Hyperthyroidism

Hypermetabolic state due to Elevated circulating T3 and T4, the resulting clinical Ø Hyperfunctioning (“toxic”) multinodular goiter
syndrome being known as thyrotoxicosis. 1° Ø Hyperfunctioning (“toxic”) thyroid adenoma
Clinical features of thyrotoxicosis: Weight loss, diarrhea, Exophthalmos, pretibial Ø Iodine-induced hyperthyroidism
myxedema, tachycardia, palpitations, Warm moist skin, proximal myopathy, 2° TSH-secreting pituitary adenoma
Nervousness , tremor, Heat intolerance and excessive sweating.
Diagnosis:
The measurement of serum TSH is the most useful single screening test for hyperthyroidism. T3, T4 and radioactive iodine uptake are used as well.
Graves’ An autoimmune disease; autoantibodies mimic the stimulatory action of TSH. Genetic susceptibility
disease: Ø Between the ages of 20 and 40, Women more than men and the most common cause of Hyperthyroidism with HLA- DR3
Pathogenesis Clinical findings
- Thyroid-stimulating immunoglobulin: ↑ thyroid hormone. Ø Thyroid enlargement, pretibial myxedema
- Thyroid growth-stimulating immunoglobulin: leads to proliferation of thyroid follicular epithelium. Ø Infiltrative ophthalmopathy
- TSH-binding inhibitor immunoglobulin: ↓ thyroid hormone. Histology
Infiltrative ophthalmopathy: 1. Infiltration of the retro-orbital space by mononuclear cells (Mostly T Ø Scalloped colloid appearance
cells). 2. Inflammatory edema. 3. Accumulation of glycosaminoglycans. 4. ↑ adipocytes
Ø Epithelial cells turn columnar, Lymphocytosis
Hypothyroidism: Insufficient circulating T4 and T3 leads to a hypometabolic state
Ø Hashimoto’s thyroiditis Clinical Features
Ø Iodine deficiency • Cretinism: During infancy, It manifests with: Severe mental retardation, short stature, coarse facial
Ø Thyroid dysgenesis features, a protruding tongue, obesity and umbilical hernia.
Causes

1°

Ø Congenital biosynthetic • Myxedema: Glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, visceral sites.
defect Non-pitting edema, a broadening and coarsening of facial features, tongue enlargement, deepening
Ø Post ablative voice.
Caused by deficiency of TSH • Hair loss (skull and eyebrows), Oligomenorrhoea, Somnolence, Bradycardia & Slowness in memory
2°

Hashimoto’s An organ specific autoimmune disease in which the immune system reacts against a variety of thyroid antigens (thyroglobulin and thyroid
thyroiditis: peroxidase): Most common cause of hypothyroidism. Female predominance of 10:1 to 20:1. Age 45-65.
Clinical Painless enlargement, Goiter, which recedes after time due to atrophy and fibrosis. Hypothyroidism, thyrotoxicosis in the early
Features stages. ↑ risk for the development of B cell non-Hodgkin lymphomas and predisposition to papillary carcinomas.
Grossly 1. Diffusely enlarged. 2. Cut surface is pale, firm, and somewhat nodular 3. In advanced cases, the gland is shrunken and fibrotic
• Infiltration of the parenchyma by lymphocytes and plasma cells, well-developed germinal centers
Histologically
• ↑ of the number of cells lining the follicles and ↓ in the amount of stored colloid. Oncocytes or Hürthle cells.
 Subacute Granulomatous Thyroiditis: (de Quervain) Riedel’s thyroiditis
• The thyroid is infiltrated by multinucleated giant cells It’s exceptionally rare. Characterized by replacement of the
• between the ages of 30 and 50, Self-limited, caused mostly by a viral infection thyroid by fibrous tissue, often with involvement of
• Most common cause of painful thyroid gland adjacent tissues (retroperitoneum). The etiology is
• fever, malaise, tenderness on palpation and variable enlargement of the thyroid unknown. Patients present with an enlarged thyroid, which
Histology is hard and immobile on palpation thereby mimicking
carcinoma. The condition may be associated with
• Disruption of thyroid follicles. Granulomatous reaction with giant cells.
retroperitoneal fibrosis.
• Polymorphonuclear infiltrate.

Multinodular Goiter
Enlargement of the thyroid, or goiter, is the most common Endemic In geographic areas where there is little iodine.
manifestation of thyroid disease, it has two subtypes: Sporadic Less common than endemic goiter; occurs in Females more than males.
• Impairment of thyroid hormone synthesis → a compensatory rise in Grossly Microscopically
Pathogenesis

the serum TSH → TSH-induced hypertrophy and hyperplasia of Asymmetrically enlarged glands. Irregular Colloid-rich
thyroid follicular cells → diffuse and symmetric enlargement of the nodules. Brown gelatinous colloid. follicles &
gland. On Cut surface, it shows: Fibrosis, Flattened follicular
• With time, Recurrent episodes of hyperplasia → a more irregular hemorrhage & cystic change. epithelium
enlargement of the thyroid termed Multinodular goiter.

