This post walks through the process of using the SPINA-Thyr to interpret thyroid lab test results.
SPINA-Thyr is a free diagnostic application.
SPINA-Thyr takes thyroid laboratory test values TSH, Free T4 and Free T3 and performs calculations that enable in-depth evaluation of thyroid function, pituitary function, and T4-T3 conversion for people who are on no thyroid therapy or T4-monotherapy.
Anyone can download and use the software. The files and basic manual are posted on Sourceforge (1).
However, interpretation of results requires knowledge of the patient’s history and clinical status at the time of the lab test. Unusual results often require advanced knowledge of thyroid disease and thyroid therapy for accurate interpretation. As with any disease diagnosis, learning is lifelong. Learning is informed by a good knowledge of the biological mechanisms, research, and clinical practice on many cases over time. See the reference list.
CLINICALLY TESTED IN RESEARCH
SPINA-Thyr has been in development since the late 1990s under the leadership of Dr. Johannes Dietrich, Specialist in internal medicine, endocrinology and diabetology, BG University Hospital Bergmannsheil, Bochum, Germany.
SPINA-Thyr’s algorithm has been evaluated in multiple clinical trials with thousands of patients. (1) Its findings correlate with a wide variety of diagnoses of thyroid disease. (2) An online slide presentation further illustrates the technical details and usefulness of the application. (5)
MANY USES OF THIS TOOL
First of all, SPINA-Thyr is a very helpful diagnostic tool before any thyroid therapy is initiated. It can assess all aspects of thyroid gland function, TSH secretion and T4-T3 conversion, even if dysfunction is mild:
- How healthy is the thyroid gland’s response to TSH?
- Is it a hyperactive thyroid, normal thyroid, or a poorly functioning thyroid?
- Is TSH secretion normal given their T4?
- Is something hindering or inflating T4-T3 conversion?
In cases of subclinical hypothyroidism, pre-therapy, SPINA software can distinguish true hypothyroidism from temporary TSH elevation in a person with a healthy thyroid and pituitary gland.
When TSH is abnormally high, it can help distinguish untreated primary hypothyroidism from TSH secreting adenomas that overstimulate a gland. With advanced knowledge its data could possibly discern TSH-receptor-blocking antibodies from syndromes of reduced receptor sensitivity to thyroid hormone (see the earlier post TSHR Antibodies can distort TSH secretion).
It also provides diagnostic tools within the context of thyroid therapy.
In cases where T4 monotherapy is unable to resolve hypothyroid symptoms despite normalized TSH levels, SPINA can diagnose the degree to which a patient may benefit from T4 dose adjustment. It can diagnose whether a patient is a poor converter of T4 hormone who may need T3 in their therapy to raise T3 to optimal levels in reference that effectively remove hypothyroid symptoms in a majority of patients. (8)
In T4 monotherapy, SPINA can also discern whether the TSH is a trustworthy guide to dosing, or whether TSH is responding abnormally to the level of T4. For example, mild hypothalamus-pituitary dysfunction during T4 therapy may result in a lower TSH than is appropriate for T4 levels. Correct diagnosis may prevent underdose, which could occur if trying to “normalize” (raise) TSH secretion from a hyposecreting pituitary.
SPINA can also detect resistance to thyroid hormone (RTH) within the pituitary gland during T4 therapy. This is a consistent pattern of an abnormally high TSH given the level of T4.
LIMITATION: T3 THERAPIES
SPINA has limited use within the context of therapies that dose synthetic T3 hormone or desiccated thyroid.
It will not be able to calculate T4-T3 conversion accurately because it cannot distinguish T3 from the dose on the one hand and T3 arising from secretion and T4 conversion on the other.
Nevertheless, if T3 doses are very small and the patient still depends largely on T4, SPINA may still assess very unusual TSH responses to a patient’s T4 levels.
The SPINA algorithm does not account for the benign lab test anomalies found in T3 therapies. The higher doses and ratios of T3 content, including desiccated thyroid, cannot be expected to have the same effect on the pituitary as T4 monotherapy, and they will yield unusual ratios even when doses are effective at restoring euthyroid status. In later posts, I will offer tips to interpret T3-therapy lab test anomalies without the use of the SPINA program.
STEP 1. DOWNLOAD
Use a desktop computer to download the software from the address in the reference list (1). Download the brief user manual for future reference. This program works best on a desktop or laptop computer with keyboard.
You will need a full set of thyroid lab results: TSH, Free T3 and Free T4, because all three are used in calculations.
