Block 7 - Endocrinology Flashcards

Question

**Pituitary Adenomas** * FSH, LH, TSH Adenoma? * Invasive Adenoma? * Giant Adenoma?

Answer 1

* **FSH, LH and TSH Adenoma:** Rare * **Invasive Adenoma:** Extra-Sella, no capsulation and local invasion. Adenomatous tissue can enter blood vessels and embolise, but not grow as metastases. Invasive growth can occur along dura, optic nerve or into sphenoid or cavernous sinus. * **Giant Adenoma:** Extra-Sella, capsulated and compressive

Answer 2

Histochemical classification uses orange-G-PAS stain

Answer 3

**_Pituitary Adenomas_** * **Macroscopic Features:** * Soft and solid, occasionally cystic. * Size ranges from microadenoma to giant adenoma. * Grey to red due to high degree of vascularity. * **Microscopic Patterns**: * Diffuse, sinusoidal or papillary. * Dystrophic calcification and endocrine amyloid (Congo red and polaroscopy).

Answer 4

**Nonfunctional Clinical Signs of Pituitary Adenoma** 1. Bitemporal hemianopia occurs due to compression of the optic chiasm 2. Hypopituitarism occurs due to compression of normal pituitary tissue 3. Hydrocephalus occurs due to upward expansion into hypothalamus and third ventricle or backward expansion to compress aqueduct 4. CN III, IV and VI palsy due to lateral expansion into cavernous sinus 5. Headache due to raised ICP

Answer 5

**Craniopharyngioma** * Solid and cystic suprasellar tumour * Derived from Rathke’s Pouch * Resembles ameloblastoma (a tooth tumour which occurs in the jaw) * Usually suprasellar, can be intrasellar * 75% show calcification * Solid and cystic areas * Cyst contains ‘motor oil fluid’ which is straw to brown cholesterol-rich fluid * **Clinical Signs** 1. Extremely infiltrative 2. Visual field defects 3. Diabetes insipidus 4. Hydrocephalus 5. Pituitary dwarfism in children (Lorraine-Levi Syndrome)

Answer 6

**_Hypopituitarism_** * Insufficient production of hormones by the anterior pituitary gland * Symptoms arise when\> 75% of the pituitary parenchyma is lost * Caused by pituitary adenomas (adults) or craniopharyngioma (children) due to mass effect or pituitary apoplexy (bleeding into an adenoma causing hemorrhagic infarction) * Can be caused by Sheehan syndrome → pregnancy-related infarction of the pituitary gland (gland doubles in size during pregnancy, but blood supply does not increase significantly, blood loss during parturition precipitates infarction). * Can be caused by Empty Sella syndrome (congenital defect of the Sella). Herniation of the arachnoid and CSF into the Sella compresses and destroys the pituitary gland. * **Clinical Signs** * **Pituitary Adenoma:** Present with features based on the type of hormone produced & May see features based on loss of other hormone production * **Sheehan Syndrome-Pregnancy-Related Infarction:** Presents as poor lactation, loss of pubic hair, and fatigue * **Empty Sella Syndrome:** Pituitary gland is absent on imaging, Empty Sella turcica

Answer 7

**Pituitary Carcinoma** * Extremely rare * Term is only used when definite metastases occur which survive and grow * Cannot predict benignancy, invasiveness or malignancy on histopathological features (they all look benign)! * Metastasis is the only criterion for diagnosis * May lead to signs of infiltration

Answer 8

**_Acute Pituitary Insufficiency_** * Portal venous system collapses due to low perfusion causing central pituitary necrosis * Due to trauma, surgery or shock states such as Sheehan syndrome * Central zone necrosis in portal venous circulation area * **Clinical Signs - Acute Pituitary Failure:** 1. Pallor 2. Lethargy 3. Coma culminating in death approximately 2 weeks later

Answer 9

**_Chronic Pituitary Insufficiency_** * **Simmond’s Disease:** * Usually \<10% of functional parenchyma left * Occurs in survivors of Sheehan syndrome, healed TB, sarcoidosis, meningitis, tumours and lymphocytic hypophysitis (autoimmune) * **Microscopy:** Scarring, calcification, ossification and specific aetiology * **Clinical Signs - Hypopituitarism:** 1. Cannot produce breast milk 2. Amenorrhoeic 3. Pale and loss of body hair 4. Myxedema 5. Addison’s Disease 6. Viscera abnormally small due to loss of growth hormone

Answer 10

**Posterior Pituitary Gland Pathology:** 1. Central Diabetes Insipidus 2. Nephrogenic Diabetes Insipidus 3. Syndrome of Inappropriate ADH (SIADH) Secretion 4. Neurohypophysal Tumours

Answer 11

**Posterior Pituitary Gland Pathology: Central Diabetes Insipidus** * ADH deficiency * Due to hypothalamic or posterior pituitary pathology such as tumour, trauma, infection, or inflammation * Water deprivation test fails to increase urine osmolality (useful for diagnosis) * Treatment is desmopressin (ADH analog)

Answer 12

**Posterior Pituitary Gland Pathology:** **Nephrogenic Diabetes Insipidus** * Impaired renal response to ADH * Due to inherited mutations or drugs (lithium and demeclocycline) * Clinical features are similar to central diabetes insipidus, but there is no response to desmopressin

Answer 13

**_Syndrome of Inappropriate ADH (SIADH) Secretion_** * Excessive ADH secretion * Most often due to ectopic production (small cell carcinoma of the lung) * Other causes include CNS trauma, pulmonary infection, and drugs (cyclophosphamide) * Treatment is free water restriction or demeclocycline * **Clinical Signs - Retention of Free Water:** * Hyponatremia and low serum osmolality * Mental status changes and seizures as hyponatremia leads to neuronal swelling and cerebral edema

Answer 14

**Posterior Pituitary Gland Pathology: Neurohypophysal Tumours** * RARE tumours * Metastases (COMMONEST!) * Astrocytoma/Pituicytoma * Seminoma (midline location) * Dermoid Epidermoid Cysts * Lymphoma * Ganglioglioma/Gangliocytoma * Granular Cell Tumour

Answer 15

**_GH Deficiency_** * **Treatment:** Synthetic human growth hormone (somatropin) * **Mechanism:** Increases amount of growth hormone (somatropin) in body. Promotes growth of skeletal, muscular and other tissues, stimulates protein anabolism and influences fat and mineral metabolism. * **Examples:** Genotropin, Scitropin, Norditropin NordiFlex and Humatrope * **Indications:** Used for the treatment of short stature in children due to GH deficiency, Turner’s syndrome, chronic renal insufficiency, Prader-Willi syndrome as well as treatment of GH deficiency in adults. * **Side Effects:** 1. Peripheral oedema 2. Paresthesia (common) 3. Hyperglycaemia 4. Benign intracranial hypertension 5. Systemic allergic reaction (rare)

Answer 16

**_GH Excess_** * **Treatment:** Long acting somatostatin analogues * **Mechanism:** Inhibits the release of GH from the anterior pituitary * **Examples:** Octreotide (Sandostatin) and Lanreotide (Somatuline) * **Indications:** Acromegaly and relief from the symptoms associated with tumours * **Side Effects:** 1. Abdominal pain 2. Nausea, vomiting 3. Hair loss (common) 4. Pancreatitis 5. Hypothyroidism (rare)

Answer 17

**_ADH Deficiency_** * **Treatment:** Vasopressin agonists or synthetic vasopressin * **Mechanism:** Increase amount of ADH in body * **Examples:** Argipressin (synthetic ADH), Desmopressin (specific vasopressin V2 receptor agonist), Terlipressin (inactive prodrug of vasopressin) and Ornipressin (vasopressin analogue) * **Indications:** Central diabetes insipidus (Argipressin and Desmopressin), bleeding oesophageal varices and hepatorenal syndrome (Terlipressin) and to reduce blood loss during some surgical procedures (Ornipressin) * **Side Effects:** Different based on drug. Headache, abdominal cramps, nausea, diarrhoea, pallor, hyponatraemia, allergic reactions, angina, MI, arrhythmias, thrombosis, gangrene and rhabdomyolysis.

Answer 18

**_ADH Excess_** * **Treatment:** Vasopressin antagonist * **Mechanism:** Blocks the effects of excess ADH in the body * **Examples:** Demeclocycline (selective ADH antagonist at renal tubules) and Tolvaptan (selective vasopressin V2-receptor antagonist) * **Indications:** Treatment of SIADH resistant to fluid restriction (Demeclocycline) and for the treatment of euvolaemic or hypervolaemic hyponatraemia (Tolvaptan). * **Side Effects:** Different based on drug. Reversible nephrogenic diabetes insipidus.

Answer 19

**_TSH Deficiency_** * **Treatment:** Thyroid hormone * **Mechanism:** Thyroid hormone replacement * **Examples:** Levothyroxine (thyroxine, T4) * **Indications:** Hypothyroidism and myxoedema * **Side Effects:** Tachycardia, heat intolerance, tremors and arrhythmias

Answer 20

**_TSH Excess_** * **Treatment:** Antithyroid hormone * **Mechanism:** Block thyroid hormone synthesis. Propylthiouracil also inhibits peripheral conversion of T4 to T3. * **Examples:** Carbimazole and propylthiouracil * **Indications:** Graves’ disease, preparation for thyroid surgery, or radioactive iodine treatment and thyroid storm * **Side Effects:** Itching, rash, mild leukopenia, nausea, vomiting, gastric discomfort, headache and arthralgia

Answer 21

**_Oxytocin Deficiency_** * **Treatment:** Oxytocin * **Mechanism:** Stimulates labour, uterine contractions, milk let-down and controls uterine hemorrhage * **Indications:** Parturition and lactation

Answer 22

**_Prolactin Excess_** * **Treatment:** Dopamine receptor agonists * **Mechanism:** Stimulate dopamine D2 receptors and inhibit prolactin secretion * **Examples:** Bromocriptine or cabergoline * **Indications:** Prolactinoma

Answer 23

**Cushing Syndrome** * Increased cortisol * Due to exogenous corticosteroids * Due to primary adrenal adenoma, hyperplasia or carcinoma * Due to ACTH secreting pituitary adenoma (Cushing disease) or paraneoplastic ACTH secretion * Cushing disease main cause! * Diagnosis is made by increased 24-hour urine cortisol levels * High-dose dexamethasone (cortisol analog) suppresses ACTH production by a pituitary adenoma (cortisol levels decrease), but fails to suppress ectopic ACTH production by a small cell lung carcinoma (cortisol levels remain high)

Answer 24

**_Cushings Syndrome_** 1. Hypertension 2. Weight gain (due to high glucose and fat storage) 3. Moon facies 4. Muscle weakness (cortisol breaks down muscle producing AAs for gluconeogenesis) 5. Abdominal striae (due to impaired synthesis of collagen with thinning of skin) 6. Truncal obesity 7. Buffalo hump 8. Skin changes (thinning, striae) 9. Osteoporosis 10. Hyperglycaemia (insulin resistance) 11. Amenorrhea 12. Immunosuppression

Answer 25

**_Hypocortisolism (Primary Adrenal Insufficiency)_** * Deficiency of aldosterone and cortisol production due to loss of gland function * **Acute:** Sudden onset (i.e. due to massive hemorrhage) which may present with shock * **Chronic:** Addison disease. Due to whole adrenal cortex atrophy or destruction by disease (autoimmune destruction most common in the Western world whilst TB most common in the developing world). * **Waterhouse-Friderichsen Syndrome**: Acute due to adrenal hemorrhage associated with septicemia (usually *Neisseria meningitidis*), DIC or endotoxic shock

Answer 26

**Adrenal Gland Pathology: Hypocortisolism (Primary Adrenal Insufficiency)** 1. Hypotension 2. Hyponatremia (increased salt craving) 3. Hypovolemia 4. Hyperkalemia 5. Weakness 6. Hyperpigmentation of skin and mucosa (due to increased MSH, a byproduct of ACTH production from POMC) 7. Metabolic acidosis (low pH and HCO3-) 8. Vomiting 9. Diarrhea 10. **NB: P**rimary **P**igments the Skin/Mucosa!

Answer 27

**_Hyperaldosteronism (Primary)_** * Due to sporadic bilateral adrenal hyperplasia * Adrenal adenoma (Conn syndrome) and adrenal carcinoma are less common causes * **Clinical Signs:** 1. High aldosterone and low renin 2. Hypertension (due to sodium retention) 3. Decreased or normal K+ 4. Metabolic alkalosis 5. No oedema due to aldosterone escape mechanism **_Hyperaldosteronism (Secondary)_** * Seen with activation of RAAS * Due to renovascular hypertension, juxtaglomerular cell tumours (renin- producing) and oedema (e.g. cirrhosis, heart failure or nephrotic syndrome) * **Clinical Signs** * As above * High aldosterone and high renin

Answer 28

**_Congenital Adrenal Hyperplasia_** * Excess sex steroids with hyperplasia of both adrenal glands * Inherited 21-hydroxylase deficiency is most common cause * 21-hydroxylase is required for the production of aldosterone and corticosteroids * In enzyme deficiency, steroidogenesis is predominantly shunted toward sex-steroid production (which does not require 21-hydroxylase) * Deficiency of cortisol leads to increased ACTH secretion (lack of negative feedback), which results in bilateral adrenal hyperplasia * **Clinical Signs:** 1. Salt wasting with hyponatremia, hyperkalemia, and hypovolemia (due to lack of aldosterone) 2. Life-threatening hypotension (due to lack of cortisol) 3. Clitoral enlargement (females) or precocious puberty (males) due to excess androgens

Answer 29

**_Neuroblastoma_** * Most common tumour of the adrenal medulla in children, usually \< 4 years old * Originates from neural crest cells * Occurs anywhere along the sympathetic chain * Histology shows Homer-Wright rosettes characteristic of neuroblastoma and medulloblastoma * Associated with overexpression of N-myc oncogene * **Clinical Signs** 1. Abdominal distension 2. Firm, irregular mass that can cross the midline 3. Less likely to develop hypertension than with pheochromocytoma 4. Can also present with opsoclonus-myoclonus syndrome (“dancing eyes-dancing feet”) 5. Increased HVA and VMA (catecholamine metabolites) in urine

Answer 30

**_Pheochromocytoma_** * Most common tumor of the adrenal medulla in adults * Derived from chromaffin cells (arise from neural crest) * May be associated with germline mutations (NF-1, VHL, RET [MEN 2A, 2B]) * Rule of 10s * **Clinical Signs** 1. Most tumors secrete epinephrine, norepinephrine, and dopamine, which can cause episodic hypertension 2. Episodic hyperadrenergic symptoms (5Ps) 3. Pressure, pain, perspiration, palpitations and pallor 4. Symptoms occur in “spells” (relapse and remit) 5. Increased catecholamines and

Answer 31

**_Pharmacology of Adrenal Disorders: Hyperaldosteronism_** * **Treatment:** Aldosterone receptor antagonist * **Mechanism:** Synthetic aldosterone receptor antagonist which acts on distal tubules to inhibit Na+ reabsorption (water excretion), K+ secretion and H+ secretion. Weak diuretics. * **Examples:** Spironolactone * **Indications:** Primary hyperaldosteronism, refractory oedema associated with secondary hyperaldosteronism e.g. cirrhosis of the liver and resistance hypertension (adjunct) * **Side Effects:** Gastric problems especially peptic ulcers, hyperkalaemia, nausea and lethargy. As a consequence of its similarity to the sex hormones, it can cause gynecomastia in males and menstrual irregularities in females.

