lPersistent symptoms of hypothyroidism or raised serum levels of thyroid stimulating hormone (TSH) despite optimum thyroid hormone replacement (up to 2.0 μg/kg body weight of levothyroxine) suggest treatment-refractory hypothyroidism
lExplore adherence to treatment and conditions that impair absorption (taking the drug with medications or food, coeliac disease, etc) or increase demand (pregnancy, other medications)
lDiscuss measures such as taking the tablet on an empty stomach in the morning an hour before other food or medications and using reminders, such as dosette boxes, to improve adherence
A 40 year old woman complains of tiredness over the past few weeks. She had a total thyroidectomy three years ago for Graves』 thyrotoxicosis and has been taking levothyroxine since then. She weighs 80 kg and is taking 150 μg daily. A blood test done in the previous week showed thyroid stimulating hormone (TSH) levels above 30 mU/L (reference range 0.4-4.5 mU/L).
Some hypothyroid patients continue to have symptoms or biochemical evidence of hypothyroidism (serum TSH above the upper laboratory reference range) despite standard thyroid replacement therapy. The prevalence of treatment-refractory hypothyroidism is not established. Studies in different populations report about a third of patients taking thyroid medications have TSH levels above the reference range, suggesting inadequate thyroid hormone replacement1-2.
Further dose increase may not always be appropriate. Patients may not be taking the treatment regularly as advised. Conditions that decrease absorption or increase demand for thyroxine may also be responsible (see box 1). A recent expert consensus report recommends identifying and addressing the likely cause before increasing the daily dose of levothyroxine above 1.9 μg/kg body weight3.
Box 1
Causes of treatment-refractory hypothyroidism (adapted from an expert consensus report3)Decreased bioavailability
Non-adherence to, or tolerability of, levothyroxine therapy
Substances that interfere with intestinal absorption (such as proton-pump inhibitor therapy, coffee, food, soya, kelp, iron, calcium, aluminium hydroxide, chromium picolinate, cholestyramine, colestipol, grapefruit juice, sevelamer hydrochloride, sucralfate, raloxifene, multivitamins)
Intestinal malabsorption (such as short bowel syndrome, lactose intolerance, gluten enteropathy, inflammatory bowel disease, infiltrative enteropathy, infection with Giardia or Helicobacter pylori)
Increased need for levothyroxine
Weight gain
Pregnancy
Increased metabolism of levothyroxine due to increased hepatic metabolism by cytochrome P450 enzymes, induced by drugs (such as phenobarbital, phenytoin, carbamazepine, rifampicin, tyrosine kinase inhibitors, rexinoid compounds)
Others
Assay interference from heterophilic antibodies and biotin-containing medications
What you should cover
Look for possible causes
Ask about adherence to treatment. Is the patient taking the levothyroxine tablets regularly?
Is she taking levothyroxine alongside other medications or with meals? Several foods and medications interfere with the absorption of levothyroxine in the intestine (see box 1). Certain medications increase the metabolism of levothyroxine.
Review her medication list, tablet box, and prescription history.
If the patient acknowledges non-adherence, explore the reasons for it in the context of her life. What else is going on in her life? Is she stressed? Does she understand what the tablets are for? Has she searched for information on the internet? Has she any concerns about side effects? Does she miss tablets because she finds it hard to wake up and because it says take on an empty stomach? Is the drug well tolerated?
Is the patient pregnant? Pregnancy increases the demand for levothyroxine.
Has the patient got any symptoms or signs to suggest malabsorption? Vomiting, diarrhoea, or weight loss accompanied by anaemia can suggest malabsorption. However, many patients have no symptoms.
What you should do
Explain why regular treatment is important and how it is to be taken
Draw up a shared management plan that incorporates the patient’s goals and preferences. Inform patients that not taking recommended levothyroxine replacement puts them at risk of weight gain, raised cholesterol levels, tiredness, depression, and, over a longer time period, myxoedema coma, which can be fatal4.
Explain that the absorption of levothyroxine tablets can be affected by other substances taken at the same time. Advise the patient to take levothyroxine on an empty stomach with water at least an hour before breakfast or any other tablets in the morning. This has been shown to optimise absorption5.
Discuss other ways to improve adherence (such as a dosette box, alarms or reminders on phone, tablet counting, etc). Measures such as taking levothyroxine at bed time, trying a different preparation of levothyroxine (brand, liquid formulation), or supervised weekly dose may be considered in patients who find it hard to adhere to treatment, but there is no evidence to support these.
Dose increase
Levothyroxine dose increment of 25-50 μg may be appropriate for patients taking other medications that decrease its bioavailability. Increasing the dose by 25-50 μg is also advised in pregnant women taking levothyroxine for optimal fetal growth and development. Monitor serum TSH every 6-8 weeks, aiming to keep it<2.5 mU/L throughout pregnancy6.
Assess the effect of advised changes
Offer the patient an initial full thyroid function test (TSH and free thyroxine levels in the blood) as well as simple screening tests for malabsorption (such as full blood count, serum levels of vitamin B12, folate, ferritin, calcium, and albumin, and coeliac antibody test). Recheck thyroid function after six weeks to see the effect of the above changes.
Referral
Consider referral to an endocrinologist if:
TSH levels remain elevated after six weeks despite the above advice and changes in the absence of malabsorption. An endocrinologist may perform levothyroxine absorption challenge tests to differentiate true malabsorption from non-adherence to treatment (pseudomalabsorption)3,7-8. Paired blood samples may need to be sent to an alternative laboratory to rule out TSH assay interference.
Symptoms or blood test results suggest true malabsorption (for example, deficiencies of vitamin B12, folate, ferritin, or calcium and positive coeliac antibody test).
Sources and selection criteria
We used an expert consensus report for diagnosis and management of treatment-refractory hypothyroidism (www.ncbi.nlm.nih.gov/pmc/articles/PMC5680379/). We have drawn recommendations during pregnancy from guidelines of the American Thyroid Association. We also referred to previous case reports and drew from experience at our centre.
Education into practice
How would you explore adherence to taking levothyroxine?
What measures will you suggest to a patient to improve adherence to treatment?
What tests will you consider in a patient with treatment-refractory hypothyroidism?
How patients were involved in the creation of this article
We interviewed two patients taking levothyroxine for hypothyroidism. Both felt they had not been adequately informed on how to take the tablets and why they must take them regularly. One of the patients noted that it was important that doctors listen to the patient to come to a shared management plan, recognising that one size would not fit all. We have attempted to cover these points in the article. A patient with hypothyroidism also reviewed this paper for The BMJ and found the tips to improve absorption of levothyroxine useful. We thank these patients for their contribution.
Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.
Contributors: SOO provided the initial idea for the paper. All authors helped in the design and writing of the paper, approved the final version, and are accountable for all aspects of the work. SOO is the guarantor.
Provenance and peer review: Commissioned; externally peer reviewed.
Laura J McNally clinical fellow 1,
Catherine I Ofiaeli general practitioner 2,
Samson O Oyibo consultant endocrinologist 1
1Peterborough City Hospital, Peterborough PE3 9GZ, UK;
2New Queen Street Surgery, Peterborough PE7 1AT
Correspondence to: S O Oyibo samoyibo@yahoo.co.uk
Reference
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