Diseases of heavy chains: causes, symptoms, diagnosis, treatment

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

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Heavy chain diseases are plasma cell diseases that are usually malignant. In most plasma cell diseases, the M protein is structurally similar to a normal antibody molecule. In contrast, in heavy chain diseases, incomplete monoclonal immunoglobulins (true paraproteins) are produced. They consist only of heavy chain components (c or 5) without light chains. Heavy chain disease has not been described. Most heavy chain proteins are fragments of their normal copies with deletions of varying lengths; these deletions result from structural mutations. The clinical picture resembles lymphoma more than multiple myeloma. Heavy chain disease is suspected in patients with clinical manifestations suggesting a lymphoproliferative disorder.

IgA heavy chain disease

IgA heavy chain disease is the most common heavy chain disease and is similar to Mediterranean lymphoma or immunoproliferative disease of the small intestine.

IgA heavy chain disease usually presents between the ages of 10 and 30 years and is geographically concentrated in the Middle East. It may be caused by an impaired immune response to invasion or infection. There is usually villous atrophy and plasma cell infiltration of the jejunal mucosa and occasionally enlargement of the mesenteric lymph nodes. Peripheral lymph nodes, bone marrow, liver, and spleen are usually spared. Rare cases of a respiratory form of the disease have been reported. Osteolytic lesions do not occur.

Almost all patients have features of diffuse abdominal lymphoma and malabsorption. Serum protein electrophoresis is normal in half of the cases; there is often an increase in the a ₂ - and b-fractions or a decrease in the f-fraction. To establish the diagnosis, it is necessary to determine the monoclonal chain by electrophoresis with immunofixation. This chain is sometimes detected in urine concentrate. If it cannot be detected in blood and urine, a biopsy is necessary. The abnormal protein can sometimes be detected in intestinal secretions. Intestinal infiltration may be pleomorphic and have no clear signs of malignancy. Bence Jones proteinuria is absent.

The course of the disease can vary. Some patients die within 1-2 years, while others live in remission for many years, especially after treatment with glucocorticoids, cytostatic drugs and broad-spectrum antibiotics.

IgG heavy chain disease

IgG heavy chain disease usually resembles aggressive malignant lymphoma, but is sometimes asymptomatic and benign.

IgG heavy chain disease occurs predominantly in elderly men, but can also develop in children. Associated chronic diseases are rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, tuberculosis, myasthenia gravis, hypereosinophilic syndrome, autoimmune hemolytic anemia, and thyroiditis. There is a decrease in the level of normal immunoglobulins. Lytic changes in bones are not typical. Sometimes amyloidosis develops. Common clinical manifestations are lymphadenopathy, hepatosplenomegaly, fever, recurrent infections. Edema of the palate is present in 1/4 of patients.

Blood tests show anemia, leukopenia, thrombocytopenia, eosinophilia, and circulating atypical lymphocytes and plasma cells. Diagnosis requires detection of free monoclonal heavy chain fragments of IgG in serum and urine by immunofixation. About half of patients have a monoclonal serum component greater than 1 g/dL (often broad and heterogeneous), and half have proteinuria greater than 1 g/24 h. Although the heavy chain proteins may include any subclass of IgG, subclass G3 is most common. In the absence of sufficient data for diagnosis, bone marrow or lymph node biopsy is performed, which reveals variable histopathology.

The median survival for aggressive disease is about 1 year. Deaths usually result from bacterial infection or disease progression. Alkylating agents, vincristine, glucocorticoids, and radiation therapy may induce temporary remission.

IgM heavy chain disease

IgM heavy chain disease is rare and has a clinical picture similar to chronic lymphocytic leukemia or other lymphoproliferative disorders.

IgM heavy chain disease most often affects people over 50 years of age. Visceral organs (spleen, liver, abdominal lymph nodes) are typically affected, but severe peripheral lymphadenopathy is usually not present. Pathological fractures and amyloidosis occur. Serum protein electrophoresis is usually within normal limits or shows hypogammaglobulinemia. Bence Jones proteinuria (type K) is present in 10-15% of patients. Diagnosis requires bone marrow examination, where vacuolated plasma cells are found in 1/3 of patients, which is a characteristic feature of the disease. Life expectancy ranges from several months to many years. The most common cause of death is uncontrolled proliferation of leukemic cells. Treatment consists of alkylating agents and glucocorticoids or may be similar to the treatment of lymphoproliferative disease, with which this pathology has the greatest similarity.