Answer 32

**_Pharmacology of Adrenal Disorders: Hypoaldosteronism_** * **Treatment:** Synthetic mineralocorticoid * **Mechanism:** Mineralocorticoid replacement therapy * **Examples:** Fludrocortisone * **Indications:** Primary adrenal insufficiency and salt-losing congenital adrenal hyperplasia * **Side Effects:** Sodium and water retention, oedema, hypokalaemia, hypertension, hypokalaemic alkalosis and heart failure

Answer 33

**_Pharmacology of Adrenal Disorders: Hypocortisolism_** * **Treatment:** Corticosteroid * **Mechanism:** Glucocorticoid replacement therapy * **Examples:** Hydrocortisone or cortisone * **Indications:** Adrenal insufficiency (primary or secondary) * **Side Effects:** Hypertension, oedema, osteoporosis, impaired wound healing, hypokalaemia, peptic ulcers, glaucoma, increased appetite, weight gain, emotional disturbance, hirsutism and impaired glucose tolerance

Answer 34

**_Clinical Features of Excess GH (Acromegaly)_** * **High GH Adult:** Large tongue (macroglossia), hands and feet, deep husky voice, heavy facial features (enlarged nose, thickened lips, prominent brow and protruded jaw), diaphoresis (excessive sweating), impaired glucose tolerance (insulin resistance and T2DM), skin tags, thickened oily skin, dental changes (separation of lower teeth), bilateral carpal tunnel, cardiovascular problems (enlarged heart), joint aches and pains, hirsutism, weight gain, sleep apnoea, high blood pressure, fatigue. * **High GH Child:** Gigantism and increased linear bone growth * **Adenoma:** Headache, vision deficits and mass effect (i.e. altered menstrual cycle, erectile dysfunction and low sex drive)

Answer 35

**_Clinical Features of Deficient GH_** * **Low GH Adult:** Increased body fat mass, reduced muscle mass, reduced bone density and osteoporosis * **Low GH Child**: Slow growth, failure to thrive, short stature, delayed puberty, hypoglycaemia and obesity

Answer 36

**Low FSH and LH:** Amenorrhea, hypogonadism, low libido, infertility, erectile dysfunction, reduced muscle mass (males), delayed puberty, mood swings, vaginal dryness, hot flushes and osteoporosis (females)

Answer 37

**_Clinical Features of Hyperprolactinemia_** * **High Prolactin:** Galactorrhea, gynecomastia, amenorrhea, low libido, erectile dysfunction, infertility and hypogonadism (high prolactin and negative feedback on GnRH and sex hormones). * **Adenoma:** Headache, vision deficits and mass effect

Answer 38

**_Hypercortisolism (Cushing Syndrome)_** ## Footnote **High Cortisol:** Hypertension (increased adrenergic receptor activity), weight gain (due to high glucose and fat storage), moon facies, malar flush, proximal myopathy and muscle weakness (cortisol breaks down muscle producing AAs for gluconeogenesis), abdominal striae, thin wrinkled skin and purpura (due to impaired synthesis of collagen with thinning of skin), truncal obesity, buffalo hump, osteoporosis, hyperglycaemia (insulin resistance), amenorrhea and infertility (negative feedback on GnRH), immunosuppression and impaired wound healing **High Sex Hormones (Adrenal Cortex):** Acne, oily skin and hirsutism (due to high ACTH)

Answer 39

**_Deficient Cortisol (Primary Adrenal Insufficiency)_** * **Low Cortisol:** Postural hypotension, weight loss, malaise, fatigue, weakness, hypoglycaemia, hyperpigmentation of skin and mucosa (due to increased MSH, a byproduct of ACTH production from POMC) and vomiting and diarrhea * **Low Aldosterone (Also Occurs with Addison's):** Hyponatremia (decreased aldosterone), hyperkalemia (decreased aldosterone), hypovolemia, hypotension and metabolic acidosis (low pH and HCO3-) * **Low Sex Hormones (Also Occurs with Addison's):** Low libido and axillary and pubic hair

Answer 40

**_Clinical Features of Deficient Cortisol (Secondary Adrenal Insufficiency)_** ## Footnote **Low Cortisol:** As above BUT no skin/mucosal hyperpigmentation (no excess MSH from excess ACTH production) and no hyperkalemia (aldosterone synthesis preserved due to intact RAAS axis)

Answer 41

**Low TH:** Cold intolerance (decreased heat production), weight gain, reduced appetite, hypoactivity, lethargy, fatigue, weakness, depressed mood, constipation, delayed reflexes, myopathy (proximal muscle weakness and increased CK), myxedema (facial/periorbital), dry and cool skin, coarse and brittle hair, bradycardia and dyspnea on exertion. **High TH:** Heat intolerance (increased heat production), weight loss, increased appetite, hyperactivity, anxiety, insomnia, hand tremor, diarrhea, brisk reflexes, thyrotoxic myopathy (proximal muscle weakness and normal CK), pretibial myxedema (Graves disease), periorbital oedema, warm moist skin, fine hair, chest pain, palpitations, and arrhythmias (increased number and sensitivity of β-adrenergic receptors)

Answer 42

**Deficient ADH (Central Diabetes Insipidus) - Low ADH:** Polydipsia (intense thirst), polyuria, nocturia and inability to concentrate urine, dehydration, tachycardia, hypotension, hypovolaemia, insomnia, weight loss, hypernatraemia and serum hyper-osmolality **Excess ADH (SIADH) - High ADH:** Low urinary output and concentrated urine, hyponatraemia, serum hypo- osmolality, nausea and vomiting, cramps or tremors, irritability, depressed mood or memory impairment, confusion, seizures and coma

Answer 43

**Outermost Layer (Outer Fibrous Tunic):** 1. **Sclera:** Tough connective tissue coat over majority of outside of eye (whites of eye) 2. **Cornea:** Transparent structure in front of eye which allows light to enter (immunoprivileged site)

Answer 44

**Middle Layer (Intermediate Vascular Tunic):** 1. **Choroid:** Vascular, pigmented layer under sclera which provides blood to retina and stops reflection of light that reaches back of eye (tunnel vision) 2. **Lens:** Focuses light on the retina 3. **Ciliary Body:** Contains ciliary muscles which attach to lens by zonular fibres and change the shape of the lens to focus light 4. **Iris:** Located in front of lens which regulates amount of light entering eye by adjusting diameter of pupil

Answer 45

**Inner Layer (Neural Tissue):** 1. **Retina:** Neural tissue that detects light 2. **Fovea:** Where light from centre of visual field strikes retina (area of greatest visual acuity) 3. **Optic Disc (Papilla):** Where optic nerve and blood vessels supplying eye pass through retina. No photoreceptor cells making it a blind spot. Overlapping visual fields cover the blind spots in each eye (perceptual closure accounts for any other missing information)

Answer 46

**Internal Chambers of Eye:** Lens and ciliary body separate eye into two chambers 1. **Anterior Chamber:** Contains clear, watery (aqueous) fluid which supplies nutrients to cornea and lens 2. **Posterior Chamber:** Consists of a small space directly posterior to the iris but anterior to the lens 3. **Vitreous Chamber:** Contains firm, jelly like material (vitreous humour) which maintains spherical structure of eye. Consistency maintains internal pressure required to keep the eye’s shape.

Answer 47

**Muscles of the Eye:** * **Extraocular Muscles:** Originate from walls of orbit and insert in the outer surface of the eyeball (see below) * **Function:** Maintain the shape of the eyeball, hold it in the orbit and allows for eye movement * **Conjugate Eye Movements:** Both eyes move in same direction (binocular vision) * **Disconjugate Eye Movements:** Both eyes move in different directions * **Saccadic Movements:** Shift fovea rapidly to new visual target (conjugate movement) * **Smooth-Pursuit Movements:** Keep image of moving target on fovea (conjugate movement) * **Vergence Movements:** Align fovea of each eye with targets located at different distances from the observer (disconjugate movement). When viewing distant object, eyes diverge and close objects are not in focus. When viewing a near object, eyes converge and distant objects are not in focus.

