Saket Kant

In early the 1980s, the term NAFLD was coined for fatty liver without a history of significant alcohol intake. In the earlypart of 2020 however, the International panel consensus has proposed revision of the nomenclature of NAFLD to metabolic(dysfunction) associated fatty liver disease (MAFLD); considering its significant association with metabolic conditions likeT2D, insulin resistance, obesity, dyslipidaemia, acute pancreatitis, etc. Actually, MAFLD is a previously recognized entity,as its relationship with T2D was observed by Beringer and Thaler in early 1970s, where-in they described the appearance offatty liver in 75% individual with T2D and findings of liver cirrhosis in 2.6% versus 0.84% in the general population. Thisrevised proposal has changed criteria to diagnose this condition; which now requires evidence of hepatic steatosis along withany one of the three features- obesity, T2DM and low/normal BMI with evidence of metabolic dysfunction. Changes in thenomenclature to MAFLD has added weight to the importance of insulin resistance and T2D in this condition, which demandsthe collaborative role of endocrinologist/physicians with hepatologist for appropriate management of this condition.⁸

NAFLD is a disease related to metabolic syndrome. IR pays a pivotal role in its pathogenesis and progression. IR is alsoa common soil for T2D and obesity; hence NAFLD is closely associated (70-80%) with these metabolic conditions.9Development of NASH is multifactorial, and IR has a key role as the initiator. As per the 2-hit hypothesis, the proposedexplanation for the pathogenesis of NASH, IR is the first hit which leads to excessive fatty acids production in the circulationpromoting the progressive changes from simple fatty liver to hepatic steatosis to NASH.¹⁰ In the current era with no approveddrugs available for NAFLD, oral antidiabetic drugs like metformin and pioglitazone are useful off label agents to reduce IR inNAFLD subjects. More studies are required for the demonstration of the underlying mechanism of pathogenesis of NAFLDto develop effective agents for the prevention and treatment of NAFLD because of insulin resistance.

NAFLD carries an increased risk of liver failure as a result of cirrhosis. In addition, several other metabolic disturbances suchas chronic inflammation, proatherogenic state, dysglyceamia, IR, and dyslipidaemia elevates the risk of CVD in NAFLDpatients.11 NAFLD is also associated with 2-3 times higher risk of dyslipidaemia, elevated coronary artery calcium (CAC)score and recurrent CV events. This overall implies that CVD is the leading cause of morbidity and mortality in NAFLD.The higher CV risk in NAFLD is due to derangement of lipoproteins, especially, high triglyceride-rich lipoproteins (TRL)in addition to increased liver fat and deranged conventional lipid profile. Statins and ezetimibe are the preferred options fordyslipidaemia in this setting which has shown to reduce CV events in some post hoc analysis.¹¹

NAFLD is a condition wherein the majority of patients are asymptomatic in the initial stages. Currently, there are no consensusguidelines screening NAFLD at an early stage. Fatty liver is generally detected incidentally with other imaging tests andbased on history/examination of the patient; a diagnosis of NAFLD can be entertained. Biopsy is the gold standard but is aninvasive test and has other limitations. Biopsy is taken only from a small section of the liver (1/50,000^th), whereas in steatosis,the extent of fat accumulation varies segment to segment and can even be focal, which may be difficult to evaluate throughbiopsy.¹² In this regard, multi-parametric magnetic resonance imaging is effective to evaluate the amount of intrahepatic fatand is widely used in clinical trials.¹² No diagnostic method however can differentiate between steatohepatitis and simplesteatosis. Therefore, to prevent the progression of disease through early and aggressive treatment, it is of utmost importanceto develop non-invasive biomarkers for identifying and staging NAFLD as also identifying those at risk of progression toend-stage liver disease at the earliest.13

Evaluation of co-morbidities associated with NAFLD is equally important; as it has a strong relationship with diabetesand metabolic syndrome, and is associated with increased risk of cardiovascular events because of increased atherogenicsmall dense low-density lipoprotein (sdLDL) particles, decreased large high density lipoprotein (HDL) particles and increasedvery-low-density lipoprotein (VLDL) or triglyceride-rich lipoprotein particles; which are responsible for development ofatherosclerotic cardiovascular disease (ASCVD).¹⁴

From the management point of view, weight loss-based lifestyle modification has a key role in prevention/progression ofNAFLD. Yoshioka N et al. observed that NAFLD remission rates reached a plateau of 44% in subjects with 2% per yearweight loss, while ≥7% weight loss also improved histological disease activity in NASH.¹⁵ However, only diet and exerciseregimens may not be able to achieve and/or maintain a 10% weight loss.

Asian and international guidelines have a different viewpoint on the pharmacological approach to treat NAFLD. TheEASLD, AASLD and Asia-Pacific guidelines recommend pharmacological approach only for patients with NASH andfibrosis, while the NICE guideline proposes therapy for subjects with an advanced liver fibrosis score (ELF test >10.51). Someinternational authorities like the AISF recommend starting drug therapy in patients with high risk for disease progression also.The present guidelines are not in line for the management/pharmacological therapy of NAFLD.^16-18

For the pharmacological management of NAFLD, metformin, pioglitazone, vitamin E, obeticholic Acid, glucagon-likepeptide-1 (GLP-1) analogues, sodium-glucose cotransporter 2 (SGLT2) inhibitors and dual peroxisome proliferator-activatedreceptor (PPAR) agonist are commonly used medications, but they have not been approved in most of the countries. A lot oftherapies targeting de novo lipogenesis, fat deposition, oxidative stress, inflammation, apoptosis and liver fibrosis are underinvestigation.

All guidelines recommend that the use of these medications is off-label and that the decision should be discussed withthe patient, carefully balancing the benefit/risk ratio.¹⁹In the early 2020s, the Drug Controller General of India (DCGI) hasapproved saroglitazar (dual PPAR α/γ agonist) for the management of NASH/NAFLD in India, the first approved drug by anycountry in the world. But its real-world experience is yet to be shared by clinicians.²⁰

Bariatric surgery is an option for reduction of weight and metabolic complications, in a specific category of patients whoare unresponsive to lifestyle changes and pharmacotherapy.²¹ For end-stage liver disease, liver transplantation is the onlyoption, but the high cost and availability of resources limit this approach.²²