MD/MS General Medicine Exam Notes

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Q.1 LONG ANSWER QUESTIONS (Attempt Any Two) — 2 x 20 = 40

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Q.1(a) Endothelial Dysfunction and Its Role in Causation of Various Diseases

Definition

Normal Endothelial Functions

• Regulates vascular tone (via NO, prostacyclin, endothelin-1)
• Prevents thrombosis (via NO, prostacyclin, tissue plasminogen activator - tPA)
• Controls permeability
• Inhibits smooth muscle proliferation
• Modulates inflammation (expresses adhesion molecules: ICAM-1, VCAM-1, E-selectin)

Mechanisms of Endothelial Dysfunction

1. Reduced NO production/bioavailability
   • Decreased eNOS activity
   • Oxidative stress - superoxide anions scavenge NO, forming peroxynitrite (ONOO-)
   • Asymmetric dimethylarginine (ADMA) - endogenous eNOS inhibitor
2. Increased endothelin-1 (ET-1) - potent vasoconstrictor
3. Upregulation of adhesion molecules - promotes leukocyte adhesion
4. Pro-thrombotic shift - increased von Willebrand factor, PAI-1; decreased tPA

Causes/Risk Factors for ED

• Hypertension, diabetes mellitus, hyperlipidemia
• Smoking, obesity
• Aging, menopause
• Hyperhomocysteinemia
• Chronic kidney disease
• Chronic inflammation

Diseases Caused/Worsened by Endothelial Dysfunction

Biomarkers of ED

• Flow-mediated dilatation (FMD) - gold standard non-invasive test
• Serum ADMA, von Willebrand factor, soluble ICAM-1
• Microalbuminuria (in diabetes/HTN)

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Q.1(b) Anatomy of a Typical Nephron; Role in Acid-Base Balance; Diuretics Used in Emergency

Anatomy of a Typical Nephron

1. Glomerulus - capillary tuft enclosed in Bowman's capsule; filters ~180 L/day; GFR ~125 mL/min
2. Proximal Convoluted Tubule (PCT)
   • Reabsorbs 65% of Na+, water, glucose, amino acids, HCO3-
   • H+ secreted via Na+/H+ exchanger (NHE3)
   • Major site of HCO3- reabsorption
3. Loop of Henle
   • Descending limb: permeable to water only (medullary concentration)
   • Thin ascending limb: Na+ passively absorbed
   • Thick ascending limb (TAL): Na+/K+/2Cl- cotransporter (NKCC2); not permeable to water - generates countercurrent
4. Distal Convoluted Tubule (DCT)
   • Na+/Cl- cotransporter (NCC)
   • PTH acts here for Ca2+ reabsorption
5. Collecting Duct
   • Principal cells: aldosterone-sensitive Na+ reabsorption / K+ secretion
   • Intercalated cells: H+ secretion (Type A) / HCO3- secretion (Type B)
   • ADH (vasopressin) inserts aquaporin-2 channels

Role of Nephron in Acid-Base Balance

Diuretics Commonly Used in Emergency Ward

• Mechanism: Inhibits NKCC2 in TAL; impairs urinary concentration
• Dose (emergency): 40-80 mg IV bolus; up to 200-400 mg IV infusion in severe cases
• Uses: Acute pulmonary edema, hypertensive emergency with fluid overload, hypercalcemic crisis, acute kidney injury with fluid overload, hyperkalemia
• Onset: 5 min IV
• Side effects: Hypokalemia, hyponatremia, metabolic alkalosis, ototoxicity

• Mechanism: Increases tubular osmolality; water diuresis without Na+ loss
• Dose: 0.5-1 g/kg IV over 30 min (20% solution)
• Emergency uses: Raised intracranial pressure (cerebral edema), acute glaucoma (raised IOP), rhabdomyolysis (prevent myoglobin cast)
• Side effects: Hyponatremia (initial), rebound cerebral edema with prolonged use, pulmonary edema if renal failure present

• Mechanism: Inhibits CA in PCT; decreases H+ secretion → HCO3- wasted → metabolic acidosis
• Emergency uses: Acute mountain sickness, acute glaucoma, metabolic alkalosis (to correct), pseudotumor cerebri
• Side effects: Hyperchloremic metabolic acidosis, hypokalemia, renal stones

