Define hypothyroidism?

It is a clinical condition resulting from reduced circulatory level of thyroid hormone.

What are primary and secondary hypothyroidism?
What is myxedema?
What is Hoffman’s syndrome?

In a patient with myxedema, there may be myotonia with pain and swelling in the muscles after exercise, called Hoffman’s syndrome.

What is Pendred’s syndrome?

It is an autosomal recessive disorder in which there is sensori-neural deafness with goiter. It is due to inborn error of thyroid hormone synthesis.

What is subclinical hypothyroidism (borderline hypothyroidism or compensated euthyroidism)?

In this condition, T3 and T4 are in the lower limit of normal and TSH is slightly high. The patient may be clinically euthyroid. This may persist for many years, though overt hypothyroidism may occur. Conversion to overt hypothyroidism is more common in men or when thyroid peroxidase (TPO) antibody is present or TSH level is more than 10 mU/L.

What is Hashimoto’s thyroiditis?

It is an autoimmune thyroiditis characterized by destructive lymphoid infiltration of thyroid leading to atrophic change with regeneration and goiter formation. It is more common in middle aged woman.


Etiology and Pathophysiology

What are the causes of hypothyroidism?
  1. Autoimmune:
    1. Spontaneous atrophic hypothyroidism
    2. Hashimoto’s thyroiditis
    3. Graves’ disease (associated with TSH receptor blocking antibody).
  2. Iatrogenic:
    1. Radioiodine therapy for thyrotoxicosis
    2. After surgery (thyroidectomy)
    3. Post-radiotherapy in neck
    4. Drugs—such as lithium, amiodarone and antithyroid drug therapy.
  3. Others:
    1. Endemic iodine deficiency
    2. Postpartum thyroiditis
    3. Rarely, dyshormonogenesis
    4. Secondary to hypopituitarism and hypothalamic disorders (rare).
What are the common causes of primary hypothyroidism?
  • Spontaneous atrophic hypothyroidism.
  • Radioactive iodine ablation.
  • Thyroidectomy.
  • Hashimoto’s thyroiditis.
What is the most common cause of primary hypothyroidism?

The most common cause of primary hypothyroidism is iodine deficiency, e.g. in mountainous regions.

What are the common causes of transient hypothyroidism?
  • Post-thyrotoxic phase of subacute thyroiditis
  • Postpartum thyroiditis
  • During the first 6 moths after subtotal thyroidectomy or I131 treatment of Graves’ disease.
 What are the causes of goitrous hypothyroidism?
  • Hashimoto’s thyroiditis
  • Graves’ disease (in such case, there is also exophthalmos and diffuse goiter with dermopathy)
  • Endemic iodine deficiency (less common)
  • Drugs—lithium, amiodarone, iodide
  • Rarely, dyshormonogenesis.
If there is goiter with hypothyroidism, what is the likely cause?

Hashimoto’s thyroiditis (Others – Graves’ disease. In such case, there is exophthalmos).

What are the causes of nongoitrous hypothyroidism?
  • Autoimmune or idiopathic (spontaneous atrophic)—commonest cause
  • Following radio-iodine therapy for thyrotoxicosis
  • Post radiotherapy in the neck
  • After surgery (thyroidectomy)
  • Secondary to hypopituitarism, hypothalamic disorders.
Why hypothyroidism in Graves’ disease?

Natural history of Graves’ disease is hyperthyroidism, followed by euthyroidism and hypothyroidism (however, hypothyroidism may occur after radioiodine therapy or surgical treatment).

What is the difference between myxedema and hypothyroidism?

Myxoedema is always associated with hypothyroidism, due to deposition of mucopolysaccharide substances, but all hypothyroidism may not be associated with deposition of mucopolysaccharide substances, so may not be associated with myxedema. (In secondary hypothyroidism, there is no myxedematous change).

Why nonpitting edema in myxedema?

Due to deposition of mucopolysaccharide substances.

What are the types of anemia in hypothyroidism?
  • Usually normocytic normochromic
  • Iron deficiency, if menorrhagia (in female)
  • May be macrocytic due to associated pernicious anemia (due to deficiency of vitamin B12).
What are the causes of anemia in hypothyroidism?
  • Anemia of chronic disorder
  • Iron deficiency
  • Vitamin B12 deficiency
  • Folate deficiency
  • Other factors responsible—menorrhagia in female, anorexia.

Note: Macrocytosis in peripheral blood, but normoblastic bone marrow occurs in hypothyroidism


Clinical manifestations

What are the common presentations of hypothyroidism?
What are the neurological features in hypothyroidism?
  1. Carpal tunnel syndrome (or tarsal tunnel syndrome).
  2. Psychosis (myxedema madness).
  3. Myxedema coma.
  4. Cerebellar syndrome.
  5. Deafness (Trotter’s syndrome).
  6. Others:
    1. Epileptic fit (due to SIADH)
    2. Peripheral neuropathy
    3. Myotonia (Hoffman’s syndrome)
    4. Proximal myopathy
    5. Pseudodementia
    6. Drop attack.
 What are the cardiovascular problems in myxedema?
  • Sinus bradycardia
  • Pericardial effusion and pericarditis
  • Congestive cardiac failure
  • Atherosclerosis (because of hyperlipidemia)
  • Ischemic heart disease
What are the features of Hashimoto’s thyroiditis?
  • The goiter is usually diffuse, moderately enlarged and firm or rubbery. Sometimes, it may be soft to hard.
  • Antithyroid antibody (very high, >1000 IU/L)—antimicrosomal (antiperoxidase) in 90% and antithyroglobulin antibodies (no rise of TSH-receptor antibody).
  • About 25% patients are hypothyroid at presentation. In the remaining patients, serum T4 is normal and TSH is normal or raised. There is risk of developing overt hypothyroidism in future. Initially, the patient may present with features of toxicosis, called Hashi-toxicosis.
  • In young patients (<20 years), ANF may be positive.
  • Since this is an autoimmune disease, it may be associated with other autoimmune diseases like – Addison’s disease, diabetes mellitus, premature ovarian failure, rheumatoid arthritis, Sjogren’s syndrome, ulcerative colitis, autoimmune hemolytic anemia.
  • Treatment – thyroxine (it reduces the size of goiter also).



What are the common findings on examination?
  • Hoarseness of voice
  • Dry scaly skin
  • Puffy face with periorbital edema
  • Sinus bradycardia
  • Nonpitting edema
  • Delayed relaxation of ankle jerk.

 What bedside physical sign will you see in myxedema?

Ankle jerk, which shows slow relaxation, also called “hung-up reflex” (other jerks may also show slow relaxation).

How slow relaxation is best elicited in the ankle? Why slow relaxation?

It is best elicited in kneel down position on a chair or bedside. Slow relaxation is due to decreased rate of muscle contraction and relaxation.



What investigations do you suggest in hypothyroidism?
  1. Serum FT3, FT4 and TSH (low FT3, low FT4 and high TSH).
  2. Autoantibody (for Hashimoto’s thyroiditis – antiperoxidase and antithyroglobulin antibody. However, if hypothyroid is associated with Graves’ disease – TSH receptor antibody may be done).
  3. Other routine tests:
    1. CBC, ESR and PBF (there may be anemia, which is usually normocytic and normochromic, may be macrocytic anemia)
    2. Ultrasonogram of the neck
    3. ECG (low voltage tracing, sinus bradycardia)
    4. X-ray chest (cardiomegaly due to pericardial effusion, heart failure)
    5. Serum total cholesterol, LDL and triglyceride (high)
    6. CPK, LDH, SGOT (all may be high—not done routinely).
Which biochemical investigations would you suggest to diagnose hypothyroidism? Why not serum T3?

Biochemical investigations are serum T4 and TSH. Measurements of serum T3 are unhelpful since they do not discriminate reliably between euthyroidism and hypothyroidism.

What are the expected findings in primary hypothyroidism?

The expected findings in primary hypothyroidism are serum T4 low and TSH raised.

What are the expected findings in secondary hypothyroidism?

The expected findings in secondary hypothyroidism are serum T4 low and TSH also low.

If single investigation is asked for hypothyroidism, which one? / Tell one single investigation to diagnose hypothyroidism.

Serum TSH level.

How to interpret thyroid function test results?
What are the biochemical abnormalities (other than thyroid hormones) in hypothyroidism?
  • Hypercholesterolemia and hypertriglyceridemia
  • Hyponatremia (due to SIADH)
  • High CPK and LDH
What are the ECG findings in hypothyroidism?

Sinus bradycardia with low voltage ECG.

How to investigate a case of secondary hypothyroidism?

Causes may be in the pituitary or hypothalamus. TRH stimulation test should be done. After giving TRH, if TSH is high, the cause is in the hypothalamus. If there is no or little rise of TSH, the cause is in the pituitary.

How to investigate hypothyroidism in pregnancy?

Hypothyroidism is difficult to diagnose in pregnancy, as normal pregnancy may be associated with many features of hypothyroidism such as cold skin, cold intolerance, weight gain, constipation. High degree of suspicion is essential.

Most sensitive investigation is TSH, which is high. Also, FT3 and FT4 should be done (Total T3 and T4 may be high in normal pregnancy due to increase TBG).

What is the radio-iodine uptake in Hashimoto’s thyroiditis?
  • Initially—increased (toxic phase)
  • After few days or weeks—normal uptake
  • Later on—less uptake (hypothyroid phase).
What are the histological findings in Hashimoto’s thyroiditis?
  • Lymphocyte infiltration, also monocyte and plasma cell
  • Hyperplasia and fibrosis
  • Hurthle cell.



What is the difference between primary and secondary hypothyroidism?
  • Primary hypothyroidism means cause in the thyroid gland. It is usually associated with myxedema.
  • Secondary hypothyroidism means cause in the pituitary (or rarely hypothalamus). In such case, myxedema is rare. There are other features of hypopituitarism also.
What questions will you ask if you suspect hypothyroidism?
  • Do you notice any change in your weight? (weight gain)
  • Do you notice any change in your voice? (hoarseness of voice)
  • Do you prefer hot or cold? (cold intolerance)
  • What is your bowel habit? (constipation)
  • What is your menstrual history (in female)? (menorrhagia).
One disease can be diagnosed by over telephone, which is the disease?

The disease is hypothyroidism.

Ask one question to a patient of hypothyroidism and what 2 clues can you get from the patient’s answer?

Ask the patient about weight change, so when he/she answers you will know if he/she is having weight gain or weight loss and you will also know if he/she has a husky voice.

What are your differential diagnoses?
  • Nephrotic syndrome
  • Cushing’s syndrome.
Why not this is nephrotic syndrome?

In nephrotic syndrome, swelling usually starts at the face, later becomes generalized. Edema is pitting in nature. There is history of scanty micturition. All these are absent in this patient. On the other hand, the patient has cold intolerance, sleepiness, lack of concentration, non pitting edema and slow relaxation of ankle jerk and change of voice. These are not found in nephrotic syndrome.

Why not Cushing’s syndrome?

In Cushing’s syndrome, there is central obesity along with relatively thin limbs. Other signs include plethoric moon face, buffalo hump, purple striae, etc. All these are absent in this patient (there may be history of prolong intake of steroid.)



How will you treat the patient?

Treat the patient by lifelong thyroxine therapy.

What is the protocol of giving thyroxine?

Thyroxine—it should be started with low dose. The dose should be increased gradually after three weeks. Single dose is preferable, should be taken before breakfast. TSH should be repeated after 6 to 8 weeks. Once TSH is normal, maintenance dose should be continued as a single daily therapy.

50 μg (one tablet) daily for 3 weeks (given in morning in empty stomach) 100 μg daily for 3 weeks.

Then maintenance dose at 100–150 μg daily 6 weeks should pass before repeating TFTs following a dose change. It is necessary to measure thyroid function every 1–2 years, once dose of thyroxine is stabilized.

Note. If the patient has deficiency of cortisol (as in hypopituitarism or Addison’s disease), corticosteroid should be given first and then thyroxine. Otherwise, if thyroxine is given first without correcting cortisol deficiency, there will be severe Addisonian crisis.

In which conditions initial small dose (25 μg) is used?
  • Patient with IHD
  • Elderly patient
Why thyroxine should be started in low dose?

Because if high dose is given, it may precipitate anginal attack.

How long will you continue the treatment?

Life long.

What is the aim of treatment?

To maintain serum TSH within the normal reference range is the aim of treatment.

