Chapter Notes: Endocrine System - 2

Table of Contents
1. Key Characteristics of Different Types of Thyroid Cancers
2. Hyperparathyroidism
3. Hypoparathyroidism
4. Pituitary Gland
5. Hyperpituitarism
6. Disorders of the Posterior Pituitary
7. Adrenal Cortex
8. Cushing Syndrome
9. Adrenogenital Syndrome
10. Adrenal Insufficiency
11. Adrenal Medulla
12. Pheochromocytoma
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Key Characteristics of Different Types of Thyroid Cancers

Papillary Carcinoma

• This is the most prevalent form of thyroid cancer.
• It usually occurs in people between the ages of 20 and 40.
• The cancer spreads through the lymphatic system.
• Papillary carcinoma has a very good prognosis.
• Under the microscope, it is characterized by the following features:
  • The presence of papillae with fibrovascular stalks.
  • The presence of calcified structures called psammoma bodies.
  • Cancer cells with distinct nuclear features, such as fine chromatin leading to "ground glass" or "Orphan Annie eye" nuclei, intranuclear inclusions known as "pseudoinclusions," and intranuclear grooves.
• There are different variants of papillary carcinoma, including:
  • The encapsulated variant, which has a good prognosis.
  • The follicular variant, which has a poorer prognosis.
  • The tall cell variant, which has the worst prognosis.
• Papillary thyroid tumors are characterized by:
  • Their popularity as the most common type.
  • The presence of palpable lymph nodes, indicating lymphatic spread.
  • Positive uptake of I (131).
  • Excellent prognosis after radiation treatment in the head and neck region.
  • The presence of psammoma bodies.

Follicular Carcinoma

• Often referred to as the "4 Fs":
• Faraway metastasis with a favourable prognosis.
• Typically exhibits vascular invasion, leading to spread through the bloodstream.
• It is the second most common type of thyroid cancer.
• Commonly affects older women, particularly those aged 40 to 50.
• Vascular invasion is a frequent occurrence, with less lymphatic spread, and metastasis to bones, lungs, liver, and other organs.
• Microscopically, follicular carcinoma is characterized by:
  • Cells forming small follicles containing colloid, without the presence of psammoma bodies.
  • Occasional presence of Hurthle cells, which have abundant eosinophilic cytoplasm.
• Follicular carcinoma is distinguished from follicular adenoma primarily by the presence of capsular invasion.

Medullary Carcinoma

• Medullary carcinoma originates from parafollicular cells (C cells) in the thyroid, which produce the hormone calcitonin.
• Approximately 80% of medullary carcinoma cases are sporadic, while the remaining cases are linked to hereditary conditions such as multiple endocrine neoplasia type II (MEN II) syndromes.
• This type of cancer is most commonly associated with amyloidosis, a condition characterized by the abnormal accumulation of amyloid protein in tissues.
• In sporadic cases, medullary carcinoma is usually unilateral, affecting one lobe of the thyroid gland. In familial cases, it is often bilateral and multicentric, occurring in multiple locations within the thyroid gland.
• Microscopically, medullary carcinoma is characterized by the presence of polygonal and spindle-shaped cells within an amyloid stroma. In familial cases, there is often evidence of multicentric C-cell hyperplasia, where there is an abnormal increase in the number of C cells in the thyroid.

Anaplastic Carcinoma

• Anaplastic carcinoma is a type of undifferentiated thyroid cancer and is known for having the worst prognosis among all types of thyroid cancers.
• This type of cancer is commonly observed in elderly female patients.
• Approximately 50% of patients with anaplastic carcinoma report a history of multinodular goitre, a condition characterized by the presence of multiple nodules in the thyroid gland.
• Microscopically, anaplastic carcinoma is characterized by the presence of highly anaplastic cells, which may include giant cells, spindle cells, a mixture of giant and spindle cells, or small cells.

Quick Revision of Frequently Asked MCQs from Thyroid Cancers

• Most common thyroid carcinoma: Papillary
• Least common thyroid carcinoma: Anaplastic
• Least malignant: Papillary
• Most malignant: Anaplastic
• Most common cancer after radiation: Papillary
• Cancer developing in Hashimoto's thyroiditis: Lymphoma
• Thyroid cancer developing in long-standing multinodular goitre: Follicular, Anaplastic (rare)
• Type of thyroid cancer in MEN syndrome: Medullary
• Thyroid cancer associated with amyloidosis: Medullary
• Psammoma bodies seen in: Papillary
• Orphan-Annie eyed nuclei seen in: Papillary
• Thyroid cancer associated with dystrophic calcification: Papillary
• Carcinoma derived from 'C' cell of thyroid: Medullary
• Carcinoma developing in thyroglossal tract: Papillary

Parathyroid Gland

• The parathyroid glands are four small glands located near the thyroid gland. They are composed of chief cells, which contain granules of parathyroid hormone (PTH), and oxyphil cells, which contain glycogen.
• PTH plays a crucial role in regulating calcium levels in the body by raising serum calcium levels and promoting the excretion of phosphate in urine.
• Malignancy is the most common cause of noticeable hypercalcemia, while primary hyperparathyroidism is the most frequent cause of asymptomatic hypercalcemia.
• In cases of malignancy, increased calcium levels can result from osteolytic metastasis or the secretion of a PTH-related peptide (PTHrP).

Medullary Carcinoma (3 Ms)

• MEN association: Medullary carcinoma is linked with multiple endocrine neoplasia (MEN) syndromes, specifically MEN IIa and MEN IIb.
• Median node dissection: This surgical procedure is often performed in cases of medullary carcinoma to remove affected lymph nodes.
• Amyloid: Medullary carcinoma is associated with amyloidosis, a condition characterized by the accumulation of amyloid protein in tissues, which can occur in the tumor stroma.

Hyperparathyroidism

Hyperparathyroidism can be classified as primary (due to the autonomous and excessive production of parathyroid hormone, PTH) or secondary. In rare instances, it may be tertiary.

Primary hyperparathyroidism

Primary hyperparathyroidism is the leading cause of asymptomatic hypercalcemia and can arise from:

• A parathyroid adenoma
• Primary hyperplasia
• Parathyroid cancer

Hyperparathyroidism can be either inherited or occur sporadically. Important genetic factors associated with sporadic hyperparathyroidism include:

• The PRAD 1 proto-oncogene on chromosome 11, which leads to increased levels of cyclin D1, promoting the growth of parathyroid cells.
• MEN I, a tumour suppressor syndrome linked to multiple endocrine neoplasia type I, located on chromosome 11q13.

Inherited syndromes related to familial hyperparathyroidism include:

• Multiple endocrine neoplasia types I and II (MEN-I and MEN-II), with associated genes on chromosome 11q and 10q, respectively.
• Familial hypocalciuric hypercalcemia (FHH), caused by a genetic mutation that reduces sensitivity to calcium, leading to increased PTH release.

Morphology

• Adenoma: Characterized by a single nodule with smaller glands surrounding the adenoma.
• Primary hyperplasia: Involves uneven enlargement of all four glands, with the presence of chief cells.
• Parathyroid carcinoma: Typically affects a single gland.

Clinical features

• Often asymptomatic, with the primary diagnostic indicators being elevated serum calcium and PTH levels.
• Potential symptoms include nephrolithiasis (kidney stones) or nephrocalcinosis (calcium accumulation in the kidneys).
• Other complications may involve osteoporosis, osteitis fibrosa cystica (changes in bone marrow), metastatic calcification (deposition in blood vessels, stomach, and heart), and neurological manifestations such as depression and lethargy.

Secondary Hyperparathyroidism

Secondary hyperparathyroidism is frequently observed in conditions such as renal failure, vitamin D deficiency, steatorrhea, and nutritional deficiencies. In these situations, the low calcium levels stimulate the release of PTH.

• Morphological examination typically reveals enlarged parathyroid glands.
• Clinical features resemble those of primary hyperparathyroidism but may also include calciphylaxis, a condition characterized by the calcification of blood vessels leading to organ damage.
• Laboratory tests usually show low serum calcium and high PTH levels.

Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism occurs when there is an excessive and autonomous activity of the parathyroid glands, continuing even in the presence of elevated calcium levels. This condition is typically managed through surgical intervention, such as parathyroidectomy.

