Annex A

ANNEX A: EMBRYOLOGY AND ANATOMY OF THE HUMAN ALIMENTARY TRACT J.-F. Bertholon and R.W. Leggett A.1. Introduction (A1) This annex summarises basic anatomical information on the human alimentary tract considered in development of the HATM and in the revision of the ICRP’s Reference Man (ICRP, 2002). Except where specific references are listed, the information was collected from the following sources: Greger and Windhorst, 1996; ICRP, 1975; Johnson, 1987, 1998; Ross et al., 1995; Williams and Warwick, 1980. (A2) The various segments of the alimentary tract are morphologically specialised for particular aspects of digestion and absorption. After preliminary maceration, moistening, and formation into a bolus by the oral cavity and the salivary glands, food passes rapidly at first through the pharynx to the oesophagus, then slowly through the gastrointestinal tract. The major alterations associated with solubilisation, digestion, and absorption occur during transit through the stomach and small intestine. Absorption occurs chiefly through the wall of the small intestine. Undigested food and other substances within the alimentary tract, such as mucus, bacteria, desquamated cells, and bile pigments, form the faeces that are excreted in the process of defecation. (A3) The alimentary mucosa, which provides an interface between the body and the external environment, has numerous functions, as follows.  Barrier function. The mucosa serves as a barrier to the entry of noxious substances, antigens, and pathogenic organisms, and controls water and electrolyte losses.  Immunological function. Along the length of the alimentary tract mucosa, lymphoid tissue cells together with phagocytes of the reticulo-endothelial system and plasmocytes secreting antibodies (immunoglobulins) serve as a first line of defence of the body.  Secretory function. At specific sites, the lining of the alimentary tract secretes digestive enzymes, hydrochloric acid, mucins, and various agents that act as local and/or general hormones.  Absorptive function. The epithelium of the mucosa absorbs metabolic substrates, i.e. the breakdown products of digestion, as well as vitamins, water, electrolytes, recyclable materials such as bile components and cholesterol, and other substances essential to the functions of the body. A.2. Embryology of the human alimentary tract (A4) In the third week of development of the embryo, gastrulation (formation of the gut) occurs with the transformation of the bilaminar germ disc into the trilaminar embryo. Three embryo layers are derived from this epiblast layer: the definitive endoderm which will line the future gut; the intra-embryonic mesoderm which will form the muscles and dermis; and the ectoderm which will differentiate to give rise 129

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to neural tissue. In the fourth week of development, the cephalocaudal and lateral folding of the embryo converts the flat trilaminar germ disc into an elongated cylinder with three concentric nested tubes. The ectoderm covers the outer surface of the embryo and is separated from the endodermal primary gut tube by the mesoderm, which contains the coelom. During the ninth week of development, the definitive mucosal epithelium differentiates from the endodermal lining of the new gut lumen. The mesodermal coating of the primitive gut tube gives rise to the submucosal connective tissue and smooth muscle layers of the definitive gastrointestinal tract. (A5) Initially, the gut tube is divided into two blind-ending tubes, cranial (foregut) and caudal (hindgut), and a central midgut that opens ventrally to the yolk sac. The buccopharyngeal membrane closes the foregut while the cloacal membrane closes the hindgut. (A6) The lips and mouth lining, the gums, and the teeth derive from the ectoderm (epidermis) together with the mesenchyme for the teeth. The parotid gland evolves from an invagination of the ectoderm, and the submandibular and sublingual glands evolve from an invagination of the endoderm. (A7) The pharyngeal lining of the branchial pouches and arches derives from the endoderm. The tonsils are formed from the endoderm lining of the second pharyngeal pouch, with the tonsillar crypts later infiltrated by lymphoid tissue. The tonsillar stroma derives from the underlying mesoderm. The pharyngeal tonsils (adenoid, tubal, lingual) develop in association with the mucus glands of the pharynx. The tongue originates from the mesoderm of pharyngeal arches 1, 3, and 4, and the muscles develop from the occipital somite. The mucosal covering is derived from pharyngeal arch endoderm. (A8) By convention, the boundaries of the foregut, midgut, and hindgut correspond with the gut regions associated with the three arteries that supply the abdominal gut tube. The gut tube and derivatives are supplied by unpaired ventral branches of the descending aorta. About five definitive aortic branches supply the thoracic part of the foregut (the pharynx and thoracic oesophagus). Three arteries serve the remainder of the gut tube: the coeliac trunk supplies the abdominal foregut (the abdominal oesophagus, stomach, and superior half of the duodenum and derivatives); the superior mesenteric trunk supplies the midgut; and the inferior mesenteric artery that supplies hindgut. (A9) The primitive abdominal gut is initially a straight tube suspended in the peritoneal cavity by a dorsal mesentery. Subsequent rotations of the developing stomach bend the presumptive duodenum into a ‘C’ shape and displace it to the right until it lies against the dorsal body wall to which it adheres and so becomes secondarily retroperitoneal. The rotation of the stomach and fusion of the duodenum create a cavity dorsal to the stomach called the ‘lesser sac’ of the peritoneal cavity. The rest of the peritoneal cavity is termed the ‘greater sac’. The lesser sac enlarges as a result of progressive expansion of the dorsal mesogastrium that connects the stomach to the posterior body wall. The resulting large, suspended fold of mesogastrium, called the ‘greater omentum’, drapes over the lower organs of the abdominal cavity. (A10) The duodenal endoderm forms the hepatic diverticulum which gives rise to the ramifying liver cords. These cords differentiate into the hepatocytes 130

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(parenchyma), the bile canaliculi of the liver, and the hepatic ducts. The mesoblastic stroma of the liver develops from mesoderm originating near the cardiac region of the stomach with colonies of haematopoietic cells that are very active in the embryo. The cystic diverticulum gives rise to the gallbladder and cystic duct. (A11) The pancreas results from fusion of the dorsal and ventral pancreatic duodenal buds. As for the duodenum, the pancreas adheres to the dorsal body wall and becomes secondarily retroperitoneal. (A12) The duct from the dorsal bud to the duodenum usually degenerates, leaving the ventral pancreatic duct, now the main pancreatic duct, as the only conduit to the duodenum. The main pancreatic duct and the common bile duct meet and empty their secretions into the duodenum at the major duodenal papilla or ampulla of Vater. (A13) The exocrine cells of the pancreas, which produce digestive enzymes, differentiate from the endoderm of the pancreatic buds. The origin of the pancreatic endocrine cells in the islets of Langerhans is unclear. (A14) At the end of the fourth week of embryo development, condensation of the mesenchyme near the body wall occurs. During the fifth week, this differentiates to form the spleen; a vascular, lymphoid organ. Thus, the spleen is not a product of the gut tube endoderm. The spleen is initially a haematopoietic organ and only later acquires a definitive lymphoid character. (A15) By the fifth week of development, the presumptive ileum, separated from the presumptive colon by a caecal primordium, forms the primary intestinal loop by elongation. The cranial part of this loop gives rise to most of the ileum, while the caudal part becomes the ascending and transverse colons. (A16) The dorsal mesenteries of the ascending and descending colon shorten so that these organs adhere to the dorsal body wall and become secondarily retroperitoneal. The transverse colon will remain an intraperitoneal organ suspended by mesentery. The most inferior portion of the colon, the sigmoid colon, also remains suspended by mesentery (see Table A.1). (A17) The portion of the primitive gut tube close to the cloacal membrane forms an expansion called the ‘cloaca’ that is later separated by the urorectal septum into a posterior rectum and an anterior primitive urogenital sinus. The urogenital sinus gives rise to the bladder, the pelvic urethra, and the definitive urogenital sinus. In the male, the definitive urogenital sinus becomes the penile urethra, and in the female, it becomes the vestibule of the vagina. All of these urogenital structures are thus derived from the hindgut endoderm. The distal edge of the urorectal septum fuses with the cloacal membrane, forming the perineum separating the anterior urogenital membrane from the posterior anal membrane. (A18) The superior two-thirds of the anorectal canal form from the distal part of the hindgut. In contrast, the inferior one-third of the anorectal canal is derived from an ectodermal pit called the ‘anal pit’ or ‘proctodeum’ and is separated from the endodermal portions of the anorectal canal by the anal membrane. This leaves, in the adult, an irregular folding of mucosa called the ‘pectinate line’. The blood supply to the anorectal canal is consistent with this dual origin; above the pectinate line, the canal is supplied by branches of the inferior mesenteric arteries and veins serving the 131

ICRP Publication 100 Table A.1. The derivatives of the primitive gut tube

Foregut

Regions of the differentiated gut tube

Organs derived from the gut tube endoderm

Pharynx Thoracic oesophagus Abdominal oesophagus Stomach Superior half of duodenum (superior to the ampulla of Vater)

Pharyngeal pouch derivatives Lungs

Midgut

Inferior half of duodenum Jejunum–ileum–caecum–appendix– ascending colon Right two-thirds of transverse colon

Hindgut

Left one-third of transverse colon Descending colon–sigmoid colon Proximal two-thirds of the rectum

Ectoderm

Distal one-third of the anorectal canal

Liver parenchyma and hepatic duct epithelium Gallbladder, bile duct system Dorsal and ventral pancreatic buds (exocrine cells and duct epithelium; probably also pancreatic endocrine cells)

Urogenital sinus and derivatives

hindgut, whereas below the pectinate line, it is supplied by branches of the internal iliac arteries and veins. Anastomoses exist between tributaries of the superior rectal vein and tributaries of the inferior rectal vein within the mucosa of the anorectal canal, which may later swell into haemorrhoids if the blood pressure in the inferior vena cava is elevated.

A.3. General overview of the postnatal alimentary tract A.3.1. General macro-anatomy of the alimentary tract (A19) The alimentary tract is a hollow tube of varying diameter consisting of the oral cavity, including mouth, teeth, salivary glands, and pharynx; the oesophagus; the stomach; the small intestine, including duodenum, jejunum, and ileum; the large intestine, including ascending, transverse and descending colon; the rectum; and the anus. The pancreas, spleen, liver, and gallbladder are closely associated organs but play more general systemic roles in the body. These organs are not included in the definition of the alimentary tract in the present document but are addressed briefly in this annex because of their relationship to the functions of the alimentary tract. (A20) The general structure of the alimentary tract wall is shown in Fig. A.1. The walls are lined with epithelial tissue that is particularly adapted to serve as a barrier between the ‘milieu exte´rieur’ and the ‘milieu inte´rieur’, and to control the exchanges 132

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Fig. A.1. General structure of the alimentary tract wall. Modified from Williams and Warwick (1980, Fig. 8.87, p. 1314).

between them. This is true for skin (epidermis) and all organs that communicate with the exterior (alimentary, respiratory, and genitourinary tracts). The walls of the tract also contain muscles that propel the contents from mouth to anus, and glands or projections (villi or microvilli) that help with the digestion of food. 133

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Dimensions and mass of segments of the alimentary tract (A21) The alimentary tract of the adult male is estimated to be about 4–5 m in length. Typical dimensions of different segments of the tract are given in Chapter 7 of this report. (A22) The lengths of the small and large intestines given in Chapter 7 refer to physiological length, i.e. intestinal length as measured in living people, rather than anatomical length, i.e. length as measured at autopsy or from material removed during surgery. Anatomical lengths are often given in standard textbooks of anatomy and are usually greater than physiological lengths. Soon after death, the wall muscles lose their tonus, resulting in elongation. Early reported values for physiological length of the intestines based on intubation methods tended to underestimate the true length due to contraction of the intestine around the tube and the tendency of the tube to take the shortest distance through the curves of the intestines. Improvements in the physiological methods have tended to eliminate these disadvantages, so recent data should be reasonably close to in-vivo values. (A23) In many cases, pertinent details concerning the methods for obtaining the weights of the different parts of the alimentary tract have not been provided with reported weights. For example, it may not be evident whether the contents were washed out thoroughly before weighing or if the intestines were stripped thoroughly of fat or connective tissue. Also, the age, body weight, nutritional status, cause of death, and time since death of a subject may not be available. (A24) To have direct evidence on which to base reference values for the weights of the oesophagus, stomach, and intestines, Tipton and Cook (1969) and collaborators at the New York Medical Examiner’s Office carefully determined the weights of these tissues in 49 male and 12 female cadavers. The average age, body mass, and height of the male subjects were 43 +/ 12 years, 73 +/ 7 kg, and 169 +/ 6 cm, respectively. Average values for the female subjects were 43 +/ 9 years, 65 +/ 6 kg, and 166 +/ 3 cm, respectively. None of the subjects died of causes known to affect the mass of the alimentary tract. (A25) Table A.2 lists typical masses for segments of the alimentary tract as a function of age and gender. Values for adult males and females are rounded central estimates based on the data of Tipton and Cook (1969). Age-specific estimates for the stomach are based on data from Scammon (1919), who collected measurements of Table A.2. Summary of typical values for masses of walls in the gastrointestinal tract (g) Component

Newborn

Oesophagus Stomach Small intestine Large intestine Right colon Left colon Rectosigmoid Total mass

2 7 30 7 7 3 56

1 year

5 years

10 years

Male

Female

5 20 85

10 50 220

18 85 370

30 120 520

30 120 520

40 150 650

35 140 600

20 20 10 160

49 49 22 400

85 85 40 683

122 122 56 970

122 122 56 970

150 150 70 1210

145 145 70 1140

134

15 years

Adult Male

Female

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stomach mass for 543 subjects in the first two decades of life. These data indicate that the growth rate of the stomach in postnatal life is equal to or slightly greater than that of the body as a whole. Age-specific estimates for the oesophagus and divisions of the intestines are based on the assumption that the rate of growth from birth to maturity parallels that of the stomach. Tissue masses are assumed to be independent of gender to 10 years of age. Blood and lymph circulation in the alimentary tract (A26) The blood supply to the small and large intestines is from the abdominal aorta via the superior mesenteric and inferior mesenteric arteries, and to the stomach via the coeliac artery. On entering the gut wall, the arteries branch and send smaller arteries around the whole gut circumference in both directions, and these meet at the antimesenteric surface (gut wall opposite the mesenteric attachment). From the circling arteries, much smaller arteries penetrate into the intestinal wall and spread beneath the epithelium to control the absorptive and secretory functions of the gut. (A27) In an intestinal villus, an arteriole and a venule interconnect via a system of multiple looping capillaries. The walls of the arterioles are highly muscular, which is important for the control of villus blood flow and, consequently, nutrient absorption. (A28) Lymphatic drainage of the right half of the oral cavity and pharynx is via the right lymphatic duct, which empties into the right subclavian vein. The left half is drained via the thoracic duct into the left subclavian vein. The alimentary tract and associated glands also drain into the thoracic duct. (A29) The initial lymph vessels have incomplete or absent basement membranes. The endothelium of these lymph vessels is anchored by collagen fibres to interstitial collagen bundles and tissue cells. These attachments are discontinuous with large intercellular gaps (up to 0.1 lm) that permit the passage of large particles. The collecting vessels have a complete basement membrane, smooth muscle, and one-way intraluminal valves that allow an efficient pumping action towards the thoracic duct. In the lymph nodes, some fluid exchange with blood vessels takes place, leading to concentration or dilution of lymph macromolecules. (A30) Each villus of the small intestine contains a central lacteal, which is a blindending lymphatic vessel. The activity of the villus smooth muscle contributes to filling and emptying of the lacteals. Lymphatic vessels are also found in the muscle layers. (A31) The large intestine lymphatics form a double layer of vessels, one beneath the epithelium and the other deeper in the mucosa. The specific function or role of this network is unknown. (A32) The lymph from the digestive tract goes through numerous lymph nodes where reticulo-endothelial cells remove particles and add proteins. Movement is towards one or several lymphatic collectors that drain mesenteric lymph into the thoracic duct and from there into the general circulation via the left subclavian vein. Spleen (A33) The spleen is covered by a capsule consisting of fibrous tissue and smooth muscle that contracts several times per minute to move blood out of the spleen 135

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towards the liver. The arteries enter at the hilus, divide, and are surrounded by lymphoid tissue, which forms large nodules scattered through the organ. The rest of the tissue is the splenic pulp; a mesh of fibres associated with large phagocytic cells (macrophages). The arterioles give way to a network of sinuses (capillaries) that drain into small collecting veins. The spleen stores red blood cells in the pulp or in the sinuses and releases them into the general circulation. (A34) During the second half of fetal life, the spleen forms red blood cells and can resume this function during postnatal life in cases of anaemia. The spleen remains a lymphopoietic organ and the nodules of lymphoid tissue support lymphocyte proliferation, leading to increased release of lymphocytes from the spleen. The macrophages of the spleen destroy aging red cells, lymphocytes, and blood platelets. A.3.2. General micro-anatomy of the alimentary tract (A35) Photomicrographs of histological sections of the wall of the intestinal tract reveal considerable variations in wall thickness both from one section of the tract to another and, microscopically, due to protrusions such as the villi. Perhaps the most representative estimate of wall thickness is the ratio of mass to smoothed area, assuming a specific gravity of one. The accuracy of such an estimate depends on the techniques used to estimate mass and area, particularly techniques used for removing secretions or other adherent material that does not belong to the alimentary tract wall. (A36) Wall thickness has also been estimated from measurements obtained from photomicrographs. Reported measurements based on this approach are fragmentary. In addition, the surface of the gastrointestinal tract is covered by a fluid layer of secretions, and no direct data on the thickness of the mucus in the human tract have been found. (A37) The alimentary tract has the same basic structural organisation throughout the entire length. Four distinctive layers form the wall of the tract: mucosa, consisting of a lining epithelium, an underlying connective tissue called the ‘lamina propria’ and a muscularis mucosae composed of smooth muscle cells; submucosa, consisting of dense irregular connective tissue; muscularis externa, consisting of two layers of smooth muscle; the visceral serosa, a simple squamous epithelium or mesothelium with a thin underlying connective tissue, is the most superficial layer of the portions of the alimentary tract that are suspended in the peritoneal cavity. The fixed portions (oesophagus, duodenum, ascending and descending colons) are attached by a loose connective tissue, the adventitia, to the adjoining structures. Mucosa (A38) The mucosa synthesises and secretes: digestive enzymes into both the lumen of the alimentary tract and on to the apical plasma membrane of surface cells; hormones; mucus; and antibodies that it receives from the connective tissue. The epithelium differs throughout the alimentary tract according to the specific function of each part of the tube, but keeps its general characteristics, i.e. polarised cells with an apical (lumenal) pole and a basolateral pole, and tight junctions between adjacent cells. 136

