Approach to Patients with

Elevated AFP without Liver Mass

Cesar Yaghi MD

Hotel Dieu de France

Université Saint Joseph

cesar.yaghi@usj.edu.lb

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 fibrolamellarcarcinoma

AFP Cutoff Sensitivity Specificity

16 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 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-Wiedemannsyndrome)

• Ovarian germ cell tumors

• Testicular germ cell tumors

• Tumors of the gastrointestinal tract

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

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

TUMOR MARKERS IN OVARIAN

MALIGNANCY

• Alpha-fetoprotein levels 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.

– 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 anencephaly

Nonseminomatous 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 decline

Liver Related conditions

• HCV

• HBV

• NAFLD?

• Liver Regeneration

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: 669–675.

Adrian M. Di Bisceglie , Journal of Hepatology Volume 43, Issue 3 2005 434 - 441

Percent of patients with raised AFP values at baseline

Di 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

Trial

Determinants of Serum AFP Levels in

HCV Infected Patients.

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.

Peter Richardson, et al. Clin Gastroenterol Hepatol. 2012 April;10(4):428-433.

ALT effect modified by time to HCC diagnosis:

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: 2393-2400, 2013

Whole-body Insulin Resistance is Associated with Elevated

Serum α-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.

• 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: 2393-2400, 2013

Predictors of AFP elevation in chronic

HCV without HCC

Baseline

variables

Regression

coefficientStandard error OR (95% CI) P-value

Age, year 0.089 0.038 1.093 (1.015–1.177) 0.018

Fibrosis stage of

METAVIR1.656 0.733 5.237 (1.244–22.037) 0.024

AST, IU/L 0.02 0.006 1.020 (1.008–1.033) 0.001

Platelet, ×109/L −0.197 0.007 0.985 (0.968–0.994) 0.003

Chen, T.-M., Journal of Gastroenterology and Hepatology, 2007, 22: 669–675.

Multivariate logistic regression for predicting AFP elevation at baseline (≥10 ng/mL)

before treatment

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.

Serum AFP levels in Patients treated

for HCV

N Screening Baseline Week 20 Week 48 Week 60

Week 60 HCV RNA negative (SVR)

Fibrosis 145 7.0±13.8 6.2±7.8 3.8±2.3 3.5±1.5 3.2±1.4

Cirrhosis 38 12.2±19.7 12.8±22.5 6.1±4.8 5.8±4.5 4.9±3.3

Mean (±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-up

Predictors of AFP elevation in chronic HCV without HCC

VariablesRegression

coefficientStandard error OR (95% CI) P-value

SVR 2.304 1.17610.014 (1.000–

100.329)0.05

Post-treatment

platelet at EOF0.024 0.012

1.025 (1.001–

1.050)0.04

Chen, T.-M., Journal of Gastroenterology and Hepatology, 2007, 22: 669–675.

Multivariate logistic 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

eradication were 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).

HCV

Estimated time to HCC according to AFP (± 20 ng/ml)

and large cell dysplasia.

F Degos, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular

carcinoma and death. Gut. 2000 July;47(1):131-136.

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 α 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=0.0026). Number

of patients at risk are shown in parentheses.

Gramenzi, et al. Gut. 2001 June;48(6):843-848.

α‐‐‐‐FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCV

Asahina, Hepatology 2013 58, (4) pages 1253-1262

α‐‐‐‐FP levels after interferon therapy and risk of hepatocarcinogenesis in chronic HCV

Asahina, Hepatology 2013 58, (4) pages 1253-1262

Α‐‐‐‐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 treatment.

Asahina, Hepatology 2013 58, (4) pages 1253-1262

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. 2007 June;1(1):49-55.

Predictive 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, 6.2 years)

Cirrhosis: 227 patients

Hie-Won Hann, et al. Eur J Cancer. 2012 October;48(15):2319-2327.

AFP levels ⩾100 ng/ml increases the risk of development of

complications during acute exacerbation of HBV infection.

Patients who developed complications of

cirrhosis

Patients without complications of

cirrhosisp Value

Albumin 34 (17–50) 45 (18–58) <0.0001

ALT 59 (11–3370) 42 (4–4820) <0.0001

Bilirubin 18 (3–323) 11 (1–553) <0.0001

AFP 17.5 (1–32202) 4 (1–4991) <0.0001

Yuen, Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications

Gut. 2005 November;54(11):1610-1614.

Alpha 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.

• No relationship was found between AFP and histopathological findings in patients with NAFLD.

Babalı, 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 ALF.

Du WB, Pan XP, Li LJ. Prognostic models for acute liver failure. Hepatobiliary Pancreat Dis

Int 2010; 9(2): 122-128.

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

Alpha-fetoprotein is a predictor of outcome in

acetaminophen-induced liver injury

Schmidt et al, Hepatology, 2004; 41:26-31

Alpha-fetoprotein is a predictor of outcome in

acetaminophen-induced liver injury

Schmidt et al, Hepatology, 2004; 41:26-31

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.

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: 1776-1781

Spontaneous survivors Died or transplanted P

A. All patients (n = 206)

AFP on admission (ng/mL) 5.4 (1.2–1365) 14.9 (1–1811) <0.001

AFP on day 3 (ng/mL) 16.4 (1.1–1162) 17.9 (2–791) 0.34

AFP ratio 2.2 (0.11–22.1) 0.87 (0.11–16.4) <0.001

B. Acetaminophen

patients (n = 80)

AFP on admission (ng/mL) 3.7 (1.2–195) 3.9 (1.5–114) 0.74

AFP on day 3 (ng/mL) (n =

67)12.3 (1.1–496) 6.0 (2.7–99) 0.13

AFP ratio (n = 67) 2.6 (0.46–22.1) 1.5 (0.36–5.2) 0.029

C. Nonacetaminophen

patients (n = 126)

AFP on admission (ng/mL) 19.4 (1.3–1365) 21.5 (1.0–1811) 0.43

AFP on day 3 (ng/mL) (n =

95)28.4 (2.6–1162) 21.5 (2.0–791) 0.57

AFP ratio (n = 95) 1.6 (0.11–15.2) 0.81 (0.11–16.4) <0.001

Schiodt et al, Liver Transplantation 2006; 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