Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy

Sarafov

et al. 2019

JGLD

Transthyretin amyloidosis (ATTR) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene. Due to the phenotypic heterogeneity, ATTR is difficult to recognize and it is often diagnosed very late. In ATTR gastrointestinal (GI) disorders play an important role in the patients’ morbidity and mortality. In some cases, GI symptoms are present even before the onset of the peripheral polyneuropathy. However, the complaints are various and it is really difficult to differentiate them from other GI disorders. We present a 61-year old male referred for diarrhea, unintentional weight loss and early satiety. He had hypotension after longstanding hypertension, numbness and tingling in the feet. We considered a broad differential diagnosis spectrum of chronic diarrhea syndrome and performed numerous laboratory, biochemical, imaging, endoscopic, histological and genetic tests. Transthyretin amyloidosis with a Glu89Gln mutation was diagnosed. Transthyretin amyloidosis is frequently misdiagnosed, representing a diagnostic challenge in GI practice. The presence of certain clinical combinations could help gastroenterologists to include ATTR in their diagnostic work-up.

Section: Discussionsupporting

confidence: 71%

Transthyretin Amyloidosis with Gastrointestinal Manifestation: a Case Report

Sarafov

et al. 2019

JGLD

“…The resulting malabsorption and cachexia are known to be a leading cause of death in hATTR amyloidosis [37,38]. Frequent diarrhea and fecal incontinence can have a significant negative impact on QOL [23,[38][39][40], leading to withdrawal from social situations [20,41]. Additionally, sexual dysfunction, which patients have described as "devastating", may also have a major impact on patients' QOL and functioning [20,21].…”

Section: Introductionmentioning

confidence: 99%

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

et al. 2019

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

“…Further research is warranted to investigate the biological effects of active amyloidogenesis on gastrointestinal structure and function, as well as any beneficial effects that tafamidis has in attenuating this aspect of the disease process. mBMI may shed some light on gastrointestinal TTR amyloidosis etiology, as there is a weak but significant negative correlation between this measure and gastric emptying (Spearman rank-order coefficient, −0.218, P = 0.006) in patients with Val30Met TTR-FAP [ 9 ]; it is reasonable to suggest that the BMI component of mBMI would be negatively impacted by the classic early-stage symptoms of gastroparesis (i.e., nausea, vomiting, and early satiety) [ 26 ]. The mechanisms by which amyloidogenesis causes gastric retention have yet to be elucidated but this problem is evident in patients with normal sympathetic and parasympathetic activity, and only weakly correlated with autonomic neuropathy [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Post Hoc Analysis of Nutritional Status in Patients with Transthyretin Familial Amyloid Polyneuropathy: Impact of Tafamidis

et al. 2014

IntroductionGastrointestinal symptoms are common among patients with transthyretin familial amyloid polyneuropathy (TTR-FAP). This post hoc analysis evaluated the nutritional status of TTR-FAP patients treated with tafamidis while enrolled in clinical trials.MethodsNutritional status was measured by the modified body mass index (mBMI = BMI × albumin level). Treatment-related changes in mBMI were reported for 71 Val30Met TTR-FAP patients who completed an 18-month, randomized, double-blind, placebo-controlled trial and who continued into its open-label, 12-month extension.ResultsAt month 18, mBMI worsened in the placebo group (n = 33) (−33 ± 16 kg/m2 g/l, P = 0.04 versus baseline) but improved in the tafamidis group (n = 38) (+37 ± 14 kg/m2 g/l, P = 0.01 versus baseline) such that the effect size between the groups was statistically significant (P = 0.001). By month 30 (completion of the open-label extension), placebo patients with 12 months of tafamidis treatment and tafamidis-treated patients with 30 months of treatment both tended to increase their mBMI (28 ± 19 kg/m2 g/l and 16 ± 18 kg/m2 g/l, respectively). Increase in BMI was most pronounced in patients with low BMI at entry into the studies.ConclusionsmBMI is well suited to monitor disease progression in TTR-FAP patients. The delay in neurological deterioration brought about by tafamidis treatment in clinical trials is associated with improvements in, or maintenance of, mBMI.FundingThis study was sponsored by Pfizer Inc., New York, USA.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-014-0023-8) contains supplementary material, which is available to authorized users.