• Mechanism: Aldosterone antagonist; blocks mineralocorticoid receptor in collecting duct
• Emergency use (relative): Refractory ascites in liver disease, hyperaldosteronism
• Note: Onset is slow (2-3 days); less used for acute emergencies

• Mechanism: Inhibits NCC in DCT
• Emergency use: Occasionally in hypertensive emergency (less preferred than loop)

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Q.1(c) Human Immune System and Its Relation to AIDS

Overview of Human Immune System

• Physical barriers: skin, mucous membranes
• Cellular: neutrophils, macrophages, NK cells, dendritic cells, mast cells, eosinophils
• Soluble: complement system, interferons, acute phase proteins, lysozyme
• Pattern recognition receptors (PRRs): Toll-like receptors (TLRs), NOD receptors

1. Humoral Immunity (B-cell mediated)
   • B cells → plasma cells → antibodies (IgM, IgG, IgA, IgE, IgD)
   • Opsonization, neutralization, ADCC, complement activation
   • Memory B cells provide long-term protection
2. Cell-mediated Immunity (T-cell mediated)
   • CD4+ Helper T cells (Th1, Th2, Th17): orchestrate immune response
   • CD8+ Cytotoxic T cells: kill virus-infected/tumor cells via perforin-granzyme
   • CD4+CD25+ Regulatory T cells (Tregs): prevent autoimmunity

• MHC I (all nucleated cells) - presents endogenous antigens to CD8+ cells
• MHC II (APCs: dendritic cells, macrophages, B cells) - presents exogenous antigens to CD4+ cells
• Complement: Classical (antibody-triggered), Lectin, Alternative pathways → MAC (membrane attack complex)
• Cytokines: IL-1, IL-2, IL-4, IL-6, IL-12, IFN-γ, TNF-α

HIV/AIDS: How HIV Subverts the Immune System

• Retrovirus (ssRNA); genus Lentivirus
• Two types: HIV-1 (pandemic) and HIV-2 (West Africa, less virulent)
• Structural genes: gag (capsid), pol (reverse transcriptase, integrase, protease), env (gp120, gp41)

1. gp120 binds CD4 receptor on helper T cells, macrophages, dendritic cells
2. Co-receptor binding: CCR5 (macrophage-tropic/R5) or CXCR4 (T-cell tropic/X4)
3. gp41 mediates fusion; viral RNA enters cell
4. Reverse transcriptase converts RNA → DNA (error-prone = rapid mutation)
5. Integrase incorporates viral DNA into host genome (provirus)
6. Protease cleaves viral polyproteins for assembly of new virions

• HIV primarily destroys CD4+ T helper cells
• Destruction via: direct cytolysis, syncytia formation, ADCC, apoptosis
• CD4+ T cell count normally 500-1500 cells/µL
• AIDS defined: CD4+ <200 cells/µL OR AIDS-defining illness
• Loss of CD4+ cells → loss of immune coordination → opportunistic infections (OI) + AIDS-defining malignancies

• Pneumocystis jirovecii pneumonia (PCP) - most common OI (CD4 <200)
• Toxoplasma encephalitis (CD4 <100)
• Cryptococcal meningitis (CD4 <100)
• CMV retinitis (CD4 <50)
• MAC (Mycobacterium avium complex) (CD4 <50)
• Kaposi's sarcoma (HHV-8; CD4 variable)
• Primary CNS lymphoma
• Invasive cervical cancer, NHL

• NRTIs: Tenofovir, Emtricitabine, Lamivudine, Zidovudine
• NNRTIs: Efavirenz, Nevirapine, Rilpivirine
• PIs: Atazanavir, Lopinavir, Darunavir
• Integrase inhibitors (INSTIs): Dolutegravir, Raltegravir (preferred first-line)
• CCR5 antagonist: Maraviroc
• Fusion inhibitor: Enfuvirtide
• First-line (WHO 2023): TDF + 3TC/FTC + DTG

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Q.2 SHORT ANSWER QUESTIONS (Attempt Any Six) — 6 x 10 = 60

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Q.2(a) Pathophysiological Basis of Rheumatoid Arthritis and Treatment with Biological Therapy

Pathophysiology of RA

• Genetic predisposition: HLA-DR4 and HLA-DR1 (shared epitope hypothesis); PTPN22 gene
• Environmental triggers: smoking (induces citrullination), periodontal infection (Porphyromonas gingivalis), viral triggers

