Monday, July 21, 2025

What is amyloidosis and why is it important to orthopaedic patients and their surgeons?

We can save lives by recognizing that tendon failure can be an early warning sign of impending heart failure.

Let me indulge you in a personal story. Imagine an 81 year old active orthopaedic surgeon with a history of bilateral carpal tunnel syndrome, trigger finger, rotator cuff tear and rupture of the long head of the biceps. This surgeon then developed atrial fibrillation that sometimes required cardioversion in the middle of a day in the operating room. When on an easy walk, his right knee buckled because of an atraumatic complete (hinge to hinge) tear of the quadriceps tendon. An alert attending cardiologist put all this together and recommended a tissue biopsy for amyloidosis at the time of quadriceps repair. Congo red positive material was present; liquid chromatography tandem mass spectrometry detected a peptide profile consistent with transthyretin type amyloid deposition, supporting the diagnosis wild-type transthyretin (ATTRwt) amyloid deposition.

 This is important because amyloidosis is a cause of heart disease (in fact one of his medical school classmates just passed away from amyloid-caused heart failure). Critically, orthopaedic manifestations often precede cardiac manifestation by years AND 
early treatment can slow progression of symptomatic heart involvement.

A technetium pyrophosphate scan demonstrated diffuse uptake in his myocardium. Compared to the uptake in the right chest at the same level, the ratio is 1.6, which is suggestive of ATTR cardiac amyloidosis 



He was placed on Tafamidis, a medication used to treat transthyretin amyloid cardiomyopathy, that works by stabilizing the transthyretin protein, preventing it from breaking down into amyloid fibrils that can damage the heart. 

By way of background, transthyretin is a protein produced mainly in the liver that transports vitamin A and thyroid hormone thyroxine throughout the body. Mutations in the TTR gene can lead to transthyretin amyloidosis, a condition where misfolded TTR proteins form amyloid deposits in connective tissues and the heart.

 Now, after successful ablation for refractory atrial fibrillation, this patient is back to regular aerobic exercise and caring for patients with shoulder disorders.


Here's a look at some of the relevant literature.

Cole, A. S., et al. (2001). "Localised deposition of amyloid in tears of the rotator cuff." J Bone Joint Surg Br 83(4): 561-564.

Age-related localised deposition of amyloid in connective tissue has been found in degenerative articular and periarticular tissue. Biopsies of the supraspinatus tendon of 28 patients undergoing repair of the rotator cuff were analysed histologically for the presence of localised deposition of amyloid. There was a long history of impingement in 20 patients, and eight patients had suffered an acute traumatic tear with no preceding symptoms. Localised deposition of amyloid identified by Congo Red staining was detected in 16 samples (57%). Amyloid was present in 14 (70%) of the degenerative tears, but in only two (25%) of the acute tears. Immunohistochemical staining showed that the amyloid deposits were positive for P component, but negative for kappa and lambda light chains, prealbumin, and beta2 microglobulin. Critical electrolyte staining revealed highly-sulphated glycosaminoglycans at sites of deposition of amyloid. The presence of localised deposition of amyloid in tears of the rotator cuff is likely to represent irreversible structural changes. These findings support the theory that impingement and tears are due to intrinsic degenerative changes within the tendons of the rotator cuff.

Wininger, A. E., et al. (2021). "Musculoskeletal pathology as an early warning sign of systemic amyloidosis: a systematic review of amyloid deposition and orthopedic surgery." BMC Musculoskelet Disord 22(1): 51.

BACKGROUND: Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival. QUESTIONS/PURPOSES: The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis. METHODS: We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT. RESULTS: This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid. CONCLUSIONS: This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients >/=70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.

Zhang, D., et al. (2021). "Orthopaedic Manifestations of Amyloidosis." J Am Acad Orthop Surg 29(10): e488-e496.

