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🧠 NEUROLOGY

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1. Parkinson's Disease and Other Movement Disorders

Parkinson's Disease (PD)

• Loss of dopaminergic neurons in substantia nigra → reduced dopamine in striatum (caudate + putamen)
• Disruption of the direct (facilitatory) and indirect (inhibitory) pathways of the basal ganglia
• Net result: increased inhibitory output from GPi/SNr → suppression of thalamus and cortex → bradykinesia
• Lewy bodies: eosinophilic cytoplasmic inclusions with alpha-synuclein core

• Tremor - resting, "pill-rolling" (4-6 Hz), suppressed by movement
• Rigidity - "lead pipe" or "cogwheel" (rigidity + tremor)
• Akinesia/Bradykinesia - slowness, reduced arm swing, hypomimia (masked facies), micrographia
• Postural instability - late sign; pull test positive

• Anosmia (often precedes motor symptoms by years)
• REM sleep behavior disorder (RBD)
• Autonomic dysfunction: orthostatic hypotension, constipation, urinary urgency
• Neuropsychiatric: depression, dementia (PD-D), hallucinations
• Pain, fatigue, sialorrhea

• Wearing-off: dose-end deterioration - treat with dose increase, COMT/MAO-B inhibitors
• Dyskinesias: peak-dose choreic movements - treat with amantadine, reduce levodopa dose
• On-off fluctuations: unpredictable motor swings

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Other Movement Disorders

• Most common movement disorder
• Postural/kinetic tremor (6-12 Hz) of hands, head, voice
• Familial (autosomal dominant, LINGO1, FUS genes)
• Relieved by alcohol (pathognomonic)
• Treatment: Propranolol, primidone, topiramate; DBS for severe cases

• Autosomal dominant - CAG repeat expansion in HTT gene on chr 4 (>36 repeats pathological)
• Triad: chorea, dementia, psychiatric symptoms
• Onset 30-50 years; anticipation occurs (earlier onset in successive generations)
• Striatal atrophy (caudate "box-car" ventricles on MRI)
• Treatment: symptomatic only - tetrabenazine/deutetrabenazine for chorea (VMAT2 inhibitors)

• Autosomal recessive - ATP7B mutation → copper accumulation in liver, brain, cornea
• Kayser-Fleischer rings (corneal copper deposits), hepatic disease, neuropsychiatric symptoms
• Tremor (wing-beating), dysarthria, dysphagia
• Low ceruloplasmin, high urinary copper, liver biopsy
• Treatment: D-penicillamine (chelation), trientine, zinc, liver transplant

• Multiple motor + ≥1 vocal tic, >1 year, onset <18 years
• Associated with ADHD, OCD
• Treatment: behavioral therapy; haloperidol, fluphenazine, clonidine, aripiprazole

• Acute dystonia: haloperidol → tx: benztropine/diphenhydramine
• Tardive dyskinesia: chronic dopamine blocker use → tx: clonazepam, tetrabenazine, valbenazine
• Akathisia: restlessness → tx: propranolol, benzodiazepines

• Irresistible urge to move legs, worse at rest/night, relieved by movement
• Associated with iron deficiency, pregnancy, renal failure
• Treatment: dopamine agonists (pramipexole, ropinirole), gabapentin, iron if deficient

• Friedreich's ataxia: autosomal recessive, GAA repeat in FXN (frataxin), onset <25 years; spinocerebellar degeneration + cardiomyopathy
• SCA1-3: spinocerebellar ataxias, dominant, CAG repeats

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2. Seizures and Epilepsy

Classification (ILAE 2017)

• Focal (from one hemisphere network)
  • Focal aware (previously "simple partial")
  • Focal impaired awareness (previously "complex partial")
  • Focal to bilateral tonic-clonic
• Generalized (both hemispheres simultaneously)
  • Tonic-clonic (grand mal)
  • Absence (petit mal) - 3 Hz spike-wave, stare, no postictal
  • Myoclonic - brief muscle jerks
  • Clonic, Tonic, Atonic (drop attacks)
• Unknown onset

Pathophysiology

• Excessive, synchronous neuronal firing
• Imbalance between excitation (glutamate, AMPA/NMDA) and inhibition (GABA)
• Seizure propagation via cortical and subcortical networks
• Status epilepticus: continuous seizure >5 min or 2 seizures without recovery

Common Epilepsy Syndromes

Investigations

• EEG: essential - inter-ictal spikes, focal slowing, hypsarrhythmia
• MRI brain: structural cause (hippocampal sclerosis, tumors, cortical dysplasia)
• Blood: glucose, electrolytes, Ca, Mg, CBC, metabolic panel
• CSF: if encephalitis/meningitis suspected
• Genetic testing: for syndromes (SCN1A-Dravet, KCNQ2, etc.)

Antiepileptic Drugs (AEDs)

Status Epilepticus (SE) Management

Epilepsy vs. Seizure - Key Distinction

• Seizure: single event - may be provoked (fever, hyponatremia, alcohol withdrawal)
• Epilepsy: ≥2 unprovoked seizures >24h apart, or 1 unprovoked + high recurrence risk, or diagnosis of epilepsy syndrome
• First unprovoked seizure recurrence risk: ~40% at 2 years

SUDEP (Sudden Unexpected Death in Epilepsy)

• Risk 1 in 1000/year for epilepsy patients; higher with uncontrolled GTC seizures
• Mechanism: postictal cardiac/respiratory depression

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3. Alzheimer's Disease

Definition

Epidemiology

• Prevalence doubles every 5 years after age 65
• ~50 million affected worldwide
• Risk factors: age, APOE ε4 allele (3x risk), family history, Down syndrome (trisomy 21 → amyloid precursor protein locus on chr 21), TBI, cardiovascular risk factors

Pathology

• Amyloid plaques: extracellular aggregates of Aβ42 peptide (cleaved from APP by β- and γ-secretase)
• Neurofibrillary tangles (NFTs): intraneuronal hyperphosphorylated tau protein (microtubule-associated)
• Neuronal loss: hippocampus, entorhinal cortex → frontal, parietal lobes
• Cholinergic deficit: loss of nucleus basalis of Meynert neurons → reduced ACh

Amyloid Cascade Hypothesis

Genetics

• APP (chr 21), PSEN1 (chr 14), PSEN2 (chr 1) mutations → familial early-onset AD (<65 years)
• APOE ε4 (chr 19) - major risk allele for sporadic late-onset AD; ε2 is protective

Clinical Features

1. Preclinical: biomarker changes (amyloid PET positive) without symptoms
2. MCI (Mild Cognitive Impairment): memory complaints, preserved ADLs; ~15%/yr convert to dementia
3. Mild AD: episodic memory loss (forgets recent events), word-finding difficulty, geographic disorientation
4. Moderate AD: aphasia, apraxia, agnosia; behavioral changes (agitation, wandering); needs assistance
5. Severe AD: non-verbal, bedbound, incontinence, dysphagia; aspiration pneumonia common cause of death

Diagnosis

• Clinical (DSM-5 Major Neurocognitive Disorder criteria)
• MoCA or MMSE (score <24 suggests impairment)
• MRI: hippocampal/medial temporal lobe atrophy (Scheltens scale)
• PET FDG: hypometabolism in temporal-parietal regions
• Amyloid PET (florbetapir/florbetaben): detects amyloid burden
• CSF: low Aβ42, high tau, high p-tau (181)
• Blood biomarkers (2026): plasma p-tau217 now validated as highly accurate

Treatment

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4. Headache and Primary Headache Disorders

Classification (ICHD-3)

1. Primary headaches (no structural cause): migraine, tension-type, cluster, others
2. Secondary headaches: structural, vascular, infectious, metabolic cause
3. Cranial neuralgias

Migraine

• Cortical spreading depression (CSD) - wave of neuronal depolarization + depression → aura
• Trigeminovascular activation - trigeminal nerve innervates meningeal vessels → release of CGRP, substance P → neurogenic inflammation → pain
• Descending pain modulation failure

• Unilateral, pulsating, moderate-severe intensity
• Aggravated by routine physical activity
• Nausea/vomiting AND/OR photophobia + phonophobia
• Duration 4-72 hours
• With aura: visual (scintillating scotoma, fortification spectra), sensory, motor, language; 20-30 min before headache; fully reversible

• Mild: NSAIDs (ibuprofen, naproxen), acetaminophen
• Moderate-severe: Triptans (sumatriptan, rizatriptan) - 5-HT1B/1D agonists → vasoconstriction + inhibit CGRP release
• Severe/refractory: Gepants (ubrogepant, rimegepant) - CGRP receptor antagonists; Ditans (lasmiditan) - 5-HT1F agonist (no vasoconstriction); IV DHE, antiemetics (metoclopramide, prochlorperazine)

• Propranolol, metoprolol (1st line)
• Topiramate, valproate
• Amitriptyline (comorbid depression/sleep)
• Anti-CGRP monoclonal antibodies: erenumab, fremanezumab, galcanezumab (highly effective, monthly SC injections)
• Botulinum toxin type A (chronic migraine >15 days/month)

Tension-Type Headache (TTH)

• Most common headache type (lifetime prevalence ~80%)
• Bilateral, pressing/tightening (non-pulsating), mild-moderate, not aggravated by activity
• No nausea/vomiting; mild photophobia OR phonophobia (not both)
• Episodic vs. chronic (>15 days/month for >3 months)
• Treatment: NSAIDs, acetaminophen, amitriptyline for prevention

Cluster Headache

• Strictly unilateral orbital/periorbital, excruciating pain (worst headache)
• Duration 15-180 min; frequency 1-8/day during cluster period
• Ipsilateral autonomic features: lacrimation, nasal congestion, ptosis, miosis, conjunctival injection, eyelid edema (SUNCT, SUNA similar but shorter)
• Male predominance (3:1); smokers; alcohol trigger
• Circadian pattern (hypothalamic activation on PET)
• Acute: 100% O2 (7-12 L/min for 15 min), sumatriptan SC/nasal
• Prevention: verapamil (first choice), lithium, topiramate; short-term: prednisolone bridge; nerve block

Trigeminal Neuralgia

• Electric shock-like, brief (<2 sec), lancinating pain in trigeminal distribution (V2/V3 > V1)
• Trigger zones (eating, talking, touching face)
• Caused by vascular compression of trigeminal root (superior cerebellar artery)
• Treatment: carbamazepine (1st line), oxcarbazepine; microvascular decompression surgery

Medication Overuse Headache (MOH)

• 15 days/month headache in pt using analgesics/triptans >10-15 days/month for >3 months

• Withdrawal (detoxification) is the treatment; prophylactic started simultaneously

Secondary Headache - Red Flags (SNOOPY)

• Systemic symptoms/signs
• Neurological deficits
• Onset sudden ("thunderclap" - SAH until proven otherwise)
• Older (new headache >50 years)
• Pattern change
• Yield on imaging (papilledema, fever)

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🏥 GASTROENTEROLOGY

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5. Inflammatory Bowel Disease (IBD)

Overview

Pathophysiology

• Dysregulated immune response to gut microbiota in genetically susceptible individuals
• Key genes: NOD2/CARD15 (Crohn's), IL-23R, HLA associations
• Th1/Th17 dominance (CD); Th2 pattern (UC)
• Increased TNF-α, IL-6, IL-12, IL-23; defective mucosal barrier (mucin defects in UC)

Crohn's Disease vs. Ulcerative Colitis

Clinical Features

• Bloody diarrhea (cardinal feature), urgency, tenesmus
• Abdominal cramping, weight loss in severe disease
• Extraintestinal manifestations (see below)

• Abdominal pain (RLQ), diarrhea (may be non-bloody), weight loss
• Perianal disease (fissures, fistulae, abscesses)
• Fever, malabsorption (B12 in terminal ileum disease)
• "String sign" on barium follow-through

Extraintestinal Manifestations

Severity Scoring

• UC: Truelove-Witts criteria (mild/moderate/severe based on stool frequency, blood, fever, HR, Hb, ESR)
• CD: Harvey-Bradshaw index, CDAI (Crohn's Disease Activity Index)

Investigations

• CBC (anemia, leukocytosis), CRP, ESR, albumin
• Fecal calprotectin: excellent marker of intestinal inflammation; useful for monitoring
• p-ANCA (70% UC), ASCA (50-60% CD)
• Colonoscopy + biopsy: gold standard
• MRI enterography (CD): assesses transmural involvement, fistulae
• CT: complications (abscess, perforation)

Treatment

• Anti-TNF: Infliximab (IV), Adalimumab (SC), Certolizumab, Golimumab - both UC and CD
• Anti-integrin: Vedolizumab (natalizumab) - gut-selective, IBD-specific; fewer systemic immunosuppression risks
• Anti-IL-12/23: Ustekinumab - CD and UC
• JAK inhibitors: Tofacitinib, Upadacitinib - UC (small molecule, oral)
• Anti-IL-23: Risankizumab, Mirikizumab

• UC: Total proctocolectomy + IPAA (ileal pouch-anal anastomosis) = curative
• CD: Strictureplasty, resection of diseased bowel (not curative; recurrence common)

Complications

• Toxic megacolon: severe UC - colon >6 cm on X-ray; treat with IV steroids, antibiotics; if no improvement in 48-72h → emergency colectomy
• Colorectal cancer (surveillance colonoscopy after 8-10 years of extensive disease)
• Malabsorption (CD), gallstones, kidney stones (oxalate - in CD with ileal disease)

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🦠 INFECTIOUS DISEASE

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6. Fever with Hepatosplenomegaly

Differential Diagnosis

• Malaria (Plasmodium falciparum, vivax, malariae) - most common worldwide; cyclical fever, rigors, anemia, thrombocytopenia
• Visceral leishmaniasis (Kala-azar) - Leishmania donovani; prolonged fever, massive splenomegaly, pancytopenia, hypergammaglobulinemia; aldehyde test positive; treated with amphotericin B
• Typhoid (Salmonella Typhi) - stepladder fever, relative bradycardia, rose spots, splenomegaly; Widal test (rising titers), blood culture (gold standard)
• Brucellosis - undulant fever, sweating, arthralgia; contact with animals/unpasteurized dairy; brucella agglutinins
• Infectious mononucleosis (EBV) - fever, pharyngitis, lymphadenopathy, hepatosplenomegaly; heterophile antibodies (Monospot), atypical lymphocytes
• Viral hepatitis (HBV, HCV, CMV, EBV)
• Schistosomiasis - portal hypertension, splenomegaly; eosinophilia; Katayama fever
• Miliary tuberculosis - choroidal tubercles, pancytopenia
• HIV with opportunistic infections
• Leptospirosis - jaundice, renal failure (Weil's disease); Leptospira serology

• Hematological malignancy: leukemia, lymphoma, myelofibrosis
• Storage diseases: Gaucher's, Niemann-Pick
• Autoimmune: SLE, Still's disease
• Portal hypertension with infection

Approach

1. Travel history, animal exposure, blood transfusions, sexual history
2. Blood smear (malaria parasite), Widal, Weil-Felix, blood culture
3. Serology: EBV, CMV, brucella, leptospira, hepatitis panel
4. Bone marrow biopsy (if pancytopenia + unexplained fever)
5. Imaging: USG abdomen (size of liver/spleen, echogenicity), CT scan

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7. Pyrexia of Unknown Origin (PUO)

Definition (Petersdorf & Beeson, 1961 - modified)

• Fever >38.3°C on multiple occasions
• Duration >3 weeks
• No diagnosis after 3 outpatient visits or 3 days of hospital investigation

1. Classic PUO (community-acquired)
2. Nosocomial PUO (hospital-acquired, not present on admission)
3. Neutropenic PUO (ANC <500/μL)
4. HIV-associated PUO

Causes (Classic PUO)

Investigation Protocol

• CBC with differential, ESR, CRP, LFT, RFT, urine R/E, blood culture (×3), urine culture
• Chest X-ray, USG abdomen
• ANA, ANCA, RF, complement

• Serology: brucella, Widal, EBV, CMV, toxoplasma, HIV, hepatitis B/C
• Blood smear for malaria, Mantoux/IGRA (TB)
• CT chest/abdomen/pelvis with contrast

• PET-CT (most sensitive for lymphoma, vasculitis, occult infections)
• Echocardiography (endocarditis)
• Bone marrow biopsy (pancytopenia, lymphoma staging)
• Biopsy of lymph node or liver

Empiric therapy

• Avoid empiric antibiotics unless patient is deteriorating (may mask diagnosis)
• Exception: empiric anti-TB in endemic areas if high suspicion

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8. HIV Infection

Virology

• HIV-1 (global pandemic) and HIV-2 (West Africa, milder)
• Retrovirus: RNA genome → reverse transcriptase → DNA → integrates into host genome as provirus
• Targets: CD4+ T cells, macrophages, dendritic cells (CCR5 and CXCR4 co-receptors)

Transmission: sexual (unprotected intercourse), blood (IDU, transfusion), vertical (mother-to-child)

HIV Life Cycle

1. Attachment: gp120 to CD4 + CCR5/CXCR4 co-receptor
2. Fusion: gp41 mediates fusion
3. Reverse transcription: RNA → DNA (by reverse transcriptase)
4. Integration: integrase inserts viral DNA into host genome
5. Transcription, translation, assembly
6. Budding and maturation: protease cleaves polyproteins

Clinical Stages

• 2-6 weeks post-exposure
• Fever, pharyngitis, lymphadenopathy, rash (maculopapular), myalgia
• High viral load, CD4 transiently falls
• Resolves in 2-4 weeks; often misdiagnosed as EBV or flu

