Causes of ‘Confusing’ Thyroid Blood Work

Normal Lab Testing

Thyroid Function Tests (TFTs) are amongst the most commonly requested lab investigations (1). For most of the population, interpreting the lab work is fairly straightforward when we look at a combination of TSH, T4 and perhaps T3.

As doctors, we learn to diagnose thyroid disease through a combination of clinical findings (signs & symptoms) as well as laboratory blood tests . Classically, thyroid blood work is easy to understand. We learn that low thyroid hormone causes a rise in TSH which equates to hypothyroidism. Likewise, high thyroid hormone results in a low TSH and those equate to hypothyroidism. This relationship is depicted below in Figures 1 and 2.

diagram showing hypothyroid state
Figure 1: Hypothyroidism is characterized by low thyroid hormones (T3 and T4), which in turn produces high TSH.

Hyperthyroid hormone feedback naturopath nd toronto
Figure 2: Hypothyroidism is characterized by high thyroid hormones (T3 and T4), which in turn results in low TSH.

 

 

 

 

 

 

 

 

 

 

For a quick review of Basic Thyroid Anatomy and Physiology, check out my article 'Thyroid Basics 101' by clicking here.

Confusing Lab Results

Results of Thyroid Function Tests can seem confusing, either because they conflict with the clinical picture or because they appear in an unusual pattern with each other. Some examples of ‘confusing’ lab results would be raised thyroid hormones (T3 and T4), but with non-suppressed TSH; or raised TSH, but with normal thyroid hormone [1].

As a Naturopath, a high proportion of my patients fall out of the normal paradigm of ‘high T4 = low TSH’ or ‘Low T4 = high TSH”.  For these patients, establishing a correct diagnosis is very important, and depends on careful clinical assessment, combined with further lab, radiological and genetic testing [2].

How Do Anomalous Thyroid Function Tests Arise?

There are a number of scenarios, each of which we will address below, but they generally fall under one of three categories [1]:

  1. Altered ‘normal physiology’
  2. Genetic defects
  3. Interference in one or other lab assays

Patients and doctors alike must recognize the sources of these anomalous tests and see the pitfalls of relying purely on blood work when making diagnoses or treatment plans. A structured approach to further investigate abnormal lab requests is required to ensure resources are not wasted and inappropriate treatment recommended.

How Do These “Confusing” Lab Results Present?

picture showing hypo and hyper thyroidism
Figure 3: A depicting feedback mechanisms related to Hypothyroidism. B depicting feedback mechanisms related to Hyperthyroidism.

 Legend:         ↔: normal     ↑: increased          ↓: decreased

First let’s recap a normal, expected result (this is how most patients will present):

  • TSH, FT4/FT3 EUTHYROID [2]
  • TSH, FT4&FT3 HYPOTHYROID [2]
    • Possible causes: autoimmune thyroiditis (hashimoto’s, atrophic), post-radioiodine therapy/thyroidectomy, hypothyroid phase of thyroiditis, drugs (amiodarone, lithium, TKI’s, ATD’s), iodine deficiency or excess, neck irradiation, Riedel’s thyroiditis, thyroid infiltration (tumor, amyloid), congenital hypothyroidism [1]
  • TSH Low, FT4/FT3 high Hyperthyroid/thyrotoxic [2]
    • Possible causes: graves, toxic multinodular goiter, toxic adenoma, thyroiditis (post viral, post-partum), drugs (amiodarone), excess Iodine intake, excess thyroxine ingestion, pregnancy-related (hyperemesis gravidarum; hydatidiform mole), congenital hyperthyroidism [1]

The anomalous results can present in a number of ways. The causes are listed here, and a brief summary provided further below. More in-depth articles may be reached by clicking the links provided.

