Endocrinological Assessment & Treatment of Obesity -- Leptin, thryoid info & mo

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Endocrinological Assessment and Treatment of Obesity

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Obesity has become a major health epidemic and has dramatically increased

over the last decades. Studies show that now approximately one-third of the

U.S. population is classified as obese and over two-thirds are

significantly overweight. While the cause is multifactorial, studies are clear

that

almost all overweight individuals have metabolic and endocrinological

dysfunction that is causing or contributing to their inability to lose weight.

It

is not simply a problem that individuals are taking in more calories than

they are consuming, but rather it is a complex vicious-cycle of

endocrinological and metabolic dysfunction. Contemporary medicine has failed to

address

these dysfunctions in overweight individuals and doctors and patients

continue to believe that all cases are a matter of will-power and lifestyle.

Thus, it is no surprise that obesity is reaching epidemic proportions.

 

 

Leptin

 

The hormone leptin has been found to be a major regulator of body weight

and metabolism and dysfunctional leptin signaling results in one of many

viscous-cycles that prevent individuals from losing weight. Leptin is secreted

by fat cells and the levels increase with the accumulation of fat. This

leptin should then feed-back to the hypothalamus as a signal that there are

adequate energy (fat) stores, and this should signal the body to burn fat

rather than continue to store excess energy.

 

 

Studies are finding, however, that the majority of overweight individuals

that are having difficulty losing weight have varying degrees of leptin

resistance. The leptin is unable to produce its normal effects of weight loss,

with the severity correlating with the degree of obesity (1-5). This

leptin resistance results in a leptin deficiency in the hypothalamus, which in

sensed as starvation, so multiple mechanisms are activated to increase fat

stores, as the body perceives a state of starvation (1-30). Baseline leptin

levels and the degree of leptin resistance is shown to be a good predictor

of a person’s likelihood of achieving successful weight loss with dieting

(68-70).

 

 

The metabolic effects of leptin resistance include a 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)( 1-29,31). These effects of leptin resistance on

thyroid hormones contribute to the drop in TSH and T3 levels that occur with

dieting and results in decreased tissue thyroid action and a depressed

metabolic rate that inhibits weight loss and promotes weight gain

(1,6,10,14,18-23,29,30-37). Unfortunately, standard thyroid function tests miss

over 80%

of this type of hypothyroidism, as the TSH, free T4 and free T3 levels are

typically in the normal range (1,6,10,14,31,38-46). In primary

hypothyroidism, diminished thyroid hormones stimulate the hypothalamus to

increase TRH

secretion, which in-turn stimulates the pituitary to secrete TSH. Thus, the

TSH serves as the basis for the diagnosis of primary hypothyroidism, but

with the suppression of TSH that occurs with leptin resistance, this feed

back is interrupted and a normal TSH level cannot be used to rule out a

significant thyroid deficiency (1,6,10,14,31,38-46).

 

 

Starvation dieting can decrease resting metabolic rate by as much as 40%

and food restriction at a level to maintain just a 10% reduction in body

weight results in significantly decreased intracellular thyroid hormone levels

and a diminished metabolic rate that does not return to normal even after

a normal diet is resumed (10,18-23,29,30,32,33-37). When combined with the

effect of leptin resistance, this accounts for the majority of regained

weight in weight reduced subjects (17-22,25,26,31,35,36,47). Low intracellular

leptin levels are inversely correlated with reverse T3 (rT3), which may

currently be the best marker, along with the T3/rT3 ratio, for diminished T4

to T3 conversion and cellular hypothyroidism in chronic illness (18,48-59).

Reverse T3 has been thought to be an inactive metabolite, but it has been

shown to be a competitive inhibitor of T3 (blocks T3 activity), directly

decreasing cellular energy production, and to directly suppresses T4 to T3

conversion (47,56-59). In fact it is shown to be a more potent inhibitor of T4

to T3 conversion than PTU (56), a medication used to decrease thyroid

hormone levels in hyperthyroidism.

(See thyroid section

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In addition, increased adipose tissue results in a maladaptive stimulation

of inflammatory cytokines, including TNF-alpha, IL-6 and CRP, which

further suppress TSH secretion and the conversion of T4 into T3, as well as

increasing the conversion of T3 into rT3 (60-64).

 

 

Diagnosis:

 

 

If individuals are having difficulty losing weight, we recommend obtaining

a metabolic panel that consists of a leptin level, TSH , free T4, free T3,

reverse T3, TPO antibody, antithyroglobulin antibody, glucose, insulin,

HgA1c, IGF-1, testosterone, CRP, TNF-alpha (highly sensitive), IL-6 (highly

sensitive), CRP, homocystine, SHBG and lipids. In addition, the relaxation

phase of the ankle or brachioradialis muscle can be measured. This has been

shown to correlate with the degree of hypothyroidism and to be a better

indicator of tissue levels of thyroid than standard thyroid function tests

(50,65,66).

 

 

While a complete review of the interpretation of these labs is beyond the

scope of this article, as it not as simple as looking at what is normal or

abnormal and ratios typically need to be evaluated. In general, however, a

leptin level greater than 10 is associated with leptin resistance. Thus, if

the leptin level is above 10, the TSH is unreliable (artificially

decreased) and a normal TSH cannot be used to rule-out significant cellular

hypothyroidism. Likewise, if the inflammatory markers CRP, TNF-alpha or IL-6 are

relatively (high normal) or overtly elevated, which is often the case with

numerous conditions including insulin resistance, diabetes, obesity, lupus,

rheumatoid arthritis, stress, sleep apnea, depression, chronic fatigue

syndrome, fibromyalgia, heart disease and insomnia, the TSH is not a reliable

indicator of tissue levels of active thyroid hormone. The T3/rT3 ratio is

typically the best marker for tissue hypothyroidism in these conditions, as

again, the TSH is not reliable if leptin resistance or inflammation is

present. Insulin levels along with the HgA1c, glucose and lipids are used to

evaluate insulin resistance, another reason for problems with weight gain. A

muscle reflex relaxation phase of greater than 110 msec also demonstrates low

tissue levels of thyroid.

 

 

Treatment:

 

 

There are new medications, Byetta and Symlin, that decrease leptin

resistance. These can be very beneficial treatments and can produce dramatic

weight loss if given in conjunction with other metabolic treatments. While

these

medications are approved for type II diabetes and are showing significant

weight loss in this patient population, they are showing promise in the

non-diabetic population as well. The amount of weight loss varies according to

the study design, but a significant percent of patients are having

dramatic weight loss, despite little or no change in diet. Again, this

demonstrates that many overweight patients have a metabolic problem rather than

a

problem of will-power. While these medications, by themselves, typically result

in modest weight loss, combining these medications with metabolic

treatments and a healthy lifestyle can allow for significant sustained weight

loss.

 

 

A thorough analysis and work up will find that many overweight patients

have, in addition to leptin resistance, dysfunction of the

hypothalamus-pituitary-thyroid axis as well as dysfunction of the peripheral

(cellular)

thyroid metabolism and utilization. Correction of these dysfunctions can result

in dramatic long term successful weight loss. If high reverse T3 is found,

T4 preparations such as Synthroid or Levoxyl are shown to be ineffective in

restoring tissue thyroid levels (67). T4/T3 preparations such as Armour

thyroid are better but timed released T3 preparations are the most effective

at restoring tissue T3 levels and often effective when Armour thyroid,

Synthroid and Levoxyl fail to restore normal tissue levels of thyroid.

 

 

 

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