Thread by @aishaikh

💥 Tweetorial on ‘Cryoglobulinemia’

⚡️What are Cryoglobulins?

⚡️When should a clinician suspect Cryoglobulinemia & Cryoglobulinemia vasculitis?

⚡️How to establish the diagnosis?

⚡️Significance of Rheumatoid Factor
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@GlomCon
#Onconephrology

⚡️Cryoglobulins are immunoglobulins that reversibly precipitate in the serum at <37 degree C & re-dissolve at >37 degree C

⚡️The fundamental mechanism behind Cryoglobulin formation is aberrant antibody (Ab) production by B cells & B cell proliferation

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⚡️Hence diseases that interfere with B cell function can cause Cryoglobulinemia such as:

☄️B cell lymphoproliferative disorders
☄️Chronic infections such as Hepatitis C virus (HCV)
☄️Autoimmune diseases

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⚡️These diseases not only lead to ⬆️ production of abnormal immunoglobulins i.e. Cryoglobulins but the cryoglobulin immune complex clearance can also be impaired

⚡️Cryoglobulins can occlude vessels & immune complexes can induce inflammatory vasculitis
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⚡️Mechanism of HCV Cryoglobulinemia Vasculitis is interesting

-HCV infects both hepatocytes & B cells owing to a common cell receptor CD81

-B cells are stimulated -> polyclonal Ab production

-Chronic HCV stimulation -> poly & monoclonal Ab production👇🏽
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⚡️Subsequently these Polyclonal & Monoclonal Abs form immune complexes, complement activation (⬇️ C4) & tissue injury

⚡️Kidney biopsy👇🏽:
-MPGN pattern
- PAS positive endoluminal pseudo-thrombi
-EM: Sub-endothelial deposits, ‘fingerprint appearance’
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⚡️Classification of Cryoglobulins is based on Immunoglobulin (Ig) composition of cryoprecipitate:

-Type I: Monoclonal Ig (usually IgM)
-Type II: Monoclonal Ig (usually IgM kappa) plus Polyclonal Ig
-Type III: Polyclonal Ig (IgM & IgG)
-Type II-III mixed👇🏽
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⚡️Now let’s review the following terms:

‘Mixed Cryoglobulinemia’ (MC)- when Cryoglobulins contain more than one immunoglobulin (Type II and Type III) - see the tweet above again👆🏽

‘Essential Cryoglobulinemia’ when no cause for MC is found
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⚡️Different types of Cryoglobulins can be associated w/ different diseases:

-Type I: B cell lymphoproliferative disorders

-Type II & Type III: Chronic infections (such as HCV), autoimmune diseases, lymphoproliferative disorders
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⚡️Let’s familiarize yourself w/ these terminologies:

-Cryoglobulinemia: presence of Cryoglobulins in serum

-Cryoglobulinemia Vasculitis: vasculitis due to Cryoglobulin containing immune complexes

These terms are NOT synonymous
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⚡️Is it possible to have + serum Cryoglobulins w/o any accompanying clinical signs or symptoms?
-Yes

⚡️What should you do in this situation?
-Look for underlying disorders associated w/ Cryoglobulinemia & closely monitor the patient
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⚡️Can Cryoglobulinemia Vasculitis occur w/o detectable serum Cryoglobulins?

-Yes. It can occur👇🏽

⚡️Early in the disease or during clinical remission

⚡️Transiently due to variability in cryoprecipitable immune complexes

⚡️False negative test

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⚡️False negative test for Cryoglobulins can occur due to ‘improper handling’ of the blood sample or due to high lipid concentration causing serum turbidity

⚡️Serum Cryoglobulins measurement requires meticulous blood sample processing👇🏽
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⚡️What is the diagnostic criteria for Cryoglobulinemia Vasculitis?

-No universal criteria

-It requires laboratory, clinical and histologic evidence
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⚡️Diagnosis of Cryoglobulinemia Vasculitis requires a combination of:
-Laboratory evidence of Cryoglobulinemia, Low C4, +RF👇🏽

-Clinical signs & symptoms👇🏽

-Histologic evidence👇🏽

Presence of disorders associated w/ Cryoglobulinemia can be helpful

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⚡️Presence of Cryoglobulins in serum is reported as:

- Cryocrit (amount of Cryoglobulins expressed as percentage of serum)👇🏽

-Concentration of serum Cryoglobulins

-Cryocrit of > 0.5% - 1% and Cryoglobulin of > 5 mg/dL are abnormal
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⚡️What is the Rheumatoid Factor (RF)?
- RF are autoantibodies directed against the Fc portion of IgG

-Cryoglobulins in Mixed Cryoglobulinemia can have RF activity
-Hence + RF can assist in diagnosis
- But + RF is NOT specific to Cryoglobulinemia..

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⚡️Presence of Rheumatoid Factor is not a specific to ‘Mixed Cryoglobulinemia’ & it can be found in several rheumatologic & non-rheumatologic conditions👇🏽
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⚡️Treatment of Cryoglobulinemia depends on the severity of disease & the underlying cause

-Treat the the underlying disease such as B cell lymphoproliferative disorder, infection or autoimmune disease

-Immunosuppressive therapy is used in severe dz👇🏽
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Let’s end the Tweetorial with a clinical case:

-68 year old male presents with AKI, purpura, ankle pain, low C4, +RF

-Kidney biopsy is done and it shows this on the PAS stain👇🏽

What do you see? Answer the poll in the next tweet
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⚡️The Kidney biopsy in the previous tweet shows:
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⚡️Answer: These are intra-capillary ‘pseudo-thrombi’ composed of Cryoglobulins

-This patient was diagnosed with MPGN due to Hepatitis C associated Cryoglobulinemia

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💥Summary:

⚡️Cryoglobulins are can cause a wide variety of clinical findings
⚡️They are associated w/ several conditions: lymphoproliferative disorders, infections, autoimmune diseases
⚡️Treatment depends on the underlying cause & disease severity

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