  • TSH,   ↔ FT4/FT3
    • Possible causes: Subclinical hyperthyroidism, recent treatment for hyperthyroidism, drugs (pharmaceutical and recreational), NTI (non-thyroidal injury), assay interference [1],[2]
  • ↓ TSH,   ↔ FT4/FT3
    • Possible causes: Subclinical hypothyroidism, poor compliance with thyroxine, malabsorption of thyroxine, drugs, assay interference, NTI (non-thyroidal injury) recovery phase, TSH resistance [1], [2]
  • ↔ or ↓ TSH,   ↓ FT4/FT3
    • Possible causes: NTI (non-thyroidal injury), central hypothyroidism, isolated TSH deficiency, assay interference[1], [2]
  • ↔ or TSH,   FT4/FT3
    • Possible causes: Assay interference, FDH (familial dysalbuminemic hyperthyroxinaemia), thyroxine replacement therapy (including poor performance), drugs (amiodarone, heparin), NTI (including psychiatric disorders), neonatal period, TSH-secreting pituitary adenoma, resistance to thyroid hormone, disorders of thyroid hormone transport or metabolism [1], [2]

Common Causes of these Confusing Thyroid Lab Work

Drug Treatment

With so much of the population taking prescription medications, and growing numbers taking multiple medications, this is of the most common causes of confusing thyroid lab work.

Pharmaceutical agents can affect the thyroid function tests in multiple ways.

Some Drugs Affect Thyroid Hormone Secretion [1]

  • Iodide
  • Amiodarone
  • Lithium
  • TKIs
  • Immune modulators

Some Drugs Affect TSH Secretion [1]

  • Dopamine agonists
  • Glucocorticoids
  • Somatostatin analogues
  • Rexinoids
  • Metformin

Some Drugs affect conversion of T4 into the more active T3 [1]

  • Propylthiouracil
  • Glucocorticoids
  • Propranolol
  • iodinated contrast media or iodine-containing supplements
  • amiodarone

Check out my article "How Your Medications and Supplements Affect your Thyroid"  by clicking here.

Poor Compliance of Thyroxine Therapy

This is another common scenario – where a patient taking pharmaceutical exogenous T4 (Levothyroxine, Synthroid®) for hypothyroidism either reports continued symptoms despite normalized blood work, or they develop anomalous blood work. Often times patients report signs and symptoms that conflict with their blood work – it is up to the doctor and patient to determine the best course of action.

Common causes of anomalous thyroid function tests amongst Levothyroxine (Synthroid®) users are listed here

  • maladministration
  • malabsorption
  • increased thyroid hormone metabolism or excretion
  • increased thyroid hormone binding capacity
  • TSH assay interference
  • Poor compliance to medications
  • Resistance to thyroid hormone
  • and sometimes is actually a normal physiological variant

For a more thorough discussion about persistent issues or anomalous lab work while on Levothyroxine (Synthroid®), click here.  

Altered Thyroid Binding Proteins

Remember, the majority of thyroid hormone produced from the thyroid gland is attached to carrier proteins. We refer to these protein carriers as Thyroid Binding Globulins (TBGs), and they include Thyroxine binding globulin, albumin and transthyretin [2]. For a basic review of thyroid physiology click here.

Altered TBG Binding

Since much of the thyroid hormone (T3 and T4) is bound to carrier proteins, anything that kicks the hormone off that protein carrier would raise free Thyroid hormone (FT3 and FT4). These would transiently elevate FT4 and FT3 concentrations and depress TSH.

Factors that displace T3 and T4 from Binding Proteins [1]

  • furosemide (especially with doses >80 mg/day and when given intravenously) [1],[3], [4]
  • aspirin [1],[3], [4]
  • nonsteroidal anti-inflammatory agents [1],[3], [4]
  • phenytoin and heparin[1], [3], [4]
  • Genetic variants of albumin (familial dysalbuminaemic hyperthyroxemia (FDH)) can cause higher albumin, thus causing over estimations of T4 (and less frequently T3) [1],[3], [4]

Altered TBG Synthesis

Naturally, increases and decreases in concentrations of TBGs are possible. Increased binding molecules would lead to increased Total T4 and Total T3; whereas lowered TBG would lower Total T4 and Total T3. With the advent of free T3 and free T4, this isn’t as much of an issue. Most doctors these days testing thyroid hormones would measure free T3 and free T4 rather than total T3 and total T4. The following may be causes for abnormal results pertaining to total T3 and T4. Transient alterations in FT4 and FT3 have occasionally been observed [1], but quickly normalize.

