Updated on: 19.06.25

Introduction

• Cryoglobulins are the circulating immunoglobulins that precipitate spontaneously and reversibly in serum at less than body temperature within 3 days.
• They are insoluble at 4 degree C.
• Can fix complement and initiate inflammatory reaction.

Etiology:

• Hematologic disorders 
  • Waldenström’s macroglobulinemia
  • Multiple myeloma
  • Non-Hodgkin’s lymphoma
  • Chronic lymphocytic leukemia
  • Monoclonal gammopathy of clinical significance
• Systemic autoimmune diseases
  • Sjögren’s syndrome
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
• Chronic viral infections 
  • Hepatitis C
  • Hepatitis B
  • Human immunodeficiency virus
  • Others (very rare): Adenovirus, herpes viruses, Epstein–Barr virus, varicella–zoster virus, human T-cell leukemia virus type 1, influenza virus, parvovirus B19, rubella virus)
• Bacterial infections (e.g., brucella, infective endocarditis, Lyme disease, rickettsia, syphilis)
• Fungal infections (e.g., coccidioidomycosis)
• Parasitic infections (e.g., echinococcosis, leishmaniasis, malaria, schistosomiasis, toxoplasmosis, trypanosomiasis)

3 types of Cryoglobulinemia- Based on immunoglobulin composition of precipitate (Both Type 2 and type 3 are called mixed cryoglobulinemia)

• Type 1- 
  • Monoclonal immunoglobins especially IgM but can be IgG or IgA
  • Associated with monoclonal gammopathies of clinical significance, Waldenström’s disease, non-Hodgkin’s lymphoma, multiple myeloma, or chronic lymphocytic leukemia
• Type 2
  • Monoclonal IgM mixed with polyclonal IgG
  • Associated with chronic hepatitis C, autoimmune disorders
  • C4 levels are low
• Type 3
  • Polyclonal IgG or Polyclonal IgM or both
  • Associated with lymphoproliferative disorders and connective tissue diseases
• Essential cryoglobulinemia: Do not have any underlying cause

Clinical effects:

• Type 1 Cryoglobulinemia: 
  • Multiple thromboses of small and medium-sized vessels (Sometimes may have signs of vascular inflammation)
  • Cutaneous involvement in the form of Raynaud phenomenon, digital ischemia, livedo reticularis, and skin necrosis is common
  • Joint involvement is rare
  • Hyperviscosity symptoms are common
  • Renal involvement is due to underlying hematological malignancy
• Type 2 and 3 (Mixed cryoglobulinemia): 
  • Complement mediated immune-complex deposition leading to small vessel vasculitis
  • Skin involvement in the form of vascular purpura is often present
  • Joint and muscle involvement is present resembling Rheumatoid arthritis (But anti ccp antibody is negative)
  • Neurological involvement: Sensory–motor polyneuropathy
  • 1/3^rd patients have renal involvement: Membranoproliferative glomerulonephritis, however end stage renal failure is rare.

Pathogenesis

Chronic inflammation (HCV, Autoimmune disease etc)

↓

Polyclonal lymphoproliferation and polyclonal hypergammaglobulinemia

Later, addition of monoclonal component due to autonomous lymphoproliferation (clonal expansion)

↓

Abnormal protein precipitates at low temperature in superficial veins in skin and acral parts of the body

↓

Immune complex formation with IgG and complement fractions

↓

Tissue damage in vasculature, nerves, joints and skin with monocyte-/ macrophage-infiltration

↓

Glomerulonephritis, arthralgia, purpura with haemorrhagic necrosis

Clinical features: (Meltzer’s triad: Skin purpura- often on the legs, arthralgia, and weakness)

• Skin involvement
  • Infiltrated purpura: Usually gravity dependent (hence starts in lower limbs and then involves upper limbs)
  • Livedo reticularis
  • Nodules
  • Bullae
  • Cold urticaria
  • Skin necrosis
  • Raynaud's syndrome subsequently leading to gangrene
• Renal involvement: 
  • Proteinuria (nephrotic range)
  • Microscopic hematuria
  • Arterial hypertension
  • Tubular dysfunction
  • Renal failure
• Hyperviscosity in Type 1 ( if IgM is >4gm/dL): 
  • Blurred vision
  • Vision loss, diplopia
  • Deafness
  • Mucosal bleeding
  • Headache
  • Confusion
  • Vertigo, nystagmus, ataxia
  • Stroke
• Joint involvement: Inflammatory, bilateral, symmetric, and nondestructive arthralgias affecting large joints 
• Tenosynovitis and myalgia
• Perpheral nerve involvement: 
  • Sensory polyneuropathy
  • Sensory–motor polyneuropathy
  • Mononeuritis multiplex
• CNS involvement (Rare): Focal deficits or neurocognitive disorder

Investigations:

• Testing for cryoglobulins
  • Blood sample must be kept at 37 degree C until centrifugation in laboratory
  • After centrifugation of blood at 37°C, serum is stored at 4°C for 7 days and then centrifuged at 4°C
  • When plasma has been frozen and then slowly thawed, cryoprecipitate appears as visible layer or band at the bottom or side of the test tube
  • Further, this can be quantified
  • This test is false positive in case of presence of cryofibrinogen
• LFT: Hypergammaglobulinemia
• Immunofixation electrophoresis: To identifies the constituent immunoglobulin
• C3 and C4 levels: Decreased 
• Due to interference with auto-analysers: pseudoleukocytosis and pseudomacrocytosis
• Additional tests to identify underlying cause
• Biopsy of targeted tissue: May provide conclusive evidence
  • Kidney: Type I membranoproliferative glomerulonephritis, with  immunoglobulin and complement (C3 and C1q) deposition, endocapillary proliferation, vasculitis, or small intrarenal artery thrombosis
  • Nerve: Perivascular lymphocytic infiltrate adjacent to affected nerves
  • Skin: Vasculitis or small vessel thrombosis

Prognosis: 

• HCV associated mixed cryoglobulinemia
  • 25 to 30%- Remain asymptomatic
  • 40 to 45%- Mild cutaneous manifestations
  • 20 to 30%- Significant organ damage
  • 7 to 12%- Progress to B-cell lymphoma
  • 2 to 5%- Rapidly progressive and life-threatening vasculitis
• Type I cryoglobulinemia: 5-year overall survival is 77 to 83%

Poor prognostic markers:

• Non–HCV-related cryoglobulinemic vasculitis (including HBV related disease, underlying autoimmune diseases, and essential forms) 
• Male patients with purpura
• Type II cryoglobulinemia

Treatment Plan:

Autoimmune disease related cryoglobulinemia: Low-dose interleukin-2 may be used. It may be used in other types of cryoglobulinemia which are refractory to above treatments.

Defining features for severe disease:

• Glomerulonephritis with impaired renal function
• Motor deficit
• Multiple mononeuropathy
• Digital ischemia/ Extensive skin necrosis
• Digestive, cardiac, or pulmonary involvement

Relapsed disease:

• Retreatment with Rituximab again

About each modality of treatment:

• Rituximab:
  • 375 mg per square meter of body-surface area 
  • On days 1, 8, 15, and 22
  • In severe or life threatening cases, may consider maintenance Rituximab
  • May cause drug-induced vasculitis flare, similar to serum sickness (between days 2 and 9 after rituximab infusion, with associated mortality exceeding 50%.)
  • Use with caution in patients with HBV associated cryoglobulinemia. Adequate prophylactic therapy for HBV infection, or monitoring HBV DNA or HBsAg title should be done
• Steroids:
  • 0.5–1.0 g of methylprednisolone for 3 consecutive days, followed by tapering doses of oral prednisolone