Acute hepatitis induced by greater celandine (Chelidonium majus)

GASTROENTEROLOGY 1999;117:1234–1237

Acute Hepatitis Induced by Greater Celandine (Chelidonium majus) JOHANNES BENNINGER,* H. THOMAS SCHNEIDER,* DETLEF SCHUPPAN,* THOMAS KIRCHNER,‡ and ECKHART G. HAHN* Departments of *Medicine I and ‡Pathology, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany

The hepatotoxic potential of conventional drugs is well known, but herbal medicines are often assumed to be harmless. In the last 2 years, we have observed 10 cases of acute hepatitis induced by preparations of greater celandine (Chelidonium majus), which are frequently prescribed to treat gastric and biliary disorders. The course of hepatitis was mild to severe. Marked cholestasis was observed in 5 patients, but liver failure did not occur. Other possible causes of liver disease (viral, autoimmune, hereditary, alcohol, and secondary biliary) were excluded by laboratory tests and imaging procedures, and liver biopsy specimens were consistent with drug-induced damage. After discontinuation of greater celandine, rapid recovery was observed in all patients and liver enzyme levels returned to normal in 2–6 months. Unintentional rechallenge led to a second flare of hepatic inflammation in 1 patient. Greater celandine has to be added to the list of herbs capable of inducing acute (cholestatic) hepatitis. A significant proportion of unexplained cases of hepatitis may be caused by greater celandine.

erbal drugs are commonly used as over-the-counter remedies and are generally believed to be innocuous.1 However, hepatotoxicity, a frequent complication of chemically defined drugs,2 has been reported after ingestion of herbal drugs or teas containing pyrrolizidine alkaloids (main plants: Heliotropium, Senecio, and Crotalaria),1,3 Teucrium chamaedrys (germander),3 and Teucrium polium,4 which in a few cases even led to liver failure with subsequent liver transplantation or death.4–6 In Germany and other European countries, the commercially available extract of greater celandine (Chelidonium majus) is widely used for gallstone disease and dyspepsia. In the last 2 years, we have observed 10 women in whom acute hepatitis occurred during intake of greater celandine.

H

Case Reports

apparent, with levels of aspartate aminotransferase (AST) of 898 IU/L (upper limit of normal, 15), alanine aminotransferase (ALT) 813 IU/L (17), ␥-glutamyltransferase (GGT) 32 IU/L (18), alkaline phosphatase (AP) 249 IU/L (105), and bilirubin 349 (17) µmol/L at that time. In another hospital, where she was admitted at the onset of jaundice, marginally positive hepatitis C antibodies despite negative HCV RNA led to the diagnosis of HCV infection. Other common viral etiologies were excluded (hepatitis A, B, and E, cytomegalovirus, and Epstein–Barr virus). During her 11-day hospital stay, the patient recovered and laboratory values decreased without specific therapy (at discharge: AST, 50 IU/L; ALT, 138 IU/L; GGT, 31 IU/L; AP, 170 IU/L; and bilirubin, 55 µmol/L). Two weeks later, symptoms and marked jaundice reappeared and laboratory values increased, with AST 353 IU/L, ALT 480 IU/L, GGT 30 IU/L, AP 192 IU/L, and bilirubin 258 µmol/L at admission to our hospital 6 weeks later. Common causes for liver diseases including autoimmune hepatitis were ruled out again. Ultrasound examination showed normal liver parenchyma and bile ducts. The patient refused to undergo liver biopsy. Intensive questioning showed that the patient had taken various herbal and homeopathic drugs including greater celandine (Neurochol C; Kytta-Siegfried Pharma, Alpirsbach, Germany), which had been prescribed by her nonmedical practitioner because of atopic eczema and had been ingested for 3 months before first symptoms appeared. During her first hospital stay, she stopped taking greater celandine but resumed it after discharge. The intake of greater celandine was discontinued immediately, and all other therapies were continued. Two months later, all liver values returned to normal with no new increases during 1 year of follow-up.

