DIAGNOSING NONALCOHOLIC FATTY LIVER DISEASE Anna Christina Dela Cruz, MD Division of Digestive Diseases and Nutrition Conflict of Interest None Upon completion of this activity, participants will be able to: Select appropriate diagnostic testing for the evaluation of gastrointestinal comorbidities in patients with diabetes.
Outline Definitions (NAFLD, NAFL, NASH) Risk Factors Outcomes in NAFLD Influence of DM on NAFLD; Influence of NAFLD on DM Barriers to Diagnosis and Treatment Initial evaluation of patient with suspected NAFLD Noninvasive Assessment of Steatosis, Steatohepatitis and Advanced Fibrosis in NAFLD Transaminases, US, Continuation Attenuation Parameter (CAP), MRS, MRI- PDFF Scoring systems/Biomarkers, Elastography
Liver biopsy Screening for NAFLD in Primary Care, Diabetes, Obesity Clinics and Family Members NAFLD Disease Burden 80-100 million Americans 2nd leading etiology for patients on transplant list, after HCV *Patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD. Wong RJ et al. Gastro 2015;148(3):54755. Definitions
NAFLD: Evidence of hepatic steatosis (HS), either by imaging/histology Lack of secondary causes of hepatic fat accumulation Threshold for significant alcohol consumption: >21 drinks/week in men and >14 drinks/wk in women Spectrum (NAFL/steatosis to NASH to cirrhosis) Nonalcoholic Fatty Liver (NAFL): 5% HS without evidence of hepatocellular injury (hepatocyte ballooning). Nonalcoholic Steatohepatitis (NASH): 5% HS and inflammation with hepatocyte injury (e.g. ballooning), with or without fibrosis Advanced Fibrosis: stage 3 or 4 fibrosis
Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Causes of Secondary Hepatic Steatosis Macrovesicular steatosis Excessive alcohol consumption Hepatitis C (genotype 3) Wilson Disease Lipodystrophy Starvation Parenteral nutrition Abetalipoproteinemia Medications (e.g., mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen, corticosteroids) Microvesicular steatosis
Reyes syndrome Medications (valproate, antiretroviral medicines) Acute fatty liver of pregnancy HELLP syndrome Inborn errors of metabolism (e.g., lecithin-cholesterol acyltransferase deficiency, cholesterol ester storage disease, Wolmans disease) Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Risk Factors Associated with NAFLD NAFLD Common Conditions With Established Association Emerging Conditions Associated
*The ATP III clinical definition of MetS requires 3 or more of the following features: (1) waist circumference >102 cm in men or >88 cm in women(2) TG level 150 mg/dL (3) HDL < 40 mg/dL in men, <50 mg/dL in women; (4) SBP 130 mm Hg or diastolic pressure 85 mm Hg and (5) fasting plasma glucose level 110 mg/dL or greater. Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Outcomes in NAFLD Younossi, Z. M. (2018), The epidemiology of nonalcoholic steatohepatitis. Clinical Liver Disease, 11: 92-94. Adams L et al. Gastroenterology 2005;129:113-121 Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357
Simple Steatosis (NAFL) vs. NASH Although simple steatosis has traditionally been associated with very low risk for progression compared to NASH, a meta-analysis of studies of paired liver biopsy studies showed that liver fibrosis progresses in patients with NAFL and NASH. Findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1-50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8-14.3 y) Another study showed progression of NAFL to NASH,
particularly those with type 2DM Singh S et al. Clin Gastroenterol Hepatol. 2015;13(4):643 McPherson S et al. J Hepatol. 2015;62(5):1148-55 M Siddiqui DDW NASH Symposium 2017 Outcomes in NAFLD Patients with NAFLD: increased overall mortality vs.
