Master of Science / Department of Clinical Sciences / Barret J. Bulmer / Degenerative valve disease is the most common cardiac affliction facing our canine population. To date, canine research has focused on characterizing the disease itself and the histopathological features. Because of the ability to routinely repair or replace diseased valves in human medicine, research focus in humans has been on perfecting these techniques rather than elucidating etiology. The recent interest in valvular interstitial cells has been primarily due to their capacity to degrade collagen with the knowledge that disorganized collagen is a hallmark characteristic of degenerative valve disease. In this project, an easily reproducible cell culture protocol for canine valvular interstitial cells was developed. These cells were phenotyped by utilization of RT-PCR and immunocytochemistry. The use of these cells in a research project looking at response to endothelin exposure with and without protection of vitamin E is demonstrated as an example of the unlimited possibilities for these cells to elucidate not only the etiology of the disease process but also the response to therapy.

Harnblase. Weiterhin bestärkt die beobachtete Kopplung die Hypothese, dass das Myofibroblastennetzwerk afferente Signale Verstärken und modulieren kann. Die Verbesserung des Verständnisses der Harnblasenfunktion ist von grundlegendem Interesse für die Behandlung von Miktionsstörungen. Eine Störung von mechanischer Stimulierbarkeit und Kopplung der suburothelialen Myofibroblasten kann eine Störung der Sensorik der Harnblase plausibel erklären und stellt einen neuen Therapieansatz dar.:1 Abkürzungsverzeichnis 2 Einführung 2.1 Hintergrund 2.2 Anatomische und physiologische Grundlagen der Harnblasenfunktion 2.2.1 Aufbau der Harnblasenwand 2.2.2 Terminologie und Klassifikation interstitieller Zellen der Harnblase 2.2.3 Phänotypisierung der suburothelialen Myofibroblasten 2.2.4 Funktionsweise der Myofibroblasten 2.2.5 Innervation des unteren Harntraktes und neuronale Kontrolle der Harnblasenfunktion 2.2.6 Lokale sensorische Netzwerke der Harnblase 3 Aufgabenstellung 4 Material und Methoden 4.1 Gewinnung und Zellkultur suburothelialer Myofibroblasten 4.2 Lösungen und Chemikalien 4.3 Calcium imaging 4.4 Datenanalyse 4.4.1 Erzeugung der FI-Ratio Datensätze 4.4.2 Automatische Fluoreszenz-Signal-Analyse 4.5 Aufbau und Anordnung der Experimente 4.5.1 Spontanaktivität 4.5.2 Mechanische Stimulation mittels Glasmikropipette 4.5.3 Mechanische Stimulation durch Scherstress 4.5.4 Hypoosmolare Stimulation 5 Ergebnisse 5.1 Spontane Kalziumaktivität humaner suburothelialer Myofibroblasten 5.2 Mechanische Stimulierbarkeit durch Druck mittels Glasmikropipette 5.2.1 Intrazelluläre Ausbreitung mechanisch induzierter Kalziumsignale 5.2.2 Interzelluläre Ausbreitung mechanisch induzierter Kalziumsignale in kultivierten humanen suburothelialen Myofibroblasten 5.3 Mechanische Stimulierbarkeit durch Scherstress 5.4 Mechanische Stimulierbarkeit durch osmotischen Stress 6 Diskussion 6.1 Beobachtete Kalziumsignale suburothelialer Myofibroblasten 6.2 Bedeutung der mechanischen Stimulierbarkeit 6.3 Identifikation der stretch-activated channels 6.4 Bedeutung der interzellulären Kopplung 6.5 Konzept zur Rolle der suburothelialen Myofibroblasten 6.6 Methodischer und experimenteller Ansatz 6.6.1 Selbst entwickelte Fluoresence Analysis Software 6.6.2 Methoden der mechanischen Stimulierbarkeit 6.7 Pathophysiologische Aspekte 7 Zusammenfassung der Arbeit 8 Literaturverzeichnis 9 Anlagen 9.1 Selbstständigkeitserklärung 9.2 Lebenslauf 9.3 Publikationen 9.4 Danksagung

