NAFLD A GREAT MASQUERADER A MULTI SYSTEM INVOLVEMENT -

MULTI SYSTEM INVOLVEMENT OF NAFLD

1. NAFLD A GREAT MASQUERADER METABOLIC DYSFUNCTION ASSOCIATED FATTY LIVER DISEASE(MAFLD)- A MULTISYSTEM DISORDER DR SUBHAYAN BATABYAL 3 rd YEAR PG RESIDENT DEPARTMENT OF MEDICINE

2. JORNAL FOR CITATION SAGE JOURNAL : Therapeutic Advances in Endocrinology and Metabolism/ Ther Adv Endocrinology Metab 2023, Vol. 14: 1–23 DOI: 10.1177/ 20420188221145549 © The Author(s), 2023. Article reuse guidelines: sagepub.com/ journalspermissions

3. INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) affecting about 25% of general population and more than 50% of DYSMETABOLIC patients is an emerging cause of chronic liver disease and its complications. Recently a international consensus of experts proposed to rename the disease as METABOLIC DYSFUNCTION ASSOCIATED FATTY LIVER DISEASE (MAFLD) coined by APASL(THE ASIAN PACIFIC ASSOCIATION FOR THE STUDY OF LIVER DISEASES) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver diseases .

4. The peculiarity of NAFLD/MAFLD lies in the presence that higher risk of not only liver related events occurs but also of EXTRAHEPATIC ISSUES mainly cardiovasculars and cancers . Available evidences suggest that these associations are not only due to sharing same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its severe form that is STEATOHEPATITIS to act as independent risk factor via promotion of atherogenic dyslipidemia and proinflamatory , profibrogenic and procoagulant systemic environment . The following presentation summarizes the available epidemiological and clinical evidence supporting the concept of MAFLD as multisystem disease and new diagnostic & management protocol in accordance to AASLD (AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES ) & AACE (AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGY) GUIDELINES.

5. TERMINOLOGIES NAFL: NON ALCOHOLIC FATTY LIVER SIMPLE HEPATIC STEATOSIS Simple accumulation of triglyceride in hepatocytes . Most benign spectrum of disease NASH: NON ALCOHOLIC HEPATIC STEATOSIS Coined by Ludwig(1980) Macro vascular fatty liver changes. Focal hepatic cell necrosis and chronic inflammatory cell infiltration leading to fibrosis with NO H/O alcohol abuse.

6. NAFLD (NON ALCOHOLIC FATTY LIVER DISEASES) NAFLD encompasses a spectrum of liver pathology with different clinical prognosis. The most benign extreme of the spectrum is HEPATIC STEATOSIS & CIRRHOSIS which is the most ominous extreme . The risk of developing cirrhosis is extremely low in individuals with isolated steatosis (NAFL) but increases as steatosis becomes complicated by liver injury and accumulation of inflammatory cells that’s STEATOHEPATITIS(NASH). Atleast a quarter of adults with NAFLD will develop NASH. NASH itself is a heterogenous condition it can improve to steatosis or normal histology ,may remain stable for years and can also progress to CIRRHOSIS. Once NAFLD related cirrhosis developes ,the annual incidence of primary liver cancers can be as high as 1-2%.

7. MAFLD METABOLIC DYSFUNCTION ASSOCIATED FATTY LIVER DISEASES

8. EPIDEMIOLOGY The global prevalence of NAFLD is estimated to be 80-100 million individuals .Racial distribution as such lowest in AFROAMERICANS –(25 %) intermediate in AMERICAN-WHITES(33%) highest in AMERICANS of Hispanic ancestry (50%). NAFLD is prevailed in 25 % of general population world wide and 9-13% of Indian population. Males are more affected than females. More incidence of NAFLD are seen in DIABETIC and OBESE patients. There is high prevalence of insulin resistance and obesity in NAFLD and half of the Indian population with NAFLD have evidence of metabolic syndrome.

