Gastrointestinal Tract - Liver Development

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Embryonic hepatic bud formation.

This section of notes gives an overview of how the liver develops. Initially, the transverse septum (septum transversum) arises at an embryonic junctional site. The junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac. The junctional region internally is where the foregut meets the Midgut. The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form. Arises at embryonic junction (septum transversum): externally is where ectoderm of amnion meets endoderm of yolk sac and internally is where the foregut meets the midgut. Mesenchymal structure of transverse septum provides a support within which both blood vessels and liver begin to form in the underlying splanchnic mesoderm.

In the early embryo, the liver and heart grow rapidly forming obvious external swellings on the ventral embryo surface. The liver's initial embryonic function is mainly cardiovascular. Firstly, as a vascular connection between the developing placental vessels to the heart. Secondly, as a haemopoietic tissue where blood stem cells reside before bone marrow development.

The fetal liver also has an endocrine role by 16-hydroxylation, that results in estriol being the major estrogen type produced in late human pregnancy.

A recent molecular study has shown that within the adult liver at least 20 discrete cell populations exist these include: hepatocytes, endothelial cells, cholangiocytes, hepatic stellate cells, B cells, conventional and non-conventional T cells, NK-like cells, and distinct intrahepatic monocyte/macrophage populations.[1]

See also liver histology showing both developmental and adult histology.

Historic Embryology
Marcello Malpighi (1628 – 1694)

Marcello Malpighi (1628 – 1694) was an Italian biologist and physician who in 1666 first named the liver lobules - "the livers of all vertebrates are conglomerate glands, being composed of lobules which in turn contain acini". He is also known for structures that bear his name in the spleen Malpighian bodies (white pulp) and renal Malpighian corpuscle (renal corpuscle). See also Mall's 1906 Liver Historical Note

GIT Links: Introduction | Medicine Lecture | Science Lecture | endoderm | mouth | oesophagus | stomach | liver | gallbladder | Pancreas | intestine | mesentery | tongue | taste | enteric nervous system | Stage 13 | Stage 22 | gastrointestinal abnormalities | Movies | Postnatal | milk | tooth | salivary gland | BGD Lecture | BGD Practical | GIT Terms | Category:Gastrointestinal Tract
GIT Histology Links: Upper GIT | Salivary Gland | Smooth Muscle Histology | Liver | Gallbladder | Pancreas | Colon | Histology Stains | Histology | GIT Development
Historic Embryology - Gastrointestinal Tract  
1878 Alimentary Canal | 1882 The Organs of the Inner Germ-Layer The Alimentary Tube with its Appended Organs | 1884 Great omentum and transverse mesocolon | 1902 Meckel's diverticulum | 1902 The Organs of Digestion | 1903 Submaxillary Gland | 1906 Liver | 1907 Development of the Digestive System | 1907 Atlas | 1907 23 Somite Embryo | 1908 Liver | 1908 Liver and Vascular | 1910 Mucous membrane Oesophagus to Small Intestine | 1910 Large intestine and Vermiform process | 1911-13 Intestine and Peritoneum - Part 1 | Part 2 | Part 3 | Part 5 | Part 6 | 1912 Digestive Tract | 1912 Stomach | 1914 Digestive Tract | 1914 Intestines | 1914 Rectum | 1915 Pharynx | 1915 Intestinal Rotation | 1917 Entodermal Canal | 1918 Anatomy | 1921 Alimentary Tube | 1932 Gall Bladder | 1939 Alimentary Canal Looping | 1940 Duodenum anomalies | 2008 Liver | 2016 GIT Notes | Historic Disclaimer
Human Embryo: 1908 13-14 Somite Embryo | 1921 Liver Suspensory Ligament | 1926 22 Somite Embryo | 1907 23 Somite Embryo | 1937 25 Somite Embryo | 1914 27 Somite Embryo | 1914 Week 7 Embryo
Animal Development: 1913 Chicken | 1951 Frog
Historic Embryology: 1906 Liver Structural Unit | 1912 Liver | 1920 Embryonic Function | 1921 Liver | 1926 Bile Capillaries and Ducts | 2008 Liver

Some Recent Findings

Human Liver (week 8, GA week 10)
  • Decoding human fetal liver haematopoiesis[2] "Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs." blood
  • A human liver cell atlas reveals heterogeneity and epithelial progenitors[3] "The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytess, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers."
  • The contributions of mesoderm-derived cells in liver development[4] "The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived cells, and interacts with the surrounding tissues and organs through the ventral mesentery. Liver development, from hepatic specification to liver maturation, requires close interactions with mesoderm-derived cells, such as mesothelial cells, hepatic stellate cells, mesenchymal cells, liver sinusoidal endothelial cells and hematopoietic cells. These cells affect liver development through precise signaling events and even direct physical contact. Through the use of new techniques, emerging studies have recently led to a deeper understanding of liver development and its related mechanisms, especially the roles of mesodermal cells in liver development. Based on these developments, the current protocols for in vitro hepatocyte-like cell induction and liver-like tissue construction have been optimized and are of great importance for the treatment of liver diseases. Here, we review the roles of mesoderm-derived cells in the processes of liver development, hepatocyte-like cell induction and liver-like tissue construction."
  • Molecular regulation of mammalian hepatic architecture[5] "The essential liver exocrine and endocrine functions require a precise spatial arrangement of the hepatic lobule consisting of the central vein, portal vein, hepatic artery, intrahepatic bile duct system, and hepatocyte zonation. This allows blood to be carried through the liver parenchyma sampled by all hepatocytes and bile produced by the hepatocytes to be carried out of the liver through the intrahepatic bile duct system composed of cholangiocytes. The molecular orchestration of multiple signaling pathways and epigenetic factors is required to set up lineage restriction of the bipotential hepatoblast progenitor into the hepatocyte and cholangiocyte cell lineages, and to further refine cell fate heterogeneity within each cell lineage reflected in the functional heterogeneity of hepatocytes and cholangiocytes. In addition to the complex molecular regulation, there is a complicated morphogenetic choreography observed in building the refined hepatic epithelial architecture. Given the multifaceted molecular and cellular regulation, it is not surprising that impairment of any of these processes can result in acute and chronic hepatobiliary diseases. To enlighten the development of potential molecular and cellular targets for therapeutic options, an understanding of how the intricate hepatic molecular and cellular interactions are regulated is imperative. Here, we review the signaling pathways and epigenetic factors regulating hepatic cell lineages, fates, and epithelial architecture."
More recent papers  
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Search term: Liver Embryology | Liver Development | Hepatic Embryology | Fetal Hepatocytes | Fetal Liver Function

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • The fate of the vitelline and umbilical veins during the development of the human liver[6] "Differentiation of endodermal cells into hepatoblasts is well studied, but the remodeling of the vitelline and umbilical veins during liver development is less well understood. We compared human embryos between 3 and 10 weeks of development with pig and mouse embryos at comparable stages, . ...We found no evidence for large-scale fragmentation of embryonic veins as claimed by the 'vestigial' theory. Instead and in agreement with the 'lineage' theory, the vitelline and umbilical veins remained temporally identifiable inside the liver after being engulfed by hepatoblasts. In agreement with the 'hemodynamic' theory, the left-right shunts develop de novo."
  • A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation[7] "How bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from embryonic day 10.5 (E10.5) to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually and followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C/mitogen-activated protein kinase signaling pathway promoted cholangiocyte maturation. CONCLUSION: Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate toward specific hepatic cell fates in vitro.
  • Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver[8] "Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. ....In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis.
  • Dynamic signaling network for the specification of embryonic pancreas and liver progenitors[9] Studies of the formation of pancreas and liver progenitors have focused on individual inductive signals and cellular responses. Here, we investigated how bone morphogenetic protein, transforming growth factor-beta (TGFbeta), and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and two permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGFbeta pathway."


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Liver Development Stages

Zorn2008 fig01.jpg

Cell lineage during hepatic development (red) from uncommitted endoderm to functional adult hepatocytes and biliary epithelium.[10]

Human Embryonic Liver Development
Carnegie Stage
Week 4

Carnegie stage 11
hepatic diverticulum development (ductal plate)
Carnegie stage 12
cell differentiation

septum transversum forming liver stroma

hepatic diverticulum forming hepatic trabeculae

Carnegie stage 13
epithelial cord proliferation enmeshing stromal capillaries
Week 5
Carnegie stage 14
hepatic gland and its vascular channels enlarge

hematopoietic function appeared

Week 7
Carnegie stage 18
obturation due to epithelial proliferation

bile ducts became reorganized (continuity between liver cells and gut)

Week 7 to 8
Carnegie stage 18 to Carnegie stage 23
biliary ductules developed in periportal connective tissue

produces ductal plates that receive biliary capillaries

Human data[11], see also liver development in the rat embryonic period (Carnegie stages 15-23).[12] (More? Detailed Timeline | Timeline human development)
Embryonic Liver Development Timeline  
Carnegie Stage Age (days) CRL (mm) Biliary system Vascular Hepatic parenchyma
14 33 7
  • Bile duct - primordial duct links primitive intestine and liver parenchyma. Thick-walled tube (95 µm diameter) small lumen (22 µm diameter).
  • Gall bladder - elongated tube further dilated, thick wall (125 µm diameter) and a narrow lumen (43 µm diameter).
  • Hepatic sinusoids - intra-hepatic vasculature present
  • Three venous tributaries flow into the liver sinusoids - right and left placental vein and a single vitelline vein.
  • Cords of liver cells fragmented by vascular network of hepatic sinusoids.
  • Between pericardial cavity (top) and mesonephros (bottom).
  • Upper pole of the liver lies close to the septum transversum and early ventricles.
  • Liver occupies the majority of abdominal cavity.
18 46 15
  • Bile duct (future common bile duct), and a common hepatic duct, in contact with liver parenchyma without penetration.
  • Primordium of accessory bile tract is an elongated and fusiform gall bladder projecting forward and by a short cystic duct that opens into common bile duct.
  • Bile duct empties into second part of duodenum on its posterior side.
  • Portal system visible - portal vein (100 µm diameter) arises from connection of upper mesenteric vein then at region of hepatic hilum (285 µm) divides into portal branches.
  • Left umbilical vein empties into anterior extremity of the left portal branch.
  • Ductus venosus (80 µm) connects the initial portion of left portal vein to the inferior vena cava.
  • Hepatic venous system 3 branches - left hepatic vein (120 µm in diameter), middle hepatic vein (220 􏰁µm in diameter) and right hepatic vein (160 µm in diameter). Flows into the sub-cardinal vein.
  • Liver parenchyma has two anatomical lobes (right and left lobe), separated by anteroposterior plane formed by placental vein.
21 53 22.5 Bile duct morphology as earlier stage. Common bile duct empties at the level of the proximal duodenum.
  • Portal vein arises from joining of splenic vein and superior mesenteric vein. At the level of the hepatic hilum, portal vein divides into two branches, right portal branch (420 µm in diameter) and left portal branch (540 µm in diameter). Right portal branch gives rise to a thin branch to caudate lobe. Ventral branch gives rise to segmental portal veins (VIII and V). Dorsal branch gives rise to the segmental portal veins (VI and VII).
  • Ductus venosus connects initial portion of left portal vein to inferior vena cava, just upstream from hepatic vein afferents.
  • Hepatic venous system as for previous stage.
Hepatic parenchyma a large rounded mass.
23 58 27 Bile duct morphology as earlier stage.
  • Portal venous system complete.
  • Ductus venosus (40 µm) connects initial portion of portal vein to middle hepatic vein.
  • hepatic venous system has changed very little from the previous stage. Three hepatic veins empty into inferior vena cava.
  • Liver parenchyma roughly oval shape, 2 symmetrical hepatic lobes. The quadrate and caudate lobes are identifiable.
  • Upper pole of the liver bounded above by diaphragm.
Data from a recent human study[13]

Links: liver | Carnegie stage 14 | 18 | 21 | 23 | simple embryonic timeline | Timeline human development

  • Size - the liver initially occupies the entire anterior body area.
  • Hepatoblast - endoderm the bipotential progenitor for both hepatocytes and cholangiocytes.
  • Vascular - mesoderm blood vessels enter the liver (3 systems: systemic, placental, vitelline)
  • Sinusoids - first blood vessels from vessels in septum transversum mesenchyme. Initially continuous endothelium, become fenestrated in fetal period and reticular development ongoing.

Adult Liver Cells

Liver structure cartoon.jpg
  1. hepatocytes - form 80% of liver, functional cells
  2. cholangiocytes - epithelial cells that line the bile ducts
  3. stellate cells - mesenchymal cells in the space of Disse
  4. Kupffer cells - liver macrophage in the sinusoids
Summary Cell Map of the Adult Human Liver
This study[1] has shown in the adult human liver at least 20 discrete cell populations exist. These include: hepatocytes, endothelial cells, cholangiocytes, hepatic stellate cells, B cells, conventional and non-conventional T cells, NK-like cells, and distinct intrahepatic monocyte/macrophage populations.

  • Parenchymal cells - hepatocytes
  • Non-parenchymal cells - endothelial cells, cholangiocytes, macrophages, hepatic stellate cells, and liver infiltrating lymphocytes- including B cells, αβ and γδ, T cells, and NK cells

Non-inflammatory macrophages are labeled ∗Kupffer cells based on their transcriptional similarity to mouse KC. The location of B cells, plasma cells, T cells, and NK cells has yet to be confirmed by immunohistochemical staining of these populations in situ so their location in this schematic is not representative of their zonated distribution.(text modified from original figure legend)

Adult human liver cells.jpg

Liver Growth

Fetal liver weight growth graph.jpg

Human Liver Growth (weight grams)[14]

Liver Buds

  • Differentiates to form the hepatic diverticulum and hepatic primordium, generates the gallbladder then divides into right and left hepatic (liver) buds.
  • Three connecting stalks (cystic duct, hepatic ducts) which fuse to form bile duct.

Left Hepatic Bud

  • left lobe, quadrate, caudate (both q and c anatomically Left)
  • caudate lobe of human liver consists of 3 anatomical parts: Spiegel's lobe, caudate process, and paracaval portion.

Right Hepatic Bud

  • right lobe

Liver Structural Origins

The Liver Lobule
  • Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
  • Vitelline Veins - form sinusoids
  • Mesenchyme - form connective tissue and Kupffer cells

Function - Haemopoiesis

Embryonic liver also involved in blood formation, after the yolk sac and blood islands acting as a primary site.

Components of Liver Formation

Mouse liver development signaling.[15]

Primitive Endoderm

  • foregut diverticulum
  • foregut-midgut junction
    • septum transversum
      • hepatic diverticulum
      • hepatic primordium
        • hepatic parenchyma
  • midgut region
  • hindgut diverticulum (pocket)

Data from mouse [16]

Hepatoblasts - endoderm-derived cells can differentiate into either:

  1. hepatocytes - populate the bulk of the liver parenchyma.
  2. cholangiocytes - line the intrahepatic bile ducts.

Links: Endoderm | Mouse Development


Stage 13

stage 13 embryo

The images below link to larger cross-sections of the mid-embryonic period (end week 4) stage 13 embryo starting just above the level of the liver and then in sequence through the liver to the level of the stomach. Note the relative position of the liver with respect to the abdominal cavity, the gallbladder and the heart.

The transverse septum differentiates to form the hepatic diverticulum and the hepatic primordium, these two structures together will go on to form different components of the mature liver and gallbladder. At this stage large vascular channels can be seen coursing through the liver primordium.

Stage 13 (serial labeled images)
Stage 13 image 073.jpg Stage 13 image 074.jpg Stage 13 image 075.jpg Stage 13 image 076.jpg Stage 13 image 077.jpg Stage 13 image 078.jpg
Stage 13 image 097.jpg Stage 13 image 098.jpg
Links: Carnegie stage 13 - serial sections | Embryo Serial Sections | Embryo Carnegie stage 13 Movies

Stage 22

Virtual Slide Features - Stage 22 Liver
Stage 22 image 034.jpg Virtual Slide - Stage 22 Liver and Ductus Venosus      All Virtual Slides

The links shown in the table below are to specific features shown on the Human embryo (stage 22) Liver and Ductus Venosus virtual slide. See also notes on Liver Development

Clicking the text will open the slide at a detailed view with the structure generally located in the centre of the view. The slide then can also be zoomed out from the set magnification using the controls in the upper left or the mouse.

Use your browser back button to return to this table.

You can also make your own selected feature view.
  1. Set the virtual slide to the region and zoom of interest.
  2. Click the Permalink (lower righthand corner).
  3. Then bookmark in your browser, or copy the web address.

See also Permalink help

Cardiovascular Liver Endocrine Musculoskeletal Neural Gastrointestinal

stomach (pylorus)

Virtual Slide Features - Stage 22 Liver
Stage 22 image 034.jpg Virtual Slide - Stage 22 Liver and Ductus Venosus      All Virtual Slides

The links shown in the table below are to specific features shown on the Human embryo (stage 22) Liver and Ductus Venosus virtual slide. See also notes on Liver Development

Clicking the text will open the slide at a detailed view with the structure generally located in the centre of the view. The slide then can also be zoomed out from the set magnification using the controls in the upper left or the mouse.

Use your browser back button to return to this table.

You can also make your own selected feature view.
  1. Set the virtual slide to the region and zoom of interest.
  2. Click the Permalink (lower righthand corner).
  3. Then bookmark in your browser, or copy the web address.

See also Permalink help

Cardiovascular Liver Endocrine Musculoskeletal Neural Gastrointestinal

stomach (pylorus)

The images below link to larger cross-sections of the end of the embryonic period (week 8) stage 22 embryo starting just above the level of the liver and then in sequence through the entire liver. (Note the sections are viewed from below, LR axis is reversed)

The rapidly developing liver also forms a visible surface bulge on the embryo directly under the heart bulge. The liver now occupies the entire ventral body cavity with parts of the gastrointestinal tract and urinary system "embedded" within its structure. Note in this image the large central ductus venosus.

Stage 22L serial labeled images
Stage 22 image 080.jpg Stage 22 image 081.jpg Stage 22 image 082.jpg Stage 22 image 083.jpg Stage 22 image 084.jpg
Stage 22 image 085.jpg Stage 22 image 086.jpg Stage 22 image 087.jpg Stage 22 image 088.jpg Stage 22 image 089.jpg
Links: Carnegie stage 22 - serial sections | Embryo Serial Sections | Embryo Carnegie stage 22 Movies

Selected Stage 22 Images

Stage 22 image 131.jpg E3 Overview of liver region for selected high power views shown below. Note the position and size of the developing liver spanning the entire abdomen and within the liver the large central ductus venosus.
Stage 22 image 181.jpg E4 Central veins of liver. Radiating appearance of hepatic sinusoids. unlabeled version
Stage 22 image 182.jpg E5 Central vein with endothelial lining, containing nucleated erythrocytes, fetal red blood cells. The fetal liver has an important haemopoietic role. unlabeled version

Week 9

Human liver week 9.jpg

Paraffin-embedded sections of human embryonic liver at 9 weeks (GA 11 weeks).[17]

  • A - (Stain - Haematoxylin Eosin)
  • B, C - Alpha-Fetoprotein (AFP)
  • D, G - Cytokeratin 18 (CK18)
  • E, H - Cytokeratin 19 (CK19)
  • F, I - Cytokeratin 7 (CK7)

Ductal Plate

The ductal plate is a primitive biliary epithelium which develops in mesenchyme adjacent to portal vein branches (periportal hepatoblasts). During liver development it is extensively reorganised (ductal plate remodelling) within the developing liver to form the intrahepatic bile ducts (IHBD). If remodelling does not occur, leading to excess of embryonic bile duct structures in the portal tract, these developmental abnormalities are described as "ductal plate malformation" (DPM).

Cholangiocyte tubulogenesis: "ductal plate" stages -> "remodeling bile duct" stage -> "remodeled bile duct"

Liver cholangiocyte tubulogenesis 01.jpg

Cartoon model of bile duct formation.[8]

See also Ductal Plate Malformations

Bile Secretion

The epithelial cells that line the bile ducts are called cholangiocytes.

The pathway below describes the production and passage of bile for final excretion into the duodenum:

  1. hepatocytes produce bile
  2. secreted into bile canaliculi
  3. connected to intrahepatic bile ducts
  4. intrahepatic bile ducts connect to the hepatic duct
  5. then the cystic duct for storage in the gallbladder
  6. then the common bile duct into the duodenum

The term extrahepatic bile ducts (EHBDs) is used to describe the hepatic, cystic, and common bile ducts.

The developing bile ducts express VEGF while hepatoblasts express angiopoietin-1, these two signals are thought to regulate arterial vasculogenesis and remodeling of the hepatic artery respectively.[18]

Liver Vascular

Vascular development data below from[19]


  • week 4 - hepatic primordium in contact with vitelline veins and the umbilical veins.
  • week 4 to 6 - efferent venous vessels form from the vitelline veins. Afferent venous liver circulation present.
  • Week 6 onward - portal vein formed from segments of the vitelline veins
    • portal sinus (from subhepatic intervitelline anastomosis) connects umbilical vein to portal system.
    • ductus venosus connects portal sinus to vena cava inferior.
  • birth - both umbilical vein and ductus venosus collapse.
    • portal vein becomes the only afferent vein of the liver.


  • week 8 - hepatic artery forms.
  • week 10 to 15 - intrahepatic arterial branches progressively extend from the central to the peripheral areas of the liver.

Hepatic sinusoids

  • week 4 - hepatic cords invade the septum transversum
    • progressively acquire structural and functional characters, through a multistage process.

Liver Blood Flow

Liver structure cartoon.jpg

Dual blood supply of the liver merges upon entry into the liver lobule at the portal field. The blood flows along the sinusoid and exits at the central vein.

  1. branches of the portal vein
  2. branches of the hepatic artery

Portal Vein - is the sole supplier to the liver until about human 20 mm CRL stage. Portal vein primary branches extend around the periphery of each primitive liver lobule. This branching process continues, from primary to secondary, with each development supplying all newly forming liver lobules. Primary branches also lie parallel to the branches of hepatic veins, that drain the blood from the centre of each early lobule.

Hepatic Artery - from the coeliac axis, initially contact the hepatic duct and gallbladder, later grows into the connective tissue about the larger bile ducts and branches of the portal vein. The hepatic artery will also supply the capsule of the liver.


Adult Liver sinusoid structure

These are the adult functional cells forming the majority of the liver (80% of the cells).

Many different functions including:

  • Storage of substances including glucose (as glycogen), vitamin A (possibly in specialized adipocytes), vitamin B12, folic acid and iron.
  • Lipid Turnover synthesis of plasmalipoproteins
  • Plasma Protein Synthesis albumin, alpha and beta globulins, prothrombin, fibrinogen
  • Metabolism fat soluble compounds (drugs, insecticides), steroid hormones turnover
  • Secretion bile (about 1 litre/day)

Kupffer Cells

Kupffer Cells are a population of tissue macrophages found in the lumen of hepatic sinusoids, their role is endocytic acting against blood-borne materials entering the liver.

Primordial (primitive) macrophages arise in the yolk sac and then differentiate into fetal macrophages, either of these enter the blood and migrate into the developing liver.[20]

Tissue macrophages are a family of cells found in many organs[21]: liver Kupffer cells, neural microglia, respiratory alveolar macrophages, and integumentary epidermal Langerhans cells. In the embryo, they have a common embryonic origin from yolk sac (YS) erythro-myeloid progenitors (EMPs). In the adult, they are self-maintained in tissues independently of hematopoietic stem cells (HSCs).[22]

Search PubMed: Kupffer cell development

Liver Associated Vessels


Liver ventral surface and associated veins (human embryo, 24-25 days, after His.)

  • ductus venosus - shunts approximately half the umbilical vein blood flow directly to the inferior vena cava.
  • portal vein - carries blood from the gastrointestinal tract and spleen to the liver.
  • left umbilical vein - carries oxygenated blood from the placenta to the embryo/fetus.
  • right umbilical vein - vessel degenerates leaving a single (left) umbilical vein.
  • vena revehens - veins from the sinusoid vessels in the liver to the inferior vena cava, that later develop into the hepatic veins.

Adult Liver Transplants


Liver animated cartoon.gif

The Liver Lobule

Adult liver Portal Triad

Liver histology 005.jpg

Links: liver histology


 ICD-11 LB20 Structural developmental anomalies of gallbladder, bile ducts or liver

LB20.00 Fibropolycystic liver disease

LB20.21 Biliary atresia - Biliary atresia is a rare disease characterised by an inflammatory biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. Untreated, this condition leads to cirrhosis and death within the first years of life.

LA90.21 Anomalous portal venous connection

Congenital Absence of Portal Vein

Congenital Absence of the Portal Vein (CAPV) is a rare abnormality where the intestinal and splenic venous drainage bypass the liver and drain directly into the systemic veins through various porto-systemic shunts.

Links: Gastrointestinal Tract - Abnormalities

Ductal Plate Malformations

  • Interlobular bile ducts - autosomal recessive polycystic kidney disease
  • Smaller interlobular ducts - von Meyenburg complexes
  • Larger intrahepatic bile ducts - Caroli's disease

Hepatobiliary cysts

Fetal hepatic cysts are generally benign, with a low likelihood of associated anomalies of the hepatobiliary tract, abnormal liver function or clinical symptoms.[24]

Maternal Liver

There are several maternal pregnancy-associated direct and indirect liver diseases, see recent review.[25]

  • Intrahepatic cholestasis of pregnancy (ICP) - most common liver disease in pregnancy, presenting mainly in the second and third trimesters, with pruritis, elevated serum bile acids, and abnormal liver function tests.[26][27] Many countries have developed guidelines to address the risks, diagnosis and management of ICP. (see Western Australia information)
    • Bile Acids levels greater than 10 μmol/L are a common diagnostic marker.
    • Liver Function Tests - significant aminotransferase increase, serum bilirubin not usually raised.
  • Hyperemesis gravidarum - the clinical term for severe form of nausea and vomiting, which are common symptoms of early pregnancy (4 - 16 weeks). Causal factors include increased human chorionic gonadotropin (hCG) and steroids, multiple pregnancy and vitamin deficiency. The condition can lead to dehydration, ketonuria, catabolism and may require hospitalisation.
  • Acute fatty liver disease of pregnancy (AFLP) - fatty infiltration of the liver, occurring usually in the third trimester though can also occur postnatally.
  • Pre-eclampsia
  • HELLP - haemolysis (with a micoangiopathic blood smear), elevated liver enzymes (LFTs) and low platelet count.

Links: PDF - Australia WA Department of Health. Cholestasis in Pregnancy. April 2016.

Animal Models


See molecular review by Zorn.[10]

  • E9.5 to E15 - liver bud undergoes growth and is the major site of haematopoiesis.
  • E13 - bi-potential hepatoblasts differentiate into hepatocytes or biliary epithelial cells.
  • E16.5 - ductal plate partially becomes bi-layered
  • E17.5 - ductal plate remodelling, focal dilations appear between the two cell layers.


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Mall FP. A study of the structural unit of the liver. (1906) Amer. J Anat. 5:227-308.


