Patient Description

Mr. A is a 36-year-old man who emigrated from Ethiopia. He was diagnosed with chronic hepatitis B virus (HBV) infection during a routine health examination shortly after his arrival in the United States and was referred to a hepatologist.

Laboratory findings upon referral were as follows: aspartate aminotransferase (AST) 29 U/L; alanine aminotransferase (ALT) 30 U/L; total bilirubin 0.8 mg/dL; platelets 240,000/mm³; hepatitis B surface antigen (HBsAg) positive; hepatitis B e antigen (HBeAg) positive; hepatitis B e antibody (anti-HBe) positive; HBV DNA 2200 copies/mL (440 IU/mL); anti-HAV positive; and anti-HCV negative.

Physical examination was unremarkable. The patient’s past medical history includes childhood jaundice, which resolved. His two siblings and parents are still living in Ethiopia; to his knowledge, they do not have liver disease nor have they been tested for HBV.

Based on the patient’s normal liver enzymes and only minimally elevated HBV DNA level, treatment was not indicated.

Clinical Decision Point 1: HCC Surveillance

Question 1: Based on this patient’s presentation, should he begin surveillance of hepatocellular carcinoma (HCC)?

1. No, due to his young age


2. No, due to his normal liver enzymes


3. No, due to only mild elevation of HBV DNA


4. Yes, due to his ethnicity

Discussion

(d) Current HCC management guidelines issued in 2010 by the American Association for the Study of Liver Diseases (AASLD) recommend that all patients from Africa with chronic HBV undergo surveillance for HCC regardless of age.¹ This recommendation expands that of the previous guidelines from 2005, which recommended that African patients with chronic HBV who are older than age 20 years be screened.² The need for HCC surveillance at an early age in this population group is due to the high HBV prevalence in Africa and the early age at which HCC develops in this group.¹ Table 1 shows the complete list of HBV carriers for whom HCC surveillance is recommended.¹

Table 1. Hepatitis B Carrier Groups for Whom HCC Surveillance is Recommended¹

Throughout this HBV curriculum program’s 6 prior years (this is the seventh year), the primary ethnic focus has been on Asians and Pacific Islanders living in the United States due to the high numbers of individuals with chronic HBV who fit that demographic. Other ethnic groups also carry a heavy HBV-related disease burden. Although 58% of the 1.32 million foreign-born individuals in the United States with chronic HBV in 2009 migrated from Asia, 11% migrated from Africa, and about 7% from Central America.³ In fact, emigrants from Africa, where hepatitis B is hyperendemic, have the highest average chronic HBsAg seroprevalence rate (10.3%).³

Among emigrants from Ethiopia specifically (151,879 in 2009), the chronic HBV prevalence rate is 9.59%, higher than that of the overall in-country population, according to a recent systematic review of seroprevalence reports from 102 countries conducted by Kowdley et al published in 2011.³ In a 1994 community-based seroepidemiologic study, the HBsAg prevalence in Addis Ababa, Ethiopia's capital city, was 7%, but the overall HBV prevalence (any marker positive) rose to over 70% in individuals age 40 to 49 years old.⁴ At age 20 years, approximately 50% of the population had evidence of past or current infection.⁴

The age at which an individual acquires HBV, as well as the rate of HBV replication, is associated with the age at which HCC develops.⁵ In HBV-endemic areas, childhood transmission results in the development of HCC in mid-adulthood.⁵ Development of HCC in young or middle adulthood is common, therefore, in Asian countries where transmission is predominantly vertical, and in Africa, where transmission is horizontal in childhood. This is in contrast to the development of HCC in the United States, which typically occurs later in adulthood, where transmission is in adolescence or adulthood via high-risk behavior or exposures.⁵

Asians typically acquire HBV via perinatal transmission. Why, then, do they develop HCC later than Africans who typically acquire HBV later in childhood?
Audio Commentary by Kris V. Kowdley, MD

Worldwide, liver cancer is the second and sixth leading cause of cancer death in men and women, respectively.⁶ Over 80% of HCC cases occur in developing countries in East Asia, Southeast Asia, and sub-Saharan Africa, which includes Ethiopia.⁵ In sub-Saharan Africa, liver cancer is the second most common cancer and second leading cause of cancer death in men; in women, it is the third most common cancer and third leading cause of cancer death.⁶ In this region, chronic HBV infection is the major cause of liver cancer.⁶

It is important to make a distinction between HCC screening and surveillance. Screening refers to using specific diagnostic tests to check for HCC in people who are at risk but are not yet known to have developed HCC.¹ Surveillance refers to the overall program of administering screening tests at regular intervals. Surveillance also involves a process of recall, in which standards are in place to determine what constitutes an abnormal result and what follow-up measures are needed. The goal of HCC surveillance is first and foremost to reduce HCC-related mortality, and second, to add a meaningful increment of survival duration.

Consequence of making the wrong choice: Choosing not to begin HCC surveillance on this patient for any of the reasons listed in options “a” through “c” above could have significant long-term consequences. Since one of the most important determinants of survival in HCC is tumor stage at diagnosis, early diagnosis via surveillance is imperative to optimize outcomes.¹ The other choices are less desirable because they would lead to the decision to delay diagnosis, and therefore, reduce the likelihood of diagnosis at a curable stage.

What is the current or potential role of nomograms or calculators of HCC risk in clinical practice? How does the role vary between populations in whom surveillance is already recommended vs populations in whom surveillance is not recommended?
Audio Commentary by Kris V. Kowdley, MD

Clinical Decision Point 2: HCC Screening Tests

Question 2: Which of the following HCC screening tests should be ordered for this patient?

1. Alpha-fetoprotein (AFP)



2. Ultrasound



3. AFP and ultrasound



4. Liver biopsy

Discussion

(b) Due to the lack of acceptable sensitivity and specificity in the AFP test, the AASLD HCC management guidelines recommend that only ultrasound imaging be used to screen for HCC.¹ Using both the AFP test and ultrasound is not recommended due to the excess cost and false positives associated with this approach.¹ An invasive liver biopsy is not needed to screen for HCC.

A good screening test must offer an optimal balance between specificity and sensitivity, characteristics with an inverse relationship to each other.¹ An additional consideration is that a test’s positive and negative predictive values are dependent on the prevalence of the condition for which the screening is taking place. For AFP, a threshold value of 20 ng/mL offers this optimal balance, yet at this value the sensitivity for detecting HCC in a population in which the prevalence is 50% is still only 60%, which means that 40% of HCCs would go undetected.¹ At this prevalence rate and the AFP 20 ng/mL threshold, the test’s positive predictive value is 84.6%. As the prevalence rate goes down, the positive predictive value also decreases. For a prevalence rate of 5%, which is more typical of clinical practice, the test’s positive predictive value falls to 41.5%. Decreasing the cut-off threshold to below 20 ng/mL would increase the number of HCCs detected but would also increase the number of false positives due to the reduced specificity.

Additional problems associated with using AFP as a screening test for HCC are that not all HCCs secrete AFP, and that patients with chronic liver disease but no HCC may have elevated levels of AFP.⁷ Further, there may be an ethnic difference in the rate of AFP elevation in chronic liver disease. Nguyen et al demonstrated that in a population with HCV-related HCC, AFP was an insensitive test in blacks, with nearly half of those with HCC presenting with normal AFP levels.⁸ It is not known, however, if these findings are applicable to HBV-related HCC.

Ultrasound has a sensitivity of between 65% and 80% and a specificity exceeding 90%.¹ It is the most widely used HCC screening test; its performance characteristics when evaluating patients with nodular cirrhosis have not been clearly defined, however.

Surveillance with ultrasound should occur at 6-month intervals.¹ This recommendation is based on tumor doubling time, regardless of the risk level of the patient.¹

Consequence of making the wrong choice: The most immediate impact of choosing AFP as the screening test would be the overuse of computed tomography (CT) scans with the associated cost and radiation risk subsequent to pursuing nonspecific elevation of AFP.

Discuss the limitations of ultrasound. How can a clinician evaluate whether ultrasound is accurate on an individual patient given limitations of operator-performance, impact of obesity, fatty liver disease, and cirrhosis?
Audio Commentary by Kris V. Kowdley, MD

Case Continues

An ultrasound was ordered and showed no abnormalities, including no evidence of HCC. The patient was counseled about his high risk of HCC and the need for repeat ultrasound evaluations every 6 months. He missed the next scheduled ultrasound but presented 1 year later with symptoms of gastroparesis. An esophagogastroduodenoscopy (EGD) was performed and showed no varices.

At his next presentation, 2 years later, there had been little change in his laboratory values. An ultrasound done a few weeks later noted a 7-mm hemangioma in the right hepatic lobe, but no evidence of cirrhosis or abnormal blood flow.

The patient was again lost to follow-up for 2 years. At the time of his next presentation, physical exam showed no hepatosplenomegaly or ascites. A complete blood count was normal but for a platelet count of 84,000/mm³. Other laboratory findings include: ALT 36 U/L; AST 34 U/L; bilirubin 0.3 mg/dL; albumin 3.9 g/dL, serum creatinine 0.94 mg/dL; HBsAg positive; HBeAg negative; anti-HBe negative; and HBV DNA 30,897 IU/mL.

Clinical Decision Point 3: Response to Thrombocytopenia

Question 3: Based on the patient’s presentation now, what is the next best step?

1. Liver biopsy



2. Ultrasound or CT imaging



3. Magnetic resonance (MR) imaging

Discussion

(c) Given the patient’s low platelet count, the patient has probable cirrhosis and portal hypertension. HCC surveillance continues to be indicated, but the patient should now also be evaluated specifically for cirrhosis. Although he had no physical signs of cirrhosis or portal hypertension, such as ascites, jaundice, and vascular spiders, this is not uncommon in patients with compensated cirrhosis.⁹

Thrombocytopenia is known to be a predictor of cirrhosis^10,11 and portal hypertension.¹ In a study that enrolled 122 patients with chronic hepatitis B and 244 patients with chronic hepatitis C, Lu et al found that thrombocytopenia is a valid surrogate marker for cirrhosis in patients with a high risk for developing HCC.¹⁰ Platelet counts less than 170,000/mm³ were associated with cirrhosis in patients with HBV, and counts less than 150,000/mm³ were associated with cirrhosis in patients with HCV.¹⁰ The sensitivity of thrombocytopenia as a marker for a pathologic diagnosis of cirrhosis is greater in HCV compared with HBV, although the specificity is similar for each: sensitivity 68.2% versus 52.5%, respectively; specificity 78% versus 76.4%, respectively.¹⁰ AASLD HCC guidelines suggest that portal hypertension should be suspected when the platelet count falls below 100,000/mm³ in combination with significant splenomegaly.¹ Although no splenomegaly was noted on this patient, splenomegaly is not easy to detect on physical exam and may be difficult to recognize on imaging because spleen length is not routinely measured on ultrasound or other imaging.

Liver biopsy is no longer considered the “gold standard” test for making diagnostic and treatment decisions, particularly in patients with chronic hepatitis B.¹² Limitations to biopsy—such as sampling error, underestimation of fibrosis, variability between observers, complications, and expense—have transitioned biopsy to a selective, rather than routine, procedure.¹² In this patient, particularly with his thrombocytopenia, biopsy should not be done due to risk of complications and lack of necessity. Noninvasive procedures are now the standard way to look for evidence of cirrhosis.

Besides platelet count, what other noninvasive predictors of fibrosis and cirrhosis can be used in patients with chronic HBV?
Audio Commentary by Kris V. Kowdley, MD

Ultrasound is commonly used as the first step in evaluating liver disease, with capabilities of detecting changes in liver histology and evidence of portal hypertension.⁹ Its specificity is sufficiently high to rule in cirrhosis with a positive finding, but its sensitivity is not high enough to rule out cirrhosis with a negative finding. Nodularity of the liver surface is the single most significant sign for the diagnosis of cirrhosis. This sign combined with portal vein mean velocity below 12 cm/second distinguishes between severe fibrosis and cirrhosis with 80% accuracy. Similarly, the sensitivity of ultrasound to detect portal hypertension is low, particularly in patients with compensated cirrhosis, although specificity is high, thereby allowing a positive sign to rule in portal hypertension but the absence of a sign cannot rule it out.

CT and MR imaging both provide a means to visualize the liver parenchyma and portal venous system.⁹ CT imaging may be useful in identifying subtle signs of cirrhosis if the liver is nodular or heterogeneous, or if lesions have been previously seen on ultrasound. MRI may be helpful to further characterize abnormal lesions, but its cost precludes it from being a first-line imaging procedure.

