Pancreatitis Associated with Valproic Acid: A ... - Wiley Online Library

Pancreatitis Associated with Valproic Acid: A Review of the Literature Scott A. Chapman, Pharm.D., G. Paulina Wacksman, Pharm.D., and Betty D. Patterson, Ph.D. Black box warnings for valproic acid caution clinicians of the potential for fatal hepatotoxicity and teratogenicity. Since 1979, case reports of pancreatitis induced by valproic acid have been published in the medical literature. As a result, pancreatitis was added to the black box warnings for valproic acid. We performed searches of MEDLINE and International Pharmaceutical Abstracts and found valproic acid-induced pancreatitis in 45 patients from 31 published articles. Demographics, clinical characteristics, and outcomes of these patients are summarized. Recommendations for monitoring the potential for pancreatitis to develop in patients receiving valproic acid therapy are described, as are potential mechanisms for inducement of pancreatitis by valproic acid. (Pharmacotherapy 2001;21(12):1549–1560) Valproic acid was approved in the United States in 1978 for treatment of absence seizures. Since that time, it has received approval, either as monotherapy or in combination with other anticonvulsant agents, for the treatment of mixed and complex partial seizures. More recently, it gained approval for treatment of acute manic episodes in bipolar disorder and for prophylaxis of migraine headaches. Valproic acid is also effective in treating myoclonic, simple partial, and generalized tonic-clonic seizures. Other unapproved uses are prophylaxis of bipolar disorder and treatment of aggression and agitation in dementia and in brain-injured patients. In general, valproic acid offers advantages over older anticonvulsants in causing fewer troublesome adverse effects. It has a lower frequency of cognitive dysfunction and central nervous system effects, allowing patients to be more alert and functional. Common adverse effects include nausea and vomiting, tremor, and From the College of Pharmacy, North Dakota State University (Drs. Chapman and Patterson), and MeritCare Medical Center (all authors), Fargo, North Dakota. Address reprint requests to Scott A. Chapman, Pharm.D., College of Pharmacy, North Dakota State University, 128 Sudro Hall, Fargo, ND 58105.

weight gain. Nausea and vomiting are less frequent with sodium divalproex.1, 2 Clinical experience indicates that valproic acid causes rare, fatal hepatotoxicity. 3, 4 More commonly, a dose-related elevation of liver enzymes is noted, which is minimal and does not require discontinuation of the drug. In addition, thrombocytopenia has been reported, as have cases of hyperammonemia.1 Pancreatitis with valproic acid was first recognized in 1979.5, 6 Since those initial reports, similar case reports have followed. Outcomes for patients with valproic acid-associated pancreatitis have ranged from full recovery after discontinuation of the drug to severe hemorrhagic pancreatitis and death. A survey of 364 physicians found that 53 (14.5%) reported seeing a case of pancreatitis associated with valproic acid.7 Whereas the true incidence of pancreatitis associated with the use of valproic acid is unknown, the Depakote (Abbott Laboratories, Abbott Park, IL) package insert reports two cases of pancreatitis without alternative explanations in 2416 patients, representing 1044 patient-years of experience. 1 Given these reports and the potential severity of this reaction, in July 2000 the Food and Drug

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PHARMACOTHERAPY Volume 21, Number 12, 2001

Table 1. Demographics, Clinical Characteristics, and Outcomes of Patients with Valproic Acid-Induced Pancreatitis Age (yrs)/ Pertinent Dosage Dosage Level Duration of Pancreatic Enzymes Gender Diagnoses (mg/kg/day) (mg/day) (µg/ml) VPA Therapy Other Drugs Symptoms (normal range) 8/M5 Seizures 30 750 NR 5 wks None AP A 1200 IU (4–80 IU) 11/F6

Seizures

45

2000

NR

NR

None

AP

A 255 U/dl (< 160 U/dl)

