Diagnosis of Nonalcoholic Fatty Liver Disease: Invasive versus Noninvasive

 

 Buy Article Permissions and Reprints

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and many other parts of the world. Its prevalence continues to rise—currently affecting ~20 to 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign nonprogressive clinical course, to steatohepatitis or NASH, a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Although currently a combination of noninvasive clinically available laboratory and imaging tests may help in the diagnostic evaluation of a patient with suspected NAFLD, a liver biopsy remains the only reliable way to precisely diagnose NASH and establish the severity of liver injury and presence of fibrosis. It also provides important information regarding prognosis as well as response to therapeutic interventions. However, a liver biopsy is an invasive and costly procedure, which is poorly suited as a diagnostic test for a condition that may affect about one-third of the U.S. population. This review provides a concise overview of the role of liver biopsy versus noninvasive diagnostic tools for the differentiation of fatty liver from nonalcoholic steatohepatitis as well as for the determination of presence and extent of fibrosis. In particular, this review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on potential future markers under investigation.

REFERENCES

• 1 Angulo P. Nonalcoholic fatty liver disease.  N Engl J Med. 2002;  346 1221-1231
  CrossrefPubMedGoogle Scholar
• 2 Wieckowska A, Feldstein A E. Nonalcoholic fatty liver disease in the pediatric population: a review.  Curr Opin Pediatr. 2005;  17 636-641
  CrossrefPubMedGoogle Scholar
• 3 Adams L A, Lymp J F, St Sauver J et al.. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.  Gastroenterology. 2005;  129 113-121
  CrossrefPubMedGoogle Scholar
• 4 Matteoni C A, Younossi Z M, Gramlich T, Boparai N, Liu Y C, McCullough A J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.  Gastroenterology. 1999;  116 1413-1419
  CrossrefPubMedGoogle Scholar
• 5 Ekstedt M, Franzen L E, Mathiesen U L et al.. Long-term follow-up of patients with NAFLD and elevated liver enzymes.  Hepatology. 2006;  44 865-873
  CrossrefPubMedGoogle Scholar
• 6 Dam-Larsen S, Franzmann M, Andersen I B et al.. Long term prognosis of fatty liver: risk of chronic liver disease and death.  Gut. 2004;  53 750-755
  CrossrefPubMedGoogle Scholar
• 7 Wieckowska A, McCullough A J, Feldstein A E. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future.  Hepatology. 2007;  46(2) 582-589
  CrossrefPubMedGoogle Scholar
• 8 Ramesh S, Sanyal A J. Hepatitis C and nonalcoholic fatty liver disease.  Semin Liver Dis. 2004;  24 399-413
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Ludwig J, Viggiano T R, McGill D B, Oh B J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.  Mayo Clin Proc. 1980;  55 434-438
  PubMedGoogle Scholar
• 10 Yeh M M, Brunt E M. Pathology of nonalcoholic fatty liver disease.  Am J Clin Pathol. 2007;  128 837-847
  CrossrefPubMedGoogle Scholar
• 11 Brunt E M. Pathology of fatty liver disease.  Mod Pathol. 2007;  20(suppl 1) S40-S48
  CrossrefPubMedGoogle Scholar
• 12 Schwimmer J B, Behling C, Newbury R et al.. Histopathology of pediatric nonalcoholic fatty liver disease.  Hepatology. 2005;  42 641-649
  CrossrefPubMedGoogle Scholar
• 13 Kleiner D E, Brunt E M, Van Natta M et al.. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.  Hepatology. 2005;  41 1313-1321
  CrossrefPubMedGoogle Scholar
• 14 Brunt E M, Janney C G, Di Bisceglie A M, Neuschwander-Tetri B A, Bacon B R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.  Am J Gastroenterol. 1999;  94 2467-2474
  CrossrefPubMedGoogle Scholar
• 15 Adams L A, Sanderson S, Lindor K D, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.  J Hepatol. 2005;  42 132-138
  CrossrefPubMedGoogle Scholar
• 16 Coton T, Matton T, Pecarrere J L, Monchy D, Debonne J M. Interobserver reproducibility of the Knodell score and the Metavir score in chronic viral hepatitis C: results of 60 liver biopsies.  Gastroenterol Clin Biol. 2001;  25 915-916
  PubMedGoogle Scholar
• 17 Ong J P, Younossi Z M. Approach to the diagnosis and treatment of nonalcoholic fatty liver disease.  Clin Liver Dis. 2005;  9 617-634 vi
  CrossrefPubMedGoogle Scholar
• 18 Adams L A, Angulo P. Role of liver biopsy and serum markers of liver fibrosis in non-alcoholic fatty liver disease.  Clin Liver Dis. 2007;  11 25-35
  CrossrefPubMedGoogle Scholar
• 19 Ratziu V, Bugianesi E, Dixon J et al.. Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.  Aliment Pharmacol Ther. 2007;  26 821-830
  PubMedGoogle Scholar
• 20 Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy: a multicentre retrospective study on 68,276 biopsies.  J Hepatol. 1986;  2 165-173
  CrossrefPubMedGoogle Scholar
• 21 Ratziu V, Charlotte F, Heurtier A et al.. Sampling variability of liver biopsy in nonalcoholic fatty liver disease.  Gastroenterology. 2005;  128 1898-1906
  CrossrefPubMedGoogle Scholar
• 22 Merriman R B, Ferrell L D, Patti M G et al.. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease.  Hepatology. 2006;  44 874-880
  CrossrefPubMedGoogle Scholar
• 23 Janiec D J, Jacobson E R, Freeth A, Spaulding L, Blaszyk H. Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies.  Obes Surg. 2005;  15 497-501
  CrossrefPubMedGoogle Scholar
• 24 Younossi Z M, Gramlich T, Liu Y C et al.. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations.  Mod Pathol. 1998;  11 560-565
  PubMedGoogle Scholar
• 25 Adams L A, Talwalkar J A. Diagnostic evaluation of nonalcoholic fatty liver disease.  J Clin Gastroenterol. 2006;  40 S34-S38
  PubMedGoogle Scholar
• 26 Yano E, Tagawa K, Yamaoka K, Mori M. Test validity of periodic liver function tests in a population of Japanese male bank employees.  J Clin Epidemiol. 2001;  54 945-951
  CrossrefPubMedGoogle Scholar
• 27 Nomura K, Yano E, Shinozaki T, Tagawa K. Efficacy and effectiveness of liver screening program to detect fatty liver in the periodic health check-ups.  J Occup Health. 2004;  46 423-428
  CrossrefPubMedGoogle Scholar
• 28 Ipekci S H, Basaranoglu M, Sonsuz A. The fluctuation of serum levels of aminotransferase in patients with nonalcoholic steatohepatitis.  J Clin Gastroenterol. 2003;  36 371
  CrossrefPubMedGoogle Scholar
• 29 Mofrad P, Contos M J, Haque M et al.. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.  Hepatology. 2003;  37 1286-1292
  CrossrefPubMedGoogle Scholar
• 30 Kunde S S, Lazenby A J, Clements R H, Abrams G A. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women.  Hepatology. 2005;  42 650-656
  CrossrefPubMedGoogle Scholar
• 31 Suzuki A, Lymp J, Sauver J S, Angulo P, Lindor K. Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis.  Liver Int. 2006;  26 1209-1216
  CrossrefPubMedGoogle Scholar
• 32 Lindor K D, Kowdley K V, Heathcote E J et al.. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.  Hepatology. 2004;  39 770-778
  CrossrefPubMedGoogle Scholar
• 33 Brunt E M, Neuschwander-Tetri B A, Oliver D, Wehmeier K R, Bacon B R. Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens.  Hum Pathol. 2004;  35 1070-1082
  CrossrefPubMedGoogle Scholar
• 34 Angulo P, Keach J C, Batts K P, Lindor K D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.  Hepatology. 1999;  30 1356-1362
  CrossrefPubMedGoogle Scholar
• 35 Dixon J B, Bhathal P S, O'Brien P E. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.  Gastroenterology. 2001;  121 91-100
  CrossrefPubMedGoogle Scholar
• 36 Palekar N A, Naus R, Larson S P, Ward J, Harrison S A. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease.  Liver Int. 2006;  26 151-156
  CrossrefPubMedGoogle Scholar
• 37 Gholam P M, Flancbaum L, Machan J T, Charney D A, Kotler D P. Nonalcoholic fatty liver disease in severely obese subjects.  Am J Gastroenterol. 2007;  102 399-408
  CrossrefPubMedGoogle Scholar
• 38 Poynard T, Ratziu V, Charlotte F et al.. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease.  BMC Gastroenterol. 2006;  6 34
  CrossrefPubMedGoogle Scholar
• 39 Zein C O, Edmison J, Schluchter M, Feldstein A E, Zein N N, McCullough A JA. NASH predictive index (NPI) for use in patients with nonalcoholic fatty liver disease.  Hepatology. 2007;  46 747A
  PubMedGoogle Scholar
• 40 Ratziu V, Giral P, Charlotte F et al.. Liver fibrosis in overweight patients.  Gastroenterology. 2000;  118 1117-1123
  CrossrefPubMedGoogle Scholar
• 41 Ratziu V, Massard J, Charlotte F et al.. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease.  BMC Gastroenterol. 2006;  6 6
  CrossrefPubMedGoogle Scholar
• 42 Angulo P, Hui J M, Marchesini G et al.. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.  Hepatology. 2007;  45 846-854
  CrossrefPubMedGoogle Scholar
• 43 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;  25 779-786
  CrossrefPubMedGoogle Scholar
• 44 Lydatakis H, Hager I P, Kostadelou E, Mpousmpoulas S, Pappas S, Diamantis I. Non-invasive markers to predict the liver fibrosis in non-alcoholic fatty liver disease.  Liver Int. 2006;  26 864-871
  CrossrefPubMedGoogle Scholar
• 45 Rosenberg W M, Voelker M, Thiel R et al.. Serum markers detect the presence of liver fibrosis: a cohort study.  Gastroenterology. 2004;  127 1704-1713
  CrossrefPubMedGoogle Scholar
• 46 Guha I N, Parkes J, Roderick P et al.. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers.  Hepatology. 2008;  47 455-460
  CrossrefPubMedGoogle Scholar
• 47 Mishra P, Younossi Z M. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD).  Am J Gastroenterol. 2007;  102 2716-2717
  CrossrefPubMedGoogle Scholar
• 48 Strauss S, Gavish E, Gottlieb P, Katsnelson L. Interobserver and intraobserver variability in the sonographic assessment of fatty liver.  AJR Am J Roentgenol. 2007;  189 W320-W323
  CrossrefPubMedGoogle Scholar
• 49 Hamaguchi M, Kojima T, Itoh Y et al.. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation.  Am J Gastroenterol. 2007;  102 2708-2715
  CrossrefPubMedGoogle Scholar
• 50 Ryan C K, Johnson L A, Germin B I, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.  Liver Transpl. 2002;  8 1114-1122
  CrossrefPubMedGoogle Scholar
• 51 Mottin C C, Moretto M, Padoin A V et al.. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients.  Obes Surg. 2004;  14 635-637
  CrossrefPubMedGoogle Scholar
• 52 Thomas E L, Hamilton G, Patel N et al.. Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study.  Gut. 2005;  54 122-127
  CrossrefPubMedGoogle Scholar
• 53 Szczepaniak L S, Babcock E E, Schick F et al.. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo.  Am J Physiol. 1999;  276 E977-E989
  PubMedGoogle Scholar
• 54 Browning J D, Szczepaniak L S, Dobbins R et al.. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.  Hepatology. 2004;  40 1387-1395
  CrossrefPubMedGoogle Scholar
• 55 Saadeh S, Younossi Z M, Remer E M et al.. The utility of radiological imaging in nonalcoholic fatty liver disease.  Gastroenterology. 2002;  123 745-750
  CrossrefPubMedGoogle Scholar
• 56 Castera L, Pawlotsky J M. Noninvasive diagnosis of liver fibrosis in patients with chronic hepatitis C.  MedGenMed. 2005;  7 39
  PubMedGoogle Scholar
• 57 Foucher J, Castera L, Bernard P H et al.. Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations.  Eur J Gastroenterol Hepatol. 2006;  18 411-412
  CrossrefPubMedGoogle Scholar
• 58 Oliveira C P, da Costa Gayotto L C, Tatai C et al.. Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet.  J Cell Mol Med. 2002;  6 399-406
  CrossrefPubMedGoogle Scholar
• 59 Roskams T, Yang S Q, Koteish A et al.. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease.  Am J Pathol. 2003;  163 1301-1311
  CrossrefPubMedGoogle Scholar
• 60 Day C P. Pathogenesis of steatohepatitis.  Best Pract Res Clin Gastroenterol. 2002;  16 663-678
  CrossrefPubMedGoogle Scholar
• 61 Wanless I R, Shiota K. The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis.  Semin Liver Dis. 2004;  24 99-106
  Article in Thieme ConnectPubMedGoogle Scholar
