24th July 2023

Pancreatico-biliary pathology

Diseases of the pancreas

The pancreas is a large organ of the abdominal cavity and is located behind the stomach. It consists of a head, neck, body and tail; the head is located at the inner curvature of the duodenum, and the tail ends adjacent to the spleen.

It has crucial endocrine and exocrine functions – the exocrine function relating to glucose metabolism and the exocrine function to the digestive tract. The focus of this section is predominantly on structural diseases or those with a direct effect on the organ itself. As such, diabetes mellitus is not covered. Further discussion of pancreatic exocrine insufficiency can be found in the Nutrition topic.

Acute pancreatitis 

Acute inflammation of the pancreas. A relatively common disease and one which carries a high mortality risk.

Causes

Gallstones and alcohol excess are the 2 most common causes, accounting for the vast majority of cases. The causes can be summarised by the “I GET SMASHED” mnemonic:

• Idiopathic
• Gallstones
• Ethanol
• Trauma
• Scorpion stings and spider bites
• Mumps or malignancy
• Autoimmune
• Steroids
• Hypertriglyceridaemia and hypercalcaemia
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Drugs

Clinical features

Acute pancreatitis classically presents with sudden onset epigastric pain, which may radiate to the back. The pain may also be more generalised. The pain is often associated with nausea, vomiting, and haemodynamic instability. Patients are not typically jaundiced, acutely (unless associated with obstructive gallstones). Patients will often have a history of gallstones or alcohol excess, which are important risk factors to enquire about from the history.

Examination likely reveals tenderness and guarding in the epigastrium. Patients may be peritonitic. Important signs of haemorrhagic pancreatitis (a life-threatening complication) include Cullen’s sign (periumbilical bruising) and Grey-Turner’s sign (flank bruising).

Other complications include pseudocysts (usually around 4-6 weeks after onset of acute illness), pancreatic abscesses, fistulae, AKI, acute respiratory distress syndrome (ARDS), and disseminated intravascular coagulation (DIC).

Assessment and diagnosis

Acute pancreatitis is a diagnosis that should be suspected clinically, and management started on that basis.

A raised serum amylase supports the diagnosis, and serum lipase is an even more sensitive marker. It is often associated with deranged LFTs. Imaging is not essential for diagnosis in the first instance, but an ultrasound scan (to demonstrate gallstones), CT, and MRI may be used to confirm – with a CT abdomen being considered the gold standard, as it can also assess for other causes of acute abdominal pain. If the cause is unknown, further modalities include magnetic resonance cholangiopancreatography (MRCP).

Classification of severity and risk stratification is important to guiding management. The APACHE II score and Glasgrow-Imrie criteria are two risk stratification tools in common usage.

Management

Management is supportive – including IV analgesia and IV fluids. An ABCDE approach should be initially taken for unstable patients. A nasogastric (NG) tube may also be indicated, as nutritional support. Once the cause is established, and the patient is stable, this should also be treated. Antibiotics are only indicated if there is evidence of an associated infection, rather than routinely.

There is a risk of rapid deterioration; patients with severe illness should be identified using the aforementioned risk tools, and ITU involved early if there is clinical concern.

If due to biliary disease, then ERCP may be used to relieve any obstruction. Surgical management may be indicated if there are complications, such as abscess formation, or necrosis. Patients with biliary causes should also have a cholecystectomy once the acute illness has stabilised.

Chronic pancreatitis 

Chronic pancreatitis refers to irreversible inflammation and/or fibrosis of the pancreas, which generally occurs as a consequence of recurrent acute pancreatitis. Repeated inflammation leads to fibrosis and calcification of the gland.

Clinically, it presents as episodic severe abdominal pain, associated with nausea and vomiting, such as in acute pancreatitis. An affected patient will have a background of previous pancreatitis. The causes are therefore the same as for acute pancreatitis; although most commonly it is patients with a history of alcohol excess who are most at risk of chronic pancreatitis, and it is generally associated with a failure to reduce alcohol intake.

Assessment and diagnosis are similar to acute pancreatitis – and it should be suspected in any patient with a background of the former. CT and MRI can be used to demonstrate the extent of fibrosis and any calcification.

Complications include pancreatitis endocrine insufficiency, and exocrine sufficiency due to the direct damage to islets of Langerhans and acinar cells, respectively. This can therefore lead to diabetes mellitus and malabsorption. Patients with chronic pancreatitis, therefore, may be malnourished.

Management is supportive, including analgesia for episodic flare ups, nutritional support, management of complications, and screening for the aforementioned complications. Patients are also at an increased risk of pancreatic cancer. Simple analgesia should be first started, i.e. paracetamol and NSAIDs, and then escalated to weak and strong opioids, as appropriate.

Crucial is risk reduction, such as alcohol and smoking cessation, and medical management of hypercalcaemia and hypertriglyceridemia.

Pancreatic cancer

Pancreatic cancer is a relatively common malignancy, being in the top 10 for both women and men. It is associated with a poor prognosis – with the 5-year survival rate being as low as 10%. Pancreatic cancers can be highly aggressive and debilitating, meaning prompt diagnosis is essential to improving survival – as it generally presents late, with advanced disease. Approximately 90% are adenocarcinomas arising from the digestive acinar cells, with the rest being non-adenocarcinomas of this cell origin, and a small minority being neuroendocrine tumours, which are associated with a better prognosis.

Causes and risk factors

Demographic risk factors include age (with the 60s being the most common decade of onset), male gender, and Afro-Caribbean ethnicity. The biggest modifiable risk factor for pancreatic cancer is smoking, with obesity and alcohol excess further lifestyle factors.

Pancreatic cancer is also associated with a positive family history, and conditions such as diabetes also increase risk. Pancreatitis is an important risk factor, especially chronic pancreatitis and hereditary pancreatitis.

Clinical features

The most common presenting feature is unexplained weight loss. Tumours at the head of the pancreas are associated with obstructive features – such as jaundice, pale stools, and dark urine – as well as pain and anorexia. Tumours of the body and tail are also associated with pain.

Pain is not necessarily a symptom, however, and hence an important maxim in medicine is that painless jaundice should be treated as suspected cancer until proven otherwise.

Assessment and diagnosis

The diagnostic investigation of choice is a CT scan. If the diagnosis is unclear, PET and endoscopic-guided ultrasound (EUS) scans can be used as further modalities. EUS is also used to obtain histological samples.

If there are features of obstruction, then an ERCP should be done to drain the bile duct.

CT of the chest, abdomen and pelvis, and PET scans, are also used for staging. If there is a suspicion of liver metastases, then an MRI should be performed.

Management

The 2 focuses of management are anti-cancer treatment and supportive care.

Analgesia and nutritional support are key. Although not necessarily a presenting feature for most patients, many will progress to experience severe and debilitating pain, which may require specialist palliative care and pain team input. Strong opioids are often indicated, and a coeliac plexus block is amongst the NICE recommendations for uncontrolled pain. Many individuals will suffer exocrine insufficiency and subsequent malnutrition – artificial feeding may be required, and pancreatic enzyme replacement.

Surgery is the first line treatment for those with resectable disease, with subsequent adjuvant chemotherapy or radiotherapy. Only around 20% of tumours are resectable. For non-resectable disease, there is also a role for palliative chemotherapy, which is the first line treatment for those able to tolerate it.

Obstruction should be relieved with either surgery or ERCP, and biliary stenting may also be indicated.

As mentioned, prognosis is poor, and many cancers are often very advanced at the time of presentation. Therefore, palliative care input is often early on and may lead the patient’s care.

Insulinomas 

Insulinomas are a rare form of pancreatic tumour, deriving from the beta cells of the islets of Langerhans in the pancreas. They are a type of neuroendocrine tumour and are generally benign, although a very small percentage may metastasise.

They are important to be aware of as a cause of hypoglycaemia, especially if severe, refractory, and unrelated to concomitant diabetes mellitus. Common symptoms are those of hypoglycaemia, i.e. sweating, tremor, presyncope and palpitations. More seriously, they can also cause neurological symptoms, such as confusion, behaviour and personality changes, visual disturbances, seizure, and coma.

Diagnosis should be suspected in any patient with symptomatic ‘true’ hypoglycaemia, which is defined by Whipple’s triad as:

• Signs and symptoms of hypoglycaemia
• Blood glucose level of less than or equal to 2.5 mmol/L
• Reversibility of symptoms with glucose administration

A full hypogylcaemia panel should then be done, including glucose, insulin and C-peptide levels. C-peptide is associated with endogenous insulin and hence will be elevated in cases of insulinoma. The prolonged fasting test is often diagnostic. Normally, endogenous insulin is suppressed in hypoglycaemia; if a patient has an insulinoma, then a 72-hour fast will fail to suppress insulin levels. CT and MRI can then be done to localise the site of the tumour.

The first line treatment for resectable tumours is surgery – which often includes removal of part of the pancreas – and the majority of insulinomas may be cured this way. Non-resectable tumours can be managed with the somatostatin analogue octreotide, which works by inhibiting insulin secretion.

Diseases of the gallbladder and biliary tree

The gallbladder is a storage and secretory organ found on the underside of the liver, in the fissure between the right and left hepatic lobes. Its primary function is to store and concentrate bile, which is used to digest fats. Bile is produced by the liver and flows through the hepatic ducts into the cystic duct (collectively known as the biliary tree) and then into the gallbladder.

The secretion of cholecystokinin (CCK) from I cells of the duodenum and jejunum stimulates the gallbladder to contract, and release bile into the common bile duct, where it enters the digestive tract via the duodenum.

As well as used in the digestion of fats, bile is also used to eliminate bilirubin from the body, as part of haemoglobin metabolism.

There are numerous pathologies related to the gallbladder and biliary tree, the most important of which for the MRCP Part 1 examination are discussed below.

Gallstones

Also referred to as cholelithiasis, gallstones are a very common pathology. They consist of concentrated deposits of bile – with cholesterol being the main component – and can cause a spectrum of disease. Many people have gallstones incidentally, which remain present in the gallbladder without causing any symptoms. If gallstones migrate, they can cause obstruction of the biliary tree, and thus become symptomatic.

Causes and risk factors

Gallstones are associated with various demographic and lifestyle risk factors. Middle age, female sex and pregnancy, obesity, and family history are among the most important. A medical maxim for patients most at risk of gallstones is the ‘four Fs’ – “fat, female, fertile and forty”.

Clinical features

As mentioned, most people who have gallstones are asymptomatic. Migration of gallstones into the ducts leads to ‘attacks’ known as biliary colic. These present with acute abdominal pain, generally in the right upper quadrant or epigastrium, which may be associated with nausea and vomiting, lasting for several hours at a time. Pain may be referred to the right shoulder. Attacks are typically after eating meals; the gallbladder contracts as part of the digestive process, leading to stones becoming dislodged.

If biliary obstruction occurs as a result of gallstones, then patients may also present with jaundice and pruritus, and a cholestatic picture (elevated ALP/GGT) on LFTs.

Gallstones can also lead to acute cholecystitis and cholangitis (see below).

Assessment and diagnosis

Ultrasound scan is the diagnostic investigation of choice, which will demonstrate the presence of gallstones in the biliary tree, and can also be used to demonstrate duct obstruction and dilation.

Management

Management depends on the extent of disease and whether the patient is symptomatic.

Most people with asymptomatic gallstones are managed conservatively – lifestyle advice is the first line measure, such as weight loss and a low-fat diet.

If gallstones are symptomatic, then cholecystectomy should be offered – this can be done electively in most cases but may need to be done as emergency management if a patient has acute severe pain or presents with complications.

Acute cholecystitis 

Acute inflammation of the gallbladder, which most commonly occurs as a complication of gallstones. Rare causes include chemotherapy and vasculitis.

Clinical features

Presents with acute right upper quadrant pain, which is typically more severe and more constant than the biliary colic of gallstones. Often associated with nausea, vomiting, and unlike gallstones is more likely to be associated with systemic upset, such as fever and rigors. Jaundice is not commonly associated.

A positive Murphy’s sign is a characteristic examination finding (severe pain on palpation of right upper quadrant during inspiration) and indicates inflammation of the gallbladder.

Assessment and diagnosis

Ultrasound is the diagnostic test of choice. Typical findings include pericholecystic fluid (fluid around the gallbladder), a distended gallbladder, oedematous gallbladder wall, and gallstones). Blood tests may be normal or show mild elevation of WCC, CRP, bilirubin and AST/ALT.

Management

Immediate management includes analgesia and IV fluids. Many patients will settle with conservative treatment, and cholecystectomy should be subsequently planned electively as definitive management.

If there are signs of superimposed infection, then broad spectrum IV antibiotics (i.e. cefuroxime and metronidazole) should be given.

Emergency cholecystectomy may be indicated if there are complications, such as generalised peritonitis (suggesting perforation), or gangrene of the gallbladder. If surgery needs to be done acutely, then a laparoscopic method is preferred due to lower complication rates – elective surgery tends to be open.

Acute cholangitis 

Also known as ascending cholangitis, this refers to infection of the biliary tree. If untreated, it can lead to biliary sepsis, which carries a significant mortality risk. Cholangitis is, therefore, a medical emergency.

Causes and risk factors

Cholangitis occurs in the context of biliary obstruction; hence, the vast majority of cases are due to gallstones. Other causes of obstruction (and therefore cholangitis) include biliary strictures, pancreatic cancer, primary sclerosing cholangitis, and amyloidosis.

Therefore, for the majority, the risk factors are the same as for gallstones.

Clinical features

Cholangitis is characterised by Charcot’s triad of abdominal pain, jaundice and fever. The pain is constant, severe, and generally localises to the right upper quadrant. Patients may become hypotensive, and there is a risk of sepsis. Confusion may also develop as the disease progresses.

The presence of jaundice is a key distinguishing feature from biliary colic and cholecystitis, in which it is more rare.

Assessment and diagnosis

Blood tests will show raised inflammatory markers and elevated cholestatic LFTs. Ultrasound scan is generally the first line imaging investigation, but ERCP is the gold standard diagnostic test. MRCP and endoscopic-guided ultrasound (EUS) are also highly sensitive.

Management

An ABCDE approach should be taken, with the first focus on resuscitation with IV fluids, and then pain control. IV antibiotics (generally cefuroxime and metronidazole) are the first line treatment for the infection.

Therapeutic drainage of the bile duct should be done once the patient is stabilised, with ERCP (which can also be used to confirm diagnosis). Surgical drainage should only be done if ERCP is contraindicated or unsuccessful (i.e. the patient is too unstable, existing bowel perforation).

Cholangiocarcinoma

Cancer of the bile duct, which may be intrahepatic, extrahepatic, or perihilar (Klatskin tumours), depending on the exact location within the duct in relation to the liver. Histologically, these tumours are adenocarcinomas. Generally advanced at presentation and therefore associated with a poor prognosis – early diagnosis is key. Median survival is around 6 months for those with metastatic disease.

Causes and risk factors

Cholangiocarcinoma are often idiopathic, and there are few identified risk factors. There is some association with chronic parasitic infections (particularly liver flukes), and Asian ethnicity, the latter of which may be due to an increased prevalence of parasitic infections in these countries.

Primary sclerosing cholangitis (see below) has a key causal link, and individuals with this condition should have close surveillance for the development of cholangiocarcinoma.

Clinical features

Signs and symptoms do not typically present until disease is advanced, which is why diagnosis is often late. The characteristic features are jaundice, pruritus, weight loss, anorexia, pale stools, and dark urine. Abdominal pain may be present but is often absent; painless jaundice is, therefore, a major red flag feature, which often distinguishes cholangiocarcinoma from disease relating to gallstones.

Assessment and diagnosis

LFTs will show a cholestatic picture (elevated ALP/GGT/bilirubin) and are often grossly deranged.

Ultrasound is often the first imaging done, as it is non-invasive and easy to arrange, and can rule out other causes. ERCP is the preferred diagnostic investigation, as it can directly demonstrate the tumour and be used to obtain histological samples. CT is also done for diagnostic and staging purposes.

Management

Surgery is the only curative treatment, but many cholangiocarcinomas are inoperable. Radiotherapy and chemotherapy are used both adjuvantly with surgery and palliatively for unresectable disease.

Primary biliary cholangitis (PBC)

Also known as primary biliary cirrhosis, PBC is an autoimmune condition which affects the bile ducts. It is also covered in greater detail in the Hepatic Pathology topic. Destruction of the epithelial cells of intrahepatic bile ducts and inflammation of the portal tract leads to progressive damage to the liver and biliary tree, which generally results in chronic, and then end-stage liver disease.

It is vastly more common in women than men, the most common age of onset is middle age, and it is associated with a spectrum of autoimmune diseases, especially Hashimoto’s thyroiditis, Sjogren’s syndrome and coeliac disease.

It most commonly presents with pruritus and fatigue, but many people are asymptomatic, with the condition diagnosed following investigation of incidental abnormal LFTs. As the disease progresses, it will manifest with the signs and symptoms of chronic liver disease and cirrhosis.

Typically, LFTs give a picture of elevated cholestatic markers (ALP/GGT). Antimitochondrial antibodies (AMA) or PBC-specific antinuclear antibodies (ANA) are further diagnostic indicators. Liver biopsy can be used to diagnose PBC, but as the serological markers are so accurate, biopsy and histology are generally not required for diagnosis.

Ursodeoxycholic acid is the first line treatment and aims to prevent disease progression. Cholestyramine is used for symptomatic relief of pruritus. Rifampicin or naltrexone can be used as second line agents.

Long term monitoring of the development of cirrhosis, and subsequent management, is also key.

Primary sclerosing cholangitis (PSC)

PSC is an autoimmune disease characterised by inflammation of the medium and large-sized bile ducts, leading to strictures and progressive fibrosis. It is also covered in greater detail in the Hepatic Pathology topic.

There is a strong association with inflammatory bowel disease (IBD), particularly ulcerative colitis. Unlike most autoimmune diseases, it is more common in men than women.

PSC is commonly asymptomatic but may present with fatigue, pruritus and abdominal pain. In more advanced disease, patients may present with features in keeping with chronic liver disease.

LFTs typically demonstrate a cholestatic pattern (raised ALP and GGT). In more advanced disease, bilirubin will also be elevated. There are no diagnostic autoantibodies associated with PSC. The key diagnostic investigation is imaging – ultrasound is first line and can be used to exclude other causes of cholestasis. MRCP is the gold standard test, with the more invasive ERCP an alternative if diagnosis is still unclear. Typically, MRCP demonstrates a “beaded’’ appearance of the ducts, caused by multiple strictures. Liver biopsy is not generally required.

Cholestyramine is used for symptomatic management of pruritus, and balloon dilation of strictures can be used to target the disease process. If the disease progresses to end-stage liver disease, transplantation is the only option.

Complications include osteopenia, chronic liver disease, cirrhosis, and cholangiocarcinoma.