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BMJ Case Rep. 2009; 2009: bcr08.2008.0761.
Published online 2009 April 14. doi:  10.1136/bcr.08.2008.0761
PMCID: PMC3027591
Unexpected outcome (positive or negative) including adverse drug reactions

Severe drug induced acute hepatitis associated with use of St John’s wort (Hypericum perforatum) during treatment with pegylated interferon α

Abstract

A 61-year-old woman with chronic hepatitis C received peginterferon α 180 μg/week, and obtained undetectable qualitative hepatitis C virus (HCV) RNA (lower limit of detection 50 IU/ml) after 8 weeks of treatment. Shortly thereafter aminotransferase values greatly increased (>20 × upper limit of normal) and did not decline after treatment suspension. The patient admitted taking St John’s wort (Hypericum perforatum) for depressed mood, recommended by a friend, during the preceding 6 weeks. Liver function tests continued to worsen and international normalised ratio (INR) prolongation developed; the patient was hospitalised. Test for antinuclear antibody was positive (1:320) and treatment with methylprednisolone was started; bilirubin and aminotransferase levels slowly declined, though a new flare occurred when steroids were tapered. After 6 months of prednisone treatment, the liver function tests returned to baseline levels. The combination of peginterferon α and St John’s wort resulted in a severe acute hepatitis in this patient. Patients should be advised of this potential toxic effect of this herbal remedy.

BACKGROUND

Herbal remedies are used extensively as alternative medical treatment for a variety of disorders. The popularity of these products is largely due to the general public’s perception that they are “natural” and therefore “safe”, compared to traditional drugs. Many herbal remedies have not been proven to be effective treatments, yet they have been associated with serious toxicity, and even fatal outcomes.1 Indeed over the last decade, an ever increasing body of literature reporting serious adverse events to these products has emerged.25 Furthermore, use of these products is rarely disclosed to the physician by the patient, and uncovering the aetiology of adverse events becomes a challenge for the physician. The association of herbal remedies and traditional drugs can also result in variations in plasma concentrations of traditional drugs and reduced efficacy.68

St John’s wort (Hypericum perforatum) is an herbal remedy used for the treatment of depression and anxiety disorders.9,10 St John’s wort contains numerous biologically active substances that bind neuroreceptors in the brain and inhibit the reuptake of selected neurotransmitters.1113 Given the widespread use of this product, several randomised controlled trials have been performed to assess its efficacy. A large systematic review of these studies concluded that St John’s wort is more effective than placebo, but less effective than standard tricyclic antidepressants, in the treatment of mild to moderate depression.10

Adverse events reported during the use of St John’s wort include gastrointestinal symptoms, dizziness or confusion, fatigue, dry mouth, restlessness, headache, and allergic skin reactions.13 Furthermore, St John’s wort can reduce the plasma concentrations or efficacy of conventional drugs, by induction of cytochrome P-450.14,15 However, there have been no reports of hepatotoxicity of this compound when taken alone.

In this report we describe a case of severe, prolonged and potentially life threatening acute hepatitis in a patient who was receiving peginterferon α therapy for chronic hepatitis C, and who simultaneously self administered St John’s wort without seeking medical advice.

CASE PRESENTATION

A 61-year-old woman with persistently elevated alanine aminotransferase (ALT) concentrations and biopsy proven chronic hepatitis C infection, genotype 1b, presented to our hepatology clinic for evaluation. The clinical examination was unremarkable except for a slightly enlarged liver.

Baseline laboratory test results are shown in table 1. The patient gave written informed consent to participate in a treatment protocol which included 12 weeks of peginterferon α monotherapy, followed by combination therapy with ribavirin based on early virological response. Antiviral treatment with pegylated interferon α-2a (40 kDa), 180 μg/week, was begun, and after 8 weeks of treatment hepatitis C virus (HCV) RNA was undetectable by polymerase chain reaction (PCR), indicating an early virological response; the patient reported no significant adverse effects. However at week 8, biochemical testing showed a pronounced elevation in aminotransferase values (ALT 700 U/l, aspartate aminotransferase (AST) 1200 U/l). Treatment with pegylated interferon α was discontinued and liver function tests were monitored closely. Three weeks after peginterferon α suspension, AST and ALT values continued to rise, intense jaundice developed, and prothrombin time became prolonged. Upon further questioning the patient reported she had been taking St John’s wort, two capsules daily for approximately 6 weeks; she claimed she was experiencing depressed mood and had been advised to take the herbal remedy by a friend. Due to the progressive worsening of the liver function tests, the patient was admitted to hospital.

Table 1
Laboratory results before antiviral treatment was begun (baseline), at hospital admission (3 weeks after peginterferon α-2a suspension), at discharge after 4 weeks of steroid treatment, and 3 and 12 months after discharge

INVESTIGATIONS

On admission the patient was in no acute distress, but quite anxious; skin and mucosae were icteric, and a pruritic urticarial rash was present on the trunk and lower extremities. Body temperature was 37.5°C, blood pressure was 130/80 mm Hg, and heart rate was 72 beats/min. There was mild pitting oedema on the lower extremities, but no clinically apparent ascites or encephalopathy. An abdominal ultrasound revealed an enlarged liver, with no focal lesions, no biliary dilatation, normal portal and hepatic veins, an enlarged spleen, and a mild peri-hepatic effusion. Laboratory values on admission are shown in table 1. A test for antinuclear antibody (ANA) was positive with a titre of 1: 320, speckled pattern. Serology for cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus (HSV), hepatitis A virus (HAV), and hepatitis B virus (HBV) HBcAb IgM was negative.

DIFFERENTIAL DIAGNOSIS

  • Hepatotoxicity from peginterferon α 2-a
  • Hepatotoxicity from St. John’s wort
  • Acute viral hepatitis (HAV, HBV, CMV, EBV, HSV)

TREATMENT

The patient was treated with intravenous methylprednisolone 2 mg/kg; after 1 week liver enzyme values started to descend and steroid tapering was begun. However, during steroid tapering liver enzymes increased again (fig 1), and oral prednisone 1 mg/kg was begun.

Figure 1
Serum aspartate aminotransferase (AST) (normal 0–36 U/), alanine aminotransferase (ALT) (normal 0–41 U/l) and total bilirubin values at baseline, during 8 weeks of peginterferon α-2a treatment, and during hospitalisation. After ...

OUTCOME AND FOLLOW-UP

The patient was discharged after 4 weeks of hospitalisation, when bilirubin values showed a clear downward trend, while γ glutamyl transferase (GGT) values declined more slowly (table 1); a repeat abdominal ultrasound revealed no perihepatic effusion, though the liver remained enlarged. Serum HCV RNA remained undetectable during hospitalisation, and for 5 months following discharge. After 5 months serum HCV RNA became detectable, and the antinuclear antibody test became negative.

DISCUSSION

This report illustrates a severe, potentially life threatening adverse event during peginterferon therapy in a patient who decided to self medicate with a herbal remedy, without informing her physician or seeking proper medical advice. This raises several issues regarding management of patients with chronic diseases. First, patient compliance and physician communication are crucial for optimising treatment; this patient, though highly educated, was quite willing to accept a friend’s referral for treatment of a medical problem (depressed mood), but failed to disclose this to her treating physician. Second, the potential for drug induced liver toxicity is present in virtually all medications; since identifying the culprit is usually a process of exclusion, the association of different drugs makes diagnosing the aetiology of toxic reactions more difficult.

This patient had shown an early virological response to peginterferon monotherapy, and qualitative HCV RNA was negative after only 8 weeks of treatment. Such an early response is predictive of a sustained response if treatment is completed with adequate adherence16; however, given the degree of hepatotoxicity encountered during this therapeutic trial, it is unlikely that another course of interferon therapy would be prescribed to this patient in the future. A moderate increase in ALT values during peginterferon therapy for chronic viral hepatitis C is quite common; the occurrence of an acute hepatitis flare (ALT >10 times the upper limit of normal), on the other hand, is a rare serious adverse event requiring treatment discontinuation. The fact that liver damage continued after peginterferon treatment was discontinued raised the suspicion for other possible causes of hepatotoxicity in this patient; however, the information regarding the self administration of St John’s wort was disclosed only after the toxic reaction was advanced to the point of requiring hospitalisation; by the patient’s own admission, she had not thought to inform her physician because she considered the drug a natural supplement and not a medication with the potential for toxicity.

The degree of hepatotoxicity was in fact alarming, with an increase of total bilirubin to 30 mg/dl, ALT >1000 IU/l, AST >2000 IU/l, and GGT >300 U/L, indicative of a mixed cytolytic and cholestatic reaction; cholestatic injury was biphasic, with GGT concentrations peaking after bilirubin had started to decline. Furthermore the prolongation of prothrombin time indicated decreased hepatic synthesis. The patient had been taking St John’s wort for approximately 6 weeks, and had continued even after peginterferon α treatment was discontinued. The sequence of events lead us to conclude that even if the initial toxicity was caused by peginterferon α, the continued addition of St John’s wort contributed to the increasing severity of the reaction. Notably, serum HCV RNA, despite returning to be detectable several months later, remained undetectable during steroid treatment of acute hepatotoxicity, therefore rebound viral replication did not contribute to hepatocellular damage.

In conclusion, by self administering a herbal remedy while receiving peginterferon therapy, this patient unknowingly jeopardised her life as well as her future prospects of receiving treatment for her chronic HCV infection.

LEARNING POINTS

  • The general public’s fascination with herbal remedies must be taken into account whenever drug induced toxicity is suspected, or in the presence of otherwise unexplained laboratory abnormalities of liver damage.
  • Until the pathophysiological mechanisms underlying adverse interactions are uncovered, all patients with chronic liver disease should be warned against the risk of toxicity of herbal remedies, and that “natural” is not synonymous with “safe”.
  • The combination of peginterferon α and St John’s wort resulted in a severe acute hepatitis in this patient. Patients should be advised of this potential toxic effect of this herbal remedy.

Footnotes

Competing interests: none.

Patient consent: Patient/guardian consent was obtained for publication

REFERENCES

1. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997; 26: 47–51. [PubMed]
2. De Smet P. A.G.M. Drug Therapy: Herbal Remedies. N Engl J Med 2002; 347: 2046–56. [PubMed]
3. Savvidou S, Goulis J, Giavazis I, et al. Herb-induced hepatitis by Teucrium polium L.: report of two cases and review of the literature. Eur J Gastroenterol Hepatol 2007; 19: 507–11. [PubMed]
4. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007; 11: 577–96. [PubMed]
5. Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. J Hepatol 2007; 47: 521–6. [PubMed]
6. Fau D, Lekehal M, Farrell G, et al. Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997; 113: 1334–46. [PubMed]
7. Foti RS, Wahlstrom JL, Wienkers LC. The in vitro drug interaction potential of dietary supplements containing multiple herbal components. Drug Metab Dispos 2007; 35: 185–8. [PubMed]
8. Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions. Life Sci 2006; 78: 2105–15. [PubMed]
9. Linde K, Mulrow CD, Berner M, et al. St John’s wort for depression. Cochrane Database Syst Rev 2005; 2: CD000448. [PubMed]
10. Gaster B, Holroyd J. St John’s wort for depression: a systematic review. Arch Intern Med 2000; 160: 152–6. [PubMed]
11. Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 1997; 30(Suppl 2): 129–34. [PubMed]
12. Gobbi M, Moia M, Pirona L, et al. In vitro binding studies with two hypericum perforatum extracts—hyperforin, hypericin and biapigenin—on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. Pharmacopsychiatry 2001; 34(Suppl 1): S45–8. [PubMed]
13. Barnes J, Anderson LA, Phillipson JD. St John’s wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2001; 53: 583–600. [PubMed]
14. Karliova M, Treichel U, Malagò M, et al. Interaction of Hypericum perforatum (St. John’s Wort) and cyclosporine A metabolism in a patient after liver transplantation. J Hepatol 2000; 33: 853–5. [PubMed]
15. Singh YN. Potential for interaction of kava and St. John’s wort with drugs. J Ethnopharmacol 2005; 100: 108–13. [PubMed]
16. Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645–52. [PubMed]

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