Amyloidosis is a disorder of misfolded proteins in human tissues, which can result in morbid cardiac and neurological disease. Historically, the utility of tissue biopsy during orthopaedic procedures to detect amyloidosis has been limited because no disease-modifying therapies were available; however, new drug therapies have recently emerged for the treatment of amyloidosis. Although these novel pharmaceuticals show promise for slowing disease progression, they are primarily effective in the early stages of amyloidosis, underscoring the importance of early diagnosis. Common orthopaedic manifestations of amyloidosis include carpal tunnel syndrome, trigger finger, spontaneous distal biceps tendon rupture, rotator cuff disease, and lumbar spinal stenosis. Carpal tunnel syndrome is frequently the earliest manifestation of amyloidosis, on average preceding a formal diagnosis of amyloidosis by over four years. By recognizing the constellation of musculoskeletal symptoms in the patient with amyloidosis, orthopaedic surgeons can play an active role in patient referral, early detection of systemic disease, and prompt initiation of disease-modifying treatment. There may be a role for selective biopsy for amyloid deposition in at-risk patients during routine orthopaedic procedures.

Perfetto, F., et al. (2022). "Transthyretin Cardiac Amyloidosis: A Cardio-Orthopedic Disease." Biomedicines 10(12).

Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, frequently male and aged, steadily precede cardiac involvement inducing a rapidly progressive heart failure with preserved ejection fraction. Although transthyretin cardiac amyloidosis remains a cardiac relevant disease, these extracardiac localisation may increase diagnostic suspicion and allow for early diagnosis assuming the role of useful diagnostic red flags, especially in light of new therapeutic opportunities that can slow or stop the progression of the disease. For the cardiologist, the recognition of these extracardiac red flags is of considerable importance to reinforce an otherwise less emerging diagnostic suspicion. For orthopedists and rheumatologists, the presence in an old patient with or without clinical manifestations of cardiovascular disease, of an unexpected and inexplicable constellation of musculoskeletal symptoms, can represent a fundamental moment for an early diagnosis and treatment is improving a patient's outcome.

Rath, J., et al. (2024). "Carpal Tunnel, Trigger Finger, and Spinal Stenosis: The Rest of the Story." S D Med 77(11): 516-525.

Amyloidosis is a deadly systemic disease in which misfolded proteins accumulate in human tissue eventually leading to morbid dysfunction in multiple organ systems. The prognosis of untreated amyloidosis is poor. Orthopedic manifestations of amyloidosis include carpal tunnel syndrome (CTS), trigger digit, distal biceps tendon rupture, rotator cuff disease, and lumbar spinal stenosis. These orthopedic conditions are early red flags for systemic amyloidosis. CTS is often the earliest manifestation and can precede the disease by over four years. With the advent of medications that can slow the progression of amyloidosis, particularly in the early stages of the disease, it is imperative to diagnose amyloidosis early on. Both primary care physicians and orthopedic surgeons can recognize the various orthopedic conditions associated with amyloidosis and play a vital role in early disease detection. Awareness of the musculoskeletal presentation of systemic amyloidosis can lead to earlier detection and treatment that can delay the progression of the disease.

