Early diagnosis key for management, QOL in transthyretin amyloidosis
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Taimur Sher, MBBS, MD a hematologist, internist and oncologist at the Mayo Clinic Cancer Center who leads the Multispecialty Amyloidosis Clinic at Mayo Clinic in Jacksonville, Florida, spoke with Healio about how to recognize and diagnose transthyretin amyloidosis, the newest FDA-approved treatments and the importance of genetic counseling in disease management.
Can you define transthyretin amyloidosis?
Sher: Transthyretin amyloidosis is of two types: wild type — wtATTR, previously also known as senile type — and familial, or hereditary type, hATTR.
Hereditary TTR amyloidosis predominantly presents with peripheral nervous system and/or cardiac involvement. The exact presentation depends upon the specific mutations present in a family and range from peripheral neuropathy only, known as familial amyloid polyneuropathy, or FAP; cardiomyopathy only, or familial amyloid cardiomyopathy, or FAC; and a combination of both (FAP/FAC overlap syndromes).
It can be difficult for clinicians and patients to recognize the signs and symptoms of hATTR. What are some “red flag” symptoms in the early stages of the disease?
Sher: The nerve involvement presents as “neuropathy,” manifesting early on as numbness, tingling and pain in hands and feet. Early on, these symptoms are intermittent and minimal; however, over time, they progress. Often, we see patients not diagnosed until they have become wheelchair-bound. It can also involve the autonomic nerves and present as dizziness and passing out that can lead to inability to stand and walk. The gastrointestinal system is also affected by the autonomic neuropathy, leading to nausea, vomiting, early satiety, weight loss, diarrhea, constipation and failure to thrive.
Heart involvement predominantly presents with heart failure with preserved ejection fraction (HFpEF), that manifests as swelling around the ankles, shortness of breath with exertion and decline in functional capacity.
Since neuropathy and heart failure are among the most common problems that physicians encounter in clinical practice, it is important to keep hATTR in the differential diagnosis. Specifically, if a patient presents with sensory or autonomic neuropathy and common causes such as diabetes, nutritional deficiencies and alcoholism are ruled out, the clinicians should consider FAP as a possible diagnosis. Likewise, if a patient presents with HFpEF and common causes such as hypertension and valvular heart disease are ruled out, then FAC enters the differential diagnosis.
I would like to make a very important point for cardiologists here — when reviewing ECGs for patients with HF, it is imperative to pay attention to what we call left ventricular strain pattern. Amyloid cardiomyopathy has a specific strain pattern that can be very helpful in distinguishing it from the most common misdiagnosis of hypertensive heart disease. This is especially important for African Americans, as one particular mutation, V122I, which causes FAC, is found in 3% to 4% of the African American population.
Reviewing family history is a key.
What procedures have been most accurate in diagnosing hATTR at an earlier stage?
Sher: The most important step in making an earlier diagnosis is to consider it in the differential diagnosis of the symptoms. Once suspected, there are two important aspects of making the correct diagnosis. First, confirm by biopsy that amyloidosis is present. Next, confirm the type of amyloidosis. The first question is answered by starting with biopsies of various tissues/organ. The site of biopsy is guided by the clinical presentation and the type of amyloidosis suspected. In every case of amyloidosis, it is important to rule out the diagnosis of the most fatal and rapidly progressing amyloidosis, called immunoglobulin light chain amyloidosis or AL, and this can be done with blood tests (serum protein electrophoresis with immunofixation and serum immunoglobulin free light chain assay). If blood tests indicate that AL is less likely, then a fat aspirate is a good place to start. If fat aspirate is negative, then it does not mean the patient does not have hATTR. In this case, further tests depend upon the symptoms.
If neuropathy is the main manifestation, then a nerve biopsy should be considered. In patients with cardiomyopathy, biopsy of the endomyocardium is the gold standard. Recently, a nuclear medicine scan, called technetium 99m pyrophosphate, or a PYP scan, has been validated to detect the presence of ATTR cardiomyopathy. This scan can differentiate between AL and ATTR and can obviate the need for heart biopsy. It is important to recognize that a Tc99mPYP scan does not differentiate between wild type and familial or hereditary TTR. The only way to differentiate this is doing genotype analysis of the patient’s TTR gene. This genotype or genetic test is very important in confirming the diagnosis and initiating the process of genetic counseling.
How is quality of life elevated — or decreased — using organ transplant vs. other treatments?
Sher: The key to effective and meaningful treatment is making the diagnosis early, as organ damage is difficult to reverse in advanced stages. Historically, liver transplantation has been the most important part of management of patients who were diagnosed early in the disease process. Liver transplant is helpful, as it takes the source of amyloidogenic TTR away (more than 95% of TTR is produced by the liver). If done early, it can improve the quality and duration of life. This improvement is not universal and depends upon several factors, most importantly on the type of mutation. Some mutations benefit from liver transplant and in some cases, a patient’s clinical condition deteriorates after liver transplant. The last 3 years have seen a seismic change in the management of TTR amyloidosis, as three new medications have been approved by the FDA for treatment of hATTR. Inotersen (Tegsedi, Akcea Therapeutics) and patiseran (Onpattro, Alnylam Pharmaceuticals) decrease the production of mutant TTR protein by the liver. The third drug, tafamidis, stabilizes the TTR protein in the organs and in blood and prevents further deposition of the amyloidosis. Inotersen and patiseran are approved for FAP and FAP/FAC overlap syndromes and improve the quality of life. Tafamidis is approved for the treatment of FAC only (including wtTTR and hTTR) and has been shown to decrease the number of hospitalizations from congestive heart failure and prolong life expectancy. The greatest challenge with these medications is they are lifelong therapies with costs that range from $ 225,000 to $450,000 per year.
What role does genetic counseling play in helping families cope with hATTR and making health decisions?
Sher: Genetic counseling is the cornerstone of the management of the families dealing with hATTR. It provides them the opportunity to learn about the nature of the disease. By being informed, the patients and families are empowered to take active part in the management. Most importantly, it helps identify asymptomatic carriers who need to be followed closely by experts in amyloidosis so timely interventions can save them the morbidity and mortality of this disease.
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