Hypoparathyroidism

• Surgical removal of the parathyroid glands, which is the most common cause.
• Congenital absence of the parathyroid glands, such as in DiGeorge syndrome. In this condition, the 3rd and 4th pharyngeal pouches do not develop properly, leading to the absence of the thyroid and parathyroid glands.
• Idiopathic causes, where the reason for the condition is unknown.

Clinical Features

The symptoms of hypoparathyroidism are due to hypocalcemia (low calcium levels in the blood), with tetanybeing the main sign. Tetany includes:

• Neuromuscular hyperexcitability, which is increased sensitivity and activity of the muscles and nerves.
• Cataract formation.
• Hypotension (low blood pressure).
• QT prolongation on an electrocardiogram (ECG), which is a longer than normal interval between heartbeats.
• Tingling sensations in the mouth, hands, and feet.
• Diagnostic tests may show:
  • Chvostek sign. When the facial nerve near the ear is tapped, it causes a contraction of the facial muscles.
  • Trousseau sign. Inflating a blood pressure cuff above systolic pressure for about 3 minutes leads to flexion at the metacarpophalangeal joint and extension at the interphalangeal joints of the hand.
• Diagnosis of hypoparathyroidism is confirmed by low serum calcium levels.
• The most common cause of Primary Hyperparathyroidism is Parathyroid adenoma.
• The best initial screening test for Primary Hyperparathyroidism is intact serum PTH levels.
• Invasion of surrounding tissue or metastasis is the only reliable sign of malignancy in parathyroid disorders.

Clinical Features of Primary Hyperparathyroidism

• Primary Hyperparathyroidism is characterized by the symptoms known as " Stones, bones, abdominal groans, and psychic moans."
• Secondary Hyperparathyroidism is most commonly caused by renal failure.
• Hypoparathyroidism is most commonly caused by the surgical removal of the parathyroid gland.
• Hyperventilation can worsen symptoms of hypoparathyroidism because it leads to alkalosis, which in turn reduces the levels of free calcium in the blood.

Pituitary Gland

The pituitary gland is a small gland weighing about 0.5 grams and is situated in a bony cavity called the sella turcica. It consists of two main parts:

• Anterior Lobe
• Posterior Lobe. This part stores two important hormones, oxytocin and antidiuretic hormone (also known as vasopressin ).

Adenoma Classification

• Adenomas can be classified into macroadenomas, which are larger than 1 centimeter, and microadenomas, which are smaller than 1 centimeter.
• There are key differences between a pituitary adenoma and normal anterior pituitary tissue:
  • In pituitary adenomas, there is no reticulin network, which is a supportive framework of fibers.
  • Pituitary adenomas exhibit cellular monomorphism, meaning the cells are similar in appearance, whereas normal tissue shows more variation.

Diagnosis

• The initial test for diagnosing certain conditions involves measuring serum IGF-I levels, which are typically elevated.
• A confirmatory test checks for the inability to suppress growth hormone (GH) production after administering a glucose load, indicating abnormal GH regulation.

Panhypopituitarism and Sheehan Syndrome

• Pituitary adenoma is the leading cause of panhypopituitarism, a condition characterized by the deficiency of all pituitary hormones.
• Sheehan syndrome occurs when the pituitary gland is damaged after childbirth due to severe blood loss or shock, leading to hormonal deficiencies.

Empty Sella Syndrome

• Primary Empty Sella Syndrome involves the arachnoid mater (a protective membrane) and cerebrospinal fluid (CSF) herniating through a defect in the diaphragm of the sella, resulting in compression of the pituitary gland.
• Secondary Empty Sella Syndrome occurs following the removal of a pituitary adenoma, leading to hypopituitarism, a condition where the pituitary gland fails to produce certain hormones.

Hyperpituitarism

Hyperpituitarism refers to a condition characterized by an excess of hormones produced by the pituitary gland, often due to a tumor or other abnormal growth in the pituitary gland.

Causes: Hyperpituitarism can be caused by various factors, including:

• Adenoma: The most common cause, where a benign tumor forms in the anterior lobe of the pituitary gland.
• Hyperplasia: An abnormal increase in the number of cells in the pituitary gland.
• Carcinoma:. malignant tumor in the pituitary gland.

Most adenomas are monoclonal or associated with Multiple Endocrine Neoplasia Type I (MEN I). Histologically, these adenomas consist of polygonal cells with little reticulin or connective tissue.

