Cryoglobulinaemia
Summary
Cryoglobulinaemia is a condition characterised by immunoglobulins that precipitate in the cold (at temperatures below 37°C) and redissolve on warming. Cryoglobulins deposit in small and medium vessels, causing vasculitis. The condition is classified into three types: Type 1 (monoclonal, associated with haematological malignancies), Type 2 (mixed with monoclonal IgM against polyclonal IgG — strongly associated with Hepatitis C), and Type 3 (mixed polyclonal). The classic clinical triad (Meltzer's triad) is purpura, arthralgia, and weakness. Renal involvement typically manifests as membranoproliferative glomerulonephritis (MPGN). Laboratory hallmarks include low C4 (with normal C3) and positive rheumatoid factor. Treatment depends on the underlying cause: Hepatitis C-associated cryoglobulinaemia is treated with direct-acting antivirals (DAAs); severe cases require rituximab and/or plasma exchange.
Key Facts
- Definition: Immunoglobulins that precipitate in the cold
- Type 1: Monoclonal (myeloma, Waldenström's); vascular occlusion
- Type 2: Monoclonal IgM + Polyclonal IgG; 90% associated with Hepatitis C
- Type 3: Polyclonal IgM + Polyclonal IgG; autoimmune diseases
- Clinical triad (Meltzer's): Purpura + Arthralgia + Weakness
- Renal involvement: Membranoproliferative glomerulonephritis (MPGN)
- Laboratory: Low C4; Positive rheumatoid factor
- Treatment: DAAs for HCV; Rituximab for severe vasculitis
Clinical Pearls
"Low C4 + RF Positive = Think Cryoglobulinaemia": The combination of low C4 (with normal or near-normal C3), positive rheumatoid factor, and vasculitic features should prompt testing for cryoglobulins.
"HCV Is the Cause in 90% of Type 2": Mixed cryoglobulinaemia (Type 2/3) is most commonly caused by Hepatitis C. Treating HCV with DAAs often cures the cryoglobulinaemia.
"Keep the Sample Warm": Cryoglobulins precipitate in the cold. Blood samples must be kept at 37°C during transport to the lab, or false negatives result.
"Type 1 = Hyperviscosity": Type 1 cryoglobulinaemia (monoclonal) causes vascular occlusion and hyperviscosity rather than immune complex vasculitis.
Why This Matters Clinically
Cryoglobulinaemia is often underdiagnosed. Recognising the clinical triad and laboratory pattern leads to testing for underlying causes (HCV, haematological malignancy, autoimmune disease) and appropriate treatment. Early treatment of HCV-associated cryoglobulinaemia prevents progressive renal and vascular damage.[1,2]
Incidence & Prevalence
| Parameter | Data |
|---|---|
| Prevalence | Rare (~1:100,000); underdiagnosed |
| HCV-associated | 40-60% of HCV patients have detectable cryoglobulins; ~10-30% symptomatic |
| Age | Middle-aged to elderly |
| Sex | Female predominance in mixed type |
Classification
| Type | Composition | Association |
|---|---|---|
| Type 1 | Monoclonal (IgM or IgG) | Myeloma, Waldenström's, CLL |
| Type 2 | Monoclonal IgM + Polyclonal IgG | Hepatitis C (90%), Autoimmune |
| Type 3 | Polyclonal IgM + Polyclonal IgG | Autoimmune, Infections |
Mechanism
Type 1 (Monoclonal):
- Excessive production of monoclonal immunoglobulin
- Precipitates in cold → Vascular occlusion (NOT immune complex)
- Hyperviscosity syndrome
Type 2/3 (Mixed):
- Immune complex formation (IgM-IgG complexes)
- Cryoprecipitation in vessels
- Complement activation (classical pathway → Low C4)
