FPIN's Clinical Inquiries

Screening for Hepatocellular Carcinoma in Patients with Hepatitis C Virus Infection

Am Fam Physician. 2013 Mar 15;87(6):online.

Clinical Question

Is measurement of serum α-fetoprotein (AFP) levels better than imaging when screening symptomatic patients with hepatitis C virus (HCV) infection for hepatocellular carcinoma?

Evidence-Based Answer

There is no evidence that it is beneficial to screen for hepatocellular carcinoma in symptomatic patients with HCV. (Strength of Recommendation [SOR]: C, based on a systematic review and case series studies.) Neither serum AFP measurement nor imaging is an ideal screening test. Patients can be screened for hepatocellular carcinoma using AFP measurement or ultrasonography; these tests have similar sensitivity and specificity. Computed tomography and magnetic resonance imaging offer increased screening sensitivity, but may be limited by cost and availability. (SOR: C, based on retrospective case series.) Combined testing with AFP measurement and ultrasonography improves sensitivity but decreases specificity.

Evidence Summary

A systematic review of five studies (two prospective cohort and three case-control studies; n = 1,734) showed that a serum AFP level greater than 20 ng per mL (20 μg per L) has a sensitivity of 41 to 65 percent, a specificity of 80 to 94 percent, a positive likelihood ratio of 3.1 to 6.8, and a negative likelihood ratio of 0.4 to 0.6 when used to screen for hepatocellular carcinoma in patients with HCV.1 At least 239 patients (14 percent) included in this meta-analysis were HCV-negative, and many were already cirrhotic, which limits extrapolation of results to the asymptomatic population.

No prospective data are available to directly compare the effectiveness of AFP measurement and imaging in identifying hepatocellular carcinoma in symptomatic patients with HCV. Case-control and case series reports of patients with end-stage liver disease who were transplant candidates showed that the sensitivity of serum AFP measurement in detecting hepatocellular carcinoma ranged from 20 percent (using the highest threshold) to 65 percent (using the lowest; Table 1).15 In these studies, the diagnostic standard was pathologic examination of the liver. Ultrasonography had similar sensitivity (43 to 59 percent) but better specificity in patients with end-stage cirrhosis.25 Tumor detection rates were 53 to 91 percent for computed tomography, and 78 percent for magnetic resonance imaging.24 A prospective cohort control study of 18,816 patients (9,373 participants in the screening group and 9,443 participants in the control group) with hepatitis B or other chronic hepatitis evaluated the utility of combining serum AFP measurement with ultrasonography to detect primary liver cancer.6 Serum AFP measurement alone (using a threshold of greater than 20 ng per mL) had a sensitivity of 69 percent (95% confidence interval [CI], 54 to 80 percent) and a specificity of 95 percent (95% CI, 94.7 to 95.3 percent) to detect liver cancer. Ultrasonography alone was more sensitive (84 percent; 95% CI, 73 to 93 percent) and specific (97 percent; 95% CI, 96.9 to 97.3 percent) than AFP measurement. Combining AFP measurement with ultrasonography improved sensitivity to 92 percent (95% CI, 80 to 97 percent), but decreased specificity to 93.5 percent (95% CI, 92 to 93 percent). The study's usefulness for evaluating for hepatocellular carcinoma in patients with HCV was limited because of the lack of study details.

Table 1.

AFP Measurement vs. Imaging for Detecting Hepatocellular Carcinoma in Liver Transplant Candidates with HCV

Study type Number of patients Cause of carcinoma Test Sensitivity (%) Specificity (%)

Systematic review (2 prospective cohort, 3 case-control)1

1,734 (239 were not HCV-positive)

NS

AFP > 20 ng per mL (20 μg per L)

41 to 65

80 to 94

Retrospective (blinded) case-control2

106 (19 with hepatocellular carcinoma)

Mixed (58 percent HCV)

AFP > 20 ng per mL

58

91

AFP > 50 ng per mL (50 μg per L)

47

96

Ultrasonography

58

94

Computed tomography

53

94

Retrospective case series3

166 (27 with hepatocellular carcinoma)

Mixed (63 percent HCV)

AFP > 20 ng per mL

63

87

AFP > 200 ng per mL(200 μg per L)

27

100

Ultrasonography

59

93

Computed tomography

91

96

Retrospective case series4

239 (all with hepatocellular carcinoma)

Mixed (55 percent HCV)

AFP > 50 ng per mL

31

96

AFP > 200 ng per mL

20

> 99

199

Ultrasonography

58

NA

164

Computed tomography

69

NA

197

Magnetic resonance imaging

78

NA

Retrospective case series5

200 (28 with hepatocellular carcinoma)

NS

Ultrasonography

43

95


AFP = α-fetoprotein; HCV = hepatitis C virus; NA = not available; NS = not specified.

Information from references 1 through 5.

Table 1.   AFP Measurement vs. Imaging for Detecting Hepatocellular Carcinoma in Liver Transplant Candidates with HCV

View Table

Table 1.

AFP Measurement vs. Imaging for Detecting Hepatocellular Carcinoma in Liver Transplant Candidates with HCV

Study type Number of patients Cause of carcinoma Test Sensitivity (%) Specificity (%)

Systematic review (2 prospective cohort, 3 case-control)1

1,734 (239 were not HCV-positive)

NS

AFP > 20 ng per mL (20 μg per L)

41 to 65

80 to 94

Retrospective (blinded) case-control2

106 (19 with hepatocellular carcinoma)

Mixed (58 percent HCV)

AFP > 20 ng per mL

58

91

AFP > 50 ng per mL (50 μg per L)

47

96

Ultrasonography

58

94

Computed tomography

53

94

Retrospective case series3

166 (27 with hepatocellular carcinoma)

Mixed (63 percent HCV)

AFP > 20 ng per mL

63

87

AFP > 200 ng per mL(200 μg per L)

27

100

Ultrasonography

59

93

Computed tomography

91

96

Retrospective case series4

239 (all with hepatocellular carcinoma)

Mixed (55 percent HCV)

AFP > 50 ng per mL

31

96

AFP > 200 ng per mL

20

> 99

199

Ultrasonography

58

NA

164

Computed tomography

69

NA

197

Magnetic resonance imaging

78

NA

Retrospective case series5

200 (28 with hepatocellular carcinoma)

NS

Ultrasonography

43

95


AFP = α-fetoprotein; HCV = hepatitis C virus; NA = not available; NS = not specified.

Information from references 1 through 5.

Recommendations from Others

The American Association for the Study of Liver Diseases recommends ultrasonography for patients with HCV and cirrhosis every six to 12 months, and recommends AFP measurement only when ultrasonography is not available.7 Based on fair-quality evidence, the National Cancer Institute found that screening would not decrease mortality from hepatocellular carcinoma, and could result in rare but serious adverse effects from diagnostic testing.8

Address correspondence to Kelly Bossenbroek Fedoriw, MD, at kbossen@email.unc.edu. Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


Copyright Family Physicians Inquiries Network. Used with permission.

REFERENCES

1. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med. 2003;139(1):46–50.

2. Gambarin-Gelwan M, Wolf DC, Shapiro R, Schwartz ME, Min AD. Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol. 2000;95(6):1535–1538.

3. Chalasani N, Horlander JC Sr, Said A, et al. Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol. 1999;94(10):2988–2993.

4. Snowberger N, Chinnakotla S, Lepe RM, et al. Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in patients with advanced cirrhosis. Aliment Pharmacol Ther. 2007;26(9):1187–1194.

5. Dodd GD III, Miller WJ, Baron RL, Skolnick ML, Campbell WL. Detection of malignant tumors in end-stage cirrhotic livers: efficacy of sonography as a screening technique. AJR Am J Roentgenol. 1992;159(4):727–733.

6. Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen. 1999;6(2):108–110.

7. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–1236.

8. National Cancer Institute. Liver (hepatocellular) cancer screening. http://www.cancer.gov/cancertopics/pdq/screening/hepatocellular/healthprofessional/allpages. Accessed December 30, 2011.

Clinical Inquiries provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group (http://www.cebm.net/?o=1025).

The complete database of evidence-based questions and answers is copyrighted by FPIN. If interested in submitting questions or writing answers for this series, go to http://www.fpin.org or e-mail: questions@fpin.org.

A collection of FPIN's Clinical Inquiries published in AFP is available at http://www.aafp.org/afp/fpin.


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