• 62 Bonnefont-Rousselot D, Ratziu V, Giral P, Charlotte F, Beucler I, Poynard T. Blood oxidative stress markers are unreliable markers of hepatic steatosis.  Aliment Pharmacol Ther. 2006;  23 91-98
  CrossrefPubMedGoogle Scholar
• 63 Chalasani N, Deeg M A, Crabb D W. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis.  Am J Gastroenterol. 2004;  99 1497-1502
  CrossrefPubMedGoogle Scholar
• 64 Horoz M, Bolukbas C, Bolukbas F F et al.. Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis.  BMC Gastroenterol. 2005;  5 35
  CrossrefPubMedGoogle Scholar
• 65 Solga S F, Alkhuraishe A, Cope K et al.. Breath biomarkers and non-alcoholic fatty liver disease: preliminary observations.  Biomarkers. 2006;  11 174-183
  CrossrefPubMedGoogle Scholar
• 66 Diehl A M. Nonalcoholic fatty liver disease: implications for alcoholic liver disease pathogenesis.  Alcohol Clin Exp Res. 2001;  25 8S-14S
  PubMedGoogle Scholar
• 67 Diehl A M. Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease.  Clin Liver Dis. 2004;  8 619-638 x
  PubMedGoogle Scholar
• 68 Abiru S, Migita K, Maeda Y et al.. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis.  Liver Int. 2006;  26 39-45
  CrossrefPubMedGoogle Scholar
• 69 Feldstein A E, Werneburg N W, Canbay A et al.. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.  Hepatology. 2004;  40 185-194
  CrossrefPubMedGoogle Scholar
• 70 Hui J M, Hodge A, Farrell G C, Kench J G, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?.  Hepatology. 2004;  40 46-54
  CrossrefPubMedGoogle Scholar
• 71 Li Z, Yang S, Lin H et al.. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.  Hepatology. 2003;  37 343-350
  CrossrefPubMedGoogle Scholar
• 72 Xu H, Uysal K T, Becherer J D, Arner P, Hotamisligil G S. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity.  Diabetes. 2002;  51 1876-1883
  CrossrefPubMedGoogle Scholar
• 73 Haukeland J W, Damas J K, Konopski Z et al.. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2.  J Hepatol. 2006;  44 1167-1174
  CrossrefPubMedGoogle Scholar
• 74 Hui J M, Farrell G C, Kench J G, George J. High sensitivity C-reactive protein values do not reliably predict the severity of histological changes in NAFLD.  Hepatology. 2004;  39 1458-1459
  CrossrefPubMedGoogle Scholar
• 75 Feldstein A E, Canbay A, Angulo P et al.. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.  Gastroenterology. 2003;  125 437-443
  CrossrefPubMedGoogle Scholar
• 76 Feldstein A E, Canbay A, Guicciardi M E, Higuchi H, Bronk S F, Gores G J. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice.  J Hepatol. 2003;  39 978-983
  CrossrefPubMedGoogle Scholar
• 77 Feldstein A E, Gores G J. Apoptosis in alcoholic and nonalcoholic steatohepatitis.  Front Biosci. 2005;  10 3093-3099
  CrossrefPubMedGoogle Scholar
• 78 Feldstein A E, Werneburg N W, Li Z, Bronk S F, Gores G J. Bax inhibition protects against free fatty acid-induced lysosomal permeabilization.  Am J Physiol Gastrointest Liver Physiol. 2006;  290 G1339-G1346
  CrossrefPubMedGoogle Scholar
• 79 Li Z, Berk M, McIntyre T M, Gores G J, Feldstein A E. The lysosomal-mitochondrial axis in free fatty acids induced hepatic lipotoxicity.  Hepatology. 2008;  47 1495-1503
  CrossrefPubMedGoogle Scholar
• 80 Wieckowska A, Zein N N, Yerian L M, Lopez A R, McCullough A J, Feldstein A E. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.  Hepatology. 2006;  44 27-33
  CrossrefPubMedGoogle Scholar
• 81 Wieckowska A, Lopez A R, Zein N N, McCullough A J, Feldstein A E. Noninvasive assessment of hepatocyte apoptosis in nonalcoholic fatty liver disease: a multi-center validation study.  Gastroenterology. 2007;  132 A729
  PubMedGoogle Scholar
• 82 Day C P. Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.  Liver Int. 2006;  26 1021-1028
  CrossrefPubMedGoogle Scholar
• 83 Huang H, Shiffman M L, Cheung R C et al.. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2006;  130 1679-1687
  CrossrefPubMedGoogle Scholar

Ariel E FeldsteinM.D. 

Departments of Pediatric Gastroenterology and Cell Biology, Cleveland Clinic

9500 Euclid Avenue, Cleveland, Ohio 44195

Email: feldsta@ccf.org