Although a vast literature attests to the belief that psychosocial disturbance is an important component of functional gastrointestinal disorders (FGID), the relation of life stress, psychological distress and personality to the development of these disorders is poorly understood. The broad objective of this thesis is to provide data on relations between psychosocial factors and FGID, especially irritable bowel syndrome (IBS) and functional dyspepsia (FD), in representative outpatient samples. Issues not previously addressed are examined in a series of studies. The first two studies are concerned with relations between psychosocial factors, extraintestinal (somatic) symptoms and the number and type of FGID syndromes present at consultation and, in IBS patients, the prospective relation of psychosocial factors to changes in symptom intensity over 16 months. The last three studies relate psychosocial factors to gastrointestinal (GI) transit, motor, and sensory function in FGID, abnormalities in these parameters representing the putative origin of symptoms in FGID. In total, 350 patients participated, representing a 95% participation rate. Important features of the methodology include the use of a recently standardised symptom-based classification system for FGID, an objective and reliable interview-based life stress instrument (The Life Events and Difficulties Schedule), and sophisticated and sensitive technologies to assess GI transit, motor and sensory function. Novel measures, which conceptually take into account the chronic, fluctuating and recurrent course of IBS and FD syndromes, and the tendency of these syndromes to coexist, are also included. Thus, measures of symptom outcome assess the number of syndromes present, while the symptom intensity variable reflects the severity and frequency of both FD and IBS symptoms, if both are present. Similarly, with respect to altered transit, and motor and sensory function, physiological outcome variables reflect not only the presence of an abnormality but the number of regions affected, and the type and number of abnormalities present. Cross-sectional findings showed for the first time that psychosocial disturbance is associated with FGID symptomatology in a quantitative manner, that chronic life stress threat is central to this process and this stress-related process is a prominent feature of a particular group of syndromes (ie IBS/FD) defined primarily by the presence of pain and discomfort. A combination of psychological, social and biological factors combined to predict the number of FGID syndromes present at entry into the study. Prominent among them was an angry, reactive and anxious (neurotic) personality, chronic life stress threat, increased coping, poor emotional support and increased age. In addition to a greater number of FD/IBS syndromes, individuals with an anger-reactive response style had experienced more intense pain and discomfort, and displayed more complete sensorimotor disturbance. Longitudinal data demonstrated (also for the first time) the strength, consistency and unequivocal direction of the relation of chronic threat to symptom intensity over time. Almost all of the within subject variance in symptom intensity levels (assessed on 3 occasions over a 16 month period) was explained by the severity of chronic threat during the previous 6 months or more. For 76% of IBS patients, the presence vs the absence of one or more highly threatening chronic stressors predicted with considerable precision, the long-term clinical outcome. Thus, no patient exposed to even one such stressor improved clinically (ie by at least 50%) over the follow-up period, while in contrast, all patients who improved clinically did so in the absence of such a stressor. For 24% of patients, however, failure to improve clinically could not be explained by any psychological, social (including life stress) or demographic factor included in this study. Key risk indicators of a poor outcome at 16 months were identified - chronic life stress threat, the severity of baseline GI symptomatology, and female gender. Life stress is important because it alone determined the magnitude and direction of change in symptom intensity over time, while the severity of baseline GI symptomatology revealed the extent of improvement required to achieve a recovery, and female gender predicted the presence of a larger number of FD/IBS syndromes in women long-term. Widespread hypomotility, which was almost exclusive to women in this study, represents one factor that may inhibit improvement (or rate of improvement) for women over time. Finally, these findings have identified a psychophysiological subgroup, with underlying psychosocial, motor (and perhaps also sensory) dysfunctions that are more specific for women than men, and which does not seem to be distinctive of any particular FGID subgroup.

Although a vast literature attests to the belief that psychosocial disturbance is an important component of functional gastrointestinal disorders (FGID), the relation of life stress, psychological distress and personality to the development of these disorders is poorly understood. The broad objective of this thesis is to provide data on relations between psychosocial factors and FGID, especially irritable bowel syndrome (IBS) and functional dyspepsia (FD), in representative outpatient samples. Issues not previously addressed are examined in a series of studies. The first two studies are concerned with relations between psychosocial factors, extraintestinal (somatic) symptoms and the number and type of FGID syndromes present at consultation and, in IBS patients, the prospective relation of psychosocial factors to changes in symptom intensity over 16 months. The last three studies relate psychosocial factors to gastrointestinal (GI) transit, motor, and sensory function in FGID, abnormalities in these parameters representing the putative origin of symptoms in FGID. In total, 350 patients participated, representing a 95% participation rate. Important features of the methodology include the use of a recently standardised symptom-based classification system for FGID, an objective and reliable interview-based life stress instrument (The Life Events and Difficulties Schedule), and sophisticated and sensitive technologies to assess GI transit, motor and sensory function. Novel measures, which conceptually take into account the chronic, fluctuating and recurrent course of IBS and FD syndromes, and the tendency of these syndromes to coexist, are also included. Thus, measures of symptom outcome assess the number of syndromes present, while the symptom intensity variable reflects the severity and frequency of both FD and IBS symptoms, if both are present. Similarly, with respect to altered transit, and motor and sensory function, physiological outcome variables reflect not only the presence of an abnormality but the number of regions affected, and the type and number of abnormalities present. Cross-sectional findings showed for the first time that psychosocial disturbance is associated with FGID symptomatology in a quantitative manner, that chronic life stress threat is central to this process and this stress-related process is a prominent feature of a particular group of syndromes (ie IBS/FD) defined primarily by the presence of pain and discomfort. A combination of psychological, social and biological factors combined to predict the number of FGID syndromes present at entry into the study. Prominent among them was an angry, reactive and anxious (neurotic) personality, chronic life stress threat, increased coping, poor emotional support and increased age. In addition to a greater number of FD/IBS syndromes, individuals with an anger-reactive response style had experienced more intense pain and discomfort, and displayed more complete sensorimotor disturbance. Longitudinal data demonstrated (also for the first time) the strength, consistency and unequivocal direction of the relation of chronic threat to symptom intensity over time. Almost all of the within subject variance in symptom intensity levels (assessed on 3 occasions over a 16 month period) was explained by the severity of chronic threat during the previous 6 months or more. For 76% of IBS patients, the presence vs the absence of one or more highly threatening chronic stressors predicted with considerable precision, the long-term clinical outcome. Thus, no patient exposed to even one such stressor improved clinically (ie by at least 50%) over the follow-up period, while in contrast, all patients who improved clinically did so in the absence of such a stressor. For 24% of patients, however, failure to improve clinically could not be explained by any psychological, social (including life stress) or demographic factor included in this study. Key risk indicators of a poor outcome at 16 months were identified - chronic life stress threat, the severity of baseline GI symptomatology, and female gender. Life stress is important because it alone determined the magnitude and direction of change in symptom intensity over time, while the severity of baseline GI symptomatology revealed the extent of improvement required to achieve a recovery, and female gender predicted the presence of a larger number of FD/IBS syndromes in women long-term. Widespread hypomotility, which was almost exclusive to women in this study, represents one factor that may inhibit improvement (or rate of improvement) for women over time. Finally, these findings have identified a psychophysiological subgroup, with underlying psychosocial, motor (and perhaps also sensory) dysfunctions that are more specific for women than men, and which does not seem to be distinctive of any particular FGID subgroup.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24131号 / 医博第4871号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 阪上 優, 教授 佐藤 俊哉, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-20T12:20:13Z No. of bitstreams: 1 flaviaaltafdarochalima.pdf: 1162345 bytes, checksum: 18a62c489991ceea8aa434e2b2a63f89 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-02T11:21:12Z (GMT) No. of bitstreams: 1 flaviaaltafdarochalima.pdf: 1162345 bytes, checksum: 18a62c489991ceea8aa434e2b2a63f89 (MD5) / Made available in DSpace on 2016-07-02T11:21:12Z (GMT). No. of bitstreams: 1 flaviaaltafdarochalima.pdf: 1162345 bytes, checksum: 18a62c489991ceea8aa434e2b2a63f89 (MD5) Previous issue date: 2012-08-14 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Introdução: A dispepsia funcional (DF) representa um transtorno gastrointestinal frequente na prática clínica. Por apresentar mecanismos etiopatogênicos diversos, a terapia medicamentosa não se mostra totalmente eficaz, razão pela qual a busca por terapias complementares como a acupuntura é fundamental. Objetivo: avaliar a eficácia da acupuntura como terapia complementar ao tratamento medicamentoso convencional em pacientes com DF. Método: ensaio clínico randomizado, com portadores de dispepsia funcional, segundo os critérios de Roma III. Dois grupos foram formados: Grupo I (terapia medicamentosa e acupuntura específica) e Grupo II (terapia medicamentosa e acupuntura não específica). Foram avaliados o índice de sintomas gastrointestinais (Gastrointestinal Scale Related Symptoms – GSRS), a presença de transtornos psíquicos (Escala Hospitalar de Ansiedade e Depressão) e a qualidade de vida (Short-form Health Survey – SF 36) no início, no fim e três meses após o tratamento. Resultados: após 4 semanas de tratamento houve melhora dos sintomas gastrointestinais no Grupo I (55 ± 12 vs. 29 ± 8,8; p = 0,001) e Grupo II (50,3 ± 10,2 vs. 46 ± 10,5; p = 0,001). A qualidade de vida foi significativamente melhor no Grupo I (93,4 ± 7,3 vs. 102,4 ± 5,1; p = 0,001). Transtornos de ansiedade (93,3% vs. 0%; p = 0,001) e depressão (46,7% vs. 0%; p = 0,004) foram significativamente menores no Grupo I. Na comparação intergrupos os sintomas gastrointestinais (29 ± 8,8 vs. 46 ± 10,5; p < 0,001) e a qualidade de vida (102,4 ± 5,1 vs. 96 ± 6,1; p = 0,021) foram significativamente melhores no Grupo I. Três meses após o tratamento, os sintomas gastrointestinais permaneceram melhores no Grupo I quando comparados aos valores pré-tratamento (38 ± 11,3 vs. 55 ± 12; p = 0,001). Conclusão: em portadores de dispepsia funcional o tratamento complementar com acupuntura foi superior ao tratamento convencional. A acupuntura pode ser uma terapia complementar eficaz no tratamento de pacientes com DF. / Introduction: Functional dyspepsia (FD) represents a frequent gastrointestinal disorder in clinical practice. By presenting various etiopathogenic mechanisms, often the drug therapy is not entirely effective. Therefore, the search for complementary therapies such as acupuncture is essential. Objective: Evaluate the effectiveness of acupuncture as a complement to conventional treatment in functional dyspepsia patients. Methods: randomized clinical trial with functional dyspepsia patients in according with ROME III criteria. Two groups were created: Group I (drug therapy and specific acupuncture) and Group II (drug therapy and non-specific acupuncture). The gastrointestinal symptoms (Gastrointestinal Scale Related Symptoms – GSRS), presence of psychiatric disorders (Hospital Anxiety and Depression Scale – HADS) and quality of life (Short-form Health Survey – SF 36) were evaluated, at the end and three months after treatment. Results: After 4 weeks of treatment there was significantly improvement of gastrointestinal symptoms in Group I (55 ± 12 vs. 29 ± 8,8; p = 0,001) and Group II (50 ± 10 vs. 46 ± 10,5; p = 0,001). Quality of life was significantly better in Group I (93,4 ± 7,3 vs. 102,4 ± 5,1; p = 0,001). Anxiety and depression disorders were significantly lower in Group I (93% vs. 0%; p = 0,001 and 46% vs. 0%; p = 0,004; respectively). Inter-group, gastrointestinal symptoms comparison and quality of life were significantly better in Group I (29 ± 8,8 vs. 46 ± 10,5; p < 0,001 and 102,4 ± 5,1 vs. 96,4 ± 6,1; p = 0,021; respectively). Three months after the treatment, gastrointestinal symptoms remained best in Group I, when compared to the pre-treatment values (38 ± 11,3 vs. 55 ± 12; p = 0,001). Conclusion: In patients with functional dyspepsia the complementary acupuncture treatment was superior to conventional treatment. Acupuncture as a complementary treatment can be effective in treating patients with FD.

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.

La présente étude en anthropologie médicale propose d’examiner la dimension socioculturelle des désordres fonctionnels gastro-intestinaux (DFGI) en considérant l’expérience de six familles québécoises francophones où un pré-adolescent souffre de symptômes associés à un DFGI. Le regard anthropologique qui nous a permis d’appréhender ces expériences de douleur s’appuie principalement sur les travaux issus de la psychiatrie transculturelle, de même que sur les influences de l’anthropologie du corps et de la phénoménologie. À travers ce regard, la somatisation est considérée comme une forme de communication de la douleur, modulée de manière importante par le contexte socioculturel et représentative d’une certaine souffrance sociale. Ce langage ponctué d’idiomes de détresse et de métaphores permet aux individus d’exprimer leur souffrance et de mobiliser un soutien social efficace pour la prendre en charge. Dès lors, le corps doit être perçu comme un corps vécu; comme un lieu de marquage du social, mais également comme un instrument de positionnement social et une frontière où des mouvements d’appartenance et de divergence sont exprimés. Par l’exploration, dans chacune de ces familles, des différentes manières de décrire les symptômes, de les interpréter et d’y réagir, nous avons procédé à la reconstruction d’histoires particulières pour voir comment ces symptômes venaient s’inscrire dans la biographie individuelle et familiale. À travers l’analyse de la construction du sens de la douleur et des pratiques adoptées pour la contrôler, la douleur abdominale nous est apparue comme intimement liée à l’expérience sociale et la médicalisation comme une base pour une meilleure appréhension de cette douleur. Par ses maux de ventre, l’enfant exprime ses limites corporelles et sociales. À l’intérieur de la famille, l’expression de cette limite peut être parfois dérangeante, confrontante, et même entraîner des rapports conflictuels. C’est ainsi qu’est « négociée » une approche appropriée à la douleur qui redéfinit les rôles de chacun par rapport à cette dernière. Le ventre devient le médiateur qui permet le compromis nécessaire au « vivre ensemble » ou au « vivre dans le monde ». À l’issue de ii cette négociation qui implique la participation du médecin traitant, les rapports sont parfois reconstruits et la relation au monde et aux autres peut devenir différente. / This study in medical anthropology is an exploration of the sociocultural dimension of functional gastrointestinal disorders (FGID) considering the experience of six frenchspeaking families of Québec where a pre-teenager suffers from symptoms associated with FGID. The anthropological perspective that allowed us to approach these experiences of pain is based mainly on work from tanscultural psychiatry, as well as on the influences of the anthropology of the body and phenomenology. Through this view, somatization is considered to be a form of communication of distress, modulated in an important way by sociocultural context and reflecting social suffering. This language punctuated with idioms of distress and metaphors allows individuals to express their suffering and to mobilize an efficient social support. From then on, the body must be seen as a lived body; as a place of social marking, but also as an instrument of social positioning and a border where movements of belonging and divergence are expressed. By exploring, in each of these families, different ways of describing the symptoms, interpret them and respond to them, we proceeded to the reconstruction of particular stories to find how these symptoms were part of the individual’s and family’s biography. Through the analysis of how those families make sense of the pain and adopte practices to control it, abdominal pain appeared to us as intimately linked to social experience and the medicalization as a basis for a better apprehension of this suffering. While telling his or her pain, the child is also expressing his or her bodily and social boundaries. Within the family, the expression of this limit can sometimes be disturbing, confrontational, even lead to conflict. Thus was “negociated” an appropriate approach to pain that redefines the roles of each in relation to it. The abdomen becomes the mediator who allows the compromises needed to “live together” or to “live in the world”. Following this “negociation” that involves the participation of the attending physician, bonding within the family is sometimes positively transformed and the relation to the world and to the others can become different.

La présente étude en anthropologie médicale propose d’examiner la dimension socioculturelle des désordres fonctionnels gastro-intestinaux (DFGI) en considérant l’expérience de six familles québécoises francophones où un pré-adolescent souffre de symptômes associés à un DFGI. Le regard anthropologique qui nous a permis d’appréhender ces expériences de douleur s’appuie principalement sur les travaux issus de la psychiatrie transculturelle, de même que sur les influences de l’anthropologie du corps et de la phénoménologie. À travers ce regard, la somatisation est considérée comme une forme de communication de la douleur, modulée de manière importante par le contexte socioculturel et représentative d’une certaine souffrance sociale. Ce langage ponctué d’idiomes de détresse et de métaphores permet aux individus d’exprimer leur souffrance et de mobiliser un soutien social efficace pour la prendre en charge. Dès lors, le corps doit être perçu comme un corps vécu; comme un lieu de marquage du social, mais également comme un instrument de positionnement social et une frontière où des mouvements d’appartenance et de divergence sont exprimés. Par l’exploration, dans chacune de ces familles, des différentes manières de décrire les symptômes, de les interpréter et d’y réagir, nous avons procédé à la reconstruction d’histoires particulières pour voir comment ces symptômes venaient s’inscrire dans la biographie individuelle et familiale. À travers l’analyse de la construction du sens de la douleur et des pratiques adoptées pour la contrôler, la douleur abdominale nous est apparue comme intimement liée à l’expérience sociale et la médicalisation comme une base pour une meilleure appréhension de cette douleur. Par ses maux de ventre, l’enfant exprime ses limites corporelles et sociales. À l’intérieur de la famille, l’expression de cette limite peut être parfois dérangeante, confrontante, et même entraîner des rapports conflictuels. C’est ainsi qu’est « négociée » une approche appropriée à la douleur qui redéfinit les rôles de chacun par rapport à cette dernière. Le ventre devient le médiateur qui permet le compromis nécessaire au « vivre ensemble » ou au « vivre dans le monde ». À l’issue de ii cette négociation qui implique la participation du médecin traitant, les rapports sont parfois reconstruits et la relation au monde et aux autres peut devenir différente. / This study in medical anthropology is an exploration of the sociocultural dimension of functional gastrointestinal disorders (FGID) considering the experience of six frenchspeaking families of Québec where a pre-teenager suffers from symptoms associated with FGID. The anthropological perspective that allowed us to approach these experiences of pain is based mainly on work from tanscultural psychiatry, as well as on the influences of the anthropology of the body and phenomenology. Through this view, somatization is considered to be a form of communication of distress, modulated in an important way by sociocultural context and reflecting social suffering. This language punctuated with idioms of distress and metaphors allows individuals to express their suffering and to mobilize an efficient social support. From then on, the body must be seen as a lived body; as a place of social marking, but also as an instrument of social positioning and a border where movements of belonging and divergence are expressed. By exploring, in each of these families, different ways of describing the symptoms, interpret them and respond to them, we proceeded to the reconstruction of particular stories to find how these symptoms were part of the individual’s and family’s biography. Through the analysis of how those families make sense of the pain and adopte practices to control it, abdominal pain appeared to us as intimately linked to social experience and the medicalization as a basis for a better apprehension of this suffering. While telling his or her pain, the child is also expressing his or her bodily and social boundaries. Within the family, the expression of this limit can sometimes be disturbing, confrontational, even lead to conflict. Thus was “negociated” an appropriate approach to pain that redefines the roles of each in relation to it. The abdomen becomes the mediator who allows the compromises needed to “live together” or to “live in the world”. Following this “negociation” that involves the participation of the attending physician, bonding within the family is sometimes positively transformed and the relation to the world and to the others can become different.