10 Other Endocrine Disorders

What is the endocrine system, and what major processes do its hormones regulate?

The endocrine system is a network of glands that releases hormones directly into the bloodstream.

Hormones regulate:

• Metabolism

• Growth and development

• Stress responses

• Reproduction

• Calcium and phosphate balance

• Bone health

Endocrine disorders often affect multiple organ systems simultaneously, so ocular findings may help detect disease early and prevent systemic morbidity, mortality, or vision loss

What three general mechanisms produce endocrine disease?

1. Hormone excess: Too much of a hormone

2. Hormone deficiency: Too little of a hormone

3. Mass effect: A tumor causes hormonal imbalance and compresses nearby structures

Example: A pituitary tumor may alter hormone secretion and compress the optic chiasm

What hormones does the thyroid produce, and what are their major physiologic functions?

The thyroid is a butterfly-shaped gland in the anterior lower neck that uses iodine to produce:

• T3: Triiodothyronine

• T4: Thyroxine

Thyroid hormones regulate:

• Metabolism

• Growth and development

• Cardiovascular function

• Thermoregulation

• Gastrointestinal function

• Muscular function

How does the hypothalamic-pituitary-thyroid axis regulate thyroid hormone production?

1. The hypothalamus releases TRH.

2. TRH stimulates the anterior pituitary to release TSH.

3. TSH stimulates the thyroid gland to produce T3 and T4.

4. T3 and T4 produce negative feedback at the hypothalamus and pituitary.

Disease can occur at three levels:

• Primary: Thyroid gland

• Secondary: Pituitary gland

• Tertiary: Hypothalamus

What thyroid laboratory patterns distinguish primary and secondary hyperthyroidism and hypothyroidism?

• Primary hyperthyroidism: ↓ TSH, ↑ T3/T4

• Secondary hyperthyroidism: ↑ TSH, ↑ T3/T4

• Primary hypothyroidism: ↑ TSH, ↓ T4

• Secondary hypothyroidism: ↓ or inappropriately normal TSH, ↓ T4

Memory rule:
In primary disease, TSH and thyroid hormone move in opposite directions. In secondary disease, the TSH level is inappropriate for the thyroid hormone level.

What is the mechanism of Graves disease, and what laboratory pattern does it produce?

Graves disease is an autoimmune cause of primary hyperthyroidism.

• Thyroid-stimulating immunoglobulins, or TSI, bind to and activate TSH receptors.

• This stimulates excessive production of T3 and T4.

• Laboratory pattern: low TSH with high T3/T4

• TSH-receptor antibodies support the diagnosis.

What are the major causes of primary versus secondary hyperthyroidism?

Primary hyperthyroidism

• Graves disease

• Toxic adenoma

• Toxic multinodular goiter

• Acute thyroiditis

Secondary hyperthyroidism

• TSH-secreting pituitary adenoma, or TSHoma

Primary disease produces low TSH and high T3/T4, whereas a TSHoma produces high TSH and high T3/T4

What systemic findings characterize hyperthyroidism?

Hyperthyroidism produces an accelerated metabolic state:

• Metabolic: Weight loss despite increased appetite, heat intolerance, sweating

• Cardiovascular: Tachycardia, palpitations, atrial fibrillation, systolic hypertension

• Neurologic: Fine tremor, hyperreflexia, anxiety, irritability, insomnia

• GI: Diarrhea and frequent stools

• Musculoskeletal: Proximal weakness and accelerated bone loss

• Dermatologic: Warm moist skin and hair thinning

• Thyroid: Goiter

Graves-specific clue: Pretibial myxedema.

How can Graves disease contribute to anemia?

Graves disease may be associated with anemia of chronic disease:

1. Chronic inflammation increases hepcidin.

2. Hepcidin decreases the availability of circulating iron.

3. Reduced available iron contributes to anemia.

Besides elevated T3/T4 and suppressed TSH, what laboratory abnormalities may occur in hyperthyroidism?

