Approach to Patients with Elevated AFP without Liver Mass. Cesar Yaghi MD Hotel Dieu de France Université Saint Joseph

Transcription

1 Approach to Patients with Elevated AFP without Liver Mass Cesar Yaghi MD Hotel Dieu de France Université Saint Joseph

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3 Alpha 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 fibrolamellar carcinoma AFP Cutoff Sensitivity Specificity 16 mcg/l 62% 89 % 20 mcg/l 60% 91 % 100 mcg/l 31% 99 % 200 mcg/l 22% 99 %

4 Conditions Associated with Increased Alpha Fetoprotein levels Liver 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 phase Other Conditions Pregnancy Prenatal screening and diagnosis of neural tube defects abdominal wall defects (Beckwith-Wiedemann syndrome) Ovarian germ cell tumors Testicular germ cell tumors Tumors of the gastrointestinal tract

5 Common Serum Markers for Cancer Diagnosis/prognosis AFP CEA CA15-3 CA19-9 CA125 PSA PSAf PAP htg HCGb Ferr NSE B2M A2M Lung x x x x x x x Pancreas x x x x x Kidney x x x x Breast x x x Ovarian x x x x x x Cervical x x Uterine x x x x Prostate x x x x x Liver x x x x x x Gastro x x x x Colon X x x x x x Bladder x Brain x Leukemia x x x Myeloma x Thyroid x x Testicular x x x x

6 Prenatal 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

7 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, Embryonalcarcinoma, Mixed tumors. 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 nongonadalorigin in the absence of fetal abdominal wall defects or anencephaly

8 Nonseminomatousgerm 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 decline

9 Liver Related conditions HCV HBV NAFLD? Liver Regeneration

10 Prevalence 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 explained Chen, T.-M., Journal of Gastroenterology and Hepatology, 2007, 22: Adrian M. Di Bisceglie, Journal of HepatologyVolume 43, Issue

11 Serum alpha-fetoprotein levels in patients with advanced hepatitis C: Results from the HALT-C Trial Percent of patients with raised AFP values at baseline Di Bisceglie, Journal of HepatologyVolume 43, Issue

12 Determinants of Serum AFP Levels in In 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 HCC. HCV Infected Patients. ALT effect modified by time to HCC diagnosis: Peter Richardson, et al. Clin Gastroenterol Hepatol April;10(4):

13 Whole-body Insulin Resistance is Associated with Elevated Serum α-fetoprotein Levels in Patients with Chronic Hepatitis C Prevalence of an elevated α-fetoprotein level ( 10 ng/ml) according to the (A) whole-body insulin sensitivity index and (B) hepatic fibrosis. Kawaguchi, Intern Med 52: , 2013

14 Whole-body Insulin Resistance is Associated with Elevated Serum α-fetoprotein Levels in Patients with Chronic Hepatitis C Calorie intake of kcal/ideal body weight/day according to the level of daily activity. Exercise and Physical Activity Guide for Health Promotion Among the markers of glucose metabolism, FPG, FSI and HOMA-IR (p< 0.001) decreased after the intervention, while WBISI increased [p<0.001]. The serum AFP level also decreased significantly after the intervention [p=0.002]. Kawaguchi, Intern Med 52: , 2013

15 Predictors of AFP elevation in chronic HCV without HCC Older age and advanced disease severity, as reflected by low platelet counts and advanced fibrosis, predisposed CHC subjects without HCC to have elevated serum AFP levels. Baseline variables Regression coefficient Standard error OR (95% CI) P-value Age, year ( ) Fibrosis stage of METAVIR ( ) AST, IU/L ( ) Platelet, 109/L ( ) Multivariate logistic regression for predicting AFP elevation at baseline ( 10 ng/ml) before treatment Chen, T.-M., Journal of Gastroenterology and Hepatology, 2007, 22:

16 Serum AFP levels in Patients treated for HCV N Screening Baseline Week 20 Week 48 Week 60 Week 60 HCV RNA negative (SVR) Fibrosis ± ± ± ± ±1.4 Cirrhosis ± ± ± ± ±3.3 Mean (±SD) serum AFP levels among patients achieving a week 20 virologicresponse and going on to complete 48 weeks or treatment and a further 12 weeks of follow-up

17 Predictors of AFP elevation in chronic HCV without HCC Predicting AFP (AFP <10 ng/ml) normalization after PEG ribavirin therapy SVR (negative hepatitis C virus-rna at EOF 48th week after treatment). Variables Regression coefficient SVR Post-treatment platelet at EOF Standard error OR (95% CI) ( ) ( ) P-value Multivariatelogistic regression for predicting normal AFP (AFP <10 ng/ml) at EOF date after Peg-IFN/RBV combination therapy After Peg-IFN/RBV combination therapy, higher platelet counts and hepatitis C viral eradicationwere determinants of normal AFP at the EOF time point. Chen, T.-M., Journal of Gastroenterology and Hepatology, 2007, 22:

18 HCV Estimated time to HCC according to AFP (±20ng/ml) and large cell dysplasia. F Degos, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut July;47(1):

19 Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis. Cumulative probability of HCC among treated and untreated patients according to baseline αfetoprotein (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=0.0026). Number of patients at risk are shown in parentheses. Gramenzi, et al. Gut June;48(6):

20 α FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCV Asahina, Hepatology , (4) pages

21 α FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCV Asahina, Hepatology , (4) pages

22 Α FP after interferon therapy and risk of hepatocarcinogenesis in 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 treatment. Asahina, Hepatology , (4) pages

23 Development of HCC in relation to AFP level, and stage of fibrosis in patients with chronic hepatitis B. Biochemical Rather than Virologic Response to Interferon Therapy may be More Closely Associated with Decrease of Hepatocellular Carcinoma Incidence in Patients with Chronic Hepatitis B Gut Liver June;1(1):49-55.

24 Predictive value of alpha-fetoprotein in the long-term risk of developing HCC in patientswith HBV infection 617 Korean American patients with HBV who had been followed for up to 22 years (median follow-up time, 6.2 years) Cirrhosis: 227 patients Hie-Won Hann, et al. Eur J Cancer October;48(15):

25 AFP levels 100 ng/ml increases the risk of development of complications during acute exacerbation of HBV infection. Patients who developed complications of Patients without complications of cirrhosis cirrhosis p Value Albumin 34 (17 50) 45 (18 58) < ALT 59 ( ) 42 (4 4820) < Bilirubin 18 (3 323) 11 (1 553) < AFP 17.5 ( ) 4 (1 4991) < Yuen, Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications Gut November;54(11):

26 Alpha fetoprotein levels in non-alcoholic fatty liver disease Babaliet al., reported the association of AFP with NAFLD10. In this studyserum 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 Hamaguchiet al20; and further observed that subjects with grade 3 steatosishad 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. No relationship was found between AFP and histopathologicalfindings in patients with NAFLD. Babalı, Hepatol Int (2009) 3: Kara, European Review for Medical and Pharmacological Sciences 2013; 17:

27 AFP in Acute Liver Failure In the course of liver injury associated with extensive necrosis, an increased serum alphafetoprotein level seems to be a sign of hepatic regeneration in response to liver injury, and is strongly associated with a favorable outcome in ALF. Du WB, Pan XP, Li LJ. Prognostic models for acute liver failure. HepatobiliaryPancreatDis Int 2010; 9(2):

28 Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury 239 patients with acetaminophen-induced ALF The threshold of 3.9 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 information. Schmidt et al, Hepatology, 2004; 41:26-31

29 Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury Schmidt et al, Hepatology, 2004; 41:26-31

30 Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury AFP above 3.9 μg/l on the day after peak ALT was a highly discriminative indicator of survival from severe acetaminophen-induced liver injury. Schmidt et al, Hepatology, 2004; 41:26-31

31 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 value Schiodt et al, Liver Transplantation 2006; 12:

32 Spontaneous survivors Died or transplanted P A. All patients (n = 206) AFP on admission (ng/ml) 5.4 ( ) 14.9 (1 1811) <0.001 AFP on day 3 (ng/ml) 16.4 ( ) 17.9 (2 791) 0.34 AFP ratio 2.2 ( ) 0.87 ( ) <0.001 B. Acetaminophen patients (n = 80) AFP on admission (ng/ml) 3.7 ( ) 3.9 ( ) 0.74 AFP on day 3 (ng/ml) (n = 67) 12.3 ( ) 6.0 (2.7 99) 0.13 AFP ratio (n = 67) 2.6 ( ) 1.5 ( ) C. Nonacetaminophen patients (n = 126) AFP on admission (ng/ml) 19.4 ( ) 21.5 ( ) 0.43 AFP on day 3 (ng/ml) (n = 95) 28.4 ( ) 21.5 ( ) 0.57 AFP ratio (n = 95) 1.6 ( ) 0.81 ( ) <0.001 Schiodt et al, Liver Transplantation 2006; 12:

33 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