Aerobic Exercise in the Management of Metabolic Dysfunction Associated Fatty Liver Disease

Sedentarism 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.info:eu-repo/semantics/publishedVersio

What is the role of caspase-2 mediated lipoapoptosis in the pathogenesis of the metabolic syndrome-associated liver disease, nonalcoholic fatty liver disease (NAFLD)?

Nonalcoholic fatty liver disease can be considered the hepatic manifestation of obesity and the metabolic syndrome. It is the number one cause of chronic liver disease in the Western world. Lipotoxicity in the liver induces epithelial lesion that triggers a wound healing response. In susceptible subjects the wound healing response is ineffective in repairing and regenerating the injured liver, leading to scarring, fibrogenesis and eventually hepatic cirrhosis. Though important advances in the knowledge of the pathogenesis of NAFLD have occurred since its firsts descriptions in 1980, gaps in knowledge still precludes Hepatologists to find an effective treatment for this pandemic. We first extensively characterized and compared two dietary mouse models of NAFLD, methionine-choline deficient (MCD) and Western diets. We found that MCD diet induces severe disease with significant fibrosis, whereas Western diet induces mild disease, but associates with obesity, insulin resistance and the metabolic syndrome. Afterwards, we demonstrated a pivotal role of caspase-2 in the development of the metabolic syndrome, NAFLD, progression to severe liver disease and hepatic fibrogenesis. Caspase-2 was up-regulated in human NAFLD and in in several different mouse models of NAFLD, correlating with the degree of fibrosis. Also, caspase-2 deficient mice were protected from the metabolic syndrome and liver injury/fibrosis in both MCD and Western diet mouse models. Finally, we found that in different mouse models of NAFLD, hepatic free coenzyme A content is decreased, which could potentiate caspase-2 activation. We conducted a preclinical trial in mice submitted to MCD diet, treating them with coenzyme A precursors. This approach failed to correct hepatic free coenzyme A levels and had no impact in liver histology or caspase-2 expression/activation. Our work places caspase-2 as a potential therapeutic target for obesity-associated diseases, such as type 2 diabetes mellitus and NAFLD.Fundação Calouste GulbenkianFundação CampalimaudMinistério da saúdeFundação para a Ciência e Tecnologi

The Growing Landscape of NAFLD-Associated Hepatocellular Carcinoma and Its Impact in Surveillance

Liver cancer is globally the third leading cause of death from cancer. Hepatocellular carcinoma (HCC) develops in patients with underlying liver disease. The fraction of HCC attributed to nonalcoholic fatty liver disease (NAFLD) shows an accelerated increase in the last decades, being already responsible for 15% of all HCC cases. Similar to other causes of liver cirrhosis, patients with NAFLD-associated cirrhosis should be enrolled in HCC-screening programs, yet these patients are under-screened, and currently are less than half likely to be proposed for HCC screening as compared to patients with HCV-associated cirrhosis. NAFLD-associated HCC has the peculiarity of occurring in precirrhotic phases in 20–50% of the cases. Currently, HCC screening in precirrhotic NAFLD patients is not routinely recommended, since the risk of developing HCC is very low. However, because NAFLD affects one-third of the worldwide population, noncirrhotic NAFLD already accounts for 6% of HCC cases. As such, it is pressing to develop stratification tools, in order to personalize the individual risk of HCC development in a patient with NAFLD, allowing precision HCC-screening programs. This review summarizes the epidemiology of NAFLD-associated HCC with a critical analysis of current HCC-screening recommendations

Rotor Syndrome Presenting as Dubin-Johnson Syndrome

A 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.info:eu-repo/semantics/publishedVersio

Safety and Immune and Clinical Responses

Funding Information: This study was funded by Associação Portuguesa para o Estudo do Fígado, which supported the costs of the antibody titer analysis of every patient at each timepoint. Publisher Copyright: © 2023 The Author(s). Published by S. Karger AG, Basel.Introduction: Three years after the beginning of the SARSCoV-2 pandemic, the safety and efficacy of COVID-19 vaccination in liver cirrhosis (LC) patients remain controversial. We aimed to study the safety, immunological, and clinical responses of LC patients to COVID-19 vaccination. Methods: Prospective multicentric study in adults with LC eligible for COVID-19 vaccination, without prior known infection. Patients were followed up until the timing of a booster dose, SARS-CoV-2 infection, or death. Spike-protein immunoglobulin G antibody titers for SARS-CoV-2 at 2 weeks, 3 months, and 6 months postvaccination were assessed. Antibody titers 200 BAU/mL at 3 months. Conclusion: COVID-19 vaccines in patients with LC were safe, without serious adverse events. The humoral and clinical responses were similar to the reported for the general population. Humoral response was adversely impacted by older age and adenovirus vector vaccines and unrelated to the liver disease severity.publishersversionepub_ahead_of_prin

Adiponectin, leptin, and IGF-1 are useful diagnostic and stratification biomarkers of NAFLD

[EN] Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p<0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.CR was funded by FEDER through the COMPETE program and by national funds through Fundação para a Ciência e a Tecnologia (PTDC/MED-FAR/29097/2017—LISBOA-01- 0145-FEDER-029097) and by European Horizon 2020 (H2020- MSCA-RISE-2016-734719). This work was also supported by Fundação para a Ciência e Tecnologia (PD/BD/135467/2017) and Portuguese Association for the Study of Liver/MSD 2017. JB was funded by Spanish Carlos III Health Institute (ISCIII) (PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 and CPII19/00008), co-financed by Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III (CIBERehd, Spain), La Caixa Scientific Foundation (HR17-00601), Fundación Científica de la Asociación Española Contra el Cáncer, and European Horizon 2020 (ESCALON project: H2020-SC1-BHC-2018-2020)

Liver and Muscle in Morbid Obesity: The Interplay of Fatty Liver and Insulin Resistance

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients. METHODS: Liver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses. RESULTS: Fifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056). CONCLUSIONS: In morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity

Celiac Disease Revisited

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New Developments in Celiac Disease Treatment

Celiac 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

Role of Hedgehog Signaling Pathway in NASH

Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease