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THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Pfizer Inc, New York, NY, USA.
Pfizer Inc, New York, NY, USA.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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2014 (English)In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, Vol. 9, no 1, 61- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients' nutritional status and health-related quality of life (HRQoL).

METHODS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL.

RESULTS: Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p < 0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p < 0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p < 0.001 for all).

CONCLUSIONS: Gastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances.

Place, publisher, year, edition, pages
BioMed Central, 2014. Vol. 9, no 1, 61- p.
Keyword [en]
Amyloid, Amyloid neuropathies, Amyloidosis, Hereditary, Cardiomyopathies, Secondary, Gastrointestinal disorders, Functional, Nutritional status, Quality of life, Transthyretin
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:umu:diva-88742DOI: 10.1186/1750-1172-9-61ISI: 000335261900001PubMedID: 24767411OAI: oai:DiVA.org:umu-88742DiVA: diva2:717127
Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2015-08-28Bibliographically approved
In thesis
1. Gastrointestinal disturbances in hereditary transthyretin amyloidosis
Open this publication in new window or tab >>Gastrointestinal disturbances in hereditary transthyretin amyloidosis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Mag-tarmstörningar vid ärftlig transthyretinamyloidos
Abstract [en]

Background

Transthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis.

Methods

The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis.

Results

Sixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (<50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p <0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p <0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p <0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p <0.01) and parasympathetic (rs = -0.3, p <0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p <0.01) and longitudinal (median density 0.0 vs. 1.8, p <0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p <0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation.

Conclusion

GI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 47 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1633
Keyword
Autonomic Nervous Systems, Cajal Interstitial Cells, Enteric Nervous System, Familial Amyloid Polyneuropathy, Functional Gastrointestinal Disorders, Gastric Emptying, Liver Transplantation, Nutrition Status, Transthyretin Amyloidosis
National Category
Gastroenterology and Hepatology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-88745 (URN)978-91-7601-024-2 (ISBN)
Public defence
2014-06-05, Hörsal B, plan 9, målpunkt T, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2014-05-15 Created: 2014-05-14 Last updated: 2015-06-09Bibliographically approved

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