Requesting and Management of abnormal TFTs.

Requesting and Management of abnormal TFTs. At the request of a number of GPs I have produced summary guidelines surrounding thyroid testing. These have been agreed with our Endocrinology leads Dr Bell and Dr Kong. We all come across abnormal TFTs as the prevalence of thyroid disease in women is at least 1 in 100 in men it is 10 fold less. I like to think of the thyroid hormones like the accelerator pedal of the car, too much and we are over revving and too little and we are not ticking over. Clinically thyroid disease is hard to diagnose and lab results make it that bit easier; with them retrospectively thyroid disease may be obvious. As ever please call to discuss any unusual results whenever you are unsure. Tests used and analytical quality At SNHSFT we routinely measure TSH, which is the most sensitive marker of thyroid dysfunction (ref range 0.1 4.0 mu/l) as well as the thyroid hormones FT4 (ref range 10-22 pmol/l) and FT3 (ref range 3.5-6.5 pmol/l). Thyroid peroxidase antibodies (TPO ref range <60 iu/ml ) are also available to help establish if the thyroid disease is autoimmune. We send away both TSH receptor antibodies and very rarely thyroglobulin. The thyroid secretes T4 and T3 in a ratio of around 12:1 most of the hormone is protein bound; a large proportion of T4 is deiodinated to T3 by the liver and kidneys changing the circulating ratio to 3:1. Total T4 levels are 60 160 nmol/l of this 0.015% is non-protein bound free T4 reference range 10-22 pmol/l (over 6000 fold less than the total hormone!). Total T3 levels are 1.2-2.7 nmol/l of this 0.33% is non-protein bound free T3 reference range 3.5 6.5 pmol/l (around 1000 fold less than the total hormone!). Free hormone assays are prone to interference but are the best they ever have been. Interference includes non-thyroidal illness, liver disease, kidney disease, common drugs such as aspirin or heparin, heterophilic antibodies and rheumatoid factor. How well the lab measures an analyte is indicated by the precision (or CV) of the quality control material, where the test is measured on the same sample over time. The table below clearly shows that TSH is easily measured; FT3 is pretty good whereas FT4 and TPO are measured quite poorly. The column difference to signify a change shows that for an analytical change in FT4, for values within the reference range, a change of around 4.0 pmol/l or around a third of the range is needed, where as a change in TSH at the very low level only requires a difference of 0.006mu/L to suggests an analytical change. Biological variation is another point to consider but would stretch out this story; suffice to say TSH is the best test analytically and the best clinically as a marker of thyroid disease. Test TSH FT4 FT3 TPO QC Mean Outcome range (95%) of repeat Difference to signify a CV % level results change 0.07 3.3 0.065 0.075 GREAT Precision! 0.006 4.48 2.9 4.22 4.74 GREAT Precision 0.36 21.07 2.9 19.9 22.3 GREAT precision 1.7 8.66 9.5 6.94 10.26 POOR 2.3 16.1 8.5 13.38 18.82 POOR 3.8 28.0 5.8 24.76 31.24 POOR 4.5 3.2 5.1 2.88 3.52 OK 0.45 6.5 2.9 6.13 6.89 GOOD 0.52 12.6 2.6 11.92 13.28 GOOD 0.91 129.1 11.2 71.4 129 POOR 80.6 296 6.5 257.8 334.2 POOR 107

