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Keywords:

  • Crohn's disease;
  • ulcerative colitis;
  • inflammatory bowel disease;
  • azathioprine;
  • 6-mercaptopurine;
  • hepatotoxicity;
  • liver injury

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background: The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA) / mercaptopurine (MP)-induced liver injury in a long-term follow-up study.

Methods: All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyl transferase, and bilirubin were periodically monitored. “Abnormality-of-LTs” was defined as LTs between N (upper limit of the normal range) and 2 N, and “liver injury/hepatotoxicity” as LTs >2 N.

Results: A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP-treated patients (690 patient-years follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient-year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs >5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs.

Conclusions: In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only ≈4% of the patients.

(Inflamm Bowel Dis)

It has been previously reported that inflammatory bowel diseases (IBDs) are frequently associated with pathologic findings in the liver and biliary tract, ranging from minor alterations, such as liver fatty changes, to severe conditions, like primary sclerosing cholangitis.1–3

The thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (MP) have been shown to be effective at inducing and maintaining remission in IBD.4–6 The occurrence of side effects, however, is a major drawback in the use of these drugs, and concerns regarding short- and long-term toxicity have restricted their use.6–8 Both acute hepatocellular hepatitis and cholestatic disease have been described during AZA/MP therapy.8 The frequency of hepatotoxicity was initially described as low, but this incidence markedly varies among different series and data are sometimes contradictory.9 Furthermore, these data are based on a relatively low number of patients and with a limited follow-up.9 Consequently, the actual incidence of hepatotoxicity in IBD patients, mainly in those receiving AZA or MP therapy, has not been determined, and its real impact and management in clinical practice has not been fully characterized. Thus, despite increasing recognition of the potential for this serious adverse event, homogeneous guidelines for monitoring liver function in patients prescribed AZA/MP are not widely employed.9

Therefore, our aim was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of ≈800 patients with IBD and, specifically, to assess the incidence of thiopurine-induced liver injury in a long-term (5-year) follow-up study.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Population

All consecutive patients with a diagnosis of IBD at the Gastroenterology Unit of the “Hospital Universitario de la Princesa” (Madrid, Spain), followed for at least 5 years, were included in this retrospective study. The diagnoses of Crohn's disease (CD) and ulcerative colitis (UC) were established by standard clinical, radiological, histological, and endoscopic criteria.10 The Vienna classification11 of CD based on Age at Diagnosis (under 40 years [A1], equal to or over 40 years [A2]), Location (terminal ileum [L1], colon [L2], ileocolon [L3], upper gastrointestinal [L4]), and Behavior (nonstricturing nonpenetrating [B1], stricturing [B2], penetrating [B3]) were used. For UC, a classification based on the location and extension of the disease was used: proctitis/proctosigmoiditis, left-side colitis (up to the splenic flexure), extensive colitis (up to the hepatic flexure), and pancolitis. At baseline, the following variables were prospectively extracted in a predefined data extraction form: age, sex, smoking habit, weight, type of IBD, age at diagnosis, duration of disease, site of involvement, and extraintestinal manifestations.

Treatment

Data of patient treatment (mainly with AZA or MP) were also recorded. Patients who had started AZA/MP treatment at another hospital were excluded. Patients who received AZA/MP primarily for other indications (renal transplant, rheumatoid arthritis, autoimmune liver disease) were also excluded. The choice of the dose of AZA was based, as usually recommended, on the patient's weight (2–2.5 mg/kg).

Clinical and Analytical Controls

Subjects receiving AZA/MP treatment were reviewed in our outpatient clinic at 2, 4, and 8 weeks, and then every 6 months. Complete blood count and LTs including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP), γ-glutamyl transferase (GGT), and bilirubin were monitored at every visit. On each visit the patient was interrogated as to any drug side effect. In the remaining patients (not taking thiopurine drugs), clinical and analytical controls were performed every 12 months.

Definitions of Drug-induced Liver Disorders

Following the International Consensus Meeting recommendations organized under the auspices of the Council for International Organizations of Medical Sciences (CIOMS),12 the following definitions of the grade of hepatic analytical alterations were considered: “Abnormality of LTs” was defined as an increase in AST, ALT, AP, GGT, or total bilirubin between N (upper limit of the normal range) and 2 N. “Liver injury” (or “hepatotoxicity”) was used if there was an increase of over 2 N in the aforementioned LTs.

Diagnostic Procedures to Evaluate Liver Injury

Patients with abnormal LTs underwent an abdominal ultrasound, serological test to rule out hepatitis B and C infection, and laboratory tests including autoantibodies (antinuclear autoantibodies, antismooth muscle autoantibodies, antiliver/kidney autoantibodies, and antimitochondrial autoantibodies).

Management of Thiopurine-induced Liver Injury

Patients with thiopurine-induced liver injury were managed following the algorithm summarized in Figure 1. In short, when mildly abnormal LTs were detected (AST, ALT, AP or GGT <5 N), AZA/MP was continued, but frequent analytical controls (e.g., in 1–2 weeks) were performed. When moderate/severe abnormal LTs were detected (AST, ALT, AP or GGT >5 N), a 50% dose reduction in AZA/MP was indicated and frequent analytical controls were performed. Finally, when severe cholestatic jaundice was present, AZA/MP was withdrawn.

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Figure 1. Management algorithm of thiopurine-induced liver injury. LTs: liver tests; AZA: azathioprine; MP: mercaptopurine. Mild abnormality of LTs: an increase in aspartate transaminase, alanine transaminase, alkaline phosphatase or γ-glutamyl transferase between N (upper limit of the normal range) and 5 N. Moderate-severe abnormality of LTs: an increase >5 N.

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Statistical Analysis

For continuous variables the mean and standard deviation were calculated. For categorical variables the percentages and corresponding 95% confidence intervals (95% CI) were provided. Categorical variables were compared with the χ2 test, and quantitative variables with Student's t-test. A P-value <0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Characteristics of Patients

Seven-hundred and eighty-six patients (401 with UC, and 385 with CD) were included in this retrospective study. The mean age was 44 ± 16 years, 54% were males, and 29% were smokers. Vienna classification of CD patients was as follows: Age at Diagnosis (A1, 77.9%; A2, 22.1%), Location (L1, 21.4%; L2, 21.4%; L3, 52.4%; and L4, 4.8%), and Behavior (B1, 45.3%; B2, 18.6%; and B3, 36.1%). UC location distribution was as follows: proctitis/proctosigmoiditis (19.4%), left-side colitis (38.4%), and extensive colitis/pancolitis (42%).

Cumulative percentage (during the 5-year follow-up) of patients taking medications were, for each drug: 5-aminosalycilates (24%), AZA (13.9%), MP (3.7%), methotrexate (0.4%), and infliximab (3.3%). Thus, 138 patients (17.6%) received thiopurine drugs (109 patients were treated with AZA and 29 with MP), giving a total of 690 patient-years of follow-up. The mean AZA dose was 123 ± 40 mg/day, while the mean dose of MP was 77 ± 26 mg/day.

Abnormality of LTs/Hepatotoxicity in All Patients

The prevalence of abnormal LTs and hepatotoxicity/liver injury during the 5-year follow-up is summarized in Table 1. The chronological evolution of these analytical abnormalities is shown in Figure 2. Thus, the percentage of patients with any abnormal LT (AST, ALT, AP, GGT, or bilirubin) was 10.4% (95% CI: 8.3%–12.6%) at 1 year, 7.9% (6%–9.8%) at 2 years, 6.1% (4.4%–7.8%) at 3 years, 6.5% (4.8%–8.2%) at 4 years, and 5.6% (4%–7.2%) at 5 years. Corresponding figures for hepatotoxicity/liver injury were: 2.2% (95% CI: 1.4%–3.4%), 1% (0.5%–2%), 1.7% (1%–2.8%), 1% (0.5%–2%), and 2.2% (1.4%–3.4%). Therefore, 120 patients (15.3%; 95% CI: 13%–18%) (49 of them taking AZA/MP) had some type of abnormality of LTs at some time during follow-up, while 39 patients (5%; 95% CI: 3.7%–6.7%) presented hepatotoxicity at some time during the 5 years of the study. Possible explanations for the abnormality of LTs in these patients are summarized in Table 2. As shown, the most frequent causes were AZA and MP treatment (38 and 11 patients, respectively), and fatty liver disease at abdominal ultrasound (49 patients).

