The Endocrine System

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1. Introduction

The human body is regulated by two main systems:

• Endocrine system

• Nervous system

A third system called the Neuroendocrine system connects the two and plays a key role in hormonal control.

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2. Neuroendocrine System

This system includes cells that produce hormones with both nerve-like and gland-like functions. These cells are called APUD cells (Amine Precursor Uptake and Decarboxylation).

Major Neuroendocrine Cells and Their Locations:

1. Gastrointestinal mucosa → Peptide hormones

2. Sympathetic ganglia → Amines

3. Adrenal medulla → Epinephrine & Norepinephrine

4. Thyroid parafollicular (C) cells → Calcitonin

5. Islets of Langerhans (Pancreas) → Insulin

6. Atrial cells (Heart) → Atrial natriuretic peptide (ANP)

Other Non-Endocrine Hormone-Like Substances:

• Acetylcholine, dopamine (neurotransmitters)

• Erythropoietin, Vitamin D3 (from kidneys)

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3. Major Endocrine Organs

The endocrine system includes six main glands:

1. Pituitary gland
2. Thyroid gland
3. Parathyroid glands
4. Adrenal glands
5. Gonads (testes/ovaries)
6. Pancreatic islets

🧠 Pancreas is part of both endocrine and neuroendocrine systems.

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4. Types of Hormones

Group I: Hormones Acting on Cell Surface Receptors

• Amino acid derivatives: Thyroid hormone, Catecholamines

• Small neuropeptides: GnRH, TRH, Somatostatin, Vasopressin

Group II: Hormones Acting on Nuclear (Intracellular) Receptors

• Large proteins: Insulin, LH, Parathormone

• Steroid hormones: Cortisol, Estrogen

• Vitamin derivatives: Vitamin A (retinol), Vitamin D

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5. Hormone Synthesis Pathway

Transcription → mRNA formation → Protein synthesis → Post-translational processing → Sorting & secretion

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6. Functions of Hormones

Function	Hormones Involved
Growth & Development	Pituitary hormones, Thyroid, Parathyroid, Steroids
Homeostasis	Thyroid, Parathormone, Insulin, Mineralocorticoids
Reproduction	Gonadal hormones, Pregnancy hormones, LH/FSH, Estrogen

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7. Hormonal Regulation: Feedback Mechanisms

• Negative Feedback: A hormone inhibits its own production when levels are high (e.g., TSH–TRH axis).

• Positive Feedback: A hormone stimulates further release (rare cases).

• Hypothalamic-Pituitary Axis: Regulates many hormones via a chain of command from the brain.

Examples:

• TRH → TSH → Thyroid hormone
• CRH → ACTH → Cortisol
• GnRH → LH/FSH → Gonadal hormones
• GHRH → GH → IGF-1

Paracrine Regulation: Hormone acts on neighboring cells

Autocrine Regulation: Hormone acts on the same cell that released it

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8. Endocrine Disorders

A. Hyperfunction (Too much hormone)

Causes:

• Hyperplasia
• Tumors (adenoma, carcinoma)
• Ectopic hormone production
• Autoimmune stimulation
• Infections
• Hormone overdose

B. Hypofunction (Too little hormone)

Causes:

• Autoimmune destruction
• Infections
• Surgical removal or radiation
• Congenital defects (e.g., Turner’s syndrome)
• Enzyme deficiency
• Hemorrhage/infarction (e.g., Sheehan’s syndrome)
• Nutritional deficiency (e.g., Iodine deficiency)

C. Hormone Resistance

• Hormone is produced in normal amounts, but the body’s receptors don't respond.
• Often due to genetic mutations in receptor or signal pathways.

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Pituitary Gland (Hypophysis)

🔹 NORMAL STRUCTURE

1. Anatomy

• Small endocrine gland (~500 mg in adults; slightly heavier in females).

• Located at the base of the brain in a bony cavity called sella turcica (part of sphenoid bone).

• Connected to the hypothalamus.

• Two main parts:

  • Anterior lobe (Adenohypophysis) – develops from oral ectoderm (Rathke’s pouch).

  • Posterior lobe (Neurohypophysis) – derived from neural ectoderm (hypothalamus).

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🔹 HISTOLOGY & FUNCTIONS

A. Anterior Pituitary (Adenohypophysis)

• Contains epithelial cells arranged in cords/islands supported by fibrovascular stroma.

• Cells are classified based on staining:

1. Chromophils (granule-containing cells)

i. Acidophils (40%) – stain pink:

• Somatotrophs → Secrete GH (Growth Hormone)

• Lactotrophs → Secrete PRL (Prolactin)

ii. Basophils (10%) – stain blue:

• Gonadotrophs → Secrete FSH, LH

• Thyrotrophs → Secrete TSH

• Corticotrophs → Secrete ACTH, MSH, β-lipoprotein, β-endorphin

2. Chromophobes (50%)

• No visible granules; may be non-secreting or inactive forms of other cells.

📌 Regulation: Controlled by hypothalamic releasing and inhibiting hormones via the hypophyseal portal system.

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B. Posterior Pituitary (Neurohypophysis)

• Contains nerve fibers and glial cells (pituicytes).

• Hormones stored here are made by the hypothalamus:

• ADH (vasopressin) → Promotes water reabsorption in kidneys; deficiency = diabetes insipidus.
• Oxytocin → Stimulates uterine contractions and milk ejection.

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DISORDERS OF THE PITUITARY GLAND

🔹 1. Hyperpituitarism

Overproduction of pituitary hormones. Mostly due to pituitary adenomas.

A. Anterior Pituitary Hyperfunction

1. Gigantism: Excess GH before epiphyseal closure (childhood) → abnormally tall stature.

2. Acromegaly: Excess GH in adults → enlarged hands, feet, jaw, thick skin.

3. Hyperprolactinaemia:

   • Caused by prolactin-secreting adenoma (prolactinoma).

