As early detection and management of gastrointestinal (GI) disturbances is key in familial amyloid polyneuropathy (FAP), gastroenterologists should be part of a multidisciplinary team to treat these patients, a study suggests.
The research, “Diagnosis and treatment of gastrointestinal dysfunction in hereditary TTR amyloidosis,” was published in the journal Clinical Autonomic Research.
People with FAP, also known as hereditary transthyretin amyloidosis, often experience GI problems such as bloating, nausea, vomiting, weight loss, and fecal incontinence. This results from early and progressive damage to the autonomic nervous system — the part of the nervous system responsible for involuntary processes such as breathing, heartbeat, and digestion.
Researchers from the Amyloidosis Research and Treatment Centre, in Italy, and Umeå University, in Sweden, reviewed the current literature to further explore how GI tract manifestations are diagnosed and treated in FAP patients.
The review showed that, as expected, GI problems are common, and a serious FAP manifestation. These problems significantly affect quality of life and are associated with a higher risk of mortality.
GI disturbances also have a negative impact on nutritional status and prognosis. They may not be detected in the early stages of the disease, resulting in under-recognition, delayed investigation, and suboptimal treatment. In addition, some patients initially present with bowel abnormalities, and often need several rounds of endoscopic evaluation before a diagnosis is ultimately established.
Existing diagnostic tools are not routinely used in clinical practice, the researchers found. Nutritional status and self-reported symptoms, measured with validated questionnaires, are currently widely accepted to monitor GI involvement in people with FAP.
Overall, the researchers noted that a clear understanding of the mechanisms underlying GI dysfunction in these patients is still lacking. Yet, similar to diabetic enteropathy — a GI manifestation in diabetes — multiple biological alterations are thought to play a role.
“Early detection and treatment of gastrointestinal disturbances is key to the successful treatment of [FAP],” the researchers said.
“Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in [FAP] and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder,” they added.
Aiming to highlight the most relevant problems found in daily management of GI manifestations in people with FAP, the scientists also analyzed two cases involving such patients.
First, they described the case of a 69-year-old woman with progressive numbness in her hands and feet, who was unable to walk on heels and toes. She also had evidence of nerve damage in the limbs and GI disturbances such as weight loss and recurrent vomiting.
Multiple GI evaluations did not help determine a diagnosis. Neurological examination showed reduced sensation and weakness at lower limbs. Meanwhile, echocardiography revealed amyloid protein infiltration in the heart tissue and excessive levels of N-terminal pro-B-type natriuretic peptide, a biomarker of cardiac disease.
Genetic testing led to a diagnosis of FAP. The patient then started treatment with Vyndaqel (tafamidis, by Pfizer), erythromycin, domperidone, and levosulpiride, as well as vitamin D supplements. Three years after initiating treatment with Vyndaqel, the woman had gained 6 kg (13.2 pounds) and her body mass index was stable.
According to the researchers, the patient’s GI symptoms are in line with gastroparesis, which is a delay in the emptying of contents from the stomach into the intestine. While the link between gastroparesis and FAP is poorly elucidated, current research suggests that gastroparesis in people with the disease probably reflects generally disturbed GI motility, and not simply impaired gastric emptying.
As a result, it is important to investigate the presence of upper GI symptoms in people with FAP to thoroughly exclude other causes, the team noted. Current diagnostic tools include endoscopy, esophageal and intestinal manometry — measurement of pressure in various parts of the intestine — and gastric emptying studies.
Treatment should aim to relieve symptoms and halt the progression of GI dysfunction. The best therapeutic strategy, the scientists said, includes a combination of specific treatment for FAP such as Vyndaqel and supportive care.
Dietary changes also may be useful and should include small-volume meals with low soluble fiber and fat content.
The investigators next described a 43-year-old man who had experienced bowel abnormalities, which consisted of periods of constipation and progressive, recurrent episodes of diarrhea. While excluding endocrine and autoimmune disorders, GI evaluations revealed gastroesophageal reflux disease.
The patient experienced progressive fatigue, profound muscle weakness, daily diarrhea, and significant weight loss over 12 months. A second-degree relative — who was not identified, but would be someone who shared 25% of the patient’s DNA, such as an uncle or a niece — was then diagnosed with FAP. On subsequent examination, the man complained of severe fatigue, erectile dysfunction, and difficulty in swallowing. FAP diagnosis was ultimately established with echocardiography and genetic testing.
Given his marked bowel abnormalities, the clinicians recommended treatment with loperamide and Xifaxan (rifaximin, by Salix Pharmaceuticals), among other therapies. The patient also was told to participate in a clinical trial of Onpattro (patisiran, by Alnylam Pharmaceuticals).
Scientists noted that this case illustrates that abnormal bowel function may be the initial manifestation among some patients with FAP.
“Treatment of lower GI disturbances is extremely important to mitigate symptoms and preserve quality of life, particularly work and social activities, and to avoid malnutrition,” the investigators said.
In the case of diarrhea, the team recommends a reduced-fat diet together with bile acid sequestrants — medicines that help lower LDL, or so-called bad cholesterol — and sufficient calories.
“Better knowledge of the mechanisms responsible for the gastrointestinal manifestations of the disease can provide novel targets for more effective supportive treatment of these symptoms,” the researchers said.
“Gastroenterologists therefore play an important role in ATTRv, and their expertise should be valued for an effective multidisciplinary approach to this disease,” they added.