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NICDAO, Jan Kevin G. B2 Micro HSB 1.

Definition of Diarrhea To be able to characterize and differentiate the abnormal volume and fluidity of the feces from soft to watery stool To be able to identify the accompanying signs and symptoms if abnormal volume and consistency of feces Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency - more than 200 grams stool in 24 hours - excess water, electrolytes, fat, other substances in intestinal lumen 2. To be able to correlate the histological structural changes in the organs involved in the different causes of diarrhea to the physiological alteration which are responsible for the clinical significance (manifestations and complications) of diarrhea 2.1 Secretory Diarrhea Large volumes of water are normally secreted into the small intestinal lumen, but a large majority of this water is efficienty absorbed before reaching the large intestine. Diarrhea occurs when secretion of water into the intestinal lumen exceeds absorption. Many millions of people have died of the secretory diarrhea associated with cholera. The responsible organism, Vibrio cholerae, produces cholera toxin, which strongly activates adenylyl cyclase, causing a prolonged increase in intracellular concentration of cyclic AMP within crypt enterocytes. This change results in prolonged opening of the chloride channels that are instrumental in secretion of water from the crypts, allowing uncontrolled secretion of water. Additionally, cholera toxin affects the enteric nervous system, resulting in an independent stimulus of secretion. Exposure to toxins from several other types of bacteria (e.g. E. coli heat-labile toxin) induce the same series of steps and massive secretory diarrhea that is often lethal unless the person or animal is aggressively treated to maintain hydration.

2.2 Osmotic Diarrhea -crypt enterocytes intracellular concentration of cyclic AMP is prolonged resulting to continuous opening of sodium channels that are instrumental in secretion of water from the crypts - abnormal ion transport In intestinal epithelial cells

Osmotic diarrhea results from the presence of osmotically active, poorly absorbed solutes in the bowel lumen that inhibit normal water and electrolyte absorption. Certain laxatives such as lactulose and citrate of magnesia or maldigestion of certain food substances such as milk are common causes of osmotic diarrhea. An increased osmotic load can be measured in the stool. This type of diarrhea ceases with fasting. 2.3 Exudative Diarrhea Diseases associated with large quantities of inflammatory exudate, that is, blood, pus, and proteinaceous material, which can produce diarrhea. These inflammatory products in themselves cause increased stool volume and frequency, but altered absorption of fluid and electrolytes also plays an important role. Mucosal inflammation can occur with diverticulitis, inflammatory bowel disease, or invasive enteric infections such as shigella, salmonella, or campylobacter. The etiology for the inflammatory response in ulcerative colitis and Crohn's disease remains poorly understood. 2.4 Deranged Motility When intestinal transport is delayed in the small bowel, as with scleroderma or blind loop syndromes, the resultant bowel stasis encourages bacterial overgrowth and subsequent bile salt deconjugation. Diarrhea is then the direct result of fat malabsorption and increased colonic secretion. In contrast, significant increases in bowel motility can deliver excessively large volumes of stool to the colon. Diarrhea can result when the maximum colonic absorptive capacity of 4 liters a day is exceeded. Also, an alteration in colonic motility such that bowel contents are emptied before adequate absorption can occur has been offered as a possible explanation for the diarrhea associated with irritable bowel disease. 2.5 Malabsorption Numerous pathologic conditions including pancreatic insufficiency, biliary disease, Crohn's disease, intestinal lymphangiectasia, and celiac disease can cause malabsorption. For several of these malabsorption syndromes, more than one pathophysiologic mechanism is responsible for the diarrhea, making a simple classification system difficult. Nonetheless, some general points can be made. The increase in stool volume secondary to fatty acid malabsorption results directly from the presence of large quantities of unabsorbed fat in the stool (i.e. steatorrhea). By excluding or modifying fat intake, this form of diarrhea often resolves. When bile salts are malabsorbed, such as occurs in disease of the terminal ileum, they are deconjugated by colonic bacteria to bile acids that directly stimulate colonic mucosal secretion, causing more diarrhea. Malabsorption and diarrhea can also occur as a result of direct loss of absorptive surface either by surgical resection of the bowel or by atrophy of the small bowel villous border, as seen in celiac disease. If an enteroenteric fistula is present, as may occur in Crohn's disease, whole sections of intestinal absorptive surface can be bypassed.

