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Indiana University School of Medicine
Indiana University School of Medicine
Pathology and Laboratory Medicine

Diagnostic Algorithms for Cardiac Amyloidosis

The prevalence of cardiac amyloidosis is unknown because the condition often goes underdiagnosed. There is emerging evidence that cardiac amyloidosis may be a relatively common cause of heart failure, especially in older individuals. The two most common forms of amyloidosis that affect the heart are AL and ATTR amyloidosis.

Red flags that may raise clinical suspicion for cardiac amyloidosis, a diagnostic algorithm to confirm or exclude a diagnosis of cardiac amyloidosis, lab/imaging ordering tips in the IU system, and FDA approved treatments are detailed below.

Indiana University Diagnostic Algorithms for Cardiac Amyloidosis

Diagnosis: Early diagnosis and treatment may help preserve organ function
  1. Look for history and physical findings of cardiomyopathy and neuropathy and unexplained left ventricular hypertrophy as well as the other signs and symptoms listed below)
  2. Ask about family history of cardiomyopathy. In the US, the Val122Ile mutation is the most common hereditary mutation. It is estimated to be found in 3-4% of African Americans
  3. Evaluate imaging and EKG for findings of unexplained left ventricular hypertrophy with discordant voltage on ECG
  4. Rule out AL amyloidosis which is a medical emergency with serum free light chains (abnormal kappa/lambda ratio of <0.26 or >1.65) or a monoclonal protein on serum or urine immunofixation. If abnormal consult with a hematologist/amyloid expert.
  5. If work-up for AL amyloidosis is negative and there is continued suspicion for cardiac amyloidosis, evaluate for transthyretin amyloidosis. ATTR can be diagnosed by biopsy diagnosis or by nonbiopsy diagnosis with a nuclear PYP scan (high uptake of PYP in patients with ATTR in patients with a negative work-up for AL). A biopsy diagnosis can be made with biopsy with protein typing by mass spectrometry followed by genetic testing.
  6. In patients with a biopsy or nonbiopsy diagnosis of ATTR, pursue genetic testing. ATTR is an autosomal dominant condition so interested family members can be screened.

Signs and Symptoms

  • Multisystem organ involvement (esp. heart, soft tissue and nerves)
  • Carpal tunnel syndrome
  • Spinal stenosis
  • Autonomic dysfunction
  • Intolerance to heart failure medications
  • Biceps tendon rupture
  • Low flow / row gradient as
  • Unexpected LVH
  • Unexplained neuropathy

Suggestive Signs and Symptoms, cardiac imaging (echo, MRI, PYP) or family history

2 main causes of cardiac amyloidosis
  • AL (medical emergency, high mortality with delayed diagnosis). Abnormal production of serum free light chains (antibody fragment) by the bone marrow
  • ATTR (typically slower, progressive): Transthyretin (a normal protein that transports thyroid hormone and vitamin A) that misfolds due to genetic changes or aging and deposits in organs and causes organ dysfunction. The heart and nerves are most affected.

FIRST: Rule out AL amyloidosis with Serum free light chains (abnormal if ration is <0.25 or >1.65), immunofixation of serum and urine (abnormal if a monoclonal protein is deteted, urinalyses for proteinuria. AL cardiac amyloidosis is a cardiac emergency with a life expectancy <6 months without treatment. Treatment is chemotherapy or stem cell transplant

AL Amyloidosis: (suspect if kappa/lambda ratio or serum free light chains is <0.26 or >1.65 or there is evidence of a monoclonal protein)

Hematology consult with possible bone marrow biopsy

Consider biopsy of affected organ (ex. Heart, kidney or fat pad)

 ATTR Amyloidosis: (suspect if AL work-up is negative and there is unexplained Hypertrophy

Biopsy diagnosis:
Cardiac biopsy with protein typing by mass spectrometry

Nonbiopsy diagnosis:
Tc99 Pyrophosphate scan + Genetic Testing

Genetic testing:
Normal: Wild-type ATTR
Mutation: Hereditary ATTR

Lab orders

Lab Orders:
To evaluate for AL Amyloidosis
Free light chains QN
IFE Ser QN (Immunofixation Serum)
UFE Urn QN (Immunofixation Serum)

Imaging:
Echo:
Echocardiogram with Cardiac Doppler (PW/CW/color)
In special instructions add comment: LV Strain

MRI:
Outside MRI Cardiac Morph / Function wo then w Contrast

Nuclear PYP:
Outside Misc Rad Request
Reason for exam: Amyloidosis
Special Instructions: Perform with PYP Image at 3 hours

FDA Approved Therapy for Transthyretin Amyloidosis

Cardiomyopathy: Transthyretin cardiac amyloidosis (hereditary OR wild-type) Tafamidis (oral)

Neuropathy-Hereditary transthyretin amyloidosis
Inotersen (SQ)
Patisiran (IV Infusion)

IU Clinical Trials: Current participation in trials for both ATTR cardiomyopathy and neuropathy