OESOPHAGUS

The oesophagus can be distinguished from the stomach at stage 13 (embryo 5 mm). It elongates during successive stages and its absolute length increases more rapidly than the embryo as a whole. Cranially it is invested by splanchnopleuric mesenchyme posterior to the developing trachea, and more caudally between the developing lungs and pericardioperitoneal canals posterior to the pericardium. (For details of tracheo-oesophageal fistulae see p. 1037). Caudal to the pericardium, the terminal, pregastric segment of the oesophagus has a short thick dorsal meso-oesophagus (from splanchnopleuric mesenchyme), while ventrally it is enclosed in the cranial stratum of the septum transversum mesenchyme. Each of the above are continuous caudally with their respective primitive dorsal and ventral mesogastria. Thus the oesophagus has only limited areas related to a primary coelomic epithelium. However, note the subsequent development of the para-oesophageal right and left pneumatoenteric recesses (see Fig. 73.7), the relation of the ventral aspect of the middle third of the oesophagus to the oblique sinus of the pericardium, and the relation of its lateral walls in the lower thorax to the mediastinal pleura. All the foregoing are secondary extensions from the primary coelom.

Fig. 73.7 A–C, Stages of development of the subdiaphragmatic foregut and the right and left pericardioperitoneal/pleuroperitoneal canals, with particular reference to the terminal oesophagus, stomach, duodenum, spleen, the lesser sac of peritoneum and omenta: seen in semicoronal section (left column) and transverse section at the levels indicated by the arrows (right column). D, E, Three dimensional schematization of the lesser sac, dorsal and ventral mesogastria.

The oesophageal mucosa consists of two layers of cells by stage 15 (week 5), but the proliferation of the mucosa does not occlude the lumen at any time. The mucosa becomes ciliated at 10 weeks, and stratified squamous epithelium is present at the end of the 5th month: occasionally patches of ciliated epithelium may be present at birth. Circular muscle can be seen at stage 15 but longitudinal muscle has not been identified until stage 21. Neuroblasts can be demonstrated in the early stages; the myenteric plexuses have cholinesterase activity by 9.5 weeks and ganglion cells are differentiated by 13 weeks. It has been suggested that the oesophagus is capable of peristalsis in the first trimester. Oesophageal atresia is one of the more common obstructive conditions of the alimentary tract: fetuses swallow amniotic fluid, and so the condition may be indicated by polyhydramnios.

STOMACH

At the end of the fourth and beginning of the fifth week the stomach can be recognized as a fusiform dilation cranial to the wide opening of the midgut into the yolk sac (Figs 73.2 and 73.3). By the fifth week this opening has narrowed into a tubular vitelline intestinal duct, which soon loses its connection with the digestive tube. At this time the stomach is median in position and separated cranially from the pericardium by the septum transversum (see Fig. 73.5A), which extends caudally on to the cranial side of the vitelline intestinal duct and ventrally to the somatopleure. Dorsally, the stomach is related to the aorta and, reflecting the presence of the pleuroperitoneal canals on each side, is connected to the body wall by a short dorsal mesentery, the dorsal mesogastrium (see Fig. 73.6). The latter is directly continuous with the dorsal mesentery (mesenteron) of almost all of the remainder of the intestine, except its caudal short segment.

Fig. 73.5 Early development of the liver and the supra-umbilical peritoneal cavities. A, The hepatic endodermal primordium proliferates ventrally into the septum transversum mesenchyme. The endodermal cells forming the hepatic trabeculae will become hepatocytes; the septum transversum mesenchymal cells will become the endothelium of the liver sinusoids and early blood cells. The developing lung buds can be seen expanding into the pericardioperitoneal cavities. B, The septum transversum mesenchyme and the stomach become enclosed by the right and left pericardioperitoneal canals (shown on transverse section). The apposition of the medial pericardioperitoneal walls form the dorsal and ventral mesogastria. The proximity of the lung buds to the developing stomach can be seen. The pleural and supra-umbilical peritoneal cavities are transiently, and bilaterally, symmetrical above the umbilicus. C, The lower border of the ventral mesogastrium denotes the connection between the supra-umbilical peritoneal cavities (pleuro-peritoneal canals) can be identified by the position of the ventral pancreatic bud and common bile duct. White arrows indicate the direction of movement of the dorsal and ventral mesogastria.

Fig. 73.6 Three-dimensional schematization of the major developmental sequences of the subdiaphragmatic embryonic and fetal gut, together with its associated major glands, peritoneum and mesenteries: left anterolateral aspect. The development sequence A–F spans 1.5 months to the perinatal period. Three-dimensional schematization of the major developmental sequences of the subdiaphragmatic embryonic and fetal gut, together with its associated major glands, peritoneum and mesenteries: left anterolateral aspect. The development sequence A–F spans 1.5 months to the perinatal period. H denotes the general disposition of the remaining viscera and mesenteric roots with their lines of attachment and principal contained vessels, which approximate to the adult state for comparison.

In human embryos of 10 mm (stage 15–16), the characteristic gastric curvatures are already recognizable. Growth is more active along the dorsal border of the viscus: its convexity markedly increases and the rudimentary fundus appears. Because of more rapid growth along the dorsal border, the pyloric end of the stomach turns ventrally and the concave lesser curvature becomes apparent (Fig. 73.3; see also Fig. 73.6). The stomach is now displaced to the left of the median plane and apparently becomes physically rotated, which means that its original right surface becomes dorsal and its left surface becomes ventral. Accordingly the right vagus is distributed mainly to the dorsal, and the left vagus mainly to the ventral, surfaces of the stomach. The dorsal mesogastrium increases in depth and becomes folded on itself. The ventral mesogastrium becomes more coronal than sagittal. The pancreaticoenteric recess (see Fig. 73.7B(ii)), hitherto usually described as a simple depression on the right side of the dorsal mesogastrium, becomes dorsal to the stomach and excavates downwards and to the left between the folded layers. It may now be termed the inferior recess of the bursa omentalis. Put simply, the stomach has undergone two ‘rotations’. The first is 90° clockwise, viewed from the cranial end, the second is 90° clockwise, about an anteroposterior axis. The displacement, morphological changes and apparent ‘rotation’ of the stomach have been attributed variously to its own and surrounding differential growth changes, extension of the pancreaticoenteric recess with changes in its mesenchymal walls, and pressure, particularly that exerted by the rapidly growing liver.

DUODENUM

The duodenum develops from the caudal part of the foregut and the cranial part of the midgut. A ventral mesoduodenum, which is continuous cranially with the ventral mesogastrium, is attached only to the foregut portion. Posteriorly the duodenum has a thick dorsal mesoduodenum which is continuous with the dorsal mesogastrium cranially and the dorsal mesentery of the midgut caudally. Anteriorly the extreme caudal edge of the ventral mesentery of the foregut extends onto the short initial segment of the duodenum. The liver arises as a diverticulum from the ventral surface of the duodenum at the foregut–midgut junction, i.e. where the midgut is continuous with the yolk sac wall (the cranial intestinal portal). The ventral pancreatic bud also arises from this diverticulum. The dorsal pancreatic bud evaginates posteriorly into the dorsal mesoduodenum slightly more cranially than the hepatic diverticulum. The rotation, differential growth, and cavitations related to the developing stomach and omenta cause corresponding movements in the duodenum, which forms a loop directed to the right, with its original right side now adjacent to the posterior abdominal wall (see Fig. 73.6). This shift is compounded by the migration of the bile duct and ventral pancreatic duct around the duodenal wall. Their origin shifts until it reaches the medial wall of the second part of the fully formed duodenum: the bile duct passes posteriorly to the duodenum and travels in the free edge of the ventral duodenum and ventral mesogastrium. Local adherence and subsequent absorption of part of the duodenal serosa and the parietal peritoneum results in almost the whole of the duodenum, other than a short initial segment, becoming retroperitoneal (sessile).

Duodenal atresia is a developmental defect found in 1 in 5000 live births (Whittle 1999). It may be associated with an annular pancreas which may compress the duodenum externally (20% of duodenal atresia), or with abnormalities of the bile duct. In 40–60% of cases the atresia is complete and pancreatic tissue fills the lumen. The condition can be diagnosed on ultrasound examination, which reveals a typical double bubble appearance caused by fluid enlarging the stomach and the proximal duodenum. Polyhydramnios is invariably present and often the indication for the scan. Duodenal atresia commonly occurs with other developmental defects, e.g. cardiac and skeletal anomalies and in Down’s syndrome.

DORSAL AND VENTRAL MESENTERIES OF THE FOREGUT

The epithelium of the stomach and duodenum does not rotate relative to its investing mesenchyme. The rotation includes the coelomic epithelial walls of the pericardioperitoneal canals, which are on each side of the stomach and duodenum and form its serosa, and the elongating dorsal mesogastrium or the much shorter dorsal mesoduodenum. A ventral mesogastrium can be seen when the distance between the stomach and liver increases. Whereas the dorsal mesogastrium takes origin from the posterior body wall in the midline, its connection to the greater curvature of the stomach, which lengthens as the stomach grows, becomes directed to the left as the stomach undergoes its first rotation. With the second rotation a portion of the dorsal mesogastrium now faces caudally (see Fig. 73.6). The ventral mesogastrium remains as a double layer of coelomic epithelium which encloses mesenchyme and forms the lesser omentum (see Fig. 73.7).

Movement of the stomach is associated with an extensive lengthening of the dorsal mesogastrium, which becomes the greater omentum, and which now, from its posterior origin, droops caudally over the small intestine, then folds back anteriorly and ascends to the greater curvature of the stomach. The greater omentum is therefore composed of a fold containing, technically, four layers of peritoneum. The dorsal mesoduodenum, or suspensory ligament of the duodenum, is a much thicker structure, and it fixes the position of the duodenum when the rest of the midgut and its dorsal mesentery elongate and pass into the umbilical cord. For a more detailed account of this process see page 1216.

SPECIAL GLANDS OF THE POSTPHARYNGEAL FOREGUT

Pancreas

The pancreas develops from two evaginations of the foregut which fuse to form a single organ. A dorsal pancreatic bud can be seen in stage 13 embryos as a thickening of the endodermal tube which proliferates into the dorsal mesogastrium (Figs 73.3 and 73.4). A ventral pancreatic bud evaginates in close proximity to the liver primordium but cannot be clearly identified until stage 14, when it appears as an evagination of the bile duct itself. At stage 16 (5 weeks) differential growth of the wall of the duodenum results in movement of the ventral pancreatic bud and the bile duct to the right side and ultimately to a dorsal position. It is not clear whether there is a corresponding shift of mesenchyme during this rotation. However, the ventral pancreatic bud and the bile duct rotate from a position within the ventral mesogastrium (ventral mesoduodenum) to one in the dorsal mesogastrium (dorsal mesoduodenum) which is destined to become fixed onto the posterior abdominal wall. By stage 17 the ventral and dorsal pancreatic buds have fused, although the origin of the ventral bud from the bile duct is still obvious. Three-dimensional reconstruction of the ventral and dorsal pancreatic buds have confirmed that the dorsal pancreatic bud forms the anterior part of the head, the body and the tail of the pancreas and the ventral pancreatic bud forms the posterior part of the head and the posterior part of the uncinate process. The ventral pancreatic bud does not form all of the uncinate process (Collins 2002).

Fig. 73.4 Development of the pancreas in a human embryo. A, An early stage, 7.5 mm embryo; lateral view. B, A later stage, 14.5 mm embryo; ventral view.

The developing pancreatic ducts usually fuse in such a way that most of the dorsal duct drains into the proximal part of the ventral duct (Figs 73.3 and 73.4). The proximal portion of the dorsal duct usually persists as an accessory duct. The fusion of the ducts takes place late in development or in the postnatal period: 85% of infants have patent accessory ducts as compared to 40% of adults. Fusion may not occur in 10% of individuals, in which case separate drainage into the duodenum is maintained, so-called pancreatic divisum. Failure of the ventral pancreatic diverticulum to migrate will result in an annular pancreas which may constrict the duodenum locally.

