All-trans-retinoic acid as a possible cause of acute pancreatitis even in the absence of hypertriglyceridemia

Abstract

The standard therapy for patients affected by acute promyelocytic leukemia (APL) is the administration of all-trans-retinoic acid (ATRA). ATRA therapy is usually well-tolerated, but it also has the potential to induce toxicity. The most severe side effect of ATRA is retinoic acid syndrome; the next is acute pancreatitis, which is a rare but serious adverse event mostly due to hypertriglyceridemia. We herein report a patient who developed ATRA-induced acute pancreatitis without hypertriglyceridemia.A 17-year-old female presented to our hospital complaining of a 3-week history of dyspnea. Her peripheral blood counts were: Hb: 4.5 g/dL, WBC: 0.96 9 10 9 /L with 9% blasts, and platelets: 48 9 10 9 /L. The biochemistry findings were significant only regarding the serum lactate dehydrogenase level of 276 IU/L. A bone marrow examination revealed an abnormal cellularity, thus indicating APL, while a cytogenetic study showed the presence of t(15;17) (q22;q21). The patient was treated with ATRA for the purpose of remission induction. On the second day of ATRA treatment, she suffered acute epigastric and upper left quadrant pain, and laboratory tests showed an elevation of amylase to 7,600 IU/L (normal range: 49-136 IU/L) and lipase to 1,680 IU/L (normal range: 11-53 IU/L), with no marked increases in triglyceride (TG). Computed tomography of the abdomen revealed no abnormal findings in either the biliary ducts or pancreas. With the cessation of ATRA, the symptoms rapidly disappeared and the pancreas-derived enzyme level thereafter decreased to the normal range. The peak level of TG was only 145 mg/dL (normal range: 30-149 mg/dL) throughout the entire course. The patient was then treated with arsenic trioxide therapy without experiencing any subsequent complications, and she has since remained in complete remission for 8 months after starting the induction treatment.Four cases of acute pancreatitis associated with the use of ATRA have been described [1-4], but only one of these presented without hypertriglyceridemia, which is one of the common side effects of ATRA [4,5]. Our case is the second such case. The pathogenesis of ATRA-induced acute pancreatitis without hypertriglyceridemia is not clear. Cytokines, such as IL-8, IL-1beta, and TNF-alpha, have been shown to be intimately involved in the inflammatory response to acute pancreatitis in general [6]. Teng et al. suggested that the increased expression of these cytokines in APL cells induced by ATRA may also play a role in the pathogenesis of ATRA-induced acute pancreatitis [4,7]. As far as the case of Teng et al. is concerned, however, this suggestion remains controversial because of the recurrence of an elevated lipase level with a second ATRA treatment even after achieving complete remission in his case. His case rather suggests that either allergic or autoimmune mechanisms might play critical roles in the development of ATRA-induced acute pancreatitis. On the other hand, the activation of pancreatic stellate cells (PSCs) is known to be implicated in the production of ...

Severe Wernicke encephalopathy and acute pancreatitis due to all-trans-retinoic acid and arsenic trioxide during treatment of acute promyelocytic leukaemia: a case report

“…[10][11][12] Here, we present a typical case of a 55year-old woman with APL who developed WE during treatment for AP after therapy with ATO and ATRA. Some previous cases [4][5][6][7][8][9] have reported that WE is induced by AP and that AP was induced by treatment with ATO and ATRA in patients with APL. However, no reports have described a case of a patient with WE and APL after treatment with ATO and ATRA, or examined whether the administration of ATO and ATRA could induce WE in patients with AP.…”

“…Some cases reported that the occurrence of AP was related to the application of arsenic, and some cases were associated with the administration of retinoic acid, which was secondary to hypertriglyceridemia or differentiation syndrome. [4][5][6][7][8][9] Wernicke encephalopathy (WE) is caused by thiamine deficiency and is strongly related to malnutrition, which may result from chronic alcohol abuse, gastrointestinal surgery, prolonged vomiting, or chemotherapy. WE, which is regarded as an acute and severe neuropsychiatric syndrome, is characterised by symptoms of confusion, ophthalmoplegia, and gait ataxia.…”

All-trans-retinoic acid induced acute pancreatitis: a single or multifactorial association?

“…I read with great interest the article by Hoshino et al [1] titled, ''All trans-retinoic acid as a possible cause of acute pancreatitis even in the absence of hypertriglyceridemia,'' in which the authors describe a very peculiar and rare case of a drug-related acute pancreatitis (AP).…”

“…Hoshino et al [1] report the second case in the literature of AP following all-trans-retinoic acid (ATRA) that presented without hypertriglyceridemia, which is one of the common side-effects of this drug. They suggested that in this case, ATRA-induced pancreatitis may have been due to the combination of increased pancreatic injury secondary to the upregulation of proinflammatory cytokines, such as IL-8, IL-1b, and TNF-a allied to a blockade in the process of pancreatic repair by pancreatic stellate cells.…”