   • In females → amenorrhoea, galactorrhoea, infertility.

   • In males → impotence, reduced libido.

4. Cushing’s syndrome: Excess ACTH → adrenal overproduction of cortisol.

B. Posterior Pituitary & Hypothalamic Hyperfunction

1. Syndrome of Inappropriate ADH Secretion (SIADH):

   • Excess ADH → water retention, hyponatremia.

   • Causes: lung cancers (e.g. small cell carcinoma), infections, trauma.

2. Precocious Puberty:

   • Early puberty (<9 yrs) due to hypothalamic or pineal tumors.

   • Features: early genital development, menstruation (girls), body hair.

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🔹 2. Hypopituitarism

Deficiency of one or more pituitary hormones.

A. Anterior Pituitary Hypofunction

Requires >75% destruction of anterior pituitary.

Causes:

• Tumors (non-secretory adenomas, craniopharyngioma)
• Sheehan’s syndrome (postpartum necrosis)
• Simmond’s disease (similar but not related to pregnancy)
• Empty sella syndrome
• Trauma, infections, infarction

Syndromes:

1. Panhypopituitarism: Combined deficiency of multiple hormones.

   • Symptoms: infertility, fatigue, hypothyroidism, adrenal insufficiency

2. Pituitary dwarfism:

   • GH deficiency in children → short stature, delayed puberty, normal intelligence.

B. Posterior Pituitary Hypofunction

• Diabetes Insipidus: ADH deficiency → polyuria, polydipsia, dilute urine.

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PITUITARY TUMOURS

1. Adenomas (most common)

• Benign tumors of anterior pituitary.

• Classified by:

• Histology: acidophil, basophil, chromophobe
• Function: hormone secreted

📌 Functional Types of Pituitary Adenomas

Type	Hormone	Clinical Syndrome
Lactotroph	PRL	Galactorrhoea, infertility
Somatotroph	GH	Gigantism, acromegaly
Corticotroph	ACTH	Cushing’s syndrome
Gonadotroph	FSH, LH	Hypogonadism
Thyrotroph	TSH	Hyperthyroidism
Null-cell	None	Pituitary failure
Mixed	GH + PRL	Mixed symptoms

Symptoms:

• Hormonal: Due to excess hormone production

• Pressure effects:

  • Compression of optic chiasma → visual defects

  • Bone erosion, headaches

2. Craniopharyngioma

• Benign tumor from Rathke’s pouch remnants.

• Common in children.

• May compress adjacent brain structures.

• Histology: cysts lined by squamous epithelium with “stellate” cells.

3. Granular Cell Tumour (Choristoma)

• Rare, in posterior pituitary.

• Usually asymptomatic.

• Discovered incidentally at autopsy.

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Summary Table: Key Hormones and Their Functions

Hormone	Produced By	Function
GH	Somatotrophs	Growth of body tissues
PRL	Lactotrophs	Milk production
ACTH	Corticotrophs	Stimulates adrenal cortex
TSH	Thyrotrophs	Stimulates thyroid
FSH/LH	Gonadotrophs	Reproductive function
ADH	Hypothalamus → stored in Posterior Pituitary	Water reabsorption
Oxytocin	Hypothalamus → stored in Posterior Pituitary	Uterine contractions, milk ejection

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ADRENAL GLAND

NORMAL STRUCTURE AND ANATOMY

• Location: On top (superior pole) of each kidney.

• Weight: About 4 grams in adults; proportionally larger in children.

• Parts:

  • Outer cortex (yellow-brown) – vital for life.

  • Inner medulla (grey) – not essential for survival.

• The adrenal gland is essential in hormone production and stress response.

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HISTOLOGY AND FUNCTION

ADRENAL CORTEX

• Divided into three zones, each with distinct hormones:

  1. Zona Glomerulosa (outermost):

     • 10% of cortex.

     • Produces mineralocorticoids, mainly aldosterone.

     • Regulates salt & water balance.

     • Controlled by potassium levels and renin-angiotensin system (not ACTH).

  2. Zona Fasciculata (middle):

     • 70% of cortex.

     • Produces glucocorticoids (cortisol) and sex steroids (e.g. testosterone).

     • Lipid-rich cells.

  3. Zona Reticularis (innermost):

     • Produces glucocorticoids and androgens.

     • Denser cells than zona fasciculata.

• Hormonal Control:

  • Glucocorticoids and androgens: under ACTH from pituitary.

  • Aldosterone: regulated by renin-angiotensin system and K⁺ levels.

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🔸 ADRENAL MEDULLA

• Part of the neuroendocrine system (derived from neuroectoderm).

• Produces catecholamines: epinephrine (adrenaline) & norepinephrine.

• Also secretes peptides like calcitonin, VIP, somatostatin.

• Metabolites: metanephrine, normetanephrine, VMA, HVA.

• In case of damage, other paraganglia compensate.

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ADRENAL GLAND DISORDERS

ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM)

1. Cushing’s Syndrome (↑ cortisol)

• Types:

• Pituitary: ACTH-secreting adenoma (Cushing’s disease).
• Adrenal: Cortical tumor/hyperplasia.
• Ectopic ACTH: From lung or other tumors.
• Iatrogenic: Due to long-term steroid therapy.

• Symptoms:

• Truncal obesity, moon face, buffalo hump.
• Muscle wasting, skin thinning, purple striae.
• Hypertension, osteoporosis, diabetes.
• Menstrual issues, hirsutism, psychiatric symptoms.

2. Conn’s Syndrome (Primary hyperaldosteronism)

• Cause: Excess aldosterone from:

• Adenoma
• Bilateral hyperplasia
• Rarely carcinoma

• Features:

• Hypertension (diastolic)
• Hypokalaemia: muscle weakness, arrhythmias
• Sodium retention, polyuria, polydipsia

3. Adrenogenital Syndrome (↑ androgens)

• In Children: Congenital adrenal hyperplasia

• In Adults: Tumors (adenoma or carcinoma)

• Features:

• Girls: masculinization
• Boys: early puberty
• Women: deep voice, hirsutism, clitoral enlargement

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ADRENOCORTICAL INSUFFICIENCY (HYPOADRENALISM)

1. Primary (Adrenal origin)

A. Acute (Adrenal Crisis)

• Causes:

  • Adrenalectomy

  • Infections (e.g. meningococcal sepsis → Waterhouse-Friderichsen syndrome)

  • Steroid withdrawal

• Symptoms:

  • Dehydration, vomiting, hypotension

  • Low Na⁺, high K⁺, hypoglycemia

B. Chronic – Addison’s Disease

• Causes:

  • TB, autoimmune adrenalitis, metastatic cancer

• Symptoms:

  • Weakness, weight loss, hyperpigmentation

  • Hypotension, loss of appetite

  • Biochem: low Na⁺, high K⁺, acidosis

2. Secondary (↓ ACTH)

• Causes:

  • Pituitary/hypothalamus disorders

  • Long-term steroid therapy

• Differences from Addison’s:

  • No hyperpigmentation

  • Normal aldosterone levels

  • Low ACTH

3. Hypoaldosteronism

• Causes:

  • Enzyme defect, brain diseases, heparin, tumor removal

• Symptoms:

  • Hyperkalaemia, acidosis

  • Common in mild renal failure & diabetics

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ADRENAL TUMOURS

ADRENOCORTICAL TUMOURS

🔸 Cortical Adenoma

• Benign, non-functional.

• May secrete cortisol, aldosterone, or androgens.

• Sometimes part of MEN-I syndrome.

• Gross: Small, bright yellow, encapsulated.

• Microscopy: Cells resemble zona fasciculata.

🔸 Cortical Carcinoma

• Rare, malignant, large tumors.

• Secrete excess hormones.

• Gross: Yellow with necrosis, hemorrhage.

• Microscopy: Anaplastic, pleomorphic cells, high mitoses.

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ADRENAL MEDULLARY TUMOURS

🔸 Pheochromocytoma (Chromaffin Tumour)

• Benign tumour of chromaffin cells.

• Secretes catecholamines → episodic hypertension.

• Associated with MEN syndromes, neurofibromatosis.

• Diagnosis: ↑ urinary VMA, metanephrine.

• Gross: Brown tumour (oxidized catecholamines).

• Microscopy:

  • Zellballen pattern (nests of cells)

  • Positive for chromogranin, NSE

🔸 Myelolipoma

• Benign, rare.

• Microscopy: Fat + hematopoietic cells.

🔸 Neuroblastoma

• Common malignant tumour in children.

• Produces catecholamines.

• Microscopy:

  • Small round blue cells

  • Homer-Wright rosettes

  • Positive for NSE, chromogranin

🔸 Ganglioneuroma

• Benign tumour from ganglion cells.
• Found in posterior mediastinum.
• Secretes catecholamines.
• Microscopy: Mature ganglion cells + nerve fibres.

🔸 Extra-Adrenal Paraganglioma (Chemodectoma)

• Arises from paraganglia (e.g. carotid body).
• Usually benign, may recur.
• Secretes catecholamines in rare cases.

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THYROID GLAND

NORMAL STRUCTURE

📍 Anatomy

• The thyroid originates embryologically from a midline invagination at the root of the tongue, descending in front of the trachea and thyroid cartilage.

• Thyroglossal duct connects the gland to the pharyngeal floor in embryonic life; it usually disappears by the 6th week.

  • Persistence of this duct may lead to a thyroglossal cyst.

  • Foramen caecum marks the proximal end in adults; the pyramidal lobe represents the distal end.

• C-cells arise from neuroectoderm.

• Adult thyroid: weighs 15–40 gm, has two lateral lobes connected by an isthmus, may have an upward pyramidal lobe.

• Cut surface: yellowish and translucent.

🔬 Histology

• Composed of lobules of colloid-filled follicles (functional units).

• Lined by cuboidal epithelium with microvilli extending into the colloid (which contains thyroglobulin).

• C-cells (parafollicular cells) are scattered among follicles and secrete calcitonin.

• Follicles are surrounded by fibrous tissue, blood vessels, lymphatics, and nerves.

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🔹 FUNCTIONS

• Produces T3 (Triiodothyronine) and T4 (Thyroxine) — regulate basal metabolic rate (BMR).

• Secretes Calcitonin from parafollicular cells — lowers blood calcium.

• Responds to TSH (thyroid-stimulating hormone) from the pituitary.

🧪 Functional Phases of Follicular Cells:

1. Resting phase: large follicles, flat cells, colloid-filled (e.g., in colloid goitre).

2. Secretory phase: cuboidal epithelium, dark pink colloid (e.g., normal state).

3. Resorptive phase: columnar cells, vacuolated/scalloped colloid (e.g., hyperthyroidism).

🔄 Hormone Synthesis & Secretion:

1. Iodide trapping by thyroid cells.
2. Oxidation of iodide by thyroid peroxidase.
3. Iodination of thyroglobulin to form MIT and DIT.
4. Coupling of MIT + DIT → T3; DIT + DIT → T4.
5. Endocytosis of colloid and proteolysis of thyroglobulin → release of T3 and T4 into circulation.

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🔬 THYROID FUNCTION TESTS

• Serum T3, T4, and TSH levels.
• Thyroglobulin & Calcitonin levels.
• Radioactive iodine uptake (RAIU) test.
• FNAC (Fine Needle Aspiration Cytology) for lesion evaluation.

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FUNCTIONAL DISORDERS

Hyperthyroidism (Thyrotoxicosis)

A hypermetabolic state caused by excess T3 & T4.

