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- Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease?Publication . Machado, Mariana VerdelhoThe epidemiology of nonalcoholic fatty liver disease goes hand-in-hand with the obesity pandemic. The pathogenesis of fatty liver has shifted from an hepatocentric view to an adipocentric view, in which the overloaded adipose tissue spills out lipids that spread to ectopic tissues and organs such as the liver, elicits inflammation, and changes its adipokines profile promoting insulin resistance and the metabolic syndrome. Up to 40% of nonalcoholic fatty liver disease (NAFLD) patients are not obese and up to 20% are actually lean. Furthermore roughly 10% of lean subjects have NAFLD. In fact, adiposopathy can occur in patients with normal weight, and it is associated with expansion of metabolically active visceral fat and a qualitatively different adipose tissue that becomes overwhelmed after challenged by a mildly positive energy balance. This defines the concept of personal fat threshold that when exceeded results in metabolic dysfunction. Overweight/obese persons have higher probability of exceeding that threshold, explaining why adiposopathy/metabolic syndrome/NAFLD is more frequent in the obese. In this article, the epidemiology, pathogenesis, and management of patients with lean NAFLD are reviewed with an emphasis on reconciling the concepts of NAFLD in its relationship with adiposity and of NAFLD in lean individuals.
- GE – Portuguese Journal of Gastroenterology: Farewell and Good LuckPublication . Pimentel-Nunes, Pedro; Bispo, Miguel; Almeida, Nuno; Machado, Mariana
- Aerobic Exercise in the Management of Metabolic Dysfunction Associated Fatty Liver DiseasePublication . Machado, Mariana VerdelhoSedentarism is the pandemic of modern times. It is associated with several medical conditions including obesity, type 2 diabetes mellitus, cardiovascular diseases and also liver disease, particularly metabolic dysfunction associated fatty liver disease (MAFLD). In an era when MAFLD is the most prevalent chronic liver disease worldwide, whilst no pharmacological therapy has been approved for it, exercise has proved to be effective in improving liver steatosis. Interestingly, exercise decreases liver fat even in the absence of weight loss. The challenge for the clinician is to motivate the obese patient with MAFLD, and associated co-morbidities, who has crystallized a sedentary behavior, at times when every need is at the distance of a click on the Internet, and the entire world can be visited behind a screen. In this review, the aggregate evidence on the mechanisms and effects of exercise in the management of MAFLD is summarized, with simple recommendations for everyday clinical practice.
- What should we advise MAFLD patients to eat and drink?Publication . Machado, Mariana VerdelhoIn a time of food abundance and waste, and when sedentarism is the norm, metabolic-associated fatty liver disease (MAFLD) has become a major health threat in the Western world. While research is committed to finding a pharmacological treatment for MAFLD, it is time to go back to the basis and address the behavioral pathogenesis of MAFLD. All patients with MAFLD, irrespective of body weight, should be submitted to thorough dietary counseling. Diet is a learned behavior and should be addressed holistically and in a personalized fashion. The benefits of a suitable diet surpass an improvement of liver disease, having the potential to improve cardiovascularand cancer-related mortality, in patients with MAFLD. This review summarizes the current state of the art of diet on MAFLD, presenting straightforward recommendations for everyday practice.
- Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia–A narrative reviewPublication . Morais, Mariana B.; Machado, Mariana VerdelhoBilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity. This article provides a comprehensive review on the pathophysiology of Dubin-Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.
- Celiac Disease RevisitedPublication . Calado, João; Verdelho Machado, Mariana
- Rotor Syndrome Presenting as Dubin-Johnson SyndromePublication . Morais, Mariana; Couvert, Philippe; Jéru, Isabelle; Machado, Mariana VerdelhoA 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease. Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile. Abdominal ultrasound was unremarkable. A panel of chronic liver diseases was negative except for increased serum (147.4 μg/dL) and urinary (179 μg/24 h) copper, with normal ceruloplasmin. No other Leipzig criteria for Wilson’s disease were found, including a negative test for ATP7B gene mutations (by exome sequencing). Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output). Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the ABBC2 gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G – p.Lys495Glu). Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4–16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis. Rotor and DubinJohnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired hepatic bilirubin excretion), respectively. We report a case of compound hereditary hyperbilirubinemia with a misleading presentation with special focus on its diagnosis, particularly the advantage of extensive unbiased genetic testing by dedicated laboratories. With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures.
- MAFLD under the lens: the role of gut microbiotaPublication . Sousa, Patrícia; Machado, Mariana VerdelhoObesity, the metabolic syndrome, and metabolic dysfunction-associated fatty liver disease (MAFLD) can be portrayed as transmissible diseases. Indeed, they can be induced, in animal models, by cohabitation or by transplantation of fecal microbiota from other animals or humans with those diseases. As such, to get a 10,000- foot view, we need to see under the lens the microbes that populate our gut. Gut microbiota participates in the harvesting of energy from nutrients, it allows the digestion of otherwise indigestible nutrients such as fibers, and it also produces short chain fatty acids and some vitamins while emitting different compounds that can regulate whole-body metabolism and elicit proinflammatory responses. The metabolic syndrome and MAFLD share physiopathology and also patterns of gut dysbiota. Moreover, MAFLD also correlates with dysbiota patterns that are associated with direct steatogenic or fibrogenic effects. In the last decade, a tremendous effort has allowed a fair understanding of the dysbiota patterns associated with MAFLD. More recently, research is moving towards the delineation of microbiota-targeted therapies to manage metabolic dysfunction and MAFLD. This review provides in-depth insight into the state-of-the-art of gut dysbiosis in MAFLD, targeting clinical hepatologists.
- Hepatocellular carcinoma screening in NAFLD: The paradox of nearly half the cases arising in non-cirrhotic low risk patientsPublication . Machado, Mariana Verdelho
- New Developments in Celiac Disease TreatmentPublication . Machado, Mariana VerdelhoCeliac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet (GFD). This is not an easy task due to a lack of awareness of the gluten content in foods and the extensive incorporation of gluten in processed foods. Furthermore, a GFD imposes a sense of limitation and might be associated with decreased quality of life in CD patients. This results in gluten contamination in the diet of four out of five celiac patients adhering to a GFD. Furthermore, one in three adult patients will report persistent symptoms and two in three will not achieve full histological recovery when on a GFD. In recent years, there has been extensive research conducted in the quest to find the holy grail of pharmacological treatment for CD. This review will present a concise description of the current rationale and main clinical trials related to CD drug therapy.