Primary hyperthyroidism: excess of thyroid hormone due to an abnormality of the thyroid gland.
Secondary hyperthyroidism: excess of thyroid hormone due to abnormal stimulation of a normal thyroid gland.
Thyrotoxicosis (vs hyperthyroidism): thyrotoxicosis can be excess circulating hormone of any source; hyperthyroidism is a result of excess production of new thyroid hormone.
Background and Epidemiology
- Overt (clinical) hyperthyroidism is thought to affect ~1.9% of women (0.8/1000/year) and 0.16% of men (0.14/1000/year)
- Subclinical hyperthyroidism is likely to be higher
There are a wide range of symptoms and signs to possibly find in a patient with thyrotoxicosis:
- Thyroid enlargement
- Diffuse, unilateral, nodular
- Dyspnoea, palpitations
- sinus tachycardia, atrial fibrillation, heart failure, resting tachycardia, use-dependent oedema
- Hyperactivity, emotional lability, insomnia, irritability, nervousness, anxiety, agitation
- Exercise intolerance, fatigue, muscle (mainly proximal) weakness
- Muscle wasting/weakness, proximal myopathy, hyperreflexia
- Change in bowel habit (increased/diarrhoea)
- Heat intolerance, increased sweating
- Warm, moist skin (excess sweating- diaphoresis)
- Increased appetite, weight change (loss or gain or stable despite intake change)
- Infertility, oligomenorrhoea, amenorrhoea
- Polyuria, thirst, generalised itch
- Skin changes e.g. onycholysis, urticaria, diffuse pigmentation, diffuse non-scarring alopecia, palmar erythema,
- Reduced libido; Gynaecomastia
NB There are also some symptoms/signs specific to different causes (see below)
- FBC, U&Es, LFTs
- TSH normal- no hyperthyroidism
- TSH increased- Check free T4
- Normal/low- consider hypothyroidism
- Free T4 high- secondary hyperthyroidism (rare)
- MRI/CT head/pituitary- look for tumour or lesion that might be the cause
- TSH Low- check free T4
- Normal- measure free T3
- Normal- likely transient cause e.g. acute illness
- High- T3 toxicosis (occurs in 10-15%)- further investigation
- If TSH is low and free T3/T4 is high, consider a thyroid uptake scan
- Low uptake
- Single cold nodule – consider thyroid cancer
- Diffusely low uptake- measure thyroglobulin
- If this is high- possible thyroiditis (ectopic thyroid hormone production or excess iodine also possible)
- If low, it is likely that exogenous hormone is the cause.
- High uptake
- Diffusely hot- Grave’s disease
- Single hot nodule- Toxic thyroid adenoma
- Multiple hot nodules- Toxic multinodular goitre
- Thyroid Antibodies
- Grave’s disease
- Toxic Thyroid adenoma
- <5% of all cases of thyrotoxicosis
- More common in women and >40 years old
- Solitary adenoma which secretes thyroid hormone (predominantly T3 thyrotoxicosis- and usually mild thyrotoxicosis.)
- Inhibits TSH secretion and therefore the rest of the thyroid gland shuts down (shrinks/atrophy)
- Symptoms are usually mild. The patient may have a palpable nodule or it may only be detected by thyroid scintigraphy (uptake scan)
- Treatment is usually radioiodine (because the inactive ‘normal’ thyroid fails to take up any radioactive iodine)
- Risk of post-treatment hypothyroidism is relatively low
- Surgery is an alternative
- Toxic Multinodular goitre
- Accounts for about 30-40% of hyperthyroid cases.
- Also most common in women >40 years. May develop from a diffuse (and often euthyroid) goitre.
- In a similar fashion with toxic nodules- multinodular goitre releases thyroid hormone and suppresses TSH secretion
- Patients can be asymptomatic (free T3/T4 may be within normal levels as well but TSH will always be low)
- There will usually be a goitre present with palpable nodules
- Treatment is usually with radioiodine (even if asymptomatic it may be appropriate if TSH is chronically and markedly suppressed as this can be a risk factor for AF and osteoporosis)
- Risk of post-treatment hypothyroidism is relatively low
- Surgery is an option for large, problematic (e.g. tracheal compression) goitres
- TSH-secreting tumour
- Extremely rare
- Consider if there are features of hyperthyroidism with raised TSH and raised thyroid hormone
- There may also be clinical signs of tumour (~80% are macroadenomas) e.g. visual disturbance, headaches
- MRI/CT imaging is the investigation of choice
- Treatment can be with octreotide and antithyroid drugs (+/- beta-blocker) but the mainstay is surgical resection
- Often causes a thyroiditis type picture
An autoimmune disease characterised by hyperthyroidism due to thyroid-stimulating antibodies.
Background and Epidemiology
- Most common cause of primary hyperthyroidism (60-90%)
- Can be associated with other autoimmune disorders (as part of polyglandular autoimmune syndromes) e.g. pernicious anaemia, type I diabetes, vitiligo, autoimmune adrenal insufficiency, systemic sclerosis, myaesthenia gravis, Sjogren’s syndrome, rheumatoid arthritis and SLE
- More common in women (7.5:1), commonly aged 30-50 but general incidence is around 0.8-2/1000 per year
- There is a strong genetic/hereditary component
- Polymorphisms in MHC (HLA-DRB1 and HLA-DQB1); CTLA4, PTPN22, TSHR1 and FCRL3
- It is hypothesised that susceptible individuals may begin produce autoantibodies after an infection (possible that some bacteria e.g. E coli and Yersinia, may have TSHR-like proteins on their cell wall; antibodies produced to fight off this infection may cross react with TSHRs
- Autoantibodies against the TSH-receptor (TRABs) are produced and stimulate the thyroid gland to produce and release thyroid hormone
- Not subject to negative feedback
- The goitre seen in Grave’s is caused not just by the action of TRABs but also due to inflammation/lymphocytic infiltration. Likewise, the ophthalmopathy of thyroid eye disease is due to retro-orbital swelling from lymphocyte and macrophage infiltration (secondary to autoantibody-mediated inflammatory process: orbital fibroblasts are known to express TSHR so this can bind to TRABs)
- NB Smoking is not directly associated with the risk of Grave’s BUT if the patient does have graves, symptoms (particularly eye disease) is worse
- due to increased inflammatory changes
- In addition to symptoms/signs of hyperthyroidism (see here), Graves’ disease also causes a number of other features specific to this diagnosis
- Diffusely enlarged thyroid gland
- there may also be a thyroid bruit (vascular bruit)
- usually soft and symmetrical
- Ophthalmopathy (thyroid eye disease)
- Early thyroid eye disease can be misdiagnosed as conjunctivitis
- Patients may have
- Tearing, gritty sensation, photophobia, eye pain (particularly on movement but also retro-orbital pain), exophthalmos, diplopia, visual loss, impaired eye movements
- Thyroid dermopathy
- inflammatory reaction in the skin can cause non-pitting, pink/purple plaques
- most commonly over the pretibial region (pretibial myxoedema) and over sites of previous trauma
- oedema can also present in the eyelid and cause further eyelid retraction and lid lag.
- Thyroid acropachy
- Again, inflammatory process of the fingertips/nails (indistinguishable from finger clubbing)
- TRAb antibody test positive and clinical features of hyperthyroidism
- Including low TSH and high free T3/T4
- Thyroid uptake scan
- In general, younger patients (<40) are prescribed anti-thyroid drugs:
- NB Usually start with high doses and titrate down to an appropriate maintenance dose
- A beta-blocker may help to control symptoms of palpitations and tachycardia in the mean time.
- Older patients with Grave’s tend to have radio-iodine treatment
- Occasionally, Grave’s can be treated with surgery, although this isn’t common
- Advise to stop smoking
- Glucocorticoids may improve opthalmopathy symptoms
- Rarely, radiotherapy can be used to aid opthalmopathy (surgery is last resort)
- The majority of patients who receive surgery/radioiodine will end up with a permanent reduction in thyroid function and so may require thyroid hormone supplementation
Background and Epidemiology
- Although commonly called SCC in situ, Bowen’s disease differs slightly in its aetiology and pathophysiology. (AK is a truer representation of SCC in situ).