9. Clinicopathological studies suggest that NAFLD is an important cause of unexplained rise of liver TRANSAMINASES (ALT) may be due to NASH. NASH is present in 25% of NAFLD cases . 25% of NASH cases will develop cryptogenic cirrhosis among 6% of NAFLD cohort . 1-2 % cases of NAFLD will develop cryptogenic hepatocellular carcinoma. Risk of advanced fibrosis and cirrhosis is high in Diabetics and obese with age >50 years.

10. CAUSES OF NAFLD ACQUIRED METABOLIC DISORDERS: DIABETES MELLITUS OBESITY DYSLIPIDEMIA INBORN ERRORS OF METABOLISM : ABETALIPOPROTENEMIA LIPID STORAGE DISEASES GLYCOGEN STORAGE DISEASE HEREDITARY FRUCTOSE INTOLERANCE HOMOCYSTINURIA TYROSINEMIA WILSONS DISEASE WOLMAN DISEASE

11. DRUG INDUCED:

12. SURGICAL PROCEDURE: BILOPANCREATIC DIVERSION EXTENSIVE SMALL BOWEL RESECTION GASTRO JEJUNAL BYPASS OTHERS : INDUSTRIAL EXPOSUE TO PETROLEUM ,METALS( Sb,pb ) INFLAMATORY BOWEL DISEASE BACTERIAL OVERGROWTH PARENTERAL NUTRITION

13. PATHOGENESIS PATHOGENESIS OF NASH : Proposed by DAY and JAMES . Described by two hit hypothesis. FIRST HIT: Disregulation of fatty acid metabolism lead to steatosis SECOND HIT : OXIDATIVE STRESS

14. PATHOGENESIS OF MAFLD The new MAFLD definition emphasizes on the BIDIRECTIONAL INTERPLAY between OBESITY , INSULIN RESISTANCE , & DYSLIPIDEMIA and INTERACTION among them. A meta analysis report by Sanyal et al . depicted NAFLD is present in 30-60% of OBESE, 50% of DIABETICS, 80-90% of DYSLIPIDEMICS.

15. GENETIC PREDISPOSITION FOR NAFLD Heritable factors clearly impact susceptibility to hepatic steatosis NASH, Liver fibrosis and liver cancer. Genetic variants are TM6SF2 or MBOAT7 ( genes involved in lipid metabolism) and palatin like phospholipase domain containing ( PNPLA3 a gene that encode for intracellular lipid trafficking ) .A recent meta analysis showed that PNPLA3 exerts a strong influence not only on hepatic fat accumulation but also on formation of NASH and liver fibrosis. A recent study showed inheritance account for 50% of risk of cirrhosis .Studies of families with adult onset obesity revealed EPIGENETIC ALTERATIONS that dysregulate metabolic pathways invoving adiposity ,insulin sensitivity, tissue remodelling .

16. NAFLD MAFLD BIDIRECTIONAL ANALYSIS

17. ROLE OF DIET Evidence exist demonstrating that diet of NASH patients is rich in mono Unsaturated fat and Cholesterol but poor in poly Unsaturated fat , fibre and vitamin E and C compared to healthy individuals. These levels of unsaturated fatty acid in Diet corelate with lower sensitivity to Insulin with high post prandial TGL level And other aspects of Metabolic syndrome

18. GUT MICROBIOTA ROLE IN NAFLD WHAT IS INTESTINAL DYSBIOSIS ? Alteration in gut flora where good bacterias decreased and colonization of pathogenic organism occurs resulting in alteration of gut permeability leading to exposure of intestinal mucosa to toxic metabolites.

