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Studies of the Mechanisms Causing Pancreatitis in Severe Hypertriglyceridemia

Bjorn Christophersen, Randi Sorby and Knut Nordstoga

Hypertriglyceridemia has been estimated to cause around 7% to 10% of the total number of cases of acute pancreatitis in man. The mechanisms involved in the progression of hypertriglyceridemia to pancreatitis are not well understood.
In this paper, we refer to different mechanisms proposed by previous authors to explain the pathogenesis. We discuss these theories in relation to our own experimental results. It has been difficult to verify previous theories because pancreas biopsies cannot easily be obtained in humans in the early, mild stages of acute pancreatitis. In patients with severe pancreatitis, the pancreas is typically grossly pathological. We have used an animal model with lipoproteinlipase deficiency. In these animals, severe hypertriglyceridemia can be induced by feeding a high-fat diet, which in turn induces the development of severe pancreatitis. By sacrificing animals at different times, it was possible with the use of light- and electron microscopy to monitor the development of acute pancreatitis from the earliest detectable changes to the most advanced, full-blown stages.
We found that the earliest detactable changes consisted of a selective degeneration of the mitochondria in the exocrine cells. At the same early stage the other intracellular structures, including the endoplasmatic reticulum, were well preserved. Mitochondria are known to be the major source of cellular free radicals liberated by the electron transport chain which may lead to oxidative stress. In normal cells antioxidant mechanisms such as vitamin E, glutathion peroxidase and others will neutralize free radicals and thus prevent oxidative stress. Our finding of an initial mitochondrial degeneration, probably caused by free fatty acids deranging the mitochondial function, support the view that antioxidants may have a role in the prevention of recurrent hypertriglyceridemia-induced pancreatitis.