Fatty Liver Disease (NAFLD) - CMS200 PDF

Fatty Liver Disease CMS200 Dr. Janis Li, ND Learning Outcomes 1. Analyze the definition, epidemiology, classification, and diagnostic criteria of NAFLD and its subtypes, including non-alcoholic steatohepatitis (NASH). 2. Interpret the risk factors and principal causes of N...

Fatty Liver Disease CMS200 Dr. Janis Li, ND Learning Outcomes 1. Analyze the definition, epidemiology, classification, and diagnostic criteria of NAFLD and its subtypes, including non-alcoholic steatohepatitis (NASH). 2. Interpret the risk factors and principal causes of NAFLD, such as obesity, diabetes, hypertriglyceridemia, insulin resistance, and metabolic syndrome, considering that non-obese individuals may also develop NAFLD. 3. Evaluate the role of maternal obesity, early-pregnancy glucose concentrations, gut dysbiosis, altered bile acid metabolism, and genetic factors in NAFLD development, as well as the protective effect of physical activity. 4. Correlate NAFLD with increased risk for cardiovascular disease, chronic kidney disease, colorectal cancer, and liver complications, such as advanced hepatic fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. 5. Compare the differences in NAFLD frequency and severity between genders and ethnicities, and examine the association between NAFLD and insulin resistance. 6. Elucidate the clinical presentation, common symptoms, and laboratory abnormalities associated with NAFLD, including elevated aminotransferase levels, hepatomegaly, and steatosis on ultrasonography. Learning Outcomes 7. Appraise the role of imaging studies, liver biopsy, and noninvasive tests for fibrosis in diagnosing and evaluating NAFLD, as well as the importance of screening high-risk populations. 8. Determine when to refer a patient with NAFLD to a specialist and the importance of addressing and treating comorbid conditions. 9. Evaluate the alternative designation "metabolic-associated (or metabolic dysfunction-associated) fatty liver disease" (MAFLD) that has been proposed for NAFLD and the relationship between the two conditions. 10.Assess the need for patient education regarding lifestyle changes, alcohol abstinence, and early intervention to improve prognosis in patients with NAFLD. 11.Justify the importance of monitoring disease progression, screening for complications, and utilizing an interprofessional approach to managing patients with NAFLD, including potential liver transplantation in advanced cases. 12.Differentiate the grading and staging systems, differential diagnosis, and clinical scoring systems used in NAFLD evaluation and management, as well as appraise the role of genetics and environmental factors in NAFLD pathogenesis. Non-Alcoholic Fatty Liver Disease (NAFLD) NAFLD is an umbrella term that includes a spectrum of conditions characterized by: Evidence of hepatic steatosis on imaging or histology (macro-vesicular steatosis) Exclusion of secondary causes of hepatic steatosis (e.g., significant alcohol consumption, chronic use of medications that can cause hepatic steatosis, hereditary disorders) Non-Alcoholic Fatty Liver Disease (NAFLD) A great introductory video available at The Canadian Liver Foundation NAFLD: Terminology Review Steatosis: abnormal retention of fat (lipids) within an organ Hepatic steatosis: fat accumulation in the liver Hepatitis: inflammation of the liver Steatohepatitis: fat accumulation and inflammation of the liver Fibrosis: scarring Cirrhosis: permanent liver damage (scar tissue replaces liver cells) Progression of NAFLD Simple steatosis or Non-alcoholic NASH with Non-alcoholic steatohepatitis hepatocellular fatty liver (NAFL) (NASH) carcinoma NAFL = 5% or greater hepatic steatosis without hepatocellular injury or fibrosis NASH = 5% or greater hepatic steatosis plus hepatocellular injury and inflammation, with or without fibrosis Signimu, CC BY-SA 3.0, via Wikimedia Commons NAFLD: Epidemiology Most common cause of liver disease in Canada NAFLD prevalence: 20-30% in western countries Affects ~20% of Canadians and ~37% of adult Americans NASH prevalence 3-5% More common in obese/overweight adults but can affect nonobese individuals Average age at diagnosis is 50 years Rising childhood obesity → increasing prevalence in children 3-10% in children NAFLD: Epidemiology Hispanics > Caucasians > African Americans In Caucasians, men > women (but no sex difference in Hispanics and African-Americans) NAFLD: Risk Factors and Causes Principal causes: Obesity (40% of patients with NAFLD) Diabetes mellitus (>20% of patients with NAFLD) Dyslipidemia/hypertriglyceridemia (>20% of patients with NAFLD) In association with insulin resistance and metabolic syndrome What is Metabolic Syndrome? Meeting any 3 of the following criteria constitutes a diagnosis of metabolic syndrome: Blood pressure Systolic BP ≥ 130 mmHg or Diastolic BP ≥ 85 mmHg or Antihypertensive pharmacotherapy in a patient with a history of hypertension Fasting glucose level ≥ 100 mg/dL (5.6 mmol/L) or Pharmacotherapy for elevated glucose level High-density lipoprotein < 50 mg/dL (1.29 mmol/L) in women; < 40 mg/dL (1.04 mmol/L) in men or (HDL) cholesterol level Pharmacotherapy for reduced high-density lipoprotein cholesterol level Triglyceride level ≥ 150 mg/dL (1.7 mmol/L) or Pharmacotherapy for elevated triglyceride level Waist circumference ≥ 35 inches (89 cm) in women; ≥ 40 inches (102 cm) in men NAFLD aka MAFLD NAFLD is considered the liver manifestation of metabolic syndrome Strong association with metabolic syndrome has led to new terminology: Metabolic-associated (or metabolic dysfunction-associated) fatty liver disease (MAFLD) NAFLD: Risk Factors and Causes Maternal risk factors: Maternal obesity High maternal early-pregnancy glucose concentrations Maternal protective factors: Breastfeeding >6 months (avoidance of early supplemental milk formula) Reduces NAFLD risk in offspring and in mother NAFLD: Risk Factors and Causes Exposures: Drugs (corticosteroids, amiodarone, diltiazem, methotrexate, tamoxifen, irinotecan, oxaliplatin, antiretroviral therapy) Toxins (vinyl chloride, carbon tetrachloride, yellow phosphorus, inorganic arsenic exposure) NAFLD: Risk Factors and Causes Dietary and nutritional factors: Excessive dietary fructose consumption Malnutrition Starvation and refeeding syndrome Total parenteral nutrition NAFLD: Risk Factors and Causes Genetic factors (in up to 35% patients) Polymorphisms of the gene encoding apolipoprotein C3 Polymorphisms of the patatin-like phospholipase domain- containing 3 (PNPLA3) gene Polymorphism of TM6SF2 Polymorphism of HSD17B13 Variants of MBOAT1 and GCKR NAFLD: Risk Factors and Causes Associated conditions: Cushing syndrome Hypopituitarism Polycystic ovarian syndrome Hypothyroidism Hypobetalipoproteinemia (low apolipoprotein B and LDL cholesterol) Obstructive sleep apnea Gut dysbiosis Altered bile acid metabolism Cholecystectomy Psoriasis NAFLD: Protective Factors Physical activity protects against the development of NAFLD Why? Brainstorming exercise Given what you know about risk factors for the development of NAFLD, what are some important questions you might want to ask your patient as part of your history taking? NAFLD: Timing and Clinical Course Slowly progressive disease – silent liver disease when there is only steatosis Early stages (simple steatosis or NAFL) are reversible NAFL → 20% develop NASH → 20% progress to cirrhosis → possible liver failure and liver cancer Risk factors for advanced hepatic fibrosis and cirrhosis: Advanced age Obesity Diabetes mellitus Strongest predictor of progression of NAFLD is the degree of inflammation on the first liver biopsy The natural history of nonalcoholic fatty liver disease depends on histopathology. Nonalcoholic fatty liver (NAFL) progresses very slowly, if at all, when fat alone is present on liver biopsy. By contrast, the presence of nonalcoholic steatohepatitis (NASH) is associated with a more accelerated progression to fibrosis. (Reproduced with permission from Parekh S, Anania FA. Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease, Gastroenterology. 2007;132(6):2191–2207.) Citation: Chapter 45 Nonalcoholic Fatty Liver Disease, Friedman S, Blumberg RS, Saltzman JR. Greenberger's CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, 4e; 2022. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3204&sectionid=266865566 Copyright © 2023 McGraw-Hill Education. All rights reserved Progression of NAFLD Signimu, CC BY-SA 3.0, via Wikimedia Commons NAFLD: Timing and Clinical Course Complications: Cardiovascular disease Hepatocellular carcinoma (annual risk 1-2%) End-stage liver disease and liver failure (develops over 10 years in 45% of patients) NAFLD can coexist with other chronic liver conditions Cardiovascular risk factors contribute to mortality in those with end stage liver cirrhosis and hepatocellular carcinoma NAFLD: Timing and Clinical Course NAFLD also predicts risk of: Cardiovascular events Chronic kidney disease Colorectal cancers Type 2 diabetes mellitus Mantovani, Alessandro et al. “Complications, morbidity and mortality of nonalcoholic fatty liver disease.” Metabolism: clinical and experimental vol. 111S (2020): 154170. doi:10.1016/j.metabol.2020.154170 NAFLD: Signs and Symptoms Most are asymptomatic Possible presentations in early stages: Fatigue Malaise Mild abdominal discomfort: right upper quadrant NAFLD: Signs and Symptoms What physical exam technique(s) can determine this? Possible presentations in advanced stages: Nausea Hepatomegaly (in 75% of Vomiting patients) Jaundice Spider angiomas Pruritis Signs of portal hypertension – Memory impairment edema, ascites, caput medusae Easy bleeding Palmar erythema Loss of appetite Gynecomastia Dupuytren contracture Petechiae Detecting Hepatomegaly Diagnostic accuracy of physical exam findings: Sensitivity Specificity LR+ LR- Physical Exam Finding (%) (%) Midclavicular liver span ≥ 10 cm on 61-92 30-43 NS NS percussion Palpable liver edge 39-71 56-85 1.9 0.6 McGee Steven R. Evidence-Based Physical Diagnosis. 4th edition 4th ed. Elsevier 2018. Diagnosing Hepatocellular Disease in Patient with Jaundice Diagnostic accuracy of physical exam findings: Physical Exam Finding Sensitivity (%) Specificity (%) LR+ LR- Spider angiomas 35-47 88-97 4.7 0.6 Palmar erythema 49 95 9.8 0.5 Dilated abdominal veins 42 98 17.5 0.6 Ascites 44 90 4.4 0.6 Palpable spleen 29-47 83-90 2.9 0.7 Palpable gallbladder 0 69 0.04 1.4 Palpable liver 71-83 15-17 NS NS Liver tenderness 37-38 70-78 NS NS McGee Steven R. Evidence-Based Physical Diagnosis. 4th edition 4th ed. Elsevier 2018. Diagnosing Cirrhosis in Patients with Chronic Liver Disease Diagnostic accuracy of physical exam findings: Physical Exam Finding Sensitivity (%) Specificity (%) LR+ LR- Spider angiomas 33-84 48-98 4.2 0.5 Palmar erythema 12-70 49-98 3.7 0.6 Gynecomastia 18-58 92-97 7.0 NS Reduction of body or pubic hair 24-51 94-97 8.8 NS Jaundice 16-44 83-99 3.8 0.8 Dilated abdominal wall veins 9-51 79-100 9.5 NS McGee Steven R. Evidence-Based Physical Diagnosis. 4th edition 4th ed. Elsevier 2018. Diagnosing Cirrhosis in Patients with Chronic Liver Disease Diagnostic accuracy of physical exam findings: Physical Exam Finding Sensitivity (%) Specificity (%) LR+ LR- Hepatomegaly 31-96 20-96 2.3 0.6 Palpable liver in epigastrium 50-86 68-88 2.7 0.3 Liver edge firm to palpation 71-78 71-90 3.3 0.4 Splenomegaly 5-85 35-100 2.5 0.8 Ascites 14-52 82-99 6.6 0.8 Peripheral edema 24-56 87-92 3.0 0.7 Encephalopathy (disordered consciousness and 9-29 98-99 8.8 NS asterixis) McGee Steven R. Evidence-Based Physical Diagnosis. 4th edition 4th ed. Elsevier 2018. Vascular spider telangiectasia. (Reproduced, with permission, from Sherlock S, Summerfield JA. Color Atlas of Liver Disease. Mosby, 1991.) Citation: 16-01 Jaundice & Evaluation of Abnormal Liver Biochemical Tests, Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current Medical Diagnosis & Treatment 2023; 2023. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3212&sectionid=269152700 Copyright © 2023 McGraw-Hill Education. All rights reserved Palmar erythema in chronic liver disease. Palmar erythema refers to reddening of the palms, specifically of the thenar and hypothenar eminences (arrows) and of the fingertips. This is a consequence of elevated circulating estrogen levels in chronic liver disease. (Used, with permission, from Neil Mehta, MD.) Citation: 16-11 Cirrhosis, Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current Medical Diagnosis & Treatment 2023; 2023. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3212&sectionid=269153543 Copyright © 2023 McGraw-Hill Education. All rights reserved Caput medusae in cirrhosis. A consequence of portal hypertension, distended and engorged superficial paraumbilical veins (arrows) that radiate from the umbilicus across the abdomen to join systemic veins, are referred to as a caput medusa (Latin for "head of Medusa"). (Used, with permission, from Neil Mehta, MD.) Citation: 16-11 Cirrhosis, Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current Medical Diagnosis & Treatment 2023; 2023. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3212&sectionid=269153543 Copyright © 2023 McGraw-Hill Education. All rights reserved Ascites, gynecomastia. (Reproduced, with permission, from Sherlock S, Summerfield JA. Color Atlas of Liver Disease. Mosby, 1991.) Citation: 16-01 Jaundice & Evaluation of Abnormal Liver Biochemical Tests, Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current Medical Diagnosis & Treatment 2023; 2023. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3212&sectionid=269152700 Copyright © 2023 McGraw-Hill Education. All rights reserved NAFLD: Differential Diagnosis Viral hepatitis (hepatitis B, hepatitis C) Alcoholic hepatitis Autoimmune hepatitis Hereditary hemochromatosis Alpha-1 antitrypsin deficiency Primary sclerosing cholangitis Wilson disease Primary biliary cholangitis Cirrhosis NAFLD: Further Testing Labs to evaluate liver function: Liver enzymes Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) May be mildly elevated; normal in up to 80% patients AST/ALT ratio < 0.8 (ALT/AST ratio > 1) in early NAFLD (in contrast to alcohol associated liver disease where AST/ALT ratio > 1.5); but AST may be > ALT (i.e., AST/ALT ratio increases) as advanced fibrosis and cirrhosis develop Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) may also be elevated NAFLD: Further Testing Labs to examine for metabolic risk factors: Lipid levels: cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein Fasting glucose or HbA1C levels Fasting glucose and fasting insulin levels can be used to calculate measures of insulin resistance: Homeostasis Model Assessment (HOMA) Normal value < 3.99 Online calculator available at https://sasl.unibas.ch/11calculators-HOMA.php Quantitative Insulin Sensitivity Check Index (QUICKI) Normal value > 0.35 Online calculator available at https://sasl.unibas.ch/11calculators-QUICKI.php NAFLD: Further Testing Consider labs to exclude other causes of liver disease: Condition Clinical Features Laboratory Evaluation Alpha1-antitrypsin Hepatomegaly and elevated liver enzyme Alpha1-antitrypsin level, phenotyping, liver deficiency levels biopsy Autoimmune More common in women and individuals Antinuclear antibody, smooth muscle hepatitis with a history of thyroid disease antibody, liver/kidney microsomal antibody testing Hereditary Bronze diabetes (darkening of skin and Complete blood count, ferritin level, hemochromatosis hyperglycemia), arthritis, congestive heart transferrin saturations, genetic testing (HFE failure, impotence, family history gene), liver biopsy with staining for iron, MRI Wilson disease Neurologic and psychological presentation 24-hour urinary copper measurement, with liver disease at young age (< 40 years), ceruloplasmin level, liver biopsy, genetic family history testing Viral hepatitis One of the main causes of chronic liver Hepatitis B surface antigen (HBsAg), hepatitis (hepatitis B or C) disease along with NAFLD and alcohol C virus antibody (anti-HCV) NAFLD: Further Testing Imaging tests: Ultrasonography: increased hepatic echogenicity Imaging test of choice Least invasive; relatively inexpensive; no exposure to radiation Computed tomography (CT) – unenhanced or contrast- enhanced Magnetic resonance imaging (MRI) NAFLD: Further Testing Diagnostic accuracy of imaging tests for the evaluation of NAFLD: Imaging Test Sensitivity (%) Specificity (%) PPV (%) NPV (%) LR+ LR- Ultrasonography 60-100 77-95 52-89 82-100 1.1-8.6 ∞-0.2 Unenhanced CT 88-95 90-99 79-98 95-98 2.7-40.7 0.02-0.05 Contrast-enhanced CT 84-87 75-86 59-72 92-94 1.4-2.7 0.06-0.09 MRI 96 93 85 98 5.9 0.02 Wilkins, Thad et al. “Nonalcoholic fatty liver disease: diagnosis and management.” American family physician vol. 88,1 (2013): 35-42. https://www.aafp.org/pubs/afp/issues/2013/0701/p35.html#afp2 0130701p35-t4 NAFLD: Further Testing Comparing the diagnostic accuracy of imaging tests and liver biopsy for the evaluation of NAFLD: Test Sensitivity (%) Specificity (%) LR+ LR- Ultrasonography 82-100 95 18.2 0.09 CT Similar to ultrasonography MRI 95 95 19 0.05 Liver biopsy (single biopsy for diagnosis for NASH) 73 92 8.6 0.3 Liver biopsy (for advanced fibrosis) 7.7 0.16 Alexander J. Nonalcoholic fatty liver disease (NAFLD). In: Stern SC, Cifu AS, Altkorn D. eds. Symptom to Diagnosis: An Evidence-Based Guide, 4e. McGraw Hill; 2020. Accessed July 2023. https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/content.aspx?bookid=2715&sectionid=249061344 NAFLD: Further Testing How do clinicians decide which patients require further testing with imaging? NAFLD: Further Testing Clinical risk scoring systems Noninvasive scoring systems to predict risk of NAFLD Can be used to screen high-risk groups (such as those with metabolic syndrome or T2DM) for NAFLD Fatty liver index (FLI) Lipid accumulation product (LAP) index Hepatic steatosis index (HSI) Nonalcoholic fatty liver disease in metabolic syndrome patients scoring system (NAFLD-MS) NAFLD: Further Testing Fatty Liver Index (FLI) Noninvasive scoring system to diagnose fatty liver (e.g., NAFLD, NASH, or alcoholic fatty liver) Online calculator available via MDCalc Calculation based on BMI, waist circumference, GGT and triglyceride levels: Fatty Liver Index (FLI) = ey / (1 + ey) × 100 Where y = 0.953 × ln (triglycerides, mg/dL) + 0.139 × BMI, kg/m2 + 0.718 × ln (GGT, U/L) + 0.053 × waist circumference, cm – 15.745 NAFLD: Further Testing Fatty Liver Index (FLI) Interpretation: Fatty Liver Index Risk Diagnosis < 30 Low Fatty liver ruled out (LR = 0.2) 30 to < 60 Indeterminate Fatty liver neither ruled in nor ruled Consider out ultrasound for confirmation/ ≥ 60 High Fatty liver ruled in clarification (LR = 4.3) NAFLD: Further Testing NAFLD in Metabolic Syndrome Score (NAFLD-MS Score) Clinical scoring system to predict development of NAFLD in patients with metabolic syndrome Clinical Predictors Points Scoring LR+ for NAFLD BMI ≥ 25 kg/m2 1.5 < 3 points = low 2.32 AST/ALT ratio ≥ 1 1 risk of NAFLD ALT ≥ 40 U/L 2 ≥ 5 points = high 7.77 Type 2 diabetes mellitus 1 risk of NAFLD Central obesity (waist-to- 1 Saokaew, Surasak et al. “Clinical risk scoring for predicting non-alcoholic fatty hip ratio ≥ 0.9 in male and liver disease in metabolic syndrome patients (NAFLD-MS score).” Liver international : official journal of the International Association for the Study of ≥ 0.8 in female) the Liver vol. 37,10 (2017): 1535-1543. doi:10.1111/liv.13413 NAFLD: Further Testing Liver Biopsy: Small sample of liver tissue removed with a biopsy needle and examined under a microscope Liver biopsy and histology is the gold standard for diagnosis NASH diagnosis can only be established with liver biopsy Biopsy Type Findings Type 1 Fatty liver alone; macrovesicular steatosis Type 2 Fatty accumulation and lobar inflammation Type 3 Fat accumulation and ballooning degeneration Diagnosis Type 4 Fat accumulation, ballooning degeneration and either Mallory of NASH hyaline or fibrosis Nonalcoholic steatohepatitis (NASH). Liver biopsy histology demonstrates diffuse steatosis as well as ballooning degeneration of hepatocytes (circles). (Used, with permission, from James P. Grenert, MD.) Citation: 16-10 Nonalcoholic Fatty Liver Disease, Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current Medical Diagnosis & Treatment 2023; 2023. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3212&sectionid=269153482 Copyright © 2023 McGraw-Hill Education. All rights reserved  NAFLD: Further Testing Grading and staging of NAFLD histological lesions: Grade Findings Stages Findings Grade 1 Steatosis up to 66%, occasional ballooning in zone 3, Stage 0 No fibrosis (mild) scattered polymorphs with or without lymphocytes, mild Stage 1 Zone 3 perisinusoidal fibrosis only or no portal inflammation Stage 2 Zone 3 perisinusoidal and Grade 2 Any degree of steatosis, obvious ballooning periportal fibrosis (moderate) predominantly in zone 3, intralobular inflammation with polymorphs and chronic inflammation, and mild to Stage 3 Bridging fibrosis moderate portal inflammation Stage 4 Cirrhosis Grade 3 Panacinar steatosis, ballooning and obvious disarray (severe) predominantly in zone 3, intralobular inflammation with scattered polymorphs with or without mild chronic and mild to moderate portal inflammation NAFLD: Further Testing NAFLD Activity Score (NAS): Used in NAFLD patients who have had a liver biopsy Score based on histology results: Steatosis grade Lobular inflammation Liver cell injury (ballooning) Score correlates with steatohepatitis diagnosis but should not be used to definitively diagnosis NASH Online calculator available via MDCalc NAFLD: Further Testing But not all NAFLD patients need a liver biopsy! Noninvasive tools can identify patients who have a higher likelihood of developing fibrosis Liver biopsy should be offered to patients who are at high risk for having NASH and advanced fibrosis based on noninvasive testing Liver biopsy should be ordered if noninvasive tests produce an indeterminate result NAFLD patients with low risk of fibrosis based on noninvasive testing do not require a liver biopsy NAFLD: Further Testing Noninvasive tests for liver fibrosis Noninvasive tests/scoring systems to predict risk of fibrosis May reduce the need for liver biopsy in patients with NAFLD AST/ALT ratio (AAR) FibroTest (FibroSure) AST/platelet count ratio index (APRI) Fibrometer BARD score Magnetic resonance elastography Enhanced liver fibrosis (ELF) panel Nonalcoholic fatty liver disease fibrosis score (NFS) Fibrosis-4 (FIB-4) index Ultrasound elastography (different techniques including transient elastography and shear wave elastography)  Diagnostic accuracy of noninvasive tests for liver fibrosis: Test Cutoff Sensitivity (%) Specificity (%) PPV NPV LR+ LR- (%) (%) AST/ALT ratio 0.8 74 78 59 88 1.4 0.1 AST/platelet count ratio 1 27 89 51 49 1.1 0.4 BARD score 2 89 44 41 90 0.7 0.1 Enhanced liver fibrosis panel 10.5 100 98 96 100 21 0-∞ FIB-4 1.3 85 65 51 91 1.0 0.1 FibroTest (FibroSure) 0.7 15 98 76 73 3.2 0.3 Fibrometer 0.8 79 96 89 91 8.5 0.09 Magnetic resonance elastography 2.74 kPa 94 73 60 97 1.5 0.04 NAFLD fibrosis score (NFS) -1.5 78 58 44 86 0.8 0.2 Wilkins, Thad et al. “Nonalcoholic fatty liver disease: diagnosis and management.” American family physician vol. 88,1 (2013): 35-42. https://www.aafp.org/pubs/afp/issues/2013/0701/p35.html#afp20130701p35-t5 NAFLD: Further Testing NAFLD Fibrosis Score (NFS): Used in NAFLD patients to estimate the amount of scarring in the liver Score based on: Age BMI Impaired fasting glucose or diabetes AST ALT Platelet count Albumin Online calculator available via MDCalc A high score (> 0.676) increases likelihood of advanced fibrosis (LR+ 16.5) NAFLD: Further Testing Fibrosis-4 (FIB-4) Index: Used in patients with liver disease to estimate the amount of liver fibrosis and need for a liver biopsy Score based on: Age AST ALT Platelet count Online calculator available via MDCalc A high score (> 3.25) is likely to have advanced fibrosis (may need liver biopsy); a low score (< 1.45) is unlikely to have advanced fibrosis NAFLD: Further Testing Ultrasound Elastography: Measures liver stiffness and stage of liver fibrosis by measuring the propagation velocity of ultrasound waves that pass through the liver Several types including transient elastography (FibroScan), point shear wave elastography, and two-dimensional shear wave elastography Cut-off values for the different stages of liver fibrosis are determined by the various ultrasound elastography techniques and equipment manufacturers Johari, Muhammad Izzad et al. “A Randomised Controlled Trial on the Effectiveness and Adherence of Modified Alternate-day Calorie Restriction in Improving Activity of Non-Alcoholic Fatty Liver Disease.” Scientific reports vol. 9,1 11232. 2 Aug. 2019, doi:10.1038/s41598-019-47763-8 NAFLD: Management and Patient Education Interprofessional approach to encourage lifestyle changes and manage comorbid conditions Encourage: Weight loss Dietary fructose restriction Increased dietary fiber Moderate exercise (to reduce abdominal obesity) Alcohol abstinence Discontinuation of hepatotoxic drugs Optimal treatment of diabetes and hyperlipidemia NAFLD: Management and Patient Education NASH patients need to be followed by specialists (hepatologists or gastroenterologists) Liver transplantation may be required in NASH patients with advanced cirrhosis NAFLD is the second most common reason for liver transplant in North America NASH with cirrhosis requires surveillance for hepatocellular carcinoma with a liver ultrasound every six months Brainstorming exercise When does a naturopathic doctor need to refer a patient with NAFLD? Suggested approach to NAFLD Clinical suspicion of Assess for likelihood of NAFLD NAFLD Obtain history, including an assessment for alcohol intake, medication review, and family history of any liver conditions Incidental finding of Perform physical exam including calculating BMI and measuring waist hepatic steatosis on circumference imaging Order lab tests: Liver function testing (i.e., liver enzyme levels such as ALT, AST) Fasting glucose or HbA1C Elevated liver Lipid profile enzymes Ferritin and iron/TIBC Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) testing If LFTs are chronically elevated or family history is positive for cirrhosis, consider other testing: antinuclear antibody and smooth muscle antibody testing; alpha1-antitrypsin and ceruloplasmin level; thyroid stimulating hormone level Continued on next slide  Continue to perform relevant Assess for likelihood of NAFLD NAFLD unlikely investigations to determine alternative cause for patient’s signs/symptoms and/or hepatic steatosis and/or elevated liver Obtain liver ultrasonography enzymes NAFLD highly likely (if not already performed) If AST/ALT If AST/ALT ratio