19. INTESTINAL DYSBIOSIS NAFLD

20. NAFLD --- MAFLD AND LIVER EVENTS Even though a minority of NAFLD patients will progress to cirrhosis and end stage liver disease ,due to its high prevalence , NAFLD is becoming the leading cause of liver related issues world wide . Consistent with available incidences , LIVER FIBROSIS is the most important factor in NAFLD. Stage 3 & 4 FIBROSIS is supposed to have the worst outcome. INCIDENCE OF EVENTS FO-F2 ( FIBROSIS STAGE) F3 ( FIBROSIS STAGE) F4 ( FIBROSIS STAGE) VARICEAL BLEED 0.00 0.06 0.70 ASCITES 0.04 0.52 1.20 HEPATIC ENCEPHALOPATHY 0.02 0.75 2.39 HEPATOCELLULAR CARCINOMA 0.04 0.34 0.14 * STUDY BY SANYAL ET AL 2022

21. NAFLD---MAFLD AND EXTRHEPATIC EVENTS NAFLD & METABOLIC DISORDERS have a strong epidemiological and clinical interplay. The prevalence of NAFLD is higher (>50% ) in obese and diabetic persons and consequently if we look in NAFLD patients ,they have a significantly higher prevalence of metabolic disorders with respect to subjects with out fatty liver. META ANALYSIS BY YOUNOSST ETAL .(2021 )ON 8,51,535 PATIENTS GLOBALLY DEMONSTRATES OF NAFLD IS 25.24% & OTHER METABOLIC ABNORMALITIES AS FOLLOWS: OBESITY 51.34 % TYPE 2 DIABETES 22.52% ARTERIAL HYPERTENSION 39.34% HYPERLIPIDEMIA 69.32% METABOLIC SYNDROME 42.54%

22. NAFLD---MAFLD AND DIABETES MELLITUS Among the studies conducted all have proved that NAFLD is associated with incident T2DM independently of multiple potential confounding factors. Several studies using non invasive imaging techniques to diagnose NAFLD, have shown NAFLD increases risk of incident of T2DM A South Korean cohort study have illustrated that occurrence of T2DM can increase upto TWO FOLDS if NAFLD is associated with another risk factor like obesity.

23. PATHOLOGICAL INTERRELATION WITH NAFLD-T2DM NAFLD is a example of ectopic lipid accumulation resulting in increased secretion of HEPATOKINES increased gluconeogenesis decreased glycogen synthesis leading to impaired INSULIN SIGNALLING . INSULIN RESISTANCE With in hepatocytes long chain fatty acids are esterified to final product DIACYLGLYCEROL(DAG) . DAG is very important in causing INSULIN RESISTANCE ,promote HEPATIC INFLMMATION and aggravates INTESTINAL DYSBIOSIS .

24. The product DAG inhibits esterification of other hepatic lipids causing Endoplasmic reticulum stress leading to activation of c jun -N terminal kinase and NfKB interferes with insulin signalling pathways INSULIN RESISTANCE DAG also induce synthesis of several inflammatory cytokines like TNF alfa ,IL-6, IL- 1beta and activates procoagulants like factor 8, PAI-1 ALTERED INTESTINAL LIPID METABOLISM DYSBIOSIS HEPATIC FIBROSIS ,CIRRHOSIS & HEPATOCELLULAR CARCINOMA

25. Conclusively from the below mentioned studies it was derived that incidence of T2DM are more common in subjects of NAFLD irrespective of other risk factors and degree of fibrosis is directly proportional to risk of incidence of T2DM . Conversely good control of T2DM seen in individuals where there is resolving of fatty liver on USG studies .

26. NAFLD---MAFLD & CORONARY ARTERY DISEASE Patients with NAFLD usually have features of metabolic syndrome and also have myriad of CAD risk factors.This finding has important clinical implications for development of CAD events among them . PATHOGENESIS : INTRAHEPATIC INFLAMMATION REALEASE OF MEDIATORS MAINLY PENTRAXIN3(PTX3) ,ADIPONECTIN DIMETHYL ARGININE(ADMA) ALTERTED ENDOTHELIAL STRUCTURE NARROW CAROTID INTIMA CAD NAFLD is presumed to directly aassociated with moderate increase in non fatal & mild increase in fatal cardiac related events.

