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 3 Insert > Header & footer 10-sep-19
Definition Non Alcoholic Fatty Liver Disease (NAFLD) Excessive hepatic fat accumulation associated with insulin resistance Definition: steatosis in >5% hepatocytes histology/ 1 H-MRS • Non-alcoholic fatty liver (NAFL) • Non-alcoholic steatohepatitis (NASH): steatosis, lobular inflammation, ballooning degeneration- fibrosis, cirrhosis, HCC • Liver Multi Scan as non-invasive diagnostic tool 1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016 4 Insert > Header & footer 10-sep-19
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 5 EASL guideline NAFLD J Hepatol 2016, Ekstedt, Hepatology 2006, Jensen et al Postgraduate medicine 2019; 10-sep-19
Risk factors NAFLD • Obesity Jensen et al Postgraduate medicine 2019 6 10-sep-19
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 of fat storage and inflammation in the liver, ↓activation of farsenoid x receptor (FXR, regulator in hepatic glucose and lipid metabolism) EASL guideline J Hepatol 2015 7 10-sep-19
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 …I maging? 8 Jensen et al Postgraduate medicine 2019 10-sep-19
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 EASL guideline J Hep 2016 9 10-sep-19
Figure 1. Diagnostic flow chart EASL/EASD/EASO 1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016 10 Insert > Header & footer 10-sep-19
How to diagnose NAFLD? Imaging First-line diagnostic test: imaging Ultrasound • limited sensitivity especially in high BMI and steatosis < 20% Sensitivity 75-81% • Reliable for moderate or severe steatosis Specificity 50-60% 11 Besutti et al, Liver International 2019 10-sep-19
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 12 Besutti et al, Liver International 2019 10-sep-19
In daily Hepatology practice … 13 Insert > Header & footer 10-sep-19
Fibroscan 14 Insert > Header & footer 10-sep-19
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% 1 EASL-EASD-EASO Clinical Practice Guidelines for the management of NAFLD, J Hepatol 2016 15 Insert > Header & footer 10-sep-19
Reference standard: biopsy Reference standard to differentiate between NAFLD and NASH NASH: steatosis, ballooning, lobular inflammation 16 Insert > Header & footer 10-sep-19
Histology in NAFLD/NASH 17 Insert > Header & footer 10-sep-19
Ballooning degeneration 18 Insert > Header & footer 10-sep-19
LUMC: multidisciplinary team for patients with suspected NAFLD 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 19 Insert > Header & footer 10-sep-19
RADIcAL study 20 Insert > Header & footer 10-sep-19
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 21 Banerjee et al, J Hepatol 2014; 10-sep-19
Multiparametric MRI LIF score 22 Pavlides et al. J. Hepatol 2016 10-sep-19
Multiparametric MRI predicts clinical outcomes in patients with chronic liver disease 23 IPavlides et al. J. Hepatol 2016; 64: 308-15 10-sep-19 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) 24 Datz et al Minerva Endocrinol. 2016, Nelson Hepatology 2011 10-sep-19
The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled study Hepatology 2015 DOI: 10.1002/hep.27662
Liver-related complications to NAFLD: Fibrosis NASH may progress to cirrhosis, liver failure and HCC Systematic review of 221 NASH patients with paired biopsies 1 • 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 1 Argo, J Hepatol 2009; 2 Wong, Gut 2010 26 10-sep-19
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 Ekstedt, Scand J Gastroenterol 2009, Argo, J Hepatol 2009; Singal, Am J Gastroenterol 27 10-sep-19 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 Vilar-Gomez Gastroenterology 2015; Chavez-Tapia, Cochrane Database Syst Rev 2010, Koh, Obes Surg 2019 28 10-sep-19
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