Workload Annually we measure 82,000 samples for TFT (TSH and FT4) investigating for thyroid disease and monitoring those on carbimazole, we also measure 12,500 tests for TSH per annum for those patients on T4 replacement. We also do around 1000 FT3 tests per year and around 800 thyroid peroxidase (TPO) tests per year but this is falling. Testing strategy. Many UK labs measure only TSH when investigating thyroid disease in primary care. Clinically TSH has an inverse logarithmic relationship to FT4 such that TSH is the first abnormal result in the development of hypo or hyperthyroidism. Hence in the vast majority of patients it is the most sensitive test for thyroid disease. We have also seen that analytically it is the most robust. However during treatment it does take a while to return to the normal range after the free hormones have been corrected. Front line TSH testing is however unreliable in pituitary disease which is one thousand times less common than thyroid disease. If hypopituitarism is suspected then both FT4 and TSH should always be requested with cortisol, prolactin, LH, FSH and either testosterone or oestradiol. Hypopituitarism should be considered clinically or when there has been a lowering of FT4 with a low/normal low TSH. Thyroglobulin Thyroglobulin should only be requested by a thyroid specialist. Although a theoretical great marker of thyroid tissue and thyroid cancer the main problem is assay interference. A recent study of 47 patients with undetectable thyroglobulin results after total thyroidectomy for differentiated thyroid cancer found that after re-assessing on different assays and looking at heterophillic antibodies and thyroglobulin auto-antibodies only 9 results were confirmed to be undetectable. This type of robust investigation is not routinely carried out by labs due to cost and time, such that until the assay is free from these common interferences measurement should be avoided. Some labs refuse to measure Thyroglobulin or have anything to do with it. Hypothyroidism. Overview of thyroid disease: Thyroxine replacement should usually only be initiated when TSH has increased to >10 mu/l. Results should be confirmed prior to treatment where TSH is between 10-20 and when FT4 is not <10pmol/L. Once on replacement treatment is life-long. Reconsider the diagnosis of hypothyroidism if a patient may have had thyroiditis or if they were recovering from an acute illness. When treating new patients with cardiac disease or risk factors for cardiac disease it is better to start replacement at a lower dose such as 25 or 50mcg o.d. and assess TSH and symptoms after 6-8 weeks then altering the dose if needed with 25mcg changes. In new hypothyroid patients without cardiac risk a starting dose of 100 mcg o.d with a 6 weeks review is acceptable. As a general rule the average patients requires 100 mcg o.d. however at extremes of weight or for other reasons the required dose can vary to normalise TSH and improve symptoms. In pregnancy an increase of upto

50 mcg daily may be needed, as a general rule a dose increase by at least 25% should occur in the first trimester independent on the TSH result. Thyroxine (T4) alone, prescribed as levothyroxine, should be used in the treatment of hypothyroidism. Tri-iodothyronine (T3) is not recommend or the use of Armour thyroid, as it is inconsistent with normal physiology, has not been scientifically proven to be of any benefit to patients and may be harmful. T3 is only occasionally used for example when treating myxoedema coma. Only TSH measurement is required when assessing patients on replacement, results of between 0.05 4.0 suggests adequate replacement therapy. Fine-tuning of TSH levels inside the reference range may be needed, often aiming for a TSH of around 1.0 miu/l with normalisation of symptoms is a successful strategy. Reduce the T4 dose when TSH is <0.05 miu/l as TSH levels below this increases bone loss, fracture and atrial fibrillation risk. Re-assess TSH levels after 6-8 weeks. When TSH is >4.0 mu/l assess compliance and dose and repeat in 6-8 weeks if dose or compliance is changed. Around 80% of oral T4 is absorbed and it is best taken on an empty stomach. Absorption may be affected by iron replacement and malabsorption. The half-life is around 7 days. Increased clearance occurs with phenytoin and carbamazepine and possibly oestrogen treatment. Upto 40% of patients on long term T4 are not optimally replaced and an annual TSH is appropriate on patients on T4. Patients with continuing symptoms after normalisation of TSH should be further investigated to determine the presence of another disease. Subclinical hypothyroidism (normal FT4 with a raised TSH but <10 miu/l) is present in around 5% of adults and upto 15% of women >55 years of age. This can usually be monitored annually. T4 replacement may occasionally be considered if results are confirmed and the patient very symptomatic or those seeking to become pregnant (in this case lower limit above 3.5miU/L may be considered as a cut-off for treatment) otherwise replacement should only commence when TSH has increased to >10miU/L. Secondary hypothyroidism (hypopituitarism) should be managed by an accredited Endocrinologist, the extent of hypopituitarism requires to be fully established prior to thyroxine treatment including correction of any cortisol deficiency. Hyperthyroidism Classically TSH is suppressed to <0.01 mu/l with a raised FT4. The most common cause will be Graves disease. However if symptoms are acute it could be due to thyroiditis which should be selflimiting often inducing hyper then hypothyroidism followed by euthyroidism which may overall take upto 5 months to normalise. Overt hyperthyroidism should be managed by a clinician with adequate experience able to evaluate the various causes and to offer various treatment options. Monitoring of TFTs of those on carbimazole or propylthyiouracil should be every 1-3 months until stable and annually if on long term treatment. Carbimazole can cause bone marrow suppression so monitoring should include clinical awareness of infections as well as a FBC pre-treatment; routine monitoring of FBC does not seem to be helpful. It may be worth considering measuring LFTs on patients treated with PTU as the risk of severe fulminant hepatic failure is 1 in 10,000.

Subclinical hyperthyroidism (TSH <0.01 mu/l with normal thyroid hormones) often occurs in the elderly. If the patient has any thyrotoxic symptoms, a goitre or ischaemic heart disease the patient should be discussed with an Endocrinologist. Repeat testing!! The UK spends around 30 milion annually solely on TFT testing. If on treatment repeat testing after 6-8 weeks to allow the thyroid gland to respond to a change of treatment. In other cases repeat in 6-12 months. Test more frequently only those with symptoms or who fulfil testing criteria e.g. Type 1 diabetes (NOT type 2), those taking Lithium or amiodarone. Guidelines from NICE surrounding TFT requesting: Referral guidelines for suspected cancer: In patients with a thyroid swelling without stridor or any of the features (a solitary nodule increasing in size, a history of neck irradiation, a family history of an endocrine tumour, unexplained hoarseness or voice changes, cervical lymphadenopathy, very young (pre-pubertal) patients, patients aged 65 years and older) then thyroid function tests should be requested. Patients with hyper- or hypothyroidism and an associated goitre are very unlikely to have thyroid cancer and could be referred, non-urgently, to an endocrinologist. Those with goitre and normal thyroid function tests who do not have any of the features indicated above should be referred non-urgently. Fertility: Women with possible fertility problems are no more likely than the general population to have thyroid disease and the routine measurement of thyroid function should not be offered. Estimation of thyroid function should be confined to women with symptoms of thyroid disease. Depression: When prescribing lithium: monitor renal and thyroid function before treatment and every 6 months during treatment (more often if there is evidence of renal impairment). Lipid modification: Only when a dyslipidaemia is present should TFTs be assessed as a potential secondary cause of dyslipidaemia (it is estimated that 4% of dyslipidaemic patient have hypothyroidism). Bipolar disorders: Assess Thyroid function on presentation and after treatment and if disease progresses. Type 1 diabetes in children, young people and adults: Assess thyroid disease at diagnosis and annually thereafter until transfer to adult services. Heavy menstrual bleeding: If this is the only symptom do not assess TFTs (or other hormones). Chronic Heart Failure: Measure in these patients to evaluate aggravating factors. Amiodarone patients should have a 6 monthly review including TFTs. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): TFTs should be done. QOF indicator: Percentage of patients with Down's Syndrome aged 18 and over who have a record of blood TSH in the previous 15 months (excluding those who are on the thyroid disease register).

Percentage of patients with a new diagnosis of dementia to have thyroid function tests recorded 6 months before or after entering on to the register. General summary points: Thyroid disease must be diagnosed with a blood test as symptoms are not specific enough. Conversely results are best not interpreted in isolation; always ask if the results are clinically consistent. The degree of thyroid result abnormality does not often correlate with clinical severity and for this reason abnormal results are not routinely telephoned. Asymptomatic opportunistic screening (except for congenital hypothyroidism) is not justified. When required thyroxine replacement should usually only be initiated when TSH has increased to >10 mu/l. Hyperthyroidism may be managed by general practitioners very experienced with the disease. Refer to an endocrinologist if needed. All women with a past history of postpartum thyroiditis should be offered an annual check of thyroid function and should also be screened prior to and at 6 to 8 weeks after future pregnancies. A very recent identified form of interference which is relevant to some labs which measure TSH using a fluorescence label is the possible interference in TSH measurement in patients undergoing fluorescein dye angiography. This is because small amounts of fluorescein can remain the body for up to 48 to 72 hours post-treatment and in the cases of patients with renal insufficiency, retention could be much longer. This interference can result falsely depressed values when tested with the tested using the Siemens TSH assay. With fluorescein interference, observed TSH values can be as low as <0.01 miu/l. These falsely low values are important when monitoring for thyroid cancer as the physician may determine that adequate suppression of TSH has been obtained. Samples should be resubmitted post fluorescein clearance to ensure there is no interference with TSH results. As a simple rule wait a week prior to a blood test after using a fluorescein dye in angiography. References Used http://www.british-thyroid-association.org/news/docs/hypothyroidism_statement.pdf Accessed 4th Jan 2013. www.thyroidmanager.org for everything you want to know about the thyroid.