STEP 2. EDIT PREFERENCES
This step is very important!
Click the “Edit” menu and select “preferences.”
1. Enter the units of measurement from the laboratory for Free T3 and Free T4 — for example, ng/dL / pg/ml, or pmol/L for both.
NOTE: You can also choose to enter data for T3 (Total T3) and T4 (Total T4). However, Total T3 and T4 are not commonly measured anymore. Free T3 and Free T4 measurement is now the standard. Free thyroid hormone testing isolates the unbound hormone (not bound to carrier proteins like thyroxine-binding globulin [TBG], or albumin) and it is therefore the hormone available to enter cells. Of course, one may also measure Total hormones when Free results are very high or very low, to confirm what is going on with thyroid hormone secretion/absorption and binding.
2. Enter the lab’s reference ranges for TSH, FT4 and FT3.
Do NOT edit the reference values for anything else, since those ranges are built into the app.
When finished, press OK to return to the main interface.
STEP 3. ENTER VALUES AND CALCULATE
After entering reference ranges and units, enter the lab results for TSH, FT3, and FT4 in the yellow fields.
Select the “T4-substitution” checkbox if the person is on T4 therapy. Taking T4 hormone will make GT “not calculable” because T4 medication is not a thyroid gland.
Leave all checkboxes empty if this person is not taking any medications.
Click “Calculate.” You can close the pop-up window and still see the result.
When you hover a mouse over the results text, a small window will pop up with the reference ranges to aid interpretation.
To save a copy, you can download results to text and print it out or save it as a PDF by clicking the “File” menu, then “Print,” and selecting options. Or you can take a screenshot.
INTERPRET GT, GD, TSHI, TTSI
If a result is above or below reference it will be marked with an asterisk.*
Use research-based knowledge to interpret results in the context of the reference ranges provided by SPINA-Thyr.
Whenever the results puzzle you, do your research and continue to learn. First consult the reference list below, and then look into other resources.
Be wise and humble enough to admit it when you don’t know enough to interpret.
1. GT: Functional thyroid capacity
- NOTE: GT will only calculate properly outside of thyroid hormone therapy. Above the results, verify that that you’ve correctly selected nothing or “T4-substitution.”
In subclinical hypothyroidism, judging by an elevated TSH with a T4 anywhere “within reference” alone is not enough to diagnose loss of thyroid function. Two lab 6 weeks apart, analyzed via SPINA, may confirm suspicion of permanently damaged thyroid tissue that is unable to secrete more T4 in response to elevated TSH.
In hypothyroid patients before therapy, the lower GT is more sensitive to low thyroid function than ultrasound calculation of thyroid volume. In Hashimoto’s thyroiditis, the thyroid may or may not shrink or expand while losing GT. Fibrosis and death of cells that produce hormone will reduce the thyroid gland’s ability to respond to TSH stimulation and therefore GT will be significantly lower, or low within reference.
If GT is high, it could be from Graves’ disease antibodies stimulating the thyroid, infectious thyroiditis, or a toxic thyroid nodule that is autonomously secreting hormone.
GT can be affected by iodine intake because thyroid hormones are synthesized by iodine; distinctive patterns appear with iodine deficiency and excess.
TECHNICAL INFO: the GT is the “calculated standardised estimate of the maximum possible T4 production per unit TSH. It is defined as the amount of T4 released per unit of time (pmol/s) at maximum glandular TSH stimulation.” (3) Therefore, it is primarily based on T4, the most abundant hormone product of the thyroid gland.
2. GD, efficiency of T4-T3 conversion
The software takes the Free T3 and Free T4 ratio and employs sensitive mathematical calculations.
- Reminder: Verify that that you’ve correctly selected nothing or “T4-substitution.” This calculation will not work during T3 therapy or desiccated thyroid therapy.
Before thyroid therapy, in subclinical or overt hypothyroidism, expect GD to be higher to the degree that GT is lower and FT4 is lower. Increased secretion of T3 as well as increased conversion of T4 to T3 often maintains Free T3 levels to prevent the appearance of hypothyroid symptoms. However, when thyroid capacity drops too low within reference (if FT3 is too close to bottom of range or below it), the failing thyroid can no longer maintain healthy Free T3 levels and therapy is needed.
Outside of thyroid therapy, High GD can be inflated by high GT (T3-secreting nodules or Graves’ disease), so interpret them in light of each other.
Within T4 therapy, a low GD is a signal of impaired T4-T3 conversion. The lower the GD, the less T3 the patient is getting out of their T4 medication.
