Pnh robbins def etiology pathogenesis flowchart Cf complications morphology dx

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Paroxysmal Nocturnal Hemoglobinuria (PNH) - Robbins

Definition

PNH is a hemolytic anemia caused by acquired somatic mutations in the PIGA gene (phosphatidylinositol glycan complementation group A), which encodes an enzyme essential for the synthesis of glycosylphosphatidylinositol (GPI) - the phospholipid anchor for many cell-surface proteins, including key complement regulatory proteins.

It is the only hemolytic anemia caused by an acquired genetic defect
Incidence: 2-5 per million (USA)
(Robbins & Kumar Pathologic Basis of Disease, p. 606)

Etiology

Factor	Detail
Gene mutated	PIGA (X-linked, subject to lyonization)
Type of mutation	Acquired somatic mutation (not germline)
Cell of origin	Hematopoietic stem cell (HSC)
Why one mutation is enough	PIGA is X-linked; a single hit on the active X inactivates it entirely
Clone behavior	Mutant clone coexists with normal stem cell progeny

Most normal individuals harbor small numbers of PIGA-mutant bone marrow cells. Clinically evident PNH arises only when these cells gain a selective advantage - hypothesized to occur in autoimmune settings (e.g., immune attack on GPI-linked antigens), which explains the frequent association with aplastic anemia.

Pathogenesis Flowchart

PIGA somatic mutation in HSC
            │
            ▼
Deficiency of GPI-linked complement regulatory proteins:
  • CD55 (Decay Accelerating Factor, DAF) - inhibits C3/C5 convertase
  • CD59 (Membrane Inhibitor of Reactive Lysis, MIRL) - most important;
         inhibits C3 convertase; prevents C5b-9 assembly
  • C8-binding protein
            │
            ▼
RBCs (and WBCs, platelets) lack GPI-anchored proteins
            │
            ├──────────────────────────────────────────┐
            ▼                                          ▼
  Unregulated Complement                     Nocturnal trigger:
  Alternative Pathway activation      Sleep → CO2 retention → ↓pH
            │                                → enhanced complement fixation
            ▼
  C5b-9 Membrane Attack Complex (MAC)
  assembles on unprotected RBC surface
            │
            ▼
  INTRAVASCULAR HEMOLYSIS
  • Hemoglobinuria (port-wine urine)  
  • Hemosiderinuria → iron deficiency
  • Chronic anemia (usually mild-moderate)
  • Paroxysmal nocturnal hemolysis (only 25% of cases)
            │
  Additional mechanisms:
  • Free Hb scavenges NO → vasoconstriction, platelet activation
  • C5b-9 damages endothelium
            ▼
  THROMBOSIS (venous, esp. hepatic/portal/cerebral veins)

Clinical Features (CF)

Feature	Detail
Anemia	Mild-moderate; chronic intravascular hemolysis
Hemoglobinuria	Dark urine (especially morning); classic but only in 25%
Hemosiderinuria	Chronic urinary iron loss → iron deficiency
Thrombosis	Most feared complication - hepatic vein (Budd-Chiari), portal vein, cerebral veins; ~40% of patients
Aplastic anemia	PNH clones seen in ≥50% of aplastic anemia patients; may precede or follow PNH
Infection susceptibility	With C5 inhibitor therapy: ↑ risk of Neisseria/meningococcal sepsis

Morphology

PNH has no distinctive morphologic finding on peripheral smear. The key features are:

Normocytic or microcytic anemia (if iron deficient from hemosiderinuria)
Evidence of intravascular hemolysis: hemoglobinemia, hemoglobinuria, hemosiderinuria
No spherocytes (unlike immune hemolytic anemia)
Bone marrow may show erythroid hyperplasia; in some cases hypoplastic (overlapping with aplastic anemia)

Complications

Thrombosis - leading cause of disease-related death; ~40% of patients
- Hepatic vein → Budd-Chiari syndrome
- Portal vein thrombosis
- Cerebral vein thrombosis
Iron deficiency - from chronic urinary hemosiderin loss
Aplastic anemia - bidirectional association with PNH
Myeloid neoplasm - ~5% develop AML or myelodysplastic neoplasm (reflects underlying genomic instability in HSCs)
Meningococcal sepsis - in patients on C5 inhibitor therapy (eculizumab)

Diagnosis

Gold standard: Flow Cytometry

Detection of red cells (and granulocytes) deficient in GPI-linked proteins - primarily CD55 and CD59.

PNH Flow Cytometry - CD55 vs CD59 scatter plots. Panel A (normal): all cells in CD55+/CD59+ quadrant. Panel B (PNH): large red cluster of cells in CD55-/CD59- quadrant representing the PNH clone.

Fig. 14.13 (Robbins) - Panel A (normal): RBCs express CD55 and CD59. Panel B (PNH patient): large population of RBCs negative for both CD55 and CD59 (red cluster) = PNH clone.

Other supportive tests:

Hemoglobinuria (urinalysis)
Hemosiderinuria (Prussian blue stain on urine sediment)
↑ LDH, ↓ haptoglobin (intravascular hemolysis markers)
Ham test (acidified serum lysis) - historical, now replaced by flow cytometry
Direct Coombs test: negative (distinguishes from immune hemolytic anemia)

Treatment

Approach	Detail
Eculizumab (anti-C5 monoclonal Ab)	Blocks C5 → prevents MAC assembly; reduces hemolysis + reduces thrombosis risk by up to 90%; risk of meningococcal infection (vaccinate prior to use)
Ravulizumab	Long-acting anti-C5 Ab
Iron supplementation	For hemosiderinuria-induced deficiency
Immunosuppression	For those with concurrent aplastic anemia
HSCT	Only cure; reserved for aplastic anemia or myeloid malignancy cases

Key point from Robbins: Eculizumab has no effect on early stages of complement (C3b deposition continues), so extravascular hemolysis persists to some degree even on treatment.

Sources:

Robbins & Kumar Basic Pathology (9780323790185), Chapter 10
Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528), Chapter 14, p. 606

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Sarcoidosis above format robbins

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Sarcoidosis - Robbins

Definition

Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating (non-caseating) epithelioid granulomatous inflammation in many tissues and organs. It is a diagnosis of exclusion - other causes of noncaseating granulomas (mycobacterial/fungal infections, berylliosis) must first be ruled out.

Bilateral hilar lymphadenopathy or lung involvement is the major presenting finding in most cases
(Robbins & Kumar Basic Pathology, p. 462)

Epidemiology

Feature	Detail
Age	Adults < 40 years (consistent predilection)
Sex	Both genders
Race	African Americans in USA (2-3x higher than those of European descent); Danish and Swedish populations also at high risk
Unique association	Higher prevalence among nonsmokers - virtually unique among pulmonary diseases

Etiology

Unknown - but evidence points to disordered immune regulation in genetically predisposed individuals exposed to undefined environmental agents.

No specific antigen or infectious agent has been confirmed
Proposed "antigens" exist but no concrete evidence linking any specific agent
Sarcoidosis recurs in new lungs after transplantation in at least 1/3 of patients - supporting a systemic immune dysregulation rather than a purely local lung phenomenon

Pathogenesis Flowchart

Genetically predisposed individual
        + undefined environmental antigen
                    │
                    ▼
        Antigen presented to CD4+ Th1 cells
        (intraalveolar and interstitial accumulation)
                    │
                    ▼
    Oligoclonal expansion of CD4+ Th1 T cells in lung
    (demonstrated by T-cell receptor rearrangement analysis)
                    │
                    ├──────────────────────────────────┐
                    ▼                                  ▼
         ↑ IL-2, IFN-γ                     ↑ IL-8, TNF, MIP-1α
    (T-cell proliferation,              (recruitment of more T cells
    macrophage activation)              and monocytes to the site)
                    │
                    ▼
        Macrophage activation
        → Epithelioid macrophage transformation
        → Multinucleated giant cell formation
                    │
                    ▼
        NONCASEATING GRANULOMA formation
        (discrete compact collection of epithelioid
         macrophages + CD4+ T cells at periphery)
                    │
                    ▼
    Early: thin layer of laminated fibroblasts
    peripherally
                    │
                    ▼
    Late: fibroblast proliferation → collagen deposition
    → HYALINIZED SCAR (replaces entire granuloma)

Note on immune paradox: Despite local accumulation of CD4+ T cells in the lung, blood levels of CD4+ T cells are often low, associated with anergy to common skin test antigens (e.g., Candida, PPD/tuberculin).

Morphology

Cardinal feature: Noncaseating epithelioid granuloma

Fig. 11.21 Sarcoidosis - Noncaseating granuloma with a large central multinucleated giant cell, surrounded by a fibrous rim, in lung tissue (H&E stain)

Fig. 11.21 (Robbins Basic Pathology) - Characteristic noncaseating granuloma with central multinucleated giant cell, rimmed by CD4+ T cells and fibroblasts.

