Non-alcoholic Fatty
Liver Disease
(NAFLD)
Meredith Clary
Objectives
 NAFLD is a spectrum
 Steatosis one of the most common
diseases in the US
 Results in cirrhosis, HCC, and CV...
NAFLD
 Spectrum of pathology involving
hepatic steatosis, +/- inflammation and
fibrosis
 No secondary causes are present...
The NAFLD Spectrum
NAFL=
Steatosis
(Fat > 5% of
hepatocytes
)
NASH:
steatohepatitis
1. Steatosis
+
2. Inflammation
+
3.
He...
Steatosis
Lobular Inflammation
Hepatocellular Ballooning
Epidemiology
 NAFLD: most common cause of
chronic liver disease in Western world
 NAFLD: ~30% of adults
◦ 75% among Obes...
An Increasing Threat
• Highly effective antiviral therapy for
HCV
• NASH projected to be most common
cause of cirrhosis an...
Cardiovascular Risk
CV disease: leading cause of mortality
in NASH patients
NAFLD Risk Factors
• Metabolic syndrome (HTN, HLD,
visceral obesity, insulin
resistance/DMII)
 40-50 yo
 Hispanic ethnic...
Hispanic Ethnicity-Dallas Heart
Study
Ethnicity
Steatosis
Prevalence
White 33%
Black 24%
Hispanic 45%
PNPLA3 (adiponutrin)
 PNPLA3 (adiponutrin) codes for enzymes
that break down TG
 Dysfunctional PNPLA3 promotes
accumulat...
I148M allele PNPLA3
Ethnicity
Homozygote
Prevalence
Europeans 5%
African Americans 2%
Hispanics 25%
Non-carrier
Heterozygo...
Pathogenesis
 Theories:
◦ Insulin resistance
◦ “Two-Hit” Hypothesis
◦ Gut-Liver Axis
Insulin Resistance
Two Hit Hypothesis
Gut-Liver Axis
Clinical Presentation
 Usually asymptomatic
 Most commonly revealed by elevated
LFTs or incidentally on abdominal
imagin...
Screening
 Should we screen at-risk patients?
 NOT currently recommended
◦ Uncertainties regarding diagnostic testing
an...
Diagnosis
• Ultrasound
• LFTs
• Exclude other causes of liver disease:
• Alcohol history (< 21 drinks/week for men and
<14...
Radiography
 U/S- recommended mode of imaging
◦ Only positive when steatosis >30% of liver
◦ Sensitivity 85% (decreased i...
Staging
Non Invasive Staging:
1. Biomarkers
2. NAFLD Fibrosis
Score
3. Fibroscan
NAFL
NASH
Invasive Staging:
Liver biopsy-...
Biopsy –
Gold Standard
 Definitive way to
differentiate NAFL from NASH
• Limitations: Risks, costly, sampling error
• Bio...
Noninvasive Staging:
Biomarkers
Hepatocyte
Ballooning
Noninvasive Staging Tools-
Fibrosis
 NAFLD Fibrosis Score
◦ Age, BMI, DM, AST/ALT ratio, Plt, albumin
◦ Used to exclude a...
Treatments
 Weight loss
 Bariatric surgery
 Vitamin E
 Pioglitazone
 Transplant
•Fish Oil
•Probiotics
•Pentoxifylline...
Treatment: Weight loss
 Mainstay treatment of NAFLD
 3–5% loss of body weight can improve
steatosis
 10% loss may be ne...
Treatment: Bariatric Surgery
 Some studies show Bariatric surgery
reduces histological features of
NAFLD
 2010 Cochrane ...
Treatment:
Vitamin E
 Anti-oxidant
 PIVENS Trial (Pioglitazone vs Vitamin E vs
Placebo for the Treatment of Nondiabetic ...
Vitamin E
Adverse Effects
 Meta-analysis: increased all-cause
mortality
 RCT: increased prostate cancer in
healthy men
...
Treatment: Pioglitazone
 PPAR-γagonist: Insulin-sensitizer
 PIVENS: Pioglitazone improved
insulin sensitivity and NASH o...
Pioglitazone
Adverse Effect
 Meta-analysis of 19 trials, pioglitazone
associated with higher rate of
Congestive Heart Fai...
Treatment:
Liver Transplant
 Transplant is the only definitive
treatment for end-stage liver disease
due to NAFLD
• Recur...
Treatment Targets
Obeticholic Acid – FXR
agonist
• Bile acid activates Farnesoid X
Receptor
• Promotes insulin sensitivity
• FLINT - Multice...
Management
 Monitor LFTs every 3 to 6 months
 Weight loss
 Preventative Care: DM, HTN, alcohol,
smoking, Hep vaccinatio...
Take Home Points
 NAFLD is a spectrum
 Steatosis one of the most common
diseases in the US
 Results in cirrhosis, HCC, ...
References
 Rahimi RS, Landaverde C. Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: Clinical Implications a...
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NAFLD

NAFLD
Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - NAFLD

  • 1. Non-alcoholic Fatty Liver Disease (NAFLD) Meredith Clary
  • 2. Objectives  NAFLD is a spectrum  Steatosis one of the most common diseases in the US  Results in cirrhosis, HCC, and CV disease  Pathogenesis incompletely understood  How to Diagnose and When to biopsy  Limited Treatments/Ongoing research
  • 3. NAFLD  Spectrum of pathology involving hepatic steatosis, +/- inflammation and fibrosis  No secondary causes are present  Alcohol intake ◦ < 21 drinks/week in Males ◦ < 14 drinks/week in Females
  • 4. The NAFLD Spectrum NAFL= Steatosis (Fat > 5% of hepatocytes ) NASH: steatohepatitis 1. Steatosis + 2. Inflammation + 3. Hepatocellular NASH cirrhosis Possible etiology Cryptogenic cirrhosis: histological findings are lost by time of biopsy
  • 5. Steatosis
  • 6. Lobular Inflammation
  • 7. Hepatocellular Ballooning
  • 8. Epidemiology  NAFLD: most common cause of chronic liver disease in Western world  NAFLD: ~30% of adults ◦ 75% among Obese or Diabetic • NASH: 5% by biopsy • Prevalence is increasing
  • 9. An Increasing Threat • Highly effective antiviral therapy for HCV • NASH projected to be most common cause of cirrhosis and liver transplant by 2020 • Projected leading cause of HCC
  • 10. Cardiovascular Risk CV disease: leading cause of mortality in NASH patients
  • 11. NAFLD Risk Factors • Metabolic syndrome (HTN, HLD, visceral obesity, insulin resistance/DMII)  40-50 yo  Hispanic ethnicity
  • 12. Hispanic Ethnicity-Dallas Heart Study Ethnicity Steatosis Prevalence White 33% Black 24% Hispanic 45%
  • 13. PNPLA3 (adiponutrin)  PNPLA3 (adiponutrin) codes for enzymes that break down TG  Dysfunctional PNPLA3 promotes accumulation of lipotoxic substances in the liver  Genome-wide association study examining NAFLD in the Dallas Heart Study
  • 14. I148M allele PNPLA3 Ethnicity Homozygote Prevalence Europeans 5% African Americans 2% Hispanics 25% Non-carrier Heterozygote Homozygote
  • 15. Pathogenesis  Theories: ◦ Insulin resistance ◦ “Two-Hit” Hypothesis ◦ Gut-Liver Axis
  • 16. Insulin Resistance
  • 17. Two Hit Hypothesis
  • 18. Gut-Liver Axis
  • 19. Clinical Presentation  Usually asymptomatic  Most commonly revealed by elevated LFTs or incidentally on abdominal imaging  Labs: ◦ LFTs are normal in 50% of patients with NAFL and 20% with NASH ◦ If Abnl, LFTs 2-5 X ULN ◦ AST:ALT < 1 ◦ Alk phos 2-3 X ULN
  • 20. Screening  Should we screen at-risk patients?  NOT currently recommended ◦ Uncertainties regarding diagnostic testing and treatments of NAFLD ◦ Unclear cost-effectiveness of screening
  • 21. Diagnosis • Ultrasound • LFTs • Exclude other causes of liver disease: • Alcohol history (< 21 drinks/week for men and <14 drinks/week for women) • Hepatitis panel • Autoimmune panel • Hemochromatosis (iron, ferritin, TIBC)
  • 22. Radiography  U/S- recommended mode of imaging ◦ Only positive when steatosis >30% of liver ◦ Sensitivity 85% (decreased in morbidly obese) ◦ Specificity 94% ◦ Does not detect fibrosis ◦ Low cost, widely available  CT, MRI: ◦ Detects steatosis ◦ expensive  MR Spectroscopy: ◦ quantifies fat ◦ Expensive, not widely available
  • 23. Staging Non Invasive Staging: 1. Biomarkers 2. NAFLD Fibrosis Score 3. Fibroscan NAFL NASH Invasive Staging: Liver biopsy- Gold standard for determining stage of liver disease Normal Liver
  • 24. Biopsy – Gold Standard  Definitive way to differentiate NAFL from NASH • Limitations: Risks, costly, sampling error • Biopsy Indications: ◦ patients with NASH who are at increased risk of advanced fibrosis ◦ patients with suspected NAFLD in whom competing etiologies for hepatic steatosis cannot be excluded without a liver biopsy • NAFLD Activity Score: Steatosis, inflammation, ballooning
  • 25. Noninvasive Staging: Biomarkers Hepatocyte Ballooning
  • 26. Noninvasive Staging Tools- Fibrosis  NAFLD Fibrosis Score ◦ Age, BMI, DM, AST/ALT ratio, Plt, albumin ◦ Used to exclude advanced fibrosis  Fibroscan (transient elastography) ◦ Form of U/S estimates liver stiffness/fibrosis ◦ Unreliable in obese patients
  • 27. Treatments  Weight loss  Bariatric surgery  Vitamin E  Pioglitazone  Transplant •Fish Oil •Probiotics •Pentoxifylline •Orlistat •Incretins •Ursodiol •Metformin •Obetacholic acid
  • 28. Treatment: Weight loss  Mainstay treatment of NAFLD  3–5% loss of body weight can improve steatosis  10% loss may be needed to improve inflammation
  • 29. Treatment: Bariatric Surgery  Some studies show Bariatric surgery reduces histological features of NAFLD  2010 Cochrane review: current lack of evidence to determine if bariatric surgery is effective
  • 30. Treatment: Vitamin E  Anti-oxidant  PIVENS Trial (Pioglitazone vs Vitamin E vs Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis) ◦ Multicenter RCT ◦ Vit E 800 IU/day for 96 weeks ◦ Vit E improved NASH on biopsy (vs placebo)(43% vs. 19%, P=0.001)
  • 31. Vitamin E Adverse Effects  Meta-analysis: increased all-cause mortality  RCT: increased prostate cancer in healthy men  Still can be considered in non-DM with biopsy-proven NASH
  • 32. Treatment: Pioglitazone  PPAR-γagonist: Insulin-sensitizer  PIVENS: Pioglitazone improved insulin sensitivity and NASH on biopsy compared to placebo, did not meet the study’s criteria for statistical significance (34% vs. 19%, P=0.04,α 0.025)
  • 33. Pioglitazone Adverse Effect  Meta-analysis of 19 trials, pioglitazone associated with higher rate of Congestive Heart Failure (2.3% vs. 1.8% control group, p=0.002)
  • 34. Treatment: Liver Transplant  Transplant is the only definitive treatment for end-stage liver disease due to NAFLD • Recurrence of NASH post-transplant in 1/3 of patients • Increasing prevalence of NAFLD in donors may limit available livers for transplantation
  • 35. Treatment Targets
  • 36. Obeticholic Acid – FXR agonist • Bile acid activates Farnesoid X Receptor • Promotes insulin sensitivity • FLINT - Multicenter double blind RCT (Lancet 2014) ◦ Obeticholic acid improved liver histology (45%) compared to placebo (21%) (p 0.0002) ◦ First to possibly reverse fibrosis ◦ Adverse Effect: may increase LDL
  • 37. Management  Monitor LFTs every 3 to 6 months  Weight loss  Preventative Care: DM, HTN, alcohol, smoking, Hep vaccinations ◦ Statins are not contraindicated  If cirrhotic, HCC screening  Refer to Liver clinic: cirrhosis or need for a biopsy  Refer for transplant: MELD >10 or complications of cirrhosis  Consider Vit E (800 IU/day) only non-DM with biopsy-proven NASH
  • 38. Take Home Points  NAFLD is a spectrum  Steatosis one of the most common diseases in the US  Results in cirrhosis, HCC, and CV disease  Pathogenesis incompletely understood  How to Diagnose and When to biopsy  Limited Treatments/Ongoing
  • 39. References  Rahimi RS, Landaverde C. Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: Clinical Implications and Treatment. Nutr Clin Pract. 2013; 28: 40-51.  Targher G, Day CP, Bonora E. Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease. N Engl J Med 2010; 363: 1341-50.  Wong RJ, Cheung R, Ahmed A. Nonalcoholic Steatohepatitis Is the Most Rapidly Growing Indication for Liver Transplantation in Patients with Hepatocellular Carcinoma in the U.S. Hepatology. 2014 Jun; (59) 6: 2188-95.  Bedogni G, Nobili V, Tiribelli C. Epidemiology of Fatty Liver: An Update. World J Gastroenterol. 2014 Jul 21; 20 (27): 9050-4.  Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends in Endocrin & Metab. 2013 Jul; 24 (11): 537-545.  Portincasa P et al. Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clinical Biochemistry 2005; 38 (3): 203-217.  Schuppan, D. and Schattenberg, J. M. (2013), Non-alcoholic steatohepatitis: Pathogenesis and novel therapeutic approaches. Journal of Gastroenterology and Hepatology, 28: 68–76.  Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617-649.  Fitzpatrick E, Dhawan A. Noninvasive biomarkers in non-alcoholic fatty liver disease: Current status and a glimpse of the future. World J Gastroenterol. Aug 21, 2014; 20(31): 10851–10863.  Ikura Y. Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades. World J Hepatol. 2014; 6 (12): 894-900.  Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008; 40(12):1461- 1465.  Ganz M, Szabo G. Immune and Inflammatory Pathways in NASH. Hepatol Int. 2013; 7 (2): 771-781.  White DL, Kanwal F, El Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin. Gastroenterol. Hepatol. 2012; 10: 1342–1359.  Browning JD, Szczepaniak LS, Dobbins R et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387–1395.  Sing S et al. Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies. Clin Gastroenterol Hepatol. 2014; 14: 602-8.  Zezos P, Renner EL. Liver Transplantation and Non-alcoholic Fatty Liver Disease. World J Gastroenterol. 2014; 20 (42): 15532-8.  Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.Hepatology. 2012;55:2005-2023.  Than N, Newsome P. A Concise Review of non-alcoholic fatty liver disease. Atherosclerosis. 2015; 239 (1): 192-202.  Ma YY et al. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2013; 19 (40): 6911-8.  Neuschwander-Tetria, Brent A et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomized, placebo-controlled trial. The Lancet 2014.  Sanyal AJ et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. New Engl J Med 2010; 362: 1675-1685.

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