Fathallah, Neila MD*; Ben Salem, Chaker MD*; Slim, Raoudha MD*; Kaabia, Naoufel MD†; Letaief, Amel MD†; Bouraoui, Kamel MD*
From the *Department of Clinical Pharmacology, Faculty of Medicine of Sousse, Sousse, Tunisia; and †Department of Infectious Diseases, Farhat Hached University Hospital, Sousse, Tunisia.
Correspondence: Neila Fathallah, MD, Department of Clinical Pharmacology, Faculty of Medicine of Sousse, Avenue Mohamed Karoui, 4002 Sousse, Tunisia. E-mail: email@example.com.
Allopurinol hypersensitivity syndrome is a severe adverse reaction characterized by rash, fever, and internal organ involvement. We report a case of fatal allopurinol-induced hypersensitivity syndrome associated with acute pancreatitis.
A 46-year-old man was treated by allopurinol for asymptomatic hyperuricemia. The patient developed a diffuse erythrodermic maculopapular eruption and fever. Laboratory analysis revealed cytolysis and cholestasis, amylases and lipases were highly elevated. Computed tomography scans revealed pancreatitis Grade C. The treatment of asymptomatic hyperuricemia should only be initiated when there is a clear indication to reduce the incidence and the severe consequences of allopurinol hypersensitivity syndrome.
Allopurinol is a xanthine oxidase inhibitor widely used in clinical practice for the treatment of hyperuricemia and gout. In most patients, the drug is generally well tolerated. However, in recent years, there has been an increase in the reported cases of allopurinol-induced severe adverse reactions including allopurinol-hypersensitivity syndrome. It most frequently develops within days to weeks after initiating allopurinol therapy. It is characterized by rash ranging from pruritic maculopapular eruption to toxic epidermal necrolysis.1 It is associated with fever and internal organ involvement including frequently acute hepatic injury and renal dysfunction. We report a case of fatal allopurinol-induced hypersensitivity syndrome associated with acute pancreatitis.
A 46-year-old man had hypothyroidism treated by levothyroxine for 11 years (100 μg daily) and a 10-year history of chronic renal failure secondarily to nephrocalcinosis. His creatinine level was about 216 μmol/L (normal, 70–120). Allopurinol therapy was started for asymptomatic hyperuricemia (200 mg daily). Two weeks later, the patient developed a generalized itching rash worsening from day to day. Allopurinol was withdrawn and the patient was firmly instructed to avoid allopurinol therapy. One month later, the patient presented with a generalized rash, fever, asthenia, and severe right upper quadrant abdominal pain occurring after self-medication by allopurinol (300 mg daily for 2 days). On examination, a diffuse erythrodermic maculopapular eruption was noticed. He had no jaundice. On palpation, a moderate tenderness was present in the right upper quadrant of the abdomen. There was no rebound tenderness or organomegaly.
Laboratory analysis revealed leukocytosis (white blood cell count was 20.9 × 109/L; normal range: 4–10 × 109/L); there was no eosinophilia. The liver enzymes showed cytolysis: aspartate aminotransferase was 141 UI/L (normal range: 3–40 IU/L); alanine aminotransferase was 188 UI/L (normal range: 3–45 IU/L); and cholestasis: total bilirubin was 99 μmol/L (normal range: 3–17 μmol/L) and gamma-glutamyl transpeptidase was 430 UI/L (normal range: 10–30 IU/L). Prothrombin time was prolonged.
Levels of amylases were at 3400 UI/L, 17 times more than the normal value (normal, <200 IU/L) and lipases at 1620 UI/L, 10 times greater than the normal value (normal, <160 IU/L). Kidney failure was evident, creatinine serum concentration was 450 μmol/L reaching 590 μmol/L few days later (normal range: 70–120 μmol/L). The evaluation of Ranson's criteria for pancreatitis mortality showed a score of 2.2
Viral serology disclosed previous infection for cytomegalovirus but was negative for Epstein-Barr virus, hepatitis B, C, HIV, and Parvovirus B19.
Antismooth muscle antibody, antimitochondrial antibody, and antinuclear antibody were absent. Computed tomography scans revealed inflammation involving pancreas and peripancreatic fat (pancreatitis Grade C).3
The patient was diagnosed as having allopurinol-induced hypersensitivity syndrome; internal organ injury included the liver, the kidneys, and the pancreas.
Allopurinol was stopped immediately and intravenous prednisolone was started. In the next few days, his clinical condition deteriorated, and he was transferred to the intensive care unit where the patient received intravenous corticosteroids (100 mg daily). His renal function had deteriorated and the patient developed metabolic acidosis. Two days later, the patient suffered from acute pulmonary edema with respiratory failure leading to endotracheal intubation and mechanical ventilation. He was treated by high doses of intravenous furosemide (240 mg daily) but unfortunately he died by cardiac arrest in the following 72 hours.
Drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms, and drug-induced delayed multiorgan hypersensitivity syndrome are all acronyms for severe idiosyncratic reaction associated with drug therapy. The most incriminated drugs are anticonvulsants, sulfonamides, allopurinol, and several other medications.4
It usually occurs on first exposure to the offending drug, with a delayed onset. Symptoms generally begin 2 to 6 weeks after the initiation of the therapy. It usually starts with fever and diffuses skin reactions varying from maculopapular rash to more severe eruptions including toxic epidermal necrolysis or exfoliative dermatitis. Various internal multiorgan failures may be involved, including hepatitis, interstitial nephritis, pneumonitis, and exceptionally pancreatitis.5
The exact pathogenesis of this syndrome is still unclear. Different hypothesis are advanced. The coexistence of immunologic factors, accumulation of drug metabolites, and viral infection is frequently reported.6
The progression of drug hypersensitivity syndrome is often unpredictable; the treatment consists on the immediate withdrawal of all putative drugs and on starting immediately the supportive care. The use of corticosteroids is controversial as they are effective against the immune response, but they may be detrimental when virus reactivation exceeds host's immunity.7
Allopurinol hypersensitivity syndrome has clinical particularities; it is more frequently associated with chronic renal insufficiency and concurrent use of thiazide diuretics. The accumulation of oxypurinol, one of allopurinol's metabolites, may act as an antigenic stimulant and induces tissue damage by toxic or immunologic mechanism.7
Our patient presented with allopurinol hypersensitivity syndrome as defined by Singer and Wallace.4 The rash, the deterioration of renal function, the acute liver damage, and the fever in the presence of allopurinol's exposure, all supported the diagnosis of allopurinol hypersensitivity syndrome. This diagnosis is mainly based on some clinical criteria. Major criteria include a deterioration of renal function, acute hepatitis, and rash. Minor criteria include fever, eosinophilia, and leukocytosis. The association of at least 2 major criteria or 1 major and 1 minor criteria is consistent with the diagnosis of allopurinol hypersensitivity syndrome.4 Eosinophilia may be absent in some cases and this should not delay the diagnosis. Clinicians should recognize and treat rapidly the different clinical shapes of allopurinol hypersensitivity syndrome.
Pancreatitis associated to hypersensitivity syndrome has been cited in few reports, and it is even exceptional during allopurinol therapy.8 We report a case of allopurinol hypersensitivity syndrome with concurrent increase in pancreatic exocrine enzyme levels. Pancreatic disorders may be explained by an immune-mediated pancreatopathy included in the multiorgan involvement.
Although about 5% of the population has asymptomatic hyperuricemia, the majority will never develop gout or cardiovascular events.9 Thus, treating asymptomatic hyperuricemia does not have clear benefits and urate-lowering agents are not indicated in these cases. In asymptomatic patients, therapeutic intervention should have the lowest risk of adverse events with the highest efficiency on preventing complications or progression of the disease. Dietary changes, reduction in alcohol consumption, and use of nondiuretic therapies for hypertension may promote serum urate lowering.10 For asymptomatic hyperuricemia, there is no evidence that treatment is warranted. The progression from asymptomatic hyperuricemia to advanced gout is quite variable from person to person. Therapeutic decisions have to take into account expected benefits and potential harms with allopurinol therapy.11
Fatal consequences because of inappropriate treatment of asymptomatic hyperuricemia are unacceptable. Treatment should only be initiated when there is a clear indication to reduce the incidence and the severe consequences of allopurinol hypersensitivity syndrome.
1. Saxena R, Loghmanee F. Fatal drug reaction due to allopurinol therapy in a 72-year-old man. Arch Pathol Lab Med
2. Steinberg WM. Predictors of severity of acute pancreatitis. Gastroenterol Clin North Am
3. Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology
4. Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome: unnecessary morbidity and mortality. Arthritis Rheum
5. Bocquet H, Bagot M, Roujeau JC. DIDMOHS: a proposed consensus nomenclature for the drug induced delayed multiorgan hypersensitivity syndrome. Arch Dermatol
6. Anderson BE, Adams DR. Allopurinol hypersensitivity syndrome. J Drugs Dermatol
7. Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol
8. Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother
9. Sommers LM, Schoene RB. Allopurinol hypersensitivity syndrome associated with pancreatic exocrine abnormalities and new-onset diabetes mellitus. Arch Intern Med
10. Terkeltaub RA. Clinical practice: gout. N Engl J Med
11. Gutiérrez-Macías A, Lizarralde-Palacios E, Martínez-Odriozola P, et al. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. BMJ
© 2010 Lippincott Williams & Wilkins, Inc.