Clinical features of systemic amyloidosis: a scoping review

Key Points

• •This scoping review maps the earliest clinical signs of AL, ATTRwt, and ATTRv amyloidosis to improve early recognition and diagnosis.
• •Distinct red flags across organ systems highlight missed diagnostic opportunities and specialty-specific presentation patterns.

Visual Abstract

Abstract

Systemic amyloidosis is a rare, multisystem disorder that is often challenging to diagnose due to vague and nonspecific symptoms that frequently overlap with other disorders. By the time patients are diagnosed, irreversible organ impairment from amyloid deposition occurrs, contributing to substantial morbidity and mortality. Although developing the American Society of Hematology (ASH) guidelines on systemic amyloidosis, we identified a critical knowledge gap in the recognition of the clinical presentation of its most common subtypes. Therefore, we conducted a scoping review of 117 studies following PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines to identify clinical “red flags” for light chain (AL) and transthyretin (ATTR; wild-type [ATTRwt] and hereditary [ATTRv]) amyloidosis. Studies were identified from the comprehensive systematic review through the ASH amyloidosis diagnosis guideline panel, data mining, and gray literature review. Data were extracted and synthesized by systems to characterize the earliest and most frequently overlooked clinical red flags for the different types of amyloidosis. Shortness of breath and fatigue, the earliest symptoms of AL amyloidosis, contrast with the carpal tunnel syndrome occurring years before ATTRwt cardiac amyloidosis is diagnosed. Weight loss, unexplained abdominal pain, and early satiety were overlooked red flags for AL amyloidosis, compared to the preceding arrhythmias often missed in evaluation for ATTRwt amyloidosis. Sensory loss was the predominant neuropathic presentation for AL amyloidosis compared to the painful length-dependent neuropathy of ATTRv amyloidosis. Awareness of the early symptoms and distinct patterns across subtypes can enhance cross-specialty awareness and support earlier diagnosis and intervention of AL and ATTR amyloidosis.

Introduction

Systemic amyloidosis causes significant morbidity, a marked decline in patient quality of life, and in cases of advanced cardiac involvement, can be fatal.1, 2, 3 Over 42 types of amyloidosis have been identified, with at least 19 implicated in systemic disease.4, 5, 6 Light chain (AL) amyloidosis and transthyretin amyloidosis (ATTR) are the most common; the latter is subclassified as wild-type (ATTRwt) and hereditary (ATTRv).4, 5, 6

The challenging patient journey and the difficulty clinicians face in reaching the diagnosis are well described.^2,7,8 Initial symptoms are often vague, and presentation may vary depending on organ involvement.^2,4,8,9 By the time the diagnosis is made, irreversible organ impairment has occurred.^2,3,7 Systemic amyloidosis remains underrecognized, underscoring a persistent knowledge gap that motivated this scoping review. Scoping reviews analyze and map the available literature and define gaps.10, 11, 12

In 2023, the American Society of Hematology (ASH) launched the process to create clinical practice guidelines for the diagnosis of systemic AL amyloidosis. Early in the process, we identified a gap in the literature regarding the symptoms and signs, colloquially referred to as “red flags,” that should trigger consideration of systemic amyloidosis as a diagnosis. To address this, we conducted a scoping review to synthesize the available literature for the major types of systemic amyloidosis. Our goal was to compare the clinical presentations and highlight distinguishing features, to raise awareness for clinicians and patients regarding the clinical features and key red flags associated with systemic AL, ATTRwt, and ATTRv amyloidosis.

Methods

We conducted this scoping review according to the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist.¹³

Search strategy and data sources

We identified studies addressing the signs, symptoms, and findings of amyloidosis through multiple methods. Studies were identified during a comprehensive review of specific questions prioritized by the ASH amyloidosis diagnosis guideline panel (supplemental Table 1). This search was conducted on PubMed, Embase, and Cochrane databases, including targeted searches of landmark studies (data mining) and gray literature.¹⁴

Eligibility criteria

The review included studies that provided insights into the clinical presentation of adult patients with systemic amyloidosis. These studies included AL, ATTRwt, and ATTRv amyloidosis. We excluded secondary amyloidosis or amyloid serum A protein (AA) amyloidosis. The scoping review included all published articles regardless of publication date, and conference abstracts reported within 3 years before the start of this work, which commenced in October 2023. Systemic amyloidosis is a rare disease, so some articles that included untyped or unspecified amyloidosis were incorporated in the larger composite analysis, particularly if the presentation aligned with either AL or ATTR amyloidosis. The review excluded articles that focused on tests to confirm the diagnosis of systemic amyloidosis, biomarkers to differentiate the different subtypes, studies on risk stratification, prognosis, and predictors of survival, narrative or literature reviews, and non-English reports.

Review methods

All articles from the ASH amyloidosis guideline systematic review were uploaded into Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia).¹⁵ Initial title and abstract screening were performed in duplicate by J.C. and H.S. Data mining was performed by J.C. to include other landmark articles.¹⁴ Articles were distributed among all authors to assess eligibility for inclusion after full-text screening, along with data extraction. For studies with conflicting decisions, J.C. and H.S. reviewed the article to finalize eligibility. Reviewers performed data extraction using a standardized form to capture information on general study characteristics, presenting symptoms, physical examination, laboratory and imaging, and key findings.

Gray literature

A review of gray literature in the public domain was conducted to determine the patient-facing information on the abovementioned 3 types of amyloidosis. This online exploration included amyloidosis patient advocacy organizations and tertiary amyloidosis treatment centers.

Data synthesis

J.C. and H.S. synthesized the results qualitatively to identify common patterns of symptoms and diagnostic findings across different types of amyloidosis. Data was organized by organ involvement, with ranges reported to capture the variability in the frequency of signs and symptoms across studies. J.C. and H.S. systematically contrasted findings across amyloidosis subtypes, focusing on data specific to AL, ATTRwt, and ATTRv in a targeted subanalysis. Only studies with a median frequency ≥20% with ≥15 participants were included in this more specific comparative frequency analysis. For descriptive statistical analysis, JMP version 17 was used. Pooled median and mean estimates were calculated as unweighted averages, whereas standard deviations and variances were reported to reflect data spread. Data were presented as both medians and means.

Results

An overview of the study process and PRISMA diagram is shown in Figure 1. A total of 565 publications were identified, of which 80 were sourced through data mining. After removal of 33 duplicates, a further 267 articles were excluded as they did not meet the eligibility criteria. The full texts of 253 studies were then reviewed in detail to assess eligibility, of which 117 studies were included in this scoping review (supplemental Table 2). Results below are organized by organ system to reflect how patients present, and we compare features of AL, ATTRwt, and ATTRv amyloidosis to highlight disease-specific patterns (Table 1).

Figure 1.

PRISMA diagram.

Table 1.

Comparative summary of initial symptoms, physical examination findings, and diagnostic workup across amyloidosis subtypes