• Positive TSH-receptor antibodies in Graves disease

• Increased lipolysis

• Increased circulating free fatty acids

• Normal or slightly decreased triglycerides

• Increased clearance of triglyceride-rich lipoproteins

The defining pattern for primary hyperthyroidism remains high T3/T4 with low TSH.

How is hyperthyroidism treated?

• Methimazole: First-line antithyroid medication

• Propylthiouracil: Alternative antithyroid medication

• Beta-blockers: Control tachycardia, palpitations, and tremor

• Glucocorticoids: Adjunctive therapy in selected cases

• Radioactive iodine ablation: Common definitive treatment in the United States

• Thyroidectomy: Surgical removal of the thyroid

Radioactive iodine commonly causes hypothyroidism, requiring subsequent levothyroxine treatment.

Why should radioactive iodine be avoided in a patient with thyroid eye disease?

Radioactive iodine may worsen thyroid eye disease, so it should not be used in patients with active TED.

If radioactive iodine is used for hyperthyroidism, destruction of the thyroid usually causes hypothyroidism and creates a need for long-term levothyroxine replacement

What is the mechanism of thyroid eye disease?

Thyroid eye disease, also called thyroid orbitopathy or thyroid ophthalmopathy, is an orbital manifestation of Graves disease.

• TSI cross-reacts with receptors on orbital fibroblasts.

• Orbital fat and extraocular muscles become inflamed and enlarged.

• This produces orbital congestion, proptosis, restricted motility, and possible optic nerve compression.

TED may precede, coincide with, or follow the systemic manifestations of thyroid disease.

Who is most likely to develop thyroid eye disease, and what is its major modifiable risk factor?

• Occurs in approximately 25%–50% of patients with Graves disease

• Most commonly presents between ages 30 and 50

• Female-to-male ratio is approximately 5:1

• Smoking is an important modifiable risk factor

Smoking also prolongs the active inflammatory phase and is associated with a more difficult disease course

What are the active and quiescent phases of thyroid eye disease?

Active phase

• Congestive and inflammatory

• Red, painful eyes

• Lasts approximately one year in nonsmokers

• May last two to three years in smokers

Quiescent phase

• Inflammation becomes inactive and stable

• Residual proptosis, diplopia, or eyelid abnormalities may persist

• Rehabilitative surgery is generally performed after stability is achieved

What are the major ocular manifestations of thyroid eye disease?

• Bilateral but frequently asymmetric involvement

• Eyelid retraction and stare

• Eyelid lag

• Proptosis

• Periorbital edema

• Resistance to globe retropulsion

• Lagophthalmos

• Conjunctival chemosis

• Exposure keratopathy

• Elevated IOP

• Restrictive ophthalmoplegia

• Optic neuropathy

Key point: The severity of TED does not necessarily correlate with the patient’s thyroid hormone levels

What does the NOSPECS classification describe in thyroid eye disease?

• Class 0: No signs or symptoms

• Class 1: Eyelid retraction and stare only

• Class 2: Soft-tissue involvement

• Class 3: Proptosis

• Class 4: Extraocular muscle involvement

• Class 5: Corneal involvement

• Class 6: Sight loss from optic nerve involvement

Mnemonic:
No signs, Only lid signs, Soft tissue, Proptosis, Extraocular muscles, Cornea, Sight loss.

Which eyelid signs are associated with Class 1 thyroid eye disease?

• Dalrymple sign: Upper-eyelid retraction

• Kocher sign: Severe retraction producing a marked stare

• von Graefe sign: Upper-eyelid lag when the patient looks downward

• Lagophthalmos: Inability to close the eyelids completely

These abnormalities increase the risk of exposure-related ocular surface disease

What symptoms and signs characterize Class 2 soft-tissue involvement in thyroid eye disease?

Symptoms

• Foreign-body sensation or grittiness

• Redness

• Tearing

• Photophobia

Signs

• Conjunctival chemosis

• Hyperemia

• Periorbital edema

• Prolapsed orbital fat

How is clinically significant proptosis identified in thyroid eye disease?

