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Heavy Chain Diseases


James R. Berenson

, MD, Institute for Myeloma and Bone Cancer Research

Last full review/revision Sep 2019| Content last modified Sep 2019
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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 (monoclonal immunoglobulin protein) 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 alpha [α], gamma [γ], mu [μ], or delta [δ]) without light chains (epsilon [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 Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma and non-Hodgkin lymphoma (see table Comparison of... read more than multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Multiple Myeloma . Heavy chain diseases are considered in patients with clinical manifestations suggesting lymphoproliferative disorders.

IgA Heavy Chain Disease (alpha 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.

Common manifestations include fever, mild anemia, difficulty swallowing (dysphagia), recurrent upper respiratory infections, and enlarged liver and spleen. Osteolytic lesions do not occur.

Almost all patients present with diffuse abdominal lymphoma and malabsorption Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more . Complete blood count (CBC) may show anemia, leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to read more , thrombocytopenia, eosinophilia Eosinophilia Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction or a parasitic infection... read more Eosinophilia , and circulating atypical lymphocytes or plasma cells. Serum protein electrophoresis is normal in half of cases; often, there are increased alpha-2 and beta fractions or a decreased gamma fraction. Diagnosis requires the detection of a monoclonal alpha chain on immunofixation electrophoresis. This chain is sometimes found in concentrated urine. If it cannot be found in serum or urine, intestinal 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 years, whereas others have remissions that last many years, particularly after treatment with corticosteroids, cytotoxic drugs, and broad-spectrum antibiotics.

IgG Heavy Chain Disease (Gamma 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 older men but can occur in children. Associated chronic disorders include rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily involves the joints. RA causes damage mediated by cytokines, chemokines, and metalloproteases. Characteristically... read more Rheumatoid Arthritis (RA) , Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes due... read more Sjögren Syndrome , systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) , tuberculosis Tuberculosis (TB) Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more Tuberculosis (TB) , myasthenia gravis Myasthenia Gravis Myasthenia gravis involves episodic muscle weakness and easy fatigability caused by autoantibody- and cell-mediated destruction of acetylcholine receptors. It is more common among young women... read more , hypereosinophilic syndrome Hypereosinophilic Syndrome Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more , autoimmune hemolytic anemia Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia is caused by autoantibodies that react with red blood cells at temperatures ≥ 37° C (warm antibody hemolytic anemia) or 37° C (cold agglutinin disease). Hemolysis... read more Autoimmune Hemolytic Anemia , and thyroiditis. Reductions in normal immunoglobulin levels occur. Lytic bone lesions are uncommon. Amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more 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 (10 g/L) (often broad and heterogeneous), and half have proteinuria > 1 g/24 hours. 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 year. 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 (mu 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 years. Visceral organ involvement (spleen, liver, abdominal lymph nodes) is common, but extensive peripheral lymphadenopathy is not. Pathologic fractures and amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more 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 Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow... read more 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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