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# DNB General Medicine — Paper 2: Model Answers

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## Q1. Generalized Lymphadenopathy / Hodgkin's Lymphoma

### a) Differential Diagnosis & Approach to Generalized Lymphadenopathy

**Definition:** Enlarged nodes (>1 cm) in ≥2 non-contiguous regions.

**Causes (Mnemonic: MIAMI):**
- **Malignant:** Hodgkin lymphoma, Non-Hodgkin lymphoma, CLL, ALL, metastatic carcinoma
- **Infections:** EBV, CMV, HIV, TB, toxoplasmosis, secondary syphilis, brucellosis
- **Autoimmune:** SLE, RA, sarcoidosis, serum sickness
- **Metabolic:** Hyperthyroidism, Gaucher's disease
- **Iatrogenic/Drugs:** Phenytoin, allopurinol, isoniazid

**Approach:**
- **History:** Duration, fever, night sweats, weight loss (B symptoms), travel, drug, sexual history
- **Examination:** Node size, consistency (rubbery = lymphoma; hard = metastasis; tender = infection), hepatosplenomegaly, rash
- **Investigations:**
  - CBC, peripheral smear, ESR, LDH, uric acid
  - HIV ELISA, Monospot, ANA, VDRL
  - Chest X-ray / CT scan
  - Lymph node excisional biopsy (histopathology + IHC + flow cytometry)
  - Bone marrow biopsy if hematologic malignancy suspected

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### b) Differences Between HL and NHL

| Feature | Hodgkin's | Non-Hodgkin's |
|---|---|---|
| Cell of origin | Reed-Sternberg (B-cell) | B-cell (85%), T-cell (15%) |
| Age | Bimodal (15–35, >55 yrs) | Any age |
| Spread | Contiguous | Non-contiguous |
| Mediastinal nodes | Common (>50%) | Less common |
| Extranodal involvement | Rare | Common |
| Bone marrow | Rarely involved | Frequently involved |
| RS cells | CD15+, CD30+ | Absent |
| Prognosis | Better (~80% cure) | Variable |

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### c) WHO Classification of Hodgkin's Lymphoma

**1. Classical HL (95%)** — RS cells CD15+, CD30+:
- Nodular Sclerosis (NS-HL): 60–70%; young women; collagen bands; mediastinal mass
- Mixed Cellularity (MC-HL): 20–25%; older males; EBV-associated
- Lymphocyte-Rich (LR-HL): ~5%; best prognosis
- Lymphocyte-Depleted (LD-HL): <1%; worst prognosis; elderly/HIV

**2. NLPHL (5%):** "Popcorn" cells; CD20+, CD15−, CD30−; indolent

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## Q2. Azotemia & Polyuria

### a) Causes of Azotemia

**PRERENAL** (BUN:Cr >20:1; FENa <1%):
- Hypovolemia, CHF, cirrhosis, nephrotic syndrome; NSAIDs, ACEi, ARBs

**INTRINSIC RENAL** (BUN:Cr ≈10:1; FENa >2%):
- Glomerular: GN, vasculitis, RPGN
- Tubular (ATN): Ischemic or nephrotoxic (aminoglycosides, contrast, rhabdomyolysis)
- Interstitial: Drug-induced AIN (NSAIDs, PPIs), leptospirosis
- Vascular: HUS/TTP, malignant hypertension

**POSTRENAL:**
- Ureteral stones, retroperitoneal fibrosis, BPH, neurogenic bladder

**Chronic:** Diabetic nephropathy, hypertensive nephrosclerosis, CKD

---

### b) Diagnostic Approach to Polyuria

**Definition:** Urine output >3 L/day.

**Step 1:** 24-hour urine to confirm true polyuria.

**Step 2 — Urine osmolality:**
- Uosm >700 → Solute diuresis (DM, mannitol, high-protein feeds)
- Uosm <300 → Water diuresis → Step 3

**Step 3 — Water Deprivation Test:**

| Response | Diagnosis |
|---|---|
| Uosm rises >50% after DDAVP | Central DI |
| <10% rise after DDAVP | Nephrogenic DI |
| Uosm >500 before DDAVP | Primary polydipsia |