Proptosis is measured with an exophthalmometer.

Lecture thresholds include:

• More than 22 mm in Caucasian patients

• More than 24 mm in African American patients

• More than a 2 mm asymmetry between the two eyes

Proptosis may compromise eyelid closure and produce ocular surface exposure

Which extraocular muscles are affected in thyroid eye disease, and what motility deficit occurs most commonly?

TED causes restrictive ophthalmoplegia from enlarged, stiff extraocular muscles.

Order of involvement:

1. Inferior rectus

2. Medial rectus

3. Superior rectus

4. Lateral rectus

5. Oblique muscles

Mnemonic: “I’M SLOW”

• Inferior rectus

• Medial rectus

• Superior rectus

• Lateral rectus

• Obliques

Inferior rectus involvement makes restricted upgaze especially common.

Why can thyroid eye disease cause elevated IOP?

Enlarged and stiff extraocular muscles exert pressure on the globe, particularly during attempted upgaze.

This can cause:

• Elevated IOP in primary gaze or upgaze

• Glaucomatous damage

• Optic nerve atrophy in severe disease

IOP should therefore be measured in primary gaze and upgaze when TED is suspected.

What corneal complications occur in advanced thyroid eye disease?

Proptosis, eyelid retraction, and lagophthalmos produce ocular surface exposure, which may progress to:

• Exposure keratitis

• Persistent epithelial damage

• Corneal ulceration

• Vision loss

Symptoms include photophobia, blurred vision, burning, irritation, and pain

What are the findings of dysthyroid optic neuropathy, and can it occur without marked proptosis?

Dysthyroid optic neuropathy results from compression of the optic nerve or its blood supply.

Findings include:

• Decreased visual acuity

• Reduced color vision

• Central or paracentral visual-field defects

• Relative afferent pupillary defect when asymmetric

• Normal or swollen optic disc

It affects approximately 5% of patients with TED and may occur without proptosis.

What findings are included in the Clinical Activity Score for thyroid eye disease?

Initial assessment awards one point for each of the following:

• Retrobulbar pain

• Pain with eye movement

• Eyelid redness

• Conjunctival redness

• Eyelid swelling

• Conjunctival chemosis

• Swollen caruncle

Subsequent assessments also consider:

• Proptosis increase of at least 2 mm

• Eye-movement decrease of at least 5°

• Visual-acuity reduction of at least one Snellen line

A CAS of 3 or more suggests active TED

What systemic and ocular testing should be performed when thyroid eye disease is suspected?

Systemic evaluation

• TSH

• T3 and T4

• TSH-receptor antibodies

Ocular evaluation

• Eyelid position and closure

• Exophthalmometry

• Extraocular motility

• IOP in primary gaze and upgaze

• Visual acuity

• Color vision

• Pupillary testing

• Visual fields

• Optic nerve examination

• Orbital CT or MRI when indicated

How is thyroid eye disease managed?

Treatment requires systemic control of thyroid dysfunction plus targeted ocular therapy.

• Refer to primary care or endocrinology

• Encourage smoking cessation, a low-sodium diet, and stress reduction

• Treat exposure with artificial tears, ointment, cyclosporine, or nighttime lid taping

• Manage diplopia with prism

• Consider strabismus surgery during the quiescent phase

• Treat severe disease with systemic corticosteroids, orbital radiotherapy, orbital decompression, or teprotumumab

Teprotumumab is an antibody treatment that can reduce proptosis in moderate-to-severe TED

What are the major causes of primary and secondary hypothyroidism?

Primary hypothyroidism

• Hashimoto thyroiditis

• Radioactive iodine or thyroidectomy

• Iodine deficiency, the most common cause worldwide

• Lithium or amiodarone

• Postpartum thyroiditis

• Neoplastic thyroid destruction

Secondary hypothyroidism

• Pituitary dysfunction causing TSH deficiency

Primary disease produces high TSH and low T4; secondary disease produces low or normal TSH with low T4

What systemic findings characterize hypothyroidism?

