Using Thyroid Hormones in Hypothyroid and Euthyroid Patients

In This Article

Abstract and Introduction

Abstract

Objective: Management of hypothyroidism is controversial because of medication cost pressures and scientific uncertainty on how to address treatment dissatisfaction experienced by some patients. The objective was to investigate the experience and preferences of UK endocrinologists in use of thyroid hormones.

Design: Web-based survey.

Patients: UK endocrinologists were invited to participate.

Measurements: Responses to questionnaire.

Results: The response rate was 21% (272/1295). While levothyroxine monotherapy is regarded as the treatment of choice for hypothyroidism, 51% of respondents stated that combined treatment with levothyroxine and liothyronine could be considered for levothyroxine-treated patients whose symptoms persist despite normalisation of serum thyroid stimulating hormone (TSH) concentration. However, only 40% are currently prescribing such treatment, and just 23% would consider taking it themselves. A small minority prescribe desiccated thyroid extract, and those most likely to do so are aged over 60 years. Most respondents stated that they have no influence over brand or formulation of levothyroxine dispensed to their patients and expect no major differences in efficacy between different formulations. A total of 9% would prescribe levothyroxine for euthyroid enlarging goitre, and 29% for euthyroid female infertility with high titre thyroid peroxidase antibodies, despite recent trials finding no benefit.

Conclusions: UK endocrine practice in management of hypothyroidism is broadly in line with international guidance. However, a minority of respondents would consider thyroid hormone supplementation in euthyroid individuals for female infertility, enlarging goitre, and other indications in which evidence of efficacy is lacking. Willingness to consider prescribing combined levothyroxine and liothyronine, for hypothyroid symptoms which persist despite normalised TSH, has increased in comparison to previous international surveys, despite inconsistent evidence of benefit.

Introduction

The UK prevalence of hypothyroidism was estimated recently at 3.6% overall, increasing from around 1 in 1000 children aged up to 10 years, to approximately 1 in 10 adults aged over 70 years.^[1] This disease burden occurs within a population that had in recent decades been regarded as iodine replete, however, concern about gradually falling iodine intake, particularly in women of child-bearing age,^[2] is borne out by the latest results of the UK National Diet and Nutrition Survey, confirming that this cohort (females aged 16–49 years) now meets World Health Organisation criteria for iodine deficiency.^[3]

Primary hypothyroidism in the United Kingdom is usually diagnosed and managed by general practitioners, within the National Health Service (NHS), which provides tax-funded healthcare. General practitioners tend to refer to NHS endocrinologists only if difficulties arise in diagnosis or management. The latest UK National Institute for Health and Care Excellence (NICE) guidance recommends levothyroxine (LT4) as first-line treatment. Prescribers are directed to achieve thyroid stimulating hormone (TSH) concentrations within the reference interval, measuring TSH every 3 months until stable, and annually thereafter.^[4]

NICE guidance does not address switching between LT4 tablet brands or formulations, despite several other European countries experiencing widespread difficulties after enforced switches.^[5] However, the UK Medicines and Healthcare products Regulatory Agency (MHRA) advises that, while generic prescribing is routinely appropriate, a specific, tolerated product can be prescribed for patients reporting persistent symptoms when switching between different LT4 tablets, and liquid LT4 can be considered if symptoms or poor control of thyroid function persist despite adherence to a specific product.^[6] LT3 is not recommended for routine use but NICE guidelines nevertheless direct readers toward NHS England Specialist Pharmacy Services (SPS) guidance, which, in limited circumstances, provides for long-term NHS-funded LT4 + LT3 combination therapy, after a trial of at least 3 months' duration under supervision of an endocrinology consultant.

LT4 tablets are among the most prescribed medications in the United Kingdom. Liquid and soft-gel capsule preparations are available, though their current cost in the United Kingdom is several times greater than tablets. The bioavailability of LT4 in liquid and soft-gel capsules is reported to be greater than for tablets, but their cost-effectiveness in adult hypothyroidism remains uncertain, even when absorption is impaired by comorbidities, concomitant medications, or behavioural factors.^[7] Nevertheless, from 2016 to 2021, nontablet LT4 preparations have taken an increasing share of the market and, together with liothyronine (LT3) and desiccated thyroid extract (DTE), have consumed 35% of UK National Health Service (NHS) expenditure in England on thyroid hormones, despite representing just 0.36% of items dispensed.^[8]

The current study is part of the Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS) project, which is designed to investigate attitudes and practice in controversial aspects of thyroidology, most notably in the use of thyroid hormones and nutritional supplements for hypothyroidism, and the management of euthyroid disorders, including goitre and female infertility.

Table 1. Demographic characteristics of respondents
Characteristic	Category	Female		Male		Total
Characteristic	Category	n	%	n	%	n	%
Age in years	21–30	3	1.1	3	1.1	6	2.2
	31–40	32	11.8	36	13.2	68	25
	41–50	44	16.2	52	19.1	96	35
	51–60	26	9.6	47	17.3	73	27
	61–70	2	0.7	23	8.5	25	9.2
	>70	0	0	4	1.5	4	1.5
	Total	107	39.3	165	60.7	272	100
Years in medical practice	0–10	14	5.1	18	6.6	32	11.8
	11–20	48	17.6	49	18.0	97	35.7
	21–30	36	13.2	52	19.1	88	32.4
	31–40	9	3.3	35	12.9	44	16.2
	>40	0	0	11	4.0	11	4.0
Specialisation^a	Endocrinology	104	38.2	160	58.8	264	97.1
	Internal medicine	54	19.9	91	33.5	145	53.3
	Others	9	3.3	9	3.3	18	6.6
Place of practice^a	University centre	38	14.0	74	27.2	112	41.2
	Regional hospital	66	24.3	96	35.3	162	59.6
	Private clinic	6	2.2	27	9.9	33	12.1
	General Practice	1	0.4	0	0	1	0.4
	Basic researcher	0	0	1	0.4	1	0.4
	Specialist Practice	7	2.6	22	8.1	29	10.7
Professional society membership^a	National endocrine societies	82	30.1	139	51.1	221	81.3
	European Thyroid Association	4	1.5	17	6.3	21	7.7
	American Thyroid Association	1	0.4	3	1.1	4	1.5
	Asian and Oceanian Thyroid Association	1	0.4	0	0	1	0.4
Frequency of treating thyroid patients	Daily	50	18.4	93	34.2	143	52.6
	Weekly	55	20.2	66	24.3	121	44.5
	Rarely	2	0.7	6	2.2	8	2.9
Number of patients treated for hypothyroidism	>100 per year	28	10.3	67	24.6	95	34.9
	51–100 per year	25	9.2	53	19.5	78	28.7
	10–50 per year	51	18.8	39	14.3	90	33.1
	Rarely treat hypothyroid patients	3	1.1	6	2.2	9	3.3

^aRespondents were permitted to select more than one option.

Table 2. Preferred LT4 formulations by UK endocrinologists in different clinical conditions
	Tablets/tablets from another manufacturer n (%)	Soft-gel capsule n (%)	Liquid solution n (%)	I expect no major changes with different formulations n (%)
Interfering drugs may influence the stability of therapy. Which LT4 preparation is in your experience least likely to be subject to variable absorption?	53 (20.7)	5 (2.0)	38 (14.8)	160 (62.5)
Which of the following preparations of LT4 would you prescribe in case of first diagnosis of hypothyroidism when the patient self-reports intolerance to various foods raising the possibility of coeliac disease, malabsorption, lactose intolerance, or intolerance to common excipients?	154 (60.6)	10 (3.9)	29 (11.4)	61 (24.0)
Which of the following preparations of LT4 would you prescribe for a patient established on LT4 who has unexplained poor biochemical control of hypothyroidism?	110 (43.7)	11 (4.4)	26 (10.3)	105 (41.7)
Which of the following preparations of LT4 would you prescribe for a patient with poor biochemical control who is unable (due to busy lifestyle) to take LT4 fasted and separate from food/drink?	83 (33.3)	22 (8.8)	35 (14.1)	109 (43.8)
Which of the following preparations of LT4 would you prescribe for a patient established on LT4 tablets who has good biochemical control of hypothyroidism but continues to have symptoms?	52 (21.1)	0 (0)	2 (0.8)	193 (78.1)

Table 3. Perceptions of the relative importance of eight potential causes of symptoms of hypothyroidism persisting despite LT4 treatment returning serum TSH to the reference interval
Possible cause	Sum of "Strongly agree" + "Agree" (n)	Sum of top 3 ranks (n)
Psychosocial factors	134	166
Comorbidities	123	130
Patient unrealistic expectation	113	129
Burden of chronic disease	93	62
Chronic fatigue syndrome	69	61
Inability of levothyroxine to restore normal physiology	39	58
Presence of underlying inflammation due to autoimmunity	38	44
Burden of having to take medication	27	40