Dr Lee Yin Mei Senior Consultant Gastroenterology NUHS
Simple steatosis (SS ), Put picture of through steatohepatitis spectrum Prevalence of NASH 3- 25%
NASH Progression only occurs in NASH: 27% develop fibrosis and 19% cirrhosis over a period of nine years. (Matteoni et al Gastroent.1999;116:1413)
Fatty Liver: Can we identify who will progress
PL- referred for abnormal LFT on health screening 50 year old female history of hypothyroidism. PMH dyslipidemia (Simvastatin 10 mg ) and hypothyroidism ( T4 75 mcg) Lipid TC 4.89 mmol/l HDL 1.09 mmol/l LDL 2.96 mmol/l TG1.89 mmmol/l
PL- referred for abnormal LFT on health screening ALB 40 ALT 30 AST 66 PLT 120 BMI 27.3 Fasting Glucose 4.5 mmol/l, 2 hour glucose (OGTT) 12 mmol/L HBs AG negative anti-HCV negative anti-HBS >1000, ANA is 1/80 +, Ig G normal, US fatty liver
Is this patient at risk for progression? Does she have NASH? Risk factors for progression 1. Obesity 2. High insulin levels 3. AST in pediatric patients with NAFLD 4. Fibrosis at first liver biopsy Schwimmer J et al J of Pediatrics 2003; 143:500 Pagadala MR, Clin Liver Dis 2012:487
Mdm PL Based on risk factors alone, she has impaired glucose tolerance, high AST, dyslipidemia and obesity, the risk of NASH is high. She is referred to NUH (Wiliamson RM, Diabetes Care 2011;34:1139)
Liver biopsy is the gold standard for diagnosis and staging of NAFLD
Pros of liver biopsy Gold standard for diagnosis of NASH and also prognosis Cons of liver biopsy 1. Cost 2. Risk of complications: pain, bleeding, mortality (Rockey AASLD Hepat 2009:1017) 3. Risk of sampling error: Hepatol Res 2007:1002
Patient is not keen for liver biopsy Anxious and wants to know if her condition is serious
Non invasive staging of NASH A) FIBROSCAN Liver stiffness measurement (LSM) LSM good correlation to degree of hepatic fibrosis in NAFLD Stage 2 fibrosis AUROC 0.83 Stage 3 or more AUROC 0.93 Cirrhosis AUROC 0.95 Wong VW Hepatology 2010;55;454
FIBROSCAN: Pros
FIBROSCAN: Cons May be invalid for lower grades of fibrosis, steatosis, older >52, and high BMI >35 falsely elevated in acute hepatitis Wong GL Gastroenterol Rep 2013:1:19 Arena U Hep 2008;47:380 Castera:Hepatology 2013:51:828
Mdm PL Fibroscan reading 10 KPa equivalent to F3-4
Non invasive staging of NASH B) Blood tests: Can elevated ALT predict fibrosis? 1/3 normal ALT had NASH or advanced fibrosis AUROC= 0.62 50% of those with elevated ALT had no fibrosis AUROC= 0.46 Verma S Liver Int 2013;33:1398 Francanzoni Hepatology 2008;48:792
Non invasive staging of NASH C) Simple non invasive fibrosis scoring systems NAFLD-FS formula: 1.675 + 0.037 x age (years) + 0.094 x BMI + 1.13 x hyperglycemia or diabetes (yes = 1, no = 0) + 0.99 AST/ALT ratio - 0.013x platelet (109/L)- 0.66x albumin (g/dL) APRI: AST (x ULN) /platelet x 100 FIB-4 [age (years) x AST (U/L) /platelet(109/L) x square root ALT (U/L)] BARD score scale 0-4: BMI > 28 =1 point, AST to ALT ratio >/ 0.8 = 2 points; diabetes mellitus = 1 point.
Predicted those with fibrosis and also excluded those without advanced fibrosis McPherson S Gut 2010; 59:1265
Correlation of NAFLD fibrosis score, FIB4 APRI and BARD with outcomes Angulo P Gastro 2013;145; 782
NAFLD-FS APRI FIB4 BARD LIVER LOW 1 1 1 1 MED 7.7* 8.8* 0.92 6.2* HIGH 34* 20.9 14.6* 6.6* MORTALITY LOW 1 1 1 1 MED 4.2* 1* 2.3 1.8 HIGH 58* 3* 6.9* 1.6
Increasing mortality with increasing fibrosis according to NAFLD FS FIB4 and APRI Deaths were from cardiovascular and non liver malignancy as only 3.2% had advanced fibrosis Kim D, Hepatology 2013; 57:1057
Risk factor for HCC Hazard Ratio 95% CI AST >40 IU/L 8.2 2.56 – 26.26; P < 0.001 Platelet < 150 × 10 3 7.19 CI: 2.26 – 23.26; P = 0.001 Age ≥ 60 years 4.27 95 % CI: 1.30 – 14.01, P =0.017 Diabetes 3.21 95 % CI: 1.09 – 9.50; P = 0.035 The annual rate of new HCC was 0.043 % Yusuke K, AJG 2012:107:253
Simple non invasive fibrosis scoring systems Pros Easy to use Safe cost effective Good NPV Cons PPV only modest (27-79%) so that patients with intermediate or high score need further investigation to confirm advance fibrosis
Mdm PL’s Score 1.821 < -1.455: predictor of absence of significant fibrosis (F0-F2 fibrosis) ≤ - 1.455 to ≤ 0.675: indeterminate score > 0.675: predictor of presence of significant fibrosis (F3-F4 fibrosis) Angulo P, Hui JM, Marchesini G et al. The NAFLD fibrosis score A noninvasive system that identifies liver fibrosis in patients with NAFLD Hepatology 2007;45(4):846-854
1. Detect steatosis on ultrasound and have clinical liver disease or abnormal LFT can do work up for NAFLD 2. Screen for risk factors and other cause of steatosis 3. Screening for liver disease in patients with high risk groups not advised at the moment as long term benefits of screening and knowledge regarding NAFLD not proven
Obesity Weight reduction improves the liver function tests in adult and pediatric NAFLD patients (Ueno T, J Hepatol. 1997; Franzese A, Dig Dis Sci 1997) Fatty infiltration on liver histology also decreases with weight loss (Andersen T , J of Hep 1991) .
Low Carbohydrate Diet (Samaha et al NEJM 2003;21:348:2074)
High intensity and several times/week Warburton et al; Am J Cardiol 2005;95(9):1080
GREACE study Lancet 2010
Metformin has no significant effect on liver histology and is not recommended (Strength – 1, Evidence - A) Pioglitazone can be used to treat steatohepatitis Long term safety and efficacy of pioglitazone in patients with NASH is not established. (Strength – 1, Evidence - B)
Vitamin E 800 IU/day improves liver histology in non-diabetic adults with NASH and therefore it should be considered as a first-line therapy (Strength - 1, Quality - B) UDCA is not recommended for the treatment of NAFLD (Strength – 1, Quality – B)
NASH is progressive and should be treated Establish diagnosis with evidence of hepatic steatosis and inflammation and no other causes for liver disease Treat the risk factors associated with the metabolic syndrome Consider Vitamin E in non diabetics with NASH
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