- It is estimated to have an incidence of around 15/100000 per year but can be higher.
- Unlike actinic keratosis, it is much more common in women
- Similar to that of SCC and AK but (in contrast to AK) there is full thickness epidermal involvement (atypical keratinocytes) and mitotic figures can be present.
- Bowen’s disease is also thought to have an inflammatory (as well as genetic) component
- Quite often, there is accompanying inflammatory, mostly lymphocytic, infiltrate in the superficial dermis
- UV exposure
- Other irradiation damage e.g. radiotherapy, photochemotherapy
- Carcinogens e.g. arsenic (could be used as an ingredient in old ointments for psoriasis/asthma
- There is a significant associated with the HPV virus (typically HPV-16)
- Chronic skin injury/conditions e.g. seborrhoeic keratosis
- Slowly growing, usually solitary, patch/plaque with clearly defined borders, scaling/hyperkeratosis, and an erythematous (pink/red) surface.
- Usually several centimetres in size.
- Usually otherwise asymptomatic
- Most commonly found on the lower limbs (shins are common). Otherwise, the head/neck and upper limbs can be sites.
- Occasionally, bowen’s disease may be found in areas not exposed to the sun e.g. sub-/peri-ungual, genital (on the penis this is known as Queyrat’s erythroplasia) or perianal
- Under the dermatoscope:
- Characterised by scaly surface and glomerularly arranged vessels (clustering throughout the lesion)
- Skin biopsy should be taken for the definitive diagnosis
- In contract to SCC and AK, topical therapy e.g. topical 5-fluorouracil (first line) or imiquimod treatments are preferred.
- Cryotherapy may be used as an alternative, particularly in smaller lesions
- Other managements e.g. surgery/curettage and PDT can also be used (the latter particularly for immunosuppressed patients; the former may be suitable for small lesions)
- Radiotherapy can be used if the area is unsuitable for other treatment options
Pre-neoplastic lesion of sun-damaged skin.
- Caused by abnormal skin development due to UV radiation.
- Considered a precancerous form of SCC
- Most common precancerous skin lesion
- It is thought that around 65% of primary SCC and 35% of primary BCC arise from lesions of actinic keratosis.
- The number of patients that progress from AK to SCC is not fully known but estimated between 1-10% (most do not progress)
- More common in men than women
- UV-radiation induced gene mutations in e.g. p53 or p16 tumour regulating genes
- In many ways the histopathology of AK is the same as that of SCC, only milder
- Atypical, pleaomorphic keratinocytes at the basal layer that can extend into the more superficial layers. The epidermis is abnormal (acanthosis, parakeratosis and dyskeratosis)- but by definition this is not full thickness abnormality. Mitotic figures may be present.
- Type I skin type
- UV exposure (including proximity to the equator)
- Consider lifestyle e.g. occupation, holidays, tanning booths etc
- Multiple flat or thickened, scaly/warty, skin-coloured/erythematous lesion
- Commonly on areas of sun exposure e.g. bald scalp, ear, face, nose, back of hands, upper limbs
- Under the dermatoscope actinic keratosis can have the following features
- erythema, with a marked pink-red ‘pseudonetwork’ surrounding hair follicles
- fine, linear-wavy vessels surround the hair follicles too
- the hair-follicle opening itself can be surrounded by a white-yellow halo (keratotic plug)
- white-yellow surface scale
- => often described as a ‘strawberry’ appearance
- NB lesions can also be pigmented and misdiagnosed- presence of the pseudonetwork is often helpful
- dense surface scale with some dot vessels
- lentigo maligna
- seborrhoeic keratosis
- Basal cell carcinoma
- Bowen’s disease
- tends to be a large plaque with a sharp outline, most commonly found on the lower limbs
- Skin biopsy is only really required if this is suspicious of malignancy.
- Treatment isn’t necessarily required, but options are
- topical treatment
- Photodynamic therapy
- Advise the patient about UV protection.