matched control population without NAFLD Most common cause of death: CVD, independent of other metabolic comorbidities Patients with histologic NASH, especially those with some degree of fibrosis: higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Fibrosis: most important histologic feature associated with long-term mortality and liver-related events NAFLD: 3rd most common cause of HCC Adams L et al. Gastroenterology 2005;129:113-121 Angulo P et al. Gastroenterology. 2015 Aug;149(2):389-97. Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357; see notes for references Influence of DM on NAFLD Outcomes
and Influence of NAFLD on DM Type2 DM: susceptible to more severe forms of NAFLD (NASH) and higher progression to HCC Coexistence of NAFLD and T2DM results in a worse metabolic profile and higher cardiovascular risk Worse atherogenic hypertriglyceridemia, low levels of HDL-C, smaller and denser LDL, independent of obesity and NASH severity Higher levels of insulinemia, and more difficult to control hyperglycemia Probably due to more severe insulin resistance at the level of the liver and impaired insulin clearance
Bril F, Cusi K. Diabetes Care 2017, 40 (3) 419-430 Hazlehurst JM et al Metabolism 2016;65:1096-1108 Koliaki C et al. Mol Cell Endocrinol 2013;379:3542 El-Serag HB et al. Gastroenterology 2004;126:460468 Wang C, et al Int J Cancer 2012;130:16391648 Lomonaco R, et al Diabetes Care 2016;39:632638 Cusi K. Gastroenterology 2012;142:711725 Bril F et al. J Clin Endocrinol Metab 2016;101:644652 Targher G et al Diabetes Care 2007;30:21192121 Barriers to Diagnosis and Treatment M Siddiqui DDW NASH Symposium 2017
Barriers to NAFLD Treatment M Siddiqui DDW NASH Symposium 2017 Barriers to NASH Diagnosis and Treatment Patients and clinicians are unaware of NASH as a potentially serious medical condition Diagnosis is missed due to a reliance on low-sensitivity diagnostic tests (transaminases or liver US) Confirmatory diagnosis (liver biopsy) rarely pursued by providers, even those at high risk of NASH Patients and physicians are uninformed that weight loss and medical treatments may reverse NASH
Bril F, Cusi K. Diabetes Care 2017, 40 (3) 419-430 Initial evaluation of suspected NAFLD Exclude other etiologies of chronic liver disease, including viral hepatitis, hemochromatosis, autoimmune liver disease, Wilson Disease, alpha-1 antitrypsin deficiency, drug-induced liver injury In patients with elevated high serum ferritin, iron saturation, especially in the context of homozygote/heterozygote C282Y HFE mutation, a liver biopsy should be considered Positive ANA/ASMA in ~20% of pts with NASH, but in patients with high titers of autoantibodies with other features of AIH (>5xULN aminotransferases, elevated IgG, high total protein to albumin ratio) work-up for AIH/liver biopsy
Evaluate for commonly associated comorbidities (central obesity, HTN, dyslipidemia, DM or insulin resistance, hypothyroidism, PCOS, Obstructive Sleep Apnea) Chalasani, N et al. NAFLD AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Detection of steatosis Liver biopsy Clinical standard for diagnosis of NASH; required by FDA for diagnosing NASH and therapeutic trials in NASH Limited by cost, sampling error and procedure-related morbidity and mortality Liver enzymes Insensitive, patients with NASH can have normal liver enzymes Epidemiological studies suggest using lower cutoff points to be considered
normal (ALT 30 IU/ml for males, 19 IU/ml for females) to improve sensitivity Poor marker of NAFLD, even with lower cut-off point Among patients with T2DM with normal aminotransferases NAFLD prevalence was up to 50% using MRS and 56% had histologic confirmation of NASH. When transaminases are elevated, usually ALT>AST, unless there is cirrhosis (AST>ALT). Portillo-Sanchez P et al. J Clin Endocrinol Metab 2015;100:22312238 Detection of hepatic steatosis Conventional ultrasound
Not sensitive, low negative predictive value Qualitative Meta-analysis: Sensitivity of 85% and specificity of 94% (but significantly lower sensitivity for mild steatosis) Limited use if mild steatosis (especially if <30% steatosis) Better than aminotransferases, but underperforms when compared to MR spectroscopy and liver biopsy CT scan Ionizing radiation, low accuracy Low sensitivity and specificity Hernaez R, Hepatology 2011;54:10821090 Bril F et al. Liver Int 2015;35:21392146 Bril F, Cusi K Dia Care 2017;40:419-430
Detection of steatosis Controlled attenuation parameter The Controlled Attenuation Parameter (CAP) specifically evaluates liver steatosis, using a process based on transient elastography (Fibroscan, which measures liver stiffness) de Ldinghen V et al. J Gastroenterol Hepatol. 2016 Apr;31(4):848-55. Detection of hepatic steatosis MRI-PDFF (proton density fat fraction) and MR Spectroscopy Gold standard for fat quantification Current noninvasive standard for screening for NAFLD in clinical
studies, but costly Some studies suggest that degree of steatosis may predict severity of histologic features (ballooning and steatohepatitis) and incidence and prevalence of diabetes in pts with NAFLD AASLD guidelines: utility of noninvasively quantifying hepatic steatosis in NAFLD in routine clinical care is Chalasani N et al. J Hepatol 2008;48:829-834. limited Targher G et al. Diabetes Metab 2016;42:142-156. Li X et al. PLoS One 2013;8:e65210. Shah RV et al. Atherosclerosis 2015;242: 211-217.