Other Patients We observed similar courses in 9 additional women after intake of greater celandine with partly severe hepatitis. In 7 patients, liver parameters were retrospectively available 1–10 months before intake of greater celandine, showing normal values. Other causes for hepatitis were ruled out in all cases,

Patient 1 A 37-year-old woman (case 5) was referred to our outpatient clinic because of cholestatic hepatitis. She had felt well until 2 months earlier when nausea and jaundice became

Abbreviations used in this paper: AP, alkaline phosphatase; GGT, ␥-glutamyltransferase. r 1999 by the American Gastroenterological Association 0016-5085/99/$10.00

November 1999

and the patients recovered completely after discontinuation of the drug. Liver biopsy demonstrated drug-induced hepatitis in 7 patients (Figure 1). The relevant data of the 10 patients are shown in Table 1.

Discussion It is notoriously difficult to prove the causal role of a certain drug in creating acute organ damage, but the etiologic role of greater celandine is clearly evident in the present cases for the following reasons. In all patients, other common causes for hepatitis were excluded and hepatitis was strictly associated with the beginning of greater celandine medication. Two patients took no other drugs, and 4 patients had no change in their standard medication for a long time. A possible etiologic role of other drugs could certainly be excluded. In 7 patients, liver enzymes in the year before the ingestion of greater celandine were available retrospectively, showing normal values and suggesting the absence of liver disease. In all patients, discontinuation of greater celandine treatment led to complete recovery and normalization of liver enzyme levels in 2–6 months. Seven of the 10 patients underwent liver biopsy, and histology was compatible

DRUG–INDUCED HEPATITIS 1235

with drug-induced damage in all cases (Figure 1).7 Unintentional rechallenge of greater celandine in the patient described (case 5) led to a second flare of hepatitis. The mechanism of hepatotoxicity of greater celandine remains unclear. An idiosyncratic reaction seems most likely because there was no dose dependency and the latent period was long and variable.7 The eosinophilic infiltrate, seen in most liver biopsy specimens, supports this hypothesis.7 Interestingly, in 8 of 9 tested patients, autoantibodies against nuclei or smooth muscle were detected at a low titer, indicating that, as in other drug-induced liver diseases, low-grade autoimmunity may develop. Because the commercially available preparations of greater celandine consist of an extract of the plant with many different ingredients, including more than 20 known alkaloids with biological activity, particularly chelidonine (to which the drugs are standardized), sanguinarine, berberine, coptisine, and chelerythrine, the hepatotoxic agent remains to be characterized.8–10 Hepatotoxicity occurred with the preparations of 5 different German manufacturers (Cholarist [Steiner, Berlin], Neurochol C; [Kytta-Siegfried Pharma, Alpirsbach], Panchelidon N [Kanoldt Arzneimittel, Ho¨chstadt], Siosol [Febena,

Figure 1. Histology of hepatitis induced by greater celandine. Liver biopsy specimen of patient 1, a 67-year-old woman, 9 months after greater celandine ingestion. (A ) Moderate portal and generalized inflammatory infiltrates in the liver (H&E; original magnification 20⫻). (B ) Periportal fibrosis and bridging collapse of reticulin fibers between portal triad and central vein (arrowheads; reticulin silver stain; 20⫻). (C ) Portal and periportal infiltrate of mainly lymphocytes and some granulocytes (H&E; 40⫻). (D ) Intralobular hepatocyte apoptosis (Councilman body) and focal aggregate of Kupffer cells and lymphocytes (H&E; 40⫻).

2

ND

5

Severe druginduced hepatitis, bridging necrosis, severe septal fibrosis (incipient cirrhosis)d

SMA 1:40

Iodide

571 870 226 96 243

1 (possibly years ago)

3 54 Gallbladder stones

2

ANA 1:160, moderate alcohol Moderate druginduced hepatitis, periportal and intralobular single cell necrosis, septal fibrosise

