9.5 — The Pancreas and Gallbladder

The pancreas manufactures enzymes powerful enough to digest an entire steak, and it stores them a few centimetres from its own protein-rich tissue. It survives that arrangement because of a series of precautions stacked on top of one another, and acute pancreatitis is what happens when they fail simultaneously.

The gallbladder, by contrast, does something conceptually simple — it stores and concentrates a fluid — and manages to be the source of one of the commonest surgical operations in the world.

The pancreas

A soft, pale, elongated gland about 15 centimetres long, weighing 80 to 100 grams, lying across the back of the abdomen behind the stomach.

It is retroperitoneal (Chapter 4.1), lying against the back wall rather than hanging free.

That position has two consequences. Pancreatic pain characteristically radiates through to the back, because the inflamed gland is against the posterior structures — and leaning forward eases it by taking the pressure off. And the pancreas is deep and hard to examine or image, which is a large part of why pancreatic cancer is diagnosed so late.

Four parts: the head, tucked into the C-shaped curve of the duodenum; the neck; the body, crossing the spine; and the tail, reaching to the spleen.

Two organs in one gland, from different tissue, doing unrelated jobs.

The exocrine pancreas — about 98 percent of the tissue — makes digestive enzymes and delivers them by duct into the duodenum (Chapter 9.3).

The endocrine pancreas — about 2 percent — is the islets of Langerhans, about a million small clusters scattered through the gland, making insulin, glucagon and other hormones and releasing them into the blood (Chapter 12.5).

They are anatomically intertwined and functionally independent, which is why chronic damage eventually causes both malabsorption and diabetes.

The duct system

The main pancreatic duct runs the length of the gland, collecting from side branches, and joins the common bile duct just before entering the duodenum. The two share a final short channel — the ampulla — guarded by a ring of muscle, the sphincter of Oddi.

That shared channel is the single most consequential piece of anatomy in this chapter.

A gallstone lodging in the ampulla blocks both ducts at once. Bile cannot drain, causing jaundice. Pancreatic secretion cannot drain, causing pancreatitis. One stone, two organs, and this is why gallstones are the leading cause of acute pancreatitis.

About 5 to 10 percent of people have an anatomical variant — pancreas divisum — in which the two embryonic pancreatic buds fail to fuse their ducts (Chapter 4.5), so most of the gland drains through a smaller accessory opening. Usually harmless, occasionally a cause of recurrent pancreatitis.

How the pancreas protects itself

Four defences, and all four are needed.

1. Enzymes are made and stored inactive. Trypsinogen, chymotrypsinogen, proelastase and procarboxypeptidase are all precursors. Only amylase and lipase are secreted in active form, and neither digests pancreatic tissue.

2. Activation happens outside the gland. Trypsinogen is activated by enterokinase, an enzyme fixed to the duodenal brush border. It exists nowhere else, so activation cannot happen upstream.

3. A trypsin inhibitor is packaged alongside the enzymes, ready to neutralise any trypsin that activates prematurely.

4. The enzymes are stored inside membrane-bound granules, separated from the cell's own contents.

Acute pancreatitis begins when trypsin is activated inside the gland. Trypsin then activates everything else — including more trypsinogen (Chapter 9.2) — and the cascade runs.

The gland digests itself, and the released enzymes and inflammatory mediators enter the bloodstream, which is why severe pancreatitis is a whole-body illness rather than a local one. Lipase released into the abdomen digests surrounding fat, and the fatty acids released bind calcium — which is why blood calcium falls in severe cases and why a low calcium is a marker of severity.

Causes, and the traditional mnemonic covers them: I GET SMASHED — Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune, Scorpion sting, Hypercalcaemia and Hypertriglyceridaemia, ERCP, Drugs.

In practice, gallstones and alcohol account for about 80 percent, and it is worth knowing that severely raised triglycerides — above about 10 mmol/L — is a real and under-recognised cause, and one that is treatable and preventable.

Presentation: severe constant upper abdominal pain radiating to the back, vomiting, and a person who leans forward for relief. Serum lipase is the preferred test, being more specific and staying raised longer than amylase.

Around 80 percent of cases are mild and settle within a week with fluids, pain relief and treatment of the cause.

Management has changed in two ways worth knowing, because both reversed long-standing practice. Aggressive early fluid resuscitation is the single most important intervention — the inflamed pancreas leaks enormous volumes into the tissues. And early feeding, by mouth or by tube, produces better outcomes than the traditional "rest the pancreas" starvation, because keeping the gut lining nourished prevents bacteria translocating from the bowel.

Chronic pancreatitis is repeated or continuous inflammation causing permanent destruction and scarring. Alcohol is the commonest cause.

Three consequences appear in order: chronic pain, then exocrine failure with steatorrhoea and weight loss once about 90 percent of function is lost, then diabetes as the islets are destroyed.

Pancreatic enzyme replacement therapy works well and is under-prescribed. The capsules must be taken with every meal and snack, in adequate dose, and with acid suppression — because the enzymes are destroyed by stomach acid and the damaged pancreas no longer secretes enough bicarbonate to neutralise it. Getting the dose and timing right transforms these patients' weight and quality of life, and it is a common area where treatment is technically available but poorly delivered.

Pancreatic cancer is the one genuinely difficult condition in this chapter, and the reason is anatomical rather than biological. The gland is deep, symptoms are vague until late, and there is no useful screening test.

The one presentation that is caught relatively early is a tumour in the head of the gland, because it compresses the bile duct and causes painless jaundice — which is exactly why that symptom triggers urgent investigation.

Risk factors that are modifiable are worth stating, because they are the practical lever: smoking roughly doubles the risk and accounts for about a quarter of cases, and obesity and chronic pancreatitis contribute. New-onset diabetes in an older person without other risk factors, particularly with weight loss, occasionally heralds it and is worth taking seriously.

Bile: made, used, recycled

The liver produces 600 to 1,000 ml of bile a day (Chapter 9.4).

Composition: bile salts (the working component), phospholipids, cholesterol, bilirubin (the waste pigment), and bicarbonate-rich fluid.

Bile salts are made from cholesterol in a multi-step pathway, and this is the body's principal route for eliminating cholesterol. About 500 mg of cholesterol is converted to bile salts every day.

And that fact is a drug target. Bile acid sequestrants — resins that bind bile salts in the gut so they cannot be reabsorbed — force the liver to make more from cholesterol, lowering blood cholesterol. They were among the first cholesterol-lowering drugs, and they are still used in specific situations, particularly for the itching of obstructive jaundice and for bile salt diarrhoea.

The enterohepatic circulation

The bile salt pool is only about 3 to 4 grams, but 20 to 30 grams are secreted per day.

The difference is recycling. About 95 percent of bile salts are reabsorbed in the terminal ileum, returned to the liver in the portal vein, and re-secreted. The pool goes round 6 to 10 times a day.

This is efficient and it creates a specific vulnerability. Disease or removal of the terminal ileum breaks the recycling (Chapter 9.3). Two things then happen: the liver cannot keep up, so fat digestion suffers; and the unabsorbed bile salts reach the colon, where they stimulate water secretion and cause bile acid diarrhoea — watery, often urgent, and characteristically responsive to a bile-binding resin.

Bile acid diarrhoea is substantially underdiagnosed, and many people labelled with diarrhoea-predominant irritable bowel syndrome in fact have it. It is worth knowing because the treatment is simple and effective.

The gallbladder

A pear-shaped sac 7 to 10 centimetres long holding 30 to 50 ml, tucked under the liver's edge.

It concentrates bile five to tenfold by actively absorbing sodium, with water following.

Emptying is triggered by cholecystokinin, released by the duodenum in response to fat and protein. The gallbladder contracts and the sphincter of Oddi relaxes.

About a third of the bile pool empties within 30 minutes of a fatty meal.

Gallstone formation requires three things together: bile supersaturated with cholesterol, a nucleus to start crystallisation, and reduced gallbladder emptying so crystals have time to grow.

This is why rapid weight loss causes gallstones — a fact that surprises people. Rapid fat breakdown floods the bile with cholesterol while reduced food intake means the gallbladder empties less often. Around 25 percent of people losing weight very rapidly, including after bariatric surgery, develop stones.

And it is why prolonged fasting and intravenous nutrition cause gallbladder sludge and stones — no fat entering the duodenum means no cholecystokinin, means no emptying.

Pigment stones — black or brown, made of bilirubin — form in chronic haemolysis. This is why people with sickle cell disease and hereditary spherocytosis develop gallstones young (Chapter 2.8).

Cholecystectomy — removal of the gallbladder — is one of the commonest operations performed, now almost always laparoscopically, with a hospital stay of a day or less.

And the honest point about it is that it treats the symptoms, not the tendency. The liver still makes the same supersaturated bile; there is simply no longer a reservoir for stones to form and lodge in. Stones can still form in the ducts afterwards, though this is uncommon.

The surgical hazard is the bile duct. Injuring the common bile duct during gallbladder removal is uncommon — under 0.5 percent — and serious, because a leak causes bile peritonitis and a stricture causes lifelong problems. This is why the operation includes a formal step of identifying the anatomy definitively before anything is divided, and why an unclear view is a reason to convert to open surgery rather than to continue.

ERCP — endoscopic retrograde cholangiopancreatography — passes an endoscope to the duodenum, cannulates the ampulla, and allows stones to be removed from the bile duct and stents to be placed. It is both diagnostic and therapeutic, and its main complication is pancreatitis, in about 3 to 5 percent, which is exactly the mechanism described above: instrumenting the shared channel.

What the next page fixes

What is left after the small intestine has taken everything useful enters a 1.5 metre tube containing about 100 trillion bacteria. Chapter 9.6 covers the large intestine and the microbiome — what those bacteria do for you, what happens when they are disturbed, and how much of what is claimed about them is actually established.