Cryoglobulinemia

Last reviewed: 23 Aug 2023

Last updated: 05 Nov 2019

Refers to the presence of cryoglobulins in the serum. Cryoglobulins are immunoglobulins that reversibly precipitate at temperatures below 98.6°F (37°C).

Type I cryoglobulinemia is mostly associated with lymphoproliferative disorders (e.g., Waldenstrom macroglobulinemia); types II and III (mixed cryoglobulinemia [MC]) with autoimmune and infectious conditions, particularly with hepatitis C virus (HCV) infection.

Clinical presentation includes a triad of purpura, weakness, and arthralgia. Multisystemic involvement may include the kidneys, liver, and nervous system.

Diagnosis is based on clinical and laboratory findings. Leukocytoclastic vasculitis is the histologic hallmark of MC.

Management of MC secondary to chronic HCV infection includes viral eradication strategies in addition to immunosuppression.

Definition

Cryoglobulinemia refers to the presence of cryoglobulins in the serum. Cryoglobulins are immunoglobulins that reversibly precipitate at temperatures below 98.6°F (37°C). Type I cryoglobulinemia is usually associated with lymphoproliferative disorders. Types II and III may be associated with infectious (hepatitis C virus infection) or autoimmune disorders.[1][2] The clinical presentation includes a triad of purpura, weakness, and arthralgia. Multisystemic involvement may occur, particularly affecting the kidneys, liver, and nervous system. Widespread small vessel vasculitis has been demonstrated on post mortem studies.[3][4]

History and exam

Key diagnostic factors

arthralgia
weakness
vasculitis
lower-extremity vascular purpura

More key diagnostic factors

Other diagnostic factors

peripheral neuropathy
sicca symptoms
hypertension
Raynaud phenomenon
lower extremity skin ulcers
diplopia
ataxia
headache
confusion
retinal hemorrhage/retinal vein thrombosis
acrocyanosis

Other diagnostic factors

Risk factors

hepatitis C virus (HCV) infection
other viral infections
autoimmune disorders
lymphoproliferative disorders

More risk factors

Diagnostic investigations

1st investigations to order

fasting qualitative serum cryoglobulins
CBC
comprehensive chemistry panel
erythrocyte sedimentation rate, CRP
urinalysis
ECG
CXR
rheumatoid factor
complement CH50, C3, C4
hepatitis C virus (HCV) antibody
hepatitis B virus antibody

More 1st investigations to order

Investigations to consider

HIV antibody
antinuclear antibody (ANA), Sjogren syndrome antigens, extractable nuclear antigen (ENA) antibody
skin biopsy

More investigations to consider

Treatment algorithm

ACUTE

mixed cryoglobulinemia

malignancy-associated cryoglobulinemia (type I)

Contributors

Authors

Gurjit S. Kaeley, MBBS, MRCP

Professor of Medicine

Chief, Division of Rheumatology and Clinical Immunology

Medical Director, Musculoskeletal Ultrasound Program

Program Director, Rheumatology Fellowship

University of Florida College of Medicine - Jacksonville

Jacksonville

Disclosures

GSK declares that he has no competing interests.

Peer reviewers

Dina Titova, MD, PhD

Rheumatologist

Road Clinic

Lakewood

Disclosures

DT has received a fee from an educational grant from the Center of Excellence for organizing CME South Sound Bond Club conference.

Antonio Palumbo, MD

Associate Professor

University of Turin

Chief

Myeloma Unit

Ospedale Molinette

Turin

Italy

Disclosures

AP declares that he has no competing interests.

Xavier Leleu, MD, PhD

Instructor in Hematology

Department of Hematology

Hopital Huriez CHRU

Lille

France

Disclosures

XL has received lecture fees and research funding from Janssen-Cilag, Celgene, Chugai, Amgen, Novartis, Mundipharma, and Roche. XL is an author of a number of references cited in this topic.

Rajan Madhok, MD, FCRP

Consultant Physician and Rheumatologist

Centre for Rheumatic Diseases

Glasgow Royal Infirmary

Glasgow

Disclosures

RM declares that he has no competing interests.

Differentials
- Small to medium vessel vasculitis
- Cryofibrinogenemia
More Differentials
Guidelines
- The management of chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver
- Recommendations on treatment of hepatitis C 2018
More Guidelines
Patient leaflets
Hepatitis C: what is it?
Hepatitis C: what treatments work?
More Patient leaflets
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Cryoglobulinemia

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic investigations

1st investigations to order

Investigations to consider

Treatment algorithm

mixed cryoglobulinemia

malignancy-associated cryoglobulinemia (type I)

Contributors

Authors

Gurjit S. Kaeley, MBBS, MRCP

Disclosures

Peer reviewers

Dina Titova, MD, PhD

Disclosures

Antonio Palumbo, MD

Disclosures

Xavier Leleu, MD, PhD

Disclosures

Rajan Madhok, MD, FCRP

Disclosures

Differentials

Guidelines

Patient leaflets

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

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