MOLECULAR BIOLOGY AND GENETICS
Most α-HCD proteins consist of multiple polymers. The molecular weight of the basic monomeric unit varies from 29,000 to 34,000. The length of the basic polypeptide subunit differs from patient to patient and in most instances is between one-half and three-fourths that of a normal α chain. Sequence data are available for several α-HCD proteins (Fig. 110–3). In all cases of α-HCD studied, the α-HCD protein belonged to the α1 subclass. Common features of the defective α chain include deleted V regions, missing CH1 domains, and the absence of light chains. Most of the proteins have short, non–Ig-related sequences of unknown origin at the amino terminus. The complete sequences of the genes encoding 3 α-HCD proteins are shown in Fig. 110–4. These three genes show striking similarity in their position and extent of the two main deletions, which encompass sequences in the V/J and the switch/CH1 region.
Structure of various α-heavy-chain disease (HCD) proteins compared with that of normal chain.* Structures shown are primary synthetic products synthesized by the HCD cells. Serum proteins were modified after synthesis and did not contain any amino acids before the hinge. **Structures shown are deduced amino acid sequences determined by complementary DNA sequencing.
, indicates unusual and heterogeneous amino acid sequences;
, unusual amino acid sequences; boxes, coding regions; lines, deletion; V, variable region; D, diversity segment; J, joining region; H, hinge region; CH
3, constant regions of heavy chains; Memb., membrane exon. YAO,87
Structure of three genes coding for different α1-heavy-chain disease proteins compared with that of normal α1 gene. Boxes indicate coding regions;
, switch region;
, inserted coding sequence;
, inserted noncoding sequence; lines, intervening (noncoding) sequences; L, leader region; V, variable region; D, diversity segment; J, joining region; S, switch region; H, hinge region; CH
3, constant regions of heavy chains; I, inserted sequence; Del, deleted sequence; Memb., membrane exon. YAO,87
SERUM, URINE, AND INTESTINAL FLUID PROTEIN FINDINGS
In contrast to other monoclonal gammopathies, the characteristic sharp spike of a monoclonal gammopathy is not found on serum protein electrophoresis in α-HCD. In about half of cases, an abnormal broad band is found in the α2- or β-globulin region, which is probably related to polymerization of the α chains. In the other half of cases, serum protein electrophoresis shows no evidence of an abnormal protein. Identification of the α-HCD protein depends on immunoselection or immunofixation. The pathologic protein may easily escape detection by immunoelectrophoresis when its serum concentration is low. In most patients, the α-HCD protein can be found in the serum. During the course of the disease, the progressive diminution of mature plasma cells and their replacement by immature immunoblasts likely is followed by a progressive decrease in the serum concentration of α-HCD protein. α-HCD protein hyposecretion also may be found during the early stage of the disease.
In most cases, the α-HCD protein also is found in the jejunal secretions.34 α-HCD protein has been found in the intestinal or gastric fluid in a few cases when it was undetectable in serum and urine. The concentration of α-HCD protein in the urine is low. Bence Jones proteinuria has never been documented.
Synthesis of the α-HCD protein by the proliferating cells has been demonstrated by immunohistochemical or immunocytochemical methods and by biosynthesis studies in vitro.35 These techniques are helpful in the recognition of nonsecreting forms of α-HCD.
HEMATOLOGIC AND METABOLIC ABNORMALITIES
Mild to moderate anemia is often found. Hypokalemia, hypocalcemia, hypomagnesemia, and hypoalbuminemia are common. The intestinal isoenzyme fraction of the alkaline phosphatase level may be increased. Results of tests to indicate malabsorption are usually positive.
Abnormal radiographic findings of the small intestine include hypertrophic and pseudopolypoid mucosal folds, occasionally associated with strictures and filling defects. The extent of the disease should be evaluated with computed tomography.
α-HCD intestinal lesions nearly always affect the duodenum and jejunum, making endoscopy with biopsy a useful tool in the evaluation of patients in whom α-HCD is suspected. Several endoscopic patterns have been defined. The infiltrated pattern is the most specific, followed by the nodular pattern. Other primary lesions (ulcerations, mosaic pattern, and mucosal fold thickening alone) are nonspecific.
In the digestive form of α-HCD, the proliferation involves at least the proximal half of the small intestine and adjacent mesenteric lymph nodes. The whole length of the small bowel, the gastric, and the colorectal mucosae that belong to the IgA secretory system may be involved.
The disease progresses in three histopathologic stages according to Galian and colleagues.36 In stage A, a mature plasmacytic or lymphoplasmacytic infiltration of the mucosal lamina propria is noted. Villous atrophy is variable. Stage B is characterized by the presence of atypical plasmacytic or lymphoplasmacytic cells and more or less atypical immunoblast-like cells extending at least to the submucosa. Subtotal or total villous atrophy is present. Stage C corresponds to an immunoblastic lymphoma. Similar to the changes described in the small intestine, three histologic stages (A, B, C) have been described in the mesenteric lymph nodes. Involvement of liver, spleen, and peripheral lymph nodes is uncommon. The histologic lesions may progress at any given site from stage A to stage B or from stage B to stage C. However, different stages can be found at the same time in different organs or even at different sites in the same organ. Thus, accurate pathologic staging of α-HCD requires a laparotomy with sampling of multiple sites in all patients with α-HCD in whom no stage C lesions are found on peroral biopsy. This recommendation is based on the observation that mesenteric lymph nodes may harbor malignant lymphoma when the intestinal mucosa reveals only a benign-appearing cellular infiltrate that one might be tempted to treat with antibiotics alone.37 A staging system based on anatomical spread of the disease, which is complementary to the Galian staging system has been published;38 however, most physicians use the Galian staging system for determining prognosis and therapeutic strategies.
In the past, confusion existed over whether Mediterranean lymphoma and α-HCD were different conditions. In 1976, a consensus panel concluded that α-HCD and Mediterranean lymphoma constitute a spectrum of disease, and the term immunoproliferative small intestinal disease (IPSID) came into use. This term is applied to small intestinal lesions whose pathologic features are identical to those of α-HCD, regardless of the type of Ig synthesized.34,39 The pattern of α-HCD pathologic lesions often includes clear lymphoepithelial lesions composed of centrocytic-like cells. This indicates that α-HCD can be considered a subtype of lymphoma arising from mucosa-associated lymph node tissue.40 The pathologic changes in the few cases of the respiratory form of α-HCD are poorly documented. In a case of the lymph node or lymphomatous form, lymph node biopsy showed diffuse plasmacytic lymphoma.
Cytogenetic abnormalities have been found in the lymphoid cells of patients with α-HCD. The clonal proliferation in this disease appears to be associated with frequent alterations of chromosome 14 at band q32 resulting from translocations that differ from those observed in the vast majority of other lymphomas. Abnormal karyotypes were reported in three of four patients.41 Two patients had a rearrangement of 14q32 resulting from a t(9;14)(p11;q32) and a t(2;14)(p12;q32). Cloning and sequencing of the der(14) breakpoint of a chromosome translocation involving the 14q32 Ig locus in 1 of these patients suggested that the translocation originated from a local pairing of the two chromosomes, 9 and 14.42 One case showed complex rearrangements, including t(5;9). No abnormalities were found in the intestinal tumor of the fourth case with immunoblastic lymphoma.