AL amyloid				ATTRwt amyloid				ATTRv amyloid
Earliest symptoms (No. of studies)	Median frequency reported	Range frequency reported	No. of patients	Earliest symptoms (No. of studies)	Median frequency reported	Range frequency reported	No. of patients	Earliest symptoms (No. of studies)	Median frequency reported	Rangefrequency reported	No. of patients
Dyspnea (N = 3)1,8,16	62.9%	30%-92%	504	Edema/volume overload (N = 4)17, 18, 19, 20	68%	45%-100%	527	Sensory or motor peripheral neuropathy (N = 15)21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33	75%	23%-100%	2810
Edema/volume overload (N = 5)8,16,19,34,35	33%	25%-81%	618	CTS (N = 5)18, 19, 20,36,37	62%	43%-100%	682	Autonomic dysfunction (N = 5)26,28,31, 32, 33	53.4%	32%-100%	752
Fatigue (N = 4)1,8,34,38	57%	57%-81%	641					Edema/volume overload (N = 3)27,33,39	63%	26%-100%	384
Weight loss (N = 5)1,8,35,38,40	36%	28%-42%	716
Most common physical examination findings	Median frequency reported	Range frequency reported	No. of patients	Most common physical examination findings	Median frequency reported	Range frequency reported	No. of patients	Most common physical examination findings	Median frequency reported	Range frequency reported	No. of patients
Heart failure (elevated JVP, S3, S4, rales) (N = 7)1,16,18,38,41, 42, 43	78%	54%-100%	1133	Heart failure (elevated JVP, S3, S4, rales) (N = 10)17,18,43, 44, 45, 46, 47, 48, 49	68%	20%-100%	957	Heart failure (elevated JVP, S3, S4, rales) (N = 4)42,43,50,51	54%	47%-61%	350
				Hypertension (N = 8)17,18,43,44,46, 47, 48, 49,52	65%	43%-92%	831	Orthostatic hypotension/autonomic neuropathy (N = 4)21,23,50,53	43.7%	30%-90%	600
				Atrial fibrillation (N = 8)41,43,46,48,52, 53, 54, 55	49%	37%-63%	560	Small and/or large fiber neuropathy (N = 5)21,23,30,50,56	42%	20%-100%	904
				Evidence of carpal tunnel (N = 4)17,44,49,54	33%	22%-49%	198
Investigations leading to amyloid diagnosis	Median frequency reported	Range frequency reported	No. of patients	Investigations leading to amyloid diagnosis	Median frequency reported	Range frequency reported	No. of patients	Investigations leading to amyloid diagnosis	Median frequency reported	Range frequency reported	No. of patients
EKG: pseudoinfarct pattern43,57 (N = 3)	50%	29%-71%	242	Elevated NT-proBNP∗,17,18,37,43,58 (N = 5)	—	—	722	Echocardiography: LVH21,33,39 (N = 3)	78.5%	60%-100%	214
EKG: low voltage16,43,57 (N = 3)	50%	29%-71%	502	EKG: conduction block26 (N = 1)	73%	73%	67	EKG: pseduoinfarct pattern33,50,53 (N = 3)	35%	24%-57%	512
Proteinuria, nephrotic range38,59 (N = 2)	65.4%	42%-89%	176	EKG: pseudoinfarct pattern17,43,60 (N = 3)	36%	24%-64%	120	EKG: low voltage43,50,53(N = 3)	39%	24%-67%	504
Elevated NT- proBNP34,61(N = 2)	88%	87%- 89%	139	EKG: low voltage43,60 (N = 2)	24%	22%-26%	367	Small fiber testing (abnormal)62,63 (N = 2)	49.5%	42%-57%	88
Frequent reported symptoms	Median frequency reported	Range frequency reported	No. of patients	Frequent reported symptoms	Median frequency reported	Range frequency reported	No. of patients	Frequent reported symptoms	Median frequency reported	Range frequency reported	No. of patients
Shortness of breath8,16,57,64,65 (N = 5)	50%	37%-92%	787	Shortness of breath ± edema17,66,67 (N = 3)	45%	31%-68%	250	Sensory loss or paresthesias26,50,68, 69, 70 (N = 5)	73.3%	60%-86%	1015
Sensory loss†,8,71 (N = 2)	51.5%	20%-83%	424	CTS17,36,66 (N = 3)	33.2%	25%-55%	392	Autonomic symptoms‡,21,26,32,33,50,68 (N = 6)	59.2%	13%-90%	1127
Autonomic symptoms71,72 (N = 2)	62%	53%-71%	190					Shortness of breath ± edema22,26 (N = 2)	64%	42%-86%	661
								Neuropathic pain22,23,32 (N = 3)	46.5%	24%-68%	388
Most common missed symptoms	Median frequency reported	Range frequency reported	No. of patients	Most common missed symptoms	Median frequency reported	Range frequency reported	No. of patients	Most common missed symptoms	Median frequency reported	Range frequency reported	No. of patients
Unintentional weight loss8,57,64,71,73,74 (N = 6)	37%	26%-83%	348	Atrial fibrillation18,26 (N = 2)	42%	26%-58%	341	Erectile dysfunction21,33,75 (N = 3)	40%	2.2%-84%	165
Abdominal pain73,74 (N = 2)	38%	23%-53%	70	Arrythmia requiring pacemaker or ICD18,26,60 (N = 3)	26%	22%-44%	461	Altered bowel habits§,33,68,69,76 (N = 4)	35%	23%-63%	1831
Early satiety8,57 (N = 2)	35.5%	23%-48%	225					Urinary incontinence53,75 (N = 2)	41.5%	23%-50%	201
								Arrythmia requiring pacemaker21,26 (N = 2)	31%	26%-36%	1669

Only findings with ≥15 cases and ≥20% frequency are included to ensure stable, clinically meaningful estimates.

EKG, electrcardiogram; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

^∗Median and frequency values were not pooled due to heterogeneity in NT-proBNP assays and reporting ranges. Studies mentioned either median or mean level of NT-proBNP in the patients.

^†Sensory loss includes numbness or loss of sensation without pain or paresthesia.

^‡Autonomic dysfunction: orthostatic hypotension, erectile dysfunction, and diarrhea and/or constipation are most frequently observed, with lower rates of urinary dysfunction, sweating abnormalities, and dry eye and mouth.

^§Altered bowel habits refers to constipation and/or diarrhea.

Context of clinical presentation

The research originated across sites in Europe (n = 45 [40%]), the United States (n = 36 [32%]), and Asia (n = 14 [13%]) and were all from academic centers (n = 117 [100%]). Most of the research was retrospective (n = 96 [82%]), and the remainder (n = 21 [18%]) were prospective (Table 2). Available studies showed that patients were typically first evaluated by a cardiologist or neurologist, and less frequently by hematologists or nephrologists. At initial evaluation, cardiac involvement alone or in combination with another major organ was reported in 20 313 patients across 62 studies. Gastrointestinal (GI) and/or hepatic involvement was the next most common, noted in 2126 patients across 10 studies. The distribution of amyloidosis subtypes is summarized in Table 2. Studies reported age as median or mean; the pooled median age was 66.0 years (interquartile range, 60-74), and the pooled mean age was 60.4 years (standard deviation, 12.7) years.

Table 2.

Summary of study characteristics

Article	No. of studies 117	Patients with amyloid (N = 25 482), n (%)
Type of study
Prospective	21	2 438 (10)
Retrospective	96	23 044 (90)
Pathway of entry, academic	117	25 482 (100)
Subspecialty reporting
Cardiology	40	3 135 (12)
Cardiology and 1 other specialty∗	4	1 038 (4)
Neurology	11	577 (2)
Gastroenterology	6	190 (0.7)
Hematology	6	593 (2)
Nephrology	4	112 (0.4)
Other/multiple	46	19 837 (78)
Organ involvement at presentation
Cardiac only	48	4 469 (18)
Cardiac and 1 other major organ	12	15 844 (62)
GI/liver	10	2 126 (8)
Localized amyloid	5	53 (0.2)
MSK	7	221 (0.9)
Neurologic	12	607 (2)
Renal	5	115 (0.5)
≥ 2 organs	12	1 840 (7)
Other	6	207 (0.8)
Type of amyloid
AL	36	2 029 (8)
ATTRwt	12	542 (2)
ATTRv	17	1 798 (7)
ATTR (all types)	20	4 203 (16)
Other†	32	16 910 (66)
Males
AL	32	1 115 (61)
ATTRwt	19	1 282 (87)
ATTRv	22	2 067 (62)
ATTR (all types)	12	987 (79)
Other†	31	10 579 (65)
Studies reporting age (n = 49), median pooled age (interquartile range)
Entire cohort	66 (60-75)
AL	61 (59- 65)
ATTRwt	79 (71-82)
ATTRv	63 (56-67)
ATTR all types	76 (73-79)
Other	62 (57-68)
Studies reporting age (n = 36),‡mean pooled age (standard deviation)
Entire cohort	60 (12.9)
AL	55 (9.1)
ATTRwt	72 (4.5)
ATTRv	57 (10.4)
ATTR all types	78 (11)
Other	55 (14.3)

MSK, musculoskeletal.

^∗Additional specialties with cardiology included neurology, hematology, or nephrology ATTRwt.

^†Other included AL, ATTRwt, ATTRm, and other familial amyloid, or untyped amyloid presumed to be ATTRwt.

^‡Age was reported for 85 of the included studies; 32 studies did not report age.

Cardiac “red flags” for systemic amyloidosis

Patient presentation

There were 48 studies with cardiac predominant presentations for systemic amyloidosis, including 15 studies that focused on AL, 10 on ATTRwt, and 10 on ATTRv amyloidosis. Shortness of breath (30%-92%) and lower extremity edema (43%-81%) were the most common symptoms of cardiac amyloidosis (CA),^17,57,66,67,79, 78, 80, 81 followed by chest pain (7%-39%)^16,67 and syncope (8%-22%).^8,77 Carpal tunnel syndrome (CTS) occurred in 25%-55% of patients with CA, preceding heart symptoms by up to 9 years before the diagnosis.^{17,18,36,66,82} Patients with ATTRwt-CA reported a history of bilateral CTS more frequently than patients with AL-CA in 8 studies.^36,44,61,83, 84, 85, 86, 87 Patients with ATTR were typically older, with median or mean ages in the 80s; they frequently presented with heart failure with preserved ejection fraction, had a higher incidence of atrial fibrillation, and a history of bilateral CTS.^44,88 Patients with AL-CA were relatively younger, presenting in their 70s^44,88

Examination findings

Physical examination findings at presentation were mostly consistent with heart failure. Ejection fraction was preserved in up to 78% of patients across the 9 studies examined.16, 17, 18^,38,89, 90, 91, 92, 93 Physical findings reported included dyspnea (68%), elevated jugular venous pressure (52%), rales (54%), S3 (31%), and S4 (23%) on auscultation,^16,17 and organomegaly (38%), specifically hepatomegaly (52%).³⁸ Arrhythmias, most commonly atrial fibrillation, were the second most common clinical finding detected among patients with CA, reported in 20% to 62%.^16,90,91 In patients with AL, atrial fibrillation was identified on examination in only 10% to 20% of patients in 2 studies.^16,18 Hypotension, with or without postural orthostasis, was observed in up to 22% of all patients with CA, 14% to 22% in AL, and up to 20% in ATTR.^8,77,92,93

Investigations

Key electrocardiogram findings in CA often included low voltage (13%-71%) and a pseudoinfarct pattern (14%-71%).^{16,17,19,39,44,50,84,94} Complete atrioventricular (AV) block heralded the diagnosis of CA in rare cases.¹⁷ Echocardiographic hallmarks were reduced global longitudinal strain with or without relative sparing of the left ventricular (LV) apex, myocardial “granular sparkling” pattern (24%-92%), increased interventricular septum thickness (71%-100%), and a restrictive LV filling pattern (31%-77%).^45,95,96 Aortic stenosis was a notable association with ATTR-CA, with rates ranging from 7% to 16% across 5 studies.^{18,46,54,61,97} Among those with low-flow, low-gradient aortic stenosis, the prevalence of ATTR-CA was even higher; therefore, Technetium-99m pyrophosphate scintigraphy has been suggested as a screening test for ATTR-CA in this population.^46,61 Cardiac magnetic resonance imaging (MRI) most often revealed asymmetric LV hypertrophy (LVH) in CA. The asymmetrical septal hypertrophy was more prominent in ATTR-CA than among patients with AL-CA (79% vs 14%; P < .001).⁹⁸ Variability in LV wall thickness reflects the differences in imaging modalities, timing of assessment, and amyloidosis subtype.^44,88