Solitary Thyroid Nodule

Palpably discrete swelling within an Incidence 1-10%, single nodules: Female/Male 4:1, ↑ throughout life,
otherwise apparently normal thyroid gland Majority Localized, non-neoplastic conditions or benign neoplasms such as follicular adenomas.
- One dominant nodule in a multinodular goiter. - Thyroid cysts. - Thyroid neoplasm.
Diagnosis
- Asymmetrical enlargement due to non-neoplastic disease (e.g. Hashimoto’s thyroiditis)

Thyroid Neoplasms
Morphologic evaluation of a nodule by fine needle aspiration, combined with histologic study of surgically resected thyroid parenchyma provide
the most definitive information about its nature (whether it’s benign or malignant).
The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation.
 Follicular Adenoma
Benign masses derived from Degree of follicular formation Pathogenesis Morphology
follicular epithelium Careful
o Macrofollicular adenomas ¡ Somatic mutations in the genes ¡ Solitary, typically discrete, spherical
evaluation of the integrity of (simple colloid) encoding for TSH receptor or, nodule compressing adjacent
the capsule is critical in o Fetal or microfollicular, the alpha subunit of Gs nonneoplastic parenchyma with a well-
distinguishing adenomas embryonal or trabecular ¡ Mutations in RAS or (PIK3CA). defined, intact capsule.
from follicular carcinomas. (during embryogenesis) ¡ (Hürthle cell change).
Genetic factors Morphology Metastasis Clinical Features/prognosis
Activation of the MAP kinase Un-encapsulated, papillary structure, psammoma 3rd or 4th decade. Painless

node metastases
Cervical lymph
pathway: Rearrangements of the bodies, orphan Annie nuclei, grooves nuclei & mass in the neck.
Papillary

tyrosine kinase receptors RET or pseudoinclusions. Can present in several ways but Excellent prognosis
NTRK1 or Activating point Follicular variant is the most common: encapsulated
mutations in BRAF. and is associated with a lower incidence of lymph node
RET/PTC (fusion) translocations metastases and extrathyroidal extension.
Chromosomes (2;3) Solitary, encapsulated, may appear like papillary Between 40-60, frequent in
translocation results in carcinoma, only lacking its nuclear features. areas with iodine deficiency.

Hematogenous
dissemination
PAX8/PPARG fusion genes, Hürthle cell variants, degenerative changes, such as Prognosis: Poorer than
Follicular

Mutations in PI-3K/AKT central fibrosis and foci of calcification may be seen papillary
signaling pathway: Gain-of- Widely invasive: Extensive invasion of adjacent thyroid
function point mutations of parenchyma or extrathyroidal tissues. They have a
RAS and PIK3CA or Loss-of- greater proportion of solid or trabecular growth pattern,
function mutations of PTEN less follicular differentiation, and ↑ mitotic activity.
(MEN-2) and are associated with Derived from parafollicular cells (C-cells). MEN: both have:
RET proto-oncogene mutation. Grossly: Sporadic (70%) originates in one lobe & Medullary carcinoma of the
thyroid & pheochromocytoma.
Medullary

Familial: Bilaterality and multicentric C-cell

Type 2A: Parathyroid adenoma
hyperplasia Type 2B: Ganglioneuroma

-
Microscopically: Acellular amyloid deposits & Sporadic clinical features:
calcitonin within the cytoplasm of the tumor cells as well mass in the neck, with
as in the stromal amyloid. Most secrete calcitonin compression effects
Ana- De novo or more commonly by Poorly differentiated highly anaplastic cells, Very >65, rapid growth rate, lethal
Widely
plastic dedifferentiation. pleomorphic & prognosis is very poor
 Adrenocortical Hyperfunction
three distinctive hyperadrenal clinical syndromes, each caused by (1) Cushing syndrome, characterized by an excess of cortisol.
abnormal production of one or more of the hormones produced by (2) Hyperaldosteronism.
the three layers of the cortex. (3) Adrenogenital or virilizing syndromes caused by an excess of androgens.
Hypercortisolism “Cushing Syndrome”: Caused by any condition that produces an elevation in glucocorticoid levels
It could be:
1-Exogenous Most common cause of Cushing syndrome is the administration of exogenous glucocorticoids (“iatrogenic” Cushing syndrome)
ACTH-dependent ACTH-independent (adrenal Cushing syndrome)
Cushing disease (ACTH-producing microadenoma; rarely CRH- Adrenal adenoma (unilateral adrenocortical
dependent pituitary hyperplasia) (associated with bilateral nodular neoplasm) → contralateral adrenal atrophy.
2-Endogenous
cortical hyperplasia). Adrenal carcinoma (unilateral adrenocortical
Ectopic corticotropin syndrome (ACTH-secreting pulmonary small-cell neoplasm) → contralateral
carcinoma, bronchial carcinoid tumor) adrenal atrophy
In pituitary In adrenal glands
The most common Depends on the cause of hypercortisolism; it could be:
Morphology alteration is termed 1- Bilateral Cortical atrophy: results from exogenous glucocorticoids.
Crooke hyaline 2- Diffuse hyperplasia: individuals with ACTH dependent Cushing syndrome
change 3- Adenoma or carcinoma. 4- Macronodular or micronodular hyperplasia.
CF Obesity or weight gain, Rounded face “Moon-like”, Easy bruising, Thin skin, Hypertension & Abdominal striae
1. Serum ACTH: 2. High dose dexamethasone suppression test:
Diagnosis - Low → Primary cause (adrenal problem). - Suppression of ACTH→ pituitary adenomas.
- High → Pituitary adenomas and ectopic ACTH. (Secondary cause) - Fail of suppression of ACTH→ ectopic ACTH.
Hyperaldosteronism: Hyperaldosteronism may be primary or secondary to an extraadrenal cause.
1° Primary, autonomous overproduction of aldosterone, with suppression of the renin-angiotensin system & ↓ plasma renin activity
Causes • Bilateral idiopathic hyperaldosteronism • Adrenocortical neoplasm (Conn syndrome) • familial hyperaldosteronism (rare)
2° This condition is characterized by increased levels of plasma renin Might present in association with:
CF Hypertension: 1° hyperaldosteronism → most common cause of 2° hypertension & ↓ renal perfusion, pregnancy, Arterial
Hypokalemia. hypovolemia and edema
Morpho- • Aldosterone-producing adenomas are almost always solitary • Adrenal cortexes are not atrophic
logy • Composed of lipid-laden cortical cells more closely resembling fasciculata cells • Spironolactone bodies.
 Adrenocortical Hypofunction
May be caused by either 1° adrenal disease or decreased stimulation of the adrenals resulting from a deficiency of ACTH (2°hypoadrenalism).
Primary Acute Adrenocortical Primary Chronic Adrenocortical Insufficiency: Secondary Adrenocortical Insufficiency
Insufficiency (adrenal crisis) Addison Disease
- Persons with chronic adrenocortical - Autoimmune adrenalitis - Any disorder of the hypothalamus and
insufficiency may develop an acute - Infections, particularly tuberculosis, AIDS. pituitary that reduces the output of ACTH
crisis after any Stress. - Metastatic Neoplasms : carcinomas of the lung leads to a syndrome of hypoadrenalism.
- Happens if steroid treatment is and breast are the source of majority of - The hyperpigmentation of primary Addison
withdrawn too rapidly. metastases in the adrenals. disease is lacking & Low serum ACTH.
CF GIT disturbance, Hyperpigmentation in patients with primary adrenal disease, Hyperkalemia, hyponatremia, volume depletion, and
hypotension, Secondary hypoadrenalism, Hypoglycemia, hypotension and dehydration
Pheochromocytoma A functioning tumor derived from the chromaffin cells of the adrenal medulla, and is classified as a paraganglioma.
CF - Overproduction of catecholamines produces isolated paroxysmal episodes of - Pain in the abdomen or chest, nausea, and vomiting
hypertension, associated with headaches, sweating, palpitations, pallor, anxiety - ↑ risk of myocardial ischemia, heart failure, renal
& nausea. injury, and stroke (cerebrovascular accident).
 Diabetes
1- A random glucose concentration > 200 mg/dL, with classical signs and symptoms. Definition:
Diagnosis

2- A fasting glucose concentration ≥ 126 mg/dL on more than one occasion. A condition characterized by an absolute or
3- An abnormal (OGTT), in which the glucose concentration > 200 mg/dL 2 hrs after a relative deficiency of insulin and/or insulin
standard carbohydrate load. resistance, inducing hyperglycemia.
MODY A rare case of DM, autosomal dominant. Due to a genetic defect in β cell function and is rather common in Gulf and Arabian countries.
Type 1 2
An autoimmune disease in which islet destruction (β-cell) is caused Interrelationship between insulin resistance in
Definition primarily by immune effector cells reacting against endogenous beta cell its target tissues and β-cell dysfunction
antigens.
Insulin absolutely required. Lifestyle modification; diet, exercise, oral drugs,
Management
often insulin supplement needed.
Development In childhood, manifests at puberty, and progresses with age. Adults with an increased prevalence in obese
Abrupt, resulting from a chronic autoimmune attack on beta cells that usually persons and in the elderly (>65).
Onset
starts many years before the disease becomes evident.
- Few if any functional B cells in the islets of Langerhans. - Insulin resistance.
Characteristics
- Extremely limited or nonexistent insulin secretion. - Beta cell dysfunction.
Genetic Factors: HLA-DR3 or HLA-DR4, CTLA4 and PTPN22. Genetic Factors: “diabetogenic” genes.
Pathogenesis Environmental event/factors: Viruses, chemicals. B-Cell Function: exhibit impaired B-cell insulin
Autoimmunity: islet cell antibodies against components of the B cells release in response to glucose stimulation.
Lymphocytic infiltrate in the islets (insulitis), macrophages and neutrophils. No reduction in the number of B- cells.
Morphology
No deposition of amyloid or fibrosis in islets Leukocytic infiltration of the islets, Fibrous tissue
¡ The exocrine pancreas in chronic T1DM often exhibits diffuse interlobular & Islet amyloid is often present particularly in
Pathology patients over 60 years of age (long-standing).
and interacinar fibrosis, accompanied by atrophy of the acinar cells.
↑ gluconeogenesis Classic triad 3P: Polyuria, Polydipsia & Polyphagia. § Polyuria and polydipsia, patients often are
§ Weight loss and weakness. Severe insulin deficiency → diabetic older than 40 years & obese.
Clinical kectoacidosis → ketone bodies § The metabolic derangements are much less
features o ketonuria & ketonemia. severe. Patients in the decompensated state
o Superimposed dehydration → metabolic ketoacidosis. develop hyperosmolar nonketotic coma.
o Infection ↑ insulin requirements → diabetic ketoacidosis. § No ketoacidosis.
 Diabetes Complications
Diabetic Macrovascular Disease Diabetic Microvascular Disease
Hyaline arteriosclerosis: Hyaline thickening ¡ Responsible for many of the complications of diabetes, including renal failure, Blindness & neuropathy.
of the wall of arterioles & narrowing of the ¡ Effects on tissue perfusion and wound healing are profound.
lumen. (in the kidneys and eyes). ¡ ↓ blood flow to the heart.
Arteriosclerosis: severe & accelerated Diabetic microangiopathy: diffuse thickening of the capillary vascular basement membranes
Diabetic nephropathy
The earliest manifestation is the Vascular changes: renal atherosclerosis and hyaline arteriosclerosis (afferent & efferent)
appearance of small amounts of Parenchymal changes: pyelonephritis with ↑ propensity to develop necrotizing papillitis.
albumin in the urine (greater than 30 Glomerular changes:
but less than 300 mg/day—i.e., Diffuse mesangial sclerosis Nodular glomerulosclerosis
microalbuminuria)
§ A diffuse ↑ in mesangial matrix along with mesangial cell § Ball-like deposits of a laminated matrix situated in
The glomeruli exhibit a unique lesion
proliferation & Basement membrane thickening. the periphery of the glomerulus.
termed Kimmelstiel-Wilson disease
§ Glomerulosclerosis marked → patients manifest the nephrotic § Nodules are PAS-positive & usually contain
or nodular glomerulosclerosis.
syndrome. May be seen with old age and hypertension. trapped mesangial cells.
Diabetic retinopathy
Diabetics have ↑ propensity for Non-proliferative changes Proliferative changes
glaucoma & cataract formation, both of Microangiopathy in the retinal blood vessels, micro aneurysms & Venous Neovascularization and fibrosis, →
which contribute to visual impairment. dilatation. Retinal hemorrhages (blots), edema & Exudates (cotton wool spots) retinal detachment & blindness.
Diabetic neuropathy
The most common and distressing Polyneuropathy:
complication Symmetric peripheral neuropathy (most frequent), affecting both motor and sensory nerves ( “glove &
¡ Microvasculopathy contributes. stocking” pattern). Pain and abnormal sensations in the extremities. Can lead to foot ulcers.
¡ Affects Sensory and Autonomic Autonomic neuropathy:
Innervations, peripheral sensory Cause impotence with bladder and bowel dysfunction.
impairment, and autonomic nerve Diabetic mononeuropathy, which may manifest as sudden footdrop or wristdrop or isolated cranial nerve
dysfunction. palsies.
Infections
↑ tendency to develop infections. Bacterial & Fungal Infections occur in poorly controlled diabetic hyperglycemia.
¡ Renal papillary necrosis may be a devastating complication of bladder infection.
¡ ↑ susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and pyelonephritis.
¡ In a person with diabetic neuropathy, a trivial infection in a toe → (gangrene, bacteremia, pneumonia)
¡ Mucormycosis: A dangerous infectious complication of poorly controlled diabetes is often fatal fungal infection tends to originate in the nasopharynx or
paranasal sinuses and spreads rapidly to the orbit and brain.
Done by: Nouf Altwaijri & Fahad Alabdullatif
Good Luck.