When T4 is high in reference range and T3 is significantly lower in range, the patient is more likely to have hypothyroid symptoms because of the reduced T3, despite a low or normal TSH.
To assess the GD a patient on T4-monotherapy, Midgley et al, 2015 defines three categories:
“poor converter” <23 nmol/s
“moderate converter” 23-29 nmol/s
“good converter” >29 nmol/s. (4)
These apply only to people taking T4 meds. Conversion rate is much higher (32-39) in people with healthy thyroid glands.
Conversion efficiency is in large part reduced by loss of functional thyroid tissue, since the thyroid gland not only secretes T3, but converts T4 into T3 (this is the theory behind the “TSH-T3 shunt”). The rate of T3 secretion and conversion both increase with higher levels of TSH stimulation of thyroid tissue. Higher TSH may also enhance T4-T3 conversion beyond the thyroid wherever TSH receptors are present.
Conversion efficiency may be further reduced by genetic defects in DIO1, DIO2, (the genes that are the basis of Deiodinase Type 1 and Deiodinase Type 2) or the more severe syndrome of “partial SBP2 deficiency” (the gene has been renamed SECISBP2). Such defects can significantly reduce the effect of TSH-driven enhancement to hormone conversion. In DIO1, DIO2 and SBP2 deficiency, deiodinase type 3 is still able to deactivate thyroid hormone at a higher rate than normal, so chronic low T3 syndrome is a risk.
Doctors, please do not increase the T4 dose in a “poor converter” with low GD whose T4 is already high-normal. This can result in even lower T3 and/or adverse cardiovascular symptoms from excess T4. Pushing the T4 level beyond a person’s set-point will decrease the action of the enzyme Deiodinase type 2 (D2) and increase the action of Deiodinase type 3 (D3). The role of Deiodinase type 3 is to convert T4 into Reverse T3 and convert T3 into T2, thereby causing a net result of T3 depletion.
A poor converter without enough thyroid tissue to supply T3 simply needs T3 therapy adjusted to optimize their Free T3 to a target at or above the average FT3 of a person with a healthy thyroid gland, according to Larisch et al, 2018. That’s an average, though, and each person is unique.
A chronically higher-normal T4 and lower-normal T3 can worsen health conditions like heart failure increase frailty in old age, and reduce lifespan, according to research conducted on the T4-T3 ratio in elderly people.
NON-THYROIDAL ILLNESS AND LOW T3
Outside of the context of thyroid therapy, if the GT is normal but GD is low, suspect non-thyroidal illness, which results in loss of T3 (low T3 syndrome). Consult graphs depicting the various phases or severity of nonthyroidal illness. Keep in mind that non-thyroidal illness presents slightly differently if the heart or blood vessels, liver, or kidney are diseased or dysfunctional.
Within thyroid therapy, if a person has non-thyroidal illness, they will lose T3 and their Reverse T3 will be significantly higher in its reference range than the person’s T4 is within its reference range. However, the TSH and T4 will not behave as they do in people not supplementing with T4 hormone. Even if a lot of that T4 is converted to Reverse T3, the treated patient’s T4 will be replenished to some degree each time they take a T4 dose.
According to the literature on non-thyroidal illness, the lower the T3 drops and the longer it remains low, the higher is the risk of continued illness and/or death, especially if a person becomes very ill.
The recovery phase of nonthyroidal illness does not always occur. In thyroid therapy, low T3 can be chronic and induced by a combination of gland loss and genetically poor conversion capacity that can’t be compensated for by T4 monotherapy.
Recovery from low T3 syndrome in a person with a healthy thyroid gland requires the body to increase thyroidal T3 secretion, according to research. First, the TSH will rise to stimulate extra T3 secretion from healthy thyroid tissue, thereby overcoming the higher rate of T3 inactivation. If TSH does not rise, consider that it may not rise soon enough to help the patient recover their T3 levels and recover health.
When considering T3 therapy in the context of nonthyroidal illness, consulting published clinical trials to avoid both underdose and overdose. Realize that clinical trials of T3 therapy are often conducted under volatile health conditions and in some cases the T3 therapy is too little and/or too late to make a difference. T3 therapy in doses enough to make a difference is well known to reduce or suppress TSH, so a person with a healthy thyroid gland will depend on thyroid hormone replacement until recovery is complete and they can safely be weaned off to return to normal TSH-driven thyroid gland function.