The ventral pancreas does not always extend anterior to the superior mesenteric vein but remains related to its right lateral surface. Initially the body of the pancreas extends into the dorsal mesoduodenum and then cranially into the dorsal mesogastrium. As the stomach rotates, this portion of the dorsal mesogastrium is directed to the left forming the posterior wall of the lesser sac. The posterior layer of this portion of dorsal mesogastrium fuses with the parietal layer of the coelom wall (peritoneum) and the pancreas becomes mainly retroperitoneal (see Fig. 73.7C). The region of fusion of the dorsal mesogastrium does not extend so far left as to include the tail of the pancreas which passes into the lienorenal (splenorenal) ligament. The anterior border of the pancreas later provides the main line of attachment for the posterior leaves of the greater omentum.

Cellular development of the pancreas

The early specification of pancreatic endoderm involves the proximity of the notochord to the dorsal endoderm, which locally represses the expression of Shh transcription factor. Endoderm caudal to the pancreatic region does not respond to notochordal signals. The ventral pancreatic endoderm does not seem to undergo the same induction. Pancreatic mesenchyme is derived from two regions. The mesenchyme which surrounds the dorsal pancreatic bud proliferates from the splanchnopleuric coelomic epithelium of the medial walls of the pericardioperitoneal canals, whereas the ventral pancreatic bud is invested by septum transversum mesenchyme and by mesenchyme derived from the lower ventral walls of the pericardioperitoneal canals.

The primitive endodermal ductal epithelium provides the stem cell population for all the secretory cells of the pancreas. Initially these endocrine cells are located in the duct walls or in buds developing from them, and later they accumulate in pancreatic islets. The remaining primitive duct cells will differentiate into definitive ductal cells. In the fetus they develop microvilli and cilia but lack the lateral interdigitations seen in the adult. Branches of the main duct become interlobular ductules which terminate as blind ending acini or as tubular, acinar elements.

The ductal branching pattern and acinar structure of the pancreas is determined by the pancreatic mesenchyme. This mesenchyme gives rise to connective tissue between the ducts which, in the fetus, appears to be important in stimulating pancreatic proliferation and maintaining the relative proportions of acinar, α and β cells during development. It also provides cell lines for smooth muscle within the pancreas. Angiogenic mesenchyme invades the developing gland to produce blood and lymphatic vessels.

The process of islet differentiation is divided into two phases (Collins 2002). Phase I, characterized by proliferation of polyhormonal cells, occurs from weeks 9–15. Phase II, characterized by differentiation of monohormonal cells, is seen from week 16 onwards. The β cells, producing insulin and amylin, differentiate first, followed by α-cells which produce glucagon. The δ cells which produce somatostatin are seen after 30 weeks. The dorsal bud gives rise mostly to α cells, and the ventral bud to most of the pancreatic polypeptide producing cells. The β cells develop from the duct epithelium throughout development and into the neonatal period. Later, in weeks 10–15, some of the primitive ducts differentiate into acinar cells in which zymogen granules or acinar cell markers can be detected at 12–16 weeks.

The pancreas in the neonate has all of the normal subdivisions of the adult. The head is proportionately large in the newborn and there is a smooth continuation between the body and the tail. The inferior border of the head of the pancreas is found at the level of the second lumbar vertebra. The body and tail pass cranially and to the left, and the tail is in contact with the spleen (see Fig. 14.4).

Liver

The liver is one of the most precocious embryonic organs and is the main centre for haemopoiesis in the fetus. It develops from an endodermal evagination of the foregut and from septum transversum mesenchyme, which is derived from the proliferating coelomic epithelium in the protocardiac region. The development of the liver is intimately related to the development of the heart. The vitelline veins, succeeded by the umbilical veins passing to the sinus venosus are disrupted by the enlarging septum transversum to form a hepatic plexus, the forerunner of the hepatic sinusoids. (See Collins, 2002 for a detailed account of hepatic development.)

Early liver development

As the head fold and early intraembryonic coelom form, the ventral parietal wall of the pericardial cavity gives rise to populations of cells termed precardiac or cardiac mesenchyme. Hepatic endoderm is induced to proliferate by this mesenchyme, although all portions of the early heart tube, truncus arteriosus, atria, ventricle, both endocardium and myocardium, have hepatic induction potency which is tissue-specific, but not species-specific. As the heart and foregut become separated by the accumulation of the cardiac mesenchyme, the mesenchyme itself is renamed septum transversum. It is seen as a ventral mass, caudal to the heart, which passes dorsally on each side of the developing gut to join the mesenchyme proliferating from the walls of the pericardioperitoneal canals. The majority of the cells within the septum transversum are destined to become hepatic mesenchyme.

In the stage 11 embryo the location of the hepatic endoderm has been identified at the superior boundary of the rostral intestinal portal. By stage 12, the hepatic endodermal primordium is directed ventrally and begins to proliferate as a diverticulum. There are two parts: a caudal part, which will produce the cystic duct and gallbladder, and a cranial part which forms the liver biliary system (Figs 73.3, 73.5A). The cells start to express liver-specific molecular markers and glycogen storage.

Around the cranial portion of the hepatic diverticulum the basal lamina is progressively disrupted and individual epithelial cells migrate into the surrounding septum transversum mesenchyme. The previously smooth contour of the diverticulum merges into columnar extensions of endoderm, the epithelial trabeculae, which stimulate the hepatic mesenchymal cells to form blood islands and endothelium. The advance of the endodermal epithelial cells promotes the conversion of progressively more hepatic mesenchyme into endothelium and blood cells, and only a little remains to form the scanty liver capsule and interlobular connective tissue. This invasion by the hepatic epithelium is completed in stage 13, when it approaches the caudal surface of the pericardial cavity, and is separated from it only by a thin lamina of mesenchyme which will give rise to part of the diaphragm.

During this early phase of development the liver is far more highly vascularized than the rest of the gut. The hepatic capillary plexus is connected bilaterally with the right and left vitelline veins. Dorsolaterally they empty by multiple channels into enlarged hepatocardiac channels, which lead to the right and left horns of the sinus venosus (see Fig. 73.9); usually the channel on the right side is most developed. Both left and right channels bulge into the pericardioperitoneal canals, forming sites for the exchange of fluid from the coelom into the vascular channels. The growth of the hepatic tissue in these regions is sometimes referred to as the left and right horns of the liver.

