Professional Documents
Culture Documents
▪ Hyperthyroidism
▪ Hypothyroidism
▪ Hyperthyroidism
▪ Hypothyroidism
Greenspan’s Basic and Clinical Endrocrinology 8th ed. Lange, 2007. p. 221
Structure of thyroid hormone
5’-monodeiodinase
T4 T3
(85%) • Hati
TRs
• Ginjal
T3 • otot skeletal TREs
Fig. A – C Synthesis of Thyroxine and Triiodothyronine Cooper DS, N Engl J Med 2005;352:905-17.
Panel D, bila tidak ada obat antitiroid, “iodinating intermediate” bereaksi dengan residu tirosin spefisik pada
thyroglobulin (Tg) membentuk monoiodotyrosine (MIT) dan diiodotyrosine (DIT).
Subsequent coupling intramolecular MIT dan DIT membentuk T3 (triiodothyronine), dan coupling dua molekul
DIT membentuk T4 (thyroxine).
Fig. D Synthesis of Thyroxine and Triiodothyronine Cooper DS, N Engl J Med 2005;352:905-17.
Point of view
▪ Hyperthyroidism
▪ Hypothyroidism
• Thyroid dysfunction
• Hyperthyroidism and hypothyroidism
• Thyroid autoimmunity
Spectrum of thyroid disorder
• Thyroid dysfunction
• Hyperthyroidism and hypothyroidism
• Thyroid autoimmunity
INDICATIONS FOR TESTING
Increased or decreased metabolism (heat or cold intolerance, weight loss or gain, depression, anxiety, etc)
TSHs
FT4
FT4 FT4
∆ Hypothyroid
(primary)
TSH µU/L
Euthyroid
Greenspan’s Basic and Clinical Endrocrinology 8th ed. Lange, 2007. p. 233
Relationship between serum free thyroxine by dialysis (FT4) ng/dL and log10 TSH
in euthyroid, hyperthyroid, hypothyroid, and T4 supressed euthyroid
• Dysfunction of the thyroid axis is common in the general population and even
more prevalent in the elderly, with an increased incidence of overt thyroid under-
or overactivity.
• The burden imposed by disorders of the thyroid in the elderly is, however,
unclear.
Boelaert K: Thyroid dysfunction in the elderly. Nat Rev Endocrinol 2013; 9: 194–204.
‘Nonthyroidal illness syndrome’
or sick euthyroid syndrome
• It is important to make a differential diagnosis between this sick euthyroid syndrome and
subclinical hyperthyroidism.
• The failure of the serum tsh to rise in response to low circulating thyroid hormone
concentrations in critical illness arises from a degree of central hypothyroidism caused by
alterations in the set point of the hypothalamo-pituitary-thyroid axis.
Boelaert K: Thyroid dysfunction in the elderly. Nat Rev Endocrinol 2013; 9: 194–204.
Point of view
▪ Hyperthyroidism
▪ Hypothyroidism
Hyperthyroidism
• refers to excess synthesis and secretion of thyroid hormones by
the thyroid gland, which results in accelerated metabolism in
peripheral tissues
Thyrotoxicosis
• Clinical syndrome that results when tissues are exposed to high
levels of circulating thyroid hormone.
Table 1. Causes of Thyrotoxicosis
Thyrotoxicosis associated with a normal or elevated radioiodine uptake over the neck
Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, Mcdougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan
MN.Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of The American Thyroid Association and American Association
of Clinical Endocrinologists. Hyperthyroidism Management Guidelines, Endocr Pract. 2011;17(3):e1-e65.
Grave’s disease (diffuse toxic goiter)
ESS
123I uptake Early Grave’s disease
Grave’s disease Drugs:
Toxic nodular goiter dopamine,
High Low corticosteroid
• Beta-adrenergic blockade
should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic
patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease.
Fig. D – F Synthesis of Thyroxine and Triiodothyronine Cooper DS, N Engl J Med 2005;352:905-17.
Fig. Effects of Anti thyroid Drugs
MMI Long-term
MMI (CBZ) low-dose
Adults : 18 months for further
Children: 36 months 12 months MMI
Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Perace SH. 2018 European Thyroid Association Guideline for the Management of
Graves’ Hyperthyroidism. Eur Thyroid 2018;7:167-186.
Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Perace SH. 2018
European Thyroid Association Guideline for the Management of
Graves’ Hyperthyroidism. Eur Thyroid 2018;7:167-186
Nakamura H et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease.
J Clin Endocrinol Metab 2007 Jun; 92:2157-62
Fig. Comparison of the efficiency of treatment with MMI 30mg/d and PTU 300mg/d or MMI 15mg/d
in patients with GD in terms of normalizing serum FT4 levels [<1.7 ng/dl (21.9 pmol/liter)]
Nakamura H et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease.
J Clin Endocrinol Metab 2007 Jun; 92:2157-62
Methimazole vs. Propylthiouracil for Hyperthyroidism
Allan S. Brett, MD reviewing Nakamura H et al. J Clin Endocrinol Metab 2007 Jun
Available from: https://www.jwatch.org/jw200706190000001/2007/06/19/methimazole-vs-propylthiouracil-hyperthyroidism
Methimazole was superior overall, and lower doses seemed sufficient for patients with mild-to-moderate hyperthyroidism.
Both methimazole and propylthiouracil (PTU) are used to treat hyperthyroidism. To compare these drugs, Japanese researchers randomized 396 patients
with Graves hyperthyroidism to receive 15 mg of methimazole once daily, 30 mg of methimazole daily (given as 15 mg twice daily), or 100 mg of PTU three
times daily.
At each of three time points (4, 8, and 12 weeks), the proportion of patients with normalized free thyroxine (T4) levels was higher in the 30-mg methimazole
group than in the other two groups. The differences were of borderline statistical significance at 4 and 8 weeks but significant at 12 weeks (normal free T4
achieved in 97%, 86%, and 78% of patients in the 30-mg methimazole, 15-mg methimazole, and PTU groups, respectively). In patients with mild or moderate
hyperthyroidism, normal free T4 was achieved at similar rates in the three groups. However, in patients with severe hyperthyroidism (i.e., free T4 ≥7 ng/dL),
higher-dose methimazole was more effective than lower-dose methimazole or PTU. Transaminase elevations and leukopenia occurred less commonly with
both doses of methimazole than with PTU. Rash was less common with lower-dose methimazole than with higher-dose methimazole or PTU.
Comment:
Based on these results, the authors favor methimazole — at doses of 15 mg/day for those with mild-to-moderate
hyperthyroidism, and 30 mg/day for those with severe hyperthyroidism.
Because other studies have reached similar conclusions, most U.S. experts already favor methimazole.
One exception is that PTU is recommended during pregnancy.
Nakamura H et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease.
J Clin Endocrinol Metab 2007 Jun; 92:2157-62
Table 2. Adverse events of antithyroid drugs
Common (1.0 – 5.0%) Skin rash
Urticaria
Arthralgia, polyarthritis
Fever
Transient mild leukopenia
Rare (0.2 – 1.0%) Gastrointestinal
Abnormalitas of taste and smell
Agranulocytosis
Very rare (<0.1%) Aplastic anemia (PTU, CBZ)
Thrombocytopenia (PTU, CBS)
Vasculitis, lupus-like, ANCA + (PTU)
Hepatitis (PTU)
Hypoglycemia (anti-insulin Abs; PTU)
Cholestatic jaundice (CBS/MMI)
PTU=propylthiouracil, MMI=methimazole, CBZ=carbimazole, ANCA=antineutrophil cytoplasmic antibody
Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Perace SH. 2018 European Thyroid Association Guideline for the Management of Graves’
Hyperthyroidism. Eur Thyroid 2018;7:167-186.
Point of view
▪ Hyperthyroidism
▪ Hypothyroidism
Bravermen LE & cooper DS. Introduction to hypothyroidism. In: bravermen LE & cooper DS (editors). Werner & ingbar’s the thyroid: a
fundamental and clinical text. 10th edition. Philadelphia: lippincott william & wilkins, 2013. P. 523-4.
Signs and symptoms of hypothyroidism in adults
Signs and symptoms of hypothyroidism tend to be
more subtle than those of hyperthyroidism
• Dry skin
• Cold sensitivity
• Fatigue
• Muscle cramps
• Voice changes
• Constipation are among the most common. Fig. Facial appearance in hypothyroidism
Note: puffy face, puffy eyes and thickened, pale skin
• General agreement that patients with primary hypothyroidism with TSH levels
above 10 miu/L should be treated
• Patients with TSH levels of 4.5–10 miu/L will benefit is less certain.
• There are virtually no clinical outcome data to support treating patients with
subclinical hypothyroidism with TSH levels between 2.5 and 4.5 miu/L.
• The possible exception to this statement is pregnancy because the rate of
pregnancy loss, including spontaneous miscarriage before 20 weeks gestation
and stillbirth after 20 weeks, have been reported to be increased in anti-thyroid
antibody–negative women with tsh values between 2.5 and 5.0.
Garger et al. Clinical practice guideline for hypothyroidsm in adults. Thyroid 2012; 22 (12)
L-thyroxine treatment of hypothyroidism
• Conversion of T4 to T3 was documented in 1970
Normal metabolic state has been attained is normalization of the TSH level down to the rage of 0,5-1.5 mU/L.
On average, this will equate to an ultimate full replacement dose of ~1.7 µg/kg/day.
Patients who have had a total thyroidectomy for example for thyroid malignancy, especially when surgery
was followed by radioiodine ablation, will have no residual thyroid tissue and their requirement will be
closer to 2.1µg/kd/day.