3. Gastrointestinal Motility To be able to identify and review the specific histological features of the different organs responsible for swallowing/transport and mixing of food 3.1 Oral Cavity Specific structures: Lips Non-keratinized mucus membrane to the keratinized squamous epithelium of the skin ( Vermillion Border) - Deeper part: bundles of striated muscles fibers Teeth - hard and heavily mineralized structures embedded in raised alveolar ridges on the maxilla and mandible Oral Pharynx- Non-keratinized Squamous epithelium Cheeks Outer layer: Stratified Squamous epithelium Submucosa: contains bucal glands Inner Layer: Stratified Squamous Non- keratinized Gums/Gingiva -Keratinized Stratified Squamous epithelium Base of cervical gingival: basal lamina-like thickening called cuticle Tongue - a mass of skeletal muscle covered with mucosa Ventral surface: Non- Keratinized Stratified Squamous epithelium Dorsal surface: partly keratinized Soft Palate- Stratified Squamous Non- keratinized epithelium Hard Palate - Stratified Squamous epithelium Salivary Gland- Cell type: a. Serous cell secretion is protein rich and watery, relatively small and basophilic b. Mucous cell- larger and more acidophilic, secretes is GAG c. Myoepithelial cell contracted cells between the basal lamina and epithelial cell of acina(stellate shape) and ducts(spindle shape) d. Basket cell- cells aroud serous acina Types of Large Salivary Gland a. Parotid gland- largest,enclosed by fibrous capsule, exclusively serous secretory cells b. Submandibular Gland- branched tubule-acinar gland. The main duct is called the Whartons duct and open at the summit of sublingual papillae. c. Sublingual Gland- smallest among the three gland of the salivary gland, a mix gland and predominantly mucous with no fibrous capsule. Major duct Batholins, minor duct Rivinus. Types of Small salivary Gland a. Labial Gland- mix mucous, excretory duct into the oral vestibule b. Buccal Gland- mix mucous, excretory duct into the oral vestibule c. Lingual Gland- anterior sublingual gland of Blandin and Nuhn is mix mucous Posterior glands of Von Ebners is purely serous d. Palatine Gland- mucous gland in the hard and soft plate

3.2 Esophagus

-layers of the esophagus are as follows: Mucosa -nonkeratinized stratified squamous epithelium: is rapidly turned over, and serves a protective effect due to the high volume transit of food, saliva and mucus. Lamina propria: sparse Muscularis mucosae: smooth muscle Submucosa: Contains the mucous secreting glands (esophageal glands), and connective structures termed papillae. Muscularis externa: -composition varies in different parts of the esophagus, to correspond with the conscious control over swallowing in the upper portions and the autonomic control in the lower portions: upper third, or superior part: striated muscle middle third: smooth muscle and striated muscle inferior third: predominantly smooth muscle 3.3 Stomach Mucosa -The first main layer. This consists of the epithelium and the lamina propria (composed of loose connective tissue), with a thin layer of smooth muscle called the muscularis mucosae separating it from the submucosa beneath. Submucosa -This layer lies over the mucosa and consists of fibrous connective tissue, separating the mucosa from the next layer. The Meissner's plexus is in this layer. muscularis externa Over the submucosa, the muscularis externa in the stomach differs from that of other GI organs in that it has three layers of smooth muscle instead of two. Inner oblique layer: -This layer is responsible for creating the motion that churns and physically breaks down the food. It is the only layer of the three which is not seen in other parts of the digestive system. The antrum has thicker skin cells in its walls and performs more forceful contractions than the fundus. Middle circular layer -At this layer, the pylorus is surrounded by a thick circular muscular wall which is normally tonically constricted forming a functional (if not anatomically discrete) pyloric sphincter, which controls the movement of chyme into the duodenum. This layer is concentric to the longitudinal axis of the stomach. Outer longitudinal layer -Auerbach's plexus is found between this layer and the middle circular layer. Serosa

-This layer is over the muscularis externa, consisting of layers of connective tissue continuous with the peritoneum. 3.4 Small intestine

Histological differences are as following: Layer Serosa Muscularis externa Submucosa Duodenum Jejunum normal normal longitudinal and circular layers, with Auerbach's (myenteric) plexus in same as duodenum between Brunner's glands and Meissner's no BG (submucosal) plexus normal no PP Contains goblet Similar to duodenum. Villi very long. Ileum Normal same as duodenum no BG Normal Peyer's patches

Mucosa: normal Muscularis mucosae Mucosa: Lamina no PP propria Mucosa: intestinal simple columnar. epithelium cells, Paneth cells

3.5 Large intestine Regions: Cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectum, and anus. Layers: 1. Mucosa- no folds and no villi, contain straight glands Cell types: a. absorptive cells- present in upper 3rd glands b. goblet cell- present in the upper and mainly in the lower 3rd of glands c. enteroendocrine glands d. stem cell

2. Submucosa contains hemoroidal plexuses that extends to the lamina propria. 3. Muscularis externa- outer longitudinal layers is incomplete and they becaome aggregated into 3 longditudinal bands called taenia coli.

4. Tunica adventitia/ Serosa - cecum, transverse colon and sigmoid colon have tunica serosa -ascending and descending colon have tunica adventitia -colons serosa charactherized by presence of teardrop-shaped adipose filled outpockings called appendices epiplocae

5.Gastrointestinal Secretions: 5.1.Salivary Gland- consist of the parotid, submandibular, and sublingual glands as well as numerous smaller buccal glands secreting both serous and mucoid secretions. The parotid secretions are mainly serous, the buccal glands mucus, and the sublingual and submandibular are a mixture of the two.

5.2.Stomach- The parietal or oxcyntic cells secrete hydrochloric acid; the peptic or chief cells secrete pepsinogen; the mucous cells secrete a bicarbonate rich mucous; and the G cells (found only in the antral glands) secrete the hormone Gastrin.

5.3.Pancreas- is a large endocrine and exocrine gland situated retroperitonealy beneath the stomach. The endocrine portion of the gland secretes Insulin and glucagon from the Islets of Langerhans . These travel down the pancreatic duct to the second part of the duodenum where it exits via the Ampulla of Vater, protected by the Sphincter of Oddi. Secretion of Bicarbonate ions-Copious quantities of Bicarbonate ion rich solutions are secreted by the ducts and ductules of the pancreas in response to the hormone Secretin.

5.4. Small Intestine-The upper small intestine secretes the hormones Cholecystokinase and secretin, mucous, Intestinal digestive juices, and possibly enzymes. Cholecystokinin (CCK)- is secreted in response to fats and peptides in the upper small intestines, particularlythe duodenum. Actions of CCK include: Secretion of Pancreatic Enzymes Contraction of Gallbladder Relaxation of the sphincter of Oddi increased tension in the pyloric sphincter, inhibiting stomach emptying Secretin- is released in response to the presence of Acid in the duodenum. Actions of Secretin include: Secretion of Copious amounts of bicarbonate rich fluid by the biliary and gall bladder ducts Secretion of alkaline rich mucous by Brunners glands increased tension in the pyloric sphincter, inhibiting stomach emptying Crypts of Lieberkuhn-These are located over the entire surface of the small intestine adjacent to the villi. They secrete a copious solution almost identical to interstitial fluid. 5.5.Biliary System-About 1500 mLs of bile are secreted every day. The bile is secreted continuously by the hepatocytes of the liver, and if not immediately required for digestion are stored in the gall bladder. Here they are concentrated up to 15 times. Initally bile fluid has about the same electrolyte concentration of interstitial fluid, but during concentration large quantities of electrolytes (but not Ca

ions) are reabsorbed.Bile contains Bile salts, an emulsifying agent neccessary for the digestion and absorption of fats; as well as bilirubin, cholesterol and fatty acids. 5.6.Large Intestine- secretes about 200 ccs of fluid a day, mainly in the form of mucous

6. Defacation To be able to identify and study the structures responsible for peristalsis and gastrointestinal reflexes in the transport and removal of the feces. 6.1 stomach- the smooth muscle of the muscularis externa is arranged in 3 layers: outer longitudinal, middle circular, and inner oblique. The stomach is empty and contracted, the mucosa and underlying submucosa are thrown into irregular, temporary folds called rugae, that flatten when it is full. - the collection of nerves and ganglion between the circular longitudinal muscles in the myenteric( auerbach) plexus 6.2 colon- concentrate the indigestible residues of food by absorbing water and electrolytes and to move them to the anus for elimination.It is shorter and less convoluted.The wall of the large intestine is lined with simple columnar epithelium. Instead of having the evaginations of the small intestine (villi), the large intestine has invaginations (the intestinal glands).

