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Home , Duodenal bulb, Duodenojejunal flexure, Duodenum, Ileum, Jejunum, Large intestine

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Clinical Practice Keywords /// Alkaline/Enzymatic Systems of life This article has been GI tract double-blind peer reviewed In this article... ● Role of and within the ● Role of liver and pancreas as accessory organs of the digestive system ● Common conditions affecting the duodenum, liver and pancreas

Gastrointestinal tract 3: the duodenum, liver and pancreas

Key points Authors John Knight is associate professor in biomedical science; Nikki Williams is The duodenum is associate professor in respiratory physiology; Yamni Nigam is professor in biomedical the first segment of science; all at the College of Health and Sciences, Swansea University. the ; the liver and Abstract After its passage through the , ingested food turned into acidic pancreas are the arrives in the first segment of the small intestine, a U-shaped tube called the two major accessory duodenum. The duodenum produces hormones and receives secretions from the organs of the liver (bile) and pancreas ( containing digestive enzymes). These various hormones, fluids and enzymes facilitate chemical digestion in the duodenum The major role of while also ensuring the acidity of chyme coming from the stomach is neutralised. This the duodenum is as is crucial to avoid autodigestion and corrosive damage to the lining of the gut. This a vessel for chemical article, the third in a six-part series exploring the , describes the digestion and, to a , functions and common pathologies of the duodenum, liver and pancreas. lesser extent, the absorption of Citation Knight J et al (2019) Gastrointestinal tract 3: the duodenum, liver and minerals pancreas. Nursing Times [online]; 115: 8, 56-60.

Chemical digestion in the duodenum art 1 and part 2 in our series about from the superior duodenal flexure; relies on bile the gastrointestinal (GI) tract approximately halfway down is the (secreted by the looked at the role of the , , the entry point liver) and pancreatic Poesophagus and stomach in of the common bile and pancreatic juice (secreted by mechanical and chemical digestion. This duct, which fuse before entering the the pancreas) third part of the series covers the anatomy duodenum. The entry of bile and and function of the duodenum – the first pancreatic juice into the duodenum is To prevent segment of the small intestine – and the regulated by a small ring of muscle, the autodigestion and role of the two major accessory organs of of Oddi; corrosion, gastric digestion, the liver and the pancreas. It l Horizontal or transverse region: the acidity is neutralised also describes common pathologies that largest section of the duodenum in the duodenum by affect these parts of the GI tract. (10-12cm long) and the main area of pancreatic juice mineral absorption; Anatomy of the duodenum l Ascending region: this passes slightly Patients with The duodenum (Fig 1) is U-shaped and upwards into the impaired digestion approximately 25-38cm long (Lopez and before connecting to the at the of may lack Khorasani-Zadeh, 2019). It consists of four . A, D, E regions: The duodenum is primarily a region of and K l Superior region: an enlarged upper area chemical digestion. It receives secretions of around 2cm called the duodenal from the liver and pancreas, and its bulb, which continues the pyloric mucosa contains large numbers of - sphincter and is connected to the liver producing (goblet) cells and Brunner’s by the hepatoduodenal ; , which secrete a watery fluid that is l Descending region: this extends rich in mucus and ions. As in downwards into the abdominal cavity the stomach (see part 2), mucus acts as a