27. A recent metaanalysis revealed a strong association between NAFLD diagnosed by imaging or biopsy and several markers of atherosclerosis like carotid intima media thickness ,increased coronary calcification, impaired flow mediated vasodilation, & arterial stiffness. Several large crossectional studies involving both diabetic and non diabetic patients have shown prevalence of CAD in NAFLD patients. To date, there are about 20 retrospective and prospective studies there is direct relationship between NAFLD and fatal cardiovascular events (odds ratio 2.5).

28. NAFLD ---CAD--- ARRYTHMIAS & AORTIC VALVE SCLEROSIS Recently conducted meta analysis revealed elevated liver enzymes is independently associated with increased incidence of ATRIAL FIBRILLATION in NAFLD patients .The association coefficient in case of USG diagnosed NAFLD is as high as five folds. Interestingly recent data have shown NAFLD is associated with QTc prolongation ,a powerful predictor of ventricular arrhythmias and sudden cardiac death which explain the fact of CAD morbidity association of NAFLD. Finally the presence of aortic valve sclerosis a progressive disease that share multiple risk factors associated with increased CAD related mortality has also been linked with NAFLD irrespective of other risk factors.

29. NAFLD ---MAFLD & CHRONIC KIDNEY DISEASE The possible link between NAFLD & CKD has recently attracted considerable scientific interest. Several large cross sectional studies involving both T2DM & non T2DM patients have shown that CKD is increased in people with NAFLD diagnose by biopsy or imaging techniques (EXCLUSION CRITERIA: ALD,CLD CIRRHOSIS ,ESRD ,HEPATITIS ,HEMOCHROMATOSIS &AIH). In recent studies it has been shown that prevalence of CKD in patient of biopsy proven NAFLD is about 20-55%

30. NAFLD---MAFLD & EXTRAHEPATIC CANCERS Emerging evidences suggests that NAFLD patients carry risk of developing not only liver related cancers but also extrahepatic cancers. It is the second most common cause of mortality in NAFLD patients. Several studies are evident of most common extra hepatic cancer associated with NAFLD is COLORECTAL CANCER. NAFLD subject are also at high risk of 1.5-20 times of developing gastrointestinal cancers such as esophagus, stomach, pancreas . Risk for developing NON GI cancers like breast ,lung, gynecological and urinary tract are also quite evident irrespective of age, sex, smoking , obesity ,diabetes & other potential confounders.

31. PATHOPHYSIOLOGY BEHIND EXTRAHEPATIC TUMOURS IN NAFLD EXCESSIVE ADIPOSITY ALTERED SEX HORMONE METABOLISM INSULIN SIGNAL PATHWAY DERANGED EXCESS IGF-1 EXTRAHEPATIC CANCERS ADIPONECTIN RESISTIN LEPTIN INTESTINAL DYSBIOSIS

32. NAFLD---MAFLD & OTHER COMORBIDITIES Subject with diagnosed NAFLD have shown the prevalence of following diseases with conflicting results : PSORIASIS INFLAMMATORY BOWEL DISEASES OBSTRUCTIVE SLEEP APNEA OSTEOPOROSIS POLY CYSTIC OVARIAN DISEASES THYROID DYSFUNCTION COGNITIVE IMPAIRMENT COPD

33. DIAGNOSTIC APPROACH TO MAFLD Details patient history of alcohol: Appropriate specialized questionare or scorring systems for evaluation of ALCOHOL CONSUMPTION Eg . CAGE QUESTIONARE, AUDIT-C

34. SYMPTOMS: MOSTLY ASSYMPTOMATIC (70%) Uncommon symptoms like RUQ pain , fatigue, malaise SIGNS: HEPATOMEGALY (60-80% ) Central obesity corelates with severity of inflammation on biopsy,and dorsocervical lipodystrophy (buffalo hump) indicating hepatocyte injury. Rarely signs of splenomegaly , spiderangioma palmarerythema may be there.

35. INVESTIGATIONS FOR NAFLD

36. Normal blood investigations are less reliable for early diagnosis of NAFLD and prevention of further progression of fibrosis. Algorithms that used certain combined test are better in seperating advanced NASH from mild diseases. ENHANCED LIVER FIBROSIS TEST(ELF TEST) NAFLD FIBROSIS SCORE BARD SCORE AST TO PLATELET RATIO INDEX(APRI SCORE) FIB4 SCORE The NAFLD FIBROSIS SCORE & FIB4 SCORE are most commonly used parameters to assess severity of NAFLD fibrosis

37. NAFLD FIBROSIS SCORE: Age Albumin BMI AST Hyperglycemia ALT Platelet count FIB 4 SCORE : Age ALT Platelet count AST BARD SCORE : BMI ALT HYPERGLYCEMIA AST

38. FIBROTEST: GGT HAPTOGLOBIN BILIRUBIN APOLIPOPROTEIN A1 A2 MACROGLOBIN FIBRO SPECT TEST: FIBRO TEST + HYALURONIC ACID TISSUE INHIBITOR OF METALLO PROTEINASE

39. MARKERS OF HEPATIC INFLAMMATION CRP PLASMA PENTRAXIN 3 SERUM FERRITIN IL-6 TNF Alfa CYTOKERATIN 18: Marker of hepatic apoptosis most accuracy for diagnosis ADIPONECTIN ENDOTHELIN 1 HYALURONIC ACID

40. IMAGING TECHNIQUES USG : the most comon baseline investigation to be done but it lacks sensitivity and specificity. FIBRONSCAN /TRANSIENT ELASTOGRAPHY : Most inexpensive and reliable & widely used to assess LIVER STIFFNESS MEASUREMENT (Normal LSM 2-7 kpa ) . Steatosis by CAP(controlled attenuation parameters) score. MR-ELASTOGRAPHY/MRI PDFF : (MRI using proton density fat fraction) is the most accurate surogate marker of liver stiffness 2D SHEAR WAVE ELASTOGRAPHY : Recently used tool better than fibroscan .

41. LIVER BIOPSY Liver biopsy indicated in FIB -4> 1.3 NFS > -1.455 LSM >8 kpa High ferritin Positive autoantibodies

42. MANAGEMENT OF MAFLD

43. STEPS IN MANAGEMENT Treatment of NAFLD is divided into 3 components : 1)Specific therapy of NAFLD related liver disease 2) treatment of NAFLD associated co morbidities 3) treatment of complications of advanced NAFLD thus concurrent MAFLD prevention. The current approach is to cut down the risk factors thus preventing NASH occurrence. LIFE STYLE MODIFICATION is the corner stone of management using a combination of dietary modification ,behavioral adjustment with increased physical activity.

44. DIET : Advised to reduce saturated/trans fat and increase PUFA with special emphasize on omega3 fatty acids. Reduce added sugar to its minimum ,try to avoid soft drinks containing sugars ,including fruit juice that contain a lot of fructose ,minimize fast food and increase fibre intake. For the heavy meat eaters ,especially those of red and processed meat ,less meat intake and emphasize on sea fish intake to be done . MEDITEERRANEAN DIET is recommended to cure NAFLD.

45. EXERCISE: About 30 minutes of daily aerobic exercise OR 8 week resistance exercise 5 times per week is associated with 13% of liver fat reduction . Improvement in INSULIN SENSITIVITY is seen also. The choice of exercise should be tailored to patient preference and functional capacity to enable long term mantainence .