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(A39) In the segments of the digestive tract in which absorption occurs, principally the small intestine and, to some extent, the large intestine, the absorbed products of digestion diffuse into the blood and lymphatic vessels of the lamina propria for distribution. Typically, the blood capillaries are of the fenestrated type and receive most of the absorbed metabolites. In addition, in the small intestine, lymphatic capillaries are numerous and receive some absorbed lipids and proteins. (A40) The immunological barrier against pathogens and other antigens consists of diffuse lymphoid tissue represented by numerous lymphocytes and plasma cells, lymphoid nodules (aggregates of lymphoid tissue), eosinophils, macrophages, and neutrophils. The diffuse lymphoid tissue and the lymphoid nodules form the gutassociated lymphatic tissue (GALT), which is localised to the antimesenteric surface. Aggregated lymphoid nodules are found in the appendix and in the distal small intestine where they form Peyer’s patches. The muscularis mucosae, which consists of two layers of smooth muscle cells, one circular and one longitudinal, produces movements of the mucosa independent of those of the rest of the wall. Submucosa (A41) The submucosa is made of irregular connective tissue containing the larger blood vessels that send branches to the mucosa and to the external layers. It also contains lymphatic vessels and nerve plexi. The nerve networks consist of parasympathetic and sympathetic fibres, sensory and motor, of the autonomic nervous system. Cell bodies (ganglion cells) of postganglionic parasympathetic neurons and motor enteric neurons are interspersed with the fibres and form the submucosal Meissner’s plexus. Muscularis externa (A42) In most parts of the digestive tract, the muscularis externa is organised in two thick layers of smooth muscle. One is circularly oriented and the other is longitudinally oriented. Contraction of the inner, circular layer constricts the lumen, while contraction of the outer, longitudinal layer shortens the tube. The slow rhythmic and co-ordinated contraction of these muscle layers under the control of the enteric nervous system produces peristalsis, i.e. waves of contraction that move the luminal contents and mix it simultaneously. (A43) A few sites along the digestive tube show a different organisation of the muscularis extema. In the proximal portion of the oesophagus and at the anal sphincter, the muscularis externa is made of striated muscle. In the stomach, there is a third, obliquely oriented, layer of smooth muscle. In the large intestine, part of the longitudinal smooth muscle layer is thickened to form three longitudinal bands called ‘teniae coli’. On contraction, they enhance the shortening of the tube to move its contents. (A44) At some locations along the digestive tract, the circular muscle layer is thickened to form sphincters or valves: pharyngoesophageal sphincter; lower oesophageal sphincter; pyloric sphincter (gastroduodenal sphincter); ileocaecal valve (the junction of the small and large intestine); and internal anal sphincter. 137

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Serosa and adventitia (A45) Large blood vessels, lymphatic vessels and nerve trunks travel through the serosa (from and to the mesentery) to reach the wall of the digestive tract. Large

Fig. A.2. Location of proliferating and differentiating cells (mouth lining, tongue, oesophagus, stomach, small intestine, large intestine). Source: Johnson (1987, Ch. 8, Fig. 1, p. 256). 138

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amounts of adipose tissue can develop in the connective tissue of the serosa (and in the mesentery). (A46) The portions of the digestive tract that do not possess a serosa, are attached to the connective tissue of adjoining structures by the layer of loose connective tissue called the adventitia. Secretory structures of the alimentary tract (A47) There is extensive osmotic fluid transport throughout the alimentary tract epithelium in both directions except in the large intestine, in which there is essentially reabsorption of fluid from the lumen to the blood. Mucus single cell glands (goblet cells) and serous glands can be found throughout the alimentary tract. The salivary glands, liver, and pancreas are separated from the tract but secrete digestive juices into it. Absorptive structures of the alimentary tract (A48) Surface projections increase the surface available for absorption. These projections include rugae, which are mucosal and submucosal folds in the stomach; plicae, which are submucosal folds seen along most of the length of the small intestine; villi, which are mucosal projections that cover the entire surface of the small intestine, where absorption of the products of digestion takes place; and microvilli, which are microscopic projections of the apical surface of absorptive cells in the intestine (brush border). Cell renewal in the alimentary tract (A49) The arrangement of proliferating and differentiating cells of the alimentary tract walls is indicated in Fig. A.2. There is a circadian rhythm in the mitotic activity of cells lining the alimentary tract with maximum activity for 15–18 h. The non-differentiated stem cells have a long cell-cycle time compared with the differentiating transitional cells, which makes the DNA relatively resistant to ionising radiation. A.4. Oral cavity, pharynx, and associated structures A.4.1. Macro-anatomy of oral cavity, pharynx, and associated structures (A50) The arrangement of the tissues of the oral cavity is illustrated in Fig. A.3. The part of the oral cavity lying between the lips and cheeks and the teeth is called the ‘vestibule’. The oral cavity proper is bounded by the teeth, the hard and soft palates, the tongue, the floor of the mouth, and the entrance to the oropharynx. A ring of lymphoid tissue, the tonsils, protects this common entrance to the digestive and respiratory tracts. The ducts of the salivary glands empty into the oral cavity. Oral cavity (A51) The tongue is composed of striated voluntary muscle and adipose tissue. The anterior two-thirds of the tongue’s upper surface are covered by mucosal elevations called ‘papillae’ and the posterior one-third with the bulges of the lingual tonsils situated lamina propria. Some of the papillae contain taste buds. The tongue has both sympathetic and parasympathetic innervation for blood vessels and glands. 139

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Fig. A.3. Oral cavity. Primary teeth: A, central incisor; B, lateral incisor; C, canine; D, first molar; E, second molar. Permanent teeth: 1, central incisor; 2, lateral incisor; 3, canine; 4, first premolar; 5, second premolar; 6, first molar; 7, second molar; 8, third molar or wisdom tooth. Modified from Solomon and Davis (1983, Fig. 21-6a, p. 578).

(A52) All teeth consist of a crown projecting above the gum and one or more roots that occupy sockets on the bone of the maxillae (Fig. A.4). Incisors have a single root, lower molars have two roots, and upper molars have three roots. The hard portions of a tooth essentially consist of dentine, enamel, and cementum. Dentine surrounds the central pulp chamber, which continues downwards into each root as a narrow canal that communicates with the periodontal membrane. In the region of the crown, a layer of enamel covers the outer surface of the dentine. The root is covered by a thin layer of cementum. There are 20 primary (milk) teeth (A–E in Fig. A.3) that begin to calcify at about 3–4 months in uterus. Eruption times vary considerably from one person to another, usually beginning at 6–8 months of age and reaching their full complement at 6–8 years. About 3 years after eruption, the roots begin to be resorbed due to pressure from underlying secondary teeth. Primary teeth are typically shed in the order in which they erupt, with the lower teeth being shed before the upper teeth. There are usually 32 secondary teeth with symmetrical sets of four teeth numbered 1–8 (Fig. A.3). Teeth 1–5 replace the primary teeth (1 replaces A, 2 replaces B, and so forth), but not the molar teeth (6–8). The first molar (6) erupts at about 6 years of age, while the wisdom teeth appear at about 18 years of age with considerable variation between subjects. (A53) The main salivary glands are the parotid, the submandibular and the sublingual glands. Numerous small salivary glands are found in the submucosa of the oral 140

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Fig. A.4. Sagittal section of a lower molar tooth. Source: Solomon and Davis (1983, Fig. 21-8, p. 579).