Chalasani, N et al. AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Noureddin M et al. HEPATOLOGY 2013;58:1930-1940 Prevalence of NAFLD (panel A) and advanced fibrosis (panel B) in the general population and in patients with T2DM according to different diagnostic tools. Fernando Bril, and Kenneth Cusi Dia Care 2017;40:419-430 2017 by American Diabetes Association Fibrosis Staging Once diagnosis of NAFLD is made- focus on evaluating risk for steatohepatitis and advanced fibrosis, which are more common in patients with T2DM
Fibrosis- most important prognostic factor associated with long-term mortality and liver-related events Angulo P et al. Gastroenterology. 2015 Aug;149(2):389-97. Noninvasive Prediction of Steatohepatitis (SH) Presence of MetS: strong predictor for the presence of SH in patients with NAFLD Increasing number of metabolic diseases, such as IR, T2DM, HTN, dyslipidemia and visceral obesity, seems to increase the risk of progressive liver disease Patients with NAFLD and multiple risk factors such as T2DM and HTN highest risk for adverse outcomes
Musso G et al, Ann Med 2011;43:617-649. Kang H et al Am J Gastroenterol 2006;101:2247-2253. Ryan MC et al. Diabetes Care 2005;28:1222-1224. Chalasani, N et al. AASLD Guidelines. Hepatology (2018); 67(1), 328-357. Noninvasive NAFLD fibrosis staging Marker AUROC AAR (AST/ALT) NPV 93%
NAFLD Fibrosis Score Age, BMI, PLT, Alb, AST/ ALT, DM/IFG 0.88 93% (0.85-0.92) NAFLD fibrosis score and FIB4: most validated score for fibrosis staging Mcpherson S et al. Gut 2010 Sep;59(9):1265-9 Harrison S et al. Gut 2008;57:14411447. Sterling R et al. Hepatology 2006; 43:1317-1325. Angulo P et al. Hepatology 2007; 45(4):846-54 Chalasani, N et al Hepatology (2018); 67(1), 328-357.
Imaging: Fibrosis staging/Stiffness Fibroscan (Vibration-controlled Transient elastography/VCTE) US: ARFI (Acoustic Radiation Force Impulse), Sheer Wave Elastography MRI elastography Vibration-controlled transient elastography (VCTE/Fibroscan) XL probe for BMI>30 Lower cut-off values Risk of overestimating liver stiffness if with CHF, extrahepatic cholestasis, ALT flare, recent food intake
Controlled attenuation parameter can assess hepatic steatosis Tapper et al: 95% sensitivity, 77% specificity, AUROC 0.93 27% yielded unreliable results, used M-probe NASH CRN, n=511, M or XL probe, failure rate: 2.6% ARFI Can be integrated to conventional ultrasound probe Similar diagnostic performance to VCTE Cut-off values vary significantly (1.48-2.96m/s) for predicting advanced fibrosis Ebinuma H et al. J Gastroenterology 2011;46(10):
1238-48. Friedrich-Rust et al. Eur J Radiol. 2012:81(3):e325-31. Yoshioka K et al. Hepatol Res. 2015:45(2):142-51. MR elastography *Excellent for identifying varying degrees of fibrosis; sensitivity 86%, specificity 91%; AUC for diagnosing advanced fibrosis 0.924 *MRE performed better than VCTE for identifying st 2 fibrosis or above, but they performed equally well in identifying stage 3 fibrosis or above (AUC 0.89 for MRE, 0.88 for TE) Loomba R et al. Hepatology 2014;60:1920-1928 Imajo K et al. Gastroenterology 2016;150:626-637.e7
Genetic polymorphisms,biomarkers Genome-wide association studies have associated several genetic polymorphisms, notably PNPLA-3 variants with steatohepatitis and advanced fibrosis in patients with NAFLD AASLD guidelines: testing for these genetic variants in routine clinical care are not recommended Other biomarkers (ELF, Fibrotest, NASH fibrosure) and lipidomics have been evaluated but Fibrotest associated with 32% in gray zone; ELF (matrix turnover proteins, AUC 0.9), approved in Europe but not available in US Rotman Y Koh C et al. Hepatology 2010;52:894903 Chalasani, N et al Hepatology (2018); 67(1), 328-
AASLD Guidelines: Noninvasive Fibrosis Staging NFS or FIB4 are clinically useful tools for identifying NAFLD pts with higher likelihood of stage 3 or 4 fibrosis VCTE or MRE are clinically useful tools for identifying advanced fibrosis in patients with NAFLD Chalasani, N et al Hepatology (2018); 67(1), 328357. When to Obtain a Liver Biopsy in patients with NAFLD Should be considered in patients with NAFLD who are at increased risk of having steatohepatitis and/or advanced
fibrosis The presence of MetS, NAFLD fibrosis score, FIB-4, or liver stiffness measured by VCTE or ME may be used for identifying patients who are risk for SH +/- adv fibrosis Liver biopsy should be considered in patients with supsected NAFLD in whom competing etiologies for hepatic steatosis and the presence and/or severity of coexisting chronic liver diseases cannot be excluded without a liver biopsy Chalasani, N et al Hepatology (2018); 67(1), 328-357. Screening for NAFLD in Primary Care, Diabetes,
and Obesity Clinics Patients with T2DM have higher prevalence of NAFLD, NASH and advanced fibrosis However, cost-effective analysis using Markov model: Screening for NASH in patients with diabetes is not cost-effective at present because of disutility associated with available treatment. Since liver biochemistries can be normal in pts with NAFLD, they may not be sufficiently sensitive as screening tests; although liver US or TE are more sensitive, their utility as screening tools is unproven Some experts advised vigilance for chronic liver disease in pts with type 2DM but not routine screening
AASLD: Routine screening not advised due to uncertainties surrounding diagnostic tests, treatment options, long-term benefits of screening/cost-effectiveness of screening There should be a high index of suspicion for NAFLD/NASH in T2DM NFS, FIB4, VCTE can be used to ID those at low/high risk for fibrosis Corey K et al. Dig Dis Sci 2016;61:2108-2117 Chalasani, N et al Hepatology (2018); 67(1), 328-357. Screening of family Members Data reporting heritability of NAFLD have been highly variable. AASLD: Systematic screening of family members for NAFLD is not recommended
Summary: Diagnosis and Staging of NAFLD Liver enzymes, conventional CT/US lack sensitivity/specificity NAFLD Fibrosis Score and FIB-4 most validated Noninvasive fibrosis staging: Fibroscan/VCTE, MR elastography Liver biopsy should be considered in patients with NAFLD who are at increased risk of having steatohepatitis and/or advanced fibrosis The presence of MetS, NAFLD fibrosis score, FIB-4, or liver stiffness measured by VCTE or ME may be used for identifying patients who are risk for SH +/- adv fibrosis Routine screening for NAFLD in DM/obesity clinics not
recommended, but increased vigilance for NAFLD/NASH in T2DM Thank you!
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