Systemic AL Amyloidosis

Complex MONDO:0017816 Pathograph 42 Show in embeddings browser Amyloidosis Plasma Cell Neoplasm

Systemic AL (immunoglobulin light-chain) amyloidosis is a clonal plasma-cell disorder in which a usually plasma-cell clone produces and secretes an amyloidogenic immunoglobulin light chain that misfolds, forms cross-beta fibrils, and accumulates extracellularly in multiple organs. Organ injury reflects both deposited fibrils and, especially in the heart, direct proteotoxic effects of soluble light chains. The heart and kidneys are most commonly involved, while nerves, the gastrointestinal tract, blood vessels, and soft tissues may also be affected. Diagnosis requires demonstration of amyloid in tissue and correct biochemical typing; detecting a monoclonal protein or plasma-cell clone alone does not establish that the deposited amyloid is AL.

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Classifications

Harrison's Part

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Mechanistic Hypotheses

Canonical AL Amyloid Deposition Model

canonical_al_amyloid_deposition CANONICAL

Evidence balance 1 support

A plasma-cell clone produces an amyloidogenic monoclonal light chain that misfolds, forms beta-sheet-rich oligomers and fibrils, deposits in the extracellular matrix of multiple organs, and causes organ-specific dysfunction.

Pathograph links

Amyloidogenic Plasma-Cell Clone -> Amyloidogenic Monoclonal Free Light-Chain Production and Secretion DIRECT The clone secretes the amyloidogenic monoclonal free light chain.

Amyloidogenic Monoclonal Free Light-Chain Production and Secretion -> Light-Chain Misfolding and Beta-Sheet Oligomerization DIRECT Amyloidogenic free light chains leave their native fold and assemble into beta-sheet-rich species.

Light-Chain Misfolding and Beta-Sheet Oligomerization -> Amyloid Fibril Formation and Extracellular Deposition DIRECT The rearranged light-chain conformation assembles through intermolecular cross-beta contacts into amyloid fibrils.

Amyloid Fibril Formation and Extracellular Deposition -> Progressive Systemic Tissue Amyloid Accumulation DIRECT Continued extracellular deposition increases total systemic tissue amyloid burden.

Amyloid Fibril Formation and Extracellular Deposition -> Myocardial Amyloid Accumulation DIRECT Light-chain fibrils accumulate extracellularly in the myocardium.

Amyloid Fibril Formation and Extracellular Deposition -> Renal Amyloid Accumulation DIRECT Light-chain fibrils accumulate in renal tissue, commonly involving glomerular structures.

Amyloid Fibril Formation and Extracellular Deposition -> Peripheral and Autonomic Nerve Amyloid Accumulation DIRECT Amyloid deposits accumulate within peripheral and autonomic nerve compartments.

Amyloid Fibril Formation and Extracellular Deposition -> Gastrointestinal Amyloid Accumulation DIRECT Light-chain amyloid deposits may involve the gastrointestinal tract.

Amyloid Fibril Formation and Extracellular Deposition -> Hepatic Amyloid Accumulation DIRECT Light-chain amyloid fibrils accumulate in the liver and contribute to hepatic organ dysfunction.

Amyloid Fibril Formation and Extracellular Deposition -> Tongue Soft-Tissue Amyloid Accumulation DIRECT Soft-tissue amyloid may accumulate in the tongue and contribute to enlargement.

Amyloid Fibril Formation and Extracellular Deposition -> Vascular Amyloid Accumulation and Fragility DIRECT Amyloid deposition in vessel walls may increase vascular fragility and produce characteristic purpura.

Progressive Systemic Tissue Amyloid Accumulation -> Systemic Multiorgan Dysfunction DIRECT Accumulated extracellular amyloid produces combined organ dysfunction and systemic illness.

Systemic Multiorgan Dysfunction -> Fatigue INDIRECT UNKNOWN INTERMEDIATES Multiorgan illness is associated with fatigue through patient-specific and incompletely resolved intermediates.

Systemic Multiorgan Dysfunction -> Weight Loss INDIRECT UNKNOWN INTERMEDIATES Multiorgan and gastrointestinal disease can accompany weight loss through incompletely resolved intermediates.

Hepatic Amyloid Accumulation -> Ascites INDIRECT UNKNOWN INTERMEDIATES Hepatic AL involvement can accompany ascites, but the cohort does not distinguish liver-specific effects from cardiac, renal, or portal-hemodynamic intermediates in each patient.

Myocardial Amyloid Accumulation -> Myocardial Stiffening and Diastolic Dysfunction DIRECT Myocardial fibril burden impairs compliance and contractile function.

Myocardial Stiffening and Diastolic Dysfunction -> Restrictive Cardiomyopathy DIRECT Reduced myocardial compliance manifests as restrictive cardiomyopathy.

Myocardial Stiffening and Diastolic Dysfunction -> Congestive Heart Failure DIRECT Progressive myocardial dysfunction manifests clinically as congestive heart failure.

Renal Amyloid Accumulation -> Glomerular Filtration Barrier Dysfunction and Protein Loss DIRECT Glomerular amyloid injury permits pathologic urinary protein loss and may progress to renal failure.

Glomerular Filtration Barrier Dysfunction and Protein Loss -> Proteinuria DIRECT Filtration-barrier disruption produces abnormal urinary protein excretion.

Glomerular Filtration Barrier Dysfunction and Protein Loss -> Nephrotic Syndrome INDIRECT KNOWN INTERMEDIATES Severe sustained protein loss can produce the nephrotic syndrome. Intermediates: nephrotic-range urinary protein loss and hypoalbuminemia

Peripheral and Autonomic Nerve Amyloid Accumulation -> Peripheral and Autonomic Nerve Dysfunction DIRECT Nerve and ganglion deposition disrupts sensory and autonomic function.

Peripheral and Autonomic Nerve Dysfunction -> Peripheral Neuropathy DIRECT Sensory-predominant nerve dysfunction manifests as peripheral neuropathy.

Peripheral and Autonomic Nerve Dysfunction -> Autonomic Dysfunction DIRECT Autonomic-fiber involvement manifests as generalized autonomic dysfunction.

Peripheral and Autonomic Nerve Dysfunction -> Gastrointestinal Dysmotility and Nutritional Impact DIRECT Autonomic neuropathy can independently contribute to gastrointestinal dysmotility symptoms.

Gastrointestinal Amyloid Accumulation -> Gastrointestinal Dysmotility and Nutritional Impact INDIRECT KNOWN INTERMEDIATES Enteric tissue involvement can contribute to dysmotility-related symptoms. Intermediates: enteric tissue involvement

Gastrointestinal Dysmotility and Nutritional Impact -> Gastrointestinal Dysmotility DIRECT Enteric and autonomic dysfunction manifests as bowel-motility disturbance.

Gastrointestinal Dysmotility and Nutritional Impact -> Early Satiety DIRECT Upper gastrointestinal dysfunction commonly presents with early satiety.

Tongue Soft-Tissue Amyloid Accumulation -> Macroglossia DIRECT Tongue soft-tissue deposition can manifest as tongue enlargement.

Vascular Amyloid Accumulation and Fragility -> Periorbital Purpura INDIRECT KNOWN INTERMEDIATES Fragile amyloid-involved vessels can bleed into periorbital tissue. Intermediates: amyloid-associated vessel-wall fragility

Show evidence (1 reference)

PMID:30361521 SUPPORT Other

"Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction."

This review states the precursor-to-fibril-to-organ-dysfunction model that defines the canonical hypothesis group.

Soluble Light-Chain Cardiotoxicity Model

soluble_light_chain_cardiotoxicity CANONICAL

Evidence balance 1 support

Soluble or prefibrillar amyloidogenic light chains exert direct cardiac proteotoxicity superimposed on structural injury from deposited fibrils, activating oxidative stress and non-canonical p38alpha MAPK signaling in cardiomyocytes and promoting contractile dysfunction and apoptosis.

Pathograph links

Amyloidogenic Plasma-Cell Clone -> Amyloidogenic Monoclonal Free Light-Chain Production and Secretion DIRECT The clone secretes the amyloidogenic monoclonal free light chain.

Amyloidogenic Monoclonal Free Light-Chain Production and Secretion -> Soluble Amyloidogenic Light-Chain Cardiotoxicity DIRECT Circulating amyloidogenic light chains can directly injure cardiomyocytes before or alongside fibril deposition.

Soluble Amyloidogenic Light-Chain Cardiotoxicity -> Cardiomyocyte Oxidative Stress and Apoptosis DIRECT Amyloidogenic light chains activate oxidative-stress and p38alpha MAPK injury pathways in cardiomyocytes.

Cardiomyocyte Oxidative Stress and Apoptosis -> Cardiomyocyte Contractile Dysfunction and Cell Loss DIRECT Oxidative injury produces contractile dysfunction and apoptotic cardiomyocyte loss.

Cardiomyocyte Contractile Dysfunction and Cell Loss -> Congestive Heart Failure INDIRECT KNOWN INTERMEDIATES Contractile dysfunction and cardiomyocyte loss can contribute to organ-level pump failure. Intermediates: reduced myocardial contractile reserve and pump dysfunction

Show evidence (1 reference)

PMID:20150510 SUPPORT In Vitro

"In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK)."

Isolated adult cardiomyocytes provide direct experimental support for a soluble-light-chain injury branch independent of extracellular fibril burden.

Discussions and Knowledge Gaps

Which strategies can rapidly improve survival and cardiac function in systemic AL patients presenting with advanced cardiac involvement while clone-directed therapy reduces new light-chain production?

KNOWLEDGE GAP OPEN gap_al_advanced_cardiac_therapy

Attached to

pathophysiology#Myocardial Stiffening and Diastolic Dysfunction pathophysiology#Soluble Amyloidogenic Light-Chain Cardiotoxicity

Advanced cardiac disease remains a major unmet need. CAEL-101 phase III programs remain active but closed to new enrollment, while the confirmatory birtamimab phase III trial was terminated after missing its primary endpoint; no fibril-clearing strategy should therefore be represented as established.

Show evidence (3 references)

PMID:30361521 SUPPORT Other

"However, effective therapies for patients with advanced cardiac involvement are an unmet need."

The review explicitly identifies the advanced-cardiac treatment gap.

clinicaltrials:NCT04512235 SUPPORT Human Clinical

"The primary purpose of this study is to determine whether CAEL-101, a monoclonal antibody that removes AL amyloid deposits from tissues and organs, improves overall survival, reduces cardiovascular related hospitalizations and it is safe and well tolerated in patients with stage IIIa AL amyloidosis."

The registry describes an ongoing investigational deposit-directed strategy but does not establish benefit.

clinicaltrials:NCT04973137 SUPPORT Human Clinical

"A Phase 3 study to evaluate the efficacy and safety of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV patients with AL amyloidosis."

The registry cache supports the confirmatory trial design; its terminated status was independently verified and prevents portraying the agent as established.

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Pathophysiology

Amyloidogenic Plasma-Cell Clone

A usually small clonal plasma-cell population produces the pathogenic light chain. The term clone is used deliberately: a large marrow expansion is not required, and clone detection alone does not prove that tissue amyloid is light-chain-derived.

Canonical AL Amyloid Deposition Model Soluble Light-Chain Cardiotoxicity Model

plasma cell CL:0000786

Downstream

Amyloidogenic Monoclonal Free Light-Chain Production and Secretion The clone secretes the amyloidogenic monoclonal free light chain.

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

"Light chain amyloidosis is a disease in which clonal plasma cells produce toxic immunoglobulin light chains that form amyloid fibrils with deposition in organs, most commonly the heart and kidneys, but also the nervous system, gastrointestinal tract, and soft tissues."

The review identifies clonal plasma cells as the source of the toxic light chains while also describing their downstream deposition.

Amyloidogenic Monoclonal Free Light-Chain Production and Secretion

The clone produces and secretes a patient-specific kappa or lambda free light chain whose sequence and stability favor misfolding. A large clone or marked absolute excess is not required for pathogenicity. This is the disease-specific amyloidogenic precursor measured by serum free-light-chain assays.

Canonical AL Amyloid Deposition Model Soluble Light-Chain Cardiotoxicity Model

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Light-Chain Misfolding and Beta-Sheet Oligomerization Amyloidogenic free light chains leave their native fold and assemble into beta-sheet-rich species.

Soluble Amyloidogenic Light-Chain Cardiotoxicity Circulating amyloidogenic light chains can directly injure cardiomyocytes before or alongside fibril deposition.

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

The review identifies the clonal immunoglobulin light chain as the toxic precursor of deposited fibrils.

Light-Chain Misfolding and Beta-Sheet Oligomerization

Destabilized light chains undergo major conformational rearrangement on the path toward beta-sheet-rich aggregation and fibril assembly.

Canonical AL Amyloid Deposition Model

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Amyloid Fibril Formation and Extracellular Deposition The rearranged light-chain conformation assembles through intermolecular cross-beta contacts into amyloid fibrils.

Show evidence (1 reference)

PMID:30894526 SUPPORT In Vitro

"The substantial conformational differences between the fibril structure and the native state imply instead that the native conformation must be largely, if not entirely, unfolded to allow fibril formation to occur (Fig. 4c)."

Patient-derived fibril structure demonstrates the extensive unfolding required for light-chain fibril formation, but does not directly resolve every proposed oligomeric intermediate.

Amyloid Fibril Formation and Extracellular Deposition

Misfolded light-chain species nucleate and elongate into insoluble cross-beta fibrils that deposit extracellularly. This is the shared central effector of amyloidogenesis; the precursor identity distinguishes AL from other amyloidoses.

Canonical AL Amyloid Deposition Model

amyloid fibril formation GO:1990000 ↑ INCREASED

extracellular region GO:0005576

Downstream

Progressive Systemic Tissue Amyloid Accumulation Continued extracellular deposition increases total systemic tissue amyloid burden.

Myocardial Amyloid Accumulation Light-chain fibrils accumulate extracellularly in the myocardium.

Renal Amyloid Accumulation Light-chain fibrils accumulate in renal tissue, commonly involving glomerular structures.

Peripheral and Autonomic Nerve Amyloid Accumulation Amyloid deposits accumulate within peripheral and autonomic nerve compartments.

Gastrointestinal Amyloid Accumulation Light-chain amyloid deposits may involve the gastrointestinal tract.

Hepatic Amyloid Accumulation Light-chain amyloid fibrils accumulate in the liver and contribute to hepatic organ dysfunction.

Tongue Soft-Tissue Amyloid Accumulation Soft-tissue amyloid may accumulate in the tongue and contribute to enlargement.

Vascular Amyloid Accumulation and Fragility Amyloid deposition in vessel walls may increase vascular fragility and produce characteristic purpura.

Show evidence (1 reference)

PMID:30361521 SUPPORT Other

The review supports fibril formation as the link between light-chain misfolding and organ injury.

Progressive Systemic Tissue Amyloid Accumulation

Continued fibril deposition expands the extracellular amyloid burden across affected organs. Accumulation can be slowed by eliminating light-chain production, and organ improvement may occur after a deep clonal response; established injury is therefore not described as uniformly irreversible.

Canonical AL Amyloid Deposition Model

Downstream

Systemic Multiorgan Dysfunction Accumulated extracellular amyloid produces combined organ dysfunction and systemic illness.

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

"Treatment directed at the clonal cells eliminates light chain production and further deposition and may enable organ improvement and decrease the risk of organ failure."

The review supports ongoing deposition as a modifiable process and avoids an absolute irreversibility claim.

Systemic Multiorgan Dysfunction

The combined burden of cardiac, renal, neurologic, gastrointestinal, and other organ involvement produces nonspecific systemic manifestations. The exact intermediate mechanisms for fatigue and weight loss vary between patients and are not collapsed into a falsely direct molecular edge.

Canonical AL Amyloid Deposition Model

Downstream

Fatigue Multiorgan illness is associated with fatigue through patient-specific and incompletely resolved intermediates.

Weight Loss Multiorgan and gastrointestinal disease can accompany weight loss through incompletely resolved intermediates.

Show evidence (1 reference)

PMID:35481407 SUPPORT Human Clinical

"The main clinical manifestations include edema, digestive symptoms, weight loss, fatigue and ascites."

This hepatic-involvement cohort documents fatigue and weight loss as clinical manifestations but does not resolve their causal intermediates.

Hepatic Amyloid Accumulation

Light-chain amyloid fibrils can accumulate in the liver. Hepatic involvement may produce organ dysfunction and manifestations such as ascites, although ascites can also reflect cardiac, renal, or portal-hemodynamic intermediates.

Canonical AL Amyloid Deposition Model

liver UBERON:0002107

Downstream

Ascites Hepatic AL involvement can accompany ascites, but the cohort does not distinguish liver-specific effects from cardiac, renal, or portal-hemodynamic intermediates in each patient.

Show evidence (2 references)

DOI:10.3389/frhem.2024.1378451 SUPPORT Other

"These light-chain fragments then aggregate and get tangled into amyloid fibrils that deposit in end organs, usually the kidney, heart, gastrointestinal tract, liver, and peripheral nervous system, leading to organ dysfunction ( 9)."

The AL-specific review directly identifies the liver as a site of light-chain fibril deposition.

PMID:35481407 SUPPORT Human Clinical

"Eighty-eight patients diagnosed AL amyloidosis with hepatic involvement between June 2004 and January 2019 were analysed retrospectively."

This dedicated cohort establishes clinically recognized hepatic involvement in systemic AL amyloidosis.

Myocardial Amyloid Accumulation

Extracellular light-chain fibrils accumulate within the myocardium, stiffen the ventricular wall, and impair filling and pump function.

Canonical AL Amyloid Deposition Model

heart UBERON:0000948

Downstream

Myocardial Stiffening and Diastolic Dysfunction Myocardial fibril burden impairs compliance and contractile function.

Show evidence (1 reference)

PMID:38960850 SUPPORT Other

"Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and aggregation of proteins into large fibrils in the extracellular compartment of the myocardium, leading to restrictive cardiomyopathy, heart failure and death."

The review directly supports extracellular myocardial fibril accumulation.

Soluble Amyloidogenic Light-Chain Cardiotoxicity

Soluble amyloidogenic light chains directly perturb cardiomyocyte function in addition to the mechanical effects of deposited fibrils.

Soluble Light-Chain Cardiotoxicity Model

cardiomyocyte CL:0000746

heart UBERON:0000948

Downstream

Cardiomyocyte Oxidative Stress and Apoptosis Amyloidogenic light chains activate oxidative-stress and p38alpha MAPK injury pathways in cardiomyocytes.

Show evidence (1 reference)

PMID:20150510 SUPPORT In Vitro

Direct cardiomyocyte exposure establishes a soluble-light-chain toxic effect.

Cardiomyocyte Oxidative Stress and Apoptosis

Non-canonical p38alpha MAPK activation drives oxidative stress, contractile dysfunction, and apoptosis in cardiomyocytes exposed to amyloidogenic light chains.

Soluble Light-Chain Cardiotoxicity Model

cardiomyocyte CL:0000746

response to oxidative stress GO:0006979 ↑ INCREASED

heart UBERON:0000948

Downstream

Cardiomyocyte Contractile Dysfunction and Cell Loss Oxidative injury produces contractile dysfunction and apoptotic cardiomyocyte loss.

Show evidence (1 reference)

PMID:20150510 SUPPORT In Vitro

This is direct experimental evidence for the node's cellular events.

Cardiomyocyte Contractile Dysfunction and Cell Loss

Soluble amyloidogenic light-chain proteotoxicity reduces cardiomyocyte contractile function and promotes apoptosis independently of the mechanical stiffness produced by extracellular fibril infiltration.

Soluble Light-Chain Cardiotoxicity Model

cardiomyocyte CL:0000746

heart UBERON:0000948

Downstream

Congestive Heart Failure Contractile dysfunction and cardiomyocyte loss can contribute to organ-level pump failure.

Show evidence (1 reference)

PMID:20150510 SUPPORT In Vitro

Direct light-chain exposure supports the modeled cellular functional loss without implying fibril-mediated restrictive physiology.

Myocardial Stiffening and Diastolic Dysfunction

Extracellular myocardial fibril infiltration impairs compliance and filling, producing restrictive physiology and contributing to heart failure.

Canonical AL Amyloid Deposition Model

heart UBERON:0000948

Downstream

Restrictive Cardiomyopathy Reduced myocardial compliance manifests as restrictive cardiomyopathy.

Congestive Heart Failure Progressive myocardial dysfunction manifests clinically as congestive heart failure.

Show evidence (1 reference)

PMID:38960850 SUPPORT Other

The review links cardiac fibril accumulation to the two modeled cardiac manifestations.

Renal Amyloid Accumulation

Amyloid accumulation in renal tissue, especially glomerular compartments, disrupts filtration-barrier integrity and creates a high protein-loss burden.

Canonical AL Amyloid Deposition Model

kidney UBERON:0002113

Downstream

Glomerular Filtration Barrier Dysfunction and Protein Loss Glomerular amyloid injury permits pathologic urinary protein loss and may progress to renal failure.

Show evidence (1 reference)

PMID:25115890 SUPPORT Human Clinical

"The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis"

The large testing and validation cohorts establish renal involvement as a common AL manifestation; the tissue-distribution detail is not directly measured by this prognostic study.

Glomerular Filtration Barrier Dysfunction and Protein Loss

Renal amyloid injury compromises the glomerular filtration barrier, producing proteinuria that may reach nephrotic range and increasing the risk of kidney failure.

Canonical AL Amyloid Deposition Model

podocyte CL:0000653

kidney UBERON:0002113

Downstream

Proteinuria Filtration-barrier disruption produces abnormal urinary protein excretion.

Nephrotic Syndrome Severe sustained protein loss can produce the nephrotic syndrome.

Show evidence (1 reference)

PMID:25115890 SUPPORT Human Clinical

"Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best."

Proteinuria and impaired filtration jointly define renal risk in the validated cohort, while the podocyte/barrier mechanism is an interpretation rather than a directly measured causal event.

Peripheral and Autonomic Nerve Amyloid Accumulation

Fibrils deposit in peripheral nerves and ganglia, with associated Schwann-cell atrophy and blood-nerve-barrier disruption.

Canonical AL Amyloid Deposition Model

Schwann cell CL:0002573

peripheral nervous system UBERON:0000010 autonomic nervous system UBERON:0002410

Downstream

Peripheral and Autonomic Nerve Dysfunction Nerve and ganglion deposition disrupts sensory and autonomic function.

Show evidence (1 reference)

PMID:38923548 SUPPORT Other

"Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve barrier disruption."

The review explicitly describes nerve deposition and adjacent cellular injury.

Peripheral and Autonomic Nerve Dysfunction

Peripheral nerve injury produces a length-dependent sensory-predominant neuropathy, while autonomic fiber involvement produces generalized autonomic failure.

Canonical AL Amyloid Deposition Model

peripheral nervous system UBERON:0000010 autonomic nervous system UBERON:0002410

Downstream

Peripheral Neuropathy Sensory-predominant nerve dysfunction manifests as peripheral neuropathy.

Autonomic Dysfunction Autonomic-fiber involvement manifests as generalized autonomic dysfunction.

Gastrointestinal Dysmotility and Nutritional Impact Autonomic neuropathy can independently contribute to gastrointestinal dysmotility symptoms.

Show evidence (1 reference)

PMID:38923548 SUPPORT Other

"Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure."

The review supports both modeled neurologic consequences.

Gastrointestinal Amyloid Accumulation

Amyloid deposited in gastrointestinal tissues can impair enteric function and contribute to a substantial symptom burden.

Canonical AL Amyloid Deposition Model

Downstream

Gastrointestinal Dysmotility and Nutritional Impact Enteric tissue involvement can contribute to dysmotility-related symptoms.

Show evidence (1 reference)

PMID:41954624 SUPPORT Human Clinical

"We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL."

The cohort documents biopsy-proven gastrointestinal AL involvement in a large clinical population.

Gastrointestinal Dysmotility and Nutritional Impact

Gastrointestinal tissue involvement and dysautonomia produce motility disturbance, including bowel irregularity and early satiety, with potential downstream nutritional consequences.

Canonical AL Amyloid Deposition Model

Downstream

Gastrointestinal Dysmotility Enteric and autonomic dysfunction manifests as bowel-motility disturbance.

Early Satiety Upper gastrointestinal dysfunction commonly presents with early satiety.

Show evidence (1 reference)

PMID:41954624 SUPPORT Human Clinical

"Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%)."

The large cohort quantifies the modeled gastrointestinal manifestations.

Tongue Soft-Tissue Amyloid Accumulation

Amyloid deposition in tongue soft tissue may enlarge the tongue. Macroglossia is characteristic but uncommon and is not treated as pathognomonic or uniquely specific to AL.

Canonical AL Amyloid Deposition Model

tongue UBERON:0001723

Downstream

Macroglossia Tongue soft-tissue deposition can manifest as tongue enlargement.

Show evidence (1 reference)

PMID:42005116 SUPPORT Human Clinical

"Classic signs included macroglossia (four patients, 16.6%)"

The mixed systemic-amyloidosis cohort documents macroglossia but does not type the sign as AL-specific.

Vascular Amyloid Accumulation and Fragility

Amyloid can deposit in blood vessels. Vessel-wall involvement is associated with fragility and purpura, including the characteristic periorbital pattern, although the cited clinical evidence is observational.

Canonical AL Amyloid Deposition Model

Downstream

Periorbital Purpura Fragile amyloid-involved vessels can bleed into periorbital tissue.

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"The third patient had a positive Congo red stain and periorbital purpura, left ventricular diastolic dysfunction, atrial fibrillation as well as congestive heart failure."

This AL case documents periorbital purpura alongside tissue-confirmed amyloidosis but does not directly assay vessel-wall mechanics.

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Histopathology

Congo Red-Positive Amyloid Deposition

Extracellular tissue deposits bind Congo red and show apple-green birefringence under polarized light. This confirms amyloid deposition but does not identify the precursor protein; biochemical typing is still required to establish AL.

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"All diagnostic specimens contained amyloid deposits that exhibited apple-green birefringence when stained with alkaline Congo red and viewed under polarized light."

The clinical series directly documents the diagnostic histologic finding.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 1

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"Congestive heart failure was present at diagnosis in 10 patients (29%) and occurred in 9 additional patients (total 54%) during follow-up."

The geographically defined cohort documents heart failure at diagnosis and during follow-up.

Digestive 2

Early Satiety HP:0033842

Show evidence (1 reference)

PMID:41954624 SUPPORT Human Clinical

"Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%)."

The large cohort identifies early satiety as the most common GI symptom.

Ascites HP:0001541

Show evidence (1 reference)

PMID:35481407 SUPPORT Human Clinical

"The main clinical manifestations include edema, digestive symptoms, weight loss, fatigue and ascites."

The dedicated hepatic-involvement cohort directly lists ascites among its main clinical manifestations.

Genitourinary 1

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:25115890 SUPPORT Human Clinical

"Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best."

The validated renal staging cohorts use proteinuria as a central renal disease measure.

Head and Neck 1

Macroglossia HP:0000158

Show evidence (1 reference)

PMID:42005116 SUPPORT Human Clinical

"Classic signs included macroglossia (four patients, 16.6%)"

The mixed systemic-amyloidosis cohort documents macroglossia but does not establish AL specificity.

Nervous System 2

Peripheral Neuropathy HP:0009830

Show evidence (1 reference)

PMID:38923548 SUPPORT Other

"Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure."

The review directly describes the sensory-predominant peripheral neuropathy phenotype.

Autonomic Dysfunction Abnormal autonomic nervous system physiology HP:0012332

Show evidence (1 reference)

PMID:38923548 SUPPORT Other

"Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure."

Generalized autonomic failure directly supports this phenotype.

Constitutional 1

Fatigue HP:0012378

Show evidence (1 reference)

PMID:35481407 SUPPORT Human Clinical

"The main clinical manifestations include edema, digestive symptoms, weight loss, fatigue and ascites."

The hepatic-involvement cohort supports fatigue as a manifestation but not its frequency across all systemic AL.

Growth 1

Weight Loss HP:0001824

Show evidence (1 reference)

PMID:35481407 SUPPORT Human Clinical

"The main clinical manifestations include edema, digestive symptoms, weight loss, fatigue and ascites."

The cohort supports weight loss as a manifestation in hepatic AL while not establishing a universal mechanism.

Other 4

Restrictive Cardiomyopathy HP:0001723

Show evidence (1 reference)

PMID:38960850 SUPPORT Other

Restrictive cardiomyopathy is an explicit consequence of myocardial amyloid accumulation in the cited review.

Nephrotic Syndrome HP:0000100

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"Nephrotic syndrome was present in 9 patients (26%) at diagnosis."

The cohort directly reports nephrotic syndrome at AL diagnosis.

Gastrointestinal Dysmotility HP:0002579

Show evidence (1 reference)

PMID:41954624 SUPPORT Human Clinical

"Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity."

The cohort directly attributes dysmotility-related symptoms in part to autonomic neuropathy.

Periorbital Purpura HP:0025552

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"The third patient had a positive Congo red stain and periorbital purpura, left ventricular diastolic dysfunction, atrial fibrillation as well as congestive heart failure."

A tissue-positive AL case directly documents the phenotype, but the source does not estimate its population frequency.

