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  1. NON-ALCOHOLIC FATTY LIVER DISEASE Dr. Anuj Satarkar JR-1 MD Pharmacology
  2. INTRODUCTION • Global Obesity Pandemic: Increased prevalence of NAFLD • Most common cause of CLD in western • Associated with : • CVD • Type 2 DM • Manifestations of Metabolic Syndrome. • Obstructive Sleep Apnoea • Vitamin D Deficiency • NAFLD/NASH: Hepatic manifestation of Metabolic Syndrome • Clinically relevant subset in terms of liver-specific outcome: NASH
  3. CONTD… • Ludwig and his colleagues coined the term NAFLD: 1980 • Cohort of middle aged patients: raised level of serum enzymes; evidence of alcoholic hepatitis on liver biopsy without alcohol consumption. • Subsequent studies: “Two-hit hypothesis” • 1st hit: Sequential progression of Isolated fatty liver to NASH: Initial lesion of hepatic steatosis. • 2nd hit: Oxidative stress leading to liver injury.
  4. SPECTRUM OF NAFLD Steatosis NASH Cirrhosis HCC 14 years 7 years
  5. DEFINITIONS • Nonalcoholic fatty liver is defined as the presence of hepatic steatosis without evidence of hepatocellular injury in absence of secondary causes of steatosis. • Macrovesicular fat accumulation in more than 5% hepatocytes. • Requires biopsy: invasive procedure. • Alternatively, presence of hepatic steatosis, determined by imaging in the absence of secondary causes of hepatic fat accumulation • USG • MRI • TE • NASH is defined as the presence of hepatic steatosis and inflammation with evidence of hepatocyte injury (ballooning) with or without fibrosis. • Biopsy in mandatory for defining NASH.
  6. EPIDEMIOLOGY • Estimated prevalence worldwide: 2.8 to 46%. • Prevalence is increasing with increased rates of Obesity and type II DM. • 33.8 % population worldwide is obese; (75 % have NAFLD) • 10.6 % have type II DM (30-60 % have NAFLD) • The community prevalence of NAFLD in India varies from 5% to 28%. • The first population-based study from India showed overall prevalence of NAFLD as 9% and around 19% in adult population*. • NAFLD is more common in men. * Amarapurkar D, et. al. Prevalence of non-alcoholic fatty liver disease: population-based study. Annals of hepatology. 2007 Jul 1;6(3):161-3
  7. ETIOLOGY • Acquired Metabolic Disorders • Obesity • Diabetes • Dyslipidemia • Kwashiorkor • Drugs • Amiodarone • Tetracyclines • Methotrexate • Long term use of Steroids • Tamoxifen
  8. • Metals • Antimony • Mercury • Phosphorous • Uranium compounds • Thallium Compounds • Inborn errors of metabolism • Familial Hepatosteatosis • Galactosemia • Glycogen Storage Disease • Wilson’s Disease • Surgical Procedures: • Biliopancreatic diversion • Extensive Small Bowel Bypass • Misc. Conditions • IBD, Industrial Exposure to Petrochemicals.
  9. RISK FACTORS • Obesity, Dyslipidemia, Type 2 Diabetes and Metabolic Syndrome are established risk factors • Hypothyroidism • Polycystic ovary syndrome • Obstructive sleep apnoea • Hypopituitarism • Hypogonadism Have been described in western countries; yet to be studied in Asia-Pacific region
  11. DIAGNOSIS • Most patients are asymptomatic. • Some: RUQ pain, fatigue and malaise • Hepatomegaly commonly seen; physical estimation is difficult due to obesity. • Usually discovered incidentally: • Hepatic steatosis on imaging. • Elevated liver biochemical test levels • Rule out significant alcohol consumption.
