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Gastrointestinal disturbances in hereditary transthyretin amyloidosis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Mag-tarmstörningar vid ärftlig transthyretinamyloidos (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-88745ISBN: 978-91-7601-024-2 (print)OAI: oai:DiVA.org:umu-88745DiVA: diva2:717161
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
List of papers
1. THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease
Open this publication in new window or tab >>THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease
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2014 (English)In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-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
Keyword
Amyloid, Amyloid neuropathies, Amyloidosis, Hereditary, Cardiomyopathies, Secondary, Gastrointestinal disorders, Functional, Nutritional status, Quality of life, Transthyretin
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-88742 (URN)10.1186/1750-1172-9-61 (DOI)000335261900001 ()24767411 (PubMedID)
Available from: 2014-05-14 Created: 2014-05-14 Last updated: 2017-12-05Bibliographically approved
2. Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy
Open this publication in new window or tab >>Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy
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2012 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 24, no 12, 1111-e568 p.Article in journal (Refereed) Published
Abstract [en]

Background: Gastrointestinal (GI) complications are common in hereditary transthyretin amyloidosis and an autonomic dysfunction has been considered to explain these symptoms. The aim of this study was to investigate the impact of autonomic neuropathy on gastric emptying in hereditary transthyretin amyloidosis and to relate these findings to nutritional status, GI symptoms, gender, and age at disease onset.

Methods: Gastric emptying was evaluated with gastric emptying scintigraphy. Spectral analysis of the heart rate variability and cardiovascular responses after tilt test were used to assess the autonomic function. The nutritional status was evaluated with the modified body mass index (s-albumine x BMI).

Key Results: Gastric retention was found in about one-third of the patients. A weak correlation was found between the scintigraphic gastric emptying rate and both the sympathetic (rs = -0.397, P < 0.001) and parasympathetic function (rs = -0.282, P = 0.002). The gastric emptying rate was slower in those with lower or both upper and lower GI symptoms compared with those without symptoms (median T50 123 vs 113 min, P = 0.042 and 192 vs 113 min, P = 0.003, respectively). Multiple logistic regression analysis showed that age of onset (OR 0.10, CI 0.020.52) and sympathetic dysfunction (OR 0.23, CI 0.100.51), but not gender (OR 0.76, CI 0.311.84) and parasympathetic dysfunction (OR 1.81, CI 0.724.56), contributed to gastric retention.

Conclusions and Inferences: Gastric retention is common in hereditary transthyretin amyloidosis early after onset. Autonomic neuropathy only weakly correlates with gastric retention and therefore additional factors must be involved.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keyword
amyloidosis, autonomic nervous system disorders, gastric emptying, hereditary, nutrition status, transthyretin
National Category
Gastroenterology and Hepatology Neurosciences
Identifiers
urn:nbn:se:umu:diva-63020 (URN)10.1111/j.1365-2982.2012.01991.x (DOI)000311565300014 ()
Available from: 2012-12-28 Created: 2012-12-27 Last updated: 2017-12-06Bibliographically approved
3. Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis
Open this publication in new window or tab >>Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis
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2013 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, no 2, 99-106 p.Article in journal (Refereed) Published
Abstract [en]

Background: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.

Methods: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.

Results: The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM 16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).

Conclusions: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
Keyword
Amyloidosis, enteric nervous system, functional, gastrointestinal disorders, hereditary, interstitial cell of Cajal, transthyretin
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-76248 (URN)10.3109/13506129.2013.787985 (DOI)000319401200007 ()
Available from: 2013-07-08 Created: 2013-07-08 Last updated: 2017-12-06Bibliographically approved
4. Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis
Open this publication in new window or tab >>Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis
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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.

Keyword
Amyloidosis, Hereditary, Functional gastrointestinal disorders, Gastric emptying, Transplantation, Liver, Transthyretin
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-103731 (URN)10.1186/s12876-015-0284-4 (DOI)000353687200001 ()25908211 (PubMedID)
Note

Originally included in thesis in manuscript form.

Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2017-12-04Bibliographically approved

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