3.5/F6

Seizures, mental retardation

55

900

69

NR

Phenytoin

AP

8/M11

Seizures

64.4

1500

72

NR

Phenytoin, clonazepam

AP, V, lethargy

A 213 U/dl (< 160 U/dl) 24-hr urine A 29,325 U (< 2000 U) A 1125 SU (< 150 SU)

10/F11

NR

30

NR

NR

3 mo

None

V

NR

11/F12

Seizures

30

1200

NR

4 mo

Phenobarbital

EP, N

A 1035 SU/dl (< 160 SU/dl)

16/M13

Seizures

40

2000

NR

5 mo

AP, N, V, weight loss

A 520 IU/L (NR)

65/M14

Seizures

52

4000

NR

13 mo

Carbamazepine, acetazolamide, methsuximide Phenytoin

AP, HOTN, dysphagia

A 302 U/L (< 200 U/L)

3/M15


85

NR

76

2 yrs

Clorazepate, carbamazepine, phenytoin

AP, V

7/F15

Seizures

50

NR

87

7 mo

AP, V

18/M15

Seizures

58

NR

43

11 mo

Methsuximide, phenobarbital, phenytoin Nitrazepam, phenytoin

A 180 U/L (45–200 U/L) L 74 U/dl (4–24 U/dl) A 260 U/L (45–200 U/L)

27/M15

Seizures

30

NR

84

4.5 yrs

Carbamazepine

AP, V

1/F16

Seizures

25

NR

59

10 days

None

41/M7

Seizures

NR

5000

NR

NR

14/F17

Seizures

50

NR

NR

3 mo

Drowsiness, anorexia, AD, V, circulatory failure AP, AD, absent BS, fever AP

1/M18

Seizures

70

NR

83.8

NR

37/M19

Seizures, aggression

NR

2000

64

17 mo

Phenytoin

Phenobarbital, phenytoin

Carbamazepine, TRH Phenobarbital, thiothixene, propranolol, benztropine, trazodone

AP, V

V, D ↑ abdominal girth, EP, confusion

A 402 U/L (23–85 U/L) L 421 U/dl (20–85 U/dl) A 650 U/L (45–200 U/L) A 3520 IU/L (100–400 IU/L) A 247 IU/L (25–115 IU/L) A 230 U/L (< 100 U/L) L 1645 U/L (< 200 U/L) A “normal” L “elevated” A 91 IU/L (23–85 IU/L) L 58 IU/L (4–24 IU/L)

PANCREATITIS ASSOCIATED WITH VALPROIC ACID Chapman et al Table 1. (cont.) Diagnostic Findings None

Laparotomy: mesenteric fat necrosis None

Naranjo Score 6

9

6

US: diffuse pancreatic enlargement Laparotomy: hemorrhagic pancreatitis Laparotomy: inflamed, necrotic pancreas US: enlarged pancreas

10

Outcome Recurrence after initial recovery with continued VPA Recovery, recurrence with rechallenge Recovery

Recovery, recurrence with rechallenge

4

Death

9


7

Recovery, three recurrences with rechallenges

Laparotomy: edematous, hemorrhagic pancreas Laparotomy: hemorrhagic necrosis of pancreas Laparotomy: pancreas inflamed

6

Death

8

Recovery

8

Recovery

US and CT: normal

8

Recovery

US: normal

5

Necropsy: hemorrhagic pancreatitis

5

Recovery, VPA continued 14 mo with no recurrence Death

CT: enlarged pancreas with pseudocyst

5

Recovery

US: normal

5

Recovery

US: enlarged pancreas US and CT: thickening of body and tail of pancreas

6

Recovery

5


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Administration (FDA) instituted new black box warnings in the package labeling for valproic acid to include the risk of pancreatitis. Review of Cases To identify publications describing pancreatitis associated with valproic acid, we searched MEDLINE from January 1966–April 2001 and International Pharmaceutical Abstracts from January 1964–April 2001 using the MeSH headings valproic acid, divalproex sodium, valproate sodium, ergenyl, Depakene, Depakote, and pancreatitis. We also contacted the FDA, which provided two additional cases that were described in a publication involving growth hormone and pancreatitis. 8, 9 A total of 44 citations were identified. Of these citations, 11 were excluded because they were published in non-English–text journals. This resulted in 33 citations involving 52 patients for review to evaluate the characteristics of pancreatitis induced by valproic acid. Each case report was reviewed for patient demographics, pertinent diagnoses, dosage and serum concentrations of valproic acid, duration of valproic acid therapy to onset of symptoms, concomitant drugs, presenting symptoms, pancreatic enzymes, diagnostic findings, and outcome of the patient. A patient was considered to have met the diagnosis of pancreatitis if the clinical presentation was consistent with the symptoms of pancreatitis, if the amylase and/or lipase elevation was greater than 3 times the upper limit of normal, if imaging studies indicated pancreatitis, and/or if visualization of the pancreas during surgery identified pancreatic damage. If the patient’s only indications of possible pancreatitis were nausea, vomiting, and/or abdominal pain—all of which could be due to gastrointestinal side effects of valproic acid or other causes—that patient was excluded. Other contributing factors, such as drugs or other disease states that could have caused pancreatitis, were identified if listed in the case report. Case reports that clearly had another identifiable cause of pancreatitis or lacked sufficient evidence to make a convincing diagnosis of pancreatitis were excluded. Following these assessments, seven patients were excluded. Two had gastrointestinal complaints without 3-fold elevation of pancreatic enzymes; moreover, these patients had normal ultrasound and/or computed tomography (CT) scans. A third patient was excluded due to the

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Table 1. Demographics, Clinical Characteristics, and Outcomes of Patients with Valproic Acid-Induced Pancreatitis (cont.) Age (yrs)/ Pertinent Dosage Dosage Level Duration of Pancreatic Enzymes Gender Diagnoses (mg/kg/day) (mg/day) (µg/ml) VPA Therapy Other Drugs Symptoms (normal range) 11/M20 Seizures, 48 NR NR 2 yrs Phenobarbital, AP, V A 850 U/L mental thioridazine (24–120 U/L) retardation L 13,700 U/L (20–208 U/L) Bipolar NR 6000 89 4 mo Diazepam, V, ataxia, A 232 U/L 40/M21 disorder, levothyroxine drowsiness (44–128 U/L) mental L 3835 U/L retardation (23–203 U/L) 26/M21 Seizures, NR 1800 NR 3 mo Carbamazepine AP A 582 U/L mental (44–128 U/L) retardation L 3983 U/L (23–203 U/L) 28/M21 Seizures, NR 1650 NR 9 mo Carbamazepine V, lethargy A 779 U/L mental (44–128 U/L) retardation L 3175 U/L (23–203 U/L) 22/M21 Seizures, NR 2750 113 14 yrs Ranitidine AP, fever A 747 IU/L mental retard↓ LOC (44–128 IU/L) ation, NCL Seizures, 39.2 NR NR 12 wks Clonazepam, Comatose, A 980 IU/L 21/M22 mental phenobarbital AD, F, (< 370 IU/L) retardation shock 11/M23

Seizures mental retardation

30

NR

NR

NR

Clonazepam

AP, V, absent BS, lethargy

31/F24

Seizures, 84 mental retardation, cerebral palsy Seizures, NR hypsarrhythmia

NR

195

NR

Phenytoin

V, lethargy fatigue

NR

NR

1 mo

NR

A 600 U (NR)

Seizures, mental retardation Seizures, renal failure-HD Seizures, renal failure-PD, aseptic peritonitis Seizures, renal failure-PD

NR

750

53–270

17 mo

Phenobarbital, phenytoin

Irritable, HOTN, absent BS, lethargy, AD V

NR

800

31.7

7 days

Carbamazepine

AP, V

NR

NR

NR

NR

Clobazam

NR

A 6045 U/L (100–300 U/L) NR

NR

NR

83

NR

Phenobarbital

AP, V

A 481 U/L (NR)

9.2/F29

Seizures, renal failure-PD

NR

NR

77

NR

Phenytoin,

V, D, dehydration

A 128 U/L (NR)

