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January 2016: Thyroid Month: Beware of Biotin

More patients are taking the dietary supplement biotin, which could be throwing off a number of test results from thyroid cancer to Graves’ disease.

The thyroid test results made no sense, so the patient’s primary care physician sought help from an endocrinologist. The physician had been treating the patient’s hypothyroidism successfully with levothyroxine for some time, when suddenly her free T4 levels spiked despite a normal thyroid stimulating hormone (TSH) level.

The physician referred the patient to Cary N. Mariash, MD, professor of clinical medicine at Indiana University in Indianapolis, where additional laboratory tests had inconsistent results: her free T4 and total T3 were elevated, but her total T4, T4 index, and TSH were normal.

Fortunately, Mariash could clear up the confusion by asking the patient a simple question: “Are you taking biotin?”

Yes, she replied, she had recently started taking 10 mg a day in hopes of improving her hair and nails. Her tests returned to normal when she stopped taking biotin. The problem had nothing to do with the patient’s thyroid — the biotin was interfering with the tests.

Mariash presented this case at the recent International Thyroid Congress because he has recently encountered several patients whose abnormal thyroid test results were caused by taking biotin and “most endocrinologists don’t know about this problem.”

Carol Greenlee, MD, an endocrinologist practicing in Grand Junction, Colo., concurs that she is encountering an increasing number of confounding lab results caused by patients taking large doses of biotin.

“I saw somebody just yesterday who has had an extensive workup for hyperthyroidism. A lot of her tests look like she has Graves, but she is taking massive doses of biotin. She probably doesn’t have any thyroid problem. We could be treating people for Graves’ disease who don’t have it, and that’s really scary.” — Carol Greenlee, MD, endocrinologist, Grand Junction, Colo.

“I saw somebody just yesterday who has had an extensive workup for hyperthyroidism. A lot of her tests look like she has Graves’, but she is taking massive doses of biotin. She probably doesn’t have any thyroid problem. We could be treating people for Graves’ disease who don’t have it, and that’s really scary,” Greenlee says.

An Unregulated Supplement
Many people have begun taking biotin mainly in the belief that it is a key contributor to keratin, and therefore can improve hair, nails, and skin. It is marketed under a number of names, including vitamin B7, vitamin H, and coenzyme R, and sometimes may be listed only as an unnamed supplement to improve hair and nails.

It is a B vitamin, and the Institute of Medicine recommends a daily intake of 30 mcg. That’s what a multivitamin such as Centrum Silver contains. But some patients, like the one Mariash treated, are taking milligram amounts, and might not consider it a medication, so not worth mentioning. It is marketed over the Internet, and Mariash recently saw a television advertisement for it, so its popularity could continue to grow.

An Issue with Assays
The problem is that almost all immunoassays today contain biotin because they rely on the biotin–streptavidin attraction to either anchor the assay’s antibodies to a capture surface or capture them once they have reacted with a patient sample, according to Stefan K. Grebe, MD, PhD, professor of laboratory medicine & pathology and co-director of the endocrine laboratory at the Mayo Clinic in Rochester, Minn.

Large amounts of biotin in a patient sample can interfere with this process. However, the effects can be confusing because, depending on the particular assay, biotin can skew the results to be either falsely high or falsely low. In the case of competitive immunoassays — usually used for low molecular weight targets (such as T4, T3, and cortisol) — biotin interference causes a falsely high result. In immunometric (sandwich) assays, it gives a falsely low result.

Other characteristics of the assay can also make a difference. For instance, a longer incubation time increases the opportunity for interference. Different assays for various analytes, even from the same manufacturer, can therefore vary in their susceptibility to biotin interference.

At the laboratory Mariash uses, the free T4 and total T3 assays use a biotin-streptavidin fluorescent detection system, so biotin can cause falsely elevated results, but the TSH and total T4 assays are not affected. In contrast, at Greenlee’s lab, biotin can lead to falsely low TSH results, but free T3 and free T4 tests are not affected. Biotin can also cause her lab’s assay for thyrotropin receptor antibodies (TRAb) to be falsely positive, which could lead to a misdiagnosis of Graves disease.

Mariash says that even though he suspected what was causing the questionable results, getting to the bottom of the problem was not easy: “I had to make a lot of phone calls to our laboratory. Finally a supervisor told me what platform they were using. Then I called the test manufacturer to get additional details, and they gave me enough information to know what was going on. But of course, they don’t give you every detail because some of it is proprietary.” Mariash’s laboratory director was unaware that biotin could be a problem.

Grebe says it may fall to the physician ordering the test to be vigilant: “When your lab results don’t make sense in terms of the clinical picture, or in terms of the constellation of lab results you have received, you should always think first of an assay interference — one of which is biotin — before you think of really exotic reasons for this to have happened, such as TSH-secreting pituitary tumors.”

Puzzling Tests and a Revelation
Greenlee had an example of these confusing results when a patient was referred to be evaluated for a possible diagnosis of adrenal carcinoma. The patient had presented complaining of fluid retention and weight gain. Her face was red and she was growing hair on her face while losing hair on top of her head. Her cortisol and testosterone test results were elevated off the charts. Her thyroid tests were also confusing, with low TSH but normal T4 and T3.

“When your lab results don’t make sense in terms of the clinical picture, or in terms of the constellation of lab results you have received, you should always think first of an assay interference — one of which is biotin — before you think of really exotic reasons for this to have happened, such as TSH-secreting pituitary tumors.” — Stefan K. Grebe, MD, PhD, professor, laboratory medicine & pathology; co-director, endocrine laboratory, Mayo Clinic in Rochester, Minn.

A normal adrenal CT scan ruled out cancer. Greenlee asked the woman to come back the next morning for fasting blood tests. This time her tests were normal. Greenlee thought that perhaps there was some mix-up at the lab, and the original tests were not this patient’s.

The solution to the mystery only emerged over time. The patient’s problems stemmed from her home remedies for her hair loss — minoxidil and biotin. Not knowing her hair loss was not unusual for an older woman, and despite warnings that it should not be used by women, she was putting minoxidil on the top of her head — resulting in a red, hairy face.

The final piece of the puzzle fell into place when Greenlee was preparing a talk and came across a reference to biotin interfering with a parathyroid hormone assay. Her research following up this clue led her to literature reports of other biotin interferences. In the case of this patient, because she had been told to fast before she was tested again, she had not taken biotin, so those results reflected her true status. The biotin interference contributed to her out-of-kilter cortisol, testosterone, and TSH results. In unraveling the mystery, Greenlee consulted with Grebe to learn more about the ins and outs of immunoassays and worked closely with her lab — making them aware of the potential interference.

Biotin Vigilance
Greenlee is now making sure her practice identifies any patients taking the supplement: “We have huge signs in my office that ask people if they are taking biotin — in each exam room, over the phlebotomy chair, and at the front desk. We had all these nice pictures on our walls, but the biotin thing alarmed us so much that we don’t care about our decorations in our office anymore.”

“It can be dangerous not to recognize it,” Mariash agrees. He also notes that clinicians need to be vigilant because laboratories can change the test platform without notice.

For the interference to occur, the patient’s biotin level needs to be high — at least three times the upper limit of the healthy adult reference range, according to Grebe. But that level is easy to achieve with the megadoses many are taking.

Grebe suggests that a clinician can ask the lab to try using another manufacturer’s test, but an easier route is to ask the patient to stop the biotin then get retested. Biotin is water soluble, so it washes out of the body quickly — even a single day can make a big difference in the test results.

And although literature reports mostly focus on problems with parathyroid and thyroid hormone tests, biotin interference could be considered as a potential contributor to almost any suspicious immunoassay result.

Seaborg is a freelance writer based in Charlottesville, Va. He wrote about expanding the definition of osteoporosis in the December issue.

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