Clinical Gastroenterology and Hepatology 2014;12:870877Factors That Affect Accuracy of a-Fetoprotein Test in Detectionof Hepatocellular Carcinoma in Patients With Cirrhosis
Purva Gopal,* Adam C. Yopp,, Akbar K. Waljee,k, Jason Chiang,# Mahendra Nehra,#
Pragathi Kandunoori,# and Amit G. Singal,#,**
*Department of Pathology, Department of Surgery, Harold C Simmons Cancer Center, #Department of Internal Medicine,**Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; kDepartment of InternalMedicine, University of Michigan, Ann Arbor, Michigan; and Center for Clinical Management Research, Ann Arbor VeteransAffairs Healthcare Systems, Ann Arbor, MichiganBACKGROUND & AIMS: Measurements of a-fetoprotein (AFP) detect hepatocellular carcinoma (HCC) with low levels ofsensitivity and specificity, and therefore are not recommended for use in liver cancer surveil-lance. However, AFP levels might accurately detect HCC in subgroups of patients. We performeda retrospective case-control study to identify features of patients with cirrhosis in whom levelsof AFP correlated with HCC.METHODS: We collected data from patients with cirrhosis, with (n [ 452) or without (n [ 676) HCC,diagnosed at Parkland Hospital in Dallas, Texas, from January 2005 through June 2012. Wedetermined sensitivities and specificities with which different levels of AFP identified thosewith HCC; multivariate logistic regression was used to associate accurate identification of HCCwith patient features (age, sex, race/ethnicity, alcohol intake, smoking, etiology of cirrhosis,presence of decompensation, and laboratory test results). We assessed the overall accuracy ofthese factors in detecting HCC using receiver operator characteristic curve analysis and theDelong method. We calculated levels of AFP that detect HCC with the highest levels of sensitivityand specificity in subgroups using receiver operator characteristic analysis.RESULTS: Themost common etiologies of cirrhosis were hepatitis C virus (HCV) infection (60%) and alcoholinduced (22%). Nearly 11%of patientswere human immunodeficiency virus (HIV)-positive. Levelsof AFP greater than 20 ng/mL detected HCC with 70.1% sensitivity and 89.8% specificity. This AFPlevel identified patients with HCC with a c-statistic of 0.87 (95% confidence interval, 0.850.89); itwas significantly more accurate in HCV-negative patients than in HCV-positive patients (c-statistic,0.89 vs 0.83; P[ .007). AFP levels of 59 ng/mL or greatermost accurately detected HCC in patientswith HCV-associated cirrhosis; levels of AFP of 11 ng/mL or greater accurately identified HCC inHCV-negative patients. The level of AFP identified early stage HCC with a c-statistic of 0.62 (95%confidence interval, 0.580.66), and had a significantly higher level of accuracy for HIV-positivepatients than for HIV-negative patients (c-statistic, 0.81 vs 0.59; P < .001).CONCLUSIONS: Based on a retrospective analysis of data from patients with cirrhosis, with or without HCC, AFPlevel most accurately detects HCC in patients without HCV infection. It detects HCC with a highlevel of accuracy in patients with cirrhosis and HIV infection.Keywords: Biomarkers; Liver Disease; AIDS; Screening.Abbreviations used in this paper: AASLD, American Association for the Studyof Liver Diseases; AFP, a-fetoprotein; ALT, alanine aminotransferase; AST,aspartate aminotransferase; CI, confidence interval; HBV, hepatitis B virus;HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immu-nodeficiency virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalco-holic steatohepatitis; OR, odds ratio; ROC, receiver operator characteristic.
2014 by the AGA Institute1542-3565/$36.00
http://dx.doi.org/10.1016/j.cgh.2013.09.053See related article, El-Serag HB et al, on page1249 in Gastroenterology.
Hepatocellular carcinoma (HCC) is the fifth mostcommon cause of cancer and the third leadingcause of cancer-related death worldwide.1 Within theUnited States and Europe, its incidence is increasingrapidly, largely driven by the current epidemic of hepati-tis C virus (HCV) and nonalcoholic fatty liver disease(NAFLD) cases.2 Prognosis for patients with HCCdepends on tumor stage at diagnosis, with curative op-tions available only for patients diagnosed at an earlystage.
May 2014 Predictors of AFP for Detection of HCC 871Surveillance with ultrasound alone at 6-month intervalsis recommended in patients with cirrhosis to detect HCC atan early stage.3 However, ultrasound remains operator-dependent, with a large gap between its efficacy and itseffectiveness in clinical practice, creating a need for effec-tive complementary biomarkers.47 a-fetoprotein (AFP),the best-studied serologic test, is attractive for surveillancebecause it is relatively inexpensive and easily obtainable.However, the most recent guidelines from the AmericanAssociation for the Study of Liver Diseases (AASLD) nolonger recommend using AFP, citing poor sensitivity andspecificity of AFP for early stage HCC. At a cut-off value of20 ng/mL, the most commonly used cut-off value in clin-ical practice, AFP has a sensitivity and specificity ofapproximately 60% and 80% for HCC, respectively.8
However, most studies have assumed that AFP per-forms equally well in all patients, independent of liverdisease etiology or severity. AFP has been shown to beincreased in several states of liver injury, including acuteliver failure, suggesting decreased specificity in cases withhigh cell turnover.9,10 Furthermore, the specificity of AFPmay vary by patient characteristics, such as sex andrace.6,1012 Many of the prior studies were limited by arelatively small sample size, inclusion of patients withonly HCV or hepatitis B virus (HBV) infection, and theinclusion of patients without cirrhosis.10,13,14 However,the majority of HCC patients in the United States andEurope have underlying cirrhosis at the time of diag-nosis,2,15 and the inclusion of patients withmilder degreesof liver disease, who carry a low risk of HCC, may haveunfairly biased results of prior studies, so the accuracy ofAFP has been underestimated. Therefore, the primary aimof our study was to identify determinants for sensitivity,specificity, and overall accuracy of AFP in a cohort ofpatients with cirrhosis. A secondary aim of our study wasto define new potential cut-off values for AFP in the sub-groups of patients in whom accuracy varies.Methods
We conducted a retrospective case-control study ofcirrhotic patients with and without HCC at Parkland Me-morial Health and Hospital System, the safety-net systemfor Dallas County. With 11 primary care clinics in low-income neighborhoods, the Parkland Memorial Health andHospital System cares for a large proportion of patientswith cirrhosis as well as patients with HCC in Dallas County.Furthermore, Parkland Hospital is one of the few safety-nethospitals with an integrated electronic medical record forthe hospital and clinics, including primary care clinics.
We included all patients diagnosedwith HCC at ParklandHospital between January 2005 and June 2012. As previ-ously described, patientswere identifiedbya combination ofInternational Classification of Diseases, 9th revision, codesfor HCC (155.0 or 155.2), a prospectively maintained list ofpatients seen in a multidisciplinary liver tumor clinic, andtumor conference presentation lists.16 Two authors (A.G.S.andA.C.Y.) adjudicatedallHCCcases to confirmthat theymetdiagnostic criteria, based on AASLD guidelines.We excludedpatientswhodidnot have anAFP level beforeHCCdiagnosis.
Our control population consisted of patients withcirrhosis who were seen at Parkland Hospital betweenJanuary 2010 and July 2011. Patients initially were identifiedusing a previously validated combination of InternationalClassification of Diseases, 9th revision, codes.17 Patientswere required to have at least one outpatient appointmentduring this time period to suggest that Parkland Hospitalwas their medical home. We excluded patients with anysuspicious liver mass on imaging and those who did nothave an AFP test during the study period (January 2010July2011). Patients were required to have at least 6 months offollow-up evaluation to confirm the absence of HCC. Thisstudy was approved by the Institutional Review Board of theUniversity of Texas Southwestern Medical Center.Data Collection
Patient demographics, clinical history, laboratory data,and imaging results were obtained through review ofcomputerized and paper medical records. Two in-vestigators (A.G.S. and A.C.Y.) independently extracted in-formation regarding HCC patients using standardizedforms, with discrepancies resolved through consensus.Similarly, 2 investigators (M.N. and P.K.) independentlyextracted information regarding non-HCC patients usingstandardized forms, with a third investigator (A.G.S.)available to resolve discrepancies. Age, sex, race/ethnicity,and lifetime alcohol and smoking history were recorded,with active alcohol abuse defined as drinkingmore than 40g/day of alcohol. Data regarding liver disease includedunderlying etiology and the presence of decompensation(ascites or encephalopathy). We classified patients ac-cording to etiology of liver disease, including HCV, HBV,alcohol-related liver disease, NAFLD, and other. Laboratorydata of interest included platelet count, creatinine, aspar-tate aminotransferase (AST), alanine aminotransferase(ALT), bilirubin, albumin, international normalized ratio,and AFP. We assessed the latest laboratory values betweenJanuary 2010 and July 2011 in non-HCC patients and thelaboratory values before diagnosis in those with HCC. Tu-mor characteristics were determined by imaging studies,which all had been interpreted by radiologists at ourinstitution.