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  • 1.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bång, Joakim
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    A case report of osteoarthritis associated with hereditary transthyretin amyloidosis ATTRV30M2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 29-30Article in journal (Refereed)
  • 2.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Forsgren, S
    Nyhlin, N
    Terazaki, H
    Sakashita, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Colonic enteric nervous system in patients with familial amyloidotic neuropathy.1999In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 98, no 1, p. 48-54Article in journal (Refereed)
    Abstract [en]

    The colonic enteric nervous system was investigated in autopsy specimens from 12 patients with familial amyloidotic neuropathy (FAP) and 9 controls. The infiltration of amyloid deposits in the enteric nervous system was studied by double staining for amyloid and nerve elements. The myenteric plexus was immunostained for protein gene product (PGP) 9.5, vasoactive intestinal peptide (VIP), substance P and nitric oxide synthase (NOS). The immunostained nerve elements were quantified by computerised image analysis. Double staining revealed that there was no amyloid infiltration in the ganglia, or in the nerve fibres in the colonic enteric nervous system of FAP patients. The relative volume density of PGP 9.5-immunoreactive nerve fibres in both the circular and the longitudinal muscle layers in FAP patients did not differ significantly from that of controls. The relative volume density of VIP-immunoreactive nerve fibres in the circular muscle layer was significantly decreased in FAP patients compared with controls, but not in the longitudinal layer. The number of VIP-immunoreactive neurons/mm2 myenteric ganglia was significantly decreased in FAP patients. There were no statistical differences in the relative volume density for substance P- and NOS-immunoreactive nerve fibres between FAP patients and controls, nor was there any difference between FAP patients and controls regarding the number of NOS- and substance P-immunoreactive neurons/mm2 myenteric ganglia. It is concluded that the colonic enteric nervous system as a whole is intact and is not damaged by amyloid infiltration. The present observation of a reduction of VIP-immunoreactive nerve fibres and neurons in myenteric plexus of FAP patients might be one of the factors that contribute to the motility disorders seen in FAP patients.

  • 3.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Nyhlin, N
    Terazaki, H
    Sakashita, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Colonic endocrine cells in patients with familial amyloidotic polyneuropathy.1999In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 245, no 5, p. 469-73Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To establish whether the endocrine cell number is affected in the colon in Japanese FAP patients.

    SETTING: Department of Medicine, Umeå University Hospital and Department of Internal Medicine and Pathology, University Hospital, Kumamoto, Japan.

    SUBJECTS: Autopsy colon tissue specimens from 11 FAP patients and nine controls as well as 12 control biopsy specimens were included in the study.

    MEASUREMENTS: Endocrine cells in the colon were detected by immunohistochemistry and quantified by computerized image analysis.

    RESULTS: The autopsy material showed a slight autolysis. Neither enteroglucagon nor pancreatic polypeptide positive cells could be detected in the autopsy material, but were present in biopsy material. There was no statistical difference between autopsy and biopsy specimens regarding the number of peptide YY (PYY), somatostatin and serotonin cells. No significant differences were noted in PYY, somatostatin and serotonin immunoreactive cells in FAP patients compared to autopsy controls, though PYY cells tended to be decreased and serotonin and somatostatin cells tended to be increased in FAP patients.

    CONCLUSION: The difference between the Swedish and Japanese patients in the endocrine cell content points to the possibility of involvement of other factors than the endocrine cell depletion of the colon might be involved in the pathogenesis of gastro-intestinal dysfunction in FAP. The tendency of PYY to decrease in Japanese FAP might contribute to the development of diarrhoea in these patients.

  • 4.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Terazaki, H
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Comparison of amyloid deposits and infiltration of enteric nervous system in the upper with those in the lower gastrointestinal tract in patients with familial amyloidotic polyneuropathy.2001In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 102, no 3, p. 227-32Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal (GI) complications in familial amyloidotic polyneuropathy (FAP) are invariably present during the course of the disease. The aim of this study was to investigate amyloid deposits in the myenteric plexus of the stomach and small intestine in FAP patients and compare the results with those of the colon. Six FAP patients were included in the study. The myenteric plexus and the number of macrophages (CD68) and blood vessels were immunostained and quantified by computerised image analysis. Double staining for amyloid and nerve elements was used to detect amyloid infiltration in the myenteric plexus. Amyloid was found predominantly in the walls of blood vessels, and was detected in the nerves of five FAP patients and in 18% of the examined ganglia of the myenteric plexus of the stomach. In the small intestine, 6% of examined ganglia showed amyloid deposits. In contrast, no deposits were found in the myenteric plexus of the colon. CD68-positive cells showed no difference in three parts of the GI tract. Most amyloid deposits were noted in the stomach, followed by the small intestine. There are significantly more blood vessels in the stomach and small intestine compared with the colon, and the amount of amyloid correlated with the number of blood vessels, and not with the amount of nerves and ganglia. The enteric nerve system is not a targeted organ for amyloid deposition in FAP.

  • 5.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nyhlin, N
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Liver transplantation restores endocrine cells in patients with familial amyloidotic polyneuropathy.2000In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 70, no 5, p. 794-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to investigate familial amyloidotic polyneuropathy, Portuguese type patients' endocrine cell content in the stomach and duodenum before and after liver transplantation, and to relate the findings to the patients' gastrointestinal disturbances.

    METHODS: Ten liver-transplanted familial amyloidotic polyneuropathy, Portuguese type patients and 10 healthy controls were seen. Endocrine cells were identified by immunohistochemistry and quantified with computerized image analysis. The activity of the cells was appraised by measurements of the cell secretory index and nuclear area. Clinical symptoms were obtained from the patients' medical records.

