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Common problems managing thyroid disease in primary care

Thyroid disorders are among the most prevalent problems in clinical endocrinology. A majority of patients with thyroid dysfunction will be managed in primary care. There is broad consensus about how to manage biochemically defined hypo and hyperthyroidism yet other areas of thyroidology remain more uncertain. Here we look at scenarios GPs commonly encounter with patients with thyroid problems.

Raised TSH: 'tired all the time'

A 56-year-old presents to her GP with a six-month history of feeling 'tired all the time'. She has gained 3kg in the past year and despite dietary modification cannot reduce her weight. She reports feeling slightly low in mood. Physical examination is unremarkable. Her FBC, U&E and fasting glucose are all normal. Her thyrotrophin (TSH) is 6.2 (reference range 0.5-5mu/l) and her serum

free thyroxine (T4) is 15.9pmol/l (12-22pmol/l).

This patient has abnormal thyroid function tests (TFTs). A moderately elevated TSH in the setting of a normal measured T4 fulfils the diagnostic criteria for subclinical hypothyroidism1. This condition has an estimated prevalence of 10 per cent in women over 552 with a rising incidence as TFTs increasingly become part of the battery of 'routine bloods'.

In many cases raised TSH will be the only abnormality detected on clinical examination and investigation, so doctors are faced with a dilemma of how to manage a symptomatic individual. The non-specific nature of many thyroid dysfunction symptoms make it difficult to determine whether the isolated finding of a raised TSH can explain some ­ if any ­ of the clinical picture.

A cross-sectional study of 25,000 subjects selected at random in Colorado found 12.1 per cent of euthyroid individuals reported symptoms of thyroid illness compared with 13.7 per cent of the subclinical hypothyroid group (p <>

This highlights the problem that despite the statistical significance generated with such a large cohort, on an individual patient basis it may be difficult to distinguish a euthyroid patient from one with thyroid dysfunction.

To treat or not to treat ­ that is the question. Proponents of thyroxine therapy argue this strategy will pre-empt the patient's progression to overt thyroid failure. The only longitudinal study undertaken on the natural history of subclinical hypothyroidism found that, on 20-year follow-up, the risk of developing hypothyroidism was 3 per cent/year in those subjects with a raised TSH and

4 per cent/year in individuals with an elevated TSH (>6mu/l) and thyroid microsomal antibody positive4.

A majority with subclinical hypothyroidism will not progress to overt disease. Furthermore there is no good evidence that expectant treatment improves outcome compared with watching and waiting.

Evidence exists that patients with subclinical hypothyroidism have a significantly higher total and low-density serum cholesterol compared with controls and that T4 treatment reduces these values5. Furthermore the Rotterdam study invoked subclinical hypothyroidism as a risk factor for ischaemic heart disease irrespective of other cardiovascular risks6.

But the Whickham survey, which followed subjects with subclinical hypothyroidism for 20 years, did not report a significant difference in cardiovascular outcome between this group and euthyroid individuals4.

Whether patients with subclinical hypothyroidism experience symptomatic benefit on thyroxine therapy is uncertain. Between 1984 and 2000 five placebo-controlled double-blind trials were carried out (mean n=41.4). Two reported a statistically significant improvement in the subclinical hypothyroid cohort receiving thyroxine compared with placebo.

Importantly, the mode serum TSH of the trial participants was 10.7mu/l whereas 72 per cent of patients with subclinical hypothyroidism have a serum TSH <10mu · 7.="" it="" is="" in="" this="" latter="" group="" that="" the="" controversy="" with="" respect="" to="" treatment="" exists.="" consensus="" statements="" from="" the="" american="" association="" of="" clinical="" endocrinologists8="" and="" the="" royal="" college="" of="" physicians1="" say="" thyroxine="" therapy="" is="" appropriate="" in="" patients="" with="" a="" tsh="">10mu/l since they have a high rate of progression to overt hypothyroidism2.

'Doctor, I need more thyroxine'

A 48-year-old has been diagnosed with symptomatic hypothyroidism by her GP with a TSH of 21.2mu/l and a T4 of 7.4pmol/l. She was commenced on 50µg od. Twelve weeks later she returns for routine follow-up. Her TSH is 1.3mu/l and her T4 is 16.7pmol/l. She reports she remains symptomatic and requests an increase in her thyroxine dose.

This is a common clinical situation:

1 per cent of the UK population is on thyroxine therapy and a sizeable proportion will continue to 'not feel right' despite being biochemically euthyroid. Many symptoms of thyroid dysfunction are vague, for example tiredness or weight gain, and studies have shown euthyroid control subjects will report symptoms of hypothyroidism9. Rendering a previously hypothyroid patient chemically euthyroid may not lead to symptomatic resolution. It may take up to three months before symptoms improve.

