Cryoglobulinemia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 8 Aug 2025

Last updated: 10 May 2024

Cryoglobulinemia may be asymptomatic or present acutely.

Mixed cryoglobulinemia (MC) is the most common type, and it is strongly associated with chronic 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 (e.g., Waldenstrom macroglobulinemia). Types II and III (MC) may be associated with infectious (most commonly hepatitis C virus [HCV] 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

Full details

Other diagnostic factors

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

Full details

Risk factors

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

Full details

Diagnostic tests

1st tests 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

Full details

Tests to consider

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

Full details

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

Morie Gertz, MD

Professor of Medicine

Division of Hematology

Mayo Clinic

Rochester

Disclosures

MG is an author of a number of references cited in this topic.

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.

Peer reviewer acknowledgements

BMJ Best Practice topics are updated on a rolling basis in line with developments in evidence and guidance. The peer reviewers listed here have reviewed the content at least once during the history of the topic.

Disclosures

Peer reviewer affiliations and disclosures pertain to the time of the review.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25.Full text Abstract

Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers. 2018 Aug 2;4(1):11. Abstract

American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Oct 2022 [internet publication].Full text

Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023 Feb;42(2):359-70.Full text Abstract

Montero N, Favà A, Rodriguez E, et al. Treatment for hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database Syst Rev. 2018 May 7;(5):CD011403.Full text Abstract

Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022 Dec;102(6s):S129-205.Full text

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials
- Small to medium vessel vasculitis
- Cryofibrinogenemia
More Differentials
Guidelines
- Management of mixed cryoglobulinemia with rituximab
- Prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease
More Guidelines
Patient information
Hepatitis C: what is it?
Hepatitis C: what are the treatment options?
More Patient information
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Cryoglobulinemia

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic tests

1st tests to order

Tests to consider

Treatment algorithm

mixed cryoglobulinemia

malignancy-associated cryoglobulinemia (type I)

Contributors

Authors

Gurjit S. Kaeley, MBBS, MRCP

Disclosures

Peer reviewers

Morie Gertz, MD

Disclosures

Antonio Palumbo, MD

Disclosures

Xavier Leleu, MD, PhD

Disclosures

Rajan Madhok, MD, FCRP

Disclosures

Peer reviewer acknowledgements

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Patient information

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice