Thiabendazole is a broad spectrum antihelmintic agent used predominantly in treatment of intestinal pinworm and strongyloides infection, which recently has been replaced by better tolerated agents. Thiabendazole therapy has been shown to cause clinically apparent cholestatic liver injury which is rare, but can be severe.
Thiabendazole (thye" a ben' da zole) is a benzimidazole antihelmintic agent similar in structure and mechanism of action to albendazole and mebendazole. The benzimidazoles act by selective binding to beta-tubulin of parasitic worms, causing their immobilization and death. Thiabendazole was approved in the United States in 1967, but has subsequently been withdrawn because of the availability of other, better tolerated antihelmintic agents, such as ivermectin, albendazole and mebendazole. Thiabendazole is, however, still available in other countries and is used in veterinary medicine in the United States. Its major indication is strongyloidiasis infestation. Thiabendazole was formerly available in chewable tablets of 500 mg under the trade name of Mintezol and as an oral suspension. The typical dose in adults was 1500 mg orally daily for 1 to 3 days. The dose in children is based upon body weight. Thiabendazole therapy is associated with frequent minor but troublesome side effects including dizziness, nausea, diarrhea, gastrointestinal upset, headaches and hair loss.
Thiabendazole therapy is associated with serum aminotransferase elevations in up to 36% of patients, but it is usually given for a brief period only and its effects on serum enzyme levels after single dose administration has not been systematically evaluated. Importantly, thiabendazole therapy has also been associated with clinically apparent liver injury which can be prolonged and severe. The onset of injury is usually within 1 to 2 weeks of finishing a 1 to 5 day course of therapy. The pattern of serum enzyme elevations is typically cholestatic. Autoantibodies are usually negative and fever, arthralgias and rash are uncommon. Several reported cases have been associated with sicca complex marked by parotid enlargement and tenderness, dry eyes and dry mouth arising before the onset of jaundice. The cholestatic injury can be associated with damage to small bile ducts and with prolonged jaundice and/or pruritus and alkaline phosphatase elevations. Several instances of prolonged cholestasis and chronic vanishing bile duct syndrome and end stage liver disease has been reported even after a single dose of thiabendazole.
Mechanism of Injury
Thiabendazole hepatotoxicity appears to be due to an immunological reaction to the drug, which is directed largely at bile, lacrimal, and salivary gland ducts.
Outcome and Management
While most reported cases of thiabendazole induced liver injury were self-limited, many were marked by severe and prolonged cholestasis. Several cases of prolonged jaundice with vanishing bile duct syndrome and evolution to cirrhosis leading to liver transplantation have been reported. Patients with acute liver injury attributed to thiabendazole should avoid repeat exposure. It is unknown whether there is cross sensitivity with other benzimidazoles (such as mebendazole), but there probably is and switching to another class of antihelmintic agents is appropriate if therapy is still needed.
Case 1. Cholestatic hepatitis followed by chronic cholestatic syndrome and cirrhosis after short course of thiabendazole.
[Modified from: Roy MA, Nugent FW, Aretz HT. Micronodular cirrhosis after thiabendazole. Dig Dis Sci 1989; 34: 938-41. PubMed Citation]
A 46 year old woman with suspected trichinosis was treated with thiabendazole (25 mg/kg twice daily for 5 days) and prednisone (40 mg/day). Two weeks later, she noted dryness of the eyes and mouth with low grade fever. Shortly thereafter she developed dark urine and pruritus. She had no history of liver disease or drug allergies and drank little alcohol. On admission, she had prominence of the parotid glands and right upper quadrant tenderness without enlargement of the liver or spleen. She was jaundiced but had no other signs of chronic liver disease. Laboratory values showed a total bilirubin of 16.4 mg/dL with a direct of 11.5 mg/dL (Table). Serum aminotransferase levels were 3 to 20 fold elevated and 5’ nucleotidase was 5 times elevated. Tests for hepatitis A and B and routine autoantibodies were normal. Ultrasound and CT scans of the abdomen showed no abnormalities and endoscopic retrograde cholangiopancreatography revealed no evidence of biliary obstruction. A liver biopsy showed marked intrahepatic cholestasis and a relative paucity of bile ducts. A salivary gland biopsy showed sialadenitis with prominent destruction of acini and ductules. She remained deeply jaundiced, but reevaluation showed no evidence for other liver disease. Over the next 8 months her symptoms of dry mouth and eyes improved, but she continued to have pruritus and mild jaundice. Two and a half years after exposure to thiabendazole she developed ascites and variceal bleeding. A repeat liver biopsy showed a micronodular cirrhosis with little inflammation and no steatosis. She remained negative for antinuclear (ANA), antimitochondrial (AMA), and antimicrosomal antibodies. Shortly thereafter, she underwent liver transplantation; the explant again showed micronodular cirrhosis.