Causes:

• Graves’ disease (most common)
• Toxic multinodular goitre
• Toxic adenoma
• Pituitary/hCG-secreting tumours, struma ovarii, thyroiditis

Symptoms:

• Emotional instability, nervousness
• Palpitations, weight loss, heat intolerance, sweating
• Fine tremors, amenorrhea, osteoporosis
• Exophthalmos (bulging eyes in Graves’ disease)

Complication:
Thyroid storm — life-threatening hyperthyroid crisis with fever, tachycardia, arrhythmia, coma

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🧊 Hypothyroidism

1. Cretinism (Congenital)

• Onset: infancy/early childhood
• Causes: thyroid agenesis, genetic enzyme defects, iodine deficiency
• Features: poor feeding, dry skin, mental retardation, big tongue, dwarfism

2. Myxoedema (Adult)

• Onset: adult life
• Causes: thyroidectomy, autoimmune thyroiditis, iodine deficiency, pituitary lesion
• Features: cold intolerance, sluggishness, constipation, puffiness, hair loss, bradycardia

Lab Findings (Both Forms):
⬇ T3, T4 | ⬆ TSH (except in secondary causes)

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🧪 THYROIDITIS

1. Hashimoto’s Thyroiditis (Chronic Autoimmune)

• Most common cause of hypothyroidism in iodine-sufficient areas.
• Common in women (30–50 yrs).
• Autoimmune: CD4+ → CD8+ → B-cell autoantibodies (anti-TPO, anti-thyroglobulin, anti-TSH receptor)

Microscopy:

• Dense lymphoid infiltrate, germinal centers
• Hurthle cells (oxyphil cells): eosinophilic cytoplasm, large nuclei
• Follicular atrophy, mild fibrosis

Clinical Features:

• Painless goitre
• Hypothyroid symptoms
• Hashitoxicosis: transient hyperthyroidism
• ↑ Risk of thyroid lymphoma

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2. Subacute Lymphocytic Thyroiditis (Silent/Postpartum)

• Painless, postpartum onset (3–6 months)
• Lymphocyte and plasma cell infiltration, follicle collapse
• May mimic Hashimoto’s on histology

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3. Subacute Granulomatous Thyroiditis (De Quervain’s)

• Viral etiology suspected (follows URI)
• Painful thyroid, fever, early hyperthyroidism → recovery in ~6 months

Microscopy:

• Early: microabscesses
• Later: granulomas with giant cells around colloid
• Late: fibrosis

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4. Riedel’s Thyroiditis (Fibrous)

• Rare, chronic, stony-hard thyroid
• May mimic carcinoma
• Compression symptoms: stridor, dysphagia
• Part of multifocal idiopathic fibrosclerosis

Microscopy:
Dense fibrosis, follicle atrophy, lymphocyte infiltration, invasion of nearby muscles

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GRAVES’ DISEASE (Diffuse Toxic Goitre)

• Triad: Hyperthyroidism + Diffuse goitre + Ophthalmopathy

• Women 30–40 years; autoimmune

Autoantibodies:

• TSI: mimics TSH → ⬆ T3/T4

• TGI: follicular cell growth

• TBII: inhibits/stimulates TSH binding

Eye Signs:
Lid lag, proptosis, stare, corneal ulcer risk

Skin Signs:
Pretibial myxoedema (plaques)

Histology:

• Small follicles, tall columnar epithelium, papillary infoldings

• Scant vacuolated colloid

• Lymphocyte-rich stroma

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GOITRE

Definition:
Goitre is an abnormal enlargement of the thyroid gland, located in the front of the neck. It can occur with normal, decreased, or increased thyroid function.

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🔹 Classification of Goitre:

1. Based on Morphology:

   • Diffuse Goitre: Uniform enlargement of the thyroid.

   • Nodular Goitre: Presence of one or more nodules.

     • Solitary Nodular Goitre

     • Multinodular Goitre

2. Based on Function:

   • Euthyroid Goitre: Normal thyroid hormone levels.

   • Hypothyroid Goitre: Low thyroid hormone levels (e.g., iodine deficiency).

   • Hyperthyroid Goitre: High thyroid hormone levels (e.g., toxic goitre).

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🔹 Types of Goitre:

1. Simple (Non-toxic) Goitre:

• Cause: Usually due to iodine deficiency.

• Stages:

  • Hyperplastic Phase: Increased TSH leads to follicular hyperplasia.

  • Colloid Involution: Gland becomes filled with colloid due to reduced stimulation.

• Features: Usually euthyroid, diffuse enlargement, no nodules.

2. Multinodular Goitre (MNG):

• Cause: Repeated cycles of hyperplasia and involution.

• Features: Irregular nodular enlargement, may become very large, often euthyroid.

• Complications:

  • Compression of nearby structures (trachea, esophagus).

  • Sudden hemorrhage in a nodule.

  • May become “toxic” and cause hyperthyroidism.

3. Endemic Goitre:

• Geographical association: Seen in regions with iodine-deficient soil and water (e.g., mountainous areas).

• Definition: Affects >10% of the population in the area.

• Cause: Dietary iodine deficiency.

4. Sporadic Goitre:

• Occurrence: Seen in individuals without geographical predisposition.

• Causes:

  • Hereditary enzyme defects.

  • Goitrogens (e.g., cassava, cabbage).

  • Drugs (e.g., lithium).

5. Toxic Goitre:

• Associated with hyperthyroidism.

• Examples:

  • Toxic multinodular goitre.

  • Toxic adenoma.

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🔹 Etiology / Causes of Goitre:

• Iodine deficiency (most common).

• Increased TSH stimulation due to:

  • Enzyme defects in hormone synthesis.

  • Goitrogens (dietary substances that inhibit thyroid hormone synthesis).

• Autoimmune disorders (e.g., Hashimoto thyroiditis, Graves' disease).

• Neoplasms (benign or malignant).