**Causes:**
- Central DI: Trauma, neurosurgery, craniopharyngioma, sarcoidosis, autoimmune
- Nephrogenic DI: Lithium, hypercalcemia, hypokalemia, CKD, genetic (V2R mutation)
- Primary polydipsia: Psychogenic, hypothalamic lesion

---

## Q3. Syncope: Etiology & Evaluation

### Etiology

**1. Reflex (~40%):**
- Vasovagal (pain, prolonged standing, emotional stress); Situational (cough, micturition); Carotid sinus syndrome

**2. Orthostatic Hypotension (~10%):**
- Autonomic failure (Parkinson's, MSA), DM, drugs (antihypertensives, diuretics, nitrates), volume depletion

**3. Cardiac (~15% — highest mortality):**
- Arrhythmic: SSS, AV block, VT/VF, Long QT (Romano-Ward), Brugada, WPW
- Structural: Severe AS, HOCM, cardiac tamponade, PE, pulmonary hypertension

**4. Cerebrovascular (<5%):** Vertebrobasilar TIA

**5. Psychogenic:** Pseudosyncope (no true LOC)

---

### Evaluation

| Test | Indication |
|---|---|
| 12-lead ECG | All patients (mandatory) |
| Echocardiogram | Structural heart disease suspected |
| Holter/Event recorder | Suspected arrhythmia |
| ILR (implantable) | Infrequent syncope (up to 3 years) |
| Tilt-table test | Vasovagal/orthostatic suspected |
| EP study | High-risk cardiac (wide QRS, structural disease) |
| CT/MRI brain | Only if neurological signs present |

**Risk stratification:** ROSE rule, San Francisco Syncope Rule, EGSYS score.

---

## Q4. Peripheral Neuropathy & NCS

### a) Clinical Features & Evaluation

**Motor:** Distal weakness, wasting, foot/wrist drop, areflexia

**Sensory:** Tingling, burning, allodynia (positive); numbness, sensory ataxia (negative)

**Autonomic:** Postural hypotension, gastroparesis, bladder dysfunction

**Patterns:**
- Stocking-glove: DM, alcohol, nutritional
- Mononeuropathy: Compression (CTS), trauma
- Mononeuritis multiplex: Vasculitis, DM, leprosy
- Polyradiculopathy: GBS, CIDP

**Evaluation:**
- Blood: FBC, HbA1c, renal/LFTs, TFTs, B12, SPEP, ANA, ANCA, HIV, VDRL
- NCS + EMG (key test)
- CSF: Albumino-cytological dissociation (GBS/CIDP)
- Sural nerve biopsy: Vasculitis, amyloid, leprosy
- Genetic testing: PMP22 (CMT1A)

---

### b) Nerve Conduction Study (NCS)

**Parameters:** Conduction velocity (myelination), Amplitude (axon number), Distal latency, F-wave (proximal), H-reflex (S1 pathway)

**Axonal vs. Demyelinating:**

| Feature | Axonal | Demyelinating |
|---|---|---|
| Amplitude | ↓↓ | Normal/mildly reduced |
| Conduction velocity | Normal/mild reduction | Markedly reduced (<75% LLN) |
| Distal latency | Normal/mild | Prolonged (>130% ULN) |
| Conduction block | Absent | Present (>50% amplitude drop) |
| Examples | DM, alcohol, uremia | GBS, CIDP, CMT1 |

---

## Q5. Antiphospholipid Syndrome (APS)

### a) Definition & aPL Antibody Types

**APS:** Autoimmune disorder with recurrent thrombosis/pregnancy morbidity + persistent positive antiphospholipid antibodies.

**Types:**
1. Lupus anticoagulant (LA) — strongest predictor of thrombosis
2. Anticardiolipin (aCL) — IgG/IgM/IgA
3. Anti-β2GPI — IgG/IgM/IgA; most specific
4. Non-criteria: Antiphosphatidylserine, antiprothrombin

---

### b) Pathogenesis, Criteria & Management

**Pathogenesis:**
- aPL bind β2GPI → endothelial activation (NF-κB → tissue factor); platelet activation (TXA2); complement activation (C5a → trophoblast injury); inhibit protein C/S and annexin A5
- Two-hit hypothesis: aPL (1st hit) + trigger (pregnancy/infection/surgery) = thrombosis

**Revised Sapporo/Sydney Criteria (≥1 clinical + ≥1 lab, 12 weeks apart):**

*Clinical:* Arterial/venous/small vessel thrombosis OR pregnancy morbidity (fetal death ≥10 wks; premature birth <34 wks; ≥3 consecutive abortions <10 wks)

*Lab (moderate-high titer):* LA (ISTH criteria); aCL IgG/IgM >40 GPL; Anti-β2GPI IgG/IgM >99th percentile

**Management:**
- Primary prevention: Low-dose aspirin ± hydroxychloroquine (SLE)
- Venous thrombosis: Warfarin INR 2–3 (indefinite); DOACs inferior
- Obstetric APS: LMWH + aspirin throughout pregnancy
- Catastrophic APS: Anticoagulation + high-dose steroids + plasma exchange/IVIG; eculizumab (refractory)

---

## Q6. Podocyte Injury & Nephrotic Syndrome

### a) Structural & Molecular Basis

**Slit diaphragm proteins & mutations:**

| Protein | Gene | Disease |
|---|---|---|
| Nephrin | NPHS1 | Congenital NS (Finnish type) |
| Podocin | NPHS2 | Familial FSGS (AR) |
| CD2AP | CD2AP | FSGS |
| TRPC6 | TRPC6 | Familial FSGS (AD) |
| WT1 | WT1 | Denys-Drash, Frasier |

**Mechanisms:**
- MCD: T-cell dysfunction → suPAR/CD80 → foot process effacement (FPE)
- FSGS: suPAR → β3-integrin → FPE; APOL1 G1/G2 → rapid progression in Africans
- MN: Anti-PLA2R → subepithelial complexes → C5b-9 (MAC) → podocyte injury
- Podocyte depletion → bare GBM → segmental sclerosis

---

### b) Prognostic & Therapeutic Implications

| Disease | Prognosis | Treatment |
|---|---|---|
| MCD | Excellent; >80% steroid CR | Prednisolone 1 mg/kg; relapsers: CYC/CNI/Rituximab |
| FSGS (steroid-resistant) | Variable; collapsing = worst | Cyclosporine ± prednisolone; genetic FSGS: RAAS blockade only |
| MN (primary) | 1/3 spontaneous remission | Low-risk: conservative; Medium/high-risk: Rituximab (MENTOR trial) or Ponticelli (CYC+steroids) |
| Genetic FSGS | Early renal failure; steroids ineffective | RAAS blockade, avoid nephrotoxins |

**All:** ACEi/ARB, BP <125/75, statins, anticoagulation if albumin <2.5 g/dL

---

## Q7. Leptospirosis

### a) Etiopathogenesis & Clinical Features

**Organism:** Leptospira interrogans — zoonosis; rodents = primary reservoir
**Transmission:** Skin/mucosa contact with contaminated water/soil; occupational risk; outbreaks post-floods

**Pathogenesis:**
- Entry → leptospiremia → LPS + toxins → endothelial injury (vasculitis)
- Liver (hepatocellular damage), Kidney (tubulointerstitial nephritis, hypokalemia), Lung (alveolar hemorrhage — commonest cause of death), Muscle (myositis, calf pain), Immune phase (uveitis)

**Clinical — Biphasic:**

*Phase 1 (Days 1–7):* Fever, rigors, severe headache, calf myalgia, **conjunctival suffusion** (pathognomonic), nausea

*Phase 2 (Days 7–21):* Aseptic meningitis; uveitis (late)

*Weil's Syndrome (10%):* **Jaundice + AKI + Bleeding**; pulmonary hemorrhage syndrome

---

### b) Faine's Criteria (Scoring)

Key scores: Conjunctival suffusion (4), Calf pain (4), Meningism (4), Flood/water exposure (5), Occupational exposure (5), Positive MAT serology (15–25)

**Score ≥26 (Parts A+B alone):** Probable → treat. With serology: Confirmed.

**Gold standard:** MAT (Microscopic Agglutination Test), titer ≥1:400.

---

### c) Management

| Severity | Drug |
|---|---|
| Mild | Doxycycline 100 mg BD PO × 7 days |
| Moderate-Severe | Benzylpenicillin 1.5 MU IV 6-hourly × 7 days OR Ceftriaxone 1 g IV daily × 7 days |

Complications: Dialysis (AKI); Ventilation + methylprednisolone (pulmonary hemorrhage); Topical steroids (uveitis)
Prophylaxis: Doxycycline 200 mg weekly (high-risk)

---

## Q8. Spondyloarthritis & Ankylosing Spondylitis

### a) Diseases Under Spondyloarthritis

- Axial: Ankylosing spondylitis (AS), Non-radiographic axSpA
- Peripheral: Psoriatic arthritis, Reactive arthritis, Enteropathic arthritis (IBD), Undifferentiated SpA, Juvenile SpA

---

### b) Role of HLA-B27

1. **UPR/Misfolding (most favored):** B27 misfolds in ER → UPR → NF-κB → TNF-α, IL-17
2. **Arthritogenic peptide:** Molecular mimicry (bacterial/self) → CD8+ T-cell joint attack
3. **B27 homodimers:** Bind NK receptors (KIR3DL2) → IL-17 production
4. **IL-23/IL-17 axis:** B27 drives IL-23 → Th17 → entheseal inflammation + syndesmophytes
5. **Gut-joint axis:** Dysbiosis → leaky gut → innate immune activation

---

### c) Diagnosis & Management

**Modified New York Criteria:** Sacroiliitis grade ≥2 bilateral (X-ray) + ≥1 clinical feature (back pain >3 months; limited lumbar motion; reduced chest expansion <2.5 cm)

**Management — Step-up:**
1. **NSAIDs** (first-line): Diclofenac, indomethacin, etoricoxib — continuous dosing
2. **Sulfasalazine:** Peripheral arthritis only
3. **Biologics** (BASDAI ≥4, failure of ≥2 NSAIDs):

**TNF Inhibitors:** Adalimumab (40 mg SC q2wks), Etanercept (50 mg SC weekly), Infliximab (5 mg/kg IV), Golimumab (50 mg SC monthly), Certolizumab pegol

**IL-17A Inhibitors:** Secukinumab (first IL-17i; 150–300 mg SC monthly), Ixekizumab, Bimekizumab (anti-IL-17A+F; 2023)

**JAK Inhibitors:** Upadacitinib 15 mg OD, Tofacitinib — oral; for biologic failures

---

## Q9. Systemic Vasculitis, ANCA-Vasculitis & GPA

### a) Classification by Vessel Size (Chapel Hill 2012)

- **Large:** Giant cell arteritis, Takayasu arteritis
- **Medium:** Polyarteritis nodosa, Kawasaki disease
- **Small (ANCA):** GPA (c-ANCA/PR3), MPA (p-ANCA/MPO), EGPA (MPO-ANCA)
- **Small (Immune complex):** Anti-GBM disease, Cryoglobulinemic vasculitis, IgA vasculitis
- **Variable:** Behçet's, Cogan's

---

### b) ANCA-Associated Vasculitis Pathogenesis

1. Priming: Infection/TNF-α → PR3/MPO on neutrophil surface
2. ANCA binding → Fc receptor cross-link → neutrophil activation
3. Degranulation → ROS + proteases → fibrinoid necrosis (pauci-immune)
4. NETs → endothelial damage; source of autoantigens
5. C5a amplification loop → target of avacopan
6. Granuloma (GPA): M1 macrophages → giant cells → necrotizing granulomatous inflammation
7. Deficient T-regs → uncontrolled ANCA-producing B cells

---

### c) Diagnostic Evaluation & Treatment of GPA

**Clinical triad:** ENT (sinusitis, saddle-nose, subglottic stenosis) + Lungs (nodules, hemorrhage) + Kidneys (rapidly progressive GN)

**Investigations:**
- c-ANCA/PR3-ANCA (sensitivity ~90%)
- Urine analysis: RBC casts; Creatinine
- Chest CT: Cavitating nodules, ground-glass opacities
- Kidney biopsy: Focal necrotizing **pauci-immune** crescentic GN (gold standard)

**Induction:**
- Rituximab + high-dose corticosteroids (first-line, RAVE trial)
- CYC + corticosteroids (alternative); IV pulse preferred
- Avacopan (approved 2021 — steroid-sparing, ADVOCATE trial)
- Methylprednisolone pulses for pulmonary hemorrhage/severe AKI

**Maintenance:**
- Rituximab 500 mg IV q6months (MAINRITSAN — superior to azathioprine)
- Azathioprine/Methotrexate: Alternatives after CYC remission

**Monitor:** PR3-ANCA titers, eGFR, urine; PCP prophylaxis (co-trimoxazole DS 3×/week)

---

## Q10. Epstein-Barr Virus (EBV) Infection

### a) Structure, Transmission & Pathogenesis

**Structure:** HHV-4, Gammaherpesvirinae; dsDNA (~172 kb)
- Envelope: gp350 (binds CD21/CR2 on B cells); gp42 (binds HLA class II)
- Icosahedral capsid (VCA proteins); dsDNA core (circularizes as episome in latency)
- Antigens: VCA IgM = acute; VCA IgG = past; EBNA = appears 3–6 wks, persists lifelong

**Transmission:** Saliva (primary); blood/organ transplant (→ PTLD); perinatal (rare)

**Pathogenesis:**
1. Oropharyngeal epithelial infection → lytic replication → viral shedding
2. B-cell entry via gp350/CD21 → circular EBV episome → latency
3. LMP1 (mimics CD40 → NF-κB → B-cell proliferation); LMP2A (mimics BCR signaling)
4. Massive CD8+ T-cell response → **atypical lymphocytes** (hallmark of IM)
5. Cytokine storm (TNF-α, IFN-γ) → fever, lymphadenopathy, hepatitis
6. Long-term: EBV in resting memory B cells (Latency 0)

**Latency Programs:**

| Type | Antigens | Disease |
|---|---|---|
| 0 | EBERs only | Healthy carriers |
| I | EBNA1 | Burkitt lymphoma |
| II | EBNA1, LMP1, LMP2 | Hodgkin lymphoma, NPC |
| III | All EBNAs + LMPs | PTLD, immunocompromised |

---

### b) Complications

**Hematologic:**
1. Hemolytic anemia — Cold agglutinin (anti-i IgM); self-limiting
2. Thrombocytopenia — Immune-mediated; usually mild
3. Aplastic anemia — Rare; T-cell suppression of marrow
4. HLH — Pancytopenia, hyperferritinemia, hypertriglyceridemia; fatal in XLP (SAP mutation)
5. PTLD — EBV-driven lymphoproliferation post-transplant; reduce immunosuppression ± rituximab
6. Burkitt lymphoma — t(8;14) c-MYC/IgH; endemic form EBV-associated
7. Splenic rupture — Avoid contact sports 4–6 weeks post-IM

**Neurologic:**
1. Aseptic meningitis — Lymphocytic; self-limiting
2. Encephalitis — Confusion, seizures; EBV PCR in CSF
3. Guillain-Barré Syndrome — Post-infectious demyelinating polyneuropathy
4. Bell's palsy (CN VII)
5. Alice in Wonderland Syndrome — Micropsia/macropsia; children
6. Acute cerebellar ataxia — Post-infectious; children
7. Transverse myelitis
8. CNS lymphoma (AIDS-related)

**Hepatic:**
1. Acute hepatitis — >80% of IM; elevated AST/ALT 2–10× ULN; usually anicteric
2. Cholestatic hepatitis — ~5%; conjugated hyperbilirubinemia; self-limiting
3. Fulminant hepatic failure — Rare (<0.5%); XLP/immunocompromised
4. Granulomatous hepatitis — Non-caseating granulomas; mimics sarcoidosis/TB
5. HLH-associated hepatitis — Hepatosplenomegaly, hemophagocytosis on biopsy

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*End of Answers — DNB General Medicine Paper 2*

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