increase fat stores, as the body tries to reverse the perceived state of starvation.
The mechanisms that are activated include diminished TSH secretion, a suppressed T4 to T3 conversion, an increase in reverse T3, an increase in appetite, an increase in insulin resistance and an inhibition of lipolysis (fat breakdown).
These mechanisms may be in part due to a down-regulation of leptin receptors that occurs with a prolonged increase in leptin.
The result? Once you are overweight for an extended period of time, it becomesincreasingly difficult to lose weight.
Mary Shomon: You've said that you feel that leptin levels above 10 may warrant treatment. Can you explain a bit more about leptin levels?
Kent Holtorf, MD: Most underweight or normal weight individuals will have leptin levels below 10, although most major labs will use a reference range of 1 to 9.5 for men and 4 to 25 for women. (It must be remembered that this range includes 95% of so-called normal people and includes many who are overweight.) Almost all patients who are of healthy weight will have a leptin less than 10.
Mary Shomon: How do you treat leptin resistance in your practice?
Kent Holtorf, MD: Treatment can be focus on treating the elevated leptin -- leptin resistance. An elevated leptin also indicates, however, that the TSH is an unreliable marker for tissue thyroid levels, as the TSH is often suppressed, along with significantly reduced T4-to-T3 conversion. In short, if your leptin is elevated, you have reduced tissue thyroid levels. Also, almost all diabetics are leptin resistant, which has been shown to reduce T4-to-T3 conversion in diabetics by as much as 50% without an increase in TSH, making it very difficult for type II diabetics to lose weight.
Because there is poor T4-to-T3 conversion, timed-released T3 is the optimal treatment -- although T4/T3 combination medications such as natural desiccated thyroid (NDT) can be used.
We check the resting metabolic rate (RMR) in our patients, and interestingly, those with elevated leptin levels indicative of leptin resistance have RMRs that are consistently below normal. These patients are often burning 500 to 600 calories less each day than someone of equal body mass.
Thus, to have a reasonable chance of losing weight, these patients can either try and reduce calories by 500 to 600 calories a day (just to keep from gaining weight), exercise for an hour or two a day (just to keep from gaining weight) or normalize the thyroid and metabolism.
Humans are a very successful species because we can store energy (fat) very well. There are many mechanisms to gain weight and leptin resistance is just one of them, so we use a multisystem approach; there is no one magic bullet, although any one treatment can have a dramatic effect on a particular patient.
In addition to optimizing the thyroid (remember, giving thyroid hormone to lose weight is not appropriate, but that’s not what we are doing, here we are correcting a deficiency), Symlin (pramlintide) and/or Byetta (exenatide) can be very effective for many. Human Chorionic Gonadrotropin (HCG) is another potential option that works for some. While I’ve found that the antidepressant Wellbutin (bupropion) does not work well for weight loss, a combination of Wellbutrin and low-dose naltrexone (LDN) is having some surprisingly good results. Topamax (topiramate) is an option for some but is not always well tolerated. Standard appetite suppressants, which boost metabolism, can be used, especially if the RMR is low.
Mary Shomon: Symlin and Byetta typically require multiple injections per day, which can discourage some people from taking them. The drugs can have some difficult side effects for some patients -- including nausea, vomiting and fatigue. How many of your patients have found these medications too difficult to continue taking? Do you have any tips that have helped patients deal with these medications?
Kent Holtorf, MD: Taking a subcutaneous shot several times a day can be problematic, but when patients have great results it is worth it for most. A few tricks: First, some people are concerned that the medications require refrigeration, but it’s usually not necessary, as these medications are very stable at normal daytime temperatures. So it’s not a problem to keep it in your purse or in the desk drawer.
The biggest side effect is nausea, which occurs in about 25% of patients. Most of the time it is mild and diminishes with continued use, but a few patients will not be able to tolerate it. For Byetta, I recommend starting with a 5 mcg injection before meals. Some patients start with half a shot for the first few days (only pushing the plunger halfway). The nausea in some people can be due to an increased production of stomach acid, so Zantac (ranitidine) or a proton pump inhibitor drug -- like Prilosec (omeprazole),, or Nexium (esomeprazole) for example -- can be helpful. There is a once-a-week shot in the FDA approval process, which has been shown to have reduced side effects as well as the increased convenience.
Mary Shomon: You've mentioned that for some patients, you have them taking up to 10 mcg injection of Byetta three times daily, with meals. What's the optimal treatment level for Symlin?
Kent Holtorf, MD: Nausea is less commonly a side effect of Symlin, compared to Byetta, so it’s preferable for some patients. For Symlin, the optimal dose is 120 mcg, three times per day. Both Byetta and Symlin have very low risks for hypoglycemia unless you are on insulin or on asulfonylurea medication for diabetes.