• Post-translational modification of arginine → citrulline by peptidylarginine deiminase (PAD) enzymes
• Generates citrullinated proteins (fibrin, vimentin, alpha-enolase)
• Anti-citrullinated protein antibodies (ACPAs/anti-CCP) - highly specific for RA

1. CD4+ T cells (Th1, Th17) activated by APCs presenting citrullinated peptides via HLA-DR
2. Th1 cells produce IFN-γ → macrophage activation → TNF-α, IL-1, IL-6
3. Th17 cells produce IL-17 → neutrophil recruitment
4. B cells differentiate into plasma cells → produce Rheumatoid Factor (IgM anti-IgG) + ACPAs → immune complexes → complement activation
5. Macrophages + fibroblast-like synoviocytes (FLS) proliferate → PANNUS formation (invasive inflammatory granulation tissue)
6. RANKL (from T cells, FLS) → osteoclast activation → bone erosion
7. MMP (matrix metalloproteinases) from FLS → cartilage destruction
8. Angiogenesis (VEGF-driven) feeds the pannus

• TNF-α - most pivotal; activates NF-κB; stimulates synoviocytes, bone erosion
• IL-1 - bone erosion, fever, acute phase response
• IL-6 - acute phase proteins (CRP, fibrinogen), anemia of chronic disease, constitutional symptoms
• IL-17 - neutrophil recruitment, cartilage damage

Biological Therapy in RA

• Etanercept (soluble TNF receptor fusion protein)
• Infliximab (chimeric anti-TNF monoclonal antibody)
• Adalimumab (fully human anti-TNF monoclonal antibody)
• Certolizumab pegol, Golimumab
• Side effects: Reactivation of latent TB, serious infections, demyelinating disease, lymphoma, injection site reactions
• Screening before use: TB (Mantoux/IGRA), Hep B surface antigen, Hep C

• Tocilizumab (IV or SC) - anti-IL-6R
• Sarilumab
• Used when TNF inhibitors fail or CRP elevation prominent; effective for systemic features

• Rituximab (anti-CD20 monoclonal antibody)
• Depletes B cells → reduces ACPA + RF production + antigen presentation
• Used in seropositive RA after TNF-inhibitor failure or when TNF-inhibitors contraindicated

• Abatacept (CTLA4-Ig fusion protein)
• Blocks CD28-CD80/86 costimulatory signal → prevents T cell activation

• Anakinra (IL-1 receptor antagonist) - less used in RA; mainly Adult-onset Still's disease

• Tofacitinib (JAK1/3 inhibitor)
• Baricitinib (JAK1/2 inhibitor)
• Upadacitinib (selective JAK1 inhibitor)
• Block intracellular JAK-STAT signaling downstream of multiple cytokine receptors
• Oral agents

1. Methotrexate (anchor DMARD) + NSAIDs + short-course steroids
2. If MTX fails: add/switch to other DMARDs (leflunomide, sulfasalazine, hydroxychloroquine) or biologics
3. Biologics/JAK inhibitors if inadequate response to 2 DMARDs

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Q.2(b) Demyelination: Process and Diseases It May Cause

What is Demyelination?

Normal Myelin Structure

• CNS myelin: Produced by oligodendrocytes (one cell myelinates many axons)
• PNS myelin: Produced by Schwann cells (one cell per internodal segment)
• Myelin is a multilayered lipid-protein membrane that:
  • Insulates the axon
  • Enables saltatory conduction (impulse jumps between Nodes of Ranvier)
  • Speeds nerve conduction velocity dramatically

Process of Demyelination

• Loss of myelin impedes saltatory conduction at Nodes of Ranvier (where Na+ channels are concentrated)
• Results in: conduction slowing or complete conduction block
• Clinically causes: weakness, sensory disturbances, visual loss, incoordination

1. Segmental demyelination (PNS) - individual internodal segments lose myelin; Schwann cells survive; remyelination possible with thin myelin sheaths; recognizable by "onion bulb" formations on biopsy
2. Wallerian degeneration - axon and myelin degenerate distal to axonal injury (not primarily demyelinating)
3. Primary demyelination (CNS) - myelin is selectively destroyed; oligodendrocytes damaged; relative axonal sparing (early); periventricular plaques in MS

• Autoimmune (T-cell + antibody mediated): MS, ADEM, GBS
• Inflammatory: direct viral invasion, para-infectious
• Metabolic/toxic: vitamin B12 deficiency, copper deficiency, alcohol, osmotic demyelination syndrome
• Genetic: leukodystrophies

Diseases Caused by Demyelination

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Q.2(c) Thermoregulation; Pathogenesis of Fever; What is Hyperthermia?

Thermoregulation

• Basal metabolic rate, muscular activity, shivering, diet-induced thermogenesis
• Thermogenic hormones: thyroid hormones, catecholamines, growth hormone

1. Radiation - infrared energy loss from skin (~60% at rest)
2. Conduction - direct contact transfer
3. Convection - moving air carries heat away
4. Evaporation - sweat evaporation (critical when ambient temp > body temp); insensible water loss

• Peripheral thermoreceptors (skin) → spinal cord → hypothalamus
• Central thermoreceptors in hypothalamus (warm and cold sensitive neurons)

• Too cold: vasoconstriction, shivering, piloerection, increased metabolism
• Too hot: vasodilation, sweating, behavioral changes

Pathogenesis of Fever

1. Exogenous pyrogens: LPS (gram-negative bacteria), bacterial cell wall components, viruses, toxins, antigen-antibody complexes
2. Activate macrophages, monocytes, dendritic cells, endothelial cells
3. Release endogenous pyrogens: IL-1β, IL-6, TNF-α, IFN-γ, IL-8, MIP-1α
4. Endogenous pyrogens reach the circumventricular organs (OVLT - organum vasculosum laminae terminalis; lacks BBB) of the anterior hypothalamus
5. Trigger phospholipase A2 → arachidonic acid → cyclooxygenase-2 (COX-2) → PGE2 (prostaglandin E2) synthesis in endothelial cells and perivascular cells
6. PGE2 acts on EP3 receptors on thermoregulatory neurons → raises the hypothalamic set point
7. Body responds to new set point: vasoconstriction + shivering (heat conservation/production) until actual temp reaches new set point
8. Resolution: Antipyretics (aspirin/ibuprofen block COX → reduce PGE2) or fever breaks naturally (sweating, vasodilation)

• NSAIDs/Aspirin: Block COX-1 and COX-2 → reduce PGE2
• Paracetamol: Central COX inhibition (mechanism debated; also endocannabinoid system)

Hyperthermia

1. Heat stroke - core temp >40°C; CNS dysfunction (delirium, coma); failure of sweating (classic) or exertional
2. Malignant hyperthermia - genetic (RYR1 mutation); triggered by halothane, succinylcholine; uncontrolled sarcoplasmic Ca2+ release → hyperthermia + rigidity; Rx: dantrolene
3. Neuroleptic malignant syndrome (NMS) - antipsychotic drugs block dopamine D2 receptors; hyperthermia + lead-pipe rigidity + altered consciousness + autonomic instability; Rx: dantrolene + bromocriptine
4. Serotonin syndrome - excess serotonergic activity; hyperthermia + tremor + clonus + diarrhea
5. Thyroid storm - extreme hyperthyroidism
6. Anticholinergic hyperthermia - decreased sweating

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Q.2(d) Basic Causative Factors for Diabetic Neuropathy; Various Types

Causative Factors (Pathogenesis)

• Glucose → Sorbitol (aldose reductase) → Fructose (sorbitol dehydrogenase)
• Sorbitol accumulates in nerve (cannot exit easily) → osmotic damage
• Depletes NADPH → reduces glutathione → increased oxidative stress
• Reduces myo-inositol → impaired Na+/K+-ATPase → axonal swelling

• Glucose non-enzymatically glycates proteins and lipids → AGEs
• AGEs cross-link myelin proteins → nerve dysfunction
• AGEs activate RAGE receptors → NF-κB → inflammation → endothelial damage
• Glycation of collagen in vessel walls → microangiopathy

• Mitochondrial overproduction of superoxide in hyperglycemia
• Activates PARP → NAD+ depletion → impaired DNA repair
• Lipid peroxidation of myelin membranes

• Endothelial dysfunction → thickened basement membrane → reduced nerve blood flow
• Endoneurial hypoxia → axonal degeneration (Wallerian degeneration)

• Reduced nerve growth factor (NGF) → impaired axonal regeneration and maintenance

• DAG accumulation from hyperglycemia activates PKC → impairs nerve blood flow

• Excess fructose-6-phosphate → UDP-GlcNAc → O-GlcNAc modification of proteins → altered gene expression

Types of Diabetic Neuropathy

• "Stocking and glove" pattern; begins in toes, moves proximally
• Sensory: tingling, burning, pain (worse at night), loss of sensation
• Motor: distal weakness; wasting of intrinsic foot muscles → foot deformities
• Loss of vibration (large fiber) first, then pain/temperature (small fiber)
• Leads to diabetic foot, Charcot arthropathy

• Cardiovascular: resting tachycardia, fixed heart rate, postural hypotension, sudden cardiac death
• GI: gastroparesis (delayed gastric emptying - nausea, vomiting, erratic glucose control), diabetic diarrhea, constipation
• Genitourinary: erectile dysfunction, neurogenic bladder (overflow incontinence)
• Sudomotor: hyperhidrosis of trunk, anhidrosis of feet → dry cracked skin
• Pupillary: reduced pupillary light reflex

• Single nerve involvement; usually abrupt onset
• Cranial mononeuropathy: CN III palsy (painful; pupil spared - vascular; cf. compressive = pupil involved), CN VI, CN VII
• Truncal mononeuropathy: mimics MI, herpes zoster; chest/abdominal pain

• Asymmetric; elderly T2DM patients
• Severe proximal lower limb pain followed by weakness and wasting (quadriceps, iliopsoas)
• May recover with glycemic control

• Multiple individual nerve involvements in random distribution
• Often associated with vasculitis of vasa nervorum

• Strict glycemic control (most important to prevent progression)
• Pain: pregabalin/gabapentin (first-line), duloxetine (SNRI), TCAs (amitriptyline), tramadol, topical capsaicin
• Autonomic: midodrine/fludrocortisone (postural hypotension), metoclopramide (gastroparesis), sildenafil (ED)

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Q.2(e) Applied Anatomy of Reflex Arc with Labelled Diagram

Components of a Reflex Arc (5 components)

1. Receptor - sensory nerve ending in skin/muscle/tendon/organ; detects stimulus
2. Afferent (Sensory) Neuron - carries impulse from receptor → dorsal horn of spinal cord; cell body in dorsal root ganglion (DRG)
3. Integration Center (Synapse) - in spinal cord gray matter (dorsal/ventral horn); may involve interneurons (polysynaptic)
4. Efferent (Motor) Neuron - carries impulse from ventral horn → effector; lower motor neuron (LMN) = alpha motor neuron
5. Effector - muscle (skeletal/smooth) or gland; produces response

Types of Reflexes:

• Ia afferent (from muscle spindle) → directly synapses on alpha motor neuron
• Example: Knee jerk (patellar reflex) - L3, L4
  • Tap patellar tendon → stretches quadriceps → muscle spindle (Ia fiber) activated → alpha MN in L3/L4 → quadriceps contraction
  • Simultaneous reciprocal inhibition of hamstrings (via inhibitory interneuron)

• Nociceptive stimulus → afferent → interneurons (multiple) → motor neurons
• Ipsilateral flexion + contralateral extension (crossed extensor reflex)

Diagram Description (Knee Jerk - Monosynaptic Stretch Reflex):

STIMULUS (Tap on patellar tendon)
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    [RECEPTOR - Muscle spindle in quadriceps]
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    [AFFERENT - Ia sensory neuron]  → cell body in DRG
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    [SPINAL CORD - Ventral horn synapse - L3/L4]
          |  (also → inhibitory interneuron → hamstring inhibited)
    [EFFERENT - Alpha motor neuron]
          |
    [EFFECTOR - Quadriceps muscle contracts → knee extends]

• LMN (arc interrupted): Hyporeflexia/areflexia + flaccid paralysis + muscle wasting
• UMN (above arc, loses inhibition): Hyperreflexia + spastic paralysis + clonus + Babinski +ve

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Q.2(f) Hemoglobin Oxygen Dissociation Curve and Clinical Importance

The Oxyhemoglobin Dissociation Curve (ODC)

• X-axis: Partial pressure of oxygen (PaO2) in mmHg
• Y-axis: Hemoglobin oxygen saturation (SaO2) in %

• Cooperative binding: binding of first O2 to one heme group increases affinity of remaining heme groups (conformational change: T-state → R-state)
• This is called positive cooperativity (Bohr effect)

Key Points on the Curve:

Factors Shifting the Curve

• CO2 increase
• Acidity (↓ pH) - Bohr effect
• DPG increase (2,3-DPG) - stored blood has less
• Exercise (↑ temperature, ↑ CO2, ↓ pH)
• Temperature increase

• Alkalosis (↑ pH)
• ↓ CO2 (hyperventilation)
• ↓ Temperature
• ↓ 2,3-DPG (stored blood, hypothyroidism)
• Fetal hemoglobin (HbF) - higher O2 affinity to extract O2 from mother
• CO poisoning (carboxyhemoglobin shifts curve left AND reduces capacity)
• Methemoglobin

Clinical Importance

1. Pulse Oximetry: SpO2 uses ODC to estimate SaO2; unreliable in CO poisoning, methemoglobinemia (falsely normal readings), hyperbilirubinemia
2. Blood Transfusion: Stored blood (high 2,3-DPG depletion) has left-shifted curve → poor O2 delivery acutely; normalizes within hours after transfusion
3. High Altitude: Hyperventilation → respiratory alkalosis → left shift → helps O2 uptake in lungs; but 2,3-DPG increases over days → right shift → helps O2 delivery
4. Fetal Hemoglobin (HbF): Left-shifted curve (P50 = 20 mmHg vs. adult 27 mmHg); allows fetus to extract O2 from maternal HbA across placenta
5. COPD/Respiratory failure: O2 saturation at PaO2 60 = 90% (shoulder); supplemental O2 needed
6. Sepsis/fever/acidosis: Right-shifted curve aids O2 delivery to tissues (adaptive)
7. CO poisoning: ODC shifts left; SaO2 falsely normal on pulse oximetry; treat with 100% O2
8. Sickle cell disease (HbS): Polymerizes when deoxygenated; slightly right-shifted (P50 ~31 mmHg); sickling in the steep portion of curve is problematic

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Q.2(g) Immunological Basis and Clinical Application of Monoclonal Antibodies

Immunological Basis

1. Immunize mouse with target antigen → mouse produces polyclonal antibodies
2. Harvest B cells (splenocytes) from mouse
3. Fuse B cells with immortal myeloma cells → Hybridoma cells
4. Hybridoma cells: immortal (from myeloma) + antibody-producing (from B cell)
5. Select in HAT medium (hypoxanthine-aminopterin-thymidine) - kills unfused myeloma cells
6. Screen clones for desired antibody specificity
7. Culture selected clone → produces monoclonal antibody indefinitely

• -omab = fully murine (high immunogenicity; HAMA response)
• -ximab = chimeric (mouse variable + human constant regions; ~65% human)
• -zumab = humanized (mouse CDRs grafted onto human framework; ~95% human)
• -umab = fully human (transgenic mice or phage display; lowest immunogenicity)

1. Neutralization - block ligand-receptor binding (e.g., bevacizumab blocks VEGF)
2. ADCC (Antibody-dependent cellular cytotoxicity) - Fc region recruits NK cells → target cell killing (e.g., rituximab)
3. CDC (Complement-dependent cytotoxicity) - Fc activates complement → MAC
4. Receptor blockade - block activating receptor (e.g., checkpoint inhibitors block PD-1, CTLA-4)
5. Intracellular delivery - antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine)
6. Signaling disruption - block downstream signal (e.g., trastuzumab blocks HER2 dimerization)

Clinical Applications

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Q.2(h) Pathological Basis of Sarcoidosis; Diagnostic Tests

Pathological Basis of Sarcoidosis

• Inhaled antigens: Mycobacterial antigens (mycobacterium tuberculosis peptides found in sarcoid granulomas), Propionibacterium acnes
• Organic dusts (beryllium, aluminum)
• Genetic susceptibility: HLA-DRB1 alleles

