NAFLD DIAGNOSIS AND MANAGEMENT: MOVING FROM THE DARK AGES TO THE RENAISSANCE

Transcription

1 NAFLD DIAGNOSIS AND MANAGEMENT: MOVING FROM THE DARK AGES TO THE RENAISSANCE Dr. Thomas Jensen M.D., Assistant Professor Medicine Dr. Amanda Wieland M.D., Assistant Professor of Medicine OBJECTIVES Recognize the Inadequacy of traditional work up for NAFLD Discuss the Rationale for Screening for NAFLD Review a practical approach to workup of NAFLD Examine data on current and potential new treatments for NAFLD DISCLOSURES Dr. Jensen has has no relevant financial disclosures for this talk Dr. Wieland has no relevant financial disclosures for this talk

2 THE TRIUMPH OF DEATH PIETER BRUEGEL THE ELDER PREVELANCE NAFLD: 10-35% NASH: 2-5% with some studies as high as 12.2% NASH Cirrhosis: Possibly 4 million Americans affected Cirrhosis and Significant Fibrosis increased 2.5 and 2 Fold in last Decade Soon will replace Hepatitis C for number one indication for Liver Transplant NAFLD SPECTRUM Rinella ME. JAMA, 2015.

3 NAFLD SPECTRUM Rinella ME. JAMA, NASH ACTIVITY GRADE = NAFLD Activity Score (NAS) of 0 to 10 NAFLD STAGE

4 QUESTION 1 True or False: Liver enzymes are the most sensitive way for detecting presence and severity of NAFLD. True False TRADITIONAL WORK-UP 45 YO Female with MetS Hx of PreDM recently diagnosed, Asthma, OSA Lab work: ALT: 66 U/L (7-52 U/L) AST: 32 U/L (12-39 U/L) Total Bilirubin 0.8 mg/dl ( mg/dl) Platelet Count: 251x10e 3 /ul 66 YO Male with T2DM Hx of DM since age 32, Rheumatoid Arthritis, CAD, OSA Lab Work: ALT: 31 U/L (7-52 U/L) AST: 36 U/L (12-39 U/L) Total Bilirubin 0.4 mg/dl ( mg/dL) Platelet Count 209x10e 3 /ul ACP CARTOON: RALPH S REACTION TO THE SUGGESTION HE WILL NEED A LIVER BIOPSY

5 LIVER ENZYMES Browning, et al. Hepatology, 2004 Mofrad, et al. Hepatology, 2003 QUESTION 1 True or False: Liver enzymes are the most sensitive way for detecting presence and severity of NAFLD. True False A RENAISSANCE IN THE APPROACH TO NAFLD Vitruvian Man, Da Vinci

6 American Association Study of Liver Disease (AASLD) July 2017 Statement: SCREENING EASL-EASD-EASO 2016 Statement: NATURAL HISTORY/PROGRESSION Bertot LC, et al., Int J Mol Sci, QUESTION 2 47 yo surgical menopausal (age 43) female with history of overweight (BMI 27) with 8kg weight gain in the last year, hx of DCIS sp lumpectomy and radiation. She is on venlafaxine for hot flashes with limited benefit and takes tamoxifen. She is incidentally found to have steatosis on limited US for RUQ pain. Her ALT is 27 and AST 15, Albumin 4.1, normal bilirubin 0.8, A1c is 5.3, fasting glucose is 89. Your next step: A. Tell her to exercise more in order to lose weight B. Change venlafaxine to estrogen patch since her early menopause is to blame for weight gain C. Get a complete ultrasound and calculate risk of fibrosis D. Perform liver biopsy

7 High Risk Patients: Obese Patient with other feature of MetS or MetS Screen for Steatosis Absent*: Repeat testing in 3-5 years Present: Review or obtain Liver Enzymes Assess for Secondary Causes *Risk Factors: DM Weight Gain Fam Hx/Genetics OSA Menopause Elevated liver Enzymes? NO YES Hepatitis C Celiac Hypothyroidism Screen ETOH Labs for Normal Hepatitis B Alpha 1 AT Hemochromatosis Wilson s (<45) Autoimmune Drugs Assess Risk for Fibrosis Low Risk Assess Risk for Fibrosis Re-Assess Risk of Fibrosis Yearly Medium or High Risk: Imaging F0/F1 Disease F2 Disease F3 or F4 Disease Monitor q 2-3 Years, consider Bx Monitor q 1-2 Years, if HSM do Bx F3: Consider Bx to Confirm or if HSM F4: Bx unless HSM Monitor q 1 year

