Mrs. N is a Vietnamese immigrant who presents for a general physical. Although she does not have any specific symptoms and has had no major health problems, she thought it would be wise to have an overall health evaluation since she recently had her 50th birthday.
She takes no prescription medications. She has, however, taken a Chinese herbal tea for the past several months for urinary frequency and occasional incontinence. The medicinal tea is to strengthen her bladder and she thinks that it has had some symptomatic benefits. When asked to identify the teaâs ingredients, she responded only that it was a mixture of herbs purchased from an herbalist at a local market. She consumes only small amounts of alcohol weekly.
Her family history is significant for two brothers having died of hepatocellular carcinoma (HCC) in their early 30s. About a decade ago, when her youngest brother was diagnosed with HCC, she was tested for hepatitis B. She was told that she is a âhealthy carrierâ with no need for treatment. She has two older sisters who are in good health, one of whom also has chronic hepatitis B infection.
On exam, she had no positive findings, other than an increased body mass index of 28. Specifically her physical exam did not reveal scleral icterus, spider angiomata, or hepatosplenomegaly. Her laboratory results were as follows: hemoglobin 13.4 g/dL; white blood cell count 4500/mm3; platelets 206,000/mm3; aspartate aminotransferase (AST) 89 U/L and alanine aminotransferase (ALT) 119 U/L; total bilirubin 1.0 mg/dL: direct bilirubin 0.2 mg/dL; albumin 4.3 g/dL; fasting blood sugar 104 mg/dL; hepatitis B surface antigen positive; e-antigen negative; e-antibody positive; hepatitis delta negative; and HBV DNA 595 IU/mL.
A liver ultrasound showed minimally increased liver echogenicity, and no splenomegaly or a mass lesion within the liver.
Clinical Decision Point 1: Initial Management
Question 1: Which of the following is the most appropriate action at this time?
- Discontinue the herbal tea and monitor ALT and HBV DNA levels every 3 months.
- Start antiviral therapy as indicated in current anti-HBV treatment guidelines.
- Obtain a liver biopsy.
- No treatment or additional surveillance is necessary due to the patientâs low risk of HCC.
(a) This patient is HBeAg negative and has low-level viremia, which is usually not associated with active liver disease. She should not, however, be considered a âhealthy carrier.â This term should be abandoned in regards to hepatitis B because all infected patients are at risk of chronic liver disease, including HCC.1 Antiviral therapy in HBeAg-negative chronic hepatitis B is often lifelong. Before a patient is committed to potentially unending treatment, a clear definition of the disease status and treatment endpoint is necessary. Findings from this patientâs liver function tests (ie, bilirubin and albumin) indicate her liver function is normal. Therefore, we can afford to spend some time to determine her HBV disease status.
The diagnostic possibilities at this time for this patient include (1) HBeAg-negative chronic hepatitis with fluctuating pattern of ALT and HBV DNA, and (2) hepatotoxicity from the herbal tea in the background of inactive HBV carrier state.1,2 Due to her discrepant HBV DNA and ALT levels, a factor extraneous to HBVâsuch as hepatotoxicity from the medicinal teaâis suspected.
Single or combination herbal products have been associated with hepatotoxicity, including acute hepatitis, cholestasis, or both.3 Signs and symptoms of drug-induced hepatotoxicity range from mild and asymptomatic liver dysfunction with elevated ALT levels but normal bilirubin levels, to the development of jaundice and liver failure requiring liver transplantation or resulting in death.2-4 The frequency, causal ingredients, and mechanisms of injury remain poorly understood, however, due to a constellation of factors including the underreported use of these products, the relative absence of clinical trials, the limited regulation of these products, the lack of quality control standards in manufacturing, and the degree to which individual variation influences toxicity.2-4 The problem is further complicated by the fact that herbal mixtures are often in crude form, comprised of root, stem, leaf, or seed of the plant(s) and may include unidentified ingredients and contaminants.2
Liver injury, induced by drugs or herbal products, may be categorized as intrinsic predictable hepatotoxicity, idiosyncratic, or unpredictable hepatotoxicity.2,3 Intrinsic hepatotoxicity is caused by products that are inherently toxic to all or most recipients given sufficient quantity of product. This type of injury is typically identified with observation of a high incidence rate of toxicity among users, or in the case of pharmaceutical drugs, in the clinical trial phase of drug development. Idiosyncratic hepatotoxicity is the more challenging injury to identify. It occurs only in individuals who have an immunoallergic susceptibility to the product or as a result of a metabolic aberration. Additionally, it may occur due to an occult drug-herb interaction.
