Non Alcoholic Steato-Hepatitis (NASH) DISCLAIMER NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILITY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS CONTENT. by Rajendra Kadari MD MPH NAFLD and NASH Criteria for Diagnosis of NASH Liver biopsy showing: Macrovesicular steatosis Lobular inflammation Hepatocyte ballooning +/_ Portal fibrosisi Absence of alcohol abuse (less than 20-140g of ethanol per week) Absence of serologic evidence of other causes for liver pathology 1
Histological appearance of NASH NAFLD and NASH Facts Up to 30% of adult population in US has NAFLD 3,7 90% of morbidly obese presenting for bariatric surgery have 310 NAFLD 3,10 2-5% of US population has NASH 3,7 Upwards of 30% of morbidly obese have NASH 3,7 NAFLD and NASH Facts Men more than women 8 Dallas heart study showed (using MR spectroscopy) steatosis in 45% Hispanics, 33% in whites and 24% in African Americans (n= 2000) African Americans have lower rates of elevated ALT, steatosis, and in patients with steatosis, lower rates of NASH and fibrosis score >F2. (Probably due to lesser visceral adiposity) 5 Hispanic and Asian population has a higher prevalence of NASH than whites. 5,8 NASH Facts Most patients with NAFLD have pure steatosis without inflammation and have been reported to have a benign clinical course. On the other hand, patients with NASH are believed to be at increased risk for advanced disease. Prevalence of cirrhosis in patients with NASH varies from 3% to 15% (with one study showing that 20% of a referral population having cirrhosis). This is compared to 38-50% of patients with alcoholic hepatitis progressing to cirrhosis over a seven year period. 1 2
Two-hit Hypothesis Pathogenesis of NASH Initial hit: Macrovesicular steatosis Insulin resistance and subsequent hyperinsulinemia -> alterations in the hepatic pathways of uptake, synthesis, degradation and secretion of free fatty acids -> ultimately to accumulation of lipids in the hepatocytes. Second hit: Steato-Hepatitis Oxidative stress, pro-inflammatory cytokines such as TNF alpha, Adiponectin etc have all been suspects Finally, hepatocyte apoptosis has also been identified as a potential key component of the second hit. Pathogenesis of NASH 4 Independent Predictors for Fibrosis Progression Proposed are: diabetes mellitus increased homeostatic insulin resistance low initial fibrosis stage BMI of 30 or greater age: 50 yrs or older AST of 45 or greater increased AST/ALT ratio of 0.8 or greater decreased platelets hyaluronic acid of 55 or greater. 3
Clinical Presentation Often are asymptomatic The most common symptoms that bring NAFLD to medical attention are malaise, fatigue, and right upper quadrant or diffuse abdominal discomfort. Diagnosis Hepatomegaly may be found on clinical examination in 75% of patients. Laboratory Diagnosis Laboratory Diagnosis NAFLD is the most common cause of unexplained persistent elevation of liver enzyme levels after infectious hepatitis and other chronic liver diseases have been excluded. Alanine aminotransferase (ALT) is the predominant liver enzyme to be elevated in NAFLD. But, is rarely increased more than 3 times the upper limits of normal. AST/ALT ration is usually less than 1. Normal serum aminotransfereases do not exclude the presence of advanced histological features. 4
Biomarkers for NASH diagnosis 3 Serum biomarker Marker of Findings ROS Oxidative stress Conflicting results: some corelation Leptin Insulin resistance Conflicting results: higher levels in some studies Adiponectin Insulin sensitivity ADP lower in NASH pts Scoring Systems for Predicting Fibrosis in NASH CRP Systemic inflammation Increased in NASH as compared to NAFLD Cytokeratin 18 fragments Hepatic apoptosis Significantly higher in NASH DHEA Oxidative stress,fibrosis Consistent inverse relationship with degree of hepatic fibrosis Scoring Systems to Predict Fibrosis in NAFLD 6 Radiological Diagnosis of NASH 5
USG in the Diagnosis of NASH Radiology Studies in Diagnosis of NAFLD 3 USG has been shown to have a specificity of 75-100% and sensitivity of 49-89% for NAFLD. The lower end of the spectrum of sensitivity and specificity is seen in patients who are morbidly obese. The higher end of the spectrum is seen in patients with at least 30% steatosis and in relatively thin patients. Unfortunately, USG/other imaging studies cannot be used to distinguish between steatosis and steatohepatitis/fibrosis and are of not much use in NASH in diagnosis. CT with Liver-Spleen Attenuation Ratios 1 USG Elastography Measures liver stiffness Stepwise increase in elasticity is shown with severity of hepatic fibrosis Sensitivity and specificity of 87 and 91% for stage IV fibrosis. 70 and 84% respectively for stages II and III fibrosis. Issues:steatosisandBMI>25hasbeenshowntoreducethe reproducibility. 6
Similar to the USG MR Elastography Sensitivity and Specificity of 98 and 99% for identifying the presence of any fibrosis. Biopsy Advantage over USG Elastography is that it identifies steatosis accurately, and fibrosis measurements were less affected by the degree of steatosis. Both these techniques need more studies to be done before being applied to regular clinical practice. Grading and Staging of NAFLD 1 NAFLD Activity Score (NAS) Developed by NIH sponsored NASH Clinical Research Network. Ideally for clinical trials. Criteria: steatosis, lobular inflammation and hepatocyte ballooning A NAS of 5 or greater is consistent with NASH, 2 or less is not associated with NASH and 3 or 4 somewhere in between. 7
Diagnostic Approach to NAFLD/NASH 9 TREATMENT Treatment proposed for NAFLD has been based on the twohit hypothesis, the first being fatty liver infiltration (linked to obesity and insulin resistance), and the second being oxidative stress. Diet 8
Macronutrients in NAFLD 3 Diet Recommendations Randomized controlled trial of low-fat vs. low-carbohydrate diet showed greater weight loss and improved lipid panels in the low-carbohydrate group Majority of the studies have shown that weight loss of 10% of body weight is efficacious in improving all the parameters of NAFLD plus in improvement in steatosis and necro-inflammation in NASH. Regarding fibrosis, studies on weight reduction with bariatric surgery are the only ones that have shown improvement. Till now, none of the adjunctive weight reducing medications have been shown to be of any additional benefit. In general, recommendation is to have a slow, consistent weight loss through diet designed to produce a caloric deficit of 500 to 1000 cal/day and by eating foods with low glycemic index as well as containing more monounsaturated FAs and n-3 PUFAs, low SFAs, and limited to no fructose and Trans FAs. Effect of Exercise Plus Diet Collectively, all the studies support the general concept that gradual weight loss through exercise and diet is associated with improvement in BMI, waist circumference, waist-to-hip ratio and serum aminotransferases. Even in patients who do not lose weight, there is significant decrease in aminotransferase levels. Medications Histological improvement of steatosis or fibrosis is also seen if there is at least 4% body weight loss. Patients should be recommended high- to moderate-intensity exercise (30 minutes, atleast three to five times a week) (which has also been advocated to reduce the risk of co morbidities associated with obesity). 9
Thiazolinediones for treatment of NASH 4 Metformin for Treatment of NASH 2 Authors N Comparator Duration Liver enzymes Histology Marchesini et al 14 None 4 mo Improved Not evaluated Nair et al 15 None 12 mo Improved Improved inflammation Uygun et al 36 Cl Calorie 6 mo Improved Improved restricted diet inflammation Bugianesi et al 55 Calorie restricted diet 12 mo Improved Improved steatosis, inflammation and fibrosis Schwimmer et al 10 None 6 mo Improved Not evaluated Loomba et al 14 None 48 wks Improved Improved steatosis and inflammation Nobili et al 57 Antioxidant 24 mo No difference No difference Potential therapies under investigation 3 Bariatric Surgery in Treatment of NASH 10
Bariatric Surgery for Treatment of NASH 4 In Conclusion Incidence of NAFLD and in turn NASH will continue to grow as long as the obesity epidemic is not controlled through broader public health measures. Diagnosis of NASH is still dependant on biopsy. There is a need for non-invasive and accurate screening tests to identify patients at risk for disease progression from NAFLD to NASH and for identifying effective treatment regimes. There is no proven effective therapy for NASH. Diet, exercise, bariatric surgery and medications (for short term) have all shown promise but more studies need to be done. References 1. www.uptodate.com 2. NAFLD and NASH selected practical issues in their evaluation and management; Vuppalanchi R, Chalasani N; Hepatology. 2009 January; 49(1): 306 317 3. Diagnosis and Therapy of NASH,; Torres DM, Harrison SA; Gastroenterology 2008; 134:1682-1689 4. Review article: diagnosis and treatment of NAFLD; Oh M K, Winn J, Poordad F; Aliment PharmacolTher. 2008 Sep 1;28(5):503-22. Epub 2008 Jun 3 5. The Histologic Spectrum of Liver disease in African-American, Non-Hispanic White and Hispanic Obesity surgery Patients; Kallawitz et al; Am J Gastroenterol. 2009 Jan;104(1):64-9 6. Are non-invasive tests accurate enough to predict hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD)? Chavez-Tapia NC, Tiribelli C; Gut. 2008 Oct;57(10):1351-3 7. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/nonalc oholic-fatty-liver-disease/ 8. Managing nonalcoholic fatty liver disease: recommendations for family physicians; Grattagliano I, Portincasa P, PalmieriVO, Palasciano G; Can Fam Physician. 2007 May;53(5):857-63. 9. Nonalcoholic fatty liver disease: a clinical review; Sass DA, Chang P, Chopra KB; Dig Dis Sci. 2005 Jan;50(1):171-80 10. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass; Boza C et al; Obes Surg. 2005 Sep;15(8):1148-53. 11