TECHNICAL INFO: The Free T3:T4 ratio is the basis of this refined calculation by SPINA-GD. In technical terms, “SPINA-GD (GD) estimates the maximum global activity of peripheral step-up deiodinases per unit of time (nmol/s) from equilibrium levels of FT3, FT4 and constants for plasma protein binding, distribution and elimination.” (3)
3. TSHI: TSH Index
The TSHI (TSH-Index, reference range 1.3 – 4.1) tells you if the pituitary gland is behaving normally in response to thyroid hormone, within normal functional parameters.
TSHI will be low to the degree that the pituitary is not secreting enough TSH in response to lower thyroid hormone levels. Low TSHI is an indication of central hypothyroidism (secondary or tertiary hypothyroidism) — a compromised hypothalamus or pituitary gland. It could be from any cause.
SPINA-Thyr distinguishes all degrees of central hypothyroidism, from mild to severe. (See articles on the difficulty of diagnosing central hypothyroidism, and tips on central hypo diagnosis during thyroid therapy.)
- If secondary hypothyroidism is mild, TSH suppression could be temporary, perhaps caused by medications or substances that reduce TSH (such as corticosteroids), fasting (calorie-deficient or protein-deficient diets), or a severe illness.
- If the patient has moderate to excessive thyroid gland secretion and very low TSH secretion, this will also result in a low TSHI. It can make one suspect either:
- a) Graves’ disease (TSH-Receptor antibodies can stimulate the gland instead of TSH, and meanwhile, TSHR stimulating antibodies can interfere with the pituitary ultrashort feedback loop and trick the pituitary into lowering its secretion rate, see ref. 7 and our article outlining research on TSAb effects on TSH)
- b) Toxic thyroid nodules (which oversecrete thyroid hormone, often secreting more T3 than T4)
- c) Infectious thyroiditis (temporary thyroid gland inflammation and hypersecretion). See the example below.
- The TSHI calculation is based on the FT4-TSH relationship only, not FT3. It does not distinguish whether TSH suppression is caused by a higher FT3 level or by some other factor such as fasting. Therefore, one must manually evaluate the FT3 and the FT3:FT4 ratio to determine the degree to which higher FT3 is a cause of a low TSHI. In normal healthy subjects, FT3 is approximately mid-reference. TSHI will be lower to the degree FT3 is significantly higher than the population mean, even if FT4 is concurrently low-normal or lower.
- Normally, TSH is more powerfully suppressed by FT4 than FT3. If a person is taking T4 monotherapy and is a poor converter, their isolated low T3 is not capable of causing their TSH to rise. The pituitary is sensitive to the thyroid hormone that dominates, and in most cases, especially in T4 monotherapy, T4 is dominant. When T4 dominates, a lower T3 will be usually be ignored by the pituitary.
In contrast to abnormally low TSH, higher than expected Pituitary TSH secretion, given a higher T4 level, can be caused by
- a) Resistance to thyroid hormone (relatively rare) — RTH — thyroid hormone receptor insensitivity to thyroid hormones in the pituitary. If the TSH is not being suppressed despite higher levels of thyroid hormone, it will report a high TTSI.
- b) TSH-secreting adenoma (rare) — If the TSH is oversecreting, whether or not the thyroid gland is responding well, this could also be a reason for a high TTSI.
- c) TSHR blocking antibodies that interfere with the pituitary ultrashort feedback loop (7) may trick the pituitary into oversecreting TSH. TSHR antibodies are found in 10% of Hashimoto’s patients, in patients with Graves’ disease (stimulating antibody, 73-100%, blocking antibody 25-75%), and in 10-75% of patients with atrophic thyroiditis (9).
TECHNICAL INFO: In technical terms, the TSHI “estimates maximum pituitary TSH reserve by extrapolating the amount of TSH feedback inhibition for a measured FT4 concentration.” (3) Therefore, if TSHI is low, consider other health factors besides FT4 that can lower or suppress TSH.
How to distinguish TSHI and TTSI: “TSH index defines the maximum possible TSH response in the FT4‐uninhibited state at a theoretical FT4 value of 0, whereas the TTSI standardises the TSH response in relation to the upper reference range of FT4. Both indices define pituitary thyrotroph function more accurately, compared to TSH measurement.” (6)
4. sGD and sTSHI
The “s” before GD and TSHI designates the “Standard Deviation” from a midpoint of reference ranges, betwen 2 SD below and 2 SD above the midpoint of reference. This value gives you an idea of how far above or below the reference midpoint the GD and TSHI are.
