AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Beta-2-microglobulin amyloidosis is a disabling condition that affects patients undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Case reports involving patients with near end-stage renal disease also exist. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant.

Beta-2-microglobulin is a major constituent of amyloid fibrils. Its accumulation has been shown to invade synovial membranes and osteoarticular sites, causing destructive osteoarthropathies, such as carpal tunnel syndrome, flexor tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures.

Visceral involvement has been found in different organs, such as the gastrointestinal tract, heart, and tongue, but overt manifestations are rare.

Pathophysiology

Beta-2-microglobulin is a glycosylated polypeptide with a molecular weight of 11,800 dalton. It comprises the beta chain of the human leukocyte antigen (HLA) class I molecule and has a prominent beta-pleated structure with characteristic amyloid fibrils. Beta-2-microglobulin is present on the surface of most nucleated cells and in most biologic fluids, including urine and synovial fluid. It circulates as an unbound monomer distributed in the extracellular space and polymerizes to form amyloid deposits in a variety of tissues.

In the normally functioning kidney, beta-2-microglobulin is cleared by glomerular filtration and is catabolized in the proximal tubules. Reference range serum levels are 1.5-3 mg/L. In renal failure, impaired renal catabolism causes an increase in synthesis and a release of beta-2-microglobulin, and levels can increase 10- to 60-fold. Retention and accumulation of this type of amyloid protein is presumed to be the main pathogenic process underlying beta-2-microglobulin amyloidosis. There is also some suggestion that the dialysis process itself may stimulate beta-2-microglobulin synthesis by activation of complements and cytokine production. However, it is unlikely that this is a significant mechanism of dialysis-related amyloidosis (DRA) since the disease is also seen in patients on CAPD and people who have never been on dialysis.

Frequency

United States

The incidence of DRA in the United States is not known; however, past studies have suggested an incidence of greater than 95% in patients on dialysis for more than 15 years.

Some European studies have suggested that DRA can be seen in as many as 20% of patients after 2-4 years of HD and in 100% after 13 years of HD. However, again, the overall incidence and prevalence of beta-2-microglobulin amyloidosis are not clear. 

Most studies have focused on HD-associated amyloidosis and have been done before high-flux dialyzer use became commonplace.

There is some mention in the literature that the incidence and the prevalence in CAPD are less than in HD (because of residual renal function), while other European studies suggest that there is no significant difference in both the incidence and the prevalence.

Beta-2-microglobulin amyloidosis evolves predictably over time and is rare in the first few years of HD.

International

Studies in Japan suggest that most patients with carpal tunnel syndrome associated with beta-2-microglobulin amyloid deposits have undergone HD for 10 years or more. In one study, up to 50% of patients developed this complication after 20 years, and the percentage was even higher after 25 years.

Mortality/Morbidity

Patients receiving long-term dialysis can experience disabling musculoskeletal complications. For individuals who are able to undergo renal transplant, progression of the disease can be halted, but regression is unlikely. Rarely, submucosal bowel deposits have resulted in massive GI bleeding. Case reports of severe pulmonary hypertension and heart failure due to beta-2-microglobulin amyloid deposits in the interstitium and/or vasculature of the cardiovascular system also exist.

Race

No data comparing the incidence of disease in different groups exist.

Sex

The sex of the individual does not seem to influence risk.

Age

The incidence correlates with the increased age of the individual and the time on dialysis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Clinical manifestations almost never appear before 5 years of dialysis therapy. Unlike other types of amyloidosis, beta-2-microglobulin amyloid is confined largely to osteoarticular sites. Visceral deposits are rare, occur after 10 or more years of dialysis, and tend not to cause symptoms in most cases. Patients often present with a characteristic triad of carpal tunnel syndrome, shoulder pain, and flexor tenosynovitis in the hands.

