Polyclonal gammopathy usually reflects one of five major disorders, including liver disease, connective tissue disorders, infections, hematologic disorders, and solid tumors. IL-6 and IL-10 have been implicated in polyclonal gammopathy, as have defects in T cells and chronic antigenic stimulation, but the exact sequence of events leading to poly clonal B-cell activation is not known. In general, treatment is directed at the underlying disease, but there are reports of polyclonal gammopathy leading to symptomatic hyperviscosity. In these cases, plasmapheresis and/or corticosteroids seem to be effective. It should also be noted that polyclonal elevations in serum immunoglobulins can sometimes interfere with the direct Coombs test, possibly via nonspecific antibody binding to red blood cells. The degree of gamma globulin elevation does not seem to be helpful in defining the underlying disease state.
In the largest recent review of polyclonal gammopathy, the majority of patients had liver disease, which covered the spectrum from autoimmune disorders (autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis) to viral hepatitis, and alcoholic liver dis ease. In fact, elevation of serum gamma globulins is a distinguishing characteristic of autoimmune hepatitis, and the levels usually correlate with activity of disease. The most common etiology for polyclonal gammopathy related to liver disease in the United States is likely infection with HCV, but in any particular clinical setting, the exact distribution likely depends on the population demographic. Other diseases affecting the liver, such as α1-antitrypsin deficiency and hemochromatosis, are also accompanied by increases in serum immunoglobulins.
Connective tissue diseases, including Sjögren syndrome, SLE, ankylosing spondylitis, and rheumatoid arthritis, are also accompanied by polyclonal gammopathy. In many of these diseases, the degree of gamma globulin elevation may reflect disease activity, although a causative link between the autoimmune phenomena and immunoglobulin levels has not been determined. Several of the periodic fever syndromes, which are sometimes classified with the connective tissue disorders, have elevated immunoglobulin levels as a part of their manifestations. Hyperimmunoglobulinemia D is one such syndrome and is linked to mutations in the mevalonate kinase gene. Patients with this disorder present in the first year of life with febrile attacks, lymphadenopathy, abdominal symptoms, arthritis, and oral and genital ulcers. Most, but not all, patients have elevated levels of polyclonal IgD during and between episodes often accompanied by elevated IgA levels. TNF receptor 1-associated periodic syndrome (TRAPS) results from mutation in the gene (TNRFRSF1A) for the TNF receptor 1 and can cause prolonged febrile attacks with abdominal pain, arthralgias, and myalgias. During attacks, polyclonal elevation of immunoglobulins (primarily IgA) is observed.
Infections, usually chronic in nature, are frequently accompanied by polyclonal gammopathy. HIV infection is a common cause, and immunoglobulin levels tend to increase slowly until the diagnosis of acquired immunodeficiency syndrome (AIDS) and then decline over the ensuing 6 to 18 months. Polyclonal gammopathy can be a clue to occult infections such as subacute bacterial endocarditis, tuberculosis, perinephric abscess, Lyme disease, and a variety of parasitic infections.
Malignant B- and T-cell disorders can cause polyclonal hypergammaglobulinemia. These diseases include CLL; large granular lymphocytic leukemia; hairy cell leukemia; and angioimmunoblastic T-cell lymphoma (AITL), a rare disease characterized by rash, widespread lymphadenopathy and extranodal involvement, autoimmune phenomena, and polyclonal gammopathy. Interestingly, despite the elevated levels of immunoglobulins observed in AITL, patients exhibit immunodeficiency and a propensity to develop opportunistic infections. Patients with myeloid disorders can also have polyclonal gammopathies; in one large series, nearly 40% of patients with MDS had hypergammaglobulinemia, and patients with immunologic abnormalities had inferior survival. The incidence of hypergammaglobulinemia is reported to approach 50% in chronic myelomonocytic leukemia (CMML). Hypergammaglobulinemia has been reported in AML both in adults and children, but it appears to be a rare phenomenon. Among solid tumors, ovarian and hepatocellular cancers are most commonly associated with polyclonal gammopathy. There are case reports of cancers, particularly lung and breast tumors, producing and releasing the secretory component (SC) of IgA into the bloodstream with the binding of SC to polyclonal IgA, producing hypergammaglobulinemia of serum sIgA.
A variety of other diseases, including asbestos exposure and several subtypes of hypersensitivity pneumonitis and idiopathic interstitial pneumonia, are associated with polyclonal gammopathy. In general, these disorders represent diffuse activation of B cells. Of note, there are reports of polyclonal gammopathy resulting in symptomatic hyperviscosity and these cases have been treated successfully with corticosteroids or plasmapheresis.
