CASE HISTORY-1 — 25-year-old married woman, regular menstruation

CASE HISTORY-2 — Patient with weakness, truncal fat, thin limbs, abdominal striae, poor wound healing

• Thin arms and legs (muscle wasting from proteolysis by excess cortisol)
• Full abdomen, back, and face (truncal/central obesity, "moon face," "buffalo hump")
• Reddish/purple striae on the abdomen (due to skin thinning and rupture of dermal collagen)
• Poor wound healing

1. Inhibits fibroblast proliferation and collagen synthesis
2. Has anti-inflammatory and immunosuppressive effects (suppresses growth factors needed for healing)
3. Increases protein catabolism, reducing availability of amino acids for tissue repair

• Cortisol stimulates gluconeogenesis in the liver (promotes hepatic glucose output)
• Cortisol induces insulin resistance in peripheral tissues (muscle and fat)
• Cortisol promotes proteolysis in muscle, releasing amino acids as gluconeogenic substrates
• Cortisol promotes lipolysis, releasing glycerol as gluconeogenic substrate
• Net result: raised fasting and postprandial blood glucose levels

CASE HISTORY-3 — 69-year-old man, tremors, mask face, monotonous speech, bradykinesia, rigidity, no intellectual deficit

• Dopamine normally facilitates movement initiation via the direct pathway (D1 receptors) and inhibits the indirect pathway (D2 receptors)
• With dopamine deficiency, the indirect pathway (which inhibits movement) becomes overactive
• This leads to excessive inhibition of the thalamus and motor cortex
• Result: reduced voluntary movement output (bradykinesia = slowness), akinesia (poverty of movement), and rigidity (constant high muscle tone from disrupted reciprocal inhibition)
• Resting tremor arises from oscillatory activity in thalamic circuits no longer properly regulated

• Levodopa (L-DOPA) + Carbidopa - the cornerstone of therapy. Levodopa crosses the blood-brain barrier and is converted to dopamine in the substantia nigra. Carbidopa is a peripheral decarboxylase inhibitor that prevents peripheral conversion of levodopa, reducing side effects and increasing CNS availability.
• Dopamine agonists - pramipexole, ropinirole (adjuvant or as initial therapy in younger patients)
• MAO-B inhibitors - selegiline, rasagiline (slow dopamine breakdown)
• Anticholinergics - benztropine (reduce tremor)
• Deep Brain Stimulation (DBS) - for advanced disease refractory to medications

CASE HISTORY-4 — Young female, ptosis, muscle weakness worse in evenings, chewing/swallowing/speaking weakness, responds to neostigmine

• Block the receptor binding site for ACh
• Cause complement-mediated destruction of the postsynaptic membrane
• Accelerate receptor internalization and degradation

• Increases the concentration and prolongs the duration of ACh at the NMJ
• Allows the limited number of remaining functional receptors to be stimulated more effectively
• Repeated binding of ACh molecules to available receptors restores sufficient neuromuscular transmission to improve muscle strength

CASE HISTORY-5 — 28-year-old female, nervousness, sweating, palpitation, amenorrhea, tachycardia, lid retraction, fine tremors, BMR +40%, cholesterol 100 mg%, pulse 120/min

• BMR +40%: Significantly elevated (normal: -10% to +10%). Indicates markedly increased metabolic rate. Values above +20% are considered abnormal; +40% is strongly suggestive of thyrotoxicosis.
• Serum cholesterol 100 mg%: Low (normal: ~150-200 mg%). Thyroid hormones stimulate LDL receptor upregulation and accelerate cholesterol catabolism, causing hypocholesterolemia in hyperthyroidism.
• Basal pulse rate 120/min: Tachycardia (normal: 60-100/min). Thyroid hormones increase cardiac sensitivity to catecholamines and directly stimulate the heart.

• Heat intolerance, sweating, nervousness, restlessness (hypermetabolism)
• Weight loss despite increased appetite
• Tachycardia, cardiac enlargement, extra systoles, dyspnea on exertion
• Fine resting tremors of outstretched hands
• Amenorrhea (excess thyroid hormones disrupt the HPG axis)
• Lid retraction and skin/lid changes

1. Serum T3 and T4 (Free T4, Free T3) - will be elevated
2. TSH (Thyroid Stimulating Hormone) - will be suppressed (low/undetectable) in primary hyperthyroidism
3. TSH receptor antibodies (TRAb / TSI) - positive in Graves' disease (confirms autoimmune etiology)
4. Radioactive Iodine Uptake (RAIU) scan - diffusely increased uptake in Graves'; focal uptake in toxic nodule
5. Thyroid ultrasound - assess gland size, vascularity, nodules

CASE HISTORY-6 — Excessive drinking, colorless urine, polyuria, polydipsia, markedly dehydrated when water withheld; urine specific gravity 1002-1004, no sugar/blood/albumin

• Central (Neurogenic) DI: Deficiency of ADH (Antidiuretic Hormone/Arginine Vasopressin) from the posterior pituitary due to damage/destruction of hypothalamic nuclei (supraoptic/paraventricular) or pituitary stalk - from tumors, trauma, surgery, inflammation (sarcoidosis), or idiopathic
• Nephrogenic DI: Kidney tubules are unresponsive to ADH (genetic mutation of V2 receptor or AQP2 channels, lithium toxicity, hypercalcemia)

1. Diabetes Mellitus - osmotic diuresis from glycosuria
2. Primary Polydipsia (Psychogenic) - compulsive water drinking; ADH is suppressed secondarily
3. Chronic renal failure - loss of concentrating ability
4. Hypercalcemia - inhibits ADH action at tubules
5. Hypokalemia - also impairs tubular response to ADH
6. Diuretic use (pharmacological)

• Central DI: Desmopressin (DDAVP) - synthetic ADH analogue, given intranasally, orally, or SC. Ensure adequate fluid intake.
• Nephrogenic DI: Low sodium/low protein diet, thiazide diuretics (paradoxically reduce urine volume by causing mild volume depletion and increasing proximal tubular reabsorption), NSAIDs (indomethacin), correct underlying cause (stop lithium, treat hypercalcemia)
• Identify and treat underlying cause (e.g., surgical removal of craniopharyngioma)

CASE HISTORY-7 — 3-year-old male child, persistent bleeding from multiple sites, joint swelling, coagulation time prolonged, bleeding time and prothrombin time normal, male relatives affected

• Males affected (X-linked recessive; males are hemizygous and manifest disease)
• Prolonged coagulation time (APTT) - reflects intrinsic pathway defect
• Normal bleeding time - platelet function is intact (primary hemostasis normal)
• Normal prothrombin time (PT) - extrinsic pathway (Factor VII) is normal
• Hemarthrosis (joint bleeding with swelling + fever) - classic in hemophilia
• Family history in male relatives

• If one X chromosome carries the mutant allele, the other normal X chromosome provides sufficient Factor VIII for normal coagulation
• Therefore females are typically carriers (one normal + one mutant X) but asymptomatic, as even 50% Factor VIII activity is adequate
• Only in rare cases (homozygous females, or Turner syndrome XO) do females manifest the disease
• Males (XY) have only one X chromosome - if it carries the mutant gene, they have no backup and manifest full disease

• Recombinant Factor VIII concentrate (preferred) - infused intravenously to restore clotting factor levels and allow the coagulation cascade to proceed normally
• Fresh Frozen Plasma (FFP) or Cryoprecipitate - contain Factor VIII; used when concentrates are unavailable
• Desmopressin (DDAVP) - in mild hemophilia A; stimulates release of stored Factor VIII from endothelial cells
• Inhibitor management with bypassing agents (Factor VIIa/aPCC) if antibodies to Factor VIII develop

CASE HISTORY-8 — Yellow discoloration of sclera and skin, pale clay-colored stools, itching, loss of appetite; Stool: stercobilinogen absent; Urine: bilirubin present; Blood: serum bilirubin 6 mg/100ml (direct); Liver enzymes elevated; Van den Bergh test: direct positive

• No bile salts enter the gut → impaired fat emulsification → fat malabsorption (steatorrhea)
• Unabsorbed fat is excreted in stools → pale/clay-colored (no stercobilin since conjugated bilirubin cannot enter gut), bulky, and foul-smelling (fatty, putrid stools)
• The pale/clay color is because stercobilin (formed from bilirubin by gut bacteria) is absent - as confirmed by absent stercobilinogen in stool

• Direct bilirubin = conjugated bilirubin (water-soluble, glucuronidated in the liver)
• In obstructive jaundice, conjugated bilirubin is produced normally by the liver but cannot be excreted into bile due to the obstruction
• It backs up into the blood (regurgitation jaundice), causing elevated direct (conjugated) bilirubin in serum
• Conjugated bilirubin reacts directly with the diazo reagent without needing alcohol → direct positive reaction
• It is water-soluble → excreted in urine (bilirubinuria, dark urine) - confirmed by bilirubin present in urine

CASE HISTORY-9 — Pulmonary function tests of two patients

• FEV1/FVC = 84% - normal/elevated (≥70-80% is normal; >80% is characteristic of restriction)
• FVC is reduced (2.5 L - reduced due to stiff, non-compliant lungs with reduced total lung capacity)
• FEV1 is proportionally reduced
• Low PEFR (200 L/min) due to small lung volumes
• Lymphocytosis on blood smear suggests a possible viral/granulomatous/autoimmune etiology (e.g., hypersensitivity pneumonitis, sarcoidosis, viral interstitial pneumonia)

• FEV1/FVC = 66% - reduced (diagnostic cut-off: <70%)
• FVC is relatively preserved (3.0 L) or may be reduced due to air trapping
• FEV1 disproportionately reduced due to airway obstruction slowing expiration
• Low PEFR (100 L/min) due to airway narrowing
• Eosinophilia on blood smear strongly suggests asthma (allergic/atopic obstructive disease)

• Caused by inadequate oxygenation of blood in the lungs
• In Patient A (restrictive): thickened alveolar-capillary membrane impairs gas diffusion; reduced lung volume means less surface area for O2 exchange
• In Patient B (obstructive): airway narrowing causes air trapping, ventilation-perfusion (V/Q) mismatch, and reduced alveolar ventilation → reduced PAO2 → reduced PaO2

CASE HISTORY-10 — 15-year-old female, sudden fever (102°F), abdominal pain, vomiting, tachycardia (100/min), BP 110/70, RR 20/min, TLC 30,000/c.mm, neutrophils 90%, appendicectomy scheduled

• The acute bacterial infection/inflammation in the appendix releases inflammatory mediators (IL-1, IL-6, TNF-α, G-CSF)
• These stimulate the bone marrow to rapidly produce and release neutrophils
• There is also marginated pool mobilization - neutrophils adhering to vessel walls are released into circulation
• Endotoxins and bacterial products directly stimulate neutrophil release
• This is an appropriate acute-phase response to bacterial inflammation - neutrophils are the first line of cellular defense, migrating to the site of infection for phagocytosis

CASE HISTORY-11 — 28-year-old female with anemia

• RBC: 1,400,000/c.mm (normal female: 4.2-5.4 million/c.mm)
• WBC: 3,900/c.mm (normal: 4,000-11,000/c.mm)
• Hb: 5.6 g/dl (normal female: 12-16 g/dl)
• Platelet: 150,000/c.mm (normal: 150,000-400,000/c.mm)
• PCV: 16.8% (normal female: 37-47%)

MCV = (PCV × 10) / RBC (millions) MCV = (16.8 × 10) / 1.4 = 120 fL Normal: 80-100 fL → Macrocytic (>100 fL)

MCH = (Hb × 10) / RBC (millions) MCH = (5.6 × 10) / 1.4 = 40 pg Normal: 27-33 pg → Elevated (hyperchromic)

MCHC = (Hb / PCV) × 100 MCHC = (5.6 / 16.8) × 100 = 33.3 g/dl Normal: 32-36 g/dl → Normochromic

1. Wintrobe's method (macro-hematocrit): Blood is collected in a Wintrobe tube and centrifuged at 3,000 rpm for 30 minutes. The height of the packed RBC column divided by total blood column × 100 = PCV.
2. Microhematocrit method: A capillary tube (75 mm long, 1 mm bore) is filled with blood and centrifuged at 12,000 rpm for 5 minutes. Read with a hematocrit reader. This is faster and requires less blood.