    RESULTS: After transplantation, a significant increase of several endocrine cell types were noted, and the pretransplant depletion of several types of endocrine cells disappeared. For no type of endocrine cell was any difference compared with controls noted after transplantation. There was no significant decrease of the amount of amyloid in the biopsies after liver transplantation. The patients' symptoms remained generally unchanged after transplantation, although a substantial time lapse between pretransplant evaluation and transplantation was present.

    CONCLUSIONS: Liver transplantation restores the endocrine cells in the upper part of the gastrointestinal tract. The restoration was not correlated with an improvement of the patients' symptoms. No decrease of the amyloid deposits was noted.

  • 6.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Liszewska, Katarzyna
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Baranda, Jorge Mejia
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Amyloid fibril composition type is consistent over time in patients with Val30Met (p. Val50Met) transthyretin amyloidosis2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 3, article id e0266092Article in journal (Refereed)
    Abstract [en]

    Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

    Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

    Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

    Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

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  • 7. Ando, Y
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, G
    Costa, P M
    Detection of a variant protein in hair: new diagnostic method in Portuguese type familial amyloid polyneuropathy.1998In: BMJ (Clinical Research Edition), ISSN 0959-8138, Vol. 316, no 7143, p. 1500-1Article in journal (Refereed)
  • 8.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Eriksson, Robert
    Clinical Neurophysiology, Umeå University Hospital, Umeå, Sweden.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis2023In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 55, no 2, article id 2239269Article in journal (Refereed)
    Abstract [en]

    Introduction: In hereditary transthyretin amyloidosis (ATTRv), two different fibrillar forms causing the amyloid deposition, have been identified, displaying substantially cardiac or neuropathic symptoms. Neuropathic symptoms are more frequent in early-onset patients, whereas late-onset patients, besides cardiac symptoms, seem to develop carpal tunnel syndrome, more often. With ultrasonography (US) of peripheral nerves, it is possible to distinguish structural changes, and enlarged cross-sectional area (CSA). The main purpose of this study was, for the first time, to elucidate US of peripheral nerves in Swedish ATTRv patients at an early stage of the disease, and to evaluate possible early enlarged CSA.

    Material and methods: This prospective study included first visit data of 13 patients, aged 30–88 years, of which 11 with late-onset age. All had a positive V30M mutation. Eight men and six women (aged 28–74 years) served as controls.

    Results: Significantly enlarged CSA was seen in ATTRv patients for the tibial nerve at the ankle (p =.001), the sural nerve (p <.001), the peroneal nerve at the popliteal fossa (p =.003), and the ulnar nerve at the middle upper arm (p =.007).

    Conclusion: US of peripheral nerves could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression.

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  • 9. Buxbaum, Joel
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Serum transthyretin levels in Swedish TTR V30M carriers2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no 2, p. 83-85Article in journal (Refereed)
    Abstract [en]

    Serum transthyretin (TTR) levels have been reported to be reduced in Portuguese and Japanese patients with TTR V30M familial amyloidotic polyneuropathy and pre-symptomatic carriers of the allele as well as in the carriers of a number of other mutant TTRs. The only published report of serum TTR levels in Swedish TTR V30M carriers suggested that serum TTR levels were elevated in a small number of cases. Since Swedish V30M carriers have a lower degree of clinical penetrance than those from other countries we wished to determine if the reportedly elevated serum TTR concentrations and the lower clinical penetrance were part of a pathologic process that differed between the Swedish carriers and those of other ethnic groups. We compared the serum TTR levels, as determined by ELISA, in 42 documented Swedish TTR V30M carriers with 16 control individuals from the same geographic area in northern Sweden. Serum TTR concentrations in the controls were statistically significantly higher than in the TTR V30M carriers, which were in the same range as those in African-Americans carrying the TTR V122I allele. Thus, Swedish TTR V30M carriers have the same reduction in serum TTR as do other ethnic groups carrying the same or other TTR mutations.

  • 10.
    Gharibyan, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Jayaweera, Sanduni Wasana
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Endogenous Human Proteins Interfering with Amyloid Formation2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 3, article id 446Article, review/survey (Refereed)
    Abstract [en]

    Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

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  • 11. Gorram, Farida
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Alarcon, Flora
    Nuel, Gregory
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Plante-Bordeneuve, Violaine
    New data on the genetic profile and penetrance of hereditary Val30Met transthyretin amyloidosis in Sweden2021In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 28, no 2, p. 84-90Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease’s risk, we performed a comprehensive study of ATTRV30M families in Sweden.

    Methods: To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates’ effect on the disease’s risk.

    Results: We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6–10] at 40 years-old, increasing to 71% [95% CI= 65–76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals.

    Conclusions: Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.

  • 12.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lång, Kenneth
    Department of Medicine, Piteå Hospital , Piteå , Sweden..
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

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  • 13.
    Holmgren, Gösta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, Hans-Eric
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonasson, Jenni
    Stafberg, Christina
    Fahoum, Saomi
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiomyopathy in Swedish patients with the Gly53Glu and His88Arg transthyretin variants.2005In: Amyloid, ISSN 1350-6129, Vol. 12, no 3, p. 184-8Article in journal (Refereed)
  • 14.
    Iakovleva, Irina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nilsson, Lina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gharibyan, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Intissar, Anan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Walfridsson, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sauer-Eriksson, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Enthalpic Forces Correlate with Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma2015In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 16, p. 6507-6515Article in journal (Refereed)
    Abstract [en]

    The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.

