Estela Monteiro

Beyond Genetic Factors in Familial Amyloidotic Polyneuropathy: Protein Glycation and the Loss of Fibrinogen's Chaperone Activity

Familial amyloidotic polyneuropathy (FAP) is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR). This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimers and Parkinsons. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease.

When Does Quality of Life Improve After Liver Transplantation? A Longitudinal Prospective Study

OBJECTIVES We sought to investigate the improvement in quality of life (mental and physical components) at 1 and 6 months after liver transplantation. METHODS A sample of liver transplant candidates (n = 60), comprising consecutive patients attending outpatient clinics of a liver transplantation central unit (25% of the patients had familial amyloid polyneuropathy [FAP] and the remaining patents had chronic liver diseases), was assessed by means of the Short Form (SF)-36, Portuguese-validated version, a self-rating questionnaire developed by the Medical Outcome Trust, to investigate certain primary aspects of quality of life, at 3 times: before, and at 1 and 6 months after transplantation. RESULTS We observed a significant improvement in quality of life (both mental and physical components) by 1 month after transplantation. Between the first month and the sixth month after transplantation, there also was an improvement in the quality of life (both mental and physical components), although only the physical components of quality of life was significantly improved. CONCLUSIONS Our findings suggested that quality of life improved early after liver transplantation (1 month). Between the first and the sixth months, there only was a significant improvement in the physical quality of life.

Impact of RIFLE classification in liver transplantation

Ferreira AC, Nolasco F, Carvalho D, Sampaio S, Baptista A, Pessegueiro P, Monteiro E, Mourão L, Barroso E. Impact of RIFLE classification in liver transplantation.
Clin Transplant 2010: 24: 394–400.

Psychiatric and psychosocial predictors of medical outcome after liver transplantation: a prospective, single-center study.

OBJECTIVE Recognizing the potential impact of psychiatric and psychosocial factors on liver transplant patient outcomes is essential to apply special follow-up for more vulnerable patients. The aim of this article was to investigate the psychiatric and psychosocial factors predicted medical outcomes of liver transplanted patients. METHODS We studied 150 consecutive transplant candidates, attending our outpatient transplantation clinic, including 84 who had been grafted 11 of whom died and 3 retransplanted. RESULTS We observed that active coping was an important predictor of length of stay after liver transplantation. Neuroticism and social support were important predictors of mortality after liver transplantation. CONCLUSION It may be useful to identify patients with low scores for active coping and for social support and high scores for neuroticism to design special modes of follow-up to improve their medical outcomes.

Adherence correlates in liver transplant candidates.

The study sought to investigate the psychiatric and psychosocial correlates of multidimensional adherence among liver transplant candidates. A liver transplant candidate sample (N = 100), comprising consecutive patients attending outpatient clinics of a liver transplantation central unit, was assessed by means of the Multidimensional Adherence Questionnaire (MAQ; Telles-Correia 2007), the Diagnostic and Statistical Manual of Mental Disorders, Revised 4th Edition (DSM-IV-TR) criteria, the Toronto Alexithymia Scale (TAS), the NEO Five-Factor Inventory (NEO-FFI) personality inventory, the Hospital Anxiety and Depression Scale (HADS), the Brief COPE, and the Psychological Assessment of Candidates for Transplantation (PACT). We found that multidimensional adherence positively correlated with personality traits (agreeableness), good social support, and coping strategies (planning).

Liver disease-related admissions in Portugal: clinical and demographic pattern

Objective To assess the burden of liver disease in Portugal. Methods Cross-sectional study conducted in 2001 among 773 187 patients, corresponding to 922 611 hospital admissions. Liver disease was defined by International Classification of Diseases (9th edition) codes 570–573. The cost of hospitalization was computed using the groups of homogeneous diagnosis defined by the Portuguese Ministry of Health. Results In 2001 there were 12 371 patients admitted for liver-related disease, for a total of 16 607 hospital admissions, corresponding to 1.6% and 1.8% of all patients and hospital admissions, respectively. The mean age of the subjects was 57 ± 16 years, with 8870 (72%) men and 3501 (28%) women. There were 2181 in-hospital deaths, corresponding to 17.6% of the patients admitted. Alcohol-related liver disease (ALD) represented 63% of hospitalizations, and non alcohol-related liver disease (NALD) represented 37%. However, among men there were 69% ALD, while in women this percentage was only 46% (P < 0.001). The median length of stay (interquartile range) for each admission was 8 (11) days in ALD and 8 (13) days in NALD, respectively. Complications were reported in 7446 admissions: upper gastrointestinal bleeding, 3436 (46.1%); ascites, 3425 (46.0%); encephalopathy, 2245 (30.2%); jaundice, 122 (1.6%). The cost of hospital admissions for liver disease was &OV0556;59.4 million, corresponding to 2.4% of all hospital health care expenses. Conclusion Although there are strong limitations depending mostly on the inadequacy of International Classification of Diseases (9th edition) regarding liver disease, present data indicate that this condition is still mainly associated with alcohol, representing an important burden in what concerns either hospitalization time or economic costs.

The impact of exercise training on liver transplanted familial amyloidotic polyneuropathy (FAP) patients.

Background Liver transplantation is nowadays the only effective answer to adjourn the outcome of functional limitations associated with familial amyloidotic polyneuropathy (FAP), a neurodegenerative disease characterized by sensory and motor polyneuropathies. Nevertheless, there is a detrimental impact associated with the after-surgery period on the fragile physical condition of these patients. Exercise training has been proven to be effective on reconditioning patients after transplantation. However, the effects of exercise training in liver transplanted FAP patients have not been scrutinized yet. Methods The study aimed to evaluate the effects of a 24-week exercise training program (supervised or home-based) on body composition, muscle strength, and walking capacity of liver transplanted FAP patients. To fulfill this goal, a sample corresponding to 33% of all FAP patients who undergone a liver transplantation in the area of Lisbon between January 2006 and December 2008 were followed over time. Three evaluation periods were accomplished: M1 (pre-exercise training period), M2 (immediate post-exercise training period), and M3 (24 weeks after M2). The former allowed an assessment of the impact of detraining in these patients. Results The exercise training program improved body composition (lean mass and total body skeletal muscle mass), weight, and walking capacity. The improvements were more pronounced within the patients with supervised exercise training compared with the patients on the home-based program. In general, the benefits of the exercise training perdure even after a 24-week detraining period. Conclusions Exercise training results in significant improvements on the physical condition of liver transplanted FAP patients.

Psychosocial Determinants of Quality of Life 6 Months After Transplantation: Longitudinal Prospective Study

OBJECTIVES We sought to investigate the psychosocial determinants of quality of life at 6 months after transplantation. METHODS A sample of liver transplant candidates (n = 60), composed of consecutive patients (25% with familial amyloid polyneuropathy [FAP]) attending outpatient clinics was assessed in the pretransplant period using the Neo Five Factor Inventory, Hospital Anxiety and depression Scale (HADS), Brief COPE, and SF-36, a quality-of-life, self-rating questionnaire. Six months after transplantation, these patients were assessed by means of the SF-36. RESULTS Psychosocial predictors where found by means of multiple regression analysis. The physical component of quality of life at 6 months after transplantation was determined based upon coping strategies and physical quality of life in the pretransplant period (this model explained 32% of variance). The mental component at 6 months after transplantation was determined by depression in the pretransplant period and by clinical diagnoses of patients. Because FAP patients show a lower mental component of quality of life, this diagnosis explained 25% of the variance. CONCLUSIONS Our findings suggested that coping strategies and depression measured in the pretransplant period are important determinants of quality of life at 6 months after liver transplantation.

Identification and quantitative analysis of human transthyretin variants in human serum by Fourier transform ion-cyclotron resonance mass spectrometry

Transthyretin (TTR) is a homotetrameric protein involved in thyroid hormone transport in blood and in retinol binding in the central nervous system. More than 80 point mutations in this protein are known to be associated with the formation of amyloid deposits and systemic amyloidotic pathologies. Age at onset varies according to the mutation but considerable variations also occur for subjects carrying the same mutation. Moreover, wild-type TTR forms amyloid deposits in systemic senile amyloidosis, a geriatric disorder. An accurate diagnostic and the choice of therapeutic options depend on the identification of the specific mutation. Previous characterization of TTR variants by mass spectrometry required the use of antibodies for sample enrichment. We developed a novel assay based on ultra high-resolution mass spectrometry to identify human TTR variants. The method, requiring a very low sample amount, is based on SDS-PAGE fractionation of human serum, followed by peptide mass fingerprinting by MALDI-FTICR-MS (matrix assisted laser desorption ionization coupled to Fourier transform ion cyclotron resonance mass spectrometry). Moreover, it is possible to perform a relative quantification of wild type and mutant TTR forms by mass spectrometry. The method was tested and validated with the V30M mutant, involved in familial amyloidotic neuropathy of Portuguese type.

Psychosocial predictors of adherence after liver transplant in a single transplant center in Portugal.

Context— Nonadherence has important implications for morbidity and mortality, reduced quality of life, and increased medical costs after transplant. Objective— To investigate which psychiatric and psychosocial factors determine adherence after liver transplant. Design— A group of 150 consecutive transplant candidates attending the outpatient clinics of the transplant unit of Hospital de Curry Cabral were studied between January 1, 2006, and December 1, 2007. Among these, 84 received a transplant and of those 84, 11 recipients died, 3 received another transplant, and 8 refused to finish the study (62 patients remained). Measures— Before transplant, prospective recipients were assessed via the Hospital Anxiety and Depression Scale, the NEO Five-Factor Inventory, and the revised Illness Perception Questionnaire. Both before and after transplant, patients were assessed with the Multidimensional Adherence Questionnaire. Results and Conclusions— Adherence to medication improved significantly from before to after transplant. This kind of adherence after transplant was associated with adherence to medication before transplant and high scores on the personal control dimension of the Illness Perception Questionnaire before transplant. Therefore it might be useful to focus on patients with poor adherence to medication and low scores on the personal control dimension of the Illness Perception Questionnaire before transplant in order to design interventions for them.