Hypothyroidism: Pathology review

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Hypothyroidism: Pathology review

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68-year-old man is brought to the physician by his partner because of increasing forgetfulness over the last 5 weeks. The patient is unable to finish his daily crossword puzzles and often has to call his partner when he is at the grocery store to help remember the list. He has had an 8-lb weight gain over this same time period. The patient has chronic hypertension, which is well-controlled with lisinopril, and he has also recently started taking laxatives several times a week to relieve constipation. Temperature is 36.5°C (97.7°F), pulse is 57/min, blood pressure is 128/86 mm Hg, and BMI is 27 kg/m2. The patient is alert and oriented to time, place, and person. Physical examination shows dry skin and a slightly distended abdomen. There is no mucosal pallor and capillary refill is less than 2 seconds. Deep tendon reflexes are delayed in the upper and lower extremities. Further testing confirms the diagnosis. Which of the following is the most appropriate pharmacotherapy for this patient?  

Transcript

Content Reviewers:

Yifan Xiao, MD

On the Endocrinology ward, two individuals came in.

The first one is 23 year old Hannah who complains of lethargy, fatigue, reduced appetite, muscle weakness and constipation.

She also says that lately she gained a bit of weight and has a low libido.

On clinical examination, she has periorbital edema, dry, cool skin, her nails are brittle and her reflexes are slow.

She also has a moderately enlarged, painless goiter.

The other one is 33 year old Quentin, who also presents with lethargy, fatigue, reduced appetite, muscle weakness, constipation and he’s also complaining about feeling cold all the time.

He said that he recently had the flu, but no other illnesses.

On clinical examination, there’s periorbital edema, dry, cool skin, brittle nails and hair, and a very painful goiter. TSH, free T3 and T4 are taken, along with antithyroid-peroxidase and antithyroglobulin antibodies.

Both Hannah and Quentin have high levels of TSH and low T3 and T4 levels, but Hannah has positive antithyroid-peroxidase and antithyroglobulin antibodies.

Both individuals seem to have hypothyroidism.

First, a bit of physiology.

Normally, the hypothalamus detects low serum levels of thyroid hormones and releases thyrotropin-releasing hormone or TRH into the hypophyseal portal system.

The anterior pituitary then releases thyroid-stimulating hormone, also called thyrotropin or simply TSH. TSH stimulates the thyroid gland.

The thyroid gland is made up of thousands of follicles, which are small spheres lined with follicular cells.

Follicular cells convert thyroglobulin, a protein found in follicles, into two iodine-containing hormones, triiodothyronine or T3, and thyroxine or T4.

Once released from the thyroid gland, these hormones enter the blood and bind to circulating plasma proteins.

Only a small amount of T3 and T4 will travel unbound in the blood, and can act upon nearly every type of cell in the body.

Once inside the cell T­4 is usually converted into T3, and it can exert its effect. T3 speeds up the cell’s basal metabolic rate.

It increases cardiac output, stimulates bone resorption, basically thinning out the bones, and activates the sympathetic nervous system.

Thyroid hormones are also involved in a number of other things, like controlling sebaceous and sweat gland secretion, hair follicle growth, and regulating proteins and mucopolysaccharide synthesis by skin fibroblasts.

Now, hypothyroidism can happen a few different ways, and all of them result in a decrease in thyroid hormones and a decreased basal metabolic rate, where cellular reactions are happening slower than normal.

There are three types of hypothyroidism. In primary hypothyroidism, the thyroid gland is the problem, because it isn’t making enough thyroid hormones.

Not only is there a lack of T3 and T4 which causes a slowing down of metabolic processes, but there are increased levels of TSH from the pituitary to try to stimulate the gland.

A secondary effect of the high levels of TSH is that it stimulates fibroblasts in the skin and soft tissues.

The stimulated fibroblasts start depositing glycosaminoglycans in the interstitium.

Secondary hypothyroidism is caused by damage to the pituitary and tertiary hypothyroidism is caused by damage to the hypothalamus.

These are sometimes called central hypothyroidism.

A high yield fact for your exam is that they can lead to a decrease in TSH release, which decreases the activity of the thyroid.

Regardless of the cause, symptoms of hypothyroidism are the same and in order to remember them better, keep in mind that hypothyroidism slows down almost everything.

They can take years to manifest and affect multiple systems.

Metabolic findings include modest weight gain, and cold intolerance due to the low basal metabolic rate.

Skin and hair findings include cool skin due to vasoconstriction, dry skin due to reduced secretion of the sweat glands and sebaceous glands.

The hair is coarse and brittle hair and there can be diffuse alopecia and the nails are also brittle.

Hypothyroidism leads to an increase in glycosaminoglycans in the interstitium, which can elevate the osmotic pressure, leading to water retention and eventually non-pitting edema.

As a result, the individual has a puffy appearance, called myxedema.

Ocular findings include periorbital edema.

Gastrointestinal findings include constipation due to low GI motility and there’s also reduced appetite.

Musculoskeletal findings include hypothyroid myopathy which presents with muscle weakness, especially proximal weakness.

Sometimes, there can also be muscle damage and in this case, CK levels are increased.

It’s not exactly understood why this happens, but it’s known that thyroid hormones have a great influence on cell metabolism and this includes muscle cell metabolism.

Sometimes, carpal tunnel syndrome can appear and it’s thought that this happens due to the accumulation of glycosaminoglycans.

There can also be myoedema which is a bump caused by local muscle contraction when triggered by light percussion with an object.

The prolonged muscle contraction is a result of the alterations in muscle fibers caused by hypothyroidism.

Reproductive findings include menorrhagia, oligomenorrhea, low libido in females and even infertility. These changes can occur due to deficient LH secretion.

Neuropsychiatric findings include hypoactivity, lethargy, fatigue, weakness, depressed mood and slower reflexes.

Finally, cardiovascular findings include bradycardia, low cardiac output and dyspnea after exercising.

Diagnosing hypothyroidism is done by measuring blood levels of TSH, T3, and T4.

In all cases, thyroid hormones will be low, but TSH levels vary. If it’s due to a primary cause, TSH will be high and if it’s due to a secondary cause, TSH will either be low or normal.

There can also by hypercholesterolemia, due to low LDL receptor expression.

Okay, let’s now start talking about causes of hypothyroidism, starting with causes of primary hypothyroidism.

First, there’s Hashimoto thyroiditis, which is the most common cause of primary hypothyroidism in countries that fortify foods with iodine.

This is an autoimmune disorder where T cells and autoantibodies like anti-thyroid peroxidase and thyroglobulin antibodies infiltrate the thyroid, remember these antibodies because this is very high yield!

Now, there is a gene complex involved in the regulation of the immune response and this is called the human leukocyte antigen system, or HLA system.

Interestingly, individuals with Hashimoto thyroiditis often have specific HLA genes in common with each other, and one that is associated with Hashimoto thyroiditis is HLA-DR3, which is high yield for your tests.

Damage to some parts of the thyroid, and the subsequent increase in TSH, leads to thyroid hypertrophy and hyperplasia.

Sources
  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Riedel's Thyroiditis: A Clinical Review" The Journal of Clinical Endocrinology & Metabolism (2011)
  4. "The History and Future of Treatment of Hypothyroidism" Annals of Internal Medicine (2016)
  5. "Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges" The Journal of Clinical Endocrinology & Metabolism (2012)
  6. "Hypothyroidism" Aust Fam Physician (2014)
  7. "Approach to the Patient with Postpartum Thyroiditis" The Journal of Clinical Endocrinology & Metabolism (2012)