Concurrent Autoimmune Hepatitis and Ulcerative Colitis With Pancytopenia
Kyawzaw Lin, MD; Aung Naing Lin, MD; Sithu Lin, MD; and Thinzar Lin, MD
Azathioprine (AZA) and its prodrug 6-mercaptopurine (6-MP), which are used for the treatment of autoimmune disease, have been associated with many dose-related or dose-unrelated complications.1,2 With long-term use of AZA or 6-MP, pancytopenia is a relatively rare complication that occurs in less than 0.1% of patients, whereas leukopenia, anemia, or thrombocytopenia individually occur in 10% of patients.2,3 By far, the most common myelotoxicity is isolated leukopenia that requires adjustment of the dosage or cessation of the medication. However, this adverse effect occurs only with long-term use and is dose-dependent. In rare cases, recent initiation of mesalamine, a 5-aminosalicylic acid (5-ASA) derivative, in a patient on 6-MP may trigger severe pancytopenia in a short time, possibly within 1 week of administration, as in the following patient’s case.
A 29-year-old man presented with worsening of pain and swelling in the posterior aspect of the right thigh, which had been associated with subjective fever 2 days prior to presentation.
History. He had 15-year history of autoimmune hepatitis (AIH) that had been well controlled with immunosuppressive agents 6-MP, sirolimus, and budesonide. His overall health status had been uneventful until 1 week after starting mesalamine therapy for recently diagnosed ulcerative colitis (UC), which had been confirmed by colonoscopy and biopsy.
He reported episodic epistaxis but denied recent infection, headache, neck stiffness, visual disturbance, nausea, vomiting, abdominal pain, fatigue, malaise, chest pain, dyspnea, palpitations, generalized muscle weakness, gum hypertrophy, and bleeding diathesis. He denied recent injuries, insect bites, arthralgia, weight change, and loss of appetite.
Physical examination. At presentation, his temperature was 37.9°C, and he had sinus tachycardia of 105 beats/min; all other vital signs were normal. A detailed physical examination revealed nonpurulent, nonfluctuating, poorly demarcated, painful swelling in the posterior aspect of the right mid-thigh, with signs of inflammation over the surrounding skin but without an entrance wound. He had no functional limitation despite the painful right thigh. Findings of other systemic examinations were unremarkable.
Diagnostic tests. Results of complete blood cell counts (CBCs) taken throughout his hospitalization are shown in the accompanying Table. Results of a peripheral blood smear revealed anisocytosis, few target cells, no fragmented red blood cells, a decreased white blood cell (WBC) count, a decreased platelet count with few giant platelets, no immature cells, and no dysplastic cells.
Liver function test results were consistent with the patient’s history of AIH, with elevated total bilirubin (3.5 mg/dL), direct bilirubin (2.2 mg/dL), aspartate aminotransferase (192 U/L), and alanine aminotransferase (164 U/L) levels. The alkaline phosphatase level was 92 U/L, and the albumin level was low at 2.9 g/dL.
The patient’s C-reactive protein level was 61.57 mg/L (reference value, < 5.00 mg/L), and the erythrocyte sedimentation rate was 68 mm/h (reference range, 0-15 mm/h). Vitamin B12 and serum folate levels were within normal limits.
Computed tomography (CT) scans of the right thigh showed soft-tissue swelling but no fasciitis or abscess (Figures 1 and 2).
Figure 2: CT scans of the right thigh showed only soft-tissue swelling (arrows) and no fasciitis or abscess.
Esophagogastroduodenoscopy (EGD) showed mild gastritis and a single smooth nodule measuring 5 to 6 mm in the antrum (Figure 3). Histopathology results of a biopsy of the nodule showed a demarcation line in the upper submucosa with a predominance of neutrophilic granulocytes and scattered macrophages, along with a platelet thrombus in the small submucosal vessel (Figure 4).
Figure 3: EGD showed mildly erythematous gastric antrum mucosa, suggestive of mild gastritis, and a single smooth nodule measuring 5 to 6 mm in the antrum (arrow).
Figure 4: Histological section of the antrum mucosa specimen showed a demarcation line in the upper submucosa with a predominance of neutrophilic granulocytes and scattered macrophages, along with a platelet thrombus in the small submucosal vessel (hematoxylin-eosin, original magni cation ×20).
Colonoscopy showed normal-appearing rectal mucosa (Figure 5). Histopathology results of a biopsy specimen suggested nonspecific colitis and showed colonic intraepithelial lymphocytosis (15-20+ lymphocytes per 100 epithelial cells) with surface epithelial damage and increased mixed inflammatory cells within the lamina propria in a patchy distribution (Figure 6).
