Heavy Chain DiseaseEdit

Heavy chain disease is a rare group of B-cell disorders defined by the production of monoclonal, truncated immunoglobulin heavy chains that lack accompanying light chains. This abnormal secretion distinguishes heavy chain disease from more common monoclonal gammopathies, where complete immunoglobulins or light chains predominate. The best-characterized form is alpha heavy chain disease, also known as immunoproliferative small intestinal disease (IPSID), which primarily affects the gut mucosa, but gamma and mu variants exist as well. It is important to distinguish heavy chain disease from heavy chain deposition diseases, a separate set of disorders in which abnormal heavy chains deposit in tissues rather than being secreted into the blood.

Types and clinical features - Alpha heavy chain disease (IPSID) - IPSID is the classic form of heavy chain disease and is most often associated with gastrointestinal involvement. Patients typically present with chronic diarrhea, malabsorption, weight loss, abdominal pain, and edema due to protein loss. The disease can progress from an inflammatory phase to an overt lymphoproliferative disorder as the mucosa becomes infiltrated by plasmacytoid cells producing truncated heavy chains. Diagnostic features include detection of a truncated alpha heavy chain in serum and characteristic histology on intestinal biopsy. IPSID has been described in various populations, with historical clustering in certain regions, and is linked to chronic antigenic stimulation and infection. Immunoproliferative small intestinal disease; Immunoglobulin; B cells; plasma cell - Gamma heavy chain disease - Gamma heavy chain disease involves production of truncated gamma heavy chains and tends to present with more generalized lymphoproliferation, including lymphadenopathy and organomegaly. The clinical course can resemble other B-cell lymphomas and may respond to regimens used for indolent or aggressive lymphoproliferative diseases. Diagnostic workup often includes serum immunofixation showing a monoclonal heavy chain without a detectable light chain, along with tissue biopsy demonstrating clonal plasma cell–type infiltrates. gamma heavy chain disease; monoclonal gammopathy; B cell lymphoma - Mu heavy chain disease - Mu heavy chain disease is rarer still and involves truncated mu heavy chains. Presentations can overlap with other plasma cell or B-cell neoplasms and may require chemotherapy regimens used for mantle cell or other B-cell malignancies, depending on the extent of disease. mu heavy chain disease; monoclonal gammopathy; B cell lymphoma

Pathophysiology - The underlying defect in heavy chain disease is the production of abnormal heavy chains that lack complete constant regions or other segments necessary to pair with light chains. These truncated heavy chains are secreted by clonal B cells and can be detected in serum or, in some cases, urine. The absence of light chains on the secreted product helps distinguish HCD from other monoclonal gammopathies. Genetic and microenvironmental factors contribute to clonal expansion and, in IPSID, to mucosal plasmacytic infiltration of the small intestine. Related concepts include immunoglobulin structure and the biology of B cells and plasma cell differentiation.

Diagnosis - Laboratory findings - Serum protein electrophoresis and immunofixation often reveal a monoclonal heavy chain without a corresponding light chain. Quantification of immunoglobulin isotypes may show a restricted heavy chain band with absent or low light chain production. Tests for free light chains are typically negative or discordant with total immunoglobulin levels. - Clinical and histological assessment - In IPSID, endoscopic biopsy of the small intestine shows mucosal infiltration by lymphoplasmacytic cells producing truncated heavy chains, sometimes with villous atrophy and varying degrees of inflammation. Immunohistochemistry and molecular studies can establish clonality and the nature of the heavy chain product. Cross-sectional imaging may be used to stage disease and assess organ involvement. See also Immunoproliferative small intestinal disease. - Differential diagnosis - Other monoclonal gammopathies such as Waldenström macroglobulinemia (often IgM-related) or multiple myeloma can resemble heavy chain disease in presentation, but the hallmark is a monoclonal heavy chain without a complete immunoglobulin. Distinguishing features include the absence of a light chain in the secreted product and specific tissue pathology. Monoclonal gammopathy; Ig isotypes

Treatment and prognosis - IPSID (alpha heavy chain disease) - In early, antibiotic-responsive stages, treatment with antimicrobials such as tetracycline or other courses targeting associated infections (for example, Campylobacter jejuni) can reduce antigenic stimulation and lead to symptomatic improvement. Nutritional support is important due to malabsorption. For more advanced disease or transformation to overt lymphoma, chemotherapy regimens used for B-cell lymphomas may be employed, including combinations like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone). Rituximab-based therapy has been used in some B-cell neoplasms with relevant marker expression. [ [Campylobacter jejuni]] exposure is sometimes discussed in IPSID context as a potential driver of mucosal immune activation. CHOP chemotherapy; CVP chemotherapy; Rituximab. - Gamma and mu heavy chain disease - These variants are managed more like other B-cell or lymphoplasmacytic neoplasms, with systemic chemotherapy tailored to disease extent and patient factors. Aggressive disease or transformation to high-grade lymphoma may necessitate intensive regimens and sometimes stem cell transplantation in select cases. See also monoclonal gammopathy and B cell lymphoma.

Epidemiology and history - Heavy chain disease is a rare condition, with alpha-HCD (IPSID) historically described in certain populations and regions, particularly where chronic mucosal immune stimulation is more common. The gamma and mu forms are far less common and can present with more generalized lymphoproliferation. The understanding of HCD has evolved with advances in immunohistochemistry and molecular diagnostics, clarifying distinctions from tissue-depositing heavy chain diseases and other monoclonal gammopathies. Immunoproliferative small intestinal disease

See also - Immunoproliferative small intestinal disease - gamma heavy chain disease - mu heavy chain disease - Heavy chain deposition disease - Monoclonal gammopathy - Waldenström macroglobulinemia - Multiple myeloma - Immunoglobulin