• Thyroiditis (e.g., subacute or chronic).

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🔹 Clinical Features:

• Visible swelling in the neck.

• May move with swallowing.

• Typically painless.

• In large goitres:

  • Compression symptoms: difficulty in breathing (dyspnea), swallowing (dysphagia), hoarseness.

• If functional:

  • Hypothyroid symptoms: Fatigue, weight gain, cold intolerance.

  • Hyperthyroid symptoms: Weight loss, palpitations, heat intolerance, tremors.

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🔹 Investigations:

• Thyroid function tests: T3, T4, TSH.

• Ultrasound: To assess nodules, cysts, and gland texture.

• Radioactive iodine uptake (RAIU) scan: To assess function of nodules.

• Fine Needle Aspiration Cytology (FNAC): For suspicious nodules.

• Serum iodine levels: In endemic areas.

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🔹 Complications:

• Compression of trachea, esophagus, or recurrent laryngeal nerve.

• Sudden hemorrhage in a nodule.

• Development of thyrotoxicosis in toxic goitre.

• Malignant transformation (rare in long-standing multinodular goitre).

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🔹 Treatment:

• Iodine supplementation: In endemic areas.

• Thyroxine therapy: To suppress TSH in non-toxic goitre.

• Surgery (thyroidectomy): For large or symptomatic goitre, suspicion of malignancy.

• Radioactive iodine: In selected hyperfunctioning goitres.

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🔹 Prevention:

• Use of iodized salt in the diet.

• Public health measures in endemic areas.

• Avoidance of goitrogenic foods (if at risk).

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THYROID TUMOURS 

🔹 GENERAL OVERVIEW

• Most thyroid tumours originate from follicular epithelial cells.

• A few arise from parafollicular (C-cells).

• Tumours may be benign (like follicular adenoma) or malignant (carcinomas).

• Thyroid carcinoma is the most common malignant thyroid tumour.

• Rare thyroid tumours: lymphomas and sarcomas.

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BENIGN TUMOUR: FOLLICULAR ADENOMA

🔸 Clinical Features

• Most common benign thyroid tumour.

• Predominantly affects adult women.

• Appears as a solitary thyroid nodule in ~1% of people.

• Needs differentiation from:

  • Dominant nodule of nodular goitre

  • Thyroid carcinoma

• Usually a cold nodule (inactive) but may rarely be hot (functional).

🔸 Gross Morphology

• Solitary, well-encapsulated nodule

• Up to 3 cm, spherical

• Color: Grey-white to red-brown

• Less colloid than normal thyroid

• May show fibrosis, calcification, cystic changes, or haemorrhages

🔸 Microscopic Types (Based on Growth Pattern)

Type	Features
1. Microfollicular (Foetal)	Small follicles, little/no colloid, loose stroma
2. Normofollicular (Simple)	Normal-sized follicles closely packed
3. Macrofollicular (Colloid)	Large follicles with abundant colloid
4. Trabecular (Embryonal)	Solid/trabecular epithelial cells, few abortive follicles
5. Hurthle cell (Oxyphilic)	Large, granular eosinophilic cytoplasm, solid trabeculae
6. Atypical adenoma	Increased mitoses, pleomorphism but no capsular or vascular invasion

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MALIGNANT TUMOURS (THYROID CARCINOMA)

🔸 Types and Frequency

Type	Frequency (%)
1. Papillary	75–80%
2. Follicular	10–20%
3. Medullary	5%
4. Anaplastic	<5%

🔸 Risk Factors

1. Radiation exposure (most important)

2. Iodine excess

3. TSH stimulation

4. Genetic mutations

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PAPILLARY THYROID CARCINOMA

Key Points

• Most common thyroid cancer (75–85%)
• Occurs in all ages (esp. young adults)
• Female:Male = 3:1
• Linked to radiation exposure
• Slow-growing, usually spreads to regional lymph nodes
• Distant metastases are rare

🔸 Microscopic Features

• Papillary pattern: Fibrovascular core lined by tumour cells
• Ground-glass nuclei (“Orphan Annie eye”)
• Psammoma bodies: Concentric calcified structures
• May also form follicles or solid sheets

🔸 Prognosis

• Excellent, 10-year survival = 80–95%

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FOLLICULAR THYROID CARCINOMA

Key Points

• Second most common type
• Middle-aged to elderly; female predominance (2.5:1)
• Associated with endemic goitre, not radiation
• More likely to spread via blood (lungs, bones)
• Lymph node metastasis is rare

Microscopic Features

• Composed of follicles (like adenoma)
• No papillae or psammoma bodies
• Key diagnostic feature: capsular and vascular invasion

Prognosis

• Moderate, 10-year survival = 50–70%

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MEDULLARY THYROID CARCINOMA

Key Points

• Derived from C-cells (parafollicular cells)
• May be sporadic or familial (MEN II syndromes)
• Secretes calcitonin and other peptides
• Amyloid deposits in stroma (from altered calcitonin)

Clinical Associations

• MEN II A: Medullary carcinoma + pheochromocytoma + parathyroid adenoma
• MEN II B: Medullary carcinoma + mucosal neuromas + pheochromocytoma

Microscopic Features

• Nests or sheets of tumour cells
• Amyloid stroma (Congo red positive)
• C-cell hyperplasia (in familial cases)

Prognosis

• Fair; better in familial form
• 10-year survival = 60–70%

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ANAPLASTIC (UNDIFFERENTIATED) THYROID CARCINOMA

Key Points

• Rarest and most aggressive form
• Affects elderly (7th–8th decade)
• Rapid growth, extensive local invasion
• Presents with neck mass, dyspnoea, dysphagia, hoarseness

Histologic Variants

Variant	Description
1. Small cell	Resembles lymphoma
2. Spindle cell	Resembles sarcoma
3. Giant cell	Large, pleomorphic cells with atypical mitoses