PCV = (MCV × RBC) / 10 (if MCV and RBC are known)

CASE HISTORY-12 — 45-year-old individual, Hb = 9 g/dl, Hematocrit = 36%

MCHC = (9 / 36) × 100 = 25 g/dl

• MCHC measures the average concentration of hemoglobin per unit volume of packed RBCs
• Low MCHC (<32 g/dl) = Hypochromic anemia → suggests iron deficiency anemia, thalassemia, or sideroblastic anemia (inadequate Hb synthesis per cell)
• Normal MCHC (32-36 g/dl) = Normochromic anemia → hemolytic anemia, aplastic anemia, acute blood loss
• High MCHC (>36 g/dl) = Hyperchromic → seen in hereditary spherocytosis (cells are spherical, not biconcave, so appear denser)
• MCHC >36 g/dl is practically impossible (cells cannot hold more Hb than their membrane allows) so it usually indicates spherocytosis

MCH = (Hb in g/dl × 10) / RBC count in millions/µL = expressed in picograms (pg) Normal: 27-33 pg

MCV = (Hematocrit % × 10) / RBC count in millions/µL = expressed in femtoliters (fL) Normal: 80-100 fL

1. Classify anemia morphologically into: microcytic hypochromic, normocytic normochromic, or macrocytic normochromic - which narrows the differential diagnosis
2. Monitor treatment response (e.g., rising MCV with B12 therapy, rising MCHC with iron therapy)
3. Differentiate causes - e.g., low MCV + low MCHC = iron deficiency vs. thalassemia; high MCV = B12/folate deficiency vs. liver disease/hypothyroidism
4. Screen for hemoglobinopathies and guide further workup (iron studies, B12/folate levels, peripheral smear)

CASE HISTORY-13 — 17-year-old boy, hemarthrosis, prolonged bleeding after tooth extraction, platelet count normal, bleeding time normal, tentative diagnosis: Hemophilia A

1. Clotting Time (CT) / Lee-White Clotting Time - This will be prolonged in Hemophilia A because Factor VIII is deficient, impairing the intrinsic coagulation pathway. The blood takes longer to form a fibrin clot.
2. Activated Partial Thromboplastin Time (aPTT) - This will be prolonged because aPTT specifically tests the intrinsic pathway (Factors XII, XI, IX, VIII) and the common pathway. Factor VIII deficiency prolongs aPTT.

1. A partial thromboplastin (phospholipid - a platelet substitute that provides a surface for coagulation)
2. An activator of the contact/intrinsic pathway (e.g., kaolin, ellagic acid, celite)

CASE HISTORY-14 — 50-year-old female with GI bleeding

• Hb: 8 g/dl (normal female: 12-16 g/dl)
• Hematocrit: 21%
• RBC: 3 million/mm³ (normal female: 4.2-5.4 million)

MCV = (Hematocrit × 10) / RBC (millions) MCV = (21 × 10) / 3 = 70 fL Normal: 80-100 fL → Microcytic (<80 fL)

MCH = (Hb × 10) / RBC (millions) MCH = (8 × 10) / 3 = 26.7 pg Normal: 27-33 pg → Hypochromic (low)

MCHC = (Hb / Hematocrit) × 100 MCHC = (8 / 21) × 100 = 38.1 g/dl

CASE HISTORY-15 — 25-year-old male, hemarthrosis left knee, excess bleeding from trivial injuries, family history of hemorrhagic disorder

• Clotting time: >30 minutes (markedly prolonged)
• Bleeding time: Normal
• aPTT: Prolonged
• Advised: Freeze-dried concentrate of Factor VIII

