NASH PROGRESS IN THE LAST DECADE

Transcription

1 PROGRESS IN THE LAST DECADE Mitchell L. Shiffman, MD, FACG Director Health System Richmond and Newport News, VA Medical Group Good Help to Those in Need A GLOBAL HEALTH PROBLEM Nigeria Australia Spain Japan Germany Taiwan S Korea USA Israel Greece Mexico Brazil China PREVALENCE (%) M Sayiner et al. Clin Liver Dis 216; 2: Page 1 of 17

2 IN THE USA RACE/ETHNICITY PREVALENCE (%) Mexico Caribbean CT scan MRI All Hispanics Caucasians Blacks MW Fleischman et al. World J Gastroenterol 214; 2: JD Browning et al. Hepatology 24; 4: SEX, RACE AND ETHNICITY Elevated ALT (%) Men Women Caucasian African American Hispanic Asian CE Ruhl and JE Everhart Clin Liver Dis 24; 8: Page 2 of 17

3 GENETICS GWAS study in 9, 229 patients Dallas Heart Study PNPLA3-allele (M) associated with steatosis and more common in Hispanics Hispanics with homozygous (MM) 2- fold increased hepatic fat content PNPLA3-allele (L) associated with less steatosis and more common in Blacks PNPLA3 codes for a lipase (Adiponutrin) which mediates TG hydrolysis Hepatic TG (gm) A AAC AA PNPLA3 Allele Frequency H S Romeo et al Nat Genetics 28; 4: PREVALENCE IN USA ~8% 2-3% % OF PATIENTS Cx ESLD P Kanwar and KV Kowdley Clin Liver Dis 216; 2: Page 3 of 17

4 AND THE METABOLIC SYNDROME INSULIN RESISTANCE Metabolic Syndrome Hypertension >13 systolic; >85 diastolic Hypertriglyceridemia >15 mg/dl Elevated fasting serum glucose >1 gm/dl Low HDL-Cholesterol <4 mg/dl male <5 mg/dl female Obesity BMI >25 Insulin Resistance 32% of persons with metabolic syndrome develop over 4-8 years 2% of patients with will develop DM in 3 years P Kanwar and KV Kowdley. Clin Liver Dis 216; 2: Y Wang et al. Exp Ther Med. 213; 6: A Kasturiratne et al. J Gastroenterol Hep. 213; Liver Institute 28: of Virginia METABOLIC SYNDROME (%) No Features of MeS MM Smits et al. J Gastroenterol Hepatol 213; 28: NCEP ATP III Central Obesity Men: >12 cm Women: >88 cm Obesity BMI >25 Fasting plasma glucose >11 mg/dl Fasting triglycerides >15 mg/dl High-density cholesterol Men: <45 mg/dl Women: <5 mg/dl Page 4 of 17

5 IDENTIFICATION OF ULTRASOUND For evaluation of non-specific abdominal pain During the evaluation of elevated liver enzymes Incorrect imaging impressions: Increased echogenicity consistent with fatty liver Increased echogenicity consistent with Correct imaging impression: Increased echogenicity consistent with chronic liver disease or fatty liver DIAGNOSTIC STUDIES Ultrasound Non-contrast CT scan Magnetic Resonance imaging Liver biopsy: All suggestive None diagnostic Only test which can currently distinguish steatosis () from Page 5 of 17

6 METABOLIC SYNDROME WHO HAS MeS (% of patients) Factor which predict : Diabetes mellitus type 2 Elevated liver transaminases 3.5 fold higher stage 3-4 fibrosis Less reliable factors for : Higher BMI Larger waist circumference Higher mean BP Lower HDL cholesterol Higher triglycerides Elevated ferritin G Marchesini et al Hepatology 23; 37: HISTOLOGIC FEATURES 1. Fat alone 2. Fat plus inflammation 3. Fat plus ballooning degeneration 4. Fat plus: Polymorphonuclear infiltrates Perisinusoidal fibrosis With or without Malloy bodies Page 6 of 17

7 D RISK OF CIRRHOSIS 4 % of Patients Benign Steatosis Activity Score: Steatosis (-3) Inflammation (-3) Ballooning (-2) Steatosis Fat + Fat + Fat + alone Inflam ballooning fibrosis LIVER HISTOLOGY CA Matteoni et al. Gastroenterology 1999; 116: VERSUS NON-INVASIVE TESTING Blood tests: fibrosis score Fib-4 APRI Shear wave elastography Free standing devise As part of ultrasound unit MRI elastography PPV: 37-79% NPV: 84-95% Too expensive for routine use Page 7 of 17

8 ELASTOGRAPHY IN FIBROSIS STAGE AND SURVIVAL Fibrosis Stage FS score (kpa) >38.6 J Boursier et al. J Hepatol 216; (in press) SURVIVAL (%) YEARS ELASTOGRAPHY IN NON-LIVER MORTALITY Fibrosis Stage FS score (kpa) >38.6 J Boursier et al. J Hepatol 216; (in press) SURVIVAL (%) YEARS Page 8 of 17

9 SURVIVAL SURVIVAL (%) YEARS N Male 31% 47% Caucasian 82% 8% Bx Age BMI ALT Death age N Rafiq and Z Younossi Clin Gastroenterol Hepatol 29; 7: `. LIVER RELATED MORTALITY SURVIVAL (%) YEARS Causes of Death Coronary Artery Disease 12% Malignancy 8% Liver Death (incl HCC) 7% Diabetes 3% Other 1% Unknown 4% N Rafiq and Z Younossi Clin Gastroenterol Hepatol 29; 7: `. Page 9 of 17

10 WHY IS LIVER MORTALITY LOW STEATOSIS (%) Progressive Stagnant A B C Fibrosis Stage Child Class Steatosis resolves in many patients with as they develop cirrhosis These patients develop stagnant, due not develop elevations in MELD score and typically die from complications of metabolic syndrome HEPATOCELLULAR CARCINOMA The risk of HCC in patients with NALD seems to be similar to that observed in other liver diseases Most commonly occurs in the setting of cirrhosis 66% male 67 years 58% obese 64% diabetes mellitus 33% of HCC in the setting of D may be in patients without cirrhosis JM Page and S Harrison Clin Liver Dis 29; 13: Page 1 of 17

11 HEPATOCELLULAR CARCINOMA IMPACT OF DIABETES RISK (%) DM No DM YEARS The vast majority of patients with HCC have: Chronic liver disease Cirrhosis Cirrhosis of any cause promotes glucose intolerance and increases the risk of diabetes mellitus H El-Serag et al Gastroenterol 24; 126: TREATMENT Weight loss Weight loss Weight loss Weight loss Weight loss Weight loss Diet Severely restrict carbohydrates Adkins or Mediterranean diet Avoid fructose Coffee 2-4 cups/d Exercise Weight loss goal: > 1% of baseline body weight 9% resolution in steatosis 45% reduction in fibrosis Only 5% of patients in trials achieve this goal E Villar-Gomez et al. Gastroenterology 215; 149: Page 11 of 17

12 FRUCTOSE SUPPLEMENTS PROMOTES FATTY ACID SYNTHESIS Glucose Fructose Fructose-1P TG Synthesis G-6P F-6P F-1,6DP Glyceraldehyde di-oh acetone-p Pyruvate Acetyl-CoA Krebs Cycle WEIGHT LOSS AND D GASTRIC BYPASS SURGERY 1% 8% 6% 4% 2% Score: % B A B A B A B A Steatosis Inflammation Grade Stage SG Mattar et al Ann Surg 25; 242; Page 12 of 17

13 MEDICAL THERAPY Modify factors associated with and causes of liver injury Weight loss drugs Improve insulin resistance (TZDs) Antioxidants (Vitamin E) Anti-inflammatory agents (Caspace inhibitors) M-Torr inhibitors (Obeticholic acid) Anti-fibrotic agents Glucagon-protein-1 receptor antagonists Modify gut-liver axis S Ganesh and VK Rusti Clin Liver Dis 216; 2: PIVENS STUDY VITAMIN E AND PIOGLITAZONE Histology Improved (%) Placebo Vitamin E Pioglitazone Randomized Multicenter NIH Sponsored Placebo Controlled Weight loss encouraged Histologic End-points: Ballooning Fibrosis Inflammation AJ Sanyal et al N Engl J Med 21; 362: Page 13 of 17

14 ROZIGLITAZONE 3.3 YEARS Baseline 1 year 4 mos Steatosis % Ballooning Inflammation Fibrosis NAS score Mean weight gain 4.25 kg Weight gain >3 kg 36% V Ratziu et al. Hepatology 21; 51: FLINT STUDY OBETICHOLIC ACID Histology Improved (%) Placebo OCA Obeticholic acid Bile acid analogue Selectively activates nuclear hormone receptor farnesoid X Reduces: Hepatic inflammation Stellate cell activation Bile acid synthesis Bile acid uptake Enhances: Enhances matrix degradation Bile acid uptake B Neuschwander-Tetrii, et al. Lancet. 215, 385: Page 14 of 17

15 FATTY LIVER VESUS TWO HIT HYPOTHESIS Fatty Liver What is the second hit? Insulin resistance Metabolic syndrome Intestinal microflora Endogenous alcohols INTESTINAL MICOBIOTA Animal models of Obese rats with have a shift in intestinal bacteria composition Transplantatiton of stool from rats with to normal weight rats causes Patients with have a shift in intestinal bacteria composition Lower percentage of Firmicutes and Actinobacteria species Higher percentage of Baceroidetes and Proteobacteria species Higher percentage Enterobacteriaceae and Escherichia organisms Enterobacteriaceae and Escherichia are fermenting organisms and produce alcohol Patients with have higher endogenous blood alcohol Page 15 of 17

16 AN ALTERATION IN GUT MICROBIOTA Firmicutes Bacteroidetes Escherichia Enterobacteriaceae Obese Normal Proteobacteria Actinobacteria L Zhu et al. Hepatology 213; 57: ENDOGENOUS ALCOHOL ETOH (um) Normal Obese The species of bacteria that are increased in patients with are fermenters and produce alcohol Intestinal production of alcohol may lead to hepatic steatosis Increase gut permeability and cause more endotoxemia L Zhu et al. Hepatology 213; 57: Page 16 of 17

17 SUMMARY Is a word wide epidemic Is associated with genetic polymorphisms of PNPLA3 Is most commonly found in patients with metabolic syndrome represents only about 2% of persons with NALF The major cause of mortality in patients with is not liver disease Weight reduction remains the primary treatment for and Page 17 of 17