Factors that raise TBG: (these things will raise total thyroid hormone, but not affect free hormone) [1], [2]

  • pregnancy
  • estrogens (oral contraceptives, hormone replacement, tamoxifen)
  • liver disorders
  • rarely hereditary disease,
  • Drugs: raloxifene, mitotane, fluorouracil, methadone and heroin

Factors that lower TBG: (these things lower total thyroid hormone, not free hormone) [1], [2]

  • Androgens
  • chronic glucocorticoid therapy
  • nicotinic acid

 

Non-thyroidal Illness aka Sick Euthyroid Syndrome

This is defined as an abnormality of HPT function that is considered secondary to something else. In other words, the thyroid lab values are off and symptoms may be present, but it’s not due to a dysfunctional hypothalamus, pituitary or thyroid gland. Something else in the body is not right, and affects this HPT system indirectly. It is actually considered an adaptive, protective mechanism.

So Non-thyroidal illness (sick euthyroid syndrome) is named accurately – abnormal thyroid blood tests can be caused by various illness that do not directly involve the thyroid gland [3]. This phenomenon is very common – and occurs in as many as 70% of patient who have been admitted to a hospital. This is a well-known phenomenon in chronically ill patients, as I discussed in another article, accessible here. This is the explanation for a person going into the hospital for one thing and coming out on thyroid medication. As you will see, treatment must be carefully considered. There is no evidence showing T3 or T4 administration to people with NTI to be useful [1].

Common Presentation of NTI

One of the classic presentations is raised thyroid hormones (T3 and T4) with a non-suppressed TSH [2]. Typically, these changes are seen as early as 24 hours after onset of NTI [1], [2].

This type of presentation has been reported in a wide range of conditions:

  • myocardial infarction
  • post-surgery
  • chronic liver disease
  • chronic renal disease
  • poor nutrition/starvation
  • sepsis
  • burns
  • Malignancy
  • acute psychiatric states: abnormal result should revert with recovery, recovery noted to be about <2 weeks

Treatment needs to be Carefully Considered

As mentioned above, this is a common phenomenon and treating based on the lab values alone can be done erroneously. If Thyroid hormone levels from prior to illness is available, it’s helpful in confirming NTI involvement [2]. Recognition is critical because therapy is often not needed and could be detrimental.

These anomalous results of thyroid function tests often revert to normal once the patient recovers from the illness [1], [2].

Click here to readmy article 'How Non-Thyroidal Illness can Affect your Thyroid Health and Blood Work". 

Assay Interference

This topic may be a bit technical. Assay interference is basically describing an issue with the test that’s measuring something in our blood. So when we measure say, TSH – the test is quite a sophisticated process –the laboratory is measuring antibodies and looking for reactions. That process, as good as it is, can have errors. Substances may interfere with parts of the test that alters the correct value of the result.  In fact assay interference is a largely known phenomenon [2], [5]. This too can lead to misinterpretation of patient’s results by the lab or the wrong course of treatment given by the doctor [5].

Resistance to Thyroid Hormone (RTH) or TSHoma

RTH refers to when our cells become resistant to T3 and T4. In other words, adequate hormone is present, but the cells don't respond to it. A TSHoma is a rare tumour that secretes TSH.

These are two distinct clinical presentations, with some similar manifestations. They both range from asymptomatic through to overt thyroid symptoms. You cannot distinguish the two on signs and symptoms alone [2]. Lab testing must be done through a Naturopathic doctor or Medical Doctor.

Both are Relatively Unlikely

Both are very uncommon – resistance to thyroid hormone occurs in about 1 for every 50 000 cases and TSHoma’s occur in about 1 per 1 million cases [1], [2]. In fact TSHoma is one of the rarest adenomas known.

We must always consider other causes, such as drug involvement or assay interference before these two.

How to Differentiate RTH and TSHoma

RTH

  • TSH response: elevated or even exaggerated response when RTH (absent response when TSHoma present)
  • Family history: 75% of RTH cases are inherited. So usually we find abnormal TFTs in first-degree relatives.
    • Associated with THRB gene defects
  • sex hormone binding globulin: a tissue marker of thyroid hormone action: normal in RTH (elevated in TSHoma)
  • serum cholesterol, creatine kinase are not as useful – but can be compared before and after T3 administration to determine resistance to hormone action

TSHoma

  • TSH response – absent response when TSHoma present (elevated or even exaggerated response when RTH)
  • serum pituitary glycoprotein α–subunit (increased with TSH secreting tumors)
  • sex hormone binding globulin: a tissue marker of thyroid hormone action: elevated in TSHoma and normal in RTH
    • falsely low in mixed GH/TSHoma

 

Thyroid Hormone Metabolism and Conversion Issues

diagram showing T3 and T4 being secreted from the thyroid gland
Figure 3: The thyroid gland actually secretes about 85-90% T4 and 10-15% T3. Once it gets to the target tissue, T4 needs to convert to T3.

Remember, as a review of basic physiology, the thyroid gland secrete a lot more T4 than T3. T4 is more suitable for transport through the bloodstream, but T3 is more metabolically active. Once T4 makes it to the target cells, it needs to be in the T3 form to impart the actions of the thyroid gland [8]. There are special enzymes called deiodinases that do the job of converting T4 to T3 [6].

There is another metabolite called Reverse-T3, which is similar in structure to T3 but has no metabolic activity. It is supposed to be produced when there are adequate amounts of T3 (to stop excessive thyroid activity). However, there are also situations whereby reverse T3 is produced in excess when it shouldn’t be. Reverse T3 is also made by the deiodinases mentioned above.

Thyroid hormones can have production issues, conversion issues and cells can become thyroid hormone resistant.

Thyroid Hormone Production Issues

The first type of thyroid hormone issue may stem from the production itself. Various factors contribute into the proper production such as tyrosine, iron, iodine, zinc and selenium [3]. There are also known factors that inhibit the proper production of thyroid hormones such as stress, environmental toxins and certain diseases. A more comprehensive list is offered in the article "How Thyroid Hormone Production, Metabolism and Conversion Issues may Affect your Blood Work. .

Conversion Issues

As mentioned above, the deiodinases work to create T3 and reverse T3. There are a number of factors that contribute to proper conversion. Vitamins, minerals and nutritional supplements all have roles to play in the conversion. Deficiencies of certain factors and too much of others can easily cause sluggish conversion or promote over production of reverse-T3.  More information on Conversion Issues can be found here. Furthermore, multiple disease processes interfere with the conversion of thyroid hormone. Learn more about the influence of other diseases on thyroid function here.

Conversion Issues Easily Lost on Lab Work

If a doctor runs TSH and T4 – and a patient is having conversion issues- the lab results may show everything to be okay. However, that person may be plagued with signs and symptoms of hypothyroidism due to inefficient T3 production or excessive reverse-T3 production. Both T3 and reverseT3 can be assessed through blood tests.

 

Cellular Sensitivity to Thyroid Hormone

Lastly, assuming proper production and conversion of thyroid hormones, we want to ensure a persons cells are responding to the thyroid hormone itself. The term cellular sensitivity describes a cell being sensitive enough to respond to thyroid hormone when it is present. If you have a lot of hormone around, and the cells are not sensing it, we call this cellular resistance.

For more information about Thyroid hormone metabolism and all the factors that contribute please click here. A more in-depth discussion allows further explanation about why gut health, liver health, aging and several other conditions may be interfering with hormone metabolism, which can be easily over looked on blood work.

Wrap Up

If you made it this far, you'll see there is a lot that contributes to thyroid health. From medications, to nutrition to other disease processes, there are many explanations why thyroid lab work may be confusing. Seeing your Naturopath or primary care physician will hopefully give you guidance in trying to treat your thyroid condition efficiently, effectively and safely.

Works Cited

About the Author

picture of me, johann de chickera, naturopathic doctor

I'm Johann de Chickera, a Naturopathic Doctor, practicing in Ontario, Canada. My clinical practice relies on keeping up with the most up-to-date research and continued education. This blog serves as a way to provide others with a compilation of everything I've learned along the way. Please click here if you're local and want to see me in practice.