Belang voor de MDL-arts Dr. M.J. Coenraad LUMC, Maag- darm- en - - PowerPoint PPT Presentation

NASH en NAFLD Belang voor de MDL-arts

• Dr. M.J. Coenraad

LUMC, Maag- darm- en leverziekten

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Agenda

Definition and epidemiology of NAFLD Diagnostic workup Liver-related complications of NASH Pharmacologic therapy and fibrosis NASH related cirrhosis and liver transplantation NASH related hepatocellular carcinoma

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Definition Non Alcoholic Fatty Liver Disease (NAFLD)

Excessive hepatic fat accumulation associated with insulin resistance Definition: steatosis in >5% hepatocytes histology/ 1H-MRS

• Non-alcoholic fatty liver (NAFL)
• Non-alcoholic steatohepatitis (NASH):

steatosis, lobular inflammation, ballooning degeneration- fibrosis, cirrhosis, HCC

• LiverMultiScan as non-invasive diagnostic tool

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1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016

Relevance of NAFLD to hepatologists?

NAFLD nowadays most common chronic liver disease in Western World and is estimated to affect 17-46% of population in developed countries NASH affects 2.7–12.2% of the population Varying estimates of progression to cirrhosis, e.g. 10% developing decompensated cirrhosis at 13.7 year mean follow up NASH cirrhosis among most frequent indications for liver transplantation in USA Hepatocellular carcinoma development in NASH cirrhosis ranging from 2.4-12% HCC may also occur in absence of cirrhosis

10-sep-19 5 EASL guideline NAFLD J Hepatol 2016, Ekstedt, Hepatology 2006, Jensen et al Postgraduate medicine 2019;

Risk factors NAFLD

• Obesity

10-sep-19 6 Jensen et al Postgraduate medicine 2019

Risk factors NAFLD

• Obesity
• Excess energy intake with associated weight gain
• Macronutrient composition of diet (high sucrose/ fructose intake, high fat)
• Insulin resistance, type 2 diabetes, metabolic syndrome
• Age
• Male sex
• Ethnicity (Hispanics/ Asian Americans)
• Genetics (PNPLA3, NCAN (rs2228603), GCKR (rs780094), LYPLAL1

(rs12137855), PPP1R3B (rs4240624), TM6SF2 (rs58542926)

• Gut dysbiosis (lipogenesis, ↑adipocyte triglyceride content, LPS-activation
• f fat storage and inflammation in the liver, ↓activation of farsenoid x

receptor (FXR, regulator in hepatic glucose and lipid metabolism)

10-sep-19 7 EASL guideline J Hepatol 2015

How to identify patients? …. especially those at risk of complications?

Is screening for NAFLD warranted? How? …Liver enzymes? >50% of patients with NAFLD have normal liver enzymes Equal prevalence of NASH in patients at high risk for NAFLD with normal and abnormal liver enzymes …Imaging?

10-sep-19 8 Jensen et al Postgraduate medicine 2019

Epidemiology NAFLD: is screening warranted?

At risk population for NASH/fibrosis: age>50, T2 DM, metabolic syndrome NON-alcoholic cirrhosis: men < 30 g/day, women < 20 g/day EASL/EASD/EASO guideline for NAFLD:

• Individuals with steatosis should be screened for MetS, independent of liver

enzymes

• Individuals with persistent abnormal liver enzymes should be screened for

NAFLD

• Subjects with obesity or metabolic syndrome should undergo liver enzyme

testing and/or ultrasound

10-sep-19 9 EASL guideline J Hep 2016

Figure 1. Diagnostic flow chart EASL/EASD/EASO

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1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016

How to diagnose NAFLD? Imaging

First-line diagnostic test: imaging Ultrasound

• limited sensitivity especially in high BMI and steatosis < 20%
• Reliable for moderate or severe steatosis

10-sep-19 11 Besutti et al, Liver International 2019

Sensitivity 75-81% Specificity 50-60%

Accuracy of imaging in NASH

Elastographic techniques TE (Transient elastography) 4 studies AUROCs ranging from 0.65 to 0.75 ARFI (Acoustic Radiation Force Impulse) 2 studies sensitivities 77%‐85%/specificities 72%‐83% MRE (ME elastography) 6 studies AUROCs ranging from 0.70 to 0.79 MR non‐elastographic techniques 1H‐MRS (MR-spectroscopy) 2 studies AUROC 0.71 for αNTP/TP and 1.00 for alanine (n=26) mpMRI (multiparametric MRI) 2 studies AUROC 0.69 (NASH vs SS), 0.80 (LIF) score

