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Hemophagocytic Lymphohistiocytosis (HLH)

Summary

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  • Rare, life-threatening hyperinflammatory syndrome characterised by excessive immune activation
  • Presents with fever, hepatosplenomegaly, cytopenias, and hemophagocytosis in bone marrow and other tissues
  • Imaging findings include hepatosplenomegaly, lymphadenopathy, and multiorgan involvement

Pathophysiology

  • Dysregulation of the immune system leading to uncontrolled activation of T lymphocytes and macrophages
  • Excessive production of inflammatory cytokines (cytokine storm)
  • Impaired natural killer (NK) cell and cytotoxic T lymphocyte function
  • Genetic (primary) and acquired (secondary) forms exist

Demographics

  • Primary HLH:
    • Typically affects infants and young children
    • Incidence: approximately 1 in 50,000 live births
  • Secondary HLH:
    • Can occur at any age
    • Associated with infections, malignancies, and autoimmune disorders

Diagnosis

  • HLH-2004 diagnostic criteria (5 out of 8 required):
    1. Fever
    2. Splenomegaly
    3. Cytopenias affecting ≥2 cell lines
    4. Hypertriglyceridaemia and/or hypofibrinogenaemia
    5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
    6. Low or absent NK cell activity
    7. Ferritin ≥500 μg/L
    8. Soluble CD25 (sIL-2 receptor) ≥2400 U/mL
  • Genetic testing for primary HLH-associated mutations

Imaging

  • Ultrasonography:
    • Hepatosplenomegaly
    • Gallbladder wall thickening
    • Lymphadenopathy
  • CT:
    • Hepatosplenomegaly
    • Ascites
    • Pleural effusions
    • Pulmonary infiltrates
    • Lymphadenopathy
  • MRI:
    • Brain: T2/FLAIR hyperintensities in white matter, basal ganglia, and thalami
    • Liver: Hepatomegaly, periportal oedema
    • Spleen: Splenomegaly, focal lesions
  • PET-CT:
    • Increased FDG uptake in liver, spleen, and lymph nodes
    • Useful for identifying underlying malignancies in secondary HLH

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  • A 20-year-old patient with known history of systemic HLH presented with seizures.
  • MRI showed diffuse supra and infratentorial white matter hyperintensities associated with microhaemorrhages and superficial siderosis.
  • There was no diffusion restriction or pathological enhancement.

Treatment

  • Prompt initiation of immunosuppressive therapy
  • HLH-2004 protocol:
    • Dexamethasone
    • Etoposide
    • Cyclosporine A
  • Supportive care:
    • Blood product transfusions
    • Antimicrobial therapy
    • Management of organ dysfunction
  • Treatment of underlying triggers in secondary HLH
  • Haeatopoietic stem cell transplantation for primary HLH and refractory cases
  • Novel therapies:
    • Alemtuzumab (anti-CD52 monoclonal antibody)
    • Emapalumab (anti-IFNγ monoclonal antibody)
    • JAK inhibitors (e.g., ruxolitinib)

Differential diagnosis

Differential diagnosis Differentiating feature
ADEM Multifocal white matter T2/FLAIR hyperintensities; may enhance; lacks microhaemorrhages and superficial siderosis
Viral encephalitis Limbic or cortical involvement; asymmetric temporal lobe changes; lacks multifocal microhaemorrhages on SWI
CNS vasculitis Multifocal infarcts in multiple vascular territories; vessel wall enhancement on high-resolution MRI
Primary CNS lymphoma Periventricular enhancing masses; diffusion restriction; lacks generalised hepatosplenomegaly on CT