Since the first description of<unk>  in association with the clinical triad of skin purpura, joint pain, and weakness by Meltzer et al. in 1967, the percentage of<unk>  diseases described as essential<unk>  or idiopathic<unk> , that is<unk>  disease that is unassociated with an underlying disorder, has fallen. 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. This form of non-essential or non-idiopathic<unk>  disease is classically grouped into three types according to the Brouet classification. The classification distinguishes three subtypes of<unk>  diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the<unk>  disease with other disorder. The following table lists these three types of<unk>  disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total<unk>  disease cases, and class of disorders associated for each type. Type Composition Percent of cases Association with other diseases Type I Monoclonal IgG, IgM, IgA, or their κ or λ light chains 10–15% Hematological diseases, particularly MGUS, smoldering multiple myeloma, multiple myeloma, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia Type II Monoclonal IgM plus polyclonal IgG or, rarely, IgA 50–60% Infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection; hematological diseases particularly B cell disorders; autoimmune diseases Type III Polyclonal IgM plus polyclonal IgG or IgA 25–30% Autoimmune diseases, particularly Sjögren syndrome and less commonly systemic lupus erythematosus and rheumatoid arthritis; infectious diseases particularly HCV infection The monoclonal or polyclonal IgM proteins involved in Types II and III<unk>  disease have rheumatoid factor activity. That is, they bind to polyclonal immunoglobulins, activate the blood complement system, and thereby form tissue deposits that contain IgM, IgG (or, rarely, IgA), and components of the complement system, including in particular complement component 4. The vascular deposition of these types of cryoglobulin-containing immune complexes and complement can cause a clinical syndrome of cutaneous small-vessel vasculitis characterized by systemic vasculitis and inflammation termed<unk>  vasculitis. Accordingly, type II and type III<unk>  diseases are often grouped together and referred to as mixed<unk>  or mixed<unk>  disease. The monoclonal IgM involved in Type I<unk>  diseases lacks rheumatoid factor activity. More recent high resolution protein electrophoresis methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of ≈10% of type II and III disease cases. It has been proposed that these cases be termed an intermediate type II-III variant of<unk>  disease and that some of the type III cases associated with the expression of low levels of a one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease.
Cryoglobulinemia
Myoglobinuria
Hemoglobinuria
Hemosiderinuria
Trimethylaminuria
Lipiduria
Pentosuria
Xanthinuria