cavity (floor of the mouth, lips, tongue, and cheeks), and empty directly into the cavity via short ducts. Secretions from the parotid and the submandibular glands, located outside the oral cavity, empty into the salivary ducts and then into the mouth. The parotid gland is located subcutaneously, below and in front of the ear. (A54) The submandibular (submaxillary) gland is located under the floor of the mouth, close to the mandible. The sublingual gland is located in the floor of the mouth anterior to the submandibular gland. Pharynx (A55) The pharynx (Figs. A.5 and A.6) is common to both the alimentary and respiratory tracts. It is a musculofibrous passage, roughly conical, and divided into three regions: the exclusively respiratory nasal pharynx; the oral pharynx at the 141

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Fig. A.5. Oral cavity and pharynx. Modified from Williams and Warwick (1980, Fig. 8.31, p. 1268).

junction of the nasal airways and the back of the oral cavity; and the laryngeal pharynx, which is also respiratory and alimentary. (A56) During deglutition (swallowing), the pharynx shortens. The inferior part moves up and reduces its length by 3 cm. (A57) For the first few years after birth, the posterior wall and the roof of the pharynx form a smooth curve so that no clear demarcation separates the nasal pharynx and the oral pharynx. After 5 years, the posterior wall and the roof of the pharynx meet at an oblique angle, which is reduced to nearly 90° by puberty. (A58) The pharyngeal tonsils and associated lingual tonsils form a ring of lymphoid tissue around the oropharyngeal orifice. They are subepithelial but the epithelium invaginates into them to form crypts. They reach a peak of development before 10 years of age and involuate thereafter. The palatine tonsils are located on each side of the oral pharynx, while the pharyngeal or adenoid tonsil is unpaired on the posterior wall of the nasal pharynx. The latter usually disappears almost completely before puberty; however, some remains may be found in adults.

A.4.2. Micro-anatomy of oral cavity, pharynx, and associated structures Oral cavity (A59) The masticatory mucosa is found on the gingiva (gums) and the hard palate. It possesses a keratinised stratified squamous epithelium which resembles that of the 142

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Fig. A.6. Pharynx, from rear. Source: Rouvie`re (1962, Fig. 269, p. 422).

skin but lacks a stratum lucidum. Some parts of this epithelium are referred to as ‘parakeratinised’ because the cells of the stratum corneum do not lose their nuclei. The underlying deep layer of loose connective tissue (lamina propria) forms the papillae and contains blood vessels and nerves. As in the skin, the papillae stabilise the masticatory mucosa, thus protecting it from frictional and shearing stress, while the stratification of the keratinised epithelium protects it from aggressive contents of food. Except in some places on the hard palate, the mucosa is firmly adherent to the underlying bone, with the reticular layer of the lamina propria blending with the periosteum. A submucosa underlying the lamina propria and containing adipose tissue and mucous glands can be found on the hard palate. In the submucosal regions, thick collagenous bands link the mucosa to the bone. 143

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(A60) A lining mucosa covers the lips, cheeks, alveolar mucosal surface, floor of the mouth, inferior surfaces of the tongue, and soft palate. This mucosal lining covers striated muscle (lips, cheeks, tongue), bone (alveolar mucosa), and glands (soft palate, cheeks, inferior surface of tongue). In general, the epithelium is nonkeratinised, although it may be parakeratinised and keratinised in some places, such as the epithelium of the external part of the lips. Keratinocytes, Langerhans’ cells, melanocytes, and Merkel’s cells are found in mucosal epithelium as in the skin. (A61) A distinct submucosa underlies the epithelium except on the inferior surface of the tongue. It contains the larger blood vessels, nerves, and lymphatic vessels that supply the subepithelial neurovascular networks in the lamina propria throughout the oral cavity. The lining mucosa has fewer and shorter papillae so that it can adjust to the movement of underlying muscle layers. (A62) The gingival mucosa, which is organised like the masticatory mucosa, is firmly attached to the teeth and underlying bony tissue. The part of the epithelium attached to the tooth is called ‘junctional’. Above it and continuous with it is the gingival sulcus, a shallow crevice around the base of the tooth. In young subjects, the epithelium is attached to the enamel. In older individuals, the epithelium is attached to the cementum due to gingival recession. (A63) The tongue has a specialised lining mucosa with various papillae (Fig. A.7). The filiform papillae lying over the anterior dorsal surface of the tongue have a dome-shaped base supporting the elongated secondary papillae. These are made of epithelial cells that synthesise keratin. The fungiform papillae protrude among the filiform papillae. This stratified epithelium contains taste buds. Some 10 or 15 large dome-shaped circumvallate papillae can be seen on the posterior dorsal surface of the tongue, and this stratified epithelium also contains taste buds. The foliate papillae are parallel ridges containing taste buds that are located perpendicular to the tongue’s axis and along its lateral edges. They are separated by deep mucosal clefts flushed by secretions from small serous glands. The taste buds are located inside the epithelium, and the liquid mixture of food and saliva can reach the neuro-epithelial cells inside them through a small opening in their apex. The supporting cells extend from the basal lamina of the epithelium to the taste pore. The basal cells, near the basal lamina, could be stem cells for the two other cell types of the taste bud. The serous secretion of salivary glands enables the taste buds to respond rapidly to changing stimuli by flushing the papillae. Pharynx (A64) The nasal pharynx is lined with a respiratory epithelium (pseudostratified ciliated columnar with goblet cells) like the nasal cavity. Parts of the pharynx exposed to food are protected by a non-keratinised stratified squamous epithelium like the oral cavity and the oesophagus. The epithelium of the pharynx is separated from the striated skeletal muscle of the pharyngeal muscles by fibro-elastic connective tissue. (A65) The tonsils contain lymphoid follicles, 1–2 mm thick, embedded in connective tissue. The follicules are composed mainly of lymphoid tissue with a germinal centre. 144

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Fig. A.7. Lingual papillae, stratified epithelium (Ep), and taste buds (TB). Modified from Ross et al. (1995, Fig. 12, p. 429).

(A66) The salivary glands develop into the mesenchyme as a cord of cells from the oral cavity epithelium. The major glands are surrounded by a capsule of connective tissue from which septa divide the secretory portions of the gland into lobules and lobes. The septa contain the larger blood vessels and the excretory ducts. The secretory gland acini may contain serous cells (protein-secreting acini) and/or mucous cells (mucin-secreting acini). The mucous cells have a large Golgi apparatus in which carbohydrates are added to a protein base to synthesise mucus glycoproteins. These are stored as mucinogen granules in the cytoplasm and are released following hormonal or neural stimulation. After discharge of most or all of the mucinogen granules and during mucus resynthesis, the cells are difficult to distinguish from serous cells. Myoepithelial contractile cells lie between the epithelial cells and the basal lamina of the epithelium in the acini and the proximal portion of the duct system and move the secretory products towards the excretory duct. Numerous lymphocytes 145

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and plasma cells populate the connective tissue surrounding the acini in both the major and minor salivary glands. (A67) The salivary ducts modify the serous secretion by absorption or secretion of specific components and adding others to form the final product, while the secretion of mucous glands is not modified. In serous and mixed glands, the ducts secrete bicarbonate and potassium ions and absorb chloride. Since more sodium is reabsorbed than potassium is secreted, the secretion becomes hypotonic. When secretion is very rapid, the re-absorption and secretion rates by the ducts peak and the saliva may become isotonic or hypertonic. The epithelium of excretory ducts is simple cuboidal but it gradually changes to pseudostratified and stratified before joining with the oral cavity epithelium. (A68) The secretion of the parotid glands is serous as is most of that of the large submandibular glands. The small sublingual glands are mainly mucus secreting in humans. A.5. Oesophagus A.5.1. Macro-anatomy of the oesophagus (A69) The position and shape of the oesophagus are shown in Fig. A.8. The upper oesophageal opening has a slit-like morphology due to the tonic contractions of the surrounding striated muscles, the inferior constrictor of the pharynx, and the cricopharyngeal muscles. In between swallowing, the muscles of the body of the oesophagus are relaxed so its anterior and posterior walls are pushed together passively. The lower oesophageal opening is closed by a sphincter made of a thick ring of tonically contracted smooth muscle. A.5.2. Micro-anatomy of the oesophagus (A70) Like the mouth and pharynx, the oesophagus is lined with a stratified squamous epithelium to resist abrasion. In humans, keratinisation does not normally occur. The lamina propria contains diffuse lymphoid tissue and lymphoid nodules. The muscularis mucosae, a layer of longitudinally organised smooth muscle, is unusually thick in the proximal portion of the oesophagus and takes part in the swallowing reflex. It forms longitudinal folds with the submucosa that flatten out as a bolus of food passes down the oesophagus, resulting in localised dilation of the lumen. (A71) Mucous tubulo-alveolar glands are scattered in the submucosa along the length of the oesophagus. The excretory duct is composed of stratified squamous epithelium. The oesophageal cardiac glands (resembling the cardiac glands of the stomach) are found in the lamina propria of the mucosa. These glands produce a neutral mucus that protects the oesophagus from regurgitated gastric secretions. (A72) The upper third of the muscularis externa is made of striated muscle that forms a continuum with the muscles of the oropharynx. Striated muscle and smooth muscle are interwoven in the middle third of the oesophagus, while the distal third of the muscularis externa is only smooth muscle as in the rest of the digestive tract. A 146

