At thirty-six years of age and gainfully employed, Lawrence was a devoted husband and parent. Though he called himself a social drinker, it was known that he would occasionally drink to excess.
One day, all of a sudden, he developed upper abdominal and chest pain. He was brought to the emergency room in severe agony and near-collapse; the doctors initially suspected a heart attack. He was soon diagnosed to have acute pancreatitis, an insufferably painful condition that can get serious in some cases, even threatening life in a few.
Lawrence was fortunate: he survived the attack and was discharged home after a week. Some others with the same diagnosis do not get so lucky; they go on to develop complications that are difficult, expensive and sometimes futile to treat.
In Lawrence’s case, the acute pancreatitis was from alcohol use. He was advised to give up alcohol, and has remained well since.
This article is written to introduce the pancreas, an organ like no other in the body—it behaves unpredictably, it is capable of destroying itself, and its diseases are known to challenge and defy even the finest medical care. In this context, the latter part of the article discusses the changing paradigms of disease and health.
Where is the pancreas located?
The pancreas is a carrot-shaped gland that sits behind the stomach. The part of the gland that helps with digestion is called exocrine pancreas, and constitutes the bulk of the organ.
The food that we eat contains carbohydrates, proteins and fat, each of which needs to be broken down into smaller fragments in order to get absorbed by our intestine. While the stomach is an efficient mixing bowl, it is really the pancreas that holds the key to our digestion.
The exocrine pancreas, being a gland, contains secretory acinar cells that are arranged in tightly bound clusters. The secretions are collected by tiny tubes which collectively drain into the small intestine through the main pancreatic duct. These secretions contain powerful digestive enzymes capable of breaking down the various components of the food mixture served by the stomach into the intestine.
The endocrine part of the pancreas, as the name suggests, manufactures hormones such as insulin and glucagon, based on the body’s constantly changing needs. These are released directly into the blood stream so that they can act at distant sites.
How does the pancreas respond to a meal?
Pancreatic acinar cells manufacture several digestive enzymes, that get packaged into zymogen granules. After a meal is consumed, these zymogen granules fuse with the cell membrane at the top of the acinar cell by a process called exocytosis, releasing the inactive enzymes into the pancreatic duct. They get switched on only upon entry into the intestine.
The activation process involves a change in the molecular structure of the enzyme, and has been likened to pulling the pin from a grenade.
The key player is trypsin, a protein-digesting enzyme, which is produced and stored within the pancreatic acinar cells in its inactive form trypsinogen. It gets activated to trypsin only after reaching the intestine. This trypsin in turn activates other pancreatic proenzymes as they arrive in the intestine. Once all the enzymes are turned on, they go to work on the food components, breaking them down to facilitate absorption.
How does the pancreas protect itself from being digested?
This is a most important question. If the enzymes manufactured by the pancreatic acinar cells are capable of digesting almost everything of biological origin, then how is it that the pancreas itself escapes being digested?
The main protection comes from safe packaging of pancreatic enzymes into zymogen granules located inside the acinar cells. Not only is the packaging tamperproof, but for extra protection, the enzymes are stored in their inactive form, also called proenzymes.
In addition, these packages contain specialised enzyme inhibitors that would swiftly pounce upon any prematurely activated trypsin and destroy it before it can cause large scale damage to the pancreas.
These inhibitors, which include SPINK (serum protease inhibitory kinase), essentially function like small hand-held fire extinguishers that can put out minor fires early—so that the whole building does not go up in flames each time there is a spark.
When these natural protective mechanisms are either overwhelmed or defective (due to errors in DNA, also known as genetic mutations), the person becomes vulnerable to pancreatitis. The SPINK-1 gene mutation for instance, has been linked to several forms of pancreatitis.
Pancreas: the body’s own fireworks storeroom
The pancreas can be compared to a store that sells fireworks. Even though each product on the store shelf is capable of catching fire and exploding, safe packaging and diligent handling prevents it from doing so. Explosions don’t happen until we bring the firecrackers home, open the packaging and light them using a candle. The carefully controlled process of lighting the firecracker at home can be compared to the activation of the proenzyme in the intestine.
Occasionally though, we do hear about accidents that happen in places that manufacture and store fireworks. Such accidents result in massive explosions with loss of human lives, and are often caused by someone carelessly smoking a cigarette within the premises.
The situation in the pancreas is eerily similar: all is well when the pancreas is healthy, safety mechanisms are in place and the drainage system is working smoothly. However, when there is an injury to the pancreas that overwhelms the inbuilt protective mechanism, the stored enzymes leak out and destroy pancreatic tissue. This is acute pancreatitis.
Just as the spark that fell out of Thomas Farriner’s bakery eventually destroyed the city of London in the Great Fire of 1666, this process that starts in a single acinar cell in the pancreas can sometimes go on to destroy the whole gland and the surrounding areas. The resulting inflammatory response can unleash cytokines that travel to faraway places in the body, shutting down entire organ systems, sometimes even causing death.
What causes acute pancreatitis?
The majority of cases of acute pancreatitis are due to alcohol consumption, while a sizeable number are the result of gallstones that block the pancreatic duct. A few cases occur from infection, calcium imbalance, trauma, drugs, genetic and immune disorders, while a good number remain of unknown cause.
The symptoms are severe abdominal pain, vomiting and collapse. What makes acute pancreatitis scary is that once it sets in, it runs its own course, and there is very little that doctors can do to limit the damage. Some patients get away with just a few days of pain, while others stay for a longer time in hospital. A smaller number end up in the ICU battling for their lives, one or more of their organ systems having shut down. Patients with more than one organ system failure are at greater risk of dying. Examples of affected organ systems include the lungs, cardiovascular system and kidneys.
Can acute pancreatitis be treated?
Much like the case of the fireworks store that caught fire, there is little that medical treatment can do to reverse the process once started. As the leaked enzymes destroy pancreatic tissue, more enzymes get released, attracting stronger inflammatory response, thus creating a vicious cycle.
Unfortunately, in spite of decades of medical research that generated hundreds of published trials, there is still no approved medication that can stop acute pancreatitis in its tracks, let alone reverse the damage.
Over the years, most of the improvements in outcomes of these patients were achieved through indirect means—specifically, better ICU care and nutrition, updated and standardised support protocols for failed organ systems, and effective endoscopic and surgical intervention in a few select cases.
What is chronic pancreatitis?
When pancreatic injury occurs over an extended period of time, it is called chronic pancreatitis, a painful condition where the patient can lose weight from impaired food absorption. People with this condition are at increased risk for pancreatic cancer. Those who drink and smoke heavily are a lot more likely to develop chronic pancreatitis. Non-alcoholic forms of chronic pancreatitis have also been described, including tropical pancreatitis, a condition reported from Kerala from the 1960’s and studied widely since.
What should be done about gallstones?
Gallstones are a cause of acute pancreatitis, but fortunately the lifetime risk of a given patient with silent gallstones developing pancreatitis is quite small. Those who have had gallstone-induced pancreatitis should have their gall bladders removed to prevent future attacks.
Why don’t all people who drink get pancreatitis? Is there a genetic component?
Though alcohol use remains the major cause of pancreatitis, not everyone who drinks will get it. The fact that nine out of ten people who drink heavily will not develop pancreatitis might seem like a paradox. Besides, for a logical layperson, it can be hard to comprehend why pancreatitis would sometimes occur even in the absence of conventional risk factors.
This calls to our attention the basic biology of disease. Conventional thinking about health and illness is largely unidimensional. Just as there is a key for every lock, many people still believe that for every disease there has to be a single cause. This simplistic approach dates back to the Koch’s postulates of the 19th century—these were used to prove whether a disease was caused by an infective agent. For example, in the case of cholera, if the vibrio bacterium caused disease after being introduced into a healthy person’s stomach, it was proof of causality.
Although applicable to infectious diseases such as typhoid or single-gene related conditions like sickle-cell anaemia, such simplistic theories do not hold true for most present-day illnesses known to man whether it is pancreatitis, diabetes, cancer or heart disease.
Many of these diseases are complex or multifactorial disorders, with genetics, lifestyle, immunity and environmental factors, both known and unknown—playing a part. Individually, each of these factors could be harmless, but when thrown into the overall mix, health outcomes can be diverse. Unlike polio or malaria, no single causative agent can be found in these instances—which makes prediction, prevention and treatment cumbersome.
For instance, five genetic mutations: SPINK 1, PRSS-1, CTRC, CASR and CFTR, have been identified that increase a person’s chance of developing pancreatitis, especially of the chronic variety. The role of environmental factors such as smoking and alcohol has also been well-established in population studies. But what is yet not clear is exactly how each of these players interact with each other in causing disease in a given individual.
The role of genes in health and disease is becoming clearer with continued research. Even in the everyday functioning of the pancreas, genes play a sizeable role. For instance, the pancreas can sense the body’s requirement of protein-digesting enzymes, based on the food habits of the person. If the person consumes predominantly a protein-based diet, the secretions will contain mostly proteases, while those who enjoy a carbohydrate-rich diet will put out more amylase in their pancreatic juice.
Just as a restaurant’s kitchen prepares food based on the order placed by customers at that time, the pancreas is able to churn out customised cocktails of digestive juices based on the body’s changing needs. The production of each enzyme is controlled by a gene, which can be switched on and off by intricate signalling mechanisms.
Diseases of the pancreas remain incompletely understood, though not for lack of trying. While much has become known about its structure and function, when it comes to medical treatment, the pancreas still reigns undefeated among all the organs in the body. Many of its ailments are of serious nature, and advances in treatment have lagged behind the progress achieved in other areas.
What does the future hold?
Moving forward from the simplistic paradigms of the past century, the future of healthcare could be one of personalised medicine where illnesses can be predicted and prevented using modelling and simulation.
Present-day healthcare commonly involves applying average values derived from large populations to single individuals. For instance, it is known that the average incidence of acute pancreatitis is four times greater in a group of drinkers when compared to a group of non-drinkers. But this observation is of limited value to a single individual who would simply like to know whether he will develop pancreatitis or not.
An individual is fundamentally different from a population, and every person has a unique set of risk factors, environment, gene set, immune system, outlook and lifestyle—each of which can influence the course of disease.
Next generation sequencing will help identify genetic predictors of disease. Using computers capable of storing and analysing massive amounts of data on all of these parameters, it will become possible to prescribe precise preventive and curative health strategies that apply to each individual. This will be a better alternative to guessing based on the average of populations.
In summary, the pancreas has important digestive and hormonal functions. The powerful enzymes that are produced and stored by the pancreas puts it at inherent risk of self-harm from acute pancreatitis, a serious illness that can lead to multi-organ failure and death. Definitive treatment for acute pancreatitis is yet to be discovered, although overall standards of care have improved. Gallstones and alcohol use are the main causes of acute pancreatitis. The combination of smoking and drinking greatly increases the risk of chronic pancreatitis. Gene mutations also play a role. To prevent pancreatitis, avoiding all modifiable risk factors is important, especially for those who have already suffered a bout.
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(The author is a senior consultant gastroenterologist and deputy medical director, Sunrise group of hospitals)
Disclaimer: All the images used in the column are arranged by the author
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