Embryology of liver

Embryology of liver

1. Embryology of the Liver Pratap Sagar Tiwari DM resident, Department of Hepatology , NAMS

2. Introduction: Liver The liver is largest internal organ & the largest gland in the human body . It lies under the diaphragm in the right upper abdomen and midabdomen and extends to the left upper abdomen. The liver has the general shape of a wedge, with its base to the right and its apex to the left .1 The normal liver extends from the 5th ICS in the Rt MCL down to the costal margin. It measures 12–15 cm coronally and 15–20 cm transversely.1 The median liver weight is 1,800 g in m and 1,400 g in F .1 Wanless I R. Physioanatomic Considerations. In: Schiff ER, Maddrey WC, Sorrell MF, editors. Diseases of the liver. 11 th edition. John Wiley & Sons Ltd;2012. Pic source : http://www.medicinenet.com/drug_induced_liver_disease/article.htm 1/26

3. Embryogenesis 0 ---------------------------2nd week-----------------------------8th week---------------------Birth Conception Germinal Stage Embryonic stage Fetal stage Pic source: https ://en.wikipedia.org/wiki/Human_embryogenesis#/media/File:HumanEmbryogenesis.svg 2/26

4. Notes of the previous slide This slide shows the quick review of the embryogenesis. The embryonic period in humans begins at fertilization and continues until the end of the 10th week of gestation (8th week by embryonic age). It starts out as formation of a single cell zygote and the process of cleavage begins, the cell divides several times to form a ball of cells called a morula covered by zona pellucida . The cells start to bind firmly together in the process of caompaction and then their cleavage continue as cellular differentiation. Further cellular division is accompanied by the formation of a small cavity between the cells. This stage is called a blastocyst. Cells differentiate in outer layer collectively called the trophoblast and the inner cell mass. The iner cell mass with later give rise to embryo proper, the amnion, yolk sac and allantois and the outer trophoblast layer will form the fetal parts of the placenta. The blastocyst reaches the uterus at roughly the 5th day after fertilization. It is here that lysis of the zona pellucida occurs,This allows the trophectoderm cells of the blastocyst to come into contact with, and adhere to, the endometrial cells of the uterus initiaing the implantation process on day 7. The inner cell mass or the embryoblast is the source of embryonic stem cells which are pluripotent cells and can develop into any of the germ layers.

5. Formation of trilamminar disk Primitive streak Bilaminar disk Hypoblast Epiblast Ectoderm Endoderm mesoderm Third wk : Formation of Primitive streak at midline causing the disk to have right and left halves. Movement of some cells from the epiblast towards the hypoblast forms the mesoderm layer The embryoblast forms an embryonic disc which is bilaminar disc with upper layer the epiblast ie the primitive ectderm and the inner layer which is the hypoblast :the primitive endoderm . 3/26

6. Mesoderm Pic source: http://pocketdentistry.com/2-development-of-the-head-face-and-mouth/ 4/26

7. Derivatives 5/26

8. Extra note Retroperitoneal SADPUCKER S = S uprarenal (adrenal) glands A = A orta/Inferior Vena Cava D = D uodenum (second and third segments) P = P ancreas U = U reters/ C = C olon (ascending and descending only) K = K idneys E = E sophagus R = R ectum Intraperitoneal S = Stomach A = Appendix L = Liver T = Transverse colon D = duodenum (only the 1st part, though) S = Small intestines P = Pancreas (only the tail though) R = Rectum (only the upper 3rd) S = Sigmoid colon S = Spleen

9. Embryonic folding During the 4th week of development a period of rapid growth begins in the embryo , the embryo begins to change shape from flat trilamminar disc into a cylinder ,a process known as embryonic folding . 6/26 Embryonic folding occurs in two planes the horizontal plane and the median plane or the cephalocaudal folding . Folding of the embryo in horizontal plane results in development of two lateral body folds . Folding in medial results in development of cranial and caudal fold. Folding in both planes takes place simultaneously resulting in rapid development of the embryo.

10. Embryonic folding The endoderm is mainly responsible for development of GI tract. As the craniocaudal and the lateral folding continues the endoderm moves towards the midline and fuses incorporating the dorsal part of yolk sac to create the primitive gut tube. The primitive gut tube differentiates into three main parts the foregut, mid gut and the hind gut . 7/26

11. Embryonic folding.. The foregut can be seen at the cranial end of the embryo. It is temporarily closed by the orophayngeal membrane which at the end of the 4th week of development ruptures to form the mouth. The midgut lies between the forgut and the hind gut and remains connected to the yolk sac until the fifth week of development. As embryonic folding continues the connection to the yolk sac narrows into a stalk called vitelline duct . The hind gut lies at the caudal end of the embryo ,it is temporarily closed by the cloacal membrane which during the 7th wk of development ruptures to form urogenital and anal opening . As a result of embryonic folding ,the major body plan is established and the three germ layers continues to differentiate giving rise to their specific tissues and their organ systems. Pic source: Copyright 2009, John Wiley & Sons, Inc. Embryonic folding 8/26

12. Note: Vitelline duct In the human embryo, the vitelline duct, also known as the omphalomesenteric duct, is a long narrow tube that joins the yolk sac to the midgut lumen of the developing fetus.[.Generally, the duct fully obliterates (narrows and disappears) during the 5–6th week of fertilization age (9th week of gestational age), but a failure of the duct to close is termed a vitelline fistula. This results in discharge of meconium from the umbilicus. A Meckel's diverticulum, a true congenital diverticulum, a vestigial remnanat of the omphalomesenteric duct (also called the vitelline duct or yolk stalk). It is the most common malformation of the gastrointestinal tract and is present in approximately 2% of the population.

13. Lateral Plate mesoderm Lateral plate mesoderm is a type of mesoderm that is found at the periphery. It will split into 2 layers , the somatic layer/mesoderm and the splanchnic layer/mesoderm The somatopleuric layer  associates with ectoderm. contributes to connective tissue of body wall & limbs. The splanchnopleuric layer associates with endoderm, circulatory system ie heart, blood vessels Spaces within the lateral plate are enclosed and forms the intraembryonic coelom. In the 4th week the coelom divides into pericardial, pleural and peritoneal cavities. 9/26

14. Embryonic folding … continue .Septum transversum During craniocaudal folding a connective tissue structure is formed caudal to the developing heart: septum transversum . The caudal part of the septum transversum is invaded by the hepatic diverticulum which divides within it to form the liver and thus gives rise to the ventral mesentery of the foregut, which in turn is the precursor of the lesser omentum , the visceral peritoneum of the liver and the falciform ligament. 10/26

15. Derivatives of gut tube 11/26 Differentiation of the gut and its derivatives depends upon reciprocal interactions between the gut endoderm and its surrounding mesoderm. Hox genes in the mesoderm are induced by a Hedgehog signaling pathway secreted by gut endoderm and regulate the craniocaudal organization of the gut and its derivatives. The endoderm cells that will form the liver express Foxa proteins, identifying it as “ future liver ” and labelling foregut as different from midgut and hindgut . 11/26

16. Note of previous slide So now the gut tube has formed, Sections of this gut begin to differentiate into the organs of the gastrointestinal tract. Hox genes which are a group of related genes that control the body plan of an embryo along the cranio -caudal axis. After the embryonic segments have formed, the Hox proteins determine the type of structures that will form on a given segment. Hox proteins thus confer segmental identity, but do not form the actual segments themselves.and which are further influenced or induced bu The Hedgehog signaling pathway which is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include basal cell carcinoma. The Hedgehog ( Hh ) signaling pathway has numerous roles in the control of cell proliferation, tissue patterning, stem cell maintenance and development. Mammals have three Hedgehog homologues, Desert (DHH), Indian (IHH), and Sonic (SHH), of which Sonic is the best studied .

17. Note of previous slide In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract and lungs fail to develop correctly. Recent studies point to the role of Hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of pharmaceutical companies. So now the gut tube has formed, Sections of this foregut begin to differentiate into the organs of the gastrointestinal tract, such as the oesophagus , stomach, liver gb and upper part of duodenum. During the fourth week of embryological development, the stomach rotates. The stomach, originally lying in the midline of the embryo, rotates so that its body is on the left. This rotation also affects the part of the gastrointestinal tube immediately below the stomach, which will go on to become the duodenum. By the end of the fourth week, the developing duodenum begins to spout a small outpouching on its right side, the hepatic diverticulum or the hepatic bud. FOX ( Forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation.