Mary Shomon: You also feel that reverse T3 is an issue. Can you tell us a little bit about reverse T3?
Kent Holtorf, MD: T4 can be either converted to T3, the active hormone that has a metabolic effect, or to reverse T3, which is the inactive form of T3, and actually blocks the effects of T3. Doctors -- including endocrinologists -- are taught that reverse T3 is just an inactive metabolite, but studies show that it has potent antithyroid effects. In fact, is has been shown to be a more potent inhibitor of thyroid effect than PTU, a medication used for hyperthyroidism. Reverse T3 inversely correlates with intracellular T3 levels, so it is also a marker for tissue hypothyroidism, with higher levels (or lower Free T3/RT3 ratio) indicating a more significant deficiency.
Mary Shomon: Why do you feel reverse T3 plays a role in making it difficult for some thyroid patients to lose weight?
Kent Holtorf, MD: The reverse T3 is produced in times of stress or starvation to reduce metabolism, and with chronic stress or dieting, RT3 can remain elevated, suppressing tissue thyroid activity and metabolism. People on chronic diets -- or those who lose significant amounts of weight -- will have a lower metabolism than a person with the same weight and muscle mass who had not lost significant weight or drastically dieted in the past. This was demonstrated in a study by Leibel published in the journal Metabolism, titled “Diminished Energy Requirements in Reduced-Obese Patients.” This study compared the basal metabolic rate in individuals who had lost significant weight to those of the same weight who had not lost significant weight in the past. The authors found that those who had dieted and lost weight in the past had, on average, a 25% lower metabolism than the control patients who had not lost significant weight.
All those trainers and health gurus that never had a weight problem who tell you to do just as they do don’t realize what a disadvantage it is for people who have had a long-term weight problem. Of course, even these trainers would not even be able to maintain their weight with a metabolism that is 20 to 40% below normal.
We test the resting metabolic rate in our thyroid patients and find it inversely correlates with the reverse T3. The higher the reverse T3, the lower the metabolism, with many such individuals having a metabolism that is 20 to 40% lower than expected for their body mass index (BMI). Nobody believes how little they eat, and they are made to feel like failures -- despite doing everything right. Until their metabolic abnormalities are addressed, diet and exercise will certainly fail to achieve long-term success.
Mary Shomon: At what point do you consider reverse T3 too high and requiring treatment?
Kent Holtorf, MD: Like everything else in medicine it is a continuum, but healthy individuals are usually below 250 pg/ml and should have a free T3/reverse T3 ratio greater than 1.8 if free T3 is in ng/dl or 0.018 if free T3 is in pg/ml.
Mary Shomon: How do you typically treat elevated reverse T3 levels?
Kent Holtorf, MD: The higher the reverse T3, the more ineffective T4 only preparations will be. T4/T3 combinations are significantly better than T4-only preparations, such as Levoxyl and Synthroid, but for the higher levels straight timed released T3 is optimal.
Mary Shomon: What dietary and lifestyle changes do you recommend along with these medical approaches?
Kent Holtorf, MD: Most patients who come in have been on numerous diets and lifestyle changes and they generally are very knowledgeable in that area. Low-carbohydrate diets will suppress thyroid function and increase reverse T3 more than comparable calorie reductions with adequate carbohydrates, so while a low-carbohydrate diet may result in initial weight loss, patients are prone to regaining weight unless the reverse T3 issue is addressed.
Mary Shomon: Can you give us a sense of the weight loss results you're having with thyroid patients who, after testing, demonstrate leptin resistance, and high reverse T3, and start your treatments for these conditions?
Kent Holtorf, MD: We try and investigate and treat as many dysfunctions and suboptimal metabolic conditions that we can. We have had success with a large range of individuals, from those who need to lose a few pounds to those who are over a hundred or more pounds overweight. The most satisfying are the people who lose 50 to 100 pounds or more. It totally changes their lives.
We are also seeing more patients who come in after gastric bypass – those who either didn’t lose weight or have gained much or all of their weight back. Most have low tissue thyroid levels as well as significant leptin resistance. They can also have a growth hormone deficiency as well.
We had one person who was eating 800 calories a day after having gastric bypass and she was still gaining weight. Nobody believed that was all she was eating until they put her in the hospital and monitored her food intake. They insisted her thyroid was fine, as she had a normal TSH, T4 and T3. When we checked her reverse T3, however, and it was over 800 and her leptin was 75. We checked her metabolic rate and it was 45% below normal. Dieting alone would, of course, never work with such a patient.
Also, toxins such as biphenyl-A can block the thyroid receptors everywhere in the body except for the pituitary, which has different receptors. So due to the ubiquitous nature of these toxins, I believe that everyone has a relative deficiency of thyroid activity that is not detected by the TSH. People blame food intake and lack of exercise for the obesity problem in this country, but I think a major problem is the thyroid-disrupting toxins, as well as stress.
Additionally, dieting is shown to not only reduce the T4-to-T3 conversion and increase reverse T3, but it is also shown to reduce the numbers of peripheral thyroid receptors -- but again, not in the pituitary -- so the same amount of thyroid has less of an effect, but the TSH is unchanged. This exemplifies the importance of clinical and target tissue assessment in the determination of overall thyroid activity in an individual. Also, women have fewer thyroid receptors than men, making them more sensitive to small decreases in serum levels of thyroid hormones.
Mary Shomon: Do you also check fasting glucose and insulin levels, and/or do glucose tolerance tests with your patients who are overweight and having difficulty losing weight?
Kent Holtorf, MD: We do fasting glucose and fasting insulin, as well as Hemaglobin A1C (HA1C) tests, to look for relative insulin resistance, not just looking at the usual “normals.” Another important lab to get is sex hormone binding globulin (SHBG). It is stimulated in the liver in response to thyroid hormone and estrogen, so it can be a useful marker for tissue level of thyroid.
In a premenopausal woman, the level should be above 70. If not, it is a good indication that there are low tissue levels of thyroid. This is especially true if the woman is on oral thyroid replacement, because -- due to first pass metabolism – her liver will have much higher thyroid levels than the rest of the tissues. Thus, if SHBG is low, the rest of the body is low thyroid.
(Note: This test is not useful if a woman is on oral estrogen replacement, because that will artificially elevate SHBG due to high estrogen level in the liver. The test is accurate for women who are using transdermal estrogen preparations, however.)
Diabetes and polycystic ovary syndrome (PCOS) also suppress SHBG, due to the suppressed intracellular T3 levels seen in these conditions. Also, if you check your SHBG before going on thyroid replacement and see little change with treatment, it is an indication that you have thyroid resistance. You also want to check the following:
· insulin-like growth factor 1 (IGF-1)
· insulin-like growth factor binding protein 3 (IGFBP3)
· dehydroepiandrosterone (DHEA)
· luteinizing hormone (LH)
· follicle stimulating hormone (FSH)
· urinary iodine
· adrenocorticotropic hormone (ACTH)
· C-reactive protein (CRP) -- inflammation decreases TSH and increases rT3
· homocysteine – a marker for low thyroid and low B vitamins
· lipids -- high cholesterol is a marker for low thyroid and high triglycerides is a marker for insulin resistance
· iron and ferritin -- ferritin is required to activated thyroid, so many symptoms that people attribute to anemia with low ferritin is actually due to low tissue thyroid activation
· vitamin D -- should be greater than 80
· thyroid peroxidase antibodies (TPO) and antithyroglobulin antibodies -- an interesting study did thyroid biopsies in people who were fatigued and found that, despite having no evidence of TPO or antithyroglobulin antibodies, most had thyroid inflammation and responded symptomatically to thyroid replacement even through the thyroid levels were in the normal range
· serotonin level -- there is often a low or low normal serotonin level with low thyroid because serotonin production is suppressed with low thyroid and antidepressants will often not work if T3 levels are suboptimal
Depressed patients will generally have a low-normal TSH and high-normal T4, a high or high-normal reverse T3 and a low-normal T3. Many doctors will check the TSH and T4 and surmise that the patient is high-normal thyroid (based on the low end TSH and high end T4) but they actually have very low cellular T3 levels (as demonstrated by their low T3/rT3 ratios). These patients often respond very well to T3 supplementation. Giving prescription natural serotonin either orally or by injection can also be very effective in treatment resistant patients (those that did not respond or responded poorly to medications) without the usual side-effects of antidepressants.
Mary Shomon: If someone has elevated blood sugar indicative of insulin resistance -- but not full diabetes -- do you put them on Glucophage (metformin) preventatively?
Kent Holtorf, MD: Yes, it makes no sense to wait until someone has diabetes to use metformin or other interventions. We also use supplements, our favorite is GlucoSX. While metformin was the mainstay for insulin resistance, we have generally bypassed metformin and proceeded right to Byetta and Symlin, due to the much greater potential for weight loss.
Mary Shomon: Many thyroid patients have been asking me about the HCG (human chorionic gonadotropin) treatments for weight loss, including prescription injections and sublinguals, and over-the-counter homeopathic sublingual forms of HCG. I've personally met a number of women who were hypothyroid, weighed over 200 lbs, and went on HCG treatments, and lost 25 or more pounds during a 40 day course of HCG treatment. I know more and more doctors who are starting to use it. What are your thoughts about this as a weight loss treatment option?
We have found HCG effective for many women. We have found prescription HCG injections to be much more effective than sublingual HCG or HCG creams. Also, because you must give a much higher dose sublingually and transdermally -- due to the decreased absorption -- it is much less expensive to do as a small subcutaneous injection.