OVERVIEW

What is heavy chain disease?

Heavy chain disease (HCD) is also a B-cell and plasma cell malignant clonal proliferative disorder characterized by the production of large amounts of structurally homogeneous incomplete immunoglobulins by clonally proliferating malignant cells (these proteins consist of abnormal heavy chains that cannot bind to light chains).

There are four types of heavy chain disease: γ, α, μ, and δ, with varying clinical manifestations depending on the type. Among them, α-HCD occurs far more frequently than γ-HCD and μ-HCD, while the rare δ-HCD has only been reported in one case worldwide.

The cause of heavy chain disease remains unclear. Diagnosis relies on the detection of monoclonal heavy chain fragments in serum or urine immunoelectrophoresis or immunofixation electrophoresis. The prognosis of different types of HCD varies significantly, with disease courses of varying lengths.

Is heavy chain disease common?

No, it is rare.

Some specific types of heavy chain disease have only been reported in isolated cases.

Is heavy chain disease hereditary?

Heavy chain disease is not a genetic disorder and cannot be inherited.

SYMPTOMS

What are the common clinical manifestations of heavy chain disease patients?

• α-HCD: α-HCD can be further divided into intestinal and pulmonary types. The majority of patients have the intestinal type, which affects the gastrointestinal tract. The most prominent symptoms include severe chronic diarrhea, abdominal pain, malabsorption, accompanied by fatigue, dehydration, and weight loss. In advanced stages, patients may develop abdominal masses, intestinal obstruction, intestinal perforation, and ascites. Some patients often have mesenteric lymphadenopathy, and hepatomegaly may occur, but superficial lymphadenopathy and splenomegaly are generally absent. Unlike other malignant hematologic diseases, fever is uncommon. The disease typically does not invade the bone marrow or other organs. The pulmonary type primarily manifests as dyspnea.

• γ-HCD: The onset is insidious, with varied manifestations. The most common symptoms resemble lymphoma—lymphadenopathy, fever, hepatosplenomegaly, and fatigue. Some patients develop palatal erythema and edema. Bone marrow and lymph node biopsies may reveal abnormal lymphocytes, plasma cells, or increased plasmacytoid lymphocytes.

• μ-HCD: The main clinical manifestations are hepatosplenomegaly and abdominal lymphadenopathy. Similar to other lymphoproliferative disorders, patients often experience systemic symptoms such as anemia, fever, weight loss, and recurrent infections. A very small number of patients show no clinical symptoms or signs.

CAUSES

What are the causes of heavy chain disease?

• α-HCD: The most common type of HCD, also known as IgA heavy chain disease. Cases were first reported in China in the 1980s. The exact cause remains unclear, but it frequently occurs in underdeveloped regions and countries with poor sanitary conditions, particularly in areas prone to intestinal parasites, bacteria, and viral infections, such as the Mediterranean and South America. Therefore, it is speculated that the disease may be associated with gastrointestinal infections. Patients are typically under 40 years old, mostly young adults aged 20–30, with no significant gender difference.

• γ-HCD: Also called IgG heavy chain disease, Fc fragment disease, or Franklin disease. The cause is currently unknown. However, clinical data show that about one-quarter of patients have coexisting autoimmune diseases, such as rheumatoid arthritis, autoimmune hemolytic anemia, or Sjögren's syndrome, suggesting that long-term chronic stimulation by autoantigens may be a contributing factor. Patients are usually elderly, with a slight female predominance.

• μ-HCD: Also referred to as IgM heavy chain disease. The etiology is similarly unclear. Most patients often have coexisting lymphoplasmacytic proliferative disorders, such as chronic lymphocytic leukemia, lymphoma, macroglobulinemia, multiple myeloma, amyloidosis, or monoclonal gammopathy of undetermined significance. The pathogenesis may involve defects in peptide chain formation in malignantly proliferating lymphoplasmacytic cells, leading to excessive production of abnormal heavy and light chains.

DIAGNOSIS

What tests are needed for heavy chain disease? Why are these tests necessary?

The diagnosis of heavy chain disease relies on immunoelectrophoresis and immunofixation electrophoresis of blood, urine, or intestinal secretions. Detection of free monoclonal heavy chains confirms the diagnosis.

Which diseases should heavy chain disease be differentiated from?

• α-HCD: Definitive diagnosis requires immunological or biochemical methods to detect monoclonal proteins in blood, urine, or jejunal fluid, or the presence of α-heavy chain fragments without light chains in lymphoplasmacytic cells via immunofluorescence or immunohistochemistry. It must be differentiated from IgA half-molecule disease and IgA-type multiple myeloma with cryptic light chains. Diagnosis is confirmed if purified pathological proteins from blood or concentrated urine are identified as α-heavy chain fragments without light chains. Differentiation between gastrointestinal α-HCD, immunoproliferative small intestinal disease, and Mediterranean lymphoma can be challenging. Additionally, intestinal tuberculosis may mimic α-HCD clinically, requiring endoscopy and pathological biopsy for confirmation.

• γ-HCD: Must be differentiated from lymphoma, multiple myeloma, and macroglobulinemia.

• μ-HCD: Clinical suspicion arises in cases of lymphoplasmacytic proliferation and bone marrow plasma cells with prominent vacuoles, along with positive urinary Bence Jones protein. However, confirmation depends on detecting free μ chains in urine. Monoclonal μ chains are difficult to identify, making diagnosis challenging. It is primarily differentiated from chronic lymphocytic leukemia and multiple lymphoma.

TREATMENT

Which department should be consulted for heavy chain disease?

Hematology.

How should heavy chain disease be treated?

• α-HCD:

  • Depending on the severity of the patient's condition and pathological stage, chemotherapy or antibiotic treatment may be chosen (as it is often associated with gastrointestinal infections, some scholars believe antibiotics may be effective). Common chemotherapy drugs include melphalan, cyclophosphamide, and prednisone.

  • Young patients with advanced disease who respond well to chemotherapy may also consider autologous stem cell transplantation.

  • Patients with localized bulky disease may undergo surgical treatment.

  • Additionally, patients with chronic diarrhea require active supportive treatment to prevent electrolyte imbalances.

• γ-HCD: There is currently no satisfactory treatment plan, and chemotherapy is only administered to symptomatic patients. Common drugs include cyclophosphamide, vincristine, and prednisone. Besides chemotherapy, there have also been cases treated with rituximab.

• μ-HCD: There are currently no specific treatment methods or cured cases. Alkylating agents and corticosteroids may be effective for some patients. Treatment mainly targets the underlying B-cell lymphoproliferative disorders, such as CLL.

Can heavy chain disease be cured?

Currently, it cannot be cured.

The disease course varies significantly among different types of patients, ranging from a few months to several decades. α-HCD generally progresses and has a poor prognosis.

A small number of patients with heavy chain disease may later develop other malignant hematological diseases, such as lymphoma or leukemia.

DIET & LIFESTYLE

What special precautions should patients with heavy chain disease take in their daily life and diet?

The survival period varies greatly among patients. In daily life, it is important to prevent infections and strengthen nutrition. There are no other special precautions.

PREVENTION

Can heavy chain disease be effectively prevented?

For patients with alpha heavy chain disease, improving nutrition and reducing intestinal infections are both effective preventive measures and necessary treatment measures.