GI Histology PDF

GI Histology  General Comments In many ways the gastrointestinal (GI) tract is a remarkable organ. The embryonic endoderm will give rise to the future GI tract. During fetal life, it is divided into three segments described as the foregut (with blood supply derived from the c...

GI Histology  General Comments In many ways the gastrointestinal (GI) tract is a remarkable organ. The embryonic endoderm will give rise to the future GI tract. During fetal life, it is divided into three segments described as the foregut (with blood supply derived from the coeliac trunk), midgut (supplied by the superior mesenteric artery) and hindgut (supplied by the inferior mesenteric artery). These parts develop into the parts of the definitive GI tract. The foregut extends from the oesophagus down to the second part of the duodenum where the common bile duct enters the GI tract. The midgut extends to the junction of the middle and distal thirds of the transverse colon (known as Cannon’s point). The more distal structures are derived from the hindgut.  Cell Proliferation The GI tract undergoes continuous development and proliferation. Its mucosa varies from the esophagus to the colon and it contains multiple cell types. New cells form from stem cells within the basal layers of the anal and esophageal squamous epithelium, in the mucous neck region of the stomach, or from the bases of the crypts in the intestines Eventually the cells are shed into the lumen or undergo apoptosis. Cellular life span is 5 to 7 days in the duodenum and jejunum, 4 to 5 days in the ileum, and 4 to 6 days in the large intestine Gastro-intestinal structure emucosa ↳ tyhazen FIG. 14.2 Structure of the gastrointestinal tract  The structure of the gastrointestinal tract conforms to a general plan that is clearly evident from the oesophagus to the anus. The tract is essentially a muscular tube lined by a mucous membrane. There are minor variations in the arrangement of the muscular component in different parts of the gut, but much more striking are the marked changes in the structure and therefore function of the mucosa in the different regions of the tract.  The gastrointestinal tract has four distinct functional layers: mucosa, submucosa, muscularis propria and adventitia  MUCOSA The mucosa is made up of three components, the epithelium, a supporting lamina propria and a thin smooth muscle layer, the muscularis mucosae, which produces local movement and folding of the mucosa. At four points along the tract, the mucosa undergoes abrupt transition from one form to another: the gastrooesophageal junction, the gastroduodenal junction, the ileocaecal junction and the rectoanal junction.  SUBMUCOSA This layer of loose collagenous connective tissue supports the mucosa and contains the larger blood vessels, lymphatics and nerves.  Muscularis propria The muscular wall proper consists of smooth muscle that is usually arranged as an inner circular layer and an outer longitudinal layer. In the stomach only, there is an inner oblique layer of muscle. The action of the two layers, at right angles to one another, is the basis of peristaltic contraction.  Adventitia This outer layer of loose supporting tissue conducts the major vessels, nerves and contains variable adipose tissue. Where the gut lies within the abdominal cavity (peritoneal cavity), the adventitia is referred to as the serosa (visceral peritoneum) and is lined by a simple squamous epithelium (mesothelium). Elsewhere, the adventitial layer merges with retroperitoneal tissues.  foundas i squamous - epithelium and In skin fi Keratin layer e the top ↓ Fig (goblet mucuscellsasines Glandular - > lubricates  Food is propelled along the gastrointestinal tract by two main mechanisms: voluntary muscular action in the oral cavity, pharynx and upper third of the oesophagus is succeeded by involuntary waves of smooth muscle contraction called peristalsis. Peristalsis and the secretory activity of the entire gastrointestinal system are modulated by the autonomic nervous system and a variety of hormones, some of which are secreted by neuroendocrine cells located within the gastrointestinal tract itself. These cells constitute a diffuse neuroendocrine system, with cells producing a variety of locally acting hormones found scattered along the whole length of the tract  Autonomic regulation of certain glandular secretions and the smooth muscle of the gut and its blood vessels is mediated by the enteric nervous system, comprising postganglionic sympathetic fibres and ganglia and postganglionic fibres of the parasympathetic nervous system, supplied by the vagus nerve. Contraction of the smooth muscle of the bowel is initiated by pacemaker cells known as interstitial cells of Cajal, modulated by the autonomic nervous system.  particularly the parasympathetic nervous system. As in other organs of the body, parasympathetic efferent fibres synapse with effector neurones in small ganglia located in or close to the organ involved. In the gastrointestinal tract, parasympathetic ganglia are concentrated in plexuses in the wall of the tract. In the submucosa, isolated or small clusters of parasympathetic ganglion cells give rise to postganglionic fibres which supply the mucosal glands and the smooth muscle of the muscularis mucosae. This submucosal plexus, Meissner plexus, also contains postganglionic sympathetic fibres arising from the superior mesenteric plexus. Larger clusters of parasympathetic ganglion cells are found between the two layers of the muscularis propria, the postganglionic fibres mainly supplying the surrounding smooth muscle. This plexus is known as the myenteric plexus or Auerbach plexus. FIG. 14.4 Components of the wall of the gastrointestinal tract (a) Colon, H&E (HP) (b) Oesophagus, H&E (LP) (c) Colon, H&E (HP)  Motility of the gastrointestinal tract: Peristalsis is the primary mechanism by which food is propelled along most of the length of the GI tract, with some voluntary muscular action involved at both extreme ends of the process. The particular anatomical arrangement of smooth muscle in the wall of the GI tract is specialised to allow constriction of the luminal diameter (via the circular layer of muscle) as well as shortening of its length (via action of the longitudinal muscle layer). The coordination of this very complex mechanism acts to progressively squeeze food along and, in certain sites such as the stomach, also facilitates churning and mixing of the food to aid digestion. The autonomic nervous system is responsible for the control of this involuntary process, primarily via parasympathetic innervation of the gut  Disorders affecting peristalsis Certain disease states and drug treatments can interfere with the normal process of peristalsis. One uncommon condition called Hirschsprung’s disease is characterised by failure of migration of ganglion cells into the GI tract, usually in the rectum and distal colon. Patients with this disorder typically present with severe and chronic constipation and may develop progressive dilatation of the bowel. In its most extreme form, absolutely no ganglion cells are present in the bowel, and some patients develop aganglionic megacolon due to this failure of propulsion of food through the bowel. A variety of drug treatments, including commonly used strong painkillers such as opiates, can produce severe constipation by interfering with normal peristaltic function.  Four basic mucosal types are found lining the gastrointestinal tract and these can be classified according to their main function:  Protective. This type is found in the oral cavity, pharynx, oesophagus and anal canal and is illustrated in micrograph (a). The surface epithelium is of stratified squamous type and, although not keratinised in humans, it may be keratinised in some animals that have a coarse diet (e.g. rodents, herbivores). A stratified mucosal lining of this type is well suited to sites of potential frictional trauma, such as that associated with the passage of food during mastication and swallowing, or during the passage of faeces through the anal canal. Secretory. This type of mucosa occurs only in the stomach and is illustrated in micrograph (b). It consists of long, closely packed tubular glands that are simple or branched, depending on the region of the stomach. These glands act to produce various combinations of acid and digestive enzymes in order to facilitate digestion of food whilst also secreting mucus to protect the mucosa itself from injury. Absorptive. This mucosal form is typical of the entire small intestine and is illustrated in image (c). The mucosa is arranged into finger-like projections called villi which serve to dramatically increase surface area of the mucosa, with intervening short glands called crypts. In the duodenum, some crypts extend through the muscularis mucosae to form submucosal glands called Brunner’s glands. This is the major histological feature that differentiates the duodenum from the jejunum and ileum. Absorptive/protective. This form lines the entire large intestine and is shown in micrograph (d). The mucosa is arranged into closely packed, straight tubular glands consisting of cells specialised for water absorption, as well as mucus-secreting goblet cells to lubricate the passage of faeces.  Lamina propria In most of the gut, the lamina propria consists of loose supporting tissue with a diffuse population of lymphocytes and plasma cells. The exception is the stomach which normally has few, if any, resident lymphoid cells. At intervals throughout the oesophagus, small and large bowels and appendix, prominent aggregates of lymphocytes with lymphoid follicles are found. There are also smaller numbers of eosinophils and histiocytes to deal with any microorganisms breaching the intestinal epithelium until a specific immune response can be mounted. The lamina propria is also typically rich in blood and lymphatic capillaries necessary to support the secretory and absorptive functions of the mucosa.  Muscularis mucosae The muscularis mucosae consists of several layers of smooth muscle fibres, those in the deeper layers orientated parallel to the luminal surface. The more superficial fibres are oriented at right angles to the surface; The activity of the muscularis mucosae keeps the mucosal surface and glands in a constant state of gentle agitation which expels secretions from the deep glandular crypts, prevents clogging and enhances contact between epithelium and luminal contents for absorption. Micrograph (a) illustrates the muscularis mucosae MM, clearly demarcating the delicate lamina propria LP from the more robust underlying submucosa SM. This arrangement is typical of the whole of the gastrointestinal tract  Submucosa The submucosa consists of collagenous and adipose connective tissue that binds the mucosa to the main bulk of the muscular wall. The submucosa contains the larger blood vessels and lymphatics, as well as the nerves supplying the mucosa. Tiny parasympathetic ganglia PG are scattered throughout the submucosa, forming the submucosal (Meissner) plexus from which postganglionic fibres supply the muscularis mucosae. Muscularis propria The typical arrangement of the two layers of the muscular wall proper is seen in micrograph (b), which shows a longitudinal section of the oesophagus. The muscularis propria MP is made up of an outer longitudinal layer and a somewhat broader inner circular layer Micrograph (c) illustrates, at high magnification, the junction of outer longitudinal LM and inner circular CM layers of the muscularis propria in the large intestine. Between the layers, there are clumps of pale-stained parasympathetic ganglion cells of the myenteric (Auerbach) plexus.  Oesophagus The initiation of swallowing is a voluntary act involving the skeletal muscles of the oropharynx. This is then succeeded by a strong peristaltic reflex that conveys the bolus of food or fluid to the stomach. Below the diaphragm, the oesophagus passes a centimetre or so into the abdominal cavity before joining the stomach at an acute angle.  Gastro-eosophageal sphincter Sphincter control appears to involve four complementary factors: - diaphragmatic contraction - greater intra-abdominal pressure - intragastric pressure being exerted upon the abdominal part of the oesophagus, - unidirectional peristalsis and maintenance of correct anatomical arrangements of the structures Glandular can be columnar or cuboidal ↳ to increase surface area · Intestinasia a esocarditis FIG. 14.6 Oesophago-gastric junction H&E (LP) At the junction of the oesophagus with the stomach, the mucosa of the tract undergoes an abrupt transition from a protective stratified squamous epithelium SE to a tightly packed glandular secretory mucosa GM. The muscularis mucosae MM is continuous across the junction, although it is less easily seen in the stomach where it lies immediately beneath the base of the gastric glands. The underlying submucosa SM and muscularis propria MP continue uninterrupted beneath the mucosal junction. The muscularis propria does not form a defined anatomical sphincter, but rather a physiological sphincter.  oesophagus songual circulars meses FIG. 14.5 Oesophagus (a-b) Masson trichrome stain  The lumen of the oesophagus is lined by a thick protective stratified squamous epithelium E. The underlying lamina propria is quite narrow and contains scattered lymphoid aggregates Ly. The muscularis mucosae MM is barely visible at this magnification. The submucosa SM is quite loose with many elastin fibres, allowing for considerable distension during passage of a food bolus. The submucosa also contains small seromucous glands , similar to salivary glands, which aid lubrication and are most prominent in the upper and lower thirds of the oesophagus. The muscularis propria is thick, and inner circular CM and outer longitudinal LM layers of smooth muscle are clearly distinguishable. Micrograph (b) shows part of the muscularis propria of the upper oesophagus at high magnification in the area of transition from skeletal to smooth muscle fibres. A bundle of smooth muscle fibres Sm is seen, with two skeletal muscle fibres Sk in their midst. Other skeletal muscle fibres are seen in transverse section in the lower right of the micrograph. The cross-striations of the skeletal muscle are just visible at this magnification. The collagen of the endomysial supporting tissue stains green with this method.  Barret oesophagus The importance of the physiological sphincter at the gastrooesophageal junction is apparent when the consequences of malfunction are considered. Reflux through the sphincter allows gastric acid into the lower oesophagus, causing the well-known symptom of ‘heartburn’. With time, the epithelium of the lower oesophagus undergoes metaplasia, Barrett’s oesophagus is the term given to this metaplastic columnar epithelium of the lower oesophagus. This metaplastic epithelium is at high risk of developing dysplasia and invasive adenocarcinoma. Oesophageal carcinoma generally has a poor prognosis.  GERD Stomach Food passes from the oesophagus into the stomach, a distensible organ, where it may be retained for 2 hours or more. In the stomach, the food undergoes mechanical and chemical breakdown to form chyme. Solid foods are broken up by a strong muscular churning action while chemical breakdown is produced by gastric juices secreted by the glands of the stomach mucosa. There is little absorption from the stomach except for water, alcohol and some drugs. Once chyme formation is completed, the pyloric sphincter relaxes and allows the liquid chyme to be squirted into the duodenum.  Stomach In the non-distended state, the stomach mucosa is thrown into prominent longitudinal folds called rugae that allow distension after eating. Anatomically, the stomach is divided into four regions: the cardia, fundus, body (corpus) and pylorus (pyloric antrum). The pylorus terminates in a strong muscular sphincter at the gastroduodenal junction FIG. 14.7 Stomach  MUCOSA The mucosa of the entire stomach has a tubular glandular form, but there are three distinctly different histological zones: The cardia is a small area of mucus-secreting glands surrounding the entrance of the oesophagus. In some individuals the cardia measures only a few millimetres or may be incomplete or absent altogether. The mucosa of the fundus and body forms the major histological region and consists of glands that secrete acid- pepsin gastric juices as well as some protective mucus. The glands of the pylorus secrete mucus of two different types and there are associated endocrine cells which secrete the hormone gastrin  The mucosa M is thrown into prominent folds or rugae and consists of gastric glands that extend from the level of the muscularis mucosae MM to open into the stomach lumen via gastric pits or foveolae GP. The muscularis propria comprises the usual inner circular C and outer longitudinal L layers, but the inner circular layer is reinforced by a further inner oblique layer O. The submucosa SM is relatively loose and distensible and contains the larger blood vessels. The serosal layer, which covers the peritoneal surface, is thin and barely visible at this magnification. The adipose tissue of the lesser and greater FIG. 14.8 Body of the stomach H&E omentum is attached along the lesser and greater curvature of the stomach (not illustrated in this micrograph). Lymph nodes and large blood vessels lie within this omental fatty tissue Structure of BODY gastric glands SecretesHC givespepsin - gastrine somatostatin  Gastric glands contain a mixed population of cells: 1- Surface mucous cells cover the luminal surface of the stomach and partly line the gastric pits. These cells have short surface microvilli and secrete protective bicarbonate ions directly into the deeper layers of the surface mucous coat. 2- Neck mucous cells are squeezed between the parietal cells in the neck and base of the gastric glands. These cells have larger secretory granules and more polyribosomes than surface mucous cells. 3- Parietal or oxyntic cells are distributed along the length of the glands but tend to be most numerous in the isthmus of the glands. These large rounded cells have an extensive and a centrally located nucleus. Parietal cells secrete gastric acid as well as intrinsic factor, a glycoprotein necessary for the absorption of vitamin B12 in the terminal ileum.  4-Chief, peptic or zymogenic cells are located towards the bases of the gastric glands. Peptic cells are recognised by their condensed, basally located nuclei and strongly basophilic granular cytoplasm. This reflects their large content of ribosomes. These are the pepsin- secreting cells 5-Neuroendocrine cells, part of the diffuse neuroendocrine system, are also found in the base of the gastric glands. They secrete 5-HT (serotonin) and other hormones. 6-Stem cells are found mainly in the neck of the gastric glands. These undifferentiated cells divide continuously to replace all other types of cell in the glands. The maturing cells then migrate up or down as appropriate. T FIG. 14.10 Gastric body mucosa (a) H&E (LP) (b) H&E (HP)  Micrograph (a) shows the full thickness of the gastric body mucosa and includes a small amount of submucosa SM. The gastric pits or foveolae F, lined by pale-stained surface mucous cells, are easily identifiable. The isthmus and neck of the glands also appear pale due to the predominance of neck mucous cells and parietal cells PC. The base of the glands, where chief (zygomatic) cells CC predominate, are stained darker in this H&E preparation. The glands extend down to the muscularis mucosae MM. Normal gastric mucosa is virtually devoid of lymphoid cells  Micrograph (b) is a high-power view of the neck and isthmus of a gastric body gland. The neck mucous cells Mu and parietal cells PC are easily visualised at this magnification. The tall columnar mucus-secreting cells of the stomach are not of the goblet cell type which are found in small and large intestines. The