The heavy chain diseases

INTRODUCTION — The heavy chain diseases (HCDs) are rare B cell proliferative disorders characterized by the production of a monoclonal (M) protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain [1-6]. The heavy chain in HCD is often incomplete or truncated and a sharp, localized peak may not be seen on the electrophoretic tracing of serum or urine.

The HCDs will be reviewed here. Heavy chain deposition disease is a different disorder that is discussed in detail elsewhere, in which abnormal heavy chains or short (truncated) heavy chains cause fibrillar or granular tissue deposits. (See "Monoclonal immunoglobulin deposition disease" and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

OVERVIEW — Three types of HCDs are recognized, based on the class of immunoglobulin heavy chain produced (eg, alpha, gamma, mu) by the malignant cell [3,5,6]:

●Alpha HCD is a form of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) that is also called immunoproliferative small intestinal disease (IPSID), Mediterranean lymphoma, or Seligmann disease. (See 'Alpha HCD' below and "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine' and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

●Gamma HCD (Franklin's disease) is typically associated with the presence of a systemic lymphoma, often of mixed lymphoid-plasmacytic character. (See 'Gamma HCD' below.)

●Mu HCD has clinical features resembling small lymphocytic lymphoma/chronic lymphocytic leukemia, often with distinctive vacuolated lymphocytes/plasma cells in the bone marrow. (See 'Mu HCD' below.)

Prognosis of the HCDs is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics [2]. (See 'Alpha HCD' below.)

PATHOPHYSIOLOGY

The normal immunoglobulin molecule — The immunoglobulin molecule is composed of two heavy and two light chains, joined by disulfide bonds (figure 1). The normal heavy chain constant region (CH region) has a number of domains, of which CH1 is responsible for light chain binding. In the absence of an associated light chain, the CH1 domain binds to heat shock protein 78 (heavy chain binding protein, BiP), and the heavy chain undergoes proteasomal degradation rather than secretion [7]. As a result, normal heavy chains without light chains are not detected in the serum. (See "Structure of immunoglobulins", section on 'Structure'.)

The abnormal heavy chain in HCD — In the HCDs, noncontiguous deletions in the switch-CH1 region prevent binding of the abnormal heavy chain to light chains as well as to heat shock protein 78, thereby avoiding proteasomal degradation [8-10]. The heavy chains are then secreted into the plasma (or jejunal fluid in the case of alpha HCD) and, if small enough, may appear in the urine.

Making the diagnosis — A patient with one of the HCDs will come to the attention of clinicians in two different ways:

●For consideration of the diagnosis of a localized or diffuse lymphomatous process and/or:

●For evaluation of the presence of a monoclonal protein in the serum, urine, or tissues (see "Laboratory methods for analyzing monoclonal proteins", section on 'Causes')

The specific diagnosis of one of the HCDs, along with the diagnosis of the underlying plasma cell/lymphocytic clonal disorder, can be made via a combination of studies of tissues and analysis of serum or urine samples.

Tissue diagnosis — Immunohistochemical staining of an affected tissue (eg, mass lesion, enlarged lymph node(s), bone marrow involvement, hepatosplenomegaly) shows the presence of a clonal population of cells staining positively for a heavy chain but negative for both kappa and lambda light chains.

Serum and urine studies — The frequency of finding a monoclonal "spike" on serum or urine protein electrophoresis is variable, and differs among the three types of HCD. On immunofixation, the abnormal protein, if present, consists of a heavy chain (ie, alpha, gamma, mu) without an associated light chain. (See "Laboratory methods for analyzing monoclonal proteins", section on 'False negative results'.)

As examples:

●In alpha HCD, there is not a distinct band or sharp peak on electrophoresis, presumably because of the tendency of these chains to form polymers of different sizes. In some patients, the abnormal proteins are found in jejunal fluid but not in the serum. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine'.)

●In gamma HCD, the electrophoretic tracing may appear broad and heterogeneous rather than showing a localized band.

●In mu HCD, panhypogammaglobulinemia is a prominent feature and a localized band is found in only 40 percent.

While not routinely available, some cases of heavy chain disease have been identified using mass spectrometry (MS) [11]. MS and other laboratory methods for analyzing monoclonal proteins in the serum and urine are discussed in more detail separately. (See "Laboratory methods for analyzing monoclonal proteins", section on 'False negative results'.)

ALPHA HCD — Alpha HCD (also called immunoproliferative small intestinal disease [IPSID], Mediterranean lymphoma, Seligmann disease) is a form of extranodal marginal zone lymphoma (EMZL) of mucosa associated lymphoid tissue (MALT), with the same histologic features of gastric EMZL with marked plasma cell differentiation. It is the most common form of HCD and occurs in patients from the Mediterranean region or Middle East, usually young males, and is often associated with relatively poor sanitation. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine'.)

Issues related to alpha HCD are discussed in detail separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine'.)

Summarized briefly, the gastrointestinal tract is involved in alpha HCD, resulting in abdominal pain, severe malabsorption with chronic diarrhea, steatorrhea, and loss of weight. Growth retardation (in children), digital clubbing, and mesenteric lymphadenopathy may also be present.

Infiltration of the jejunal mucosa with plasmacytoid cells is the most frequent pathologic feature. The duodenum and ileum are less often affected. The diagnosis depends on the recognition of a monoclonal alpha heavy chain without an associated light chain in the serum, urine, intestinal secretions, or cells infiltrating the intestinal mucosa.

The serum protein electrophoretic pattern is normal in one-half of cases, and in the remainder an unimpressive broad band may appear in the alpha-2 or beta mobility regions. The amount of alpha heavy chain in the urine is small.

In the absence of therapy, alpha HCD typically is progressive and fatal. The usual treatment is with antibiotics such as tetracyclines and eradication of any concurrent infection (eg, parasites, viruses, Helicobacter pylori, Campylobacter jejuni) [12,13]. Patients who do not respond adequately to antibiotics are treated with therapies directed at the marginal zone lymphoma, which may include chemotherapy, rituximab, and/or involved-site radiation therapy. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)", section on 'Campylobacter jejuni' and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)", section on 'Small intestine MZL'.)

GAMMA HCD — Patients with gamma HCD typically present with systemic symptoms, lymphadenopathy, splenomegaly, and/or anemia, and occasionally with palatal and uvular swelling [1,14]. The median age of patients with gamma HCD is 60 to 70 years, although the condition has been noted in persons younger than age 20.

In one of the largest reported series of 23 patients with gamma HCD seen at the Mayo Clinic, the following findings were present [14]:

●Monoclonal spike on electrophoresis – 83 percent

●Lymphadenopathy – 35 percent

●Hemoglobin <10 g/dL – 35 percent

●Bone marrow involvement – 32 percent

●Splenomegaly – 30 percent

●Skin involvement – 30 percent

●Platelet count <100,000/microL – 17 percent

●Hepatomegaly – 4 percent

The clinical findings ranged from an asymptomatic state (eg, monoclonal gammopathy of undetermined significance, MGUS) to an aggressive lymphoproliferative process.

Autoimmune manifestations are seen in about one-third of patients (eg, idiopathic thrombocytopenia purpura, hemolytic anemia, vasculitis, systemic lupus erythematosus, rheumatoid arthritis) [1,3,14,15].

Gamma HCD is typically associated with a polymorphous infiltrate, including admixtures of lymphocytes, plasmacytoid lymphocytes, plasma cells, immunoblasts, and eosinophils [1,3,16,17].

The electrophoretic pattern often shows a broad-based band more suggestive of a polyclonal increase but the gamma chains are monoclonal. The diagnosis is established by immunofixation, which shows that the abnormal protein consists only of gamma heavy chains without associated light chains. The monoclonal gamma chains have significant deletions of amino acids, including the CH1 domain of the constant region.

Treatment is indicated only for symptomatic patients. There is only anecdotal experience with any regimen for the treatment of this disease. Options include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP regimen) (table 1) or, if the abnormal cells express CD20, the anti-CD20 antibody rituximab plus CHOP (R-CHOP) (table 2), or myeloma regimens such as cyclophosphamide, bortezomib, dexamethasone (CyBorD) [2,3,14,18-20].

The prognosis of gamma HCD is variable and ranges from the asymptomatic presence of a stable monoclonal heavy chain in the serum or urine (eg, MGUS) to a rapidly progressive downhill course of a few weeks duration (eg, highly aggressive lymphoma). In the Mayo Clinic series, the median survival was 7.4 years with an extremely wide range (1 month to more than 21 years) [14].

MU HCD — Mu HCD is the least common of the HCDs and is characterized by a monoclonal mu chain fragment in the serum. It has features resembling chronic lymphocytic leukemia/small lymphocytic lymphoma (eg, anemia, hepatosplenomegaly), although peripheral adenopathy is less common than in CLL [1]. Osteolytic lesions or pathologic fractures have been reported in occasional patients. Unlike alpha and gamma HCD, some patients with mu HCD have increased free light chain secretion (Bence Jones proteinuria), and may develop cast nephropathy or amyloidosis [21,22].

Common features include characteristic vacuolated plasma cells or lymphoid cells in the bone marrow and panhypogammaglobulinemia [2,18,23]. The serum protein electrophoretic pattern is usually normal except for hypogammaglobulinemia.

The course of mu HCD is variable, and survival ranges from a few months to many years. Asymptomatic patients are observed without therapy, while symptomatic patients are treated similar to patients with non-Hodgkin lymphoma. There is only anecdotal experience with any regimen for the treatment of this disease. Reported treatment has included rituximab (if the tumor expresses CD20) with or without chemotherapy regimens used for indolent non-Hodgkin lymphomas. The regimen is selected to mimic that of the lymphoma that the tumor most closely mimics.  

SUMMARY AND RECOMMENDATIONS

●Definitions – The heavy chain diseases (HCD) are rare B cell proliferative disorders characterized by the production of a monoclonal (M) protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain. The heavy chain is often incomplete or truncated and a sharp, localized peak may not be seen on the electrophoretic tracing of serum or urine. (See 'The abnormal heavy chain in HCD' above.)

●Clinical presentation – The clinical presentation of the HCDs is that of a patient with a low grade B cell malignancy.

•Alpha HCD – The gastrointestinal tract is most commonly involved in alpha-HCD, resulting in abdominal pain, malabsorption with chronic diarrhea, steatorrhea, and loss of weight. Infiltration of the jejunal mucosa with plasmacytoid cells is the most frequent pathologic feature. The diagnosis depends on the recognition of a monoclonal alpha heavy chain without an associated light chain in the serum, urine, intestinal secretions, or the cells infiltrating the intestinal mucosa. (See 'Alpha HCD' above.)

•Gamma HCD – Patients with gamma HCD most often present with systemic symptoms, lymphadenopathy, hepatosplenomegaly, and anemia, and occasionally with palatal and uvular swelling. Autoimmune manifestations are seen in about one-third of patients. Gamma HCD is typically associated with a polymorphous infiltrate, including admixtures of lymphocytes, plasmacytoid lymphocytes, plasma cells, immunoblasts, and eosinophils. The abnormal protein consists only of gamma heavy chains without an associated light chain. (See 'Gamma HCD' above.)

•Mu HCD – Mu chain HCD has features resembling chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; eg, anemia, hepatosplenomegaly), although peripheral adenopathy is less commonly seen than in CLL. Vacuolated lymphocytes/plasma cells in the bone marrow and panhypogammaglobulinemia are commonly seen. The abnormal protein consists only of mu heavy chains without an associated light chain. (See 'Mu HCD' above.)

●Diagnosis – The diagnosis of one of the HCDs can be made on histopathologic examination of affected tissues and/or analysis of serum or urine samples by electrophoresis and immunofixation. A typical monoclonal "spike" in the serum or urine may not always be present. On serum or urine immunofixation or immunohistochemical staining of affected tissues, the abnormal protein consists of a heavy chain (ie, alpha, gamma, mu) without an associated light chain. (See 'Making the diagnosis' above.)

●Management – Reports concerning the treatment of the HCDs are largely anecdotal. Accordingly, with the exception of initial treatment of alpha HCD with appropriate antibiotics, which can be curative in some cases, all of the recommendations given below are based on low quality evidence.

•Alpha HCD – We recommend eradication of any concurrent infection (eg, parasites, viruses, Helicobacter pylori, Campylobacter jejuni) with appropriate antibiotics as initial treatment of alpha HCD (Grade 1C). (See 'Alpha HCD' above.)

For those with symptomatic disease who do not respond adequately to antibiotics, chemotherapy similar to that used to treat non-Hodgkin lymphoma is most appropriate.

•Gamma HCD – Treatment is indicated only for symptomatic patients. There is only anecdotal experience with any regimens. Options include cyclophosphamide, vincristine, and prednisone, with or without doxorubicin (eg, the CHOP regimen) (table 1), or, if the abnormal cells express CD20, the anti-CD20 antibody rituximab, or myeloma regimens such as cyclophosphamide, bortezomib, dexamethasone (CyBorD). (See 'Gamma HCD' above.)

•Mu HCD – Treatment for symptomatic patients with mu HCD is similar to that employed in patients with non-Hodgkin lymphoma. (See 'Mu HCD' above.)