A Case Report

Stylianos Kornaros MD, PhD.

Third Surgical Department, Tzanio Teaching

Hospital, Piraeus, Greece.

Valproic Acid and Pancreatitis:

Which is the Mechanism?

Key words:

Valproic acid, Acute pancreatitis, Case report,

Potential mechanism

ABSTRACT

Context: Pancreatitis is a rare, life threatening side effect of the use of valproic

acid.

However, more observations are needed to determine the frequency of this

complication, as well as to elucidate any association with the potential patient

subgroups. Potential mechanisms for the onset of pancreatitis have not yet been

localized.

Case report: A 72-year old patient was reported who, after having been treated

for epilepsy for a period of two years with Valproate Sodium (500 mg/day) and

carbamazepine (100 mg/day) has manifested acute pancreatitis. In this patient, no

other cause of pancreatitis was found and operative intervention revealed dotted

spots of necrosis in peripancreatic tissue, without any lithiasis of the gallbladder

or dilatation of the common bile duct.

Conclusion: Acute pancreatitis is a rare complication of valproic acid use. Efforts

were made so as to explain the potential mechanism of this side effect.

INTRODUCTION

Valproic acid is mainly used for the treatment of absence

seizures, even though it has been shown to be effective in a

wide variety of partial and generalized seizures. It is also used

for the treatment of acute manic episodes in bipolar disorder

and for the prophylaxis of migraine headaches.

Pancreatitis associated with valproic acid has been

observed in children (1,2), as well as in adults (3).

Outcomes for patients with valproic acid associated

pancreatitis have ranged from full

recovery after discontinuation of the drug to severe

hemorrhagic pancreatitis and death.

The true incidence of pancreatitis associated with the use

of valproic acid is still unknown.

We present a case of pancreatitis, identified during an

operation of the patient treated with valproate sodium and

carbamazepine over a two year long period.

CASE REPORT

A 72-year old man was admitted to the hospital complaining

of severe abdominal pain with signs of extravagant epigastric

tenderness and abdominal distension. He had been suffering

from epilepsy for three years and during the last two years

had undertaken a treatment which consisted of 500 mg

valproate sodium (Depakine®) and 100 mg carbamazepine

(Tegretol®) per day. He also received isosorbide mononitrate

(Monosordil®) for his coronary insufficienciency.

Laboratory tests showed an elevated serum amylase (800

IU) but also an elevation of

WBC (11000), ASAT (157 IU), and ALAT (120 IU).

However, bilirubin, alkaline phosphatase and γGT were

normal.

US and CAT examinations upon admission lacked any

special evidence of abnormality in

the upper abdomen. After two days, the initial diagnosis

of acute pancreatitis , due to recurring and intense symptoms,

was believed to be uncertain and, as a result , it was mandatory

to operate on the patient.

Operative findings: An abundance of fluid exudate was

observed in the peritoneal cavity and especially beneath

the liver. There was an edema of the pancreas, of the

hepatoduodenal ligament and of the peritoneal sheet of the

gallbladder. Many dotted spots of peripancreatic necrosis

were noted as well as peripancreatic and epiploic fat necrosis.

The common bile duct was not dilated. A cholecystectomy

was performed and no signs of any lithiasis or microlithiasis

of the gallbladder were found.

The post-operative course of the patient, except of the

left pleural effusion, were satisfactory and the patient was

discharged the eleventh post-op day, with a slight elevation of

γGT (158 IU), only..

DISCUSSION

The mechanism by which valproic acid induces pancreatitis

is still unknown. Depletion of the free radical scavangers,

superoxide dismutase, catalase and glutatione peroxidase is

estimated to be the cause of pancreatitis in a patient receiveing

valproic acid (4). Valproic acid is eliminated mainly through

β-oxidation into mitochondria. It has been proposed that

valproic acid in pancreatitis, even it inhibits β-oxidation

enzymes involved in branched-chain amino acids or an

increase of toxic metabolites of valproic acid, occur, due to

genetic deficiency of β-oxidation enzymes (5). On the contrary,

as no change in amino acid levels in serum and urin has been

observed among patients with valproic acid pancreatitis, this

theory is discarded (6).

The pharmacological effects of valproic acid in CNS

involve a variety of mechanisms (7), including: increased

gamma-aminobutyric acid (GABA)-ergic transmission,

reduced release and/or effects of excitating amino-acids,

modulation of dopaminergic and serotoninergic transmission,

as well as prolongation of the inactivation gate closure of

voltage-gated sodium channels during repolarization of nerve

fiber (fig. 1).

In relation to previous effects, we propose a mechanism

whereby valproic acid acts on transport, mediated by carrier

proteins in acinar epithelial cells of the terminal ducts of

the pancreas. This action provokes changes of the protein

molecules that open or close the “gates” and conformational

changes of carrier proteins of Na+-K+ pump. As a result,

a malfunction of primary transport or co-transport with

sodium system occurs, provoking the shedding of pancreatic

enzyme into intercellular space, caused by the destruction of