Granuloma Structure:

Core: Compact collection of epithelioid macrophages
Periphery: Rim of CD4+ T cells + laminated fibroblasts
Cells: Multinucleate giant cells (macrophage fusion)
Special inclusions (sometimes seen):
- Schaumann bodies - laminated concretions of calcium and proteins
- Asteroid bodies - stellate inclusions within giant cells
End stage: Hyalinized scar (fibrosis replaces granuloma)

Organ-by-organ Morphology:

Organ	Finding
Lung (90%)	Interstitial granulomas (NOT air spaces); "lymphangitic" distribution around bronchioles, venules, pleura; BAL shows ↑ CD4+ T cells; 5-15% → diffuse interstitial fibrosis → honeycomb lung
Lymph nodes (75-90%)	Intrathoracic hilar + paratracheal enlarged; painless, firm, rubbery, non-matted (non-adherent), no necrosis (unlike TB)
Skin (25%)	Erythema nodosum (bilateral tender red nodules, anterior legs - hallmark of acute sarcoidosis); discrete painless subcutaneous nodules with noncaseating granulomas
Eye (20-50%)	Iritis / iridocyclitis (unilateral or bilateral); choroiditis, retinitis, optic nerve involvement; lacrimal gland → sicca syndrome (dry eyes)
Parotid (<10%)	Painful enlargement; xerostomia; combined uveitis + parotitis = Mikulicz syndrome
Spleen (75%)	Usually normal grossly but granulomas microscopically; 10% clinically enlarged
Liver	Granulomas in portal triads (~75%); only ~1/3 have hepatomegaly or abnormal LFTs
Bone marrow	Granulomas in up to 40%; rarely causes severe manifestations

Clinical Features (CF)

Presentation	Detail
Asymptomatic	Discovered incidentally on CXR as bilateral hilar adenopathy
Respiratory (2/3 of symptomatic)	Dyspnea, dry cough, vague substernal discomfort
Constitutional	Fever, fatigue, weight loss, anorexia, night sweats
Peripheral lymphadenopathy	1/3 of patients
Skin	Erythema nodosum, subcutaneous nodules
Eye	Iritis, iridocyclitis, visual impairment
Lab finding	Hypercalcemia + hypercalciuria (macrophages in granulomas produce biologically active vitamin D)

Complications

Progressive pulmonary fibrosis → cor pulmonale → death (10-15% of patients)
Honeycomb lung (5-15% of lung-involved patients)
Visual impairment (corneal opacities, glaucoma, blindness from untreated uveitis)
Hypercalcemia → renal stones, nephrocalcinosis
Cardiac sarcoidosis → arrhythmias, heart block, sudden death
Neurosarcoidosis → cranial nerve palsies, meningitis, diabetes insipidus

Diagnosis

A definitive test does not exist. Diagnosis requires ALL of the following:

Clinical + radiologic findings consistent with sarcoidosis
Exclusion of other disorders (especially tuberculosis - must be actively excluded)
Histopathologic identification of noncaseating granulomas in involved tissue (biopsy)

Investigation	Finding
Chest X-ray	Bilateral hilar lymphadenopathy (most common presenting finding)
Tissue biopsy	Noncaseating epithelioid granulomas (no central necrosis)
BAL	↑ CD4+ T cells; CD4:CD8 ratio > 3.5 (highly suggestive)
Serum ACE	Elevated (produced by granuloma macrophages); supports diagnosis but not specific
Serum calcium	Elevated (due to macrophage 1α-hydroxylase activity → active vitamin D)
Kveim test	Historical; no longer in routine use
Mantoux/PPD	Typically negative (anergy) - helps exclude TB

Prognosis & Treatment

Outcome	%
Full recovery with minimal/no residual disease	65-70%
Permanent lung dysfunction or visual impairment	~20%
Death (progressive pulmonary fibrosis + cor pulmonale)	10-15%

Course: Unpredictable - chronic progressive disease OR periods of activity with remissions
Remissions may be spontaneous or induced by steroid therapy (often permanent)
Corticosteroids are first-line treatment for significant organ involvement

Sources:

Robbins & Kumar Basic Pathology (9780323790185), Chapter 11, p. 462-463
Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528), Chapter 15

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