1. Antigen (unknown) presented by APCs (alveolar macrophages, dendritic cells) via HLA-II to CD4+ T cells
2. Predominant Th1 response: CD4+ Th1 cells produce IL-2, IFN-γ
3. IFN-γ activates macrophages → epithelioid cells
4. IL-2 drives T cell proliferation → lymphocytosis in BAL (CD4:CD8 ratio >3.5:1 - characteristic)
5. TNF-α from macrophages fuses epithelioid cells → multinucleated giant cells (Langhans-type)
6. Non-caseating granuloma forms: central collection of epithelioid macrophages and giant cells + peripheral rim of CD4+ T cells + fibroblasts
7. Peripheral blood shows lymphopenia (T cells sequestered in lungs)
8. Anergy to tuberculin (Kveim-Siltzbach test historically positive)
9. Polyclonal hypergammaglobulinemia + elevated ACE (from granuloma macrophages)
10. Calcium metabolism: 1-alpha-hydroxylase in granuloma macrophages → excess 1,25-dihydroxyvitamin D3 → hypercalcemia/hypercalciuria

• Asteroid bodies - star-shaped lipid inclusions in giant cells
• Schaumann bodies - laminated concentric calcified inclusions
• Hamazaki-Wesenberg bodies - yellow-brown ovoid bodies

• Lungs (most common; 90%): interstitial lung disease, pulmonary hypertension, perilymphangitic distribution on CT
• Lymph nodes: Bilateral hilar lymphadenopathy (BHL) - most common radiological finding
• Skin (25%): Erythema nodosum (acute, good prognosis), lupus pernio (chronic, poor prognosis), subcutaneous nodules, maculopapular rash
• Eyes (25%): Anterior uveitis (most common ocular manifestation), posterior uveitis, band keratopathy
• Liver/Spleen: Granulomatous hepatitis, splenomegaly
• Heart: Heart block (AV block), ventricular arrhythmia, dilated cardiomyopathy, sudden death
• Nervous system (5-10%): Cranial nerve palsies (CN VII = facial palsy most common), aseptic meningitis, hypothalamic involvement, peripheral neuropathy
• Bone/Joints: Phalangeal bone cysts (Perthes-Jüngling lesion), arthritis, dactylitis

Diagnostic Tests for Sarcoidosis

1. Compatible clinical/radiological picture
2. Histological evidence of non-caseating granuloma
3. Exclusion of other causes (TB, berylliosis, fungal)

• Stage 0: Normal
• Stage I: BHL (bilateral hilar lymphadenopathy) only - best prognosis
• Stage II: BHL + pulmonary infiltrates
• Stage III: Pulmonary infiltrates without BHL
• Stage IV: Pulmonary fibrosis (honeycombing, reticular shadowing)

• Perilymphangitic distribution (along bronchovascular bundles, pleura, interlobular septa)
• Beading of bronchovascular bundles
• Bilateral hilar + mediastinal lymphadenopathy
• "Galaxy sign," "sarcoid cluster sign"

• Elevated in ~75% of active sarcoidosis
• Produced by granuloma macrophages (epithelioid cells)
• Useful for monitoring disease activity; NOT specific (elevated in TB, berylliosis, diabetes, asthma)
• Normal does not exclude sarcoidosis

• Lymphocytosis (>15% lymphocytes; normal <10%)
• CD4:CD8 ratio >3.5:1 (highly suggestive; normal ~2:1)

• Bronchoscopic endobronchial biopsy/transbronchial biopsy - positive in 80-90%
• EBUS-TBNA (endobronchial ultrasound-guided needle aspiration) - sampled lymph nodes
• Skin biopsy (if skin lesions present - easier; avoid erythema nodosum which is non-specific)
• Liver biopsy, peripheral lymph node biopsy

• Full blood count: lymphopenia, eosinophilia (occasionally)
• Elevated ESR, CRP (non-specific)
• Hypercalcemia (10-20%), hypercalciuria
• Elevated serum 1,25-dihydroxyvitamin D3
• Elevated alkaline phosphatase (liver involvement)
• Polyclonal hypergammaglobulinemia
• LDH elevated

• Many cases remit spontaneously
• Indications for treatment: severe/progressive lung disease, hypercalcemia, cardiac/neurological/ocular involvement
• First-line: Oral corticosteroids (prednisolone 20-40 mg/day)
• Second-line: Methotrexate, azathioprine, hydroxychloroquine (skin/eye)
• Third-line: TNF-inhibitors (infliximab, adalimumab) for refractory cases

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QUICK REVISION TABLE

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