NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management

Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, or growth hormones (GH) may cause secondary forms of NAFLD, which exhibit specific pathophysiologic features and, in theory, the possibility to receive an effective treatment. Here, we critically discuss epidemiological and pathophysiological features, as well as principles of diagnosis and management of some common endocrine diseases, such as polycystic ovary syndrome (PCOS), hypothyroidism, hypogonadism, and GH deficiency. Collectively, these forms of NAFLD secondary to specific endocrine derangements may be envisaged as a naturally occurring disease model of NAFLD in humans. Improved understanding of such endocrine secondary forms of NAFLD promises to disclose novel clinical associations and innovative therapeutic approaches, which may potentially be applied also to selected cases of primary NAFLD

Do Nonalcoholic Fatty Liver Disease and Fetuin-A Play Different Roles in Symptomatic Coronary Artery Disease and Peripheral Arterial Disease?

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with both atherosclerotic cardiovascular disease (CVD) and Fetuin-A. However, the association of Fetuin-A with atherosclerosis is more controversial. We hypothesized that the pathogenic interplay of NAFLD, Fetuin-A and atherosclerosis varies based on arterial site. Accordingly, we aimed to assess NAFLD prevalence, Fetuin-A values and their relationship with symptomatic atherosclerosis occurring in different localizations: coronary artery disease (CAD) vs. peripheral arterial disease (PAD)

Caratterizzazione del profilo metabolico, dell’entità del danno epatico e dello stile di vita in una coorte di pazienti adulti con malattia di Gaucher

