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Nonalcoholic Fatty Liver Disease [NAFLD]

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Presentation on theme: "Nonalcoholic Fatty Liver Disease [NAFLD]"— Presentation transcript:

1 Nonalcoholic Fatty Liver Disease [NAFLD]
Masi Khaja, M.D

2 Objectives Epidemiology Natural History Clinical Presentation
Pathogenesis Approach to Diagnosis Treatment

3 What is NAFLD?

4 Nonalcoholic Fatty Liver Disease [NAFLD]
Histology based No significant alcohol intake [<20 g/d male; <10 g/d female] Excluding 2nd causes STEATOSIS STEATOHEPATITIS Histology based – steatosis with necrosis, inflammation & perisinusoidal fibrosis [zone 3 around central vein] [ETOH & HCV = fibrosis initially portal distribution] BRIDGING FIBROSIS CIRRHOSIS

5 Hepatic Steatosis Cytoplasm is replaced by small bubbles of fat that do not displace the nucleus Cytoplasm is replaced by large bubbles of fat that displaces the nucleus to the edge of the cell

6 Grading for Steatosis [Adapted from Brunt et al
Grading for Steatosis [Adapted from Brunt et al. Am J Gastroenterol 1999] GRADE 1: <33% hepatocytes affected GRADE 2: 33% to 66% of hepatocytes affected GRADE 3: > 66% of hepatocytes are affected

7 Nonalcoholic Steatohepatitis [NASH]
Ludwig et al. [1980 – Mayo Clinic] – coined the term NASH 20 patients evaluated over 10-year period Histologic evidence of alcoholic hepatitis but no history of alcohol abuse or other causes of liver disease: Hallmark: moderate to severe macrovesicular steatosis with lobular inflammation 70% Mallory bodies 70% perisinusoidal, centrilobular, and/or septal fibrosis 15% cirrhosis 60% F [54 yrs]; 90% obese [>110% of ideal body weight]; 25% dyslipidemia +/- DM Asymptomatic 90% abnormal LFT; 75% hepatomegaly; 25% splenomegaly; 5% ascites

8 Steatohepatitis Macrovesicular steatosis Mallory bodies
Cytologic ballooning Scattered lobular inflammation

9 Grading for Steatohepatitis [Adapted from Brunt et al
Grading for Steatohepatitis [Adapted from Brunt et al. Am J Gastroenterol 1999] GRADE 1 [mild]: Steatosis – predominantly macrovesicular, involves up to 66% of lobules Ballooning – occasionally observed; zone 3 hepatocytes Lobular inflammation – scattered & mild acute [polymorphs] & chronic inflammation [mononuclear cells] GRADE 2 [moderate]: Steatosis – any degree; usually mixed macro & microvesicular Ballooning – obvious & present in zone 3 Lobular inflammation – polymorphs may be noted associated with ballooned hepatocytes, +/- pericellular fibrosis  mild chronic inflammation Portal inflammation – none, mild to moderate GRADE 3 [severe]: Steatosis – usually >66% [zone 3 or panacinar]; commonly mixed steatosis Ballooning – predominantly zone 3; marked Lobular inflammation – scattered acute & chronic inflammation] Portal inflammation – mild to moderate

10 Staging for Fibrosis [Adapted from Brunt et al
Staging for Fibrosis [Adapted from Brunt et al. Am J Gastroenterol 1999] STAGE 1: zone 3 perivenular, perisinusoidal, or pericellular fibrosis; focal or extensive STAGE 2: as above, with focal or extensive periportal fibrosis STAGE 3: bridging fibrosis, focal or extensive STAGE 4: cirrhosis

11 NASH & Cirrhosis A nodule of liver tissue is circumscribed by scar tissue Steatosis decreases & may disappear

12 Cirrhosis in NASH vs. HCV
Hui et al. Hepatology 2003 23 NASH v. 46 HCV [age & gender matched] F/U mean 84 mo 9/23 NASH cirrhosis liver-related morbidity 8 ascites  HE 1 variceal bleeding 8 cases of liver cancer in HCV-cirrhosis vs. none in NASH cirrhosis No difference in complication-free or overall survival NASH vs. HCV

13 Risk Factors for Fibrosis
AST/ALT <1 >1 <1 >1 4 47 66 12 13 + DM  Obesity - <45 >45 Age [years] Mayo Clinic Data are [%] of Patients with Fibrosis