🔸 Prognosis

• Very poor, <10% survive 5 years

• Median survival = ~2 months

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🔍 COMPARISON TABLE: Thyroid Carcinoma Types

Feature	Papillary	Follicular	Medullary	Anaplastic
Frequency	75–80%	10–20%	5%	<5%
Age	All ages	Middle-Old age	Middle-Old/familial	Old age
Radiation link	Strong	Weak	None	Weak
Cell origin	Follicular	Follicular	Parafollicular C	Follicular
Spread	Lymph nodes	Blood (lungs, bones)	Lymph nodes	Both
Psammoma bodies	Present	Absent	Absent	Absent
Calcitonin secretion	No	No	Yes	No
Amyloid	No	No	Yes	No
Survival (10 years)	80–95%	50–70%	60–70%	<10%

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PARATHYROID GLANDS

1. Normal Structure

A. Anatomy

• Normally 4 parathyroid glands:

  • Superior pair from the 3rd branchial pouch

  • Inferior pair from the 4th branchial pouch

• Located posterior to the thyroid gland, separated by connective tissue.

• Adult gland:

  • Oval, yellowish-brown, flattened

  • Weight: 35–45 mg each

• Number and location may vary between individuals.

B. Histology

• Composed of parenchymal cells arranged in cords/sheets, plus stromal fat.

• Three types of cells:

  1. Chief cells: Most abundant; secrete parathyroid hormone (PTH).

  2. Oxyphil cells: Larger, less common; may secrete PTH.

  3. Water-clear cells: Rare, may be derived from chief cells.

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2. Functions of Parathyroid Hormone (PTH)

PTH helps regulate serum calcium and bone metabolism, along with calcitonin and vitamin D.

PTH actions:

1. Bone:

   • Stimulates osteoclasts → bone resorption → ↑ serum calcium

   • Calcitonin opposes PTH by inhibiting bone resorption

2. Kidneys:

   • Increases calcium reabsorption

   • Decreases phosphate reabsorption → ↑ phosphate excretion

3. Intestines:

   • Enhances production of active Vitamin D (1,25-dihydroxycholecalciferol)

   • Leads to ↑ calcium absorption from intestine

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3. Parathyroid Disorders

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A. Hyperparathyroidism

Excess PTH production → ↑ serum calcium.

Types:

1. Primary: Due to intrinsic parathyroid gland disease

2. Secondary: Due to disease elsewhere in the body (e.g., renal failure)

3. Tertiary: Persistent PTH secretion after resolution of secondary cause

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Primary Hyperparathyroidism

Causes:

• Parathyroid adenoma (80%)

• Primary hyperplasia (15%)

• Parathyroid carcinoma (2–3%)

• May occur in MEN syndromes

Clinical Features:

• ↑ PTH, hypercalcaemia, hypophosphataemia, hypercalciuria

• Presentations:

  • Kidney stones/nephrocalcinosis

  • Bone changes: osteitis fibrosa cystica

  • Metastatic calcifications

  • Neuropsychiatric symptoms: depression, psychosis, coma

  • Hypertension

  • Other signs: pancreatitis, peptic ulcers

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Secondary Hyperparathyroidism

Causes:

• Chronic renal failure (most common)

• Vitamin D deficiency → rickets, osteomalacia

• Malabsorption syndromes

Clinical Features:

• ↓ serum calcium (mild hypocalcaemia)

• Symptoms related to underlying disease

• In severe cases: renal osteodystrophy
  (bone softening, fibrosis, and soft tissue calcification)

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Tertiary Hyperparathyroidism

• Occurs after long-standing secondary hyperparathyroidism
• Autonomous PTH secretion continues despite correction of underlying cause
• Often due to nodular hyperplasia in gland

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B. Hypoparathyroidism

Deficiency of PTH → hypocalcaemia

Types:

1. Primary hypoparathyroidism
2. Pseudo-hypoparathyroidism
3. Pseudopseudo-hypoparathyroidism

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Primary Hypoparathyroidism

Causes:

• Surgical removal or damage (e.g., thyroidectomy, neck dissection)

• Idiopathic/autoimmune (esp. in children)

Clinical Features:

• ↓ serum calcium, ↑ phosphate, ↓ urinary calcium

• Manifestations:

• Tetany (muscle spasms, convulsions)
• Cataract formation
• Intracranial calcification → CNS symptoms
• Cardiac conduction abnormalities
• Dental defects

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Pseudo-Hypoparathyroidism

• Tissues unresponsive to PTH, despite normal PTH levels

• Inherited (autosomal dominant)

• Mostly seen in females

Features:

• Hypocalcaemia, hyperphosphataemia, hypercalciuria

• Physical traits:

  • Short stature, short fingers/toes, round face, flat nose

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Pseudopseudo-Hypoparathyroidism

• Similar physical features to pseudo-hypoparathyroidism

• But normal calcium/phosphate levels

• Normal response to PTH

• Considered an incomplete form of pseudo-hypoparathyroidism

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C. Parathyroid Tumours

1. Parathyroid Adenoma

• Most common tumour

• Often first discovered due to hyperparathyroidism

Gross Features:

• Small (<5 cm), well-circumscribed, encapsulated, yellowish-brown

• Weight: Up to 5 gm or more

Microscopic Features:

• Mostly chief cells in cords/sheets

• May include oxyphil and water-clear cells

• Surrounded by normal parathyroid tissue and fat (helps differentiate from hyperplasia)

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2. Parathyroid Carcinoma

• Rare, but causes severe hyperparathyroidism

• Irregular shape, may invade nearby tissues

• Often well-differentiated

• Diagnosis: based on invasion or metastasis

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ENDOCRINE PANCREAS

I. NORMAL STRUCTURE OF THE ENDOCRINE PANCREAS

• The pancreas is one organ but has two functional parts:

  • Exocrine: Produces digestive enzymes.