This thesis focuses on the characterization of rhythmic activity in the colon of healthy subjects and patients diagnosed with refractory constipation; this activity is mediated by pacemaker cells in the gastrointestinal system, the Interstitial cells of Cajal (ICC). The myogenic activity described are the cyclic motor patterns (CMP) and haustral activity; characterization of these motor patterns in healthy subjects provided control values for the subsequent comparison in patients. Frequency analysis of CMP revealed a novel high-frequency activity (7-15cpm) unrelated to the breathing artefact. Three categories of cyclic motor patterns were observed: (1) CMP following mass peristaltic events (HAPW); (2) those that occur in isolation of other colonic motor patterns (HAPW) in the colon; and (3) low-frequency (2-6cpm), prominently retrograde rhythmic activity in the rectum. CMP were scarcely present in majority of the patients; however, elevated retrograde CMP in the distal colon and rectum in some patients plays a role in retarding flow of colonic content. A detailed characterization of haustral activity (comprised of 2 boundaries and the activity within a haustrum) is reported for the first time using high-resolution colonic manometry. Furthermore, we find that over expression of haustral boundary activity in patients serves as a disproportionate hindrance in colonic transit. An in-depth methodology is developed for the identification and subsequent analysis of haustral activity and CMP; this provides transparency in the data acquisition and analysis. Lastly, a sphincter at the rectosigmoid junction, sphincter of O’Beirne is presented in a patient case report. The persistent presence and paradoxical contractions of this sphincter served to impede flow colonic content, an important factor contributing to the pathophysiology of severe refractory constipation. / Thesis / Master of Science (MSc) / Colonic manometry tests and measures strength and coordination of colonic muscles contractions. This tool was used to understand the rhythmic colonic motor patterns and their contribution to motility in healthy subjects and patients with constipation. Rhythmic activity in the gut is mediated by pacemaker cells, Interstitial cells of Cajal (ICC). We present a detailed characterization of ICC-mediated rhythmic activity that (1) occurs in the small pouches making up the colon (haustra) and (2) is greater than 5cm along the length of the colon (cyclic motor patterns-CMP).CMP possess high-frequency activity (7-15cpm), in addition to activity observed in the low-frequency range (2-6cpm). Activity in the haustra, or haustral activity, is comprised of 2 boundaries with activity within these bounds (intra-haustral activity); the overexpression in patients serves to retard flow of colonic content. Sphincter of O’Beirne is the last haustral boundary at the rectosigmoid junction; its persistent presence was characterized in a patient with refractory constipation.

<p>The kidney regulates the excretion of water and electrolytes, which maintains homeostasis and enables control of arterial blood pressure. Hyaluronan, a large negatively charged interstitial glucosaminoglycan, is heterogeneously distributed within the kidney, primarily found in the medulla.</p><p>Medullary hyaluronan content changes depending on the state of body hydration and plays a part in fluid regulation through its water binding and viscoelastic properties. </p><p>The aim of this thesis was to provide new insight into the regulation of intrarenal hyaluronan during different states of body hydration, during completion of kidney development, and during diabetes mellitus.</p><p>Dehydration reduces medullary interstitial hyaluronan in parallel with reduced hyaluronan synthase 2 gene expression and increased urinary hyaluronidase activity. Acute hydration results in an increase in medullary hyaluronan, an increase that requires nitric oxide and prostaglandins. Urinary hyaluronidase activity decreases during hydration. The elevation of hyaluronan is important for reducing water permeability of the interstitium i.e. favoring diuresis.</p><p>Changes in hyaluronan concentration constitute a morphoregulatory pathway that plays a key role in nephrogenesis. The reduction in neonatal hyaluronan depended on an angiotensin II mediated process that does not appear dependent on lymph vessel formation. If angiotensin II is blocked with an ACE inhibitor, hyaluronan accumulates, which results in structural and functional abnormalities in the kidney. </p><p>Renomedullary hyaluronan is elevated during uncontrolled diabetes, which coincides with induction of hyaluronan synthase 2 mRNA, hyperglycemia, glucosuria, proteinuria and overt diuresis. The levels of hyaluronan are probably at a <i>terminus ad quem</i> as no further response was seen during hydration. The higher interstitial expression of hyaluronan during diabetes may be involved in the progression of diabetic nephropathy.</p><p>This thesis in physiology provides new mechanistic insights into the regulation of renal hyaluronan during various aspects of fluid handling.</p>

