IS LIVER BIOPSY NECESSARY IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE?

Transcription

1 Rev. Med. Chir. Soc. Med. Nat., Iaşi 2016 vol. 120, no. 3 INTERNAL MEDICINE - PEDIATRICS UPDATES IS LIVER BIOPSY NECESSARY IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE? R. S. Gavril 1, Laura Mihalache 2*, Lidia Arhire 2, Cristina Grosu 3, Andreea Gherasim 2, Otilia Nita 2, A. C. Oprescu 4, Mariana Graur 2 University of Medicine and Pharmacy Grigore T. Popa Iasi Faculty of Medicine 1. Department of Medical Specialties (I); 2. Department of Medical Specialties (II); 3. Department of Medical Specialties (III); 4. Sf. Spiridon Clinical Emergency Hospital *Corresponding author. laura_mvlad@yahoo.com IS LIVER BIOPSY NECESSARY IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE? (Abstract): Nonalcoholic fatty liver disease is the most common cause of liver disease in the Western world. Liver biopsy is considered the gold standard in the diagnosis and progression of the disease and its usefulness cannot be neglected in terms of research. But in current clinical practice, liver biopsy tends to be replaced by less expensive and noninvasive methods allowing the identification of cardiovascular and metabolic risks. Given the fact that a small percentage of individuals with nonalcoholic fatty liver disease will progress to cirrhosis, attention will be focused more on cardiovascular risk as nonalcoholic fatty liver is now regar d- ed as a distinct component of the metabolic syndrome. The aim of the clinician is to identify the early stages of fatty liver, using in this purpose simple and easily accessible methods. Many techniques have been proposed for the diagnosis of nonalcoholic fatty liver, from simple clin i- cal factors (anthropometric indices measuring, blood pressure), laboratory biomarkers, imaging methods and scores, which should allow early treatment. This review describes different methods for identifying nonalcoholic fatty liver and various stages of this disease. Keywords: NAFLD, LIVER BIOPSY, NON-INVASIVE DIAGNOSIS Nonalcoholic fatty liver disease (NAFLD) is a major problem of the 21st century and is the primary cause for liver disease in the western Europe. Even if it is generally benign, it can be associated with major hepatocellular impairment, inflammation and necroptosis, nonalcoholic steatohepatitis (NASH) being present in 20-30% of the subjects. Few of them will develop hepatic cirrhosis. Moreover, the issue of fatty hepatocytes goes further, because it increases the incidence of cardiovascular disorders and doubles the risk of diabetes mellitus, irrespective of the severity of hepatic impairment (1). Also, the cardiovascular risk is doubled by metabolic syndrome, and approximately one third of the subjects with NAFLD have metabolic syndrome (2). Liver biopsy can be seen as a useful method for scientific research and liver disease staging. However, for the NAFLD patient, non-invasive and cheap methods are needed, which will allow the early diagnosis of the liver disease and the under- 503

2 R. S. Gavril et al. lying cardiovascular risk. NAFLD DIAGNOSIS Currently, the available non-invasive methods for NAFLD diagnosis are represented by a set of symptoms and signs, and a combination of clinical and laboratory tests. Although some of these markers are usually useful for diagnosing an NAFLD patient, they do not have a high specificity and sensitivity capable of distinguishing between NAFLD and NASH and determining the degree of fibrosis. Liver biopsy is currently the gold standard for NAFLD diagnosis because it allows the exclusion of different causes of liver injury and it can estimate the severity of adipose infiltration in the liver, inflammation of the lobes, hepatocyte ballooning and fibrosis. Even though it is the gold standard, liver biopsy has some limits; it is an invasive procedure, it is associated with certain risks and its analysis can be influenced by pathologist s subjective judgment (3). An important issue that requires mentioning is the quality of non-invasive methods compared to liver biopsy for diagnosing NASH. Currently, the available noninvasive methods for NASH diagnosis are represented by signs and symptoms, biochemical tests and combinations of physical examination and laboratory tests. Once the NAFLD diagnosis is made, its severity should be assessed, which is useful to predict the disease course. When determining the NAFLD stage, 2 factors are related to severity: degree of fibrosis and of inflammation (4). Physical examination is non-specific for assessing the severity of NAFLD. The conditions usually associated with the severity of this disease include obesity, old age, diabetes mellitus and high blood pressure. Typical biomarkers only one biomarker cannot diagnose NAFLD or differentiate among steatohepatitis, NASH or liver cirrhosis. Even though a slightly elevated serum aminotransferase level is the first change noted in NAFLD patients, the transaminases are within normal ranges in most of these subjects. Moreover, all the histologic changes seen in NAFLD subjects may be associated with normal transaminases. Serum gamma-glutamyl transpeptidase (GGT) is usually elevated in NAFLD subjects and is reportedly associated with increased mortality. Despite this, the diagnosis of NAFLD cannot be made solely based on GGT levels (5). Inflammation a proinflammatory status typical to metabolic syndrome was shown to be related with the course of steatohepatitis and liver damage in NAFLD. Inflammatory markers may also have a diagnostic potential. A study (6) described a relationship between cytokine level and NASH. Moreover, the level of TNF-alpha correlates with the degree of inflammation and fibrosis. It has been found that adiponectin level is notably lower in the early stage of NASH as opposed to simple steatosis. Another study (7) reported a relationship between leptin, hormone produced in the adipose tissue, and the histologic appearance of hepatic parenchyma. Hyaluronic acid (HA) and CC-chemokine ligand 2 (CCL-2), which are also markers of inflammation, were also proved to be elevated in NASH subjects. Fibrosis Markers of fibrosis are represented by HA and type IV 7s collagen. In a study of 112 NAFLD subjects it has been noted that these 2 biomarkers could exclude late stages of fibrosis. In NAFLD patients, assessing HA levels has proved to be helpful in predicting advanced stages of fibrosis (8). Hepatocyte apoptosis has a major role 504

3 Is liver biopsy necessary in patients with nonalcoholic fatty liver disease? in liver damage in NAFLD subjects. Lately, a particular product of liver cell apoptosis, caspase cleaved fragments of Cytokeratin 18 (CK18) have proved to be significantly elevated in NASH patients, compared to steatosis patients or healthy subjects. Moreover, it has been shown that the serum CK18 level, measured by ELISA test, was significantly higher in NASH patients, compared to controls and steatohepatitis patients. CK18 proved to be a predictor of NASH. NASH patients who underwent metabolic surgery, procedure which was shown to have a favorable effect on BMI, had lower CK18levels (9). NON-INVASIVE METHODS Regarding biomarkers, different scores have been proposed in order to recognize NAFLD. SteatoTest - is a mix between FibroTest (which is a marker of fibrosis in patients with hepatitis B or C and alcoholic liver disease) and ActiTest (surrogate marker of hepatocyte necrosis in hepatitis B and C) and body mass index (BMI), triglycerides, cholesterol and blood sugar levels, adjusted for gender and age (10). Fatty liver index (FLI) (11) is a mixed method based on four parameters: waist circumference, BMI, triglycerides and GGT, which allows the prediction of fat deposition in the liver with an 84% certainty. The score was initially used to diagnose subjects at high risk of steatosis, who needed ultrasonography and lifestyle changes; then it was certified as marker of prognosis, used to predict the intima media thickness, coronary diseases, insulin resistance, but also the nine-year incident diabetes and atherosclerosis (12). Lipid accumulation product (LAP) is calculated using the waist circumference and the serum triglyceride levels; it was reported as a predictor for the risk of diabetes, cardiovascular diseases and mortality of all cause in patients with high risk of cardiovascular disease. The natural LAP logarithm, adjusted for gender, has a sufficient accuracy in recognizing subjects with liver steatosis who need ultrasonography (13). HAIR Score is useful for predicting NASH in patients suffering from severe obesity (BMI>35kg/m 2 ). This score is based on 3 factors; their presence being scored 1 point each: 1. Hypertension: 1 point; 2. ALT> 40UI/L: 1 point; 3. Insulin resistance index >5.0: 1 point. The total score is obtained by summing the scores for the 3 factors. A HAIR score of 3 practically confirms NASH (14). BAAT Score the presence of only one of the factors below rules out septal fibrosis and liver cirrhosis: 1. BMI>=28kg/m 2 : 1 point; 2. Age >=50: 1 point; 3. ALT (alanine aminotransferase) >= 2x (normal value): 1 point; 4. Triglycerides>=1.7mmol/L (150mg/dl): 1 point. A final score of 1 or 0 has a negative prognostic value of 100% for fibrosis (sensitivity 100% and specificity 46%) (15). NICE Model - is based on the presence of the metabolic syndrome (using International Diabetes Federation criteria), ALT levels and caspase-cleaved CK18 fragment levels (assessed through biopsy). A score of over or equal to 5 allows for the accurate diagnosis of NAFLD in patients with morbid obesity (16). NASH Score System for Morbidly Obese - consists of 6 parameters, namely obstructive sleep apnea, type 2 diabetes, hypertension, ALT>=27U/L, AST >=27U/L and Caucasian race. Two points are assigned to Caucasian race and one point is assigned to the rest of the five components. The probability of NASH is determined based on the summed points (17). Another study (18) reported that approximately 90% of the 505

4 R. S. Gavril et al. patients with early-stage NASH could be predicted by assessing the serum adiponectin level, serum type IV collagen 7S level and insulin resistance. Resistin and adiponectin are synthesized especially in fat tissue and play a major role in insulin resistance. Low levels of adiponectin are present in NAFLD patients. IMAGING METHODS Imaging methods cannot make the difference between NASH and steatosis, but the diagnosis they provide orient therapy designed to reduce the cardiovascular risk. Ultrasonography - is an available, noninvasive and cheap method used to detect hepatic steatosis; its specificity is 66-95% and sensitivity 60-94%; the assessment of liver steatosis is subjective, on a threepoint scale (severe, moderate and intermediate) (19). Computed tomography (CT) - permits a better analysis, superior to ultrasound, by measuring the mean liver attenuation in Hounsfield units (HU), but there is variability in interpreting hepatic attenuation on CT scans (19). Magnetic resonance imaging (MRI) for assessing liver steatosis two methods can be used: magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS). MRI has a 100% accuracy in detecting liver steatosis. Even though it is a highly accurate method for detecting and dynamically quantifying steatohepatitis, it is expensive and not readily available (20). Elastography (Fibroscan) Multiple meta-analyses suggest that liver stiffness measurement using Fibroscan is a useful method for the evaluation of early stages of cirrhosis and severe hepatic fibrosis. Acoustic radiation force impulse (ARFI) is a method by which the elastic properties of a surface are evaluated, giving realtime images in mode B. Unlike elastography, this method is not restricted to subjects with high BMI (21). Magnetic resonance elastography method used to study the elastic properties of an area of interest in the liver tissue (22). CONCLUSIONS Due to the high prevalence of NAFLD, we believe that cheap and non-invasive methods are needed in order to diagnose this hepatic impairment. Liver biopsy, regarded as the golden standard, has few benefits for patients (especially those with early-stage NAFLD who are more at risk of cardiovascular disease than hepatic complications); it is useful, however, in medical research, even if the ethical aspect remains a matter of debate. We conclude that non-invasive methods (risk scores, biomarkers and imaging methods) can replace liver biopsy in early stages of NAFLD. Further studies are required to validate new non-invasive diagnosis methods. REFERENCES 1. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of noninvasive tests for liver disease severity. Ann Med 2011; 43: Gavril RS. Non-alcoholic fatty liver disease (NAFLD): a new cardiovascular risk factor. Rom J Diabetes Nutr Metab Dis 2015; 22:

5 Is liver biopsy necessary in patients with nonalcoholic fatty liver disease? 3. Adams LA, Feldstein AE. Nonalcoholic steatohepatitis: risk factors and diagnosis. Expert Rev Gastroenterol Hepatol 2010; 4: Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of nonalcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2011; 33(5): Haring R, Wallaschofski H, Nauck M, Dorr M, Baumeister SE, Volzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50(5): Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 2008; 28(4): Haukeland JW, Damas JK, Konopski Z et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006; 44(6): Suzuki A, Angulo P, Lymp J, Li D, Satomura S, Lindor K. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease. Liver Int 2005; 25(4): Gherasim A, Arhire LI, Padureanu SS, Ungureanu C, Gavril RS, Mihalache L. Nutritional factors affecting weight loss at three months after laparoscopic sleeve gastrectomy. Obes Facts 2015; 8: Lassailly G, Caiazzo R, Hollebecque A et al. Validation of noninvasive biomarkers (FibroTest, SteatoTest, and NashTest) for prediction of liver injury in patients with morbid obesity. Eur J Gastroenterol Hepatol 2011; 23: Bedogni G, Bellentani S, Miglioli L et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006; 6: Balkau B, Lange C, Vol S, Fumeron F. Group Study D.E.S.I.R Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol 2010; 10: Bedogni G, Kahn HS, Bellentani S, Tiribelli C. A simple index of lipid over accumulation is a good marker of liver steatosis. BMC Gastroenterol 2010; 10: Dixon JB, Bhathal PS, O Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001; 121: Ratziu V, Giral P, Charlotte F et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: Anty R, Iannelli A, Patouraux S et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol Ther 2010; 32(11): Ulitsky A, Ananthakrishnan AN, Komorowski R et al. A noninvasive clinical scoring model predicts risk of nonalcoholic steatohepatitis in morbidly obese pacients. Obes Surg 2010; 20(6): Tarek I, Tamimi AR, Elogouhari HM et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol 2011; 54: Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Noninvasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol 2009; 51: Meisamy S, Hines CD, Hamilton G et al. Quantification of hepatic steatosis with T1-independent, T2- corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology 2011; 258: Friedrich-Rust M, Romen D, Vermehren J et al. Acoustic radiation force impulseimaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol 2012; 81: Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011; 259: