Pancreatitis crónicaCorrelación de perfiles metabolómicos con su diagnóstico y estudio de la pérdida de función pancreática

Abstract

Chronic pancreatitis is a chronic inflammatory disease of the pancreas with parenchymal fibrosis. It produces a loss of functional tissue and leads in advanced stages to both exocrine and endocrine pancreatic insufficiency. Early detection of this disease is highly challenging, given that most of its specific diagnostic symptoms and signs appear at a late stage. Nevertheless, despite its underdiagnosis, there is an elevated prevalence of this disease in the general population. The early detection of chronic pancreatitis is important for multiple reasons. First, resulting exocrine pancreatic insufficiency carries a high risk of malnutrition and is an independent risk factor for cardiovascular disease. In addition, endocrine damage produced by the disease can lead to pancreatogenic (type 3c) diabetes, which is usually erroneously classified as type 2 diabetes. This is because diagnostic criteria do not differ between types 3c and 2 at endocrine level and the possible involvement of an underlying pancreatic disease is not considered. Finally, it has been widely demonstrated that chronic pancreatitis is one of the main risk factors for the development of pancreatic cancer. There is an urgent need to overcome the above limitations by developing novel diagnostic approaches to these pancreatic diseases. Metabolomics is an emerging technique that can facilitate the detection of diseases of difficult diagnosis, because the serum metabolome has been found to represent the functional status of cells, tissues, organs, and even the whole organism. Hence, the identification of changes in metabolic patterns in the serum of patients provides valuable data on functional changes produced by a given disease, helping to establish its diagnosis. To date, studies on the clinical applicability of metabolomics in the pancreas have largely centered on the early diagnosis and follow-up of pancreatic cancer and the response to its treatment. However, there is a need to focus efforts on the early identification of groups at risk of such diseases as chronic pancreatitis in order to implement the early follow-up of patients and improve their clinical outcomes. The hypothesis of this doctoral thesis is that the study of serum metabolite patterns permits the early diagnosis of chronic pancreatitis and associated exocrine pancreatic insufficiency. For the present study, a sample of peripheral blood was drawn from 32 patients with chronic pancreatitis and exocrine pancreatic insufficiency, 21 patients with chronic pancreatitis but not exocrine pancreatic insufficiency, and 60 healthy individuals. Serum obtained from each participant was analyzed by high-resolution mass spectrometry. Multivariate analysis was used to identify three serum metabolites with the capacity to discriminate between patients with chronic pancreatitis and healthy individuals. These metabolites are related to the proinflammatory role of the microbiota, the dysfunction of pancreatic β cells, and inflammatory, apoptotic, and fibrogenic mechanisms. Study of metabolite patterns in sera from patients with chronic pancreatitis grouped according to the presence or absence of exocrine pancreatic insufficiency identified four metabolites that discriminated between the groups. In addition, mass spectrometry analysis of serum metabolites from 21 patients with pancreatogenic diabetes and 9 with type 2 diabetes yielded a panel of five metabolites that distinguished between these diseases in an efficacious manner. Taken together, these results demonstrate the usefulness of metabolomics as a tool to identify different risk groups for pancreatic disease, opening up the possibility to establish useful biomarkers for their early diagnosis. An investigation was also conducted into the involvement of exocrine and endocrine pancreatic insufficiency in the progression of chronic pancreatitis, revealing an elevated prevalence of both insufficiencies during the course of the disease, with variable clinical repercussions as a function of their severity and the administration or not of appropriate treatment. The study also showed how the loss of exocrine and endocrine pancreatic function increases in parallel to the progression of chronic pancreatitis and is exacerbated by the consumption of tobacco and alcohol. Furthermore, the tobacco habit proved to be a crucial proinflammatory factor, evidenced by the elevation of acute-phase reactants in the patients with chronic pancreatitis who smoked. Finally, with the aim of favoring the early diagnosis and treatment of exocrine pancreatic insufficiency, a review was conducted to provide an update of knowledge on different etiopathogenic and therapeutic aspects of this insufficiency. In relation to the diagnosis, the utilization of a combination of clinical, analytical, and pancreatic function test results is proposed to improve its detection. With regard to the therapy, replacement treatment with pancreatic enzymes has proven able to normalize anthropometric but not nutritional parameters in these patients.