Figure 5: Colonoscopy showed normal-appearing rectal mucosa.
Figure 6: Histological section of the colonic mucosa specimen showed colonic intraepithelial lymphocytosis (15-20+ lymphocytes per 100 epithelial cells) with surface epithelial damage and increased mixed in ammatory cells within the lamina propria in a patchy distribution (hematoxylin-eosin, original magni ca- tion ×100).
Treatment. The patient was promptly placed in reverse isolation for neutropenic fever with active infection and was started on an antibiotic regimen and granulocyte colony-stimulating factor (GCSF) therapy. 6-MP and mesalamine had been discontinued at the time of admission.
The antimetabolite compounds diaminopurine and thioguanine were discovered by biochemists Hitchings and Elion in 1950.4 After finding that these compounds interfered with the metabolism of bacteria, they turned attention to a related compound, 6-MP. Their years of extensive research into the compounds’ ability to stop WBC replication by blocking DNA synthesis resulted in the drugs being used in the treatment of leukemia.4,5 Hitchings and Elion would go on to develop AZA, a less-toxic prodrug of 6-MP, to induce immunosuppression in patients after organ transplant.5 AZA came to be recognized as a breakthrough miracle in immunosuppressive medicine.
By nonenzymatic reaction via glutathione in neutrophils, AZA is converted in vivo into 6-MP and a number of metabolites, which are believed to be responsible for some of the immunosuppressive effects of AZA.6,7 6-MP is further degraded by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the liver and gastrointestinal tract into active 6-thioguanine (6-TG) nucleotides, including inosinic acid and thioguanylic acid. Intracellular 6-TG competes with natural endogenous purine bases, resulting in abnormal or mutated nucleic acid synthesis. This creates negative feedback inhibition of key enzymes such as 5-phosphoribosyl-1-pyrophosphate amidotransferase, which is cornerstone of de novo purine synthesis, and HGPRT, which is responsible for the synthesis of inosinic acid and thioguanylic acid. Thus, 6-TG suppresses the formation of purine (adenine and guanine) substrates essential for DNA and RNA synthesis, resulting in reduction of circulating B lymphocytes and T lymphocytes and causing cytotoxic and immunosuppressive effects.6,8-10
Alternatively, xanthine oxidase (XO) and thiopurine methyltransferase (TPMT) metabolize 6-MP into inactive metabolites such as 6-thiouric acid by hydroxylation and 6-methylmercaptopurine (6-MMP) by methylation, respectively.6,8-10 In short, synthesis of abnormal DNA and RNA occurs by replacing physiological nucleotides with nucleotides derived from 6-MP, which in turn leads to self-destruction.
Although initially investigated as leukemia therapies, the main clinical use of 6-MP and AZA today is for the treatment of autoimmune diseases and transplant rejection.2,5,11,12 Clinically, it is recommended that either 6-MP or AZA be started with a low dose and titrated to maximum dose based on body weight, either as monotherapy or as an adjuvant with a corticosteroid.
The adverse effects are usually dose-dependent and include suppression of bone marrow (> 20% of cases), including anemia, leukopenia, and thrombocytopenia; extrahepatic malignancy (3% of cases) after 10 years; and hepatic toxicity (< 5% of cases). Apparent dose-independent adverse effects include gastrointestinal tract symptoms (5%-20% of cases); allergic reactions such as fever, rash, and arthritis; various infections related to immunosuppressive effects; genitourinary tract symptoms such as hyperuricemia, uricosuria, and oligospermia; renal toxicity; and pulmonary fibrosis in rare cases. Discontinuation or reduction of the 6-MP or AZA dose is beneficial in 10% of AIH cases.1,6,7
Other medications such as 5-ASA and sulfa-containing drugs potentiate myelotoxicity of 6-MP or AZA. Concomitant use with other immunosuppressants and immunomodulators is associated with an increased rate of opportunistic infections. The myelotoxicity results either from genetic deficiency of TPMT or from the inhibition of TPMT by sulfa-containing compounds (especially 5-ASA and sulfasalazine) and the inhibition of XO by allopurinol and febuxostat. Inhibition or deficiency of TPMT and XO disrupts 6-MP or AZA catabolism, resulting in accumulation of active 6-TG products that potentiates life-threatening myelosuppression and opportunistic infections.
