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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: July 25, 2020.



Penicillamine is chelating agent used to decrease copper stores in Wilson disease, which also has immunomodulatory activity in rheumatic diseases such as rheumatoid arthritis, scleroderma and systemic lupus erythematosus. Penicillamine is capable of causing hypersensitivity reactions, some of which are accompanied by liver injury which is typically cholestatic.


Penicillamine (pen" i sil' a meen) is d-isomer of dimethylcysteine, a breakdown product of penicillin, which was originally isolated from the urine of patients with liver disease receiving penicillin. It was later found to have chelating properties against copper and used in Wilson disease. Penicillamine was also found to lower levels of immune complexes, which led to its use in several rheumatic and immune disorders such as rheumatoid arthritis, scleroderma, systemic lupus erythematosus and primary biliary cirrhosis. Penicillamine was approved for use in Wilson disease in 1960 and is still widely used for that rare indication. The use of penicillamine for rheumatic disorders has decreased markedly with the availability of more modern, potent and less toxic agents. Penicillamine is available in generic forms and under the brand names of Cuprimine and Depen in capsules of 125 and 250 mg and tablets of 250 mg. The usual dose in 250 mg four times daily, increasing based upon effect and tolerance to a maximum of 2 grams daily. Lower doses were used in rheumatic diseases. Common side effects include gastrointestinal upset, metallic taste, bone marrow suppression, rash, pruritus, induction of autoimmune diseases and drug fever. Severe adverse events include aplastic anemia, agranulocytosis, thrombocytopenia, renal dysfunction, proteinuria, Goodpasture syndrome, myasthenia gravis, pemphigus and acute hypersensitivity reactions.


Penicillamine has been linked to a characteristic pattern of liver injury arising 1 to 6 weeks after starting therapy, with a distinctly cholestatic pattern of serum enzyme elevations (Case 1). The jaundice due to penicillamine can be severe and prolonged and result in protracted, symptomatic cholestasis, but most cases are self-limited. Immunoallergic manifestations of rash, fever and eosinophilia are common, but not invariable. Interesting, most cases of acute liver injury attributed to penicillamine were reported in patients with rheumatic diseases, only rare instances being reported in Wilson disease.

Other toxicities of penicillamine therapy such as bone marrow suppression, neutropenia and severe dermatologic features can accompany the hepatic injury. Furthermore, in instances with severe nonhepatic penicillamine toxicities, some degree of hepatic involvement such as mild-to-moderate serum enzyme elevations may occur. Long term toxicities of penicillamine include induction of autoimmune conditions (glomerulonephritis, pneumonitis, lupus-like syndrome) that may be accompanied by autoantibody formation, but autoimmune hepatitis-like syndromes have not been reported.

Likelihood score: A (well established cause of clinically apparent liver injury).

Mechanism of Injury

The liver injury caused by penicillamine appears to be due to hypersensitivity as shown by its brief latency and the frequency of immunoallergic symptoms and signs. Susceptibility to penicillamine hypersensitivity has been linked to HLA DR3, sulphoxidation status and previous gold allergy, but these factors have not been specifically linked to hepatotoxicity from penicillamine.

Outcome and Management

The hepatotoxicity of penicillamine is typically self-limited, although recovery may be delayed. However, there have been several instances of progressive cholestasis resulting in death or need for liver transplantation arising after acute, severe cholestatic liver injury due to penicillamine. While the pathology of these cases has stressed the chronic cholestatic features and progressive fibrosis, there is little information on bile duct injury and loss. Nevertheless, these instances probably represent vanishing bile duct syndrome. Monitoring of routine liver tests is recommended before and every 6 months during therapy with penicillamine. While ursodiol and corticosteroids are often used in patients with prolonged cholestasis after hepatotoxicity from penicillamine (and other drugs), there is little evidence that they are beneficial. There may be cross reactivity between penicillamine hypersensitivity and allergic responses to penicillin, but this is not invariable. Nevertheless, caution should be employed in use of penicillins in patients with severe penicillamine hypersensitivity.

Drug Class: Antirheumatic Agents; Chelating Agents, Wilson Disease Agents

Other Drugs in the Subclass, Wilson Disease: Dimercaprol, Trientine, Zinc


Case 1. Immunoallergic hepatitis due to penicillamine.(1)

A 58 year old woman with scleroderma accompanied by arthritis, Raynaud’s phenomenon, skin tightening over the face and hands, and lung involvement was placed on penicillamine in a dose of 1.8 g daily. Three weeks later she developed fever and generalized maculopapular rash, followed two days later by dark urine and jaundice. All medications were stopped. She had no previous history of liver disease or drug allergies and did not drink alcohol. Over-the-counter medications included vitamins only. Laboratory testing showed serum bilirubin of 7.4 mg/dL, mild ALT elevations (90 U/L), and marked increases in alkaline phosphatase levels (Table). She had mild eosinophilia (5%) and leukocytosis. Over the next few days, fever and rash resolved and 3 weeks after onset, laboratory tests had returned to normal or near normal.

