Paper - Congenital Anomalies of the Liver (1929)
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Congenital Anomalies of the Liver
H. E. MacManon, M.D. (From the Pathological Laboratory of the Boston City Hospital, Boston, Mass.)
Received for publication June 1, 1929.
The microscopic study of a large series of livers from premature and full-term infants, infants one to several months of age, children and adults has shown clearly that congenital anomalies may occur within the liver in regard to the arrangement of the liver cells, the lobules, the intrahepatic bile ducts, and also in the mesenchymal architecture of the portal areas. The importance of these variations is probably more of embryologic or biologic interest, and yet they should be recognized by the pathologist as forming a histologic basis of some of the more unusual forms of intractable jaundice of infancy. Furthermore, they should be considered carefully both in the differential diagnosis of healed forms of cirrhosis and in the interpretation of some of the unusual histologic lesions at times seen in the fully developed liver.
Embryology of the Liver
The development of the human liver, according to the majority of anatomists, recapitulates broadly the forms recognized in the evolution of the animal scale. The liver begins as a ventral outgrowth of the entodermal tube, a stage seen in the amphioxus in which the liver is merely a cecal diverticulum of the digestive canal. In the shark, this outpouching has developed into considerable size; it is formed of epithelial tubes with lumina, known as hepatic cylinders. In the amphibians there is further development, the cylinder and lumina are smaller, and the organ is a modified tubular gland composed of these cylinders of hepatic cells arranged around bile ducts. A similar picture is seen in the 10, 12, 14 and 16 mm. human embryo, in which the liver is composed of a network of reticulating cylinders bordered by endothelial-lined spaces, but at this stage the intrahepatic bile ducts have not yet developed.
In the further development of the embryo the tubular form is lost and smaller and smaller meshes of hepatic cells arise from these primary cylinders. At first these appear simply as a network of trabeculae lacking an orderly arrangement, but later they become grouped into lobular units.
There are different theories regarding the embryogenesis of the intrahepatic bile ducts. Minot! favored the view that they arose from the hepatic duct — “the origin of the interlobular ducts is as yet but imperfectly understood, but we may surmise that they arise as evaginations of the hepatic duct: certain it is that they are always ‘distinct from the hepatic cells.” According to Arey,” “at eight weeks hollow interlobular ducts appear spreading inward from the hepatic duct along the larger branches of the portal vein.” Schiifer,3 Lewis,’ Hertwig,® von Meyenberg ° and Keith’ regard at least the smaller periportal ducts as arising from the liver cells, while von Meyenberg in his interpretation of liver cysts concluded that the large periportal ducts arose from the hepatic duct. According to Keith, “the ducts of the liver, unlike those of any other gland, arise by a secondary process. Undifferentiated cells lying along the distribution of the portal vein in the liver, group themselves into cords, develop lumina, become covered with mesodermal tissue and then form the intrahepatic bile ducts.”
Lewis describes the process as follows: “The trabeculae form cords extending along the surface of the periportal mesenchyma and in them a lumen is formed. In places the cells on the mesenchymal side of the lumen are distinctly flatter than those toward the portal capillaries. In a later stage the mesenchyma has increased so that it surrounds the ducts which were seen forming along its surface. Their epithelium has become regularly cuboidal or columnar.”
The commonly accepted view regarding the development of the extrahepatic biliary system is that the hepatic ducts arise within the stalks of the solid hepatic buds, that is from the anterior portion of the hepatic diverticulum; while from the caudal portion are developed the common bile duct, the gall bladder, and the cystic duct at the junction of the common bile duct and the gall bladder. Moreover, in addition to arising from different portions of the original hepatic anlage, these structures develop in different stages so that one portion may have a lumen while another is still a solid cord of cells.
The primary vessels of the liver are the two vitelline veins which form a close anastomosis with each other. With invasion by liver tissue and the formation of sinusoids, these veins become resolved into a distributing and collecting group. The distal group comprises the system of hepatic veins, whereas the proximal portion of the two vitelline veins forms a single vessel which represents the portal vein of later stages. About the fifth week of embryonic life the left umbilical vein establishes a communication with the vascular plexus of the liver, so that placental blood as well as blood from the intestines now passes through the liver. Soon afterward, a large channel, the ductus venosus, develops between the proximal and distal groups of vitelline vessels; this conveys the larger portion of placental blood directly into the inferior vena cava.
Very early the common bile duct, the cystic and hepatic ducts are surrounded by mesenchyma. With the development of the hepatic circulation the mesenchyma spreads along the ramification of the portal vein into the substance of the liver. Periportal ducts form, and branches of the hepatic artery, together with nerves and lymphatics extend along into this loose mesenchyma so that the wide portal areas show a rather sharp contrast to the little connective tissue that surrounds the thin-walled central veins.
In brief, the development of the mammalian liver may be traced from a simple diverticulum of the foregut, through a compound tubular structure composed of reticulating cylinders, through a stage in which the liver is composed of a network of liver cell trabeculae lacking orderly arrangement, and finally into the mature form in which it is divided into lobular units. The peripheral bile ducts appear to develop from undifferentiated parenchyma cells bordering the portal areas. These form larger ducts which communicate with branches of the hepatic duct which arise outside of the liver. The gall bladder, cystic and common ducts develop independently. The mesenchyma of the portal areas extends in along the portal vein and increases with the appearance of branches of the hepatic artery, nerves and lymphatics.
In this short review of the embryology of the liver we have stressed a few of the more important developmental processes which form the basis of some of the more common congenital anomalies seen in later months.
The number of anomalies that might arise in an organ having such a complicated process of development could be very large, and probably many of the minor variations are often overlooked.
Holmes ® describes congenital obliteration of the bile ducts as _ they affect the hepatic, cystic, common duct and gall bladder, and reviews the gross morphologic relation in one hundred reported cases. He favors the view that the obliteration is a developmental anomaly rather than infectious, and points out that in at least sixteen of these cases surgical relief was possible, while Thomson® first drew attention to the cirrhosis of the liver which may result from an obliterative process in the large biliary system.
Boyden !° has described the gross morphologic anomalies of the mammalian gall bladder. Meckel ™ reported a case of complete absence of the gall bladder, and Kermisson and Hébert ” collected three cases in which there was no trace of the hepatic, cystic or common ducts.
In the liver, the more common gross anomalies are irregularities in form, in the number of lobules and in the presence of cysts; while a very much rarer finding is the presence of one or more accessory livers.
The congenital histologic variations of the liver, exclusive of those changes which occur as a result of some abnormality in the extrahepatic biliary system, may be separated into two groups: first, those in which there has been simply a retardation in the normal process of development, in which case the liver of a full-term child may structurally resemble, in part at least, the liver of a developing fetus; and secondly, those in which there is a true developmental anomaly involving either the parenchyma or the connective tissue forming the portal areas.
Group I. Two varieties were found that fall into this group. In one which occurred in a full-term child who lived seven months the structure resembled a network of reticulating cylinders, in which tubules of eight and ten liver cells surround large and small lumina. This simulated in arrangement the developing liver of a young mammalian embryo, or the mature liver of an amphibian.
The second example occurred in a full-term child who lived several months and was jaundiced since birth. As in the former case, the extrahepatic biliary system was normal. The liver was composed of an anastomosing network of poorly defined trabeculae of liver cells separated by wide endothelial-lined spaces. The liver cells varied in size and shape and were poorly defined, while some contained six and eight nuclei. They were arranged in single rows, sometimes in double rows with a distended bile capillary between. There was no lobulation, but here and there the parenchyma was traversed by irregular portal areas in which normal periportal ducts could be followed. The jaundice which occurred in this case probably resulted from a lack of continuity of the bile capillaries, which in turn was dependent on the disorderly arrangement of the liver cells.
Group II. Probably one of the commonest variations seen in the liver of newborn infants is the irregularity in the amount of mesenchyma in the portal areas. Sometimes an unusually large amount of connective tissue has grown in along the large vessels. In the infant this tissue may be arranged loosely and appears very conspicuous. In later life with condensation and increase in the number and size of the lobules it becomes a much less noticeable feature. At either age, it appears to cause no functional disturbance. Two of the cases of this type were complicated by the presence in the portal connective tissue of many blood-forming cells similar to those lying in the perisinusoidal spaces.
Another type of anomaly likewise involving primarily the mesenchyma occurred in a full-term child who lived nine weeks. This child had also been jaundiced since birth. The portal connective tissue in all portal areas was increased in amount and was very condensed. The portal vessels were numerous, small and compressed. The periportal ducts were increased in number and could be traced as double rows of cells often showing no lumen. These duct cells resembled the poorly differentiated embryonic type, and lacked the normal development into the mature cuboidal and columnar forms. It is possible that this abnormality is primarily a maldevelopment of the periportal ducts; however, the increase and condensation of the mesenchyma is such an outstanding feature that the duct anomaly is probably secondary.
