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“Metabolic dysfunction-associated fatty liver disease (MAFLD)” is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.

Comprehensive disease classification and staging is required to address unmet needs of aging populations Globally, citizens exist for sustained periods in states of aging-related disease and multimorbidity. Given the urgent and unmet clinical, health care, workforce, and economic needs of aging populations, we need interventions and programs that regenerate tissues and organs and prevent and reverse aging-related damage, disease, and frailty ( 1 ). In response to these challenges, the World Health Organization (WHO) has called for a comprehensive public-health response within an international legal framework based on human rights law ( 1 ). Yet for a clinical trial to be conducted, a disease to be diagnosed, intervention prescribed, and treatment administered; a corresponding disease classification code is needed, adopted nationally from the WHO International Classification of Diseases (ICD). Such classifications and staging are fundamental for health care governance among governments and intergovernmental bodies. We describe a systematic and comprehensive approach to the classification and staging of organismal senescence and aging-related diseases at the organ and tissue levels in order to guide policy and practice and enable appropriate interventions and clinical guidance, systems, resources, and infrastructure.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients’ organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients’ health and the mid- and long-term effects of the pandemic on their wellbeing.

A new definition and classification of chronic kidney disease–mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Metabolic syndrome (MTS) is a cluster of concurrent metabolic abnormal conditions. MTS and its component metabolic diseases are heterogeneous and closely related, making their relationships complicated, thus hindering precision treatment. : We collected seven groups of samples (group a: healthy individuals; group b: obesity; group c: MTS; group d: hyperglycemia, group e: hypertension, group f: hyperlipidemia; group g: type II diabetes, n=7 for each group). We examined the molecular characteristics of each sample by metabolomic, proteomic and peptidomic profiling analysis. The differential molecules (including metabolites, proteins and peptides) between each disease group and the healthy group were recognized by statistical analyses. Furthermore, a two-step clustering workflow which combines multi-omics and clinical information was used to redefine molecularly and clinically differential groups. Meanwhile, molecular, clinical, network and pathway based analyses were used to identify the group-specific biological features. : Both shared and disease-specific molecular profiles among the six types of diseases were identified. Meanwhile, the patients were stratified into three distinct groups which were different from original disease definitions but presented significant differences in glucose and lipid metabolism (Group 1: relatively favorable metabolic conditions; Group 2: severe dyslipidemia; Group 3: dysregulated insulin and glucose). Group specific biological signatures were also systematically described. The dyslipidemia group showed higher levels in multiple lipid metabolites like phosphatidylserine and phosphatidylcholine, and showed significant up-regulations in lipid and amino acid metabolism pathways. The glucose dysregulated group showed higher levels in many polypeptides from proteins contributing to immune response. The another group, with better glucose/lipid metabolism ability, showed higher levels in lipid regulating enzymes like the lecithin cholesterol acyltransferase and proteins involved in complement and coagulation cascades. : This multi-omics based study provides a general view of the complex relationships and an alternative classification for various metabolic diseases where the cross-talk or compensatory mechanism between the immune and metabolism systems plays a critical role.

Summary This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Introduction Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. Methods IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. Results This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. Conclusions This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Background & aims Although metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with high multimorbidity and mortality, existing classification systems and risk prediction models largely ignore the heterogeneity of MASLD. Improved subtype definition could improve prediction of outcomes and inform new precision treatment strategies. Methods We analyzed individuals with MASLD from population-based electronic health record resource from UK Biobank (n = 125,197) and Health examinee dataset of Nanfang Hospital (n = 995). We identified subtypes with K-means clustering method. The Cox proportional hazard regression model analyzed the relationship between variables and MASLD-related complications. Results After identifying five clusters across seven clinical indicators which were age, body mass index, monocyte/lymphocyte ratio, aspartate aminotransferase, waist-hip ratio, low-density lipoprotein-cholesterol, and cholesterol, we labelled MASLD subtypes: (1) Metabolic-Dyslipidemia, (2) Younger, (3) Obesity, (4) Inflammatory, and (5) Hepatotoxic. Metabolic outcomes differed across these five subtypes. Hepatotoxic MASLD showed an increased risk of severe liver diseases compared to Metabolic-Dyslipidemia MASLD [HR = 13.9, 95% CI 10.7–18.1]. The extrahepatic complications were highest in Inflammatory MASLD. These two groups were defined as the high-risk group with higher health burden than other three groups, which classified as low-risk group. Differential single-nucleotide polymorphisms were concentrated on chromosomes 1 and 19 when comparing the high- and low-risk groups, and the annotated genes enrichment pathways were primarily related to lipid metabolism and transport. Conclusions Patient subtypes derived by clinical indicators are a valuable addition to existing MASLD classification systems, which could provide a valuable tool to aid in selecting specific treatment approaches. Graphical Abstract

The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.

We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.

Background Cancer development is mediated by oxidative stress and inflammation, which may correlate with metabolic disorders. The aim of this study was to evaluate antioxidant vitamins status and metabolic parameters in patients with oral cancer according to tumor-node-metastasis (TNM) stages. Methods A total of 194 patients with oral cancer were enrolled in this study. The patients were stratified for four groups according to cancer stages and that the statistics are comparisons across these groups. The levels of antioxidant vitamins (ubiquinone, β-carotene, vitamin A and E), metabolic parameters, oxidative stress, antioxidant enzymes activity, and inflammatory markers were measured. Results More than half of the subjects had high blood pressure, central obesity, hyperglycemia, and hyperlipidemia regardless of TNM stage. With regard to antioxidant vitamins status, 46 and 94% of patients had β-carotene and ubiquinone deficiency, respectively. Patients in T3 and T4 stages had significantly lower antioxidant enzyme (catalase, p  = 0.03) activity and higher inflammatory markers levels (high sensitivity C-reactive protein and interleukin-6, p  < 0.01) than patients in the other stages. In addition, the level of β-carotene was negatively associated with waist circumference, and ubiquinone was positively associated with the level of high-density lipoprotein cholesterol ( p  < 0.05). Higher β-carotene and ubiquinone levels were negatively associated with hypertriglyceridemia and the risk of metabolic syndrome ( p  < 0.05). Conclusions A high proportion of patients with oral cancer had ubiquinone or β-carotene deficiency and metabolic disorders. The level of ubiquinone or β-carotene was negatively associated with the risk of central obesity, hypertriglyceridemia, and metabolic syndrome. Since patients with oral cancer suffer from high oxidative stress and inflammation (particularly in the T3 and T4 stages), supplementation with antioxidant vitamins such as ubiquinone or β-carotene could be preferentially applied.