[citation needed] Currently, most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins.
[citation needed] This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification.
These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering Waldenström's macroglobulinemia, or Waldenström's macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free κ light chains, or free λ light chains are extremely high in patients with non-IgM MGUS, non-IgM smoldering multiple myeloma, or multiple myeloma.
The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy.
Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, blue discoloration of the arms or legs (acrocyanosis), necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, inadequate levels of oxygen in the blood (hypoxemia), and congestive heart failure.
One or more skin lesions including palpable purpura, ulcers, digital gangrene, and areas of necrosis occur in 69-89% of these mixed disease cases (see attached photograph); less common findings include painful peripheral neuropathy (often manifesting as mononeuritis multiplex in 19-44% of cases), kidney disease (primarily membranoproliferative glomerulonephritis (30%), joint pain (28%), and, less commonly, dry eye syndrome, Raynaud phenomenon (i.e., episodic painful reductions in blood flow to the fingers and toes).
[16][17] Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection.
[16] A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of Hepatitis B-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases.
[20] People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins.
Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e.g., stroke, mental impairment, and myelitis) and/or cardiovascular (e.g., congestive heart failure, myocardial infarction) disturbances; vasculitis-driven intestinal ischemia, intestinal perforation, cholecystitis, or pancreatitis, causing acute abdominal pain, general malaise, fever, and/or bloody bowel movements; vasculitis-driven pulmonary disturbances (e.g., coughing up blood, acute respiratory failure, X-ray evidence of diffuse pulmonary infiltrates caused by diffuse alveolar hemorrhage); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis.
[2][9][17] Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (see plasma cell dyscrasia, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia).
Recently, evidence of hepatitis C infection has been reported in the majority of mixed disease cases with rates being 70-90% in areas with high incidences[spelling?]
[16] Mixed cryoglobulinemic disease associated with autoimmune disorders is treated with immunosuppressive drugs: a combination of a corticosteroid with either cyclophosphamide, azathioprine, or mycophenolate or combination of a corticosteroid with rituximab have been used successfully to treated mixed disease associated with autoimmune disorders.