The mucosa appears smooth at the gross level because it has no villi. Numerous straight, tubular glands are present. They extend all the way to the muscularis mucosae. The glands and the surface are lined with simple columnar epithelium whose cell types are as described for the small intestine. However Paneth cells are usually absent in the adult human and enteroendocrine cells are rare. Columnar absorptive cells and goblet cells are abundant. Goblet cells are more prevalent in the crypts than along the surface, and their number increases distally toward the rectum. The mucus facilitates the passage of the increasingly solid colonic contents, and covers bacteria and particulate matter. The absorptive cells have short, irregular microvilli, and although they secrete a glycocalyx, it has not been shown to contain digestive enzymes. The absorptive cells actively transport electrolytes. Water is also absorbed as it passively follows the electrolytes. As in the small intestine, undifferentiated cells are found at the base of the crypts. The lamina propria is highly cellular. It is particularly rich in lymphoid cells and and lymph nodules may interrupt the regular spacing of the crypts and extend into the submucosa (this is particularly evident in the appendix). The extensive development of GALT reflects the abundance and variety of microorganisms and noxious end products of metabolism. As in the small intestine, lymphatic vessels form a network around the muscularis mucosae. However, no lymph vessels extend into the lamina propria between colonic crypts. The muscularis mucosae has a circular and longitudinal layer. The submucosa is quite dense, similar to that of the small intestine. The muscularis externa consists of an inner circular and outer longitudinal layer. The inner circular layer is typical, but the outer longitudinal layer of the colon is very thin, except for three extremely thick longitudinal bands, called teniae coli. Bundles of muscle from the teniae coli

penetrate the circular layer at irregular intervals. These discontinuities in the muscularis externa allow segments of the colon to contract independently. A contraction in one segment (2-5 cm) will peak over about 30 seconds, and disappear during the next 60. The lumen may almost be occluded during a contraction, allowing all the fecal matter to be in touch with the colon wall. The fecal matter is dug into and rolled - much like spading earth. The longitudinal layer contracts at the same time as the circular layer. Unstimulated portions between the contracting segments bulge outward, forming saccules or haustra. The next contraction would be in another area. All but 80 ml of the daily load of 450 ml of chyme are aborbed. Peristaltic movements in the colon (longitudinal layer) result in mass movements distally of colonic contents. They are not frequent (about once a day in a typical person). The entire transverse colon is covered with a serosa, whereas parts of the ascending and descending colon have an adventitia. 6.3 rectum - The upper rectum contains one to four crescentic plicae, the rectal folds or valves of Houston. Typically there are three folds: left superior, right middle, and left inferior. The rectum is very similar to the caecum, mainly composed of non keratinising, non ciliated columnar epithelium. The mucosa forms into longitudinal ridges, called rectal columns. These end at the anorectal junction.

The rectum is usually divided into two parts. The upper part (about 12-17 cm) largely resembles the colon, but the crypts are longer, more widely spaced and lined almost entirely with goblet cells. The rectum also has more abundant diffuse lymphatic tissue and lymph nodules, and lacks teniae coli in the muscularis externa. The lower part of the rectum (about 2.5-3.5 cm) is the upper part of the anal canal. Here the mucosa is thrown into about 8 permanent, longitudinal folds (columns of Morgagni), which terminate distally about 1.5 cm from the anal orifice. The bases (distal ends) of the columns are connected by transverse folds of the mucosa, called the anal valves. Above the anal valves, the mucosa is lined by simple columnar epithelilum with many goblet cells. Crypts are present. At the level of the anal valves (transition to lower part of anal canal), the epithelium becomes non-keratinized stratified squamous. There are no crypts. The nonkeratinized epithelium extends to the anal orifice, where it becomes epidermis. (Aside from the stratified squamous, keratinized epithelium at the anal orifice, other typical skin structures, such as hairs, sebaceous glands and sweat glands, appear.) Along the way to the epidermis of the anal orifice, different types of epithelium may be seen in the anal canal, such as stratified cuboidal or stratified columnar.

