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Mount Sinai Medical Center
New York, New York
Aaron Walfish, MD has no relevant conflicts of interest. to report.
I’ve been a GI specialist for more than 14 years, and in that time I have encountered relatively few patients with GI manifestations of hereditary amyloid transthyretin amyloidosis (hATTR). I see exponentially more cases of gastroesophageal reflux disease, celiac disease, polyps, and hepatitis, to name a few. Indeed, hATTR is a rare disease. Yet I don’t let that deter me from actively looking for it. There are few diseases that take more of an insidious and devastating toll on a patient’s health and quality of life than amyloidosis. And while this is ultimately a fatal condition for most, early detection provides significant opportunities to use new treatment modalities to delay progression to later stages, thereby preserving a better quality (and quantity) of life for many of our patients.
Hereditary ATTR results from misfolding of the transthyretin proteins produced in the liver due to inherited autosomal dominant mutations. The resulting amyloid fibrils deposit in organs and tissues and progressively cause organ dysfunction leading to death. Many systems of the body can be affected, but the GI manifestations that often precede the later complications of the disease are often missed because they are so subtle. Furthermore, these elusive symptoms are often attributed to more common etiologies, such as irritable bowel syndrome. As a result, patients continue to have unchecked progressive disease, visit many specialists in search of relief, and are often subjected to repeated endoscopies and unnecessary treatments.
What can primary care and GI specialists do? Vigilance is key. Although subclinical in earlier disease, it’s important to remember that gastric and bowel abnormalities may be one of the first clinical signs of hATTR. The Transthyretin Amyloidosis Outcomes Survey (THAOS) was the first global, multicenter, longitudinal, observational survey to collect data on patients with ATTR amyloidosis. According to the THAOS, unexplained weight loss is a major red flag for possible hATTR, followed by early satiety, diarrhea, and/or constipation. Fecal incontinence is also a sign to look for, so be sure to ask your patients about this because they may not otherwise volunteer the information.
In addition, there are other salient clues that can lead the clinician to consider hATTR. As I described in my patient case review, our patient Kurt’s upper endoscopy showed food in his stomach despite being without food for many hours. This suggested a potential neuropathic gastroparetic component, which is emblematic of hATTR. The patient also had temporary improvement with the use of rifaximin, likely due to treatment of bacterial overgrowth, which frequently occurs with hATTR amyloidosis. In addition, while hATTR is not an inflammatory disease, recent studies show that fecal calprotectin levels are elevated in patients with hATTR. This patient also had orthostatic hypotension and carpal tunnel syndrome—both classic findings seen in many patients with hATTR. One other clue: The patient had a close relative with a history of amyloidosis.
If you suspect hATTR in one of your patients with GI symptoms, it is often best to refer the patient to a specialist to confirm the diagnosis and initiate appropriate treatment. The diagnosis should be based on histologic evidence of amyloid deposits in an involved organ, or indirectly through subcutaneous abdominal fat tissue aspiration, rectal mucosa biopsies, or salivary gland biopsies. To help solidify the diagnosis, the biopsies should be extracted not only from abnormal lesions, but also from mucosa that appears normal. Staining with Congo red should then be performed, looking for the classic green birefringence under polarized light. Next, immunohistochemistry for hATTR should be done, followed by genetic counseling and genetic testing to confirm hATTR. Whole-body 123I-labeled serum amyloid P component (SAP) scintigraphy can be used when appropriate to evaluate the extent of amyloid involvement and monitor response to treatment.
Genetic testing—always in conjunction with genetic counseling—is key to making a definitive diagnosis and preparing patients and their families for what lies ahead. Fortunately, there are confidential, no-cost programs available through companies and services like Alnylam Act (offered by Alnylam and Invitae) and hATTR Compass Genetic Testing Program (offered by Akcea Therapeutics and Ambry Genetics) that are invaluable to help patients and their families take this critical diagnostic step.
After years of therapeutic nihilism, there are now treatments for hATTR that offer new hope to patients and their families. Discussion of treatment options is beyond the scope of this blog, but the very fact that we now have effective weapons against hATTR makes our mutual efforts for early and accurate diagnosis more important than ever before.
Aaron Walfish, MD
Have you ever considered rare motility disorders like hATTR in your differential diagnosis for patients with recalcitrant GI symptoms? Join the discussion by posting a comment below.