What is the pathophysiology of Hemophagocytic Lymphohistiocytosis (HLH) in pediatric and adult patients?

Pathophysiology of Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a severe hyperinflammatory syndrome driven by aberrantly activated macrophages and cytotoxic T cells, resulting from either genetic defects in lymphocyte cytotoxicity (primary HLH) or acquired immune dysfunction in response to various triggers (secondary HLH), both converging on a common terminal pathway of uncontrolled hypercytokinemia and tissue damage. 1

Core Pathogenic Mechanisms

Defective Cytotoxic Function

• Primary (Genetic) HLH: Mutations affecting perforin, UNC13D, STX11, and STXBP2 impair the transport, processing, and function of cytotoxic granules in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). 2
• This leads to defective killing of target cells and failure to contract the immune response, resulting in persistent stimulation of lymphocytes and histiocytes. 2
• The inability to eliminate activated immune cells and infected cells perpetuates the inflammatory cascade. 2

Secondary (Acquired) HLH Pathogenesis

• Secondary HLH represents an inability of the immune system to adequately restrict stimulatory effects of various triggers, including infections (particularly EBV and CMV), malignancies (especially T-cell and NK-cell lymphomas), and autoimmune/autoinflammatory disorders. 1, 3
• While inherited variations in HLH-associated genes may play a role in adult-onset HLH, acquired immune dysfunction in response to triggers is the primary mechanism. 1
• Persistent immune stimulation from these triggers drives the same terminal pathway as genetic forms. 4

The Cytokine Storm and Hyperinflammation

Sustained T-Cell and Macrophage Activation

• Sustained, aberrant activation of cytotoxic CD8+ T cells is a core pathogenic mechanism, with these cells failing to undergo normal apoptosis and immune contraction. 4
• Activated macrophages and histiocytes proliferate uncontrollably, leading to the characteristic hemophagocytosis (though this finding is neither sensitive nor specific). 5

Hypercytokinemia

• Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, with massive release of inflammatory cytokines including IFN-γ, TNF-α, IL-6, IL-1, and IL-18. 2
• This cytokine storm drives the characteristic clinical manifestations: persistent high fever, hepatosplenomegaly, cytopenias, coagulopathy, and progressive multiorgan dysfunction. 6, 4
• The hyperferritinemia (often >5000 ng/mL) reflects both macrophage activation and hepatocyte damage from the inflammatory cascade. 6

Common Terminal Pathway with Different Roots

Convergence Despite Heterogeneity

• Primary and secondary HLH, including MAS-HLH, are hyperferritinemic hyperinflammatory syndromes with a common terminal pathway but with different pathogenetic roots. 1
• In primary HLH, the genetic defect is the root cause, while in secondary HLH, the trigger (infection, malignancy, autoimmunity) overwhelms normal immune regulation. 1
• Both pathways converge on uncontrolled T-cell and macrophage activation with resultant inflammatory cytokine release. 4

Tissue Damage and Organ Dysfunction

Mechanisms of End-Organ Damage

• The cytokine storm and activated immune cells infiltrate multiple organs, causing direct tissue damage. 2
• Hepatitis with elevated transaminases and bilirubin, coagulopathy with hypofibrinogenemia, pulmonary edema, and renal dysfunction are hallmarks of progressive disease. 6
• Neurologic involvement occurs through CNS infiltration by activated lymphocytes and cytokine-mediated inflammation. 6
• Without treatment to suppress the overactive immune system, this leads to terminal multiple organ failure and death. 1, 7

Age-Related Differences in Pathophysiology

Pediatric vs. Adult Presentations

• Primary (genetic) HLH is most common in children, though it can occur in adolescents and young adults. 1
• Secondary (acquired) HLH is by far the most common in adults, with different triggers, organ reserve, and clinical presentations compared to pediatric patients. 1
• Hypomorphic biallelic perforin mutations can cause late-onset HLH in adults and predispose to hematologic malignancies. 3

Critical Clinical Implications

Why Early Recognition Matters

• The pathophysiology explains why HLH can present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome, making diagnosis challenging. 1
• The uncontrolled inflammatory cascade progresses rapidly, and early recognition may prevent irreversible organ damage and subsequent death. 1
• Treatment must target both the hyperinflammation (with immunosuppression) and the underlying trigger (antimicrobials, chemotherapy, or disease-modifying therapy). 6