Table 1. Prevalence (%) of Abnormality of Liver Tests (LTs) and Hepatotoxicity (HT) in Patients with Inflammatory Bowel Disease (N = 786)
 1st year2nd year3rd year4th year5th year
LTsHTLTsHTLTsHTLTsHTLTsHT
  1. Abnormality of liver tests: ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; GGT, γ-glutamyl transferase; or BR, bilirubin between N (upper limit of the normal range) and 2 N.

  2. Hepatotoxicity or liver injury: >2 N.

AST0.9010101.40.11.70.1
ALT1.80.51.70.32.40.43.10.32.50.3
AP9.11.85.90.41.70.10.8010.1
GGT2.50.82.40.63.11.33.40.93.72
BR1.10.1101.40.11.101.30.1
ANY10.4 (n = 82)2.2 (n = 17)7.9 (n = 62)1 (n = 8)6.1 (n = 48)1.7 (n = 13)6.5 (n = 51)1 (n = 8)5.6 (n = 44)2.2 (n = 17)
thumbnail image

Figure 2. Prevalence of abnormal liver tests (LTs) and hepatotoxicity during the 5-year follow-up in all patients (N = 786). ALT: Alanine transaminase; AST: aspartate transaminase; AP: alkaline phosphatase; GGT: γ-glutamyl transferase; BR: bilirubin. Abnormality of liver tests: AST, ALT, AP, GGT, or BR > between N (upper limit of the normal range) and 2 N. Hepatotoxicity or liver injury: >2 N.

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Table 2. Possible Explanations for the Abnormal Liver Tests (N = 120 Patients)
Possible CauseNumber of PatientsPercentage of Patients
Azathioprine treatment2723.3
Mercaptopurine treatment2219
Alcohol intake65.2
Hepatitis B virus21.7
Hepatitis C virus21.7
HIV10.9
Hemochromatosis10.9
Primary sclerosing cholangitis32.6
Autoimmune hepatitis10.9
Hypothyroidism10.9
Methotrexate treatment10.9
Fatty liver disease (ultrasound)4940.8
Obesity65.2
Diabetes32.6
Hypercholesterolemia65.2
No associated disease3428.3
Unknown43.3

Abnormality of LTs/Hepatotoxicity in Patients Treated with AZA/MP

Among the 138 patients treated with AZA/MP, 89 never presented abnormalities of LTs during follow-up, while 49 patients had some type of abnormality of LTs at some time during the 5 years of the study. The yearly incidence of abnormal LTs and hepatotoxicity during follow-up in patients receiving AZA/MP treatment is summarized in Table 3. The chronological evolution of these analytical abnormalities is shown in Figure 3. Thus, the percentage of patients taking AZA/MP with abnormal LTs (AST, ALT, AP, GGT, or bilirubin) was 23.9% (95% CI: 17%–31%) at 1 year, 18.8% (12%–25%) at 2 years, 9.4% (4.6%–14%) at 3 years, 14.5% (8.6%–20%) at 4 years, and 11.6% (6.3%–17%) at 5 years. Corresponding figures for hepatotoxicity were 4.5% (95% CI: 2%–9.2%), 2.2% (0.7%–6.2%), 3% (1.1%–7.2%), 1.5% (0.4%–5.1%), and 3% (1.1%–7.2%).

Table 3. Prevalence (%) of Abnormal Liver Tests (LTs) and Hepatotoxicity (HT) in Patients with Inflammatory Bowel Disease Receiving Azathioprine or Mercaptopurine Treatment (N = 138)
 1st year2nd year3rd year4th year5th year
LTsHTLTsHTLTsHTLTsHTLTsHT
  1. Abnormality of liver tests: ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; GGT γ-glutamyl transferase; or BR, bilirubin between N (upper limit of the normal range) and 2 N.

  2. Hepatotoxicity or liver injury: >2 N.

AST0.702.201.5030.72.20
ALT30.730.73.72.260.74.50.7
AP19.43.715.71.51.502.201.50
GGT302.20.71.50.76.70.74.52.2
BR30.71.5030303.70
ANY23.94.518.72.29.7314.21.511.93
thumbnail image

Figure 3. Prevalence of abnormal liver tests and hepatotoxicity during the 5-year follow-up in patients treated with azathioprine or mercaptopurine (N = 138). ALT: Alanine transaminase; AST: aspartate transaminase; AP: alkaline phosphatase; GGT: γ-glutamyl transferase; BR: bilirubin. Abnormality of liver tests: AST, ALT, AP, GGT, or BR > between N (upper limit of the normal range) and 2 N. Hepatotoxicity or liver injury: >2 N.

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In summary, among those patients treated with AZA/MP (with a total of 690 patient-years of follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% (95% CI: 5.2%–9%) and 2.6% (1.7%–4.1%) per patient and year of follow-up.

Statistically significant differences were not demonstrated when comparing the male/female ratio or the mean age between patients with and without AZA/MP-related liver injury.

Management of Thiopurine-induced Liver Injury

Full details of the 138 patients receiving AZA/MP treatment, and in particular of the 49 patients with abnormal LTs during thiopurine treatment, are summarized in Figure 4. As shown, only 18 out of these 138 patients had LTs >2 N, and in most of these patients (11/18) the abnormality of LTs was classified as mild (<5 N). In addition, most of these patients spontaneously normalized LTs, despite AZA/MP being maintained at the same dose. Finally, AZA/MP treatment was withdrawn due to hepatotoxicity (LTs >5 N and lack of decrease despite 50% dose reduction in AZA/MP dose) in 5/138 patients (during the 5-year follow-up), that is, in only 3.6% (95% CI: 1.6%–8.2%) of the cases. In these 5 patients LTs normalized after thiopurine treatment was discontinued.

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Figure 4. Flowchart of liver test (LT) results in patients treated with azathioprine (AZA) or mercaptopurine (MP).

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AZA/MP Withdrawal for Causes Other than Hepatotoxicity

In addition to the 5 aforementioned patients in whom AZA/MP was withdrawn due to hepatotoxicity, these drugs had to be withdrawn in 12 more patients for the following reasons: gastrointestinal intolerance (3 patients), myelotoxicity (3 patients), pancreatitis (3 patients), pneumonia (1 patient), and hypersensitivity reaction (with fever and rash; 2 patients).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

IBD is frequently associated with pathologic findings in the liver and biliary tract. Several series evaluating LTs in these patients reported abnormal findings both in CD and in UC ranging from 3% to almost 50%.2, 3, 13–19 More recently, a multicenter study described a 12% prevalence of hepatobiliary alterations among patients with IBD.20 In our study, 15% of the patients presented some type of abnormality of LTs at some time during the 5 years of the study, although only 5% had true hepatotoxicity (e.g., an increase >2 N in LTs).

The lack of universally standardized definitions of adverse drug reactions represents an important limitation of studies evaluating drug-induced liver toxicity.12 Furthermore, assessment of the risk/benefit ratio of a drug takes into account not only the incidence but also the severity of its adverse effects. Thus, lack of a definition of the reaction and of measuring its severity may result in the use of inaccurate or misleading terms, induce bias in evaluating safety, and lead to unjustified actions.12 Therefore, we classified the grade of hepatic analytical alterations using the proposed definitions of the International Consensus Meeting recommendations organized under the auspices of the Council for International Organizations of Medical Sciences (CIOMS)12: “Abnormality of LTs” or “liver injury”/“hepatotoxicity.”

When abnormal LTs are detected in a patient with IBD, several causes need to be ruled out: the patient should be interrogated as to drug intake (mainly thiopurines), alcohol abuse, serological test to rule out hepatitis A, B, and C infection, and laboratory tests including autoantibodies should be considered, and patients must undergo an abdominal ultrasound with the aim of excluding biliary tract abnormalities, focal lesions, portal hypertension, or hepatic steatosis.12 In this respect, nonalcoholic fatty liver disease, due to overweight (sometimes as a consequence of improvement of IBD activity) or to previous steroid treatment, may be responsible for some cases of abnormal LTs.

Possible explanations for the abnormal LTs in our patients are summarized in Table 2. As shown, the most frequent causes were AZA and MP treatment (38 and 11 patients, respectively), and fatty liver disease at abdominal ultrasound (49 patients). A recent study evaluated the prevalence of ultrasonography hepatobiliary changes in a large IBD population and found these abnormalities in more than 50% of the cases.1 Liver enlargement and steatosis were found in >35% of both CD and UC patients, a higher prevalence than among healthy controls.1 Other studies have also confirmed that more patients with IBD than controls have liver steatosis, with percentages ranging from 13% to almost 100%.20, 21 However, ultrasound changes including hepatomegaly or a dysechoic liver echo pattern have also been observed in the absence of any LT abnormalities in about 60% of IBD patients.19

The incidence of AZA/MP-associated hepatotoxicity markedly varies among different series and the data are sometimes contradictory.9 Furthermore, these data are based on a relatively low number of patients with a limited follow-up.9 Our study includes a large sample of patients (N = 786) with IBD in general, and also a high number of AZA/MP-treated patients (N = 138). Furthermore, our patients received thiopurine drugs for 5 years, giving a total of 690 patient-years of follow-up. Previous studies evaluating the incidence of AZA/MP-induced liver injury in patients with IBD are summarized in Table 4.7, 22–54 When all the studies were considered, including a total of 3485 patients, the mean overall prevalence of AZA/MP-induced liver disorders (abnormal LTs, without taking into account the follow-up period) calculated from these studies was 3.4%.9 However, when only studies where the follow-up time was specifically stated were considered, the mean annual drug-induced liver disorder rate (abnormal LTs per patient-year) was only 1.4%.9 In summary, the incidence of hepatotoxicity in IBD patients receiving AZA/MP, calculated from previously (mainly retrospective) published studies, seems to be only ≈1%–2% per patient and year of treatment.

Table 4. Studies Evaluating Incidence of Thiopurine-induced Liver Disorders in Patients with Inflammatory Bowel Disease
AuthorNo. PatientsThiopurine DrugMean Time Follow-up (Months)Drug-induced Liver Disorder (%)Definition of Liver Disordera
  • AZA, azathioprine; MP, mercaptopurine; LTs, liver tests; NA, nonavailable.

  • a

    Abnormal LTs defined as an increase in aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP) or total bilirubin between N (upper limit of the normal range) and 2 N. “Liver injury” defined as an increase of over 2 N. NAn nonavailable definition (in most cases it was stated that abnormal LTs were considered diagnostic criteria,

  • b

    or “hepatitis” was diagnosed clinically

  • c

    or by liver biopsy,

  • d

    but the precise level of abnormality of LT was not specified).

  • e

    Although hepatitis occurred in 11 patients, only 1 patient had hepatitis that could be shown to have been directly induced by MP.

Ansari et al22106AZA60/106 (0%)NA
Bastida et al23161AZA/MP921/161 (13%)Abnormality of LTs
    16/161 (10%)Liver injury
Bouhnik et al24157AZA/MP144/157 (2.5%)NAb
Candy et al2531AZA150/31 (0%)NA
Caprilli et al2610AZA30/10 (0%)NA
Cuffari et al2725MP171/25 (4%)NAd
De Jong et al2850AZA280/50 (0%)NA
Dubinsky et al2992AZA/MP>416/92 (17%)NAb
Ewe et al3021AZA40/21 (0%)NA
Fraser et al31622AZA5317/622 (2.7%)NAb
George et al32105MP3.55/105 (5%)NAb
Goldenberg et al3374AZA/MP240/74 (0%)NA
Goldstein et al3424MP7.40/24 (0%)NA
Hanauer et al35131MP240/131 (0%)NA
Hawthorne et al3633AZA120/33 (0%)NA
Hindorf et al37364AZA/MP1819/364 (5.2%)Liver injury
Jewell et al3880AZA10/80 (0%)NA
Kirk et al3924AZA60/24 (0%) 
L. Sanroman et al4034AZA255/34 (15%)NA
Mantzaris et al4170AZA241/70 (1.4%)NA
Markowitz et al4227MP184/27 (15%)NA
O'Donoghue et al4351AZA120/51 (0%)NA
O'Brien et al4478AZA/MP191/78 (1.3%)NA
Oren et al4532MP90/32 (0%)NA
Present et al7396MP6011/396 (2.8%)eNAb
Present et al4639MP240/39 (0%)NA
Qasim et al47110AZA34/110 (3.6%)NAb
Regueiro et al4858AZA31/58 (1.7%)NAc
Rhodes et al4915AZA20/15 (0%)NA
Rosenberg et al5010AZA60/10 (0%)NA
Rosenberg et al5115AZA60/15 (0%)NA
Schawab et al5283AZA3/83 (3.6%)Abnormality of LTs
    2/83 (2.4%)Liver injury
Summers et al5339AZA90/39 (0%)NA
Weersma et al54318AZA7/318 (2.2%)NAc

Nevertheless, the progressive increasing number of reports of AZA/MP-induced liver disorders suggests that this adverse drug reaction may be underrecognized and underreported.9 In this respect, it is worth mentioning that almost all studies evaluating the hepatotoxicity potential of thiopurines are retrospective, and that until very recently no prospective studies had been published. Thus, Bastida et al23 in 2005 performed the first prospective epidemiological study that specifically addressed the incidence of thiopurine-induced hepatotoxicity in IBD patients. A cohort of 161 patients was prospectively followed for a median of 271 days. Abnormal LTs and hepatotoxicity was detected in 13% and 10% of the patients, respectively, a figure considerably higher than that reported in retrospective studies. These figures are closer to those reported in our study, where the incidence of abnormal LTs and hepatotoxicity in patients treated with AZA/MP was, respectively, 7.1% and 2.6% per patient and year of follow-up. Despite the retrospective nature of our study, the management scheme (indications, dose, criteria of adverse effects and definition of liver injury, and decision to pursue or discontinue treatment) was homogeneous since the same clinicians provided care from the onset of AZA/MP treatment in this single-center study.

It is unknown whether risk factors exist for thiopurine-induced hepatotoxicity. Although previous reports have shown an increased risk of AZA/MP-induced hepatotoxicity in men,23, 55 we could not confirm this association in our study. At the same time, age was not found to be a risk factor for liver injury in our patients taking AZA/MP.

At present, it is unknown whether there is any difference in the hepatotoxicity potential of AZA and MP, as prospective comparative studies between both drugs have not been performed.9 In our study, both drugs were associated with a similar incidence of hepatotoxicity. From the data included in Table 4, a mean incidence of hepatotoxicity of 2.1% can be calculated in those studies prescribing AZA, and 2.7% in those with MP, suggesting a similar risk with both drugs.9 Thus, although it has been suggested that, compared with MP, hepatotoxicity is less frequent, milder, and less dose-dependent with AZA,56 the hepatotoxicity potential of both drugs in patients with IBD seems to be similar, and, if differences exist, they are probably minor. This observation suggests that the risk with different thiopurine drugs is probably too small to influence the choice of agent.

There are no clear recommendations for the management of thiopurine-induced liver injury. Our proposed algorithm for AZA/MP-induced hepatotoxicity is summarized in Figure 1. A small percentage of AZA/MP-treated patients present a slight elevation of LTs that do not have clinical implications and the abnormalities in LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of these drugs. In our study, only 18 of the 138 patients taking AZA/MP had LTs >2 N, and in most of these patients the abnormal LTs were classified as mild (<5 N). Furthermore, it should be underlined that most of these patients had spontaneously normalized LTs despite AZA/MP being maintained at the same dose. Similarly, abnormal LTs resolved spontaneously while continued on MP in 4 out of 5 patients in the study by George et al32 and in 3 out of 4 patients in the study by Markowitz et al.42 However, when abnormalities in LTs are more marked (a precise cutoff point has not been established, but we suggest a figure >5 N), but without associated jaundice, the dose of AZA/MP may be reduced by 50%. It is probably not necessary to withdraw AZA or MP, but frequent clinical and analytical controls (e.g., weekly or monthly) should be strictly performed after reducing the dose. With this strategy, AZA/MP treatment had to be withdrawn due to hepatotoxicity (LTs >5 N and lack of decrease despite 50% dose reduction in AZA/MP dose) in only 5/138 (3.6%) of our patients.

A favorable evolution of LTs after withdrawal of AZA/MP, with liver enzymes returning to normal after stopping the medication in all patients, has been reported.24, 31, 57 In our study all 5 patients in whom AZA/MP was withdrawn due to hepatotoxicity had normalized LTs after treatment was discontinued. However, it should be noted that in unusual cases thiopurines may induce a severe cholestatic jaundice that, in contrast with the acute hepatocellular hepatitis generally associated with AZA/MP, may not regress but even progress despite thiopurine withdrawal.58 Therefore, these drugs should be withdrawn, and not only tapered, in those patients presenting a clinically significant jaundice during thiopurine treatment.

In summary, this study shows that in IBD patients AZA or MP treatment induces abnormal LTs in a relatively high proportion of cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only ≈4% of the patients.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES