Inflammation of the pancreas is known aspancreatitis, with common causes including chronicalcohol use andgallstones. Because of its role in the regulation of blood sugar, the pancreas is also a key organ indiabetes.Pancreatic cancer can arise followingchronic pancreatitis or due to other reasons, and carries a very poor prognosis, as it is often only identified after it has spread to other areas of the body.
The word pancreas comes from theGreek πᾶν (pân, "all") & κρέας (kréas, "flesh"). The function of the pancreas in diabetes has been known since at least 1889, with its role in insulin production identified in 1921.
The pancreas (shown here in pink) sits behind thestomach, with the body near the curvature of theduodenum, and the tail stretching to touch thespleen.
The pancreas is an organ that in humans lies in theabdomen, stretching from behind thestomach to the left upper abdomen near thespleen. In adults, it is about 12–15 centimetres (4.7–5.9 in) long,lobulated, and salmon-coloured in appearance.[7]
Anatomically, the pancreas is divided into ahead,neck,body, andtail. The pancreas stretches from the inner curvature of theduodenum, where the head surrounds twoblood vessels: thesuperior mesenteric artery andvein. The longest part of the pancreas, the body, stretches across behind the stomach, and the tail of the pancreas ends adjacent to thespleen.[7]
The neck of the pancreas separates the head of the pancreas, located in the curvature of the duodenum, from the body. The neck is about 2 cm (0.79 in) wide, and sits in front of where theportal vein is formed. The neck lies mostly behind the pylorus of the stomach, and is covered with peritoneum. Theanterior superior pancreaticoduodenal artery travels in front of the neck of the pancreas.[7]
The body is the largest part of the pancreas, and mostly lies behind the stomach, tapering along its length. The peritoneum sits on top of the body of the pancreas, and thetransverse colon in front of the peritoneum.[7] Behind the pancreas are several blood vessels, including theaorta, thesplenic vein, and theleft renal vein, as well as the beginning of thesuperior mesenteric artery.[7] Below the body of the pancreas sits some of thesmall intestine, specifically the last part of the duodenum and thejejunum to which it connects, as well as thesuspensory ligament of the duodenum which falls between these two. In front of the pancreas sits the transverse colon.[8]
The pancreas narrows towards the tail, which sits near to the spleen.[7] It is usually between 1.3–3.5 cm (0.51–1.38 in) long, and sits between the layers of theligament between the spleen and the left kidney. Thesplenic artery andvein, which also passes behind the body of the pancreas, pass behind the tail of the pancreas.[7]
The pancreas has a rich blood supply, with vessels originating as branches of both thecoeliac artery andsuperior mesenteric artery.[7] Thesplenic artery, the largest branch of the celiac trunk, runs along the top of the pancreas, and supplies the left part of the body and the tail of the pancreas through its pancreatic branches, the largest of which is called thegreater pancreatic artery.[7] Thesuperior andinferior pancreaticoduodenal arteries run along the back and front surfaces of the head of the pancreas adjacent to the duodenum. These supply the head of the pancreas. These vessels join together (anastamose) in the middle.[7]
The pancreas drains into lymphatic vessels that travel alongside itsarteries, and has a rich lymphatic supply.[7] Thelymphatic vessels of the body and tail drain intosplenic lymph nodes, and eventually intolymph nodes that lie in front of the aorta, between the coeliac and superior mesenteric arteries. The lymphatic vessels of the head and neck drain into intermediate lymphatic vessels around the pancreaticoduodenal, mesenteric and hepatic arteries, and from there into the lymph nodes that lie in front of the aorta.[7]
This image shows apancreatic islet when pancreatic tissue is stained and viewed under a microscope. Parts of the digestive ("exocrine") pancreas can be seen around the islet, more darkly. These contain hazy dark purple granules of inactive digestive enzymes (zymogens).A pancreatic islet that usesfluorescent antibodies to show the location of different cell types in the pancreatic islet. Antibodies against glucagon, secreted by alpha cells, show their peripheral position. Antibodies against insulin, secreted by beta cells, show the more widespread and central position that these cells tend to have.[9]
The pancreas contains tissue with anendocrine andexocrine role, and this division is also visible when the pancreas is viewed under a microscope.[10]
The majority of pancreatictissue has a digestive role. The cells with this role form clusters (acini) around smallducts, and are arranged in lobes that have thinfibrous walls. The cells of each acinus secrete inactive digestive enzymes calledzymogens into the smallintercalated ducts which they surround. In each acinus, the cells are pyramid-shaped and situated around the intercalated ducts, with thenuclei resting on thebasement membrane, a largeendoplasmic reticulum, and a number of zymogen granules visible within thecytoplasm. The intercalated ducts drain into largerintralobular ducts within the lobule, and finallyinterlobular ducts. The ducts are lined by a single layer ofcolumn-shaped cells. There is more than one layer of cells as the diameter of the ducts increases.[10]
The tissues with anendocrine role within the pancreas exist as clusters of cells calledpancreatic islets (also called islets ofLangerhans) that are distributed throughout the pancreas.[9] Pancreatic islets containalpha cells,beta cells, anddelta cells, each of which releases a different hormone. These cells have characteristic positions, with alpha cells (secretingglucagon) tending to be situated around the periphery of the islet, and beta cells (secretinginsulin) more numerous and found throughout the islet.[9]Enterochromaffin cells are also scattered throughout the islets.[9] Islets are composed of up to 3,000 secretory cells, and contain several small arterioles to receive blood, and venules that allow the hormones secreted by the cells to enter thesystemic circulation.[9]
The size of the pancreas varies considerably.[7] Severalanatomical variations exist, relating to the embryological development of the twopancreatic buds. The pancreas develops from these buds on either side of the duodenum. Theventral bud rotates to lie next to thedorsal bud, eventually fusing. In about 10% of adults, anaccessory pancreatic duct may be present if the main duct of the dorsal bud of the pancreas does not regress; this duct opens into theminor duodenal papilla.[11] If the two buds themselves, each having a duct, do not fuse, a pancreas may exist with two separate ducts, a condition known as apancreas divisum. This condition has no physiologic consequence.[12] If the ventral bud does not fully rotate, anannular pancreas may exist, where part or all of the duodenum is encircled by the pancreas. This may be associated withduodenal atresia.[13]
10,000 protein coding genes (~50% of all human genes) are expressed in the normal human pancreas.[14][15] Less than 100 of these genes are specifically expressed in the pancreas. Similar to thesalivary glands, most pancreas-specific genes encode for secreted proteins. Corresponding pancreas-specific proteins are either expressed in the exocrine cellular compartment and have functions related to digestion or food uptake such as digestivechymotrypsinogen enzymes and pancreatic lipasePNLIP, or are expressed in the various cells of the endocrinepancreatic islets and have functions related to secreted hormones such asinsulin,glucagon,somatostatin andpancreatic polypeptide.[16]
The pancreas originates from theforegut, a precursor tube to part of thedigestive tract, as adorsal and ventral bud. As it develops, the ventral bud rotates to the other side and the two buds fuse together.
The pancreas forms duringdevelopment from two buds that arise from theduodenal part of theforegut, an embryonic tube that is a precursor to thegastrointestinal tract.[11] It is ofendodermal origin.[11] Pancreatic development begins with the formation of adorsal and ventralpancreatic bud. Each joins with the foregut through a duct. The dorsal pancreatic bud forms the neck, body, and tail of the developed pancreas, and the ventral pancreatic bud forms the head and uncinate process.[11]
The definitive pancreas results from rotation of the ventral bud and the fusion of the two buds.[11] During development, the duodenum rotates to the right, and the ventral bud rotates with it, moving to a position that becomes more dorsal. Upon reaching its final destination, the ventral pancreatic bud is below the larger dorsal bud, and eventually fuses with it. At this point of fusion, the main ducts of the ventral and dorsal pancreatic buds fuse, forming the main pancreatic duct. Usually, the duct of the dorsal bud regresses, leaving themain pancreatic duct.[11]
The cells of the exocrine pancreas differentiate through molecules that induce differentiation includingfollistatin,fibroblast growth factors, and activation of theNotch receptor system.[17] Development of the exocrine acini progresses through three successive stages. These are the predifferentiated, protodifferentiated, and differentiated stages, which correspond to undetectable, low, and high levels of digestive enzyme activity, respectively.[17]
Pancreatic progenitor cells differentiate into endocrine islet cells under the influence ofneurogenin-3 andISL1, but only in the absence ofnotch receptor signaling. Under the direction of aPax gene, the endocrine precursor cells differentiate to form alpha and gamma cells. Under the direction ofPax-6, the endocrine precursor cells differentiate to form beta and delta cells.[17] The pancreatic islets form as the endocrine cells migrate from the duct system to form small clusters aroundcapillaries.[9] This occurs around the third month of development,[11] and insulin and glucagon can be detected in the humanfetal circulation by the fourth or fifth month of development.[17]
The pancreas maintains constant blood glucose levels (shown as the waving line). When the blood glucose level is too high, the pancreas secretes insulin and when the level is too low, the pancreas secretes glucagon.
Cells within the pancreas help to maintain blood glucose levels (homeostasis). The cells that do this are located within the pancreatic islets that are present throughout the pancreas. When blood glucose levels are low,alpha cells secreteglucagon, which increases blood glucose levels. When blood glucose levels are highbeta cells secreteinsulin to decrease glucose in blood.Delta cells in the islet also secretesomatostatin which decreases the release of insulin and glucagon.[9]
Glucagon acts to increase glucose levels by promoting thecreation of glucose and thebreakdown of glycogen to glucose in the liver. It also decreases the uptake of glucose in fat and muscle. Glucagon release is stimulated by low blood glucose or insulin levels, and during exercise.[18] Insulin acts to decrease blood glucose levels by facilitating uptake by cells (particularlyskeletal muscle), and promoting its use in the creation of proteins, fats and carbohydrates. Insulin is initially created as a precursor form calledpreproinsulin. This is converted toproinsulin and cleaved byC-peptide toinsulin which is then stored in granules in beta cells. Glucose is taken into the beta cells and degraded. The end effect of this is to causedepolarisation of the cell membrane which stimulates the release of the insulin.[18]
The main factor influencing the secretion of insulin and glucagon are the levels of glucose in blood plasma.[19] Low blood sugar stimulates glucagon release, and high blood sugar stimulates insulin release. Other factors also influence the secretion of these hormones. Someamino acids, that are byproducts of the digestion ofprotein, stimulate insulin and glucagon release. Somatostatin acts as an inhibitor of both insulin and glucagon. Theautonomic nervous system also plays a role. Activation ofBeta-2 receptors of thesympathetic nervous system bycatecholamines secreted from sympathetic nerves stimulates secretion of insulin and glucagon,[19][20] whereas activation ofAlpha-1 receptors inhibits secretion.[19]M3 receptors of theparasympathetic nervous system act when stimulated by the rightvagus nerve to stimulate release of insulin from beta cells.[19]
The pancreas has a role in digestion, highlighted here. Ducts in the pancreas (green) conduct digestive enzymes into the duodenum. This image also shows apancreatic islet, part of the endocrine pancreas, which contains cells responsible for secretion ofinsulin andglucagon.
The pancreas plays a vital role in thedigestive system. It does this by secretingpancreatic juice, a fluid that contains digestive enzymes, into theduodenum, the first part of thesmall intestine that receives food from thestomach. These enzymes help to break down carbohydrates, proteins and lipids (fats). This is theexocrine role of the pancreas. The cells responsible for this arecentroacinar cells arranged in clusters calledacini. Secretions into the middle of the acinus accumulate inintralobular ducts, which drain to the mainpancreatic duct, which drains directly into theduodenum. About 1.5–3 liters of fluid are secreted in this manner every day.[8][21]
The cells in each acinus are filled with granules containing the digestive enzymes. These are secreted in an inactive form termedzymogens or proenzymes. When released into the duodenum, they are activated by the enzymeenterokinase present in the lining of the duodenum. The proenzymes are cleaved, creating a cascade of activating enzymes.[21]
Enzymes that break down starch and other carbohydrates includeamylase.[21]
These enzymes are secreted in a fluid rich inbicarbonate. Bicarbonate helps maintain analkaline pH for the fluid, a pH in which most of the enzymes act most efficiently, and also helps to neutralise the stomach acids that enter the duodenum.[21] Secretion is influenced by hormones includingsecretin,cholecystokinin, andVIP, as well asacetylcholine stimulation from thevagus nerve. Secretin is released from theS cells which form part of the lining of the duodenum in response to stimulation by gastric acid. Along with VIP, it increases the secretion of enzymes and bicarbonate. Cholecystokinin is released fromIto cells of the lining of the duodenum and jejunum mostly in response to long chain fatty acids, and increases the effects of secretin.[21] At a cellular level, bicarbonate is secreted from centroacinar and ductal cells through a sodium and bicarbonatecotransporter that acts because of membrane depolarisation caused by thecystic fibrosis transmembrane conductance regulator. Secretin and VIP act to increase the opening of the cystic fibrosis transmembrane conductance regulator, which leads to more membrane depolarisation and more secretion of bicarbonate.[22][23][24]
A variety of mechanisms act to ensure that the digestive action of the pancreas does not act to digest pancreatic tissue itself. These include the secretion of inactive enzymes (zymogens), the secretion of the protective enzymetrypsin inhibitor, which inactivates trypsin, the changes in pH that occur with bicarbonate secretion that stimulate digestion only when the pancreas is stimulated, and the fact that the low calcium within cells causes inactivation of trypsin.[21]
In pancreatitis, enzymes of the exocrine pancreas damage the structure and tissue of the pancreas. Detection of some of these enzymes, such asamylase andlipase in the blood, along with symptoms and findings onmedical imaging such asultrasound or aCT scan, are often used to indicate that a person has pancreatitis. Pancreatitis is often managed medically withpain relief, and monitoring to prevent or manage shock, and management of any identified underlying causes. This may include removal of gallstones, lowering of blood triglyceride or glucose levels, the use ofcorticosteroids forautoimmune pancreatitis, and the cessation of any medication triggers.[27]
Chronic pancreatitis refers to the development of pancreatitis over time. It shares many similar causes, with the most common being chronic alcohol use, with other causes including recurrent acute episodes andcystic fibrosis. Abdominal pain, characteristically relieved by sitting forward or drinking alcohol, is the most common symptom. When the digestive function of the pancreas is severely affected, this may lead to problems with fat digestion and the development ofsteatorrhoea; when the endocrine function is affected, this may lead to diabetes. Chronic pancreatitis is investigated in a similar way to acute pancreatitis. In addition to management of pain and nausea, and management of any identified causes (which may includealcohol cessation), because of the digestive role of the pancreas,enzyme replacement may be needed to preventmalabsorption.[27]
Pancreatic cancer, shown here, most commonly occurs as anadenocarcinoma in the head of the pancreas. Because symptoms (such as skin yellowing, pain, or itch) do not occur until later in the disease, it often presents at a laterstage and has limited treatment options.Relative incidences of various pancreaticneoplasms, with pancreatic cancers in red/pink color.[28]
Pancreatic adenocarcinoma is the most common form of pancreatic cancer, and is cancer arising from the exocrine digestive part of the pancreas. Most occur in the head of the pancreas.[27] Symptoms tend to arise late in the course of the cancer, when it causes abdominal pain, weight loss, or yellowing of the skin (jaundice). Jaundice occurs when the outflow ofbile is blocked by the cancer. Other less common symptoms include nausea, vomiting, pancreatitis, diabetes or recurrentvenous thrombosis.[27] Pancreatic cancer is usually diagnosed bymedical imaging in the form of anultrasound orCT scan with contrast enhancement. Anendoscopic ultrasound may be used if a tumour is being considered for surgical removal, and biopsy guided byERCP or ultrasound can be used to confirm an uncertain diagnosis.[27]
Because of the late development of symptoms, most cancer presents at an advancedstage.[27] Only 10 to 15% of tumours are suitable for surgical resection.[27] As of 2018[update], when chemotherapy is given theFOLFIRINOX regimen containingfluorouracil,irinotecan,oxaliplatin andleucovorin has been shown to extend survival beyond traditionalgemcitabine regimens.[27] For the most part, treatment ispalliative, focus on the management of symptoms that develop. This may include management ofitch, acholedochojejunostomy or the insertion of stents withERCP to facilitate the drainage of bile, and medications to help control pain.[27] In the United States pancreatic cancer is the fourth most common cause of deaths due to cancer.[32] The disease occurs more often in the developed world, which had 68% of new cases in 2012.[33] Pancreatic adenocarcinoma typically has poor outcomes with the average percentage alive for at least one and five years afterdiagnosis being 25% and 5% respectively.[33][34] In localized disease where the cancer is small (< 2 cm) the number alive at five years is approximately 20%.[35]
There are several types of pancreatic cancer, involving both the endocrine and exocrine tissue. The many types ofpancreatic endocrine tumors are all uncommon or rare, and have varied outlooks. However theincidence of these cancers has been rising sharply; it is not clear to what extent this reflects increased detection, especially throughmedical imaging, of tumors that would be very slow to develop.Insulinomas (largely benign) andgastrinomas are the most common types.[36] For those with neuroendocrine cancers the number alive after five years is much better at 65%, varying considerably with type.[33]