Valerian, pancreatic enzymes, loperamide

425 873 451 421 77

4 46 Right-sided abdominal pain 6

5

ND

SMA 1:40

Various herbal and homeopathic drugs

353 480 192 30 258

3

5 37 Atopic eczema

3

Moderate drug induced hepatitis, lowgrade single cell necrosis

None

None

89 152 451 179 Normal

3

6 65 Dyspepsia

aNormal

GC, greater chelandine; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; ND, not determined. ranges: AST, 1–15 IU/L; ALT, 1–17 IU/L; AP, 33–105 IU/L; GGT, 4–18 IU/L; bilirubin (total), 1.7–17.1 µmol/L. bGilbert–Meulengracht syndrome. cIn addition to several other drugs. dControl biopsy 6 months later: minimal single cell necrosis and septal fibrosis (incipient cirrhosis). eControl biopsy 6 months later: low-grade periportal hepatitis and portal fibrosis.

Time until nor6 malization of liver parameters after withdrawal of GC (mo)

Moderate druginduced hepatitis, periportal and intralobular single cell necrosis, septal fibrosis

Histology

Autoantibodies ND

Iodide, estradiol/levonorgestrel

None

ANA 1:160

77 123 65 48 26b

350 460 282 286 17

Other important findings

4

9

Duration of GC ingestion at diagnosis (mo) Liver parameters at diagnosisa AST (IU/L) ALT (IU/L) AP (IU/L) GGT (IU/L) Bilirubin (␮mol/L) Other medication

2 46 Gallbladder stones

1 67 Constipation

Patient Age ( yr ) Indication for GC

Table 1. Cases of Acute Hepatitis Induced by Greater Celandine

3

ND

Thyroxine, silymarin, acetylsalicylic acid, zinc, hymecromone, amitriptylinec ANA 1:160

320 540 370 230 22

3

7 40 Gallbladder stones

577 734 431 275 104

2 (irregularly before)

9 40 Dyspepsia

Thyroxine, Magnesium, atenolol, estradiol nifedipine, triamterene, hydrochlorothiazide ANA 1:160, HCV ANA 1:160 antibody⫹ (RNA⫺) Moderate drugSevere druginduced hepainduced hepatitis, perititis, severe portal and periportal and intralobular intralobular single cell liver cell necrosis, necrosis, septal periportal and fibrosis septal fibrosis 2 2

192 328 140 118 Normal

4

8 66 Dyspepsia

3

Severe druginduced hepatitis, lowgrade single cell necrosis

ANA 1:40

Estradiol

688 1338 368 133 371

3

10 41 Dyspepsia

1236 BENNINGER ET AL. GASTROENTEROLOGY Vol. 117, No. 5

November 1999

Cologne], and spasmo gallo sanol [Sanol, Monheim]), with 2 of the preparations (spasmo gallo sanol and Neurochol C) containing additional herbal drugs, suggesting that greater celandine was the toxic agent. Interestingly, herbal preparations containing greater celandine are also marketed in the United States (e.g., via several websites: www1.viaweb.com/vitanet/; www.sequentialhealing.com/herbs/greater-celandine.html; and www.herbsinfo.com/pages/pvision.htm). Because we observed these 10 cases in an area of approximately 1,000,000 inhabitants within 2 years, we assume that the number of unknown cases may be much higher than suggested in 2 recent reports describing 3 patients with possible hepatotoxicity induced by greater celandine.11,12 Four of the patients were initially examined in other hospitals, where patients did not report the use of greater celandine or where the possible role of greater celandine as an herbal drug for hepatitis was not taken into consideration. Doctors are recommended always to ask their patients about any medicines they are taking, whether prescribed or otherwise, when liver damage by drugs is suspected or common tests for hepatitis do not reveal the cause of hepatic injury.

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DRUG–INDUCED HEPATITIS 1237

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Received February 5, 1999. Accepted July 26, 1999. Address requests for reprints to: Johannes Benninger, M.D., Medizinische Klinik I mit Poliklinik, Friedrich-Alexander-Universita ¨t Erlangen-Nu ¨rnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany. e-mail: [email protected]; fax: (49) 9131-853-6909. A preliminary report of this study was presented at the annual meeting of the American Association for the Study of Liver Diseases, Chicago, Illinois, November 4–10, 1998.