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In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.
COMMITTEE AND AUTHOR DISCLOSURE
Statements of Disclosure of Relevant Financial Relationships have been obtained from Raj Vuppalanchi, MD. Dr. Vuppalanchi has disclosed that he has no relevant financial relationships with any commercial interests.
After reading this article, the reader should be able to:
- Identify the problem responsible for the high prevalence of non-alcoholic fatty liver disease (NAFLD).
- Discuss the conditions associated with the NAFLD histologic phenotype.
- Describe the link between metabolic syndrome and the development of NAFLD.
- Compare and contrast liver biopsy with transient elastography as tools for diagnosing and staging NAFLD.
- Summarize the treatment for NAFLD with and without nonalcoholic steatohepatitis.
Date of original release: July 2014
Date of expiration: July 2015
Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.
A 52-year-old white male is found to have elevated liver enzymes (aspartate aminotransferase [AST] 80 U/L, alanine aminotransferase [ALT] 91 U/L) on routine blood monitoring of atorvastatin therapy (10 mg/day). Liver enzymes fail to normalize two weeks after discontinuing treatment. A viral hepatitis panel is negative; right upper quadrant ultrasound shows fatty infiltration of the liver. His previous medical history includes diagnoses of prediabetes, hypertension, dyslipidemia, coronary artery disease (cardiac catheterization and stent placement three months earlier), and obstructive sleep apnea. He takes aspirin, clopidogrel, and lisinopril daily.
The patient is referred to the Digestive and Liver Disease Clinic at Indiana University Health University Hospital for further evaluation. On physical examination, he is found to be overweight (body mass index [BMI] = 29) and to have mild hepatomegaly with no signs of cirrhosis. After excluding other potential causes for the patient’s liver enzyme elevations, non-alcoholic fatty liver disease (NAFLD) is considered the likely cause.
Overview of NAFLD
Owing to the global obesity epidemic, NAFLD has become a primary cause of chronic liver disease worldwide, with prevalence in the United States exceeding 30 percent.1 NAFLD represents a spectrum of liver changes ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) with inflammation; progressive fibrosis; and ultimately, cirrhosis.
Several conditions are associated with the NAFLD histologic phenotype (Table 1), but the vast majority of patients with the condition seen in clinical practice have the metabolic syndrome. Insulin resistance (IR) is the hallmark of the metabolic syndrome, and NAFLD is its hepatic manifestation.2
Physical, Laboratory, and Radiographic Findings
“Most patients with NAFLD are asymptomatic, although some may complain of fatigue, malaise, and right upper abdominal discomfort,”3 says Raj Vuppalanchi, MD, staff physician with IU Health Physicians Digestive & Liver Disorders and associate professor of medicine at Indiana University School of Medicine. “Liver evaluation is typically triggered by laboratory testing showing elevated aminotransferases or by the incidental detection of hepatic steatosis on abdominal imaging.”
Hepatomegaly and mild or moderate increases (two to five times normal) in AST and ALT may be present in patients with NAFLD. When levels of these liver enzymes are elevated, the ratio of AST to ALT is usually less than one. (In contrast, this ratio is generally greater than two in alcoholic fatty liver disease.) The magnitude of the AST elevation does not predict the degree of fibrosis, however, and AST/ALT levels may be normal in patients with clinically relevant histologic damage. Alkaline phosphatase, transferrin saturation, and serum ferritin concentrations may also be elevated in NAFLD, but serum albumin and bilirubin levels are usually within the normal range unless cirrhosis is present.
Radiographic findings characteristic of NAFLD are increased echogenicity on ultrasound, decreased hepatic attenuation on computed tomography, and an increased fat signal on magnetic resonance imaging (MRI).
Case Study (cont.)
The patient is informed that he has several risk factors for NAFLD, and that this condition may account for his persistently elevated AST and ALT levels (his alkaline phosphatase and serum bilirubin values are normal). He is told that additional testing is necessary to confirm the diagnosis and evaluate the liver. He expresses concern about undergoing a liver biopsy, particularly since the procedure will require that he temporarily discontinue antiplatelet therapy taken to protect his recently placed coronary stent.
Diagnosis and Staging
“The diagnosis of NAFLD requires demonstration of hepatic steatosis and exclusion of significant alcohol consumption or other causes of hepatic steatosis,”4 Dr. Vuppalanchi explains. “Liver biopsy has long been the gold standard for diagnosing NASH and for staging liver fibrosis, guiding therapy, and predicting prognosis (Figure 1). But it is an invasive and expensive test that is, on rare occasions, associated with pain and complications, such as life-threatening bleeding.”
Another limitation to liver biopsy is that it samples only a very small piece of the liver, which can lead to incorrect staging if the sample is inadequate or not representative of the remaining liver.5 Sampling error is estimated to occur in 25 to 30 percent of liver biopsies.6 Variability in histologic interpretation may further contribute to discrepancies in NAFLD/NASH staging.
Given these limitations to liver biopsy, the desire of patients to avoid invasive testing, and the imperative to identify NAFLD patients at high risk for NASH, who may benefit from more intensive management, a major goal of research has been the development of noninvasive techniques for assessing liver fibrosis. Transient elastography (TE) performed using the FibroScan® (Echosens) is one such test. The device (Figure 2) was approved by the Food and Drug Administration (FDA) in April 2013 and is in use at a few major US medical centers, including IU Health, which has the only FibroScan in the state.
TE is an ultrasound-based tool that measures liver stiffness as a surrogate for fibrosis in patients with NAFLD, NASH, hepatitis (See "Role of Transient Elastography in Hepatitis C Infection"), and other chronic liver diseases. The in-office procedure involves placing a probe on the skin of the right upper quadrant of the abdomen (Figure 3) that transmits a mild amplitude, low frequency (50 Hz) vibration through the intercostal space. The vibration induces an elastic shear wave that propagates within the hepatic tissue; pulse-echo ultrasound acquisition is used to measure its velocity (in meters/second). Because velocity is directly related to tissue stiffness—the stiffer the tissue, the faster the shear wave propagates—liver stiffness can be calculated and is expressed in kilopascals (kPa).
“We use transient elastography as a point-of-contact test in all patients with suspected NAFLD to establish baseline stiffness, diagnose or exclude advanced fibrosis and cirrhosis, and assist in management decisions,” Dr. Vuppalanchi reports. “Testing is painless, rapid (completed under 15 minutes), and reproducible, and the results are immediately available. Importantly, because transient elastography acquires information from a much larger portion of the liver than does biopsy, the risk of sampling error is significantly reduced.”
The in-office procedure involves placing a probe on the skin of the right upper quadrant of the abdomen (Figure 3) that transmits a mild amplitude, low frequency (50 Hz) vibration through the intercostal space.
Case Study (cont.)
TE is performed during the initial visit, and median liver stiffness is measured at 5.6 kPa (normal is <7 kPa). The patient is reassured that his NAFLD has a favorable prognosis and is told that his liver status can be monitored with yearly TE examination.
A high degree of correlation between liver stiffness measurement (LSM) and the stage of liver fibrosis was found in a practice audit of 2335 FibroScan examinations.7 Low reliability results occurred in approximately five percent of individuals and were primarily linked to older age, obesity,* higher liver stiffness, and the operator, the latter underscoring the need for adequate training. When FibroScan results are combined with the NAFLD fibrosis score (Table 2), these two complementary, easy-to-perform tests have been shown to accurately diagnose or exclude the presence of severe liver fibrosis and reduce by 50 to 60 percent the number of needed diagnostic liver biopsies.2
“Studies of LSM are currently ongoing at IU School of Medicine, and we are hopeful that this approach—alone or in combination with other noninvasive testing—will one day replace liver biopsy in the management of NAFLD,” Dr. Vuppalanchi points out.
“Treatment for NAFLD without NASH focuses exclusively on lifestyle changes,” says Dr. Vuppalanchi. “These changes involve: 1) better control of risk factors and comorbidities, 2) 10 percent weight loss over six to 12 months (choice of diet is left up to the patient), and 3) a minimum of three hours of aerobic exercise weekly.”
The management of NASH includes lifestyle changes plus liver-directed therapy, which currently consists of antioxidant therapy with vitamin E 800 IU daily or pioglitazone 15 or 30 mg/day. Dr. Vuppalanchi also recommends that patients with NASH consider enrolling in clinical trials of potentially promising new treatment strategies.
“The IU School of Medicine is one of eight centers in the NASH Clinical Research Network recruiting patients for clinical studies,” Dr. Vuppalanchi points out. “The Network was formed in 2002 to conduct research on the natural history, pathogenesis, and treatment of NASH. Information collected from observational and clinical studies enrolling both adult and pediatric patients is creating a database for use by researchers seeking to develop new therapies to slow the progression of NASH or prevent its development.”
According to Dr. Vuppalanchi, the importance of controlling cardiovascular risk factors, such as dyslipidemia, in patients with NAFLD cannot be overstated. A meta-analysis of 40 published articles assessing the natural history of the disease linked it to increased overall mortality from both liver-related and cardiovascular disease.9
Case Study (cont.)
The patient is advised to work with his primary care physician to achieve the recommended lifestyle changes. He is also encouraged to restart statin therapy for dyslipidemia, as research shows that patients with NAFLD and elevated liver enzymes are not at increased risk for statin-related heptotoxicity.8
“Testing is painless, rapid (completed under 15 minutes), and reproducible, and the results are immediately available. Importantly, because transient elastography acquires information from a much larger portion of the liver than does biopsy, the risk of sampling error is significantly reduced.”
Role of Transient Elastography in Hepatitis C Infection
Highly effective interferon-free combination drug regimens are revolutionizing the treatment of hepatitis C (HCV) infection. Sustained virologic response (SVR) rates of 94 to 99 percent were achieved in a phase 3 randomized study of sofosbuvir plus ledipasvir in patients with HCV genotype 1 infection who had not had a SVR to previous interferon-based treatment.10 Yet this success comes at a very high price. Sofosbuvir (Sovaldi®, Gilead) costs $1000 a pill—$84,000 for the typical 12-week course—and the price of a combination sofosbuvir-ledipasvir tablet, if approved by the FDA, is expected to be substantially higher.
According to the Centers for Disease Control and Prevention, an estimated 3.2 million people in the United States have chronic HCV, and each year, approximately 17,000 new cases are reported.11
“Clearly, our healthcare system cannot afford to treat everyone with chronic HCV with these new drugs,” says Dr. Vuppalanchi. “Transient elastography can help clinicians stage the disease to determine whether treatment is more or less urgent. For example, there is less urgency to treat patients with mild disease and a FibroScan stiffness score of less than 7 kPa.”
Nonetheless, disease stage is not the only determinant of HCV therapy, and Dr. Vuppalanchi stresses that the decision of when to start or reinitiate treatment must be made on the basis of discussions between the patient and his or her physician.
“The IU School of Medicine is one of eight centers in the NASH Clinical Research Network recruiting patients for clinical studies. The Network was formed in 2002 to conduct research on the natural history, pathogenesis, and treatment of NASH.”
Dr. Vuppalanchi received his medical degree from the Gandhi Medical College in Hyderabad, India; took his residency training in internal medicine at the Long Island College Hospital, affiliated with the State University of New York in Brooklyn; and completed fellowships in clinical pharmacology and hepatology at IU School of Medicine. His primary areas of research are NAFLD, NASH, HCV, and hepatocellular carcinoma, and he is the principal investigator or co-investigator for several ongoing clinical trials.
The author of more than 40 peer-reviewed medical journal articles, Dr. Vuppalanchi lectures in the United States and abroad and is a member of the American College of Gastroenterology and the American Association of Study of Liver Disease.
Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013;178(1):38-45.
Petta S, Vanni E, Bugianesi E, et al. The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. Liver Int. 2014.
Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology. 2009;49(1):306-317.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592-1609.
Vuppalanchi R, Unalp A, Van Natta ML, et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic Fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(4):481-486.
Afdhal NH. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol (N Y). 2012;8(9):605-607.
Pang JX, Pradhan F, Zimmer S, et al. The feasibility and reliability of transient elastography using Fibroscan(R): a practice audit of 2335 examinations. Can J Gastroenterol Hepatol. 2014;28(3):143-149.
Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci. 2005;329(2):62-65.
Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617-649.
Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.
Centers for Disease Control and Prevention. Hepatitis C general information. Available at: http://www.cdc.gov/hepatitis/c/cfaq.htm.
Choudhury J, Sanyal AJ. Clinical aspects of fatty liver disease. Semin Liver Dis. 2004;24(4):349-362.
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854.