Diabetes mellitus type 1 is a chronicautoimmune disease in which theimmune system attacks the insulin-secreting beta cells of the pancreas.[38] Insulin is needed to keepblood sugar levels within optimal ranges, and its lack can lead tohigh blood sugar. As an untreated chronic condition, complications including acceleratedvascular disease,diabetic retinopathy,kidney disease andneuropathy can result.[38] In addition, if there is not enough insulin for glucose to be used within cells, the medical emergencydiabetic ketoacidosis, which is often the first symptom that a person with type 1 diabetes may have, can result.[39] Type 1 diabetes can develop at any age but is most often diagnosed before age 40.[38] For people living with type 1 diabetes, insulin injections are critical for survival.[38] An experimental procedure to treat type 1 diabetes ispancreas transplantation or isolatedtransplantation of islet cells to supply a person with functioning beta cells.[38]
Diabetes mellitus type 2 is the most common form of diabetes.[38] The causes for high blood sugar in this form of diabetes usually are a combination ofinsulin resistance and impaired insulin secretion, with both genetic and environmental factors playing a role in the development of the disease.[40] Over time, pancreatic beta cells may become "exhausted" and less functional.[38] The management of type 2 diabetes involves a combination of lifestyle measures, medications if required and potentiallyinsulin.[41] With relevance to the pancreas, several medications act to enhance the secretion of insulin from beta cells, particularlysulphonylureas, which act directly on beta cells;incretins which replicate the action of the hormonesglucagon-like peptide 1, increasing the secretion of insulin from beta cells after meals, and are more resistant to breakdown; andDPP-4 inhibitors, which slow the breakdown of incretins.[41]
It is possible for a person to live without a pancreas, provided that the person takes insulin for proper regulation of blood glucose concentration andpancreatic enzyme supplements to aid digestion.[42]
The pancreas was first identified byHerophilus (335–280 BC), aGreekanatomist andsurgeon.[43] A few hundred years later,Rufus of Ephesus, another Greek anatomist, gave the pancreas its name. Etymologically, the term "pancreas", a modernLatin adaptation ofGreek πάγκρεας,[44] [πᾶν ("all", "whole"), and κρέας ("flesh")],[45] originally meanssweetbread,[46] although literally meaning all-flesh, presumably because of its fleshy consistency. It was only in 1889 whenOskar Minkowski discovered that removing the pancreas from a dog caused it to become diabetic.[47] Insulin was later isolated from pancreatic islets byFrederick Banting andCharles Best in 1921.[47]
The way the tissue of the pancreas has been viewed has also changed. Previously, it was viewed using simplestaining methods such asH&E stains. Now,immunohistochemistry can be used to more easily differentiate cell types. This involves visible antibodies to the products of certain cell types, and helps identify with greater ease cell types such as alpha and beta cells.[9]
Pancreatic tissue is present in allvertebrates, but its precise form and arrangement varies widely. There may be up to three separate pancreases, two of which arise from thepancreatic bud, and the otherdorsally. In most species (including humans), these "fuse" in the adult, but there are several exceptions. Even when a single pancreas is present, two or three pancreatic ducts may persist, each draining separately into the duodenum (or equivalent part of the foregut).Birds, for example, typically have three such ducts.[48]
Inteleost fish, and a few other species (such asrabbits), there is no discrete pancreas at all, with pancreatic tissue being distributed diffusely across themesentery and even within other nearby organs, such as theliver orspleen. In a few teleost species, the endocrine tissue has fused to form a distinct gland within the abdominal cavity, but otherwise it is distributed among the exocrine components. The most primitive arrangement, however, appears to be that oflampreys andlungfish, in which pancreatic tissue is found as a number of discrete nodules within the wall of the gut itself, with the exocrine portions being little different from other glandular structures of the intestine.[48]
^Gyr, K.; Beglinger, C.; Stalder, G. A. (1985-09-21). "[Interaction of the endo- and exocrine pancreas]".Schweizerische Medizinische Wochenschrift.115 (38):1299–1306.ISSN0036-7672.PMID2865807.
^Alonso-Magdalena, Paloma; Tudurí, Eva; Marroquí, Laura; Quesada, Ivan; Sargis, Robert M.; Nadal, Angel (2019). "Toxic Effects of Common Environmental Pollutants in Pancreatic β-Cells and the Onset of Diabetes Mellitus".Encyclopedia of Endocrine Diseases. pp. 764–775.doi:10.1016/B978-0-12-801238-3.64325-8.ISBN978-0-12-812200-6.
^Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. (January 2015). "Proteomics. Tissue-based map of the human proteome".Science.347 (6220): 1260419.doi:10.1126/science.1260419.PMID25613900.S2CID802377.
^abcdBarrett, Kim E. (2019). "Regulation of Insulin Secretion; Glucagon".Ganong's review of medical physiology. Barman, Susan M.,, Brooks, Heddwen L., Yuan, Jason X.-J. (26th ed.). New York. pp. 433–437.ISBN978-1-260-12240-4.OCLC1076268769.{{cite book}}: CS1 maint: location missing publisher (link)
^Hall, John E (2016).Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia: Elsevier. pp. 990–994.ISBN978-1-4557-7016-8.
^Wang, Y; Miller, FH; Chen, ZE; Merrick, L; Mortele, KJ; Hoff, FL; et al. (2011). "Diffusion-weighted MR imaging of solid and cystic lesions of the pancreas".Radiographics.31 (3): E47-64.doi:10.1148/rg.313105174.PMID21721197. Diagram by Mikael Häggström, M.D.
^abRyan DP, Hong TS, Bardeesy N (September 2014). "Pancreatic adenocarcinoma".The New England Journal of Medicine.371 (11):1039–49.doi:10.1056/NEJMra1404198.PMID25207767.
^Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update".Current Treatment Options in Oncology.13 (1):24–34.doi:10.1007/s11864-011-0172-2.PMID22198808.S2CID7329783.
^abcdefgBarrett, Kim E.; Barman, Susan M.; Brooks, Heddwen L.; Yuan, Jason X.-J.; Ganong, William F. (2019). "Hypoglycaemia & Diabetes Mellitus in Humans".Ganong's review of medical physiology (26th ed.). New York: McGraw-Hill Education. pp. 440–441.ISBN978-1-260-12240-4.OCLC1076268769.
Barrett, Kim E. (2019).Ganong's review of medical physiology. Barman, Susan M.,, Brooks, Heddwen L., Yuan, Jason X.-J. (26th ed.). New York.ISBN978-1-260-12240-4.OCLC1076268769.{{cite book}}: CS1 maint: location missing publisher (link)
Beger HG, ed. (2018).The pancreas: an integrated textbook of basic science, medicine, and surgery (third ed.). Hoboken, NJ.ISBN978-1-119-18841-4.OCLC1065547789.{{cite book}}: CS1 maint: location missing publisher (link)
Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J (2015).Harrison's Principles of Internal Medicine (19 ed.). McGraw-Hill Professional.ISBN978-0-07-180215-4.
Ralston SH, Penman ID, Strachan MW, Hobson RP, eds. (2018).Davidson's principles and practice of medicine (23rd ed.). Elsevier.ISBN978-0-7020-7028-0.
Standring, Susan; Borley, Neil R.; et al., eds. (2008).Gray's anatomy: the anatomical basis of clinical practice (40th ed.). London: Churchill Livingstone.ISBN978-0-8089-2371-8.
Standring, Susan, ed. (2016).Gray's anatomy: the anatomical basis of clinical practice (41st ed.). Philadelphia.ISBN978-0-7020-5230-9.OCLC920806541.{{cite book}}: CS1 maint: location missing publisher (link)
Young, Barbara; O'Dowd, Geraldine; Woodford, Phillip (2013).Wheater's functional histology: a text and colour atlas (6th ed.). Philadelphia: Elsevier.ISBN978-0-7020-4747-3.