Introduzione La malattia di Gaucher (MG) è una malattia lisosomiale ereditaria caratterizzata da accumulo di glicosfingolipidi nelle cellule del sistema reticolo-endoteliale causato da deficit dell’enzima glucocerebrosidasi. L’epato-splenomegalia, piastrinopenia e alterazioni ossee sono le principali manifestazioni della MG tipo 1, insieme ad un profilo metabolico con aumentato dispendio energetico, stato infiammatorio, insulino-resistenza ed ipolipemia. Il coinvolgimento epatico è frequente e spazia da forme benigne fino alla fibrosi epatica e cirrosi. La terapia enzimatica sostitutiva e di riduzione del substrato sono risultate efficaci sulle complicanze viscerali ed ossee e sul miglioramento della spettanza e qualità di vita. I pazienti risultano quindi esposti alle possibili complicanze di uno stile di vita inadeguato e dei fattori di rischio cardio-metabolici con potenziale ricaduta sulle complicanze metaboliche ed epatiche. Descrizione degli studi Lo studio è stato progettato per caratterizzare il profilo metabolico e l’entità della malattia epatica in una coorte di pazienti adulti con MG tipo 1 e per valutare la loro relazione con le variabili MG-relate e con lo stile di vita, in quanto le conoscenze attuali sono molto limitate. I pazienti sono stati valutati al basale e alle visite di controllo, raccogliendo dati di severità di malattia e terapia; parametri antropometrici e metabolici; lo stile di vita è stato valutato con questionari validati; la composizione corporea mediante DEXA e la malattia epatica mediante ecografia addominale, risonanza magnetica ed elastometria epatica (Fibroscan®). Studio preliminare – In una coorte di 37 pazienti con MG, la fibrosi epatica significativa, definita da valori di rigidità > 7 kPa, è stata evidenziata in una parte rilevante di pazienti (19%) ed è risultata associata con la severità di malattia e con una minore durata di terapia. Tra i pazienti stabili in terapia, la fibrosi epatica è risultata significativamente associata anche alle variabili della sindrome metabolica (MetS), suggerendo un potenziale ruolo delle comorbidità metaboliche nella progressione della malattia epatica. Studio 1 – In un sottogruppo di 20 pazienti, le comorbidità metaboliche sono ampiamente rappresentate e la steatosi epatica, definita da un CAP ≥ 250 dB/min, è stata riscontrata nel 40% dei pazienti. La steatosi è risultata associata alla MetS ma non alle variabili di severità di malattia e alla terapia. Inoltre, i pazienti con steatosi presentavano un profilo metabolico peggiore rispetto al gruppo senza steatosi. Studio 2 – Valutazione delle comorbidità metaboliche ed epatiche in relazione allo stile di vita e alla composizione corporea. Dall’analisi dei questionari sulla dieta ed attività fisica, è emersa un’elevata prevalenza di dieta non equilibrata ed inattività fisica. Lo studio della composizione corporea ha mostrato un’aumentata massa grassa e ridotta massa magra ed ossea. La dieta non equilibrata e la sedentarietà sono associate agli indici di adiposità e alle variabili della MetS, suggerendo che lo stile di vita inadeguato possa avere un ruolo sulle complicanze epato-metaboliche nei pazienti in terapia stabile. Studio 3 – Infine, è stata valutata la modifica del profilo metabolico nel tempo e gli outcomes epatici in uno studio longitudinale di follow-up. Conclusioni I fattori di rischio cardio-metabolici, la steatosi e la fibrosi epatica sono altamente prevalenti e sembrano relati allo stile di vita inadeguato nella nostra coorte di pazienti adulti con MG. Pertanto, il controllo dello stile di vita e dei fattori di rischio metabolici dovrebbero essere parte integrante della terapia, preferibilmente in ambito multidisciplinare, con lo scopo di prevenire complicanze epato-metabolicheBackground Gaucher disease (GD) is a rare inherited lysosomal storage disorder, characterized by glycosphingolipids accumulation in cells of the reticulo-endothelial system due to deficiency of the lysosomal enzyme acid beta-glucosidase. Hepato-splenomegaly, cytopenia and bone disease represent the main features of type 1 GD. GD patients present a peculiar metabolic profile characterized by increased energy expenditure, systemic inflammation, peripheral insulin resistance and hypolipidemia. Liver disease is frequent and variable, ranging from benign hepatomegaly to fibrosis or cirrhosis. Enzyme replacement therapy and substrate reduction therapy have proven to be very effective on visceral and bone disease and to improve patients’ morbidity and quality of life. Aging GD patients, as the general population, may develop lifestyle-related metabolic risk factors with a potential impact on morbidity and mortality. Description of the studies Limited data are available about body composition, metabolic features, liver disease and lifestyle in GD. This project was designed to characterize the metabolic profile and the liver disease burden in a cohort of adult type 1 GD patients and to evaluate their relationship with GD variables and lifestyle. Patients were evaluated at baseline and follow-up visits, collecting data about GD severity and therapy, anthropometric and metabolic parameters; lifestyle habits were evaluated by validated questionnaires; body composition was assessed by DEXA and liver disease by abdominal ultrasound, magnetic resonance and liver transient elastometry (Fibroscan®). Preliminary study - In a cohort of 37 adult type 1 GD patients, a notable proportion (19%) showed significant liver fibrosis, defined as liver stiffness > 7 kPa, which was associated with GD severity features and a short therapy duration. Among patients on stable ERT, liver fibrosis was also significantly associated with the metabolic syndrome components, suggesting a potential role of metabolic comorbidities in liver disease progression. Study 1 – Within a subgroup of 20 patients of the cohort, metabolic comorbidities were widely represented and liver steatosis, defined as CAP value ≥ 250 dB/min, was detected in 40% of them. Significant steatosis was associated with metabolic syndrome, but not with GD severity variables and therapy duration. Moreover, patients with liver steatosis showed a worse metabolic profile and higher liver stiffness than the counterpart without steatosis. Study 2 – Then, we aimed at evaluating metabolic and liver-related comorbidities in relation to lifestyle and body composition. Analysis of the dietary and physical activity questionnaires showed, respectively, a high prevalence of unbalanced diet and physical inactivity. Body composition evaluation showed an increased fat mass and decreased bone and lean mass. Unbalanced diet and sedentariness were positively associated with indices of adiposity and metabolic syndrome features, suggesting that unhealthy lifestyle had a potential role on metabolic and liver complications in GD patients on stable ERT. Study 3 – Finally, we aimed at evaluating changes in metabolic profile over time and at identifying predictors of liver-related outcome in a longitudinal follow-up study. Conclusions Cardiometabolic risk factors, liver steatosis and fibrosis are highly prevalent and seem to be mainly related to unhealthy lifestyle in our adult GD cohort on stable therapy. For that reason, a cardiometabolic and lifestyle assessment in GD patients is advisable. Moreover, lifestyle changes and control of metabolic risk factors should be part of the therapeutic approach for GD patients, preferably by a multidisciplinary team, aimed at preventing metabolic and liver-related complication

Telomere shortening: An innocent bystander at the crossroad of NASH with ageing and cardiometabolic risk?

Editorial of "Leucocyte telomere shortening is associated with nonalcoholic fatty liver disease-related advanced fibrosis.

Epidemiology and pathophysiology of the association between NAFLD and metabolically healthy or metabolically unhealthy obesity

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Hypothyroidism and nonalcoholic fatty liver disease - A chance association?

Nonalcoholic fatty liver disease (NAFLD) defines the clinical-pathological spectrum of hepatic lipotoxicity, which may progress to hepatic fibrosis and its complications. Thyroid hormone is a master regulator of cell metabolism and body fat distribution. Whether hypothyroidism is associated or not with an increased risk of developing NAFLD and its fibrotic progression is both clinically and physiopathologically relevant. Indeed, answering this research question would carry major pathogenic and therapeutic implications. PubMed database was searched using relevant key-words such as hypothyroidism; NAFLD; nonalcoholic steatohepatitis; cirrhosis; hepatocellular carcinoma; epidemiology; pathogenesis; natural history. The epidemiological studies and the meta-analyses published so far were identified as well as those studies addressing the physiopathology underlying this association. Many observational studies have investigated the association between either subclinical or overt hypothyroidism and NAFLD. Data are conflicting: some original and meta-analytical studies demonstrated that hypothyroidism, (mainly subclinical hypothyroidism), was common, occurring in approximately 25% of individuals with imaging-defined or biopsy-proven NAFLD; other studies, however, failed to identify a significant association between hypothyroidism and NAFLD. Moreover, such an association is biologically plausible based on the specific physiopathological impact of thyroid hormone and thyroid stimulating hormone (TSH) on metabolism of hepatocytes and accumulation and distribution of body fat. The findings from the present review support a significant association between primary hypothyroidism and risk of development and progression of NAFLD. However, further studies evaluating the relative importance of subclinical versus overt hypothyroidism as well as addressing the mechanisms underlying the association of hypothyroidism with NAFLD are eagerly awaited

Extra-hepatic manifestations and complications of nonalcoholic fatty liver disease

This review article aims to synthesize the evidence regarding nonalcoholic fatty liver disease (NAFLD) as a systemic disorder. We critically discuss the metabolic syndrome and its components; the cardiovascular and the endocrine system; chronic respiratory disorders; the musculoskeletal system; the skin; and extrahepatic tumors. We conclude that, while some of these extra-hepatic conditions clearly predispose to the development of secondary forms of NAFLD (typically hypothyroidism-induced NAFLD), others result from pre-existent NAFLD (e.g., certain extra-hepatic tumors) and others (such as Type 2 Diabetes) have, with NAFLD, mutual and bidirectional associations. Analyzed data imply that NAFLD is not merely a hepatic disease. It is also and possibly more importantly, a systemic disorder requiring a special awareness, a multidisciplinary approach and a multidimensional vision

A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?

Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD

Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD

Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of alcohol-like hepatic histological changes, which occur in the absence of any competing causes of chronic liver disease, notably including significant alcohol consumption. A close and bi-directional relationship links NAFLD with the metabolic syndrome (MetS), and concurrent MetS will hasten the progression to more severe forms of NAFLD, including cirrhosis and hepatocellular carcinoma (HCC). Patients with NAFLD will typically exhibit atherogenic dyslipidemia and increased cardiovascular risk (CVR). Statins are among the most widely prescribed lipid-lowering drugs. Their use has historically been hampered, in individuals with liver disease, owing to the fear of hepatotoxicity. However, studies suggest that statins are not only effective in reducing cardiovascular events, but may also exert multiple beneficial effects on the liver. CVR in those with NAFLD has extensively been covered by our group and others. This updated clinical narrative review will critically examine the effects of statins on the pathogenesis of NAFLD, including the key elementary pathological lesions of NAFLD, i.e. steatosis, inflammation and fibrosis, and its liver-related complications, i.e. cirrhosis, portal hypertension and HCC