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Fig 1. Physiology of the duodenum is a polypeptide comprising around 42 amino . As its name suggests, GIP Superior region Pyloric sphincter inhibits the release of gastric secretions in the stomach, helping to avoid damage to the small intestine. It also promotes the Stomach release of by the beta cells of the Ascending region pancreas (Pederson and McIntosh, 2016). Circular fold Duodenojejunal flexure Vasoactive intestinal Descending VIP is a neuropeptide consisting of 28 region amino acids and produced by cells Jejunum throughout the GI tract. Its role is poorly Major understood but it is thought to regulate duodenal papilla the composition of pancreatic juice and bile, as well as blood flow in gut tissue. However, VIP also has effects outside of the Horizontal region GI tract: it induces peripheral vasodilation, thereby lowering , while increasing the strength of myocardial con- protective barrier against autodigestion ranging from four to 83. It is released by traction. It is also thought to play a role in and lubricates the passage of chyme. the enteroendocrine I-cells of the duo- regulating immune responses (Igarashi et The mucosal lining of the duodenum denum and jejunum. As Rehfeld (2017) al, 2011). also contains tall columnar epithelial cells explains, CCK: and extends into and finger- l Inhibits gastric emptying; Chemical digestion in the like projections (villi), which increase the l Helps prevent the duodenum overfilling; duodenum surface area for absorption. How- l Stimulates the production of Chemical digestion in the duodenum ever, nutrient absorption is not the duode- pancreatic enzymes; relies on the secretions of the two major num’s speciality and occurs mainly further l Stimulates the contraction of the accessory organs of the GI tract, the: down the small intestine in the jejunum wall of the gall bladder, l Liver, which produces bile; and , where the villi are longer, more prompting it to release bile; l Pancreas, which produces pancreatic numerous and found at greater density. l Relaxes the sphincter of Oddi, allowing juice. bile and pancreatic juice to be released Bile and pancreatic juice are mixed and production in the into the duodenum; discharged into the duodenum every time duodenum l Enhances the activity of Brunner’s the sphincter of Oddi opens under the The pyloric sphincter, which separates the glands, increasing their output of influence of CCK. stomach and duodenum, periodically bicarbonate-rich secretions; opens to release small portions of acidic l Reduces sensations of hunger, together Liver and bile production chyme (see part 2). This sudden increase in with other hormones such as The liver is the largest internal of the acidity stimulates the release of several . ; it weighs around 1.3kg in hormones including: women and 1.8kg in men. Located in the l ; Gastric inhibitory polypeptide upper right quadrant of the , just l ; Synthesised by the enteroendocrine below the diaphragm, it has over 500 docu- l Gastric inhibitory polypeptide (GIP); K-cells of the duodenum and jejunum, GIP mented functions. Its major role in l Vasoactive intestinal peptide (VIP). Fig 2. Stomach, liver, pancreas and duodenum Secretin Secretin, a comprising 27 amino acids, is secreted by the entero- Liver endocrine S-cells of the duodenum and Stomach jejunum. It stimulates the production and release of bicarbonate ions by the pan- creas; these accumulate in the pancreatic Pancreas juice, giving it an alkaline pH of around 8-8.6. Neutralising the acidity of chyme Common bile prevents damage to the mucosa in subse- duct quent sections of the GI tract and provides Sphincter of the a pH favourable to the activity of pancre- common atic enzymes (Jun et al, 2016). Descending region of the duodenum Cholecystokinin Cholecystokinin (CCK) exists in several Sphincter of Oddi Sphincter of the pancreatic duct

PETER LAMB PETER forms with numbers of amino acids

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digestion is the production of bile, which Fig 3. Emulsification of by bile is concentrated and stored in the gall bladder (Fig 2). In a healthy person, the liver releases around 600ml of bile into the duodenum each day. This is done in small amounts as the gall bladder contracts in response to CCK (Hundt et al, 2019). Large fat globule Bile is a yellowish green fluid that con- tains mostly: l ; l Bile salts, including taurocholate and sodium glycocholate; l Cholesterol; l Phospholipids; l Bile pigments and biliverdin, Emulsion of tiny which come from the breakdown of Bile salts fat droplets erythrocytes. Bile salts play an important role in chemical digestion in the duodenum. They lower the surface tension of large fat glob- l Bicarbonate ions; breaking down into maltose. As it ules, causing them to collapse into smaller l Pancreatic enzymes. catalyses starch digestion in the duo- droplets (Fig 3). This process is called One of its key roles is to neutralise denum (inside space of the duo- emulsification, as it creates an emulsion of acidity in the chyme coming through from denum), it is also called luminal tiny fat droplets with a larger surface area the stomach. This is essential to prevent (Williams, 2019). for subsequent breakdown by fat- autodigestion and ulceration of subse- Pancreatic amylase can function over a digesting enzymes (). The digestion quent sections of the GI tract. broad neutral-to-alkaline pH range. Amyl- of fats by bile and lipases also allows the ases are most efficient in an environment efficient absorption of fat-soluble vita- Pancreas and pancreatic with a neutral-to-alkaline pH. The activity mins such as vitamins A, D, E and K. production of salivary amylase slows down in the Beyond pancreatic juice, the pancreas also acidic environment of the stomach, but Pancreas and pancreatic juice produces several enzymes that continue, the enzymatic digestion of production in the duodenum, the chemical digestion resumes in the alkaline environment of the The pancreas is a small, elongated started in the mouth and stomach. duodenum. around 15cm long and weighing around 110g; it is located in the loop of the duo- Pancreatic Pancreatic denum and is covered by the lower portion Pancreatic lipase is the most active of the digestion starts in the stomach, of the stomach (Fig 2). The pancreas is an gut lipases. Like salivary and gastric where attacks the peptide bonds of important organ in the endocrine and lipases (see parts 1 and 2), it breaks down large molecules, breaking down digestive systems, playing key roles in triglyceride fats into fatty acids and glyc- into smaller chains of amino acids termed both the regulation of blood- levels erol, working mostly on the emulsified fat polypeptides (see part 2). The next stage of and digestion. droplets created by bile salts. For maximal protein digestion relies on several pancre- The endocrine portion of the pancreas activity on fat droplets, pancreatic lipase atic proteases: consists of tiny clusters of cells called islets requires the presence of the small protein l ; of Langerhans, which produce several key co-enzyme , which is itself pro- l ; hormones involved in controlling blood- duced by the pancreas (Ross et al, 2013). l Carboxypeptidase; sugar levels and regulating appetite. Weight-loss drugs such as l Elastase. The digestive portion of the pancreas, inhibit pancreatic lipase, thereby reducing Trypsin is the major present in or exocrine pancreas, takes up around 80% the digestion and absorption of fats. Orl- pancreatic juice. To avoid autodigestion of the organ’s mass. It consists of thou- istat is reported to reduce the absorption and damage to the pancreatic acini and sands of acini, small berry-like structures of dietary fat by up to 30%. However, the ducts, it is initially secreted as the inactive that secrete pancreatic juice into tiny use of such drugs is often associated with precursor (or ) . Once ducts. These connect and eventually fuse side-effects such as abdominal in the duodenal lumen, trypsinogen is before discharging their secretions into and diarrhoea, as undigested fats collect in converted into trypsin by the action of the the central pancreatic duct, which itself the colon and irritate it (Qi, 2018; Al- enzyme (or enterokinase), fuses with the before Suwailem et al, 2006). which is produced by the mucosal cells of entering the duodenum at the major duo- the duodenum and jejunum. Trypsin then denal papilla (Fig 2). Pancreatic amylase catalyses the activation of the other pan- Around 1-2.5L of pancreatic juice is pro- digestion starts in the creatic into their active forms duced each day by an adult pancreas. As mouth with salivary amylase (see part 1). chymotrypsin, carboxypeptidase and explained by Agrawal and Aoun, (2014), Like salivary amylase, pancreatic amylase elastase (Goodman, 2010). pancreatic juice consists mostly of: attacks the glycosidic bonds between adja- Carboxypeptidase – an exopeptidase –

PETER LAMB PETER l Water; cent glucose molecules in , catalyses the removal of single amino acids

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from the ends of protein and polypeptide minerals (, calcium, phosphorus and molecules, gradually reducing their trace elements of zinc and copper) are Gallstones are one of the most common length. Trypsin, chymotrypsin and absorbed in the duodenum (Kiela and pathologies of the GI tract, usually forming elastase – all endopeptidases – attack the Ghishan, 2016). Patients who have had as a result of the consolidation of bile salts peptide bonds in the central portions of extensive ulceration or that has and cholesterol. Many people have, in their proteins and polypeptides. This results in required the removal of all or part of the gall bladder, a collection of gritty deposits the generation of smaller chains of amino duodenum may need to take mineral sup- resembling wet sand, known as biliary acids called (Fig 4), which are plements to compensate for reduced min- sludge. Over time, the particulates can subsequently digested in the jejunum and eral absorption. aggregate to form a . Many text- ileum by the action of intestinal peptidase books quote the ‘five Fs’ – female, fair, fat, (see part 4). Common problems forty and fertile – as major risk factors for Duodenal ulceration developing gallstones, but these criteria Pancreatic nucleases ‘ ulcer’ is an umbrella term used to are now regarded as poor indicators of All food consumed by comes from describe ulcers in the stomach or duo- risk. However, being female, being over- plant, animal, fungal or bacterial sources. denum. Gastric and duodenal ulcers used weight and being middle-aged are recog- As all cells, whatever their origin, contain to be attributed to stress and poor diet – nised risk factors (Bit.ly/NHSGallstones). deoxyribonucleic (DNA) and ribonu- particularly the consumption of greasy and Many people who have gallstones are cleic acid (RNA), the human body can spicy foods – but it is now accepted that unaware of them, as they do not usually digest these by breaking them down into with is the cause symptoms unless they start to travel their building blocks, which are called major precipitating factor (see part 2). The out of the gall bladder. Each year, around nucleotides. DNA is composed of four use of non-steroidal anti-inflammatory 2-4% of people with gallstones experience major nucleotide bases: adenine, cytosine, drugs significantly increases the risk of symptoms (Gurusamy and Davidson, guanine and thymine; RNA has the same peptic ulcers (Kaur et al, 2012). 2014). – the pain associated bases, except that thymine is replaced by Symptoms of gastric and duodenal with gallstones – usually occurs when gall- uracil (Knight and Andrade, 2018). ulcers are very similar. Patients often expe- stones leave the gall bladder and begin to Pancreatic juice contains the pancreatic rience a burning epigastric pain, often scrape their way along the highly inner- nucleases DNase and RNase, enzymes that described as ‘gnawing’, and can point to its vated bile ducts. It is usually experienced break down DNA and RNA (VanPutte et al, location. Some with duodenal ulcers expe- in the upper right quadrant and commonly 2017). The digestion of nucleic acids allows rience pain either on an empty stomach or radiates to the back, particularly around some of the nucleotide bases to be recycled occurring two to three hours after food the right shoulder blade. Biliary colic, and used as building blocks for human consumption, which tallies with gastric described as agonisingly painful, with epi- DNA synthesis during cell division, and emptying times. However, the only way to sodes typically lasting 1-5 hours, is often for RNA during the process of transcrip- locate a peptic ulcer with absolute certainty associated with , and tion that precedes protein synthesis. is to visualise it, usually via . bloating. The pain is so intense that opi- Duodenal ulcers must be treated oids are often required to alleviate it. Mineral absorption in the because of the risk of perforation and life- A gallstone that is stuck in the bile duct duodenum threatening complications such as perito- can lead to obstructive . The two The duodenum is primarily dedicated to nitis and sepsis. As with gastric ulcers (see bile pigments bilirubin and biliverdin digestion, but the presence of short villi in part 2), treatment relies on the combina- accumulate in the liver and overspill into relatively small numbers indicates that tion of a proton pump inhibitor to reduce the blood, causing the urine to be dark col- some nutrient absorption does also take stomach acid secretion and two oured. They eventually turn the skin and place here. Small amounts of sugars, to eradicate H. pylori infection (triple the sclera (whites of the eyes) to the amino acids and fats, but large amounts of therapy) (Narayanan et al, 2018). greenish-yellow colour that is typical of jaundice. Fig 4. Enzymatic protein digestion in the duodenum In patients who have asymptomatic gallstones, watchful waiting is usually the The endopeptidases trypsin, chymotrypsin and elastase approach that should be adopted, while attack peptide bonds in the central portions of protein the National Institute for Health and Care chains, generating smaller chains of amino acids (peptides) Excellence (2014) recommends the removal of the gall bladder () for those with symptoms; this is usually done by (Gurusamy and Davidson, 2014). Patients who have had their gall bladder removed are less efficient when it comes to digesting fats; this means that undigested fat is carried over into the , where it may irritate the mucosa. These The exopeptidase carboxypeptidase attacks peptide bonds patients are susceptible to recurrent diar- at the end of the protein chain, releasing amino acids one at rhoea with copious amounts of foul- a time and gradually reducing the length of the chain smelling, pale-coloured and oily stools

PETER LAMB PETER (steatorrhoea).

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Pancreatitis resulting from PEI, gall bladder disease or Bit.ly/StatPearlsBile Igarashi H et al (2011) Vasoactive intestinal peptide is an inflammation of the pan- cholecystectomy – may impair the absorp- (VIP) and VIP receptors: elucidation of structure creas that can lead to permanent scarring tion of key fat-soluble vitamins, so patients and function for therapeutic applications. and structural damage to soft tissue and may need to take supplements to avoid International Journal of Clinical Medicine; 2: 4, life-threatening complications. Acute deficiencies. 500-508. Jun I et al (2016) Molecular mechanisms of pancreatitis is commonly caused by gall- pancreatic bicarbonate secretion. Pancreapedia: stones that have travelled along the 1-2.5L Exocrine Pancreas Knowledge Base. doi: 10.3998/ common bile duct and have become QUICK Quantity of pancreatic panc.2017.01 trapped in a position where they obstruct FACT juice produced by the Kaur A et al (2012) Peptic ulcer: a review on pancreas each day etiology and pathogenesis. International Research the pancreatic duct. Pancreatic juice Journal of Pharmacy; 3: 6, 34-38. becomes trapped in the pancreas and pan- Kiela PR, Ghishan FK (2016) Physiology of intestinal creatic enzymes may start to digest the absorption and secretion. Best Practice and Research – Clinical Gastroenterology; 30: 2, 145-159. internal pancreatic tissue, triggering Each year, around 8,800 people are diag- Kleeff J et al (2016) Pancreatic cancer. Nature severe inflammation and pain. nosed with pancreatic cancer, which Reviews – Disease Primers; 2: 16022. may also be caused causes around 5.2% of cancer deaths in the Knight J, Andrade M (2018) Genes and by excessive consumption of and is UK. It is the most deadly of the common chromosomes 3: genes, proteins and mutations. Nursing Times [online]; 114: 9, 60-64. particularly associated with binge , with five-year survival rates below Lopez PP, Khorasani-Zadeh A (2019) Anatomy, drinking. The exact mechanism is unclear, 5% (Pancreatic Cancer UK, 2015). Pancre- abdomen and , duodenum. Bit.ly/ but it is thought that alcohol may activate atic cancer is predicted to overtake breast StatPearlsDuodenum Meher S et al (2015) Role of biomarkers in pancreatic enzymes while they are still in cancer as the fourth most common cause diagnosis and prognostic evaluation of acute the pancreas, leading to autodigestion and of cancer death by 2030 (Pancreatic Cancer pancreatitis. Journal of Biomarkers; 2015: 519534. inflammation. Pancreatitis is also often UK, 2015). Age is the main risk factor and Narayanan M et al (2018) and seen in patients with and most cases are diagnosed after the age of Helicobacter pylori infection. Missouri Medicine; 115: 3, 219-224. can be triggered by certain drugs, such as 50. Modifiable risk factors include National Institute for Health and Care Excellence the tetracycline. smoking, and inactivity. (2014) Gallstone Disease: Diagnosis and The symptoms of pancreatitis are sim- Around 95% of pancreatic cancers arise Management. nice.org.uk/cg188 Pancreatic Cancer UK (2015) Pancreatic Cancer: ilar to those of gallstones, with upper in the exocrine pancreas. The remaining Some Key Facts. Bit.ly/PCUKFacts radiating into the back. 5% affect the endocrine pancreas; they are Pederson RA, McIntosh CH (2016) Discovery of The pain often becomes worse after generally less aggressive and have a better gastric inhibitory polypeptide and its subsequent and may be associated with a fever. Some prognosis. Symptoms associated with fate: personal reflections. Journal of Investigation; 7: Suppl 1, 4-7. patients experience relief when they lean pancreatic cancer are not usually present Pham A, Forsmark C (2018) : forward (Bit.ly/NHSPancreatitis). Most until the disease is fairly advanced; they review and update of etiology, risk factors, and cases of mild pancreatitis will resolve and include unexpected weight loss, abdom- management. F1000Research; 7, pii: F1000 Faculty symptoms gradually disappear after about inal discomfort and/or pain, steatorrhoea, Rev-607. Qi X (2018) Review of the clinical effect of orlistat. a week. However, severe cases often require nausea and, sometimes, diabetes. IOP Conference Series: Materials Science and hospital admission, possibly in a high- Pancreatic cancer is usually treated Engineering; 301, 012063. dependency unit, and opioids for pain with , which may be curative (if the Rehfeld JF (2017) Cholecystokinin: from local gut hormone to ubiquitous messenger. Frontiers in relief. Even with treatment, acute pancrea- tumour is discovered early) or palliative. ; doi: 10.3389/fendo.2017.00047. titis has an overall mortality of around Many patients may also undergo chemo- Ross LE et al (2013) Identification of amino acids 10-15%, rising to 30-40% in patients with therapy or radiotherapy with the aim of in human colipase that mediate adsorption to severe disease (Meher et al, 2015). reducing the size of the tumour (Kleeff et emulsions and mixed micelles. Biochimica et Biophysica Acta; 1831: 6, 1052-1059. Unresolved acute pancreatitis can turn al, 2016). Treatments specifically targeting VanPutte CL et al (2017) Seeley’s Anatomy and into chronic pancreatitis, most often seen pancreatic tumour cells have been recently Physiology. New York, NY: McGraw-Hill. in patients with alcohol dependency. This developed but are not yet widely available Williams JA (2019) Amylase. Pancreapedia: Exocrine Pancreas Knowledge Base. doi: 10.3998/ is characterised not only by chronic pain, (Amanam and Chung, 2018). NT panc.2019.02. but also by long-term inflammation of the pancreas that can lead to progressive tissue ● Part 4 of our six-part series on the fibrosis as a result of the deposition of col- anatomy and physiology of the GI tract For more on this topic online lagenous scar tissue. Chronic pancreatitis discusses the jejunum and ileum. l Anatomy and physiology of ageing 3: can damage both the exocrine and endo- the-digestive-system crine pancreas; when more than 90% of the References Agrawal S, Aoun E (2014) The physiology of the Bit.ly/NTDigestiveSOL exocrine pancreas is destroyed, pancreatic pancreas. Practical Gastroenterology; 9, 48-56. exocrine insufficiency (PEI) develops and Al-Suwailem K et al (2006) Safety and mechanism CLINICAL normal digestion can no longer take place. of action of orlistat (tetrahydrolipstatin) as the first SERIES Gastrointestinal tract series local antiobesity drug. Journal of Applied Sciences PEI most frequently manifests as poor Part 1: The mouth and oesophagus Jun Research; 2: 4, 205-208. digestion of fats leading to steatorrhoea. Amanam I, Chung V (2018) Targeted therapies for Bit.ly/NTGITract1 Around 50% of patients with chronic pancreatic cancer. Cancers (Basel); 10: 2, pii: E36. Part 2: The stomach Jul pancreatitis also experience significant Goodman BE (2010) Insights into digestion and Bit.ly/NTGITract2 damage to the endocrine pancreas and a absorption of major in humans. Advances Part 3: The duodenum, liver and pancreas Aug in Physiology Education; 34: 2, 44-53. Part 4: The jejunum and ileum Sep progressive loss of , which (2014) Gallstones. Gurusamy KS, Davidson BR Part 5: The large intestine Oct can lead to diabetes (Pham and Forsmark, British Medical Journal; 348: g2669. Part 6: Gut microbes Nov 2018). Poor digestion of fats – whether Hundt M et al (2019) Physiology, Bile Secretion.

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