  • Endocrine: Produces hormones, mainly involved in glucose metabolism.

• The endocrine pancreas is made of islets of Langerhans (clusters of endocrine cells):

  • Scattered throughout the pancreas, more in the tail.

  • Have no ducts—they release hormones directly into the blood.

  • Total endocrine tissue weight: 1–1.5 grams.

✨ Major Endocrine Cell Types in Islets:

Cell Type	% of Islet Cells	Hormone Secreted	Function
β-cells	~70%	Insulin	Lowers blood glucose
α-cells	~20%	Glucagon	Raises blood glucose
δ-cells	5–10%	Somatostatin	Inhibits insulin & glucagon
PP (F) cells	1–2%	Pancreatic Polypeptide	GI effects

✨ Minor Endocrine Cell Types:

Cell Type	Hormone	Function
D1 cells	VIP (Vasoactive intestinal peptide)	Causes hyperglycemia & secretory diarrhea
Enterochromaffin cells	Serotonin	Can cause carcinoid syndrome in tumors

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II. DIABETES MELLITUS (DM)

Definition:

A metabolic disorder characterized by chronic hyperglycemia and disturbed metabolism of carbohydrates, fats, and proteins.

Epidemiology:

• Affects ~1% of the population.
• Type 2 DM incidence is rapidly increasing due to obesity & inactivity.
• Major complications: Kidney failure, heart disease, blindness, gangrene.

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III. CLASSIFICATION OF DIABETES MELLITUS (ADA 2007)

1. Type 1 DM (~10%)

• Previously: Juvenile-onset / Insulin-dependent (IDDM)

• Subtypes:

  • Type 1A: Autoimmune destruction of β-cells.

  • Type 1B: Idiopathic β-cell loss (non-autoimmune).

2. Type 2 DM (~80%)

• Previously: Maturity-onset / Non-insulin dependent (NIDDM)

• Now also seen in obese adolescents.

• Linked with insulin resistance and impaired insulin secretion.

3. Other Specific Types (~10%):

• MODY (genetic β-cell defects)
• Genetic insulin resistance
• Pancreatic diseases
• Hormonal disorders (e.g., Cushing’s)
• Drug/chemical-induced
• Infections (e.g., rubella)
• Rare immune forms
• Genetic syndromes (e.g., Down’s)

4. Gestational Diabetes:

• Occurs in ~4% of pregnant women.
• May revert post-delivery but increases future risk of DM.

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🔍 IV. PATHOGENESIS OF DIABETES

🔄 Normal Insulin Physiology:

• Produced by β-cells from pre-proinsulin → proinsulin → insulin + C-peptide.
• Stimulus: Glucose (via GLUT2 transporters).
• Insulin acts via receptors with tyrosine kinase activity, triggering:
• Glucose uptake, glycogen storage, lipogenesis, and protein synthesis.

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🧪 Type 1 DM – Autoimmune β-Cell Destruction

1. Genetic factors: HLA DR3/DR4 on chromosome 6.

2. Autoimmune mechanisms:

   • Islet cell antibodies (e.g., anti-GAD)

   • Lymphocyte (CD8+) infiltration → β-cell destruction.

   • Seen with other autoimmune diseases (Graves’, Hashimoto's, etc.).

3. Environmental triggers:

   • Viral infections (e.g., coxsackie B)

   • Cow milk exposure (hypothetical)

   • Chemical toxins (e.g., alloxan)

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🧪 Type 2 DM – Insulin Resistance & β-Cell Dysfunction

1. Stronger genetic link (80% twin concordance).

2. Obesity & lifestyle factors contribute.

3. Insulin resistance:

   • Target tissues (muscle, liver) respond poorly to insulin.

   • Free fatty acids & TNF-α impair insulin action.

4. β-cell dysfunction:

   • Initially increased insulin (compensation)

   • Later β-cells can’t keep up → relative insulin deficiency.

5. Liver glucose production increases due to insulin resistance.

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🔬 V. MORPHOLOGIC FEATURES IN PANCREAS

Feature	Type 1 DM	Type 2 DM
Islet Infiltrate	Insulitis (CD8+ T-cells)	No inflammation
β-cell Mass	Depleted	Normal or mildly reduced
Amyloidosis	Rare	Common (amylin deposits)
Degranulation	Present	Absent

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VI. CLINICAL FEATURES

Common Signs in Both Types:

• Polyuria (excess urination)
• Polydipsia (excess thirst)
• Polyphagia (excess hunger)
• Weight loss
• Weakness

Type 1 DM:

• Onset: Early (<35 years), abrupt.
• Body: Usually normal or underweight.
• Prone to ketoacidosis.
• Insulin-dependent.

Type 2 DM:

• Onset: Later (>40 years), gradual.
• Body: Often obese.
• May be asymptomatic initially.
• Prone to hyperosmolar coma, not ketoacidosis.

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VII. COMPLICATIONS OF DIABETES

A. Microvascular (Due to chronic hyperglycemia):

• Retinopathy – Eye damage
• Nephropathy – Kidney failure
• Neuropathy – Nerve damage

B. Macrovascular (Mainly in type 2):

• Atherosclerosis
• Heart disease
• Stroke
• Peripheral vascular disease

Pathogenesis of Complications:

1. Non-enzymatic Glycosylation:

• HbA1C (glycated hemoglobin) is used to monitor blood sugar control.
• Glycosylation of proteins → vessel wall damage.