Fig. 73.9 Development of the vitelline, umbilical and terminal cardinal vein complexes: the early symmetric condition. A, Early symmetrical arrangement of cardinal and umbilical veins entering the sinus venosus, and blood from the yolk sac passing via vitelline veins through anastomoses forming in the septum transversum mesenchyme (green). B, The developing duodenum is surrounded by transverse duodenal intervitelline anastomoses. Changes in the developing gut and umbilical veins cause shifts in the routes taken by venous blood flowing to the sinus venosus.

The liver remains proportionately large during its development and constitutes a sizeable organ dorsal to the heart at stage 14 then more caudally placed by stage 16. By this stage hepatic ducts can be seen separating the hepatic epithelium from the extrahepatic biliary system, but even at stage 17 the ducts do not penetrate far into the liver.

Maturation of the liver

At 3 months’ gestation, the liver almost fills the abdominal cavity and its left lobe is nearly as large as its right. When the haematopoietic activity of the liver is assumed by the spleen and bone marrow, the left lobe undergoes some degeneration and becomes smaller than the right. The liver remains relatively larger than in the adult throughout the remainder of gestation. In the neonate it constitutes 4% of the body weight, compared to 2.5–3.5% in adults. It is in contact with the greater part of the diaphragm and extends below the costal margin anteriorly, and in some cases to within 1 cm of the iliac crest posteriorly. The left lobe covers much of the anterior surface of the stomach and constitutes nearly one-third of the liver (see Fig. 14.4). Although its haemopoietic functions cease before birth its enzymatic and synthetic functions are not completely mature at birth.

Development of intrahepatic biliary ducts

The development of the intrahepatic biliary ducts follows the branching pattern of the portal vein radicles (Collins 2002). The cranial hepatic diverticulum gives rise to the liver hepatocytes, the intrahepatic large bile ducts (right and left hepatic ducts, segmental ducts, area ducts and their first branches) and the small bile ducts (septal bile ducts, interlobular ducts and bile ductules). The portal and hepatic veins arise together from the vitelline veins. Early in development the accumulation of mesenchyme around these veins is similar, whereas later mesenchyme increases around the portal veins. This is a prerequisite for bile duct development. Primitive hepatocytes surround the portal vein branches and associated mesenchyme and form a sleeve of cells termed the ductal plate. Portions of the ductal plate divide to produce lines of epithelial cells which migrate close to a portal vein branch where they differentiate into bile ducts. As the bile ducts develop, angiogenic mesenchymal cells form blood vessels which connect to the hepatic artery from 10 weeks. Thus the portal triads are patterned by the portal vein radicles which initially induce bile duct formation and then artery formation. The development of the biliary system extends from the hilum to the periphery. Abnormalities of the biliary tree are associated with abnormalities of the branching pattern of the portal vein. The developing bile ducts remain patent throughout development; the solid stage of ductal development previously promulgated has been refuted. Atresia of the extrahepatic bile ducts has been noted, often in association with extrahepatic atresia. The cause of this condition is not clear; inflammatory process may be involved, although some cases have features of ductal plate malformation (Howard 2002).

Development of extrahepatic biliary ducts

The caudal part of the hepatic endodermal diverticulum forms the extrahepatic biliary system, the common hepatic duct, gallbladder, cystic duct and common bile duct.

The bile duct, which originated from the ventral wall of the foregut (now duodenum), migrates with the ventral pancreatic bud first to the right and then dorsomedially into the dorsal mesoduodenum. The right and left hepatic ducts arise from the cranial end of the common hepatic duct from 12 weeks’ gestation.

Atresia of the extrahepatic bile ducts in neonates occurs alone or in conjunction with a range of other anomalies, including situs inversus, malrotation, polysplenia and cardiac defects. In such cases the intrahepatic bile ducts have a mature tubular shape but also show features of ductal plate malformation.

In the neonate the gallbladder has a smaller peritoneal surface than in the adult, and its fundus often does not extend to the liver margin. It is generally embedded in the liver and in some cases may be covered by bands of liver. After the second year the gallbladder assumes the relative size it has in the adult.

PRIMARY INTESTINAL (OR MIDGUT) LOOP

The midgut loop can first be seen at stage 15 when a bulge, the caecal bud, can be discerned on the lower limb of the loop, caudal to the yolk stalk (which arises from the apex or summit of the loop) (Fig. 73.3). Later, the original proximal limb of the loop moves to the right and the distal limb to the left (Fig. 73.3C). The longest portion of the dorsal mesentery is at the level of the yolk stalk: there is less relative lengthening near the caudal end of the duodenum or the cranial half of the colon. The midgut extends into the umbilical coelom having already rotated through an angle of 90° (anticlockwise viewed from the ventral aspect). This relative position is approximately maintained so long as the protrusion persists, during which time the proximal limb which forms the small intestine elongates greatly. It becomes coiled, and its adjacent mesentery adopts a pleated appearance. The origin of the root of the mesentery is initially both median and vertical, while at its intestinal attachment it is elongated like a ruffle and folded along a horizontal zone. The mesenteric sheet and its contained vessels has spiralled through 90°. The distal, colic, part of the loop elongates less rapidly and has no tendency to become coiled. By the time the fetus has attained a length of 40 mm (10 weeks), the peritoneal cavity has enlarged and the relative size of the liver and mesonephros is much less. The re-entry of the gut occurs rapidly and in a particular sequence during which it continues the process of rotation. The proximal loop returns first, with the jejunum mainly on the left and the ileum mainly on the right of the subhepatic abdominal cavity. As they re-enter the abdominal cavity the coils of jejunum and ileum slide inwards over the right aspect of the descending mesocolon, and so displace the descending colon to the left. The transverse colon passes superiorly to the origin of the root of the mesentery (Fig. 73.6). The caecum is the last to re-enter and at first lies on coils of ileum on the right. Later development of the colon leads to its elongation and to the establishment of the hepatic and splenic flexures. A timetable for intestinal rotation in staged human embryos is given by Kim et al (2003).

