Making best use of the endocrine lab
Consultant Dr Anthony Robinson outlines the more common endocrine conditions, and how GPs can best use the available tests to diagnose them effectively
ndocrinological testing is easier if you know the question you are asking, know how to do the test and what to do with the result. The main principle of interpreting results is to remember the feedback loops. This can be illustrated by the commonest requested test: thyroid function. If the patient is becoming hypothyroid because of gland failure the thyroid stimulating hormone (TSH) will rise as the gland fails. The message is increasing from the pituitary gland because of a reduction in thyroxine production. But if the pituitary gland is at fault then no extra message will be sent, as it is the failure of the messenger and not the gland (ie, low normal TSH, with low free T4). This principle holds good for all endocrine testing in deciding the location of the disease process.
Furthermore, use the laboratory to help you. If you give clear clinical details, and ask a question, this will allow the clinical staff to help to interpret your results and suggest further investigations if clinically relevant. If no clinical information is given then a simple result will be returned which you will have to interpret!
Thyroid function tests
If hypothyroidism is suspected and TSH is raised but free T4 or T3 is normal, the laboratory will suggest repeating the test in six to 12 weeks. TSH may rise due to inter-current illness, and on repeating may be normal. When repeating the tests, however, ask for thyroid antibodies as well. If these are raised the patient is inevitably going to become hypothyroid, and thyroxine should be started even though the patient is in a state of compensated hypothyroidism (raised TSH, normal T4). If the TSH is only raised to between 5 and 10, you could advocate continued monitoring until TSH exceeds 10 or the patient becomes symptomatic, but I am a kind person by nature and try to stop my patients suffering unduly.
If hyperthyroidism is the clinical diagnosis, then the TSH will be suppressed with a raised T4 or T3 (depending on which test the laboratory performs). This may be Graves' disease (usually with positive thyroid antibodies), or due to a multi-nodular goitre or single adenoma (negative thyroid antibodies). The latter needs surgery or radioactive iodine to return to normality, while Graves' disease has an approximately 50 per cent chance of going into remission with antithyroid drugs.
Occasionally patients may develop a thyroiditis, usually viral in origin, associated with a painful swelling of the thyroid gland. There is an initial release of thyroxine (hyperthyroid phase), followed by a stunned phase where the patient may develop symptoms of hypothyroidism. Usually the thyroid recovers, but may remain hypothyroid long-term, especially if the antibodies are positive. During the thyrotoxic phase ?-blockers are a useful treatment, if severe the patient may require steroids (endocrine opinion should be considered if severe).
To further illustrate the feedback loop, if TSH is raised and T4 raised then this is consistent with the rare TSHoma in the pituitary.
Pituitary disease is rare and mainly effects the anterior part of the gland. This is responsible for control of thyroxine, cortisol and the sex hormones. It is the site of production of prolactin and growth hormone.
If excess growth hormone is suspected then IGF-1 (stimulated by growth hormone) is a good screen to exclude the condition. If low-normal then the disease is not likely, if raised then a glucose tolerance test with measurement of growth hormones will confirm the diagnosis. This should be also be performed if clinically suspicion is high, but IGF-1 is only at the top of the normal range. A random growth hormone is useless as a diagnostic tool due to the pulsatile nature of growth hormone.
· Male. Erectile dysfunction is common and rarely due to testosterone deficiency. If the patient complains of a loss of libido and erectile dysfunction, then measuring a 0900 hours testosterone level with sex hormone binding globulin (SHBG) is indicated. SHBG gives an indication of levels of free testosterone, which only a few laboratories in the country can offer. Testosterone like cortisol has a diurnal variation so is best measured at a standard time.
If testosterone is low then measure follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin and ferritin (excludes the rare haemochromatosis). If prolactin is raised then a pituitary microadenoma is the likely cause as prolactin has a negative feedback on testosterone production. If LH and FSH are low then there is a pituitary problem (hypogonadal hypogonadism). If FSH and LH are raised then there is an end organ problem (previous trauma, mumps etc). The latter patients just need testosterone replacement, depending on age and patient wishes. Remember that low testosterone is a cause of osteoporosis.
· Female. Amenorrhoea will need investigating if greater than six months, with a previous regular cycle. Pregnancy should obviously be excluded, and then FSH, LH and prolactin sent. Hyperprolactinaemia will result in amenorrhoea, with breast tenderness and galactorrhoea. If LH and FSH are raised this is consistent with early menopause, if low then there is pituitary disease. Oestradiol levels do not add to the information and are only of use in monitoring oestrogen implant.
Polycystic ovarian syndrome (PCOS) is a clinical diagnosis, which may have raised LH:FSH ratios, with raised androgens (androsteriondione, DHEAS and testosterone) with a normal SHBG. Most women with PCOS don't have a regular cycle and this is done to exclude the menopause or pituitary disease rather than confirm the diagnosis.
If you are trying to determine ovulation then a 21-day progesterone needs to be sent if a regular 28-day cycle. The day may need to be amended in patients with shorter or longer cycles.
Prolactin is a stress hormone and can be raised by difficult venepuncture as well as certain drugs (for example, antiemetics and antipsychotics) and is raised in hypothyroidism, severe renal or liver failure. A stressful venepuncture may lead to prolactin being as high as twice the normal range. Drugs may raise the level into the thousands. For a microprolactinoma the levels will depend on the laboratory, but may be 2,000-6,000, and more than 10,000 for a macroprolactinoma.
A non-functioning tumour causes stalk compression and may lead to prolactin levels of 1,000-3,000.
Macroprolactin (an apparently inactive aggregate) can interfere with the assay and give a false reading, so needs to be excluded by the laboratory. If the prolactin remains high despite these moves the patient needs an endocrine review.
Cushing's syndrome can be caused by pituitary, adrenal or ectopic disease. It is diagnosed by finding raised 24-hour urinary-free cortisols, which should be performed twice if clinical suspicion is high. An overnight dexamethasone suppression test (1mg dexamethasone at midnight, followed by a 0900 cortisol) is another method. Most laboratories would expect a cortisol value below 50mmol/l to exclude Cushing's.
Addison's disease is the commonest form of cortisol deficiency. The patient usually has signs of pigmentation as well as symptoms. A 0900 cortisol can help, and is probably diagnostic if below 100mmol/l and excluded if above 550mmol/l (laboratories may vary). A Synacthen test will confirm the diagnosis.
This can be performed in the surgery using an IM injection. There is a remote possibility of anaphylaxis. If hypocortisolism is diagnosed an ACTH sample should be sent to confirm Addison's disease (high result), or pituitary disease (low result).
Primary hyperparathyroidism is the third commonest endocrine disorder. It is diagnosed by the usual finding of a raised calcium level with a low-normal phosphate, and normal alkaline phosphatase. A parathyroid hormone level is then requested, and if this is high-normal or raised the diagnosis is confirmed.
There is rarely an endocrine cause for hypertension. If the patient is young without a family history and has significant hypertension then Conn's syndrome should be excluded. Urea and electrolytes can help (off diuretics, angiotensin drugs). Potassium is usually low or at the bottom end of the normal range.
Phaeochromocytoma is very rarely the cause of sustained hypertension. Ask for 24-hour urine for catecholamines. These must go in an acid-containing container. If raised avoid ?-blockade due to the risk of precipitating a crisis.
When a patient complains of excessive sweating/flushing, if investigation appears appropriate, ask for a 24-hour urine for 5HIAA, and catecholamines. Checking sex hormones may be relevant depending on age and history.
Making best use of the endocrine lab
· Men with low testosterone with raised prolactin (suspect pituitary microadenoma)
· Men with low LH and FSH (suspect hypogonadal hypogonadism)
· Women with hyperprolactinaemia
· Women with low LH and FSH (suspect pituitary disease)
· High prolactin despite lab removal of macroprolactin
· Raised 24-hour urinary free cortisols (suspect Cushing's syndrome)
· Cortisol at 0900 hours above 50mmol/l after overnight dexamethasone suppression test (suspect Cushing's syndrome)
· Hypocortisolism (suspect Addison's disease or pituitary disease)
· Raised calcium, low-normal phosphate and normal alkaline phosphatase with a high-normal or raised PTH (suspect primary hyperparathyroidism)
· Raised 24-hour urine for catecholamines (suspect phaeochromocytoma)
Blood tests that need to be in lab within 30 minutes
· Adrenocorticotropic hormone (ACTH)
· Parathyroid hormone (PTH)
Hormones to be measured at 0900 hours