Approach to Patients with Elevated AFP without …

1 Approach to Patients with Elevated AFP without Liver MassCesar Yaghi MDHotel Dieu de FranceUniversit Saint Fetoprotein in HCC Levels greater than 500 mcg/L (normal in most laboratories is between 10 and 20 mcg/L) in a high-risk patient is diagnostic of HCC HCC is often diagnosed at a lower AFP level in Patients undergoing screening Not all tumors secrete AFP, and serum concentrations are normal in up to 40 percent of small HCCs AFP levels are normal in the majority of Patients with fibrolamellarcarcinomaAFP CutoffSensitivitySpecificity16 mcg/L 62%89 %20 mcg/L 60%91 %100 mcg/L 31%99 %200 mcg/L 22%99 %Conditions Associated with Increased Alpha Fetoprotein levelsLiver Related HCC Chronic liver disease without HCC may be slightly higher in Patients with cirrhosis due to hepatitis C In one report, serum AFP decreased significantly in Patients with cirrhosis from hepatitis C, treated with peginterferon plus ribavirin Acute hepatitis Acute Liver Failure in regenerative phaseOther Conditions Pregnancy Prenatal screening and diagnosis of neural tube defects abdominal wall defects (Beckwith-Wiedemannsyndrome)

2 Ovarian germ cell tumors Testicular germ cell tumors Tumors of the gastrointestinal tractCommon Serum Markers for Cancer Diagnosis/prognosisAFPCEACA15-3CA19-9CA1 25 PSAPSAfPAPhTGHCGbFerrNSEB2MA2 MLungxxxxxxxPancreasxxxxxKidneyxxxxBreas txxxOvarianxxxxxxCervicalxxUterinexxxxPr ostatexxxxxLiverxxxxxxGastroxxxxColonXxx xxxBladderxBrainxLeukemiaxxxMyelomaxThyr oidxxTesticularxxxxPrenatal screening and diagnosis of neural tube defects Alpha-fetoprotein Historically, maternal serum alpha-fetoprotein (AFP) has been used as a screening test for open NTDs. AFP can be measured in maternal serum, amniotic fluid, and fetal plasma. The maternal serum AFP (MSAFP) concentration is much lower than that in amniotic fluid or fetal plasma. It rises in early pregnancy, peaks between 28 and 32 weeks of gestation, and then falls TUMOR MARKERS IN OVARIAN MALIGNANCY Alpha-fetoproteinlevels are often >1000 ng/mL, especially with pure endodermal sinus (yolk sac) tumors Some types of ovarian germ cell tumors Endodermal sinus tumor, Embryonal carcinoma, Mixed tumors.

3 In the setting of pregnancy, Some suggest that a MSAFP level above 9 multiples of the median should prompt concern for germ cell tumors of either gonadal or nongonadal origin in the absence of fetal abdominal wall defects or anencephalyNonseminomatous germ cell tumors Three serum tumor markers have established roles in the management of men with testicular germ cell tumors: The beta subunit of human chorionic gonadotropin (beta-hCG) Alpha fetoprotein (AFP) Lactate dehydrogenase (LDH) Half-life of AFP The half-life of AFP is approximately five to seven days. Following effective therapy, normalization of the serum AFP concentration over 25 to 30 days is indicative of an appropriate declineLiver Related conditions HCV HBV NAFLD? Liver RegenerationPrevalence of Elevated AFP in Patients with CHC The reported prevalence of Elevated AFP in Patients with CHC varies from 10% to 43% the higher frequency of AFP elevations in women and blacks with chronic hepatitis C remains inadequately explainedChen, , Journal of Gastroenterology and Hepatology, 2007, 22: 669 675.