• Osteoarticular manifestations  
• • Carpal tunnel syndrome: This syndrome is the most common presenting feature. It usually is bilateral and progressive. Patients report numbness, paresthesias, pain, and swelling in the region of the distal median nerve. Pain usually is worse during dialysis and at night. Progression to contraction of the hand and atrophy of the muscles can occur. However, it is important to remember that all cases of carpal tunnel in dialysis patients are not amyloid related and that other causes like ischemia may be the cause of carpal tunnel syndrome.
  • Flexor tenosynovitis: This disorder is often referred to as trigger finger or trigger thumb. Patients can flex the finger, but, with re-extension, the patient may feel a painful snap that refers to the dorsum of the hand.
  • Scapulohumeral arthropathy: Amyloid may deposit in and around the rotator cuff, resulting in shoulder pain that is worse while in the supine position. Patients often report difficulties dressing.
  • Spondyloarthropathy: The cervical spine is most often affected, and patients often present with neck and back pain.
  • Bone cysts: Thin-walled bone cysts are common and are most frequently found in the carpal bones. They are also observed in the femoral heads, humerus, acetabulum, and spine. Patients may experience stiffness and/or pain over the affected area.
  • Pathologic fractures: Fractures can develop in bones weakened by bone cysts. The femoral neck is most commonly involved. Patients may experience a sudden onset of leg pain while walking.
• Systemic manifestations: Most individuals with systemic manifestations have undergone dialysis for longer than 10-15 years, and they generally are asymptomatic.
• • GI involvement: Macroglossia, dysphagia, small bowel ischemia, malabsorption, and pseudoobstruction can occur because of subepithelial, submucosal, and blood vessel amyloid deposits.
  • Cardiovascular involvement: Myocardial, pericardial, and cardiac valves may be involved. Beta-2-microglobulin amyloid deposits have also been identified in small pulmonary arteries and veins.
  • Genitourinary tract: Renal and bladder calculi containing beta-2-microglobulin deposits causing obstruction have been described. Beta-2-microglobulin amyloid has also been identified in the prostate and the female reproductive tract.

Physical

The most common physical findings include carpal tunnel syndrome, musculoskeletal deformities, bone cysts, lytic bone lesions, and pathologic fractures caused by amyloid deposition within joints, intervertebral discs, and tendon sheaths. Systemic manifestations are rare.

• Osteoarticular involvement
• • Carpal tunnel syndrome: Patients experience weakness and atrophy of the thenar muscle, along with decreased strength in abduction, opposition, and flexion of the thumb.
  • Flexor tenosynovitis: Amyloid deposits may result in prominence of the tendons of the hands on extension. Patients often experience decreased digital mobility and soft tissue swelling over flexor tendon sheaths.
  • Scapulohumeral arthropathy: Deposits in and around the rotator cuff may cause soft tissue thickening around the shoulder, referred to as the shoulder pad sign. The patient's capacity to abduct or internally rotate the arm is limited.
  • Spondyloarthropathy: Paravertebral ligaments and intervertebral discs may be destroyed or dislocated, resulting in spinal cord impingement or paraplegia.
  • Bone cysts: Cysts grow in size and number in the wrist, humeral head, hip, and patella. As cysts enlarge, soft tissue swelling and swollen joints with subsequent spontaneous tendon rupture and pathologic fracture may occur. Cysts do not regress with renal transplantation.
• Systemic manifestations: If systemic involvement occurs, small, localized deposits are observed around blood vessels and in the mucosa of the GI tract, heart, lungs, and genitourinary tract. In rare cases, fatal GI hemorrhages, cardiac arrhythmias, and renal vein thromboses have occurred.

Causes

Retention of amyloidogenic protein remains a key factor in patients on dialysis. Several factors affecting retention have been implicated.