Key Points

Medication:Penicillamine (1.8 g daily)
Pattern:Cholestatic (R=0.3)
Severity:2+ (jaundice, not hospitalized)
Latency:3 weeks
Recovery:3 weeks
Other medications:Vitamin B6

Laboratory Values

Time After
Time After
Alk P
14 days0Worsening fever over 4 days followed by rash and jaundice
24 days09033.47.45% eosinophils
26 days2 days4332.45.8
33 days9 days2114.51.6
39 days15 days97.80.9
Normal Values<30<4.5<1.2


An early report without viral serology to exclude acute viral hepatitis or modern imaging to exclude biliary obstruction, but the progression of symptoms and laboratory test abnormalities were very typical of drug induced hypersensitivity and liver injury. The latency to onset of symptoms of fever, rash and malaise was 2 to 3 weeks, with jaundice appearing soon thereafter. Immunoallergic symptoms and signs were present and the pattern of serum enzyme elevations was distinctly cholestatic, features that are typical of penicillamine induced liver injury. The features of hypersensitivity usually resolve within a week of stopping therapy, whereas the cholestasis and jaundice are slower to improve. Corticosteroids appear to improve the immunoallergic symptoms and signs promptly, but their effect on the liver injury is less clear.



Penicillamine – Generic, Cuprimine®


Antirheumatic Agents

Chelating Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Penicillamine52-67-5C5-H11-N-O2-Simage 134970687 in the ncbi pubchem database


Rau R, Weber S, Böni A. Schweiz Med Wochenschr. 1972;102:1226–8. [Allergic-toxic liver damage due to D-penicillamine] German. [PubMed: 5055042]


References updated: 25 July 2020

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    (HLA testing done on 86 patients with rheumatoid arthritis started on penicillamine including 22 on long term [5-7 years] therapy; HLA-DR4 was associated with thrombocytopenia [94% vs 67%] and HLA-B8/DR3 with proteinuria [60% vs 9%], but no association with effectiveness; no cases of hepatotoxicity).
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    (65 year old woman with rheumatoid arthritis developed thrombocytopenia 3 months after starting penicillamine [platelet count 10,000/µL, white cell count 3000/µL, hemoglobin 6.7 gm/dL] and subsequently developed jaundice [bilirubin 10.0 mg/dL, AST 80 U/L, Alk P 120 U/L], dying 17 days later with bone marrow, renal and hepatic failure).
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    (37 year old woman with rheumatoid arthritis developed fever, granulocytopenia and jaundice 10 days after starting penicillamine [without rash or eosinophilia], with intrahepatic cholestasis on liver biopsy and subsequent persistent jaundice and cholestasis and death from sepsis 14 months later).
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    (28 year old woman who was intolerant to penicillamine was successfully treated with trientine prepared by an improved method, with prompt cupruresis and improvement in neurologic symptoms).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
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  • Weiss KH, Stremmel W. Evolving perspectives in Wilson disease: diagnosis, treatment and monitoring. Curr Gastroenterol Rep. 2012;14(1):1–7. [PubMed: 22083169]
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  • Weiss KH, Thurik F, Gotthardt DN, Schäfer M, Teufel U, Wiegand F, Merle U, et al. EUROWILSON Consortium. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11:1028–35.e1. [PubMed: 23542331]
    (Retrospective analysis of 380 patients with Wilson disease from referral centers in Germany and Austria, including 141 who were treated with trientine and 326 with penicillamine, found similar rates of improvement in liver disease but higher rate of improvement in neurologic features with penicillamine, along with higher rates of adverse events leading to discontinuation [29% vs 7%], although there were no therapy related deaths; reasons for discontinuation in the penicillamine group included arthralgias, gastrointestinal upset, myalgias, leukopenia, rash, lupus erythematosus and increase in ANA titers; no mention of ALT elevations or hepatotoxicity).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which was attributed to penicillamine or other agents used to treat Wilson disease).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one case was attributed to penicillamine in a woman with scleroderma who developed fatigue, jaundice and rash 3 weeks after starting penicillamine [bilirubin 5.6 rising to 10.5 mg/dL, ALT 308 U/L, Alk P 377 U/L], resolving slowly and with persistent, mild elevations in ALT and Alk P during long term follow up).
  • Pfeiffenberger J, Beinhardt S, Gotthardt DN, Haag N, Freissmuth C, Reuner U, Gauss A, et al. Pregnancy in Wilson's disease: management and outcome. Hepatology. 2018;67:1261–9. [PubMed: 28859232]
    (Among 282 pregnancies in 136 patients with Wilson disease analyzed in a retrospective, multicenter study, spontaneous abortion was less common among patients being treated with penicillamine [17%] or zinc [10%] than untreated patients [41%], which was proportionally greater than with trientine [28%] and similar to that in patients who discontinued therapy during pregnancy [36%]; worsening of liver disease arose in some patients on treatment but was self-limiting and resolved after delivery; birth defects were found in 7 of 209 [3%] newborns overall and in 4 of 98 women taking penicillamine).
  • Roberts EA. Update on the diagnosis and management of Wilson disease. Curr Gastroenterol Rep. 2018;20:56. [PubMed: 30397835]
    (Review of recent advances in the understanding of the pathogenesis, clinical features, diagnosis, and treatment of Wilson disease).
  • Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int. 2019;39:2136–52. [PubMed: 31206982]
    (Systematic review of literature on therapies of Wilson disease found no differences in outcomes with penicillamine vs zinc, but higher rates of adverse events and discontinuations with penicillamine; no mention of hepatotoxicity or ALT elevations).


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