Gastrointestinal Tract Terms  
  • allantois - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.
  • amnion - An extra-embryonic membrane, ectoderm and extraembryonic mesoderm in origin, also forms the innermost fetal membrane, that produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membrane led to the description of reptiles, bird, and mammals as amniotes.
  • amniotic fluid - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.
  • atresia - is an abnormal interruption of the tube lumen, the abnormality naming is based upon the anatomical location.
  • buccal - (Latin, bucca = cheek) A term used to relate to the mouth (oral cavity).
  • bile salts - Liver synthesized compounds derived from cholesterol that function postnatally in the small intestine to solubilize and absorb lipids, vitamins, and proteins. These compounds act as water-soluble amphipathic detergents. liver
  • buccopharyngeal membrane - (oral membrane) (Latin, bucca = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract. This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomodeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.
  • celiac artery - (celiac trunk) main blood supply to the foregut, excluding the pharynx, lower respiratory tract, and most of the oesophagus.
  • cholangiocytes - epithelial cells that line the intra- and extrahepatic ducts of the biliary tree. These cells modify the hepatocyte-derived bile, and are regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules. liver
  • cloaca - (cloacal cavity) The term describing the common cavity into which the intestinal, genital, and urinary tracts open in vertebrates. Located at the caudal end of the embryo it is located on the surface by the cloacal membrane. In many species this common cavity is later divided into a ventral urogenital region (urogenital sinus) and a dorsal gastrointestinal (rectal) region.
  • cloacal membrane - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.
  • coelomic cavity - (coelom) Term used to describe a space. There are extra-embryonic and intra-embryonic coeloms that form during vertebrate development. The single intra-embryonic coelom forms the 3 major body cavities: pleural cavity, pericardial cavity and peritoneal cavity.
  • crypt of Lieberkühn - (intestinal gland, intestinal crypt) intestinal villi epithelia extend down into the lamina propria where they form crypts that are the source of epithelial stem cells and immune function.
  • duplication - is an abnormal incomplete tube recanalization resulting in parallel lumens, this is really a specialized form of stenosis. (More? Image - small intestine duplication)
  • esophageal - (oesophageal)
  • foregut - first embryonic division of gastrointestinal tract extending from the oral (buccopharyngeal) membrane and contributing oesophagus, stomach, duodenum (to bile duct opening), liver, biliary apparatus (hepatic ducts, gallbladder, and bile duct), and pancreas. The forgut blood supply is the celiac artery (trunk) excluding the pharynx, lower respiratory tract, and most of the oesophagus.
  • galactosemia - Metabolic abnormality where the simple sugar galactose (half of lactose, the sugar in milk) cannot be metabolised. People with galactosemia cannot tolerate any form of milk (human or animal). Detected by the Guthrie test.
  • gastric transposition - clinical term for postnatal surgery treatment for esophageal atresia involving esophageal replacement. Typically performed on neonates between day 1 to 4. (More? gastrointestinal abnormalities | PMID 28658159
  • gastrointestinal divisions - refers to the 3 embryonic divisions contributing the gastrointestinal tract: foregut, Midgut and hindgut.
  • gastrula - (Greek, gastrula = little stomach) A stage of an animal embryo in which the three germ layers (endoderm/mesoderm/ectoderm) have just formed. All of these germ layers have contributions to the gastrointestinal tract.
  • gastrulation - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo (endoderm/mesoderm/ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes. (More? gastrulation)
  • Guthrie test - (heel prick) A neonatal blood screening test developed by Dr Robert Guthrie (1916-95) for determining a range of metabolic disorders and infections in the neonate. (More? Guthrie test)
  • heterotaxia - (Greek heteros = different; taxis = arrangement) is the right/left transposition of thoracic and/or abdominal organs.
  • hindgut - final embryonic division of gastrointestinal tract extending to the cloacal membrane and contributing part of the transverse colon (left half to one third), descending colon, sigmoid colon, rectum, part of anal canal (superior), urinary epithelium (bladder and most urethra). The hindgut blood supply is the inferior mesenteric artery.
  • inferior mesenteric artery - main blood supply to the hindgut
  • intestine - (bowel) part of the gastrointestinal tract (GIT) lying between the stomach and anus where absorption of nutrients and water occur. This region is further divided anatomically and functionally into the small intestine or bowel (duodenum, jejunum and ileum) and large intestine or bowel (cecum and colon).
  • intestinal perforation - gastrointestinal abnormality identified in neonates can be due to necrotizing enterocolitis, Hirschsprung’s disease or meconium ileus.
  • intraembryonic coelom - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.
  • meconium ileus intestine obstruction within the ileum due to abnormal meconium properties.
  • mesentery - connects gastrointestinal tract to the posterior body wall and is a double layer of visceral peritoneum.
  • mesothelium - The mesoderm derived epithelial covering of coelomic organs and also line their cavities.
  • Midgut - middle embryonic division of gastrointestinal tract contributing the small intestine (including duodenum distal bile duct opening), cecum, appendix, ascending colon, and part of the transverse colon (right half to two thirds). The midgut blood supply is the superior mesenteric artery.
  • neuralation - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.
  • neural crest - region of cells at the edge of the neural plate that migrates throughout the embryo and contributes to many different tissues. In the gastrointestinal tract it contributes mainly the enteric nervous system within the wall of the gut responsible for peristalsis and secretion.
  • peritoneal stomata - the main openings forming the pathways for drainage of intra-peritoneal fluid from the peritoneal cavity into the lymphatic system.
  • pharynx - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.
  • recanalization - describes the process of a hollow structure becoming solid, then becoming hollow again. For example, this process occurs during GIT, auditory and renal system development.
  • retroperitoneal - (retroperitoneum) is the anatomical space (sometimes a potential space) in the abdominal cavity behind (retro) the peritoneum. Developmentally parts of the GIT become secondarily retroperitoneal (part of duodenum, ascending and descending colon, pancreas)
  • somitogenesis The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/4 hours (mouse 1 pair/90 min) until on average 44 pairs eventually form.
  • splanchnic mesoderm - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.
  • stomodeum - (stomadeum, stomatodeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.
  • stenosis - abnormal a narrowing of the tube lumen, the abnormality naming is based upon the anatomical location.
  • superior mesenteric artery - main blood supply to the Midgut.
  • viscera - the internal organs in the main cavities of the body, especially those in the abdomen, for example the Template:Intestines.
  • visceral peritoneum - covers the external surfaces of the intestinal tract and organs within the peritoneum. The other component (parietal peritoneum) lines the abdominal and pelvic cavity walls.
  • yolk sac - An extraembryonic membrane which is endoderm origin and covered with extraembryonic mesoderm. Yolk sac lies outside the embryo connected initially by a yolk stalk to the midgut with which it is continuous with. The endodermal lining is continuous with the endoderm of the gastrointestinal tract. The extra-embryonic mesoderm differentiates to form both blood and blood vessels of the vitelline system. In reptiles and birds, the yolk sac has a function associated with nutrition. In mammals the yolk sac acts as a source of primordial germ cells and blood cells. Note that in early development (week 2) a structure called the "primitive yolk sac" forms from hypoblast, this is an entirely different structure.
  • yolk stalk - (vitelline duct, omphalomesenteric duct, Latin, vitellus = yolk of an egg) The endodermal connection between the midgut and the yolk sac. See vitelline duct.
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