Case Continues

A CT scan with IV contrast was performed. The radiologist sent the following report:

Review how chronic hepatitis B infection can, over time, lead to cirrhosis.
Audio Commentary by Kris V. Kowdley, MD

Clinical Decision Point 4: Treatment Decision

Question 4: Based on the patient’s lab values and CT result, should he start anti-HBV treatment at this time?

1. No, due to his normal liver enzymes



2. No, due to his HBeAg negative status



3. No, but recheck HBV DNA and liver enzymes in 3 months



4. Yes

Discussion

(d) Although AASLD chronic hepatitis B treatment guidelines suggest that, in general, liver enzymes should be elevated to at least twice the upper limit of normal (ULN) before initiating anti-HBV treatment, the guidelines also state that HBeAg-negative or -positive patients who have evidence of significant fibrosis or cirrhosis and HBV DNA levels greater than 2000 IU/mL should begin treatment, regardless of liver enzyme elevation.¹³ The US Algorithm concurs that treatment should be initiated if there is evidence of significant histologic disease whether or not liver enzymes are elevated, but also expands treatment candidacy to those patients who also have low levels of viral replication (<2000 IU/mL for HBeAg-negative patients and <20,000 IU/mL for HBeAg-positive patients).¹⁴

HBeAg positivity is not a requirement for therapy, since patients with HBeAg-negative chronic hepatitis B, which is associated with pre-core or core promoter mutations, have greater histologic damage despite lower HBV DNA levels compared with HBeAg-positive disease.¹³ A lower HBV DNA threshold, therefore, is typically suggested for treatment of patients with HBeAg-negative disease in the absence of cirrhosis.¹³

HBV DNA levels do fluctuate over time and in the event of fluctuation, retesting has been recommended after a period of 3 months. In this case, however, immediate treatment would be reasonable because of the presence of cirrhosis and a HBV DNA level that exceeds 20,000 IU/mL.

Case Continues

The patient was started on first-line anti-HBV therapy (either tenofovir 300 mg/day or entecavir 0.5 mg/day would be appropriate) and repeat HBV DNA testing was ordered for 3 months. A repeat EGD to examine for esophageal varices was recommended, and repeat imaging for HCC surveillance has been scheduled in 6 months.

Conclusion

Patients with chronic hepatitis B have an increased risk of cirrhosis and HCC. This risk appears to be higher in immigrants from Africa. Surveillance for HCC is recommended in this population group, and in other groups identified as high risk, regardless of presence or absence of cirrhosis.

What language and cultural barriers arise when caring for patients from Eastern or Sub-Saharan Africa? What strategies can clinicians use to overcome these barriers?
Audio Commentary by Kris V. Kowdley, MD

In the setting of chronic hepatitis, patients with thrombocytopenia may have cirrhosis. Imaging studies should be done and may suggest features of cirrhosis. Liver biopsy is not required in such cases to confirm the presence of cirrhosis.

Patients with chronic hepatitis B and evidence of cirrhosis who have ongoing viral replication should be considered for antiviral therapy, even if liver enzymes are normal.

References

1. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2010:1-35. Accessed 5/15/12 at: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf.


2. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.


3. Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2011 Nov 22. [Epub ahead of print]


4. Abebe A, Nokes DJ, Dejene A, Enquselassie F, Messele T, Cutts FT. Seroepidemiology of hepatitis B virus in Addis Ababa, Ethiopia: transmission patterns and vaccine control. Epidemiol Infect. 2003;131:757-770.


5. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7:448-458.


6. American Cancer Society. Global Cancer Facts & Figures 2nd ed. Atlanta, GA. American Cancer Society; 2011. Accessed 5/16/12 at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-027766.pdf.


7. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138:493-502.


8. Nguyen MH, Garcia RT, Simpson PW, Wright TL, Keeffe EB. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology. 2002;36:410-417.


9. Berzigotti A, Ashkenazi E, Reverter E, Abraldes JG, Bosch J. Non-invasive diagnostic and prognostic evaluation of liver cirrhosis and portal hypertension. Dis Markers. 2011;31:129-138.


10. Lu SN, Wang JH, Liu SL, et al. Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma. Cancer. 2006;107:2212-2222.


11. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307:832-842.


12. Reiss G, Keeffe EB. Role of liver biopsy in the management of chronic liver disease: selective rather than routine. Rev Gastroenterol Disord. 2005;5:195-205.


13. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:1-36.


14. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315-1341.