Introduction

The monoclonal gammopathies include those diseases in which there is a proliferation of a single clone of immunoglobulin-forming cells that produce a homogeneous heavy chain, light chain, or complete molecule. The amino acid sequence of the variable (V) regions is fixed, and only one type (? or ?) of light chain is produced. Polyclonal gammopathies result from proliferation of many B cell clones, resulting in a diffuse increase of immunoglobulins.

1. Monoclonal Gammopathy of Uncertain Significance (MGUS)

Introduction

Essentials of Diagnosis

• M protein in the serum without symptoms or signs of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma.
• Less than 10% plasma cells in the bone marrow.

General Considerations
The incidence of MGUS increases with age and may approach 3% in persons 70 years of age or older. Lymphoid malignancies, amyloidosis, or multiple myeloma will develop in as many as one-third of patients with apparently benign monoclonal gammopathies. No specific therapy is necessary, but close observation is required. MGUS patients should be periodically monitored for changes in serum M proteins, urinary Bence-Jones proteins, evidence of renal failure, anemia, hypercalcemia, lytic bone lesions, or bone marrow plasmacytoses. Risk of developing a malignant disorder is 12% at 10 years, 25% at 20 years, and 30% at 25 years. Parameters that suggest a favorable prognosis include (1) concentrations of homogeneous immunoglobulin less than 2 g/dL, (2) no increase in concentration of the immunoglobulin from the time of diagnosis, (3) no decrease in the concentration of normal immunoglobulins, (4) absence of a homogeneous light chain in the urine, and (5) normal hematocrit and serum albumin.

Clinical Findings

A. Symptoms and Signs
No clinical symptoms are associated with MGUS. In patients with MGUS, the quantity of M protein is stable, and the lymphadenopathy, splenomegaly, or bony lesions seen with multiple myeloma are absent.

B. Laboratory Findings
The diagnosis of MGUS is made upon finding of a monoclonal spike on serum protein electrophoresis, confirmed by immunoelectrophoresis to be a homogeneous immunoglobulin with either ? or ? light chains.

Preferences
_{Blade J, Kyle RA: Monoclonal gammopathies of undetermined significance. In: Malpas JS et al (editors). Myeloma: Biology and Management, 2nd ed. Oxford University Press; 1998.}

Kyle RA et al: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564.

2. Multiple Myeloma (See See in Blood Disorders)

3. Waldenstrom’s Macroglobulinemia (See in Blood Disorders)

4. Amyloidosis

Introduction Essentials of Diagnosis

• The diagnosis is based on clinical suspicion, family history, and preexisting long-standing infection or debilitating illness.
• Microscopic examination of biopsy (eg, gingival, renal, rectal) or surgical specimens is diagnostic.
• Fine-needle biopsy of subcutaneous abdominal fat is a simple and reliable method for diagnosing secondary systemic amyloidosis.

General Considerations
Amyloidosis is a group of disorders manifested by impaired organ function due to infiltration with insoluble protein fibrils. Different fibrils can be correlated with the clinical syndromes. In primary amyloidosis (AL), the protein fibrils are monoclonal immunoglobulin light chains, whereas in secondary amyloid (AA), protein deposits are derived from acute phase reactant apolipoprotein precursors. Familial amyloidosis syndromes commonly cause infiltrative neuropathies. Other types of amyloidosis may also be hereditary. Over 20 types of fibrils have been identified in amyloid deposits. Amyloidosis due to deposition of ß₂-microglobulin in carpal ligaments occurs in chronic hemodialysis patients.

Clinical Findings

A. Symptoms and Signs
The symptoms and signs of primary amyloidosis are due to amyloid infiltration and subsequent malfunction of the infiltrated organ (eg, nephritic syndrome and renal failure, cardiomyopathy and cardiac conduction defects, intestinal malabsorption and pseudo-obstruction, carpal tunnel syndrome, macroglossia, peripheral neuropathy, end-organ insufficiency of endocrine glands, respiratory failure, capillary damage with ecchymosis). Secondary amyloidosis is more often limited to the liver, spleen, and adrenals. Familial syndromes commonly cause infiltrative neuropathies.

B. Laboratory Tests
The diagnosis of primary amyloidosis is based on clinical suspicion with corroboration provided by detection of a monoclonal gammopathy on serum protein electrophoresis and microscopic examination of abdominal fat pad aspirates; rectal or gingival biopsies reveal amyloid protein (green birefringence under polarizing microscope after Congo red staining). In systemic disease, rectal or gingival biopsies show a sensitivity of about 80%, bone-marrow biopsy about 50%, and abdominal fat aspiration between 70% and 80%. The latter is a simple and reliable method for diagnosing systemic amyloidosis.

Differential Diagnosis
When evaluating a patient with suspected primary amyloidosis, it is important to consider other causes of the presenting symptoms and signs, including multiple myeloma, hemochromatosis, sarcoidosis, Waldenstrom’s macroglobulinemia, metastatic tumors, and other cause of nephrotic syndrome, such as lupus nephritis.

Treatment
Treatment of localized amyloid tumors is by surgical excision. There is no effective treatment of systemic amyloidosis, and death usually occurs within 1-3 years. Care is generally supportive, although hemodialysis and immunosuppressive therapy may be useful. When concomitant multiple myeloma is found, it is treated in the standard way. Secondary disease is usually approached by aggressively treating the predisposing disease, but remission of fibril deposition does not occur. Bone marrow transplant after chemotherapy has been used in selected patients.

5. Heavy Chain Disease

(a, ?, u)

These are rare disorders in which the abnormal serum and urine protein is a part of a homogeneous a, ?, or u heavy chain. The clinical presentation is more typical of lymphoma than multiple myeloma, and there are no destructive bone lesions. Gamma chain disease presents as a lymphoproliferative disorder with autoimmune features. Alpha chain disease is frequently associated with severe diarrhea and infiltration of the lamina propria of the small intestine with abnormal plasma cells. Mu chain disease is associated with chronic lymphocytic leukemia. Preferences _{Ando Y et al: A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo. Lab Invest 2003;83:1751. Attaelmannan M et al: Understanding and identifying monoclonal gammopathies. Clin Chem 2000;46:1230. Gorender P et al: Abdominal amyloidosis. Clin Radiol 2004;59:109.}