💊

Medical Actions

Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone

Category: Therapeutic Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986 Regimen: Bortezomib/Cyclophosphamide/Daratumumab/Dexamethasone regimen Ontology label: Bortezomib/Cyclophosphamide/Daratumumab/Dexamethasone Regimen NCIT:C181577

Agent: daratumumab NCIT:C74007 bortezomib CHEBI:52717 cyclophosphamide CHEBI:4027 dexamethasone CHEBI:41879

Subcutaneous daratumumab/hyaluronidase-fihj with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) is the approved, evidence-based frontline regimen for most newly diagnosed patients. It is not recommended for Mayo cardiac stage IIIB or NYHA class IIIB/IV disease outside controlled clinical trials; eligibility and dosing also require attention to frailty and organ dysfunction.

Mechanism Target:

INHIBITS Amyloidogenic Plasma-Cell Clone — The regimen suppresses the clonal cells that produce the pathogenic light chain.

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

"Treatment directed at the clonal cells eliminates light chain production and further deposition and may enable organ improvement and decrease the risk of organ failure."

This review supports the clone as the mechanistic target of systemic AL therapy.

INHIBITS Amyloidogenic Monoclonal Free Light-Chain Production and Secretion — Clone suppression rapidly reduces production of the amyloidogenic precursor.

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

"Treatment directed at the clonal cells eliminates light chain production and further deposition and may enable organ improvement and decrease the risk of organ failure."

The source explicitly links clone-directed treatment to elimination of light-chain production.

Show evidence (2 references)

PMID:42118698 SUPPORT Human Clinical

"With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121)."

The final randomized-trial analysis demonstrates both organ-deterioration and overall-survival benefit.

PMID:34192431 SUPPORT Human Clinical

"Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression."

The primary ANDROMEDA publication supports the four-drug regimen and its hematologic and organ-progression outcomes.

High-Dose Melphalan with Autologous Stem-Cell Transplantation

Category: Therapeutic Action: autologous hematopoietic stem cell transplantation Ontology label: Autologous Hematopoietic Stem Cell Transplantation NCIT:C16039

Agent: melphalan NCIT:C633

High-dose melphalan followed by autologous hematopoietic stem-cell transplantation is a separate clone-directed strategy for carefully selected fit patients; it is not a generic option for every patient with systemic AL.

Mechanism Target:

INHIBITS Amyloidogenic Plasma-Cell Clone — High-dose therapy suppresses the clonal source of amyloidogenic light chains.

Show evidence (1 reference)

PMID:30361521 SUPPORT Other

"Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of amyloid light chain production in the majority of patients."

The review directly links high-dose chemotherapy and autologous transplantation to suppression of amyloid light-chain production.

Show evidence (1 reference)

PMID:34783272 SUPPORT Other

"High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma."

The specialty guideline establishes high-dose melphalan with autologous transplantation as a systemic AL treatment strategy.

Supportive Organ-Directed Care

Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747

Individualized supportive care treats symptoms and complications of cardiac, renal, neurologic, gastrointestinal, and soft-tissue involvement while clone-directed therapy takes effect. Specific interventions depend on the affected organ and treatment tolerance.

Target Phenotypes: Congestive Heart Failure HP:0001635 Proteinuria HP:0000093 Autonomic Dysfunction HP:0012332 Gastrointestinal Dysmotility HP:0002579

Show evidence (1 reference)

PMID:33099432 SUPPORT Other

"Supportive care manages the symptoms of organ involvement and the side effects of treatment."

The supportive-care review directly supports symptom- and treatment-toxicity management without overprescribing a single protocol.

Individualized Therapy for Relapsed Disease

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Relapsed systemic AL has no single universal salvage regimen. Selection among anti-CD38, proteasome-inhibitor, immunomodulatory, alkylator-based, and selected transplant approaches depends on the depth and duration of the initial response, prior drug-class exposure, fitness or frailty, and end-organ dysfunction. A previously unused active class is generally preferred when feasible; venetoclax remains a separate investigational option for selected t(11;14)-positive disease.

Mechanism Target:

INHIBITS Amyloidogenic Plasma-Cell Clone — Salvage therapy is selected to regain suppression of the pathogenic clone after relapse.

Show evidence (1 reference)

PMID:35838162 SUPPORT Other

"At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients' fitness/frailty and end organ damage."

The specialty guideline directly supports individualized, exposure-aware relapse selection constrained by patient fitness and organ damage.

Show evidence (1 reference)

PMID:35838162 SUPPORT Other

The guideline defines the principal decision factors for relapse therapy; named drug classes are examples within that individualized framework.

Venetoclax for Relapsed t(11;14)-Positive Disease

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: venetoclax CHEBI:133021

Venetoclax has produced deep hematologic responses in retrospective relapsed or refractory cohorts enriched for somatic t(11;14), but remains off-label and investigational in systemic AL pending prospective randomized confirmation.

Mechanism Target:

INHIBITS Amyloidogenic Plasma-Cell Clone — Venetoclax can suppress susceptible t(11;14)-positive plasma-cell clones.

Show evidence (1 reference)

PMID:33431806 SUPPORT Human Clinical

"t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients."

The retrospective response association supports clone suppression in the selected cytogenetic subgroup but is not randomized mechanistic evidence.

Show evidence (2 references)

PMID:33431806 SUPPORT Human Clinical

"These promising results require confirmation in a randomized clinical trial."

The authors explicitly bound the retrospective results and support the investigational label.

PMID:35838162 SUPPORT Other

"Targeted agents like venetoclax need urgent prospective evaluation."

The specialty guideline confirms that prospective evaluation is still required.

🔬

Biochemical Markers

Serum Free Immunoglobulin Light Chains (Abnormal concentration or ratio)

Pathograph Readouts

Readout Of Amyloidogenic Monoclonal Free Light-Chain Production and Secretion Threshold Dependent Diagnostic

An involved light-chain excess or abnormal ratio raises suspicion for a clonal light-chain source but does not type tissue amyloid.

Show evidence (1 reference)

PMID:41592868 SUPPORT Other

"The use of serum immunofixation, urine immunofixation and serum free light chains enhances the clinical suspicion of AL amyloidosis."

The guideline supports free-light-chain measurement as part of the diagnostic screen.

Show evidence (1 reference)

PMID:41592868 SUPPORT Other

"The use of serum immunofixation, urine immunofixation and serum free light chains enhances the clinical suspicion of AL amyloidosis."

The guideline establishes the biomarker's diagnostic context.

Difference Between Involved and Uninvolved Free Light Chains (Quantified as dFLC)

Pathograph Readouts

Pharmacodynamic Marker Of Amyloidogenic Monoclonal Free Light-Chain Production and Secretion Positive Pharmacodynamic

A lower dFLC after therapy indicates reduced production of the involved amyloidogenic free light chain.

Show evidence (1 reference)

PMID:23091105 SUPPORT Human Clinical

"There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival."

The multicenter study validates precursor reduction as a response measurement associated with survival.

Show evidence (1 reference)

PMID:23091105 SUPPORT Human Clinical

"There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival."

The study directly supports dFLC reduction as a clinically meaningful response biomarker.

NT-proBNP (Elevated with cardiac stress)

Pathograph Readouts

Readout Of Myocardial Stiffening and Diastolic Dysfunction Positive Prognostic

Higher NT-proBNP contributes to adverse cardiac risk staging; serial change can also report cardiac response after therapy.

Show evidence (1 reference)

PMID:23091105 SUPPORT Human Clinical

"Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP)."

The response-criteria study directly supports NT-proBNP as a cardiac function readout; its prognostic-stage use is documented separately.

Show evidence (1 reference)

PMID:23091105 SUPPORT Human Clinical

This supports NT-proBNP for cardiac monitoring as well as prognostic use.

Cardiac Troponin T (Elevated with cardiac injury)

Pathograph Readouts

Correlates With Myocardial Stiffening and Diastolic Dysfunction Positive Prognostic

Higher cardiac troponin T contributes to adverse Mayo prognostic stage.

Show evidence (1 reference)

PMID:22331953 SUPPORT Human Clinical

"In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS)."

Cardiac troponin T is independently prognostic in the validated staging model; the specific relationship to this modeled cardiac node is represented conservatively as partial correlation rather than causation.

Show evidence (1 reference)

PMID:22331953 SUPPORT Human Clinical

"In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS)."

The staging cohort establishes troponin T as an independent prognostic biomarker.

🔬

Diagnosis

Monoclonal-Protein Screening

Initial clonal screening combines serum immunofixation, urine immunofixation, and serum free-light-chain measurement. A positive screen increases suspicion but cannot substitute for tissue confirmation and amyloid typing.

free immunoglobulin light chain measurement NCIT:C156517

Results: A monoclonal protein or abnormal free-light-chain result supports suspicion for AL and prompts tissue confirmation and clone evaluation.

Show evidence (1 reference)

PMID:41592868 SUPPORT Other

"The use of serum immunofixation, urine immunofixation and serum free light chains enhances the clinical suspicion of AL amyloidosis."

The guideline explicitly recommends the three-part monoclonal-protein screen as a suspicion-enhancing step.

Surrogate-Tissue Biopsy

Abdominal fat-pad and bone-marrow sampling provide minimally invasive tissue for Congo red staining. Combined testing detects many, but not all, AL cases; a negative surrogate biopsy does not exclude disease, and involved-organ biopsy may be needed when suspicion remains high.

Results: Congo red-positive amyloid in fat pad or bone marrow supports systemic amyloidosis; a negative combined result leaves residual diagnostic risk.

Show evidence (1 reference)

PMID:41460224 SUPPORT Human Clinical

"Among 2,213 patients with AL amyloidosis who underwent both FP and BM sampling, combined testing increased detection to 85% (40% positive in both; 32% FP-only; 13% BM-only)."

The large cohort quantifies the benefit and residual false-negative risk of combined surrogate sampling.

Congo Red Tissue Confirmation

Tissue is stained with Congo red and examined under polarized light to demonstrate amyloid. A positive stain confirms amyloid deposition but not AL type.

Congo red staining method NCIT:C154782

Results: Congo red-positive deposits with apple-green birefringence establish tissue amyloid and must be followed by precursor typing.

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"All diagnostic specimens contained amyloid deposits that exhibited apple-green birefringence when stained with alkaline Congo red and viewed under polarized light."

The series directly documents the Congo-red/polarized-light diagnostic pattern.

Mass-Spectrometry Amyloid Typing

Laser microdissection followed by liquid chromatography and mass spectrometry identifies the protein composing a Congo red-positive deposit and distinguishes AL from ATTR and other amyloid types.

Results: Detection of an immunoglobulin light-chain amyloid proteomic signature establishes the AL precursor type in the sampled deposit.

Show evidence (1 reference)

PMID:30834260 SUPPORT In Vitro

"LMD-LC-MS correctly typed AL amyloidosis in all 22 FFPE tissue samples despite tissue origin."

This ex vivo multi-organ study directly supports mass-spectrometric AL typing across fixed tissue sites.

Plasma-Cell Clone and Organ Assessment

Bone-marrow morphology, flow cytometry, and plasma-cell FISH characterize the underlying somatic clone, including clinically relevant t(11;14), while cardiac, renal, neurologic, and gastrointestinal assessments establish organ burden. Cardiac troponin, NT-proBNP, and dFLC support prognostic staging.

Results: Clone characterization guides treatment selection; organ measurements and Mayo staging define risk but do not replace tissue amyloid typing.

Show evidence (2 references)

PMID:22331953 SUPPORT Human Clinical

"In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS)."

The staging cohort supports the three principal prognostic measurements; marrow/FISH and broader organ-assessment details are standard diagnostic context not directly evaluated by this source.

PMID:33431806 SUPPORT Human Clinical

"Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three."

The retrospective cohort shows why defining t(11;14) status can affect treatment selection, without by itself validating the full diagnostic work-up.

📈

Progression

Prognostic risk and treatment response

Cardiac involvement is the dominant prognostic determinant. Prognosis is not uniformly fixed by baseline organ damage: rapid reduction of the amyloidogenic free light chain is associated with survival benefit, and organ responses can follow effective clone suppression.

Show evidence (2 references)

PMID:23091105 SUPPORT Human Clinical

"There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival."

The multicenter cohort directly relates depth of precursor reduction to survival.

PMID:23091105 SUPPORT Human Clinical

This supports both the prognostic importance of cardiac disease and the possibility of measurable post-treatment cardiac change.

🪜

Stages

Mayo 2012 Prognostic Staging System

Prognostic stage is assigned from three adverse factors: dFLC at least 18 mg/dL, cardiac troponin T at least 0.025 ng/mL, and NT-proBNP at least 1,800 pg/mL. Zero through three adverse factors correspond to stages I through IV. The IIIa/IIIb labels used by some cardiac trials refer to a separate European-modified staging convention and are not subdivisions of this Mayo 2012 four-stage score.

Mayo 2012 Stage I Mayo 2012 Stage II Mayo 2012 Stage III Mayo 2012 Stage IV

Show evidence (1 reference)

PMID:22331953 SUPPORT Human Clinical

"Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively."

The derivation and validation study provides the exact thresholds and stage mapping.

Renal Outcome Staging System

Renal risk is stratified by proteinuria above 5 g/24 h and eGFR below 50 mL/min. Neither adverse factor defines stage I, one defines stage II, and both define stage III, with increasing risk of progression to dialysis.

Renal Stage I Renal Stage II Renal Stage III

Show evidence (1 reference)

PMID:25115890 SUPPORT Human Clinical

"Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best."

The testing and validation cohorts establish the two renal risk thresholds.

📊

Prevalence

Olmsted County, Minnesota, 1990-2015

Annual Incidence 1.2 per 100,000 (0.8–1.6) 1–9 per 100,000

Age- and sex-adjusted incidence per 100,000 person-years in a geographically defined US population; this is an incidence estimate, not point prevalence.

Show evidence (1 reference)

PMID:30713046 SUPPORT Human Clinical

"The incidence rate of AL amyloidosis from 1990 through 2015 adjusted for age and sex was 1.2 per 100,000 person-years (95% CI, 0.8-1.6 per 100,000 person-years)."

This population-based cohort provides the rate and confidence interval represented in the structured incidence fields.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Systemic AL Amyloidosis:

Transthyretin Amyloidosis

Overlapping Features ATTR amyloidosis is the principal alternative precursor diagnosis when cardiac amyloid is suspected. AL uses an immunoglobulin light chain, whereas ATTR uses wild-type or variant transthyretin. Clinical and imaging features overlap, so a monoclonal-protein result alone cannot type the tissue deposit; precise biochemical typing is required when AL remains possible.

Distinguishing Features

AL amyloid is composed of an immunoglobulin light chain; ATTR amyloid is composed of transthyretin.
A monoclonal-protein screen raises suspicion for AL but does not itself identify the protein in a tissue deposit.
Congo red establishes amyloid but not its type; mass spectrometry or another validated typing method identifies the precursor.
Cardiac involvement can occur in either disease, so demographic heuristics are not diagnostic substitutes.