4 Adrian M. Di Bisceglie , Journal of Hepatology Volume 43, Issue 3 2005 434 - 441 Percent of Patients with raised AFP values at baselineDi Bisceglie , Journal of Hepatology Volume 43, Issue 3 2005 434 - 441 Serum alpha-fetoprotein levels in Patients with advanced hepatitis C: Results from the HALT-C TrialDeterminants of Serum AFP Levels in HCV Infected the presence of HCC, the AFP and ALT levels are nearly independent of one another. Sharp contrast with the strong positive correlation between AFP and ALT at all levels in the absence of Richardson, et al. Clin Gastroenterol Hepatol. 2012 April;10(4) effect modified by time to HCC diagnosis: Whole-body Insulin Resistance is Associated with Elevated Serum -fetoprotein Levels in Patients with Chronic Hepatitis CPrevalence of an Elevated -fetoprotein level ( 10 ng/mL) according to the (A) whole-body insulin sensitivity index and (B) hepatic fibrosis. Kawaguchi, Intern Med 52: 2393-2400, 2013 Whole-body Insulin Resistance is Associated with Elevated Serum -fetoprotein Levels in Patients with Chronic Hepatitis C Calorie intake of 25-35 kcal/ideal body weight/day according to the level of daily activity.

5 Exercise and Physical Activity Guide for Health Promotion Among the markers of glucose metabolism, FPG, FSI and HOMA-IR (p< ) decreased after the intervention, while WBISI increased [p< ]. The serum AFP level also decreased significantly after the intervention [p= ].Kawaguchi, Intern Med 52: 2393-2400, 2013 Predictors of AFP elevation in chronic HCV without HCCB aseline variablesRegression coefficientStandard errorOR (95% CI)P-valueAge, ( ) stage of ( ) , ( ) , 109/L ( ) , , Journal of Gastroenterology and Hepatology, 2007, 22: 669 675. Multivariate logistic regression for predicting AFP elevation at baseline ( 10 ng/mL) before treatmentOlder age and advanced disease severity, as reflected by low platelet counts and advanced fibrosis, predisposed CHC subjects without HCC to have Elevated serum AFP AFP levels in Patients treated for HCVNS creening Baseline Week 20 Week 48 Week 60 Week 60 HCV RNA negative (SVR) ( SD) serum AFP levels among Patients achieving a week 20 virologic response and going on to complete 48 weeks or treatment and a further 12 weeks of follow-upPredictors of AFP elevation in chronic HCV without HCCV ariablesRegression coefficientStandard error OR (95% CI) ( ) platelet at ( ) , , Journal of Gastroenterology and Hepatology, 2007, 22: 669 675.

6 Multivariatelogistic regression for predicting normal AFP (AFP <10 ng/mL) at EOF date after Peg-IFN/RBV combination therapyAfter Peg-IFN/RBV combination therapy, higher platelet counts and hepatitis C viral eradicationwere determinants of normal AFP at the EOF time point. Predicting AFP (AFP <10 ng/mL) normalization after PEG ribavirin therapy SVR (negative hepatitis C virus-RNA at EOF 48th week after treatment).HCVE stimated time to HCC according to AFP ( 20 ng/ml) and large cell Degos, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut. 2000 July;47(1) of interferon therapy on the natural history of hepatitis C virus related probability of HCC among treated and untreated Patients according to baseline fetoprotein (AFP) serum levels (treated AFP <20 ng/ml v untreated <20 ng/ml, ns; treated AFP 20 ng/ml v untreated AFP 20 ng/ml, p= ). Number of Patients at risk are shown in , et al. Gut. 2001 June;48(6):843-848.

7 FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCVA sahina, Hepatology 201358, (4) pages 1253-1262 FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCVA sahina, Hepatology 201358, (4) pages 1253-1262 FP after interferon therapy and risk of hepatocarcinogenesisin chronic HCV Post-IFN treatment ALT and AFP levels are significantly associated with hepatocarcinogenesis. Measurement of these values is useful for predicting future HCC risk after IFN , Hepatology 201358, (4) pages 1253-1262 Development of HCC in relation to AFP level, and stage of fibrosis in Patients with chronic hepatitis Rather than Virologic Response to Interferon Therapy may be More Closely Associated with Decrease of Hepatocellular Carcinoma Incidence in Patients with Chronic Hepatitis BGut Liver. 2007 June;1(1) value of alpha-fetoprotein in the long-term risk of developing HCC in Patients with HBV infection 617 Korean American Patients with HBV who had been followed for up to 22 years (median follow-up time, years)Cirrhosis: 227 patientsHie-Won Hann, et al.

