Acetaminophen-induced acute pancreatitis: A case report and literature review

INTRODUCTION

Acute pancreatitis is a common disease in the clinic, and the mortality rate in patients with severe pancreatitis is high. Biliary stones, alcohol consumption, metabolic disorders and tumors are the most frequent causes of acute pancreatitis. Drug-induced acute pancreatitis is implicated in only a minority of cases, with an incidence of 0.1%-2%[1]. To date, over 130 kinds of drugs have been reported to cause acute pancreatitis, including acetaminophen[2]. It is well known that acetaminophen overdose causes hepatic toxicity, but it is a rare cause of acute pancreatitis. Only 11 cases of pancreatitis and hepatic impairment have been associated with acetaminophen at doses ranging from 4 to 120 g. Unlike previous reported cases, we report a case of acute pancreatitis caused by low doses of acetaminophen but without liver damage (Tables 1 and 2).

CASE REPORT

A 32-year-old woman presented with nausea and vomiting for 12 h associated with dizziness and epigastric pain. Before attending the hospital, she took eight Tylenol tablets containing acetaminophen (325 mg acetaminophen per tablet) after quarreling with her husband. She denied taking other drugs, alcohol consumption, gallbladder stones, trauma, autoimmune diseases and diabetes mellitus. The upper abdomen was soft with mild tenderness. Jaundice, hepatosplenomegaly, ascites, and Murphy’s sign were absent.

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Laboratory examinations showed the following:Hemoglobin 10.8 g/dL, white blood cells 5.5 × 10-9/L,neutrophils 65%, and platelets 169 × 10-9/L. Emergency biochemical tests showed aspartate aminotransferase 13 U/L (7-40 U/L), glutamic oxaloacetic transaminase 13 U/L (13-35 U/L), serum albumin 3.3 g/dL, serum amylase 990 U/L (0-96 U/L), serum lipase 49.5 U/L(13-60 U/L) and triglycerides 0.6 mmol/L (0.34-1.70 mmol/L). Two days later, blood biochemistry showed aspartate aminotransferase 13 U/L, glutamic oxaloacetic transaminase 13 U/L, alkaline phosphatase 52 U/L (35-100 U/L), serum albumin 40.9 g/L, serum amylase 433 U/L, serum lipase 136.6 U/L, triglycerides 0.6 mmol/L, and serum creatinine 53 μmol/L (45-84 μmol/L). Viral hepatitis markers (A, B, C, D and E),antinuclear antibody Hep-2, antineutrophil cytoplasmic antibody (ANCA), peripheral-ANCA and cytoplasmic-ANCA were negative. Serum IgG4 was 1.08 (0.03-2)g/L. Abdominal ultrasonography showed no abnormalities in the pancreas. However, magnetic resonance cholangiopancreatography (MRCP) showed that the pancreas was bulky without exudation. In addition to routine treatment for pancreatitis, N-acetylcysteine was administered to the patient to prevent disease progression. Five days after admission, she was able to drink water and take a liquid diet. Her serum amylase level decreased and abdominal pain resolved. However,that night she complained of severe upper abdominal pain radiating to the midcentral back with nausea and hypoglycemia. Contrast-enhanced computed tomography (CT) demonstrated swelling of the pancreas,especially the head of the pancreas, with fluid collection around the pancreas (Figure 1). Therefore, the patient was fasted again. In the following days, abdominal pain gradually alleviated and her diet gradually transitioned to semi-liquids as laboratory examinations revealed serum amylase of 281 U/L and lipase of 263.7 U/L with normal aminotransferase (13 U/L) after three days of pancreatic secretion/enzyme activity suppression and symptomatic treatment. On day 10 after admission,the patient requested early discharge as she had no abdominal pain or other feelings of discomfort. The patient was seen as an outpatient and laboratory examinations revealed serum amylase of 97 U/L and lipase of 15 U/L two weeks later. The patient refused further CT examination.

In nine of these cases, different degrees of abnormal liver function were present and two cases had no evidence of hepatotoxicity (Table 1). Our patient showed no liver damage but pancreatitis, which may be related to the dose of acetaminophen and the different underlying mechanisms of liver toxicity and pancreatic toxicity. The recommended maximum therapeutic dose of acetaminophen is 4 g/d for an adult,and asymptomatic elevations in aminotransferases are sometimes seen with chronic use at the maximum recommended daily dose of 4 g[20,21]. In our patient, the maximum therapeutic dose was not reached and was lower than 3 g. In contrast, all other patients took more than 3 g acetaminophen, the highest dose being 120 g and the lowest dose approximately 4 g[17,13]. A reliable dose-dependent relationship between acetaminophen poisoning and severity of acute pancreatitis is lacking,which was also stated in the case reported by Praveen Jinnur[16,17,22]. He believed that normal liver function was attributed to individual susceptibility rather than dose-related drug toxicity[16]. Similarly, a retrospective study, which included 814 patients with acetaminophen poisoning, showed that acetaminophen-associated acute pancreatitis occurred in patients without fulminant hepatic failure and in two patients without significant hepatotoxicity[23]. Consistent with these findings is the theory that acetaminophen-induced pancreatitis is related to an idiosyncratic reaction rather than intrinsic drug toxicity, which is in line with Gilmore and Tourvasa who considered that pancreatitis and hepatitis have different viral causes, as did Hisato Igarashi and Zachary Cavanaugh[7,14,17]. Interestingly, 5 of 11 cases were similar to ours that patients took an excess of acetaminophen at a time, which made us doubt whether the frequency and single overdose of acetaminophen were related with pancreatic toxicity. Unfortunately, no adequate evidence-based basis has been found because understanding of drug-induced acute pancreatitis is largely based on case reports and critical reviews.

DISCUSSION

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Table 1 Summary of 11 cases of acetaminophen-induced acute pancreatitis

aA detailed medical history was difficult to obtain from this patient due to her confused mental state; b3.97-5.3 g/d for 1 mo; cAbdominal CT showed features suggestive of acute pancreatitis, AMS was not available. APAP: Acetaminophen; AMS: Serum amylase; ALT: Alanine aminotransferase; TBil: Total bilirubin; NA: Not available; NAC: N-acetylcysteine; H: High.

Year Age/gender APAP (g) Serum APAP AMS (IU/L) ALT (IU/L) TBil NAC Ref.1977 31/F 60 NA 1440 300 H No [7]1977 41/F 25 NA 1250 NA H No [8]1986 19/M 25 62 μg/mL 1500 380 NA Yes [9]1991 34/F 9.37-13 77.7 μg/mL 936 225 NA Yes [10]1995 48/F 25 NA 300 8700 NA No [11]1997 74/F NAa 31 μg/mL 787 3070 H Yes [12]2001 47/M 4 NA 498 408 H No [13]2009 35/F 3.97-5.3b NA 1414 75 (H) Normal No [14]2009 17/F 15 Below 529 Normal Normal No [15]2012 40/F H NA NAc Normal Normal Yes [16]2014 19/F 78-120 208.4 μg/mL 638 9689 H NA [17]

Figure 1 Magnetic resonance cholangiopancreatography and computed tomography findings. A: MRCP shows the bulky pancreas without exudation on admission; B: CT demonstrates swelling of the pancreas, especially the head of the pancreas, with fluid around the pancreas 8 d after admission. MRCP: Magnetic resonance cholangiopancreatography; CT: Computed tomography.

Acetaminophen is frequently used for pain and fever in the clinic and is easily obtained from any pharmacy without prescription. Acetaminophen, when taken in an overdose, is a well-known cause of hepatic toxicity,but is rarely the etiologic agent of acute pancreatitis.To date, 11 case reports have been published describing acetaminophen-induced pancreatitis (Table 1)[7-17].The first case was reported by Gilmore and Tourvas in 1977. Since then, another ten cases of acetaminopheninduced pancreatitis have been described. In most of these cases, a positive rechallenge was not performed.However, Hisato Igarashi et al[14] reported a 35-year-oldwoman who experienced a similar situation each time after three overdoses of acetaminophen due to severe pain in the lower limbs after experiencing high levels of stress. In our case, the diagnosis of acute pancreatitis was made based on clinical findings in combination with blood test results and confirmed by image examinations.MRCP indicated pancreatitis by its advantage over CT or ultrasound (US) because of its T1-weighted images with an advantage to differentiate between simple effusion and hemorrhagic necrosis of the peripancreatic fatty tissue and to depict acute pancreatic hemorrhage and its T2-weighted images with better sensibility of upper abdominal fluid collections[18,19]. Secondly, the diagnosis of acetaminophen-induced pancreatitis was established by excluding common etiologies such as gallstone pancreatitis, hyperlipidemic pancreatitis and ethanolinduced acute pancreatitis and other suspicious drugs that have been reported to cause pancreatitis.

Table 2 Causes of acute pancreatitis

Causes of acute pancreatitis Common causes Gallstones, alcohol misuse, hyperlipidemia Other causes Hypercalcemia, autoimmune, idiopathic, drugs,trauma, tumor

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Acetaminophen-induced acute pancreatitis.

A 32-year-old woman presented with nausea and vomiting for 12 h associated with dizziness and epigastric pain.

Biliary pancreatitis, alcohol-induced pancreatitis, hyperlipidemic pancreatitis and codeine-induced pancreatitis.

ARTICLE HIGHLIGHTS

Case characteristics

In conclusion, less than 4 g acetaminophen can cause acute pancreatitis without liver damage, which indicates that the mechanism of pancreatitis is different from that of hepatitis, and the severity of acute pancreatitis may not have a reliable dose-dependent relationship. Although drug-induced acute pancreatitis is rare and easily ignored, we should be aware of this condition in high-risk patients with a history of drug overdose, especially Class Ⅰ and Class Ⅱ drugs,and both timely and appropriate treatment should be administered.

Drug-induced acute pancreatitis is rare with a reported incidence of 0.1%-2%, but should not be overlooked[1,3].However, drug-induced pancreatitis remains a difficult and challenging diagnosis due to atypical clinical and laboratory tests, which is usually established by excluding other causes. A positive rechallenge is the most effective proof but cannot be performed due to ethical reasons.Our patient took an overdose of a drug containing acetaminophen in a suicide attempt. However, during the follow-up period, the typical conditions associated with acetaminophen overdose did not occur. In general, druginduced acute pancreatitis is more frequent in children,women, the elderly, and in patients with advanced HIV infection and inflammatory bowel disease[4,5]. A single-center study with about 328 patients with acute pancreatitis from Australia revealed that drug-induced acute pancreatitis appeared to be more common in middle-aged women, which was attributed to the es-trogens by an unclear mechanism[6]. Our patient was a young woman and thus a high-risk individual. Based on the weight of evidence including the presence of a rechallenge, latency, and the number of case reports,Badalov et al[3] divided drugs into five categories including acetaminophen, which was categorized as Class Ⅱ. It has been reported that drugs belonging to Class Ⅰ and Class Ⅱ have the “most evidence” of causing acute pancreatitis as shown by published case reports[2].

Clinical diagnosis

This patient was fortunately taken to the hospital in time and treated with N-acetylcysteine, which can prevent hepatotoxicity following acetaminophen overdose by replenishing hepatic glutathione stores. In patients who receive N-acetylcysteine within the first eight hours after an acute overdose, the risk of hepatotoxicity is less than 5%, whereas delays beyond 10 h are associated with an increased risk of hepatic injury[20]. In other cases,they either took a large dose of acetaminophen or did not receive timely treatment, or they were patients at high risk, such as those with known alcohol consumption,which may have led to drug-induced pancreatitis with different levels of liver damage.

Differential diagnosis

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Laboratory diagnosis

Laboratory workup revealed a significant elevation of serum amylase of 990 U/L but normal aminotransferases.

Imaging diagnosis

Magnetic resonance cholangiopancreatography showed that the pancreas was bulky without exudation. Computed tomography demonstrated swelling of the pancreas, especially the head of the pancreas, with fluid collection around the pancreas.

Treatment

Abrosia, routine treatment for pancreatitis, and N-acetylcysteine were administered to the patient.

Related reports

A total of eleven cases of acetaminophen-induced acute pancreatitis have been reported in the literature but this case took the lowest dose of acetaminophen without liver damage.

Experiences and lessons

Acetaminophen-induced acute pancreatitis is rare and should be considered in the differential diagnosis of acute pancreatitis, especially in high-risk patients with an overdose of suspected drugs.

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