6.4 anus - is lined with a non-keratinising stratified squamous epithelium.

7. Major Causes of the specific mechanism of diarrhea diseases. To be able to identify and understand the specific target or involved structure of the etiology of diarrhea diseases in the following organs:

7.1 Stomach- Problem and abnormalities in the stomach will cause maldigestion of foods. IT secretes protein-digesting enzymes and strong acids to aid in food digestion, (sent to it via osophageal peristalsis through smooth muscular contortions (called segmentation) before sending partially digested food to the small intestines. The stomach realeses enzymes such as gastrin. The hormone gastrin causes an increase in the secretion of HCl from the parietal cells, and pepsinogen from chief cells in the stomach. It also causes increased motility in the stomach. Gastrin is released by G- cells in the stomach in response to distenstion of the antrum, and digestive products(especially large quantities of incompletely digested proteins). If the stomach has abnormalities, there will be maldigestion and will result to malabsorption of foods, retained food will attract water to be drawn in to the bowels, thus diarrhea will follow.

7.2. Intestines- There is malabsorbtion of foods mostly in the small bowel which causes water to be drawn in to the bowels. There is malabsorption in the intestines due to probable mucosal damge or abnormality including the absorptive finger-like projections called villi. This mucosal damage will result to decrease intestinal wall surface area and decreased ability of food absorption, thus increasing the probability of undigested food and malabsorption. Another reason can be, there is rapid movement of food through the intestines (hypermotility). If the food moves too quickly through the gatrointestinal tract, there is not enough time for the foods to be absored, thus there is retention of food in the bowel that will soon attract water to be drawn in the intestines. Some mucosal abnormalities include coeliac disease, cows' milk intolerance (Lactose intolerance), soya milk intolerance and fructose malabsorption.

7.3 Biliary- Bile acids (also called bile salts) are produced in the liver, secreted into the biliary system, stored in the gall bladder and are released after meals stimulated by cholecystokinin. They are important for the digestion and absorption of fats (lipids) in the small intestine. Usually over 95% of the bile acids are absorbed in the terminal ileum and are taken up by the liver and resecreted. This enterohepatic circulation of bile acids takes place 4-6 times in 24 hours and usually less than 0.5g /24h of bile acids enter the large intestine. When larger amounts of bile acids enter the large intestine, they stimulate water secretion and intestinal motility in the colon, which causes symptoms of chronic diarrhea.

7.4 Pancreas- is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, and a digestive organ, secreting pancreatic juice containing digestive enzymes that assist the absorption of nutrients and the digestion in the small intestines. These enzymes help to further break down the carbohydrates, proteins and lipids in the chyme. Diarrhea is seen in patients with pancreatic abnormalities (pancreatitis) particularly in this case problems with the pancreatic acini, because of loss of pancreatic function or insufficiency of digestive enzymes secretion. If no digestive enzymes are produced by the pancreatic acini there will be no breakdown of foods in to smaller particles thus there will be malabsorption of food. Retained

foods in the intestines will then attract water to be drawn in the intestines thus ending up with diarrhea.

8. Structural sources of the contents of the feces for fecalysis To be able to know the general etiology and the altered structure/s responsible for the diarrhea 8.1 Macroscopic (quantity, form, consistency, and color) Watery stools are characteristic of disorders of the small bowel, whereas loose, semisolid stools are associated more often with disorders of the large bowel. Voluminous, greasy stools suggest intestinal malabsorption, and the presence of blood, mucus and pus suggest inflammatory enteritis or colitis. Oil droplets in the toilet water are most always diagnostic of pancreatic insufficiency. Profuse watery diarrhea secondary to small bowel hyper secretion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens. Invasive bacteria and Entamoeba histolytica often cause bloody diarrhea.

8.2 Mucus Stool normally contains a small amount of mucus, but passing stools with visible amounts of mucus could be from one of several different diseases or conditions. Mucus in the stool is a common symptom of irritable bowel syndrome (IBS) and ulcerative colitis (a form ofinflammatory bowel disease), and is seen to a lesser degree in Crohn's disease. A bacterial infection, anal fissure, or a bowel obstruction may also cause the passage of mucus along with stool. In ulcerative colitis, the mucus membrane of the large intestine (colon) becomes inflamed and develops ulcers. These ulcers bleed and may also produce pus and mucus. The mucus may be voluminous enough that it can be seen as it is passed along with the stool. In IBS, there may be increased mucus production by the lining of the intestine. That mucus is then passed in the stool. Mucus is more often associated with diarrhea-predominant IBS than with constipation-predominant IBS or alternating type IBS (IBS-A). Bacterial infections, such as those from Campylobacter, Salmonella, Shigella, and Yersinia, may cause mucus to be passed in the stool.

8.3 Microscopic (fat, meat fibers, leukocytes, RBC)

Presence of one of the types of leukocytes, polymorphonuclear leukocytes in stool of a person may signify a pathogenic infection of the digestive tract. Shigellosis, commonly known as bacillary dysentery, is a common cause of leukocytosis of the stool and is also one of the leading watery diarrhea causes. Shigella infection is usually caused due to feco-oral contamination. Besides diarrhea; fever, vomiting, stomach cramps and body ache are also common symptoms of shigellosis.

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High levels of fat in the stool may be caused by diseases such as pancreatitis,sprue (celiac disease), cystic fibrosis, or other disorders that affect the absorption of fats. The presence of undigested meat fibers in the stool may be caused by pancreatitis. White blood cells in the stool may be caused by inflammation of the intestines, such as ulcerative colitis, or a bacterial infection. Blood in the stool may be caused by bleeding in the digestive tract.

9. Organs and tissues affected by the complication of diarrhea 9.1 To be able to identify the specific structures involved in the compensatory mechanism during diarrhea. 9.1.1 Skin Due to dehydration, skin becomes dry and cold, becomes the blood vessels are constricted to be able to concentrate the flow of blood to the essential organs.

9.1.2 Pituitary gland There will be frequent secretion of ADH from the posterior pituitary gland to be able to conserve the water/electrolytes loss due to dehydration. 9.1.3 Heart and Blood vessels In the case of hypovolemia, the heart will pump faster to be able to compensate in delivering blood to the system. At the same time, blood vessels will constrict, rendering a greater pressure increasing the distributing capacity of the blood. 9.1.4 Kidneys There will be the activation of the JG apparatus to decrease fluid and electrolyte excretion as counteract for the loss of fluid during diarrhea.

9.2 To be able to identify the specific structure of the primary organ or tissues affected by the physiologic alteration during the occurrence of diarrheal complication. 9.2.1 Blood Loss of fluids and electrolytes during dehydration can manifest a decrease in the electrolytes in the blood serum. 9.2.2 Kidneys

Inflammatory bowel disease, gastroenteritis, pancreatitis(chronic or recurring) that causes diarrhea may lead to acute renal failure. Other factors like high or low blood pressure (many causes possible)abnormal electrolyte concentrations (sodium, potassium, chloride, calcium, phosphorus, magnesium)due to dehydration may be involved in the occurrence of renal failure

9.2.3 Heart and Blood Vessels A decrease in electrolytes due to dehydration may cause improper functioning of the heart since it needs electrolytes (specifically potassium) to function as well. 9.2.4 Brain If not treated adequately, brain damage may occur since inadequate supply of nutrients and electrolytes is presumptive due to loss of fluids. 9.2.5 Skin and soft tissues Skin becomes cold and dry due to vasoconstriction. Skin with decreased turgor remains elevated and returns slowly to its normal position. Decreased skin turgor is a late sign in dehydration. It occurs with moderate to severe dehydration. Fluid loss of 5% of the body weight is considered mild dehydration, 10% is moderate, and 15% or more is severe dehydration. Soft tissues at the same time lose its turgor.