Download Cryoglobulinemia

Cryoglobulinemia
Andrew J Avery
A.M. Report
08/19/09
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)
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
Cryoglobulins
Prevalence
• The prevalence of clinically-significant
cryoglobulinemia has been estimated at
approximately 1:100,000
• 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%
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
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
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
Clinical Manifestations
Signs & Sx
Type I
Type II
Type III
Purpura
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Gangrene/Acrocyano
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+/-
Arthralgias>Arthritis
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Renal
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+
Neurologic
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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%).
Palpable Purpura
Clinical Manifestations
• Musculoskeletal: Arthralgias and myalgias are common
•
•
in type Type II and III CGs (>70%). 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
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.
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
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
Skin lesion in mixed cryoglobulinemia
(PAS Stain)
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.
Renal involvement in type II
cryoglobulinemia
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
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, CGrelated, end-organ-threatening vasculitis or
thrombosis
-Type I (malignancy related): chemo and/or
radiation for bone lesions
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
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