mucus produced by these mucous cells protects the epithelium from autodigestion by acid gastric juice. The parietal cells are recognised by their copious eosinophilic cytoplasm and central nucleus, which is often described as a ‘fried egg’ appearance  Parietal cell - Secretion of hydrochloric acid - Secretion of a glycoprotein called intrinsic factor which is essential for the absorption of vitamin B12 in the terminal ileum  Physiological control of gastric acid secretion Acid production by parietal cells is controlled via the autonomic nervous system and through the action of hormones. Parasympathetic innervation by branches of the vagus nerve results in release of acetylcholine, which acts on muscarinic M3 receptors on parietal cells. The hormone gastrin is produced by G cells in the antrum in response to rising gastric pH, and it acts via CCK2 receptors on the parietal cells. Histamine also increases acid secretion, acting via H2 receptors. As acid production increases, the pH in the gastric antrum falls. In response to this, the D cells in the antrum produce another hormone, somatostatin, and this acts on the antral G cells to reduces secretion of gastrin.  Chief (zymogen or peptic) cells CC synthesise and secrete the proteolytic enzyme pepsin, are the principal cell type in the basal third of the gastric glands ~ makes pepsin Chief cells have basally located nuclei and extensive granular cytoplasm packed with rough endoplasmic reticulum, the ribosomes accounting for the cytoplasmic basophilia. The inactive pepsin precursor, pepsinogen, is synthesised by the ribosomes and stored in numerous secretory granules located towards the luminal surface. bas it has mitochondria chief peptically Pepsinogen remains inactive until it reaches Pink are Looks FIG. 14.12 Base of gastric gland the lumen of the stomach where it is activated Looks blue bes it has a lot of ribosomes by the low pH of the gastric juices. Secretion of an inactive precursor molecule prevents autodigestion of the gastric glands The much larger parietal cells are round with large, centrally located nuclei and eosinophilic (pink-stained) cytoplasm due to the numerous mitochondria that are a feature of highly metabolically active cells.  The secretory activity of both parietal and peptic cells is controlled by the autonomic nervous system and via the hormone gastrin, which is secreted by neuroendocrine cells of the pyloric region  ANTRUM FIG. 14.14 Pyloric stomach (a) H&E (LP) (b) Immunohistochemical staining for gastrin (MP)  In contrast to the simple tubular glands of the fundus and body, the pyloric glands are branched and coiled and the gastric pits P occupy about half the thickness of the pyloric mucosa (a). The glands are lined almost exclusively by mucus- secreting cells which are similar to the neck mucous cells of the gastric body and fundus. A small number of acid-secreting parietal cells are also scattered among the pyloric glands Scattered among the pyloric mucous cells are neuroendocrine cells that secrete the peptide hormone gastrin and are thus called G cells  The G cells are stained brown G and are found mainly in the neck of the glands. The presence of food in the stomach stimulates the secretion of gastrin into the bloodstream. Gastrin then promotes secretion of pepsin and acid by the gastric glands of the fundus and body, as well as enhancing gastric motility. Other neuroendocrine cells in the pylorus secrete various other hormonal products, including somatostatin, which is involved in the regulation of insulin, glucagon, gastrin and growth hormone secretion. PYLORIC SPHINCTER muscle Semit FIG. 14.15 Pyloric stomach hypertrophy The pyloric sphincter PS marks a sharp transition from the glandular secretory type mucosa of the stomach S to the villous absorptive type mucosa of the duodenum D and the remainder of the small intestine. The pyloric sphincter consists of a marked thickening of the circular layer of the muscularis at the gastroduodenal junction. Note the continuity of both the circular CM and longitudinal LM layers of the muscularis between the pylorus and duodenum. The inner oblique layer of the muscularis propria is found only in the body of the stomach.  Helicobacter pylori infection H. pylori infection is a major cause of gastritis and peptic ulceration. The organism does not invade the tissues but inhabits the protective mucus layer which covers the surface of the mucosa. It has a unique ability to survive the acid environment of the stomach because of a bacterial enzyme, urease. This allows it to produce ammonia by splitting urea, raising pH in the immediate vicinity of the organism. It typically colonises the antrum and, by producing a localised alkaline environment here, H. pylori interferes with normal physiological control of gastric acid secretion. The falsely high antral pH stimulates secretion of gastrin by the antral G cells, which acts upon the parietal cells in the body to increase acid production still further. This excess acid production overwhelms normal mucosal defence mechanisms, leading to the formation of an acute ulcer.  Small intestine 14.16 Small intestine, monkey (caption continues opposite) (a) Duodenum, H&E (LP) (b) Ileum, H&E 14.16 Small intestine, monkey (caption continues opposite) (a) Duodenum, H&E (LP) (b) Ileum, H&E  Duodenum The duodenum consists of an inner circular layer CM and an outer longitudinal layer LM, as in the rest of the small intestine. The tall columnar cells of Brunner’s glands have extensive poorly stained mucigen-filled cytoplasm and basally located nuclei. The presence of chyme in the duodenum stimulates Brunner’s glands to secrete a thin, alkaline mucus that helps to neutralise the acidic chyme and protect the duodenal mucosa from autodigestion. Other products of Brunner’s glands include lysozyme and epidermal growth factor  Chyme also stimulates the release of two peptide hormones, secretin and cholecystokinin-pancreozymin (CCK) from neuroendocrine cells scattered throughout the duodenal mucosa. Secretin and CCK promote pancreatic exocrine secretion into the duodenal lumen via the pancreatic duct. CCK also stimulates contraction of the gallbladder, thus propelling bile into the common bile duct. The pancreatic and common bile ducts merge to empty their contents into the duodenum via a single short duct that opens into the second part of the duodenum via the ampulla of Vater.  Pancreatic juice is alkaline due to a high content of bicarbonate ions and thus helps to neutralise the acidic gastric contents entering the duodenum. The pancreas also secretes a variety of digestive enzymes, including the proteolytic enzymes trypsin and chymotrypsin. Like pepsin in the stomach, these are secreted in an inactive pro-enzyme form. On entering the duodenal lumen, trypsin is activated by the enzyme enterokinase, secreted by the duodenal mucosa. Activated trypsin in turn activates chymotrypsin. The pancreatic enzymes, which also include amylase and lipases, initiate the processes of luminal digestion (see textbox overleaf). The biliary secretions contain bile acids which act as emulsifying agents and are particularly important in the absorption of lipids.  Ileum The mucosa M is thrown into transverse folds, the plicae circulares PC (also called valvulae conniventes or folds of Kerckring), covered with villi V. The muscularis mucosae MM lies immediately beneath the crypts and is difficult to see at this magnification. The vascular submucosa SM extends into the plicae circulares. The inner circular CM and outer longitudinal LM layers of the muscularis propria lie deep to this and there is an outer layer of serosa S. Peyer’s patches P dominate the mucosa at the left of the field  The small intestine has the same basic structure throughout, except for the following features: Brunner’s glands are only found in the duodenum. The villi tend to be longest in the duodenum and become shorter towards the ileum. Lymphoid tissue becomes more prominent in the ileum and is fairly inconspicuous in the duodenum. The proportion of goblet cells in the epithelium increases distally. Plicae circulares are most prominent and numerous in the jejunum and proximal ileum and are generally absent in the proximal duodenum and distal ileum. FIG. 14.17 Duodenum H&E This micrograph of the human duodenum is stained by the standard H&E method. The duodenal mucosa has the typical form found elsewhere in the small intestine, with numerous elongated villi V, between the bases of which are shorter crypts C. In the distal duodenum, the height of the villi is about four times the length of the crypts. The pale-stained Brunner’s glands occupy the entire submucosa SM deep to the muscularis mucosae MM. A small component of the Brunner’s gland is sometimes found in the lamina propria where the duct of the gland empties into the base of a mucosal crypt. The Brunner’s glands secrete alkaline mucins into the lumen of the small intestine.  The small intestine, comprising the duodenum, jejunum and ileum, is the principal site for absorption of digestion products from the gastrointestinal tract. Digestion begins in the stomach and is completed in the small intestine in association with the absorptive process. Four factors combine to provide an enormous surface area: The small intestine is extremely long (4 to 6 m in humans). The mucosa and submucosa are thrown up into circularly arranged folds called plicae circulares PC or valves of Kerckring which are particularly numerous in the jejunum. The mucosal surface is made up of numerous finger-like projections called villi V. Thousands of microvilli Mv are present at the luminal surface of the enterocytes E, the columnar cells covering the villi. These cells are responsible for the process of absorption  Inner circular CM and outer longitudinal LM layers of the muscularis are responsible for continuous peristaltic activity of the small intestine. The peritoneal aspect of the muscularis is invested by the loose collagenous serosa Se, which is lined on its peritoneal surface by mesothelium Lymphoid aggregations known as Peyer’s patches PP are a prominent feature within the lamina propria of the small intestine.  The products of protein and carbohydrate digestion , namely amino acids and monosaccharides, respectively, enter the intestinal capillaries and pass via the portal vein to the liver. In contrast, reconstituted triglycerides pass into intestinal lymphatics known as lacteals L, and thence via the thoracic duct to the general circulation, bypassing the liver. FIG. 14.19 Intestinal villi and crypts H&E  Cell types in the small intestine epithelium include: Enterocytes, the most numerous cell type, are tall columnar cells with surface microvilli that are seen as a brush border in light micrographs. These cells are the main absorptive cells. Goblet cells are scattered among the enterocytes and produce mucin for lubrication of the intestinal contents and protection of the epithelium. Paneth cells are found at the base of the crypts and are distinguished by their prominent eosinophilic apical granules. These cells have a defensive function. Neuroendocrine cells produce locally acting hormones that regulate gastrointestinal motility and secretion. Stem cells, found at the base of the crypts, divide continuously to replenish all of the above four cell types. Intraepithelial lymphocytes, which are mostly T cells, provide defence against invasive organisms.  The lamina propria LP extends between the crypts and into the core of each villus and contains a rich vascular and lymphatic network into which digestive products are absorbed. The muscularis mucosae MM lies immediately beneath the base of the crypts.  Coeliac disease Coeliac disease (or coeliac sprue or gluten-sensitive enteropathy) is caused by an immunological response to gluten (gliadin), a component of wheat, oats, barley and rye. Individuals with this condition present with symptoms of malabsorption, including weight loss, diarrhoea, steatorrhoea, anaemia and vitamin deficiencies. The immune response damages the small bowel mucosa, resulting in loss of the surface villi and elongation of the crypts. Blood tests reveal characteristic anti-endomysial antibodies, as well as specific antibodies against tissue transglutaminase. Endoscopic biopsy of the small intestine is usually performed for diagnosis. The confirmation of diagnosis must be by resolution of the symptoms and histological changes after a period of time on a gluten-free diet. FIG. 14.26 Crypts of Lieberkühn  The majority of cells in the crypt bases are stem cells that divide regularly to replenish the epithelial cells of the villi. Paneth cells P, which form part of the innate immune system, exhibit intensely eosinophilic apical cytoplasmic granules. The granules of Paneth cells contain antimicrobial peptides (defensins) and protective enzymes such as lysozyme and phospholipase A. These products, secreted into the small bowel, provide the first line of defence against any pathogens that survive passage through the stomach. The lumen of the small bowel is virtually sterile. Paneth cells are long-lived (weeks) in comparison to the short lifespan (3-5 days) of enterocytes and goblet cells. Endocrine cells E also contain eosinophilic cytoplasmic granules which are found in a subnuclear position, in contrast to the apical granules of Paneth cells. Secretory products of gut endocrine cells include hormones such as secretin, somatostatin and 5-HT (serotonin). In general, each endocrine cell produces only one hormone. Ileocaecal junction  Indigestible food residues from the ileum are propelled by peristalsis into the distended first part of the large intestine, the caecum, through the cone-shaped ileocaecal valve. There is an abrupt transition in the lining of the valve from the small intestinal villiform pattern S to the glandular form in the large intestine L. The ileocaecal valve consists of a thickened extension of the muscularis propria MP that provides robust support for the mucosa. Lymphoid tissue Ly in the form of large Peyer’s patches is found in the mucosa. Colon  The principal functions of the large intestine are the recovery of water and salt from faeces and the propulsion of increasingly solid faeces to the rectum prior to defaecation  The muscular wall is consequently thick and capable of powerful peristaltic activity. As in the rest of the gastrointestinal tract, the muscularis propria of the large intestine consists of inner circular CM and outer longitudinal layers LM but, except in the rectum, the longitudinal layer forms three separate longitudinal bands called taeniae coli  Consistent with its functions of water absorption and faecal lubrication, the mucosa consists of cells of two types: absorptive cells and mucus-secreting goblet cells. These are arranged in closely packed straight tubular glands or crypts, which extend down to sit on to the muscularis mucosae MM.  Lamina propria fills the space between the glands and contains numerous blood vessels into which water is absorbed. In the lamina propria, lymphatics are very scantly, if present at all. The lamina propria also contains collagen, as well as lymphocytes and plasma cells. form part of the defence mechanisms against invading pathogens, along with intraepithelial lymphocytes and the lymphoid aggregates, which are smaller than Peyer’s patches. These are found in the lamina propria and submucosa.  Appendix - The appendix is a small, blind-ended, tubular sac extending from the caecum just distal to the ileocaecal junction. - The general structure of the appendix conforms to that of the rest of the large intestine. - The most characteristic feature of the appendix, particularly in the young, is the presence of masses of lymphoid tissue in the mucosa and submucosa FIG. 14.31 Appendix  Anorectal junction The rectum is the short, dilated, terminal portion of the large intestine. The rectal mucosa RM is the same as the rest of the large bowel except that it has even more numerous goblet cells. At the anorectal junction J, it undergoes an abrupt transition to become stratified squamous epithelium SS in the anal canal. Branched tubular circumanal glands open at the recto-anal junction into small pits at the distal ends of the columns of Morgagni. The anal canal forms the last 2 or 3 cm of the gastrointestinal tract and is surrounded by voluntary muscle that forms the anal sphincter. Here, the stratified squamous epithelium undergoes a gradual transition to skin containing sebaceous glands and large apocrine sweat glands. FIG. 14.32 Anorectal junction H&E REVIEW OF GASTROINTESTINAL TRACT  Liver The liver, like the pancreas, develops embryologically as a glandular outgrowth of the primitive foregut. The major functions of the liver may be summarised as follows:  Fat ,carbohydrates , protein and various drug and tocin metabolism  Storage of glycogen, iron and vitamins.  Secretion of bile.  The main functional cell in the liver is a type of epithelial cell called the hepatocyte. These cells are arranged as thin plates separated by fine vascular sinusoids through which blood flows. The close association of liver cells and the circulation allows absorption of nutrients from digestion, as well as secretion of products into the blood. Blood flow into the liver sinusoids comes from terminal branches of both the hepatic portal vein and hepatic artery. The liver is therefore unusual in having both arterial and venous blood supplies, as well as separate venous drainage. With the exception of most lipids, absorbed food products pass directly from the gut to the liver via the hepatic portal vein. This brings blood that is rich in amino acids, simple sugars and other products of digestion but relatively poor in oxygen. The oxygen required to support liver metabolism is supplied via the hepatic artery. After passing through the sinusoids, venous drainage of blood from the liver occurs via the hepatic vein into the vena cava. The main blood vessels and ducts run through the liver within a branched collagenous framework termed the portal tracts. These tracts also contain the bile ducts that transport bile away from the liver to be secreted into the small bowel  The liver is a solid organ composed of tightly packed pink-staining plates of hepatocytes. The outer surface of the liver is covered by a capsule composed of collagenous tissue C called Glisson’s capsule, covered by a layer of mesothelial cells M from the peritoneum. The sinusoids can just be seen as pale-stained spaces between the plates of liver cells. The hepatic sinusoids form a very low-resistance system of vascular channels that allows blood to come into contact with the hepatocytes over a huge surface area  Portal tracts P contain the main blood vessels running into the liver The other structures that run in the portal tracts are branches of the bile ducts B. Less conspicuous than the portal tracts are the centrilobular venules (hepatic venules) V that drain the liver. These are tributaries of the hepatic vein and take blood away from the liver. The very close association of the sinusoidal vasculature of the liver with the hepatocytes is essential for normal function. Certain diseases of the liver cause obliteration of the normal sinusoidal arrangement and this then causes impairment of liver function.  