TUBERCULOSIS - A Complete MBBS First Year Account

For AIT (Answer-in-Time) Questions in Anatomy, Physiology & Biochemistry

OVERVIEW / INTRODUCTION

PART I - BIOCHEMISTRY PERSPECTIVE

1. The Organism - Mycobacterium tuberculosis

2. The Biochemistry of the Cell Wall (Most Important Biochemistry Topic)

1. Cytoplasmic membrane - standard phospholipid bilayer
2. Peptidoglycan layer - linked to arabinogalactan by a phosphodiester bond
3. Arabinogalactan - a complex polysaccharide covalently linked to peptidoglycan
4. Mycolic acids (most important!) - very long-chain (C70-C90) branched fatty acids, esterified to arabinogalactan. These are unique to mycobacteria and related genera.
5. Free lipids in the outer layer:
   • Cord factor (trehalose dimycolate) - causes serpentine "cord-like" growth in culture, inhibits neutrophil migration, toxic to mitochondria
   • Phthiocerol dimycocerosate (PDIM) - contributes to phagosomal escape and virulence
   • Sulfolipids - inhibit phagolysosome fusion
   • Lipoarabinomannan (LAM) - major surface glycolipid, immunomodulatory, inhibits macrophage activation by IFN-γ

• Resistance to common antibiotics (beta-lactams, etc.) - the thick waxy layer reduces permeability
• Resistance to desiccation - survives months in dried sputum
• Resistance to host digestive enzymes after phagocytosis
• Slow growth - the thick cell wall slows nutrient transport

3. Purified Protein Derivative (PPD) / Tuberculin

4. Biochemistry of Drug Action (Important for Exams)

PART II - PHYSIOLOGY PERSPECTIVE

1. Respiratory Physiology and TB

• Particles >10 μm are filtered by nasal hairs and mucus
• Particles 5-10 μm are trapped by the mucociliary ladder
• Particles <5 μm (droplet nuclei) - reach alveoli - the infective units of TB

2. The Immune (Physiological) Response to TB

1. MTB bacilli land in the alveolus and are phagocytosed by alveolar macrophages
2. MTB survives inside the phagosome by:
   • Blocking phagolysosome fusion (sulfolipids, LAM)
   • Preventing acidification of the phagosome
   • Escaping reactive oxygen and nitrogen species
3. Without adequate immune control → unchecked bacillary proliferation → bacteremia with seeding of multiple sites

1. Alveolar macrophages present MTB antigens via Class II MHC to CD4+ T cells in draining lymph nodes
2. Macrophages secrete IL-12 → drives differentiation of CD4+ T cells into Th1 subset
3. Th1 cells release IFN-γ → feeds back to activate macrophages
4. Activated macrophages:
   • Complete phagolysosome fusion
   • Produce reactive nitrogen intermediates via inducible nitric oxide synthase (iNOS) → most important mycobactericidal mechanism
   • Produce reactive oxygen species (ROS)
   • Release TNF → recruits more monocytes
   • Differentiate into epithelioid histiocytes → aggregate to form granulomas
5. Sensitized T cells accumulate around the granuloma
6. Tuberculin test becomes positive (conversion) - sign that immunity has developed

3. Physiological Basis of Symptoms

4. Hypoxic Drive in TB

PART III - ANATOMY PERSPECTIVE

1. Anatomical Sites of TB Involvement

A. Primary TB - The Ghon Complex

B. Secondary (Reactivation) TB - Apical Localization

• Higher oxygen tension (obligate aerobe thrives here)
• Relatively poor lymphatic drainage
• Lower blood flow relative to ventilation (high V/Q ratio)

C. Anatomy of the Granuloma (Tubercle)

1. Central caseous necrosis - cheese-like amorphous material (contains dead macrophages, bacteria, lipid). Unique to TB among common granulomas.
2. Epithelioid macrophages - activated macrophages with abundant pale cytoplasm
3. Langhans giant cells - multinucleate cells formed by fusion of epithelioid macrophages; nuclei arranged in a horseshoe or peripheral ring pattern (distinguishes from foreign body giant cells where nuclei are central)
4. Lymphocytes - surrounding cuff of CD4+ T cells
5. Fibroblasts - peripheral rim, producing fibrous capsule

• Left (mycobacterial expansion): Nascent granuloma - macrophages (pink) engulf virulent mycobacteria (red rods); apoptotic bodies released; chemotactic signals recruit more macrophages
• Middle (immune control): T lymphocytes (blue) are recruited as adaptive immune response begins; secondary granuloma forms
• Right (equilibrium): Mature granuloma - T lymphocytes surround a core of macrophages containing bacteria; bacterial growth is controlled but not eradicated

D. Anatomical Spread of TB

• From Ghon focus to hilar nodes (part of Ghon complex)
• Further to mediastinal, supraclavicular, or abdominal nodes

• Via thoracic duct → superior vena cava → systemic circulation
• Miliary TB: uniform seeding of multiple organs (appears as millet seed-sized nodules on CXR)
• Sites seeded: meninges (TB meningitis), bone marrow, liver, spleen, kidney, adrenal (Addison's disease), fallopian tubes, epididymis

• Pleura → TB pleuritis / pleural effusion
• Pericardium → tuberculous pericarditis
• Chest wall (rare)

• Liquefied caseous material drains through a bronchus → cavity formation
• Spread to new lung segments/lobes via the bronchial tree
• Most contagious stage

E. Extrapulmonary TB - Anatomical Locations

F. Anatomy of the Lung - Relevant to TB

• Posterior segment of upper lobe (S2) - most common in both lungs
• Apical segment of upper lobe (S1)
• Superior segment of lower lobe (S6)

PART IV - PATHOLOGICAL SUMMARY (Integrating All Three Subjects)

Types of TB Lesions (Morphology)

Fate of Primary TB in 95% of Patients:

1. Cell-mediated immunity develops (~3 weeks post-infection)
2. Granuloma walls off the infection
3. Caseous material desiccates and calcifies
4. Ghon complex → Ranke complex (radiologically visible calcified scar)
5. Latent TB - bacilli remain viable within granuloma for decades

Reactivation (5% lifetime risk; rises with immunosuppression):

• Triggers: HIV infection (CD4 <200/μL), malnutrition, diabetes, steroids, anti-TNF therapy, silicosis, aging
• Reactivation TB localizes to the lung apex (high O2 tension)

PART V - DIAGNOSIS (Integration)

QUICK REVISION TABLE FOR EXAMS

SAMPLE EXAM QUESTION ANSWERS