Hypothyroidism

AETIOLOGY

1. Iodine deficiency: most common cause world-wide; uncommon in Australia.
2. Hashimoto (Autoimmune chronic lymphocytic) thyroiditis: most common cause in Australia.
3. Hypothyroid stage (can be permanent) of any thyroiditis – post viral, autoimmune etc.
4. Drugs:
   1. CBZ/PTU, lithium, RAI, amiodarone. 
5. Transient
   1. Subacute thyroiditis
   2. Silent thyroiditis
   3. Postpartum thyroiditis
   4. Early postablative therapy
      1. Preceding history of viral infection, pregnancy or radioiodine ablation
      2. Evidence of an enlarged tender thyroid on examination (subacute thyroiditis)
6. Infiltrative diseases:
   1. Reidels thyroiditis
   2. Scleroderma
   3. TB
   4. haemochromatosis
7. Neonatal/congenital
   1. Thyroid agenesis/ectopia
   2. Genetic disorders affecting thyroid hormone synthesis
   3. Transplacental passage of TSH receptor blocking antibody
      1. Family history of thyroid disease/hypothyroidism
      2. Maternal medication use during pregnancy
8. Postablative therapy or surgery
   1. Radioiodine therapy
   2. Thyroidectomy
      1. History of previous radioiodine therapy or thyroid surgery
      2. Evidence of a surgical scar or skin changes suggestive of previous external neck irradiation on examination

Clinical Features

• Symptoms are influenced by the severity of the hypothyroidism, as well as its rapidity of onset. 
• Slow failure of thyroid function caused by autoimmune thyroiditis typically presents insidiously over years.
• spectrum of clinical presentations range from clinically unapparent disease to myxoedema coma, a rare endocrine emergency
• Given the poor specificity of the symptoms of hypothyroidism, patients may manifest clinical features that are suggestive of the diagnosis without any abnormality of thyroid function. 
• Thyroid hormone supplementation in such a situation has shown no clear response and is not justified.

Appearance	Puffy and pale facies Dry, brittle hair Sparse eyebrows Dry, cool skin Thickened and brittle nails Myxoedema – fluid infiltration of tissues
Energy and nutrient metabolism	Cold intolerance Weight gain Fatigue
Nervous system	Headache Paraesthesias (including carpal tunnel syndrome) Cerebellar ataxia Delayed relaxation of deep tendon reflexes
Cognitive/ psychiatric	Reduced attention span Memory deficits Depression
Cardiovascular	Bradycardia Diastolic hypertension Pericardial effusion Decreased exercise tolerance
Musculoskeletal	Myalgias Arthralgias
Gastrointestinal	Anorexia Constipation
Reproductive system	Irregular or heavy menses Infertility

Investigations:

• Any raised TSH should be repeated in 2-8 weeks time.

• Elevated TSH with reduced T4 confirms hypothyroidism.
• Elevated TSH with normal T4 is subclinical hypothyroidism.
• If normal TSH with reduced T4:
  • Consider HPA causes if there are features of clinical hypothyroidism with other features of HPA failure – eg electrolyte disturbances, polyuria, hypotension, bitemporal hemianopia. If Addison is suspected, it is important to correct this first prior to thyroxine therapy as otherwise it can exacerbate the symptoms.
  • Seen transiently with any illness. Repeat TFT when well. 
• Raised TSH with raised T4: can see this in patients taking thyroxine who are generally non-compliant, then take a big dose right before getting a TFT checked.

Thyroid antibody testing

• Anti-TPO should be tested:
  • if raised in the setting of chronic hypothyroidism, this confirms thyroiditis (usually Hashimoto in this setting – are positive in 95% of patients with autoimmune thyroiditis. 
  • TPO positivity is seen in 10–15% of the general population and is not an indication for treatment where there is no biochemical abnormality of thyroid function

• Anti-TG is rather non-specific and is now reserved for thyroid cancer follow-up.

Imaging:

• diagnosis of hypothyroidism in itself is not an indication for thyroid imaging
• Thyroid USS is only required if clinically there is a nodule / goitre.
• No role for radionuclide imaging unless there is a nodule or goitre (see approach to thyroid nodules).

MANAGEMENT

Treat any underlying causes (stop precipitating drug, iodine supplements etc.)

Levothyroxine replacement

• average daily dose of thyroxine is 1.6 µg per kilogram body weight
• storage temperatures of 8°C to 15°C were required to maintain potency.
  • Eltroxin does not have to be stored at refrigerated temperature, however it is essential it is kept below 25 degrees Celsius
• Starting dose is 50-100mcg per day. Consider 12.5-25mcg per day for older patients or those with a cardiac history. Take dose on an empty stomach 30min prior to food.
• Aim of therapy is resolution of symptoms and TSH in the normal range. Aim for lower limits of reference range in pregnancy, and in patients who are symptomatic despite TSH being in the high-normal limits of reference range. Also, if symptoms worsen with thyroxine therapy then consider HPA causes with Addison disease.
• TSH should be checked minimum of 4 weeks when initiating therapy or changing doses. 
• LT4 has a half-life of 1 week: can do alternate day dosing increases if it’s a hassle to break pills in half.
• Typically, thyroxine is administered on a daily basis. However, due to its half life of approximately 1 week, weekly administration is occasionally an option where compliance is an issue. 
• Adjustments: thyroxine dose should be increased by 12.5–25 µg/day if the TSH remains above target. In Australia
• Its long half life also means dosing should be adjusted at an interval of no less than 6–8 weeks to allow a steady state to be achieved
• Once stabilised, TSH can be monitored q6-12 months.
  • unless there are situations that may alter thyroxine requirements (eg. significant weight change, commencement of a proton pump inhibitor or the oral contraceptive pill, or plans for pregnancy).

Drug Interactions

• Patients should be instructed to take their thyroxine on an empty stomach, at least half an hour before other drugs (this includes espresso coffee).
• Medicines that may increase thyroxine requirements include:
  • the oral contraceptive pill
  • anti-epileptic medication (eg. carbamazepine, phenytoin)
  • some antibiotics (eg. rifampicin)
  • the new tyrosine kinase inhibitors (eg. imatinib).
• Drugs that have been shown to reduce absorption include:
  • calcium carbonate
  • ferrous sulphate
  • multivitamins
  • cholestyramine
  • phosphate binders
  • proton pump inhibitors.
  • Malabsorptive conditions 
    • small bowel bypass
    • inflammatory bowel disease
    • coeliac disease
    • lactose intolerance
    • Helicobacter pylori infection and chronic gastritis

Pregnant Patients

• Unless contraindicated, all pregnant women should supplement with iodine 150mcg per day.
• bHCG has thyrotropic properties – the reference range of TSH reduces in pregnancy:
  • 1^st trim: 0.1-2.5
  • 2^nd trim: 0.2-3
  • 3^rd trim: 0.3-3
• All pregnant woman with TSH outside these ranges should be referred to an endocrinologist.
• Overt hypothyroidism:
  • Prevalence 0.3–0.5%
  • TSH >2.5 with low T4 or TSH >10 irrespective of T4 level
  • is associated with adverse pregnancy outcomes and impaired fetal neurocognitive development ^🡪 Treatment with levothyroxine is recommended. The goal is to normalise maternal serum TSH values within the trimester specific pregnancy reference range
• Subclinical hypothyroidism (SCH)
  • Prevalence 2–2.5%
  • TSH between 2.5–10 with normal T4 levels
  • Evidence is variable as to the effect of SCH on pregnancy and the fetus
    At this stage, the associated risk of obstetric complications has been more clearly demonstrated than the risk of neurocognitive deficits in the fetus.
  • treatment with levothyroxine to normalise maternal serum TSH or 4 weekly monitoring of TSH. Obtain TPO Ab levels while awaiting specialist review
• Known history of hypothyroidism (prior to pregnancy)
  • Levothyroxine adjustment should be made as soon as pregnancy is confirmed
    Aim to normalise TSH levels (ie. TSH <2.5) by increasing levothyroxine by two additional tablets weekly or by 25–30% and monitor thyroid function test  4 weekly

Subclinical Hypothyroidism in Non-Pregnant Woman

• No formal guidelines – following is suggested from AFP
• persistently elevated serum TSH with thyroid hormone levels within the reference range.
• is detected in 4–8% of the general population 
• 15–18% of women aged more than 60 years.
• Approximately 4–18% of patients will progress to overt hypothyroidism each year with an increased risk with the following factors:
  • presence of antithyroid antibodies (twofold increase in risk)
  • presence of a goitre
  • more pronounced TSH elevation
  • history of radioiodine ablation therapy, external radiation therapy and chronic lithium therapy.
• risks of not treating subclinical hypothyroidism:
  • progression to overt hypothyroidism, cardiovascular effects, dyslipidaemia and neuropsychiatric effects.
• Recommendation:
  • Levothyroxine therapy is usually recommended where the serum TSH is greater than 10 mIU/L.
  • TSH-  5–10 mIU/L and the patient is symptomatic, a 3–6 month trial of levothyroxine replacement is appropriate. 
  • TSH 5–10 mIU/L and there is the presence of anti-TPO antibodies, or a goitre, an alternative option to thyroxine therapy 
• Where treatment is commenced, an initial dose of levothyroxine of 25–50 µg/day can be used with a target TSH level between 1.0 and 3.0 mIU/L. 
• The TSH level should be measured in 6–8 weeks after commencement of therapy, and annual reviews once the TSH level is stable.