8 Eur J Cancer. 2012 October;48(15) levels 100 ng/ml increases the risk of development of complications during acute exacerbation of HBV who developed complications of cirrhosisPatients without complications of cirrhosisp ValueAlbumin34 (17 50)45 (18 58)< (11 3370)42 (4 4820)< (3 323)11 (1 553)< (1 32202)4 (1 4991)< , Prognostic determinants for chronic hepatitis B in Asians: therapeutic implicationsGut. 2005 November;54(11) fetoprotein levels in non-alcoholic fatty liver disease Babali et al., reported the association of AFP with NAFLD10. In this study serum AFP levels were found to be higher in Patients with NAFLD when compared to those of healthy subjects NAFLD Patients according to their ultrasonography scores as described by Hamaguchi et al20; and further observed that subjects with grade 3 steatosis had higher AFP levels when compared with grade 1 and 2 steatosis. M. KARA: AFP serum levels were not different between two groups. In subgroup analysis, AFP levels were also found to be similar in Patients with NASH and SS.

9 No relationship was found between AFP and histopathological findings in Patients with , Hepatol Int (2009) 3:551 555 Kara, European Review for Medical and Pharmacological Sciences 2013; 17: 1536-1541 AFP in Acute Liver Failure In the course of liver injury associated with extensive necrosis, an increased serum alpha-fetoprotein level seems to be a sign of hepatic regeneration in response to liver injury, and is strongly associated with a favorable outcome in WB, Pan XP, Li LJ. Prognostic models for acute liver failure. Hepatobiliary Pancreat Dis Int 2010; 9(2): is a predictor of outcome in acetaminophen-induced liver injury 239 Patients with acetaminophen-induced ALF The threshold of had a sensitivity of 100%, a specificity of 74%, a positive predictive value of 45%, and a negative predictive value of 100%. In many cases, the increase in AFP preceded the decrease in INR and thereby provided additional prognostic et al, Hepatology, 2004; 41:26-31 Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injurySchmidt et al, Hepatology, 2004; 41:26-31 Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injurySchmidt et al, Hepatology, 2004; 41:26-31 AFP above g/L on the day after peak ALT was a highly discriminative indicator of survival from severe acetaminophen-induced liver injury.

10 Alpha-fetoprotein and prognosis in acute liver failure Prospective study from the US ALF study group 206 Patients various etiologies Higher absolute values of serum alpha-fetoprotein do not predict a favorable outcome Changes in AFP (AFP ratio) during ALF seem to be of prognostic valueSchiodt et al, Liver Transplantation2006; 12: 1776-1781 Spontaneous survivors Died or transplantedPA. All Patients (n = 206)AFP on admission (ng/mL) ( 1365) (1 1811)< on day 3 (ng/mL) ( 1162) (2 791) ( ) ( )< Acetaminophen Patients (n = 80)AFP on admission (ng/mL) ( 195) ( 114) on day 3 (ng/mL) (n = 67) ( 496) ( 99) ratio (n = 67) ( ) ( ) Nonacetaminophenpatients (n = 126)AFP on admission (ng/mL) ( 1365) ( 1811) on day 3 (ng/mL) (n = 95) ( 1162) ( 791) ratio (n = 95) ( ) ( )< et al, Liver Transplantation2006; 12: 1776-1781 Approach to Patients with Elevated AFP without Liver Mass Remember to look for other possible causes of increased AFP (Testicular, Ovarian, GI tract tumors, Pregnancy) HCV: Increased AFP following treatment increases the risk of HCC and warrants surveillance even in the absence of Cirrhosis HBV: Increased AFP puts the patient at higher risk of developing HCC Not Enough data in NAFLD In ALF, AFP may predict the outcome and may help in decision making in ALF