Hypothyroidism produces generalized slowing:

• Metabolic: Fatigue, weight gain, cold intolerance

• Reproductive: Menstrual irregularity or heavy periods

• Cardiovascular: Bradycardia and low cardiac output

• Neurologic: Lethargy, depression, slowed reflexes, memory impairment

• GI: Constipation

• Musculoskeletal: Myalgias, stiffness, carpal tunnel syndrome

• Dermatologic: Dry skin, hair loss, coarse or brittle hair

Severe disease may progress to life-threatening myxedema coma.

What ocular and adnexal findings may occur in hypothyroidism?

• Periorbital edema

• Madarosis

• Loss of the lateral third of the eyebrows

These findings reflect the generalized tissue and hair changes associated with reduced thyroid hormone activity

What is the mechanism and clinical course of Hashimoto thyroiditis?

Hashimoto thyroiditis is autoimmune destruction of the thyroid.

• Anti-thyroid peroxidase antibodies attack thyroid peroxidase.

• T3 and T4 synthesis becomes impaired.

• Immune-mediated destruction of follicular cells produces hypothyroidism.

• The thyroid may initially enlarge and form a goiter.

• Late disease produces fibrosis and atrophy, leaving a small, shrunken gland.

Anti-TPO antibodies are tested when autoimmune hypothyroidism is suspected.

What is the standard treatment for hypothyroidism?

The standard treatment is oral synthetic levothyroxine, which replaces T4.

Examples include:

• Synthroid

• Tirosint

• Unithroid

Monitor TSH and T4, especially in primary hypothyroidism. Intravenous levothyroxine is reserved for emergency situations, such as severe decompensated hypothyroidism

Why can a pituitary mass produce characteristic ocular and neurologic findings?

The pituitary gland rests in the sella turcica, approximately 10 mm below the optic chiasm.

A growing pituitary mass may:

• Compress the optic chiasm

• Extend into the cavernous sinus

• Affect cranial nerves III, IV, V1, V2, and VI

• Alter endocrine function through excess or deficient hormone secretion

What are the major types of pituitary adenoma and their hormonal effects?

• Prolactinoma: Most common; produces prolactin

• ACTH-secreting adenoma: Causes Cushing disease

• Growth hormone-secreting adenoma: Causes acromegaly in adults or gigantism in children

Prolactinoma manifestations include:

• Women: Amenorrhea, galactorrhea, infertility

• Men: Erectile dysfunction and gynecomastia

What ocular findings suggest a pituitary adenoma?

• Bitemporal hemianopia: Optic chiasm compression

• Optic atrophy

• Reduced color vision

• Diplopia or ptosis from cavernous sinus involvement

If the adenoma causes Cushing disease, excess cortisol may also contribute to:

• Posterior subcapsular cataracts

• Steroid-associated glaucoma

What is the mechanism and clinical presentation of Cushing disease?

Cushing disease is caused by an ACTH-secreting pituitary adenoma.

• Excess ACTH stimulates the adrenal cortex.

• Cortisol and androgen production increase.

Major findings:

• Moon face

• Buffalo hump

• Central obesity with thin extremities

• Easy bruising

• Purple abdominal, breast, or thigh striae

• Hypertension

• Diabetes

• Osteoporosis

• Infertility

• Depression or irritability

• Posterior subcapsular cataracts

What is the effect of a growth hormone-secreting pituitary adenoma in adults versus children?

• Adults: Acromegaly

• Children: Gigantism

Associated findings include:

• Coarse facial features

• Enlarged hands and feet

• Jaw overgrowth

• Hypertension

• Cardiomyopathy

The different presentations occur because children still have open growth plates, whereas adults do not.

How do Cushing syndrome and Cushing disease differ?

• Cushing syndrome: Clinical state caused by chronic excess cortisol from any source

• Cushing disease: Cushing syndrome specifically caused by an ACTH-secreting pituitary adenoma

Causes of Cushing syndrome include:

• Exogenous glucocorticoid use

• Adrenal adenoma or carcinoma

• Pituitary ACTH-secreting adenoma

What is the mechanism and systemic presentation of Addison disease?

Addison disease is primary adrenal insufficiency, causing deficient:

• Cortisol

• Aldosterone

• Adrenal androgens

Possible causes include autoimmune destruction, infection, and metastatic disease.

Findings include:

• Fatigue and weakness

• Weight loss

• Bronze hyperpigmentation

• Hypoglycemia

• Hypotension or postural hypotension

• Hyperkalemia

• Nausea, vomiting, or diarrhea

• Dehydration

• Depression

What is an adrenal crisis, and why is it an emergency?

An adrenal crisis is acute, severe adrenal insufficiency.

It may produce:

• Profound fatigue

• Severe hypotension

• Vascular collapse

• Hypoglycemia

• Vomiting

• Severe dehydration

• Renal shutdown

It is a medical emergency because circulatory collapse and metabolic abnormalities can rapidly become life-threatening

What ocular complications are associated with Addison disease?

Addison disease has no direct ocular complications in the lecture. Ocular complications are primarily secondary to corticosteroid replacement treatment:

• Posterior subcapsular cataracts

• Steroid-induced glaucoma

• Rare central serous chorioretinopathy

How can hyperthyroidism and hypothyroidism be rapidly distinguished clinically?

Hyperthyroidism: “Everything speeds up”

• Weight loss

• Heat intolerance

• Tachycardia

• Tremor and hyperreflexia

• Anxiety

• Diarrhea

• Warm, moist skin

Hypothyroidism: “Everything slows down”

• Weight gain

• Cold intolerance

• Bradycardia

• Slowed reflexes

• Lethargy or depression

• Constipation

• Dry skin and coarse hair

Which endocrine disorders in this lecture are associated with posterior subcapsular cataracts and glaucoma?

• Cushing disease/syndrome: Excess endogenous cortisol

• Addison disease treatment: Chronic corticosteroid replacement

• Other prolonged exogenous corticosteroid exposure

The characteristic cataract is a posterior subcapsular cataract, and steroid exposure can also produce ocular hypertension or glaucoma

What are the most important vision-threatening findings in thyroid eye disease?

1. Dysthyroid optic neuropathy

   • Decreased vision or color vision

   • Central or paracentral field defect

   • Possible RAPD

   • May occur without proptosis

2. Severe exposure keratopathy

   • Epithelial breakdown

   • Corneal ulceration

   • Vision loss

These findings require urgent escalation of treatment

What are the highest-yield endocrine and ocular associations to memorize?

• Primary hyperthyroidism: ↓ TSH, ↑ T3/T4

• Secondary hyperthyroidism: ↑ TSH, ↑ T3/T4

• Primary hypothyroidism: ↑ TSH, ↓ T4

• Secondary hypothyroidism: ↓/normal TSH, ↓ T4

• Graves disease: TSI activates TSH receptors

• Hashimoto thyroiditis: Anti-TPO antibodies destroy the thyroid

• TED: Orbital fat and extraocular muscle inflammation

• Smoking: Major modifiable TED risk factor

• NOSPECS: No signs, Only lid signs, Soft tissue, Proptosis, EOM, Cornea, Sight loss

• I’M SLOW: Inferior, Medial, Superior, Lateral, Obliques

• CAS ≥3: Active TED

• Most commonly restricted movement: Upgaze

• Optic neuropathy: Can occur without proptosis

• Pituitary adenoma: Bitemporal hemianopia from chiasmal compression

• Prolactinoma: Most common pituitary adenoma

• Cushing disease: Pituitary ACTH adenoma

• Cushing syndrome: Cortisol excess from any cause

• GH excess: Acromegaly in adults, gigantism in children

• Addison disease: Low cortisol, aldosterone, and androgens

• Adrenal crisis: Hypotension, hypoglycemia, dehydration, and vascular collapse