The Curbsiders podcast

#427 Kittleson Rules Amyloidosis

February 19, 2024 | By

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The clinical picture of an underrecognized disease

Amyloidosis demystified. Learn the clinical clues that suggest possible amyloidosis and how to order the correct tests to diagnose this disease. We are joined by Dr. Michelle Kittleson who shows us the ropes of treating fibril accumulation, @MKittlesonMD (Cedars Sinai). 

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Show Segments

  • Introduction
  • Case Presentation: Mr. Smith
  • Differential Diagnosis of Heart Failure with Preserved Ejection Fraction
  • Understanding Amyloidosis
  • Clinical Clues and Red Flags for Amyloidosis
  • Physical Examination Findings
  • Workup for Amyloidosis
  • Treatment Options
  • AL Amyloidosis and Hematologist’s Role
  • ATTR Amyloidosis and Cardiologist’s Role
  • Other Therapies for TTR Amyloidosis
  • Therapy on the Horizon
  • Cost and Access to Tafamidis
  • Alternative Therapies and Supplements
  • Monitoring and Side Effects of Tafamidis
  • Symptomatic Management and Anticoagulation
  • Take Home Points

Amyloidosis Pearls

  1. Don’t stop at the diagnosis of HFpEF, figure out if there is an underlying cause for the patient’s disease.
  2. Amyloidosis is an under-recognized cause of HFpEF; a little more than 1 in 8 cases of HFpEF may be attributed to amyloidosis (González-Lopéz et al 2015).
  3. Amyloidosis is caused by misfolded protein fibril aggregates accumulating in tissues. The two most common types of amyloidosis affecting the heart are due to misfolded monoclonal immunoglobulin light chains (L) or transthyretin (TTR).
  4. Fibril deposition in the heart leads to thick ventricle walls, and this infiltrative disease can cause persistent troponin elevation despite clean coronaries (Morioka et al 2022). 
  5. Amyloid fibrils also deposit into nerves resulting in peripheral neuropathy, autonomic dysfunction, and erectile dysfunction.
  6. Fibril deposits (particularly TTR) into tendons result in tendinopathies like biceps tendon rupture and carpal tunnel syndrome–be particularly suspicious of bilateral carpal tunnel in individuals >60-years-old. 
  7. Patients with amyloidosis often have orthostatic hypotension related to autonomic neuropathy (Palma et al 2019).
  8. A patient who has an echo with left ventricular wall thickness > 12mm and one red flag should get further workup (Garcia-Pavia et al 2021).
  9. First step of amyloidosis diagnosis is to exclude AL-CM with a monoclonal protein screen comprising serum immunofixation electrophoresis (IFE), urine IFE, and kappa/lambda free light chains. 
  10. If the monoclonal protein screen is positive, the patient needs an urgent hematology referral to receive a biopsy for definitive diagnosis and  address potential AL-CM.
  11. The second step is ordering a technetium-99m pyrophosphate (Tc-PYP) scintigraphy to look for ATTR-CM; a negative monoclonal protein screen and a positive Tc-PYP scan is sufficient to diagnose ATTR-CM (Kittleson et al 2023|ACC Expert Consensus).
  12. Treatment for AL-CM is driven by hematologists and comprises chemotherapies like daratumumab (anti-CD38), bortezomib (proteasome inhibitor), cyclophosphamide, and high dose dexamethasone (Bloom et al 2023). 
  13. The only FDA approved treatment for ATTR cardiomyopathy is tafamidis (Kittleson et al 2023|ACC Expert Consensus).
  14. Anticoagulation is recommended for amyloidosis patients with atrial fibrillation, regardless of their CHADS-VASc score, due to the high thromboembolic risk associated with the disease (Garcia-Pavia et al 2021).

Amyloidosis

The differential diagnosis for dyspnea with edema does not stop with the heart. Heart failure with a preserved ejection fraction (HFpEF) is a diagnosis of exclusion; a patient with dyspnea and edema could be suffering from kidney pathology like nephrotic syndrome or liver pathology like cirrhosis causing portal hypertension or reduced protein metabolism.  Amyloidosis is an under-recognized cause of HFpEF; a little more than 1 in 8 cases of HFpEF may be attributed to amyloidosis (González-Lopéz et al 2015). Cardiac amyloidosis should be carefully considered in patients with HFpEF, especially in patients without traditional risk factors like women, older individuals, chronic hypertension, coronary disease, diabetes, and chronic kidney disease (Lee et al 2020). Now that there is disease directed therapy for cardiac amyloidosis, don’t stop at the diagnosis of HFpEF, figure out if there is an underlying cause for the patient’s disease. 

Pathophysiology and Nomenclature

Amyloidosis is caused by misfolded protein fibril aggregates accumulating in tissues. The two most common types of amyloidosis affecting the heart are due to misfolded monoclonal immunoglobulin light chains (L) or transthyretin (TTR). The nomenclature for amyloidosis includes an “A” for amyloidosis and a “CM” for cardiomyopathy. AL-CM occurs in the context of plasma cell dyscrasias, from monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma. The protein transthyretin that causes ATTR-CM is a thyroid protein transporter also known as prealbumin, but it is not a synthetic precursor to albumin (Sanguinetti et al 2022). ATTR-CM can be caused by mutated transthyretin (ATTRv-CM) or wildtype protein (ATTRwt-CM), previously referred to as senile amyloidosis (Kittleson et al 2023|ACC Expert Consensus). 

Past Medical History Concerning for Amyloidosis

Due to the tendency of amyloid fibrils to deposit in specific tissues (heart, nerves, and tendons), an amyloidosis diagnosis can unify seemingly disparate clinical findings. Fibril deposition in the heart leads to thick ventricle walls, and this infiltrative disease can cause persistent troponin elevation despite clean coronaries (Morioka et al 2022). Amyloid fibril deposition can also interfere with cardiac electrical conduction; unexplained atrioventricular block or prior pacemaker implantation can be clues suggesting the presence of amyloidosis (Hartnett et al 2021). To aid in your clinical decision making, there is a point-based risk score to identify patients with increased risk of ATTR-CM using 3 clinical parameters (age, male sex, and hypertension diagnosis) and 3 echocardiographic (echo) parameters (ejection fraction, posterior wall thickness, and relative wall thickness) (Davies et al 2022). Kittleson pet peeve: increased left ventricular (LV) wall thickness on an echo does not mean hypertrophy; the increased thickness can be from an infiltrative disease like amyloidosis, and calling it hypertrophy can cause premature closure. Amyloid fibrils also deposit into nerves resulting in peripheral neuropathy, autonomic dysfunction, and erectile dysfunction. Patients with amyloidosis can have a pronounced intolerance to vasodilating medications like angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium channel blockers (CCBs) (Kittleson et al 2023|ACC Expert Consensus). Fibril deposits into tendons result in tendinopathies. Carpal tunnel syndrome in adults older than 60–particularly bilateral carpal tunnel syndrome–is a red flag for amyloidosis (aus dem Siepen et al 2019 and Genova et al 2020). Other tendon manifestations include biceps tendon rupture (Geller et al 2017) and spinal stenosis (aus dem Siepen et al 2019). Amyloid tendinopathies can predate the development of symptomatic cardiac amyloid depositions by six or seven years and could be considered harbingers of disease (Perfetto et al 2022).

Physical Exam 

ATTR-CM is a disease of older individuals, generally 60-years-old and above, with an insidious onset. AL-CM can occur in younger individuals, presenting more acutely than ATTR-CM. Due to autonomic dysfunction, patients with amyloidosis often have orthostatic hypotension (Palma et al 2019), a systolic decrease of 20 mmHg or a diastolic decrease of 10 mmHg within three minutes of standing. AL-CM is associated with macroglossia, easy bruising, and periorbital purpura (Hoffman et al 2020 and Bloom and Gorevic 2023). Additional cardiac findings are common, atrial fibrillation is present in around 70% of patients (Hartnett et al 2021), and there may be a systolic ejection murmur of aortic stenosis; ATTR-CM is present in 16% of patients with severe calcific AS undergoing TAVR (Castaño et al 2017). 