La fibrillation atriale (FA) est l’arythmie cardiaque la plus couramment rencontrée en pratique clinique. Sa pathophysiologie étant encore mal connue, elle est difficile à traiter. Plusieurs paramètres ont été décrits comme impliqués dans l’initiation de la fibrillation atriale ; cependant, les mécanismes précis d’initiation de la fibrillation atriale ne sont pas élucidés. Dans cette étude, des approches histologiques, biochimiques, transcriptomiques et génétiques seront abordées afin d’identifier les substrats intervenant dans l’initiation de la fibrillation atriale humaine. Ainsi, il a été mis en évidence des cellules interstitielles de type Cajal au sein des manchons myocardiques des veines pulmonaires pouvant être à l’origine des foyers ectopiques, une possible origine embryonnaire précoce via l’absence d’expression du gène pitx2 chez les patients en fibrillation atriale, une surexpression des voies du système nerveux autonome à la fois adrénergique et cholinergique, une modification du flux potassique du courant IKs via une intervention des protéines régulatrices KCNE et de protéines du cytosquelette musculaire. De plus, une des complications de la fibrillation atriale est la survenue d’accidents vasculaires cérébraux ; il a été montré dans cette étude une surexpression au niveau de l’oreillette gauche du facteur Von Willebrand chez les patients en fibrillation atriale ainsi qu’une augmentation du VEGF sérique dans la forme paroxystique de la fibrillation atriale. Ces nouvelles données permettent d’accroître les connaissances de la fibrillation atriale et d’envisager par la suite la possibilité de nouvelles stratégies thérapeutiques plus efficaces. / Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. As its pathophysiology is still poorly understood, it is difficult to treat. Several parameters have been described as involved in the initiation of atrial fibrillation, but the precise mechanisms of initiation of atrial fibrillation are not understood. In this study, histological, biochemical, genetic and transcriptomic approaches have been performed in order to identify the substrates involved in the initiation of human atrial fibrillation. Thus, it has been demonstrated presence of interstitial cells Cajal-like in myocardial sleeves of pulmonary veins that may be the cause of ectopic foci, a possible early embryonic origin through lack of expression of the pitx2 gene in atrial fibrillation patients, overexpression of the autonomic nervous system to both adrenergic and cholinergic pathways, a change in the flow of potassium current IKs through intervention of KCNE regulatory proteins and cytoskeletal muscle protein. In addition, a complication of atrial fibrillation is the occurrence of stroke. It has been shown at left atrial level an overexpression of Von Willebrand factor in patients with atrial fibrillation and an increase of serological VEGF in paroxysmal subtype of atrial fibrillation. These new data allow completing the knowledge on atrial fibrillation and subsequently considering the possibility of new therapeutic strategies that could be more effective.