  • 15.
    Iakovleva, Irina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hall, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oelker, Melanie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sandblad, Linda
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structural basis for transthyretin amyloid formation in vitreous body of the eye2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 7141Article in journal (Refereed)
    Abstract [en]

    Amyloid transthyretin (ATTR) amyloidosis is characterized by the abnormal accumulation of ATTR fibrils in multiple organs. However, the structure of ATTR fibrils from the eye is poorly understood. Here, we used cryo-EM to structurally characterize vitreous body ATTR fibrils. These structures were distinct from previously characterized heart fibrils, even though both have the same mutation and type A pathology. Differences were observed at several structural levels: in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments. Thus, our results show that ATTR protein structure and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation. By analyzing and matching the interfaces between the amino acids in the ATTR fibril with those in the natively folded TTR, we are able to propose a mechanism for the structural conversion of TTR into a fibrillar form.

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  • 16. Janunger, T
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, G
    Lövheim, O
    Ohlsson, P I
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Tashima, K
    Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser.2000In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 7, no 2, p. 137-40Article in journal (Refereed)
    Abstract [en]

    Cardiac failure in transthyretin (TTR) amyloidosis patients has been shown to be caused by different mutations in the TTR gene. In the present case, a 73-year-old man from Northern Sweden was evaluated for heart failure. Amyloid deposits were found in subcutaneous fat and in intestinal biopsies. The presence of a variant form of TTR was detected in the plasma by electrospray ionisation mass spectrometry (ESI-MS). The mutation was located by single-strand conformation polymorphism (SSCP) analysis of the TTR gene where a band shift was seen in exon 2. Direct sequencing of exon 2 revealed a single base-pair substitution (G1724T). This transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser). Mass spectrometry analysis excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples. Congo red and immunostaining of duodenum biopsy specimens confirmed the presence of systemic ATTR amyloidosis, and clinical examination, including echocardiography, found evidence of a restrictive cardiomyopathy. He had 10 years previously been operated for a bilateral carpal tunnel syndrome, but otherwise no symptoms were present that could be attributed to his systemic amyloidosis. No axonal polyneuropathy was noted at nerve conduction studies. This novel mutation is the second amyloidogenic TTR mutation found in the Swedish population.

  • 17.
    Jayaweera, Sanduni Wasana
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Surano, Solmaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pettersson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oskarsson, Elvira
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lettius, Lovisa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gharibyan, Anna L.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 411Article in journal (Refereed)
    Abstract [en]

    Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

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  • 18.
    Lindmark, Krister
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Solekrans, L.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Prevalence of transthyretin cardiac amyloidosis in a community-based heart failure population2019In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, p. 132-132Article in journal (Other academic)
  • 19.
    Löfbacka, Viktor
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Combining ECG and echocardiography to identify transthyretin cardiac amyloidosis in heart failure2021In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 41, no 5, p. 408-416Article in journal (Refereed)
    Abstract [en]

    AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure. The aim of this study was to evaluate the efficacy of electrocardiography (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients.

    METHODS: We investigated 58 patients with heart failure and an IVSd >14mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis heart failure (HF) patients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups.

    RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/ R in -aVR), the sensitivity was 100% and specificity was 95% using a cut off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%.

    CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other etiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

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  • 20. Mambule, C
    et al.
    Ando, Y
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, G
    Sandgren, O
    Stigbrandt, T
    Tashima, K
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Enhancement of AA-amyloid formation in mice by transthyretin amyloid fragments and polyethylene glycol.2000In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1474, no 3, p. 331-6Article in journal (Refereed)
    Abstract [en]

    The mechanism behind amyloid formation is unknown in all types of amyloidosis. Several substances can enhance amyloid formation in animal experiments. To induce secondary systemic amyloid (AA-type amyloid) formation, we injected silver nitrate into mice together with either amyloid fibrils obtained from patients with familial polyneuropathy (FAP) type I or polyethylene glycol (PEG). Mice injected with silver nitrate only served as controls. Amyloid deposits were detectable at day 3 in animals injected with amyloid fibrils and in those injected with PEG, whereas in control mice, deposits were not noted before day 12. Our results indicate that amyloid fibrils from FAP patients and even a non-sulfate containing polysaccharide (PEG) have the potential to act as amyloid-enhancing factors.

  • 21.
    Marberg, Therese
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderberg, Karin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Self-reported gastrointestinal symptoms are more common in liver transplanted transthyretin amyloidosis patients than in healthy controls and in patients transplanted for end-stage liver disease2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 47-48Article in journal (Refereed)
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  • 22.
    Matsunaga, N
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Rosenberg, P
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nagai, R
    Lundström, O
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Horiuchi, S
    Ando, Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Advanced glycation end product is implicated in amyloid-related kidney complications2005In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 65, no 4, p. 263-272Article in journal (Refereed)
    Abstract [en]

    Background. Kidney failure is a common complication in familial amyloidotic polyneuropathy (FAP). It has been suggested that advanced glycation end products (AGEs) play an important role in the development and pathogenesis of FAP.

    Material and methods. To evaluate the impact of AGEs on FAP patients' kidney dysfunction, we measured AGE in serum and urine of 28 FAP patients and 18 healthy controls by AGE-specific enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry utilizing antibodies to AGE and the receptor for AGE (RAGE) were used on kidney tissue from 3 FAP patients and 3 diabetic patients to disclose a correlation between amyloid deposits and AGE -RAGE.

    Results. The glomeruli of FAP patients were heavily deposited with amyloid and the glomerular size was enlarged. The space between Bowman's capsule and glomerulus was totally covered by the enlarged glomerulus. AGE and RAGE were deposited in glomeruli and tubuli and correlated with amyloid deposits. Decreased AGE levels in the liver-transplanted FAP patients' serum compared with that of non-transplanted patients were noted, and AGE concentration in serum tended to be higher in non-transplanted FAP patients compared with normal control subjects. There were no differences in the AGE urine levels in FAP patients compared with controls. No correlation could be found between AGE in urine and serum compared with serum albumin, serum creatinine and creatinine clearance.

    Conclusions. The accumulation of AGE, RAGE and amyloid in the kidney of FAP patients suggests that these molecules play an important role in the origin and pathogenesis of renal failure in FAP patients.

  • 23. Matsunaga, Noriko
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forsgren, Sture
    Nagai, Ryoji
    Rosenberg, Peter
    Horiuchi, Seikoh
    Ando, Yukio
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Advanced glycation end products (AGE) and the receptor for AGE are present in gastrointestinal tract of familial amyloidotic polyneuropathy patients but do not induce NF-kappaB activation.2002In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 5, p. 441-7Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy (FAP), Portuguese type, is a hereditary amyloidosis caused by mutated transthyretin (ATTR) in which an exchange of valine for methionine at position 30 has taken place (ATTR Val30Met). Gastrointestinal complications, such as nausea, diarrhoea and malabsorption, have a significant impact on survival since the cause of death in the majority of cases is a consequence of extreme malnutrition due to dysmotility of the gastrointestinal tract. Recently, a role of the receptor for advanced glycation end products (RAGE) has been implicated in amyloid toxicity. Transthyretin (TTR) amyloid fibrils have been shown to have affinity for RAGE and subsequently induce NF-kappaB activation and apoptosis. Since gastrointestinal dysfunction plays an important role in FAP, we wanted to investigate if amyloid toxicity in the gastrointestinal tract is related to RAGE, NF-kappaB activation and apoptosis. Gastrointestinal tract autopsy samples were studied for the distribution of amyloid, RAGE, advanced glycation end products (AGE) and NF-kappaB. Furthermore, we examined the immunoreactivity of an apoptotic marker to investigate if an apoptotic pathway contributes to amyloid toxicity. The distribution of RAGE and AGE strongly correlated to that of amyloid deposits. Sequential immunofluorescence staining revealed a clear relationship between TTR, AGE and RAGE. No correlation between NF-kappaB, apoptotic marker and amyloid deposits was found. We conclude that RAGE-AGE or RAGE-TTR interaction might play important roles for gastrointestinal dysfunction and amyloid toxicity, although not through NF-kappaB activation and apoptosis.

  • 24.
    Mejia Baranda, Jorge
    et al.
    Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Ljungberg, Jenny
    Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Oskarsson, Viktor
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Piteå Research Unit, Region Norrbotten, Piteå, Sweden.
    Epidemiology of hereditary transthyretin amyloidosis in the northernmost region of Sweden: a retrospective cohort study2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 2, p. 120-127Article in journal (Refereed)
    Abstract [en]

    Introduction: Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse.

    Methods: We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs).

    Results: Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84–2.47) cases in 2006–2009 to 4.92 (95%CI, 3.46–6.78) cases in 2016–2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006–2018 (95%CI, 1.78–3.77). However, there were indications of lower SMRs over time (2006–2012, 2.96 [95%CI, 1.73–4.74]; 2013–2018, 2.32 [95%CI, 1.23–3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87–5.13]; yes, 2.09 [95%CI, 1.08–3.64]).

    Conclusion: The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis–with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.

  • 25. Nyhlin, N
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    El, Salhy M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Reduction of free radical activity in amyloid deposits following liver transplantation for familial amyloidotic polyneuropathy.2002In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 251, no 2, p. 136-41Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Liver transplantation halt the progress of familial amyloidotic polyneuropathy (FAP). Oxidative stress has been implicated in amyloid toxicity and formation. The objective of this study was to establish whether markers for oxidant stress and antioxidant capacity change following liver transplantation in patients with FAP.

    DESIGN: Morphometric and biochemical study.

    SETTING: Tertiary referral centre.

    SUBJECTS: Duodenal biopsy samples from 16 patients, taken before and after liver transplantation were used for morphometry. Serum samples from 14 patients, seven of whom had received transplants, were analysed regarding antioxidant capacity.

    INTERVENTION: Liver transplantation.

    MAIN OUTCOME MEASURES: Immunohistochemistry was used to stain for the lipid peroxidation product 4-hydroxynonenal (HNE), and Congo red staining was used for amyloid detection. Positive areas were quantified by point counting. Total antioxidant capacity (TAC) was measured with a colourimetric assay.

    RESULTS: In tissue, a decrease of HNE was noted after liver transplantation, whereas no significant changes were detected for amyloid deposits. No difference between transplanted and not transplanted patients was noted for total antioxidant capacity measured in serum.

    CONCLUSION: To our knowledge, this is the first description of a reduction of markers for free radical activity after cessation of amyloid formation. The findings implicate that amyloid formation in transthyretin (TTR) amyloidosis generates oxidative stress, whereas amyloid deposits as such are less toxic to sourrounding tissues.

