Individuals with chronic liver disease experience progressive muscle wasting, weakness, fatigue, and decreased quality of life. Liver transplantation is the only treatment for end-stage liver disease with cirrhosis; however, muscle wasting, strength impairments, activity limitations, and health related quality of life do not return to the level of healthy adults. Currently there is no plan of care for rehabilitation of individuals post-liver transplantation. These individuals are only instructed to gradually increase walking and activity. Walking may increase lower extremity muscle strength; however, walking at a self-selected pace is less effective than resistance exercise. The purpose of this dissertation was to compare the benefits of a home exercise program of targeted lower extremity resistance exercise with benefits of progressive walking in individuals who have undergone liver transplantation. In Chapter 2 we performed a study to validate the ability of several outcome measures to detect changes in strength and activity performance in the population with liver disease and post-liver transplantation. The strength impairment measures of Grip Strength, Heel Rising, and Bridging along with activity limitation measures 30 Second Chair Stand and Six Minute Walk Test (6MWT) were able to differentiate strength and activity performance across levels of liver disease severity including post liver transplantation. Liver disease severity was moderately correlated with the strength impairment measures Bridging and Heel Rising but was not correlated with Grip strength. Liver disease severity was moderately correlated with 6MWT and 30-Second Chair-Stand but was not correlated with the SF-36 physical function scale. Strength impairment measures were strongly correlated with the activity limitation measures. Heel Rising and Bridging were strongly correlated with 30-Second Chair-Standing and 6MWT. Grip strength was moderately correlated with 30-Second Chair-Standing. In Chapter 3 we conducted a randomized controlled trial to assess the benefits of resistance exercise to progressive walking as a treatment plan for improving strength and activity performance in individuals post liver transplantation. We also examined the relationships of the change in muscle strength to the change in activity performance. Both the exercise and walking groups improved in strength and activity performance; however, the group performing the resistance exercise improved more. Bridging, 30 Second Chair Standing, Heel Rising, and 6MWT increased more for the exercise group than the walking group. Additionally, changes in strength were related to the changes in activity performance and health related quality of life. Bridging was correlated with Heel Rising, 30 Second Chair Standing, 6MWT, and the Chronic Liver Disease Questionnaire. In Chapter 4 we discuss the clinical relevance of the results of the studies described in the above chapters. We conclude Bridging, Heel Rising, 30 Second Chair Standing, and 6MWT are valid outcome measures to measure changes in strength and activity performance in the population with liver disease. Individuals post liver transplantation improve in strength and activity performance through progressive walking; however, the addition of resistance exercise to the current treatment plan is necessary for greater improvement. Additionally it is clinically relevant that this population was adherent to a home exercise program. Subjects adherent to the exercise program increased in strength and activity performance greater than subjects who were non-adherent.

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Thesis--University of Helsinki. / Includes bibliographical references.

Thesis--University of Helsinki. / Includes bibliographies.

Thesis (M.D.)--Boston University

Orientador: Maria Aparecida Mesquita / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-09T19:06:25Z (GMT). No. of bitstreams: 1 Cruz_CristianeKibuneNagasakoVieirada_M.pdf: 1050615 bytes, checksum: 568a2814333ee1681714d9d75ec14548 (MD5) Previous issue date: 2007 / Resumo: A disfunção autonômica (DA) parece ser freqüente na cirrose hepática (CH) de etiologia alcoólica, enquanto que os dados referentes à prevalência e repercussões clínicas desta complicação na cirrose de etiologia não alcoólica são controversos. Existem evidências na literatura de que o método da análise da variabilidade da freqüência cardíaca (VFC) em 24 horas é mais sensível que a pesquisa dos reflexos cardiovasculares para a avaliação da função autonômica. Esta técnica foi pouco utilizada na investigação de pacientes com CH. Estudos prévios em cirróticos demonstraram a presença de alterações da motilidade intestinal que predisporiam à ocorrência de supercrescimento bacteriano. Os mecanismos responsáveis por estas alterações não foram ainda esclarecidos. Considerando que o sistema nervoso autônomo (SNA) participa do controle da motilidade intestinal, parece provável que a DA esteja associada com as alterações da motilidade intestinal na CH. Os objetivos deste estudo foram investigar a presença de alterações do SNA parassimpático e simpático em pacientes com CH de etiologia não alcoólica, utilizando os métodos dos testes de reflexos cardiovasculares e da análise da VFC em 24 horas, e avaliar a associação das alterações autonômicas encontradas com a gravidade da disfunção hepática, com alterações do trânsito intestinal, e com o aparecimento de complicações da CH. Foram estudados trinta e quatro pacientes com diagnóstico de CH de etiologia não alcoólica, divididos em Child-Pugh A (13) e Child-Pugh B/C (21). A atividade autonômica foi avaliada através dos testes de reflexos cardiovasculares e da análise da VFC em 24 horas. O estudo do tempo de trânsito orocecal (TTOC) foi realizado pelo teste do H2 no ar expirado, após ingestão de lactulose. De acordo com os testes de reflexos cardiovasculares, a presença de disfunção parassimpática foi encontrada em 4 pacientes Child A (30,8%) e em 6 pacientes Child B/C (28,4%; p>0,05). A análise da VFC em 24 horas mostrou que os parâmetros relacionados com a atividade parassimpática (LF, lnLF, pNN50) e simpática (LF, lnLF) estavam significativamente (p<0,05) diminuídos nos pacientes Child B/C, tanto em relação ao grupo controle, como também em relação aos pacientes Child A. A avaliação individual mostrou a presença de disfunção parassimpática em 3 pacientes Child A (23,1%) e em 12 (57%; p=0,07) Child B/C. A diminuição da atividade simpática concomitante foi encontrada em 8 dos 12 pacientes Child B e C, com lesão parassimpática. Em relação ao TTOC, não houve diferença estatística entre os valores do TTOC no grupo Child A (52±17 minutos) e no grupo controle (52±13 minutos). Em contraste, os pacientes Child B/C apresentaram valores mais altos do TTOC (71±34minutos) em relação aos controles (p=0,02). Apenas dois pacientes apresentaram resultados sugestivos de supercrescimento bacteriano. O tempo de seguimento foi de 19±12 meses. Ao final do estudo, cinco pacientes (24%) Child B/C evoluíram para óbito. Os valores dos parâmetros representativos da atividade parassimpática (HF, lnHF) nesses pacientes foram significativamente (p=0,04) menores que os encontrados nos pacientes do grupo Child B/C que continuavam vivos. A encefalopatia foi a complicação mais freqüente, acometendo 42,8% dos pacientes durante o período de seguimento. Houve associação estatística entre a presença de DA e a incidência de encefalopatia hepática (p<0,05). Não houve correlação entre os parâmetros da atividade autonômica com os valores do TTOC. Também não houve associação entre TTOC prolongado e complicações da CH. Em conclusão, nossos resultados demonstraram que a DA é achado freqüente nos pacientes com CH de etiologia não alcoólica e está associada com o grau de disfunção hepática, sendo mais freqüente nos pacientes com CH Child B e C. Nossos dados não demonstraram associação entre a alteração da função autonômica e o prolongamento do trânsito intestinal observado nesses pacientes. A presença da DA é um fator predisponente para a ocorrência de encefalopatia hepática, e parece influir no prognóstico da doença / Abstract: Autonomic dysfunction (AD) is common in patients with alcoholic hepatic cirrhosis but information on its occurrence and clinical relevance in patients with non-alcoholic liver disease is contradictory. 24-hour heart rate variability (HRV) is considered to be more sensitive than the cardiovascular reflexes to detect autonomic damage. Only a few studies used this technique in the investigation of autonomic function in cirrhotic patients. Previous studies have demonstrated that intestinal transit is delayed in patients with cirrhosis, and that this alteration predisposes to bacterial overgrowth, bacterial translocation and risk of infections. The reasons for that remain unclear. Since the autonomic nervous system participates in the regulation of gastrointestinal motility, it seems likely that AD may play a role in the intestinal motility alterations observed in cirrhosis. Therefore, our aims were to assess autonomic function in patients with non-alcoholic hepatic cirrhosis, and to investigate the relationship of AD with severity of disease, delayed intestinal transit and the clinical outcome. Thirty four patients with non-alcoholic hepatic cirrhosis classified as Child¿s A (n=13) and Child¿ B/C (n=21) were studied. Autonomic function was assessed by using standard cardiovascular reflexes tests and 24- hour HRV analysis. Orocaecal transit time (OCTT) was measured using the lactulose hydrogen breath test. According to cardiovascular reflexes tests, 4 patients Child A (30.8%) and 6 patients Child B/C (28.4%), were found to have evidence of parasympathetic damage. The 24-hour HRV analysis showed that parameters reflecting parasympathetic (HF, lnHF, pNN50) and sympathetic (LF, lnLF) function were significantly decreased (p<0,05) in comparison with both controls and Child¿s A patients. Individual analysis showed parasympathetic damage in three patients Child A (23,1%) and in 12 (57%) Child B/C (p=0.07). Eight patients had combined sympathetic damage. No diference was found in OCTT values between Child¿ A patients (52±17 minutes) and controls (52±13 min). In contrast, OCTT values were significantly higher in Child¿ B/C patients (71±34minutes) than in controls. Bacterial overgrowth occurred in only two patients. The mean follow-up time was 19±12 months. At the end of the study, five Child¿s B/C patients (24%) have died. The values of parameters representative of parasympathetic function (HF, lnHF) were significantly lower (p<0.05) in these patients in comparison with survivors of Child¿s B/C group. Hepatic encephalopathy was the most frequent complication during follow-up, occurring in 42.8% of Child¿s B/C patients. AD was significantly associated with encephalopathy (p<0.05), but did not correlate with OCTT values. In conclusion, our study showed that autonomic dysfunction in common in patients with non-alcoholic liver disease and is related to the severity of hepatic dysfunction. Our results did not show a relationship between delayed intestinal transit and AD. The presence of autonomic damage predisposes these patients to the development of encephalopathy and may be associated to higher mortality / Mestrado / Clinica Medica / Mestre em Clinica Medica

Abstract Cytochrome P450 2A6 (CYP2A6) is involved in the 7-hydroxylation of coumarin, C-oxidation of nicotine, and the metabolism of tobacco specific nitrosamines. Initially in 1995 Fernandez-Salguero et al. reported a genotyping method for three alleles: CYP2A6*1 (wild-type), CYP2A6*2 (variant 1), and CYP2A6*3 (variant 2). Later studies presented in this thesis indicated that the original genotyping method produces erroneous results for the CYP2A6*3 allele due to unspecific PCR conditions and previously unknown CYP2A6*1B allele. Furthermore, the CYP2A6*2 allele genotyping caused erroneous genotypes (CYP2A6*2/*2 was misclassified as CYP2A6*1/*2). In this work, new PCR based genotyping methods were developed for CYP2A6*2 and for several new alleles (CYP2A6*1B, CYP2A6*4A/*4D and CYP2A6*5). In population-based studies, the deletion alleles (pooled as CYP2A6*4) turned out to be more prevalent among Asians (15.1%) than Caucasians (0.5%). The frequencies of the other inactive alleles varied within 0–3% in both populations. Asians totally lacked the CYP2A6*2 allele, whereas Caucasians lacked the CYP2A6*5 allele. The frequencies of two wild-type alleles, CYP2A6*1A and CYP2A6*1B alleles were 66.5% and 30.0% in Caucasians, and 43.2% and 40.6% in Asians, respectively. Correlation studies between the phenotype, as tested by the administration of coumarin, and the genotype demonstrated that individuals with the CYP2A6*2/*2 genotype were totally defective, while CYP2A6*1/*2 subjects exhibited intermediate and CYP2A6*1/*1 subjects full capablility of producing 7-hydroxycoumarin. Upon phenotyping with nicotine, individuals with the CYP2A6*1/*2 or CYP2A6*1/*4 genotype were shown to have a lower enzyme activity (one fourth of the normal activity), compared to those with the CYP2A6*1/*1 genotype. Defective CYP2A6 activity has been hypothesised to reduce the risk of environmentally (especially tobacco smoke) induced diseases either by decreasing production of genotoxic metabolites or by preventing addiction to tobacco smoking. However, in our case-control studies on Spanish patients with liver cirrhosis (n = 83) and liver cancer (n = 90) and their controls (n = 237) no significant association between the CYP2A6 genotypes and disease proneness was found. The odds ratio (OR) for developing liver cancer was was 1.4 (95% confidence interval [CI] 0.5–3.7) for genotypes containing at least one CYP2A6*2 allele. For liver cancer the respective OR was 1.3 (95% CI 0.4–4.5). Similarly, no statistically association between CYP2A6 alleles and the risk of lung cancer was observed in our Finnish study population cinsisting of 177 cases and 1089 controls; the OR for combined CYP2A6 variant allele containing genotypes (CYP2A6*1/*2 and CYP2A6*1/*4) was 1.19 (95% CI 0.56–2.45). Our studies therefore do not indicate any major modifying role for the CYP2A6 genotypes in individual susceptibility to environmentally induced diseases.

Background & Aims: Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin (T-V), and octreotide and somatostatin (O-S). However, the benefit/harm balance is unclear. Our aim was to assess the efficacy and safety of T-V versus O-S for the management of AVB. Methods: We performed a systematic search for randomized controlled trials (RCTs) in PubMed, Scopus, and CENTRAL. Our main outcomes were mortality and adverse events. Secondary outcomes were bleeding control, rebleeding, blood transfusion, hospital stay. We evaluated the certainty of evidence using GRADE methodology. Results: We included 21 RCTs. The risk of mortality (RR: 1.01; 95%CI: 0.83-1.22), bleeding control (RR: 0.96; 95%CI: 0.91-1.02; I2=53%), early rebleeding (RR: 0.91; 95%CI: 0.66-1.24: I2=0%), late rebleeding (RR: 0.94; 95 CI: 0.56-1.60; I2=0%), blood transfusion (MD: 0.04; 95%CI:-0.31-0.39; I2=68%) and hospital stay (MD:-1.06; 95%CI:-2.80-0.69; I2=0%) were similar between T-V and O-S groups. Only 15 studies reported adverse events, which were significantly higher in the T-V compared to the O-S group (RR 2.39; 95%CI: 1.58-3.63; I2=57%). The certainty of evidence was moderate for the main outcomes, and low or very low for others. Conclusions: In cirrhotic patients with AVB, those treated with T-V had similar mortality risk compared to O-S. However, the use of T-V showed an increased risk of adverse events compared to O-S. / Revisión por pares