1. Non-alcoholic fatty liver disease: from liver disease to cardiometabolic risk Francesco Angelico Corso di Laurea in Medicina e Chirurgia "F"

2. Sedentary lyfestile

4. Le foie gras

5. Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging chronic liver disease worldwide. In the last decades, it reached epidemic proportions and the prevalence in the general population is ranging between 20-30% and increases until 70-90% in patients with severe obesity or with type 2 diabetes. NAFLD has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide.

6. Non alcoholic fatty liver is the third most common indication for liver transplantation in the United States and is projected to eventually overtake the hepatitis C virus and alcoholic liver disease as the leading cause of liver transplant.

8. NAFLD represents a spectrum of disorders characterized by excessive accumulation of fat in the liver that occurs in individuals in the absence of significant alcohol consumption

9. SIMPLE FATTY LIVER (NAFL) The only histologic finding is the presence of steatosis NON ALCOHOLIC STEATO- HEPATITIS (NASH) Steatosis associated with hepatocellular injury/inflammation with or without fibrosis NAFLD

10. Fat + Inflammation Fat Inflammation Ballooning Degeneration Fat Ballooning Degeneration Fibrosis +/-Mallory Bodies FAT Stage I Stage II Stage III Stage IV Histologic progression of NAFLD NAFL NASH

11. A clinical silent disease Symptoms Symptoms None 20-75% Right upper quadrant pain 25-48% Fatigue 50-75% Obstructive sleep apnea 40% Signs Signs Overweight/obese 85-90% Hepatomegaly 25-50% Acanthosis nigrigans 10-15% Laboratory Laboratory AST, ALT – modest elevation “normal enzymes” up to 80% of patients

12. Diagnosis NAFLD is a diagnosis of exclusion NAFLD is a diagnosis of exclusion -Alcoholic Hepatitis -Drug induced Hepatitis -Viral Hepatitis (B and C) -Autoimmune Hepatitis -Metabolic (Wilson and Hemochromatosis)

13. The most challenging DDX is alcoholic hepatitis The histologic picture of both conditions is similar Consumption of alcohol less than 10 g/d in women and 20 g/d in men

16. Mechanisms that contribute to the pathogenesis of fatty liver Extrahepatic mechanisms Extrahepatic mechanisms Lipolysis (in the adipose tissue)Lipolysis (in the adipose tissue) Increased fatty acid efflux to the liverIncreased fatty acid efflux to the liver Intrahepatic mechanisms Intrahepatic mechanisms Neo lipogenesisNeo lipogenesis Reduced -oxidation of fatty acidsReduced β-oxidation of fatty acids

17. ↑ De novo lipogenesis ↑ FFA Esterification TRIGLYCERIDES decreased β-oxidation VLDL Adipose tissue Insulin resistance Hyperglycaemia Excess dietary fat Increased lipolysis Mechanisms of hepatic fat accumulation Mechanisms of hepatic fat accumulation. Increased FFA efflux

18. Origin of hepatic triglycerides in NAFLD 60% comes from non-esterified fatty acids (adipose tissue) 10% comes from dietary lipids (chilomicrones) 30% comes from hepatic lipogenesis ( 5% in non steatotic liver )

19. Fatty liver and insulin resistance 2 hypotheses: Insulin resistance is responsible for the excessive accumulation of triglycerides in the liver Triglycerides, or their intermediate metabolites, play a causal role in the development of insulin resistance

21. Mitochondrion FFA ↓ FA oxidation ↑ Long chain CoA DAG TAG ↑ PKC Mithocondrial dysfunction ROS production Tyrosine kinase Insulin receptor Hyperinsulinemia Insulin ↓ GSK3 P P ↓ Glycogen synthesis NUCLEUS CYTOPLASM HEPATOCYTE ↑ FOXO DNA ↑ Gluconeogenesis ↓ FOXO P P

22. ↑ De novo lipogenesis ↑ FFA Esterification TRIGLYCERIDES decreased β-oxidation VLDL Adipose tissue HYPERINSULINEMIA Excess dietary fat Increased lipolysis Mechanisms of hepatic fat accumulation Mechanisms of hepatic fat accumulation. Increased FFA efflux Atherogenic dyslipidemia

23. Fatty liver is the hepatic component of the metabolic syndrome DiabetesHypertension Visceral Obesity FATTY LIVER Atherogenic dyslipidemia TG HDL

24. Metabolic Syndrome: Overview The syndrome is closely related to insulin resistance, in which the body can’t use insulin efficiently. Metabolic Syndrome is not a disease, but rather a cluster of disorders of your body’s metabolism, including: o oHigh blood pressure o oHigh insulin levels o oExcess body weight o oAbnormal lipid levels o oAbnormal fasting blood glucose Each of these disorders is by itself a risk factor for other diseases. In combination, however, these disorders dramatically boost the chances of developing potentially life-threatening illnesses, such as diabetes, heart disease or stroke.

25. Diagnostic Criteria for Metabolic Syndrome AHA/NHLBI Scientific Statement; Circulation 2005; 112:e285-e290. ≥3 Components Required for Diagnosis Components Defining Level Increased waist circumference Men Women ≥ 102 cm ≥ 88 cm Elevated triglycerides ≥150 mg/dL (or medical Rx) Reduced HDL-Cholesterol Men Women <40 mg/dL <50 mg/dL (or medical Rx) Elevated blood pressure ≥130 / ≥85 mm Hg (or medical Rx) Elevated fasting glucose ≥100 mg/dL (or medical Rx)

26. Fat topography in subjects with metabolic syndrome Intra-muscolar Intra-hepatic Subcutaneous Intra-abdominal

27. Women >88 cm (80cm) = Increased risk Men >102 cm (90cm) = Increased risk Lean MEJ et al. Lancet; 1998; 351:853-6 Body fat distribution Apple shaped obesity cm

29. TWO UNFORTUNATE VICTIMS OF THE METABOLIC SYNDROME ? CARDIOVASCULAR DISEASE NAFLD OBESITY METABOLIC SYNDROME INSULIN RESISTANCE

30. PNPLA3 - Patatin-like phospholipase 3 LAL - Lysosomal Acid Lipase

31. Normal insulin resistance in patients with genetic steatosis Gene Liver fat Hepatic IR Peripheral IR PNPLA3-MMyesno Hypo-Beta lipoproteinemia yesno CESD (LAL deficiency) yesno

32. NAFLD includes a wide spectrum of liver diseases ranging from simple fatty liver to NASH, which may progress to fibrosis and more severe liver complications such as cirrhosis, and hepatocellular carcinoma. This is why patients have been traditionally referred to hepatologists.

33. Natural History of NAFLD ( ~ 8-13 yrs) Steatosis NASH and/or F1-F2 fibrosis Severe fibrosis (F3) Cirrhosis 12-40% 5-10% 0-50% HCC Liver Death/ OLTx 25-50% (Child’s A) Ratzui 2002 Harrison 2003 Fassio 2004 Adams 2005 Sanyal 2006 Ekstedt 2006 14% 7% 25% 13% 8%

34. SIMPLE STEATOSIS NASHCIRRHOSISHCC 30-90% 10-20%3-5% in 20 yrs? From simple steatosis to hepatocellular carcinoma CC

35. THE “TWO HIT” HYPOTHESIS Pathogenesis THE “TWO HIT” HYPOTHESIS FIRST HITSECOND HIT NAFLDNASH

36. Most people with fatty liver, in the absence of significant hepatic fibrosis, do not develop severe liver disease. Conversely, they have an increased chance of developing cardiovascular diseases (CVD). Indeed, CVD is the single most important cause of morbidity and mortality in this patient population and many patients will die of CVD before the development of end-stage liver disease. Fatty liver and cardiovascular disease

39. 20-year survival of 100 patients with steatosis on biopsy and elevated ALT

41. Survival and mortality at 30 years in 256 patients with NAFLD at biopsy

44. 85 subjects with positive biopsy for NAFLD / NASH and 160 controls

46. Retrospective study of 5468 subjects studied with coronary CT and abdominal ultrasound

48. FATTY LIVER CV risk factors Metabolic Syndrome CVD DEATH Steatohepatitis FibrosisCirrhosis LIVER DEATH

49. CARDIOLOGISTINTERNISTDIABETOLOGIST EPATOLOGIST GASTRO- ENTEROLOGIST Cirrhosis Arteriosclerosis Diabetes STEATOSIS

50. Control of cardiometabolic risk factors ? Cirrhosis Arteriosclerosis Diabetes STEATOSIS There are no effective therapies

51. Need for liver biopsy Atypical liver enzyme pattern (e.g. cholestatic) Atypical patient (non-obese, no MetS risk factors) Possibility of partecipation in clinical trials Suspicion of cirrhosis (spiders, platelets, splenomegaly, ultrasound findings) NAFLD When to obtain a GI opinion/referral?

52. FATTY LIVER NORMAL LIVER How to defend ourselves ?

53. INSULIN RESISTANCE ↑ ↑ FFA PNPLA3 genotype Gut/derived signals & toxins Adipokines NORMAL NAFLD Oxidative stress & Free radicals Hyperinsulinaemia Hyperglicaemia Type 2 DM ATHEROSCLEROSIS Inflammatory cytokines ATHEROGENIC DYSLIPIDEMIA mitochondrial dysfunction OBESITY GUT DIET METABOLIC SYNDROME NAFLD AND CARDIO- METABOLIC RISK CIRRHOSIS Vit. D deficiency LAL-D

54. Main targets of intervention in NAFLD  Overweight and obesity  Sedentary lifestyles  Insulin resistance  Oxidative stress  Atherogenic dyslipidemia  Vitamin D deficiency  Hepatocyte protection  Cardiovascular risk  Treatment of comorbidities  Mitochondrial dysfunction

56. Take home messages NAFLD is a very common disease NAFLD is a very common disease Fatty liver is associated with increased overall mortality Fatty liver is associated with increased overall mortality Patients with NAFLD in the past were always referred to the hepatologist and the gastroenterologist Patients with NAFLD in the past were always referred to the hepatologist and the gastroenterologist The cardiovascular risk in NAFLD is underestimated The cardiovascular risk in NAFLD is underestimated CV diseases are the leading cause of death in NAFLD CV diseases are the leading cause of death in NAFLD

57. Take home messages Some therapies with insulin-sensitizing drugs and antioxidants appear to slow the progression of liver damage Some therapies with insulin-sensitizing drugs and antioxidants appear to slow the progression of liver damage The effective control of classical cardiovascular risk factors is crucial to reduce the high risk for diabetes and cardiovascular The effective control of classical cardiovascular risk factors is crucial to reduce the high risk for diabetes and cardiovascular disease Treatment of the metabolic syndrome and of atherogenic dyslipidemia is very important Treatment of the metabolic syndrome and of atherogenic dyslipidemia is very important