A school of thought exists that advocates the goal of thyroxine therapy should be to achieve symptomatic benefit rather than biochemical euthyroidism10. And in one study it was reported that a patient's visual analogue scales of well-being was highest on doses of thyroxine resulting in a TSH of <0.2mu>

The current understanding of thyroid physiology is a normal serum TSH indicates that particular patient's hypothalamic-pituitary-thyroid axis is at set point and there is a lack of evidence to support the benefit of a subjective improvement in well-being against the risks of an iatrogenic hyperthyroid state, which include atrial fibrillation12 and osteoporosis13.

Thyroid cancer

A 69-year-old presents with a lump in the neck he noticed while shaving. He has no previous history of thyroid disease. On examination a solitary thyroid nodule is palpable.

The most frequent presentation of thyroid carcinoma is a lump in the neck14. Other symptoms may include those of local invasion such as a hoarse voice or metastases such as bone pain. In this patient, thyroid function tests (TFTs) should be requested.

Euthyroid patients with a thyroid nodule should be referred to a surgeon or endocrinologist with an interest in thyroid cancer. Patients with hyper or hypothyroidism in the context of a thyroid nodule should be routinely referred to an endocrinologist15.

Aside from TFTs it has been shown that initiation of other investigations by the GP leads to increased delay and cost in making the diagnosis of cancer16.

In suspected cases of thyroid cancer a fine needle aspiration will be performed in a specialist setting followed by a histological diagnosis and TNM staging. In most cases patients will undergo a total thyroidectomy followed by remnant ablation therapy with radioactive iodine.

The goal of thyroxine replacement therapy is lifelong suppression of TSH (<0.1mu ).="" most="" patients="" require="" a="" dose="" of="" t4="" of="" 175-200µg="" daily="" to="" achieve="" this.="" the="" tumour="" marker="" for="" thyroid="" cancer="" is="" thyroglobulin,="" which="" is="" secreted="" by="" both="" normal="" and="" cancerous="" thyroid="">

In patients managed with total thyroidectomy and I131 ablation, detectable serum thyroglobulin is highly suspicious of residual or recurrent tumour. Thyroglobulin should be sampled four-six weeks post-thyroidectomy and three-monthly thereafter. This is usually undertaken by a thyroid cancer multidisciplinary specialist team (MDT).

Follow-up of a patient treated for thyroid carcinoma should be lifelong by the MDT since 5-20 per cent of treated patients develop local or regional recurrences and 10-15 per cent develop distant metastases, commonly to lung and bone.

The overall 10-year survival rate

for middle-aged adults with differentiated thyroid carcinoma is

80-90 per cent15.

Gritty eyes but normal TFTs

A 27-year-old presents with gritty, sore eyes. On examination she has bilateral proptosis and chemosis. Eye movement testing reveals lid lag on downward gaze. Her TSH is 2.7mu/l and her T4 is 17.2 pmol/l.

Clinically this patient has Graves' eye disease although she is biochemically euthyroid. It is reported some 10 per cent of patients with Graves' ophthalmopathy are euthyroid, but a majority of these will have laboratory evidence of thyroid autoimmune disease, including antibodies directed against the TSH receptor17.

Whether clinical Graves' eye disease or hyperthyroidism occurs first, the other manifestation will occur within 18 months of the first in 85 per cent of patients18. In terms of thyroid disease the patient should be tested for the presence of anti-TSH receptor and anti-thyroid peroxidase receptor antibodies at baseline and have regular follow-up tests of thyroid function.

In clinically mild cases of euthyroid Graves' eye disease local interventions may provide symptomatic relief. These include artificial tears, use of an eye protector during sleep and elevation of the head of the bed. In more severe or rapidly progressive cases high-dose corticosteroids may be required, sometimes in conjunction with retro-orbital irradiation or surgical intervention.

Thyroiditis

A 32-year-old presents with a three-week history of a lump in the neck but otherwise feels well. On examination a firm symmetrical goitre is palpable. Her TSH is <0.1mu and="" her="" t4="" is="" 37pmol/l.="" how="" should="" she="" be="" managed?="" what="" further="" investigations="" may="" be="">

This patient is biochemically hyperthyroid, but this is not a diagnosis in itself and several differentials exist. Absence of the typical symptoms and signs of Graves' disease would make this unlikely. Other important points in the history would be recent pregnancy, drug history (particularly amiodarone and lithium), personal and family history of thyroid dysfunction and autoimmune diseases and symptoms of a recent upper respiratory tract infection. Useful investigations at this stage include free triiodothyronine (T3), thyroid peroxidase (TPO) antibody titre, C reactive protein (CRP), white cell count, and erythrocyte sedimentation rate (ESR).

A history of recent parturition would suggest post-partum thyroiditis, a self-limiting autoimmune condition which has a prevalence of

5-7 per cent19. The natural history is of hyperthyroidism one-six months post-partum with clinical features that are in general more subtle than Graves' disease.

It is the result of leakage of thyroid hormone from destroyed thyrocytes, a phase that lasts one-two months. This period of hyperthyroidism may be followed by a four-six month hypothyroid phase, a consequence of thyrocyte loss.

Eighty per cent of women will recover normal thyroid function at one year20. The T4:T3 ratio is high since large levels of stored hormone leak from the gland but the peripheral conversion to T3 does not increase proportionately. The TPO titre is frequently raised. The thyrotoxic phase if clinically significant is managed with ?-blockers. Anti-thyroid drugs are not warranted as the aetiology is of thyroid hormone leak rather than over-production.

In symptomatic hypothyroidism thyroxine therapy may be necessary until thyroid function recovers. After a first episode there is a 70 per cent recurrence rate in future pregnancies21.

In the absence of a history of recent parturition, but with a painful neck swelling, tenderness on examination of the goitre, fever often with a history of a recent upper respiratory tract infection, the diagnosis of painful subacute 'viral' thyroiditis is likely.

The ESR and CRP will typically be raised, and the T4:T3 ratio will be high for the same reasons described above.

The natural history is similar to that of postpartum thyroiditis, although the prognosis is slightly better with 95 per cent of patients euthyroid at one year. In 2 per cent of patients, recurrence will occur22. In cases of diagnostic doubt, a 24h 123I uptake scan may be useful in differentiating viral thyroiditis from Graves' disease, the former having a low uptake of the radioisotope.

Alternatively colour-flow Doppler ultrasonography may help with the distinction since the thyroid gland in Graves' is hypervascular. Symptomatic relief is the aim of management, usually with non-steroidal analgesia, but high-dose steroid treatment may be required in severe cases.

A ?-blocker is indicated only in cases of symptomatic thyrotoxicosis.

References

1 Vanderpump MP et al. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. The Research Unit of the Royal College of Physicians, the Endocrinology and Diabetes Committee of the Royal College of Physicians and the Society for Endocrinology. BMJ 1996;313:539-44

2 Vanderpump MP, Tunbridge WM. Epidemiology and prevention of

clinical and subclinical hypothyroidism. Thyroid 2002;12:839-47

3 Cannaris GJ et al. The Colarado thyroid disease prevalence study.

Arch Int Med 2000;60:526-34

4 Vanderpump MP et al. The incidence of thyroid disorders in the community:

a 20-year follow-up of the Whickham Survey. Clin Endocrinol 1995;43:55-69

5 Danese MD et al. Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: A quantitative review of the literature. J Clin Endocrinol Metab 2003;85:2993-3001

6 Hak AE et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.

Ann Int Med 2000;132:270-8

7 Chu JW and Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary.

J Clin Endocrinol Metab 2001;86:4591-9

0

8 AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism.

Endocr Pract 2002;8:457-69

09 Zulewski H et al. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls.

J Clin Endocrinol Metab 1997;82:771-5

10 Skinner GR et al. Thyroxine should be tried in clinically hypothyroid but biochemically euthyroid patients. BMJ 1997;314:1764

11 Carr D et al. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin-releasing hormone test using a thyrotrophin assay with measurements of

free thyroid hormones and clinical assessment. Clin Endocrinol 1988;28:325-33

12 Sawin CT et al. Low serum thyrotropin concentrations as a risk factor

for atrial fibrillation in older persons.

NEJM 1994;331:1249-52

13 Uzzan B et al. Effects on bone mass

of long-term treatment with thyroid hormones: a meta-analysis. J Clin Endocrinol Metab 1996;81:4278-89

14 Belfiore A et al. Cancer risk in patients with cold thyroid nodules: relevance of iodine uptake, sex age and multinodularity.

Am J Med 1992;93:363-9

15 Guidelines for the Management of Thyroid Cancer in Adults British Thyroid Association. Royal College of Physicians 2001

16 Ortiz R et al. Effect of early referral to an endocrinologist on efficiency and cost of evaluation and development of treatment plan in patients with thyroid nodules.

J Clin Endocrinol Metab 1998;83:3803-7

17 Salvi M et al. Patients with endocrine opthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities.

J Clin Endocrinol Metab 1990;70:89-94

18 Marocci C et al. Studies on the occurrence of opthalmopathy in Graves' disease.

Acta Endocrinol (Copenh) 1989;120:473-8

19 Muller AF et al. Post-partum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care.

Endocrine Reviews 2001;22:605-30

20 Pearce EN et al Thyroiditis.

NEJM 2003;348:2,646-55

21 Lazarus JH et al. Clinical aspects of recurrent postpartum thyroiditis.

Brit J Gen Pract 1997;47:305-8

22 Iitaka M et al. Incidence of subacute thyroiditis recurrences after a prolonged latency: 24-year survey.

J Clin Endocrinol Metab 1996;81:446-9

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