Clinical course

Because of the nonspecific nature of these clinical signs and examination findings, misdiagnosis was common, with ∼30% of patients initially diagnosed with hypertensive or hypertrophic cardiomyopathy, or cardiac hypertrophy secondary to aortic stenosis.^18,61 Recognizing subtype-specific patterns can aid in differentiation. Although AL-CA and ATTRv-CA commonly present with systemic symptoms and multisystem involvement, ATTRwt is often limited to cardiac and musculoskeletal manifestations such as carpal tunnel and spinal canal stenosis.^18,38,93

Neurological “red flags” for systemic amyloidosis

Patient presentation

Twelve studies focused on neurologic presentations of systemic amyloidosis; 9 reported on ATTRv (predominantly Val30Met variant) and 3 on AL amyloidosis. Sensory neuropathy, typically described as paresthesia and pain, was reported in 45% to 100% of patients with ATTRv across 6 studies.21, 22, 23, 24, 25^,75 In AL amyloidosis, peripheral neuropathy was also a frequent initial complaint, affecting 36% of patients (153/424), with sensory loss reported in 20% to 83% and paresthesia in 25%.^40,99,100 Although sensory neuropathy is not considered a typical feature of ATTRwt, it was reported in 28% of patients in a large screening study of ATTR (n = 957, ATTRwt-67) and is possibly an underreported manifestation of ATTRwt amyloidosis.²⁶

Motor impairments were frequently described in ATTRv, with prevalence ranging from 8.3% to 93%. Early-onset phenotypes (<50 years of age) are more likely to present with small fiber and autonomic dysfunction, whereas later-onset phenotypes present with pansensory and sensorimotor impairments, including sensory ataxia, and multifocal deficits.^{21,62,68,75,101} Distal weakness, loss of tendon reflexes, and mobility impairments developed later in the clinical course.^21,23

Autonomic symptoms were reported in all studies of ATTRv amyloidosis, frequency ranging from 10% to 73%.^40,99,100 Similarly, in AL amyloidosis, autonomic neuropathy was reported in over half of the patients at presentation (53%-71%).^71,72 Autonomic symptoms described were postural instability, erectile dysfunction, constipation or alternating diarrhea and constipation, and early satiety consistent with gastroparesis. Weight loss can be seen among 37% to 83% of AL amyloidosis presentations due to autonomic GI dysmotility or direct amyloid infiltration.^{8,57,64,71,73,74}

Examination findings

Neurologic examination findings were elicited with more advanced AL amyloidosis, associated with features of multisystem involvement.⁸ Orthostatic hypotension (41%-80%)^34,40,99 and length-dependent sensory neuropathy (14%-90%)^1,40,99 were described in smaller cohorts. No included studies provided detailed neurological examination findings for ATTRv.

Investigations

Nerve conduction studies in both ATTRv and AL amyloidosis identified an axonal pattern sensorimotor neuropathy.⁹⁹ However, it should be noted that with isolated small fiber involvement,^62,63 traditional nerve conduction studies are frequently unremarkable. A demyelinating pattern of neuropathy is typically suggestive of alternative diagnoses, such as chronic inflammatory demyelinating polyneuropathy.

Clinical course

Amyloidosis-associated neuropathy progressed faster and included a higher burden of autonomic dysfunction compared to neuropathy related to other etiologies.^62,75 Late diagnosis and misdiagnosis are common for both AL and ATTRv amyloidosis, with up to 5 years of delay in diagnosis from symptom onset.^21,25 This delay is particularly observed in late-onset ATTRv variants, where <50% of individuals may have a known family history.^21,24,27 Amyloidosis-associated neuropathy was frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy, motor neuron disease, toxic and idiopathic neuropathy, lumbar canal stenosis, or primary cardiac or GI disease.^21,25,99

Renal “reg flags” for systemic amyloidosis

Patient presentation

Renal involvement is a common manifestation of systemic amyloidosis, but just 5 studies reported renal involvement as a red flag for systemic amyloidosis.102, 103, 104, 105, 106 Peripheral edema and foamy urine were cited as early symptoms in up to 30% of reported cases.¹ Patients frequently presented with volume overload.^34,99,107

Examination findings

None of the included studies specified physical examination findings associated with renal involvement.

Investigations

Nephrotic-range proteinuria was the most commonly reported laboratory pattern, identified in 33% to 68% of the included studies. AL amyloidosis was the most often cited cause of clinical renal amyloidosis.108, 109, 110, 111, 112 When patients with subnephrotic proteinuria (<3.5 g/24 hours) were included, proteinuria as the heralding sign of amyloidosis increased to 23% to 100%.108, 109, 110, 111 Renal impairment and renal failure were also noted as the first presentation of systemic amyloidosis (34%-42%).^1,104,105 In several instances, the diagnosis was only confirmed after a kidney biopsy.¹⁰⁵

Clinical course

Because of the insidious onset and overlap with cardiac volume overload symptoms, renal amyloidosis was often underrecognized until later in the disease course. Time from symptom onset to presentation was not elucidated, given the nonspecificity of the presentation. Notably, nephrotic syndrome has been described in ATTR amyloidosis, but in the included studies no data were specified on the prevalence of either ATTRwt or ATTRv.

GI and hepatic “red flags” of systemic amyloidosis

Patient presentation

GI amyloidosis usually signals systemic disease, and symptoms may precede diagnosis by 1 to 2 years.^73,113,114 Among the 10 included studies, AL amyloidosis was the most commonly reported subtype (80%). Most common symptoms of GI amyloidosis were unintentional weight loss (17%-72%),^{73,74,76,115,116} diarrhea (11%-81%),^{73,74,114,115,117} alternating diarrhea and constipation (18%-65%),^76,113 abdominal pain (9%-53%),^{73,74,114,115,117} bloating (81%),¹¹⁷ fatigue (60%),⁷³ and nausea/vomiting (6%-62%).^74,115,117 Some studies also described early satiety (18%-26%),^74,76 constipation (3%-31%),^116,117 and upper GI reflux/regurgitation (5%-9%).^74,114,115 In hepatic amyloidosis, symptoms were less specified in the literature, but fatigue (60%) and abdominal pain (53%) were most frequently described.⁵⁹

Examination findings

There were no specific examination findings described for GI amyloidosis. In hepatic AL amyloidosis, hepatomegaly (81%) was the most frequent examination finding, followed by ascites (42%).^73,116

Investigations

Anemia was reported in up to 75% of patients with GI amyloidosis, reflecting chronic disease, malabsorption, and suboptimal nutrition.^74,114, 115, 116^,118 Liver function test abnormalities were described in 3% to 80% of those with hepatic involvement, but were typically late findings.^73,116 Hypercholesterolemia, found in up to 80% of hepatic amyloidosis cases in a study, was less commonly evaluated.^73,116

Clinical course and outcomes

Symptoms started 1 to 2 years before the diagnosis.^73,113,114 Misdiagnosis was not systematically reported but is presumed to be common, particularly when GI symptoms were attributed to more prevalent GI disorders. Hepatomegaly may be seen in systemic amyloidosis without direct hepatic infiltration, reflecting passive congestion from cardiac involvement.⁵⁹ Approximately 10% of patients with CA could have mild elevation in aspartate transaminase and alkaline phosphatase values^59,119

Musculoskeletal “red flags” for systemic amyloidosis

Patient presentation

In 14 studies highlighting musculoskeletal presentations in ATTRwt, ATTRv, and AL amyloidosis, half were reported in association with CA.^36,47,82,84, 85, 86, 87 Patient ages ranged from 38 to 86 years. CTS was the most frequently reported tenosynovial manifestation, followed by biceps tendon rupture and spinal canal stenosis.^36,61,86,120 The interval from symptom onset to amyloidosis diagnosis was commonly delayed, with a lag time of 3 to 5 years.^36,37,85 CTS is a harbinger of CA, for both ATTR (wild-type and variant) and AL.^44,121 Bilateral CTS increases the likelihood of coexistent CA and is more likely to be linked to underlying ATTR-CA^37,85,122

Examination findings

Although formal physical examination findings were not uniformly reported, CTS was the most common tenosynovial abnormality. Bilateral CTS increases the likelihood of coexistent CA, particularly if echocardiographic findings of LVH are present.^37,85,122 Although CTS is not unique to amyloidosis, its presence in older males may prompt further assessment in the appropriate context.^37,123

Investigations

LVH on echocardiography was frequently observed among individuals with coexisting CA, increasing suspicion for ATTRwt.^37,85,122 Cardiac biomarker elevation in older males (>50 years) or abnormal technetium-labeled bone scintigraphy were also used to identify early cardiac involvement in patients with tenosynovial manifestations.^37,123 Individuals who were screened for CA following a diagnosis of CTS were often asymptomatic from a cardiovascular standpoint and demonstrated less advanced cardiac involvement compared to those diagnosed with ATTRwt-CA through conventional pathways.³⁷

