Laboratory diagnosis of thyroid disorders

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Laboratory diagnosis of thyroid disorders

• Andrea Horvath
• Department of Clinical Chemistry
• University of Szeged

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Tests of thyroid function

• Tests of thyroid status (TSH, T4, T3)
• Screening
• Diagnosis
• Monitoring treatment
• Tests of hypothalamic-pituitary-thyroid axis (TRH
  test)
• Tests to determine the cause of thyroid disease
• Immunological tests (ATA, TPO/AMA, TRAb, TSAb)
• Thyroglobulin
• Radionuclide scan/uptake
• Ultrasound scan
• FNA cytology, histology

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Tests of thyroid status

• Sensitive or ultrasensitive TSH
• Total T4, free T4
• Total T3, free T3

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Sensitive TSH assays

• Advantages
• Subclinical hypothyroidism TSH ? T4/T3 normal
• Subclinical hyperthyroidism - TSH ? T4/T3 normal
• Disadvantages
• Does not diagnose
• Pituitary hypothyroidism TSH ? T4/T3?
• Thyroid hormone resistance TSH normal, ? T4/T3?
• Does not differentiate
• Hyperthyroidism TSH T4/T3 ?
• Sick euthyroidism TSH ? T4/T3 normal

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Clinical case the tired ladies 1

• History
• Three young women consulted their doctors
  complaining of tiredness.
• Patient 1 Long history of epilepsy, on
  phenytoin
• Patient 2 No history of any illness, on
  contraceptive pill
• Patient 3 History of palpitations, dizziness of
  one years duration
• Laboratory investigations
• Test Patient 1 Patient 2 Patient 3 Ref. Range
• tT4 55 230 180 70-160 nmol/L
• TSH 1.0 1.5 2.0 0.3-6.0 mU/L

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Clinical case the tired ladies 2

• Differential diagnosis
• Patient 1 Patient 2 Patient 3
• Phenytoin effect Estrogen effect Method
  interference
• Low TBG High TBG High TBG
• Pituitary hypothyroid Pituitary
  hyperthyroid Pituitary hyperthyroid

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Further laboratory investigations
Clinical case the tired ladies 3

• Test Patient 1 Patient 2 Patient
  3 Ref.range
• tT4 55 230 180 7-160 nmol/L
• Free T4 9.5 14.8 24.5 9.4-25.0 pmol/L
• TSH 1.0 1.5 2.0 0.3-6.0 mU/L
• TBG 13.5 35.0 17.0 13.0-28.0 mg/L
• Diagnosis Phenytoin Estrogen
  Dysalbuminaemic
• effect effect hyperthyroxinaemia

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Conditions with discrepant TT4 and fT4

• Hereditary binding protein abnormality
• TBG excess or deficiency
• Dysalbuminaemia
• Abnormal prealbumin
• Estrogen excess
• Pregnancy
• Contraceptive pill or HRT
• Acquired deficiency of binging proteins
• Severe liver disease
• Nephrotic syndrome
• Androgen excess, anabolic steroids
• Drugs altering T4 binding to TBG
• Salicylates
• Phenytoin, carbamazepine
• phenylbutazone
• Autoantibodies to total T4

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TRH test

• To diagnose secondary or tertiary hypothyroidism
• Pituitary (no TSH response)
• Hypothalamic (normal or delayed TSH
  response)

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Tests to determine the aetiology of thyroid
diseases

• Immunological tests
• Anti-thyroglobulin (ATA)
• Anti-thyroid peroxidase (TPO)
• Anti-microsomal antigen (AMA)
• Thyroid receptor antibodies (TRAb)
• Thyroid stimulating antibodies (TSAb)
• Thyroglobulin

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TPO/microsomal antibodies

• Thyroid disorders
• Hashimotos thyroiditis (gt95 )
• Primary myxoedema (gt95 )
• Graves disease (80 )
• Post-partum thyroiditis (80 )
• Thyroid carcinoma (25 )
• Thyroid adenoma (20 )
• Non-thyroid, autoimmune diseases (10-30 )
• Healthy individuals (5 )
• Women (10 )
• Men (1-2 )

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The Wickham study

• 3 of population had positive TPO/AMA and raised
  TSH, suggestive of Hashimotos thyroiditis.
• Patients with positive TPO/AMA
• TSH gt6 mU/L 80
• TSH gt10 mU/L 60
• Patients with positive TPO/AMA and borderline
  raised TSH may progress to overt hypothyroidism
  at the rate of 5-10 per annum.