8 LIVER BIOPSY VS FIBROSCAN FIBROSCAN Controlled Attenuation Parameter (CAP) Elastography Karlas et al, 2016 QUESTION 2 47 yo surgical menopausal (age 43) female with history of overweight (BMI 27) with 8kg weight gain in the last year, hx of DCIS sp lumpectomy and radiation. She is on venlafaxine for hot flashes with limited benefit and takes tamoxifen. She is incidentally found to have steatosis on limited US for RUQ. Her ALT is 27 and AST 15, Albumin 4.1, normal bilirubin 0.8, A1c is 5.3, fasting glucose is 89. Your next step: A. Tell her to exercise more in order to lose weight B. Change venlafaxine to estrogen patch since her early menopause is to blame for weight gain C. Get a complete ultrasound and calculate risk of fibrosis D. Perform liver biopsy

9 CASE 1: 40 YO FEMALE Background History PMH: PCOS on metformin, Pre-DM, Obesity Meds: Metformin 1000mg BID, Lexapro 20mg Soc Hx: Tob 8 years quit 2005, Rare etoh use PE, Labs and Imaging PE: BMI 35, silver stretch marks stomach, no AN, few coarse hairs on face Labs: ALT 21, AST 12, Alb 4.2, Alk phos 50, A1c 5.8, TC 135, Trigs 111, HDL 37, LDL 75, TSH 0.79, ferritin 25, Vit D 33, Celiac negative, CBC wnl PC 216 US: Increased liver echogenicity NAFLD FS: High Risk (-1.455, 0676) FIB-4: Low Risk (1.45, 3.25) CASE 2: 54 YO FEMALE Background History PMH: T2DM (12 years), HTN, Obesity Medications; Degludec 114 units, sitagliptin 50mg+metformin 1000mg BID, Losartan 100mg, HCTZ 25mg Soc: No tob, rare etoh use PE, Labs and Imaging PE: BMI 30, enlarged liver, diminished vibrational sense, telangiectasias chest, diminished fat on arms and legs Labs: ALT 42, AST 41, Albumin 3.8, Platelet Count 64 NAFLD FS: (-1.455, 0.676) FIB-4: (1.45, 3.25) CT Scan: Showed Hepatosplenomegaly Liver Biopsy: Stage 4 Fibrosis confirmed CASE 3: 58 YO MALE Background History PE, Labs and Imaging PMH: T2DM since age 36, Nephropathy, OSA, HTN, HLD Medications: U units AM and PM, canagliflozin 100mg, metformin 1000mg BID, simvastatin 40mg, lisinopril 20mg PE: BMI 42, Hepatomegaly, Diminished vibrational sense and Achilles DTR Labs: ALT 32, AST 20, Platelet Count, A1c 8.0, Platelet Count: Not Done Ultrasound: Hepatomegaly with steatosis

10 QUESTION 3 57 yo female with hx T2DM on metformin 1000mg BID and Glipizide 10mg BID (7 years, A1c risen to 8.2 from 6.9), obesity (BMI 33), HTN (on Lisinopril 20mg), HLD (On Atorva 20mg), and Osteopenia (Vitamin D and Calcium) found to have ALT 68, AST 40. US revealed hepatomegaly with steatosis. Secondary workup was negative. Biopsy revealed NASH with Stage 1 fibrosis. Besides lifestyle modifications you would suggest: Increase Glipizide to 20mg BID and stop statin Start Pioglitazone 45mg and stop statin Start Vitamin E 800 IU and continue statin Start Liraglutide, titrate to 1.8mg and continue statin POTENTIAL THERAPEUTIC TARGETS Sumida Y, et al. J Gastroenterol, 2017 INSULIN SENSITIZERS Medication Trial Outcomes Overall Recommendation Metformin Metanalysis 9 RCT with 417 No histological improvement in steatosis, inflammation, Not for treatment of NAFLD, but participants 4-12 months hepatocellular ballooning or fibrosis compared to placebo still primary for T2DM and may (Li Y, Biomed Rep, 2013.) have benefits in cirrhosis and HCC. Pioglitazone PIVENS Trial. 80 Nondiabetic Primary End: Improvement in NAS Score, but not Improvement in NASH in both patients with bx proven hepatocellular ballooning Diabetics and Nondiabetics, NASH on Pio 30mg for 96 Secondary Endpoint: NASH resolution 47% vs though caution in CHF and weeks. (Sanyal A, NEJM, 21%(p=0.001) and Fibrosis improvement 44% vs 31% osteoporosis 2010.) (P=0.12) GLP-1 (Liraglutide) Phase 2 RCT 26 Outcome: 39% resolution of NASH vs 9% Placebo and 9% overweight/obese NASH on progression fibrosis vs 36% in placebo. Liraglutide vs 26 on Placebo Outcomes associated with weight loss. 48 weeks. (Armstrong, Lancet, 2016) SGLT Inhibitors E_Lift Study: Empagliflozin Primary Outcome: Reduction of liver steatosis 10mg vs Placebo 20 weeks 16.2% to 11.6% vs 16.4% to 15.6% Placebo. in T2DM (Endo Society 100 th Annual Meeting) Consider in the management of NASH in T2DM Limited data to recommend use specifically for NASH

11 ANTIOXIDANTS AND OTHER MEDS Medication Trial Outcomes Overall Recommendation Vitamin E PIVENS Trial. 84 Primary Outcome: Improvement in Hepatocellular Can consider in nondiabetics Nondiabetic patients with bx Ballooning and NAS Score proven NASH on Vit E Secondary Outcome: Resolution of NASH in 36% Limitations with 800IU, risk 800IU for 96 weeks. vs 21% placebo (p=0.05), NS improvement in for all cause mortality, (Sanyal A, NEJM, 2010.) fibrosis 41% vs 31% in placebo (p=0.24) stroke, prostate cancer, consider 400IU Statins Atorvastatin: 10 mg a day Atorvastatin Outcomes: Improvement in steatosis Very limited data for 24 months in 17 follow up (Grade 1.6 to 0.8) and NAS (4.1 to 2.9), but 4/17 biopsies. (Hyogo et al. had fibrosis progression Strongly recommend for Metabolism 2008.) treatment of hyperlipidemia Simvastatin Outcome: No significant improvements in NAFLD to prevent CVD (If Simvastatin: 40mg for 12 in steatosis, NAS score or fibrosis liver enzymes <3x ULN) months (10) vs placebo (6) (Nelson A, et al. J Clin Gastroenterol, 2009). FUTURE DIRECTIONS Medication Trial Outcomes Future Research Obetacholic Acid (FXR FLINT Trial: Phase 2 FXR Outcomes: 35% improvement in fibrosis compared Phase 3 Regenerate Trial Agonist) Agonist 141 to OCA vs 142 to 19% Placebo, Steatosis 61% vs 38%, NS placebo 72 weeks in NASH resolution of NASH 22% vs 13% Possibility of FDA approval patients Elfibranor (PPAR α/δ Golden 505 Trial: Patients agonist) with bx proven NASH 93 80mg Elfibranor, mg Serlonsertib (ASK1 inhibitors) Elfibranor and 92 to placebo for 52 weeks (Ratzui V, et al., Gastroenterology, 2016) Phase 2: 72 patients randomized to Serlonsertib 18mg or 6mg w/wo Simtuzumab 125mg (LOXL2 inhibitor) or Simtuzumab alone for 24 weeks (Loomba R, et al. Hepatology 2017.) SE: Itching and increase in LDL Outcomes: Resolution of NASH (resolution of ballooning with no or mild inflammation) 19% in 120mg group vs 12% Placebo Modest improvements in Glucose, Lipids, inflammatory markers Outcomes: 43% and 30% reduction in Fibrosis compared to 20% simtuzumab alone, 20% progressed to cirrhosis compared to 3% and 7% in Serlonsertib groups. Reductions in steatosis by 2020/2021 Phase 3 Trial RESOLVE IT Phase 3 Stellar 3 WEIGHT LOSS IN THE TREATMENT OF NAFLD/NASH Weight loss is the primary and most effective treatment to date in reversing the disease: Improvements in steatosis, ballooning, inflammation and fibrosis correlate with percent weight loss (Vilar-Gomez, et al., 2015): Romero-Gomez M, et al., 2017