Answer 48

**_Extraocular Muscles_** 1. **Lateral Rectus** → Move eyes in horizontal plane away from nose (abduction) 2. **Medial Rectus** → Move eyes in horizontal plane towards nose (adduction) 3. **Superior Rectus** → Elevation, adduction and intorsion (medial rotation) 4. **Inferior Rectus** → Depression, adduction and extorsion (lateral rotation) 5. **Superior Oblique** → Depression, abduction and intorsion 6. **Inferior Oblique** → Elevation, abduction and extorsion **NB:** All rectus muscles originate from common tendinous ring (annulus of Zinn) and insert onto sclera of eye. Superior oblique originates from sphenoid bone and inserts posteriorly onto the eyeball. Lateral oblique originates from orbital surface of maxilla and inserts laterally onto the eyeball.

Answer 49

**Nerves of the Eye:** **Cranial Nerves:** CN II, III, IV and VI (see below) **Horizontal Gaze Centre:** Located in paramedian pontine reticular formation (PPRF) **Vertical Gaze Centre:** Located in rostral midbrain formation **Interneuron Pathway:** Medial longitudinal fasciculus in pons is a very important interneuron pathway between abducens nucleus in the pons and oculomotor nucleus in the midbrain (CN III and VI) which allows for conjugate eye movements

Answer 50

**Physiology of Vision:** * **Visual Fields:** The angle of view, or the space that can be viewed by the retina when the eye is fixated straight ahead (normally 120 degrees) * **Visual Acuity:** The ability of the eye to distinguish detail, depends upon the spacing of the photoreceptors in the retina, and the precision of the eye’s refraction * **Accommodation:** Focus on near and distant objects (accommodate) by changing the shape of the lens due to the ciliary body (under PNS control) * **Near Vision:** Ciliary muscles contract causing the lens to round up * **Distant Vision:** Ciliary muscles relax and the suspensory ligaments pull the lens into a flatter shape

Answer 51

**Regulation of Light:** Contraction or relaxation of inner circular muscle of iris smooth muscle regulates how much light enters eye * **Bright Light:** PNS stimulation contracts inner circular muscle, causing pupillary constriction, decreasing amount of light entering eye * **Dim Light:** Lack of PNS stimulation allows relaxation of inner circular muscle and pupillary dilation, increasing amount of light entering eye * **Fight or Flight Response:** SNS stimulation contracts outer radial muscle, causing pupillary dilation, increasing amount of light entering eye * **Innervation:** Oculomotor nerve (CN III) fibres which originate in the Edinger Westphal nucleus of the midbrain

Answer 52

**Refraction of Light Waves:** The bending of a wave when it enters a medium * Visible light detected by human ranges from 750nm to 350 nm (between infrared and UV rays) * Both cornea and lens have convex surfaces, causing light waves entering eye to converge onto retina * A given point in visual field comes to focus on a single point on retina * Focus mainly due to the cornea as the lens is responsible for fine adjustments * Passage of light waves through convex lens causes retinal image to be inverted and reversed * Light rays strike the curved surface of the cornea, pass through to the aqueous humour and slow down and refract (bend) at the lens to converge onto the retina * Light rays that enter the centre of the eye pass straight to the retina * Focal distance (m) is calculated from the lens to the focal point and is expressed in dioptres (1/m) e.g. A 3 dioptre lens brings parallel rays of light to focus at 1/3m

Answer 53

**Phototransduction:** Photoreceptors depolarise in response to absence of stimuli or scotopic conditions (darkness). On exposure to light, retinal dissociates from opsin, initiating a sequence of reactions that decrease levels of cGMP inside cells, causing hyperpolarisation of photoreceptors and activation of bipolar cells (rods turn off, which turns on bipolar cells allowing nerve conduction). 1. Activation of the receptor protein (rhodopsin in rods) 2. Activated receptor protein (rhodopsin) stimulates G-protein transducin and GTP is converted to GDP in the process 3. In turn, activated transducin activates the effector protein phosphodiesterase which converts cGMP to GMP 4. Falling concentrations of cGMP cause the transduction channels to close, decreasing Na+ current and causing hyperpolarisation of the photoreceptor (due to ongoing efflux of K +) 5. Hyperpolarisation of the cell causes voltage-gated calcium channels to close 6. As the calcium levels in the photoreceptor cell drops, the amount of the neurotransmitter glutamate that is released by the cell also drops. This is because calcium is required for the glutamate -containing vesicles to fuse with cell membrane and release their contents. 7. This reduces glutamate release which thus reduces the inhibition of retinal ganglion cells (activates them), leading to excitation of these nerve (glutamate normally has inhibitory effect here)

Answer 54

**Neural Pathway:** 1. From ganglion cells, signals travel in optic nerve (CN II) and the optic nerves exits the eye at optic disc 2. The optic nerves combine in the optic chiasm 3. Proportion of nerve fibres cross over to opposite side of brain 4. Information from right and left sides of visual field are processed in left and right sides of brain, respectively (nasal retina goes to opposite side, temporal retina goes to same side) 5. Almost all ganglion cell axons synapse in the lateral geniculate nucleus (thalamus). Signals are then sent to the primary visual cortex. 6. The remainder branch off to synapse in the superior colliculi and the pretectal area (cranial nerve nuclei areas) for direct eye movements. **NB:** Optic radiations travel through the temporal and parietal lobes and so can be vulnerable to strokes

Answer 55

**Integration of Vision:** At primary visual cortex * **Primary Visual Cortex:** The primary cortical region that receives, integrates and processes visual information that is relayed from the retinas. * **Ventral Stream:** Critical for visual perception (vision for perception) * **Dorsal Stream:** Mediates the visual control of skilled actions (vision for action) * **Parietal Visual Cortical Areas:** Deal with motion and spatial reasoning * **Temporal Visual Areas:** Process complex perception of patterns and forms into recognisable objects

Answer 56

**_Disorders of Visual Pathway: Retina_** * **Causes** 1. Retinitis Pigmentosa 2. Diseases of the retina 3. Retinal detachment 4. Retinal vessel occlusion * **Defects** 1. **Central Scotoma:** A partial loss of vision or blind spot in an otherwise normal visual field seen with macula lesions (due to trauma or age) 2. **Peripheral Scotoma**: Occurs with macula lesions involving fovea sparing

Answer 57

**Retinitis Pigmentosa:** Inherited retinal degeneration. Painless, progressive vision loss beginning with night blindness (rods affected first). Bone spicule-shaped deposits around macula. Tunnel vision.

Answer 58

**Retinal Detachment:** Separation of neurosensory layer of retina (photoreceptor layer with rods and cones) from outermost pigmented epithelium (normally shields excess light and supports retina) causing degeneration of photoreceptors and vision loss.

Answer 59

**Central Retinal Artery Occlusion:** Acute, painless monocular vision loss. Retina cloudy with attenuated vessels and “cherry-red” spot at fovea.

Answer 60

**Retinal Vein Occlusion:** Blockage of central or branch retinal vein due to compression from nearby arterial atherosclerosis. Retinal hemorrhage and venous engorgement and oedema in affected area.

Answer 61

**Disorders of Visual Pathway: Optic Nerve** * **Causes** 1. Optic neuritis (MS) 2. Optic atrophy 3. Retinal vessel occlusion 4. Anterior ischemic optic neuropathy 5. Papilledema * **Defects** 1. Ipsilateral blindness (anopia) or scotoma 2. Centrocecal Scotoma: Loss of vision in the fovea centralis region and a blind spot 3. Pupillary Light Reflex: Loss of afferent limb. 4. Absent direct pupillary light reflex. Consensual light reflex maintained.

Answer 62

**_Disorders of Visual Pathway: Optic Chiasm_** * **Causes** 1. Pituitary adenoma 2. Craniopharyngioma 3. Parasellar aneurysm of the internal carotid artery 4. Meningioma * **Defects** 1. Bitemporal heteronymous hemianopsia (middle lesions) 2. Binasal hemianopsia (bilateral lesions)

Answer 63

**_Disorders of Visual Pathway: Optic Tract_** * **Cause** → MCA infarction * **Defect** → Contralateral homonymous hemianopsia

Answer 64

**_Disorders of Visual Pathway: Lateral Geniculate Nucleus_** * **Cause**: MCA infarction (MCA → Anterior choroidal artery → Posterior cerebral artery → Lateral choroidal artery) * **Defect**: Contralateral homonymous hemianopsia

Answer 65

**_Disorders of Visual Pathway: Optic Radiations_** * **Cause** → MCA infarction * Upper quadrantanopsia indicates temporal lobe lesion * Lower quadrantanopsia indicates parietal lobe lesion * **Defects** 1. Contralateral upper homonymous quadrantanopsia (anterior/lateral bundle lesions) 2. Contralateral lower homonymous quadrantanopsia (posterior/medial lesions)

Answer 66

**Conjunctivitis:** Inflammation of the conjunctiva causing red eyes due to viral or bacterial infection or allergy.

Answer 67

**Myopia (Near-Sightedness):** Eye too long for refractive power of cornea (too curved) and lens and light is focused in front of retina. People have good near vision but poor distance vision. Correct with concave (diverging) lens.

Answer 68

**Hyperopia (Far-Sightedness):** Eye too short for refractive power of cornea (too little curvature) and lens and light is focused behind retina. Distant objects can be seen clearly, but close ones do not come into proper focus. Correct with convex (converging) lenses.

Answer 69

**Astigmatism:** Abnormal curvature of cornea causing different refractive power at different axes. Correct with cylindrical lens.

Answer 70

**Presbyopia:** Aging-related impaired accommodation (focusing on near objects), primarily due to decreased lens elasticity, changes in lens curvature and decreased strength of the ciliary muscle. Patients often need “reading glasses” (magnifiers).

Answer 71

**Cataracts:** Painless, often bilateral, opacification (clouding) of lens, often resulting in decreased vision (due to UV or trauma).

Answer 72

**Glaucoma:** Optic disc atrophy with characteristic cupping (thinning of outer rim of optic nerve), usually with elevated intraocular pressure (IOP) and progressive peripheral visual field loss if untreated.

Answer 73

**Uveitis:** Inflammation of uvea with specific name based on location within affected eye. Anterior uveitis is iritis and posterior uveitis is choroiditis and/or retinitis.

Answer 74

**Age-Related Macular Degeneration:** Degeneration of macula (central area of retina). Causes distortion (metamorphopsia) and eventual loss of central vision (scotomas).

Answer 75

**Diabetic Retinopathy:** Retinal damage due to chronic hyperglycemia due to microvasculature effects.

Answer 76

**Papilloedema:** Optic disc swelling (usually bilateral) due to raised ICP. Enlarged blind spot and elevated optic disc with blurred margins.

Answer 77

**Grave's Ophthalmopathy:** Autoimmune inflammatory disorder of the orbit and periorbital tissues, characterised by upper eyelid retraction, lid lag, swelling, erythema, conjunctivitis, and bulging eyes (exophthalmos). Most commonly occurs with Grave's disease. Autoantibodies target the fibroblasts in the eye muscles, and those fibroblasts can differentiate into adipocytes. Fat cells and muscles expand and become inflamed. Veins become compressed, and are unable to drain fluid, causing oedema.

Answer 78

**_Cells and Layers of the Retina:_** * **Pigmented Epithelium:** A layer of dark tissue beneath the photoreceptors which absorbs excess light so the photoreceptors can give a clearer signal. Moves nutrients to (and waste from) the photoreceptors to the choroid. Also blood retinal barrier. * **Photoreceptors:** Specialised cells that respond to light and enable phototransduction * **Horizontal Cells:** Laterally interconnecting neurons summate inputs from photoreceptors * **Bipolar Cells:** Responsible for 30% of input to retinal ganglion cells (regulated by am acrine cells) * **Amacrine Cells:** Responsible for 70% of input to retinal ganglion cells * **Ganglion Cells:** Receive visual information from photoreceptors via bipolar cells and amacrine cell and transmit it to the thalamus and visual cortex

Answer 79

**Photoreceptors (Rods and Cones):** Convert a light signal into a nerve signal (i.e. an electrical impulse). * **Distribution:** Uneven across the retina * **Rods:** Provide ability to see black and white in low light conditions. High sensitivity to light but low visual acuity. 100 million per retina. * **Cones:** Provide ability to see colour (red, blue and green), but only in bright light. Low sensitivity to light but high visual acuity. 3 million per retina. * **Outer Segment:** Has disks that contain photopigment * **Inner Segment:** Contains the nucleus * **Synaptic Terminal:** Contains stores of neurotransmitter used for communicating with nerves * **Rhodopsin:** Light sensitive pigment located in disks in outer segment. Comprises protein called opsin, which is bound to vitamin A derivative called retinal.

Answer 80

**_Anatomy of the Eye_** * **Fovea:** Region of highest visual acuity and contains 100% cones at highest density to ensure that most light is processed. Directed towards whatever focus of visual attention. Ratio of photoreceptors to ganglion cells is about 2:1. Percentage of rods increase towards the periphery. * **Macula:** Area around the fovea which has a pale yellow pigmentation * **Optic Disc (Papilla):** Where optic nerve and blood vessels supplying eye pass through retina. * **Retinal Blood Supply:** * **Arterial Supply:** Central retinal artery (first branch of ophthalmic artery) enters eye at optic disk. Branches are end arteries so if blocked that part of the retina dies. * **Venous Drainage:** Central retinal vein into cavernous sinus and/or superior ophthalmic vein

Answer 81

**_Grades of Hypertensive Retinopathy_** * **Grade 1:** Silver wiring of arteries * **Grade 2:** PLUS AV nipping/nicking * **Grade 3:** PLUS hemorrhages (flame- shaped) and exudates (cotton-wool spots or hard lipid residues) * **Grade 4:** PLUS papilloedema

Answer 82

**_Categories of Diabetic Retinopathy Severity_** * **Category 1 → Mild Non-Proliferative:** Micro-aneurysms * **Category 2 → Moderate Non-Proliferative:** Multiple retinal hemorrhages * **Category 3 → Severe Non-Proliferative:** Starts to form new vessels with exudate formation * **Category 4 → Proliferative:** Neovascularization (fragile new vessels) \* Non-Proliferative can have cotton wool spots (white and fluffy), hard exudates (yellow and waxy), flame hemorrhages and micro-aneurysms

Answer 83

**Microaneurysms** are localised **outpouchings** of **capillaries** that leak plasma constituents into the retina. They may be clinically indistinguishable from small dot and blot haemorrhages (see below).

Answer 84

**Dot and blot haemorrhages** arise from **bleeding** **capillaries** in the middle layers of the retina. They may look like microaneurysms if small enough. It is not particularly important to be able to distinguish between small haemorrhages and microaneurysms as they are both parts of pre-proliferative retinopathy.

Answer 85

**Cotton wool spots** ## Footnote **Cotton wool spots** appear as small, **fluffy**, **whitish** superficial **lesions**. They are accumulations of dead nerve cells from ischaemic damage.