A fibrilação atrial (FA) é a arritmia cardíaca mais comum na prática clínica e que apresenta a maior morbidade, principalmente com o avançar da idade. O sistema nervoso autonômico, particularmente o balanço adrenérgico/colinérgico, tem profunda influência na ocorrência de fibrilação atrial. A FA pode ser gerada e mantida por uma variedade de mecanismos eletrofisiológicos e uma mudança na atividade autonômica poderá afetar cada um deles de forma diferente. Além do sistema nervoso autônomo, simpático e parassimpático, envolvidos na gênese e manutenção da FA, já é sabido que existem vários outros fatores envolvidos e, dentre eles, as células intersticiais tipo-Cajal (CITC), semelhantes às células intersticiais que contribuem para a atividade motora peristáltica do trato gastrointestinal. Essas células foram encontradas no miocárdio atrial e ventricular, e poderiam ser a origem da atividade deflagradora de focos elétricos ectópicos geradores de FA. O presente estudo teve como objetivos analisar possíveis alterações na expressão miocárdica dos receptores beta-adrenérgicos e quantificar as células intersticiais tipo-Cajal nos átrios de corações humanos, em particular, no esquerdo, e sua relação com a fibrilação atrial permanente (FAP). Para o primeiro objetivo, foram estudados 19 casos de corações de autópsias de portadores de FAP e cardiopatia crônica definida (grupo I), e 19 corações pareados com as mesmas cardiopatias, porém sem evidências de qualquer arritmia supraventricular (grupo II). Foram ressecadas uma amostra no teto do átrio direito, duas no átrio esquerdo, e uma em terminação nervosa envolvida em tecido gorduroso no epicárdio do átrio esquerdo (fat-pad). A expressão miocárdica dos receptores beta-adrenérgicos 1 a 3 e da quinase-5 do receptor adrenérgico acoplado à proteína G (GRK5) foi avaliada pela proporção positiva no miocárdio nos cortes citados. Não houve diferença estatisticamente significante entre os dois grupos quando analisamos a expressão dos receptores adrenérgicos (beta-1, beta-2, beta-3 e GRK5), independentemente do uso ou não de beta-bloqueador. Para o segundo objetivo, foram estudados 6 casos de corações de autópsias de portadores de FAP e cardiopatia crônica definida (grupo I), e 6 corações pareados com as mesmas cardiopatias, porém sem evidências de qualquer arritmia supraventricular (grupo II). As CITC foram avaliadas na região média da parede diafragmática do átrio esquerdo. Não houve alterações estatisticamente significantes entre os grupos estudados, quando avaliamos o número de células positivas no miocárdio pela área do miocárdio em mm2, o número de células positivas no corte inteiro pela área do miocárdio em mm2 ou o número de células positivas no corte inteiro/área do corte inteiro em mm2, seja em relação a cada corte individualmente, ao átrio esquerdo isoladamente e a todos os cortes juntos. Em conclusão, nem alterações na expressão de receptores beta-adrenérgicos nem a presença de células tipo-Cajal parecem ter maior papel na patogênese da fibrilação atrial permanente / Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, presenting the highest morbidity, especially with advancing age. The autonomic nervous system, particularly the adrenergic/cholinergic balance, has a profound influence on the occurrence of AF. AF can be generated and maintained through a variety of electrophysiological mechanisms, and a change in autonomic activity may affect each of mechanism differently. In addition to the autonomous, sympathetic, and parasympathetic nervous systems involved in the genesis and maintenance of AF, there are several other factors known to be involved, including the interstitial cells of Cajal (ICCs), similar to the interstitial cells that contribute to the peristaltic motor activity of the gastrointestinal tract. These cells were found in the atrial and ventricular myocardium, and could be the source of the triggering activity of ectopic electrical foci that generate AF. In the present study, we aimed to analyze the possible changes in the myocardial expression of beta-adrenergic receptors and to quantify ICCs in the atria of human hearts, in particular in the left atrium, and its relation with permanent AF (PAF). For the first objective, we studied 19 hearts from autopsies of patients with PAF and defined chronic cardiomyopathy (group I), and 19 paired hearts with the same cardiomyopathy but without evidence of any supraventricular arrhythmia (group II). A tissue sample from the ceiling of the right atrium, two from the left atrium, and one from the nerve ending involved in the adipose tissue in the epicardium of the left atrium (fat pad) were resected. The myocardial expression of beta-adrenergic receptors 1 and 3, and of the G protein-coupled receptor kinase 5 (GRK5) was assessed according to the positive proportion in the myocardium in the mentioned sections. There was no statistically significant difference between the two groups in the expression of adrenergic receptors (beta-1, beta-2, beta-3, and GRK5), regardless of the use or nonuse of beta-blockers. For the second objective, six hearts from autopsied patients with PAF and defined chronic cardiopathy (group I) were studied, along with six paired hearts with the same cardiopathies but without evidence of any supraventricular arrhythmia (group II). The ICCs were evaluated in the middle region of the diaphragmatic wall of the left atrium. There were no statistically significant changes between the groups when we evaluated the number of positive cells in the myocardium by area of the myocardium in mm2, the number of positive cells in the full section by area of the myocardium in mm2, or the number of positive cells in the full section/area of the full section in mm2, be it in relation to each section individually, the left atrium alone, or all sections together. In conclusion, neither changes in the expression of beta-adrenergic receptors nor the presence of ICCs seem to have a large role in the pathogenesis of permanent AF

