Alpha heavy chain disease

Alpha heavy chain disease (HCD) is the most prevalent form of heavy chain diseases, a rare family of syndromes associated with or representing a B cell malignancy variant. The hallmark characteristic and the pathogenic mechanism of HCD is the synthesis of a mutant, misfolded immunoglobulin heavy chain (IgH) which cannot form a quaternary conformation with the immunoglobulin light chain (IgL) and/or be degraded by the proteasome. The isotype of mutated IgH (α,γ or μ) determines the nomenclature of HCD subtypes. More than 400 cases of alpha HCD have been reported in the literature. The distinct epidemiology of the disease, affecting low socioeconomical status individuals in the Mediterranean, North Africa, and Middle East, suggests an environmental etiologic agent. It typically affects individuals in their second and third decade of life, with a slight male predominance. Alpha HCD typically involves the small intestine (predominantly duodenum and jejunum), and presents as a malabsorption syndrome with symptoms and signs related to the severity and duration of involvement. A lymphomatous variant with predominant involvement of lymph nodes, spleen, and liver; as well as a respiratory variant with diffuse pulmonary infiltrates and restrictive pattern of respiratory function, have been reported. Diagnosis is based on laboratory findings and histologic analysis of involved organs. Based on the probable infectious pathogenesis, emphasis is on primary prevention via improvement of sanitary conditions and hygiene. Left untreated, alpha HCD locally progresses and eventually spreads systemically. A prolonged trial (> 6 months) of antimicrobial therapy is the first therapeutic approach even in the absence of a documented pathogen, followed by abdominal radiation and/or doxorubicin-based combination chemotherapy regimens plus minus surgical debulking. The five year overall survival rate after combination chemotherapy is 67%. Autologous hematopoietic stem cell transplantation should be considered in patients with relapsed/refractory disease.