Workup for Amyloidosis 

There can be clues to a diagnosis of amyloidosis in common studies that your patient has likely already completed. An electrocardiogram (ECG) with low voltage suggests the presence of amyloid infiltration, or more accurately, discordantly low voltage for the left ventricular wall thickness (Garcia-Pavia et al 2021). Lab values changes include elevated BNP and troponin elevation despite clean coronaries (Morioka et al 2022). A patient who has an echo with left ventricular wall thickness > 12mm and one red flag should get further workup (Garcia-Pavia et al 2021).

First step of diagnosing amyloidosis is to exclude AL-CM with monoclonal protein screen, serum immunofixation electrophoresis (IFE), urine IFE, and lambda and kappa free light chains. IFE is more sensitive and specific than serum protein electrophoresis and should be preferentially used (Vermeersch et al 2008). If the monoclonal protein screen is positive, the patient needs an urgent hematology referral to address potential AL-CM. Definitive diagnosis of AL-CM requires a biopsy. It is ok to start with a surrogate site like a fat pad, but if that biopsy is negative, an affected organ biopsy of the heart or kidney will be necessary, as a surrogate site biopsies are insufficiently sensitive to exclude amyloidosis if there is a high clinical suspicion (Gillmore et al 2014). 

If the monoclonal protein scan is negative, the next step is ordering a technetium-99m pyrophosphate (Tc-PYP) scintigraphy to look for ATTR-CM. It’s important to rule out AL-CM first, because AL-CM can cause a false positive Tc-PYP delaying appropriate treatment (Gillmore et al 2016). A negative monoclonal protein screen and a positive Tc-PYP scan is sufficient to diagnose ATTR-CM (Kittleson et al 2023|ACC Expert Consensus)

Once a patient is diagnosed with ATTR-CM, they should undergo genetic testing for variant forms of transthyretin. The most important variant to remember is Val124Ile; this variant is present in 3-4% of Black Americans (Chandrashekar et al 2012). Other common variants are Val30Met, Leu111Met, and Glu89Gln (Gentile et al 2023). Genetic testing in ATTR-CM affects available treatment options and triggers screening in first degree relatives. Relatives with a positive genetic screen should get an echo when they are 10-years-younger than the age when the index patient was diagnosed (Kittleson et al 2023|ACC Expert Consensus).

You do not need a cardiac MRI (CMR) to diagnose amyloidosis. CMR could be helpful if you have a broad differential and need to distinguish between hypertrophic cardiomyopathy (HCOM), Fabry disease, myocarditis, sarcoidosis, hemochromatosis, pericardial construction, or an idiopathic constrictive pericarditis. CMR may also be useful in a patient diagnosed with AL amyloidosis based on a non-cardiac tissue biopsy and the hematologist would adjust their treatment based on possible cardiac involvement (Dorbala et al 2021).

Amyloidosis Treatment 

Treatment for AL-CM is driven by hematologists and comprises chemotherapies like daratumumab (anti-CD38), bortezomib (proteasome inhibitor), cyclophosphamide, and high dose dexamethasone (Bloom et al 2023). Cardiologists play a supportive role in AL-CM treatment by helping to maintain fluid balance.

ATTR-CM is treated primarily by cardiologists. The only FDA approved treatment for ATTR cardiomyopathy is tafamidis (Kittleson et al 2023|ACC Expert Consensus). Tafamidis works by stabilizing the benign tetramer form of TTR reducing tissue accumulation (Maurer et al 2018). This drug has no suggested monitoring or significant side effects. Unfortunately, tafamidis costs around $225,000 per year, so access can be a challenge. Working with specialists and patient assistance programs can help get this drug into the hands of patients who need it. A less expensive option without proven clinical efficacy is the NSAID diflunisal, but this drug is not strongly supported by evidence and has bleeding and renal side effects (Choi et al 2022). 