14 Role of Liver Biopsy AGAINST IN FAVOR Prognosis usually good
No effective treatment Risk Cost IN FAVOR Excludes other diseases Identifies type of fatty liver Estimates prognosis

15 Clinical Predictors of Fibrosis in NAFLD
Ratziu et al. Gastroenterology, 2000 93 overweight [BMI >25] patients with NAFLD Septal fibrosis 30% Cirrhosis 11% Variable OR 95% CI P Age 50 14.1 <0.001 BMI 28 5.7 0.006 Serum triglycerides 1.7 5 0.01 ALT 2N 4.6 0.02

16 Non-Invasive Markers of Fibrosis in NASH
The BARG [Harrison et al. Hepatology 2003 abstract] Scoring system for advanced fibrosis [stage 3-4] BMI  28 AST/ALT  0.8 HgbA1c > 5.2 Sensitivity 71% & specificity 76% PPV 64% & NPV 81%

17 Diagnosis

18 Keys to the Diagnosis of NASH
Clinical History of chronic mild elevation of AST/ALT Exclude xs ETOH use by corroborated hx W: >20 g daily [17 oz beer, 7 oz wine, 2 oz distilled spirits] M: >60 g daily [50 oz beer, 20 oz wine, 5 oz distilled spirits] Asymptomatic or nonspecific constitutional symptoms – Fatigue most common sx No stigmata of chronic liver disease [except NASH cirrhosis] – 15% of pt may present for the first time with features of cirrhosis Exclude medications & dietary abnormalities by history

19 Keys to the Diagnosis of NASH [2]
Laboratory AST & ALT 2-4x ULN [AST:ALT <1] Remainder of LFTs nl/near nl HBsAg, anti-HCV, ASMA & AMA [-] ANA  1/320 NL ceruloplasmin, 1-antitrypsin & transferrin saturation Radiology [not required for Dx] U/S – bright [hyperechoic/echogenicity] liver CT-scan – low-density liver compared with spleen [darker] MRI- focal fat appears bright on T1-weighted imaging Liver Bx

20 Relatively insensitive for the detection of fatty liver with fibrosis
NASH & X-ray Relatively insensitive for the detection of fatty liver with fibrosis Increased echogenicity of the liver parenchyma

21 Natural History

22 NAFLD/NASH Prevalence
[%] Population Screening Autopsy Morbid Obesity [BMI >35] NAFLD 15-29 15-25 71-100 NASH 1.2 25-50 Highest prevalence yrs age M=F DM: NAFLD 50% Morbidly obese & DM: NAFL 100%; NASH 50%; Cirrhosis 19%

23 Prevalence of Obesity in the United States
_

24 Natural History Not Well Determined
LIVER RELATED DEATH 40% 20-25% NASH CIRRHOSIS 10 years 10 years 2% ? Rapid wt loss NASH is NOT a Benign Disease 5-year survival 67% [ETOH 38%] 10-year survival 59% [ETOH 15%] Hepatocellular Cancer Subacute Failure At the time of diagnosis, 7-38% of patients with NASH have evidence of bridging fibrosis or cirrhosis

25 Pathophysiology

26 Conditions Associated with NAFLD/NASH
Chronic Metabolic Syndrome [“10 NASH”] Over weight DM Dyslipidemia Subacute Metabolic Syndromes JI bypass TPN Rapid wt loss Drugs & Toxins Corticosteroids Tamoxifen Amiodarone Industrial Solvents Inherited Metabolic Diseases Lipodystrophy [insulin resistance] Abetalipoproteinemia Wilson’s disease

27 Environment & Genetics
Pathogenesis of NASH Environment & Genetics NASH Genome Nutrition

28 Pathogenesis of NASH [2] Environment
Socioeconomics Public Problems Nutritional Practices Obesity/DM Hepatic Steatosis NASH

29 Pathogenesis of NASH [3] Genetic Determinants
STEATOSIS Obesity/Lipodystrophy Insulin signaling IKK [inhibitor kappa beta kinase enzyme that induces TNF & other cytokines  insulin resistance] Fatty acid metabolism PPAR [peroxisomes] PPAR [peroxisomes] MTP AOX OXIDATIVE STRESS Iron Homeostasis HFE Cytochrome P450 CYP2E1 Inflammation Cytokines TNF Fibrogenesis

30 Pathogenesis of NASH [4] The “Two Hit” Hypothesis
Inflammation & Fibrosis Normal Steatosis VULNERABLE 1st “HIT” [fat accumulation in the liver] Insulin resistance Hyperinsulinemia Hepatic leptin resistance FFA flux into the liver FFA oxidant Triglyceride export 2nd “HIT” [cell injury {oxidative stress} & fibrosis] oxidative stress [CYP2E1, iron] [superoxide, hydroxyl & hydroxyethyl radicals] Lipid peroxidation [hydrogen peroxide] TNF [endotoxin from the gut] TGF Leptin

31 Pathogenesis of NASH [5] Fat Accumulation in the Liver
Decreased Fatty Acid Oxidation Hyperinsulinemia Genetic Deficiencies Leptin deficiency/resistance Drugs Increased Fatty Acid Influx Obesity Insulin resistance Diet Triglyceride VLDL Genetic deficiencies Drugs Insulin resistance Increased Fatty Acid Synthesis Hyperinsulinemia XS CHO Feeding Leptin deficiency/resistance

32 Pathogenesis of NASH [6] Insulin Resistance
Obesity Hyperlipidemia Disrupted Insulin Signaling Lipolysis in peripheral adipose tissue Insulin Resistance FFA Hyperinsulinemia Hepatic FFA production Suppression of hepatic FFA oxidation Diabetes

33 Pathogenesis of NASH [7] Molecular Mechanisms for NAFLD-related Insulin Resistance
IKK [inhibitor kappa beta kinase] Insulin Resistance NF-B [nuclear factor kappa beta] NAFLD TNF TNF activates IKK which initiates a self-reinforcing positive feedback loop that perpetuates insulin resistance & the production of TNF

34 Treatment

35 Pathophysiology Based Treatment
Insulin Resistance OBESITY DM Steatosis Oxidative Stress NASH

36 Treatment General Consideration
Hepatotoxic agents should be avoided Etoh Drugs Hydrocarbon solvents Appetite suppressive agents are not recommended Need for liver biopsy Treat co-morbidities

37 Treatment [2] Treat Co-morbidities
DM No data Lipids Clofibrate ineffective Gemfibrozil may work HMGCoA reductase inhibitors efficacy unknown Pt with LFT do NOT  susceptibility to hepatotoxicity from Statins Chalasani et al Gastroenterology 2004 Wt loss

38 Treatment [3] Wt loss Diet [4 studies]
ALT improves Histologic data are inconsistent Histologic exacerbation if wt loss >1.6g/wk Starvation-induced flux of fat from peripheral stores to the liver Luyckx et al. Diabetes Metab 1998 Diet & Exercise [5 studies] Both ALT & steatosis improve More effective than wt loss alone Orlistat [lipase inhibitor]

39 Orlistat Steatosis (%) Activity (Grade) Fibrosis (Stage) Pre Post
Steatosis (%) Activity (Grade) Fibrosis (Stage) Pre Post Case 1 66 <33 1 Case 2* 3 3 3 Case 3 50 2 * Post-treatment biopsy data reflect third liver biopsy done 33 months after initiation of Orlistat Harrison et al, 2003, Am J gastro

40 Treatment [4] Wt loss Guidelines
Gradual [31/2 lbs per week] Diet [individualized] Reduced caloric + balanced AHA Low glycemic diet Graduated exercise program

41 Treatment [5] Wt loss Bariatric Surgery:
Jejunoileal bypass – causes NASH Laparoscopic adjustable gastric banding [LAGB] Dixon et al. Hepatology 2004 36 pt: baseline liver biopsy: NASH in 23 & steatosis in 12 Mean wt loss 34±17 kg F/U bx 25.6±10 mo: Significant improvement in lobular steatosis, necroinflammatory changes and fibrosis [p<0.001 for all] Only 4 of the repeat bx had NASH

42 Treatment [6] Potential Pharmacologic Treatment
Insulin-sensitizing agents: Thiazolidinediones Metformin Lipid-lowering agents: HMG-CoA RIs Fibrates Cytoprotective agents Ursodeoxycholic acid Anti-oxidants: Vitamin E Hepatic iron reduction Betaine S-adenosyl-methionine N-acetyl cysteine Probucol

43 Treatment [7] NASH & Insulin-Sensitizing Agents
PI Treatment N Duration Histology/Outcome Caldwell Am J Gastro 2001 Troglitazone [Rezulin] 10 4-6 mo ↓inflammation Nair Aliment Pharmacol Ther 2004 Metformin 15 12 mo ↓ALT/AST & IR [3 mo] No improvement after 3 mo Sanyal Hepatology 2002 Pioglitazone ±Vit E 21 6 mo ↓steatosis, ballooning Tetri Hepatology 2003 Rosiglitazone [Avandia] 4 mg bid 22 48 weeks ↓steatosis, inflammation, ballooning & fibrosis [zone 3] Within 6 months of stopping treatment: ALT Wt gain in 67% [peripheral fat] Promrat Hepatology 2004 [Actos] 30 mg qd 18 66% ↓steatosis, inflammation, ballooning & fibrosis Nl ALT in 72%

44 Treatment [8] NASH & Vitamin E
PI Treatment N Duration Histology/Outcome Lavine J Pediatr 2000 Vit E IU 11 4-10 mo N/A, ↓ALT Hasegawa α tocopherol 12 12 mo ↓ 5/9 steatosis, inflammation & fibrosis Sanyal Clin Gastro Hepatol 2004 Pioglitazone ±Vit E 21 6 mo Vit E alone improved steatosis Combination improved steatosis, ballooning & pericellular fibrosis Kugelmas Exercise 16 12 weeks No difference Harrison Vit E + C vs. placebo 23 Similar ↓ fibrosis in both groups

45 Histologic Changes: Placebo Group
50% 44% 39% Patients 28% 28% 11% Harrison, Am J Gastro 2003

46 Histologic Changes: Vitamin Group
* 50% 44% 39% 39% Patients 11% 5% *p=0.013 Harrison, Am J Gastro 2003

47 Treatment [9] Cytoprotective Agents
Ursodeoxycholic acid [UCDA] Ref N Study Type Duration AST/ALT Histology Laurin, 1996 24 Open label 12 mo Improved Steatosis Improved Guma, 1997 Randomized, open 6 mo Not performed Ceriani, 1998 31

48 Treatment [9] NASH & Ursodeoxycholic Acid
Lindor et al Hepatology 2004 Placebo-controlled trial 174 liver Bx-proven NASH [166 analyzed] 2 year study LFT and histology end points UDCA mg/kg/d Follow-up pathology in 95 persons

49 Treatment [10] NASH & Ursodeoxycholic Acid
Safe & well-tolerated 40% steatosis improved spontaneously 20% fibrosis improved spontaneously [? Sampling variability] No difference in biochemistries & liver histology UDCA at a dose of mg/kg/d was NOT effective in pt with NASH

50 Treatment [11] Summary Reduce insulin resistance Lipid Lowering Agents
Wt loss Thiazolidinediones Metformin Lipid Lowering Agents Fibrates Statins Lipotropic Agents Betaine Choline Reduce Oxidant Stress Hepatic iron reduction Vit E Reduce TNF Antibiotics Probiotics Cytoprotection Ursodiol

51 NASH & OLTx 1-2% of OLTx Post-OLTx NASH recurs in 30%
Causes multifactorial: Persistent hypertriglyceridemia Obesity DM Corticosteroid – promote fatty liver & DM Cyclosporine – mitochondrial toxicity

52 Conclusions

53 NAFLD NAFL NASH Cirrhosis Steatosis [macrovesicular] Steatosis
Inflammation Ballooning  Mallory’s Hyaline  Fibrosis Fibrosis Inflammation  Steatosis Hepatocellular Cancer

54 Current Treatment Algorithm
Confirm Histology [Prognosis] Treat Co-morbidity No Proven Treatment [Vitamin E ?]

55 Future Treatment Algorithm
Confirm Histology Treat Co-morbidity Anti-oxidants Insulin Sensitizers Anti-cytokine Pentoxyfyline Anti-TNF Probiotics Vitamin E Betaine Glitazones Glucophage

56 Steatosis & HCV

57 Steatosis & HCV Key Concepts
Hepatic steatosis is a common finding in patients with HCV – 31% - 72% of such patients Hepatic steatosis more common in HCV G3 [independent risk factor]  development & progression of fibrosis in HCV patients Wt loss may diminish hepatic steatosis Hickman et al Gut 2002 Eradication of HCV  hepatic steatosis in G3 pt but not G1 [independent of any change in body weight] Degree of steatosis is inversely proportional to the likelihood of achieving response to therapy in the first 12 weeks Poynard et al Hepatology 2003

58 Discussion


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