Acute Necrotizing Pancreatitis Following Olanzapine Treatment and 759C/T Polymorphism of HTR2C Gene: A Case Report

Discussion

Olanzapine can predispose to the development of hypertriglyceridemia, hyperglycemia, hyperlipidemia and weight gain. In fact, there is evidence of an approximate doubling of serum triglyceride levels in patients treated with olanzapine (2, 3), although increases as marked as that observed for our patient are rare. Despite intense basic and clinical research, the nature of the pathogenesis of pancreatitis remains largely unknown. However, it seems that in our case, severe hypertriglyceridemia with serum levels >1,000 mg/dl might have predisposed to pancreatitis. In fact, when triglyceride levels are elevated, chylomicrons tend to be present, and may obstruct capillaries, leading to pancreatic inflammation and pancreatitis. Moreover, excess free fatty acids from triglycerides may generate further cytotoxic injury, releasing inflammatory mediators and aggravating the pancreatitis (4).

Researchers have suggested that pancreatitis is better understood as a spectrum of a syndrome whose heterogeneous nature derives from the complex interplay between lifestyle factors (e.g. diet and medication), genetics and resultant differences in pathophysiology (5). Given the temporal association and the absence of other known risk factors, the onset of acute pancreatitis in our patient is most likely attributable to the intake of olanzapine. Using the casuality scale of Naranjo et al., pancreatitis qualified as a probable adverse drug reaction to olanzapine (6). Furthermore, most cases of antipsychotic-induced acute pancreatitis occur within six months of treatment and more often in males (7).

Since 2000, several cases of olanzapine associated pancreatitis have been reported (8-10), among which there is only one report of acute necrotizing pancreatitis (11). However, in some cases, other predisposing factors such as alcohol abuse were present. Moreover, it remains unclear whether the effect of olanzapine on the pancreas may be mediated through direct drug-induced injury as in the liver, or whether it represents the consequence of global metabolic changes, in particular triglyceride elevation (12).

Although the exact mechanism of causation of hyperlipidemia by olanzapine is unknown, the disruption of hypothalamic regulation of serum glucose levels, potent anticholinergic activity, 5-HT2C antagonism, hyperprolactinemia and leptin resistance may be involved in the pathogenesis. In our patient, the presence of the 759C/T polymorphism of HTR2C gene possibly underlines a genetic predisposition to the adverse metabolic effects of olanzapine. Specifically, the 759C/T HTR2C genetic polymorphism and in particular lower frequency of the T variant has been associated with abnormalities of fasting levels of glucose, total cholesterol, low-density lipoprotein and triglycerides in blood, although there are contradictory results in association studies (13-15).

In conclusion, we hypothesize that the aforementioned polymorphism may have led to susceptibility to extreme triglyceride elevation following olanzapine treatment and consequent pancreatic injury. Clinicians need to be alert and improve screening in order to reduce drug-induced complications. In the future, genetic testing could contribute to better prescribing decisions.