Medical Doctor Hindu Rao Hospital & NDMC Medical College India
Dr.Vinod Nikhra is a Senior Consultant Physician and Faculty at NDMC Medical College and Hindu Rao Multi-specialty Public Hospital, New Delhi, India. He is a healthcare administrator, academician and clinician. He has been a Visitor at Cleveland Clinic Foundation, Cleveland and an Observing Physician at Alabama Medical Center a tertiary care hospital in Opelika, Alabama, USA. He has been elected a Fellow by International Medical Sciences Academy and the Royal Society of Medicine, London. He has been Editor of Madhya, the midage, the official Journal of Association for Health in Middle Age during 2003-2006. He has been on Reviewer panel of, among others, the Family Practice, an Oxford University medical journal and International Journal of Obesity. His published books include,ËœAging slowly, Living longer and The Anti-obesity Guide. Over the years he has contributed about hundred papers in leading national and international medical journals, some of which are available on www.researchgate.in.
ABSTRACT :- CARDIOVASCULAR DISEASE, METS AND NAFLD: There exists a near-ubiquitous relationship between Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (METS or MetS). Both, MetS and NAFLD have been, in turn, related to increased incidence and prevalence of cardiovascular disease (CVD). Further, as a fallout of the modern-day sedentary lifestyle and altered dietary practices with enhanced intake of sweetened non-alcoholic and alcoholic drinks, there is increased prevalence of adiposity, MetS and type 2 diabetes mellitus (T2DM). NAFLD - PREVALENCE AND ASSOCIATIONS: NAFLD is a highly prevalent metabolic disorder having as key feature, the insulin resistance (IR), accompanied with impaired insulin sensitivity (IS) in liver and other organs including muscles and adipose tissues. Further, the incidence of NAFLD is high in conditions associated with IR such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia and metabolic syndrome (MetS). Intrahepatic triglyceride accumulation, or steatosis, is the hallmark of NAFLD that develops when the rate of fatty acids (FAs) influx (FAs uptake from plasma and de novo lipogenesis) exceeds the rate of FAs efflux (FA oxidation and secretion of triglycerides as VLDL). A subset of NAFLD patients go on to develop non-alcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis. ETIOLOGY AND PATHOLOGICAL MECHANISMS: The pathogenesis of NAFLD has been described by the ‘two hits’ hypothesis. The first ‘hit’ is deposition of FAs and triglyceride in hepatocytes (steatosis), and the second ‘hit’ is the progression of steatosis to NASH. The etiology of NAFLD is complex with factors like overnutrition, dysbiosis, increased fat mass, endocrine disruptors and oxidant injury, pro-inflammatory cytokines and altered adipokines involved to variable extent. The pro-inflammatory cytokines appear to interfere with insulin signaling by activating various inflammatory pathways. The pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), activate intracellular kinases such as JNK and IKKβ and the activation of downstream transcription factors like AP-1 and NF-κB results in the impairment of insulin receptor signaling. METABOLIC CROSS-TALKS - LIVER AND OTHER ORGANS: The target organs can have differential responses to insulin and the skeletal muscle is more sensitive to insulin than the liver and adipose tissue. Thus, IR in skeletal muscle is observed early during development of NAFLD, T2DM and MetS, occurring long before IR in the liver and adipose tissue. There results a metabolic cross-talk involving liver, muscles and adipose tissue, which brings about a cascade of metabolic alterations: (a) The skeletal muscle IR impairs insulin-stimulated muscle glucose uptake → ↑ glucose delivery to the liver; (b) The hepatic selective IR leads to decreased hepatic glycogen synthesis, increased hepatic gluconeogenesis and ↑ liver triglyceride levels and hepatic de novo lipogenesis (DNL); (c) The adipose IR impairs insulin-mediated suppression of lipolysis → ↑ release of glycerol and fatty acid (FAs) → redirected to the liver, driving hepatic lipid synthesis further; (d) ↑ glycerol delivery to the liver → hepatic gluconeogenesis via substrate push; (e) Diacylglycerol (DAG)-mediated activation of protein kinase C epsilon impairs hepatic insulin signaling →↓ insulin-stimulated hepatic glycogen synthesis; (f) The ↑ glucose uptake in the liver activating the carbohydrate response element-binding protein (ChREBP), stimulates intracellular glycolysis, providing metabolic precursor materials for DNL; and (g) The increased FAs may activate the intrinsic apoptosis pathway in hepatocytes via c-Jun N-terminal kinase (JNK), which promotes progression from simple steatosis to NASH and advanced hepatic fibrosis. The adipocyte secretome, including FFAs and adipokines, is closely linked to the evolution and progression of NAFLD. THERAPEUTIC OPTIONS AND IMPLICATIONS: Hepatic steatosis is defined by the presence of ≥5% lipid laden hepatocytes on a liver biopsy or ≥10% fatty infiltration of the liver on magnetic resonance imaging (MRI). The presence of hepatic steatosis alone is associated with a low risk for progression to cirrhosis. But, those with NASH or NAFLD and fibrosis are at risk of progressive liver disease and require therapeutic intervention. The lifestyle modifications include dietary modifications and increasing physical activity. Pioglitazone increases adiponectin levels and decreases in hepatic fat. Omega-3 fatty acids and pentoxifylline are useful. Vitamin E supplementation may Improve steatosis and inflammation, whereas metformin, ursodiol and orlistat have no therapeutic benefit. Bariatric surgery may help and its impact on NAFLD may extend beyond through weight loss alone. CONCLUSION – THE PROGNOSTIC IMPLICATIONS: The accumulation of fat affects physiology of hepatocytes and is accompanied by various homeostatic and metabolic alterations. The presence of hepatic steatosis alone is associated with a low risk for progression to cirrhosis, but those with NASH or NAFLD and fibrosis are at risk of progressive liver disease and carry adverse prognostic implications. In addition, there are various associated metabolic disorders like T2DM and CVD resulting from enhanced atherosclerosis afflict health status and complicate the QOL issues. The NAFLD associated liver diseases present a modern-day clinical challenge due to their meagre response to lifestyle measures and available treatment options. There is observed a poor adherence to the treatment and follow up due to overnutrition, overweight and obesity often being considered normal health variables.