• Type of dialysis membrane  
• • The healthy kidney can eliminate endogenous end products of metabolism, as well as exogenous toxins that are both large and small molecular weight substances. Cuprophan and cellulose acetate membranes previously used in conventional HD have small pores and cannot clear substances with molecular weights higher than 200 dalton. This makes them impermeable to beta-2-microglobulin, elevating its serum levels. The newer cellulose triacetate dialyzers and the high-flux synthetic dialyzers remove molecules with a higher molecular weight and do a better job of removing beta-2-microglobulin.
  • High cut-off high-flux dialysis and online hemodiafiltration have been shown to be superior in the removal of beta-2-microglobulin, possibly decreasing beta-2 amyloidosis.
  • Beta-2-microglobulin amyloidosis has also been described in patients receiving long-term CAPD, despite the permeability characteristics of the peritoneal membrane. Clearance of middle molecules is better, making CAPD a more biocompatible mode of treatment. However, data are conflicting. Some report the prevalence of beta-2-microglobulin amyloidosis in patients on long-term CAPD as comparable to the prevalence in patients on HD. Other data show that plasma levels of beta-2-microglobulin are lower in patients on CAPD, suggesting that accumulation of amyloid may occur more slowly. Some of this may also be related to residual renal function. Results of long-term studies are needed.
• Prolonged uremic state and/or decreased diuresis: Poor biocompatibility of membranes cannot completely explain beta-2-microglobulin because several reports note individuals treated exclusively by CAPD. Cases have also been described in patients with chronic renal failure who have not yet started dialysis. Inadequate diuresis and prolonged uremia are suggested contributing factors.
• Elevated levels of cytokines: Dialysis is an inflammatory stimulus, inducing cytokine production and complement activation. The released cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), are thought to stimulate the synthesis and release of beta-2-microglobulin by macrophages and/or augment the expression of HLA class I antigens, which increases beta-2-microglobulin expression.
• Advanced glycation end products
• • Following the identification of advanced glycation end products (AGE) in beta-2-microglobulin amyloid deposits, the role of AGE has been the focus of much research.
  • • AGE is a heterogeneous group of carbohydrate molecules formed by nonenzymatic glycation and oxidative reactions between reducing sugars and protein amino groups. HD and peritoneal dialysis both are ineffective in removing these low–molecular weight proteins from circulation. As AGE-modified beta-2-microglobulin accumulates, chemotaxis is enhanced, stimulating macrophages to release proinflammatory cytokines, as well as interfering with collagen synthesis. It has been suggested that the interaction of AGE-beta-2-microglobulin with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of DRA, is mediated by the receptor for AGEs or RAGE.
    • RAGE is a central binding site for AGEs formed in vivo. AGE-beta-2-microglobulin-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of patients on long-term HD, a process that may ultimately lead to bone and joint destruction.
  • Oxidation of beta-2-microglobulin may also enhance amyloid deposition. Studies suggest that increased oxidative stress during HD and exposure of beta-2-microglobulin to hydroxyl radicals stimulate the autoxidation of unstable molecules, leading to augmented AGE production.
• Dialysate: Acetate and/or bacterial lipopolysaccharide (endotoxin) may enter the blood via the dialyzer and stimulate the release of cytokines, inducing beta-2-microglobulin production.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Secondary hyperparathyroidism is the most common bone disease found in patients with end-stage renal disease. Bone erosions, tendon ruptures, and osteosclerosis can be the source of bone pain or polyarthralgias. DRA bone lesions differ from renal osteodystrophy in that the presence of the amyloid deposits interfere with normal bone tissue dynamics while in renal osteodystrophy, the abnormality is in the underlying metabolic process itself, causing bone turnover to be either increased or decreased. In the case of pathological fractures in patients on dialysis, it is essential that DRA be distinguished from renal osteodystrophy because there are implications for healing.

Aluminum overload: Patients with end-stage renal disease sometimes receive aluminum-containing antacids to control serum phosphate levels. Absorbed aluminum can be toxic to osteoblasts, leading to the development of osteomalacia.