Sood, R. F., et al. (2021). "Diagnosing Systemic Amyloidosis Presenting as Carpal Tunnel Syndrome: A Risk Nomogram to Guide Biopsy at Time of Carpal Tunnel Release." J Bone Joint Surg Am 103(14): 1284-1294.
BACKGROUND: As carpal tunnel syndrome often precedes other signs of systemic amyloidosis, tenosynovial biopsy at the time of carpal tunnel release may facilitate early diagnosis and treatment. However, evidence-based guidelines for amyloidosis screening during carpal tunnel release have not been established. We sought to develop a predictive model for amyloidosis after carpal tunnel release to inform screening efforts. METHODS: We performed a retrospective cohort study of adults without known amyloidosis undergoing at least 1 carpal tunnel release from 2000 to 2019 with use of the national Veterans Health Administration database. After estimating the cumulative incidence of amyloidosis after carpal tunnel release, we identified risk factors, constructed a predictive nomogram based on a multivariable subdistribution-hazard competing-risks model, and performed cross-validation. RESULTS: Among 89,981 patients undergoing at least 1 carpal tunnel release, 310 were subsequently diagnosed with amyloidosis at a median interval of 4.5 years, corresponding to a cumulative incidence of 0.55% (95% confidence interval [CI]: 0.47% to 0.63%) at 10 years. Amyloidosis diagnosis following carpal tunnel release was associated with an increased hazard of heart failure (hazard ratio [HR], 4.68; 95% CI: 4.26 to 5.55) and death (HR, 1.27; 95% CI: 1.07 to 1.51) after adjustment for potential confounders. Age, male sex, Black race, monoclonal gammopathy of undetermined significance or multiple myeloma, rheumatoid arthritis, atrial fibrillation, spinal stenosis, and bilateral carpal tunnel syndrome were independently associated with increased risk of amyloidosis diagnosis and were included in the risk nomogram. CONCLUSIONS: Amyloidosis diagnosis after carpal tunnel release is rare but is associated with poor outcomes. We present an amyloidosis-risk nomogram to help guide tenosynovial biopsy at time of carpal tunnel release. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Sood, R. F. and A. B. Lipira (2022). "Risk of Amyloidosis and Heart Failure Among Patients Undergoing Surgery for Trigger Digit or Carpal Tunnel Syndrome: A Nationwide Cohort Study With Implications for Screening." J Hand Surg Am 47(6): 517-525 e514.
PURPOSE: Tenosynovial biopsy during carpal tunnel release (CTR) leads to an earlier diagnosis of amyloidosis. Surgery for trigger digit-trigger release (TR)-may provide a similar opportunity. We sought to characterize the risk of amyloidosis diagnosis after TR and/or CTR. METHODS: We conducted a retrospective cohort study of adults without diagnosed amyloidosis undergoing TR and/or CTR in the Veterans Health Administration from 1999 to 2019, including matched controls. We used competing-risks methodology to estimate the cumulative incidence and adjusted subdistribution hazard ratios (sHRs) of amyloidosis, heart failure, and death after TR and/or CTR. RESULTS: Among the 126,788 patients undergoing TR and/or CTR, amyloidosis was diagnosed in 52 of 26,757 patients undergoing TR alone at a median of 4.7 years after surgery (10-year cumulative incidence: 0.26%, 95% CI: 0.18% to 0.34%), 396 of 91,384 patients undergoing CTR alone at a median of 5.1 years after surgery (10-year cumulative incidence: 0.60%, 95% CI: 0.53% to 0.67%), 50 of 8,647 patients undergoing both TR and CTR at a median of 3.1 years after surgery (10-year cumulative incidence: 0.80%, 95% CI: 0.54% to 1.1%), and 54 of 113,452 controls at a median of 5.0 years after the index date (10-year cumulative incidence 0.053%, 95% CI: 0.037% to 0.070%). In the adjusted analysis, patients who underwent TR and/or CTR had a higher risk of amyloidosis (TR: sHR(adj) 4.80, 95% CI: 3.33-6.92; CTR: sHR(adj) 10.2, 95% CI: 7.74-13.6; TR and CTR: sHR(adj) 14.9, 95% CI: 9.87-22.5) and heart failure (TR: sHR(adj) 1.91, 95% CI: 1.83-1.99; CTR: sHR(adj) 2.02, 95% CI: 1.97-2.07; TR and CTR: sHR(adj) 2.18, 95% CI: 2.04-2.33) but not death compared with the controls. Among the patients who underwent TR, age, Black race, prior CTR, heart failure, and the number of digits released were independent risk factors for amyloidosis. CONCLUSIONS: Patients undergoing TR and/or CTR are at increased risk of incident amyloidosis and heart failure compared to controls. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Bottom line:
Wild-type transthyretin (ATTRwt) amyloid deposition is common in tendons and ligaments of older adults, even in the absence of systemic symptoms.

Orthopedic conditions—especially CTS, rotator cuff tears, and lumbar stenosis—can precede ATTRwt cardiomyopathy by years.
These musculoskeletal manifestations should be recognized as red flags, prompting consideration of systemic amyloidosis workup, particularly in older men.

Early detection through tissue biopsy during orthopedic surgery, combined with cardiac imaging and TTR genotyping, may allow for timely treatment, improving outcomes.


Early diagnosis may help keep our patients soaring


Red-tailed hawk
Seattle 
2024


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Here are some videos that are of shoulder interest
Shoulder arthritis - what you need to know (see this link).
How to x-ray the shoulder (see this link).
The ream and run procedure (see this link).
The total shoulder arthroplasty (see this link).
The cuff tear arthropathy arthroplasty (see this link).
The reverse total shoulder arthroplasty (see this link).
The smooth and move procedure for irreparable rotator cuff tears (see this link)
Shoulder rehabilitation exercises (see this link).