UMBILICAL CORD

During the period when the midgut loop protrudes into the umbilical coelom, the edges of the ventral body wall are becoming relatively closer, forming a more discrete root for the umbilical cord. Somatic mesenchyme, which will form the ventral body wall musculature, migrates into the somatopleuric mesenchyme and passes ventrally toward the midline. The umbilical cord (see p. 181) forms all of the ventral body wall between the pericardial bulge and the developing external genitalia. It encloses a portion of the extraembryonic coelom, the umbilical coelom, into which midgut loop protrudes. When the midgut loop is abruptly returned to the abdominal cavity the more recognizable umbilical cord forms. The vitellointestinal duct and vessels involute. The cranial end of the allantois becomes thinned and its lumen partially obliterated, and it forms the urachus. The mesenchymal core of the umbilical cord is derived by coalescence from somatopleuric amniotic mesenchyme, splanchnopleuric vitellointestinal (yolk sac) mesenchyme, and splanchnopleuric allantoic (connecting stalk) mesenchyme. These various layers become fused and are gradually transformed into the viscid, mucoid connective tissue (Wharton’s jelly) which characterizes the more mature cord. The changes in the circulatory system result in a large cranially oriented left umbilical vein (the right umbilical vein regresses), and two spirally disposed umbilical arteries (see p. 181).

MATURATION OF THE SMALL INTESTINE

ENTERIC HINDGUT

The development of the large intestine, whether derived from mid- or hindgut, seems to be similar. The proximal end of the colon can be first identified at stage 15 when an enlargement of a local portion of gut on the caudal limb of the midgut loop defines the developing caecum. An evagination of the distal portion of the caecum forms the vermiform appendix at stage 17 (Fig. 73.3). Apart from the embryonic studies of Streeter (1942) there is little information about the development of the large intestine in humans. The early endodermal lining of the colon appears stratified, and mitoses occur throughout the layers. A series of longitudinal folds arise initially at the rectum and caecum and later in the regions of colon between these two points. The folds segment into villi with new villi forming between. The developing mucosa invaginates into the underlying mesenchyme between the villi to form glands which increase in number by splitting longitudinally from the base upwards. The villi gradually diminish in size and are absent by the time of birth.

MATURATION OF THE LARGE INTESTINE

The similarity of development of the small and large intestines is further mirrored in their cytological differentiation. Fetal gut from 11 weeks shows dipeptidase activity in the colon as well as in the small intestine. Throughout preterm development meconium corpuscles are seen in the colon and in the small intestine: they are believed to be the phago-cytosed remains of neighbouring cells which have died as a result of programmed cell death.

There is little direct evidence of colonic function in the human fetus and neonate. However, the specific results of mammalian studies are being correlated to human studies where possible. A number of distinct and important differences between the function of adult and fetal colon have been reported.

ANAL CANAL

Mesenchymal proliferation occurs around the rim of the ectodermal aspect of the anal membrane which thus comes to lie at the bottom of a depression, the proctodeum (see Figs 78.4, 78.7E). With the absorption and disappearance of the anal membrane the anorectum communicates with the exterior. The lower part of the anal canal is formed from the proctodeal ectoderm and underlying mesenchyme, but its upper part is lined by endoderm. The line of union corresponds with the edges of the anal valves in the adult. The dual origin of the anal canal is reflected in its innervation: the endodermal portion is innervated by autonomic nerves, and the ectodermal proctodeum is innervated by spinal nerves.

In the fourth and fifth weeks a small part of the hindgut, the postanal gut, projects caudally beyond the anal membrane (Fig. 73.3B); it usually disappears before the end of the fifth week.

Imperforate anus is a term used to describe many different anorectal malformations. The most common is anal agenesis, which is found in almost 50% of all cases of imperforate anus. The condition is usually associated with a fistula, which opens into the vulva (females) or into the urethra (males). It is more rare for the anal membrane to fail to perforate. The condition cannot reliably be diagnosed prenatally by ultrasound diagnosis, and it may be confused with Hirschsprung’s disease (see below) and colonic atresia. The prognosis is good for low lesions of the anal canal. The principal concern in all cases is the degree of bowel control, urinary control and in some cases sexual function, which is compromised by the condition. Anorectal malformations may be indicators of other abnormalities, for example those forming the ‘VATER’ syndrome (Vertebral, Anal, Tracheo-Oesophageal and Renal abnormalities).

ENTERIC NERVOUS SYSTEM

Enteric neurones are derived from trunk neural crest cells at somite levels 1–7 and from 28 onwards (see Fig. 24.19 and p. 374). After neurulation the crest cells begin their ventral migration and invade the gut via the dorsal mesentery (see Fig. 24.11). Glial cells associated with the gut have been identified as arising from similar levels. The local splanchnopleuric mesenchyme patterns the crest cells such that those which enter the gut layers attain an enteric fate, whereas those that remain outside the gut become committed as parasympathetic postganglionic neurones. The enteric neurones also migrate to the glands of the gut, e.g. the pancreas.

GUT-ASSOCIATED LYMPHOID TISSUE

Individual lymphocytes appear in the lamina propria of the gut from approximately week 12 of development, and lymphoid aggregates, Peyer’s patches, have been noted between 15 and 20 weeks: it is not clear whether these cells migrate in from distant sources or differentiate from the investing mesenchyme. The endodermal epithelium overlying the lymphoid aggregates is often distorted into a dome shape. The cells within the dome are a mixed population of enterocytes, endocrine cells, goblet cells and M cells. M cells are specialized to provide a mechanism for the transport of micro-organisms and intact macromolecules across the epithelium to the intraepithelial space and lamina propria. They have been observed in the fetus by 17 weeks; it is believed that they are formed by a specialized epithelial/mesenchymal interaction of the endoderm and underlying lymphoid type mesenchyme.

