Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and encompasses a spectrum of pathology from simple steatosis to inflammation and significant fibrosis that leads to cirrhosis. NAFLD and its comorbid conditions extend well beyond the liver. It is a multisystemic clinical disease entity with extrahepatic manifestations such as cardiovascular disease, type 2 diabetes, chronic kidney disease, hypothyroidism, polycystic ovarian syndrome, and psoriasis. Indeed, the most common causes of mortality in subjects with NAFLD are cardiovascular disease, followed by malignancies and then liver-related complications as a distant third. This review focuses on several of the key extrahepatic manifestations of NAFLD and areas for future investigation. Clinicians should learn to screen and initiate treatment for these extrahepatic manifestations in a prompt and timely fashion before they progress to end-organ damage.

Role of Mitofusins and Mitophagy in Life or Death Decisions

“…Although patients can exhibit steatosis without further complications, in many cases steatosis evolves to hepatic inflammation, fibrotic restructuring, cirrhosis, hepatocellular carcinoma and ultimately liver failure (Parthasarathy et al, 2020; Figure 4). Other disorders can constitute risk factors for NAFLD development, such as type 2 diabetes mellitus, obesity, metabolic syndrome, cardiovascular disease, and chronic kidney disease (VanWagner and Rinella, 2017;. Interestingly, a bidirectional link was observed for some of these, since NAFLD is a risk factor for the development of cardiovascular disease, atherosclerosis and chronic kidney disease (VanWagner and Rinella, 2017).…”

PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels

“…Nonalcoholic fatty liver disease (NAFLD) is currently recognized not only as a major cause of liver-related morbidity and mortality, but it may be also actively involved in the development and progression of chronic kidney disease (CKD) (1,2). NAFLD exacerbates systemic/hepatic insulin resistance and promotes the release of several pro-inflammatory, pro-fibrogenic and pro-oxidant mediators, which are also factors potentially involved in the pathophysiology of CKD (3,4). Recent studies have reported that the rs738409 polymorphism in the patatin-like phospholipase domaincontaining protein 3 (PNPLA3) gene, (i.e., the major common genetic variant associated with a greater predisposition to progressive forms of NAFLD (5-7)), was associated with decreased estimated glomerular filtration rate (eGFR) and increased albuminuria, irrespective of the presence of NAFLD (6,7).…”

Hypothyroidism-Induced Nonalcoholic Fatty Liver Disease (HIN): Mechanisms and Emerging Therapeutic Options

“…Considering the burden of NAFLD and that no current licensed therapy exists, THs and their metabolites, along with the THR-β agonist and other liver specific analogs have been tested in the last few years as a potential NAFLD therapy [ 7 , 59 , 60 , 171 ].…”

“…Considering the common and possible evolution to NASH and cirrhosis, NAFLD has become one of the main causes of liver transplantation [ 6 ]. It is characterized by comorbid manifestations that extend beyond the liver and in an all-cause mortality/morbidity relationship, plenty of evidence highlights its association with metabolic disorders, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), gallstone disease, cardiovascular, and endocrine illnesses (hypothyroidism, polycystic ovarian syndrome, or hypogonadism) [ 7 , 8 , 9 , 10 , 11 , 12 ]. As NAFLD is considered the cause or the consequence of metabolic syndrome, which is reflected primarily by raised visceral adiposity that promotes insulin resistance (IR), glucose intolerance, and overall a lipotoxic status, it is possible that its metabolic substrates may share pathogenic factors with hypothyroidism [ 13 , 14 , 15 , 16 ].…”