  12. SIGNIFICANT ALCOHOL CONSUMPTION • More than 210 gm alcohol per week for men = 30 gm / day • More than 140 gm alcohol per week for women = 20 gm / day
  13. LFT • Normal or mildly elevated Aspartate aminotransferase(AST) and Alanine Transaminase(ALT); with ALT more than AST. • Normal AST: 8-33 U/L • Normal ALT: 7-56 U/L • AST/ALT Ratio: • Normal- <1 • NAFLD- <1 (0.8); if >0.8, indicates severe disease • Alcoholic disease > 1.5 • ALP(Alkaline Phosphatase) • Normal: 44-147 IU/L • In NAFLD, Isolated rise in ALP may be seen.
  14. CONTD… FIB-4 SCORE: • Takes into consideration • Age • Platelet count • AST • ALT • Calculation requires Fib-4 calculator. • Provides immediate results. • Rules out advanced fibrosis. • < 1.30 = F0 – F1 • > 2.67 = F3 – F4
  15. CONTD… LIPID PROFILE • Total cholesterol • Normal: <200 mg/dL; 200-239 mg/dL: borderline high; 240 or more: High • Low-density lipoprotein (LDL) Cholesterol: Normal: <110 mg/dL • High-density lipoprotein (HDL) Cholesterol: Normal >60 mg/dL • Triglycerides • Normal: <150 mg/dL • NAFLD: Raised
  16. OTHER INVESTIGATIONS • Fasting Plasma Glucose • Post Prandial Glucose • HbA1c • HBsAg • HCV Ab • TSH
  17. IMAGING USG • Can detect fatty liver only if the liver fat is >12%. • Useful only for advanced fatty liver; • Sensitivity: 84.8%; Specificity: 93.6% for detecting ≥20–30% steatosis. • Easily available. • Inexpensive without any radiation risk.
  19. FIBROSCAN • Novel, non-invasive technique to assess hepatic fibrosis and steatosis. • Vibration-controlled transient elastography. • Works by measuring shear wave velocity; delivered using a handheld probe (M or XL), in the intercostal space over the right lobe of liver. • Returning shear wave velocities are used to generate the liver stiffness measurement (LSM): Higher the velocity, higher is the stiffness.
  20. CONTD… • Controlled attenuation parameter (CAP): detects amount of fat • Many patients: with fatty liver on conventional imaging; significant fibrosis on Fibroscan • Limitations • Difficult in patients with morbid obesity and patients with ascites. • Cannot detect necroinflammation.
  21. MRI-PROTON DENSITY FAT FRACTION • Measures fat content • Compares proton signals arising out of fat, relative to those arising out of water. • Noninvasive standard of care for quantification of liver fat. • MRI-PDFF declines over time; • co-relates with reduction in liver fat content. • Surrogate marker for improvement in necroinflammation. • Advantage: • Sensitivity is higher • Can assess complete liver. • Disadvantage: • Not patient friendly • Costly
  22. LIVER BIOPSY • Current gold standard method used in diagnosis and prognosis. • Expensive and invasive procedure. • High sampling error. • Risk of complications: • Pain • Bleeding • Death (very rare)
  23. TREATMENT • Lifestyle modification and weight reduction in obese subjects: cornerstone of therapy • Improve liver histology, transaminitis and quality of life. • As little as 5% weight loss may result in regression of fibrosis. • Weight loss goals: Rarely achieved by lifestyle modifications alone. • Lifestyle changes alone are insufficient to stop disease progression
  24. CONTD… • Pharmacological treatment of NAFLD remains elusive. • In last 12 years, after vitamin E and pioglitazone, seven other drugs have shown promise as a drug treatment for NASH in phase 2 – 3 trials: • Obeticholic acid • Cenicriviroc • Lanifibranor • Resmetirom • Liraglutide • Saroglitazar • Latest being semaglutide • However, till now, none of these drugs have received FDA approval.
  25. PPAR • Peroxisome Proliferator-Activated Receptors • A group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. • Essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein) • Regulates many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. • Represent relevant clinical targets for NAFLD
  26. • Three types of PPARs have been identified: alpha, gamma, and delta (beta) • α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others • β/δ (beta/delta) - expressed in many tissues, especially in brain, adipose tissue, and skin • γ (gamma) - although transcribed by the same gene, this PPAR, by way of alternative splicing, is expressed in three forms: • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen • γ2 - expressed mainly in adipose tissue; it is 30 amino acids longer than γ1 • γ3 - expressed in macrophages, large intestine, white adipose tissue
  27. SAROGLITAZAR • Given approval for treatment of NASH by the Drug Controller General of India (DCGI) in March 2020. • A novel dual peroxisome proliferator-activated receptors (PPAR) alfa/gamma agonist • Used for diabetic dyslipidaemia; targets some pathogenic mechanisms of NASH. • PPAR alfa agonism: lipid accumulation • PPAR gamma agonism: hepatic inflammation • Dose: 4 mg/day
  29. ADVERSE EFFECTS OF SAROGLITAZAR • Gastritis (stomach inflammation) • Nausea. • Vomiting. • Asthenia (weakness) • Flatulence • Dyspepsia • Bloating • Chest discomfort. • Dizziness. • Pyrexia
  30. PIOGLITAZONE • PPAR Gamma Agonist • Decreases Insulin resistance and hepatic steatosis up-regulation of Adiponectin. • Recommended in treatment of both diabetic and non-diabetics with biopsy-proven NASH. • Dose: 30 mg • Adverse effects: • Increase in body weight • Osteoporosis • Association with bladder cancer has been suggested.
  31. LANIFIBRANOR • a pan-PPAR (peroxisome proliferator–activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. • MoA: anti-fibrotic, anti-inflammatory as well as beneficial metabolic changes in the body by activating each of the three PPAR isoforms, known as PPARα, PPARδ and PPARɣ. • Still under investigation in phase 2-3 clinical trial
  32. VITAMIN E • A key fat-soluble antioxidant • Has the most evidence for its ability to provide a therapeutic benefit. • Efficacy of Vitamin E. in NAFLD is unclear. • Has the ability to reduce the oxidative stress • Retards the pathogenesis of NASH • Therefore provide a therapeutic benefit • Dose: 800 IU/day
  33. CONTD… • Antioxidant Effect of Vitamin E • Oxidative stress is created when the production of reactive oxygen species (ROS) overwhelms antioxidative pathways. • Vitamin E is one of the most powerful chain-breaking antioxidants in the human body. • alpha-tocopherol form is the most prevalent and active in tissue and human plasma. • Anti-Inflammatory and Anti-Apoptotic Properties of Vitamin E • Vitamin E supplementation: Increased adiponectin mRNA and protein levels. • Adiponectin: Important molecule;works by suppressing hepatic fatty acid synthesis and reducing inflammation in patients with NASH. • Vitamin E is also a powerful player in cell death and apoptosis pathways
  34. ADVERSE EFFECTS OF VIT. E • Cardiovascular risk in Diabetic patients. • Modest increase in prostrate cancer rates
  35. OBETICHOLIC ACID • Semi-synthetic bile acid analogue. • Chemical structure 6α-ethyl-chenodeoxycholic acid. • MoA: Highly potent FXR agonist. • FXR receptors are expressed in Liver and Intestines. • Selectively binds and activates the FXRs of the enterocytes and the hepatocytes, thereby reducing the risk to liver and bile ducts due to toxic levels of bile acids. • Uses: • Primary Biliary Cholangitis • NASH • Portal Hypertension • Bile acid diarrhoea
  36. CENICRIVIROC • Experimental drug candidate for the treatment of HIV infection and in combination with Tropifexor for non-alcoholic steatohepatitis. • CCR-2 and CCR-5: Chemokine Receptor 2 and Chemokine Receptor 5. • Expressed on various cell populations including macrophages, dendritic cells and memory T cells in the immune system • MoA: Cenicriviroc is an inhibitor of CCR2 and CCR5 receptors, allowing it to function as an entry inhibitor which prevents the virus from entering into a human cell. Inhibition of CCR2 may have an anti-inflammatory effect.
  37. THANK YOU!