12 BARIATRIC SURGERY OUTCOMES BEFORE AND AFTER August yo female T2DM (Lantus 40 unit BID, metformin-a1c 8.8), HTN (Lisnopril-HCTZ, metoprolol), HLD (Atorva 20mg, Fish Oil), Morbid Obesity (BMI 40.44/243lbs) US: Hepatic Steatosis NFS: FIB-4: March month Post-Op Sleeve gastrectomy BMI 36.99/220 lbs On Lantus 15 units only BS avg 135, metoprolol for hx of SVT NFS: FIB4: TREATMENT OVERVIEW Sumida Y, et al. J Gastroenterol, 2017

13 QUESTION 3 57 yo female with hx T2DM on metformin 1000mg BID and Glipizide 10mg BID (7 years, A1c risen to 8.2 from 6.9), obesity (BMI 33), HTN (on Lisinopril 20mg), HLD (On Atorva 20mg), and Osteopenia (Vitamin D and Calcium) found to have ALT 68, AST 40. US revealed hepatomegaly with steatosis. Secondary workup was negative. Biopsy revealed NASH with Stage 1 fibrosis. Besides lifestyle modifications you would suggest: Increase Glipizide to 20mg BID and stop statin Start Pioglitazone 45mg and stop statin Start Vitamin E 800 IU and continue statin Start Liraglutide, titrate to 1.8mg and continue statin CONCLUSION Health Care Providers must recognize the advancing epidemic of NAFLD New tools developed in the last 5-10 years help to make screening and staging of disease more practical Diagnosis can help promote appropriate discussions on potential treatments especially lifestyle modifications New emerging therapies provide additional hope to prevent progression to End Stage Liver Disease Test Reference Components Result Fatty Liver Index Bedgoni G, etal.,2006. Waist Circumference, GGT, AUROC 0.84; 2 cut offs <30 rule out, >60 rule Triglycerides, BMI in Se 87%, Sp 86% SENSITIVITY OF VARIOUS NONINVASIVE haptoglobin, apolipoprotein and Sp 70% A1, total bilirubin, GGT, SCREENING TOOLS: NAFLD Steatotest Poynard T, et al., Alpha-2 macroglobulin, fasting glucose, triglycerides, cholesterol, ALT, age, AUROC 0.7; 2 cut offs 0.3 and 0.72 Se 90% gender, BMI NAFLD Liver Fat Score Kotronen A, et al., 2009 Presence of Metabolic AUROC 0.87; 2 cut offs and Se Syndrome, Presence of Type 95% Sp 95% 2 diabetes, ALT, AST Ultrasound Saadeh S, et al., Lee SS, et al., Van Werven JR, et al., De Moura Almeida A, et al., Steatosis >30% Se % and Sp 98%, Any Steatosis Sen % and Sp % CT Scan Park SH, et al., Non-contrast Liver HU/Spleen At 0.8 Sensitivity 82% with Specificity 100% HU MRI Lee SS, et al., Any steatosis Sen %, Sp % Van Werven JR, et al., MR Spectroscopy Lee SS, et al., Van Werven JR, et al., Any steatosis Sen % and Sp %

14 Test Reference Components Result Cytokeratin 18 Buzzetti E, et al.,2015. Levels varied in studies AUROC for NASH vs NAFLD SENSITIVITY OF VARIOUS NONINVASIVE SCREENING TOOLS: NAFLD VS 93% for F2 NASH/FIBROSIS Ferritin Kowdley KV, et al., ULN NASH F2 AUROC 0.57 APRI Score Tapper EB, et al., 2014 AST:Platelet Ratio*100 Score >1 had Se 30% and Sp NAFLD Fibrosis Score Angulo P, et al., Age, presence of DM/IR, BMI, AST, ALT, platelets, albumin < for No significant fibrosis Se 82% and Sp 77% NPV 93%, >0.676 for Significant fibrosis Se 51% Sp 98% PPV 90% FIB-4 Score Sumida Y, et al., Shah AG, et al., Age, ALT, AST, Platelets AUROC 0.88, At cutoff 1.45 Se 90% Sp 64% NP 98%, 3.25 cutoff Se 48% Sp 95% PPV 53% Fibroscan (US Elastography) Wong VW-S, et al., Sirli R, et al., 2014 AUROC F F , F MR Elastography Kim D,et al Above kpa 4.15 For Advanced Fibrosis AUROC 0.95 with Se 85% and Sp 93% SECONDARY CAUSES OF NAFLD Lysosomal Lipase Deficiency Kneeman JM, et al., Therap Adv Gastroenterol, 2012.