Factors That Affect Accuracy of α-Fetoprotein Test in Detection of Hepatocellular Carcinoma in Patients With Cirrhosis

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<ul><li><p>Clinical Gastroenterology and Hepatology 2014;12:870877Factors That Affect Accuracy of a-Fetoprotein Test in Detectionof Hepatocellular Carcinoma in Patients With Cirrhosis</p><p>Purva Gopal,* Adam C. Yopp,, Akbar K. Waljee,k, Jason Chiang,# Mahendra Nehra,#</p><p>Pragathi Kandunoori,# and Amit G. Singal,#,**</p><p>*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 &amp; 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 &lt; .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.</p><p> 2014 by the AGA Institute1542-3565/$36.00</p><p>http://dx.doi.org/10.1016/j.cgh.2013.09.053See related article, El-Serag HB et al, on page1249 in Gastroenterology.</p><p>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.</p><p>http://dx.doi.org/10.1016/j.cgh.2013.09.053http://linkinghub.elsevier.com/retrieve/doi/10.1053/j.gastro.2014.01.045</p></li><li><p>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</p><p>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</p><p>Study Population</p><p>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.</p><p>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.</p><p>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</p><p>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. Early stage HCC was defined using the Milancriteria (1 tumor </p></li><li><p>872 Gopal et al Clinical Gastroenterology and Hepatology Vol. 12, No. 5We determined the sensitivity, specificity, positivepredictive value, and negative predictive value of AFP forthe detection of HCC. We dichotomized AFP at a cut-offvalue of 20 ng/mL because this is the most commonlyreported and used cut-off value in clinical practice. Weassessed overall accuracy, indicating the degree of correctclassification, by the c-statistic using receiver operatorcharacteristic (ROC) curve analysis. A c-statistic rangesfrom 0 to 1, with 1 indicating perfect prediction and 0.5indicating prediction by chance alone; values between 0.7and 0.8 generally are considered acceptable.18</p><p>We determined predictors of sensitivity and specificityusing the Fisher exact test and the Mann-Whitney rank-sum tests for categoric and continuous variables, respec-tively. We assessed the following potential independentvariables: age, sex, race, ethnicity, body mass index, eti-ology of liver disease, presence of hepatic decompensa-tion, human immunodeficiency virus (HIV) serostatus,platelet count, creatinine, albumin, AST level, bilirubin,international normalized ratio, and tumor stage. Variablessignificant on univariate analysis were included in multi-variate logistic regression analysis. After Bonferroniadjustment, P values of .05 and .025 were consideredsignificant for univariate and multivariate analyses,respectively. We used the Delong method to comparec-statistics between groups and to identify predictors ofoverall accuracy. Finally, we determined new optimalcut-off values to maximize sensitivity and specificity inthese subgroups using ROC curve analysis. All data anal-ysis was conducted using Stata 11 (College Station, TX).Results</p><p>Patient Characteristics</p><p>Between January 2005 and June 2012, there were457 patients with cirrhosis who were diagnosed withHCC. We excluded 5 patients who did not have an AFPlevel before HCC diagnosis. Between January 2010 andJuly 2011, there were 914 patients with cirrhosis whowere seen in an outpatient setting at Parkland Hospital,of whom 238 patients were excluded for a lack of AFPlevel or insufficient follow-up duration.</p><p>The baseline characteristics of the remaining 1128patients (452 HCC and 676 non-HCC) are shown inTable 1. The median age of patients was 55 years, andthe majority of patients were men, with a higher pro-portion of men among HCC patients (78% vs 66%; P 40 U/L 2.50 1.284.88 1.93 0.814.58 71% vs 50%Platelet level &gt;100,000/mL 1.64 1.082.49 1.25 0.742.13 73% vs 62%Bilirubin level &gt;2 mg/dL 1.67 1.072.61 1.23 0.702.16 77% vs 66%</p><p>SpecificityHCV etiology 0.11 0.050.25 0.18 0.080.41 83% vs 98%AST level &gt;40 U/L 0.24 0.130.43 0.06 0.010.42 87% vs 99%Black race 0.31 0.180.52 0.47 0.270.81 80% vs 93%</p><p>aEarly stage HCC was defined using the Milan criteria (1 tumor </p></li><li><p>Table 4. Performance Characteristics of AFP for Detection of HCC by HCV Status</p><p>Sensitivity SpecificityPercentage</p><p>classified correctlyPositive</p><p>likelihood ratioNegative</p><p>likelihood ratio</p><p>HCV-positive patients20 ng/mL 70.4% 82.6% 76.9% 4.0 0.3659 ng/mLa 59.6% 93.9% 78.0% 9.8 0.43200 ng/mL 45.9% 98.9% 74.3% 41.5 0.55</p><p>HCV-negative patients11 ng/mLa 74.6% 96.2% 89.6% 19.5 0.2620 ng/mL 69.6% 98.0% 89.4% 36.3 0.31200 ng/mL 60.1% 100% 87.6% 190 0.41</p><p>aNewly derived optimal cut-off value to maximize accuracy.</p><p>May 2014 Predictors of AFP for Detection of HCC 875the prevalence likely has peaked.1 With the growingepidemic of obesity and diabetes, NASH is anticipated tobe the major etiology for HCC in the future. In addition tothis shift in epidemiology, ultrasound may be less sen-sitive for the detection of HCC in obese patients, creatinga need for effective biomarkers that can be used incombination.4,7 Among patients with NAFLD in ourstudy, AFP had a sensitivity and specificity greater than80%, and strong accuracy (c-statistic, 0.81).</p><p>Implementing different AFP cut-off values for HCV-positive and HCV-negative patients could, in part, miti-gate any difference in AFP accuracy. Patients withoutHCV infection appear to have less nontumoral secretionof AFP, so even low-level AFP increases in these patientsshould raise suspicion for the development of HCC. Incontrast, patients with HCV infection often haveincreased AFP levels in the absence of HCC so thosewith low-level increases may be able to be monitoredclosely in most cases.10 Although we found cut-off valuesof 11 ng/mL and 59 ng/mL for HCV-negative andHCV-positive patients, respectively, further studies arenecessary to confirm our results and validate optimalcut-off values.</p><p>In addition to HCV infection, we found several othercharacteristics that influenced the sensitivity and/orspecificity of AFP, including AST level, black race, and HIVstatus. The association between AST levels and AFPspecificity is not surprising because AFP can be secretedfrom nontumoral cells in states of high cell turnover.Similar findings were reported previously in an ancillarystudy from the Hepatitis C Antiviral Long-term TreatmentAgainst Cirrhosis (HALT-C) Trial, in which increasedse...</p></li></ul>