Chronic pancreatitis is persistent, chronic
inflammation of the pancreas often due to repeated bouts of acute pancreatitis. While a history of acute pancreatitis might
lead to chronic pancreatitis these diseases have distinct histopathologies. Acute pancreatitis is inflammation caused
by destruction of the pancreas by its own digestive enzymes—a process called autodigestion,
and is generally reversible. Chronic pancreatitis is inflammation due to
irreversible changes to the pancreatic structure, like fibrosis, atrophy and calcification. The pancreas is a long, skinny gland the length
of a dollar bill and is located in the upper abdomen, or the epigastric region, behind
the stomach. It plays endocrine roles—for example, alpha
and beta cells make hormones like insulin and glucagon that are secreted into the bloodstream,
but it also plays exocrine roles— for example, acinar cells make digestive enzymes that are
secreted into the duodenum to help digest food. These pancreatic digestive enzymes break down
macromolecules like carbohydrates, lipids and proteins found in food, but these macromolecules
are also found in the cells of the pancreas. To protect the pancreas, the acinar cells
manufacture inactive forms of the enzymes called proenzymes, or zymogens. These zymogens are normally activated by proteases
which cleave off a polypeptide chain, which is kind of like pulling the pin on a grenade. For additional security, the zymogens are
kept away from sensitive tissues in storage vesicles called zymogen granules, and are
packaged with protease inhibitors that prevent enzymes from doing damage if they become prematurely
active. To digest a meal, these zymogens are released
into the pancreatic duct, and delivered to the small intestine where they are activated
by the protease trypsin. Trypsin is a pancreatic digestive enzyme that
is produced as the zymogen trypsinogen. Normally, trypsinogen isn’t activated until
it is cleaved by protease enteropeptidase which is found in the duodenum. But if trypsinogen and these zymogens become
activated too early, then it can cause acute pancreatitis, and this might happen as a result
of any injury to the acinar cells, or anything that prevents the normal secretion of the
proenzymes into the duodenum. The two leading causes of acute pancreatitis
are alcohol abuse and gallstones. With alcohol abuse it goes like this: alcohol
increases zymogen secretion from acinar cells while decreasing fluid and bicarbonate production
from the ductal epithelial cells. As a result, the pancreatic juices become
really thick and viscous, potentially forming a plug that can block the duct. A blocked duct is bad news because pancreatic
juices start backing up, increasing the pressure, and leading to distention of the duct itself. At the cellular level, one consequence of
this is that membrane trafficking becomes chaotic. Zymogen granules might fuse with lysosomes
bringing trypsinogen into contact with lysosomal digestive enzymes. Trypsinogen might then be turned into activated
trypsin which begins the cascade of digestive enzyme activation and autodigestion of the
pancreas—which is acute pancreatitis. Alcohol also contributes to pancreatitis in
other ways, though, for example, stimulating acinar cells to release inflammatory cytokines
which attracts a strong immune reaction. Neutrophils arrive quickly at the scene, and
often release superoxide and their own proteases, which contribute to the problem. Finally, it’s thought that high consumption
and subsequent oxidative metabolism of alcohol may produce enough reactive oxygen species
to overwhelm cellular defenses and damage the cells. In addition to alcohol abuse, other known
causes of acute pancreatitis that frequently turn into chronic pancreatitis include tumors,
trauma to the pancreas, and cystic fibrosis. In fact, the term cystic fibrosis refers to
the pancreatic cysts and fibrosis that develop in patients with mutations in the CFTR gene. That gene encodes for an ion transporter,
and mutations in that transporter cause the pancreatic secretions to become thick and
sticky, leading to obstruction of the ducts. Importantly, cystic fibrosis is the main cause
of chronic pancreatitis in children. Repeated bouts of acute pancreatitis can progress
to chronic pancreatitis. With each bout there is potential for ductal
dilatation and damage to the pancreatic tissue. As part of the subsequent healing process
pancreatic stellate cells lay down fibrotic tissue which causes narrowing, or stenosis
of the ducts, as well as acinar cell atrophy. In addition, in certain conditions like alcoholic
acute pancreatitis calcium deposits of various sizes can accumulate on the plugs that form
in the ducts. This gradual process of healthy pancreatic
tissue getting replaced by misshaped ducts, fibrosis, and calcium deposits is chronic
pancreatitis. Early diagnosis of chronic pancreatitis is
challenging. People with chronic pancreatitis often have
continuous or intense intermittent abdominal pain in the epigastric region, that sometimes
radiates to the back. This pain may or may not be linked to eating
meals, and it tends to last for at least several hours. Even though elevated lipase and amylase levels
are suggestive of acute pancreatitis, in chronic pancreatitis there may not be enough healthy
pancreatic tissue to make those enzymes, so they may or may not be elevated. Often times, the diagnosis relies on imaging
studies that can identify the structural changes to the pancreas. For example, abdominal x-rays and CT-scans
might show calcification in the pancreas. The pancreatic ducts themselves can be visualized
with endoscopic retrograde cholangiopancreatography or ERCP, which is a technique where an endoscope
is passed down through the mouth, to the duodenum, where it is used to deliver contrast medium
to the pancreatic ducts. Subsequent fluoroscopy contrast studies can
reveal structural changes to the pancreatic ductal system. For example the duct may take on a chain-of-lakes
pattern due to alternating stenosis and dilation of the ducts. An alternative technique that can also evaluate
the pancreatic ductal systems is magnetic resonance cholangiopancreatography (MRCP). As the acinar cells become impaired they produce
fewer pancreatic digestive enzymes, which results in pancreatic insufficiency. These individuals can have trouble absorbing
foods and dietary fats, often lose weight, and even develop a deficiency in vitamins
A, D, E and K—which are fat soluble vitamins. Without digestive enzymes, fat might pass
right through the intestines undigested, leading to greasy and smelly stools—called steatorrhea. A long-term consequence of chronic pancreatitis
is the development of diabetes mellitus, which happens as the recurrent inflammation begins
to damage the alpha and beta cells of the pancreas. In addition, some individuals develop pancreatic
pseudocysts which in the context of chronic pancreatitis is often the result of ductal
obstruction, which increases pressure, induces leakage and results in accumulation of peripancreatic
fluid in fibrous granulation tissue either within or just outside of the pancreas. Not surprisingly, repeated inflammation can
also give rise to pancreatic cancer on rare occasions. Treatment of chronic pancreatitis involves
controlling pain and trying to control the risk factors—things like drinking less alcohol,
eating less meat, and reducing obesity. Individuals with pancreatic insufficiency
might require replacement digestive enzymes and nutritional supplements, and those with
diabetes might need insulin-replacement therapy. Alright as a quick recap, chronic pancreatitis
happens when irreversible changes to the pancreatic structure, such as fibrosis, atrophy and calcification
begin to decrease the functions of the organ. Eventually, this leads to pancreatic insufficiency,
which makes it difficult to digest food as well as the destruction of alpha and beta
cells, which makes it difficult to produce hormones like insulin.
