eMedicine Specialties > Hematology > Plasma Cell Disorders

Amyloidosis, Immunoglobulin-Related

Author: Slavomir Urbancek, MD, PhD, Head, Department of Dermatology, FD Roosevelt Hospital, Slovakia; Scientific Secretary, Slovak Dermatovenereological Society
Coauthor(s): Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain; Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Daniel R Jacobson, MD, Professor of Medicine, Boston University School of Medicine; Chief of Oncology, Veterans Affairs Boston Healthcare System; Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute; Carol A Bogdan, MD, Consulting Staff, Coastal Cancer Center, Myrtle Beach, SC
Contributor Information and Disclosures

Updated: Feb 12, 2009

Introduction

Background

Immunoglobulin-related amyloidosis is a monoclonal plasma cell disorder in which the secreted monoclonal immunoglobulin protein forms insoluble fibrillar deposits in 1 or more organs. In nearly all cases, the deposits contain immunoglobulin light (L) chains or L-chain fragments, termed L chain–type amyloidosis (AL). In a few reported patients, the amyloid deposits have contained immunoglobulin heavy (H) chains; these are termed H chain–type amyloidosis  AH). Before the discovery that the major fibril component in these patients was an immunoglobulin fragment, patients with light chain–type amyloidosis were described as having primary (in the sense of idiopathic) amyloidosis or, when the burden of monoclonal plasma cells was large, myeloma-associated amyloidosis.

Immunoglobulin L and H chains are 2 of 20 different fibril proteins that have been described in human amyloidosis. For a general discussion of the human amyloidoses, the types of human amyloidosis, and an approach to the diagnosis of amyloidosis, see Amyloidosis, Overview.

L chain–type amyloidosis (AL) is related to both multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS). These monoclonal plasma cell disorders can be categorized according to the total body burden of monoclonal plasma cells. When this burden is large, the diagnostic criteria for multiple myeloma are fulfilled; when this burden is lower, MGUS is diagnosed. Multiple myeloma and MGUS fall on a continuum, with 20% of patients with MGUS progressing to multiple myeloma within 10 years.

In most patients with a monoclonal plasma cell disorder, whether multiple myeloma or MGUS, the monoclonal L chain secreted by the clone remains soluble in the bloodstream. However, in some patients, the physicochemical characteristics of the immunoglobulin L chain or L-chain fragment lead to its deposition as amyloid. Thus, some patients with light chain–type amyloidosis meet the diagnostic criteria of multiple myeloma, whereas other patients can be considered as having MGUS in which the clonal immunoglobulin product is amyloidogenic.

In addition to cases of monoclonal gammopathy in which the secreted clonal immunoglobulin remains in solution and those in which secreted clonal immunoglobulin forms amyloid deposits, a third group consists of cases in which the monoclonal proteins accumulate in various organs, but the deposits do not form fibrils. Patients with this form are described as having nonamyloid monoclonal immunoglobulin deposition disease (MIDD). The relationship among the plasma cell dyscrasias and the amyloidoses is depicted in Image 1 and below.

Pathophysiology

The most common light chain–type amyloidosis precursor proteins are L chains of the lambda (l) class. The lambda light chain–type amyloidosis is approximately twice as prevalent as the kappa (k) light chain–type amyloidosis, and L chains of the V_l 6 class are the most amyloidogenic. Clonal plasma cell proliferative diseases in which the V_l 6 gene is expressed are always associated with amyloid deposition. Among V_k genes, the V_k 1 subgroup is overrepresented among amyloid-forming L chains.

Within the V region families, certain amino acid residues occurring at particular positions in the L-chain sequence render those chains are more amyloidogenic, with a combination of such residues increasing the chances of a particular L-chain protein being associated with tissue amyloid deposition. Another structural feature that appears to predispose to L chain – type amyloid deposition is enzymatic glycosylation of the L chain. Although 15% of human L chains bear sugar residues, almost one third of amyloidogenic L chains are glycosylated. Why certain amino acid and glycosylation characteristics in L chains predispose to amyloid formation remains unknown.

L chain – type amyloid deposits contain intact L chains, L-chain fragments, or both (most patients). The fragments always include the amino terminus of the chain and range in mass from 5000 to 16,000 d. In 90% of patients, the deposited peptides include at least some constant region sequence; therefore, the peptides react with commercially available anti–L chain sera, which are specific for constant region determinants. These observations explain why 10% of deposits do not bind either commercial anti-k or anti-l antisera.

L chain – type amyloid deposits can develop in any organ system. The most common organs involved are the kidneys, the heart, the gastrointestinal (GI) tract, the peripheral nerves, and the liver. In most cases, the deposits affect multiple organ systems. Factors leading to the specific pattern of organ involvement in a particular patient are not understood.

In a minority of cases, localized amyloid deposits, including amyloid masses (amyloidomas), may be found in various sites, even in the absence of systemic disease. The pathogenesis of localized light chain–type amyloidosis is not well understood, but a small, localized clone of plasma cells apparently produces immunoglobulin, which forms deposits near the site of synthesis. In some patients, plasma cells have been demonstrated histologically, accompanying the localized amyloid deposits. In one patient, DNA sequencing revealed that local plasma cells were producing the locally deposited L chains.

Researchers from the University of Arkansas for Medical Sciences (UAMS) studied the gene profile of more than 500 patients treated for multiple myeloma at UAMS.¹ Of the about 25,000 genes in the body, the UAMS team found the expression of just 17 genes revealed which form of the disease the patients had.¹ A gene is expressed when its DNA is transcribed into RNA, which is later transcribed into protein. The expression level of those 17 genes becomes an overpowering and overriding predictor of outcome in therapy. It is questionable whether a drug that targets those genes will be developed.

Frequency

United States

Annually, 1-5 cases of immunoglobulin-related amyloidosis per 100,000 people occur.

The best available direct data on L chain–type amyloidosis prevalence in the United States come from Olmstead County, Minn, where the annual prevalence of L chain–type amyloidosis was calculated to be approximately 1 case per 100,000 people. The population in this location is primarily of northern European ancestry. Whether this prevalence applies to different populations is not known.

Based on indirect calculations, the prevalence may be higher. The annual incidence of multiple myeloma is approximately 5 cases per 100,000 people, and the prevalence of L chain–type amyloidosis in patients with myeloma is approximately 20-35%, producing an overall incidence of combined L chain–type amyloidosis and myeloma of 1-1.5 cases per 100,000 people. Only 1 in 5 patients with L chain–type amyloidosis has frank myeloma; therefore, the total number of patients with L chain–type amyloidosis type is 5 times the number of patients with L chain–type amyloidosis and myeloma, or at least 5 cases per 100,000 people.

International

The prevalence of L chain–type amyloidosis appears to be the same in all populations. The only population-based direct measurement comes from the United States.

Mortality/Morbidity

Symptoms of immunoglobulin-related amyloidosis reflect the organs containing amyloid deposits. Factors that cause deposits in different organs in different patients are unknown. Cardiac deposition is the most severe consequence of systemic L chain–type amyloidosis, eventually occurring in most patients. Cardiac L chain–type amyloidosis is the cause of death in most patients with systemic L chain–type amyloidosis.

Race

L chain–type amyloidosis affects people of all racial and ethnic groups. No data are available comparing the incidence of disease in different groups.

Sex

The male-to-female incidence ratio of L chain–type amyloidosis is 2:1.

Age

The median age at diagnosis of immunoglobulin-related amyloidosis in the largest published series (from the Mayo Clinic) was 64 years.²

Clinical

History

The most common presenting symptoms of immunoglobulin-related amyloidosis, including weakness and weight loss followed by purpura, particularly in loose facial tissue, are nonspecific. Other symptoms and physical findings vary widely, depending on which organs contain deposits. Amyloid deposition in a particular organ leads to similar clinical consequences and, therefore, similar complaints, regardless of the type of amyloid deposited. For example, cardiac L chain–type amyloidosis and cardiac transthyretin (TTR) amyloidosis cause similar symptoms.

Clinical features and management outcome were evaluated in a case series of 24 patients with periocular and orbital amyloidosis.³ Signs and symptoms included a visible or palpable periocular mass or tissue infiltration (95.8%), ptosis (54.2%), periocular discomfort or pain (25%), proptosis or globe displacement (21%), limitations in ocular motility (16.7%), recurrent periocular subcutaneous hemorrhages (12.5%), and diplopia (8.3%).³ Seven patients had B cells or plasma cells producing monoclonal immunoglobulin chains that were deposited as amyloid light chains.³

• Renal involvement
  • The kidneys are the most frequent sites of deposition, with nephrotic syndrome being common; therefore, complaints of peripheral edema are common.
  • Patients can present with renal failure.
• Cardiovascular involvement
  • Involvement of the heart and the peripheral vasculature often leads to postural hypotension, with patients complaining of lightheadedness.
  • Patients also develop weakness, palpitations, dyspnea, and peripheral edema due to congestive heart failure and arrhythmias.
  • Occasionally, deposits in the coronary arteries (usually the smaller intracardiac arterioles) may cause anginal symptoms similar to those typical of atherosclerotic coronary artery disease.
• Peripheral neuropathy
  • Patients whose disease involves the peripheral nerves often report dysesthesia, decreased sensation, and decreased strength.
  • Symptoms usually affect the lower extremities more severely than the upper extremities.
• Gastrointestinal (GI) involvement:
  • Most patients with L chain–type amyloidosis have histologic evidence of infiltration of the gut, particularly in the blood vessels. However, deposition is symptomatic in only a minority of patients.
  • The most common GI symptoms are constipation or alternating constipation and diarrhea. Gastric L chain–type amyloidosis can cause hematemesis, nausea, and vomiting. Intestinal L chain–type amyloidosis can impair motility and cause hemorrhage, obstruction, constipation, and diarrhea or alternating constipation and diarrhea.
  • Myeloma-associated amyloidosis may rarely be first evident as subacute liver failure.⁴
• Carpal tunnel syndrome: Approximately 20% of patients with L chain–type amyloidosis initially report weakness and paresthesia of one or both hands, suggesting carpal ligament involvement.

Physical

• General features
  • The most common initial physical findings in individuals with immunoglobulin-related amyloidosis include peripheral edema, hepatomegaly, purpura, orthostatic hypotension, peripheral neuropathy, carpal tunnel syndrome, and macroglossia.
  • Peripheral edema and hypotension result from congestive heart failure and nephrotic syndrome.
  • Purpura results from vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.
• Cardiac involvement
  • Cardiac amyloidosis typically causes diastolic dysfunction; congestive heart failure; and arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.
  • The physical findings observed are not specific for cardiac amyloidosis.
• Ecchymosis
  • Bleeding may be a severe manifestation of L chain–type amyloidosis or of any of the systemic amyloidoses.
  • Subendothelial deposition leads to capillary fragility and mucocutaneous bleeding.
  • A deficiency in coagulation factor X, resulting from its binding to L chain–type amyloid fibrils, can exacerbate bleeding.
• Neuropathy
  • In approximately 20% of people with L chain–type amyloidosis, deposition occurs in the peripheral nerves, causing sensorimotor peripheral neuropathy. Nerve deposition leads to symmetric sensory impairment and weakness, accompanied at times by painless ulcers similar to those of diabetic neuropathy. Cranial neuropathy is occasionally observed. Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, or impotence.
  • Patients with familial TTR amyloidosis commonly present with a combination of severe peripheral and autonomic neuropathy. Consider the alternative diagnosis of TTR amyloidosis in a young patient with severe amyloid neuropathy but no other severe organ involvement (see Amyloidosis, Transthyretin-Related and Amyloidosis, Overview).
• Orthostatic hypotension
  • L chain–type amyloidosis and other systemic amyloidoses can lead to severe orthostatic hypotension, to the point of producing syncope and preventing normal activity.
  • Poor cardiac contractility resulting from myocardial deposition, autonomic neuropathy resulting from amyloid deposits in the peripheral nerves, and impaired arteriolar responsiveness resulting from endothelial deposition may contribute to orthostatic hypotension.
  • Treating heart failure or the nephrotic syndrome with diuretics may exacerbate hypotension.
• Hepatosplenomegaly
  • Hepatic and splenic depositions causing hepatomegaly and/or splenomegaly are common and usually asymptomatic.
  • Rarely, spontaneous rupture of the liver or the spleen may present as a surgical emergency.
• Macroglossia
  • Macroglossia is present less frequently at diagnosis than was reported in earlier case series, probably because of earlier diagnosis.
  • When present, macroglossia can become severe enough to interfere with swallowing and breathing.
  • When it occurs, macroglossia highly suggests amyloidosis of the amyloid L-chain type, because this physical finding has apparently been described only in L chain–type amyloidosis and occasionally in β ₂ -microglobulin (B2M) amyloidosis.
• Musculoskeletal system
  • L chain–type amyloidosis deposits in the joints resembling seronegative rheumatoid arthritis may lead to a clinical examination.
  • Deposits in the glenohumeral articulation may cause localized pain and swelling ("shoulder pad" sign), whereas deposits in skeletal muscle may produce pseudohypertrophy.
• Localized L chain–type amyloidosis
  • For unknown reasons, localized L chain–type amyloidosis most commonly occurs in the respiratory tract.
  • Localized pulmonary L chain–type amyloidosis often remains localized (ie, does not progress to systemic disease).
  • Localized L chain–type amyloidosis may involve the ureter or the urinary bladder, causing hematuria.
  • Amyloidomas are often found in the soft tissues, including the mediastinum and the retroperitoneum.
  • Skin involvement can manifest as plaques and nodules.

Causes

No cause is known for any of the monoclonal plasma cell dyscrasias. Some evidence supports an etiologic role for human herpesvirus 8 (HHV-8), but this proposed etiology remains controversial.

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