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Fig. A.8. Oesophagus. Modified from Bader and Mellie`re (1970, Fig. 23, p. 11).

ring-like thickening of this muscle forms the lower oesophageal sphincter, which prevents regurgitation of acidic gastric juices. (A73) The oesophagus is fixed to adjoining structures in the thoracic cavity by an adventitia while a serosa covers the shorter intra-abdominal part. A.6. Stomach A.6.1. Macro-anatomy of the stomach (A74) The macro- and micro-anatomy of the stomach are shown in Fig. A.9. The stomach is located left of the midline of the trunk, beneath the diaphragm. The upper and central parts of the stomach are the fundus and the corpus, respectively. These provide a reservoir for ingested material and have the capacity for large variations in volume. The corpus also mixes the food with the gastric juices. A bubble of air is constantly trapped in the fundus. 147

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Fig. A.9. Macro- and micro-anatomy of the stomach. Modified from Johnson (1987, Ch. 26, Fig. 1, p. 818), Ross et al. (1995, Plate 73, p. 477) and Bader and Mellie`re (1970, Fig. 21, p. 32).

(A75) The cardia near the oesophageal opening forms the cephalic end of the stomach. The antrum forms the caudal end and is connected to the duodenum by the pylorus. The left lateral surface is the greater curvature and the right lateral surface is the lesser curvature. (A76) The inner surface of the empty stomach has longitudinal folds called ‘rugae’ that allow easy expansion of the stomach volume. The rugae disappear when the stomach is fully distended. A.6.2. Micro-anatomy of the stomach (A77) The epithelium that lines the surface and the gastric pits of the stomach mainly consists of a single layer of surface mucous cells (goblet cells) that have a 148

ICRP Publication 100 Table A.3. Cell types in regions of stomach Region of stomach

Cell type

Function or secretory product

Cardia

Surface mucous Undifferentiated mucous

Mucus Cell renewal

Fundus

Surface mucous Mucous neck Parietal Zymogen or chief A cell G cell Argentaffin

Mucous Cell renewal HCl, Intrinsic factor Pepsinogen Enteroglucagon Gastrin Serotonin Histamine Motilin

Pylorus

Argyrophil Surface mucous Parietal G cell

Secretin Mucus HCl Gastrin

large apical cup of mucinogen granules. These cells release an insoluble mucus which forms a thick layer (500 lm) that protects the epithelium from the acidic gastric juices. Gastric glands empty into the bottom of the gastric pits which appear as openings in the mucosal surface (see Table A.3). (A78) The cardia, near the oesophageal sphincter, contains the cardiac glands. Secretions from these glands, in combination with those of the oesophageal cardiac glands, contribute to the gastric juice and also help to protect the oesophageal epithelium against gastric reflux. The glands are tubular, somewhat tortuous, and occasionally branched. They are composed mainly of mucus-secreting cells, with occasional interspersed entero-endocrine cells. (A79) The fundus contains the fundic glands (or ‘gastric glands’) that are present throughout the entire gastric mucosa except for the small regions that contain the cardiac and pyloric glands. They are branched tubular glands that extend from the bottom of the gastric pits to the muscularis mucosa. The upper part (neck) is composed of cells secreting a soluble mucus when stimulated by the vagal nerves, interspersed with some parietal (oxyntic) cells. (A80) The parietal cells are also found in the deeper parts of the gland. These are stimulated by neural and locally released mediators (gastrin, acetylcholine, and histamine) to secrete concentrated HCl via a well-developed intracellular canalicular system. These cells contain many mitochondria, consistent with a large energy demand. The parietal cells also secrete a glycoprotein called ‘intrinsic factor’ which binds with vitamin B12 and permits its absorption in the ileum. The lower part of the glands contain chief cells which secrete the pro-enzyme pepsinogen and a weak lipase. Entero-endocrine cells are dispersed throughout the fundic glands along the epithelium basal lamina. These secrete the polypeptide hormone gastrin into the blood, and this stimulates the secretion of HCl. The undifferentiated parent (stem) cells of all these mature cells are located in the upper neck region of the glands. The cellular mitotic activity deep in the pits and in the immediate neck region of 149

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the gastric glands provides continuous renewal of the surface mucous cells. They differentiate during upward migration to the lumenal surface of the stomach, and are shed within a few days into the stomach lumen, as indicated by studies using 3Hthymidine. Other cells from the mucous neck migrate down into the gastric glands and differentiate into parietal cells, chief cells, and entero-endocrine cells which have a long life span of about 1 year. (A81) The antrum, localised between the fundus and the pyloric sphincter, contains the pyloric glands. These are branched, coiled tubular glands with a relatively wide lumen. They contain mainly surface mucous cells with interspersed gastrinsecreting cells and some parietal cells. These glands empty into deep gastric pits. (A82) The lamina propria of the gastric mucosa is restricted mainly to the limited spaces surrounding the gastric pits and glands. It contains mainly reticular fibres with associated fibroblasts and smooth muscle cells. Lymphocytes, plasma cells, macrophages, and some lymphoid nodules are also found in this layer of the mucosa. (A83) The muscularis mucosa of the gastric mucosa has a thin inner circular and an outer longitudinal muscle layer. Strands of smooth muscle cells, thought to facilitate the outflow of the gastric secretions, extend towards the surface in the lamina propria from the inner layer. The submucosa contains connective tissue with variable amounts of fat cells and blood vessels, as well as the submucosal (Meissner’s) plexus which innervates the vessels of the submucosa and the smooth muscle of the muscularis mucosae. (A84) The muscularis externa of the stomach is divided into an outer longitudinal layer, a middle circular layer, and an inner oblique layer. The longitudinal layer is absent from much of the anterior and posterior stomach surfaces, and the circular layer is poorly developed in the region of the cardia. Ganglion cells and unmyelinated nerve fibres between the muscle layers form the myenteric (Auerbach’s) plexus that innervates the muscle layers. (A85) The serosa (visceral peritoneum) of the stomach is continuous with the parietal peritoneum of the abdominal cavity via the omentum.

A.7. Liver, biliary tree, and pancreas A.7.1. Macro-anatomy of the liver (A86) The liver is the largest internal organ and receives the venous blood flow from the digestive tube, pancreas, and spleen. It receives all absorbed metabolic substrates and nutrients, and is also the first organ exposed to absorbed toxic substances and invading bacteria from the gut. The hepatic portal vein carries approximately three-quarters of the liver’s blood supply and the remainder is well-oxygenated blood from the hepatic artery, a branch of the coeliac trunk of the aorta. Blood from the two sources is mixed in the sinusoidal capillaries (sinusoids) that bathe the hepatocytes (Fig. A.10). Thus, liver cells are never exposed to fully-oxygenated blood. Within the liver, the branches of the portal vein and hepatic artery are closely associated with the draining branches of the bile duct and lymphatic systems. 150

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Fig. A.10. Liver lobule architecture. Source: Solomon and Davis (1983, Fig. 21-29, p. 596).

(A87) The sinusoids are in intimate contact with the hepatocytes and provide an exchange surface for substances between the blood and the liver cells. The sinusoids lead to a venous network through which blood leaves the liver. The major hepatic vein empties into the inferior vena cava. (A88) The lymphatic capillaries travel with the bile ducts to the hilum of the liver. About 80% of the hepatic lymph follows this pathway and drains into the thoracic duct, forming the major portion of the thoracic duct lymph. (A89) The portal blood carried to the liver contains nutrients, toxins, and bacteria from the intestine; blood cells and breakdown products of blood cells from the spleen; and endocrine secretions of the pancreas. A.7.2. Micro-anatomy of the liver (A90) The structural components of the liver include: hepatocytes, organised as ‘plates’ of cells; a stroma of connective tissue; blood vessels, nerves, lymphatic vessels, and bile ducts; and sinusoidal capillaries (sinusoids) between the plates of hepatocytes. (A91) The discontinuous sinusoidal endothelium has a basal lamina that is absent over large areas. The pores through the endothelial layer are large fenestrae, without diaphragms in the cells. There are large gaps between neighbouring endothelial cells. (A92) The size of the fenestrae changes dynamically in response to ethanol, pressure, and hormones such as serotonin. They allow free access of particles less than 151

