Thyrotoxicosis

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DEFINITION
Excess of thyroid hormone supply to the peripheral tissues, leading to classical clinical manifestations including increased metabolism and fight-flight responses, due to a variety of causes.

Medical therapies are usually effective; surgical reasonable with medical fails or patient chooses such.
- safe but carries special challenges

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EPIDEMIOLOGY
Varies by cause.
But ~2% lifetime risk in women, 0.2% in men.
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AETIOLOGY

Pathogenesis
Any condition that raises T3/T4 levels.
'Hyperthyroidism': overactive thyroid gland.
'Thyrotoxicosis': excess leak of hormones from a non-hyperactive gland.
- long usage often equates these terms.

Sieve

IEMs
Partial T3/T4 resistance (some tissues resistant, others suffer hyperthyroidism).
Toxic MNG (Plummer's disease - an IEM as is caused by enzyme defects) (up to 25%).

Transplacental
Maternal Grave's.

Inflammatory
De Quervain’s Thyroiditis.
Subacute painless thyroiditis.
Hashimoto’s.
Grave’s disease (up to 80% overall).
- autoimmune; antibodies bind to and stimulate TSH receptors --> hyperplasia and overproduction

Tumours
Toxic adenoma (<10%).
Pituitary TSH-secreting tumour (rare).
- sometimes referred to as secondary
Hyperactive carcinoma of the thyroid (rare).
Ectopic TSH, from tumours of lung, breast &c, or struma ovarii (dermoid cyst / teratoma in the ovary).
HCG secreting hydatiform mole, choriocarcinoma.

DPT
Factitious (taking T4,T3 tabs).

Iatrogenic
Supra-optimal T4/T3 therapy.
The Jod-Basedow phenomenon – iodine given to an abnormal thyroid, eg after endemic goitre.
Thyroid storms during surgery.
Drugs – esp amiodarone-associated
- also lithium, metoclopramide, clomiphene, domperidone, iodides (Kelp tabs), contrast medium.

Physiological
Post-partum hyperthyroidism.
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BIOLOGICAL BEHAVIOUR

Pathophysiology
Affect every organ system in the body, but presentation varies by age/comorbidity etc.
--> hypermetabolic state
--> increased BMR induces constiutional symptoms and negative protein balance.
Upregulation of adreno-receptors causes hyperarousal.

Natural history
Varies by specific disorder.

Complications
Cardiac
- often the earliest sign of hyperthyroidism.
Circulatory overload, and increased HR, filling rate and contraction force increases cardiac output.
And hence work of heart.
Arrythmias are common (principally AF)
Cardiac insufficiency may be precipitated or aggravated, esp in elderly.
CHF
Thyrotoxic Crisis
Thyroid storm
Other
Psychosis
Jaundice
Osteoporosis
Inferteility
Cachexia

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MANIFESTATIONS

Symptoms

Local
Varies by cause.

Systemic
Constitutional Symptoms
Weight loss (50%) (+/- incr. appetite 40%).
Fatigue / weakness (60%).
Heat intolerance/sweating (70%).
Excess growth in children.

Endocrine
(Head to toe possibilities).
Hair: fragile hair.
Skin: warm moist sweaty skin (70%).
Brain: irritible/labile, nervous (85%), sleeplessness, psychosis.
Eyes: lid retraction, lid lag (and exophthalmos in Graves)
- sympathetic effect on eyelids
- mucopolysaccharide deposition in the orbit
- usually bilateral
- diplopia
Neuromuscular: tremor (65%), proximal myopathy, hyper-reflexia
Skeletal: bone resorption, hypercalcaemia (50%).
Haem: generalised lymphadenopathy
Resp: dyspnoea (75%) due to weak resp muscles - usually shallow rapid breathing.
Cardio: arrhythmia (15% older people), tachycardia or papitations (90%), flow murmurs, wide pulse pressure, angina/CHF in elderly.
Abdo: frequent BMs, hunger with weight loss, liver may show fatty infiltration / some periportal fibrosis.
Renal: increased sodium / water retention.
Reproductive: gynaecomastia, oligomenorrhoea.

Signs
As per cause.
Consider:
- goitre, thyroid bruit


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INVESTIGATIONS

Biochemistry
Take care interpreting blood results as thyroid hormones alter a number of substrate levels.
TSH is investigation of greatest sensitivity.
Serum T3/T4 are often elevated.
Measuring free rather than bound T3/T4 is more accurate, as transporting globulin is open to influence by other conditions.
Suppressed TSH and elevated free T4 = positive predictive value 95%.

Antibody Testing
E.g. Graves
Thyroid-stimulating immunoglobulin often present
As are antimicrosimal, antithyroblobulin and antithyroperoxidase antibodies.
Thyroiditis
Also increased.
See notes

Haematology
Increased red cell mass, but haematocrit normal due to water retention.

Imaging
RAIU (radioactive iodine uptake) - not routine, as per suspicion.
- diffusely, symmetrically elevated in Graves
- can be elevated or normal with TMNG or STN (focus)
USS - as per suspicion.

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MANAGEMENT

Medical
Either as long term control or preparation for surgery.
Two basic strategies: thionamide inhibition or radiation.

Iodine
Historical interest; first used therapy - now rarely
Reduces iodine transport, organification and release of T4 in the overactive gland.
Aqueous solution, eg 6mg per drop, several drops 3x daily.
Use beyond 2wks is not recommended.

B-adrenergic Blockers
Controls symptoms, but no effect on thyrotoxic state.
Some reduction in peripheral T4-T3 conversion.
Propanolol, metoprolol, atenolol used.
Typically propranolol, 10-40mg 4x daily.

Antithyroid Drugs
Thionamide inhibition.
Propylthiouracil (PTU) and carbimazole most commonly used.
Inhibit synthesis of T4/T3 and compete with thyroglobulin for iodination.
- do this by inhibiting organification of iodine and coupling of iodothyronine.
PTU also reduces peripheral conversion of T4 to T3.
PTU usually started at around 100mg tds, carbimazole 10-30 od.
Low dose carbimazole has fewer side effects and better compliance (od dosing).
PTU is preferred in pregnancy and lactation.
Us. improvement in 2 weeks, euthyroid in 8 (latent period while stored hormones are still released from gland).
Measure serum T3/T4 every 4-6 weeks, TSH less useful as remains suppressed for months.
Taper dose to 30-50% initial dose once control achieved.
Relapse after cessation is common.

Radiation
Radioactive iodine therapy is generally highly effective.
- but takes weeks to months to work.
Controversy over long term effects e.g. carcinogenesis.

Operative
Obviously indicated if suspicious lesion, growth concern, or compressive symptoms
- other hyperthyroid states can be considered for surgery as below
Can do a total, sub-total (leaving a rim of tissue) or near-total.

By Specific Causes

Graves

1. Thionimides
Control 90% in 3-4 wks
Continued for 12-18 months, then tapered, then over half relapse
Side effects include joint pain, rash (5%), rarely agranulocytosis and allergic hepatitis (follow bloods)
Beta blockade often added for symptom control
- potassium-iodide tablets if asthmatic (large dose of iodine temporarily inhibits iodine organification; Wolff Chaikoff effect)
PPT better than carbimazole in pregnancy (avoid the latter)

2. Radioactive Iodine
Used for most. 80-90% response.
- contraindicated by pregnancy; avoid falling pregnant for 12mo+
555 MBq
Works over months.
- patients often become hypothyroid
May temporarily worsen thyrotoxicosis and opthalmopathy (trial steroids).
- covered with carbimazole for a month

3. Surgery
Indicated when:
- suspect nodules or cancer concern
- Pts don't want rad or young children (less responsive and risk of rad more controversial)
- pregnant or lactating and unresponsive
- poor compliance
- relapse
- salvage for unsatisfactory outcomes or side effects
- opthalmopathy: may be slightly more effective in improving eye signs
- emergency of thyroid storm
- cosmesis for enlarged goitre
Can prepare pts in <6wks, allows immediate relief of mass effect and long term cure in 99%
Surgery may have cost benefit over other therapies but difficult to factor in all costs; anyway, acceptable. 
Disadvantages (reduced risk with experienced surgeon):
- risks to nerves (chronic vocal cord dysfunction in 5%)
- risk to parathyroids (chronic in ~4%, temporary 8%)
--> temporary Rx with calcium and calcItriol for 6-8 wks until fx returns.
--> mitigated by mincing glands and placing in muscle (takes 6-8wks to take, success in ~100%)
- bleeding or infection
- need for thyroid supplementation
- anaesthetic risk
- scar (4-8cm), can be placed in a skin crease