Dupuytren contracture is a type of palmar fasciitis observed in people with chronic alcoholism and people with chronic diabetes.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The diagnosis of beta-2-microglobulin amyloidosis is established primarily by its clinical appearance on tissue or bone biopsy.
• Blood  
• • The reference range of the serum concentration of beta-2-microglobulin is 1.5-3 mg/L. Serum levels of beta-2-microglobulin can be elevated to values of 50-100 mg/L. Beta-2-microglobulin levels correlate with elevated serum creatinine levels and are inversely related to the glomerular filtration rate.
  • Hematologic findings frequently reveal a normochromic, normocytic anemia.

Imaging Studies

• Radiographs: Radiologic lesions typically present prior to the onset of pain. Joint erosions (usually involving large joints), lytic and cystic bone lesions (typically juxta-articular), pathological fractures (most commonly involving the femoral head), spondyloarthropathies (usually involving the cervical area), and vertebral compression fractures may be observed. However, conventional radiography may underestimate the extent of the disease.
• CT scans reveal amyloid deposits of intermediate attenuation. CT scans can be used to identify pseudotumors and pseudocystic areas in the juxta-articular bone. CT is the best method for detecting small areas of osteolysis in cortical bone or osseous erosion, and it may be helpful in the assessment of the distribution and extent of destructive changes.
• MRI shows characteristic long T1 and short T2 relaxation times, resulting in low-to-intermediate signal intensity. MRI is helpful in differentiating destructive spondyloarthropathies from inflammatory processes and infections. In evaluating amyloidosis, MRI may provide considerably more information than that obtained from conventional radiographic, CT, and sonographic studies.
• Ultrasound is useful in the detection of tendon thickness. Rotator cuff thickness greater than 8 mm, thickening of joint capsules (especially of the hip and knee), and retention of synovial fluid may be observed.

Other Tests

• Electron microscopy: Typically, 8- to 10-nm wide, nonbranching, curvilinear fibrils are observed.
• Scintigraphy (radiolabeled P-component scans, including iodine I 123 serum amyloid P and iodohippurate sodium I 131 beta-2-microglobulin and the more natural I 111 beta-2-microglobulin) detects involved lesions using local deposition of tracers. The cells surrounding the amyloid deposit take up the circulating tracer, making it a useful means of evaluating the total body burden of amyloid. This method has primarily been used in Europe and is not available in North America.

Procedures

• Biopsy with Congo red staining and with immunostaining  
• • The criterion standard for diagnosis is histological identification using Congo red and immunohistochemical staining of biopsy specimens or centrifuged synovial fluid sediments. Puncture biopsies are obtained from cystic bone lesions and intra-articularly in synovia. Unlike other types of amyloidosis, rectal biopsy and subcutaneous fat aspiration are of little value. The most common site from which biopsies are obtained is the sternoclavicular joint.
  • Immunohistochemical reaction of biopsy specimen: Antisera to Abeta-2-microglobulin are taken up by the Congo red–positive areas but not by other types of amyloidosis.

Histologic Findings

Obtaining a biopsy of the affected bone or synovium, followed by routine hematoxylin and eosin staining, reveals homogeneous eosinophilic material. Amyloid deposits are positive for Congo red staining, showing green birefringence of the amyloid fibrils under polarized light. Specific immunostaining of amyloid deposits by monoclonal anti–beta-2-microglobulin antibody confirms the diagnosis of beta-2-microglobulin amyloidosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

At present, no adequate treatment of beta-2-microglobulin amyloidosis exists. Medical therapy is limited to symptomatic approaches in ameliorating joint pain and inflammation.

