Consider hATTR amyloidosis in your differential diagnosis

Due to the rapid natural progression of the disease, patients with hATTR amyloidosis require an early and accurate diagnosis.^1-3 Because the symptoms of hATTR amyloidosis may overlap with those of other diseases, detailed diagnostic history may help to identify patients with hATTR amyloidosis^1,2,4,5

• Polyneuropathy^6-10
• Cardiomyopathy^11-13

Clinical manifestation	Potential diagnoses
Ataxia and foot numbness	CIDP
Motor involvement	ALS Motor polyradiculoneuropathy
Upper limb neuropathy	Carpal tunnel syndrome Idiopathic polyneuropathy Paraneoplastic neuropathy CIDP Motor neuron diseases
Weakness in feet, ankles, legs	Charcot-Marie-Tooth disease
Pain and tingling with alcohol abuse	Alcoholic neuropathy
Polyneuropathy with diabetes	Diabetic neuropathy
Polyneuropathy with evidence of amyloid deposition	AL amyloidosis AA amyloidosis

Clinical manifestation	Potential diagnoses
Clinical manifestationAtaxia and foot numbness	Potential diagnosis CIDP
Clinical manifestationMotor involvement	Potential diagnoses ALS Motor polyradiculoneuropathy
Clinical manifestationUpper limb neuropathy	Potential diagnoses Carpal tunnel syndrome Idiopathic polyneuropathy Paraneoplastic neuropathy CIDP Motor neuron diseases
Clinical manifestationWeakness in feet, ankles, legs	Potential diagnosis Charcot-Marie-Tooth disease
Clinical manifestationPain and tingling with alcohol abuse	Potential diagnosis Alcoholic neuropathy
Clinical manifestationPolyneuropathy with diabetes	Potential diagnosis Diabetic neuropathy
Clinical manifestationPolyneuropathy with evidence of amyloid deposition	Potential diagnoses AL amyloidosis AA amyloidosis

For patients with neuropathic symptoms, the most common misdiagnosis previously received is CIDP.¹⁴

AA=amyloid A; AL=amyloid light chain; ALS=amyotrophic lateral sclerosis; CIDP=chronic inflammatory demyelinating polyneuropathy.

Diagnostic assessment	Potential diagnoses
Left ventricular hypertrophy Diastolic dysfunction Heart failure with preserved ejection fraction	Hypertensive heart disease Hypertrophic cardiomyopathy Fabry disease AL amyloidosis

For patients with cardiomyopathy, accurate diagnosis may be even more critical, as some medications for common cardiac conditions may be harmful. These medications may interact with amyloid fibrils and exert negative effects.¹⁵

Recognize the red-flag symptoms. Suspect hATTR amyloidosis.

• Polyneuropathy
• Cardiomyopathy

Progressive symmetric sensory-motor neuropathy and ≥1 of the following:

Bilateral carpal
tunnel syndrome

Nephropathy
(eg, proteinuria or renal failure)

Early autonomic dysfunction
(eg, sexual dysfunction
or postural hypotension)

Gastrointestinal complaints
(eg, vomiting, chronic diarrhea,
constipation, or
diarrhea/constipation)

Unexplained
weight loss

Cardiovascular manifestations
(eg, conduction block, cardiomyopathy, or arrhythmia)

Vitreous opacities

Positive family history

Additional signs: Rapid disease progression and failure to respond to immunomodulatory treatment

Adapted from Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9.

Clinical findings that may indicate hATTR amyloidosis

Historical and physical findings

Heart failure with a normal or preserved ejection fraction in the absence of hypertension, particularly in men Hypotension in a person with previous hypertension Evidence of right-sided heart failure: loss of appetite, hepatomegaly, ascites, and lower extremity edema Intolerance of commonly used cardiovascular medications: digoxin, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers Bilateral carpal tunnel syndrome

Imaging findings
ECG	Low QRS voltage ± thick interventricular septum (low voltage to mass ratio) Pseudo-infarction pattern Progressive reduction in QRS voltage over time
Echo	Thick interventricular septum Refractile myocardium (granular sparkling) Low tissue Doppler velocities, strain, or strain rate
CMRI	Thick interventricular septum Subendocardial late gadolinium enchancement
Scintigraphy Scan	Cardiac uptake of 99mTc-DPD or 99mTc-PYP

In addition, consider hATTR amyloidosis in a patient who has a family history of ANY of these symptoms

Adapted from Dharmarajan K, Maurer M. J Am Geriatr Soc. 2012;60(4):765-774.

ECG=electrocardiogram; CMRI=cardiac magnetic resonance imaging;
^99mTc-DPD=technetium-^99m-3,3-diphosphono-1,2-propanodicarboxylic acid; ^99mTc-PYP=technetium-^99m-pyrophosphate.

Whether patients present primarily with cardiomyopathy or polyneuropathy, obtaining a family history is an important step in the diagnostic process.^1,2,16

Though patients may be unaware of hATTR amyloidosis in their family, inquiring about relatives who have experienced any of the symptoms, including symptoms different from their own, or who have died prematurely, can help identify a family history.

Confirming an hATTR amyloidosis diagnosis

When you suspect hATTR amyloidosis, the diagnostic process may include^1,4,15:

• Cardiac and/or neurologic examination
• Genetic testing
• Tissue biopsy
• Identification of the amyloid protein

• Diagnostic tools for patients presenting with polyneuropathy^1,4,17
• Diagnostic tools for patients presenting with cardiomyopathy^4,15

Complete neurologic examination
Electromyography Sympathetic skin response (SSR) Heart rate deep breathing Sudoscan assessment of electrochemical skin conductance Medical history Laboratory tests to exclude mimicking polyneuropathies

Genetic analysis to determine pathologic mutation

Tissue biopsy + Congo red staining
Salivary gland Abdominal subcutaneous adipose tissue Rectal mucosa Sural nerve Skin Gastric

Identification of amyloid protein
Immunohistochemistry Mass spectrometry

Cardiac examination
Electrocardiography Echocardiography Cardiac serum biomarkers Cardiac magnetic resonance imaging Nuclear scintigraphic imaging with 99mTc-DPD or 99mTc-PYP

Genetic analysis to determine pathologic mutation

Tissue biopsy + Congo red staining

Identification of amyloid protein
Immunohistochemistry Mass spectrometry

Alnylam Act^™

Third-party genetic testing and counseling programs offered at no charge

Genetic testing and counseling may help to:

• Identify risk of disease for patients and their family members
• Shorten the time to diagnosis and prevent misdiagnoses
• Determine if patients are eligible to participate in clinical trials
• Provide information about support resources such as patient advocacy organizations

The Alnylam Act^™ program was developed to reduce barriers to genetic testing and counseling to help people make more informed decisions about their health. While Alnylam provides financial support for this program, tests and services are performed by independent third parties. Healthcare professionals must confirm that patients meet certain criteria to use the program. Alnylam receives de-identified patient data from this program, but at no time does Alnylam receive patient identifiable information. Alnylam receives contact information for healthcare professionals who use this program. Genetic testing is available in the U.S. and Canada. Genetic counseling is only available in the U.S. Healthcare professionals who use this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use or support any Alnylam product.