The normal liver of a pig and also of a camel (Mall *) is divided into distinct and separate lobules by strands of connective tissue.
Occasionally the human liver may show this reversion in varying degrees. The human liver may be resolved into well defined lobules partly by rows of liver cells at the periphery which lie at right angles to the radiating trabeculae, and partly by narrow bands of connective tissue.
This division into lobules may be much more irregular and much more complete. Narrow bands of mesenchymal tissue may extend from one portal area to another dividing the parenchyma into single and compound lobules, often lacking any visible central veins. In one case of this type, in a child twenty months old showing other congenital stigmata, the peripheral connective tissue was bordered by young sprouting periportal ducts which had not become detached from the lobule by the surrounding mesenchymal tissue (Figs. 1 and 2).
This last case is of unusual interest because it shows a complete border of periportal ducts developing from the undifferentiated peripheral parenchyma cells. Bloom" has recently attempted to prove that the change of liver cell cords into bile duct epithelium is dependent on the former being surrounded by connective tissue. According to this author, ‘“‘when the connective tissue is absent, the epithelium surrounding the lumen of the tube is continuous and morphologically indistinguishable from the remainder of the hepatic parenchyma.” In the case reported here this transformation occurs in the absence of surrounding connective tissue, which suggests that some factor other than connective tissue may control the embryogenesis of these periportal ducts. Furthermore, there is evidence to show that the cells of the periportal ducts are relatively less differentiated in the infant than in the adult. In an adult, a toxin that kills off all the liver cells of a lobule leaving only the periportal ducts, results in the regeneration of cells, simulating the periportal duct cell, which apparently never form true liver cells. In an infant’s liver that has suffered a similar destructive lesion, the periportal cells may regenerate in the form of tubules, resembling by the morphology of the cell and the presence of bile in the lumina, liver cells; and by the tubular arrangement of the cells, poorly formed bile ducts (Fig. 3).
There is another anomaly of the liver which occurs more frequently that is characterized by an increase in number and size of the periportal bile ducts. Many of these, even in the seven-month fetus, are unusually dilated and appear as distended tubules and small irregular cysts. These cyst-like ducts contain eosin-staining finely granular coagulum. The cells lining the dilated ducts are small, rather uniform and cuboidal, and have little cytoplasm, whereas the nucleus is relatively large and resembles that in the liver cells. At the margin of the portal areas are ducts that are incompletely formed; the row of cells lying adjacent to peripheral mesenchyma resembles bile duct epithelium, whereas the cells toward the lobule are like liver cells and are continuous with the liver cells of the lobule.
A well marked case in an eight-month fetus showed the liver parenchyma divided up irregularly into uneven lobules by coarse bands of loose mesenchyma. The large, dilated, poorly formed periportal bile ducts were distributed along the surface of the portal connective tissue (Fig. 4). The larger portal areas contained as many as six to eight thin-walled moderately large blood vessels.
In another case, in a full-term child one month old, the many dilated ducts were less prominent. The cells lining the ducts were uniform in size and better defined, but were still relatively undifferentiated. There was more connective tissue in the former case, and most of the ducts were completely surrounded by it.
The liver of a child three months old showed a similar picture. The number of dilated bile ducts was about the same as that in the earlier cases, but with further condensation of the stroma they were less conspicuous. They did not appear to be increasing in number or in size, and the duct cells showed no mitoses. The cells were more mature and in places tended to become low columnar, with the nuclei more toward the base. Normal portal areas were seen at the margin of many of the more recently formed lobules, but the greater part of the liver still lacked normal lobulation (Fig. 5).
This type of anomaly persists with the growth of the individual. An excellent example was seen in a child 15 years of age. The large portal areas showed an increase in both number and size of the ducts as well as an increase in blood vessels and connective tissue. The epithelium of the ducts was generally of a very uniform cuboidal type, although at times it was low columnar. The presence of bile within these ducts demonstrates that they are part of the functioning biliary system (Fig. 6).
The liver of an adult, which grossly may appear quite normal, may show this same malformation. Here, however, with the growth of liver cells and condensation of the portal connective tissue, this anomaly which formed such an outstanding feature in the fetus may appear relatively insignificant (Fig. 7).
Sometimes, as not infrequently happens both in the embryo and adult, a portion of a duct becomes detached and separated off as an epithelial-lined cyst. This may increase in size and result in compression of the surrounding stroma. The watery fluid that is secreted into the cyst may so distend the wall that with gradual thinning and elongation of the epithelial cells they resemble a delicate wall of endothelium (Fig. 8). In time the epithelium may atrophy, and then the fluid is absorbed, the walls contract, and the space becomes obliterated by fibrous tissue.
In this type of congenital malformation of the ducts the process begins with an abnormal development of the periportal bile ducts. When once formed they do not disappear but become gradually less conspicuous with the later development of the liver. Whether the anomaly is primarily the result of anomalous development of the periportal bile ducts, or whether it is secondary to an increase in mesenchyma that is commonly present, is a debatable question; however, the unusual regularity with which this anomaly is associated with the bilateral congenital cystic kidney would suggest that we are dealing with a primary developmental defect of parenchymatous origin. In the infant the liver may be normal in size, contour and color. It may cut with slightly increased resistance. Fibrous bands may be irregularly followed extending into the liver from the transverse septum. In the adult the liver may be grossly normal or filled with large and small cysts. According to Moschcowitz }* the congenital cysts of the liver arise from aberrant ducts, one type of cyst arising from ‘inflammatory hyperplasia of these ducts,” the other by retention of fluid as a result of congenital obstruction.
Congenital anomalies of the liver are relatively infrequent. They may involve the biliary system, the liver cells or the stroma. Several of the more common types are described and explained on an embryologic basis. One type that is characterized by an increase and dilatation of the periportal bile ducts, accompanied by an increase in connective tissue in the portal areas, may persist throughout life. Associated with this type of anomaly are the congenital cysts of the liver occasionally seen at birth and also in later life. Moreover, this anomaly, with or without cyst formation, very commonly accompanies bilateral congenital cysts of the kidneys.
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Schafer, E. A. Quain’s Elements of Anatomy, i. London, 1898.
Lewis, F. T. Keibel and Mall, Manual of Human Embryology, ii. Philadelphia, 1912.
Hertwig, O. Lehrbuch der Entwicklungsgeschichte des Menschen und der Wirbelthiere, Ed. 10. Jena, 1915..
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Holmes, J. B. Ass. J. Dis. Child., 1916, xi, 405.
Thomson, J. Edinburgh M.J., 1892, xxxvii, 604.
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Description of Plates
Fig. 1. Photomicrograph of the liver of a full-term child who lived twenty months. The parenchyma is divided into single and compound lobules, many of which lack central veins. Developing periportal bile ducts border the periphery of the lobules. x 50.
Fig. 2. A higher power photomicrograph of the liver in Fig. 1. The portal connective tissue contains well formed vessels and bile ducts. The small embryonic periportal bile ducts lie at the periphery of the lobule. The liver cells lack uniformity. The trabecular arrangement is lost, and bile capillaries are indistinct. x 150. AMERICAN JOURNAL OF PaTHOLOoGy. VoL. V
Fig. 3. Photomicrograph of the liver of a three-months-old child showing the healing stage of an acute toxic hepatitis. The liver cells of the lobules have been killed. The trabecular spaces are filled with endothelial leucocytes. Regenerating periportal bile ducts border the portal areas. The morphology and the presence of bile in bile capillaries bordered by the cells suggest that they are liver cells, whereas their arrangement more closely resembles poorly formed bile ducts. x 100.
Fig. 4. Photomicrograph of the liver of an eight-month fetus. Large dilated cyst-like periportal ducts border the peripheral mesenchyma. The liver cells are separated by wide endothelial-lined sinusoids and are arranged as a loose network of interlacing trabeculae. There are many foci of cells showing hematopoiesis in the perisinusoidal spaces. x 100.
Fig. 5. Photomicrograph of the liver of a full-term child who lived for three months. The many dilated bile ducts stand out in sharp contrast to the moderately condensed stroma. The cells lining the bile ducts are uniform in size and more differentiated than in the preceding case. x 150.
Fig. 6. Low power photomicrograph of the liver of a child 15 years of age. The larger portal areas contain many dilated bile ducts. The presence of bile in some of these suggests that they form part of the functioning biliary system. X 50. Samah skebhan eadianaanndinn nena?
Fig. 7. Photomicrograph of the liver of an adult showing the same anomaly of the bile ducts. They are increased in number, moderately dilated and lined with a uniform cuboidal type of epithelium. The connective tissue stroma, as in the earlier cases, is also considerably increased. x 100.
Fig. 8. Photomicrograph of the liver from an elderly male. It shows the same bile duct anomaly. Here some of the ducts have become isolated, and as cyst-like spaces are distended with clear fluid. The bile duct epithelium is extremely compressed. The unusual amount of connective tissue surrounding the cysts suggests an old healed inflammatory lesion. x 50.
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