• Prolonged clotting time: Factor VIII is deficient → the intrinsic coagulation pathway is blocked at the step where Factor VIII acts as a cofactor with Factor IXa to activate Factor X. Without Factor X activation, the common pathway (thrombin generation → fibrin formation) cannot proceed normally → clot formation is markedly delayed.
• Normal bleeding time: Bleeding time tests primary hemostasis (platelet plug formation - platelet count, platelet function, and von Willebrand factor). In Hemophilia A, platelets are entirely normal → bleeding time is normal. The defect is only in the secondary hemostasis (coagulation cascade).
• Prolonged aPTT: aPTT tests the intrinsic + common pathway. Factor VIII deficiency prolongs aPTT. The PT (extrinsic pathway) would be normal.

• aPTT is the gold standard test for intrinsic pathway disorders
• Used to diagnose: Hemophilia A (Factor VIII), Hemophilia B (Factor IX), Factor XI/XII deficiencies, and lupus anticoagulant
• Used to monitor heparin therapy (heparin acts on antithrombin III and prolongs aPTT; therapeutic target is 1.5-2.5× normal)
• A mixing study (patient plasma + normal plasma) can differentiate factor deficiency (corrects on mixing) from inhibitor/anticoagulant (does not correct)

CASE HISTORY-16 — 42-year-old woman, menorrhagia, provisional diagnosis: von Willebrand factor deficiency

• Bleeding time: 16 min (Normal: 2-7 min) → Prolonged
• Reticulocytes: 8% (Normal: 0.5-2.5%) → Elevated (compensatory for blood loss from menorrhagia)
• Platelet count: 315,000 cells/c.mm → Normal
• aPTT: Prolonged
• Factor VIII: Slight reduction in plasma levels

1. Primary hemostasis - Platelet adhesion:
   • When a vessel is injured, subendothelial collagen is exposed
   • vWF acts as a molecular bridge, binding to collagen on one end and to glycoprotein Ib (GPIb) receptors on platelets on the other end
   • This tethers platelets to the damaged vessel wall (especially under high shear stress in small vessels) - initiating the platelet plug
   • Without vWF, platelets cannot adhere → primary plug fails → prolonged bleeding time
2. Secondary hemostasis - Carrier for Factor VIII:
   • vWF forms a non-covalent complex with Factor VIII in plasma
   • This protects Factor VIII from premature proteolytic degradation
   • Ensures adequate Factor VIII levels for the intrinsic coagulation cascade
   • vWF deficiency → Factor VIII degraded faster → reduced Factor VIII → mild impairment of intrinsic pathway → prolonged aPTT

CASE HISTORY-17 — Individual with excessive/prolonged bleeding; Bleeding time = 4 min, Clotting time = 12 min

• Bleeding time = 4 minutes: This is within the normal range (Normal: 2-7 minutes by Duke's method; 1-6 minutes by Ivy method). Primary hemostasis (platelet function, platelet count, vWF-mediated adhesion) is intact and normal.
• Clotting time = 12 minutes: This is prolonged (Normal: 5-11 minutes by Lee-White method, or up to 15 min depending on method). Secondary hemostasis (the coagulation cascade) is impaired. This indicates a deficiency of one or more coagulation factors involved in the intrinsic or common pathway.

• Factor II (Prothrombin), Factor VII, Factor IX, Factor X (pro-coagulants)
• Protein C, Protein S (anticoagulants)
• Also: Factor VII (extrinsic pathway) and Factors II, IX, X (intrinsic/common pathway)

• Factors II, VII, IX, X are synthesized as inactive precursors (PIVKA - Proteins Induced by Vitamin K Absence)
• The intrinsic pathway (Factors IX, X) and common pathway (Factor II) are deficient
• This prolongs clotting time (intrinsic + common pathway affected)
• PT is also prolonged (Factor VII, which is extrinsic, is also Vitamin K-dependent)
• Bleeding time remains normal because platelet function and vWF are unaffected

• Normal (Duke's method - earlobe prick): 1-5 minutes
• Normal (Ivy's method - forearm, BP cuff at 40 mmHg): 2-7 minutes

• Normal (Lee-White method): 5-11 minutes (at 37°C in glass)