46. OBESITY MANAGEMENT WEIGHT REDUCTION: In obese individuals 7-10 % reduction of body weight improves steatosis and hepatic steatosis . In Non obese individuals even with normal BMI 3-5% of weight reduction is associated with good results. MEDICINAL TREATMENT FOR OBESITY : APETITE SUPRESSANT : phentermine / sibutramine ABSORPTION INHIBITORS : Orlistat BARIATRIC SURGERY :( COCHRANE STUDIES) BMI>40 BMI>35 with comorbidities AASLD GUIDELINES: Premature to consider foregut surgeries specifically to treat NAFLD Foregut surgeries is not contraindicated in otherwise eligible Patients with NASH OR NAFLD without cirrhosis.

47. PHARMACOLOGICAL THERAPIES 1) INSULIN SENSITIZING AGENTS: METFORMIN : Dubbed in RCT named TONIC STUDY NO SIGNIFICANT IMPROVEMENT IN LIVER HISTOLOGY NO ROLE IN IMPROVEMENT THIAZOLIDINEDIONES: a) Rosiglitazone --- improved liver enzyme and steatosis ,no role to curb down inflammation. b) Pioglitazone --- improve steatosis ,reduce inflammation,no role in fibrosis reduction, much greater weight gain. * Rosiglitazone ---much higher risk of cardiovascular mortality. ** THIAZOLIDINEDIONES are associated with weight gain, bladder cancer and bone fractures.

48. 2) ANTI-OXIDANT AGENTS: VITAMIN E:

49. PIVENS STUDY PIOGLITAZONE ,VIT E, PLACEBO TIME-18 months ADULTS: With NASH Without DM, Cirrhosis, Hep C, heart failure Limited alcohol intake over last 5 years RCT : PIOGLITAZONE GROUP -80 subjects VIT E -84 subjects PLACEBO-83 subjects PRIMARY OUTCOME : VIT E vs PLACEBO : PIOGLITAZONE vs PLACEBO 43% improvement vs 19% 34% improvement vs 19% significant nonsignificant

50. PIVENS CONCLUSION VIT E was superior to placebo in improving NASH without T2DM. PIOGLITAZONE may have role in treating patients with biopsy proven NASH however long term safety and efficacy not yet established. AASLD GUIDELINES PIOGLITAZONE can be used to treat certain patients with biopsy proven NASH who have T2DM but long term safety & efficacy has not yet established. VIT E 800 IU/ day improves liver histology in NASH. NOT RECOMMENDED in other chronic liver diseases ,diabetes ,cirrhosis, NAFLD without biopsy . Recent meta analysis suggests VIT E may increase risk of cardiovascular mortality , hemorrhagic stroke,& prostate cancers.

51. 4) URSODEOXYCHOLIC ACID(UDCA ):No histological improvement seen 5) OMEGA 3 FATTY ACIDS : Supportive trials for benefit issues are very less to proven its use. 6)STATINS: GREACE STUDY : Concludes that STATINS significantly improves liver biochemistries and cardiovascular outcomes in patients with NASH. AASLD GUIDELINES: STATINS CAN BE USED TO TREAT DYSLIPIDEMIA IN PATIENTS WITH NAFLD AND NASH.

52. NEWER APPROACHES Mainly targets the ANTI INFLAMMATORY +ANTI FIBROTIC & METABOLIC PATHWAYS : CCR2/5 ANTAGONIST – CENCRIVIROC ASK 1 INHIBITOR- SELONSERTIB CASPASE INHIBITOR- EMRICASEN FXR STIMULANT – OBETICHOLIC ACID GLP1 ANALOGUE – LIRAGLUTIDE/SEMAGLUTIDE ( HELPFUL FOR OBESITY + T2DM MANAGEMENT ALSO ) THR B AGONIST – ELAFIBINOR SAROGLITAZAR ALLOGENIC FECAL MICROBIATA TRANSPLANTATION

53. LIVER TRANSPLANTATION Patients with NAFLD in whom end stage liver disease developed should be evaluated . Outcome of LIVER TRANSPLANTATION in these patients is good. NAFLD can recur after liver transplantation. Risk factors for recurrent NAFLD after liver transplantation are triglyceridemia, DM ,obesity & glucocorticoid therapy.

54. ALORGITHM TO DIAGNOSIS & MANAGEMENT *EASL

55. AACE GUIDELINELINES ON CIRRHOSIS MANAGEMENT ** Patients with NASH cirrhosis should be screened for esophageal varices , & Hepatocellular carcinoma .

56. AACE GUIDELINES ON HYPERTENSION IN NAFLD

57. AACE GUIDELINES ON WEIGHT MANAGEMENT IN NAFLD

58. AACE GUIDELINES ON DIABETES MANAGEMENT

59. AACE GUIDELINES ON DYSLIPIDEMIA MANAGEMENT

60. SUMMARIZING THE JOURNAL EPIDEMIOLOGICAL GROUNDS OF NAFLD. UNDERSTANDING BROADER CONSEQUENCES OF NAFLD FOR CLD,HCC, T2DM,CARDIAC DISEASES. EVIDENCE THAT NAFLD IS ASSOCIATED WITH HIGHER RISK OF T2DM AND LEAD TO CARDIAC DISEASES LIKE LV DYSFUNCTION,LVH,AF & CALCIFICATION. ABILITY OF NAFLD TO EASE THE OCCURRENCE OF HEPATIC DYSFUNCTION AND EXTRAHEPATIC CANCERS AND MULTI SYSTEM INVOLVEMENT VIA BIOMOLECULAR MECHANISM. JUSTIFICATION OF RENAMING NAFLD AS MAFLD ( MULTI SYSTEM DYSFUNCTION ASSOCIATED FATTY LIVER DISEASE) DIAGNOSTIC APPROACH TO NAFLD ,NEWER INVESTIGATING TOOLS. NEW TREATMENT GUIDELINES ACCORDING TO AASLD & AACE.

61. TAKE HOME MESSAGES NAFLD is more common than alcoholic liver disease worldwide. RENAMING fatty liver disease is not about being pedantic but calling the world most common liver disease NON ALCOHOLIC propagates confusion ,undermines efforts to spur a sense of urgency and deflects attention from effective system wide intervention NAFLD patients in the past were referred to gastroenterologist but in the last centuries several studies have revealed that NAFLD wears a MASK of HEPATIC INVOLVEMENT underneath which multi systems are deranged like CARDIAC,ENDOCRINE METABOLIC & EVEN CANCERS HENCE A GREAT MASQUERADE. Any patient coming to us with vague symptoms likely of NAFLD should not be treated lightly and all parameters that can get involved must be thoroughly screened . Cardiovascular risk in NAFLD is often underestimated while cardiovascular causes are leading cause of mortality in NAFLD individuals hence proper control of diabetes ,dyslipidemia must be taken care of which is the sole responsibility of physician or any primary health centre.

62. Extent of fibrosis can be easily measured by using simple panel scores which led to early diagnosis and further guided to the level of intervention required. Till date no FDA approved drug is there to treat particularly NAFLD . LIFE STYLE MODIFICATION is the mainstay of treatment including DIET MODIFICATION ,WEIGHT REDUCTION & EXERCISE . Some therapies with Insulin sensitizers , antioxidants and anti inflammatory drugs may slow down the progress. The current nomenclature MAFLD (METABOLIC DYSFUNCTION ASSOCIATED FATTY LIVER DISESE) is thus reshaping the field of hepatology all round the globe saving lives of several patients.

63. REFERENCES 1.) SAGE JOURNAL : Therapeutic Advances in Endocrinology and Metabolism/ Ther Adv Endocrinology Metab 2023, Vol. 14: 1–23 DOI: 10.1177/ 20420188221145549 © The Author(s), 2023. Article reuse guidelines: sagepub.com/ journalspermissions 2 .) ZAKIM & BOYERS HEPATOLOGY 3.) HARRISONS PRINCIPLE OF INTERNAL MEDICINE