Show evidence (2 references)

PMID:29700090 SUPPORT Other

"The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is paramount in light of recent therapeutic advances that can significantly improve prognosis."

The review directly supports biochemical typing rather than reliance on a nonspecific cardiac phenotype.

PMID:29700090 SUPPORT Other

"Most cases of cardiac amyloidosis are of either transthyretin type, which may be acquired in older individuals or inherited in younger patients, or acquired monoclonal immunoglobulin light chain (AL) type."

This identifies the two dominant precursor classes without using age as a stand-alone diagnostic rule.

📊

Related Datasets

Tumor cells in light-chain amyloidosis and multiple myeloma show different transcriptional rewiring of the normal plasma cell development geo:GSE175386

human BULK RNA SEQ n=141

PMID:34133718

Identified by GEO DataSets index search for Systemic AL Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Single cell and clonal analysis of AL amyloidosis plasma cells and their bone marrow microenvironment geo:GSE292189

AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5’ single cell RNA sequencing on 9 newly diagnosed, treatment naive AL amyloidosis patients and 8 healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of CD16 monocytes and subsets of CD4+ T cells in AL amyloidosis patients.

human SINGLE CELL RNA SEQ n=52

PMID:40493887

Protein profiles of fat biopsies from patients affected by AL amyloidosis and healthy controls. massive:MSV000090875

Abdominal subcutaneous adipose tissue protein profiles from control subjects, and ALK (Kappa) and ALL (Lambda) amyloidosis patients. Raw data were acquired by LTQ, Orbitrap and QExactive instruments. For major chromatographic details refers to doi:10.1182/blood-2011-07-365510, doi:10.3109/13506129.2012.674989, doi:10.3390/molecules26071913.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("AL Amyloidosis"). Retrieved 2026-08-02.

🔬

Clinical Trials

NCT03201965 PHASE_III COMPLETED

ANDROMEDA randomized newly diagnosed systemic AL patients to D-VCd or VCd; registry completion was independently verified on 2026-07-18, and efficacy is represented above from the peer-reviewed trial publications.

Show evidence (1 reference)

clinicaltrials:NCT03201965 SUPPORT Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants."

The cached registry summary supports the randomized comparison; completion status was verified against the live registry.

NCT04512235 PHASE_III ACTIVE_NOT_RECRUITING

CARES evaluates CAEL-101 added to plasma-cell-directed therapy in patients labeled "Mayo stage IIIa" by the registry. This trial label follows the European-modified cardiac convention, not a substage of the modeled Mayo 2012 score. Active-not-recruiting status was independently verified on 2026-07-18.

Show evidence (1 reference)

clinicaltrials:NCT04512235 SUPPORT Human Clinical

The cache supports trial purpose and population, not efficacy; live status was independently verified.

NCT04504825 PHASE_III ACTIVE_NOT_RECRUITING

CARES evaluates CAEL-101 added to plasma-cell-directed therapy in patients labeled "Mayo stage IIIb" by the registry. This trial label follows the European-modified cardiac convention, not a substage of the modeled Mayo 2012 score. Active-not-recruiting status was independently verified on 2026-07-18.

Show evidence (1 reference)

clinicaltrials:NCT04504825 SUPPORT Human Clinical

The cache supports trial purpose and population, not efficacy; live status was independently verified.

NCT06022939 PHASE_III RECRUITING

This phase III study compares D-VCd induction followed by melphalan/autologous transplantation with D-VCd consolidation and daratumumab maintenance in newly diagnosed AL. Recruiting status was independently verified on 2026-07-18.

Show evidence (1 reference)

clinicaltrials:NCT06022939 SUPPORT Human Clinical

"This phase III trial compares the effect of adding a stem cell transplant with melphalan after completing chemotherapy with daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy with Dara-VCD alone for treating patients with newly diagnosed amyloid light..."

The cache supports the randomized treatment comparison; live recruiting status was independently verified.

NCT04973137 PHASE_III TERMINATED

AFFIRM-AL evaluated birtamimab plus standard care in Mayo stage IV AL and was terminated after not meeting its primary endpoint; termination status and registry reason were independently verified on 2026-07-18.

Show evidence (1 reference)

clinicaltrials:NCT04973137 SUPPORT Human Clinical

"A Phase 3 study to evaluate the efficacy and safety of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV patients with AL amyloidosis."

The cache supports trial design; live registry review established the terminated status and stated failure of the primary endpoint.

{ }

Source YAML

click to show

name: Systemic AL Amyloidosis
creation_date: "2026-06-18T00:00:00Z"
category: Complex
disease_term:
  preferred_term: systemic AL amyloidosis
  term:
    id: MONDO:0017816
    label: primary systemic amyloidosis
parents:
- Amyloidosis
- Plasma Cell Neoplasm
description: >-
  Systemic AL (immunoglobulin light-chain) amyloidosis is a clonal plasma-cell
  disorder in which a usually plasma-cell clone produces and secretes an
  amyloidogenic immunoglobulin light chain that misfolds, forms cross-beta
  fibrils, and accumulates
  extracellularly in multiple organs. Organ injury reflects both deposited
  fibrils and, especially in the heart, direct proteotoxic effects of soluble
  light chains. The heart and kidneys are most commonly involved, while nerves,
  the gastrointestinal tract, blood vessels, and soft tissues may also be
  affected. Diagnosis requires demonstration of amyloid in tissue and correct
  biochemical typing; detecting a monoclonal protein or plasma-cell clone alone
  does not establish that the deposited amyloid is AL.
synonyms:
- immunoglobulin light-chain amyloidosis
- primary systemic amyloidosis
- systemic light-chain amyloidosis
prevalence:
- population: Olmsted County, Minnesota, 1990-2015
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.2
  rate_low: 0.8
  rate_high: 1.6
  notes: >-
    Age- and sex-adjusted incidence per 100,000 person-years in a geographically
    defined US population; this is an incidence estimate, not point prevalence.
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence rate of AL amyloidosis from 1990 through 2015 adjusted for
      age and sex was 1.2 per 100,000 person-years (95% CI, 0.8-1.6 per 100,000
      person-years).
    explanation: >-
      This population-based cohort provides the rate and confidence interval
      represented in the structured incidence fields.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_al_amyloid_deposition
  hypothesis_label: Canonical AL Amyloid Deposition Model
  status: CANONICAL
  description: >-
    A plasma-cell clone produces an amyloidogenic monoclonal light chain that
    misfolds, forms beta-sheet-rich oligomers and fibrils, deposits in the
    extracellular matrix of multiple organs, and causes organ-specific
    dysfunction.
  evidence:
  - reference: PMID:30361521
    reference_title: "Systemic immunoglobulin light chain amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Systemic immunoglobulin light chain amyloidosis is a protein misfolding
      disease caused by the conversion of immunoglobulin light chains from their
      soluble functional states into highly organized amyloid fibrillar
      aggregates that lead to organ dysfunction.
    explanation: >-
      This review states the precursor-to-fibril-to-organ-dysfunction model that
      defines the canonical hypothesis group.
- hypothesis_group_id: soluble_light_chain_cardiotoxicity
  hypothesis_label: Soluble Light-Chain Cardiotoxicity Model
  status: CANONICAL
  description: >-
    Soluble or prefibrillar amyloidogenic light chains exert direct cardiac
    proteotoxicity superimposed on structural injury from deposited fibrils,
    activating oxidative stress and non-canonical p38alpha MAPK signaling in
    cardiomyocytes and promoting contractile dysfunction and apoptosis.
  evidence:
  - reference: PMID:20150510
    reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we report that amyloidogenic light chain (AL-LC) proteins
      provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
      adult cardiomyocytes through activation of p38 mitogen-activated protein
      kinase (MAPK).
    explanation: >-
      Isolated adult cardiomyocytes provide direct experimental support for a
      soluble-light-chain injury branch independent of extracellular fibril
      burden.
pathophysiology:
- name: Amyloidogenic Plasma-Cell Clone
  description: >-
    A usually small clonal plasma-cell population produces the pathogenic light
    chain. The term clone is used deliberately: a large marrow expansion is not
    required, and clone detection alone does not prove that tissue amyloid is
    light-chain-derived.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  evidence:
  - reference: PMID:33099432
    reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Light chain amyloidosis is a disease in which clonal plasma cells produce
      toxic immunoglobulin light chains that form amyloid fibrils with deposition
      in organs, most commonly the heart and kidneys, but also the nervous system,
      gastrointestinal tract, and soft tissues.
    explanation: >-
      The review identifies clonal plasma cells as the source of the toxic light
      chains while also describing their downstream deposition.
  downstream:
  - target: Amyloidogenic Monoclonal Free Light-Chain Production and Secretion
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    - soluble_light_chain_cardiotoxicity
    description: The clone secretes the amyloidogenic monoclonal free light chain.
    evidence:
    - reference: PMID:33099432
      reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Light chain amyloidosis is a disease in which clonal plasma cells produce
        toxic immunoglobulin light chains that form amyloid fibrils with
        deposition in organs, most commonly the heart and kidneys, but also the
        nervous system, gastrointestinal tract, and soft tissues.
      explanation: >-
        The source directly links clonal plasma cells to production of toxic
        immunoglobulin light chains.
- name: Amyloidogenic Monoclonal Free Light-Chain Production and Secretion
  description: >-
    The clone produces and secretes a patient-specific kappa or lambda free light
    chain whose sequence and stability favor misfolding. A large clone or marked
    absolute excess is not required for pathogenicity. This is the disease-specific
    amyloidogenic precursor measured by serum free-light-chain assays.
  role: trigger
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33099432
    reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Light chain amyloidosis is a disease in which clonal plasma cells produce
      toxic immunoglobulin light chains that form amyloid fibrils with deposition
      in organs, most commonly the heart and kidneys, but also the nervous system,
      gastrointestinal tract, and soft tissues.
    explanation: >-
      The review identifies the clonal immunoglobulin light chain as the toxic
      precursor of deposited fibrils.
  downstream:
  - target: Light-Chain Misfolding and Beta-Sheet Oligomerization
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Amyloidogenic free light chains leave their native fold and assemble into beta-sheet-rich species.
    evidence:
    - reference: PMID:30361521
      reference_title: "Systemic immunoglobulin light chain amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Systemic immunoglobulin light chain amyloidosis is a protein misfolding
        disease caused by the conversion of immunoglobulin light chains from
        their soluble functional states into highly organized amyloid fibrillar
        aggregates that lead to organ dysfunction.
      explanation: >-
        The review directly links soluble light chains to their misfolded
        fibrillar state.
  - target: Soluble Amyloidogenic Light-Chain Cardiotoxicity
    causal_link_type: DIRECT
    hypothesis_groups:
    - soluble_light_chain_cardiotoxicity
    description: Circulating amyloidogenic light chains can directly injure cardiomyocytes before or alongside fibril deposition.
    evidence:
    - reference: PMID:20150510
      reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we report that amyloidogenic light chain (AL-LC) proteins
        provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
        adult cardiomyocytes through activation of p38 mitogen-activated protein
        kinase (MAPK).
      explanation: >-
        Direct exposure of isolated cardiomyocytes to amyloidogenic light chains
        supports the soluble-proteotoxicity edge.
- name: Light-Chain Misfolding and Beta-Sheet Oligomerization
  description: >-
    Destabilized light chains undergo major conformational rearrangement on the
    path toward beta-sheet-rich aggregation and fibril assembly.
  role: amplifier
  conforms_to: amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30894526
    reference_title: "Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The substantial conformational differences between the fibril structure
      and the native state imply instead that the native conformation must be
      largely, if not entirely, unfolded to allow fibril formation to occur
      (Fig. 4c).
    explanation: >-
      Patient-derived fibril structure demonstrates the extensive unfolding
      required for light-chain fibril formation, but does not directly resolve
      every proposed oligomeric intermediate.
  downstream:
  - target: Amyloid Fibril Formation and Extracellular Deposition
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: The rearranged light-chain conformation assembles through intermolecular cross-beta contacts into amyloid fibrils.
    evidence:
    - reference: PMID:30894526
      reference_title: "Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This conformation is then able to associate into the intermolecular
        hydrogen bond network of a cross-β sheet.
      explanation: >-
        The structural study directly supports cross-beta assembly from the
        misfolded light-chain conformation.
- name: Amyloid Fibril Formation and Extracellular Deposition
  description: >-
    Misfolded light-chain species nucleate and elongate into insoluble cross-beta
    fibrils that deposit extracellularly. This is the shared central effector of
    amyloidogenesis; the precursor identity distinguishes AL from other
    amyloidoses.
  role: central_effector
  conforms_to: amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  cellular_components:
  - preferred_term: extracellular region
    term:
      id: GO:0005576
      label: extracellular region
  evidence:
  - reference: PMID:30361521
    reference_title: "Systemic immunoglobulin light chain amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Systemic immunoglobulin light chain amyloidosis is a protein misfolding
      disease caused by the conversion of immunoglobulin light chains from their
      soluble functional states into highly organized amyloid fibrillar
      aggregates that lead to organ dysfunction.
    explanation: >-
      The review supports fibril formation as the link between light-chain
      misfolding and organ injury.
  downstream:
  - target: Progressive Systemic Tissue Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Continued extracellular deposition increases total systemic tissue amyloid burden.
    evidence:
    - reference: PMID:33099432
      reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Light chain amyloidosis is a disease in which clonal plasma cells produce
        toxic immunoglobulin light chains that form amyloid fibrils with
        deposition in organs, most commonly the heart and kidneys, but also the
        nervous system, gastrointestinal tract, and soft tissues.
      explanation: >-
        The source supports systemic organ deposition of light-chain fibrils.
  - target: Myocardial Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Light-chain fibrils accumulate extracellularly in the myocardium.
    evidence:
    - reference: PMID:38960850
      reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
        aggregation of proteins into large fibrils in the extracellular
        compartment of the myocardium, leading to restrictive cardiomyopathy,
        heart failure and death.
      explanation: >-
        This cardiac-amyloidosis review directly locates accumulated fibrils in
        the extracellular myocardial compartment.
  - target: Renal Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Light-chain fibrils accumulate in renal tissue, commonly involving glomerular structures.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The kidney is involved in 70% of patients with immunoglobulin light-chain
        (AL) amyloidosis
      explanation: >-
        The large clinical cohorts establish frequent renal involvement, while
        the specific fibril-deposition step is inferred rather than directly
        assayed in this source.
  - target: Peripheral and Autonomic Nerve Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Amyloid deposits accumulate within peripheral and autonomic nerve compartments.
    evidence:
    - reference: PMID:38923548
      reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid
        sheets in the peripheral nervous system.
      explanation: >-
        The review directly attributes amyloid neuropathy to fibril deposition
        in peripheral nerves.
  - target: Gastrointestinal Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Light-chain amyloid deposits may involve the gastrointestinal tract.
    evidence:
    - reference: PMID:41954624
      reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of
        whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66%
        had biopsy-proven GI AL.
      explanation: >-
        The large cohort documents symptomatic and biopsy-proven gastrointestinal
        AL involvement.
  - target: Hepatic Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Light-chain amyloid fibrils accumulate in the liver and contribute to hepatic organ dysfunction.
    evidence:
    - reference: DOI:10.3389/frhem.2024.1378451
      reference_title: "AL amyloidosis: an overview on diagnosis, staging system, and treatment"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These light-chain fragments then aggregate and get tangled into amyloid
        fibrils that deposit in end organs, usually the kidney, heart,
        gastrointestinal tract, liver, and peripheral nervous system, leading to
        organ dysfunction ( 9).
      explanation: >-
        The AL-specific review explicitly includes the liver among the organs in
        which light-chain fibrils deposit.
  - target: Tongue Soft-Tissue Amyloid Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Soft-tissue amyloid may accumulate in the tongue and contribute to enlargement.
    evidence:
    - reference: PMID:33099432
      reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Light chain amyloidosis is a disease in which clonal plasma cells produce
        toxic immunoglobulin light chains that form amyloid fibrils with
        deposition in organs, most commonly the heart and kidneys, but also the
        nervous system, gastrointestinal tract, and soft tissues.
      explanation: >-
        This supports soft-tissue deposition in AL generally but does not by
        itself establish tongue-specific deposition.
  - target: Vascular Amyloid Accumulation and Fragility
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Amyloid deposition in vessel walls may increase vascular fragility and produce characteristic purpura.
    evidence:
    - reference: PMID:30713046
      reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AL amyloidosis (immunoglobulin light chain) is an uncommon disease that
        is characterized by the presence of amyloid fibrils that are deposited
        mainly in the heart, kidneys, gastrointestinal tract, peripheral nerves
        and blood vessels of virtually all organs.
      explanation: >-
        The source supports vascular deposition, while the fragility consequence
        remains a mechanistic interpretation.
- name: Progressive Systemic Tissue Amyloid Accumulation
  description: >-
    Continued fibril deposition expands the extracellular amyloid burden across
    affected organs. Accumulation can be slowed by eliminating light-chain
    production, and organ improvement may occur after a deep clonal response;
    established injury is therefore not described as uniformly irreversible.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  evidence:
  - reference: PMID:33099432
    reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment directed at the clonal cells eliminates light chain production
      and further deposition and may enable organ improvement and decrease the
      risk of organ failure.
    explanation: >-
      The review supports ongoing deposition as a modifiable process and avoids
      an absolute irreversibility claim.
  downstream:
  - target: Systemic Multiorgan Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Accumulated extracellular amyloid produces combined organ dysfunction and systemic illness.
    evidence:
    - reference: PMID:30361521
      reference_title: "Systemic immunoglobulin light chain amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Systemic immunoglobulin light chain amyloidosis is a protein misfolding
        disease caused by the conversion of immunoglobulin light chains from
        their soluble functional states into highly organized amyloid fibrillar
        aggregates that lead to organ dysfunction.
      explanation: >-
        The source directly links fibrillar aggregates to organ dysfunction.
- name: Systemic Multiorgan Dysfunction
  description: >-
    The combined burden of cardiac, renal, neurologic, gastrointestinal, and
    other organ involvement produces nonspecific systemic manifestations. The
    exact intermediate mechanisms for fatigue and weight loss vary between
    patients and are not collapsed into a falsely direct molecular edge.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  evidence:
  - reference: PMID:35481407
    reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations include edema, digestive symptoms, weight
      loss, fatigue and ascites.
    explanation: >-
      This hepatic-involvement cohort documents fatigue and weight loss as
      clinical manifestations but does not resolve their causal intermediates.
  downstream:
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Multiorgan illness is associated with fatigue through patient-specific and incompletely resolved intermediates.
    evidence:
    - reference: PMID:35481407
      reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical manifestations include edema, digestive symptoms,
        weight loss, fatigue and ascites.
      explanation: >-
        The cohort supports the symptom association but not a single direct
        causal route.
  - target: Weight Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Multiorgan and gastrointestinal disease can accompany weight loss through incompletely resolved intermediates.
    evidence:
    - reference: PMID:35481407
      reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical manifestations include edema, digestive symptoms,
        weight loss, fatigue and ascites.
      explanation: >-
        The cohort supports the association while the graph explicitly records
        unknown intermediate mechanisms.
- name: Hepatic Amyloid Accumulation
  description: >-
    Light-chain amyloid fibrils can accumulate in the liver. Hepatic involvement
    may produce organ dysfunction and manifestations such as ascites, although
    ascites can also reflect cardiac, renal, or portal-hemodynamic intermediates.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: DOI:10.3389/frhem.2024.1378451
    reference_title: "AL amyloidosis: an overview on diagnosis, staging system, and treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These light-chain fragments then aggregate and get tangled into amyloid
      fibrils that deposit in end organs, usually the kidney, heart,
      gastrointestinal tract, liver, and peripheral nervous system, leading to
      organ dysfunction ( 9).
    explanation: >-
      The AL-specific review directly identifies the liver as a site of
      light-chain fibril deposition.
  - reference: PMID:35481407
    reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-eight patients diagnosed AL amyloidosis with hepatic involvement
      between June 2004 and January 2019 were analysed retrospectively.
    explanation: >-
      This dedicated cohort establishes clinically recognized hepatic
      involvement in systemic AL amyloidosis.
  downstream:
  - target: Ascites
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: >-
      Hepatic AL involvement can accompany ascites, but the cohort does not
      distinguish liver-specific effects from cardiac, renal, or portal-hemodynamic
      intermediates in each patient.
    evidence:
    - reference: PMID:35481407
      reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical manifestations include edema, digestive symptoms,
        weight loss, fatigue and ascites.
      explanation: >-
        Ascites is documented in the hepatic-involvement cohort, while the
        causal intermediates are not resolved.
- name: Myocardial Amyloid Accumulation
  description: >-
    Extracellular light-chain fibrils accumulate within the myocardium, stiffen
    the ventricular wall, and impair filling and pump function.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:38960850
    reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
      aggregation of proteins into large fibrils in the extracellular
      compartment of the myocardium, leading to restrictive cardiomyopathy,
      heart failure and death.
    explanation: >-
      The review directly supports extracellular myocardial fibril accumulation.
  downstream:
  - target: Myocardial Stiffening and Diastolic Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Myocardial fibril burden impairs compliance and contractile function.
    evidence:
    - reference: PMID:38960850
      reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
        aggregation of proteins into large fibrils in the extracellular
        compartment of the myocardium, leading to restrictive cardiomyopathy,
        heart failure and death.
      explanation: >-
        The source links extracellular myocardial fibrils to restrictive cardiac
        dysfunction and heart failure.
- name: Soluble Amyloidogenic Light-Chain Cardiotoxicity
  description: >-
    Soluble amyloidogenic light chains directly perturb cardiomyocyte function in
    addition to the mechanical effects of deposited fibrils.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20150510
    reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we report that amyloidogenic light chain (AL-LC) proteins
      provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
      adult cardiomyocytes through activation of p38 mitogen-activated protein
      kinase (MAPK).
    explanation: >-
      Direct cardiomyocyte exposure establishes a soluble-light-chain toxic
      effect.
  downstream:
  - target: Cardiomyocyte Oxidative Stress and Apoptosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - soluble_light_chain_cardiotoxicity
    description: Amyloidogenic light chains activate oxidative-stress and p38alpha MAPK injury pathways in cardiomyocytes.
    evidence:
    - reference: PMID:20150510
      reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we report that amyloidogenic light chain (AL-LC) proteins
        provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
        adult cardiomyocytes through activation of p38 mitogen-activated protein
        kinase (MAPK).
      explanation: >-
        The experimental result directly supports this cellular injury edge.
- name: Cardiomyocyte Oxidative Stress and Apoptosis
  description: >-
    Non-canonical p38alpha MAPK activation drives oxidative stress, contractile
    dysfunction, and apoptosis in cardiomyocytes exposed to amyloidogenic light
    chains.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20150510
    reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we report that amyloidogenic light chain (AL-LC) proteins
      provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
      adult cardiomyocytes through activation of p38 mitogen-activated protein
      kinase (MAPK).
    explanation: >-
      This is direct experimental evidence for the node's cellular events.
  downstream:
  - target: Cardiomyocyte Contractile Dysfunction and Cell Loss
    causal_link_type: DIRECT
    hypothesis_groups:
    - soluble_light_chain_cardiotoxicity
    description: Oxidative injury produces contractile dysfunction and apoptotic cardiomyocyte loss.
    evidence:
    - reference: PMID:20150510
      reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we report that amyloidogenic light chain (AL-LC) proteins
        provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
        adult cardiomyocytes through activation of p38 mitogen-activated protein
        kinase (MAPK).
      explanation: >-
        The isolated-cardiomyocyte experiment directly supports contractile
        dysfunction and apoptosis downstream of oxidative injury.
- name: Cardiomyocyte Contractile Dysfunction and Cell Loss
  description: >-
    Soluble amyloidogenic light-chain proteotoxicity reduces cardiomyocyte
    contractile function and promotes apoptosis independently of the mechanical
    stiffness produced by extracellular fibril infiltration.
  role: consequence
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20150510
    reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we report that amyloidogenic light chain (AL-LC) proteins
      provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
      adult cardiomyocytes through activation of p38 mitogen-activated protein
      kinase (MAPK).
    explanation: >-
      Direct light-chain exposure supports the modeled cellular functional loss
      without implying fibril-mediated restrictive physiology.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced myocardial contractile reserve and pump dysfunction
    hypothesis_groups:
    - soluble_light_chain_cardiotoxicity
    description: Contractile dysfunction and cardiomyocyte loss can contribute to organ-level pump failure.
    evidence:
    - reference: PMID:20150510
      reference_title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we report that amyloidogenic light chain (AL-LC) proteins
        provoke oxidative stress, cellular dysfunction, and apoptosis in isolated
        adult cardiomyocytes through activation of p38 mitogen-activated protein
        kinase (MAPK).
      explanation: >-
        The cellular injury is directly observed, while translation from the
        in-vitro phenotype to clinical heart failure is appropriately modeled as
        indirect and partially supported.
- name: Myocardial Stiffening and Diastolic Dysfunction
  description: >-
    Extracellular myocardial fibril infiltration impairs compliance and filling,
    producing restrictive physiology and contributing to heart failure.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:38960850
    reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
      aggregation of proteins into large fibrils in the extracellular
      compartment of the myocardium, leading to restrictive cardiomyopathy,
      heart failure and death.
    explanation: >-
      The review links cardiac fibril accumulation to the two modeled cardiac
      manifestations.
  downstream:
  - target: Restrictive Cardiomyopathy
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Reduced myocardial compliance manifests as restrictive cardiomyopathy.
    evidence:
    - reference: PMID:38960850
      reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
        aggregation of proteins into large fibrils in the extracellular
        compartment of the myocardium, leading to restrictive cardiomyopathy,
        heart failure and death.
      explanation: >-
        Restrictive cardiomyopathy is an explicit downstream manifestation in
        the cited review.
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Progressive myocardial dysfunction manifests clinically as congestive heart failure.
    evidence:
    - reference: PMID:30713046
      reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congestive heart failure was present at diagnosis in 10 patients (29%)
        and occurred in 9 additional patients (total 54%) during follow-up.
      explanation: >-
        The longitudinal cohort directly documents heart failure as an AL
        manifestation.
- name: Renal Amyloid Accumulation
  description: >-
    Amyloid accumulation in renal tissue, especially glomerular compartments,
    disrupts filtration-barrier integrity and creates a high protein-loss burden.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:25115890
    reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The kidney is involved in 70% of patients with immunoglobulin light-chain
      (AL) amyloidosis
    explanation: >-
      The large testing and validation cohorts establish renal involvement as a
      common AL manifestation; the tissue-distribution detail is not directly
      measured by this prognostic study.
  downstream:
  - target: Glomerular Filtration Barrier Dysfunction and Protein Loss
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Glomerular amyloid injury permits pathologic urinary protein loss and may progress to renal failure.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
        mL/min predicted progression to dialysis best.
      explanation: >-
        The cohort links protein loss and filtration impairment to renal outcome;
        the tissue-level barrier mechanism is a supported interpretation rather
        than a directly assayed causal step.
- name: Glomerular Filtration Barrier Dysfunction and Protein Loss
  description: >-
    Renal amyloid injury compromises the glomerular filtration barrier, producing
    proteinuria that may reach nephrotic range and increasing the risk of kidney
    failure.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:25115890
    reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
      mL/min predicted progression to dialysis best.
    explanation: >-
      Proteinuria and impaired filtration jointly define renal risk in the
      validated cohort, while the podocyte/barrier mechanism is an interpretation
      rather than a directly measured causal event.
  downstream:
  - target: Proteinuria
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Filtration-barrier disruption produces abnormal urinary protein excretion.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
        mL/min predicted progression to dialysis best.
      explanation: >-
        The renal outcome study directly measures proteinuria as a defining renal
        manifestation.
  - target: Nephrotic Syndrome
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - nephrotic-range urinary protein loss and hypoalbuminemia
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Severe sustained protein loss can produce the nephrotic syndrome.
    evidence:
    - reference: PMID:30713046
      reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Nephrotic syndrome was present in 9 patients (26%) at diagnosis.
      explanation: >-
        This geographically defined cohort directly documents nephrotic syndrome
        at AL diagnosis.
- name: Peripheral and Autonomic Nerve Amyloid Accumulation
  description: >-
    Fibrils deposit in peripheral nerves and ganglia, with associated Schwann-cell
    atrophy and blood-nerve-barrier disruption.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  - preferred_term: autonomic nervous system
    term:
      id: UBERON:0002410
      label: autonomic nervous system
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Amyloid fibrils deposit in the endoneurium of peripheral nerves, often
      extensive in the dorsal root ganglia and sympathetic ganglia, leading to
      atrophy of Schwann cells in proximity to amyloid fibrils and blood-nerve
      barrier disruption.
    explanation: >-
      The review explicitly describes nerve deposition and adjacent cellular
      injury.
  downstream:
  - target: Peripheral and Autonomic Nerve Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Nerve and ganglion deposition disrupts sensory and autonomic function.
    evidence:
    - reference: PMID:38923548
      reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinically, amyloid neuropathy is manifested as a length-dependent
        sensory predominant neuropathy associated with generalized autonomic
        failure.
      explanation: >-
        The cited review directly links amyloid neuropathy to both sensory and
        autonomic dysfunction.
- name: Peripheral and Autonomic Nerve Dysfunction
  description: >-
    Peripheral nerve injury produces a length-dependent sensory-predominant
    neuropathy, while autonomic fiber involvement produces generalized autonomic
    failure.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  - preferred_term: autonomic nervous system
    term:
      id: UBERON:0002410
      label: autonomic nervous system
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, amyloid neuropathy is manifested as a length-dependent sensory
      predominant neuropathy associated with generalized autonomic failure.
    explanation: >-
      The review supports both modeled neurologic consequences.
  downstream:
  - target: Peripheral Neuropathy
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Sensory-predominant nerve dysfunction manifests as peripheral neuropathy.
    evidence:
    - reference: PMID:38923548
      reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinically, amyloid neuropathy is manifested as a length-dependent
        sensory predominant neuropathy associated with generalized autonomic
        failure.
      explanation: >-
        The phenotype is explicit in the source.
  - target: Autonomic Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Autonomic-fiber involvement manifests as generalized autonomic dysfunction.
    evidence:
    - reference: PMID:38923548
      reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinically, amyloid neuropathy is manifested as a length-dependent
        sensory predominant neuropathy associated with generalized autonomic
        failure.
      explanation: >-
        Generalized autonomic failure directly supports this manifestation.
  - target: Gastrointestinal Dysmotility and Nutritional Impact
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Autonomic neuropathy can independently contribute to gastrointestinal dysmotility symptoms.
    evidence:
    - reference: PMID:41954624
      reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autonomic neuropathy was frequent (43% clinician attributed; 23% via
        autonomic reflex testing) and contributed to dysmotility-related
        symptoms, often without GI biopsy positivity.
      explanation: >-
        The cohort explicitly supports dysautonomia as a parallel contributor to
        gastrointestinal symptoms even without biopsy-positive GI deposition.
- name: Gastrointestinal Amyloid Accumulation
  description: >-
    Amyloid deposited in gastrointestinal tissues can impair enteric function and
    contribute to a substantial symptom burden.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  evidence:
  - reference: PMID:41954624
    reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of
      whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66%
      had biopsy-proven GI AL.
    explanation: >-
      The cohort documents biopsy-proven gastrointestinal AL involvement in a
      large clinical population.
  downstream:
  - target: Gastrointestinal Dysmotility and Nutritional Impact
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - enteric tissue involvement
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Enteric tissue involvement can contribute to dysmotility-related symptoms.
    evidence:
    - reference: PMID:41954624
      reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autonomic neuropathy was frequent (43% clinician attributed; 23% via
        autonomic reflex testing) and contributed to dysmotility-related
        symptoms, often without GI biopsy positivity.
      explanation: >-
        The cohort shows that GI symptoms have both biopsy-positive tissue and
        autonomic contributors; this specific deposition-to-dysmotility edge is
        therefore conservatively marked partial.
- name: Gastrointestinal Dysmotility and Nutritional Impact
  description: >-
    Gastrointestinal tissue involvement and dysautonomia produce motility
    disturbance, including bowel irregularity and early satiety, with potential
    downstream nutritional consequences.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  evidence:
  - reference: PMID:41954624
    reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms most commonly included early satiety (61%), bowel irregularities
      (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%).
    explanation: >-
      The large cohort quantifies the modeled gastrointestinal manifestations.
  downstream:
  - target: Gastrointestinal Dysmotility
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Enteric and autonomic dysfunction manifests as bowel-motility disturbance.
    evidence:
    - reference: PMID:41954624
      reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autonomic neuropathy was frequent (43% clinician attributed; 23% via
        autonomic reflex testing) and contributed to dysmotility-related
        symptoms, often without GI biopsy positivity.
      explanation: >-
        Dysmotility-related symptoms are explicitly linked to autonomic
        neuropathy in the cohort.
  - target: Early Satiety
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Upper gastrointestinal dysfunction commonly presents with early satiety.
    evidence:
    - reference: PMID:41954624
      reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Symptoms most commonly included early satiety (61%), bowel irregularities
        (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%).
      explanation: >-
        Early satiety is the most commonly reported gastrointestinal symptom in
        this cohort.
- name: Tongue Soft-Tissue Amyloid Accumulation
  description: >-
    Amyloid deposition in tongue soft tissue may enlarge the tongue. Macroglossia
    is characteristic but uncommon and is not treated as pathognomonic or
    uniquely specific to AL.
  role: effector
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  locations:
  - preferred_term: tongue
    term:
      id: UBERON:0001723
      label: tongue
  evidence:
  - reference: PMID:42005116
    reference_title: "Rheumatological Manifestations of Systemic Amyloidosis: A Retrospective Single-Centre Study From a Tertiary Care Hospital in India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Classic signs included macroglossia (four patients, 16.6%)
    explanation: >-
      The mixed systemic-amyloidosis cohort documents macroglossia but does not
      type the sign as AL-specific.
  downstream:
  - target: Macroglossia
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Tongue soft-tissue deposition can manifest as tongue enlargement.
    evidence:
    - reference: PMID:42005116
      reference_title: "Rheumatological Manifestations of Systemic Amyloidosis: A Retrospective Single-Centre Study From a Tertiary Care Hospital in India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Classic signs included macroglossia (four patients, 16.6%)
      explanation: >-
        This supports the manifestation in systemic amyloidosis but only
        partially supports the AL-specific causal edge.
- name: Vascular Amyloid Accumulation and Fragility
  description: >-
    Amyloid can deposit in blood vessels. Vessel-wall involvement is associated
    with fragility and purpura, including the characteristic periorbital pattern,
    although the cited clinical evidence is observational.
  role: consequence
  conforms_to: amyloidogenesis#Organ Dysfunction
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The third patient had a positive Congo red stain and periorbital purpura,
      left ventricular diastolic dysfunction, atrial fibrillation as well as
      congestive heart failure.
    explanation: >-
      This AL case documents periorbital purpura alongside tissue-confirmed
      amyloidosis but does not directly assay vessel-wall mechanics.
  downstream:
  - target: Periorbital Purpura
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - amyloid-associated vessel-wall fragility
    hypothesis_groups:
    - canonical_al_amyloid_deposition
    description: Fragile amyloid-involved vessels can bleed into periorbital tissue.
    evidence:
    - reference: PMID:30713046
      reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The third patient had a positive Congo red stain and periorbital purpura,
        left ventricular diastolic dysfunction, atrial fibrillation as well as
        congestive heart failure.
      explanation: >-
        The case supports the phenotype association; the vessel-fragility
        intermediate is mechanistically plausible but not directly measured.
phenotypes:
- category: Cardiovascular
  name: Restrictive Cardiomyopathy
  description: >-
    Myocardial amyloid accumulation and soluble-light-chain injury impair
    ventricular compliance and produce restrictive physiology.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:38960850
    reference_title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac amyloidosis (CA) is caused by the misfolding, accumulation and
      aggregation of proteins into large fibrils in the extracellular
      compartment of the myocardium, leading to restrictive cardiomyopathy,
      heart failure and death.
    explanation: >-
      Restrictive cardiomyopathy is an explicit consequence of myocardial
      amyloid accumulation in the cited review.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Cardiac involvement may progress to symptomatic congestive heart failure and
    is a major determinant of survival.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congestive heart failure was present at diagnosis in 10 patients (29%) and
      occurred in 9 additional patients (total 54%) during follow-up.
    explanation: >-
      The geographically defined cohort documents heart failure at diagnosis
      and during follow-up.
- category: Renal
  name: Proteinuria
  description: >-
    Renal amyloid injury commonly produces urinary protein loss, which may be
    nephrotic-range and is central to renal risk stratification.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:25115890
    reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
      mL/min predicted progression to dialysis best.
    explanation: >-
      The validated renal staging cohorts use proteinuria as a central renal
      disease measure.
- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Severe glomerular protein loss can present as nephrotic syndrome.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nephrotic syndrome was present in 9 patients (26%) at diagnosis.
    explanation: >-
      The cohort directly reports nephrotic syndrome at AL diagnosis.
- category: Neurologic
  name: Peripheral Neuropathy
  description: >-
    Peripheral nerve involvement typically produces a length-dependent,
    sensory-predominant neuropathy.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, amyloid neuropathy is manifested as a length-dependent sensory
      predominant neuropathy associated with generalized autonomic failure.
    explanation: >-
      The review directly describes the sensory-predominant peripheral
      neuropathy phenotype.
- category: Neurologic
  name: Autonomic Dysfunction
  description: >-
    Autonomic nerve involvement may produce generalized dysautonomia, often
    accompanying peripheral neuropathy or gastrointestinal dysmotility.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:38923548
    reference_title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, amyloid neuropathy is manifested as a length-dependent sensory
      predominant neuropathy associated with generalized autonomic failure.
    explanation: >-
      Generalized autonomic failure directly supports this phenotype.
- category: Gastrointestinal
  name: Gastrointestinal Dysmotility
  description: >-
    Enteric tissue involvement and autonomic neuropathy can impair
    gastrointestinal motility and produce bowel irregularity.
  phenotype_term:
    preferred_term: Gastrointestinal dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
  evidence:
  - reference: PMID:41954624
    reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autonomic neuropathy was frequent (43% clinician attributed; 23% via
      autonomic reflex testing) and contributed to dysmotility-related symptoms,
