This comprehensive review highlights major advances in understanding and treating systemic light chain amyloidosis (AL amyloidosis), a serious condition where abnormal proteins damage organs. Over the past 40 years, treatments targeting the underlying plasma cell disorder have dramatically improved patient outcomes, with survival rates steadily increasing. The article covers new insights into how the disease develops, improved diagnosis methods, detailed staging systems that predict survival, and emerging treatments that offer hope to patients.
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Understanding Systemic Light Chain Amyloidosis: Causes, Symptoms, and New Treatments
Table of Contents
- Introduction: What is AL Amyloidosis?
- How AL Amyloidosis Develops in the Body
- How Common is AL Amyloidosis?
- Symptoms and Clinical Presentation
- Getting an Accurate Diagnosis
- Staging and Predicting Outcomes
- Treatment Approaches and Management
- Supportive Care for Symptoms
- Conclusion and Future Directions
- Source Information
Introduction: What is AL Amyloidosis?
Systemic immunoglobulin light chain amyloidosis (AL amyloidosis) is a serious disease where abnormal proteins build up in organs and tissues, causing progressive damage and organ failure. Over the past four decades, treatment approaches have undergone transformative changes, leading to marked and steady progress in patient outcomes.
Substantial progress has been made through treatments targeting the underlying plasma cell disorder, mostly adapted from multiple myeloma treatments. The past decade has seen remarkable advancements that have instilled hope among patients with AL amyloidosis. This review focuses on recent advances in understanding how the disease develops, its clinical features, risk stratification methods, and therapeutic advances.
Amyloidosis comprises a group of diseases triggered by the misfolding of a soluble precursor protein. This misfolding leads to the formation of oligomers, aggregates, and amyloid fibrils characterized by pleated β-sheets, which are deposited extracellularly in various organs and tissues. The result is progressive organ dysfunction, organ failure, and eventual death.
Organ dysfunction occurs due to the disruption of architecture caused by amyloid deposits, direct cytotoxic effects from protein aggregates or oligomers, or both. A total of 42 soluble precursor amyloidogenic proteins that can form extracellular amyloid fibrils have been identified to date.
How AL Amyloidosis Develops in the Body
The defining feature of systemic amyloidosis is abnormal folding of a normal soluble precursor protein. In AL amyloidosis, the abnormal folding results from either a proteolytic event or an amino acid sequence that renders an immunoglobulin light chain thermodynamically and kinetically unstable, leading to self-aggregation.
These aggregates interact with glycosaminoglycan and serum amyloid P protein, promoting fibril formation and stabilizing amyloid deposits in tissues. This disrupts tissue architecture and ultimately causes organ dysfunction. Emerging evidence from laboratory models suggests that amyloidogenic precursor aggregates also have direct cytotoxic effects that contribute to organ dysfunction.
AL amyloidosis is typically associated with a plasma cell disorder that produces lambda immunoglobulin light chains in 75-80% of cases and kappa light chains in the remaining 20-25%. The chromosomal translocation t(11;14), which brings together the immunoglobulin heavy-chain locus and the oncogene cyclin D1, is characteristic of AL amyloidosis, occurring in approximately 50% of cases.
Somatic mutations in the IGLV group of genes, encoding the light chain variable region, decrease protein stability, which facilitates amyloid fibril formation. This process involves several steps:
- Clonal plasma cells in the bone marrow secrete antibodies and free light chains into circulation
- Light chains misfold and oligomerize
- Oligomers aggregate into cross-β amyloid fibrils
- These fibrils deposit in tissues, causing organ damage
How Common is AL Amyloidosis?
Epidemiologic data on AL amyloidosis are limited, primarily because of the absence of comprehensive population databases. The prevalence of this disease tends to increase with advancing age. In the Olmsted County Project in Minnesota, the overall incidence rate of AL amyloidosis was 8.9 cases per 1 million person-years between 1950 and 1989.
This increased to 10.5 cases per 1 million person-years between 1970 and 1989, and further increased to 12.0 cases per 1 million person-years between 1990 and 2015. A calculated crude incidence rate of 10.4 cases per 1 million person-years was reported across 38 countries.
As of 2018, approximately 74,000 cases of AL amyloidosis had been diagnosed globally in the preceding 20 years. The estimated incidence was 10 cases per 1 million population, and the estimated 20-year prevalence was 51 cases per 1 million population.
A real-world study based on a U.S. health care claims database showed a significant increase in the prevalence of AL amyloidosis, from 15.5 cases per 1 million population in 2007 to 40.5 cases per 1 million population in 2015, while the incidence rate remained steady, ranging from 9.7 to 14.0 cases per 1 million person-years.
Symptoms and Clinical Presentation
In the majority of cases, AL amyloidosis is characterized as a rapidly progressive disease with various clinical syndromes. Common nonspecific symptoms include fatigue and weight loss; however, organ-specific symptoms often lead to the diagnosis. Diagnostic delays occur because of low awareness among clinicians.
The kidneys are commonly affected in AL amyloidosis (in 60-70% of patients). Kidney effects typically manifest as:
- Nephrotic-range proteinuria (severe protein loss in urine)
- Hypoalbuminemia (low blood protein levels)
- Secondary hyperlipidemia (elevated blood fats)
- Edema (swelling)
The heart is also frequently involved (in 70-80% of patients), and cardiac involvement is the leading cause of death. Early signs include low voltage on electrocardiography and concentric ventricular thickening on echocardiography, along with diastolic dysfunction. Patients with cardiac AL amyloidosis are at risk for the development of atrial thrombi and thromboembolic complications.
Nervous system symptoms include small-fiber neuropathy and autonomic dysfunction, manifested as:
- Gastrointestinal motility disturbances
- Early satiety
- Dry eyes and mouth
- Orthostatic hypotension (blood pressure drop when standing)
- Neurogenic bladder
Other characteristic findings include macroglossia (enlarged tongue) in approximately 10-20% of patients, periorbital ecchymosis (raccoon eyes), and submandibular gland enlargement. Liver involvement causes cholestasis and hepatomegaly, while splenic involvement manifests as functional hyposplenism.
Getting an Accurate Diagnosis
Nonspecific symptoms linked to AL amyloidosis often contribute to diagnostic delays. Consideration of AL amyloidosis is crucial in patients with unexplained proteinuria, restrictive cardiomyopathy, peripheral neuropathy with autonomic features, carpal tunnel syndrome in both wrists, or hepatomegaly without imaging abnormalities.
The diagnosis of AL amyloidosis requires evidence of amyloid deposits in tissue and evidence of a plasma cell dyscrasia. Tissue amyloid deposits show green birefringence when stained with Congo red dye and viewed with polarized light microscopy. Fine-needle aspiration of abdominal fat is a simple procedure that is positive for amyloid deposits in approximately 70-75% of patients with AL amyloidosis.
If clinical suspicion is high and abdominal fat-pad aspiration is negative, biopsy of an affected organ may be necessary. Examination of specimens from both abdominal fat and bone marrow biopsies identifies 85% of patients with AL amyloidosis.
After tissue diagnosis, confirmation requires demonstration of a plasma cell dyscrasia through:
- Serum or urine immunofixation electrophoresis
- Immunoglobulin free light chain assay
- Presence of lambda or kappa restricted plasma cells in bone marrow
Cardiac imaging is critical for assessment. Echocardiography with strain imaging and Doppler techniques identifies early signs, while cardiac magnetic resonance imaging provides information on myocardial thickness and extracellular volume. Advanced techniques like mass spectrometry are important for confirming the protein subunit and distinguishing between different types of amyloidosis.
Staging and Predicting Outcomes
The survival of patients with systemic AL amyloidosis is heavily dependent on the severity of cardiac dysfunction at diagnosis. Patients diagnosed late in the clinical course (when heart damage is often advanced) have a median survival of 3-6 months, while patients without cardiac involvement can survive for many years.
Several staging systems use biomarkers of plasma cell dyscrasia and cardiac and kidney involvement to predict outcomes:
Mayo Clinic 2004 staging system:
- Stage I: Neither troponin T >0.035 ng/ml nor NT-proBNP >332 pg/ml - Reference risk
- Stage II: One marker above cutoff - 2.5 times higher risk of death
- Stage III: Both markers above cutoff - 6.7 times higher risk of death
Mayo Clinic 2012 staging system (added dFLC >180 mg/liter):
- Stage I: 0 markers above cutoff - Reference risk
- Stage II: 1 marker above cutoff - 1.7 times higher risk
- Stage III: 2 markers above cutoff - 4.1 times higher risk
- Stage IV: 3 markers above cutoff - 6.3 times higher risk
European modification (2013) identified very high-risk patients with NT-proBNP >8500 pg/ml, who have 11.1 times higher risk of death. The Boston University system (2019) predicts median overall survival ranging from >12 years for stage I to 1 year for stage IIIb.
A renal staging system uses estimated glomerular filtration rate <50 ml/min/1.73 m² and urinary protein excretion >5 g/24 hr to predict 2-year risk of dialysis:
- Stage I: Both criteria below cutoff - 0-3% risk
- Stage II: One criterion above cutoff - 11-25% risk
- Stage III: Both criteria above cutoff - 60-75% risk
Treatment Approaches and Management
Substantial increases in survival rates have been observed among patients with AL amyloidosis. A longitudinal natural history study spanning 40 years revealed a consistent improvement in survival over time, with 5-year overall survival increasing from 20% in the 1970s to 45% in the 2000s and exceeding 60% in the current era.
Treatment goals include achieving rapid and deep hematologic response (reduction in abnormal light chains) and organ response. The depth of hematologic response correlates with improved organ function and survival. Complete hematologic response is associated with the best outcomes, with median overall survival not reached at 10 years.
Current treatment approaches include:
- Chemotherapy regimens targeting plasma cells
- Proteasome inhibitors (such as bortezomib)
- Immunomodulatory drugs
- Monoclonal antibodies
- Stem cell transplantation for eligible patients
Recent advancements include novel agents that specifically target amyloid deposits and the use of combination therapies that have significantly improved response rates. The introduction of daratumumab, a monoclonal antibody, has shown particularly promising results in recent clinical trials.
Supportive Care for Symptoms
Supportive care is essential for managing symptoms and improving quality of life in AL amyloidosis patients. Specific supportive measures include:
For fluid retention: Salt restriction and loop diuretics
For orthostatic hypotension: Behavioral modifications, thigh-high stockings, and medications including midodrine, pyridostigmine, or droxidopa
For neuropathy: Gabapentin, pregabalin, serotonin-norepinephrine reuptake inhibitors (duloxetine or venlafaxine), and analgesic agents
For diarrhea: Loperamide, diphenoxylate-atropine, tincture of opium, octreotide, and testing for small-bowel intestinal bacterial overgrowth
For malnutrition: Nutritional support and monitoring
These supportive measures help manage symptoms while patients undergo treatment for the underlying plasma cell disorder.
Conclusion and Future Directions
The care of patients with systemic AL amyloidosis has undergone transformative changes over the past four decades, leading to marked progress in outcomes. Substantial advancements have been made in understanding the disease pathogenesis, improving diagnostic accuracy, developing sophisticated staging systems, and implementing effective treatments.
Current research continues to focus on developing novel therapies that target both the plasma cell clone and the amyloid deposits directly. The future of AL amyloidosis treatment looks promising with ongoing clinical trials investigating new agents and combination therapies.
Early diagnosis remains critical for improving outcomes, as cardiac involvement at diagnosis significantly affects survival. Increased awareness among healthcare providers and patients about the signs and symptoms of AL amyloidosis is essential for reducing diagnostic delays.
With continued research and clinical advances, the prognosis for patients with AL amyloidosis continues to improve, offering hope for better quality of life and longer survival for those affected by this serious condition.
Source Information
Original Article Title: Systemic Light Chain Amyloidosis
Authors: Vaishali Sanchorawala, MD
Publication: The New England Journal of Medicine, June 27, 2024
DOI: 10.1056/NEJMra2304088
This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine. It maintains all original data, statistics, and clinical information while making the content accessible to patients and caregivers.