The Drug-Induced Liver Injury Network (DILIN) study, an observational, multicentre prospective study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, is currently under way to study idiosyncratic liver injury due to drug and complementary or alternative medicine, including herbal products.5 The goals of this study are to develop a database of drug-induced liver injury cases; identify the clinical, environmental, and genetic risk factors that predict injury; develop standardized instruments and terminology; and perform careful longitudinal follow-up of affected patients. It is hoped that this study will expand an understanding of the risks of hepatotoxicity associated with herbal and other xenobiotic and drug products (see Table).2
Table. Herbals That Have Been Associated with Hepatotoxicity.2
|Black cohosh (Actaea racemosa/Cimicifuga racemosa)
|Chaparral (Larrea tridentate)
|Comfrey (Symphytum officinale) and other herbs containing pyrrolizidine alkaloids
|Germander (Teucrium chamaedrys)
|Greater celandine (Chelidonium majus)
|Impila (Callilepis laureola)
|Kava (Piper methysticum rhizome)
|Mistletoe (Viscum album)
|Pennyroyal (Mentha pulegium)
|Skullcap (Scutellaria laterifolia)
|Valerian (Valeriana officinalis)
Chinese Herbal Medicines
|Jin Bu Huan (Lycopodium serratum)
|Ma huang (Ephedra sinica)
|Shou-wu-pian (Polygonum multiflorum)
Although it would not be wrong to perform a liver biopsy at this time, it is a less-appropriate option than discontinuing the tea and monitoring the patient. If chemical hepatotoxicity is present in addition to hepatitis B, the biopsy may be confusing, as drug-induced hepatitis may present as portal inflammation.6
Treatment guidelines published by the American Association for the Study of Liver Diseases (AASLD) recommend instituting HCC surveillance in patients at high risk for HCC, including Asian women older than 50 years, as well as other patients with family history of HCC.1 Therefore, this patient should be screened with ultrasound every 6 to 12 months due to her age and family history. Recent cohort studies have correlated HBV DNA levels and HCC risk.7,8 The current guidelines, however, do not utilize HBV DNA levels in determining candidates for surveillance.
Audio Commentary by Dr. Kim
The patient agreed to discontinue the Chinese herbal tea and was asked to return in 3 months. At that time, her aminotransferases improved significantly, to AST 23 U/L and ALT 31 U/L. Her HBV DNA, however, rose to 8500 IU/mL.
Audio Commentary by Dr. Kim
In the ensuing months, she was followed on a quarterly basis. She continued to feel well. Subsequent laboratories showed that her ALT levels fluctuated between 15 U/L and 38 U/L and her HBV DNA between 8500 IU/mL and 53,100 IU/mL. She remained e-antigen negative. Semiannual ultrasound exams showed no evidence of change or a mass lesion.
Clinical Decision Point 2: Utility of Diagnostic Testing
Question 2: Which of the following is the most helpful in determining the next course of action?
- Hepatitis B genotyping
- Liver biopsy
- Precore/core promoter mutation assay
(b) The improvement of ALT levels after discontinuing the herbal tea suggests that the tea may have been associated with some degree of hepatotoxicity in this patient. Alternatively, the changes in ALT levels may be part of a fluctuating pattern due to HBV infection The current increase in her HBV DNA level, however, demonstrates that viral replication is ongoing. With the herbal teaâs confounding effect removed, the status of HBV-related liver disease and the diagnosis of HBeAg-negative chronic hepatitis B infection may now be assessed and confirmed.
The role of liver biopsy is controversial. In general, it is of greatest benefit when the need for treatment is unclear, as is the case for this patient. Evaluation of liver histology on biopsy is a more sensitive and accurate indicator of liver disease than ALT levels.9 The risk for abnormal liver histology and mortality due to liver disease is greatest for patients older than age 40 years or with a family history of HCC. The decision to biopsy or not, therefore, should consider factors such as patient age, ALT levels, e-antigen status, HBV DNA levels, and family history.1,9
The current AASLD guidelines recommend considering a liver biopsy if the ALT level is elevated to two times the upper limit of normal and the DNA level is elevated to 20,000 U/mL.1 The guidelines fail to make a specific recommendation about a patient who has minimally abnormal ALT levels yet HBV DNA levels that exceed 20,000 U/mL. The concern at this point is whether she has ongoing liver inflammation (ie, HBeAg-negative chronic hepatitis) and thus will benefit from antiviral therapy. As mentioned earlier, the decision to start therapy commits this patient to being on therapy indefinitely. The decision to start therapy, therefore, must be informed by evidence of liver disease. A liver biopsy tends to be useful in this setting to determine the severity of liver disease. The guidelines recommend that treatment should be considered if a biopsy shows moderate to severe inflammation or significant fibrosis.1
The utility of genotyping in hepatitis B patients remains to be defined especially among Asian patients who primarily have genotype B or C.10 Increasing evidence indicates that genotype C is associated with poorer prognosis, including a higher risk of end-stage liver disease and HCC, compared with genotype B.11-14 The evidence to date, however, is not strong enough to incorporate genotype information in the treatment or follow-up of these patients. In general, genotyping may be useful if interferon is being considered as a therapeutic agent. Sustained response rates after interferon therapy tend to be higher for genotype A patients, followed by genotypes B and C, and then genotype D.15
In theory, the detection of precore or basal core promoter mutation would support the diagnosis of HBeAg-negative chronic hepatitis B. These mutants appear in a subset of patients at approximately the same time that HBeAg seroconverts to anti-HBe (see Figure).16 The development of these mutations allows the virus to evade anti-HBe immunity by switching off HBeAg expression, which is not needed for viral replication.17 Both mutations, therefore, allow active replication, and progressive liver inflammation, despite the absence of the HBeAg.10 There may be some marginal value of detection of these mutations in this patient because their presence makes it more likely that this patient has e-antigen negative chronic hepatitis B. The impact of such knowledge on the treatment decision, however, is less than that of histologic information at this time.
Figure. Appearance of Precore/Core Promoter Mutants16
Reprinted from Tong S, et al. Int J Med Sci. 2005;2:2-7, with permission from Ivyspring International Publisher.
Audio Commentary by Dr. Kim
The patient underwent a liver biopsy, which showed grade 1 inflammation and stage 0 fibrosis. Mild steatosis was also present.
Clinical Decision Point 3: Response to Biopsy Results
Question 3: What is the most appropriate course of action in response to this biopsy result?
- Discuss advantages and disadvantages of antiviral therapy in this setting and make a decision that is mutually comfortable between the patient and the physician.
- Institute immediate therapy with an oral antiviral agent with high genetic barrier, as such a therapy has been shown to decrease the risk of HCC.
- If antiviral therapy is going to be instituted, peginterferon is preferred in this setting because of the greater likelihood of surface antigen loss.
(a) HBeAg-negative patients are usually classified as inactive carrier or e-antigen negative chronic HBV. This patient, however, falls somewhere in between these two classifications. Biochemically, her ALT level has been essentially normal, whereas her HBV DNA suggests a reasonable degree of replication. The biopsy results indicate that this patient has a minimal degree of chronic liver disease given the absence of fibrosis. In addition, the degree of mild inflammation would suggest that her liver disease progression would be slow. Therefore, compelling reasons are lacking to support institution of antiviral therapy for the purpose of prevention of cirrhosis.
Other factors must be considered, however. The HBV DNA levels seen in this patient have been associated with increased risk of HCC, according to data from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B (REVEAL-HBV) study.18 This prospective cohort study followed 3653 HBsAg-positive patients for a mean of 11.4 years. Within this period there were 164 cases of HCC and 346 deaths. Correlation of HBV DNA levels with development of HCC demonstrated that elevated HBV DNA levels (â¥2000 IU/mL) are a strong risk predictor of HCC independent of HBeAg, serum ALT level, and liver cirrhosis.