• The treatment of joint pain includes nonsteroidal anti-inflammatory drugs, intra-articular injections of prednisolone, 10% hydrocortisone cream, and low-dose oral prednisone in severe cases.
• Conservative treatment includes physical and occupational therapy. Wrist splints, cervical collars, lumbar corsets, knee braces, and immobilization for spondyloarthropathies often are helpful.
• Improvement of dialysis membranes: High-flux biocompatible polyacrylonitrile and polysulfone membranes have increased middle molecule removal and thereby enhance beta-2-microglobulin removal during HD and hemofiltration.
• Online hemodiafiltration: This has been associated with the maximal removal of beta-2-microglobulin.
• Dialysate preparations: Use of ultrapure, sterile, and apyrogenic dialysate may aid in decreasing stimulation and in releasing cytokines. It also may decrease plasma levels of acute phase proteins.
• Direct hemoperfusion-type adsorption column (Lixelle): This was developed to selectively eliminate beta-2-microglobulin from the circulating blood of patients with DRA. Lixelle treatments reduce the circulating levels of beta-2-microglobulin and inflammatory cytokines, thereby improving the symptoms of patients with DRA. While these treatments have been used and studied in Japan, they are not currently used in the United States.

Surgical Care

Surgical intervention, including carpal tunnel release with surgical decompression of the median nerve or release of the transverse carpal ligaments under endoscopic visualization, flexor tenosynovectomy or percutaneous first annular pulley release, spinal stabilization or laminectomy, or total joint replacement, may be effective in alleviating pain and restoring function. Unfortunately, orthopedic interventions have high failure rates in DRA compared with the general population. If during the course of a surgery, beta-2-microglobulin amyloidosis is suspected, then a biopsy should be performed at that time.

• Renal transplantation 
• • Renal transplantation is the treatment of choice for beta-2-microglobulin amyloidosis. It lowers the blood concentration of beta-2-microglobulin to the reference range, halting the progression of the disease.
  • Osteoarticular symptoms, such as joint pain, swelling, and stiffness, disappear within the first week after transplantation. Cystic lesions usually remain unchanged, and regression of amyloid deposits probably does not occur.
  • Transplantation is not an option for all patients. Renal transplantation has already failed in some patients on long-term dialysis when they develop beta-2-microglobulin amyloidosis, and others may not be suitable candidates.

Consultations

• A rheumatology specialist may be needed.
• Initiate early consideration for renal transplantation.

Diet

• No known diet directly affects beta-2-microglobulin.
• Patients with renal failure should receive the appropriate dietary management for that condition.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medical treatment presently exists to reverse or alter the disease course. Low-dose steroids and nonsteroidal anti-inflammatory agents are symptomatic approaches in ameliorating joint pain and inflammation.

Drug Category: Immunosuppressive agents

Used to suppress the inflammatory process.

Drug Category: Topical analgesics

Penetrate deep for temporary relief of minor aches and pains of muscles and joints associated with arthritis.

Drug Category: Nonsteroidal anti-inflammatory agents

These agents have analgesic, anti-inflammatory properties and antipyretic activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• A nephrologist should care for patients with beta-2-microglobulin amyloidosis on an ongoing basis.

Deterrence/Prevention

• Although this is hard to assess, possible ways of preventing or at least of decreasing the incidence of DRA are the use of a high-flux dialyzer, online hemodiafiltration, and ultrapure dialysate and adsorbent columns.
• Based on the Disease Outcomes Quality Initiative (DOQI) guidelines, there is no indication for routine monitoring of beta-2-microglobulin.

Complications

• The most severe complication involves beta-2-microglobulin amyloid deposits destroying paravertebral ligaments and intervertebral discs, which can result in paraplegia.
• Cardiac involvement with subsequent fatal arrhythmias and massive GI bleeding has been described.

Prognosis

• The prognosis of beta-2-microglobulin amyloidosis depends on the duration of dialysis, the age of the patient, the age of the patient at the start of dialysis, and the type of dialysis membrane that is used. Ultimately, residual renal function is probably the best determinant of beta-2-microglobulin levels in HD patients and may supersede enhanced convective clearance by hemodiafiltration.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The physician must be certain that the type of amyloidosis has been determined definitively.
• Involve rheumatologic, surgical, and transplant consultants early.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 22, 2008