Hepatocytes are large polyhedral cells with round nuclei, peripherally dispersed chromatin and prominent nucleoli. The nuclei vary greatly in size, reflecting an unusual cellular feature; more than half of the hepatocytes contain twice the normal (diploid) complement of chromosomes within a single nucleus. The cytoplasm is otherwise strongly eosinophilic due to numerous mitochondria, with a fine basophilic granularity due to extensive free ribosomes and rough endoplasmic reticulum. Fine brown granules of the ‘wear-and-tear’ pigment lipofuscin are present in variable FIG. 15.2 Hepatocytes amounts, increasing with age. The sinusoids are lined by flat endothelial lining cells SC which are readily distinguishable from hepatocytes by their flattened condensed nuclei and attenuated poorly stained cytoplasm. Portal triad  This micrograph shows a typical portal tract containing three main structures. The largest is a terminal branch of the hepatic portal vein PV (terminal portal venule) which has a thin wall lined by endothelial cells. Smaller-diameter thick-walled vessels are terminal branches of the hepatic artery A with the structure of arterioles. A network of bile canaliculi is located within each plate of hepatocytes, these drain into bile collecting ducts lined by simple cuboidal or columnar epithelium, known as the canals of Hering, which in turn drain into the bile ductules B. The bile ductules are usually located at the periphery of the tract. The bile ductules merge to form larger, more centrally located trabecular ducts which drain via intrahepatic ducts into the right and left hepatic ducts, the common hepatic duct and then to the duodenum via the common bile duct. Because these three structures are always found in the portal tracts, the tracts are often referred to as portal triads. Lymphatics L are also present in the portal tracts but, since their walls are delicate and often collapsed, they are less easily identified. Surrounding the portal tract are anastomosing plates of hepatocytes H, between which are the hepatic sinusoids S. These receive blood from both the hepatic portal and hepatic arterial systems. The layer of hepatocytes immediately bordering the portal tract is known as the limiting plate. FIG. 15.4 Liver (a) Reticulin The structural integrity of the liver is maintained by a delicate meshwork of extracellular matrix in the form of a fine meshwork of reticulin fibres (collagen type III). The reticulin meshwork supports both the hepatocytes and the sinusoidal lining cells (endothelial cells). These micrographs have both been stained by a silver method that shows reticulin as a black- stained material. Micrograph (b) shows more detail of the reticulin scaffolding. Single layers of hepatocytes in the liver cell plates H lie immediately upon the reticulin framework. On the other side of the reticulin layer are the hepatic sinusoidal spaces. Some sinusoidal lining cells SC can just be seen. The sinusoids are lined by a discontinuous fenestrated endothelium which has no basement membrane and is separated from the hepatocytes by a narrow space (the space of Disse) which drains into the lymphatics of the portal tracts. FIG. 15.5 Hepatic vasculature and biliary system  This diagram shows the hepatic vascular system and the bile collecting system.  The hepatic portal vein and hepatic artery branch repeatedly within the liver. Their terminal branches run within the portal tracts and empty into the sinusoids. Blood from both systems percolates between plates of hepatocytes in the sinusoids, which converge to drain into a terminal hepatic (centrilobular) venule. These drain to intercalated veins and then to the hepatic vein, which drains into the inferior vena cava.  Bile is secreted into a network of minute bile canaliculi situated between the plasma membranes of adjacent hepatocytes. The canalicular network drains into a system of bile ducts located in the portal tracts. Bile then flows through the extrahepatic biliary tree and is finally discharged into the second part of the duodenum. c FIG. 15.6 Perfusion method (LP) This preparation shows one of the techniques used by early histologists in mapping hepatic blood flow. The hepatic portal vein (supplying the liver) has been perfused with a red dye, and the hepatic vein (draining the liver) has been back-perfused with a blue dye. Thus it can be seen how liver units can be defined by a number of portal tracts peripherally (stained red), with blood draining to a single terminal hepatic venule (stained blue) at the centre.  Liver architecture The structural unit of the liver can be considered as a conceptually simple hepatic lobule. However, the physiology of the liver is more accurately represented by a unit structure known as the hepatic acinus. Hepatic lobule The hepatic lobule is roughly hexagonal in shape and is centred on a terminal hepatic venule (centrilobular venule) V. The portal tracts T are positioned at the angles of the hexagon. The blood from the portal vein and hepatic artery branches flows away from the portal tract to the adjacent central veins.  Hepatic acinus The hepatic acinus is a more physiologically useful model of liver anatomy, although more difficult to define histologically. The acinus is a roughly berry-shaped unit of liver parenchyma centered on a portal tract. The acinus lies between two or more terminal hepatic venules and blood flows from the portal tracts through the sinusoids to the venules. The acinus is divided into zones 1, 2 and 3 and the hepatocytes in these zones have different metabolic functions Hepatic acinus Zone 1 is closest to the portal tract and receives the most oxygenated blood, while zone 3 is furthest away and receives the least oxygen. FIG. 15.8 Liver lobule H&E (MP) This micrograph illustrates a single human liver lobule and includes parts of a number of hepatic acini, each centred on a portal tract. The irregular hexagonal boundary of the lobule is defined by portal tracts T and sparse collagenous tissue C. Sinusoids originate at the lobule margin and course between plates of hepatocytes to converge upon the terminal hepatic (centrilobular) venule V. The plates of hepatocytes are usually only one cell thick and so each hepatocyte is exposed to blood on at least two sides. The plates of hepatocytes branch and anastomose to form a three- dimensional structure like a sponge. FIG. 15.9 Sinusoid lining cells Perls Prussian blue (HP) The sinusoid lining cells include at least three cell types. The majority of cells lining the hepatic sinusoids are endothelial cells E with flat darkly stained nuclei and thin fenestrated cytoplasm. Scattered among the endothelial cells are large plump phagocytic cells with ovoid nuclei. Known as Küpffer cells K, these form part of the monocyte-macrophage defence system \and, with the spleen, participate in the removal of spent erythrocytes and other particulate debris from the circulation. The third cell type, known as stellate cells, Ito cells or hepatic lipocytes. This cell type has lipid droplets containing vitamin A in their cytoplasm. These cells have the dual functions of vitamin A storage and production of extracellular matrix and collagen.  