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Heavy Chain Diseases

by James R. Berenson, MD

Heavy chain diseases are neoplastic plasma cell disorders characterized by overproduction of monoclonal immunoglobulin heavy chains. Symptoms, diagnosis, and treatment vary according to the specific disorder.

Heavy chain diseases are plasma cell disorders that are typically malignant. In most plasma cell disorders, M-proteins are structurally similar to normal antibody molecules. In contrast, in heavy chain diseases, incomplete monoclonal immunoglobulins (true paraproteins) are produced. They consist of only heavy chain components (either α, γ, μ, or δ) without light chains (ε heavy chain disease has not been described). Most heavy chain proteins are fragments of their normal counterparts with internal deletions of variable length; these deletions appear to result from structural mutations. The clinical picture is more like lymphoma than multiple myeloma. Heavy chain diseases are considered in patients with clinical manifestations suggesting lymphoproliferative disorders.

IgA Heavy Chain Disease

(-Chain Disease)

IgA heavy chain disease is the most common heavy chain disease and is similar to Mediterranean lymphoma (immunoproliferative small intestinal disease).

IgA heavy chain disease usually appears between ages 10 and 30 and is geographically concentrated in the Middle East. The cause may be an aberrant immune response to a parasite or other microorganism. Villous atrophy and plasma cell infiltration of the jejunal mucosa are usually present and, sometimes, infiltration of the mesenteric lymph nodes. The peripheral lymph nodes, bone marrow, liver, and spleen usually are not involved. A respiratory tract form of the disease has been reported rarely. Osteolytic lesions do not occur.

Almost all patients present with diffuse abdominal lymphoma and malabsorption. CBC may show anemia, leukopenia, thrombocytopenia, eosinophilia, and circulating atypical lymphocytes or plasma cells. Serum protein electrophoresis is normal in half of cases; often, there is an increased α 2 and β fraction or a decreased γ fraction. Diagnosis requires the detection of a monoclonal α chain on immunofixation electrophoresis. This chain is sometimes found in concentrated urine. If it cannot be found in serum or urine, biopsy is required. The abnormal protein can sometimes be detected in intestinal secretions. The intestinal cellular infiltrate may be pleomorphic and not overtly malignant. Bence Jones proteinuria is absent.

The course is highly variable: Some patients die in 1 to 2 yr, whereas others have remissions that last many years, particularly after treatment with corticosteroids, cytotoxic drugs, and broad-spectrum antibiotics.

IgG Heavy Chain Disease

(-Chain Disease)

IgG heavy chain disease is generally similar to an aggressive malignant lymphoma but is occasionally asymptomatic and benign.

IgG heavy chain disease occurs primarily in elderly men but can occur in children. Associated chronic disorders include RA, Sjögren syndrome, SLE, TB, myasthenia gravis, hypereosinophilic syndrome, autoimmune hemolytic anemia, and thyroiditis. Reductions in normal immunoglobulin levels occur. Lytic bone lesions are uncommon. Amyloidosis sometimes develops.

Common manifestations include lymphadenopathy and hepatosplenomegaly, fever, and recurring infections. Palatal edema occurs in about one quarter of patients.

The CBC may show anemia, leukopenia, thrombocytopenia, eosinophilia, and circulating atypical lymphocytes or plasma cells. Diagnosis requires demonstration by immunofixation of free monoclonal heavy chain fragments of IgG in serum and urine. Of affected patients, half have monoclonal serum components > 1 g/dL (often broad and heterogeneous), and half have proteinuria > 1 g/24 h. Although heavy chain proteins may involve any IgG subclass, the G3 subclass is especially common. Bone marrow or lymph node biopsy, done if other tests are not diagnostic, reveals variable histopathology.

The median survival with aggressive disease is about 1 yr. Death usually results from bacterial infection or progressive malignancy. Alkylating agents, vincristine, or corticosteroids, and radiation therapy may yield transient remissions.

IgM Heavy Chain Disease

(-Chain Disease)

IgM heavy chain disease, which is rare, produces a clinical picture similar to chronic lymphocytic leukemia or other lymphoproliferative disorders.

IgM heavy chain disease most often affects adults > 50 yr. Visceral organ involvement (spleen, liver, abdominal lymph nodes) is common, but extensive peripheral lymphadenopathy is not. Pathologic fractures and amyloidosis may occur. Serum protein electrophoresis usually is normal or shows hypogammaglobulinemia. Bence Jones proteinuria (type κ) is present in 10 to 15% of patients. CBC may show anemia, leukopenia, thrombocytopenia, eosinophilia, and circulating atypical lymphocytes or plasma cells.

Diagnosis usually requires bone marrow examination; vacuolated plasma cells are present in two thirds of patients and, when present, are virtually pathognomonic. Death can occur in a few months or in many years. The usual cause of death is uncontrollable proliferation of chronic lymphocytic leukemia cells.

Treatment depends on the patient’s condition but may consist of alkylating agents plus corticosteroids or may be similar to treatment of the lymphoproliferative disorder that it most closely resembles.

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