  • 26. Nyhlin, N
    et al.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    el-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Endocrine cells in the upper gastrointestinal tract in relation to gastrointestinal dysfunction in patients with familial amyloidotic polyneuropathy.1999In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 6, no 3, p. 192-8Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal (GI) dysfunction is a common complication of familial amyloidotic polyneuropathy (FAP). In previous reports, a decreased content of small and large intestinal endocrine cells has been found in patients with FAP and it has been suggested that this may contribute to the development of GI disturbances. The aim of the present study was to investigate the endocrine cell content in the stomach and duodenum of FAP patients, and to correlate the findings with gastric emptying. Fifteen patients with FAP were included in the study. Twenty-eight subjects with macroscopically and histologically normal mucosa were used as controls for endocrine cell contents and 14 healthy subjects for gastric scintigraphy. The endocrine cells were identified by immunohistochemistry and quantified with image analysis. Gastric emptying time was detected by scintigraphy and endoscopy. The number of chromogranin A-immunoreactive (IR) cells was reduced in all investigated parts of the GI tract except bulbus duodeni. Gastrin/CCK cell content was reduced in duodenum, but tended to be increased in antrum of the stomach (P = 0.07). Otherwise, the content of all other endocrine cells types in the upper GI tract was reduced compared with controls. A correlation with malnutrition was found for gastric inhibitory polypeptide and secretin cell content in bulbus duodeni. Gastric scintigraphy disclosed delayed gastric emptying of solid food, but the finding was not correlated to the decreased content of neuroendocrine cells. The severity of endocrine cell depletion was not correlated to duration of GI disturbances. The present study showed that the endocrine cells of the stomach are affected in FAP patients and that the abnormalities in the upper GI endocrine cells occur early during the course of the disease.

  • 27.
    Obayashi, Konen
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ueda, Mitsuharu
    Nakamura, Masaaki
    Okamoto, Sadahisa
    Yamashita, Taro
    Miida, Takashi
    Ando, Yukio
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Impact of serotonin transporter and catechol-O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients.2008In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 398, no 1-2, p. 10-4Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol-O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients. METHODS: Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion. RESULTS: A significantly higher LA allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the LA allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted. CONCLUSION: A high expression of serotonin transporter induced by LA allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.

  • 28. Obayashi, Konen
    et al.
    Tasaki, Masayoshi
    Jono, Hirofumi
    Ueda, Mitsuharu
    Shinriki, Satoru
    Misumi, Yohei
    Yamashita, Taro
    Oshima, Toshinori
    Nakamura, Teruya
    Ikemizu, Shinji
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Yukio
    Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine2013In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 419C, p. 127-131Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). METHODS: Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. RESULTS: Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. CONCLUSIONS: These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP.

  • 29.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Metabolomics analysis for diagnosis and biomarker discovery of transthyretin amyloidosis2021In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 28, no 4, p. 234-242Article in journal (Refereed)
    Abstract [en]

    Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p <.05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.

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  • 30.
    Paulsson Rokke, Hedvig
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sadat Gousheh, Nima
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspected transthyretin amyloidosis2020In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 15, no 1, article id 278Article in journal (Refereed)
    Abstract [en]

    Background: The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has not yet been evaluated. The aim was to evaluate the diagnostic accuracy of skin punch biopsies from abdominal fat in patients with suspected ATTR amyloidosis.

    Material and methods: Data were evaluated from patients who had undergone abdominal fat pad biopsies using a skin punch due to suspected amyloidosis from 2006 to 2015. The biopsies had been analysed using Congo red staining to determine the presence of amyloid, and immunohistochemistry or Western blot to determine the type of amyloidosis. The final diagnosis was based on the clinical picture, biopsy results and DNA sequencing. Minimum follow-up after the initial biopsy was 3 years.

    Results: Two hundred seventy-four patients (61% males) were identified, and in 132 (48%), a final diagnosis of amyloidosis had been settled. The majority (93%) had been diagnosed with hereditary transthyretin (ATTRv) amyloidosis, and therefore subsequent analyses were focused on these patients. Overall, our data showed a test specificity of 99% and a sensitivity of 91%. Ninety-eight (94%) of the patients had neuropathic symptoms at diagnosis, whereas 57 (55%) had signs of amyloid cardiomyopathy. Subgroup analyses showed that patients with merely neuropathic symptoms displayed the highest test sensitivity of 91%, whereas patients with pure cardiomyopathy displayed the lowest sensitivity of 83%. However, no significant differences in sensitivity were found between patients with or without cardiomyopathy or between the sexes.

    Conclusions: Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspect ATTRv amyloidosis, including patients presenting with cardiomyopathy. In addition, the method enables typing not only of the precursor protein but also of the amyloid fibril type, which is related to the phenotype and to the outcome of the disease.

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  • 31.
    Planté-Bordeneuve, Violaine
    et al.
    Department of Neurology, Henri Mondor University Hospital, APHP, Créteil, France; Paris Est-Créteil University, Créteil, France; Inserm U.955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France.
    Gorram, Farida
    Department of Neurology, Henri Mondor University Hospital, APHP, Créteil, France; Paris Est-Créteil University, Créteil, France; Inserm U.955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Mazzeo, Anna
    Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    Gentile, Luca
    Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    Cisneros-Barroso, Eugenia
    Research Health Institute of the Balearic Islands (IdISBa), Internal Medicine Department, Son Llàtzer University Hospital, Palma de Mallorca, Spain.
    Gonzalez-Moreno, Juan
    Research Health Institute of the Balearic Islands (IdISBa), Internal Medicine Department, Son Llàtzer University Hospital, Palma de Mallorca, Spain.
    Losada, Ines
    Research Health Institute of the Balearic Islands (IdISBa), Internal Medicine Department, Son Llàtzer University Hospital, Palma de Mallorca, Spain.
    Waddington-Cruz, Marcia
    CEPARM, Federal University of Rio de Janeiro, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil.
    Pinto, Luiz Felipe
    CEPARM, Federal University of Rio de Janeiro, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil.
    Parman, Yeşim
    Department of Neurology, Neuromuscular Unit Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
    Fanen, Pascale
    Paris Est-Créteil University, Créteil, France; Inserm U.955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France; Department of Genetics, Henri Mondor University Hospital, APHP, Créteil, France.
    Alarcon, Flora
    Laboratory MAP5 UMR CNRS 8145 Paris University, Paris, France.
    Nuel, Gregory
    Stochastics and Biology Group, Department of Probability and Statistics (LPSM, UMR CNRS 8001), Sorbonne University, Paris, France.
    A multicentric study of the disease risks and first manifestations in Hereditary transthyretin amyloidosis (ATTRv): insights for an earlier diagnosis2023In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 30, no 3, p. 313-320Article in journal (Refereed)
    Abstract [en]

    Background: In hereditary transthyretin amyloidosis (ATTRv), early manifestation and age at onset (AO) may vary strikingly. We assessed the disease’risk (penetrance), AO and initial features in ATTRv families to gain insights on the early disease presentation. Methods: Genealogical information, AO and first disease manifestations were collected in ATTRv families, from Sweden, Italy (Sicily), Spain (Mallorca), France, Turkey, Brazil. Penetrance was computed using a non-parametric survival method. Results: We analysed 258 TTRV30M kindreds and 84 carrying six other variants (TTRT49A, F64L, S77Y, S77F, E89Q, I107V). In ATTRV30M families, the earliest disease risk was found at age 20 years in the Portuguese and Mallorcan families and at age 30-35 years, in the French and Swedish groups. The risks were higher in men and in carriers of maternal descent. In families carrying TTR-nonV30M variants, the earliest disease risk ranged from 30 y-o in TTRT49A to 55 y-o in TTRI107V families. Peripheral neuropathy symptoms were the most frequent initial manifestations. Among patients carrying TTRnonV30M variants, about 25% had an initial cardiac phenotype, one third a mixed phenotype. Conclusion: Our work provided solid data on the risks and early features of ATTRv in a spectrum of families to enhance an early diagnosis and treatment.

  • 32.
    Samuelsson, Kristin
    et al.
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jovanovic, Ana
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Egervall, Karl
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Press, Rayomand
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hereditary transthyretin amyloidosis in Sweden: Comparisons between a non-endemic and an endemic region2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 4, p. 220-227Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden.

    Methods: The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017.

    Results: In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies.

    Conclusion: There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm.

  • 33.
    Schmidt, Hartmut H.
    et al.
    Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen (formerly of University Hospital Munster, Munster, Germany), Essen, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Planté-Bordeneuve, Violaine
    Department of Neurology, East Paris University, Hospital Henri Mondor – Public Assistance Hospital of Paris, Créteil, France; Mondor Biomedical Research Institute – IMRB, INSERM, U955 Team 10 “Biology of the Neuro-Muscular System”, Créteil, France.
    Muñoz-Beamud, Francisco
    Hereditary Amyloidosis Unit, Department of Internal Medicine, Juan Ramón Jiménez Hospital, Huelva, Spain.
    Lladó, Laura
    Liver Transplantation Unit, Department of Surgery, and the Multidisciplinary Familial Amyloidosis Unit, Hospital Universitari de Bellvitge, Barcelona, Spain; Biomedical Research Institute, IDIBELL, University of Barcelona, Barcelona, Spain.
    Gillmore, Julian D.
    National Amyloidosis Centre, Division of Medicine, University College London Medical School, London, United Kingdom.
    Mazzeo, Anna
    Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    Li, Xingyu
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Arum, Seth
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Jay, Patrick Y.
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Adams, David
    Neurology Department, Université Paris-Saclay, U1195, INSERM, Le Kremlin Bicêtre, France; Neurology Department, AP-HP, CHU Bicêtre, Le Kremlin Bicêtre, France.
    Anan, Intissar (Contributor)
    Umeå University Hospital.
    Nordh, Erik (Contributor)
    Umeå University Hospital.
    Unéus, Erica (Contributor)
    Umeå University Hospital.
    Pilebro, Björn (Contributor)
    Umeå University Hospital.
    Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation2022In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 22, no 6, p. 1646-1657Article in journal (Refereed)
    Abstract [en]

    Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, −6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, −5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

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  • 34.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Karlsson, A
    Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 263, no 3, p. 294-301Article in journal (Refereed)
  • 35.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Rydh, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Gastric emptying before and after liver transplantation for familial amyloidotic polyneuropathy, Portuguese type (Val30Met).2003In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 10, no 2, p. 121-6Article in journal (Refereed)
    Abstract [en]

    Liver transplantation is an accepted treatment of familial amyloidotic polyneuropathy (FAP), Portuguese type (Val30Met), and the outcome so far seems promising. Gastric retention with nausea and vomiting are common complications of the disease, and may interfere with immuno-suppression therapy and prolong recovery after liver transplantation. The aim of this study was to assess the frequency of gastric retention in FAP patients and to evaluate the impact liver transplantation has on gastric emptying. Twenty-two patients, who had undergone liver transplantation, and had been re-examined for gastric retention after the procedure, were included in the study. Gastric emptying was recorded by scintigraphy after the ingestion of a 99m-technetium (99mTc)-labelled meal (omelette). The half-time (T50) of the emptying phase was calculated. Gastrointestinal symptoms before and after transplantation were recorded, and the majority of patients were also subjected to an upper endoscopic examination, where the presence of solid residual in the stomach was regarded as consistent with gastric retention. A high frequency of gastric retention was noted among the patients both before and after transplantation, and no significant improvement for the group was noted, even though decreased gastric emptying was noted for patients with a duration of the disease for less that 4 years. Patients who improved their nutritional status after transplantation had a faster gastric emptying than those who deteriorated. From our findings it can be concluded that gastric retention is a common complication of FAP and that gastric emptying in patients with longstanding disease (> or = 4 years) is unchanged after liver transplantation.

  • 36.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lång, K
    Wikström, L
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    El-Salhy, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, G
    Tashima, K
    Scavenger treatment of free radical injury in familial amyloidotic polyneuropathy: a study on Swedish transplanted and non-transplanted patients.2001In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 61, no 1, p. 11-8Article in journal (Refereed)
    Abstract [en]

    Since oxidative stress has been implicated in amyloid diseases, a study of scavenger treatment of hereditary transthyretin amyloidosis was undertaken on 23 familial amyloidotic polyneuropathy (FAP) patients. Nine patients had undergone a liver transplantation for the disease. Twenty patients completed the 6-month study period of scavenger treatment (vitamin C, 1 g, three times daily, vitamin E, 0.1 g, three times daily and acetylcysteine, 0.2 g three times daily). They were evaluated clinically and by immunohistochemical measurement of hydroxynonenal (HNE), a product of lipid peroxidation, in biopsy specimens. For non-transplanted patients, no improvement was found for HNE in relation to the amyloid content in biopsy specimens, whereas a tendency to a decreased amount was noted for transplanted patients. Clinically, no differences were found for non-transplanted patients, but an increased nutritional status, measured by a modified body mass index (mBMI) was noted for transplanted patients. In summary, scavenger treatment with the drugs and doses used in the present study appears to be unable to decrease lipid peroxidation in amyloid-rich tissue in non-transplanted FAP patients. For transplanted patients, lipid peroxidation tended to decrease, and the nutritional status measured by mBMI improved, even though the findings may be explained by liver transplantation alone, scavenger treatment may facilitate recovery after transplantation.

  • 37.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish landscape of hereditary ATTR amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 93-94Article in journal (Refereed)
    Abstract [en]

    Northern Sweden is a well-known clustering area for hereditary transthyretin (TTR) amyloid (ATTR) amyloidosis caused by the Val30Met mutation. However, several additional mutations have been found in the Swedish population, of which many, such as the Ala45Ser, Gly57Arg and His88Arg mutations, have not been reported outside of Sweden to the best of our knowledge. We aim to give an overview of the various mutations found in the Swedish population.

  • 38.
    Suhr, Ole Bernt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wijayatunga, Priyantha
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Westermark, Per
    Ihse, Elisabet
    Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211983Article in journal (Refereed)
    Abstract [en]

    Background: The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). The type of amyloid fibril exerts an impact on the phenotype of the disease, and on the outcome of diagnostic procedures and therapy. The aim of the present study was to investigate if the type of amyloid fibril remains the same within ATTR Val30Met amyloidosis families. Methods: Fifteen families were identified in whom at least two first-degree relatives had their amyloid fibril composition determined. The type of ATTR was determined by Western blot in all but two patients. For these two patients a positive 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy indicated ATTR Type A. Results: In 14 of the 15 families, the same amyloid fibril composition was noted irrespective of differences in age at onset. In the one family, different ATTR fibril types was found in two brothers with similar ages at onset. Conclusions: Family predisposition appears to have an impact on amyloid fibril composition in members of the family irrespective of their age at onset of disease, but if genetically determined, the gene/genes are likely to be situated at another location than the TTR gene in the genome.

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  • 39.
    Unéus, Erica Irene
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Bäckström, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Margareta
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors2022In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 13, article id 816636Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

    Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

    Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

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  • 40.
    Unéus, Erica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Visualisation of amyloid deposition within the brain of long-term hereditary transthyretin amyloidosis survivors by 18F-flutemetamol positron emission tomography2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no S1, p. 287-287, article id EPR3027Article in journal (Other academic)
    Abstract [en]

    Background and aims: Hereditary transthyretin amyloid (ATTRv) amyloidosis caused by the transthyretin (TTR) Val30Met (p.V50M) mutation is characterised by peripheral neuropathy, and central nervous (CNS) complications has rarely been reported. However, liver transplantation has prolonged the patients’ survival, and CNS complications attributed to amyloid angiopathy caused by CNS synthesis of variant TTR have been reported. The aim of the study was to ascertain CNS amyloid deposition in long-term ATTRv survivors.

    Methods: 20 ATTR Val30Met patients with symptoms from the CNS and a median disease duration of 16 years (9-25 years) together with five Alzheimer (AD) patients, who served as positive controls were included in the study. Amyloid CNS deposits were assessed by 18F- flutemetamol PET/CT examination utilising relative z scores with pons as reference.

    Results: Expectedly, all Alzheimer patients had an clearly increased global composite z score above 2.0 compared with 55% of the ATTRv patients. There was an increased local uptake corresponding to cerebellum in 12 ATTRv patients compared to only one in the AD group (fig 1). Four of these ATTRv patients had a global composite z score within the normal range. No correlation between duration after 9 years and amyloid CNS deposition was noted.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is increased and is often noted in the cerebellum. However, not all patient display amyloid CNS deposition, thus, additional causes for CNS complications should always be considered.

  • 41.
    Wange, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ericzon, Bo-Göran
    Pennlert, Johanna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Atrial Fibrillation and Central Nervous Complications in Liver Transplanted Hereditary Transthyretin Amyloidosis Patients2018In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 102, no 2, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    Background. Central nervous system (CNS) complications are increasingly noted in liver transplanted (LTx) hereditary transthyretin amyloid (ATTRm) amyloidosis patients; this suggests that the increased survival allows for intracranial ATTRm formation from brain synthesized mutant TTR. However, atrial fibrillation (AF), a recognised risk factor for ischemic CNS complications, is also observed after LTx. The aim of the study was to investigate the occurrence of CNS complications and AF in LTx ATTRm amyloidosis patients. Methods. The medical records of all LTx ATTRm amyloidosis patients in the county of Vasterbotten, Sweden, were investigated for information on CNS complications, AF, anticoagulation (AC) therapy, hypertension, cardiac ischemic disease, hypertrophy, and neurological status. Results. Sixty-three patients that had survived for 3 years or longer after LTx were included in the analysis. Twenty-five patients had developed 1 or more CNS complications at a median of 21 years after onset of disease. AF was noted in 21 patients (median time to diagnosis 24 years). Cerebrovascular events (CVE) developed in 17 (median time to event 21 years). CVEs occurred significantly more often in patients with AF (P < 0.002). AC therapy significantly reduced CVEs, including bleeding in patients with AF (P = 0.04). Multivariate analysis identified AF as the only remaining regressor with a significant impact on CVE (hazard ratio, 3.8; 95% confidence interval 1.1-9.5; P = 0.029). Conclusions. AF is an important risk factor for CVE in LTx ATTRm amyloidosis patients, and AC therapy should be considered. However, the increased bleeding risk with AC therapy in patients with intracranial amyloidosis should be acknowledged.

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  • 42.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rydh, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hornsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy2012In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 24, no 12, p. 1111-e568Article in journal (Refereed)
    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.

  • 43.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mundayat, Rajiv
    Pfizer Inc, New York, NY, USA.
    Karayal, Onur N
    Pfizer Inc, New York, NY, USA.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    THAOS: Gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease2014In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 9, no 1, p. 61-Article in journal (Refereed)
    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.

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  • 44.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Obayashi, Konen
    Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Ando, Yukio
    Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis2013In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, no 2, p. 99-106Article in journal (Refereed)
    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.

  • 45.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Bjorn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Effect of doxycycline and ursodeoxycholic acid on transthyretin amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 78-79Article in journal (Refereed)
    Abstract [en]

    Doxycycline has been shown to disrupt transthyretin amyloid (ATTR) fibrils [1] and tauro-ursodeoxycholic acid (TUDCA) has been shown to reduce TTR toxic aggregates in mice [2]. Further, in 2010 Cardoso et al. showed that a combined doxycycline/TUDCA treatment had a synergistic effect, decreasing ATTR deposition. Ursodeoxycholic acid (UDCA) is a bile acid used for the treatment of certain cholestatic syndromes with an efficacy similar to that of TUDCA. Based on this knowledge, we wanted to explore if treatment with doxycycline and UDCA (Dox/Urso) would prevent disease progression in ATTR amyloidosis. UDCA was selected since TUDCA is not available in Sweden.

  • 46.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Management of gastrointestinal complications in hereditary transthyretin amyloidosis: a single-center experience over 40 years2018In: Expert Review of Gastroenterology & Hepatology, ISSN 1747-4124, E-ISSN 1747-4132, Vol. 12, no 1, p. 73-81Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin amyloidosis (ATTRm amyloidosis) is a rare disease caused by the deposition and accumulation of insoluble non-native transthyretin fibrils in the body. The disease inevitably results in widespread organ disruption, and poor life expectancy. The GI tract is one organ system vulnerable to disruption and, although the clinical presentation of the disease varies, GI involvement affects most patients with ATTRm amyloidosis.

    Areas covered: This article presents our experience with diagnosing and treating the GI symptoms of ATTRm amyloidosis patients at our center over the last 40 years, in the Swedish clustering area of the disease. Our aim is to help other physicians to better manage GI complications in patients with this rare but widespread condition.

    Expert commentary: GI symptoms are debilitating complications for ATTRm amyloidosis patients to experience, yet with the appropriate questioning and diagnosis methods, symptomatic treatments of these symptoms can be implemented to provide relief. Further, patients with fewer GI complications and a good nutritional status are also better candidates for liver transplantation which, in selected cases, is the best disease-modifying treatment of ATTRm amyloidosis to date.

  • 47.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sundström, Torbjorn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Outcome of gastric emptying and gastrointestinal symptoms after liver transplantation for hereditary transthyretin amyloidosis2015In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 15, article id 51Article in journal (Refereed)
    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.

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  • 48.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Törnblom, H.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindberg, G.
    Abnormal small bowel motility in patients with hereditary transthyretin amyloidosis2018In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 30, no 9, article id e13354Article in journal (Refereed)
    Abstract [en]

    Background: Gastrointestinal complications are common in hereditary transthyretin amyloid (ATTRm) amyloidosis. The underlying mechanisms have not been fully elucidated, and the patients' small bowel function remains largely unexplored. The aim of the present study was to compare the small bowel motility in ATTRm amyloidosis patients with that in non-amyloidosis patient controls.

    Methods: ATTRm amyloidosis patients undergoing evaluation for liver transplantation were consecutively investigated with 24-hour duodenojejunal manometry (n=19). The somatostatin analogue octreotide was used to induce fasting motility. Patients with age at onset of 50years were defined as late-onset cases. For each patient, three age- and sex-matched patient controls (n=57) were selected from the total pool of investigated patients.

    Key Results: Manometry was judged as abnormal in 58% of the patients and in 26% of the patient controls (P=.01). Patients displayed significantly more daytime phase III migrating motor complexes than patient controls (median 4 vs 2, P<.01), and had a higher frequency of low-amplitude complexes (16% vs 4%; however, this difference did not reach statistical significance, P=.10). Furthermore, late-onset patients showed a delay in octreotide response (5.4 vs 3.8minutes, P<.01), but this was not observed for early-onset patients or within the control group.

    Conclusions and Inferences: Patients with ATTRm amyloidosis displayed abnormalities in their small bowel motility more frequently than non-amyloidosis patient controls, and the manometric pattern was probably best consistent with a combined neuromyopathic disorder. The delayed octreotide response in late-onset patients warrants further investigation.

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  • 49.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 39-40Article in journal (Refereed)
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