VIII. CONTRASTING FEATURES OF TYPE 1 VS TYPE 2 DM

Feature	Type 1 DM	Type 2 DM
% of Cases	10–20%	80–90%
Age of Onset	<35 years	>40 years
Onset	Abrupt	Gradual
Body Type	Normal/lean	Often obese
HLA link	Yes	No
Insulin Levels	Low	Normal/high
Insulitis	Present	Absent
Amyloidosis	Rare	Common
Treatment	Insulin	Diet, exercise, oral drugs ± insulin
Acute Risk	Ketoacidosis	Hyperosmolar coma

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COMPLICATIONS OF DIABETES MELLITUS

Due to chronic hyperglycemia, diabetes affects almost every tissue and organ, leading to two major categories of complications:

🔹 I. Acute Metabolic Complications

These develop suddenly and are often life-threatening.

1. Diabetic Ketoacidosis (DKA)

• Mostly seen in: Type 1 Diabetes.

• Caused by: Severe insulin deficiency + excess glucagon.

• Mechanism:

  • ↓ Insulin → ↑ Lipolysis → ↑ Free Fatty Acids (FFAs).

  • FFAs → converted to ketone bodies in the liver (acetoacetic acid & β-hydroxybutyric acid).

  • Leads to ketonaemia, ketonuria, and metabolic acidosis.

• Precipitating Factors: Missed insulin doses, infection, stress.

• Symptoms: Nausea, vomiting, deep & rapid breathing (Kussmaul’s breathing), mental confusion, coma.

• Outcome: Most patients recover with treatment.

2. Hyperosmolar Hyperglycaemic State (HHS)

• Mostly seen in: Type 2 Diabetes.

• Cause: Severe dehydration due to prolonged hyperglycemia and loss of water via urine.

• Symptoms:

  • No ketone formation (non-ketotic).

  • Severe CNS symptoms.

  • Extremely high blood sugar and plasma osmolality.

  • High risk of thrombotic and bleeding issues.

• High mortality compared to DKA.

3. Hypoglycemia

• Occurs in: Type 1 Diabetes.

• Causes:

• Excess insulin,
• Skipped meals,
• Stress.

• Complications:

  • Permanent brain damage,

  • Rebound hyperglycemia (Somogyi effect).

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II. Late (Chronic) Systemic Complications

Usually develop 15–20 years after diagnosis.

1. Atherosclerosis

• Occurs earlier and more severely in diabetics.

• Contributing factors:

  • Hyperlipidemia, low HDL, obesity, hypertension, ↑ platelet stickiness, nonenzymatic glycation.

• Complications:

  • Coronary artery disease,

  • Silent myocardial infarction,

  • Stroke,

  • Gangrene (esp. of toes and feet, 100× more common).

2. Diabetic Microangiopathy

• Thickening of basement membrane in small vessels of:

  • Skin, retina, kidney, muscle, peripheral nerves.

• Cause: Chronic hyperglycemia → ↑ glycosylation of proteins.

3. Diabetic Nephropathy

• Major cause of death in diabetics.

• Renal changes:

  • Diabetic glomerulosclerosis (diffuse or nodular),

  • Hyaline arteriolosclerosis,

  • Pyelonephritis and renal papillary necrosis,

  • Armanni-Ebstein tubular lesions.

4. Diabetic Neuropathy

• Most commonly symmetric peripheral neuropathy.

• Pathological changes:

  • Schwann cell damage, axonal injury, segmental demyelination.

• Possible mechanisms:

  • Microangiopathy or

  • Sorbitol/fructose accumulation causing ↓ myoinositol.

5. Diabetic Retinopathy

• Leading cause of blindness.

• Two types:

  • Background (non-proliferative),

  • Proliferative.

• Other eye issues: Early cataracts, glaucoma.

6. Infections

• Diabetics are more prone due to:

  • ↓ white blood cell function,

  • ↓ cellular immunity,

  • ↓ blood supply (due to vascular changes),

  • Hyperglycemia.

• Common infections: Tuberculosis, pneumonia, pyelonephritis, otitis, carbuncles, foot ulcers.

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DIAGNOSIS OF DIABETES MELLITUS

A. Clinical Suspicion

• Symptoms: Polyuria, polydipsia, weight loss.

• Confirmation: Blood glucose > 200 mg/dL (random) with symptoms.

B. Diagnostic Criteria (ADA 2007)

Test	Normal	Pre-diabetes (IFG/IGT)	Diabetes Mellitus
Fasting Glucose	<100 mg/dL	100–125 mg/dL	≥126 mg/dL
2-hour after 75g GTT	<140 mg/dL	140–199 mg/dL	≥200 mg/dL
Random Glucose (with symptoms)	–	–	≥200 mg/dL

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LABORATORY TESTS FOR DIAGNOSIS

1. Urine Tests

• Glucosuria:

  • Not reliable alone.

  • May occur in non-diabetics with low renal threshold.

• Ketonuria:

  • Indicates severity.

  • Positive in DKA.

2. Blood Sugar Estimation

• Fasting Glucose:

  • 126 mg/dL = diagnostic.

• Post-prandial or GTT: Done if fasting glucose is borderline.

• Venous blood glucose is 15% lower than plasma glucose.

3. Oral Glucose Tolerance Test (OGTT)

• Used for borderline cases.

• Patient prep: High-carb diet for 3 days, then overnight fasting.

• Procedure:

  • Fasting sample → give 75g glucose → sample every 30 mins for 2 hrs.

• Interpretation as per ADA criteria.

4. Glycosylated Hemoglobin (HbA1C)

• Reflects 3-4 months average blood glucose.

• Useful for monitoring diabetic control.

• Not for initial diagnosis.

• Influenced by anemia, hemoglobinopathies, and kidney disease.

5. Glycated Albumin

• Indicates glycemic control over 1–2 weeks.

6. C-Peptide Assay

• Indicates endogenous insulin production.

• Helps differentiate type 1 vs. type 2 DM.

7. Autoantibodies (GAD, ICA)

• Detectable in type 1 DM.

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Additional Screening Tests

• For complications:

  • Microalbuminuria (kidney involvement),

  • Lipid profile (dyslipidemia),

  • Thyroid function tests (autoimmune thyroiditis in type 1 DM).