As células intersticiais de Cajal (CIC) têm sido estudadas como participante do peristaltismo em vários sistemas. Sua presença no trato geniturinário pode sustentar a importância dessas células na fisiopatologia da estenose da junção ureteropielica (JUP). O Objetivo desse estudo foi avaliar a densidade das CIC em pacientes adultos e no final da adolescência, portadores de estenose da JUP, submetidos à pieloplastia e verificar se há associação entre a densidade das CIC com os achados clínicos e de imagem pré e pós-operatórios, notadamente ultrassonografia e cintilografia renal. Foram estudados 23 pacientes com estenose da JUP, submetidos à pieloplastia desmembrada pela técnica videolaparoscópica na Divisão de Clínica Urológica do Departamento de Cirurgia do HCFMUSP, de forma consecutiva, pelo mesmo grupo de cirurgiões, no período entre fevereiro de 2011 a janeiro de 2012. Foi realizada análise imunohistoquímica para expressão do receptor de tirosina quinase (c-KIT) em todas as amostras das JUP e quantificada a densidade das CIC. Os pacientes foram acompanhados periodicamente para avaliação da resposta clínica e dos exames de imagem. Foi encontrado que a média de idade da amostra foi de 34,83 anos. Houve predomínio do gênero masculino (56,5%). O rim direito foi o mais acometido (56,5%). A hidronefrose grave foi identificada na maioria dos pacientes (52,2%). A média da função renal do rim acometido estimada pela cintilografia, pré e pós-operatória foi de respectivamente, 33,7 e 33,4%. Dos 23 pacientes, 20 apresentaram melhora do padrão cintilográfico de drenagem ureteral. Houve predomínio de pacientes que apresentavam alta densidade das CIC (52,2%). Houve significância estatística quando associado a densidade das CIC e a melhora do padrão ultrassonográfico (p= 0,032). Contudo, não houve associação entre a densidade das CIC e as outras variáveis clínicas ou de imagem. Pode-se concluir que a densidade das CIC pode ser um bom preditor da resposta ultrassonográfica pósoperatória em pacientes adultos com estenose da JUP submetidos à pieloplastia / The interstitial cells of Cajal (ICC) have been studied as peristalsis participating in various systems. Its presence in the genitourinary tract can sustain the importance of these cells in the pathophysiology of ureteropelvic junction obstruction (UPJO). The aim of this study was to evaluate the density of ICC in adults and in the late adolescence patients with UPJO, undergoing pyeloplasty and to check if there is association of changes in the ICC density with clinical findings, as well as pre and postoperative images, especially ultrasound and diuretic radioisotope renography. We selected 23 patients with UPJO, undergoing laparocopic dismembered pyeloplasty in the Urology Division of the HC-FMUSP Department of Surgery, consecutively, by the same group of surgeons in the period between February 2011 and January 2012. It was performed immunohistochemical analysis for tyrosine kinase receptor expression (c-KIT) in all samples of UPJO quantified the ICC density. The patients were followed up periodically to evaluate the clinical response and imaging. The average age of the sample was 34.83 years. There was a predominance of males (56.5%). The right kidney was the most affected (56.5%). Severe hydronephrosis was identified in most patients (52.2%). The average renal function affected estimated by diuretic radioisotope renography, pre and post-operative was respectively 33.7 and 33.4%. Of the 23 patients, 20 had an improvement on diuretic radioisotope renography pattern of ureteral drainage. There was a predominance of patients with high ICC density (52.2%). There was statistical significance when associated with ICC density and the improvement of ultrasonographic pattern (p = 0.032). However, there was no association between the ICC density and other clinical or imaging variables. It can be concluded that the density of the ICC maybe a good predictor of post-operative ultrasound response in adult patients with UPJO undergoing pyeloplasty

The kidney regulates the excretion of water and electrolytes, which maintains homeostasis and enables control of arterial blood pressure. Hyaluronan, a large negatively charged interstitial glucosaminoglycan, is heterogeneously distributed within the kidney, primarily found in the medulla. Medullary hyaluronan content changes depending on the state of body hydration and plays a part in fluid regulation through its water binding and viscoelastic properties. The aim of this thesis was to provide new insight into the regulation of intrarenal hyaluronan during different states of body hydration, during completion of kidney development, and during diabetes mellitus. Dehydration reduces medullary interstitial hyaluronan in parallel with reduced hyaluronan synthase 2 gene expression and increased urinary hyaluronidase activity. Acute hydration results in an increase in medullary hyaluronan, an increase that requires nitric oxide and prostaglandins. Urinary hyaluronidase activity decreases during hydration. The elevation of hyaluronan is important for reducing water permeability of the interstitium i.e. favoring diuresis. Changes in hyaluronan concentration constitute a morphoregulatory pathway that plays a key role in nephrogenesis. The reduction in neonatal hyaluronan depended on an angiotensin II mediated process that does not appear dependent on lymph vessel formation. If angiotensin II is blocked with an ACE inhibitor, hyaluronan accumulates, which results in structural and functional abnormalities in the kidney. Renomedullary hyaluronan is elevated during uncontrolled diabetes, which coincides with induction of hyaluronan synthase 2 mRNA, hyperglycemia, glucosuria, proteinuria and overt diuresis. The levels of hyaluronan are probably at a terminus ad quem as no further response was seen during hydration. The higher interstitial expression of hyaluronan during diabetes may be involved in the progression of diabetic nephropathy. This thesis in physiology provides new mechanistic insights into the regulation of renal hyaluronan during various aspects of fluid handling.

Background Transthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis. Results Sixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (&lt;50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p &lt;0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p &lt;0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p &lt;0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p &lt;0.01) and parasympathetic (rs = -0.3, p &lt;0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p &lt;0.01) and longitudinal (median density 0.0 vs. 1.8, p &lt;0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p &lt;0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation. Conclusion GI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.

No description available.