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Bay Four

          Patterns, pearls and practical medicine

Odd thyroid function tests

  • For odd or borderline TFTs – always repeat the test
  • Erratic TSH levels may be due to interfering foods, medications or inconsistent treatment
  • Some drugs like steroids can interfere with conversion of T3 to T4
  • Most labs send TSH and then T4 if abnormal (sometimes T3 too). A small change in T4 can lead to a large change in TSH
  • However, ensure full TFTs sent if:
      • Patient has pituitary disease
      • Patient has recently started treatment for thyroid disease
      • Pregnancy
      • Patient may have a rare thyroid disease

Discordant TFTs

  • Pre-lab events – consider clinical context
      • Effect of age – elderly people tend to have higher TSH levels. 10% of those aged >80 will have an abnormal value
      • Pregnancy
      • Thyroxine treatment
      • Confounding medications
      • NTI (non-thyroidal illness, previously known as sick euthyroid syndrome)
  • Lab events – assay interference
      • Heterophile antibodies
      • Anti-animal IGs
      • Anti-iodothyronine antibodies
      • Familial dysalbuminemic hyperthyroxinemia
      • Dystransthyretinemic hyperthyroxinemia
  • Post lab events – may be due to rarer genetic conditions
      • Resistance to thyroid hormone
      • Disorders of TH transport or metabolism
      • Thyrotropinoma (TSH-oma)

High TSH and Normal T3/T4

  • Subclinical hypothyroidism
  • Poor adherence to thyroxine treatment
  • Malabsorption
  • Drugs (ASMs, rifampicin, amiodarone)
  • Obesity
  • Non-thyroidal illness (in the recovery phase)
  • Assay error (especially if TSH is rising whilst increasing the dose of thyroxine, and the patient becomes clinically thyrotoxic)
  • TSH resistance
  • Macro-TSH
      • This is when a circulating antibody binds to the TSH and stops it being eliminated from the body
      • The TSH level will come back as very high, but it is biologically inactive due to the bound antibody, and the patient is clinically euthyroid
      • This may account for 1% of cases of apparent subclinical hypothyroidism
      • Mostly due to TSH-IgG complexes, minatory due to anti-mouse antibody
      • There are specific tests for this
  • Paraprotein-related TSH assay interference (TSH normalises once paraprotein removed)

High TSH and High T4

  • Often means irregular thyroxine use if on treatment (especially if the bloods are taken within hours of the medication). T3 should be normal.
  • Assay error common
  • TSH-oma (do MRI and check sex-hormone binding globulin)
  • Thyroid hormone resistance syndrome

Normal / near normal TSH and High T3/T4

  • Often assay error but multiple other causes including
      • Poor adherence to thyroxine
      • Drugs (salicylates, frusemide, phenytoin, amiodarone, heparin)
      • Acute illness (including psychiatric disorders)
      • TSH secreting adenoma
      • Thyroid hormone resistance syndrome
      • Disorders of thyroid hormone transport/metabolism
      • FDH, DTTRH
  • The approach
      • Check clinical context first
          • Ask about recent illness
          • Examine: clinically hypo/hyper/eu-thyroid?
          • Check for new medications (eg amiodarone, biotin supplements, chloral hydrate, furosemide, heparin, thyroxine)
      • Discuss with lab next
          • Consider which result is surprising (ie the TSH or T4) in relation to the clinical status of the patient
          • TSH assay interference – can be due to macro TSH, or heterophile or anti-reagent antibodies
          • T3/T4 assay interference – can be due to anti-iodothyronine antibodies, heterophile or anti-reagent antibodies, biotin, displacement (heparin, furosemide), binding protein genetic variants
      • Finally, consider specific conditions
        • Rare genetic causes of raised T4 (SECIS, TRU-TCA1-1, DIO1)
        • If raised T3 (and abnormal T4:T3 ratio) – consider iodine deficiency, genetic causes, thyroid cancers (rare)
        • If raised T3 and T4, consider TSH-oma and resistance to T4
            • Can be difficult to distinguish
            • Could check MRI pituitary and other pituitary function tests (but incidentalomas are common)
            • Can also check sex hormone binding globulin levels (tends to be normal in TH resistance syndrome, raised in TSH-oma, but not always)
            • Check serum TSH response to intravenous TRH – tumours don’t respond

Normal (or near normal) TSH and Low T3/T4

  • Consider central hypothyroidism (rare)
      • Check random cortisol / pituitary screen and look for signs of pituitary disease
      • Check T3 – if low, central hypothyroidism likely
  • Drugs (rifampicin, ASMs)
  • Iodine deficiency
  • Isolated TSH deficiency
  • Assay error
  • Non-thyroidal illness

