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Perth Haematology :: Dr Steven Ward

Cryoglobulins

 

CRYOGLOBULINS

 

= Serum immunoglobulin (Ig) which precipitate in the cold (<37°C) forming immune complexes (IC)

 

Classification:

 

 

Type

Immune Complexes

Ig

%

Monoclonal

I

Monoclonal Ig

IgM (IgG)

10-15%

Mixed Cryoglobulins

II

Monoclonal IgM and polyclonal IgG

 

50-60%

III

Polyclonal IgM and polyclonal IgG

 

25-30%

 

 

Associations:

Infection:

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Viral:       Hep C, Hep B, Hep A, EBV, CMV, HIV

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Bacterial: Syphilis, Lyme Disease, leprosy, Q fever, strep nephritis, subacute bacterial endocarditis

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Parasitic: Kala-azar, Toxoplasma, malaria, schisosomiasis, trypanosomiasis

 

Haematological:                              Auto-immune Disease:

NHL                                           Sjögren’s                           Pulmonary Fibrosis

HD                                            SLE                                  Biliary Cirrhosis

CLL                                           PAN                                 Primary APS

Myleoma                                    Scleroderma                      IBD

CML                                          Rheumatoid                       Phemphigus vulgaris

Waldenström’s                           Autoimmune Thyroiditis

Castleman’s                                Temporal arteritis

MDS                                          Dermato- poly-myositis

TTP                                          Henoch-Schönlein Purpura

Cold Agg disease                          Sarcoidosis

 

Laboratory features:

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Collect blood in pre-warmed tube at 37°C and keep at 37°C until completely clotted. Samples must be kept warm.

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Then centrifuge

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Keep centrifuged serum in fridge (2-4°C) and inspect daily for up to 7 days. Cryoprecipitate will develop (within 24 hr for Type I and II, up to 7 days for Type III).

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Cryoglobulin will be resoluble by warming.

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Determine Type by immunofixation electrophoresis

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Cryoglobulins can be seen on standard blood films as pale globules.

 

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If a monoclonal protein is detected – investigate as for any paraprotein for lymphoproliferative and plasma cell disorders

 

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Cryoglobulin levels do not correlate with disease severity or prognosis.

 

Hepatitis C and Mixed Cryoglobulins

Hepatitis C has been discovered to be the most common cause of MC, ranging form 35-95% in different series. Conversely 20-55% of hepatitis C patient will develop MC.

HCV RNA is found to be 20-1000 x more concentrated in the cryoprecipitate than serum.

The lymphoid cell CD81 marker may be the receptor for HCV on B-cells.

In the liver the intraportal lymphoid nodules that develop in hepatitis C have a “CLL-like” immunophenotype. These nodules, however, remain stable for long periods. Low grade lymphoma develops in 6-28% over 4-10 years.

 

Clinical Features

Type I

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rarely leads to vasculitis;

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causes peripheral vascular occlusion: hyperviscosity, purpura, acrocyanosis, Raynaud’s, dystrophic ulcers.

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Assoc with lymphoproliferative disorders

 

Type II/III (MC)

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Purpura

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Weakness

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Arthralgia

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Small-medium vessel vasculitis: hepatitis; membrano-proliferative glomerulonephritis, neuropathy

 

Criteria for Mixed Cryoglobulinaemia Syndrome:

 

Criteria

Serology

Pathology

Clinical

Major

Mixed Cryo

Low C4

Leukocytoclastic vasculitis

purpura

Minor

Rheum Factor

HCV

HBV

Clonal B cell infiltrate

Chronic hepatitis

MPGN

Peripheral neuropathy

Skin ulcers

 

Definite MC Syndrome:

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Serum MC ±low C4 + purpura + vasculitis (all major)

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Serum MC ± low C4 + 2 minor clinical features + 2 minor serological/pathological features

 

Incomplete or possible MC syndrome:

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MC or low C4 + 1 minor clinical feature + 1 minor serological feature ± pathological features

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Purpura and/or vasculitis + 1 minor clinical feayures + minor serological feature ± pathological features

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2 minor clinical features + 2 minor serological features ± pathological features

 

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Essential MC Syndrome: absence of well known associations (infections, immunological, neoplastic)

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Secondary MC Syndrome: Secondary to above associations.

 

Cutaneous / vasculitic features

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Purpura 55-100%  Type II/III > Type I

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Intermittent; palpable; spares face; exacerbated by cold in only 10-30%

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Vasculitis – hyperpigmentation; ulcers; 2y to IC deposits ± inflammation ± HCV

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Raynaud’s in 30%

 

Renal

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Renal features in 1/3 MC – great morbidity

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Usually follows purpura

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Proteinuria, microscopic haematuria, hypertension, moderate RnF

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20% are nephrotic; 20-30% acute nephritis

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80% membrano-proliferative glomerulonephritis

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ESRF is rare (15%)

 

Nervous System

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Common; peripheral neuropathy; esp Type II/III (up to 85%)

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Sensory neuropathy then painful paraesthesia then motor involvement

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Mononeuritis multiplex

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CNS – rare; usually ischaemic – stroke, TIA, confusion

 

Autoimmune disorders

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Especially 1y Sjogren’s (5-60%); SLE (7-90%) in Type II/III

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? HCV in Sjogrens

 

Liver

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HCV; abn LFT, hepatomegaly, chronic hepatitis, fatty change, cirrhosis, ca.

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Liver failure in 25%

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HCV + MC – more fibrosis and cirrhosis

 

Lung

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Pulmonary fibrosis, acute infiltrates, fever, cough

 

 

Treatment

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Type I: treat underlying LPD

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Type II/III: treat underlying disorder – eg HCV

 

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HCV Rx: IFN and ribavirin

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Purpura responds first, then neuropathy then renal failure

 

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Non-HCV: immunosuppression: steroids, cyclophosphamide, CyA, Azathioprine

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Plasmapheresis

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Rituximab (Type I, aslo Type II/III and HCV)