      often without GI biopsy positivity.
    explanation: >-
      The cohort directly attributes dysmotility-related symptoms in part to
      autonomic neuropathy.
- category: Gastrointestinal
  name: Early Satiety
  description: >-
    Early satiety is a common symptom among patients with clinically attributed
    gastrointestinal AL involvement.
  phenotype_term:
    preferred_term: Early satiety
    term:
      id: HP:0033842
      label: Early satiety
  evidence:
  - reference: PMID:41954624
    reference_title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms most commonly included early satiety (61%), bowel irregularities
      (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%).
    explanation: >-
      The large cohort identifies early satiety as the most common GI symptom.
- category: Hepatic
  name: Ascites
  description: >-
    Ascites can occur with hepatic AL involvement, but the available cohort does
    not establish a liver-specific mechanism or a frequency across all systemic
    AL amyloidosis.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:35481407
    reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations include edema, digestive symptoms,
      weight loss, fatigue and ascites.
    explanation: >-
      The dedicated hepatic-involvement cohort directly lists ascites among its
      main clinical manifestations.
- category: Head and Neck
  name: Macroglossia
  description: >-
    Tongue enlargement from soft-tissue amyloid is a characteristic but uncommon
    clue. It is not treated here as pathognomonic or as uniquely specific to AL.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:42005116
    reference_title: "Rheumatological Manifestations of Systemic Amyloidosis: A Retrospective Single-Centre Study From a Tertiary Care Hospital in India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Classic signs included macroglossia (four patients, 16.6%)
    explanation: >-
      The mixed systemic-amyloidosis cohort documents macroglossia but does not
      establish AL specificity.
- category: Hematologic
  name: Periorbital Purpura
  description: >-
    Periorbital purpura is a characteristic vascular-fragility clue in AL
    amyloidosis, although it is not present in most patients.
  phenotype_term:
    preferred_term: Periorbital purpura
    term:
      id: HP:0025552
      label: Periorbital purpura
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The third patient had a positive Congo red stain and periorbital purpura,
      left ventricular diastolic dysfunction, atrial fibrillation as well as
      congestive heart failure.
    explanation: >-
      A tissue-positive AL case directly documents the phenotype, but the source
      does not estimate its population frequency.
- category: Constitutional
  name: Fatigue
  description: >-
    Fatigue is a nonspecific manifestation of systemic illness and multiorgan
    involvement rather than a disease-defining sign.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:35481407
    reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations include edema, digestive symptoms, weight
      loss, fatigue and ascites.
    explanation: >-
      The hepatic-involvement cohort supports fatigue as a manifestation but not
      its frequency across all systemic AL.
- category: Constitutional
  name: Weight Loss
  description: >-
    Unintentional weight loss may accompany systemic and gastrointestinal disease
    but is nonspecific.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:35481407
    reference_title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations include edema, digestive symptoms, weight
      loss, fatigue and ascites.
    explanation: >-
      The cohort supports weight loss as a manifestation in hepatic AL while not
      establishing a universal mechanism.
progression:
- phase: Prognostic risk and treatment response
  notes: >-
    Cardiac involvement is the dominant prognostic determinant. Prognosis is not
    uniformly fixed by baseline organ damage: rapid reduction of the
    amyloidogenic free light chain is associated with survival benefit, and
    organ responses can follow effective clone suppression.
  evidence:
  - reference: PMID:23091105
    reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a strong correlation between the extent of reduction of
      amyloidogenic free light chains (FLCs) and improvement in survival.
    explanation: >-
      The multicenter cohort directly relates depth of precursor reduction to
      survival.
  - reference: PMID:23091105
    reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac involvement is the major determinant of survival, and changes in
      cardiac function after therapy can be reliably assessed using the cardiac
      biomarker N-terminal natriuretic peptide type B (NT-proBNP).
    explanation: >-
      This supports both the prognostic importance of cardiac disease and the
      possibility of measurable post-treatment cardiac change.
histopathology:
- name: Congo Red-Positive Amyloid Deposition
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  description: >-
    Extracellular tissue deposits bind Congo red and show apple-green
    birefringence under polarized light. This confirms amyloid deposition but
    does not identify the precursor protein; biochemical typing is still
    required to establish AL.
  diagnostic: true
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All diagnostic specimens contained amyloid deposits that exhibited
      apple-green birefringence when stained with alkaline Congo red and viewed
      under polarized light.
    explanation: >-
      The clinical series directly documents the diagnostic histologic finding.
diagnosis:
- name: Monoclonal-Protein Screening
  diagnosis_term:
    preferred_term: free immunoglobulin light chain measurement
    term:
      id: NCIT:C156517
      label: Free Immunoglobulin Light Chain Measurement
  description: >-
    Initial clonal screening combines serum immunofixation, urine
    immunofixation, and serum free-light-chain measurement. A positive screen
    increases suspicion but cannot substitute for tissue confirmation and
    amyloid typing.
  results: >-
    A monoclonal protein or abnormal free-light-chain result supports suspicion
    for AL and prompts tissue confirmation and clone evaluation.
  evidence:
  - reference: PMID:41592868
    reference_title: "American Society of Hematology (ASH) 2026 Guidelines on Diagnosis of Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The use of serum immunofixation, urine immunofixation and serum free light
      chains enhances the clinical suspicion of AL amyloidosis.
    explanation: >-
      The guideline explicitly recommends the three-part monoclonal-protein
      screen as a suspicion-enhancing step.
- name: Surrogate-Tissue Biopsy
  description: >-
    Abdominal fat-pad and bone-marrow sampling provide minimally invasive tissue
    for Congo red staining. Combined testing detects many, but not all, AL cases;
    a negative surrogate biopsy does not exclude disease, and involved-organ
    biopsy may be needed when suspicion remains high.
  results: >-
    Congo red-positive amyloid in fat pad or bone marrow supports systemic
    amyloidosis; a negative combined result leaves residual diagnostic risk.
  evidence:
  - reference: PMID:41460224
    reference_title: "Detection yield of surrogate tissue biopsies across amyloidosis classes: a large-scale analysis of 4,027 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 2,213 patients with AL amyloidosis who underwent both FP and BM
      sampling, combined testing increased detection to 85% (40% positive in
      both; 32% FP-only; 13% BM-only).
    explanation: >-
      The large cohort quantifies the benefit and residual false-negative risk
      of combined surrogate sampling.
- name: Congo Red Tissue Confirmation
  diagnosis_term:
    preferred_term: Congo red staining method
    term:
      id: NCIT:C154782
      label: Congo Red Staining Method
  description: >-
    Tissue is stained with Congo red and examined under polarized light to
    demonstrate amyloid. A positive stain confirms amyloid deposition but not AL
    type.
  results: >-
    Congo red-positive deposits with apple-green birefringence establish tissue
    amyloid and must be followed by precursor typing.
  evidence:
  - reference: PMID:30713046
    reference_title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All diagnostic specimens contained amyloid deposits that exhibited
      apple-green birefringence when stained with alkaline Congo red and viewed
      under polarized light.
    explanation: >-
      The series directly documents the Congo-red/polarized-light diagnostic
      pattern.
- name: Mass-Spectrometry Amyloid Typing
  description: >-
    Laser microdissection followed by liquid chromatography and mass
    spectrometry identifies the protein composing a Congo red-positive deposit
    and distinguishes AL from ATTR and other amyloid types.
  results: >-
    Detection of an immunoglobulin light-chain amyloid proteomic signature
    establishes the AL precursor type in the sampled deposit.
  evidence:
  - reference: PMID:30834260
    reference_title: "Mass Spectrometry Amyloid Typing Is Reproducible across Multiple Organ Sites."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      LMD-LC-MS correctly typed AL amyloidosis in all 22 FFPE tissue samples
      despite tissue origin.
    explanation: >-
      This ex vivo multi-organ study directly supports mass-spectrometric AL
      typing across fixed tissue sites.
- name: Plasma-Cell Clone and Organ Assessment
  description: >-
    Bone-marrow morphology, flow cytometry, and plasma-cell FISH characterize the
    underlying somatic clone, including clinically relevant t(11;14), while
    cardiac, renal, neurologic, and gastrointestinal assessments establish organ
    burden. Cardiac troponin, NT-proBNP, and dFLC support prognostic staging.
  results: >-
    Clone characterization guides treatment selection; organ measurements and
    Mayo staging define risk but do not replace tissue amyloid typing.
  evidence:
  - reference: PMID:22331953
    reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a multivariate model that included these characteristics as well as cTnT
      and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently
      prognostic for overall survival (OS).
    explanation: >-
      The staging cohort supports the three principal prognostic measurements;
      marrow/FISH and broader organ-assessment details are standard diagnostic
      context not directly evaluated by this source.
  - reference: PMID:33431806
    reference_title: "Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status
      was unknown. Patients received a venetoclax-containing regimen for at least
      one 21- or 28-day cycle; the median prior treatments was three.
    explanation: >-
      The retrospective cohort shows why defining t(11;14) status can affect
      treatment selection, without by itself validating the full diagnostic
      work-up.
differential_diagnoses:
- name: Transthyretin Amyloidosis
  description: >-
    ATTR amyloidosis is the principal alternative precursor diagnosis when
    cardiac amyloid is suspected. AL uses an immunoglobulin light chain, whereas
    ATTR uses wild-type or variant transthyretin. Clinical and imaging features
    overlap, so a monoclonal-protein result alone cannot type the tissue deposit;
    precise biochemical typing is required when AL remains possible.
  distinguishing_features:
  - AL amyloid is composed of an immunoglobulin light chain; ATTR amyloid is composed of transthyretin.
  - A monoclonal-protein screen raises suspicion for AL but does not itself identify the protein in a tissue deposit.
  - Congo red establishes amyloid but not its type; mass spectrometry or another validated typing method identifies the precursor.
  - Cardiac involvement can occur in either disease, so demographic heuristics are not diagnostic substitutes.
  evidence:
  - reference: PMID:29700090
    reference_title: "Cardiac amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The need for a high index of suspicion and the critical importance of
      precise biochemical typing of the amyloid deposits is paramount in light of
      recent therapeutic advances that can significantly improve prognosis.
    explanation: >-
      The review directly supports biochemical typing rather than reliance on a
      nonspecific cardiac phenotype.
  - reference: PMID:29700090
    reference_title: "Cardiac amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most cases of cardiac amyloidosis are of either transthyretin type, which
      may be acquired in older individuals or inherited in younger patients, or
      acquired monoclonal immunoglobulin light chain (AL) type.
    explanation: >-
      This identifies the two dominant precursor classes without using age as a
      stand-alone diagnostic rule.
stages:
- name: Mayo 2012 Prognostic Staging System
  description: >-
    Prognostic stage is assigned from three adverse factors: dFLC at least 18
    mg/dL, cardiac troponin T at least 0.025 ng/mL, and NT-proBNP at least 1,800
    pg/mL. Zero through three adverse factors correspond to stages I through IV.
    The IIIa/IIIb labels used by some cardiac trials refer to a separate
    European-modified staging convention and are not subdivisions of this Mayo
    2012 four-stage score.
  substages:
  - name: Mayo 2012 Stage I
    description: None of the three adverse biomarker thresholds is met.
    evidence:
    - reference: PMID:22331953
      reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL,
        cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV
        with scores of 0 to 3 points, respectively.
      explanation: A score of zero maps directly to Mayo 2012 stage I.
  - name: Mayo 2012 Stage II
    description: One of the three adverse biomarker thresholds is met.
    evidence:
    - reference: PMID:22331953
      reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL,
        cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV
        with scores of 0 to 3 points, respectively.
      explanation: A score of one maps directly to Mayo 2012 stage II.
  - name: Mayo 2012 Stage III
    description: Two of the three adverse biomarker thresholds are met.
    evidence:
    - reference: PMID:22331953
      reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL,
        cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV
        with scores of 0 to 3 points, respectively.
      explanation: A score of two maps directly to Mayo 2012 stage III.
  - name: Mayo 2012 Stage IV
    description: All three adverse biomarker thresholds are met.
    evidence:
    - reference: PMID:22331953
      reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL,
        cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV
        with scores of 0 to 3 points, respectively.
      explanation: A score of three maps directly to Mayo 2012 stage IV.
  evidence:
  - reference: PMID:22331953
    reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT
      ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with
      scores of 0 to 3 points, respectively.
    explanation: >-
      The derivation and validation study provides the exact thresholds and
      stage mapping.
- name: Renal Outcome Staging System
  description: >-
    Renal risk is stratified by proteinuria above 5 g/24 h and eGFR below 50
    mL/min. Neither adverse factor defines stage I, one defines stage II, and
    both define stage III, with increasing risk of progression to dialysis.
  substages:
  - name: Renal Stage I
    description: Proteinuria is at or below 5 g/24 h and eGFR is at or above 50 mL/min.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteinuria below and eGFR above the thresholds indicated low risk (0 and
        4% at 3 years in the testing and validation cohorts, respectively).
      explanation: The low-risk combination defines renal stage I.
  - name: Renal Stage II
    description: One adverse renal factor is present.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
        mL/min predicted progression to dialysis best.
      explanation: Stage II is the intermediate category with one adverse factor.
  - name: Renal Stage III
    description: Proteinuria exceeds 5 g/24 h and eGFR is below 50 mL/min.
    evidence:
    - reference: PMID:25115890
      reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        High proteinuria and low eGFR indicated high risk (60% and 85% at 3
        years).
      explanation: The high-risk two-factor combination defines renal stage III.
  evidence:
  - reference: PMID:25115890
    reference_title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50
      mL/min predicted progression to dialysis best.
    explanation: >-
      The testing and validation cohorts establish the two renal risk thresholds.
biochemical:
- name: Serum Free Immunoglobulin Light Chains
  biomarker_term:
    preferred_term: serum free immunoglobulin light chain
    term:
      id: NCIT:C84260
      label: Serum Free Immunoglobulin Light Chain
  presence: Abnormal concentration or ratio
  notes: >-
    Serum free-light-chain testing is interpreted with serum and urine
    immunofixation during diagnostic evaluation.
  readouts:
  - target: Amyloidogenic Monoclonal Free Light-Chain Production and Secretion
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      An involved light-chain excess or abnormal ratio raises suspicion for a
      clonal light-chain source but does not type tissue amyloid.
    evidence:
    - reference: PMID:41592868
      reference_title: "American Society of Hematology (ASH) 2026 Guidelines on Diagnosis of Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The use of serum immunofixation, urine immunofixation and serum free light
        chains enhances the clinical suspicion of AL amyloidosis.
      explanation: >-
        The guideline supports free-light-chain measurement as part of the
        diagnostic screen.
  evidence:
  - reference: PMID:41592868
    reference_title: "American Society of Hematology (ASH) 2026 Guidelines on Diagnosis of Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The use of serum immunofixation, urine immunofixation and serum free light
      chains enhances the clinical suspicion of AL amyloidosis.
    explanation: >-
      The guideline establishes the biomarker's diagnostic context.
- name: Difference Between Involved and Uninvolved Free Light Chains
  biomarker_term:
    preferred_term: serum free immunoglobulin light chain
    term:
      id: NCIT:C84260
      label: Serum Free Immunoglobulin Light Chain
  presence: Quantified as dFLC
  notes: >-
    Reduction in dFLC is used to classify hematologic response and provides an
    early pharmacodynamic readout of clone-directed therapy.
  readouts:
  - target: Amyloidogenic Monoclonal Free Light-Chain Production and Secretion
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >-
      A lower dFLC after therapy indicates reduced production of the involved
      amyloidogenic free light chain.
    evidence:
    - reference: PMID:23091105
      reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There was a strong correlation between the extent of reduction of
        amyloidogenic free light chains (FLCs) and improvement in survival.
      explanation: >-
        The multicenter study validates precursor reduction as a response
        measurement associated with survival.
  evidence:
  - reference: PMID:23091105
    reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a strong correlation between the extent of reduction of
      amyloidogenic free light chains (FLCs) and improvement in survival.
    explanation: >-
      The study directly supports dFLC reduction as a clinically meaningful
      response biomarker.
- name: NT-proBNP
  biomarker_term:
    preferred_term: N-terminal fragment brain natriuretic protein
    term:
      id: NCIT:C88524
      label: N-Terminal Fragment Brain Natriuretic Protein
  presence: Elevated with cardiac stress
  readouts:
  - target: Myocardial Stiffening and Diastolic Dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher NT-proBNP contributes to adverse cardiac risk staging; serial change
      can also report cardiac response after therapy.
    evidence:
    - reference: PMID:23091105
      reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac involvement is the major determinant of survival, and changes in
        cardiac function after therapy can be reliably assessed using the cardiac
        biomarker N-terminal natriuretic peptide type B (NT-proBNP).
      explanation: >-
        The response-criteria study directly supports NT-proBNP as a cardiac
        function readout; its prognostic-stage use is documented separately.
  evidence:
  - reference: PMID:23091105
    reference_title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac involvement is the major determinant of survival, and changes in
      cardiac function after therapy can be reliably assessed using the cardiac
      biomarker N-terminal natriuretic peptide type B (NT-proBNP).
    explanation: >-
      This supports NT-proBNP for cardiac monitoring as well as prognostic use.
- name: Cardiac Troponin T
  biomarker_term:
    preferred_term: troponin T
    term:
      id: NCIT:C38041
      label: Troponin T
  presence: Elevated with cardiac injury
  readouts:
  - target: Myocardial Stiffening and Diastolic Dysfunction
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: Higher cardiac troponin T contributes to adverse Mayo prognostic stage.
    evidence:
    - reference: PMID:22331953
      reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In a multivariate model that included these characteristics as well as
        cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently
        prognostic for overall survival (OS).
      explanation: >-
        Cardiac troponin T is independently prognostic in the validated staging
        model; the specific relationship to this modeled cardiac node is
        represented conservatively as partial correlation rather than causation.
  evidence:
  - reference: PMID:22331953