4. Notes on pre-op preparation
Evaluate co-existing cardiac, resp, renal disease
Thionamide inhibition using ptu or carbimazole
- e.g. ptu 50-100 mg po tds
- carbimazole 10-15 mg tds then 5 mg tds once euthyroid.
- educate pt on risks
- if euthyroid at 3-4 weeks, fine, else increase dose up to 600 mg total per day
- discontinue at surgery
Check calcium
Rule out pregnancy
Beta-blockers if pt has symptomatic tachycardia, hypertension, tremor, sweating
- propranolol preferred; also inhibits peripheral conversion of T4 to T3; e.g. 40-320 mg/day, dosed tds to qid
- aim for a stable heart rate ~80.
- propranolol continued intraoperatively for safety (risk of thyroid storm), and post-op weaned for a week if not given thionomides

Alternative agents
Iopanoic acid is an alternate agent; blocks conversion of T4 to T3, decreasing hypothyroid state.
- begins within 24h, peaks at 14d.
Administration of concentrated iodine also has pre-op value
- inhibits release of T4 and T3, decreasing hypothyroid state.
- begins within 24h and peaks at 14d/
- thereafter, acts as a substrate and hyperthyroidism returns.
--> best if pt already euthyroid when given to reduce rebound hyperthryoidism.
- given 10-14d prior to surgery and then discontinued; given supersaturated potassium iodide diluted in a glass of water, fruit juice, milk or broth, or Lugol solution.

5. Choice of operation
Either total or subtotal.
- 'near-total'; even when aiming to do a total, a sliver may be left behind, e.g. next to parathyroids, at ligament of Berry and at the surgicalpoles.
- remnant size poorly correlated with euthyroid outcome anyway.
Recurrence after subtotal is problematic; 5-20% cf 1% for total.
- and can occur 1-30y after surgery, and operation riskier.
--> therefore do a Total thyroidectomy
--> but ok to leave a tiny rim of thyroid around parathyroids (esp as they are often vascularized from the anterior aspect)
- sup. parathyroids more regularly located than inferiors, which may be displaced by goitre.
- if any concern about vascularity, reimplant in muscular pocket.
--> a single viable parathyroid can do the job.
Do direct laryngoscopy first to document vocal cord function.

Toxic MNG
Can have a long subclinical phase.
(More common in areas of iodine deficit)
Show as hot nodules
- may be autonomous or not autonomous (responding to TSH suppression).
- thyroxine suppression for toxic MNG generally infeffective.
Surgery
These are rarely malignant; like 2-3%
Same treatments for TMNG as Graves:
- thionamides, RAI, Surgery
Remission less common by thionamides and RAI, recurrence greater.
Majority treated with RAI first;
- often large doses and repeat treatments
- should be favoured more for those with poor health / not good candidates
Surgery preferred for:
- large goitres, compression symptoms
- and reasonable in all cases of TMNG
Similar approach for Graves; even less concern about small remnants.
--> resolution prompt and permanent.
Pre-op preparation same as for Graves
- supplementation with iodine is not beneficial, because MNG is not homogenously hypervascular.
- iodide supplementation can exacerbate hyperthyroidism (Jod-Basedow)

Amiodarone-associated thyrotoxicosis
Iodine rich, class III antiarrhythmic widely used.
- expands the iodine pool; form of the Jod-Basedow effect
Typically in patients with some preexisting goitre, often subclinical.
- but can also induce a chemical thyroiditis and release of hormone in absence of pre-existing disease.
Can exacerbate underlying cardiac rhythm problem that it was initially prescribed for.
Notoriously refractory to medical management.
No treated well with radioactive iodine; cessation of amiodarone may help but may not be preferable if cardiac arrhythmias require it.
Surgical thyroidectomy is prompt and effective therapy.
Necessary to do a thorough pre-op workup; most do well and surgery is commonly the most effective option.

Solitary Toxic Nodule
Benign monoclonal follicular adenomas
<1% are cancer.
May progress from a hot nodule to an autonomous hot nodule, to STN.
Often when 2.5-3cm.
By definition, not suppressible by thyroxine administration.
If a hot nodule under observation continues to grow to 3cm+, or clinical concern
--> lobectomy
After lobectomy, most pts become euthyroid.
FNA can help but is unlikely to avert surgery.
Low risk of malignancy but surgery also rules this out.
If not worrisome, the RAI is an option.
- poor candidates or surgery averse pts.
- neeeds large doses and high relapse rates.
Surgery is a lobectomy.
- nodulectomy can compomise excision margin; not recommended.
- no role for frozen section.
Pre-op Preparation same for Graves.


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References
Harrison's.
Doherty and Skogseid's Surgical Endocrinology.
Cameron 10th
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