An 81-year-old woman reports progressively increasing bilateral shoulder pain for 2 months. Over the past 2 weeks, she has developed burning pain in her right thumb, index, and middle fingers. Medical history is significant for type 2 diabetes mellitus and end-stage renal disease due to diabetic nephropathy. The patient has received hemodialysis for the past 10 years. Vital signs are normal. Examination reveals normal heart and lung sounds. There is no organomegaly. Both shoulders are hypertrophied. There is thenar atrophy on the right hand and soft tissue fullness at the right wrist. Which of the following is most likely responsible for this patient's current condition?
Major types of systemic amyloidosis | ||||
Primary | Secondary | Age related | Dialysis related | |
Disease | Plasma cell dyscrasia | Chronic infection/ | Elderly men | ESRD on dialysis |
Precursor ↓ Misfolding ↓ Amyloid | Immunoglobulin ↓ Increased ↓ AL | Serum ↓ Increased ↓ AA | Transthyretin ↓ Accumulation ↓ ATTR* | β2-Microglobulin Decreased ↓ Aβ2M |
Clinical | Nephropathy, hepatosplenomegaly, cardiomyopathy (AL > AA), peripheral neuropathy, macroglossia, skin bruising | Cardiomyopathy, CTS, other peripheral neuropathy | Scapulohumeral arthritis, CTS | |
Amyloid names begin with "A" followed by the precursor protein abbreviation. *ATTR also occurs in a hereditary form that affects younger patients. CTS = carpal tunnel syndrome; ESRD = end-stage renal disease. | ||||
This patient on long-term hemodialysis has carpal tunnel syndrome and shoulder pain/hypertrophy, most likely due to dialysis-related amyloidosis (DRA).
Amyloidosis is a group of multisystem disorders, all characterized by misfolded proteins. Misfolding results from increased production, decreased clearance, inherited mutations, or age-related deposition of protein subunits. Structural transformation of precursor proteins into beta-pleated sheets leads to aggregation and polymerization into amyloid fibrils. Resistant to degradation, amyloid accumulates in extracellular tissues, causing organ dysfunction. Each precursor protein generates specific amyloid fibrils predisposed to particular organs.
In DRA, beta2-microglobulin (beta2-m) is the precursor protein and a component of major histocompatibility class I molecules on all nucleated cells. Continuously shed in plasma, beta2-m has near-total clearance by normal kidneys. However, in end-stage renal failure, it is inadequately eliminated despite dialysis and deposited in tissue as beta2-m amyloid. Disease most often involves osteoarticular structures as connective tissue components (eg, glycosaminoglycans, type-1 collagen) stabilize beta2-m amyloid fibrils and inhibit their depolymerization. Typical manifestations include:
DRA prevalence increases with age and dialysis duration. Although improved dialysis membranes provide better clearance of beta2-m, its prevalence remains significant.
(Choice A) Free immunoglobulin light chains are produced in excess by clonal expansion of plasma cells in multiple myeloma and deposited as AL amyloid. AL amyloid typically results in nephrotic syndrome, hepatomegaly, restrictive cardiomyopathy, and neuropathy. Macroglossia and periorbital purpura are less common but characteristic.
(Choice B) Serum amyloid A is an acute phase protein excessively produced due to elevated cytokines in chronic infectious or inflammatory conditions (eg, tuberculosis, rheumatoid arthritis). Accumulation produces AA amyloid, which deposits primarily in the kidneys, liver, and spleen. This patient has no chronic infectious or inflammatory conditions.
(Choices D and E) Transthyretin is a protein named for its function (transports thyroxin and retinol). Inherited mutation or age can cause its deposition as amyloid with prominent cardiac involvement.
Educational objective:
Beta2-microglobulin is renally cleared and poorly dialyzed. It accumulates as amyloid in dialysis patients, increasing in prevalence with dialysis duration, and has a predilection for osteoarticular surfaces. Shoulder pain and carpal tunnel syndrome are common. Bone cysts and pathologic fractures may also occur.