5. TTSI: Thyrotroph thyroid hormone resistance index
TTSI data can help diagnose Resistance to Thyroid Hormone (RTH). RTH means the thyroid hormone receptors in the pituitary gland require more T4/T3 than normal to stimulate them in order to bring down the TSH.
To the degree TTSI is significantly elevated (reference 100-150), a patient may have RTH. According to a clinical study by Pohlenz et al, 1999, cited in the SPINA-Thyr manual:
- Normal TTSI is 136 (reference 100-150)
- Mild pituitary-selective RTH = 308
- Severe pituitary-selective RTH = average 747
- Generalized RTH (even beyond the pituitary) = average 1559.
If TTSI is high, consult research publications and experts regarding therapy and do not trust TSH to indicate thyroid hormone (in)sufficiency.
In RTH syndromes, the person has a biological requirement for higher Free T3 and possibly higher Free T4 levels than the normal levels found in healthy controls, at the upper limit of reference or slightly higher.
In RTH, the therapeutic goal is not always to normalize the TSH with T4 medication because doing so may result in excess T4. Some tissues may become thyrotoxic while others may be euthyroid or hypothyroid, depending on the degree to which affected thyroid receptor variants are expressed in those tissues. Usually RTH affects thyroid hormone receptor beta (TRAB gene).
(NOTE: If TTSI is extremely low, it is usually because TSHI is low (subnormal secretion of TSH), and in this case you can ignore the TTSI, and the TSHI is the more important clinical indicator.)
An example can illustrate a rare and complicated case of diagnosis.
This screenshot (copied here from above) is from the laboratory results of a patient who was not on any thyroid therapy. (The reference ranges are in the “preferences” image.)
- The doctor had diagnosed thyroiditis, which seems likely given high GT.
- However, they had overlooked concurrent low pituitary TSH secretion (low TSHI, low TTSI).
- If the pituitary was healthy, the TSH should not have been suppressed given the patient’s T4 and T3 levels. As long as T4 levels are lower than those needed to suppress TSH, repeat laboratory testing and SPINA-Thyr analysis can confirm the abnormally low pituitary TSH secretion.
- If TSH secretion was lowered by medication or fasting or illness, it would not normally completely suppress the TSH.
- Graves’ disease antibodies may suppress TSH at the ultrashort feedback loop on the pituitary (7) and cause high GT. The patient’s T4 and T3 may not be able to rise above reference if the thyroid gland has been damaged from prior autoimmune attack.
- Graves’ TSH-receptor “blocking” antibodies (TBAb) can counterbalance TSH-receptor “stimulating” antibodies (TSAb) and result in net euthyroid hormone secretion from the gland: “The co-presence of TBAb and TSAb in the serum of a patient has been speculated to have a counteracting effect, similar to a tug-of-war.”(8)
In this case, it would be wise to test for Graves’ antibodies, either using a TSAb- specific assay or the TBII test which measures both types of antibodies together. If these antibodies are not present, thyroiditis combined with a hypopituitary diagnosis may be more likely. One would then test other pituitary hormone levels to see if they are lower than they should be.
(1) Dietrich, J. W. (2019, April 26). SPINA: Structure parameter inference approach. Download from http://spina.sourceforge.net/ — the manual is at https://sourceforge.net/projects/spina/files/ — you may need to right-click files to download.
(2) Dietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016). Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00057
(3) Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). The role of functional thyroid capacity in pituitary thyroid feedback regulation. European Journal of Clinical Investigation, 48(10), e13003. https://doi.org/10.1111/eci.13003
(4) Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056
(5) Dietrich, J. W., Fischer, M. R., Jauch, J., Pantke, E., Gartner, R., & Pickardt, C. R. (1999). Spinathyr: A novel systems theoretic approach to determine the secretion capacity of the thyroid gla. Retrieved January 1, 2019, from PowerShow website: http://www.powershow.com/view1/16f96d-ZDc1Z/SPINATHYR_A_NOVEL_SYSTEMS_THEORETIC_APPROACH_TO_DETERMINE_THE_SECRETION_CAPACITY_OF_THE_THYROID_GLA_powerpoint_ppt_presentation
(6) Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). The role of functional thyroid capacity in pituitary thyroid feedback regulation. European Journal of Clinical Investigation, 48(10), e13003. https://doi.org/10.1111/eci.13003
(7) Dietrich, J. W., Tesche, A., Pickardt, C. R., & Mitzdorf, U. (2004). Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis. Cybernetics and Systems, 35(4), 315–331. https://doi.org/10.1080/01969720490443354
(8) Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064
(9) Fröhlich, E., & Wahl, R. (2017). Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.00521