In patients taking thyroxine, measure serum T3 levels may be a better indicator of the metabolic state than
serum T4 levels but dosage adjusments are best determined by clinical criteria and TSH.
However, in patients with pituitary or hypothalamic disease in whom it is not feasible to monitor TSH as an
indicator of dosage adequacy, measurement of serum fT4 and and T3 are generally adequate to monitor
dosage.
Complication of untreated hypothyroidism
• Myxedema coma
• Myxedema and heart disease
• Hypothyroidism and neuropsychiatric disease
Measurement of serum TSH is the primary screening test:
• For thyroid dysfunction
• For evaluation of thyroid hormone replacement in patients with primary
hypothyroidism
• For assessment of suppressive therapy in patients with follicular cell–derived
thyroid cancer.
Pitfalls encountered
when interpreting serum TSH level
• TSH tend to be lowest in the late afternoon and highest around the hour of sleep.
• In light of this, variations of serum TSH values within the normal range of up to 40%–50% do
not necessarily reflect a change in thyroid status.
Garger et al. Clinical practice guideline for hypothyroidsm in adults. Thyroid 2012; 22 (12)
Point of view
▪ Hyperthyroidism
▪ Hypothyroidism
• The u.S. Centers for disease control (CDC) advises that people who are immunocompromised are at
higher-risk of severe illness from COVID-19. Immunocompromised people have a weaker immune
system and have a harder time fighting infections. However, the immune system is complex, and
having autoimmune thyroid disease does not mean that a person is immunocompromised or will be
unable to fight off a viral infection.
• Thus far, there is no indication that patients with autoimmune thyroid disease are at greater risk of
getting covid-19 or of being more severely affected should they acquire the covid-19 infection.
• Everyone should continue to practice the recommended hand hygiene and social distancing
recommendations to avoid covid-19 infection.
Hyperthyroidism
How do patients taking methimazole for hyperthyroidism tell the
Q difference between a COVID-19 infection or side effects of
methimazole?
• Many patients with graves’ disease and other types of hyperthyroidism are treated with the medication known as
methimazole (or a similar medication called propylthiouracil [PTU]). A rare side effect of these antithyroid medications is a
condition called agranulocytosis (occurring in 0.2-0.5% of people taking the medication), in which the number of the
immune cells that fight infection decrease. Patients may have symptoms such as fever or sore throat. If these occur,
patients are often told to stop the methimazole and go to a laboratory to have blood testing done.
• As fever and signs of illness can also overlap with the symptoms of covid-19 infection, many patients who happen to also
be taking methimazole may be concerned that they have become infected with covid-19. Should they quarantine at home if
they have some of these symptoms?
• Because agranulocytosis with fever can represent a serious infection, the possibility should not be ignored.
Agranulocytosis is less common in patients who have been taking methimazole for a long time or when the dose of the
medication is low (e.g. 15 mg in one study), but it can still occur. If a fever or other symptoms of an infection start while
taking methimazole, it is best to contact your endocrinologist or other provider to determine how best to be evaluated.
• Patients should always seek medical attention for symptoms that seem urgent or life-threatening. Any patient with new
fever, cough, or other typical symptoms of COVID-19 infection should seek medical attention immediately, regardless of
methimazole use.
Hyperthyroidism
Q How can methimazole be given to patients with critical illness?
• Methimazole is an oral medication and stopping these medications can lead to worsening of hyperthyroidism. During a
critical respiratory illness, especially when a ventilator (breathing machine) is required, a patient may not be able to take
medications by mouth. When treatment of hyperthyroidism is necessary, different routes for giving methimazole may be
used. Providers taking care of patients with critical illnesses will be able to determine the best approach for making sure
that a patient with hyperthyroidism continues to receive treatment as needed.
• The placement of a naso-gastric tube or a dobhoff tube allows the same methimazole pill to be delivered to the gut
(digestive system) in a patient who is unable to swallow.
• If the enteric route (through the stomach) is not available, these medications can be prepared for intravenous (iv) use: IV
methimazole has been given by adding 500mg of methimazole powder to 0.9% sodium chloride solution to a final volume
of 50ml and administering the correct dose as a slow IV push over 2 minutes.
• PTU is relatively insoluble. An IV formulation used in one report was made by dissolving tablets in isotonic saline with an
alkaline ph (ph 9.25).
• Enema or suppository formulations have also been used and require specific preparation.
Summary
• Treatment of choice in hyperthyroidism is anti thyroid drug, radioactive iodine (i131), or thyroidectomy.
Treatment of choice is anti thyroid drug methimazole. Stopping these medications can lead to
worsening of hyperthyroidism
• Treatment for hypothyroidism is levothyroxine. Levothyroxin is consider to have narrow therapeutic
index. The consequent necessity for careful titration of doses has had an impact on the issue of
switchability or bioequivalence.
• Certain cases such as subclinical hypothyroidism or subclinical hyperthyroidism, clinical consideration
should be taken whether patients need to be treated
Thank you