Mercaptopurine: What is it? How does it work? Therapy, Diagnosis and Mechanism

It is a purine analog that is effective both as an anticancer agent and an immunosuppressant, and is used to treat leukemia and autoimmune diseases.

Mercaptopurine therapy is associated with a high rate of serum aminotransferase elevations that may be accompanied by jaundice . In addition, mercaptopurine has been linked to cases of clinically apparent acute liver injury and long-term treatment of nodular regenerative hyperplasia.

Act in this way

Mercaptopurine is an analogue of purine that acts as an antimetabolite by antagonizing the purine metabolism that produces a general inhibition of DNA, RNA and subsequent protein synthesis.

Mercaptopurine also has anti-inflammatory and immunosuppressive activity, inhibiting the maturation of T cells and blocking delayed hypersensitivity reactions.

Mercaptopurine was introduced in the 1950s for the treatment of leukemia and lymphoma and was formally approved for use in the United States in 1953. It is still used in the therapy of acute lymphocytic leukemia and labeling for autoimmune diseases such as Crohn’s disease .

Mercaptopurine is available generically and under the brand name Purinethol in 50 mg tablets. The usual dose is 1 to 3 mg per kilogram or 50 to 150 mg per day, and is usually administered long-term.

Common side effects include nausea, abdominal discomfort, rash, aphthous ulcers,and bone marrow suppression related to the dose.

Hepatotoxicity of Mercaptopurine

Mercaptopurine has been associated with several forms of hepatotoxicity.

Patients receiving mercaptopurine for leukemia often have transient and asymptomatic increases in serum aminotransferase or alkaline phosphatase levels and a proportion of these patients develop jaundice, particularly when given in high doses.

In the series of patients with autoimmune diseases (such as inflammatory bowel disease) treated with mercaptopurine, up to 30% developed elevations of serum aminotransferase and these can be persistent as long as treatment continues, resolving with dose reduction or interruption.

Liver biopsy usually shows steatosis and a centrilobular lesion with little inflammation.

Mercaptopurine can also cause acute, clinically evident liver injury, which usually presents with fatigue and jaundice and a cholestatic or mixed pattern of serum enzyme elevations 1 to 6 months after starting therapy, but sometimes later, particularly after of an increase in the dose.

Serum enzyme levels are often not very high, certainly not in the range that occurs with acute viral hepatic.

Rash, fever, and eosinophilia are rare and autoantibodies are usually not found. Liver biopsy usually shows a mixed hepatocellular-cholestatic lesion with cholestasis, focal hepatocellular necrosis, bile duct injury, and varying amounts of inflammation.

The lesion is idiosyncratic and similar to cholestatic hepatitis associated with azathioprine. Liver injury usually resolves when stopped, but prolonged cholestasis has been reported and some cases have been fatal.

In large case series and registries, mercaptopurine is usually among the top 20 causes of drug-induced liver damage, and if combined with cases due to azathioprine [a prodrug of mercaptopurine] would be among the 10 most frequent causes.

Mercaptopurine Therapy

Chronic therapy with mercaptopurine and other thiopurines can lead to nodular regeneration and symptomatic portal hypertension.

This chronic hepatotoxicity usually presents with fatigue and signs and symptoms of portal hypertension (ascites, varices), with mild abnormalities of liver enzymes and minimal jaundice that occurs from 6 months to many years after the onset of mercaptopurine.

Liver biopsy shows nodular regenerative hyperplasia without significant fibrosis and variable amounts of sinusoidal dilatation and central vein injury.

This syndrome may progress to liver failure, particularly if mercaptopurine is continued, but the gradual improvement in suspension treatment is typical.

Rarely, the onset of this syndrome can be acute with abdominal pain and ascites, a situation in which the liver biopsy usually shows sinusoidal dilatation, central congestion and sinusoidal endothelial cells suggestive of veno-occlusive disease, which is currently called sinusoidal obstructive syndrome .

Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of liver dysfunction and portal hypertension.

Many cases present initially with unexplained thrombocytopenia, and progressive decreases in platelet counts may be the most sensitive marker for the development of non-cirrhotic portal hypertension.

Finally, long-term therapy with mercaptopurine and other thiopurines has been implicated in the development of malignancies, including hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL).

Both complications are rare but have been reported in several dozen case reports and small case series.

In none of the cases, the role of thiopurine treatment as the cause of the malignant ones has been demonstrated, and similar cases have been described in patients with autoimmune diseases or after a solid organ transplant who have not received thiopurines.

Hepatocellular carcinoma usually appears after years of therapy with azathioprine or mercaptopurine and in the absence of accompanying liver disease (although sometimes with focal hepatic glycogenosis).

HCC is most often found in an imaging study of an unrelated condition. The prognosis is more favorable than that of CHC associated with cirrhosis.

Hepatosplenic T-cell lymphoma has been reported primarily in young men with inflammatory bowel disease and long-term immunosuppression with a thiopurine with or without tumor necrosis factor therapy. The typical presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia.


The diagnosis is made by bone marrow or liver biopsy that shows a marked infiltration with malignant T cells. HSTCL is not very sensitive to antineoplastic therapy and has a high mortality rate. Likelihood score: A (well-known cause of clinically apparent liver damage).

Mechanism of action of Mercaptopurine

It is believed that mercaptopurine has a direct hepatotoxic effect related to the dose and similar types of lesions can be reproduced in animal models.

The toxic effects of mercaptopurine, and particularly myelotoxicity, have been linked to higher levels of methyl mercaptopurine, a product of one of the metabolic pathways of mercaptopurine metabolism. Mercaptopurine undergoes extensive hepatic metabolism to other thiopurines through three different routes.

Patients with low levels or a deficiency of thiopurine methyltransferase, which mediates one of these metabolic pathways, have a higher complication rate of mercaptopurine use, particularly bone marrow suppression, but may not be at increased risk of liver injury.

The acute cholestatic hepatitis associated with mercaptopurine, on the other hand, are most likely due to the idiosyncratic reaction, although it is also common with higher doses of thiopurine.