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Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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2015 (English)In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 15, 51Article in journal (Refereed) Published
Abstract [en]

Background: Hereditary transthyretin amyloid (ATTR) amyloidosis is a rare but fatal autosomal dominant condition that is present all over the world. A liver transplantation has been shown to halt the progress of the disease in selected patients and is currently considered to be the standard treatment. Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality. The aim of this study was to evaluate the long-term outcome of gastric emptying, gastrointestinal symptoms and nutritional status after liver transplantation for the disease.

Methods: Swedish patients with hereditary ATTR amyloidosis transplanted between 1990 and 2012 were included. A standardized method for measuring gastric emptying with a Tc-99m-labelled meal followed by scintigraphy was utilized. Validated questionnaires were used to assess gastrointestinal symptoms and the modified body mass index (mBMI), in which BMI is multiplied by s-albumin, was used to evaluate nutritional status. Non-parametrical statistical tests were used.

Results: Gastric emptying rates and nutritional statuses were evaluated approximately eight months before and two and five years after liver transplantation, whereas gastrointestinal symptoms were assessed in median nine months before and two and nine years after transplantation. No significant change was found in gastric emptying (median half-time 137 vs. 132 vs. 125 min, p = 0.52) or nutritional status (median mBMI 975 vs. 991 vs. 973, p = 0.75) after transplantation. Gastrointestinal symptom scores, however, had increased significantly over time (median score 7 vs. 10 vs. 13, p < 0.01).

Conclusions: Gastric emptying and nutritional status were maintained after liver transplantation for hereditary ATTR amyloidosis, although gastrointestinal symptom scores had increased over time.

Place, publisher, year, edition, pages
2015. Vol. 15, 51
Keyword [en]
Amyloidosis, Hereditary, Functional gastrointestinal disorders, Gastric emptying, Transplantation, Liver, Transthyretin
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:umu:diva-103731DOI: 10.1186/s12876-015-0284-4ISI: 000353687200001PubMedID: 25908211OAI: oai:DiVA.org:umu-103731DiVA: diva2:818868
Note

Originally included in thesis in manuscript form.

Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2017-12-04Bibliographically 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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Wixner, JonasSundström, TorbjornKarling, PontusAnan, IntissarSuhr, Ole B.

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