Prolactinoma

• Prolactinoma is the most prevalent type of pituitary tumor.
• Small microadenomas produce excess prolactin, leading to symptoms such as amenorrhea, galactorrhea, and infertility.
• Women are diagnosed earlier due to menstrual issues, making microadenomas more common in females.

Stalk Effect

• Any mass in the suprasellar area can disrupt the normal inhibition of prolactin secretion by the hypothalamus, leading to hyperprolactinemia.
• This phenomenon is known as the "stalk effect," where a mass in the suprasellar region interferes with hypothalamic control of prolactin secretion.

Growth Hormone Adenoma

• Growth hormone adenoma is the second most common type of pituitary adenoma.
• About 40% of patients experience ongoing GH activity, resulting in excess insulin-like growth factor I (IGF-I), leading to gigantism in children and acromegaly in adults.
• Gigantism: Characterized by tall stature and long limbs.
• Acromegaly: Features include a prominent jaw (prognathism), a flat broad forehead, enlarged hands and feet, and growth of internal organs such as the heart, spleen, and kidneys.

Other Pituitary Tumors

• Corticotroph Cell Adenoma: Produces ACTH, leading to Cushing disease.
• Thyrotrope Adenoma: Secretes TSH, causing hyperthyroidism.
• Gonadotrope Adenoma: Secretes FSH and LH.

Hypopituitarism

Hypopituitarism is a condition characterized by the insufficient production of hormones by the pituitary gland, typically occurring when more than 75% of the gland is damaged. Hormones like growth hormone (GH) and gonadotropins (FSH and LH) are often affected early in this condition. The causes of hypopituitarism include:

• Tumors or cysts compressing pituitary tissue
• Pituitary surgery or radiation exposure
• Pituitary apoplexy, which is sudden bleeding in a pituitary adenoma
• Ischemic necrosis of the pituitary gland
• Sheehan syndrome, where the pituitary is damaged after childbirth due to severe bleeding
• Empty sella syndrome

The symptoms of hypopituitarism vary depending on which hormone is deficient. Some examples include:

• Growth failure due to a lack of GH
• Loss of libido and amenorrhea (absence of menstruation)
• Infertility resulting from gonadotropin deficiency
• Hypothyroidism due to insufficient thyroid-stimulating hormone (TSH)
• Hypoadrenalism from a lack of adrenocorticotropic hormone (ACTH)
• Changes in skin color due to a deficiency in melanocyte-stimulating hormone (MSH)

Disorders of the Posterior Pituitary

Diabetes Insipidus

• Diabetes Insipidus occurs when there is a deficiency of antidiuretic hormone (ADH), also known as vasopressin.
• This deficiency leads to symptoms such as polyuria, which is frequent urination, and polydipsia, which is excessive thirst.
• As a result of this condition, individuals may experience hypernatremia, characterized by high sodium levels in the blood, and hyperosmolality, indicating an increased concentration of solutes in the blood.
• The underlying issue is the kidneys' inability to retain free water, causing dehydration.

Syndrome of Inappropriate ADH Secretion (SIADH)

• SIADH is marked by the excessive production of antidiuretic hormone (ADH).
• This leads to oliguria, or reduced urine output, and water retention in the body.
• Consequently, individuals with SIADH may develop hyponatremia, which is low sodium levels in the blood, and cerebral edema, or swelling of the brain.
• Common causes of SIADH include ectopic ADH secretion, often associated with small cell lung cancer, injury to the hypothalamus or pituitary gland, and certain medications such as vincristine.

Adrenal Cortex

The adrenal gland consists of two primary parts: the adrenal cortex and the adrenal medulla. The cortex itself is divided into three layers, each responsible for producing specific hormones:

• Zona glomerulosa: This outer layer produces mineralocorticoids, which are essential for regulating sodium and potassium levels in the body.
• Zona fasciculata: The middle layer produces glucocorticoids, hormones that play a crucial role in metabolism and the body's response to stress.
• Zona reticularis: The innermost layer produces sex steroids, including androgens and estrogens, which are involved in sexual development and function.

Hyperadrenalism refers to an overactivity of the adrenal glands, leading to excess hormone production. It can manifest in various conditions, including:

Cushing Syndrome

Causes of Cushing Syndrome

• Primary Hypersecretion: This is often due to a microadenoma producing ACTH, a condition known as Cushing disease. It is most commonly seen in women aged 20 to 30 years.
• Adrenal Over-Secretion: Caused by adenomas or carcinomas, this form of Cushing syndrome is ACTH-independent and is referred to as adrenal Cushing syndrome.
• Ectopic ACTH Secretion: This is often associated with conditions such as small cell lung cancer and carcinoid tumors.
• Exogenous Corticosteroids: These are corticosteroids administered from outside the body.

Changes in the Adrenal Gland

• Cortical Atrophy: This occurs with exogenous glucocorticoids, which inhibit ACTH, leading to atrophy of the adrenal cortex. However, the zona glomerulosa, which is responsible for producing aldosterone, operates independently of ACTH and is not affected.
• Diffuse Hyperplasia: This refers to a uniform increase in the size of the adrenal cortex.
• Nodular Hyperplasia: This involves the formation of nodules within the adrenal cortex due to increased cell proliferation.

Diagnostic Indicators

• There is an increased level of 24-hour free cortisol in the urine, along with a loss of the normal diurnal pattern of cortisol secretion, which means that cortisol levels are elevated throughout the day instead of being higher in the morning and lower at night.
• To differentiate between the various causes of Cushing syndrome, the dexamethasone suppression test is used. This test helps determine whether the cause of elevated cortisol levels is due to pituitary, adrenal, or ectopic sources.

Adrenogenital Syndrome

Adrenogenital syndrome is a disorder of the adrenal glands characterized by the excessive production of androgens, leading to virilization. This condition can arise from adrenocortical carcinoma or, more frequently, from congenital adrenal hyperplasia (CAH). CAH encompasses a group of inherited metabolic disorders resulting from a deficiency of the enzymes necessary for cortisol production. When cortisol production is impaired, there is a compensatory increase in androgen levels, causing virilization. The deficiency of cortisol leads to elevated levels of adrenocorticotropic hormone (ACTH), resulting in the enlargement of the adrenal glands, a condition known as hyperplasia.

CAH can manifest as three specific syndromes:

• Salt-wasting syndrome: This syndrome is characterized by the complete absence of the enzyme 21-α hydroxylase, leading to a severe deficiency of both cortisol and aldosterone.
• Simple virilizing adrenogenitalism: This form of CAH is marked by genital ambiguity in newborns due to a partial deficiency of 21-α hydroxylase, resulting in an excess of androgens.
• Non-classic adrenogenitalism: This variant may be asymptomatic or present with mild symptoms such as hirsutism (excessive hair growth) in females.

In individuals with adrenogenital syndrome, the adrenal glands are typically enlarged bilaterally and exhibit a brown, nodular cortex due to the depletion of lipid stores.

The adrenal cortex consists of three layers, from outermost to innermost:

• Zona glomerulosa: This outer layer is responsible for the production of mineralocorticoids, such as aldosterone.
• Zona fasciculata: The middle layer produces glucocorticoids, primarily cortisol.
• Zona reticularis: The innermost layer produces androgens and some glucocorticoids.

Cushing Syndrome

• Exogenous corticosteroid use is the most common cause of Cushing syndrome.
• Pituitary Cushing refers to Cushing's disease caused by a pituitary adenoma:
• Adrenal Cushing:
• Ectopic Cushing:

In Cushing syndrome, there is a presence of light basophilic material due to the build-up of intermediate keratin filaments in the cytoplasm, known as Crooke hyaline change in the pituitary.

Almost 90% of CAH cases result from 21-α hydroxylase deficiency, which leads to problems converting progesterone to 11-deoxycorticosterone.

In cases of 21-α hydroxylase deficiency, excessive androgen activity causes signs of masculinization in females, which can range from:

• Clitoral hypertrophy and pseudohermaphroditism in infants.
• Oligomenorrhea, hirsutism, and acne in post-pubertal females.

For males, androgen excess can lead to:

• Enlargement of the external genitalia and precocious puberty in younger patients.
• Oligospermia in older males.

Hyperaldosteronism

Hyperaldosteronism is a condition characterized by the overproduction of aldosterone, a hormone produced by the adrenal glands. This condition can be classified into primary and secondary types based on the underlying causes and the levels of renin, another hormone involved in blood pressure regulation.

Primary Aldosteronism is marked by diastolic hypertension (high blood pressure) and decreased renin secretion. In this condition, the adrenal glands produce excess aldosterone independently of renin levels. Causes:

• Adrenocortical adenoma (Conn syndrome): This is the most common cause of primary hyperaldosteronism, where a benign tumor in the adrenal cortex leads to excess aldosterone production.
• Primary adrenocortical hyperplasia: This condition results from the overactivity of the aldosterone synthase gene, CYP11B2, leading to increased production of aldosterone.
• Glucocorticoid-remediable hyperaldosteronism: This rare form is caused by a genetic fusion between the CYP11B1 (11β hydroxylase) and CYP11B2 (aldosterone synthetase) genes, leading to abnormal regulation of aldosterone production.
• Decreased renal perfusion: Conditions that reduce blood flow to the kidneys can stimulate aldosterone production.
• Hypovolemia and edema: Conditions such as congestive heart failure (CHF) and cirrhosis can lead to increased aldosterone levels due to perceived low blood volume.
• Pregnancy: Hormonal changes during pregnancy can lead to increased aldosterone production.

Secondary Aldosteronism involves increased renin secretion along with aldosterone. This type is often associated with conditions that stimulate renin release, such as renal artery stenosis or heart failure.

Morphology: Adrenal adenomas in hyperaldosteronism are typically unilateral, with a higher incidence on the left side compared to the right. These adenomas may contain eosinophilic laminated cytoplasmic inclusions known as "spironolactone bodies," which become visible after treatment with the diuretic spironolactone.

Clinical Features: Individuals with hyperaldosteronism may experience symptoms such as hypokalemia-induced polyuria (increased urination), polydipsia (increased thirst), and muscle weakness. Excessive aldosterone secretion can also lead to metabolic alkalosis, a condition characterized by elevated blood pH due to increased bicarbonate levels. Edema is less common in primary hyperaldosteronism due to the "escape effect," where the body adapts to the excess aldosterone by excreting sodium and water.

• Aldosterone-Producing Adenoma is a specific type of adrenal gland tumor that leads to hyperaldosteronism.

Adrenal Insufficiency

Adrenal insufficiency can be classified into primary and secondary types. Primary adrenal insufficiency, also known as primary hypoadrenalism, occurs when there is a problem with the adrenal glands themselves. In contrast, secondary adrenal insufficiency, or secondary hypoadrenalism, happens when there is insufficient stimulation of the adrenal glands due to a deficiency of adrenocorticotropic hormone (ACTH).

1. Primary Acute Adrenocortical Insufficiency
Primary Acute Adrenocortical Insufficiencyis a sudden and severe condition that can arise due to various triggers such as:

• Stressful Events. Situations that put extreme physical or emotional stress on the body can precipitate this condition.
• Rapid Withdrawal of Steroid Medications. Abruptly stopping corticosteroid medications that have been taken for a prolonged period can lead to adrenal crisis.
• Severe Adrenal Bleeding. Conditions that cause significant bleeding into the adrenal glands can impair their function.

Waterhouse-Friedrichsen Syndrome. This is a severe complication that can occur when acute adrenal insufficiency is associated with bleeding in the adrenal glands due to a Neisseria infection, such as septicemia, particularly in children. In this syndrome:

• Bleeding typically begins in the medulla (the inner part of the adrenal gland) before affecting the cortex (the outer part).

2. Primary Chronic Adrenocortical Insufficiency (Addison Disease)

• Addison's disease is a long-term condition characterized by the gradual decline of adrenal gland function.
• The primary cause of adrenal gland damage in this condition is often idiopathic atrophy, which results from an autoimmune response where the body's immune system mistakenly attacks and destroys adrenal tissue.
• Autoimmune adrenalitis is frequently linked with Autoimmune Polyendocrine Syndrome (APS) types 1 and 2, which are conditions where multiple endocrine glands are affected by autoimmune disorders.
• Other factors that can lead to the loss of adrenal cortex include:
  • Tuberculosis. A bacterial infection that can affect the adrenal glands.
  • Sarcoidosis. An inflammatory disease that can impact various organs, including the adrenal glands.
  • AIDS. The immunodeficiency virus can lead to various complications, including adrenal insufficiency.
  • Adrenal Bleeding. Trauma or other causes of bleeding into the adrenal glands.
  • Trauma. Physical injury to the adrenal glands.
  • Cancer Metastasis. Spread of cancer to the adrenal glands from other parts of the body.

Clinical Features

• Initial Symptoms. Patients often experience a gradual onset of weakness and fatigue, feeling unusually tired with minimal exertion.
• Gastrointestinal Symptoms. Common issues include loss of appetite, nausea, vomiting, weight loss, and diarrhea, which can contribute to overall weakness and poor health.
• Hyperpigmentation. In individuals with primary adrenal insufficiency, elevated levels of ACTH(adrenocorticotropic hormone) due to low cortisol levels stimulate melanocytes, leading to increased pigmentation of the skin. This hyperpigmentation is particularly noticeable in:
  • Sun-exposed areas of the skin
  • Pressure points such as the neck, elbows, knees, and knuckles

3. Secondary Adrenocortical Insufficiency
Secondary adrenal insufficiency arises from dysfunction in the hypothalamus or pituitary gland, which can occur due to various factors, including:

• Cancer affecting these regions
• Infections leading to inflammation or damage
• Bleeding in the hypothalamus or pituitary
• Radiation therapy causing injury to these areas

In cases of secondary adrenal insufficiency, particularly those related to pituitary dysfunction, typical laboratory findings such as hyponatremia (low sodium levels) and hyperkalemia (high potassium levels) are usually not observed.

Adrenal Medulla

The adrenal medulla is made up of specialized cells called chromaffin cells, along with supporting cells known as sustentacular cells. This part of the adrenal gland is responsible for producing epinephrine and norepinephrine and is controlled by the autonomic nervous system.

Pheochromocytoma

Pheochromocytoma is a type of tumour that occurs in the adrenal medulla and leads to the excessive production of catecholamines. Patients with this condition commonly experience:

• Intense headaches
• Feelings of anxiety
• Increased sweating
• Rapid heart rate (tachycardia)
• Palpitations
• Episodes of high blood pressure (hypertensive episodes)

This tumour is known to follow the "rule of 10s," which includes the following characteristics:

• 10% of cases are bilateral (affecting both adrenal glands)
• 10% are extra-adrenal (occurring outside the adrenal glands)
• 10% are malignant (cancerous)
• 10% occur in children
• 10% are not associated with hypertension

The size of the tumour can range from small to large, and its appearance is typically yellow-tan, turning brown when incubated. The tumour contains clusters of chief or chromaffin cells along with sustentacular cells, known as zellballen. These cells have abundant cytoplasm filled with catecholamine granules, and their nuclei exhibit a characteristic "salt and pepper" pattern in their chromatin. Important markers for identifying this tumour include chromogranin and synaptophysin in chief cells, and S-100 for sustentacular cells.

A definitive diagnosis of malignancy in pheochromocytoma is based on the presence of metastasis. Diagnostic tests typically reveal elevated levels of free catecholamines and their breakdown products, such as vanillylmandelic acid (VMA) and metanephrines in urine samples.

In cases of secondary adrenocortical insufficiency, the absence of skin darkening observed in primary Addison's disease is due to low levels of melanotropic hormone. The zellballen pattern is also seen in carotid body tumours, a type of parasympathetic paraganglioma.

Initially, it was believed that 10% of pheochromocytoma cases were familial. However, recent studies suggest that 25% of individuals with pheochromocytoma and paraganglioma have a germline mutation.

Pheochromocytoma is an example of a tumour that follows the "rule of 10s."

Multiple Endocrine Neoplasia (MEN) III includes:

• Medullary thyroid carcinoma
• Medulla of adrenal (pheochromocytoma)
• Mucosal neuroma

MEN II includes two M's (and one P):

• Medullary thyroid carcinoma
• Medulla of adrenal (pheochromocytoma)
• Parathyroid hyperplasia

MEN I includes three P's:

• Pituitary tumours
• Pancreas tumours (insulinoma, gastrinoma)
• Parathyroid tumours (hyperplasia)