Monocyte-macrophage disorders

Question 1

Gaucher disease

Answer 1

Description:

• inborn error of metabolism that affects the recycling of cellular glycolipids. One of the most common lysosomal storage diseases.
• autosomal recessive disorder due to mutations in the gene glucocerebrosidase 1 (GBA1), located on chromosome 1q21. 80% of these mutations are single-nucleotide substitutions. Three mutant alleles are particularly frequent (inc N370S missense mutation, L444P, and c.84insG mutation)
• Glucocerebroside (also called glucosylceramide) and several related compounds that ordinarily are degraded to glucose and lipid components, accumulate within the lysosomes of cells.

Pathogenesis:

• deficiency of a lysosomal enzyme glucocerebrosidase (known as GCase); a component of the cell membrane that is distributed widely in many organs.
• deficiency of GCase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages, and also in the brain (leading to neurodegeneration)
• The clinical manifestations of GD result from the accumulation of the lipid-laden macrophages in the spleen, liver, bone marrow, bone, and other tissues/organs.
• Gaucher cells and neighboring macrophages overexpress and secrete lysosomal proteases, inflammatory mediators, chemotactic factors. This leads to an inflammatory and hyperplastic cellular response, followed by chronic inflammation, healing, and fibrosis.
• Several pathologic processes occur within bone: decreased mineral density, marrow infiltration, and infarction of bone. This is due to osteoclast dysregulation, mass cytokine production, marrow fibrosis, osteoclerosis

Types:

• type 1: most common. Can present in children or adults. Anaemia, thrombocytopenia, osteopenia, parkinson’s disease, hepatosplenomegaly, ILD, pulmonary HTN, haem malignancies, developmetal delay.
• Type 2: Presents in 1st year of life. Thrombocytopenia, oculomotor dysfunction, seizures, apnoea, hypertonia, hepatosplenomegaly
• Type 3 (a, b and c): progressive dementia, ataxia, myoclonus, supranuclear gaze palsy, severe vertebral compression fractures, osteonecrosis of long bones, severe anaemia/thrombocytopenia

Clinical manifestations:

• Splenomegaly seen in 85% pts
• Thrombocytopenia seen in 68% pts
• Hepatomegaly seen in 63% pts
• Osteopenia 55%
• growth retardation 36%
• Anemia in 34%
• bleeding
• bone pain 33%
• pathologic fractures 7%
• bone crisis 7%

Diagnosis:

• GBA (glucosylceramide or acid beta-glucosidase) genotyping to confirm a deficiency of glucocerebrosidase

Features on history/exam:

• Hx of pathologic fractures, bone pain, SOB, easy bleeding or bruising,
• PHx of blood transfusions, splenectomy, perinatal deaths
• Famiy hx of consanguinity, parkinson’s disease, LBD
• examine skin for bleeding/bruising/anaemia; eyes for pingueculae (brownish patch of tissue on sclera; a non-specific finding in GD); splenomegaly; hepatomegaly; developmental delay (children); neuro-opthal involvement; abnormal spine (scoliosis, kyphosis); psychosocial testing; audiometry testing

Labs:

• FBE, WCC, LFTs, iron + ferritin, TFTs, coags
• measure glucocerebrosidase (GCase)
• GBA1 genotyping
• serum electrophoresis (evaluate for clonal gammopathies)

Imaging:

• MRI or abdo USS of liver and spleen to assess for megaly/cirrhosis/fibrosis/lesions
• femoral X rays and spinal x rays to assess for fractures. Erlenmeyer flask deformity of long bones (specific radiographic abormality involving constriction of the diaphysis and flaring of the metaphysis. Characterised by abnormal cortical thinning and lack of the concave di-metaphyseal curve. An abnormality of the distal femur due to lack of modeling of the di-metaphysis)
• cxr and other x rays where patient reports pain
• DXA bone scan to measure osteopenia

Management:

• Enzyme replacement therapy
• 6-12monthly physical exam, FBE, beta-glucosidase and mutation analysis, serum electrophoresis
• 12-24monthly liver/spleen USS, x rays, DXA scan
• chest HRCT + PFTs if develops resp symptoms

Question 2

Hemophagocytic lympho-histiocytosis

Answer 2

Description:

• HLH is a syndrome of excessive inflammation and tissue destruction due to abnormal immune activation. Poor prognisis (few months) if untreated.
• triggered by infection or anything that disrupts immune homeostasis (immunodeficiency). Associated illness is common in adults with HLH (infection, malignancy, rheum, immunodeficiency)
• characterised by single episode or relapsing episodes (esp with familial HLH). Presents with fever, cytopenias, hepatitis, inflammatory CNS features (encephalitis)
• aggressive, life-threatening

Epi:

• typically presents in infants (birth to 18mo), but can occur in adults with immune dysregulation
• 25% of HLH is familial

Terminology:

HLH syndrome:

• pathologic immune activation
• often associated with genetic defects of lymphocyte cytotoxicity

HLH disease:

• distinctive immune activation is the core problem
• may be associated with a specific genetic and/or environmental causes

HLH disease mimics:

• Other disorders that resemble HLH syndrome

Macrophage activation syndrome (MAS) / Reactive hemophagocytic syndrome

• a form of HLH that occurs primarily in patients with juvenile idiopathic arthritis or other rheumatologic diseases

Pathophys of HLH:

• Dysfunctional immune system, triggered by / associated with:
• Infection e.g. primary EBV, kawasaki, CMV, parvovirus, HSV, VZV, measles, HIV, H1N1, SARS-CoV2 (COVID-19)
• immunodeficiency
  
  • X linked lymphoproliferative disease, Griscelli syndrome, chronic granulomatous disease, others
  • HIV
  • malignancy: B, T, NK cell leukemia. AML, ALL
  • Rheum conditions: juvenile arthritis (Stills disease). HLH in the setting of Rheum disease is referred to as MAS (macrophage activation syndrome)
• Genetic predisposition
  
  • Autosomal recessive genetic defects encoding important components of perforin-dependent cytotoxicity.
  • Familial HLH is due to mutations in PRF1/Perforin, UNC13D/Munc13-4, and others.
  • consanguinity
• Excessive cytokine release due to chronic granulomatous disease
• hyperinflammatory/dysregulated immune state
• lack of normal macrophage and lymphocyte function perimits overactivation (mac’s and lymph’s typically downregulate the immune system, preventing it from becoming overactive)
• Steps / cells involved:
• Toll-like receptors (TLRs) are activated by bacteria, fungi, viruses, mycoplasma
• macrophages: act as APCs that present foreign antigen to lymphocytes. Macrophages secrete excessive amounts of cytokines, leading to excessive tissue damage and organ failure in HLH
• NK cells and CTLs display impaired cytotoxic function, disrupted normal feedback mechanisms, and therea are abnormal numbers of lymphocyte subsets —> this leads a to failure to eliminate activated macrophages in HLH —> Leads to excessive macrophage activation and cytokine storm. Macrophages also phagocytise (engulf) host RBCs, WBCs, plts
  
  • NK cells and CTLs would typically eliminate activated macrophages via perforin-dependent cytotoxicity (creates a pore in the macrophage, leading to apoptosis and cell lysis)
• Cytokine storm with persistent activation of macrophages, NK cells, CTLs

Clinical presentation:

• Febrile illness with multiorgan/system involvement i.e. splenomegaly, cytopenias, low fibrinogen, elevated ferritin
• other system involvement
• Bleeding, DIC
• Neurologic features: seizure, encephalitis, ataxia, PRES (posterior reversible encephalopathy syndrome - vasogenic oedema in posterior cerebrum)
• resp: ARDS
• CVS: hypotension
• Renal: AKI, SIADH
• skin: rash, petechiae, purpura

Diagnosis:

• BMAT or biopsies of LN/spleen/liver demonstrating hemophagocytosis (host blood cells within activated macrophages) …. but this is not required for the diagnosis
• Cytokine levels are extremely high –> IL6, IL10, IL12, IL2, IL16, IL18. Typically test soluble IL2-receptor alpha (sCD25 or sIL2R)
• Labs: cytopenias (anaemia, thrombocytopenia), VERY high ferritin, hepatitis (transaminitis), elevated LDH and bilirubin, high triglycerides, abnormal coags (high D dimer, low fibrinogen, abn coags).
• Should also test immunoglobulins, lymphocyte subsets, flow cytometry
• Lumbar puncture shows high lymphocytes (pleocytosis). Should test for viruses/PCR.

Imaging:

• should send CT neck/C/A/P or PET for occult malignancy
• brain MRI for infiltrates

Management:

• induction
• weekly dexamethasone and etoposide (VP-16)
• Intrathecal methotrexate and hydrocortisone are given to those with central nervous system disease.
• If not improving
• allogeneic hematopoietic cell transplantation (HCT)
• esp pts with genetic mutation, CNS disease, or relapse