Clinical course

CTS may precede the clinical onset of CA by 5 to 9 years.^37,82,85,121 Among individuals undergoing carpal tunnel release, concurrent CA is detected in only 1.2% to 4.5% of cases, underscoring the long preclinical window.^37,82,85,121

Multisystemic “red flags” for systemic amyloidosis

Patient presentation

Multisystem presentation was defined as involvement of ≥2 major systems (cardiac, renal, or liver/GI),¹²⁴ and for this scoping review, also included neurologic and musculoskeletal systems. A multisystem pattern of involvement was most frequently observed in AL amyloidosis. In these cases, fatigue (60%-70%), shortness of breath (50%-52%), and edema (39%-61%) were frequently reported at initial presentation.^1,8,34,35 Diarrhea (21%-79%) and autonomic symptoms such as orthostatic hypotension or erectile dysfunction (52.9%) were among the earliest reported complaints.^8,35,72 In contrast, predominant peripheral neuropathy was the presenting symptom in only 28% of patients and typically emerged later in the clinical course.^8,35,72 Extensive cardiac involvement (42%-76%) often reflected a delayed diagnosis; earlier multisystem manifestations were missed or misattributed.^1,8,35 In ATTRwt amyloidosis, true multisystem presentations were less frequently reported. Symptoms were primarily cardiac, often accompanied by a preceding history of CTS.^2,26,83

ATTRv presentation was more heterogeneous. Five studies highlighted that clinical symptoms varied by specific mutations and penetrance. In some cohorts, autonomic, sensory, or motor neuropathies were the dominant early complaints in 23% to 100% of individuals.^2,24,26, 27, 28^,50,125,126 Multisystem features included mixed cardiac and neurologic symptoms in 25% to 48% of patients.^{2,26,27,50,125,126} Between 13% to 30% presented with cardiac symptoms without neuropathy.^27,125 CTS was less frequent (8%-18%) than in ATTRwt cohorts.^27,28 Autonomic dysfunction frequently manifests as GI symptoms, including changes in bowel habits, delayed gastric emptying, or steatorrhea.^24,26,125

Examination findings

Clinical findings included signs of volume overload and arrhythmias identified on examination.^{1,34,35,72,127} Hepatomegaly and signs of orthostatic hypotension were variably noted in those with hepatic or autonomic involvement, respectively, but not consistently across studies.

Investigations

For AL amyloidosis, the presence of monoclonal protein was a consistent finding. In many cases, a small M-spike (<1 g/dL) was detected via serum electrophoresis; serum-free light chains may be within reference ranges.^34,35 Nephrotic-range proteinuria was identified in 32% to 64% of patients, often serving as early diagnostic clues.^{1,34,35,72,127} Renal impairment with reduced estimated glomerular filtration rate (eGFR) is a less frequent initial finding, typically emerging in the setting of nephrotic syndrome, where it is seen in up to 34% of cases.³⁴ There was no consistent thematic presentation of laboratory findings heralding ATTRwt or ATTRv.

Cardiac evaluations were the most frequently pursued across all subtypes of systemic amyloidosis. Investigations such as electrocardiogram (EKG), echocardiogram, and cardiac MRI were done to establish the diagnosis.^2,53,125 On EKG, low voltage (11%-24%) and pseudoinfarct (17%-24%) patterns were observed.^50,128 Echocardiography commonly revealed increased intraventricular septum thickness.^1,125,128 Abnormal cardiac MRI was reported in 25% to 28%; histologic confirmation via endomyocardial biopsy was required in cases of ambiguous noninvasive findings.^1,83,128

Clinical course

No additional data specific to clinical course, trajectory, or diagnostic delays were reported in the studies addressing multisystem presentations.

Localized presentations of amyloidosis

Five of the included studies described presentation with localized amyloidosis, without systemic involvement.129, 130, 131, 132, 133 The presentation varied depending on the site of involvement, and no consistent patterns were elicited. Other notable publications have described the diverse and site-specific presentations of localized amyloidosis, which may occur virtually anywhere in the body.^134,135

Comparative clinical features across systemic amyloidosis subtypes

In a targeted subanalysis, the major clinical features across systemic amyloidosis subtypes were compared, focusing on symptom onset, examination findings, investigations, and commonly missed presentations, as summarized in Table 1. These are visually represented by the heat map in Figure 2.

Figure 2.

Heat map comparison of presenting symptoms, examination findings, and missed clues in amyloidosis subtypes. (A) Heat maps showing the frequency of earliest complaints, frequent complaints, and overlooked or ignored symptoms in AL, ATTRwt, and ATTRv amyloidosis. (B) Heat map of common physical examination findings across AL, ATTRwt, and ATTRv amyloidosis. HF, heart failure; HTN, hypertension; VS, vital signs; PPM/ICD, permanent pacemaker/implantable cardioverter-defibrillator.