18. Development of Liver Liver development requires two linked processes: Differentiation of the various hepatic cell types from their embryonic progenitors. The arrangement of those cells into structures that permit the distinctive circulatory, metabolic and excretory functions of the liver. Mediated by many essential regulators which include signaling molecules, and transcription factors. 12/26

19. Notes of the previous slide So summarizing the events until now… Following gastrulation, embryos are composed of three germ layers: the ectoderm, mesoderm, and endoderm. The initial liver bud is mainly composed of hepatoblasts . Hepatoblasts are a liver stem cell that can later be turned into hepatocytes or cholangiocytes , cells which line bile ducts. The major epithelial cells of the liver – hepatocytes and cholangiocytes – are derived from the endoderm. However, these cells represent only about two-thirds of the liver volume. The remaining one-third consists of a variety of cells derived primarily from the mesoderm, including vascular cell types: Kupffer cells, stellate cells, fibroblasts, and leukocytes. Therefore, liver development requires the coordinated integration of the cells from distinct embryonic layers. Liver development requires two linked processes: differentiation of the various hepatic cell types from their embryonic progenitors and the arrangement of those cells into structures that permit the distinctive circulatory, metabolic, and excretory functions of the liver and these are further controlled or mediated by many essential regulators which include several signaling molecules and transcription factors.

20. Development of Liver: Stages Specification liver bud formation and expansion epithelial differentiation stage Endoderm cells adjacent to the cardiogenic mesoderm begin to differentiate into hepatoblasts . Hepatoblasts proliferate and penetrate the endoderm basement membrane to form the liver bud (25d). The liver bud then expands in size, intercalating into the adjacent septum transversum mesenchyme. During the epithelial differentiation stage, hepatoblasts mature into hepatocytes or differentiate into cholangiocytes . 13/26

21. Notes to the previous slide The first stage of liver development is specification, during which endoderm cells after receiving inductive signals from the adjacent cardiogenic mesoderm and the septum transversum mesenchyme (STM) via BMP, bone morphogenetic protein &FGF, fibroblast growth factor begin to differentiate into hepatoblasts , These factors are important in development. For example, in the absence of FGF signaling from the cardiac mesoderm, the ventral endoderm develops into pancreas, but too high a concentration of FGF results in differentiation toward lung. This is followed by liver bud formation and expansion: the hepatoblasts proliferate and penetrate the endoderm basement membrane (of the most caudal portion of foregut) to form the liver bud or also called hepatic diverticulum . In humans, this occurs at approximately day 25 . Initially, the liver bud is separated from the mesenchyme of the septum transversum by basement membrane. Shortly, however, the basement membrane surrounding the liver bud is lost,and cells delaminate from the bud and invade the septum transversum as cords of hepatoblasts — bipotential cells that differentiate into hepatocytes and cholangiocytes .

22. Development of liver and biliary passages The hepatic diverticulum enlarges rapidly and divides into two parts ie pars hepatica(cranial bud) and pars cystica (caudal bud) as it grows between the layers of the ventral mesentery . Caudal bud Inferior Superior Gall bladder, cystic duct Ventral pancreas Ref: Sleisenger and Fordtran's Gastrointestinal and Liver Disease 14/26

23. Pars hepatica It is the larger cranial part of the hepatic diverticulum . Gives rise to: Hepatocytes Hepatic sinusoids Kupffer cells and hematopoietic tissue Intrahepatic bile ducts The liver grows rapidly to fill a large part of the abdominal cavity. At first, the 2 lobes are of the same size but soon the right become larger . 15/26

24. Pars cystica Becomes the gall bladder and the stem of the diverticulum forms the cystic duct . The stalk connecting the hepatic and the cystic ducts to the duodenum becomes the common bile duct . The right and the left branches of the pars hepatica canalized to form the right and the left hepatic ducts . Bile begins to flow at about the 12th week. 16/26

25. Development of Liver Pars cystica Endoderm Pars hepatica Hepatocytes Hepatic sinusoids Kupffer cells and hematopoietic tissue Intrahepatic biliary tree Gall bladder Extrahepatic bile ducts (cystic duct ,CBD) Ventral mesentery Mesoderm Visceral peritoneum of liver Falciform ligament Septum Transversum Cardiogenic mesoderm Hepatoblast Hepatic diverticulum Kupffer cells derive from circulating monocytes and possibly yolk sac macrophages . Reference : Sherlock's Diseases of the Liver and Biliary System, 12th Ed 17/26

26. Formation of the capsule & ligaments of the liver As the septum transversum is penetrated by the growing pars hepatica: The mesoderm of the septum transversum between the liver and the anterior abdominal wall becomes the FALCIFORM LIGAMENT. The mesoderm of the septum transversum between the liver and the foregut (stomach and duodenum) forms the LESSER OMENTUM . The mesoderm on the surface of the liver differentiates into CAPSULE AND PERITONEAL COVERING. 18/26

27. Fate of ventral & dorsal mesentery Derived from the septum transversum is the ventral mesentery and the growth of the liver divides the ventral mesentery into lesser omentum and falciform ligament. 19/26

28. Vascular Development related to Liver Extraembryonic Major Venous system Intraembryonic Vitelline veins Cardinal Veins Umbilical Veins Sinus venosus 20/26

29. Notes to the previous slide During early development, there are 3 major venous systems in the embryo—2 extraembryonic and 1 intraembryonic. The extraembryonic venous systems are the omphalomesenteric (vitelline) and umbilical (placental) veins, and the intraembryonic system includes the cardinal veins that drain the venous blood of the embryo to the heart. All of these systems converge into the sinus venosus , a cavity that is incorporated into the heart.

30. Development of Vitelline & umbilical veins A: 4 th week B. 5 th week . Note the plexus around the duodenum, formation of the hepatic sinusoids, and initiation of left to right shunt between the vitelline veins. 21/26 Before entering the sinus venosus, the vitelline veins form a plexus around the duodenum and pass through the septum transversum. The liver cords growing into the septum interrupt the course of the veins and an extensive vascular network, the hepatic sinusoids,forms. There is also initiation of the left to right shunting between the vitelline veins

31. Development of Vitelline & umbilical veins A. 2 nd mnth B.3 rd mnth . Note formation of the ductus venosus , portal vein , hepatic portion of IVC. The splenic & SMV enter the PV. 22/26 Blood from the left side of the liver is rechanneled towards the right, resulting in an enlargement of the right vitelline vein (right hepatocardiac channel). The right hepatocardiac channel forms the hepatocardiac portion of the inferior venacava . The proximal part of the left vitelline vein disappears. The anastomotic network around the duodenum develops into a single vessel, the portal vein. The superior mesenteric vein derives from the right vitelline vein. The distal portion of the left vitelline vein also disappears. The superior segment of vitelline veins becomes the hepatic veins

32. Development of Vitelline & umbilical veins A. 2 nd mnth B.3 rd mnth . Note formation of the ductus venosus , portal vein , hepatic portion of IVC. The splenic & SMV enter the PV. 22/26 The umbilical veins run from the placenta to the heart and during fetal life are the predominant afferent vessels that supply the liver. Initially the umbilical veins pass on each side of the liver but some connect to the hepatic sinusoids. The proximal part of both umbilical veins and the remainder of the right umbilical vein then disappear. The left vein is the only one to carry blood from the placenta to the liver. With the increase of the placental circulation, a direct communication forms between the left umbilical vein and the right hepatocardiac channel, the ductus venosus . The ductus venosus bypasses the sinusoidal plexus of the liver. After birth the left umbilical vein and the ductus venosus are obliterated and form the ligamentum teres hepatic or the round ligament and ligamentum venosum respectively.

33. Arterial supply of liver The arterial supply of the liver begins as an offshoot from the celiac trunk at around the eighth week of gestation. By the 10th week, the first arterial radicles are visible in the central portion of the liver, and by the fifteenth week, they reach the periphery of the liver. 23/26

34. Congenital anomalies of liver Riedel lobe is a tongue-like, inferior projection of the right lobe of the liver beyond the level of the most inferior costal cartilage . It is not considered a true accessory lobe of the liver but an anatomical variant of the right lobe of the liver. Congenital solitary nonparasitic cysts of the liver Congenital Hepatic Fibrosis Congenital vascular malformation of the liver Intrahepatic Biliary Atresia Mesenchymal Hamartoma Accessory and Ectopic Lobes of the Liver 24/26

35. Congenital anomalies of liver Anomalous supradiaphragmatic lobe 25/26

36. Ductul plate malformations Intrahepatic bile ducts (IHBDs) develop from bi-potential liver progenitor cells( hepatoblasts ) in contact with the mesenchyme of the portal vein and thus form the “ ductal plates .” The ductal plates are remodeled into mature tubular ducts. Lack of remodeling results in “ductal plate malformation ”. A proposal is that virtually all congenital diseases of IHBDs represent examples of DPM . DPM are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis.

37. Classification of DPM Autosomal recessive polycystic kidney disease (hepatic ARPKD) (50% of children, 70% of families ): DPM of interlobular bile ducts associated with tubular dilatation of collecting renal tubules Caroli disease : DPM of the larger IHBDs Caroli syndrome: Caroli disease + congenital hepatic fibrosis Von Meyenburg complexes: DPM of smaller interlobular ducts (liver cysts in autosomal dominant polycystic kidney disease) Mesenchymal hamartoma Meckel syndrome Non- syndromal ductal plate malformation

38. End of slides…………..TO BE CONTINUED References: Harrison & Gastroenterology & Hepatology Schiff's Diseases of the Liver, 11th Edition Sherlock's Diseases of the Liver and Biliary System, 12th Edition Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Review and Assessment- Ninth Edition Suchy 2014 26/26