In addition, this patientâs family history of HCC is concerning. A potential rationale of instituting antiviral therapy at this time (ie, early-stage disease) would be, therefore, the long-term benefit of preventing HCC. This outcome of treatment has not been demonstrated in a randomized trial in this setting, however. On the other hand, the disadvantage of using antiviral therapy at this time would be the concern for emergence of antiviral resistance with long-term therapy. In addition, cost may be a significant factor depending on the insurance coverage. In the absence of evidence to strongly sway the decision either for or against treatment, careful discussion and mutual consensus between the patient and physician would be the correct course of action.
A randomized trial of lamivudine in patients with advanced fibrosis and active liver disease showed that antiviral therapy can reduce the risk of end-stage liver disease and HCC. Given the long natural history of HBV infection, it is unlikely that a randomized trial will be performed to assess the benefit of antiviral therapy for early-stage liver disease, such as this patientâs, because unrealistically large numbers of patients will be required to demonstrate a benefit. To date, no study has demonstrated that antiviral therapy in the setting of (near) normal ALT levels and moderate elevation of HBV DNA levels reduces the risk of HCC in the future.
Trials to date of peginterferon in e-antigen negative patients enrolled patients with abnormal ALT in addition to detectable HBV DNA levels.19,20 These trials have reported modest proportions of patients achieving sustained response. However, given the tendency of HBeAg-negative patients to have fluctuating ALT and HBV DNA levels, further follow-up data are needed to demonstrate long-term benefit of peginterferon therapy on disease progression, including decompensated cirrhosis and HCC.
Audio Commentary by Dr. Kim
After careful discussion of the pros and cons of antiviral therapy, the patient declined to go on antiviral therapy. She remains compliant with the HCC surveillance program. After 3 years of follow-up, her status has not changed, with largely normal ALT levels and low levels (<20,000 IU/mL) of HBV DNA.
Audio Commentary by Dr. Kim
HBeAg-negative patients must be monitored carefully. The AASLD guidelines recommend seeing these patients on a quarterly basis to characterize them into inactive carriers versus those with HBeAg-negative chronic hepatitis B. The treatment duration for HBeAg-negative patients remains undetermined and is likely to be lifelong. Therefore, it is important for the clinician to have compelling evidence that the advantages of therapy outweigh its potential disadvantages. Drug-induced hepatotoxicity from other sources, such as from herbal remedies, must be considered and ruled out to accurately assess liver disease status attributable to HBV infection.
Surveillance for HCC should be considered in these patients, as they tend to be older. In addition to age, the degree of underlying liver disease and family history must be taken into account. The impact of antiviral therapy, however, on the risk of HCC in noncirrhotic patients has not been shown.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.
- Seeff LB. Herbal hepatoxicity. Clin Liver Dis. 2007;11:577-596.
- Willett KL, Roth RA, Walker L. Workshop overview: hepatotoxicity assessment for botanical dietary supplements. Toxicol Sci. 2004;79:4-9.
- Pittler MH, Ernst E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther. 2003;18:451-471.
- ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/results?term=idiosyncratic+liver+injury. Accessed February 20, 2008.
- Kaplowitz N. Drug-induced liver injury. Clin Infect Dis. 2004;38(suppl 2):S44-48.
- Chen CJ, Iloeje UH, Yang HI. Long-term outcomes in hepatitis B: the REVEAL-HBV Study. Clin Liver Dis. 2007;11:797-816.
- Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol. 2006;101:1797-1803.
- Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
- Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125:444-451.
- Guettouche T, Hnatyszyn HJ. Chronic hepatitis B and viral genotype: the clinical significance of determining HBV genotypes. Antivir Ther. 2005;10:593-604.
- Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes. Hepatology. 2002;35:1274-1276.
- Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology. 2000;118:554-549.
- Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265-272.
- Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129.
- Tong S, Kim KH, Chante C, Wands J, Li J. Hepatitis B virus e antigen variants. Int J Med Sci. 2005;2:2-7.
- Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology. 2003;38:619-628.
- Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73.
- Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.
- Marcellin P, Lau GKK, Bonino F, et al. Sustained response to peginterferon alfa-2a (PEGASYSÂ®) in HBeAg-negative chronic hepatitis B. 1-year follow-up data from a large, randomised multinational study. J Hepatol. 2005;42(suppl 2):185-186. Abstr 512.