    reference_title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a multivariate model that included these characteristics as well as cTnT
      and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently
      prognostic for overall survival (OS).
    explanation: >-
      The staging cohort establishes troponin T as an independent prognostic
      biomarker.
treatments:
- name: Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone
  description: >-
    Subcutaneous daratumumab/hyaluronidase-fihj with bortezomib,
    cyclophosphamide, and dexamethasone (D-VCd) is the approved, evidence-based
    frontline regimen for most newly diagnosed patients. It is not recommended
    for Mayo cardiac stage IIIB or NYHA class IIIB/IV disease outside controlled
    clinical trials; eligibility and dosing also require attention to frailty and
    organ dysfunction.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: daratumumab
      term:
        id: NCIT:C74007
        label: Daratumumab
    - preferred_term: bortezomib
      term:
        id: CHEBI:52717
        label: bortezomib
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  regimen_term:
    preferred_term: Bortezomib/Cyclophosphamide/Daratumumab/Dexamethasone regimen
    term:
      id: NCIT:C181577
      label: Bortezomib/Cyclophosphamide/Daratumumab/Dexamethasone Regimen
  target_mechanisms:
  - target: Amyloidogenic Plasma-Cell Clone
    treatment_effect: INHIBITS
    description: The regimen suppresses the clonal cells that produce the pathogenic light chain.
    evidence:
    - reference: PMID:33099432
      reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Treatment directed at the clonal cells eliminates light chain production
        and further deposition and may enable organ improvement and decrease the
        risk of organ failure.
      explanation: >-
        This review supports the clone as the mechanistic target of systemic AL
        therapy.
  - target: Amyloidogenic Monoclonal Free Light-Chain Production and Secretion
    treatment_effect: INHIBITS
    description: Clone suppression rapidly reduces production of the amyloidogenic precursor.
    evidence:
    - reference: PMID:33099432
      reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Treatment directed at the clonal cells eliminates light chain production
        and further deposition and may enable organ improvement and decrease the
        risk of organ failure.
      explanation: >-
        The source explicitly links clone-directed treatment to elimination of
        light-chain production.
  evidence:
  - reference: PMID:42118698
    reference_title: "Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone in Newly Diagnosed Amyloidosis: ANDROMEDA Final Survival Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With a median follow-up of 61.4 months, significant improvement was
      observed with D-VCd versus VCd in major organ
      deterioration-progression-free survival (hazard ratio, 0.44; 95% CI,
      0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI,
      0.42-0.90; P=0.0121).
    explanation: >-
      The final randomized-trial analysis demonstrates both organ-deterioration
      and overall-survival benefit.
  - reference: PMID:34192431
    reference_title: "Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with newly diagnosed AL amyloidosis, the addition of
      daratumumab to bortezomib, cyclophosphamide, and dexamethasone was
      associated with higher frequencies of hematologic complete response and
      survival free from major organ deterioration or hematologic progression.
    explanation: >-
      The primary ANDROMEDA publication supports the four-drug regimen and its
      hematologic and organ-progression outcomes.
- name: High-Dose Melphalan with Autologous Stem-Cell Transplantation
  description: >-
    High-dose melphalan followed by autologous hematopoietic stem-cell
    transplantation is a separate clone-directed strategy for carefully selected
    fit patients; it is not a generic option for every patient with systemic AL.
  action_category: THERAPEUTIC
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: autologous hematopoietic stem cell transplantation
    term:
      id: NCIT:C16039
      label: Autologous Hematopoietic Stem Cell Transplantation
    therapeutic_agent:
    - preferred_term: melphalan
      term:
        id: NCIT:C633
        label: Melphalan
  target_mechanisms:
  - target: Amyloidogenic Plasma-Cell Clone
    treatment_effect: INHIBITS
    description: High-dose therapy suppresses the clonal source of amyloidogenic light chains.
    evidence:
    - reference: PMID:30361521
      reference_title: "Systemic immunoglobulin light chain amyloidosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Several new classes of drugs, such as proteasome inhibitors and
        immunomodulatory drugs, along with high-dose chemotherapy and autologous
        haematopoietic stem cell transplantation, have led to rapid and deep
        suppression of amyloid light chain production in the majority of
        patients.
      explanation: >-
        The review directly links high-dose chemotherapy and autologous
        transplantation to suppression of amyloid light-chain production.
  evidence:
  - reference: PMID:34783272
    reference_title: "Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      High dose intravenous melphalan and autologous stem cell transplantation
      was developed for the treatment of AL amyloidosis in the early 1990s and
      was prompted by its success in multiple myeloma.
    explanation: >-
      The specialty guideline establishes high-dose melphalan with autologous
      transplantation as a systemic AL treatment strategy.
- name: Supportive Organ-Directed Care
  description: >-
    Individualized supportive care treats symptoms and complications of cardiac,
    renal, neurologic, gastrointestinal, and soft-tissue involvement while
    clone-directed therapy takes effect. Specific interventions depend on the
    affected organ and treatment tolerance.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Congestive Heart Failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  - preferred_term: Autonomic Dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  - preferred_term: Gastrointestinal Dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
  evidence:
  - reference: PMID:33099432
    reference_title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive care manages the symptoms of organ involvement and the side
      effects of treatment.
    explanation: >-
      The supportive-care review directly supports symptom- and
      treatment-toxicity management without overprescribing a single protocol.
- name: Individualized Therapy for Relapsed Disease
  description: >-
    Relapsed systemic AL has no single universal salvage regimen. Selection among
    anti-CD38, proteasome-inhibitor, immunomodulatory, alkylator-based, and
    selected transplant approaches depends on the depth and duration of the
    initial response, prior drug-class exposure, fitness or frailty, and end-organ
    dysfunction. A previously unused active class is generally preferred when
    feasible; venetoclax remains a separate investigational option for selected
    t(11;14)-positive disease.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Amyloidogenic Plasma-Cell Clone
    treatment_effect: INHIBITS
    description: Salvage therapy is selected to regain suppression of the pathogenic clone after relapse.
    evidence:
    - reference: PMID:35838162
      reference_title: "Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        At relapse, the two guiding principles are the depth and duration of
        initial response, use of a class of agents not previously exposed as well
        as the limitation imposed by patients' fitness/frailty and end organ
        damage.
      explanation: >-
        The specialty guideline directly supports individualized, exposure-aware
        relapse selection constrained by patient fitness and organ damage.
  evidence:
  - reference: PMID:35838162
    reference_title: "Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At relapse, the two guiding principles are the depth and duration of initial
      response, use of a class of agents not previously exposed as well as the
      limitation imposed by patients' fitness/frailty and end organ damage.
    explanation: >-
      The guideline defines the principal decision factors for relapse therapy;
      named drug classes are examples within that individualized framework.
- name: Venetoclax for Relapsed t(11;14)-Positive Disease
  description: >-
    Venetoclax has produced deep hematologic responses in retrospective relapsed
    or refractory cohorts enriched for somatic t(11;14), but remains off-label
    and investigational in systemic AL pending prospective randomized
    confirmation.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: venetoclax
      term:
        id: CHEBI:133021
        label: venetoclax
  target_mechanisms:
  - target: Amyloidogenic Plasma-Cell Clone
    treatment_effect: INHIBITS
    description: Venetoclax can suppress susceptible t(11;14)-positive plasma-cell clones.
    evidence:
    - reference: PMID:33431806
      reference_title: "Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        t(11;14) patients had higher hematologic response (81% vs. 40%) and
        higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62)
        than non-t(11;14) patients.
      explanation: >-
        The retrospective response association supports clone suppression in the
        selected cytogenetic subgroup but is not randomized mechanistic evidence.
  evidence:
  - reference: PMID:33431806
    reference_title: "Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These promising results require confirmation in a randomized clinical
      trial.
    explanation: >-
      The authors explicitly bound the retrospective results and support the
      investigational label.
  - reference: PMID:35838162
    reference_title: "Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Targeted agents like venetoclax need urgent prospective evaluation.
    explanation: >-
      The specialty guideline confirms that prospective evaluation is still
      required.
clinical_trials:
- name: NCT03201965
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ANDROMEDA randomized newly diagnosed systemic AL patients to D-VCd or VCd;
    registry completion was independently verified on 2026-07-18, and efficacy
    is represented above from the peer-reviewed trial publications.
  evidence:
  - reference: clinicaltrials:NCT03201965
    reference_title: "A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD)
      compared with CyBorD alone in treatment of newly diagnosed amyloid light
      chain (AL) amyloidosis participants.
    explanation: >-
      The cached registry summary supports the randomized comparison; completion
      status was verified against the live registry.
- name: NCT04512235
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    CARES evaluates CAEL-101 added to plasma-cell-directed therapy in patients
    labeled "Mayo stage IIIa" by the registry. This trial label follows the
    European-modified cardiac convention, not a substage of the modeled Mayo 2012
    score. Active-not-recruiting status was independently verified on 2026-07-18.
  evidence:
  - reference: clinicaltrials:NCT04512235
    reference_title: "A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIa AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary purpose of this study is to determine whether CAEL-101, a
      monoclonal antibody that removes AL amyloid deposits from tissues and
      organs, improves overall survival, reduces cardiovascular related
      hospitalizations and it is safe and well tolerated in patients with stage
      IIIa AL amyloidosis.
    explanation: >-
      The cache supports trial purpose and population, not efficacy; live status
      was independently verified.
- name: NCT04504825
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    CARES evaluates CAEL-101 added to plasma-cell-directed therapy in patients
    labeled "Mayo stage IIIb" by the registry. This trial label follows the
    European-modified cardiac convention, not a substage of the modeled Mayo 2012
    score. Active-not-recruiting status was independently verified on 2026-07-18.
  evidence:
  - reference: clinicaltrials:NCT04504825
    reference_title: "A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary purpose of this study is to determine whether CAEL-101, a
      monoclonal antibody that removes AL amyloid deposits from tissues and
      organs, improves overall survival, reduces cardiovascular related
      hospitalizations and it is safe and well tolerated in patients with stage
      IIIb AL amyloidosis.
    explanation: >-
      The cache supports trial purpose and population, not efficacy; live status
      was independently verified.
- name: NCT06022939
  phase: PHASE_III
  status: RECRUITING
  description: >-
    This phase III study compares D-VCd induction followed by melphalan/autologous
    transplantation with D-VCd consolidation and daratumumab maintenance in newly
    diagnosed AL. Recruiting status was independently verified on 2026-07-18.
  evidence:
  - reference: clinicaltrials:NCT06022939
    reference_title: "A Phase III, Randomized Study of Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone (Dara-VCD) Induction Followed by Autologous Stem Cell Transplant or Dara-VCD Consolidation and Daratumumab Maintenance in Patients With Newly Diagnosed AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phase III trial compares the effect of adding a stem cell transplant
      with melphalan after completing chemotherapy with daratumumab,
      cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy
      with Dara-VCD alone for treating patients with newly diagnosed amyloid light
      chain (AL) amyloidosis.
    explanation: >-
      The cache supports the randomized treatment comparison; live recruiting
      status was independently verified.
- name: NCT04973137
  phase: PHASE_III
  status: TERMINATED
  description: >-
    AFFIRM-AL evaluated birtamimab plus standard care in Mayo stage IV AL and was
    terminated after not meeting its primary endpoint; termination status and
    registry reason were independently verified on 2026-07-18.
  evidence:
  - reference: clinicaltrials:NCT04973137
    reference_title: "A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects With Light Chain (AL) Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Phase 3 study to evaluate the efficacy and safety of birtamimab plus
      standard of care compared to placebo plus standard of care in Mayo Stage IV
      patients with AL amyloidosis.
    explanation: >-
      The cache supports trial design; live registry review established the
      terminated status and stated failure of the primary endpoint.
discussions:
- discussion_id: gap_al_advanced_cardiac_therapy
  prompt: >-
    Which strategies can rapidly improve survival and cardiac function in
    systemic AL patients presenting with advanced cardiac involvement while
    clone-directed therapy reduces new light-chain production?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Myocardial Stiffening and Diastolic Dysfunction
  - pathophysiology#Soluble Amyloidogenic Light-Chain Cardiotoxicity
  rationale: >-
    Advanced cardiac disease remains a major unmet need. CAEL-101 phase III
    programs remain active but closed to new enrollment, while the confirmatory
    birtamimab phase III trial was terminated after missing its primary endpoint;
    no fibril-clearing strategy should therefore be represented as established.
  evidence:
  - reference: PMID:30361521
    reference_title: "Systemic immunoglobulin light chain amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, effective therapies for patients with advanced cardiac involvement
      are an unmet need.
    explanation: >-
      The review explicitly identifies the advanced-cardiac treatment gap.
  - reference: clinicaltrials:NCT04512235
    reference_title: "A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIa AL Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary purpose of this study is to determine whether CAEL-101, a
      monoclonal antibody that removes AL amyloid deposits from tissues and
      organs, improves overall survival, reduces cardiovascular related
      hospitalizations and it is safe and well tolerated in patients with stage
      IIIa AL amyloidosis.
    explanation: >-
      The registry describes an ongoing investigational deposit-directed
      strategy but does not establish benefit.
  - reference: clinicaltrials:NCT04973137
    reference_title: "A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects With Light Chain (AL) Amyloidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Phase 3 study to evaluate the efficacy and safety of birtamimab plus
      standard of care compared to placebo plus standard of care in Mayo Stage IV
      patients with AL amyloidosis.
    explanation: >-
      The registry cache supports the confirmatory trial design; its terminated
      status was independently verified and prevents portraying the agent as
      established.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
references:
- reference: "DOI:10.3389/frhem.2024.1378451"
  title: "AL amyloidosis: an overview on diagnosis, staging system, and treatment"
- reference: "PMID:20150510"
  title: "Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway."
- reference: "PMID:22331953"
  title: "Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements."
- reference: "PMID:23091105"
  title: "New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes."
- reference: "PMID:25115890"
  title: "A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis."
- reference: "PMID:29700090"
  title: "Cardiac amyloidosis."
- reference: "PMID:30361521"
  title: "Systemic immunoglobulin light chain amyloidosis."
- reference: "PMID:30713046"
  title: "Incidence of AL Amyloidosis in Olmsted County, Minnesota, 1990 through 2015."
- reference: "PMID:30834260"
  title: "Mass Spectrometry Amyloid Typing Is Reproducible across Multiple Organ Sites."
- reference: "PMID:30894526"
  title: "Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis."
- reference: "PMID:33099432"
  title: "Supportive Care for Patients with Systemic Light Chain Amyloidosis."
- reference: "PMID:33431806"
  title: "Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis."
- reference: "PMID:34192431"
  title: "Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis."
- reference: "PMID:34783272"
  title: "Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines."
- reference: "PMID:35481407"
  title: "The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement."
- reference: "PMID:35838162"
  title: "Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group."
- reference: "PMID:38923548"
  title: "Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis."
- reference: "PMID:38960850"
  title: "Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects."
- reference: "PMID:41460224"
  title: "Detection yield of surrogate tissue biopsies across amyloidosis classes: a large-scale analysis of 4,027 patients."
- reference: "PMID:41592868"
  title: "American Society of Hematology (ASH) 2026 Guidelines on Diagnosis of Light Chain Amyloidosis."
- reference: "PMID:41954624"
  title: "Determinants of gastrointestinal disease burden and survival in systemic AL amyloidosis."
- reference: "PMID:42005116"
  title: "Rheumatological Manifestations of Systemic Amyloidosis: A Retrospective Single-Centre Study From a Tertiary Care Hospital in India."
- reference: "PMID:42118698"
  title: "Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone in Newly Diagnosed Amyloidosis: ANDROMEDA Final Survival Analysis."
- reference: "clinicaltrials:NCT03201965"
  title: "A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis"
- reference: "clinicaltrials:NCT04504825"
  title: "A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis"
- reference: "clinicaltrials:NCT04512235"
  title: "A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIa AL Amyloidosis"
- reference: "clinicaltrials:NCT04973137"
  title: "A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects With Light Chain (AL) Amyloidosis"
- reference: "clinicaltrials:NCT06022939"
  title: "A Phase III, Randomized Study of Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone (Dara-VCD) Induction Followed by Autologous Stem Cell Transplant or Dara-VCD Consolidation and Daratumumab Maintenance in Patients With Newly Diagnosed AL Amyloidosis"
datasets:
- accession: geo:GSE175386
  title: Tumor cells in light-chain amyloidosis and multiple myeloma show different transcriptional rewiring of the normal plasma cell development
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 141
  publication: PMID:34133718
  notes: Identified by GEO DataSets index search for Systemic AL Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE292189
  title: Single cell and clonal analysis of AL amyloidosis plasma cells and their bone marrow microenvironment
  description: AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5’ single cell RNA sequencing on 9 newly diagnosed, treatment naive AL amyloidosis patients and 8 healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of CD16 monocytes and subsets of CD4+ T cells in AL amyloidosis patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 52
  publication: PMID:40493887
  notes: Identified by GEO DataSets index search for Systemic AL Amyloidosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: massive:MSV000090875
  title: Protein profiles of fat biopsies from patients affected by AL amyloidosis and healthy controls.
  description: Abdominal subcutaneous adipose tissue protein profiles from control subjects, and ALK (Kappa) and ALL (Lambda) amyloidosis patients. Raw data were acquired by LTQ, Orbitrap and QExactive instruments. For major chromatographic details refers to doi:10.1182/blood-2011-07-365510, doi:10.3109/13506129.2012.674989, doi:10.3390/molecules26071913.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("AL Amyloidosis"). Retrieved 2026-08-02.

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