 In hypothyroidism, if there is no response after thyroxine therapy, what are the possibilities?
  • Noncompliance or insufficient dose
  • Associated hypopituitarism or Addison’s disease
  • Pernicious anemia.
Tell the follow up of hypothyroid patient during treatment.
  1. Clinical: Check for weight loss and decreased edema every two weeks till patient becomes euthyroid.
  2. Biochemical: TSH is checked every 3–6 weeks until patient is euthyroid.
    1. After that monthly follow up for 3 months.
    2. Then every 3–6 months follow up.
What are the clinical criteria of remission of hypothyroidism?
  • Reduction of weight
  • Decreased edema
  • Relief of constipation
  • Husky voice takes about 3–6 months to normalize.
If the patient has ischemic heart disease with hypothyroidism, how to treat?
  • Thyroxine should be given in low dose (25μg). Dose should be increased slowly up to the optimum dose
  • b-blocker (propranolol) should be added
  • Coronary dilator, calcium antagonist may be added
  • Coronary angiography followed by angioplasty or coronary artery bypass surgery may be needed.
How to treat an elderly patient with hypothyroidism?

Treatment is same. But one should take care whether the patient is suffering from any ischemic heart disease. Following thyroxine, it may precipitate angina and myocardial infarction. Treatment is same as above.

Tell the treatment of hypothyroidism in pregnancy.

thyroxine should be given (100 to 150 μg once daily). Requirement of thyroxine is relatively high (40 to 50%) in pregnancy, because of increased metabolism of thyroxine by the placenta and also increased serum TBG in pregnancy which binds thyroxine, resulting in less FT3 and FT4.

Dose of thyroxine should be adjusted to maintain normal TSH (serum TSH and FT4 should be measured during each trimester).

What is treatment subclinical hypothyroidism (borderline hypothyroidism or compensated euthyroidism)?

Thyroxine therapy may be given if TSH is persistently raised above 10 mU/L or when there are symptoms or high titre of thyroid antibodies or lipid abnormalities. If only TSH is marginally high with vague symptoms, thyroxine may be given sometimes. However, in female TSH should be normalized during pregnancy to avoid any adverse effect in fetus.

If TSH is marginally raised, the test should be repeated after 3 to 6 months.



What will happen if inadequate replacement is given during pregnancy?

Inadequate maternal thyroxine replacement may result in congenital hypothyroidism of the baby.

What is myxedema coma? What are the mechanisms? How to treat?

Myxedema coma is characterized by depressed level of consciousness or even coma. Convulsion may occur. It is rare, may occur in severe hypothyroidism, usually in elderly. CSF studies shows high pressure and protein is also high. There is 50% mortality.

Causes of myxedema coma:

  • Syndrome of inappropriate ADH secretion (SIADH. Coma is due to hyponatremia)
  • Hypoxemia
  • Hypercapnia
  • Hypothermia
  • Hypoglycemia
  • Other factors—cardiac failure, infection, use of sedative.

Treatment of myxedema coma: It is better to be treated in ICU. Before starting treatment, blood is

taken for FT3, FT4, TSH and cortisol.

  1. T3 (rapidly acting) 20 μg, 8 hourly usually IV given (parenteral T4 is not available, also slow to start action). If parenteral T3 is not available, oral thyroxine through Ryle’s tube should be given.
  2. IV hydrocortisone—100 mg 8 hourly (especially if suspicion of hypopituitarism).
  3. Other treatment:
    1. Slow rewarming
    2. High flow O2 therapy
    3. IV fluid and glucose
    4. Antibiotic, if infection is suspected
    5. Assisted ventilation may be necessary (as in any unconscious patient).
What is myxdema madness?

It may occur in severe hypothyroidism in the elderly. There is dementia or psychosis or delusion. Sometimes, these features may occur shortly after starting thyroxine replacement. Depression is common in hypothyroidism.

What is sick euthyroid syndrome?

In any severe acute nonthyroidal illness or after surgery, there may be abnormal thyroid function tests although the patient is euthyroid, it is called sick euthyroid syndrome. It may occur after myocardial infarction, pneumonia, cerebrovascular disease (CVD) and drugs (dopamine and steroid).

Usually, there is normal TSH, normal or low T4 and low T3. Levels are usually mildly below normal and thought to be mediated by interleukins (IL-1 and IL-6). Test should be repeated after recovery of systemic illness.

Biochemical thyroid function should not be done in patient with acute nonthyroidal illness, unless there is good evidence of thyroid disease (such as goiter and exophthalmos).

Mechanisms of sick euthyroid syndrome:

  • Reduced production or affinity of TBG to T4 and T3.
  • Reduced peripheral conversion of T4 to T3, occasionally, more rT3 (inactive reverse T3).
  • Reduced hypothalamic pituitary TSH production, hence low T3 and T4.



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