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0.2 lm in diameter, but are too small for passage of erythrocytes or unprocessed large chylomicrons. This filtration system regulates fat uptake by parenchymal cells. Endothelial cells possess specialised endocytotic mechanisms and receptors, which allow the specific uptake from the serum of apoproteins (transferrin, ceruloplasmin, apolipoproteins), enzymes, and other particles. Liver lobules (A93) The classic hexagonal lobule is made of anastomosing plates of hepatic cells, one to two cells thick, separated by the system of sinusoids that perfuses the cells with mixed portal and arterial blood. At the centre of the lobule is a central vein into which the sinusoids drain. The plates of cells radiate from the central vein to the periphery of the lobule. At the angles of the hexagon are the portal areas (portal canals); loose connective tissue in which the branches of the portal vein, hepatic artery, bile ducts, lymphatics and nerves are located. This connective tissue is continuous with the fibrous capsule of the liver in the periphery. (A94) The hepatocytes can be separated into three concentric elliptical zones surrounding the portal vein (zonation). Zone 1 is closest to the portal vein, with cells in this region being the first exposed to nutrients and toxins and the first to be altered following bile duct occlusion (biliary stasis). Given the localisation of these cells in close proximity to sinusoid blood supply, they are the last to die and the first to regenerate in cases of circulatory impairment. Zone 2 lies between Zones 1 and 3 with no clear limits. The cells in this zone have both functional and morphological characteristics between those of Zones 1 and 3. Zone 3 is furthest from the portal vein and closest to the terminal hepatic vein. The cells in Zone 3 are less exposed to toxic substances and to biliary stasis, but are the first to die from reduced blood perfusion (centrilobular ischaemic necrosis). These important differences between Zones 1 and 3 are reflected in their enzyme content and metabolic activity. Ku¨pffer cells (A95) The Ku¨pffer cells form a mononuclear phagocytic system (macrophages) in the liver. They can proliferate in situ or be recruited from extrahepatic sources. They form part of the lining of the sinusoid, but do not form junctions with neighbouring endothelial cells. They send processes in the sinusoidal lumen in order to incorporate (phagocytose) circulating particulate material (cellular debris, parasites, viruses, bacteria) and to take up (endocytosis) macromolecules (immune complexes, bacterial endotoxins). They are involved in the destruction of aging red blood cells that reach the liver from the spleen, and store iron in the form of ferritin in the cytoplasm. (A96) Ku¨pffer cell activation by endotoxin results in an increased production of signal molecules (cytokines, eicosanoids, interleukins) that act on other cell types in the liver. Ku¨pffer cells play an important role in antigen processing and production of cytotoxic substances (superoxide anions, tumour necrosis factor). Perisinusoidal space (space of Disse) (A97) The perisinusoidal space lies between the basal cell membranes of the hepatocytes and the basal cell membranes of the endothelial and Ku¨pffer cells that line the sinu152

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soids. Hepatocytes send irregular microvillous processes into this space in order to increase the surface area available for exchange with the blood plasma that fills this space. (A98) Two cell types are found in the perisinusoidal space. The pit cells are defence cells and are termed ‘liver-specific natural killer cells’ and classified as large granular lymphocytes. The fat-storing Ito cells contain a large proportion of the body’s vitamin A content. They synthesise components of the extracellular matrix (collagen and laminin). They send long branching processes connecting with the endothelial cells which, by contracting under the influence of thromboxanes and endothelin, play a role in the control of sinusoidal blood flow. They also secrete cellular growth factors. Some toxins (CCl4, ethanol) make them increase their secretion of fibres, proliferate, and transform to myofibroblast-like cells; an evolution that can lead to liver fibrosis. (A99) In the fetal liver and in cases of chronic anaemia in the adult, the space of Disse contains islands of blood-forming cells. Hepatocytes (A100) The hepatocytes constitute about 80% of the cell population of the liver. These are special epithelial cells with a long life span (1 year) that separate the sinusoids and space of Disse from the bile canaliculi. The cell surface that faces the perisinusoidal space corresponds to the basal membrane of other epithelial cells, while the surfaces that face neighbouring cells and the bile canaliculus correspond, respectively, to the lateral and apical membranes of other epithelial cells. (A101) Many hepatocytes are binucleate and contain four times the amount of DNA of a regular cell. They have a unique capacity for regenerating a normal parenchyma after losses due to hepatotoxic processes, disease, or surgery. (A102) Due to their constant synthetic activity, numerous mitochondria and several Golgi complexes are found in these cells. The Golgi complexes near the bile canaliculus are involved in the secretion of bile, while those near the sinusoidal surfaces of the cell contain granules of lipoproteins (very-low-density lipoproteins) and other lipoprotein precursors that are released into the blood circulation. They are rich in peroxisomes, which process the hydrogen peroxide produced in many of the cytoplasmic metabolic activities. The smooth endoplasmic reticulum varies with metabolic activity (degradation and conjugation of toxins and drugs, synthesis of cholesterol and the lipid portion of lipoproteins). The lysosomes store pigment granules (lipofuscin), partially digested cytoplasmic organelles, phospholipids, and iron (as a ferritin complex). The energy-rich hepatocytes contain large deposits of glycogen and lipids. The size and number of lipid inclusions increase when the hepatocytes process certain hepatotoxins, including ethanol. (A103) The fetal liver has numerous haematopoietic cells among the hepatocytes. Their rapid disappearance before term contributes to the increase in liver metabolic activity. A.7.3. Macro-anatomy and micro-anatomy of the biliary system (A104) The biliary system starts with the canaliculi into which the hepatocytes secrete the bile, and ends with large ducts opening into the gallbladder and the intestine. 153

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The bile canaliculus is formed by grooves in neighbouring cell membrane and is sealed by tight junctions (zona occludens), zona adherens, gap junctions, and desmosomes. The hepatocytes send short, irregular microvilli to increase the membrane surface area and thus the secretory capacity. The bile canaliculi form a ring around the hepatocytes and constitute a network that drains into small bile ducts; the ‘ductules’. The bile flows in a direction opposite to the flow of blood, towards the portal canal. (A105) The ductules are lined with cuboidal cells and carry the bile through the boundary of the lobule to the interlobular bile ducts in the portal space. The epithelium lining the bile ducts gradually becomes columnar with microvilli similar to that of the extrahepatic bile ducts and the gallbladder. The connective tissue surrounding the epithelium gets denser with elastic fibres and smooth muscle cells appearing when the ducts near the hilum join to form the common hepatic duct. The hepatic duct is about 3 cm long with a wall similar to that of the gallbladder as described below, i.e. with all of the layers of the alimentary canal present, except for a muscularis mucosa. (A106) The cystic duct connects the common hepatic duct to the gallbladder and carries bile in both directions. The common bile duct (7 cm long) then carries hepatic and gallbladder bile to the duodenum at the ampulla of Vater. A thickening of the muscularis externa of the duodenum at the ampulla forms the sphincter of Oddi, which controls the flows of bile and pancreatic juice into the duodenum. (A107) The gallbladder is a distensible pear-shaped organ that is attached to the postero-inferior surface of the liver. Bile is concentrated in the gallbladder and the tall columnar epithelial cells are similar to the absorptive cells of the intestine. The lamina propria of the mucosa resembles that of the colon which is also specialised in the absorption of electrolytes and water. Beneath the lamina propria is a muscularis externa that has numerous collagen and elastic fibres among the bundles of smooth muscle cells, which allow the secretion of bile during digestion. Despite its origin from a foregut-derived tube, the gallbladder does not have a muscularis mucosae or a submucosa. External to the muscularis externa is a thick layer of dense connective tissue that contains large blood vessels, an extensive lymphatic network, and autonomic nerves. The gallbladder is tubular in shape in the newborn.

A.7.4. Macro-anatomy and micro-anatomy of the pancreas (A108) The pancreas (Fig. A.11) is surrounded by an anastomotic circle of arteries, branches of the coeliac trunk, and the superior mesenteric artery. Branches from these arteries form the arterial plexus in the interlobular connective tissue. (A109) The islets of Langerhans have a distinct arterial blood supply that divides within the islets into a capillary glomerulus. Efferent vessels emerge into the interacinar capillary tissue, where they divide to form a true interacinar capillary plexus. The blood is collected from the interacinar capillary plexus by small venules that unite to form a single intralobular vein before leaving the lobule to empty into the interlobular vein. This arrangement results in the exocrine pancreas receiving a large part of its blood flow through the islets, and being exposed to high concentrations of islet hormones. 154

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Fig. A.11. Pancreas. Modified from Bader and Mellie`re (1970, Fig. 14, p. 23 and N° 25, Fig. 1, p. 1).

(A110) The endocrine cells of the islets of Langerhans (A secreting glucagons, B secreting insulin, D secreting somatostatin, and PP secreting pancreatic polypeptide) differentiate from the digestive epithelium. The cells of the acini, exocrine secretory units, derive from the epithelial cells of the pancreatic ducts. A.8. Small intestine A.8.1. Macro-anatomy of the small intestine (A111) The small intestine is a long, coiled, and looped tube divided into three segments: duodenum, jejunum, and ileum. The proximal duodenum and the distal ileum are relatively fixed in position within the peritoneal cavity by connective tissue. However, the remainder of these two segments and the entire jejunum are not attached and are free within the peritoneal cavity. (A112) Anatomically, the duodenum becomes the jejunum at the ligament of Treitz, approximately 25 cm from the pylorus. No anatomical or histological boundary separates the jejunum from the ileum, but the proximal 40% of the remaining small intestine is considered to be the jejunum and the distal 60% is considered to be the ileum. A.8.2. Micro-anatomy of the small intestine (A113) The wall of the small intestine has several features that greatly increase the absorptive surface area (Fig. A.12). The valvulae conniventes (Kerckring folds) are permanent semilunar folds that contain a core of submucosa. They are most numerous in the distal part of the duodenum and the beginning of the jejunum, and are gradually reduced in size and concentration in the rest of the jejunum and the ileum. The villi are finger-like and leaf-like projections of the mucosa that extend into the 155

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Fig. A.12. Small intestine wall. Source: Greger and Windhorst (1996, Fig. 62-1, p. 1260).

intestinal lumen. The microvilli of the enterocytes provide the major amplification of the lumenal surface. Each cell possesses several thousand closely packed microvilli; they give the apical region of the cell a striated appearance (brush border). The absorptive surface of the intestinal mucosa is increased about three-fold by valvulae conniventes (plicae circulaire), another 10-fold by villi, and still another 20-fold by microvilli, resulting in an area of approximately 200 m2. (A114) The morphology of the intestinal absorptive surface differs between mature and juvenile animals. In infants, ridge-shaped small intestinal villi predominate, whereas in children above 3 years of age and in adults, the villi are finger- or leafshaped. Children have shorter villi and microvilli, and have a smaller overall surface area for absorption. However, nutrients and other substances are at least as efficiently absorbed in children as in adults. Small intestinal mucosa (A115) The villi (Fig. A.13) completely cover the surface of the small intestine, giving it a velvet-like appearance when viewed with the naked eye. The core of the villus consists of an extension of the lamina propria with a network of fenestrated capillaries located just beneath the epithelial basal lamina. The lamina propria of the villus also contains a central, blind-ending lymphatic capillary; the ‘lacteal’. Smooth muscle cells derived from the muscularis mucosa extend into the villus and accompany the lacteal, while myofibroblasts seem to bridge the villus transversely. The intermittent contraction of these two cell types can squeeze the content of the lacteal out of the villus. (A116) The intestinal glands (crypts of Lieberku¨hn) are simple blind-ended tubular structures that extend from the muscularis mucosae through the thickness of the lamina propria, where they open on to the lumenal surface of the intestine at the base of the villi. The glands are composed of a simple columnar epithelium in continuity with the epithelium of the villi. (A117) The lamina propria surrounds the glands and contains numerous cells of the immune system (lymphocytes, plasma cells, macrophages, eosinophils), particu156

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Fig. A.13. Mouse small intestinal mucosa. Source: Potten (1995, Fig. 1, p. 3).

larly in the villi. It also contains nodules of lymphoid tissue that represent a major component of the GALT. The nodules are particularly large (called ‘Peyer’s patches’) and numerous in the ileum, where they are preferentially located on the side of the intestine opposite the mesenteric attachment. 157

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(A118) The muscularis mucosae consists of two thin layers of smooth muscle cells: an inner circular layer and an outer longitudinal layer. Strands of smooth muscle cells extend from the muscularis mucosae into the lamina propria of the villi, and can control the villus form and thus the absorptive surface. Epithelial cell types (A119) The differentiated cells of the intestinal epithelium include mucin-secreting goblet cells, Paneth cells, entero-endocrine cells, microfold (M) cells, a modified enterocyte that covers enlarged lymphoid nodules in the lamina propria, and enterocytes (the absorptive cells). (A120) The enterocytes are specialised cells for the transport of substances from the lumen of the intestine to the circulatory system. They are tall columnar cells in which the microvilli increase the apical surface area by as much as 600 times. Each microvillus has a core of actin; microfilaments anchored to the plasma membrane at the tip and along the shaft of the microvillus. These microfilaments extend into the cell body and insert into the terminal web; a network of actin and myosin microfilaments that forms a layer in the most apical cytoplasm and attaches laterally to the zona adherens between cells. The contractile function of the terminal web may help to close the gaps left in the epithelial sheet by the exfoliation of aging cells. The glycocalyx of the microvilli consists of glycoproteins that project from the apical plasma membrane of the enterocytes. It provides additional surface for absorption and includes enzymes secreted by the absorptive cells that are essential for the final steps of digestion of proteins and sugars. Enterocytes are bound to one another and to the other cells of the epithelium by junctional complexes. The lateral membranes of adjoining enterocytes show lateral interdigitations or plications that increase the surface area of plasma membrane containing transport enzymes. These lateral plications separate during active absorption, especially of electrolytes, water, and lipids, thus increasing the volume of the intercellular compartment. The increased hydrostatic pressure from the accumulated solutes and water causes a directional flow through the basal lamina into the lamina propria. (A121) The cytoplasm of the enterocytes has elongated mitochondria that provide energy for the transport function of the cells and a well-developed smooth endoplasmic reticulum that is involved in the absorption of fatty acids and glycerol and in the resynthesis of neutral fat. The Golgi complex and lateral free ribosomes and rough endoplasmic reticulum synthesise glycoprotein enzymes that are inserted into the apical plasma membrane. (A122) The goblet cells are interspersed among the other cells of the intestinal epithelium with increasing density from the proximal to the distal small intestine. The apical accumulation of mucinogen granules restricts the nucleus, the extensive rough endoplasmic reticulum, free ribosomes, and the mitochondria to the basal portion of the cell. (A123) The Paneth cells are found at the base of the crypts. They have a basophilic (rich in nucleic acid synthesising proteins) basal cytoplasm, a supranuclear Golgi complex, and a large apex filled with acidophilic (due to an arginine-rich protein) secretary granules that also contain the antibacterial enzyme lysozyme, other glyco158

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proteins, and zinc. This antibacterial action, associated with the phagocytosis of certain bacteria and protozoa, gives Paneth cells a regulatory role for the normal intestine flora. (A124) The entero-endocrine cells are similar to those found in the stomach. They are concentrated in the lower portion of the intestinal crypt, but migrate slowly and can be found at all levels of the villus unit. They contain secretory vesicles that contain different mediators such as bioactive amines (5-hydroytryptamine, histamine) or peptides (somatostatin, cholecystokinin, secretin, gastric inhibitory peptide). Endocrine cells may produce more than one peptide or amine and play an important role in the local control of gastrointestinal function. (A125) The M cells are specialised epithelial cells that overlie Peyer’s patches and other large lymphoid nodules. They are nearly squamous, have microfolds rather than microvilli on their apical surface, and capture macromolecules from the lumen in endocytic vesicles that discharge their contents into the epithelial intercellular space close to lymphocytes that have migrated there. The antigens that reach lymphocytes in this manner can stimulate a response in the GALT. (A126) The intermediate cells constitute the majority of cells in the lower half of the intestinal crypt and usually undergo one or two divisions before they differentiate into either absorptive or goblet cells. They have short, irregular microvilli and small mucin-like secretary droplets, which they lose if they develop into absorptive cells. GALT (A127) The GALT is an immunological barrier found throughout the length of the gastrointestinal tract. It consists of lymphoid nodules, lymphocyte aggregates, macrophages, plasma cells, and eosinophils in the lamina propria of the intestinal mucosa, with lymphocytes also insinuated between epithelial cells (intra-epithelial lymphocytes). The lymphoid nodules are in greater quantity in the ileum where they form clusters called ‘Peyer’s patches’. There are 15–30 such patches in the human intestine, with only a few in the jejunum and the vermiform appendix. (A128) In co-operation with the overlying epithelial cells, particularly the M cells, the lymphoid tissue samples the antigens in the epithelial intercellular spaces. The intra-epithelial lymphocytes process antigens and probably migrate to lymphoid nodules in the lamina propria, where they undergo blastic transformation leading to antibody secretion by newly differentiated plasma cells. Most of the plasma cells of the lamina propria of the intestine secrete dimeric immunoglobulin A (IgA) rather than the more common IgG; other plasma cells produce IgM and IgE. IgA is transported across the epithelium and linked to a basal membrane glycoprotein synthesised by the enterocytes. The epithelial cells then incorporate the complex of IgA and secretary glycoprotein by endocytosis, and subsequently release it by exocytosis at the apical plasma membrane. In the gut lumen, IgA binds to antigens, toxins, and micro-organisms in a process called ‘immune exclusion’ which has an important protective role. (A129) IgM is also found in the lumen of the gut, probably following a similar secretory pathway. Mast cells are also present in the lamina propria, often close to nerve plexi, and respond to specific antigens by binding to membrane receptors. 159

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Epithelial cell renewal in the small intestine (A130) The epithelial stem cells are localised in the base of the intestinal crypts and multiply to give rise to committed and differentiated cells, including absorptive enterocytes, goblet cells, auto-endocrine cells, and Paneth cells. All epithelial cells other than Paneth cells migrate from the crypt on to the villus and are shed at the tip of the villus. (A131) Paneth cells remain in the base of the crypt near the stem cells from which they derive. They have a life span of about 4 weeks and are then replaced by differentiation of a nearby ‘committed’ cell in the crypt. (A132) The pericryptal fibroblast sheath constitutes a population of replicating cells with their stem cell zone beneath the base of the crypt, adjacent to the stem cell zone of the epithelium (in the small intestine as well as the colon). These cells differentiate in parallel with the epithelial cells, and they secrete fine collagen fibres that are associated with the basement membranes of the crypt epithelial cells. Small intestinal submucosa (A133) The submucosa consists of a dense connective tissue and localised sites that contain aggregates of adipose cells. A specific characteristic of the duodenum submucosa is the existence of tubulo-alveolar glands, called ‘Brunner’s glands’, which have secretary cells that are both zymogen secreting and mucus secreting. Their secretion also protects the proximal small intestine and activates duodenal enzymes by neutralising the acid-containing chyme from the stomach with alkaline glycoproteins and bicarbonate ions (pH of the secretion 8.1–9.3). Small intestinal muscularis externa (A134) Smooth muscle cells are arranged in an inner circular layer and an outer longitudinal layer and are co-ordinated by the myenteric (Auerbach’s) plexus located between these two muscle layers. The contraction of the circular muscle layer creates segmentation of the intestinal contents, while the co-ordinated contraction of the circular and longitudinal muscle layers produce peristalsis which moves the intestinal contents along the length of the tract.

A.9. Large intestine A.9.1. Macro-anatomy of the large intestine (A135) The large intestine is anatomically divided into seven segments from proximal to distal in the following order: caecum; ascending colon; hepatic flexure; transverse colon; splenic flexure; descending colon; and sigmoid colon. The caecum forms a blind pouch just distal to the ileocaecal valve, and the appendix is a thin, finger-like extension of this pouch. The transverse and sigmoid parts of the colon are intraperitoneal and connected to the posterior abdominal wall by the mesentery. (A136) Blood and lymph circulation in the large intestine are illustrated in Fig. A.14. 160

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Fig. A.14. Blood and lymph circulation in the large intestine. Modified from Bader and Mellie`re (1970, Fig. 8, p. 13).

A.9.2. Micro-anatomy of the large intestine (A137) There are differences in the wall structure between the large intestine and the small intestine. The mucosa has a ‘smooth’ surface; neither plicae circulares nor villi are present. The outer longitudinal layer of the muscularis externa exhibits three equally spaced bands (taeniae coli). Paneth cells are normally absent in the adult human colon. Mucosa (A138) The mucosa of the large intestine (Fig. A.15) shows an orderly pattern of straight tubular glands (crypts of Lieberku¨hn), lined with the simple columnar 161

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Fig. A.15. Colon cross-section, X3O. Muc, mucosa. SubM, submucosa. ME, muscularis externa with ME(c) circular, ME(l) longitudinal and TC, tenia coli. S, serosa. Modified from Ross et al. (1995).

epithelium surface from which they invaginate to extend through the full thickness of the mucosa. (A139) The colonic absorptive cells are similar in morphology to the enterocytes of the small intestine, and re-absorb water and electrolytes by a similar membrane transport process. The cells are capable of rapid glycocalyx secretion but they do not secrete digestive enzymes. There is active transport of fluid in the wide intercellular spaces. (A140) Goblet cells are particularly numerous in the large intestine compared with the small intestine, and produce mucins continuously to lubricate the bowel. The proportion increases with distance, approaching 50% of epithelial cells near the rectum, to facilitate the progression of the increasingly more solid colonic contents. Goblet cells mature deep in the crypts and are pushed towards the lumenal surface by replication of stem cells. Lamina propria (A141) There are some specific structural features in the lamina propria of the colon. The pericryptal fibroblast sheath is more developed than in the small intestine. At all levels of the mucosa, the fibroblasts retain some morphologic apposition to the basal lamina of the epithelium by extending cytoplasmic processes through the collagen table to make contact with the basal lamina. Most of the pericryptal fibroblasts develop the morphologic and histochemical characteristics of macrophages when they reach the level of the lumenal surface. The macrophages in the core of the lamina propria could derive from the pericryptal fibroblasts. The collagen table is a thick layer of collagen and proteoglycans between the basal lamina of the epithelium and that of the fenestrated absorptive venous capillaries. These components are secreted by migrated mature fibroblasts from the pericryptal sheath. This layer plays a role in the control of the flow rate of water and electrolytes from the epithelium to the vascular compartment. No lymphatic vessels can be found in the lamina propria. 162

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GALT (A142) The GALT of the large intestine is continuous with that of the terminal ileum and is more developed, showing large nodules that distort the crypts and extend into the submucosa, due to the great number and variety of micro-organisms and noxious endproducts of metabolism normally present in the lumen of the colon. Lymphatic vessels form a network around the muscularis mucosae and around the muscularis externa as they do in the small intestine, but no vessels or associated smooth muscle cells extend towards the free surface from that layer. Cell renewal in the large intestine (A143) As in the small intestine, all of the mucosal epithelial cells of the colon arise from stem cells located at the bottom of the crypts. The lower third of the crypt constitutes the replicative zone where newly generated cells undergo two to three more divisions as intermediate cells while they begin their migration up the crypt to the luminal surface, where they are shed at the midpoint between two adjacent crypts. The turnover times of the epithelial cells of the colon are similar to those of the small intestine, i.e. about 6 days for the absorptive cells and goblet cells, and up to 4 weeks for the entero-endocrine cells. Senile epithelial cells are shed into the lumen. Muscularis externa (A144) In the colon, the outer layer of the muscularis externa is very thin and forms the visible longitudinal bands of muscle that are called ‘taeniae coli’. Bundles of muscle from the teniae coli penetrate the inner, circular layer of muscle at irregular intervals along the length and circumference of the colon. These discontinuities in the muscularis externa allow segments of the colon to contract independently, forming separated saccules called ‘haustra’. Submucosa and serosa (A145) The submucosa corresponds to the general description already given. Where the large intestine is directly in contact with other structures (as on much of its posterior surface), its outer layer is an adventitia; elsewhere, the outer layer is a typical serosa. Micro-anatomy of the appendix (A146) The appendix differs from the rest of the colon in having a complete layer of longitudinal muscle in the muscularis extema; however, its most conspicuous feature is the large number of lymphoid nodules that fuse and extend into the submucosa. In many adults, the normal structure of the appendix is lost, and the appendage is filled with fibrous scar tissue.

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A.10. Rectum and anal canal A.10.1. Macro-anatomy of the rectum and anal canal (A147) The rectum is a dilated distal portion of the alimentary tract. The upper part is marked by the presence of the transverse rectal folds. The upper two-thirds (which derive from the primitive posterior intestine) are only associated with the peritoneum on the anterior and lateral sides. The lower third (which derives from the primitive cloacum) is totally extraperitoneal. (A148) Blood from the upper rectum is drained by the mesenteric veins which are part of the portal system. Blood from the lower part of the rectum and the anal canal is drained by the rectal veins, upper and lower, and the rectal venous plexus. A.10.2. Micro-anatomy of the rectum and anal canal (A149) The mucosa of the rectum is similar to that of the rest of the distal colon, having straight, tubular intestinal glands (crypts) with many goblet cells. (A150) In the rectum, the two layers of smooth muscle are uniformly thick with no taeniae coli, as in the small intestine. (A151) The anal canal extends from the anorectal junction to the anus. The upper part of the anal canal has longitudinal folds called ‘anal columns’. Depressions between the anal columns are called ‘anal sinuses’. The submucosa of the anal columns contains the terminal ramifications of the superior rectal artery and the rectal venous plexus. Enlargements of these submucosal veins constitute internal haemorrhoids. (A152) The upper portion of the anal canal has simple columnar epithelium and the lower portion has stratified squamous epithelium in continuity with that of the skin of the perineum. A stratified columnar epithelium may be found in the middle portion. Anal glands extend into the submucosa and even into the muscularis extema. These are branched, straight tubular glands that secrete mucus on to the anal surface through ducts lined with a stratified columnar epithelium. (A153) The muscularis mucosae disappears at about the level of the recto-anal margin, but at the same level, the circular layer of the muscularis extema thickens to form the internal anal sphincter. The external anal sphincter is formed by the striated muscles of the perineum. (A154) Large apocrine glands, the circumanal glands, hair follicles, and sebaceous glands are found in the skin surrounding the anal orifice.

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