10-sep-19 12 Besutti et al, Liver International 2019

In daily Hepatology practice…

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Fibroscan

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Serum biomarkers for fibrosis

NAFLD fibrosis score: Age, DM/ impaired fasting glucose, BMI, platelets, albumin, AST, ALT AUROC 0.84, sensitivity 46%, specificity 93% FIB-4 index: Age, ALT, AST, platelets AUROC 0.80, sensitivity 33%, specificity 98%

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1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016

Reference standard: biopsy

Reference standard to differentiate between NAFLD and NASH NASH: steatosis, ballooning, lobular inflammation

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Histology in NAFLD/NASH

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Ballooning degeneration

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LUMC: multidisciplinary team for patients with suspected NAFLD

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MDL-artsen Internist-vasculair geneeskundigen Endocrinoloog PhD studenten Research verpleegkundigen Target population: patients with suspected NAFLD Standardized work-up including transient elastography Liver biopsy if intrinsic liver disease with consequences for therapy suspected/ cannot be excluded Assess suitability for participation in clinical studies

RADIcAL study

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Multiparametric Magnetic Resonance Imaging

cT1 mapping Fibrosis imaging Proton spectroscopy Hepatic steatosis measurement T2* mapping Iron content imaging Liver Inflammation and Fibrosis Score (LIF score): 0-4

10-sep-19 21 Banerjee et al, J Hepatol 2014;

Multiparametric MRI LIF score

10-sep-19 22 Pavlides et al. J. Hepatol 2016

Multiparametric MRI predicts clinical outcomes in patients with chronic liver disease

10-sep-19 23 IPavlides et al. J. Hepatol 2016; 64: 308-15 Pavlides et al. J. Hepatol 2016

Dysmetabolic iron overload syndrome (DIOS)

Disturbed iron homeostasis in 1/3 of NAFLD patients

• elevated serum ferritin
• normal or mildly elevated transferrin saturation.
• Histology: mild hepatic iron deposition in hepatocytes or reticuloendothelial

system Inhibition of iron mobilisation from hepatocytes and Kupffer cells (hepcidin/ferroportin) related to inflammation and metabolic derangements Excess iron aggravates natural course of NAFLD Cellular damage by formation of toxic hydroxyl radicals Patients with RES iron more likely to have advanced histologic features including: fibrosis (p=0.049), portal inflammation (p=0.002), hepatocellular ballooning (p=0.006) and definite NASH (p=0.007)

10-sep-19 24 Datz et al Minerva Endocrinol. 2016, Nelson Hepatology 2011

Hepatology 2015 DOI: 10.1002/hep.27662

The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled study

Liver-related complications to NAFLD: Fibrosis

NASH may progress to cirrhosis, liver failure and HCC Systematic review of 221 NASH patients with paired biopsies1

• 39% with progressive fibrosis in median 5.3 y
• Risk factors for advanced fibrosis; age, inflammation in index biopsy

Prospective study with paired biopsies 3y interval (n=52)2 50% fibrosis at baseline (4% F3-F4) 27% progression > 1 stage Risk factors:  waist circumference and high baseline LDL

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1Argo, J Hepatol 2009; 2Wong, Gut 2010

NASH associated fibrosis

Other factors associated with fibrosis or progression:

• Heavy alcohol drinking
• Older age
• Diabetes mellitus
• BMI > 28
• Metabolic syndrome
• Histologic features: necroinflammation, hepatocyte ballooning
• Genetic predisposition: PNPLA3 and Neurocan (NCAN) polymorphisms

10-sep-19 27 Ekstedt, Scand J Gastroenterol 2009, Argo, J Hepatol 2009; Singal, Am J Gastroenterol 2014

Management of fibrosis in NAFLD

Effect of weight loss in overweight/obese on fibrosis? RCT lifestyle intervention vs control (n=293) 52 weeks lifestyle change If ≥10% weight reduction :90% had resolution of NASH, 45% had regression of fibrosis Bariatric surgery: both improvement or worsening of fibrosis reported Obes Surg. 2019, Singapore, retrospective study N=192 pt for bariatric surgery between 2010 and 2016 Bariatric surgery resulted in weight reduction and an improvement in the NAFLD fibrosis score

10-sep-19 28 Vilar-Gomez Gastroenterology 2015; Chavez-Tapia, Cochrane Database Syst Rev 2010, Koh, Obes Surg 2019

Effect of pharmacologic therapy on fibrosis in NAFLD

Design Effect on fibrosis RCT Vitamin E vs. pioglitazon vs. placebo No improvement in fibrosis score Reduction in steatosis and inflammation RCT TNFα-i Pentoxifylline vs. placebo Improvement of fibrosis in

• 0.2 PTX vs. +0.4 placebo (p=0.038)

Subgroup analysis for statin use in hepatitis C HALT-C cohort Fibrosis progression in 10% statin users vs. 29% non-users HR 0.31 (CI 0.10-0.97) RCT 72 weeks FXR agonist obeticholic acid vs placebo Improvement of fibrosis OCA 35% vs placebo 19% (RR 1.8 (1.1-2.7) (p=0.004) Significant decrease in NAS (-0.9, p 0.001) RCT GLP-1 agonist liraglutide (1·8 mg daily sc.) vs. placebo for 48 weeks RR of fibrosis progression 0·2 (0·1–1·0) p=0·04 Resolution of definite NASH RR 4·3 (95% CI 1·0–17·7) p=0·019 RCT Selonsertib (ASK-1 inhibitor) vs. placebo (simtuzumab) for 24 weeks Reduction in fibrosis in 43% (26-63); 30% (14-50) vs. placebo 20% (3-56) RCT Cenocriviroc (CCR2/5 antagonist) vs placebo No worsening of fibrosis CVC 20% vs. placebo 10%; P = 0.02. No difference in NAS

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Sanyal, NEJM 2010; Zein, Hepatology 2011; Simon, J Hepatol 2015; Neuschwander-Tetri, Lancet 2015; Amstrong et al., Lancet 2016; Loomba et al Hepatology 2018; Friedman et al. Hepatology 2018

End-stage liver disease in NASH: indication for liver transplantation?

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MELD

ELTR

J Hepatol 2012, Adam et al. ELTR report 1968-2009 N=83816 pt, 145 centres 52% cirrhosis  (21% viral, 19% alcohol) 14% primary liver tumors  11% cholestatic disease 8% ALF 5% Metabolic ELTR registry, Adam et al. J Hepatol 2012

NASH as indication for liver transplantation

UNOS database 2004-2013: 170% increase in new waitlist registrants for NASH, 2nd leading disease USA scientific Registry of Transplant Recipients 35,781 patients underwent LT; 1959 for NASH 1.2% in 2001 and 9.7% in 2009 transplanted for NASH Survival at 1 and 3 years 84% and 78%

32 Charlton, Gastroenterology 2011; Wong, Gastroenterology 2015

NAFLD as indication for wait list registration

NAFLD and hepatocellular carcinoma

Evidence for association between NAFLD or NASH and increased HCC risk Systematic review of 17 cohort studies, 18 case-control/cross sectional studies, 26 case series NAFLD without cirrhosis: 0- 3% HCC mortality up to 20y NASH- cirrhosis 2.4% in 7 y to 12.8% over 3 y

White, Clin Gastroenterol Hepatol 2012

HCC in absence of cirrhosis: results from a large cohort in the Netherlands

Retrospective analysis of 1221 patients with HCC between 2005 and 2012 from 5 Dutch tertiary referral centers 238 out of 1221 HCC patients no underlying cirrhosis (19%) 238 Non-cirrhotic HCC vs 983 cirrhotic HCC:

• NAFLD 24% vs 11%
• Unifocal 67% vs. 48%
• Diameter 8 cm vs. 4 cm
• Resection 50% vs. 10%
• Mortality rate HR 0.49 (95% CI 0.38-0.63)

Van Meer, Van Erpecum, Coenraad et al. Eur J Gastroenterol Hepatol 2016

Risk factors for HCC

Other risk factors involved in development of HCC in NAFLD Obesity Type 2 diabetes Older age Regular alcohol consumption Excess hepatic iron stores (sinusoidal iron deposition) Genetic predisposition

• PNPLA3 (rs738409 C>G) in HCC in NAFLD, obese, ALD and HCV
• Neurocan (NCAN) rs2228603T allele in ALD related HCC

Hepatology 2010; J Hepatol 2013; Dig Liver Dis 2012; J Gastroenterol 2013; Hepatology 2014; J Hep 2014

Development of HCC in NASH

J Hepatol 2012; 56: 1384

Is surveillance for HCC in NAFLD indicated?

AASLD guideline No recommendation can be made since HCC incidence in NASH cirrhosis is unknown APASL guideline HCC surveillance not recommended for NASH related cirrhosis Dutch guideline HCC surveillance not recommended for NASH related cirrhosis EASL-EORTC guideline HCC surveillance recommended in all cirrhotic patients

Hepatology 2010, J Hepatol 2012, Hepatol Int 2010, Neth J Med 2014

HCC surveillance in relation to NAFLD

Retrospective analysis1 of patients with HCC from 5 Dutch tertiary referral centers 2005-2012 357/1074 (33%) underwent surveillance for HCC NAFLD 21% nonsurveillance vs 7% surveillance group (p<0.05) HCC screening rate varies by etiology of cirrhosis2 1996-2010 n=156 patients with cirrhosis Screening rate

• NASH cirrhosis

30%

• Viral hepatitis

58%

• Alcoholic cirrhosis

63%

1Meer, Man, Coenraad et al., J Hepatol 2015, 2Patwardhan, Dig Dis Sci 2011

Effect of pharmacologic treatment on HCC

Metformin inhibits mTOR pathway Meta-analysis: Metformin associated with reduced risk of development of HCC in type 2 diabetes, HR 0.24 (95% CI 0.13-0.46) Metformin not associated with improved survival in 701 diabetic patients with HCC, HR 1.0 (95% CI 0.8-1.3) Statins: anti-angiogenic and anti-proliferative properties Case-control study: statin use inversely associated with HCC, HR 0.32 (95% CI 0.15-0.67) Meta-analysis: Statin use associated with reduced risk of HCC development, HR 0.63 (95% CI 0.52-0.76)

Zhang, Scand J Gastroenterol 2013; Bhat, WJG 2014; McGlynn, Cancer Epidemiol 2014; Singh, Gastro2013

Outcomes for curative therapy for NASH related HCC

Single center retrospective analysis of 303 patients undergoing curative treatment for HCC between 2000-2010 NASH HCV/ ALD p Number 52 (17%) 162 (54%) Age (y) 65 58 0.023 Female sex 48% 17% <0.001 Metabolic s. 45% 14% <0.001 MELD score 9 10 <0.024 3 y OS 60.9% 36.2% 0.029 RFS (mo) 60 56 0.303

Reddy, Hepatology 2012

Conclusions

Most common liver disorder Western world; 17-46% adults Subjects with obesity or metabolic syndrome should undergo screening for NAFLD by liver enzyme testing and/or ultrasound NAFLD may progress to cirrhosis, liver failure or HCC Pharmacologic therapy subject of research Outcome after liver transplantation for NASH related cirrhosis and curative treatment for HCC in NASH comparable to that in other chronic liver diseases

Metformin and lactic acidosis? 250 diabetic patients with NASH cirrhosis

10-sep-19 43 Zhang, Hepatology 2014

Retrospective study 250 patients with diagnosis cirrhosis (57% NASH) and diabetes using metformin 172 continued vs 78 discontinued No lactic acidosis observed

TE for screening of liver fibrosis: cost-effectiveness analysis from 6x prospective cohorts in Europe and Asia

Exploration of cost-effectiveness of transient elastography (TE) as a screening method to detect liver fibrosis in a primary care pathway Real-life individual patient data from six independent prospective cohorts (five from Europe and one from Asia) In 6,295 participants (55±12 yr, BMI 27±5 kg/m2, liver stiffness 5.6±5.0 kPa) 9.1 kPa TE cut-off provided best accuracy for significant fibrosis (≥F2) TE with the proposed cut-offs outperformed accuracy of fibrosis scores# Screening with TE was cost effective: 6,217 €/QALY (95% CI 5,832 - 6,601) in the general population. Conclusions: Screening for liver fibrosis with transient elastography in primary care is a cost-effective intervention for European and Asian populations and may even be cost-saving.

10-sep-19 44 Serra-Burriel, J Hepatol 2019