• Average 8-10 years without treatment
• May have persistent generalized lymphadenopathy (PGL)
• Ongoing viral replication, gradual CD4 decline

• CD4 <200 cells/μL OR AIDS-defining illness
• AIDS-defining illnesses (CDC Category C):
  • PCP (Pneumocystis jirovecii pneumonia) - most common in CD4 <200; bilateral interstitial infiltrates; LDH elevated; Rx: TMP-SMX
  • Toxoplasma encephalitis - ring-enhancing lesions, basal ganglia; CD4 <100; Rx: pyrimethamine + sulfadiazine
  • CMV retinitis - "pizza pie" fundus; CD4 <50; Rx: ganciclovir/valganciclovir
  • Cryptococcal meningitis - CD4 <100; India ink positive; high opening pressure; Rx: amphotericin B + flucytosine → fluconazole
  • Kaposi's sarcoma - HHV-8; violaceous skin/oral lesions
  • MAC (Mycobacterium avium complex) - CD4 <50; fever, weight loss, diarrhea, hepatosplenomegaly; Rx: clarithromycin + ethambutol ± rifabutin
  • Esophageal candidiasis
  • Wasting syndrome

Diagnosis

• ELISA (4th gen detects p24 Ag + HIV Ab): screen
• Western blot/immunoblot or HIV RNA PCR: confirm
• Window period: 2-6 weeks (p24 Ag); 3-12 weeks (Ab)
• CD4 count and HIV RNA viral load: staging and monitoring

ART (Antiretroviral Therapy)

• Dolutegravir: high barrier to resistance, excellent efficacy, once daily

• PrEP: TDF/FTC (Truvada) or TAF/FTC (Descovy) - for high-risk uninfected individuals
• PEP: within 72 hours of exposure; 28-day course; TDF+FTC+RAL or DTG

• CD4 <200: TMP-SMX (PCP + toxoplasma prophylaxis)
• CD4 <100: Fluconazole (cryptococcal)
• CD4 <50: Azithromycin (MAC); ganciclovir (CMV - selected patients)

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9. Sepsis

Definitions (Sepsis-3, 2016)

• Sepsis: life-threatening organ dysfunction caused by a dysregulated host response to infection
  • SOFA score increase ≥2 from baseline
• Septic shock: sepsis + vasopressor requirement to maintain MAP ≥65 mmHg + lactate >2 mmol/L despite adequate fluid resuscitation
• SIRS (older concept): 2 of - fever >38°C or <36°C, HR >90, RR >20, WBC >12,000 or <4,000

Pathophysiology

• Microbial PAMPs (LPS, peptidoglycan) → TLRs on immune cells → cytokine cascade (TNF-α, IL-1, IL-6)
• Systemic inflammatory response → endothelial damage → capillary leak → tissue hypoperfusion
• Coagulopathy: TF expression → DIC
• Mitochondrial dysfunction → cellular hypoxia even with adequate O2 delivery
• Adrenal insufficiency, GI barrier failure

Organ Dysfunction (SOFA Score Components)

Management ("Hour-1 Bundle" - Surviving Sepsis Campaign)

1. Measure lactate (resuscitation goal: lactate <2 mmol/L)
2. Obtain blood cultures (×2, before antibiotics)
3. Give broad-spectrum antibiotics
4. IV crystalloid 30 mL/kg for hypotension or lactate ≥4 mmol/L
5. Vasopressors if MAP <65 mmHg: norepinephrine (1st choice) → vasopressin (2nd) → epinephrine

• Community-acquired: Piperacillin-tazobactam ± vancomycin (if MRSA risk)
• Hospital-acquired: Carbapenem (meropenem/imipenem) ± vancomycin ± antifungal
• De-escalate within 48-72 hours based on cultures
• Duration: typically 7-10 days (4-5 days for good responders)

• Corticosteroids: Hydrocortisone 200 mg/day IV (if refractory septic shock despite fluids + vasopressors)
• Blood glucose control: target 140-180 mg/dL
• Lung-protective ventilation if ARDS: tidal volume 6 mL/kg, PEEP optimization
• Renal replacement therapy if severe AKI

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10. Meningitis

Classification

• Bacterial (pyogenic) - medical emergency
• Viral (aseptic) - usually self-limiting
• Tuberculous (chronic, subacute)
• Fungal (Cryptococcal - immunocompromised)
• Autoimmune/carcinomatous

Common Organisms

Clinical Features

• Classic triad: fever + headache + neck stiffness (present in only ~44% simultaneously)
• Photophobia, phonophobia
• Kernig's sign: unable to extend knee with hip flexed at 90°
• Brudzinski's sign: passive neck flexion → involuntary knee flexion
• Jolt accentuation: worsening headache on horizontal head rotation at 2-3 Hz (suggests meningeal irritation)
• Altered consciousness (indicates severity)
• Petechial/purpuric rash: N. meningitidis (meningococcemia) - medical emergency
• Papilledema (raised ICP)

CSF Analysis

When NOT to do LP first:

Bacterial Meningitis - Management

• Adults: Ceftriaxone 2g IV q12h + Vancomycin (if pneumococcal + penicillin resistance risk)
• Add Ampicillin if age >50 yr, pregnant, immunocompromised (Listeria coverage)
• Neonates: Ampicillin + Cefotaxime + Gentamicin

• Pneumococcus: Ceftriaxone, penicillin G (if sensitive)
• Meningococcus: Penicillin G or ceftriaxone; chemoprophylaxis contacts (rifampicin/ciprofloxacin/ceftriaxone single dose)
• TB: RHEZ (Rifampicin, INH, Ethambutol, Pyrazinamide) × 2 months; then RH × 7-10 months; add dexamethasone
• Cryptococcal: Amphotericin B + Flucytosine (2 weeks) → Fluconazole (consolidation/maintenance); therapeutic LPs for high pressure

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11. Infectious Disease - Key Chapters

Tuberculosis (TB)

• Mycobacterium tuberculosis; aerobic, slow-growing, acid-fast bacillus (Ziehl-Neelsen/auramine stain)
• Primary TB: Ghon focus (subpleural), Ghon complex (focus + hilar nodes), Ranke complex (calcified)
• Post-primary/reactivation TB: upper lobe cavitation, fibrosis; cough, hemoptysis, night sweats, weight loss
• Military TB: hematogenous spread → "millet seed" nodules on CXR
• Diagnosis: Mantoux (TST), IGRA (QuantiFERON-Gold), Sputum AFB smear + culture, GeneXpert MTB/RIF (rapid, PCR-based)
• Treatment - Standard: 2RHEZ + 4RH (Rifampicin, INH, Ethambutol, Pyrazinamide × 2 months; then RH × 4 months)
• Drug resistance: MDR-TB (resistant to R+H) → bedaquiline, linezolid, moxifloxacin; XDR-TB (also resistant to fluoroquinolones + injectables)
• Hepatotoxicity: INH, Rifampicin, Pyrazinamide; monitor LFTs

Typhoid Fever

• Salmonella enterica serovar Typhi (oral-fecal route)
• Stepladder fever, relative bradycardia, splenomegaly, rose spots (maculopapular, trunk)
• Widal test (rising agglutinin titers - O≥1:80 and H≥1:160 significant); Blood culture (gold standard, 1st week); Bone marrow culture (highest yield)
• Complications: intestinal perforation (ileal Peyer's patches), hemorrhage, hepatitis, myocarditis, meningism
• Treatment: Ceftriaxone or Ciprofloxacin or Azithromycin; Chloramphenicol (historical)

Malaria

• Plasmodium species: P. falciparum (most dangerous - cerebral malaria, blackwater fever), P. vivax, P. ovale, P. malariae, P. knowlesi
• Febrile paroxysms: P. vivax/ovale (48h - tertian), P. malariae (72h - quartan), P. falciparum (irregular)
• Diagnosis: Thick and thin blood smear, Rapid Diagnostic Tests (RDTs for PfHRP2), PCR
• Severe/complicated malaria (P. falciparum): cerebral malaria (coma), severe anemia (Hb <7), hypoglycemia, ARDS, AKI, DIC, hyperparasitemia (>5%)
• Treatment: Artemisinin-based combination therapy (ACT) - Artemether-lumefantrine for uncomplicated; IV artesunate for severe malaria
• P. vivax/ovale: add Primaquine (8-aminoquinoline) to eliminate hypnozoites (liver dormant stage); check G6PD first

Leptospirosis

• Leptospira interrogans; animal urine-contaminated water; occupational (farmers, sewage workers)
• Biphasic illness: septicemic phase (fever, myalgia, conjunctival suffusion) → immune phase (Weil's disease: jaundice, AKI, bleeding, myocarditis)
• Diagnosis: leptospira IgM ELISA, MAT (microscopic agglutination test - gold standard); blood culture (1st week), urine culture (2nd week)
• Treatment: Doxycycline (mild), IV Penicillin G/Ceftriaxone (severe Weil's disease)

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🫦 ENDOCRINOLOGY

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12. Disorders of Thyroid, Pituitary, Adrenal Cortex

THYROID DISORDERS

Hypothyroidism

Hyperthyroidism

• Beta-blockers (propranolol): for symptomatic relief
• Antithyroid drugs: Methimazole (carbimazole) or Propylthiouracil (PTU - preferred in 1st trimester, thyroid storm); block thyroid peroxidase; agranulocytosis (0.5%) - CBCs; PTU also blocks T4→T3 conversion
• Radioactive iodine (RAI, I-131): definitive; contraindicated in pregnancy; worsens GO
• Surgery: thyroidectomy; for large goiter, non-compliant, or failure of other treatments

Thyroid Storm (Thyrotoxic Crisis)

• Precipitants: surgery, infection, iodine load
• Burch-Wartofsky score >45 = thyroid storm
• Treatment: PTU → KI (Lugol's) → corticosteroids (block T4→T3, adrenal reserve) → propranolol → cholestyramine

Thyroid Cancer

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PITUITARY DISORDERS

Anterior Pituitary Hormones (GH, FSH, LH, TSH, ACTH, Prolactin - mnemonic: GF-LAP or GOFAST)

Hypopituitarism

• Causes: pituitary adenoma, Sheehan's syndrome (postpartum necrosis), craniopharyngioma, sarcoidosis, surgery/radiation
• Sequence of loss: GH first → Gonadotropins → TSH → ACTH (most life-threatening) → Prolactin (late)
• Sheehan's: failure to lactate postpartum, amenorrhea, adrenal crisis

Acromegaly

• GH excess from pituitary adenoma (usually macroadenoma) after fusion of epiphyses
• Clinical: Frontal bossing, prognathism, large hands/feet (ring size ↑), macroglossia, organomegaly, carpal tunnel, hypertension, diabetes, sleep apnea, colon polyps
• Diagnosis: IGF-1 elevated (screening); GH non-suppressed during OGTT (gold standard)
• Treatment: Transsphenoidal surgery (1st choice) → Somatostatin analogues (octreotide, lanreotide) → Dopamine agonists (cabergoline) → Pegvisomant (GH receptor antagonist) → Radiotherapy

Prolactinoma

• Most common functioning pituitary tumor
• Clinical: Women - amenorrhea, galactorrhea, infertility; Men - hypogonadism, erectile dysfunction (often macroadenoma with visual field loss)
• Diagnosis: Prolactin >200 ng/mL suggests macroprolactinoma; exclude hypothyroidism, drugs (haloperidol, metoclopramide, risperidone)
• Treatment: Dopamine agonists (cabergoline > bromocriptine) - 1st line even for macroadenomas; surgery if visual compromise or resistance

Diabetes Insipidus (DI)

• Central DI: ↓ADH secretion (post-neurosurgery, trauma, tumors, Langerhans cell histiocytosis)
• Nephrogenic DI: ADH resistance (lithium, hypercalcemia, hypokalemia, hereditary)
• Features: polydipsia, polyuria (low osmolality), hypernatremia if fluid not replaced
• Water deprivation test: urine fails to concentrate; ADH given → central responds (urine concentrates), nephrogenic does not
• Treatment: Central - Desmopressin (DDAVP); Nephrogenic - low-salt diet, thiazides, NSAIDs, amiloride (lithium-induced)

SIADH

• Cause: CNS disorders, lung disease (SCLC - ectopic ADH), drugs (carbamazepine, cyclophosphamide, SSRIs)
• Hyponatremia + low serum osmolality + inappropriately concentrated urine (U_osm >100, U_Na >40)
• Treatment: fluid restriction; hypertonic saline if severe/symptomatic; vaptans (tolvaptan) for SIADH

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ADRENAL CORTEX DISORDERS

Adrenal Cortex Anatomy

• Zona Glomerulosa: Aldosterone (mineralocorticoid) - RAA system
• Zona Fasciculata: Cortisol (glucocorticoid) - ACTH regulated
• Zona Reticularis: Androgens (DHEA-S)
• Mnemonic GFR - Salt, Sugar, Sex (from outer to inner)

Cushing's Syndrome (Hypercortisolism)

• Exogenous (most common): iatrogenic glucocorticoid use
• Cushing's disease (pituitary ACTH-secreting adenoma - 70% of endogenous)
• Ectopic ACTH (SCLC, carcinoid - 15%)
• Adrenal adenoma/carcinoma (15%)

• Central obesity, moon face, buffalo hump (supraclavicular + dorsocervical fat pads)
• Purple/violaceous striae (>1 cm wide - distinguishes from simple obesity)
• Proximal muscle weakness
• Hypertension, hyperglycemia, osteoporosis
• Thin skin, easy bruising, poor wound healing
• Hirsutism, acne, oligo/amenorrhea (adrenal androgen excess)
• Psychiatric: depression, psychosis, cognitive impairment
• Immunosuppression (lymphopenia, susceptibility to infections)

1. Screening: 24h urinary free cortisol (×2) OR overnight 1 mg DST (dexamethasone suppression test - cortisol should suppress to <1.8 μg/dL) OR late-night salivary cortisol
2. If confirmed: ACTH levels - if suppressed (<5 pg/mL) → ACTH-independent (adrenal); if elevated → ACTH-dependent
3. High-dose DST (8 mg): Cushing's disease suppresses by >50%; ectopic does not
4. CRH stimulation test: pituitary adenoma responds (↑ACTH, ↑cortisol); ectopic does not
5. Bilateral inferior petrosal sinus sampling (BIPSS): gold standard to distinguish pituitary from ectopic; IPS:peripheral ACTH ratio >2 basal, >3 post-CRH

• Cushing's disease: transsphenoidal surgery (1st); bilateral adrenalectomy if failed → Nelson's syndrome risk
• Adrenal adenoma: adrenalectomy
• Ectopic ACTH: treat primary tumor; if not resectable - steroidogenesis inhibitors (metyrapone, ketoconazole, mifepristone, osilodrostat)

Addison's Disease (Primary Adrenal Insufficiency)

• Weakness, fatigue, weight loss
• Hyperpigmentation (bronzing) - especially buccal mucosa, palmer creases, pressure areas (↑ ACTH → MSH-like effect on MC1R)
• Postural hypotension, nausea, vomiting, abdominal pain
• Salt craving (mineralocorticoid deficiency)

• Hyponatremia, hyperkalemia, hypoglycemia, eosinophilia
• Short Synacthen test: give 250 μg ACTH IM/IV → cortisol should rise to >18-20 μg/dL at 30 min; failure confirms adrenal insufficiency

• Precipitant: infection, surgery, trauma, steroid withdrawal
• Severe hypotension, vomiting, altered consciousness, hypoglycemia
• Management: IV Hydrocortisone 100 mg STAT → 200 mg/24h; IV normal saline 1L rapidly; glucose

• Hydrocortisone (15-20 mg/day in divided doses) + Fludrocortisone 0.1 mg/day (aldosterone replacement)
• Sick day rules: double dose during illness; medic-alert bracelet

Conn's Syndrome (Primary Hyperaldosteronism)

• Most common cause of secondary hypertension (up to 10% of hypertensives)
• Causes: bilateral adrenal hyperplasia (60-70%), aldosterone-producing adenoma (30-40%)
• Hypertension + hypokalemia (may be normokalemic) + low renin
• Screening: Aldosterone-to-Renin Ratio (ARR) >30 (with aldosterone >15 ng/dL)
• Confirmatory: Salt loading or fludrocortisone suppression (aldosterone non-suppressed)
• Subtype differentiation: CT adrenal; adrenal vein sampling (gold standard)
• Treatment: Adrenalectomy (adenoma); spironolactone/eplerenone (hyperplasia)

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13. DKA and HHS

Diabetic Ketoacidosis (DKA)

• Blood glucose >250 mg/dL (may be lower in euglycemic DKA)
• Ketones (serum/urine)
• pH <7.3 and/or bicarbonate <15 mEq/L

• Insulin deficiency + glucagon excess → hyperglycemia + lipolysis → free fatty acids → hepatic beta-oxidation → ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone)
• Osmotic diuresis → dehydration, electrolyte loss
• Anion gap metabolic acidosis

1. IV Fluids: 1L normal saline in 1st hour; then 250-500 mL/h; switch to 0.45% NaCl; switch to D5 when glucose <200-250 mg/dL
2. Insulin: Regular insulin 0.1 U/kg bolus → 0.1 U/kg/h infusion (or 0.14 U/kg/h without bolus); do NOT start until K+ >3.5 mEq/L; transition to SC when pH >7.3, AG normal, patient eating
3. Potassium: Repletion essential even if normal/high initially (total body depletion); replace if K+ <5.5 mEq/L when insulin started; target K+ 3.5-5.0
4. Bicarbonate: Only if pH <6.9 and cardiovascular compromise (controversial)
5. Phosphate: Replace if <1 mg/dL (especially with respiratory depression)

Hyperosmolar Hyperglycemic State (HHS)

• Glucose >600 mg/dL
• Serum osmolality >320 mOsm/kg
• No significant ketosis (small ketones acceptable)
• pH >7.3, bicarb >15

• Occurs in T2DM (usually older patients)
• More severe dehydration (5-10L fluid deficit vs 3-5L in DKA)
• Higher glucose, osmolality
• No acidosis
• Higher mortality (~20% vs 1-5% in DKA)
• Neurological features more prominent (seizures, focal deficits)

• Fluids: 1-2L NS over 1-2h; then depending on hemodynamics; slower rehydration (correct over 24-48h to avoid cerebral edema)
• Insulin: Start after initial fluids; lower doses needed; target glucose reduction 50-70 mg/dL/h
• Potassium: aggressive replacement
• Anticoagulation: heparin (high thrombotic risk due to hyperviscosity)

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14. Pheochromocytoma

Definition

Associations (Hereditary)

• MEN2A: pheochromocytoma + medullary thyroid carcinoma + hyperparathyroidism (RET mutation)
• MEN2B: pheo + medullary TC + mucosal neuromas + marfanoid habitus
• Von Hippel-Lindau (VHL): pheo + hemangioblastoma + clear cell RCC + pancreatic cysts
• Neurofibromatosis type 1 (NF1): pheo + café-au-lait spots + neurofibromas
• SDH mutations (SDHB, SDHC, SDHD): hereditary paraganglioma-pheochromocytoma syndrome; SDHB associated with malignancy

Clinical Features - "Spells"

• Hypertensive crises (episodic or sustained) - most common
• Classic triad: Headache + Palpitations + Diaphoresis (sweating) - episodic ("5 H's": Hypertension, Headache, Hyperhidrosis, Heart palpitations, pallor/anxiety)
• Pallor (not flushing), anxiety, tremor, weight loss
• Orthostatic hypotension after episode
• Paradoxical hypertension with beta-blockers (unopposed alpha)

Diagnosis

• Plasma free metanephrines (best - sensitivity >97%): normetanephrine + metanephrine
• 24-hour urinary metanephrines + catecholamines (epinephrine, norepinephrine, dopamine, VMA)
• Clonidine suppression test: if borderline plasma NE → clonidine 0.3 mg → normal suppresses, pheo does not

• CT adrenal (1st choice): large, heterogeneous, rich vascular lesion; >10 HU unenhanced (lipid-poor)
• MRI: T2 hyperintense ("lightbulb bright"); preferred in pregnancy, children, paraganglioma
• MIBG scan (metaiodobenzylguanidine, 123I): functional imaging; extra-adrenal/metastatic disease
• Ga-68 DOTATATE PET: superior to MIBG for SDH-related tumors

Preoperative Management (ESSENTIAL)

1. Alpha-blockade first (10-14 days before surgery): Phenoxybenzamine (irreversible, non-selective) or doxazosin/prazosin
2. Beta-blockade AFTER alpha-blockade (avoid before alpha - may precipitate hypertensive crisis due to unopposed alpha)
3. High-sodium diet + fluid loading (counteract alpha-blockade-induced hypotension)
4. Surgery: laparoscopic adrenalectomy (preferred); cortical-sparing for bilateral (MEN2)
5. Intraoperative crisis: Phentolamine (IV alpha-blocker) or nitroprusside; avoid dopamine

Malignant Pheochromocytoma

• No histological criteria to define malignancy - only metastasis confirms malignancy
• Preferred site: bone, liver, lung, lymph nodes
• Treatment: ¹³¹I-MIBG therapy (high-dose), Lutetium-177 DOTATATE, sunitinib, CVD chemotherapy (cyclophosphamide + vincristine + dacarbazine)

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15. Dyspnoea Grading Scales

1. MRC (Medical Research Council) Dyspnea Scale

2. Modified MRC (mMRC) Scale - same as MRC 0-4

3. NYHA (New York Heart Association) - Heart Failure

4. GOLD Classification (COPD) - Spirometric

• GOLD 1: FEV1 ≥80% predicted (mild)
• GOLD 2: FEV1 50-79% (moderate)
• GOLD 3: FEV1 30-49% (severe)
• GOLD 4: FEV1 <30% (very severe)

5. BORG Scale (Perceived Exertion/Breathlessness)

6. WHO Functional Classification (Pulmonary Hypertension) - similar to NYHA

7. MMRC and CAT (COPD Assessment Test) in GOLD ABCD Assessment

• A: Low symptoms (mMRC 0-1, CAT <10) + low risk (GOLD 1-2, 0-1 exacerbations)
• B: High symptoms (mMRC ≥2, CAT ≥10) + low risk
• E (formerly C+D): ≥2 exacerbations or ≥1 hospitalization (high risk)

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🫘 NEPHROLOGY

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16. Acute and Chronic Kidney Injury

Acute Kidney Injury (AKI)

• ↑ Serum creatinine ≥0.3 mg/dL within 48h
• ↑ Serum creatinine ≥1.5× baseline within 7 days
• Urine output <0.5 mL/kg/h for ≥6h

• Hypovolemia (bleeding, dehydration, GI losses)
• Decreased CO (CHF, sepsis)
• Renal artery stenosis, NSAIDs/ACEi in bilateral RAS
• Hepatorenal syndrome
• FeNa <1% (kidney retains sodium to restore volume)

• ATN (acute tubular necrosis): most common; ischemic (prolonged pre-renal) or nephrotoxic (aminoglycosides, contrast, myoglobin)
• Glomerulonephritis (rapidly progressive GN, IgA nephropathy)
• Interstitial nephritis (drugs - NSAIDs, penicillins; infections - leptospirosis)
• Vascular: thrombotic microangiopathy (TTP/HUS), renal vein thrombosis
• FeNa >2%, muddy brown casts in ATN

• Obstruction: BPH, stones, bladder cancer, cervical cancer, retroperitoneal fibrosis
• Hydronephrosis on ultrasound
• Relieve obstruction (foley catheter, nephrostomy)

• Urine dipstick, U/A with microscopy, spot urine Na/Cr, FeNa
• USG kidneys (size, echogenicity, hydronephrosis)
• Serology if GN suspected: ANA, ANCA (pauci-immune GN - Wegener's/MPA), anti-GBM (Goodpasture), complement, ASO

• Acidosis (severe, pH <7.1)
• Electrolytes (hyperkalemia refractory to medical treatment)
• Intoxication (lithium, salicylates, methanol, ethylene glycol)
• Overload (fluid overload unresponsive to diuretics)
• Uremia (pericarditis, encephalopathy, bleeding diathesis - BUN >100 mg/dL)

Chronic Kidney Disease (CKD)

• Anemia: EPO deficiency → normocytic, normochromic; treat with ESA (erythropoiesis-stimulating agents - epoetin, darbepoetin) + IV iron (target Hb 10-12 g/dL)
• CKD-MBD: ↓ activated vitamin D → ↓ Ca absorption → ↑ PTH (secondary hyperparathyroidism) → osteitis fibrosa cystica; hyperphosphatemia; calcification; treat with phosphate binders, activated vit D, calcimimetics (cinacalcet)
• Cardiovascular: leading cause of death in CKD; hypertension, LVH, accelerated atherosclerosis
• Fluid/electrolyte: hyperkalemia, metabolic acidosis, hyponatremia
• Uremia: nausea, pericarditis, encephalopathy, platelet dysfunction (bleeding), uremic frost
• Hypertension: ACEi or ARB (reduce proteinuria + slow progression) - preferred
• GI: nausea, anorexia, peptic disease

• Hemodialysis (HD): 3×/week; AV fistula preferred access
• Peritoneal dialysis (PD): continuous (CAPD) or cycler-assisted
• Renal transplantation: best outcomes; HLA matching; immunosuppression (tacrolimus + MMF + prednisolone)

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🩸 HEMATOLOGY

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17. Anemias

Iron Deficiency Anemia (IDA)

• Iron stores depleted → bone marrow iron depleted → microcytic hypochromic anemia
• Stages: pre-latent (stores ↓) → latent (serum iron ↓, TIBC ↑) → IDA (Hb ↓)

• General: pallor, fatigue, exertional dyspnea, palpitations
• Specific: Pica (craving dirt/ice), Koilonychia (spoon nails), Angular cheilitis, Glossitis, Dysphagia (Plummer-Vinson/Paterson-Kelly syndrome - upper esophageal web + IDA + achlorhydria → risk of postcricoid carcinoma)

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Vitamin B12 Deficiency

• Pernicious anemia (most common in developed world): autoimmune gastritis → intrinsic factor deficiency → B12 malabsorption; anti-IF antibody (specific, 50-70%); anti-parietal cell antibody (sensitive, 80-90%)
• Dietary (strict vegans)
• Gastrectomy, ileal resection, Crohn's ileitis
• Fish tapeworm (Diphyllobothrium latum)
• Metformin use (reduces IF/ileal absorption)

• Posterior columns (vibration, proprioception loss - hands before feet) + lateral corticospinal tracts (weakness, spasticity, hyperreflexia + extensor plantars)
• Peripheral neuropathy (glove-stocking)
• Cognitive impairment
• B12 deficiency can cause neuro without anemia; folate deficiency does NOT cause SACD

• Serum B12 <200 pg/mL
• ↑ Serum methylmalonic acid + ↑ homocysteine (both elevated in B12 deficiency; only homocysteine elevated in folate deficiency)
• Schilling test (historical): measures B12 absorption with/without IF

• IM Hydroxocobalamin (1 mg IM): 6 doses over 2 weeks (loading) → 1 mg IM every 3 months (if malabsorption - pernicious anemia)
• Oral high-dose B12 (1000 μg/day) effective if dietary deficiency or no malabsorption

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Hemolytic Anemias

• Intrinsic (intracorpuscular defects): hereditary - membranopathies, enzymopathies, hemoglobinopathies
• Extrinsic (extracorpuscular): immune, non-immune

• Jaundice (unconjugated bilirubin ↑)
• Splenomegaly
• Reticulocytosis
• ↑ LDH, ↓ haptoglobin (binds free Hb → consumed)
• ↑ Urinary urobilinogen
• Hemoglobinuria + hemoglobinemia (intravascular hemolysis)

• Intravascular: complement-mediated, mechanical (prosthetic valves); hemoglobinemia, hemoglobinuria, hemosiderinuria; PNH, G6PD crisis, TTP
• Extravascular: splenic macrophage destruction; spherocytes, spherocytosis, immune HA

Hereditary Spherocytosis (HS)

• Most common hereditary hemolytic anemia in Northern Europeans
• Mutations in spectrin, ankyrin, band 3 → RBC membrane instability → spherocyte formation → splenic destruction
• Autosomal dominant (75%)
• Features: hemolytic anemia + jaundice + splenomegaly; aplastic crisis (Parvovirus B19)
• Blood film: spherocytes (no central pallor), ↑ MCHC
• EMA binding test (eosin-5-maleimide) - gold standard diagnostic
• Osmotic fragility test: ↑ fragility
• Treatment: Folic acid supplementation; splenectomy (curative - RBCs still spherocytic but survive longer); vaccinate before splenectomy (meningococcal, pneumococcal, Hib)

G6PD Deficiency

• X-linked recessive (G6PD gene on X chromosome)
• G6PD enzyme protects RBCs from oxidative stress by generating NADPH (glutathione pathway)
• Triggers for hemolytic episodes: oxidant drugs (primaquine, dapsone, nitrofurantoin, rasburicase), infections, fava beans (broad beans)
• Blood film during crisis: bite cells (Heinz body removal by spleen), Heinz bodies (denatured Hb, seen on crystal violet stain)
• Diagnosis: G6PD enzyme assay (do NOT test during crisis - reticulocytes have higher enzyme activity → false normal)

Sickle Cell Disease (SCD)

• Beta-globin gene mutation: Glu→Val at position 6 → HbS (alpha2 beta2-S)
• HbSS = sickle cell anemia; HbSC, HbS/beta-thalassemia = variants
• Sickling under hypoxia, acidosis, dehydration → vaso-occlusion → ischemia

• Vaso-occlusive crisis (pain crisis): most common; treat with fluids, analgesia (NSAIDs, opioids), oxygen
• Acute chest syndrome (ACS): fever + respiratory symptoms + pulmonary infiltrates; exchange transfusion + antibiotics
• Stroke (young patients, hemorrhagic and ischemic)
• Splenic sequestration: splenomegaly + acute anemia; transfusion
• Aplastic crisis: Parvovirus B19; transfusion
• Priapism: painful erection; urological emergency

• Hydroxyurea: increases HbF → dilutes HbS → reduces sickling; reduces hospitalizations by 50%
• Chronic transfusion: stroke prevention (TCD velocity >200 cm/s)
• Voxelotor (HbS polymerization inhibitor), Crizanlizumab (anti-P-selectin)
• Gene therapy/editing (curative): LentiGlobin, CRISPR-Cas9 (CTX001/exa-cel) - approved 2023

Autoimmune Hemolytic Anemia (AIHA)

• Warm AIHA (IgG): most common; SLE, CLL, lymphoma, drugs (methyldopa, penicillin); splenic destruction; DAT (direct antiglobulin test/Coombs) positive (IgG); treat with steroids, rituximab, splenectomy
• Cold AIHA (IgM): Mycoplasma pneumoniae, EBV (cold agglutinin disease); complement-mediated intravascular hemolysis; acrocyanosis in cold; avoid cold; rituximab; do NOT give steroids

Thalassemia

• Quantitative reduction in globin chain synthesis

• 1 gene deletion: silent carrier
• 2 gene deletions: alpha-thal trait (mild microcytic anemia)
• 3 gene deletions: HbH disease (beta4 tetramers; moderate hemolysis)
• 4 gene deletions: Hb Bart's hydrops fetalis (incompatible with life - gamma4 tetramers)

• Beta-thal minor (trait): one abnormal allele; mild microcytic anemia, raised HbA2 (>3.5%)
• Beta-thal major (Cooley's anemia): both alleles abnormal; severe hemolytic anemia, transfusion-dependent; chipmunk facies (frontal bossing, maxillary hyperplasia), hepatosplenomegaly, iron overload; treatment: regular transfusions + chelation (deferoxamine, deferasirox, deferiprone) + HCT (curative)
• Beta-thal intermedia: intermediate severity; transfusion occasionally needed

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Aplastic Anemia

• Idiopathic/autoimmune (most common ~70%): T-cell mediated destruction of HSCs
• Drugs: chloramphenicol (classic), benzene, NSAIDs, carbamazepine, gold
• Viral: Hepatitis (non-A, non-B, non-C), EBV, CMV, Parvovirus B19
• PNH (paroxysmal nocturnal hemoglobinuria) - clonal, associated with aplastic anemia
• Radiation
• Constitutional: Fanconi's anemia (FA), Diamond-Blackfan (pure red cell aplasia)

• Anemia (pallor, fatigue), Infections (neutropenia), Bleeding (thrombocytopenia)

• CBC: pancytopenia
• Blood film: no abnormal cells; normocytic normochromic anemia
• Bone marrow biopsy: hypocellular marrow with fat replacement (<25% cellularity in severe)
• Exclude: PNH (flow cytometry - CD55/CD59 deficiency), cytogenetics (Fanconi's), viral serology

• Severe AA (SAA): BM cellularity <25% + 2 of 3: ANC <500, Platelets <20,000, Reticulocytes <20,000 (or <1%)
• Very severe: ANC <200
• Moderate: not meeting SAA criteria

• Age <40 + matched sibling donor: Allogeneic HSCT (curative; 1st line)
• Age >40 OR no matched donor: Immunosuppressive therapy (IST): Anti-thymocyte globulin (ATG) - horse or rabbit + Cyclosporine + Eltrombopag (TPO agonist - stimulates residual HSCs); overall response ~75%
• Supportive: RBC/platelet transfusions, G-CSF for neutropenic infections, iron chelation
• PNH clone: anticomplement therapy (eculizumab/ravulizumab)

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18. Hodgkin's and Non-Hodgkin's Lymphoma

Hodgkin's Lymphoma (HL)

1. Nodular Sclerosis (~65-70%): most common; collagen bands dividing lymph node; mediastinal mass (young women)
2. Mixed Cellularity (~25%): more RS cells; elderly; EBV strongly associated
3. Lymphocyte-Rich: best prognosis; RS cells rare
4. Lymphocyte-Depleted: worst prognosis; many RS cells; AIDS patients
5. Nodular lymphocyte-predominant HL (NLPHL): LP cells ("popcorn cells"); CD20+, CD15-, CD30-; late relapses but excellent prognosis

• Painless, rubbery cervical/supraclavicular lymphadenopathy (most common presentation)
• Mediastinal mass: SVC obstruction, dry cough
• B symptoms (systemic): fever (Pel-Ebstein - cyclical), night sweats, >10% weight loss in 6 months
• Alcohol-induced pain (characteristic of HL): pain at lymph node sites after drinking alcohol
• Pruritus (generalized)
• Splenomegaly

• Excisional lymph node biopsy (gold standard)
• CT chest/abdomen/pelvis, PET-CT (preferred for staging and response)
• Bone marrow biopsy (if advanced stage)
• CBC, ESR, LDH, albumin, uric acid

• Early stage (I-II, favorable): ABVD ×2 cycles + involved-field radiation (or 4 cycles ABVD if no radiation)
• Early stage (I-II, unfavorable/bulky): ABVD ×4 cycles + consolidative radiation
• Advanced stage (III-IV): ABVD ×6 cycles OR BEACOPPescalated (higher response, more toxicity)
• ABVD = Adriamycin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine
• Relapsed/refractory: Brentuximab vedotin (anti-CD30 ADC) + bendamustine; autologous HSCT; pembrolizumab/nivolumab (anti-PD-1 - CD30+ RS cells express PD-L1)
• PET-adapted therapy now standard (interim PET guides escalation/de-escalation)

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Non-Hodgkin's Lymphoma (NHL)

• B-cell lymphomas (~85%)
• T-cell/NK-cell lymphomas (~15%)
• Indolent vs. Aggressive

Key Indolent B-cell Lymphomas

• 2nd most common NHL; t(14;18) translocation → BCL-2 overexpression → anti-apoptosis
• Follicular pattern; CD20+, CD10+, BCL-2+, BCL-6+
• Indolent; responds to treatment but relapses; transformation to DLBCL possible (~30% at 10 years)
• Treatment: Watch and wait (if asymptomatic, low burden) → R-CHOP or obinutuzumab-CHOP; lenalidomide + rituximab; autologous HSCT; CAR-T

• Tissue phase of CLL; same biology (CD5+, CD23+)

• Gastric MALT: H. pylori driven; localized → H. pylori eradication alone can cure (stage I-II)
• t(11;18) translocation = H. pylori-independent; requires chemo

Key Aggressive B-cell Lymphomas

• Most common NHL (25-30%)
• Aggressive but potentially curable
• Germinal center (GCB subtype - better prognosis) vs. Non-GCB/Activated B-cell (ABC) by Hans algorithm
• Treatment: R-CHOP ×6 cycles (Rituximab + Cyclophosphamide + Hydroxydaunorubicin + Oncovin/vincristine + Prednisone)
• Cure rate ~60-70% with R-CHOP
• Relapsed/refractory: R-ICE/R-DHAP → autologous HSCT; CAR-T cells (axicabtagene ciloleucel, tisagenlecleucel) for relapsed after ≥2 lines
• Polatuzumab vedotin + R-CHP replacing CHOP in some centers

• High-grade; c-MYC translocation: t(8;14) [also t(8;2), t(8;22)]
• CD20+, CD10+, BCL-6+, BCL-2 negative, Ki-67 ~100%
• Starry-sky pattern (tingible body macrophages)
• Types: Endemic (African - jaw/facial bone, EBV related), Sporadic (abdominal), HIV-related
• Treatment: Intensive chemotherapy (R-CODOX-M/IVAC, DA-EPOCH-R); tumor lysis syndrome prevention

• t(11;14) → Cyclin D1 overexpression; CD5+, CD23-, Cyclin D1+
• Aggressive despite follicular pattern; GI involvement (lymphomatous polyposis)
• Treatment: R-CHOP → autologous HSCT; ibrutinib (BTK inhibitor) for relapsed

• DLBCL in brain; periventricular, ring-enhancing; common in HIV (EBV related) and immunosuppressed
• Treatment: High-dose methotrexate-based chemotherapy; avoid WBRT initially

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19. Multiple Myeloma (MM)

• Clonal plasma cells produce M-protein (monoclonal immunoglobulin - IgG>IgA>IgD>IgE; or light chains only = Bence Jones)
• Plasma cells secrete IL-6 (survival signal), RANK-L (osteoclast activation → bone disease), DKK1 (Wnt inhibitor → impaired osteoblast), VEGF

Diagnostic Criteria

• Calcium: serum Ca >11 mg/dL (or >1 mg/dL above ULN)
• Renal: creatinine >2 mg/dL (or CrCl <40 mL/min)
• Anemia: Hb <10 g/dL (or >2 g/dL below LLN)
• Bone: ≥1 lytic lesion or osteoporosis with fracture

• Sixty percent: clonal PCs ≥60%
• Light chain ratio: involved/uninvolved free light chain ratio ≥100
• MRI: >1 focal lesion on MRI (≥5 mm)

Clinical Features

• Bone pain (most common - backache, pathological fractures, vertebral compression)
• Anemia (normocytic normochromic)
• Hypercalcemia: constipation, nausea, polyuria, confusion, bone pain
• Renal failure: myeloma cast nephropathy (light chains + Tamm-Horsfall → tubular plugging), amyloidosis, hypercalcemia
• Recurrent infections: immunoparesis (↓ normal immunoglobulins), neutropenia, impaired opsonization
• Hyperviscosity syndrome: (IgA/IgM > IgG); headache, visual disturbances, mucosal bleeding, confusion → plasmapheresis urgently
• Peripheral neuropathy: amyloid or thalidomide-induced
• POEMS syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes

Investigations

• Serum and urine protein electrophoresis (SPEP/UPEP): M-spike
• Serum free light chains (kFLC, λFLC): ratio >100 = myeloma-defining
• Immunofixation electrophoresis: identifies heavy + light chain class
• BM biopsy + aspirate: ≥10% clonal plasma cells; CD38+, CD138+, CD19-, CD45-
• Whole-body MRI (preferred) or PET-CT or skeletal survey (X-ray: "punched out" lytic lesions - rain-drop skull)
• Beta-2 microglobulin, albumin, LDH (ISS staging)

• Stage I: β2M <3.5 mg/L + albumin ≥3.5 g/dL + no high-risk cytogenetics + LDH normal
• Stage II: Neither I nor III
• Stage III: β2M ≥5.5 mg/L + high-risk cytogenetics [t(4;14), t(14;16), del(17p)] or LDH elevated

Treatment

1. Induction: VRd (Bortezomib + Lenalidomide + Dexamethasone) × 4-6 cycles; or DRd (Daratumumab + Rd)
2. Autologous HSCT (melphalan conditioning) → deepens response
3. Maintenance: Lenalidomide until progression

• DRd (Daratumumab + Lenalidomide + Dexamethasone) - current standard
• VMP, Rd regimens

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20. Leukemias

CML (Chronic Myeloid Leukemia)

• Chronic phase (~85% at diagnosis): myeloid proliferation, splenomegaly, low-grade symptoms; duration ~3-6 years untreated
• Accelerated phase: blast 10-19%, basophils ≥20%, thrombocytopenia/thrombocytosis, cytogenetic evolution
• Blast crisis: blasts ≥20% (myeloid 70%, lymphoid 30%); behaves like AML/ALL; poor prognosis

• Often incidental (WBC >100,000/μL), splenomegaly (massive), leukostasis
• Hyperviscosity, leukocyte count can cause blurred vision, priapism

• TKIs (Tyrosine Kinase Inhibitors) - first-line: Imatinib (gleevec, 1st gen); Dasatinib, Nilotinib (2nd gen); Ponatinib (3rd gen, for T315I mutation)
• Response monitoring: BCR-ABL1 PCR every 3 months (target: major molecular response - MMR 0.1%)
• Treatment-free remission (TFR): discontinue TKI after deep molecular response ≥2 years (30-40% maintain remission)
• Allogeneic HSCT: reserved for blast crisis, TKI failure, T315I with ponatinib failure

AML (Acute Myeloid Leukemia)

• t(15;17) → PML-RARα → arrest at promyelocyte stage
• DIC is hallmark (release of procoagulant granules) → life-threatening hemorrhage
• Characteristic: Faggot cells (bundles of Auer rods)
• Treatment: ATRA (all-trans retinoic acid) + ATO (arsenic trioxide) - no chemotherapy needed for low-risk; highly curative (~90%)

• Induction: "7+3" regimen (cytarabine 7 days + daunorubicin/idarubicin 3 days)
• Response: complete remission (CR) = blasts <5%, ANC >1000, Plt >100,000
• Consolidation: high-dose cytarabine (HiDAC) OR allogeneic HSCT (for adverse/intermediate risk with donor)
• Venetoclax (BCL-2 inhibitor) + azacitidine: for older/unfit patients (VIALE-A trial)
• Midostaurin (FLT3 inhibitor): added to 7+3 for FLT3+ AML

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CLL (Chronic Lymphocytic Leukemia)

• Most asymptomatic (incidental lymphocytosis)
• Lymphadenopathy, splenomegaly, hepatomegaly
• B symptoms (fatigue, fever, weight loss)
• Infections (hypogammaglobulinemia - immunoparesis)
• Autoimmune hemolytic anemia (AIHA) - Coombs positive (10-25%)
• Autoimmune thrombocytopenia (ITP)

• Rai 0 (low risk): watch and wait
• Symptomatic disease: BTK inhibitors - Ibrutinib or Acalabrutinib (1st gen/2nd gen BTKi); Venetoclax + Obinutuzumab (BCL-2 + anti-CD20); FCR (fludarabine + cyclophosphamide + rituximab - fit patients with mutated IGHV)
• Richter's transformation: CLL → DLBCL (aggressive); poor prognosis; R-CHOP + allo-HSCT
• Allogeneic HSCT: selected high-risk young patients

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ALL (Acute Lymphoblastic Leukemia)

• B-ALL (85%): CD19+, CD10+, TdT+; Philadelphia chromosome positive (25% of adult B-ALL) → worst prognosis
• T-ALL (15%): CD3+, CD7+, TdT+; mediastinal mass common; adolescent males; CNS involvement

• Age 1-9 years
• WBC <50,000/μL
• ETV6-RUNX1 t(12;21) - most common translocation in ALL
• Down syndrome (trisomy 21)

• Age <1 yr (infant ALL - KMT2A rearrangement) or >10 yr
• WBC >100,000
• Philadelphia chromosome t(9;22)
• CNS involvement at diagnosis
• T-ALL

1. Induction (~4 weeks): Vincristine + Dexamethasone + Asparaginase ± Anthracycline; achieve CR
2. CNS prophylaxis (intrathecal MTX ± cranial radiation - now mostly IT chemo)
3. Consolidation (high-dose MTX, cytarabine)
4. Maintenance (~2-3 years): oral 6-mercaptopurine + weekly methotrexate

• Ph+ ALL: TKI (dasatinib/ponatinib) added to chemotherapy backbone
• Blinatumomab (BiTE antibody - anti-CD19×CD3) - impressive in R/R B-ALL; now frontline
• Inotuzumab ozogamicin (anti-CD22 ADC) for R/R
• CAR-T cells (tisagenlecleucel): B-ALL patients ≤25 years; remarkable responses

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21. Myeloproliferative Disorders (MPD)

Classic Myeloproliferative Neoplasms (MPN)

• JAK2 V617F (point mutation chr 9): present in PV (95-99%), ET (50-60%), PMF (50-60%)
• CALR (calreticulin exon 9 insertion/deletion): ET (25-30%), PMF (25-35%)
• MPL (thrombopoietin receptor W515L/K): ET (3-5%), PMF (5-10%)

Polycythemia Vera (PV)

• Elevated RBC mass + JAK2 V617F mutation
• WHO 2022: Hb >16.5 g/dL (M) or >16.0 (F) + BM biopsy + JAK2 V617F

• Aquagenic pruritus (after hot bath - histamine release from basophils) - pathognomonic
• Facial plethora, splenomegaly, hypertension
• Thrombosis (arterial > venous - DVT, Budd-Chiari, portal vein thrombosis, stroke, MI)
• Elevated Hb, Hct, WBC, platelets

• Phlebotomy (target Hct <45%): reduce thrombotic risk
• Low-dose aspirin (81 mg): all patients
• Cytoreduction (if high risk - age >60 or prior thrombosis): Hydroxyurea (1st line); Ruxolitinib (JAK1/2 inhibitor - for resistant/intolerant)
• Interferon-alpha: preferred in young/pregnant patients

Essential Thrombocythemia (ET)

• Platelet count persistently >450,000/μL
• JAK2, CALR, or MPL mutation (80-90% of cases)
• Exclude other causes

• Headache, visual disturbances, erythromelalgia (burning pain in hands/feet with erythema - platelet-mediated)
• Thrombosis (arterial + venous), paradoxical bleeding (acquired VWD with very high platelets)
• Microcirculatory symptoms

• Low risk: age <60, no thrombosis, JAK2 wildtype
• High risk: age ≥60 OR prior thrombosis
• Intermediate: age ≥60 OR JAK2+ without prior thrombosis

• Low risk: observe ± aspirin
• High risk: Hydroxyurea + aspirin; Anagrelide (reduces platelet production, MAPK pathway); Interferon; Ruxolitinib (2nd line)

Primary Myelofibrosis (PMF)

• Bone marrow fibrosis (reticulin → collagen) → marrow failure → extramedullary hematopoiesis (liver, spleen)
• Massive splenomegaly (often with left-sided symptoms, early satiety)

• Constitutional symptoms: fever, night sweats, weight loss
• Leukoerythroblastic blood picture: myelocytes, metamyelocytes + nucleated RBCs
• Tear-drop cells (dacrocytes) on blood film - pathognomonic of marrow fibrosis
• Anemia, thrombocytopenia (late)

• BM biopsy: reticulin/collagen fibrosis + atypical megakaryocytes
• JAK2/CALR/MPL mutation
• Splenomegaly + leukoerythroblastic blood picture

• Symptomatic: Ruxolitinib (JAK1/2 inhibitor) - reduces spleen size, improves constitutional symptoms + survival
• Allogeneic HSCT: only curative option (high-risk disease)
• Hydroxyurea for high counts; Danazol/thalidomide/lenalidomide for anemia

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22. Von Willebrand Disease and Hemophilia

Von Willebrand Disease (VWD)

1. Primary hemostasis: mediates platelet adhesion to subendothelial collagen (via GP1b-α on platelets)
2. Carrier protein for Factor VIII: protects FVIII from proteolytic degradation

• Prolonged bleeding time (or PFA-100)
• aPTT prolonged (if FVIII very low, e.g., type 2N, 3)
• PT normal
• ↓ VWF:Ag (ELISA), ↓ VWF:RCo (ristocetin cofactor activity - functional)
• Ristocetin-induced platelet aggregation (RIPA): ↓ in most types; ↑ at low doses in type 2B
• VWF multimer analysis: distinguishes subtypes

• DDAVP (Desmopressin): releases VWF from Weibel-Palade bodies (endothelial storage) → increases VWF 3-5x; works for type 1 (most responsive), some type 2; CONTRAINDICATED in type 2B (may worsen thrombocytopenia)
• VWF/FVIII concentrates (e.g., Humate-P, Wilate): for type 3, type 2B, surgery/major bleeding, DDAVP failures
• Recombinant VWF (Vonicog alfa): approved; for type 3
• Antifibrinolytics (tranexamic acid, epsilon-aminocaproic acid): adjunctive for mucosal bleeding (menorrhagia, dental)
• Hormonal therapy (combined OCP): for menorrhagia in type 1

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Hemophilia

• Hemophilia A: FVIII deficiency (most common, 1:5000 males)
• Hemophilia B: FIX deficiency (Christmas disease, 1:30,000 males)
• Both X-linked recessive; females are carriers (50% FVIII/FIX activity); rarely symptomatic

Factor Levels and Severity:

• Hemarthroses (joint bleeding) - most common: knee, elbow, ankle; warm, swollen joint; repeated → hemophilic arthropathy (joint destruction, fixed contractures)
• Muscle hematomas: iliopsoas (groin pain, hip flexion) - can compress femoral nerve
• Life-threatening: intracranial hemorrhage (any head trauma), retroperitoneal, GI
• Mucocutaneous bleeding: less common (platelet function normal)

• Prolonged aPTT (intrinsic pathway - FVIII or FIX involved); PT normal, BT normal, Platelets normal
• Mixing study: aPTT corrects with normal plasma = factor deficiency (vs. inhibitor where it doesn't correct)
• Factor VIII assay (hemophilia A), Factor IX assay (hemophilia B)

• Hemophilia A: Recombinant FVIII concentrates (Advate, Kogenate, Eloctate); plasma-derived FVIII/VWF (for VWD+hemophilia A)
• Hemophilia B: Recombinant FIX concentrates (BeneFIX, Rixubis, Alprolix)
• DDAVP (desmopressin): mild hemophilia A only (raises FVIII 3-5x temporarily); NOT in hemophilia B

• Emicizumab (Hemlibra): bispecific antibody mimicking FVIIIa function (bridges FIXa and FX); subcutaneous weekly/biweekly/monthly; works regardless of FVIII inhibitors; GAME-CHANGER
• Fitusiran (anti-antithrombin): siRNA → reduces antithrombin → restores hemostasis
• Concizumab (anti-TFPI)

• Valoctocogene roxaparvovec (Roctavian, FDA approved 2023): AAV5 gene therapy for hemophilia A; single IV infusion; sustained FVIII expression
• Etranacogene dezaparvovec (Hemgenix): gene therapy for hemophilia B; FIX Padua variant

• Develop in ~30% of severe hemophilia A (rare in B)
• Low-titer (<5 BU/mL): increase FVIII dose; High-titer (≥5 BU): bypassing agents needed
• Bypassing agents: rFVIIa (NovoSeven) OR aPCC (FEIBA - activated prothrombin complex concentrate)
• Immune tolerance induction (ITI): high-dose FVIII daily to eradicate inhibitors
• Emicizumab: works even with inhibitors (doesn't use FVIII pathway)

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Summary Tables

Mnemonic Reference

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