Journal of Internal Medicine最新文献

Knowledge about Gaucher disease (GD), considered a model for rare diseases, has considerably increased since its discovery. The pathophysiology of this lysosomal disorder is better known, and specific therapies that can control many aspects of the disease have been developed, particularly for the most common form, Type 1 GD. Yet, in part because of the rarity of GD, but also because of a lack of awareness by physicians, diagnostic delay too often leads to a belated management of patients having accumulated comorbidities. Gaucher cells, the most visible consequence of glucocerebrosidase deficiency, have been known for many years. However, the pathophysiological mechanisms underlying some major lesions, such as bone disease, predisposition to Parkinson's disease in Type 1 GD, or neurological involvement in Type 2 and Type 3 GD, remain poorly understood. Diagnostic, therapeutic, and follow-up issues associated with these symptoms remain critical to optimize the care of these patients. In this review, clinical characteristics, pathophysiology, diagnosis, treatment, and prognosis of GD are successively considered, highlighting for each of them the remaining challenges. Continued efforts to better understand pathophysiological mechanisms, use of the most modern methods such as artificial intelligence, international collaboration, and development of new therapeutic strategies seem essential for the future of this rare disease.

Editorial

Current population estimates suggest over a third of adults in the world have hepatic steatosis, and the majority would meet criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) [1]. This was previously termed non-alcoholic fatty liver disease until an international multi-society consensus to change the name in 2023 [2] to facilitate a proactive diagnosis rather than being a diagnosis of exclusion.

However, only a small proportion of patients with MASLD will have a major adverse liver outcome in their lifetime, such as decompensated cirrhosis or developing a hepatocellular carcinoma (HCC). The major risk for adults with hepatic steatosis is a major adverse cardiovascular event (MACE), particularly myocardial infarction, with an increased lifetime odds of coronary artery disease rising by 33% compared to adults without steatosis [3].

The counterfactual is MASLD is a leading indication for liver transplantation across Europe and North America, in part due to the success of the Hepatitis C eradication programmes internationally. MASLD is also a rapidly rising cause of liver-related deaths in the WHO global burden of disease study, behind alcohol-related liver disease and viral hepatitis. Modelling of trajectories of liver disease–related deaths from seven international liver disease cohorts suggests MASLD related deaths will have doubled between 2015 and 2030 [4]. It is also driving the rise in HCC in non-cirrhotic liver disease across the western world, with one multicentre French cohort reporting 72% of non-cirrhotic HCC diagnoses were made incidentally over an 11-year period [5].

Crucially, fibrosis progression rates (FPRs) in MASLD are slow, and addressing cardiometabolic risk factors can halt—and even reverse—progression whilst improving all-cause morbidity and mortality from MACE. Importantly, fibrosis is the only histological feature which is known to determine the risk of liver-related events, with progressive stages of fibrosis conferring the highest risk of adverse outcomes [6, 7]. Therefore, identifying patients with MASLD with advanced fibrosis is pivotal in terms of risk stratification. Emerging data suggested that Type 2 diabetes (T2D) is one of the strongest potentiators of fibrogenesis, and FPRs in those with T2D are enhanced [8]. However, a substantial proportion of this evidence comes from clinical trials or those attending secondary care diabetes services; thus, real-world evidence, particularly from primary care settings, is to be welcomed.

In this context, Balkhed et al. provide valuable normative data when screening for MASLD amongst T2D patients in the primary care setting [9]. Steatosis prevalence in T2D has historically been reported at 50%–70% [10], and multiple societies such as the European Association for the Study of the Liver and the Ame

Cholecystokinin (CCK) is a classic gut hormone that has been known for almost a century to regulate gallbladder emptying, pancreatic enzyme secretion, and gastrointestinal motor activity. In 1968, the CCK structure was identified by Viktor Mutt and Erik Jorpes from porcine gut extracts as a peptide of 33 amino acid residues. Based on that structure, physiological, immunochemical, molecular, and cell biological research has since expanded the insight into the biology of CCK remarkably. Thus, CCK was the first identified intestinal satiety signal to the brain. Moreover, the CCK gene is now known to be expressed in different molecular forms not only in the gut, but very much so in central and peripheral neurons, in addition to extra-intestinal endocrine cells, immune cells, cardiomyocytes, spermatogenic cells, and certain fat cells. Accordingly, CCK peptides function not only as hormones. They are also neurotransmitters, paracrine growth and satiation factors, anti-inflammatory cytokines, incretins, adipokins, myokines, potential fertility factors, and tumor markers. Consequently, CCK biology has now opened windows for insights into pathophysiology with diagnostic and therapeutic possibilities in metabolic disorders (obesity, eating disorders, and diabetes mellitus), gallbladder disease, neuropsychiatric diseases (cerebral tumors, memory, and anxiety disorders), cardiac diseases (prognosis in heart failure), neuroendocrine and pediatric tumors, as well as perhaps infertility.

Extensively studied over the past four decades, the TP53 gene has emerged as a pivotal watchman in cellular defense and a key factor in cancer biology. TP53 is the most frequently mutated gene in human malignancies, 50% of which carry alterations to it. Initially, the functions of p53 were thought to be restricted to cell-cycle arrest and apoptosis. With time, however, a growing number of functions have been discovered, illustrating p53's role as a master switch between any cellular stress and cellular or multicellular responses that contribute to its anti-tumor activity. Indeed, the peculiar landscape of TP53 mutations and its high heterogeneity are linked both to the structure of the protein and its ubiquitous function in regulating cellular homeostasis. Mutations in p53 are associated with poor response to therapy and shorter survival in most cancer types, and the diagnosis of p53 mutations is currently used to improve case management in some types of leukemia and lymphoma. Although TP53 has been defined as a tumor suppressor gene, overexpressed mutated p53 variants found in human tumors are defined as dominant oncogenes with a potential gain of function, which makes the gene a very attractive target for developing new cancer treatments. Beyond its role in cancer, our review also highlights TP53's significance in non-neoplastic conditions, such as bone marrow failure syndromes and certain developmental disorders, where chronic p53 activation plays a crucial role in cellular stress responses, demonstrating its broader biological importance.