Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of the disease characterized by the accumulation of lipids in liver cells not associated with the consumption of alcohol. It causes cellular dysfunction and, in some patients, leads to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis.
Growth Linked to Obesity Epidemic
Data from the Dallas Heart Study suggests that up to 30% of adults have NAFLD, of which 79% have normal aminotransferase levels. The prevalence of NAFLD was 80-90% in obese adults, 50-70% in patients with Type 2 diabetes, and up to 90% in patients with hyperlipidemia. In children, the overall prevalence of NAFLD is 3-10%, rising up to 40-70% among children(1).
- Cirrhosis from NAFLD is 10x higher than that of hepatitis C, for which there are quality metrics around screening baby boomers.
- In 2016, the prevalence of NAFLD was estimated at 85.3 million Americans, with 17.3 million having NASH.
- By 2030, the prevalence is expected to increase to 101 million with NAFLD and 27 million with NASH. Of those with NASH, the number of patients with advancing fibrosis is expected to double from 7.1 million to 14.1 million, with the greatest increases among patients with fibrosis (2.1-4.5 million) and cirrhosis (1.4 – 3.5 million)(2). As a perspective, in 2016, it was estimated that only 2.6 million Americans were chronically infected with hepatitis C and 200,000 of these with cirrhosis. (3)
- NAFLD is linked to increasing rates of end-stage liver disease, liver cancer, and the need for a liver transplant. Currently, the number two indication for liver transplant behind hepatitis C, NAFLD, is on track to become the number one cause for liver transplant in the coming years.
- NAFLD tends to be diagnosed at an older age and due to its silent course, liver failure is often the first presentation at diagnosis of NAFLD-related cirrhosis (38-45%) of cases.
- Once cirrhosis decompensates, patients with NAFLD have a rapidly progressive hepatic deterioration leading to similar overall and liver-related mortality as cirrhosis of other etiologies(4).
Type 2 Diabetes and Mortality Rates
- Diabetics have higher all-cause mortality with NAFLD than without, and higher rates of cardiovascular disease (CVD) mortality and morbidity. American Diabetes guidelines recommend evaluating patients with Type 2 diabetes or pre-diabetes and elevated ALT or fatty liver on ultrasound for NAFLD.
- Increased rates of NAFLD seen in patients with metabolic syndrome are, most notably, those with Type 2 diabetes, obesity, and hypercholesterolemia.
- Type 2 diabetes patients with NAFLD have higher all-cause mortality than those without NAFLD.
- Most striking is that simple steatosis will increase the risk of CVD mortality by 2x over a shorter period than those with Type 2 diabetes alone. Patients with prediabetes and Type 2 diabetes are of particular concern with NAFLD(5).
- Although the presence of NAFLD results in worse atherosclerotic dyslipidemia and makes it more difficult to control hyperglycemia, the presence of Type 2 diabetes accelerates the progression of liver disease in patients with NAFLD(6).
- NAFLD is an independent predictor and associated with a > 2x increase in developing Type 2 diabetes(7).
- Type 2 diabetes has a 5.36 (4.41 – 6.51) age-adjusted hospital readmission rate for NAFLD compared to the Type 2 diabetes population(8).
- ADA Standards of Medical Care in Diabetes Level C recommendations (9).
- Patients with Type 2 diabetes or prediabetes and elevated liver enzymes (alanine aminotransferase) or fatty liver on ultrasound should be evaluated for the presence of NASH and liver fibrosis.
- Noninvasive tests, such as elastography or fibrosis biomarkers, may be used to assess the risk of fibrosis, but referral to a liver specialist and liver biopsy may be required for definitive diagnosis.
- Interventions that improve metabolic abnormalities in patients with diabetes (weight loss, glycemic control, and treatment with specific drugs or hyperglycemia or dyslipidemia) are also beneficial for fatty liver disease.
NAFLD: Quantitative Risk of Liver Mortality by Fibrosis Stage
- A meta-analysis of 5 cohort studies with N = 149 patients with NAFLD followed for 17,452 patient – yrs
- Liver-related mortality exponentially increased with fibrosis stage.
Costs of Liver Disease
- The costs associated with NAFLD are significant, even in advance of pharmacological treatments.
- A lifetime Markov model estimated that there are 6.65 million adults (18+ years old) with NASH in the U.S. and that there were 232,000 incident cases in 2017. Lifetime costs of all NASH patients in the U.S. in 2017 were $222.6 billion and the cost of the advanced NASH population was $95.4 billion(10).
- Based on retrospective claims assessments, the costs of diagnosing NASH can be substantial. Per the OptumLabs Data Warehouse, between 2010-2014, 108,000 patients matched (1:1 with NAFLD and controls without) (11).
- The total annual cost of care for NAFLD patients with private insurance–increased from $4,547 to $7,804 for new diagnosis and $3,789 for long term management versus match control of $2,289.
- The total annual cost of care for NAFLD patients with Medicare Advantage–increased from $6,566 to $9,062 for a new diagnosis and $5,363 for the long term versus a matched control of $4,111.
- Over the same period, the annual healthcare costs of non-NAFLD patients increased by 5-10% after the index date, in line with expected increases in annual rates.
- The most effective treatment for NAFLD is lifestyle modification, most notably diet and exercise. In studies, a >3% weight loss can reverse steatosis in up to 100% of patients studied and a loss of >10% can regress liver fibrosis in up to 45% (12).
- In the coming years, the pharmacological treatment market is expected to reach $21-$35 billion (13).