14/M29

Seizures, renal failure-PD

NR

NR

80

5.5 yrs

NR

AP, N, V

A 2571 U/L (NR)

4.5/M25

19/M26

43/F27

8/M28

4.3/F29

A 360 IU/L (25–115 IU/L) L 4707 IU/L (< 370 IU/L) NR

NR

PANCREATITIS ASSOCIATED WITH VALPROIC ACID Chapman et al Table 1. (cont.) Diagnostic Findings None

Naranjo Score 5

Outcome Recovery

US: pancreas not visualized

6

Recovery

US: pancreatitis

6

Recovery

Pancreatic pseudocyst (method of detection not reported) Laparotomy: pancreatic pseudocyst CT: ascites, peripancreatic edema, enlarged pancreas CT: pancreatic edema

6

Recovery

6

Recovery

4

Death, liver insufficiency

5

Recovery

Autopsy: diffuse hemorrhagic and firm pancreas

5

Death

US: enlarged pancreas Abdominocentesis: hemorrhagic ascites, amylase 945 U Sonogram: pancreatic pseudocyst None

5

Recovery

8

Recovery

8

Recovery

Laparotomy: retropancreatic abscess

4

US and X-ray: nondiagnostic

4

CT and US: pancreatitis, peripancreatic pseudocyst CT: edematous pancreas

4

Death, after recurrences at 3 and 11 mo with continued VPA use Recovery, VPA resumed after renal transplant with no recurrence Death

5

Recovery, no recurrence with rechallenge 21 mo after transplant

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presence of gallstones, and two more because the authors of the reports did not provide any diagnostic evidence of pancreatitis. Two patients were excluded because lipase elevation was present without any additional findings consistent with pancreatitis. As a result, 31 publications involving 45 patients were included in the final review. To determine the strength of the association between exposure to valproic acid and development of pancreatitis, we evaluated the findings for each patient using the Naranjo adverse drug reaction (ADR) probability scale.10 This scale measures the degree of likelihood that an ADR occurred by adding the weighted responses to 10 questions to be answered as “yes,” “no,” or “do not know.” A score of 9 or above is considered a definite reaction; 5–8, a probable reaction; 1–4, a possible reaction; and 0 or less, a doubtful reaction. Table 1 3, 5–9, 11–35 shows the demographics, clinical characteristics, and outcomes of the 45 patients included in the final review. Mean age was 15.1 ± 13.7 years (range 1–65 yrs). Most patients were relatively young, with 29 of the 45 patients (64.4%) less than 20 years of age. Twenty-eight (62%) were men. Mean dosage of valproic acid at presentation was 47.6 ± 16.9 mg/kg/day (range 25–84 mg/kg/day) for the 23 patients whose dosages were reported as milligrams/kilograms/day. For the 16 patients whose dosages were expressed as milligrams/day, the mean dosage was 2146.9 ± 1562.2 mg/day (range 750–6000 mg/day). Of the 24 cases reporting plasma valproic acid concentrations at initial presentation, the concentrations ranged from 14.7–2189 µg/ml (normal 50–100 µg/ml). Five patients (20.8%) had levels below 50 µg/ml, 14 (58.3%) had levels from 51–100 µg/ml, and 5 (20.8%) had levels above 100 µg/ml. These data suggest that there is no correlation between valproic acid dosage or plasma concentration and development of pancreatitis. The duration of time patients were receiving valproic acid before onset of symptoms was known in 33 (73.3%) of the patients; in these patients, it ranged from 0.25–168 months. Thirty percent of the patients developed symptoms within 3 months of starting valproic acid; 58% developed symptoms within 12 months of beginning valproic acid. Ten patients (30%) developed pancreatitis 2 years or more after the start of valproic acid. Most patients presented with complaints of

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Table 1. Demographics, Clinical Characteristics, and Outcome of Patients with Valproic Acid-Induced Pancreatitis (cont.) Age (yrs)/ Pertinent Dosage Dosage Level Duration of Pancreatic Enzymes Gender Diagnoses (mg/kg/day) (mg/day) (µg/ml) VPA Therapy Other Drugs Symptoms (normal range) 13/M29 Seizures, NR NR NR 4 yrs Phenytoin AP, N A 1400 U/L renal failure(< 130 U/L) PD 23/M30 Seizures, 45 NR 35 15 mo Phenobarbital AP, V A 2658 UI/L renal failure(130–250 HD UI/L) Seizures, NR NR NR 2 yrs NR AP, V A 232 U/L 14/F31 renal failure(5–81 U/L) PD L 465 U/L (4–24 U/L) 12/M31 Seizures, NR NR NR 2 yrs NR AP, AD, A 880 U/L renal failureEP (5–81 U/L) HD L 1530 U/L (4–24 U/L) 40/F32 Seizures, VPA NR NR 2189 1 yr NR ↓ LOC, A 232 IU/L overdose minimal (70–300 IU/L) response to pain 27/F33 Seizures, VPA NR NR 1440 6 yrs Phenobarbital Deep coma A > 5000 U/L overdose, (< 350 U/L) diabetes L 25,000 U/L mellitus (< 160 U/L) 6/M8 Seizures, NR NR NR NR Growth NR A 734 IU/L hypopituhormone, L 2022 IU/L itarism gabapentin (NR) 9/M9 Seizures, NR NR NR 4 yrs Growth AP, V A 2085 IU/L hypopituhormone L 8340 IU/L itarism (NR) Seizures 55 NR 32 21 wks None AP, V, NR 3.6/F3 lethargy 6.6/F3

Seizures

50

NR

100

12 wks

None

AP, V, lethargy

NR

5/M3


30

NR

62

4 wks

AP, V, lethargy

NR

25/M34

Seizures

NR

NR

NR

3 wks

Ethosuximide, phenobarbital, primidone, carbamazepine NR

AP

A 5980 U (< 300) U

26/F35

Seizures, NR possible VPA overdose, mephenytoin overdose

1250

14.7

NR

Mephenytoin

Comatose

A 1373 U/L (25–125 U/L) L 810 U/L (7–58 U/L)

VPA = valproic acid; AP = abdominal pain; N = nausea; V = vomiting; SU = Somogyi units; EP = epigastric pain; HOTN = hypotension; AD = abdominal distention; BS = bowel sounds; D = diarrhea; LOC = loss of consciousness; F = fever; A = amylase; L = lipase; CT = computed tomography; US = ultrasound; TRH = thyroid-releasing hormone; NR = not reported; HD = hemodialysis; PD = peritoneal dialysis; NCL = neuronal ceroid lipofuscinosis.

abdominal pain, vomiting, and lethargy. Two patients were hemodynamically unstable at initial presentation. In patients who had amylase and lipase levels reported at the time of diagnosis, levels varied from normal to markedly elevated. Diagnostic tests (e.g., laparotomy, CT scan,

ultrasonography) were performed in many patients to confirm pancreatitis and/or rule out other possible illnesses. Several patients were receiving concomitant antiepileptic drugs or other agents. Most of those drugs have not been associated with pancreatitis. However,

PANCREATITIS ASSOCIATED WITH VALPROIC ACID Chapman et al Table 1. (cont.) Diagnostic Findings CT: enlarged pancreas, possible pseudocyst NR

Naranjo Score 3

Outcome Death

5

Recovery

CT: ascites, enlarged pancreas, infiltration of peripancreatic fat

3

Death , after recurrence with continued VPA

CT: ascites, enlarged pancreas, infiltration of peripancreatic fat

4

Recovery

Autopsy: hemorrhagic pancreatitis

5

Death

NR

8

Recovery

NR

2

Recovery

US: normal

4

Recovery


5

Death, liver failure


5



5


Laparotomy: hemorrhagic pancreatitis None

6


7

Recovery

carbamazepine, 36 growth hormone, 37 and ranitidine 38 have been associated with pancreatitis in rare instances (Table 2). Many patients recovered from their symptoms when they discontinued valproic acid. However, 13 patients died, representing 29% of the patients reported. Of the seven patients who were rechallenged, five experienced recurrence. One

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patient had repeated signs and symptoms of pancreatitis after three rechallenges. The two patients who did not have recurrence of pancreatitis on rechallenge were in end-stage renal disease and were receiving dialysis. It is of interest that both of these patients received renal transplants and did not require hemodialysis before restarting valproic acid. Of the case reports reviewed, nine patients had concomitant end-stage renal disease requiring dialysis, 11 were mentally retarded, one had cerebral palsy, and one had neuronal ceroid lipofuscinosis. Two patients had hypopituitarism and were receiving growth hormone.8, 9 Three of the 45 patients took intentional overdoses of valproic acid. All of them were women (ages 40, 27, and 26 yrs), who presented with altered mental status. One had a plasma valproic acid level of 2189 µg/ml and a serum amylase level of 232 IU/L (normal 70–300 IU/L) at presentation. 32 This patient developed hypotension, renal failure, and adult respiratory distress syndrome; she died despite treatment with fluids and vasopressors. Postmortem histologic examination revealed necrotic, hemorrhagic pancreatic tissue. The second patient with an overdose had a serum valproic acid level of 1440 µg/ml at presentation.33 Serum amylase and lipase levels were approximately 5000 U/L (normal 350 U/L) and above 25,000 U/L (normal < 160 U/L), respectively. Other complications were respiratory depression requiring mechanical ventilation, liver and renal damage, severe thrombocytopenia, and moderate anemia. This patient recovered following a 7-day period of deep coma and mechanical ventilation. The third patient with an overdose ingested an unknown amount of valproic acid together with an estimated maximum of 12,000 mg of mephenytoin.35 She was comatose and cyanotic and with slight lateral nystagmus at presentation. Her valproic acid level was 14.7 µg/ml on admission. Her serum amylase level peaked at 1373 U/L on day 2, and her serum lipase level peaked at 810 U/L on day 9. The patient recovered 10 days after the overdose. When assessing the strength of the association between valproic acid and development of pancreatitis, three cases were found to be definite (≥ 9 on the ADR probability scale), 32 were probable (5–8 on the ADR probability scale), 10 were possible (1–4 on the ADR probability scale), and none were doubtful (≤ 0 on the ADR probability scale).

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PHARMACOTHERAPY Volume 21, Number 12, 2001 Table 2. Drugs Used Concomitantly in Reported Instances of Valproic Acid-Induced Pancreatitis No. of Patients Drug Implicated as a Cause Concomitant Drug Receiving the Drug of Acute Pancreatitis Phenytoin 12 No Phenobarbital 10 No Carbamazepine 9 One case report36 Clonazepam 5 No Clobazam 1 No Acetazolamide 2 No Methsuximide 2 No Growth hormone 2 Rare37 Nitrazepam 1 No Diazepam 1 No Levothyroxine 1 No Ranitidine 1 Rare38 Thyroid-releasing hormone 1 No Thiothixene 1 No Trazodone 1 No Thioridazine 1 No Propranolol 1 No Benztropine 1 No Clorazepate 1 No

Discussion Valproic acid has been used as an antiepileptic drug for over 20 years. In addition to its usefulness in treating a wide variety of seizure types, it has become a first-line agent in treatment of acute mania and in prophylaxis of bipolar disorder. It is also widely used in prophylaxis of migraine headache and in management of aggressive behaviors in organic brain syndromes. All of these conditions require long-term or indefinite administration of the drug, which increases the risk for toxic reactions.4, 39–41 Monitoring liver function tests and platelet counts is recommended in patients receiving valproic acid, especially early in the course of therapy when adverse effects are most likely to be seen. Concerns regarding fetal teratogenicity, including spina bifida and fetal valproate syndrome, require screening for pregnancy before starting valproic acid therapy, as well as birth control measures during therapy. Pancreatitis associated with valproic acid is a well-recognized adverse reaction, the severity of which has led to the black box warning. Pancreatitis can be either acute or chronic. Some common causes of acute pancreatitis are gallstones, alcohol consumption, hyperlipidemia, structural abnormalities involving the pancreatic ducts or the bile duct, cystic fibrosis, hereditary pancreatitis, pregnancy, pancreatic trauma, and

idiopathic pancreatitis.42, 43 Several drugs have also been implicated as inducers of pancreatitis.44 The clinical presentation of acute pancreatitis is that of moderate-to-severe abdominal pain, with nausea and vomiting. Laboratory findings that support the diagnosis of pancreatitis are a serum lipase and/or amylase level of more than 3 times the upper limit of normal. Radiographic imaging methods that aid in establishing the diagnosis are abdominal ultrasonography, abdominal CT, endoscopic retrograde cholangiopancreatography, magnetic resonance imaging, and endoscopic ultrasound.42 Each year, 50,000–80,000 cases of acute pancreatitis are reported in the United States.45 Of those, approximately 80% involve a mild, selflimiting form of acute pancreatitis. The severe, potentially life-threatening form of this disease, occurring in the remaining 20%, may have associated infection of the necrotic tissue and multiorgan dysfunction syndrome. Mortality rates in patients with the severe form range from 15–40%. Variations in mortality rates reflect differences in the degree of pancreatic necrosis involved and infection.46 The mechanism by which valproic acid induces pancreatitis is unknown. However, it has been theorized that depletion of the free radical scavengers superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase occurs in patients receiving valproic acid.7, 47, 48 Normally, free radicals are reduced by SOD, CAT, and

PANCREATITIS ASSOCIATED WITH VALPROIC ACID Chapman et al glutathione peroxidase. Depletion of free radical scavengers could lead to an excess of the superoxide radical (O2–), due to SOD depletion, excess hydrogen peroxide (H2O2) secondary to CAT depletion, and excess hydroxyl free radical (OH – ) secondary to an additional electron transferred from chelates of ferrous iron and cuprous copper to H 2 O 2 . The excess of free radicals could result in endothelial permeability and lipid peroxidation, ultimately leading to tissue damage. Research involving a perfused canine pancreas model has demonstrated that oxygen-derived free radicals (O 2 – , HO – ) and hydrogen peroxide (H 2 O 2 ), acting as cytotoxic oxidants, play a major role in the pathophysiology of acute pancreatitis regardless of the initial insult.47 In this study, acute pancreatitis was induced by three distinct mechanisms: infusion of oleic acid (to simulate alcohol-induced hyperamylasemia), partial duct obstruction followed by secretin stimulation, and a 2-hour period of ischemia. Organ weight gain, edema, and hyperamylasemia were the end points used to measure pancreatic injury. When free radical scavengers SOD and CAT were added to the experimental models, there was a significant reduction in the monitored injury response. The results suggest that free radicals contribute to pancreatic damage by overwhelming the protective free radical scavengers during insult. To function properly, free radical scavengers require an adequate supply of the trace elements selenium, copper, zinc, and manganese.7 One research group showed a decrease in the free radical scavenging enzymes glutathione peroxidase and SOD, as well as a decrease in the trace elements selenium and copper, in patients receiving valproic acid.48 They hypothesized that this decrease in trace elements contributed to the decrease in free radical scavengers, with a subsequent increase in the amount of free radicals in the body. This increase in free radicals may result in sufficient cellular damage to cause pancreatitis and hepatotoxicity. The researchers further suggested that trace element supplementation may decrease the risk of valproic acid pancreatitis. A second research group echoed this position and further suggested the possibility of genetically predetermining atrisk patients based on the activity of their free radical scavenger system before starting valproic acid therapy.7 Another proposed theory for valproic acidinduced pancreatitis involves the effect of

1557

valproic acid on mitochondrial b-oxidation. It has been established that valproic acid is eliminated primarily through mitochondrial boxidation,1 an enzyme system also involved in branched-chain amino acid metabolism. A research group demonstrated that valproic acid inhibited b-oxidation enzymes involved in branched-chain amino acid and straight-chain fatty acid metabolism. 49 They proposed that patients with a genetic deficiency in the enzymes involved in mitochondrial b-oxidation of valproic acid may experience an increase in toxic metabolites. Another group screened serum and urine amino acid levels in patients who developed pancreatitis during valproic acid therapy. 21 They did not observe a change in amino acid levels, and they discounted the boxidizing enzyme deficiency theory for valproic acid-induced pancreatitis. As mentioned above, there are many causes of pancreatitis. Our review of each case report considered the likelihood of pancreatitis being associated with valproic acid versus another cause. Variability in the amount of detail provided about each patient makes it somewhat difficult to critique each case thoroughly for a definite association between valproic acid and pancreatitis. Patients who clearly had other identifiable causes for pancreatitis were excluded from the data analysis. Of the patients who were included, two were receiving growth hormone, which has been remotely linked to pancreatitis,8, 9 and nine had renal failure and were receiving peritoneal dialysis or hemodialysis, which have been reported as causes of pancreatitis. 50, 51 While the supporting evidence for pancreatitis associated with valproic acid varied among the patients, the scores assigned to each patient using the ADR scale 10 show that many of the case reports have a definite or probable association. Screening and evaluation of valproic acidinduced pancreatitis is complicated, since many of the presenting symptoms also occur independently as common adverse effects of the agent. Abdominal pain and nausea with vomiting are frequent clinical findings in patients with pancreatitis, occurring in 95% and 80% of patients, respectively. Abdominal distention and low-grade fever are also common findings. Less frequently, hypotension, jaundice, and mental status changes occur.4 Nausea is the most frequent adverse effect of valproic acid. It is less likely to occur with sodium divalproex, which is enteric coated, and thus avoids direct irritation of the stomach. In

1558


recent studies, the frequency of nausea in patients with mania or migraine headache who were receiving valproic acid was 22–31%, compared with 10–15% for placebo.1 Vomiting occurs less frequently, occurring in 11–12% of patients taking the drug compared with 1–3% for placebo. Abdominal pain was reported in 9% of patients taking valproic acid, compared with 4–8% for placebo. Fever and hypotension occurred in less than 5% of patients treated with the agent. Transient elevations of serum amylase levels without the development of pancreatitis have also been noted, further complicating the issue of routine screening of pancreatic enzymes in patients receiving valproic acid. Following the first reports of valproic acid-associated pancreatitis, recommendations were made to monitor serum amylase levels in all patients receiving the drug, especially in those with symptoms of gastrointestinal or abdominal discomfort or pain. 11 According to these recommendations, elevations in pancreatic enzyme elevations warranted discontinuation of valproic acid. One study has attempted to assess the usefulness of monitoring amylase levels in patients receiving valproic acid.52 Measurement of amylase in 61 patients, aged 4–45 years, receiving valproic acid over a 6–36-month period revealed that 19.7% had elevated amylase levels (defined as > 85 IU). Only one patient developed clinical evidence of pancreatitis, with a serum amylase level of 246 IU. (This patient was excluded from our analysis because the patient’s symptoms and clinical course were not described by the authors, except for toxic encephalopathy thought to be due to an interaction between phenytoin and valproic acid.) In all of the patients, elevated amylase levels returned to normal with continued valproic acid therapy. There was no correlation between amylase level and dosage of valproic acid (r = -0.041) or valproic acid level (r = 0.012). The authors concluded that pancreatic enzymes may be transiently elevated during valproic acid therapy and may not predict valproic acid-associated pancreatitis. Therefore, they felt routine screening of pancreatic enzymes may not be warranted. A similar frequency of pancreatic enzyme elevation was observed in a related study.53 In this study, which involved 134 patients, the researchers noted a significant increase in the number of patients with elevated serum or urine

amylase levels who were receiving valproic acid compared with those not receiving the drug (23.9% vs 5.6%, p