When thyroid labs do not add up, physicians should ask patients about biotin supplements

Abstract

A 69-year-old woman with a remote history of Graves’ disease treated with radioactive iodine ablation, who was maintained on a stable dose of levothyroxine for 15 years, presented with abnormal and fluctuating thyroid function tests which were confusing. After extensive evaluation, no diagnosis could be made, and it became difficult to optimise the levothyroxine dose, until we became aware of the recently recognised biotin-induced lab interference. It was then noticed that her medication list included biotin 10 mg two times per day. After holding the biotin and repeating the thyroid function tests, the labs made more sense, and the patient was easily made euthyroid with appropriate dose adjustment. We also investigated our own laboratory, and identified the thyroid labs that are performed with biotin-containing assays and developed strategies to increase the awareness about this lab artefact in our clinics.

Background

Already 1.5 years ago, the Food and Drugs Administration (FDA) in the USA released a safety communication about biotin affecting lab results,¹ and physicians up to pace with the literature may be familiar with biotin’s effect on labs. This case took place at that time. MKSAP 18 (which stands for Medical Knowledge Self Assessment Program, an authoritative internal medicine source in the USA), among other sources² writes, ‘biotin interference causes falsely high results with competitive immunoassays used to measure small molecules (free T₄, free T₃, total T₄ and Total T₃) and causes falsely low results with sandwich assays used to measure large molecules (TSH).’² All our thyroid function labs use Beckman Coulter assays. We use a competitive immunoassay for free T₃ and free T₄. However, the thyroid-stimulating hormone (TSH) assay in many laboratories (such as ours) is not biotin-based, and our patient’s TSH values were genuine. Therefore, it is important to be simply familiar that biotin can affect thyroid function and other lab results in various ways.

Case presentation

A 69-year-old woman with a medical history of post-ablative hypothyroidism maintained on levothyroxine for thyroid replacement who underwent radioactive iodine ablation for Graves’ disease 17 years prior and whose levothyroxine dose had been appropriate with clinical and biochemical euthyroidism presented with abnormal and confusing thyroid labs about 18 months prior to endocrine consultation. Her levothyroxine dose had been adjusted up and down, ranging from 50 to 100 μg/day with thyroid function tests that did not add up: elevated TSH and elevated free T4 and free T3.

Her symptoms over this period were variable and nonspecific, but were marked by weight gain and increasing depression. Her thyroid function tests are detailed chronologically in tables 1 and 2 (from January 2017 to February 2019). At presentation, in January 2017, she was clinically euthyroid, and her physical examination was overall unremarkable with no goitre. Her thyroid labs were: TSH 14.96 (reference 0.35–4.01), free thyroxine (T₄) 1.95 ng/dL (reference 0.61–1.37) and free triiodothyronine (T₃) 5.4 pg/mL (reference 2.8–4.4). Furthermore, a stimulating thyrotropin receptor antibody assay showed a level of 7.05 IU/II (reference 0.00–1.75). At a decision limit of 1.75, this assay has 97% sensitivity and 99% specificity for Graves’ disease. Her thyroid sonography revealed an atrophic gland with no nodules. Though a diagnosis of Graves’ disease was tentatively considered, her elevated TSH was puzzling, as well as the absence of clear-cut hyperthyroid symptoms.

Table 1.

Thyroid function tests were abnormal and did not correspond to clinical symptoms

Date	25/1/2017	6/2/2017	17/3/2017
TSH* (µIU/mL)	14.96	22.33	33.34
T4, free† (ng/dL)	1.95	1.15	1.57
T4, total‡ (µg/dL)			1.88
T3, free§ (pg/mL)	5.4	5.5	7.4
T3, total¶ (ng/dL)		208	272

*TSH ((µIU/mL), 0.35-4.01).

†T_⁴, free (ng/dL, reference 0.61–1.37).

‡T₄, total (µg/dL, reference 4.30–12.50).

§T₃, free (pg/mL, reference 2.8–4.4).

¶T₃, total (ng/dL, reference 87–178).

TSH, thyroid-stimulating hormone.

Date	24/7/2017	11/9/2017	10/10/2017
TSH	12.62	8.63	7.80
T4, free	1.55	1.98	1.81
T4, total	7.5	6.96	6.19
T3, free	6.6	7.6	7
T3, total	259	322	326

TSH, thyroid-stimulating hormone.

Table 2.

After discontinuation of biotin 10 000 μg (and later, resuming it but holding it for 5 days prior to lab tests), thyroid function tests normalised and the patient was easily adjusted onto the appropriate levothyroxine dose

Date	26/12/2017	22/2/2018	6/4/2018	2/7/2018
TSH	0.54	0.19	0.41	0.45
T4, free	1.46	1.38	0.86	0.90
T4, total	9.85	10.35
T3, free	3.3	3	2.8	2.7
T3, total	102	84

TSH, thyroid-stimulating hormone.

Date	8/10/2018	21/2/2019
TSH	0.97	0.67
T4, free	0.98	0.91
T4, total
T3, free	2.9	2.8
T3, total

TSH, thyroid-stimulating hormone.

During the next 10 months, her levothyroxine dosage was changed multiple times, ranging from 25 to 100 μg/day. At one point, levothyroxine was completely stopped as a trial, and her weight gain and fatigue deteriorated, with more marked elevation of TSH, but still free T₄ and free T₃ continued to be elevated. The diagnosis remained uncertain; possibilities like resistance to thyroid hormone, pituitary tumour and HAMA interference were considered.