- The first drug is obeticholic acid (OCA) from Intercept Pharma is expected to launch later this year. Over 18 months, OCA has been demonstrated to improve fibrosis in 37% of patients versus 23% on placebo. The main side effect was pruritus or itching, which occurred in 51% of patients treated. Initially, Intercept expects 3.5 million Americans will be candidates for OCA.(14). It will likely have a year head start after the next entrant and is projected to cost $10,000 to $18,000 per patient per year(15).
- FibroScan® is a cost-effective assessment and monitoring tool that is available today. It is rapid, non-invasive, and easily integrated into clinical practice.
- An FDA-cleared technology for the diagnosis and monitoring of adult patients as part of an overall evaluation of liver health, FibroScan® non-invasively and quantitatively estimates liver stiffness with patented VCTE™ and liver fat with CAP™.
- FibroScan® is designed as a portable point of care tool that can be operated by a medical assistant and interpreted by a healthcare professional. It is supported by over 2,500 peer-reviewed publications and is the reference in most of the international liver guidelines.
- FibroScan® benefits include:
- Rapid, painless, point of care tool for providing immediate information about the stiffness of the patient’s liver and the amount of liver fat present.
- When combined with blood biomarkers, scores can be a cost-effective way for primary care physicians to risk-stratify patients with NASH and advancing fibrosis for further specialist workup.
- Designed to provide consistent measurements over time, irrespective of operator or device, and valuable information on liver health, FibroScan® supports lifestyle and therapeutic interventions that can improve outcomes, reduce costs and improve patient satisfaction and engagement.
- The American Association for the Study of Liver Diseases (AASLD) does not currently recommend routine screening for NAFLD or NASH but does recommend FibroScan® as part of an overall approach to identifying patients with NAFLD or NASH.
- AASLD states there should be a high index of suspicion for NAFLD and NASH in patients with Type 2 diabetes. Clinical decision aids, such as NFS, fibrosis-4 index (FIB-4), or vibration controlled transient elastography (VCTE), can be used to identify those at low or high risk for advanced fibrosis(16).
- FibroScan® examinations should be performed on a patient who has not eaten in at least three hours and is not indicated for use in pregnant women or individuals who have an implantable electronic device, such as a pacemaker.
FibroScan® FAST™ Score
- A recent study evaluated the FAST™ Score(17) calculator, a tool for clinicians to calculate the probability of a patient with a suspicion of NAFLD as having active fibrotic-NASH (NASH+NAS ≥4+ F≥2). The calculator takes into account liver stiffness measurement by VCTE™, liver fat by CAP™ and inflammation by AST, and was developed based on a prospective multicenter study and published in peer-reviewed literature.
- In clinical trials to develop NASH drugs, over 50% of patients fail to meet the inclusion criteria, with the majority not having fibrotic-NASH(18). By improving the quality of referrals to liver specialists, FibroScan® based scores may reduce unnecessary referrals and provide better tools for managing patients at risk for progressive liver disease at the point of care.
- As treatments become available for fibrotic NASH, having FibroScan® and tools like FAST™ available in point of care improve diagnostic accuracy, reduce costs, and make diagnosis more efficient.
- The FAST™ score and calculator are presented as an educational service intended for licensed healthcare professionals. While this score is about specific medical and healthcare issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.
- Estes C et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States for the period 2016– 2030. J Hepatol (2018), https://doi.org/10.1016/j.jhep.2018.05.036
- Estes, 2018.
- Hofmeister M et al. Estimating the Prevalence of Hepatitis C Virus Infection in the United States, 2013-2016.
- 2019 Mar;69(3):1020-1031. doi: 10.1002/hep.30297. Epub 2018 Nov 6.
- Raluka S, et al. NAFLD and liver transplantation: Current burden and expected challenges. J Hepatol. 2016 December; 65(6): 1245–1257. doi:10.1016/j.jhep.2016.07.033.
- Bril, F et al. Endocrinol Metab Clin N Am – (2016) – http://dx.doi.org/10.1016/j.ecl.2016.06.005 endo.theclinics.com 0889-8529/16/
- Hazlehurst, Jonathan M, Woods, C, Marjot, T et al. Non Alcoholic fatty liver disease, and diabetes. J Metabolism, 2016.01.001
- Mantovani, et al. Diabetes Care 41:372, 2018 Byrne et al. J Hepatol 62:S47,2015
- Wild et al. J Hepatol 64:1358, 2016
- Journal of Clinical and Applied Research & Education. Diabetes Care January 2019
- Younossi, etal, Burden of Illness, and Economic Model for Patients with Non-Alcoholic Steatohepatitis (NASH) in the United States. doi: 10.1002/hep.30254
- Allen, A et al. Hepatology, Vol. 68, No.6, 2018, 2230-2237
- Hanna WIN, et al. Clin Liver Dis. 2016:20: 339-350
- Ioannou, Lore; The $35 billion race to cure a silent killer that affects 30 million Americans; CNBC; Jan. 2, 2019; https://www.cnbc.com/2018/12/21/the-35-billion-race-for-a-cure-for-a-liver-disease-that-affects-millions; accessed April 8, 2020
- Source: ICPT Investor Presentation 12/16/19
- OptumRx Drug Pipeline Insights report 1Q2020
- Chalasani, et al. AASLD Practice Guidance. Hepatology Vol. 67, No. 1, 2018
- Newsome, Philip et al. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study; The Lancet; April 1, 2020; https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30383-8/fulltext
- NASH Tag 2020