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Thyroglobulin

• Increased concentration in
• Goitre
• Hyperthyroidism
• Thyroiditis
• Thyroid cancer
• Clinical use
• Not for initial diagnosis of thyroid cancer
• Monitoring thyroid cancer treatment

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Use of TFTs in clinical practice

• Establish the diagnosis
• Monitor treatment
• Screening for thyroid disease

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Diagnosis of thyroid disease

• Hypothyroidism
• Hyperthyroidism
• Non-thyroidal illness (NTI)

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Clinical case the bodybuilder 1

• History
• A 34-year-old male complained of extreme fatigue
  and muscle weakness, so that he could not even
  lift his am to wash his teeth.
• Examination
• Dry skin, bradycardia, delayed relaxation of
  reflexes, periorbital oedema, loss of power,
  hypotonia.
• Laboratory investigations
• Test Reference range
• tT4 lt20 70-160 nmol/L
• TSH gt150 0.3-6.0 mU/L

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Clinical case the bodybuilder 2

• Diagnosis Primary hypothyroidism, myxoedema
• Further laboratory investigations
• Test Reference range
• TPO antibodies positive
• Creatinine kinase 5,540 25-200 IU/L
• Cholesterol 8,8 3.9-5.5 mmol/L

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Treatment Thyroxine

• Test Day1 Day30 Day60 Day90 Ref. Range
• tT4 lt20 - - - 70-160 nmol/L
• TSH gt150 87.5 34.6 10.2 0.3-6.0 mU/L
• CK 5,540 1,200 437 185 25-200

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Clinical case the confused lady 1

• History
• A 64-year-old lady with a two-week history of
  severe headache, confusion and hyponatraemia of
  114 mmol/L was admitted to hospital. The
  laboratory diagnosis of SIADH was made.
• Laboratory investigations
• Test Reference range
• tT4 55 70-160 nmol/L
• Free T4 6.5 9.4-25.0 pmol/L
• TSH 0.35 0.3-6.0 mU/L

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Clinical case the confused lady 2

• Differential diagnosis
• Secondary or tertiary hypothyroidism
• Pituitary disease
• Further investigations
• Test Reference range
• Prolactin 26.500 lt600 mU/L
• FSH lt0.5 gt30 U/L (postmenopausal)
• LH lt0.5 gt30 U/L (postmenopausal)
  Estrogen lt45 lt45 pmol/L (postmenopausal)
  Cortisol 185 280-700 nmol/L (900h)CT CT scan
  of the skull pituitary macroadenoma

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Hypothyroidism

• TSH (mU/L) T4/T3 Diagnosis Management
• High low primary start
  replacement
• (gt20) hypothyroidism monitor TSH
• Borderline high borderline NTI/compensated
  check TPO/AMA
• (5-20) or normal hypothyroidism
  monitor TSH, T4
• Normal borderline sick
  euthyroid/NTI monitor TSH
• drug effect
• Low or normal low secondary assess
  pituitary
• hypothyroidism function, CT scan
• TRH test

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Other findings in hypothyroidism

• Menorrhagia, hyperprolactinaemia
• Normocytic or pernicious anaemia
• Hypercholesterolaemia
• Myopathy, raised CK
• Decreased FVIII, IX, platelet adhesion

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Clinical case the slim waitress 1

• History
• 40-year-old female with a 3-month history of
  malaise, myalgia, weight loss, diarrhoea, palmar
  erythema and tachycardia.
• Examination
• Diffusely enlarged thyroid with vascular bruit,
  lid lag, no exophtalmos, mild proximal muscle
  weakness.
• Laboratory investigations
• Test Reference range
• Free T4 34.6 9.4-25 pmol/L
• TSH lt0.1 0.3-6.0 mU/L
• TSAb positive

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Clinical case the slim waitress 2

• Diagnosis Graves disease
• Treatment Carbimazole
• Laboratory investigations
• Test Day1 Day30 Day60 Reference range
• Free T4 34.6 15.8 13.1 9.4-25 pmol/L
• TSH lt0.1 lt0.1 4.3 0.3-6.0 mU/L

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Hyperthyroidism

• TSH (mU/L) T4/T3 Diagnosis Management
• Low high primary start treatment
• (lt0.1) hyperthyroidism monitor T4
  (T3) and TSH
• Borderline low normal or compensated
  exclude goitre or
• (0.1-0.5) borderline hyperthyroidism
  nodule, follow-up
• Low or borderline normal sick euthyroid/NTI
  follow-up
• drug effect
• Normal or high high secondary hyper-
  assess pituitary
• thyroidism, thyroid function, refer
• hormone resistance to specialist, CT

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Monitoring thyroid treatment

• Hypothyroid on T4 replacement
• Primary TSH (2-3-monthly or annually)
• Secondary T4
• Hyperthyroid on anti-thyroid drugs
• TSH, T4, (T3), FBC
• Thyroid cancer patient on block replacement
• TSH, T4 (T3), thyroglobulin
• (detectable Tg indicates local or metastatic
  recurrence)

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Screening for thyroid disease

• Mass screening of the general public is
  ineffective
• Thyroid function tests are not indicated in
  acutely ill patients
• Case finding for thyroid disease is warranted
• Autoimmune disease (DM, pernicious anaemia,
  Addisons disease)
• Family history of thyroid disease
• Post-partum (4-8 weeks after delivery)
• Radiotherapy to the neck
• Amiodarone treatment
• gt60 year old female
• Psychiatric illness (female)
• Neonatal or paediatric cases
• Screening for congenital hypothyroidism (5-7 days
  after birth)
• Prolonged jaundice

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The sick euthyroid syndrome

• Condition TT4 fT4 T3 TSH
• Acute illness N?? N ? N?
• Recovery phase N N N N??
• Psychiatric illness N? N? N? N?

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