Cryoglobulinemia

1
Cryoglobulinemia

• Andrew J Avery
• A.M. Report
• 08/19/09

2
Introduction

• Precipitation of blood proteins at temperatures
  lower than 37ºC is referred to as
  cryoprecipitation
• Cryoglobulins are either immunoglobulins or a
  mixture of immunoglobulins and complement
  components that precipitate from both serum and
  plasma (if just plasma, then called
  cryofibrinogen)

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Introduction

• Wintrobe and Buell are credited with the first
  description of the cryoprecipitation phenomenon.
  In 1933, they described a patient with signs and
  symptoms of hyperviscosity associated with
  multiple myeloma

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Cryoglobulins
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Prevalence

• The prevalence of clinically-significant
  cryoglobulinemia has been estimated at
  approximately 1100,000
• Detectable levels of circulating CGs have been
  seen in a significant proportion of patients with
  chronic infections and/or inflammation
• HIV-15-20
• Connective Tissue Dz-15-25
• HEP C-40-50

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Brouet Classification

• Uses the immunological analysis of the CG to
  delineate the clonality of the responsible CG
• Type I Criterion is presence of isolated
  monoclonal Ig 5-25 of cases most commonly
  ass. w/ LPD
• Type II A mixture of polyclonal Ig in
  association with a monoclonal Ig 40-60 of
  cases most commly ass. w/ chronic viral inf
• Type III Mixed cryoglobulins consisting of
  polyclonal Ig 40-50 of cases most commonly
  ass. w/ CTD

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Etiology and Pathogenesis

• CGs are often detectable in the serum of healthy
  pts, thus speculated that CGs reflect the ongoing
  physiological clearance of endogenous immune
  complexes by Igs with RF activity
• Pathogenic CG responses may result from several
  factors next slide

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Etiology and Pathogenesis

• Chronic immune stimulation and/or
  lymphoproliferation, resulting in the production
  of higher concentrations of mono-, oligo-, or
  polyclonal CG.
• Immune complex formation among CG and/or their
  target antigens
• Defective and/or insufficient clearance of the
  resulting immune complexes, which accumulate and
  mediate disease

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Clinical Manifestations
Signs Sx Type I Type II Type III
Purpura
Gangrene/Acrocyano / /-
ArthralgiasgtArthritis
Renal
Neurologic
Liver /-
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Clinical Manifestations

• Cutaneous Nearly all pts with CG syndromes
  develop erythematous macules to purpuric papules
  of the lower extremities (90-95).
• More commonly in Type I CG are infarction,
  hemorrhagic crusts and ulcers (10-25) raynaud
  phenomenon, livedo reticularis, acrocyanosis and
  post-inflammatory hyperpigmentation (30-50).

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Palpable Purpura
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Clinical Manifestations

• Musculoskeletal Arthralgias and myalgias are
  common in type Type II and III CGs (gt70). Most
  commonly affect metacarpophalangeals, proximal
  phalangeals, knees, and ankles
• Neuropathy Affects 70-80 of pts with mixed CG
  (Type II III). Thought to be 2/2 vasculitis
• Pulmonary Generally affects Types II III
  (40-50). PFTs often reveal evidence of small
  airways disease and impairment of gas exchange
  sx generally range from dyspnea to cough and
  pleurisy

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Clinical Manifestations

• Renal Renal disease in mixed CG often results
  from immune complex disease less frequently 2/2
  thrombotic dz (more common in Type I)
• Membranoproliferative glomerulonephritis seems to
  be more common in mixed CG
• Isolated proteinuria or hematuria occur much more
  frequently than nephrotic or nephritic syndromes
  or acute renal failure.

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Clinical Manifestations

• Other Sjogrens syndrome (4-20) Raynaud
  phenomenon (50) hepatomegaly, abnormal liver
  function tests or abnormal liver biopsy (90)
  lymphadenopathy (20) splenomegaly (30)
  abdominal pain (20). All of the above are more
  common in Types II III
• CNS, heart, and retinal vessels are rarely
  affected unless in association with
  hyperviscosity due to type I CG

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Cutaneous Pathological Findings

• Mixed CG most often reveal leukocytoclastic
  vasculitis (50), less commonly inflammatory or
  noninflammatory purpura (10-20), noninflammatory
  hyaline thrombosis (10), or post-inflammatory
  sequelae (10)
• Type I CGs more often induce noninflammatory
  thrombotic lesions, sometimes with evidence of
  cutaneous infarction or hemorrhage

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Skin lesion in mixed cryoglobulinemia (PAS Stain)
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Renal Pathological Findings

• Light and immunofluorescence microscopy In Mixed
  CG, most common is membranoproliferative
  glomerulonephritis (60-80), with endocapillary
  proliferation and subendothelial and/or
  intraluminal deposits of CGs, immunoglobulin,
  and/or complement proteins
• Type I CG generally produce noninflammatory
  glomerulopathies, including thrombotic and
  hypocellular lesions, without evidence of
  vasculitis.

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Renal involvement in type II cryoglobulinemia
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Laboratory Findings

• Measureable Cryoglobulins Types II III (1 to 5
  mg/dL) Type I (5 to 10 mg/dl)
• Complement Normal in Type I Decreased CH50,
  C1q, C2 and C4 and normal C3 in Types II III
• Elevated ESR and CRP
• Autoantibodies Types II III often have
  elevated RF, ANA (many others as well)
• Evidence of Viral Inf HCV, HBV, HIV, EBV

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Treatment

• Mild Dz Mild symptoms, such as fatigue,
  arthralgias and myalgias, in the absence of clear
  evidence for end-organ damage. Initial trx is
  cold avoidance and nsaids. Low dose prednisone
  for inflam sx not responsive to nsaids
• Mod-Severe Dz pathologically-proven, CG-related,
  end-organ-threatening vasculitis or thrombosis
• -Type I (malignancy related) chemo and/or
  radiation for bone lesions

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Treatment

• Type I (non-malignancy)-Prednisone and
  Cycylophosphamide
• Types II III-generally involves
  immunosuppression and may also require
  plasmapheresis May be combined with antiviral
  therapy when indicated
• Severe Dz hyperviscosity syndrome or vasculitis
  in Type I CG, or life or organ threatening
  vasculitis in mixed CG (Types II or III) warrants
  the addition of plasmapheresis to quickly reduce
  the CG burden

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Prognosis

• The presence of CG does not seem to confer a
  significant morbidity or mortality risk over and
  above the underlying conditions
• Survival Mean survival is approximately 70 at
  10 years after the onset of symptoms, 50 at 10
  years after diagnosis, with death typically
  resulting from infection and cardiovascular
  disease