By Saif Borgan M.D.
This Endocrine Review Course is hosted by Dr. Saif Borgan (Cleveland Clinic trained board certified endocrinologist in the United States) and Dr Kristen Lee (Endocrine Fellow at Northwestern Univer
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Hello and welcome to this episode. Today we will be discussing an approach to a low TSH.
We will be going over 2 review studies from The Journal of Clinical Endocrinology and Metabolism and then Cleveland Clinic Journal of Medicine. But first today’s question:
A 50-year-old postmenopausal woman with no other notable history presenting with palpitations, frequent bowel movements, and tremors. She has no family history of thyroid dysfunction. She has mild tachycardia. Her thyroid gland is 20 g and nontender to palpation. Her TSH is < 0.1.
What is the best next step in evaluating this patient?
A Thyrotropin receptor antibodies
B Check Total T4
C Check Free T4 and T3
D Thyroid US
And the answer is T4 and Total T3. These questions, while seemingly simple, are actually guaranteed on board exams.
Initial thyroid function evaluation should start with TSH. In this case the TSH is low and there is clinical suspicion for hyperthyroidism. If TSH is suppressed, the immediate next step is to check T4 and T3 to confirm and further characterize the thyroid dysfunction (overt vs subclinical). This is worth repeating: investigating the cause of the suppressed TSH by checking thyroid hormones is important in determining how to proceed with evaluation and treatment.
In this question, checking the Free T4 is favored over total T4 because Total T4 levels can be affected by alterations in binding proteins. Checking T4 only is not sufficient because there are cases of isolated T3 thyrotoxicosis. Ordering receptor antibodies or starting treatment are premature at this point. Thyroid US is not a routine part of the diagnostic algorithm to hyperthyroidism. For this case, an iodine uptake scan could be performed to differentiate thyroiditis from true hyperthyroidism, but this would not be the best next step in this question.
An Approach to Low TSH
If the T4 and T3 level are normal, repeat TSH, T4, and T3 in 6-8 weeks before giving a diagnosis. When TSH suppression is transient, most times thyroid dysfunction will be resolved in this time. A suppressed TSH that is not normalized in this period requires more investigation.
Low TSH can be differentiated by level of TSH suppression such as mild (TSH 0.1 – 0.4 mIU/L) milli-international units per liter and complete TSH suppression TSH < 0.1 mIU/L. It is unclear the incidence of low TSH within the population but in a representative sample of the US without known thyroid condition that 0.7% of patients had suppressed TSH (< 0.1 mU/L) and 1.8% of patients had a TSH level below the reference range (< 0.4 mU/L)
It can be helpful to think of the etiologies of low TSH 1) in their relation to the pituitary/hypothalamus or 2) in terms of accuracy of the assay measurement / drug effect
Relationship to Pituitary/Hypothalamus
· Category #1: low TSH due to an appropriate pituitary response to high thyroid hormone, the pituitary is actively attempting to reduce thyroid hormone production because of advanced or early elevated thyroid hormone levels
In this category differentiating the source of the excess thyroid hormone can be helpful
· #1 Excess endogenous thyroid hormone production from multinodular goiter, autonomous thyroid nodule, Graves’ disease,
· #2 Exogenous thyroid hormone commonly from excess levothyroxine supplementation (iatrogenic or intentional in context of high risk thyroid cancer) or ingestion of natural thyroid preparations (athletic performance and integrative health) – in these cases exogenous T4 is suppressing TS
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Endocrine Review Course Learning Objectives:
- Discuss thyroid hormone axis
- Discuss how thyroid hormone is produced
- Discuss the differences between T4 and T3
- Discuss the types of diodinase enzyme
- Discuss how thyroid hormone enters the cell
- List actions of thyroid hormone (on a molecular level)
TRANSCRIPT
Hello, my name is Kristen Lee and I am an Endocrinology fellow at Northwestern University in Chicago, Illinois. I am joining the Endocrine Review team and hope to help my colleagues pass the endocrine boards!
Todays question is: which of the diodinase enzymes is most active in illness?
Diodinase 1, 2 , 3 or 4.
And the Answer is Diodinase THREE
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The learning objectives today:
In order to better understand and interpret thyroid laboratory findings we first need to take a step back and discuss the thyroid hormone regulatory pathway.
In particular the thyroid hormone axis
Starting at the hypothalamus, thyrotropin-releasing hormone (TRH) induces the pituitary to secrete thyroid stimulating hormone (TSH). TRH interacts with the thyrotrophic cell receptor to influence TSH glycoclysation which informs TSH bioactivity.
TSH production is made in a pulsatile circadian fashion with its peak between 2am-4am (referred to as the nocturnal TSH surge) and its trough between 4p and 8p. In a euthyroid human, TSH is produced at between 50-200 milliunits/day and can increase to up to > 4000 mU/day in primary hypothyroidism. The half-life of TSH is betwee n 50 and 80 minutes. TSH bioactivity changes based on TSH glycosylation variability; due to different glycosylation nocturnal TSH is less bioactive which is why TSH does not lead to increased thyroid hormone production at night.
After TSH production, T SH binds to thyroid releasing hormone receptors on the thyroid follicular cells activating the thyroid synthesis cascade.
The Thyroid Synthesis Cascade
There are five steps in the thyroid synthesis process. First the precursor protein thyroglobulin (TG) is made from thyrocytes in the thyroid follicular cells; this precursor protein does not yet contain iodine. Step #2 iodide is brought from the circulation to the thyrocytes and into the follicular cells. Step 3: the enzyme thyroid peroxidase (TPO) is activated and exacts three roles: oxidation, organification, and coupling reaction to ultimately form the four-iodine atom containing Thyroxine (T4). T4 is the major thyroid hormone product of the thyroid synthesis circulating in the bloodstream. T4 the inactive form of thyroid hormone is converted to the active form of thyroid hormone triiodothyronine (T3), comprised of 3 iodine atoms.
The thyroid produces 90% inactive T4 thyroid hormone and 10% active thyroid hormone T3. Thyroid hormone is stored bound to thyroglobulin in the follicular stores. Upon TSH stimulation proteolytic enzymes cleave thyroglobulin and T4 and T3 are released into the bloodstream. Thyroid hormones are lipophilic and are transported in the blood via transport proteins. Both circulating thyroid hormones (T4 and T3) exert direct negative feedback on TRH synthesis in the hypothalamus. Peripheral deiodination of T4 to T3 in the liver and kidney accounts for approximately the other 80-90% of circulating T3.
There are three types of deiodinase enzymes, type I (DIO1), II (DIO2), and III(DIO3).
DIO1 primarily functions in the liver, kidney, and thyroid. DIO2 predominates in the brown adipose tissue, skeletal muscle, heart, and CNS. DIO3 is primarily located in the CNS, skin, and placenta. The majority of T4 to T3 conversion is through catalyzation by deiodinase ty
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Endocrine Review Course Learning Objectives:
- Understanding the meaning of the term "Non-alcoholic Fatty Liver Disease (NAFLD)"
- Discuss the difference between steatosis and steatohepatitis
- Understand which patient populations require screening for steatohepatitis related fibrosis
- Know the components of FIB4 score
- Understand the step-wise process in NAFLD screening and diagnosis
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Endocrine Review Course Episode 17 Learning Objectives:
- Describe the physiological mechanism counter regulating insulin induced hypoglycemia.
- Describe 3 levels of hypoglycemia severity
- Be aware of the recommendations published by the Endocrine Society on management of individuals at high risk for hypoglycemia
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Endocrine Review Course Episode 16 Learning Objectives:
- Describe the differences between regular insulin and regular insulin analogs
- Describe the difference in pharmaco-kinetics between concentrated U-500 regular insulin and U-100 regular insulin
- List the clinical benefits of using concentrated insulin in specific populations
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Endocrine Review Course Episode 15 Learning Objectives:
- Be aware of patient selection factors for pancreatic transplant alone (PTA) and simultaneous kidney pancreas transplant (SKPT)
- Be aware of the rejection rates for SKPT and PTA
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Endocrine Review Course Episode 14 Learning Objectives:
- Explain the typical presentation of Necrobiosis Lipidoica
- Suspect Lipodystrophy as a cause of sudden onset erratic glycemic control in a previously well controlled patient with Diabetes
- Identify an atypical presentation of Acanthosis Nigricans
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Endocrine Review Course Episode 13 Learning Objectives:
- Describe the typical presentation of diabetic distal symmetric sensory polyneuropathy.
- Be familiar with screening recommendations for Neuropathy in patients with Type 1 and type 2 Diabetes.
- List other causes of Neuropathy
- Know FDA approved and off-label treatments of Diabteic Neuropathy
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Endocrine Review Course Episode 12 Learning objectives:
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Endocrine Review Course Episode 11 Learning Objectives:
Errata: Potassium check 1 month after starting Finerenone
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The podcast currently has 21 episodes available.
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