Answer 86

**Topography of Anterior Neck:** 1. Superficial (Investing) Fascia 2. Pretracheal Fascia 3. Infrahyoid Muscles 4. Thyroid Gland 5. Trachea 6. Oesophagus

Answer 87

**Anatomy of Thyroid Gland:** * A butterfly-shaped gland located just inferior to the larynx (voice box) * Composed of right and left lateral lobes, one on either side of the trachea * Lobes connected by an isthmus anterior to the trachea * About 50% of thyroid glands have a small third lobe, called the pyramidal lobe, that extends superiorly from the isthmus * Normal mass is about 30g

Answer 88

**Histology of Thyroid Gland:** * Gland composed of microscopic spherical sacs called thyroid follicles * The wall of each follicle consists primarily of follicular cells, most of which extend to the lumen * A basement membrane surrounds each follicle * When the follicular cells are inactive their shape is low cuboidal to squamous, but under the influence of TSH * they become active in secretion and range from cuboidal to low columnar in shape * Parafollicular cells or C cells lie between the thyroid follicles

Answer 89

**Relation to Parathyroid Gland:** * Four small glands on posterior side of thyroid gland * Disc-like glands embedded in the thyroid gland (dorsal surface)

Answer 90

**Function of Thyroid Hormones (T3 and T4):** 1. **Increase Basal Metabolic Rate:** Increase the rate of oxygen consumption under standard or basal conditions (awake, at rest, and fasting), by stimulating the use of cellular oxygen to produce ATP. When the basal metabolic rate increases, cellular metabolism of carbohydrates, lipids, and proteins increases. Exceptions are adult brain, testes, uterus, lymph nodes, spleen (and anterior pituitary, turn off TSH production). 2. **Increase Temperature:** Play an important role in the maintenance of normal body temperature. Stimulate synthesis of additional Na+/K+ ATPase pumps which use large amounts of ATP. As cells produce and use more ATP, more heat is given off, and body temperature rises. This phenomenon is called the calorigenic effect. 3. **Increase Metabolism:** Stimulate protein synthesis and increase the use of glucose and fatty acids for ATP production. They also increase lipolysis and enhance cholesterol excretion, thus reducing blood cholesterol level. 4. **Increase Catecholamines:** Enhance some actions of noradrenaline and adrenaline because they upregulate beta receptors. This increases heart rate, contractility, cardiac output, stroke volume and blood pressure. 5. **Increase Growth:** Together with human growth hormone and insulin, thyroid hormones accelerate body growth, particularly the growth of the nervous and skeletal systems. Deficiency of thyroid hormones during fetal development, infancy, or childhood causes severe mental retardation and stunted bone growth.

Answer 91

**_Thyroxine / Tetraiodothyronine (T4)_** * **Synthesis** → Follicular Cells of Thyroid Gland * **Functions** 1. Increase basal metabolic rate 2. Stimulate synthesis of proteins 3. Increase use of glucose and fatty acids for ATP production 4. Increase lipolysis 5. Enhance cholesterol excretion 6. Accelerate body growth 7. Contribute to development of nervous system

Answer 92

**_Calcitonin_** * **Synthesis** → Parafollicular Cells of Thyroid Gland * **2 Functions** 1. Lowers blood levels of Ca2+ and HPO42- by inhibiting bone resorption by osteoclasts and by accelerating uptake of calcium and phosphates into bone extracellular matrix 2. Inhibits osteoclasts which decreases bone resorption

Answer 93

**_Parathyroid Hormone_** * **Synthesis** → Chief Cells of Parathyroid Gland * **Functions** 1. Increases blood Ca2+ and Mg2+ levels and decreases blood HPO42- levels 2. Promotes Ca2+ release into the blood by increasing bone resorption by osteoclasts (increases RANKL and decreases OPG which increases osteoclast numbers) 3. Increases Ca2+ reabsorption (DCT regulated reabsorption) and HPO42- excretion by kidneys, reducing the amount lost in the urine 4. Promotes formation of calcitriol (active form of vitamin D by kidneys), which increases rate of dietary Ca 2+ and Mg2+ absorption at small intestine, reducing the amount lost in the faeces

Answer 94

**Synthesis of Thyroid Hormones:** 1. **Iodide Trapping:** Thyroid follicular cells trap iodide ions (I-) by actively transporting them from the blood into the cytosol. The thyroid gland normally contains most of the iodide in the body. 2. **Synthesis of Thyroglobulin:** While the follicular cells are trapping I-, they are also synthesising thyroglobulin (TGB), a large glycoprotein that is produced in the rough endoplasmic reticulum, modified in the Golgi complex, and packaged into secretory vesicles. The vesicles then undergo exocytosis, which releases TGB into the lumen of the follicle. 3. **Oxidation of Iodide:** Some of the amino acids in TGB are tyrosines that will become iodinated. However, negatively charged iodide ions cannot bind to tyrosine until they undergo oxidation (removal of electrons) to iodine (I2). As the iodide ions are being oxidised, they pass through the membrane into the lumen of the follicle. 4. **Iodination of Tyrosine:** As iodine molecules (I2) form, they react with tyrosines that are part of TGB molecules. Binding of one iodine atom yields monoiodotyrosine (T1), and a second iodination produces diiodotyrosine (T2). The TGB with attached iodine atoms, a sticky material that accumulates and is stored in the lumen of the thyroid follicle, is termed colloid. 5. **Coupling of T1 and T2:** Two T2 molecules join to form T4, or one T1 and one T2 join to form T3. 6. **Pinocytosis and Digestion of Colloid:** Droplets of colloid reenter follicular cells by pinocytosis and merge with lysosomes. Digestive enzymes in the lysosomes break down TGB, cleaving off molecules of T3 and T4. 7. **Secretion of Thyroid Hormones:** T3 and T4 are lipid soluble, and so diffuse through the plasma membrane into interstitial fluid and then into the blood. T4 normally is secreted in greater quantity than T3, but T3 is several times more potent. After T4 enters a body cell, most of it is converted to T3 by removal of one iodine. 8. **Transport in the Blood.** More than 99% of both the T3 and the T4 combine with transport proteins in the blood, mainly thyroxine-binding globulin (TBG) and travel to site of action.

Answer 95

**_Regulation of Thyroid and Parathyroid Hormones:_** * **Thyroid Hormones (T3 and T4)** 1. Secretion is increased by thyrotropin-releasing hormone (TRH), which stimulates release of thyroid-stimulating hormone (TSH) in response to low thyroid hormone levels, low metabolic rate, cold, pregnancy, and high altitudes 2. TRH and TSH secretions are inhibited in response to high thyroid hormone levels 3. High iodine level suppresses T3/T4 secretion * **Calcitonin** 1. High blood Ca2+ levels stimulate secretion 2. Low blood Ca2+ levels inhibit secretion * **Parathyroid Hormone** 1. Low blood Ca2+ levels stimulate secretion 2. High blood Ca2+ levels inhibit secretion

Answer 96

**Hormones and Expression of Target Genes:** 1. Hormone travels in blood to distant sites of action 2. Hormone binds to receptors on target organ 3. Binding elicits specific signal transduction pathway (via second messengers) 4. Produces cellular response and changes in gene expression (nucleus) 5. Results in specific cellular function

Answer 97

**Transmembrane Receptors:** Receptors that span the cell membrane 1. **Enzyme-linked receptors:** Intracellular component is an enzyme that is activated by binding (insulin receptor activates protein kinase) 2. **Ion channel-linked receptors:** Binding of a ligand opens/closes an ion channel (neurotransmitter) 3. **G protein-coupled receptors:** Binding of first messenger activates secondary messenger to elicit cellular response (adrenaline)

Answer 98

**Activation of G protein-coupled receptors** 1. Hormone binds to a specific receptor 2. The bound receptor causes replacement of the GDP bound to Gs by GTP, activating Gs 3. Gs (alpha subunit) moves to adenyl cyclase and activates it 4. Adenyl cyclase catalyzes the formation of cAMP from ATP 5. cAMP activates protein kinase A (PKA) 6. Phosphorylation of cellular proteins by PKA causes cellular response 7. cAMP is degraded, reversing the activation of PKA

Answer 99

**Hormones that act on** **Transmembrane Receptors** 1. Peptide hormones 2. Catecholamines (monoamines) 3. GFs 4. Water-soluble hormones

Answer 100

**Intracellular Receptors:** Receptors found within the cytoplasm or nucleus of a cell **Nuclear receptors:** Ligands bind to receptor (cytoplasmic/nuclear) causing a conformational change, allowing complex to interact with DNA and increase/decrease transcription of a specific gene(s) 1. Steroid passes through plasma membrane and binds to receptor in cytoplasm 2. Activated receptor binds to specific regulatory sequence of DNA (hormone response elements) 3. Binding to DNA modifies the rate of transcription of the associated gene 4. Modified transcription leads to modified translation of regulated gene product **Hormones:** 1. Steroid hormones 2. Thyroid hormones 3. Lipid-soluble hormones

Answer 101

**Thyroid Gland Pathology: Thyroglossal Duct Cyst** * Cystic dilation of thyroglossal duct remnant * Thyroid develops at the base of tongue and then travels along the thyroglossal duct to the anterior neck * Thyroglossal duct normally involutes however a persistent duct may undergo cystic dilation * Presents as an anterior neck mass that moves during swallowing The thyroid anlage begins in the region of the foramen cecum at the base of the tongue; as the gland develops, it descends to its definitive midline location in the anterior neck. Remnants of this developmental process may persist, resulting in 1- to 4-cm cysts that are lined by stratified squamous epithelium when located near the base of the tongue or by pseudostratified columnar epithelium in lower locations. Transitional epithelial differentiation patterns also occur. The fibrous cyst wall often includes lymphoid aggregates or thyroid remnants. Malignant transformation of the lining epithelium is exceedingly rare. The definitive treatment is surgical excision.

