Subclinical Hypothyroidism

ID: 83 yo female with refractory hypertension (on multiple antihypertensives with SBP ~170)

  • Has subclinical hypothyroidism which is being treated with levothyroxine (?link to refractory hypertension)


  • Primary hypothyroidism is characterized by a high serum thyroid-stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration
  • Subclinical hypothyroidism is defined biochemically as a normal free T4 concentration in the presence of an elevated TSH concentration. Secondary (central) hypothyroidism is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated

Primary hypothyroidism: 95%

  • TSH high, serum free T4 is low; subclinical (TSH high, serum free T4 normal)
  • Chronic autoimmune/lymphocytic (Hashimoto’s) thyroiditis: most common cause of hypothyroidism. Mainly older women. Anti-TPO (thyroid peroxidase) antibodies present in 75% of cases.
  • Iatrogenic: radioiodine, external Neck radiation, thyroidectomy
  • Iodine: deficiency (urine iodone <45 mcg/d) or excess
  • Drugs: rifampin, carbamazepine, phenobarbital, phenytoin, valproate, estrogen, cholestyramine, sucralfate, FeSO4, AlOH, CaCO3, lithium, interferon alpha, sunitinib, PPI? coffee?. Numerous mechanisms.
  • Infiltrative diseases: hemochromatosis, scleroderma, leukemia, tuberculosis, PCP

Hashimoto’s thyroiditis:

  • Presence of high serum concentrations of abs to thyroid peroxidase (TPO) and thyroglobulin
  • Do not routinely measure TPO abs in patients with primary overt hypothyroidism because almost all have chronic autoimmune thyroiditis – can be measured in subclinical hypothyroidism to predict likelihood of progression to permanent overt hypothyroidism

Secondary hypothyroidism: <1 %

  • TSH deficiency
  • Pituitary necrosis (eg. Sheehan’s syndrome), trauma, pituitary tumors
  • Treat with Thyrotropin (TSH, Thyrogen). Usually also need to replace other pituitary hormones.

Tertiary (central) hypothyroidism: <1%

  • TRH deficiency
  • Hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases.
  • Treat with Protirelin (TRH, Relefact TRH). Usually also need to replace other pituitary hormones.

In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as T4 secretion falls. As a result, the symptoms and the serum free T4 value must be used to make the diagnosis. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is suspected (eg, a young woman with amenorrhea and fatigue)

Hypothalamus — TRH –> Anterior Pituitary — TSH –> Thyroid Gland

Signs and symptoms:

CNS Fatigue, weakness, paresthesia, depression, cognitive dysfunction, decreased hearing, slow speech
HEENT Periorbital edema, tongue enlargement
RESP Dyspnea on exertion, pleural effusion, sleep apnea
CVS Bradycardia, diastolic hypertension, pericardial effusion, nonpitting edema (severe hypo), ↑ risk of CVD (HF, CHD, stroke, lipids)
GI Constipation, decreased taste
GU/Renal Menorrhagia, pubertal delay, galactorrhea, hyperprolactinemia
LIVER Ascites
ENDO Weight gain, ↑ LDL, ↑ total cholesterol
Lytes/HEME Hyponatremia (rare, only in severe), normochromic, normocytic hypoproliferative anemia
MSK/Bone Growth delay, myalgia, cramps, weakness, bradykinesia, carpal tunnel syndrome
DERM Dry, coarse skin, eczema thinning of hair, loss of eyebrows, cold sensitivity, brittle nails

The clearance of many drugs, including antiepileptic, anticoagulant, hypnotic and opioid drugs, is decreased in hypothyroidism. Thus, drug toxicity may occur if drug dose is not reduced. In addition, drugs that are administered at effective doses in patients who are hypothyroid may become less effective during T4 replacement.

Goal: Normalize TSH, T4, T3 + eliminate S&Sx.


  • Synthetic Levothyroxine (T4):
    • Young healthy adults: Start “full replacement dose”: 1.6 mcg/kg/d (50-200ug/d)
    • ELDERLY: Start 50 mcg/d; may be 1 μg/kg/d in elderly (50-100 μg/d).
    • CAD: Start 12.5-25 μg/d and monitor for angina.
    • 12.5-25 mcg/d dosage adjustments. Initiate with T4 monotherapy.
  • T4+T3 not superior to T4 alone on body weight, lipids, symptoms, cognition, QOL.
  • IV formulation available (500μg/vial = $125)

Do you treat in subclinical hypothyroidism?:

  • TSH > 10 mU/L: treat to prevent progression to overt hypothyroidism
    • data linking subclinical hypothyroidism with atherosclerosis and myocardial infarction and the increased risk of progression to overt hypothyroidism
    • supported by ATA, AACE, European thyroid association guidelines
  • TSH 7-9.9 mU/L: treat most under age 65-70 yo d/t association of increased CV mortality in younger patients. ?benefit in older patients and concerns of safety in older pts (↑ risk of exacerbation and induction of angina and CAD)
  • TSH ULN-6.9mU/L: treat <65 to 70 who have sxs suggestive of hypothyroidism. Consider if high titers of anti-TPO abs, and patients with goiter. For older patients, these levels of TSH may be age-appropriate.

  • Infertility or attempting pregnancy: suggest initiating T4 replacement (TSH values above 1st trimester-specific normal reference range with normal free T4)


  • Re-measure TSH 4-8 weeks after initiation or dose change.
  • Questionable role for fT4, no role for T3 in routine monitoring.
  • TSH annually once stable & when conditions change.
  • Avoid chronically low TSH even if asymptomatic due to osteoporosis risk (TSH <0.1 to 3.6 x ↑ in hip fracture risk & 4.5 x ↑ in vertebral fracture risk vs. normal TSH in women >65 y/o. [Ann Intern Med 2001;134:561-568, BMJ 2011;342:d2238].)
  • NOTES: Targeting lower half of TSH range no better than upper half w.r.t. Sx, QOL, cognition. [JCEM 2006:91: 2624 –2630].
  • Factors possibly requiring UPWARD dosage adjustment: worsened thyroid function, pregnancy, hi-fiber diet, concurrent rifampin, carbamazepine, phenobarbital, phenytoin, estrogen, cholestyramine, sucralfate, FeSO4, AlOH, CaCO3, lithium, nephrotic syndrome
    • ASSESS ADHERENCE (most common reason)
  • Factors possibly requiring DOWNWARD dosage adjustment: nephrotic syndrome, weight loss, androgen therapy.

Primary Hypothyroidism & Pregnancy:

  • Screening in normal healthy women: no consensus.
  • Recommendations range from screen all women before pregnancy (AACE) to screen only if high-risk (family history or goiter).
  • TREAT with T4 if TSH > ~4 mU/L.
  • If not on T4 therapy prior to pregnancy, no consensus about optimal initial dose. Some have suggested 1.2-1.4 mcg/kg/d initially. A retrospective study showed T4 50mcg/d (avg) was associated with reduced pregnancy loss and increased preterm delivery, preeclampsia, gestational diabetes.
  • Women with pre-existing primary hypothyroidism: Counsel women with primary hypothyroidism before pregnancy. If already on T4 before detecting pregnancy: Increase L-thyroxine intake by 20-30% immediately + contact caregivers urgently. [e.g. take an extra L- thyroxine dose twice weekly beginning immediately]
  • MONITORING: TSH ~q4 weeks until ~20 weeks, and at least once ~30 weeks. T4 requirements go up as early as 4-6 weeks of pregnancy, and increase through weeks 16-20, then plateau until delivery. 50 and 85% of LT4-treated hypothyroid women need a dose increase during pregnancy. Target TSH: 0.4-2.5 mU/L throughout pregnancy. Return to preconception T4 dose following delivery, TSH @ 6 weeks.

Considering patient’s refractory hypertension which is uncontrolled on multiple antihypertensives, trialing treatment of subclinical hypothyroidism to manage hypertension is appropriate (go low and slow).



  • Normal: 150-400 x 10^9/L
  • Thrombocytopenia: PLT <150
  • <100: risk of surgical bleeding in high risk surgical patients (i.e. neurosurgery, major cardiac, orthopaedic surgery)
  • <50: risk of surgical bleeding
  • <10-20: risk of severe spontaneous bleeding


  • Post-operative consumption (platelets are being used to help heal wounds post-op)
  • Infections (e.g. HIV, hepatitis C, sepsis with disseminated intravascular coagulation)
    • Thrombocytopenia: independent risk factor for morality in the ICU (sepsis)
  • HIT Type I: not ab mediated (direct effect of heparin) and fall in PLTs (nadir: 100) typically resolves with continued heparin administration
  • HIT Type II: ab-mediated (nadir >20) and may lead to thrombosis until heparin is discontinued
  • Other drug causes: quinine, sulfonamides, acetaminophen, cimetidine, ibuprofen, naproxen, ampicillin, piperacillin, vancomycin, glycoprotein IIb/IIIa inhibitors
  • Nutrient deficiencies (e.g. vitamin B12, folate, copper)
  • Pregnancy

Platelets: also an acute phase reactant (increase in inflammation/infection/trauma)


Currently, I have been seeing patients with hypophosphatemia, and for a few, this has been persistent despite ongoing replacement..

Causes of hypophosphatemia:

  • Acute respiratory alkalosis
    • Rise in intracellular pH stimulates phosphofructokinase activity which in turn stimulates glycolysis → ↑ in demand for phosphate, which is driven intracellularly to form glycolytic intermediate metabolites
      • A similar phenomenon is observed with an increase in intracellular pH, which occurs in metabolic alkalosis
    • Extreme hyperventilation (PCO2 <20mmHg) in normal subjects can also lower serum phosphate concentrations to below 0.32 mmol/L
    • References:
  • Refeeding syndrome
    • Concern of referring syndrome in malnourished, alcohol abuse
  • Stress-induced
    • Dieticians are able to calculate patients’ metabolic needs and assess if the feeds are sufficient in meeting this. Had a patient with status epilepticus with persistently low phosphate levels despite frequent replacement. Dietician calculated her needs and found that it significantly exceeded her feeds. After replacing feeds (and also accounting for the fact that patient is on propofol), phosphate levels were generally WNL
  • Increased losses (e.g. diarrhea, large NG loss)
  • Diabetic Ketoacidosis

Drug causes of hypophosphatemia:

  • Phosphate binders – e.g. calcium supplements
  •  ↑ urinary excretion – e.g. carbonic anhydrase inhibitors, bisphosphonates, corticosteroids
  • Cause vitamin D deficiency or resistance – e.g. phenytoin, phenobarbital
  • IV iron administration
  • Acetaminophen poisoning
  • References: Medicationinducedhypophos

Symptoms of hypophosphatemia:

  • Respiratory failure
  • Cardiac abnormalities
  • CNS dysfunction
  • Difficulty weaning from venilation


  • Address underlying causes
  • Supplement phosphate
    – e.g. NaPO4 IV 15 mmol (=20mmol Na), KPO4 IV 15 mmol (= 22 mmol K+)

    • ICU Rapid Resource at VGH: 20-40 mmol PO4/day
  • Monitor serum levels at least daily
  • Monitor renal function daily – if AKI, risk of accumulation!
  • Monitor for hyperphosphatemia (symptoms: paresthesia, flaccid paralysis, mental confusion, hypertension, cardiac arrhythmias, tissue calcification)

Angelman Syndrome

Angelman syndrome – aka. 15q11-13 MATERNAL DELETION SYNDROME

  • “Neurodevelopmental” genetic disorder
    • Deletions account for >70% of cases
    • Deletions in region of BP1 to BP3 can be subclassified into class I and II deletions
      • Class I are larger and extend from BP1-BP3 ∴ greater disease severity with need for more seizure medications, greater difficulties in expressive language and higher incidence of autism spectrum disorders
  • Characteristics:
    • Severe to profound intellectual disability
    • Postnatal microcephaly
    • Movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs
    • Distinctive facial features as adult – “coarse”
    • may present with: frequent laughter or smiling, apparent happy demeanor, easily excitable personality, often with hand flapping movement, hypermotoric behaviour, fascination with water, mouthing behaviours and a short attention span
      • but with age, tend to become less excitable and sleeping issues tend to improve

  • Other manifestations:
    • 80% have seizures
      • abnormal EEG with large-amplitude slow-spike waves (seen even when no seizures)
    • Sleep – often compromised with frequent waking and altered sleep cycles
    • Obesity
    • Constipation
    • Scoliosis
    • Limited verbal communication
    • Self-injurious behaviour
    • Feeding problems and gastroesophageal reflx
  • Management:
    • Seizures:
      • If mild, may respond well to clonazepam
    • Severe sleep disturbances
      • Melatonin and/or clonidine


Forest Plot

Forest Plot: graphical representation of a meta-analysis

  • usually big studies draw the report
  • Bigger studies tend to have a smaller standard error



  • Know what outcome you are measuring
  • Horizontal entries represents studies included but does not mean all the studies that were found in the search
  • Tips of the diamond refer to the confidence interval
  • Size of square = weight in analysis
  • Weighting is based on inverse variance – low variance = high precision = higher weight
  • Narrower CI = proportional to N



Types of Analyses

  • Intention to Treat Analysis (ITT):
    • all participants that are randomized must be included in the final analysis and analyzed according to the treatment group to which they were originally assigned, regardless of the treatment received, withdrawals, loss to f/u or cross-overs
    • However…in many instances in randomized trials the term intention-to-treat was inappropriately described and participants improperly excluded.
    • Generally preferred as they are unbiased, and also because they address a more pragmatic and clinically relevant question.
    • Principles
      1. Keep participants in the intervention groups to which they were randomized, regardless of the intervention they actually received.

      2. Measure outcome data on all participants.

      3. Include all randomized participants in the analysis.

      There is no clear consensus on whether all criteria should be applied (Hollis 1999). While the first is widely agreed, the second is often impossible and the third is contentious, since to include participants whose outcomes are unknown (mainly through loss to follow-up) involves imputing (‘filling-in’) the missing data.

  •  Modified Intention to Treat Analysis (mITT):
    • No clear definition and can vary from trial to trial
    • Primary factor that characterizes the mITT: Post-randomization exclusion
    • Lies between true ITT and per-protocol analyses
      • E.g. patient receives at least 1 dose of medication and 1 efficacy measurement…as long as that happens they were included in that study
      • Also consider the number that was censored
    • More likely to report post-randomization exclusion and more likely to be associated with industry sponsorship
  • As-Treated: subjects analyzed according to whether they got treatment or not (regardless of allocation) → May be used for safety events
  • Sensitivity analysis: a repeat of the primary analysis or meta-analysis, substituting alternative decisions or ranges of values for decisions that were arbitrary or unclear
    • Asks the question: “Are the findings robust to the decisions made in the process of obtaining them?”
    • For dichotomous outcomes, should odds ratios, risk ratios or risk differences be used?

    • And for continuous outcomes, where several scales have assessed the same dimension, should results be analysed as a standardized mean difference across all scales or as mean differences individually for each scale?

    • Different from subgroup analysis:
      I. sensitivity analyses do not attempt to estimate the effect of the intervention in the group of studies removed from the analysis, whereas in subgroup analyses, estimates are produced for each subgroup.
      II. in sensitivity analyses, informal comparisons are made between different ways of estimating the same thing, whereas in subgroup analyses, formal statistical comparisons are made across the subgroups.

Intention to Treat and Per Protocol

Intention to Treat Per Protocol
All subjects who were randomized are analyzed at the end of the trial according to the treatment to which they were originally assigned

  • Included if dropped out
  • Included if non-compliant (with treatment or following up monitoring)
  • Included in original group even if treatment changed

This does not fix problems related to loss to f/u

Superiority studies: Conservative
– since the groups are made more artificially similar = makes it harder to show a difference
– minimizes risk of Type I error

Non-inferiority studies: Less conservative
– “is the drug non-inferior = no different than the other”
– difference will not be as visible

All subjects are included only if they received the intended intervention in accordance with the protocol
= ideal patients

  • Excluded if dropped out
  • Excluded if non-compliant (with treatment or follow-up monitoring)
  • Analyzed in new group if treatment changed
  • Does not test for practical benefit of an intervention

Superiority studies: less conservative
– if there is a benefit, it would be the most visible difference

Non-inferiority studies: conservative
– easier to find difference = we want to exacerbate the difference when doing non-inferiority study