Heavy chain diseases (HCDs) belong to the larger group of plasma cell (or B cell proliferative) disorders. The diseases are characterized by the presence of structurally defective monoclonal immunoglobulin heavy chains carrying various mutations, usually large deletions. Three main groups, which are classified according to the class of the aberrant heavy chain proteins, constitute the HCDs: alpha-HCD, gamma-HCD, and mu-HCD.
The three groups of HCDs (alpha-HCD, gamma-HCD, and mu-HCD) are regarded as variants of non-Hodgkin lymphoma; all have abnormal heavy chains, usually with parts of the constant region deleted, but otherwise have diverse features . The abnormal heavy chains, which have lost the ability to bind light chains or chaperone molecules, are also parts of the B cell receptor, and therefore, possibly through spontaneous aggregation of the receptors, may be responsible for the uncontrolled division of the neoplastic B cells .
Alpha-HCD has the least diversified presentation and the highest prevalence within the HCDs , though still a rare disease. It typically affects young people of Mediterranean origin . This disease most often damages the gastrointestinal system and causes a malabsorption syndrome with weight loss, diarrhea, nausea and other digestive symptoms. Rarely, a respiratory form is also encountered.
The presentation of gamma-HCDs, which affect middle-aged and older people, is very heterogeneous . The majority (two-thirds) of the patients have disseminated disease, whereas about a quarter have the disease localized to the bone marrow or other locations, most frequently the skin. About ten percent of the patients show only gammopathy. Gamma-HCD is associated with autoimmune diseases in about a quarter of the patients.
People suffering from the disseminated form of the disease present with the general symptoms of lymphoproliferative conditions, such as fever, weight loss, mild anemia and other general complaints. Lymphadenopathy and splenomegaly are common; hepatomegaly is less frequent . Lymphadenopathy may eventually lead to edema of the soft palate.
Mu-HCD occurs mainly in late middle-aged adults. In the early examples of Mu-HCD, a strong association with chronic lymphocytic leukemia was suspected, but by now the two diseases seem more distinct , with only about a third of mu-HCD patients also diagnosed with chronic lymphocytic leukemia. The presentation of Mu-HCD is variable, as is its association with other conditions such as multiple myelomas, plasmacytoma, and other diseases, such as amyloidosis . Splenomegaly is observed in almost all cases, and hepatomegaly is frequent. Lymphadenopathy is present in almost half the cases. Bone lesions and fractures are also fairly common and may be ascribed to lymphocytic infiltration of the bone .
Alpha-HCD is accompanied by some abnormal laboratory results. Some of these are general, such as mild anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia. Plasma alkaline phosphatase levels are often high, owing to an increase in the intestinal isoform of the enzyme . Serum electrophoresis can be normal, and the electrophoretic pattern is not revealing . Thus, the diagnosis of the disease, that is the identification of the abnormal heavy chain, has to rely on immunological methods . The mutated protein is also present in intestinal secretions, but absent, or only in very small concentrations, in urine. If otherwise undetected, the defective heavy chain has to be identified by an intestinal biopsy.
Alpha-HCD primarily affects the duodenum and jejunum, and these parts of the small bowel are heavily infiltrated by plasma cells mixed with small lymphocytes. Endoscopy of the upper part of the gastrointestinal tract has been used to identify mucosal abnormalities. Of the several types of anomaly identified, the patterns of infiltration are the most sensitive predictors of the disease . The disease has been classified as the immunoproliferative small intestinal disease (IPSID); an association with Campylobacter jejuni infection has been proposed for this and other lymphomas of the small intestine.
Diagnosis of gamma-HCDs is challenging because this disease presents as a spectrum of disorders. The difficulty in differentiating the gamma-HCDs from other lymphoproliferative diseases is reflected by the fact that the 2008 World Health Organization classification places this condition as a separate disease within the heavy chain disease group, but then also discusses gamma-HCD as a variant of lymphoplasmacytic lymphoma . It may also be difficult to distinguish gamma-HCD from inflammation or infections.
The disease is accompanied by general symptoms, such as anemia. The complete blood cell count often reveals eosinophilia and thrombocytopenia. Serum protein electrophoresis shows the monoclonal gamma heavy chain in about three-quarter of the patients. The defective gamma chain is often present in the urine. Diagnosis is by immunological detection of the abnormal heavy chain in the serum or urine, with no immunologically observable light chains. The sites affected are mainly the bone marrow, spleen, and lymph nodes, but extranodal sites are also involved . The histology is variable. Hyperuricemia frequently occurs in advanced stages.
For diagnosing Mu-HCDs, exploration of the bone marrow is often necessary. The marrow contains multivacuolated plasma cells, observed in the majority (two-thirds) of the patients; thus, this is a characteristic but not universal feature of the disease. Almost half of the patients present with osteolytic lesions, necessitating the evaluation of the state of the skeleton.
Serum or urine protein electrophoresis and immunofixation are indispensable for diagnosis. The mu heavy chains are shown by these methods to be present in the form of heterogeneous polymers without associated light chains  . However, light chains are produced, and being unbound to the heavy chains, are often excreted in the urine.