- Vasculitis of small/medium vessels
- Deposition in glomeruli → MPGN
Hepatitis C and Cryoglobulinaemia
| Feature | Details |
|---|---|
| Mechanism | HCV triggers B-cell proliferation → RF-producing B cells |
| Lymphoproliferation | Chronic B-cell stimulation → Risk of lymphoma |
| Immune complexes | HCV + anti-HCV + IgM-RF form cryoprecipitating complexes |
Meltzer's Triad
| Feature | Description |
|---|---|
| Purpura | Palpable, often on lower limbs |
| Arthralgia | Joint pain without deformity |
| Weakness | Fatigue and malaise |
Multi-System Involvement
| System | Manifestation |
|---|---|
| Skin | Palpable purpura; Livedo reticularis; Ulcers; Digital gangrene |
| Renal | MPGN; Proteinuria; Haematuria; Renal impairment |
| Neurological | Peripheral neuropathy (sensorimotor); Mononeuritis multiplex |
| Joints | Arthralgias; Rarely arthritis |
| Hepatic | Hepatomegaly (HCV infection) |
| Sicca | Dry eyes/mouth (overlap with Sjögren's) |
Type 1 Specific Features
| Feature | Notes |
|---|---|
| Hyperviscosity | Headache, visual changes, confusion |
| Raynaud's phenomenon | Cold exposure triggers |
| Acral necrosis | Finger/toe gangrene |
| Livedo reticularis | Violaceous net-like pattern |
Skin
- Palpable purpura (especially lower limbs, buttocks)
- Livedo reticularis
- Ulcers (ankles)
- Digital ischaemia or gangrene
Neurological
- Sensory loss (stocking distribution)
- Weakness (if motor involvement)
- Absent reflexes
Other
- Hepatosplenomegaly (HCV, lymphoma)
- Joint tenderness without swelling
- Hypertension (renal involvement)
Blood Tests
| Test | Finding | Interpretation |
|---|---|---|
| Cryoglobulins | Positive | Must keep sample warm; takes 7 days |
| Complement C4 | Low | Classical pathway consumption |
| Complement C3 | Normal or low | |
| Rheumatoid factor | Positive | IgM anti-IgG |
| HCV serology and RNA | Positive (90% Type 2) | Underlying cause |
| FBC | Anaemia; Thrombocytopenia | Chronic disease; Hypersplenism |
| U&E, eGFR | Raised creatinine | Renal involvement |
| SPEP/UPEP | Paraprotein | Type 1 (myeloma) |
Urine
| Test | Finding |
|---|---|
| Urinalysis | Proteinuria, Haematuria |
| 24h protein | Nephrotic range possible |
Renal Biopsy
| Histology | Features |
|---|---|
| MPGN Type 1 | Subendothelial deposits; Double contours ("tram-track") |
| Intraluminal thrombi | Cryoglobulin precipitates |
| Immunofluorescence | IgG, IgM, C3 deposition |
Management Algorithm
CRYOGLOBULINAEMIA MANAGEMENT
↓
┌────────────────────────────────────────────────────────────┐
│ CONFIRM DIAGNOSIS │
├────────────────────────────────────────────────────────────┤
│ ➤ Cryoglobulin test (keep sample at 37°C!) │
│ ➤ Complement: Low C4 (often normal C3) │
│ ➤ Rheumatoid factor: Positive │
│ ➤ Classify type (immunofixation): Type 1, 2, or 3 │
└────────────────────────────────────────────────────────────┘
↓
┌────────────────────────────────────────────────────────────┐
│ IDENTIFY UNDERLYING CAUSE │
├────────────────────────────────────────────────────────────┤
│ TYPE 1: │
│ ➤ Screen for myeloma, Waldenström's, CLL │
│ ➤ SPEP, UPEP, immunofixation, bone marrow if needed │
│ │
│ TYPE 2/3: │
│ ➤ Hepatitis C serology + RNA (~90% of mixed type) │
│ ➤ Hepatitis B │
│ ➤ HIV │
│ ➤ Autoimmune screen (ANA, ENA, Sjögren's) │
└────────────────────────────────────────────────────────────┘
↓
┌────────────────────────────────────────────────────────────┐
│ TREATMENT │
├────────────────────────────────────────────────────────────┤
│ HCV-ASSOCIATED (Type 2): │
│ ➤ Direct-Acting Antivirals (DAAs) — first-line │
│ ➤ Treating HCV often cures cryoglobulinaemia │
│ │
│ MILD DISEASE (Purpura, Arthralgias): │
│ ➤ Treat underlying cause │
│ ➤ Avoid cold exposure │
│ ➤ NSAIDs or low-dose steroids for symptoms │
│ │
│ MODERATE-SEVERE DISEASE (Renal, Neuropathy, Ulcers): │
│ ➤ Rituximab (anti-CD20) — first-line immunosuppression │
│ ➤ Corticosteroids (Prednisolone 1 mg/kg) │
│ ➤ Cyclophosphamide if rituximab-refractory │
│ │
│ LIFE-THREATENING (RPGN, Severe Vasculitis): │
│ ➤ Plasma exchange (PLEX) │
│ ➤ + Rituximab + Corticosteroids │
│ │
│ TYPE 1 (Monoclonal): │
│ ➤ Treat underlying malignancy │
│ ➤ Plasma exchange for hyperviscosity / acute ischaemia │
└────────────────────────────────────────────────────────────┘
| Complication | Notes |
|---|---|
| RPGN | Rapidly progressive renal failure |
| Digital gangrene | Especially Type 1 |
| B-cell lymphoma | Chronic B-cell stimulation (HCV-associated) |
| Chronic kidney disease | Progressive MPGN |
| Severe neuropathy | Motor and sensory deficits |
| Factor | Outcome |
|---|---|
| HCV eradication with DAAs | Excellent; often cures cryoglobulinaemia |
| Type 1 (malignancy) | Depends on underlying condition |
| Renal involvement | Worse prognosis without treatment |
| Rituximab response | Good in majority |
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| EASL HCV Guidelines | EASL | 2020 | DAA treatment; cryoglobulinaemia management |
What is cryoglobulinaemia?
Cryoglobulinaemia is a condition where abnormal proteins in your blood clump together in cold temperatures. These clumps can block small blood vessels and cause inflammation.
What causes it?
Most commonly, it's linked to Hepatitis C virus infection. It can also occur with blood cancers or autoimmune diseases.
What are the symptoms?
- Purple spots on the skin (especially legs)
- Joint pain
- Tiredness
- Kidney problems
- Numbness or tingling in hands/feet
How is it treated?
- Treating the Hepatitis C with antiviral tablets often cures it
- Avoiding cold temperatures
- Medications to reduce inflammation (steroids, rituximab)
- Plasma exchange for severe cases
- Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol. 2002;55(1):4-13. PMID: 11825916
High-Yield Exam Topics
| Topic | Key Points |
|---|---|
| Classification | Type 1 (monoclonal); Type 2/3 (mixed) |
| HCV association | 90% of mixed cryoglobulinaemia |
| Meltzer's triad | Purpura + Arthralgia + Weakness |
| Lab findings | Low C4; RF positive; Cryoglobulins positive |
| Renal | MPGN Type 1 |
| Treatment | DAAs for HCV; Rituximab for severe |
| Sample handling | Keep warm (37°C) |
Sample Viva Question
Q: How do you diagnose and manage HCV-associated cryoglobulinaemia?
Model Answer: Diagnosis requires: positive cryoglobulin test (sample kept at 37°C), low C4, positive rheumatoid factor, and positive HCV RNA. Renal biopsy may show MPGN. Treatment: First-line is Direct-Acting Antivirals (DAAs) to eradicate HCV — this often cures the cryoglobulinaemia. For severe disease (renal involvement, neuropathy), add Rituximab ± corticosteroids. Plasma exchange for life-threatening manifestations.
Last Reviewed: 2025-12-24 | MedVellum Editorial Team