Hepatic cirrhosis Diseases where there is repeated liver cell destruction, the liver responds by cell division to replace dead liver cells (regeneration) and by depositing collagenous tissue (scarring). The combination of nodules of regenerated liver cells separated by bands of scar tissue is termed cirrhosis. In cirrhosis, the liver cells that are separated from a normal sinusoidal blood flow have reduced function (e.g. reduced synthesis of albumin and reduced secretion of bile). The scarring and interruption of the low-resistance sinusoidal system has important consequences. Blood from the portal vein cannot drain from the liver and portal hypertension develops. The common causes of cirrhosis are diseases in which there is continued liver cell damage and death. Chronic ethanol abuse is an important cause. Infection with hepatitis viruses B and C often leads to chronic hepatitis and a risk of cirrhosis. Certain autoimmune diseases are also recognised to cause chronic hepatitis and cirrhosis in susceptible patients. Rare causes include excessive storage of iron and copper due to genetic metabolic diseases.  Gallbladder FIG. 15.13 Gallbladder  The gallbladder is a muscular sac lined by a simple columnar epithelium. It has a capacity of about 100 mL in humans. The presence of lipid in the duodenum promotes the secretion of the hormone cholecystokinin- pancreozymin (CCK) by neuroendocrine cells of the duodenal mucosa, stimulating contraction of the gallbladder and forcing bile into the duodenum. Bile is an emulsifying agent, facilitating the hydrolysis of dietary lipids by pancreatic lipases.  The simple epithelial lining of the gallbladder is seen to consist of very tall columnar cells with basally located nuclei.  Numerous short irregular microvilli account for the unevenness of the luminal surface.  The lining cells concentrate bile 5- to 10-fold by an active process, the resulting water passing into lymphatics in the lamina propria LP.  The wall of the cystic duct, is formed into a twisted mucosa-covered fold F known as the spiral valve of Heister  The flow of bile and pancreatic juice into the duodenum is controlled by the complex arrangement of smooth muscle known as the sphincter of Oddi. The components of this structure include the choledochal sphincter at the distal end of the common bile duct, the pancreatic sphincter at the end of the pancreatic duct, and a meshwork of muscle fibres around the ampulla. This arrangement controls the flow of bile and pancreatic juice into the duodenum and, at the same time, prevents reflux of bile and pancreatic juice into the wrong parts of the duct system. When the choledochal sphincter is closed, bile is directed into the gallbladder where it is concentrated.  Pancreas The pancreas is a large gland which, like the liver, develops embryologically as an outgrowth of the primitive foregut. The pancreas has both exocrine and endocrine components. The endocrine pancreas is described in detail in another chapter. The exocrine pancreas, which forms the bulk of the gland, secretes an enzyme-rich alkaline fluid into the duodenum via the pancreatic duct. The high pH of pancreatic secretions is due to a high content of bicarbonate ions and serves to neutralise the acidic chyme as it enters the small intestine from the stomach. The pancreatic enzymes degrade proteins, carbohydrates, lipids and nucleic acids by the process of luminal digestion. Like pepsin in the stomach, the pancreatic proteolytic enzymes trypsin and chymotrypsin are secreted in an inactive form. Enterokinase, an enzyme secreted by the duodenal mucosa, activates protrypsin to form trypsin. Trypsin then activates prochymotrypsin to form chymotrypsin. This mechanism prevents autodigestion of the pancreas.  The other pancreatic enzymes are secreted in the active form. Pancreatic secretion occurs continuously, the rate being modulated by hormonal and nervous influences. Secretin, a hormone released by neuroendocrine cells scattered in the duodenum, promotes the secretion of copious watery fluid rich in bicarbonate. Cholecystokinin-pancreozymin (CCK), also derived from duodenal neuroendocrine cells, stimulates the secretion of enzyme-rich pancreatic fluid. Gastrin, secreted by neuroendocrine cells of the gastric pylorus, has a similar action on the pancreas to that of CCK. The pancreas is richly innervated by the autonomic nervous system, which also modulates secretory activity  The pancreas is a lobulated gland covered by a thin collagenous capsule which extends as delicate septa Sp between the lobules. The exocrine component of the pancreas consists of closely packed secretory acini which drain into a highly branched duct system. Most of the secretion drains into the main pancreatic duct, which joins the common bile duct to drain into the duodenum via the ampulla of Vater. In most people, a small accessory pancreatic duct drains into the duodenum more proximally. Interlobular ducts D can be seen in this micrograph. Their surrounding supporting tissue reinforces the septal framework. The endocrine tissue of the pancreas forms islets of Langerhans I of various sizes scattered throughout the exocrine tissue. Occasional adipocytes Ac are scattered throughout the parenchyma. These are scanty in young adults but are seen in increasing numbers in older people, reflecting the natural atrophy of the gland with age.  Each acinus is made up of an irregular cluster of pyramid-shaped secretory cells, the apices of which surround a minute central lumen which represents the end of the duct system. The smallest of the tributaries are known as intercalated ducts. Adjacent acini are separated by inconspicuous supporting tissue containing numerous capillaries.  Micrograph (a) shows the general arrangement of the glandular acini A. An intralobular duct is seen in upper midfield and a larger interlobular duct in lower midfield, the latter having a much broader sheath of supporting tissue S.  At higher magnification in micrograph (b), the cells of each pancreatic acinus have a roughly triangular shape in section, their apices projecting towards a central lumen of a minute duct. The acinar cells are typical protein-secreting cells. The nuclei are basally located and surrounded by basophilic cytoplasm which is crammed with rough endoplasmic reticulum. The apices of the cells are packed with eosinophilic secretory granules containing proenzymes. The centres of the acini frequently contain one or more nuclei of centroacinar cells C with pale nuclei and sparse pale-stained cytoplasm. These represent the terminal lining cells of intercalated ducts. Cells of similar appearance can be seen between the acini and those of intercalated ducts D passing to join the larger intralobular ducts I. The cells lining the intercalated ducts secrete water and bicarbonate ions into the pancreatic juice