|Medication:||Thiabendazole (25 mg/kg twice daily for 5 days)|
|Pattern:|| Cholestatic pattern (R=~0.8)|
||5+ (ultimately leading to cirrhosis and liver transplantation)|
|Other medications:||Prednisone 40 mg daily for short period|
|Time After Starting
||AMA and ANA negative
||Sicca syndrome resolved
| Normal Values
Thiabendazole typically causes an acute cholestatic hepatitis, but in half of cases the cholestatic hepatitis has been preceded by onset of a sicca syndrome with dry eyes and dry mouth and parotid enlargement, with salivary gland biopsies showing inflammation and damage to acini and ductules. The cholestatic hepatitis may also be characterized by damage to bile ducts and result in a prolonged jaundice or cholestasis, with persistence of liver test abnormalities for months or years. In its most severe form, this prolonged cholestasis is also marked by vanishing bile duct syndrome and chronic cholestasis that can result in cirrhosis, portal hypertension and end stage liver disease. The condition resembles primary biliary cirrhosis, but typically presents in an acute fashion with jaundice and symptoms, whereas primary biliary cirrhosis usually presents insidiously with liver test abnormalities and pruritus long before onset of jaundice. Interestingly, primary biliary cirrhosis can also be associated with keratoconjunctivitis sicca, and the histology of the involved salivary and lacrimal glands resembles that of primary biliary cirrhosis with intense inflammation and damage to small bile ducts, with rupture and granulomatous inflammation in the acute phase. This striking syndrome, several cases of which have been reported after short courses of thiabendazole, has not been reported with the other antihelmintic benzimidazoles, mebendazole and albendazole.
REPRESENTATIVE TRADE NAMES
Thiabendazole – Mintezol®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
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References updated: 12 December 2013
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Davidson RN, Weir WR, Kaye GL, McIntyre N. Intrahepatic cholestasis after thiabendazole. Trans R Soc Trop Med Hyg 1988; 82: 620. PubMed Citation (17 year old boy developed dry mouth 1 day after finishing 3 day course of thiabendazole for strongyloides infection, becoming jaundiced 2 weeks later [bilirubin rising to 23.8 mg/dL, ALT 102 U/L, Alk P 350 U/L], biopsy showed severe intrahepatic cholestasis, jaundice resolved in 6 and serum enzyme elevations in 12 months).
Roy MA, Nugent FW, Aretz HT. Micronodular cirrhosis after thiabendazole. Dig Dis Sci 1989; 34: 938-41. PubMed Citation (46 year old woman developed dry eyes and mouth 2 weeks after a 5 day course of thiabendazole for trichinosis, followed by jaundice and pruritus 1 week later [bilirubin 16.4 mg/dL, ALT 487 U/L], liver biopsy showed intrahepatic cholestasis and paucity of bile ducts, with prolonged jaundice and pruritus and variceal hemorrhage 2.5 years later: Case 1).
Bion E, Pariente EA, Maitre F. Severe cholestasis and sicca syndrome after thiabendazole. J Hepatol 1995; 23: 762-3. PubMed Citation (56 year old man developed severe dry mouth and eyes 2 weeks after a 3 day course of thiabendazole, followed 3 days later by jaundice [bilirubin rising to 27.2 mg/dL, ALT 5.5 times ULN, Alk P 8 times ULN, GGT 29 times ULN], liver biopsy showed intrahepatic cholestasis and salivary gland biopsy sialadenitis, slow recovery and persistent GGT elevation 6 years later).
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Eland IA, Kerkhof SC, Overbosch D, Wismans PJ, Stricker BH. [Cholestatic hepatitis ascribed to the use of thiabendazole]. Ned Tijdschr Geneeskd 1998; 142: 1331-4. Dutch. PubMed Citation (Two women with cholestatic hepatitis arising 2-3 weeks after 2 day course of thiabendazole for strongyloidiasis, with slow and incomplete recovery).
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thiabendazole for the treatment of strongyloidiasis. PLoS Negl Trop Dis 2011; 5 :e1254. PubMed Citation (Controlled trial of thiabendazole [2 daily doses for 2 days] vs ivermectin [single dose] in 198 patients with Strongyloidiasis found similar efficacy, but fewer side effects with ivermectin; no mention of hepatotoxicity or ALT elevations).
Groh M, Blanche P, Calmus Y, Guillevin L. Thiabendazole-induced acute liver
failure requiring transplantation and subsequent diagnosis of polyarteritis
nodosa. Clin Exp Rheumatol 2012; 30 (1 Suppl 70): S107-9. PubMed Citation (33 year old man with chronic hypereosinophilia developed severe liver injury after experimental therapy with thiabendazole which resulted in vanishing bile duct syndrome, hepatic failure and liver transplantation; few details given).
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