Homozygous genetic deficiency of TPMT is found in 0.3% to 0.5% of the population, while low TPMT activity is reported in 11% of the population.8,13 However, not all persons with severe enzyme deficiency experience myelosuppression, and persons with heterozygous deficiency can respond well to dose reductions of 6-MP or AZA.9,10 Some authors have recommended testing for TPMT deficiency before the initiation of AZA or 6-MP therapy, but routine screening is not beneficial due to the rarity of myelosuppression with low doses and the inability to predict outcomes by assessing genotypes and phenotypes.5,7,9 As a precaution, AZA or 6-MP should not be started in patients with severe pretreatment cytopenia (eg, WBC count < 2500/µL or platelet count < 50 × 103/µL) or with TPMT deficiency.2,9,10,13
Outcome of the Case
Our patient’s established AIH had been in stable remission from the age of 14 years with a dual-medication regimen of 6-MP and a low to intermediate dose of budesonide instead of single high-dose corticosteroid regimen in order to reduce long-term adverse effects of corticosteroids on linear growth, bone development, and cosmesis.2,14-16 The adverse effects and his response to medications had been monitored throughout this time with appropriate blood tests. The course of his AIH management had been uneventful until his recent biopsy-confirmed diagnosis of UC, for which mesalamine had been administered in the 3 weeks before his symptoms had developed.
He presented with neutropenic fever, right posterior thigh cellulitis, and mild bleeding diathesis. However, his CBC results had been recorded as within the normal range before mesalamine had been initiated. Therefore, pancytopenia could have resulted from the potentiating effects of mesalamine on the 6-MP and budesonide combination regimen. This rapid occurrence of myelosuppression most likely resulted from mesalamine-induced inhibition of TPMT, leading to inhibition of the catabolism of 6-MP to inactive 6-MMP and accumulation of other active metabolites, particularly 6-TG nucleotides.
His severe pancytopenia with cellulitis was managed with the cessation of 6-MP and mesalamine and with the administration of appropriate antibiotics together with GCSF. His cell counts had improved significantly within 10 days of treatment.
The Take-Home Message
The combination of 6-MP and mesalamine used for AIH and other inflammatory diseases can have dose-related bone-marrow toxicity, either synergistically or separately, with long-term use, although in our patient’s case, it occurred in a relatively short period of a few days. Such situations require immediate dose adjustment or cessation of the immunosuppressive agents. Pancytopenia is a rare but potentially catastrophic complication of 6-MP and mesalamine, either as monotherapy or combination therapy. Such patients should be monitored closely for the adverse effects of these immunosuppressive agents, with prompt referral to specialist care if signs and symptoms develop. Moreover, patients should be informed about recognizing potential adverse effects and instructed to report any symptoms early.
Kyawzaw Lin, MD; Aung Naing Lin, MD; Sithu Lin, MD; and Thinzar Lin, MD, are physicians in the Internal Medicine Department at The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, in Brooklyn, New York.
- Purixan [package insert]. Franklin, TN: Rare Disease Therapeutics; 2017.
- Vierling JM. Diagnosis and treatment of autoimmune hepatitis. Curr Gastroenterol Rep. 2012;14(1):25-36.
- Lowry PW, Franklin CL, Weaver AL, et al. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut. 2001;49(5):656-664.
- Elion GB. Historical background of 6-mercaptopurine. Toxicol Ind Health. 1986;2(2):1-9.
- Hawwa AF, Millership JS, Collier PS, et al. Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol. 2008;66(4):517-528.
- Mosesso P, Palitti F. The genetic toxicology of 6-mercaptopurine. Mutat Res. 1993;296(3):279-294.
- Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43(4):329-339.
- Gisbert JP, González-Guijarro L, Cara C, Pajares JM, Moreno-Otero R. Thiopurine methyltransferase activity in patients with autoimmune hepatitis [in Spanish]. Med Clin (Barc). 2003;121(13):481-484.
- Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997;126(8):608-614.
- Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998;129(9):716-718.
- Dassopoulos T, Sultan S, Falck-Ytter YT, Inadomi JM, Hanauer SB. American Gastroenterological Association Institute technical review on the use of thiopurines, methotrexate, and anti–TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013;145(6):1464-1478.e5.
- Czaja AJ. Autoimmune hepatitis: focusing on treatments other than steroids. Can J Gastroenterol. 2012;26(9):615-620.
- Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther. 1989;46(2):149-154.
- Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: A 20-year experience. Hepatology. 1997;25(3):541-547.
- Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33(3):544-553.
- Banerjee S, Rahhal R, Bishop WP. Azathioprine monotherapy for maintenance of remission in pediatric patients with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2006;43(3):353-356.