Answer 102

**Thyroid Gland Pathology: Lingual Thyroid** * Persistence of thyroid tissue at the base of tongue * Presents as a base of tongue mass The thyroid gland consists of two lateral lobes connected by a thin isthmus, usually located below and anterior to the larynx. It develops embryologically from an evagination of the pharyngeal epithelium that descends from the foramen cecum at the base of the tongue to its normal position in the anterior neck. This pattern of descent explains the occasional presence of ectopic thyroid tissue at the base of the tongue (lingual thyroid) or at other sites high in the neck.

Answer 103

**Hypothyroidism Pathologies** 1. Cretinism 2. Myxedema 3. Hashimoto Thyroiditis 4. Subacute Granulomatous Thyroiditis (de Quervain) 5. Riedel Thyroiditis 6. Other

Answer 104

**_Hypothyroidism Pathology: Cretinism_** * Hypothyroidism in neonates and infants (congenital) * Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis, iodine deficiency or dyshormonogenetic goiter (due to congenital defect in thyroid hormone production, most commonly thyroid peroxidase) * Clinically manifests as pot-bellied, pale, puffy-faced child with protruding umbilicus, protuberant (enlarged) tongue and poor brain development (6 P’s), short stature with skeletal abnormalities and coarse facial features

Answer 105

**Hypothyroidism Pathology: Myxedema** * Hypothyroidism in older children or adults * Most common causes are iodine deficiency and Hashimoto thyroiditis * Other causes include drugs (lithium) and surgical removal or radio-ablation of the thyroid * Clinical features are based on decreased basal metabolic rate and decreased sympathetic nervous system activity (general hypothyroidism features)

Answer 106

**Hypothyroidism Pathology: Hashimoto Thyroiditis** * Most common cause of hypothyroidism in iodine-sufficient regions * Autoimmune destruction of the thyroid gland, associated with HLA-DRS and antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies * Progressive depletion of thyroid epithelial cells, replaced by mononuclear cell infiltration and fibrosis * Associated with increased risk of non-Hodgkin lymphoma (typically of B-cell origin) * May be hyperthyroid early in course due to thyrotoxicosis during follicular rupture * Histologic findings include Hürthle cells (eosinophilic metaplasia of cells that line follicles) and chronic lymphoid aggregates with germinal centers * Clinically manifests as moderately enlarged, nontender thyroid

Answer 107

**Subacute Granulomatous Thyroiditis (de Quervain)** * Self-limited disease often following a flu-like illness (such as viral infection) * May be hyperthyroid early in course, followed by hypothyroidism * Histological findings include granulomatous inflammation * Clinically manifests as raised ESR, jaw pain and very tender thyroid (de Quer*vain* is associated with *pain*)

Answer 108

**Hypothyroidism Pathology: Riedel Thyroiditis** * Chronic inflammation with extensive fibrosis of the thyroid gland * Thyroid replaced by fibrous tissue with inflammatory infiltrate * Fibrosis may extend to local structures (trachea, esophagus), mimicking anaplastic carcinoma. * One third are hypothyroid * Considered a manifestation of IgG4-related systemic disease (i.e. autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis). * Clinical manifests as fixed ('hard as wood') nontender thyroid and painless goiter

Answer 109

**Hyperthyroidism Pathologies** 1. Graves Disease (Diffuse Toxic Hyperplasia) 2. Multinodular Goiter 3. Thyroid Storm (Thyrotoxicosis Crisis) 4. Jod-Basedow Phenomenon 5. Hyperfunctioning adenoma or carcinoma (see below) 6. TSH-secreting pituitary adenoma (secondary hyperthyroidism) 7. Struma ovarii (ovarian teratoma with ectopic thyroid)

Answer 110

**Hyperthyroidism Pathology:** **Graves Disease (Diffuse Toxic Hyperplasia)** * Most common cause of hyperthyroidism * Autoantibody (IgG) that stimulates TSH receptor (type II hypersensitivity) * Leads to increased synthesis and release of thyroid hormone * Classically occurs in women of childbearing age (20-40 years) * Histological findings include irregular follicles with scalloped colloid (colloid that has been removed for secretion into blood) and chronic inflammation * Laboratory findings include increased total and free T4 and decreased TSH, hypocholesterolemia and increased serum glucose * Treatment involves B-blockers, thioamide, and radioiodine ablation * Thyroid storm is a potentially fatal complication

Answer 111

**Clinical features of Graves** 1. Hyperthyroidism 2. Diffuse goiter (constant TSH stimulation leads to thyroid hyperplasia and hypertrophy) 3. Exophthalmos and pretibial myxedema (fibroblasts behind the orbit and overlying the shin express the TSH receptor and activation results in glycosaminoglycan (chondroitin sulfate and hyaluronic acid) buildup, inflammation, fibrosis and oedema)

Answer 112

**Hyperthyroidism Pathology: Multinodular Goiter** * Enlarged thyroid gland with multiple nodules * Due to relative iodine deficiency * Usually nontoxic (euthyroid) * Rarely, regions become TSH-independent leading to T4 release and hyperthyroidism (toxic goiter) With time, recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed *multinodular goiter*. Virtually all long-standing simple goiters convert into multinodular goiters. **Multi- nodular goiters produce the most extreme thyroid enlarge- ments and are more frequently mistaken for neoplasms than any other form of thyroid disease.** Because they derive from simple goiter, they occur in both sporadic and endemic forms, having the same female-to-male distribution and presumably the same origins but affecting older individuals because they are late complications.

Answer 113

**Hyperthyroidism Pathology:** **Thyroid Storm (Thyrotoxicosis Crisis)** * Uncommon but serious complication that occurs when hyperthyroidism is incompletely treated/untreated and then significantly worsens in the setting of acute stress such as infection, trauma or surgery * Due to elevated catecholamines and massive hormone excess * Presents with agitation, delirium, fever, diarrhea, coma, tachyarrhythmia (cause of death), hyperthermia, vomiting and hypovolaemic shock. May see raised LFTs. * Treat with 4Ps including β-blockers (Propranolol), Propylthiouracil, corticosteroids (Prednisolone) and Potassium iodide (Lugol iodine)

Answer 114

**Hyperthyroidism Pathology:** **Jod-Basedow Phenomenon** * Thyrotoxicosis if a patient with iodine deficiency and partially autonomous thyroid tissue (autonomous nodule) is made iodine replete * Opposite of Wolff-Chaikoff effect

Answer 115

**Thyroid Neoplasm Pathologies** 1. Thyroid Adenoma 2. Thyroid Cancer 3. Papillary Carcinoma (75-85% of cases) 4. Follicular Carcinoma (10-20% of cases) 5. Medullary Carcinoma (5% of cases) 6. Undifferentiated / Anaplastic Carcinoma (\<5% of cases) 7. Lymphoma

Answer 116

**Multinodular goiter.** ## Footnote (A) Gross morphology demonstrating a coarsely nodular gland containing areas of fibrosis and cystic change. (B) Photomicrograph of a hyperplastic nodule with compressed residual thyroid parenchyma on the periphery. Note the absence of a prominent capsule, a distinguishing feature from follicular neoplasms.

Answer 117

**Thyroid Neoplasm Pathology: Thyroid Adenoma** * Benign solitary growth of the thyroid (commonest neoplasm) * Most are nonfunctional * Rarely cause hyperthyroidism via autonomous thyroid hormone production ("toxic") * Most common histology is follicular with absence of capsular or vascular invasion (unlike follicular carcinoma).

Answer 118

**Thyroid Neoplasm Pathology: Thyroid Cancer** * Typically diagnosed with fine needle aspiration * Treated with thyroidectomy * Complications of surgery include hoarseness (due to recurrent laryngeal nerve damage), hypocalcemia (due to removal of parathyroid glands) and transection of recurrent and superior laryngeal nerves (during ligation of inferior thyroid artery and superior laryngeal artery, respectively)

Answer 119

**Causes of Graves Disease:** 1. B and T lymphocyte-mediated autoimmune disorder 2. Genetic predisposition given that 50% of patients with Graves disease have a family history of autoimmune disorders (Type 1 DM, Hashimoto's disease, pernicious anemia, myasthenia gravis) 3. May be triggered by surgery/trauma of the thyroid gland and possibly severe psychological stress

Answer 120

**Pathophysiology of Graves Disease:** 1. TSH-receptor stimulating IgG immunoglobulin (type II hypersensitivity reaction) 2. Autoantibody acts as an agonist on TSH receptors and activates thyroid 3. Leads to increased synthesis and release of thyroid hormone (hyperthyroidism) 4. Constant TSH stimulation leads to thyroid hyperplasia and hypertrophy (diffuse goiter) 5. Autoantibody also acts on orbital fibroblasts causing fibroblast proliferation, hyaluronic acid synthesis and differentiation of fibroblasts to adipocytes (opthalmopathy with exophthalmus) 6. Autoantibody also acts on dermal fibroblasts (shin) and causes deposition of glycosaminoglycans in connective tissue (pretibial myxedema)

Answer 121

**Clinical Features of Graves Disease:** 1. Symptoms of hyperthyroidism 2. **Diffuse Goiter:** Smooth, uniformly enlarged goiter and bruit may be heard at the superior poles of the lobes 3. **Ophthalmopathy:** Exophthalmos, ocular motility disturbances, lid retraction and conjunctival conditions 4. **Dermopathy (Pretibial Myxedema):** Non-pitting oedema and firm plaques on the anterior/lateral aspects of both legs

Answer 122

**Diagnosis of Graves Disease:** Often apparent on clinical examination and is confirmed through detection of specific thyroid antibodies * **1) Blood Test:** Reduced/undetectable TSH and raised T3/T4 * **2) Thyroid Antibodies** * ↑ TRAbs (specific) * ↑ anti-TPO and anti-Tg (nonspecific) * **3) Thyroid Scintigraphy** * A nuclear medicine procedure that produces a visual display of functional thyroid tissue based on the selective uptake of various radionuclides by thyroid tissue * Indicated if TRAbs are low to establish a diagnosis * Shows a diffuse uptake of radioactive iodine (123I) * Contraindicated in pregnancy * **4) Thyroid Ultrasound (With Colour Doppler)** * Indicated in pregnant women if TRAbs are low * Shows an enlarged, hypervascular thyroid

Answer 123

**Treatment of Graves Disease:** * **Goal:** To inhibit the production of thyroid hormones and to block the effect of the hormones on the body * **β-blockers:** Rapid control of hyperthyroidism symptoms * **Antithyroid Drugs:** 1. **Carbimazole:** Block thyroid hormone synthesis 2. **Propylthiouracil:** Block thyroid hormone synthesis and also inhibits peripheral conversion of T4 to T3 1. Patients with a small goiter and mild hyperthyroidism may undergo remission on antithyroid drugs alone (in about 50% of cases) 2. Once remission is achieved, drugs are slowly tapered and stop * **Radioactive Iodine Ablation:** * First-line therapy in nonpregnant patients with small goiters * Second-line therapy in patients who relapse after long-term therapy with antithyroid drugs * **Surgery:** Near-total thyroidectomy is rarely done in Graves disease * **Complications of Therapy:** 1. Permanent hypothyroidism after radioactive iodine ablation or surgery (requires lifelong thyroid replacement therapy) 2. New-onset/exacerbation of Graves ophthalmopathy after radioactive iodine ablation 3. Hoarseness due to transection of recurrent laryngeal nerve 4. Hypocalcaemia due to removal of parathyroid gland

Answer 124

**_Autoimmune Diseases_** 1. **Autoimmune Hepatitis (Liver)** → Anti-smooth muscle 2. **Antiphospholipid Syndrome** → Anti-phospholipid 3. **Coeliac Disease (GI Tract)** → Anti-endomysial IgA, Anti-gliadin IgA, Anti-tissue transglutaminase IgA 4. **Diabetes Mellitus Type 1 (Pancreas)** → Anti-glutamic acid decarboxylase 5. **Goodpasture's Syndrome** → Anti-glomerular basement membrane 6. **Graves Disease (Thyroid)** → Anti-TSH receptor 7. **Hashimoto’s Thyroiditis (Thyroid)** → Anti-thyroid peroxidase (microsomal) & Anti-thyroglobulin 8. **Myasthenia Gravis (Nerves and Muscles)** → Anti-acetylcholine receptor 9. **Pernicious Anaemia (Stomach)** → Anti-intrinsic factor & Anti-parietal cell 10. **Primary Biliary Cirrhosis (Liver)** → Anti-mitochondrial 11. **Systemic Lupus Erythematous (SLE)** → Anti-nuclear antibodies (ANA), Anti-dsDNA & Anti-Sm (Smith antigen)

Answer 125

**Graves as Autoimmune Disease:** * **Autoantibody:** TSH-receptor stimulating IgG immunoglobulin (TRAbs) which acts as an agonist on TSH receptors and activates thyroid gland and extra-thyroid tissues * **Receptor:** Thyroid stimulating hormone receptor (TSHR), a G protein-coupled receptor * **Location of TSH Receptors:** 1. Thyroid follicular cells (main location) 2. Retro-orbital fibroblasts and adipose tissue 3. Pretibial space fibroblasts and adipose tissue

Answer 126

**Murtagh's 10-Point Plan for Consultation:** 1. Tell the patient the diagnosis, or if not possible, describe the problem as it relates to the presenting symptoms (signpost, explain in simple terms without medical jargon, pace the information and use resources) 2. Establish the patient’s knowledge of the diagnosis 3. Establish the patient’s attitude to the diagnosis and management 4. Educate the patient about diagnosis 5. Develop a management plan for the presenting problem (immediate, long-term and preventive) 6. Explore other preventive opportunities (immunisation, screening tools and smoking, alcohol and safe sex advice) 7. Reinforce the information 1. Use the patient’s own results (e.g. X-rays and ECGs) 2. Encourage the patient to participate in the decision making and in accepting some degree of responsibility for his or her own management 8. Provide take-away information (patient instruction leaflets, diagrams and resource contacts) 9. Evaluate the consultation 10. Arrange follow-up and document

Answer 127

* **Acute adrenal insufficiency**: Make a clinical diagnosis and defer detailed testing until after empiric glucocorticoids are given. * **Chronic adrenal insufficiency**: Use stepwise endocrine testing in all patients. 1. Morning cortisol 2. Morning ACTH 3. ACTH stimulation test * [**Primary adrenal insufficiency**](https://next.amboss.com/us/article/Ug0bu2#Z7b47bf57fd367b1b9891e4155e39236f): Screen for hypoaldosteronism and hypoandrogenism. * **Secondary and tertiary adrenal insufficiency**: Differentiating between the two is often not required, as it does not influence management. * **All patients**: Investigate for an underlying cause.