As we became aware of biotin-induced interference with thyroid labs, we noticed that the patient had been taking biotin 10 000 μg of biotin two times per day. When she stopped biotin, her lab work appeared to start corresponding with the clinical picture (mild hypothyroidism), with elevated TSH, and low normal T4 and T3. With minor dose adjustments, the thyroid labs normalised. A few months later, the patient wished to resume biotin, which she held for 5 days before obtaining thyroid functions tests. Her lab results were unaffected.

Outcome and follow-up

The patient continues to take biotin 10 000 μg two times per day. However, she holds it for 5 days before obtaining any lab work. She wishes to continue using biotin for hair, nail and skin care.

Discussion

Biotin (vitamin B₇) is a water-soluble vitamin. Biotin deficiency is unusual in modern times as the vitamin is found in many foods and is supplemented in small amounts in parenteral nutrition solutions and elsewhere. The recommended daily intake for adult males and females is only 30 μg/day. On the other hand, supra-nutritional amounts of biotin are often taken over the counter for hair, skin and nail benefits in the thousands of micrograms (eg, 20 000 μg/day as in our patient). Biotin has also been studied as a treatment for other uses. For example, biotin has been used for inherited metabolic diseases³ and a few recent studies concluded that high-dose biotin may benefit patients with primary progressive multiple sclerosis.^{4 5}

However, many case reports in the past few years have reported supra-nutritional doses of biotin affecting thyroid function tests.^{3 6–9} While the matter is somewhat complicated with sandwich and competitive immunoassays being different, biotin interference typically causes thyroxine and triiodothyronine levels to give a falsely hyperthyroid picture and TSH levels may be affected as well. Not all TSH assays are based on biotin (ours are not), but biotin can still have an impact. In addition, biotin also interferes with the detection of anti-thyrotropin antibodies, so it can even result in a laboratory pattern identical to Graves’ disease.^{3 10} With how common some symptoms of hyperthyroidism are (eg, anxiety), it is not far-fetched to surmise that a few patients may have had radioactive ablation of their thyroid gland unnecessarily, especially in the USA where this is done sometimes before a trial of antithyroid medications.

But besides affecting thyroid function tests, biotin affects many other tests using immunoassays (both competitive and non-competitive immunoassays),¹¹ and these include troponin.¹² In fact, at least one death from acute coronary syndrome was reported to the US FDA as possibly preventable if it were not for biotin interfering with the troponin assay. In November 2017, the FDA released a safety communication about biotin affecting lab tests.¹

Notably, high-dose biotin causes some assays to be falsely increased while others are falsely decreased. An assessment in 2018 found that, ‘The most notable false reductions were in high-sensitivity troponin T, thyroid-stimulating hormone and follicle-stimulating hormone results, while the most notable false increases were in triiodothyronine and vitamin D results.’¹³ However, the high-dose biotin affected a number of other tests and the investigators counselled holding the biotin before almost any lab test. It’s controversial how long to hold biotin before a lab test, and some reports challenge the claims of the lab assay manufacturers,^{9 14} but we had success with holding for 2 days in this patient.

Patient’s perspective.

The good news is that today’s medicine is so specialised. The bad news is that today’s medicine is so specialised. Along with this, doctors are under increasing pressure to diagnose and treat patients that make it next to impossible to spend time with a patient to get to know them (body, mind and spirit; see below). Their time is so limited that they are unable to communicate, let alone communicate effectively, with the other doctors who are involved with their patient’s care.

There is a psychological effect on the patient when there are multiple diagnoses (in my case cancer, thyroid condition, arthritis, etc.) and multiple providers, the diagnoses are often at war with each other, and especially when it comes to prescribing medications. To which doctor does a patient listen?

There is a need to treat body, mind and spirit (spirit to me means ‘that which makes a person good’ which may or may not include religious beliefs; my atheist friends understand this definition but squirm). Our bodies can be compared with a train: if you disconnect the engine (let’s say it’s the mind), the rest of the cars can’t go anywhere (body, spirit). If the middle car gets removed (let’s say it’s the body), the train doesn’t go anywhere.

I sort of suspect that taking on the medical establishment and system is not appropriate for this article but the lack of communication between doctors, from a patient’s standpoint, is frustrating to say the least. At one point when my husband and I were both going through cancer at the same time, we had 15 doctors between us. Have you ever tried to keep 15 doctors happy? Ever tried to keep them aware of all that was going on? Maybe sometime the two of us should write an article about how to reform the medical system. I'd like to form a grass-roots movement to include healthcare workers, pharmacists, dentists and patients and caregivers to get the insurance companies and big business out of the examination room.

Learning points.

• Biotin (vitamin B₇) is often taken over the counter for hair, nails and skin. It is also being studied for medical use in some diseases. While it does not disrupt thyroid function itself, it distorts the value that thyroid function assays give. It can even affect anti-thyrotropin receptor antibody tests and give a laboratory picture identical to Graves’ disease.

• It is worthwhile to rule out biotin supplementation before making a diagnosis of abnormal thyroid function (especially before irreversible treatments such as radioactive iodine ablation). Patients do not always recognise the name biotin, so it is prudent to ask if the patient is taking any supplement for hair, nails or skin.

• If a patient insists on taking high-dose biotin, they may do so without affecting thyroid function tests if they hold it for long enough before doing the labs. In our experience, biotin should be held for at least 2 days. However, one should keep in mind that biotin affects more labs besides just thyroid function tests.