Low TSH and Normal T4

  • Subclinical hyperthyroidism (TSH will normalise by itself in 75%)
  • T3 toxicosis (so add on T3)
  • Drugs (eg steroids, dopamine)
  • Acute illness
  • Recent treatment for hyperthyroidism (TSH yet to correct)

Low TSH and Low T4

  • Central hypothyroidism
  • Non-thyroid illness (NTI)

Assay error

  • Suspect if discordance with clinical features, previous TFTs and other lab tests.
  • Particularly if TSH high and T3/4 high (differential is a pituitary tumour and thyroid hormone resistance syndrome)
  • Many patients receive unnecessary treatment.
  • Can occur with over the counter supplements like Biotin (bloods look hyperthyroid but patient not). Stop biotin and recheck TFTs > 72 hours (and consider testing in another lab)
  • Lab error may also be due to heterophile antibodies (patients with pets at home) if elevated T3/T4 and normal TSH
  • Can occur with heparin and frusemide
  • Macro-TSH (see above)
  • Some people have variants of TSH which render it untestable (it doesn’t bind to the antibody in the test) – giving a falsely low TSH level (although its biologically active and working inside the patient). Rare.
  • If TSH assay interference suspected
      • Can split one blood sample into two samples, and send to different labs
      • TSH can be dramatically different between labs – for example, TSH may be undetectable in reality, but comes back as very high when heterophile antibodies mimic TSH in the test – this is a false positive
      • A false negative can occur when TSH present but blocked from binding to the antibody used in the testing
      • Can do a dilution test
      • PEG precipitation
      • Gel filtration chromatography (the gold standard)
  • T3/T4 assay interference
      • Can result in a clinically hypothyroid person having a very high TSH (as expected) but also a surprisingly high T3/T4
      • Can add a wash step to the analysis (two step assay)
      • The same result in different analysers can still be the wrong result!
  • Familial dysalbuminaemic hyperthyroxinaemia (FDH)
      • Causes assay interference
      • Mutation in binding proteins
      • Causes falsely positive results in T3/T4

Medications and supplements that interfere with TFTs

  • Amiodarone treatment
      • 50% have some thyroid dysfunction (but most euthyroid clinically)
      • Very long half-life (so can occur after drug stopped)
      • Can be high T4, low T3 and TSH high initially but resolves
      • Amiodarone hypothyroidism – high TSH and low T4 (13%)
      • Amiodarone induced thyrotoxicosis (2%)
          • Type 1 — if a person with underlying thyroid disease is exposed to the high iodine content of amiodarone, this may lead to excess thyroid hormone synthesis and release. The long half-life of amiodarone may cause hyperthyroidism for up to one year after it is discontinued. Treat type 1 with carbimazole or lithium.
          • Type 2 is due to glandular damage and can treat with prednisolone. Decreased uptake on scan. Discuss with cardiology before stopping amiodarone.
          • Can give 40mg carbimazole and 40mg prednisolone and then investigate
  • Medications which affect levothyroxine absorption include:
      • Iron
      • Bile acid sequestrants
      • PPIs
      • Calcium carbonate
      • Ciprofloxacin
  • Biotin supplements
      • Can mimic hyperthyroidism results (ie low TSH), including positive TRAb antibody – ask about them (usually have to be on a high dose)
      • Can also cause a high T4 level
      • If it causes both high T4 and low TSH – it mimics standard thyrotoxicosis
  • Heparin
      • Can cause free fatty acids to displace thyroid hormone from key binding proteins (this continues in the blood tube at room temperature, and the dose correlates with what’s happening in the patient)
      • Patient never becomes clinically thyrotoxic
      • Elevated T4, normal TSH

Notes on other causes

  • Thyroid hormone resistance syndrome
      • Autosomal Dominent (90% have family members affected and a detectable mutation)
      • Normal TSH but elevated T3 and T4.
      • Goitre, affected colour vision, AF
      • Consider genetic testing
  • T3 thyrotoxicosis
      • Low TSH, normal T4, high T3. Due to toxic adenoma
      • Might simply represent early hyperthyroidism
  • Sick euthyroid / Non-thyroidal illness (NTI)
      • Low/normal TSH, low T3/4 (usually low T3, normal T4)
      • Do not need thyroxine
      • Differential is secondary hypothyroidism / hypopituitarism, or meds that affect thyroid function – consider checking other pituitary hormones
      • Repeat TFTs later
      • Affects 65% of critically ill patients – best not to routinely check
  • Pregnancy – T4 goes up a bit in early pregnancy, TSH falls
  • Poor compliance with thyroxine treatment
      • Consider weekly dosing
      • Be aware that lots of other causes can mimic poor compliance when interpreting TFTs – check for these (eg diet, drugs, changes in binding capacity, malabsorption, changes in metabolism)

 

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