There are a number of emerging therapies for ATTR-CM with satisfying mechanisms of action. While tafamidis stabilizes TTR, there are drugs in development that either reduce the production of TTR or facilitate the removal of infiltrated fibrils. Reducing protein production is accomplished with gene silencing mRNA analogues like patisiran (Adams et al 2018), inotersen (Benson et al 2018), eplontersen (Coelho et al 2023), and vutrisiran (Adams et al 2023). These medications are not currently approved for cardiac amyloidosis, but some are approved to slow the progression of neuropathy in individuals with variant TTR. The APOLLO-B trial looked at the co-administration of patisiran and tafamidis, but failed to get FDA approval, likely due to a modest improvement in the secondary endpoint of 6 minute walk distance (Maurer et al 2023). There are also drugs in development to remove already deposited fibrils, the monoclonal antibody (N1006 – great name) was shown to stimulate ATTR phagocytosis, and initial data shows improvement in PYP scans (Garcia-Pavia et al 2023). Treatment for amyloidosis is an exciting research field. 

Medical Management

Outside of the disease directed therapies discussed above, primary care providers can help with medical management of amyloidosis symptoms. Patients with cardiac amyloidosis have a narrow therapeutic window for diuretic therapy; they easily become too dry or volume overloaded. Dr. Kittleson suggests partnering closely with patients, empowering them to guide their treatment and being comfortable with a little edema. Due to the autonomic dysfunction and fixed cardiac stroke volume, patients with cardiac amyloidosis tend to be less tolerant of vasodilators and beta blockers; they often do better off of these medications–and you may become their favorite doctor if you discontinue them.  In fact, have a low threshold to stop vasodilators that are otherwise beneficial in heart failure (including angiotensin-neprilysin inhibitors, ACE inhibitors, angiotensin receptor blockers) in patients with hypotension or progressive kidney dysfunction as the unique physiology of amyloidosis places them at risk of potential harm without demonstrated benefit as in other forms of heart failure. 

Addressing neuropathy and autonomic dysfunction are important aspects of caring for a patient with amyloidosis.  Patients with ATTRv-CM and neuropathy are eligible for gene silencing agents and should be referred to neurology. All other patients can be treated with pregabalin, gabapentin, duloxetine, or tricyclic antidepressants. Autonomic dysfunction can be managed with medications (midodrine, droxidopa, and fludrocortisone) or interventions (compression stockings and abdominal binders). 

Due to the high thromboembolic risk associated with the disease, anticoagulation is recommended for amyloidosis patients with atrial fibrillation, regardless of their CHADS-VASc score (Garcia-Pavia et al 2021).


Links

  1. Mastering the Art of Patient Care

Goal

Listeners will learn to identify, diagnose, and help manage cardiac amyloidosis

Learning objectives

After listening to this episode listeners will…

  1. Recognize the clinical history and symptoms that suggest cardiac amyloidosis
  2. Familiarize themselves with the diagnostic algorithm for cardiac amyloidosis
  3. Learn how to partner with cardiologists and other specialists to manage patients living with amyloidosis
  4. Appreciate the current therapeutic approach for management of cardiac amyloidosis 

Disclosures

Dr. Kittleson reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Gorth DJ, Kittleson MM, Williams PN, Watto MF. “#427 Kittleson Rules Amyloidosis”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date February 19, 2024.

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Episode Credits

Written and Produced by; Deborah Gorth, MD, PhD
Infographic and Cover Art: Meryl Gorth, RD, MPH and Deborah Gorth, MD, PhD
Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP
Reviewer: Sai S. Achi MD MBA
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP
Technical Production: PodPaste
Guest: Michelle Kittleson, MD, PhD

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The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org and search for this episode to claim credit.

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