There are similarly specialized epithelial cells between the enterocytes. Intraepithelial leukocytes typically account for 15% of the epithelial cells of the gut in the adult. They have been observed at 11 weeks, with a distribution of 2–3 intraepithelial leukocytes/100 gut epithelial cells. Both T and B lymphocytes have been described in the developing gut wall. For an account of the development of the immune cells of the gut consult Butzner & Befus (1989). The neonatal gut becomes colonized by a range of bacterial flora, some of which exist in a symbiotic relationship with their host, some of which may be considered pathogenic.

PERITONEUM

Peritoneum develops from a specific portion of the intraembryonic coelomic walls (pp. 189, 199). Initially the intraembryonic coelomic epithelium is a pseudostratified germinal layer from which cellular progeny with different fates arise in specific sites and at specific developmental times. The portion which will give rise to the peritoneum is derived from the lower portion of the pericardioperitoneal canals and the somatopleure and splanchnopleure associated with the lower foregut, midgut and upper portions of the hind gut (see Figs 12.2, 73.1).

The proliferative splanchnopleuric epithelium produces cell populations for the mucosa and muscularis of the gut and also the lamina propria and epithelium of the visceral peritoneum (the serosa of the gut wall). The somatopleuric epithelium gives rise to the lamina propria and epithelium of the parietal peritoneum. The visceral and parietal peritoneal layers constitute a mesothelium, which denotes their origin from the intraembryonic mesoderm of the coelomic wall.

As the gut grows, splanchnic mesenchyme accumulates around the endodermal epithelium and the whole unit generally moves ventrally. There is a concomitant enlargement of the caudal ends of the developing pericardioperitoneal (pleuroperitoneal) canals and developing peritoneal cavity. The medial walls of the intraembryonic coelom move closer and there is a relative decrease in the mesenchyme between them. The regions where the medial portions of the intraembryonic coelom come together are termed mesenteries. They are composed of two layers of peritoneum with intervening mesenchyme and contain the neurovascular structures which pass to and from the gut. At the caudal ends of the pleuroperitoneal canals the gut has both ventral and dorsal mesenteries, whereas caudal to this there is only a dorsal mesentery (Figs 73.6, 73.7).

The mesenteries attached to the gut lengthen to permit large movements or rotations of the gut tube. Later, when part or the whole of the mesentery lies against the parietal peritoneum, their apposed surfaces fuse and are absorbed, i.e. they become sessile. Only those viscera developed in direct apposition to one of the primary coelomic regions, or a secondary extension of the latter, retain a partial or almost complete visceral serous cover. Thus the original line of reflexion of mesenteries becomes altered, or in some cases the organ may become retroperitoneal. These mechanisms are significant throughout the subdiaphragmatic gut, but are predominant in the small and large intestine. All serous membranes may vary their thickness, lines of reflexion, disposition, ‘space’ enclosed and their channels of communication, by a process of areal and thickness growth on one aspect combined with cavitation (leading to expanding embryonic recess formation) on the other (Figs 73.6, 73.7).

Although all of the gut tube and its derived glands are associated with mesenteries formed as described above, the nomenclature for some portions of the gut and glands is different. Thus the mesenteries of the stomach are called omenta and the reflections of peritoneum around the liver, which develop from a confluence of splanchnopleuric, somatopleuric and septum transversum-derived portions, are called ligaments.

The movements of the developing viscera within the peritoneal cavity occur with associated movements of the mesothelia which surround them. The descriptions of peritoneal cavity development which follow are thus describing a sequence of changes which affect a complex space and its boundaries.

NEONATAL PERITONEAL CAVITY

The fully formed peritoneal cavity, although complex topographically, remains a single cavity with numerous intercommunicating regions, pouches and recesses (see Fig. 14.5). The only small peritoneal sacs to separate completely from the main cavity are the infracardiac bursa (Fig. 73.7(B(i)) and the tunica vaginalis testis (see Fig. 78.17).

In fetal life the greater omental cavity extends to the internal aspect of the lateral and caudal edges of the omentum. Postnatally a slow but progressive fusion of the internal surfaces occurs with obliteration of the most dependent part of the cavity: this proceeds rostrally and, when mature, the cavity does not usually extend appreciably beyond the transverse colon. Transverse mesocolon–greater omentum fusion begins early while the umbilical hernia of the midgut has not returned. It starts between the right margin of the early greater omentum and near the root of the presumptive mesocolon, and later spreads to the left.

In the neonate the peritoneal cavity is ovoid (see Fig. 14.4). It is fairly shallow from anterior to posterior because the bilateral posterior extensions on each side of the vertebral column, which are prominent in the adult, are not present. Two factors lead to the protuberance of the anterior abdominal wall in the neonate and infant. The diaphragm is flatter in the newborn, which produces a caudal displacement of the viscera. The pelvic cavity is very small in the neonate, which means that organs which are normally pelvic in the adult, i.e. urinary bladder, ovaries and uterus, all extend superiorly into the abdomen (see Figs 14.5, 78.9, 78.10). The pelvic cavity is joined to the abdominal cavity at less of an acute angle in the neonate because there is no lumbar vertebral curve and only a slight sacral curve.

The peritoneal attachments are similar to the adult. However, the greater omentum is relatively small: its constituent layers of peritoneum may not be completely fused, and it does not extend much below the level of the umbilicus (see Fig. 14.5). Generally the length of the mesentery of the small intestine and of the transverse and sigmoid mesocolons are longer than in the adult, whereas the area of attachment of the ascending and descending colons is relatively smaller. The peritoneal mesenteries and omenta contain little fat.

SUPRARENAL GLANDS IN THE NEONATE

The suprarenal glands are relatively very large at birth (see Figs 14.4 and 78.8) and constitute 0.2% of the entire body weight, compared with 0.01% in the adult. The left gland is heavier and larger than the right, as it is in the adult. At term each gland usually weighs 4 g; the average weight of the two glands is 9 g (average in the adult is 7–12 g). The glands involute rapidly in the neonatal period when each gland loses 25% of its mass; the average weight of both glands is 5 g by the end of the second week, and 4 g by 3 months. Birth weight is not regained until puberty. The cortex of the suprarenal gland is thicker than in the adult and the medulla of the gland is small. Early studies on fetal suprarenal glands described extensive degeneration and necrosis of fetal zone cells; however, it is believed that these studies showed disease processes rather than the normal involution of the gland. With normal involution the fetal zone cells of the postnatal gland become smaller and they assume the appearance and organization typical of zona fasciculata.

INFERIOR VENA CAVA

The inferior vena cava of the adult is a composite vessel which develops on the posterior abdominal wall dorsal to the developing peritoneal cavity. It forms as a consequence of the temporal remodelling of successive venous complexes (see Fig. 13.4). The precise mode of development of its postrenal segment (caudal to the renal vein) is still somewhat uncertain. Its function is initially carried out by the right and left postcardinal veins (Fig. 73.8; see also Fig. 13.4), which receive the venous drainage of the lower limb buds and pelvis and run in the dorsal part of the mesonephric ridges, receiving tributaries from the body wall (intersegmental veins) and from the derivatives of the mesonephroi.

Fig. 73.8 The inferior vena cava develops within the posterior abdominal wall. It is a composite vessel formed by temporal remodelling of successive somatic venous anastomoses. (For early venous development see Fig. 13.4.)

The early postcardinal veins communicate across the midline via an interpostcardinal anastomosis. This remains as an oblique transverse anastomosis between the iliac veins, and becomes the major part of the definitive left common iliac vein. It diverts an increasing volume of blood into the right longitudinal veins, which accounts for the ultimate disappearance of most of those on the left.

The supracardinal veins receive the larger venous drainage of the growing body wall. The right supracardinal vein persists and forms the greater part of the postrenal segment of the inferior vena cava. The continuity of the vessel is maintained by the persistence of the anastomosis between the right supracardinal and the right subcardinal in the renal collar. The left supracardinal disappears, but some of the renal collar formed by the left supracardinal–subcardinal anastomosis persists in the left renal vein. Both supracardinal veins drain cranially into the subcardinal veins. On the right side, the subcardinal vein comes into intimate relationship with the liver. An extension of the vessel takes place in a cranial direction and meets and establishes continuity with a corresponding new formation that is growing caudally from the right vitelline hepatocardiac (common hepatic) vein. In this way, on the right side a more direct route is established to the heart and the prerenal (cranial) segment of the inferior vena. In summary, the inferior vena cava is formed from below upwards by the confluence of: the common iliac veins, a short segment of the right postcardinal vein, the postcardinal–supracardinal anastomosis, part of the right supracardinal vein, the right supracardinal–subcardinal anastomosis, right subcardinal vein, a new anastomotic channel of double origin (the hepatic segment of the inferior vena cava), and the cardiac termination of the right vitelline hepatocardiac vein (common hepatic vein).

Only the supracardinal part of the inferior vena cava receives intersegmental venous drainage. The postrenal (caudal) segment of the inferior vena cava is on a plane that lies dorsal to the plane of the prerenal (cranial) segment. Thus the right phrenic, suprarenal and renal arteries, which represent persistent mesonephric arteries, pass behind the inferior vena cava, whereas the testicular or ovarian artery, which has a similar developmental origin, passes anterior to it.

In some animals, the right postcardinal vein constitutes a large part of the postrenal segment of the inferior vena cava. In these cases the right ureter, on leaving the kidney, passes medially dorsal to the vessel and then, curving round its medial side, crosses its ventral aspect. Rarely, a similar condition is found in humans, and indicates the persistence of the right postcardinal vein and failure of the right supracardinal to play its normal part in the development of the inferior vena cava.

PORTAL CIRCULATION

The heart first differentiates in splanchnopleure that, after head fold formation, forms the dorsal wall of the primitive pericardial cavity (floor of the rostral foregut) and may therefore be considered a highly specialized vitelline vascular derivative. At the caudal extremity of the splanchnopleuric gut tube (the future lower rectum and upper anal canal) the vitelline venous drainage makes connections with the internal iliac radicles of the postcardinal complex.

The development of the gut occurs contemporaneously with changes to the early symmetrical embryonic circulation (see Ch. 13). A symmetrical, segmental system of somatic arteries remains and supplies the body wall of the trunk. The underlying arrangement of these vessels is only slightly modified by subsequent development. The main changes to the embryonic arrangement occur with the growth of the foregut, liver and paired viscera, i.e. kidneys and suprarenal glands.

The early development of the ventral splanchnic arteries is outlined in Chapter 13. Three main arterial trunks, the coeliac trunk, superior mesenteric and inferior mesenteric arteries, supply the fore- mid- and hind gut respectively. From the gastric terminal segment of the future oesophagus to the upper rectum, the developing endodermal epithelium is surrounded by splanchnopleuric mesenchyme permeated by a capillary plexus which drains into an anastomosing network of veins. This plexus is particularly dense ventrally associated with the central midgut region where, for a while, it receives a network of small veins from the definitive yolk sac. Later, in normal development, these vessels atrophy as the yolk sac diminishes. More rostrally the splanchnopleuric capillaries associated with the foregut and upper portions of the yolk sac form longitudinal channels anterolateral to the gut and these become increasingly well defined as the embryonic abdominal vitelline veins. Entering the septum transversum, the right and left vitelline veins incline slightly, becoming parallel to the lateral aspects of the gut. They establish connections with capillary plexuses in the septal mesenchyme, then continue, finally curving to enter the medial part of the cardiac sinual horn of their corresponding side. The parts of the gut closely related to the presinual segments of the vitelline veins are the future subdiaphragmatic end of the oesophagus, primitive stomach, the superior (first) and descending (second) regions of the duodenum, and the remainder of the duodenal tube.

The principal ascending vitelline veins flanking the sides of the abdominal part of the foregut receive venules from its splanchnopleuric capillaries, and those of the septal mesenchyme. Within these venular nets, enlarged (but still plexiform) anastomoses connect the two vitelline veins (Fig. 73.9; see Fig. 13.1C). A subdiaphragmatic intervitelline anastomosis develops in the rostral septal mesenchyme, lying a little caudal to the cardiac sinuatrial chamber, connecting the veins near their sinual terminations. (The channel is sometimes termed suprahepatic because of the position of the hepatic primordium; with expansion of the latter it becomes partly intrahepatic.) The presumptive duodenum is crossed by three transverse duodenal intervitelline anastomoses. Their relation to the gut tube alternates so that the most cranial, the subhepatic, is ventral, the intermediate is dorsal and the caudal is ventral (Fig. 73.9B). It has become customary to describe the paraduodenal vitelline veins and their associated anastomoses as forming a figure 8. At this early stage when left and right embryonic veins are still symmetric, the cranial duodenal anastomosis becomes connected with the subdiaphragmatic anastomosis by a median longitudinal channel, the primitive median ductus venosus, which is dorsal to the expanding hepatic primordium, but ventral to the gut. The further development of the vitelline veins and anastomoses is, as indicated, closely interlocked, with rapid hepatic expansion and gut changes, and umbilical vein disposition and modification is closely involved.

CHANGES IN THE VITELLO-UMBILICAL VEINS

Progressive changes in the vitello-umbilical veins are rapid, profound and closely linked with regional modifications in shape and position of the gut, expansion and invasion of venous channels by hepatic tissue, asymmetry of the heart and cardiac venous return. The principal events are summarized in Figs 73.9, 73.10 and 73.11.

Fig. 73.10 Development of the vitelline, umbilical and terminal cardinal vein complexes: a mid-stage of asymmetry has been reached between the early symmetric condition (see Fig. 73.9) and the definitive late prenatal state. The extent of the liver within the septum transversum mesenchyme is shown in green.

Fig. 73.11 The condition of some main upper abdominal and intrathoracic right atrial terminal veins in the later prenatal months. The rotation of the stomach and movement of the duodenum produce relative changes in the final arrangement of duodenal intervitelline anastomoses which form the hepatic portal vein.

From the cranial portion of the early hepatic evagination of the foregut, interconnected sheets and ‘cords’ of endodermal cells, the presumptive hepatocytes, penetrate the septum transversum mesenchyme. Hepatic mesenchyme is composed of a mixed population of cells with endothelial/angiogenic and connective tissue lineages. Capillary plexuses develop within this mesenchyme and, possibly under the influence of the endodermal hepatic sheets, the plexuses become more profuse by further addition of angioblastic septal mesenchyme, which also forms masses of perivascular intrahepatic haemopoietic tissue. These processes extend along the plexiform connections of the vitelline, and later the umbilical, veins until their intrahepatic (trans-septal) zones themselves become largely plexiform. Initially capillary in nature, they transform into a mass of rather wider, irregular, sinusoidal vessels with a discontinuous endothelium containing many phagocytic cells. The lengths of vitelline veins involved in these processes are the intermediate parts of the segments extending from the subhepatic (cranioventral duodenal) to the suprahepatic (subdiaphragmatic) transverse intervitelline anastomoses, and the corresponding lengths of the umbilical veins. Thus at this early stage the liver sinusoids are perfused by mixed blood reaching them through a series of branching vessels collectively called the venae advehentes, or afferent hepatic veins: they are, deoxygenated from the gut splanchnopleure via vitelline vein hepatic terminals and oxygenated from the placenta via hepatic terminals of the umbilical veins (Fig. 73.10). Blood leaves the liver through four venae revehentes (efferent hepatic veins); two on each side reach and open into their respective cardiac sinual horns. This full complement of four hepatocardiac veins is only transient, and becomes reduced to one dominant, rapidly enlarging channel. The originally bilaterally symmetric cardinal vein complexes, both rostral and caudal, develop transverse or oblique anastomoses so that the cardiac venous return is ultimately restricted to the definitive right atrium.

These cardiac and concomitant hepatoenteric changes are accompanied by events in supra-, intra- and subhepatic parts of the vitello-umbilical veins. Some vessels enlarge, persisting as definitive vessels to maturity and, in places, they are joined later by other channels that become defined in already established capillary plexuses. Other vessels retrogress, either disappearing completely or remaining as vestigial tags and, occasionally, vessels of fine calibre. Some vessels of crucial importance in the circulatory patterns of embryonic and fetal life become obliterated postnatally and transformed to substantial fibrous cords. Both right and left umbilical hepatocardiac and the left vitelline hepatocardiac veins continue, for a time, to discharge blood into their sinual horns; however, they begin to retrogress (Figs 73.9 and 73.10). The right umbilical channel atrophies completely. The left channels also disappear, but their cardiac terminals may, on occasion, be found as conical fibrous tags attached to the inferior wall of the coronary sinus. The right vitelline hepatocardiac vein continues enlarging and ultimately forms the terminal segment of the inferior vena cava. The latter receives the right efferent hepatic veins and new channels draining the territories of the left efferent hepatic veins. These collectively form the upper and lower groups of right and (secondary) left hepatic veins. The terminal caval segment also shows the orifice of the right half of the intervitelline subdiaphragmatic anastomosis, and a large new connection with the right subcardinal vein.

The hepatic terminals of the right and left duodenal parts of the vitelline veins are destined to form the corresponding branches of the hepatic portal vein, the left branch incorporating the cranial ventral intervitelline anastomosis. With rotation of the gut and formation of the duodenal loop, segments of the original vitelline veins and the caudal transverse anastomosis atrophy (indicated in Fig. 73.10 and 73.10), while new splanchnopleuric venous channels, the superior mesenteric and splenic veins, converge and join the left end of the dorsal intermediate anastomosis. The numerous other radicles of the portal vein and its principal branches, including the inferior mesenteric vein, are later formations.

For a period, placental blood returns from the umbilicus via right and left umbilical veins, both discharging through afferent hepatic veins into the hepatic sinusoids, where admixture with vitelline blood occurs. At approximately 7 mm crown–rump length, the right umbilical vein retrogresses completely. The left umbilical vein retains some vessels discharging directly into the sinusoids, but new enlarging connections with the left half of the subhepatic intervitelline anastomosis emerge. The latter is the start of a bypass channel for the majority of the placental blood, which continues through the median ductus venosus and finally the right half of the subdiaphragmatic anastomosis, to reach the termination of the inferior vena cava (Fig. 73.11).

FETAL/NEONATAL UMBILICAL VESSELS