Chapter 71: Heavy-Chain Diseases

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Heavy-Chain Diseases. In: Lichtman MA, Kaushansky K, Kipps TJ, Prchal JT, Levi MM. Lichtman M.A., Kaushansky K, Kipps T.J., Prchal J.T., Levi M.M. Eds. Marshall A. Lichtman, et al.eds. Williams Manual of Hematology, 8e New York, NY: McGraw-Hill; . http://hemonc.mhmedical.com/content.aspx?bookid=1783&sectionid=121723057. Accessed September 21, 2018.

MLA Citation
. "Heavy-Chain Diseases." Williams Manual of Hematology, 8e Lichtman MA, Kaushansky K, Kipps TJ, Prchal JT, Levi MM. Lichtman M.A., Kaushansky K, Kipps T.J., Prchal J.T., Levi M.M. Eds. Marshall A. Lichtman, et al. New York, NY: McGraw-Hill, , http://hemonc.mhmedical.com/content.aspx?bookid=1783&sectionid=121723057.

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DEFINITION

The heavy-chain diseases (HCDs) are neoplastic disorders of B cells that produce monoclonal immunoglobulins (Ig) consisting of truncated heavy chains without attached light chains.
The diagnosis is established from immunofixation of serum, urine, or secretory fluids in the case of α-HCD or from immunohistologic analysis of the proliferating lymphoplasmacytic cells in nonsecretory disease.
In decreasing order of incidence, HCD involves synthesis of defective α, γ, or μ heavy chains.
There is a high frequency of autoimmune disorders preceding or concurrent with the diagnosis of HCD, particularly γ-HCD.
Table 71–1 summarizes the clinical features of the three types of HCD.

TABLE 71–1SUMMARY OF FEATURES OF THE HEAVY-CHAIN DISEASES

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TABLE 71–1 SUMMARY OF FEATURES OF THE HEAVY-CHAIN DISEASES

	Type of Heavy-Chain Disease
Feature	α	γ	μ
Year described	1968	1964	1969
Incidence	Rare	Very rare	Very rare
Age at diagnosis	Young adult (<30 years)	Older adult (60–70 years)	Older adult (50–60 years)
Demographics	Mediterranean region	Worldwide	Worldwide
Structurally abnormal monoclonal protein	IgA	IgG	IgM
MGUS phase	No	Rarely	Rarely
Urine monoclonal light chain	No	No	Yes
Urine abnormal heavy chain	Small amounts	Often present	Infrequent
Sites involved	Small intestine, mesenteric lymph nodes	Lymph nodes, marrow, spleen	Lymph nodes, marrow, liver, spleen
Pathology	Extranodal marginal zone lymphoma (MALT or IPSID)	Lymphoplasmacytoid lymphoma	Small lymphocytic lymphoma, CLL
Associated diseases	Infection, malabsorption	Autoimmune diseases	None
Therapy	Antibiotics, chemotherapy	Chemotherapy	Chemotherapy

CLL, chronic lymphocytic leukemia; Ig, immunoglobulin; IPSID, immunoproliferative small intestinal disease; MALT, mucosa-associated lymphoid tissue; MGUS, monoclonal gammopathy of undetermined significance.

Adapted with permission from Witzig TE, Wahner-Roedler DL: Heavy chain disease. Curr Treat Options Oncol 3:247, 2002.

Source: Williams Hematology, 8th ed, Chap. 112, Table 112–1, p. 1710.

ETIOLOGY AND PATHOGENESIS

The etiology of γ-HCD and μ-HCD is unknown.
In α-HCD, the lymphoplasmacytic infiltration of the intestinal mucosa is thought to be a response of the alimentary tract immune system to protracted luminal antigenic stimulation.

CLINICAL AND LABORATORY FEATURES

γ-HCD

Median age at presentation is in the late sixties.
Clinical features different from those of myeloma because renal disease and osteolytic lesions rarely occur.
Has various clinical and pathologic features that can be divided into three broad categories:

— Disseminated lymphoproliferative disease.

— Localized proliferative disease: Approximately 25 percent of patients.

— No apparent proliferative disease: Approximately 15 percent of patients.
Most γ-HCD proteins are dimers of truncated heavy chains without associated light chains.
The serum protein electrophoretic pattern is extremely variable, but a monoclonal peak is detected in over two-thirds of patients.
The median value of the monoclonal spike at diagnosis in one study of 19 patients was 1.6 g/dL.
The amount of HCD protein in the urine usually is small (<1 g/24 h), but may reach 20 g/24 h.
Patients commonly have moderate, normochromic, normocytic anemia.
Autoimmune hemolytic anemia has been reported.
Bone lesions are rare.