NAFLD and Extra-Hepatic Comorbidities: Current Evidence on a Multi-Organ Metabolic Syndrome

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its incidence is definitely increasing. NAFLD is a metabolic disease with extensive multi-organ involvement, whose extra-hepatic manifestations include type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, chronic kidney disease, osteoporosis, and polycystic ovarian syndrome. Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis, and urolithiasis. The most common cause of mortality in NAFLD is represented by cardiovascular disease, followed by liver-related complications. Therefore, clinicians should learn to screen and initiate treatment for these extra-hepatic manifestations, in order to provide appropriate multidisciplinary assessments and rigorous surveillance. This review evaluates the current evidence regarding extra-hepatic associations of NAFLD, focusing on the pathogenic hypothesis and the clinical implications.

The diagnostic conundrum in non-alcoholic fatty liver disease

“…However, the pathophysiologic relationship between NAFLD and insulin resistance is still not completely clear, as demonstrated by the fact that there are epidemiological studies showing that NAFLD is not invariably associated with MetS [27]. Moreover, several evidences showed an association between NAFLD and other extra-hepatic manifestations (endocrinopathies, osteoporosis, polycystic ovarian syndrome, psoriasis, and sleep apnea) [11]. Furthermore, NAFLD has been independently associated with fatal/non-fatal CVD and arrhythmic complications, including atrial fibrillation [28].…”

“…Even if the most common cause of death among NAFLD patients is represented by cardiovascular disease (CVD), independently of presence of other metabolic comorbidities, NAFLD itself is becoming a major cause of liver-related mortality [11]. Patients with both simple steatosis or NASH may develop progressive liver fibrosis, but only NASH patients show a higher risk of rapid progression in AF [12].…”

Neurologic Manifestations of Systemic Disease: Sleep Disorders

“…Untreated OSA may exacerbate liver injury because of oxidative stress and systemic inflammation [46] and is a risk in conversion from NAFLD to liver fibrosis [47]. Trials with CPAP have shown inconsistent results in markers of liver injury following treatment of OSA [48].…”

Physical exercise and liver “fitness”: Role of mitochondrial function and epigenetics-related mechanisms in non-alcoholic fatty liver disease

“…Usually described as the hepatic manifestation of metabolic syndrome, NAFLD includes a spectrum of conditions, from hepatic steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis, characterized by lipid accumulation in liver cells [[1], [2], [3]]. NAFLD is associated with common metabolic disorders, such as, obesity [4], increased cardiovascular risk [5,6], chronic kidney disease [7], insulin resistance (IR) and type 2 diabetes (T2DM) [8], but it has also been associated with obstructive sleep apnea, osteoporosis, psoriasis, periodontitis, hypothyroidism, male sexual dysfunction, polycystic ovarian syndrome, colonorectal cancer, and urolithiasis, proposing NAFLD as a metabolic disease with extra-hepatic manifestations and multi-organ involvement [9,10].…”