Patient-facing information

The patient-focused literature (gray literature) for AL and ATTR amyloidosis was reviewed by our patient advocate (D.B.) with a view to the relevance of the available patient information.136, 137, 138, 139, 140 These websites portrayed symptoms of either AL or ATTR amyloidosis with graphical illustrations and symptom descriptors. The information was easily accessible, included the most common symptoms, and used nonmedical terminology. In review of the gray literature and literature reviews, no single publication offered a comprehensive discussion from a patient perspective.

Discussion

To our knowledge, this is the first comprehensive scoping review to critically characterize the clinical “red flags” for AL, ATTRwt, and ATTRv amyloidosis, distinguishing the earliest, most frequent, and commonly overlooked symptoms, examination findings, and investigations.

ATTRwt amyloidosis rarely presents with multisystem involvement; restrictive cardiomyopathy is most common, and CTS, preceding CA in 25% to 55% is a distinct early indicator compared with ATTRv or AL types (Table 1; Figure 2). Bilateral CTS may warrant cardiac screening.^37,141 Systemic arterial hypertension was another notable association for ATTRwt.

Although periorbital purpura and macroglossia strongly suggest AL amyloidosis, these are less common and delayed signs; patients more commonly report shortness of breath, fatigue, and edema early in the course (Figure 2).⁸ Sensorimotor neuropathy and autonomic symptoms were early signs of ATTRv amyloidosis, contrasting with AL and ATTRwt amyloidosis (Table 1). The earliest symptoms, often obscure, contrast with the frequently reported symptoms, which are reported later in the clinical course (Table 1; Figure 2).⁸ Frequently reported symptoms for AL amyloidosis included sensory dysfunction and autonomic symptoms, CTS, and sensory neuropathy for ATTRv amyloidosis, and CTS for ATTRwt. Cardiac symptoms and signs were the most frequent and some of the earliest manifestations for AL, ATTRwt, and ATTRv amyloidosis (Figure 2).

Missed “red flags” for AL amyloidosis included unintentional weight loss, early satiety, and abdominal discomfort (Table 1).^{8,38,59,74,99,142} For ATTRwt, overlooked indicators were new-onset atrial fibrillation or other arrhythmias requiring pacing.^18,26,143 Thickened myocardium can be misattributed to hypertrophic cardiomyopathy or aortic stenosis.^{18,46,61,97,144} ATTRwt can coexist with AL amyloidosis or in a patient with monoclonal gammopathy of undetermined signficance (MGUS), and these differentials must be considered.^4,145 In ATTRv amyloidosis, sexual dysfunction, altered bowel habits, and new-onset arrhythmias were frequently missed in evaluation.^{18,21,26,56,68,125,146} Late-onset ATTRv should be considered in older patients with suggestive symptoms, as family history is often absent.^68,75,101

Hematologists are rarely the first to see these patients, as patients often present to cardiology or neurology initially. The available literature was biased toward academic centers, yet patients are likely first present in community or primary care settings. These striking observations reinforce the importance of broad awareness of amyloidosis across specialties, such that it merits consideration early on as a differential diagnosis by clinicians.^147,148

In this review, we aimed to include most studies on the 3 major types of systemic amyloidosis. Several limitations warrant consideration. Studies in which AA amyloidosis could not be differentiated were excluded to maintain type-specific analysis of systemic amyloidosis, although this may underrepresent the full presentation spectrum. To maintain accurate representation in the subanalysis of amyloidosis symptoms and examination findings in Figure 2 and Table 1, only confirmed amyloidosis type-specific data were included, although this may introduce a form of selection bias.

This scoping review of the clinical “red flags” for AL, ATTRwt, and ATTRv amyloidosis highlights areas in which clinical vigilance is warranted and underscores areas for prospective research and clinical tools to assist clinicians in contextualizing the early symptoms of amyloidosis. Standardized structured symptom templates to elicit the pertinent symptomatology and patient-directed questionnaires based on these data could aid earlier recognition of systemic amyloidosis.

The impetus for this analysis was linked to our patient advocate’s (D.B.) journey, which made evident the lack of comprehensive formative information on the signs and symptoms of systemic amyloidosis. Published studies assessing awareness and knowledge of systemic amyloidosis are limited, and thematic analyses of the varied presentations are lacking.148, 149, 150 This comparative review of symptom frequency across amyloidosis subtypes could inform a machine-learning based symptom triage tool using natural language processing and pattern recognition algorithms trained on clinical data, to assist in the generation of prioritized differential diagnoses, and earlier clinical suspicion, particularly in nonspecialist settings.¹⁵¹ Ultimately bridging patients’ experience with data-driven platforms may be the key to transforming the diagnostic landscape of systemic amyloidosis.

Conflict-of-interest disclosure: The authors declare no competing financial interests.