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Natural History of Nonalcoholic Fatty Liver Disease (NAFLD)

Adapted from Diehl AM. NEJM 2017;377:2063-72

NAFLD: progression of disease

Liver histology in NAFLD

Histology scoring

• NAS (NAFLD Activity Score), reflects disease activity: unweighted composite of
  • Steatosis (0 to 3)
  • Lobular inflammation (0 to 3)
  • Ballooning (0 to 2)
• SAF Score: semi-quantitative score of
  • Steatosis (0 to 3)
  • Activity (lobular inflammation + ballooning) = NAS (0 to 8)
  • Fibrosis (0 to 4)

Adapted from Chalasani N. Practice Guidance from the AASLD;Hepatology 2018;67:328-357

Screening for NAFLD

Adapted from Chalasani N. Practice Guidance from the AASLD;Hepatology 2018;67:328-357

Non-invasive Scores of NAFLD

* NFS: www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score or gihep.com/calculators/hepatology/nafld-fibrosis-score
** FIB-4: www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis or gihep.com/calculators/hepatology/fibrosis-4-score

Assessment of NAFLD

• Non invasive evaluation
  • Presence of metabolic syndrome: predictive of steatosis > LIVER BIOPSY
  • NFS*, FIB-4, vibration controlled transient elastography, magnetic resonance elastography: predictive of advanced fibrosis > LIVER BIOPSY
  • Serum ferritin and iron saturation: if high, marker of possible hepatic injury and/or hemochromatosis (homozygote or heterozygote C282Y HFE mutation) > LIVER BIOPSY
  • High serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (> 5 ULN aminotransferases, high globulins, or high total protein to albumin ratio) > work-up for autoimmune liver disease
  • Consider presence of commonly associated comorbidities (central obesity, hypertension, dyslipidemia , diabetes or insulin resistance, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea)

* NFS is based on 6 variables (age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio) and is calculated using the published formula http://gihep.com/calculators/hepatology/nafld-fibrosis-score/

Adapted from Chalasani N. Practice Guidance from the AASLD;Hepatology 2018;67:328-357

Likelihood of NASH and fibrosis in patients with NAFLD

• Patients at risk for clinical progression
  • Steatosis = 1
  • Ballooning = 1
  • Inflammation = 1
  • NAS (NAFLD Activity Score) = 4
  • = F2

Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

Comorbidities of NAFLD

HR of * 17 ; ** 2 ; *** 1.9

Adapted from Kim GE. J Hepatol 2018;68:140-6 ;
Chalasani N. Practice Guidance from the AASLD; Hepatology 2018;67:328-357

Management of patients with NASH and fibrosis

• Not recommended : Metformin, GLP-1 agonists (liraglutide), Systematic bariatric surgery, Ursodeoxycholid acid

Adapted from Chalasani N. Practice Guidance from the AASLD ; Hepatology 2018;67:328-357 ;
Diehl AM. NEJM 2017;377:2063-72

Endpoints in clinical trials of NAFLD and NASH

Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

NASH-new serum non-invasive biomarkers

• Not yet fully validated
  • Could diagnose NASH and its severity
  • Could identify patients likely to respond to therapy
• Chitinase-3-like protein 1(CHI3L1) – YKL-40
• Enhanced Liver Fibrosis (ELF) Test
  • Comprised of TIMP-1 (tissue inhibitor of matrix metalloproteinase-1), PIII-NP (mino -terminal peptide of type III procollagen), and hyaluronic acid
• Pro C3
  • Derived from synthesis of type III collagen
  • FIB-C3 Score
• HepQuant STAT
  • Quantitative liver function test 60 min after oral administration of 4 mg tetra-deuterated cholic acid
• Non-invasive score-4 (NIS4)
  • Detect patients with NAS = 4 and F = 2
  • Comprised of Chitinase-3-like protein 1(CHI3L1), alpha2-macroglobulin, microRNA 34a (MIR34a), and HbA1C

Adapted from Harrison SA. AASLD 2017

Current Status of Pharmacologic Treatments for NASH

• No approved therapies for NASH
• Currently available therapeutics with (some) proven efficacy
  • Vitamin E
  • Pioglitazone

NASH: targets for therapeutics

• Endpoints for clinical trials
  1. Disease Activity (steatohepatitis) = NAFLD Activity Score (NAS)
  2. Disease Progression = Fibrosis Stage
  3. Clinical outcomes : Cirrhosis (MELD, Portal hypertension), Liver-related outcome, death

Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print) ; Diehl AM. NEJM 2017;377:2063-72

NASH – Pharmacological agents in development

Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

Results of trials for individual treatment agents *

* Enrollment criteria and durations of therapy differed between studies, and the primary endpoint definitions were not identical

Adapted from Konerman MA. J Hepatol 2018 (Epub ahead of print)

NASH Combination of metabolic damages to the liver
	Prevention and Lifestyle Modifications are key !