Department of Physiology: Digestive system-Offline information

Constipation: The colon of the large intestine has four regions: the ascending colon, the transverse colon, the descending colon, and the sigmoid colon. Water is removed from the non-digestible intestinal contents entering the ascending colon from the small intestine. At this point, bacteria begin their action; they use cellulose as an energy source as they produce fatty acids and vitamins that can also be used by their host. They also release hydrogen gas and sulfur-containing compounds that contribute to human flatulence (gas). Feces, which consist of non-digested intestinal contents, bacteria, and sloughed-off intestinal cells, begin to form in the transverse colon. From there, they are propelled down the descending colon toward the rectum by periodic, firm contractions called peristalsis. When sufficient feces are in the rectum (130–200 grams), a defecatory urge is felt. The involuntary defecation reflex contracts the rectal muscles and relaxes the internal anal sphincter, a ring of muscle that closes off the rectum (Fig. 15B). Then, feces move toward the anus. A pushing motion, along with relaxation of the external anal sphincter, propels feces from the body. Since these activities are under voluntary control, it is possible to control defecation. Defecation normally occurs from three times a week to three times a day; therefore, some variation in occurrence is nothing to worry about. However, if the frequency of defecation declines and if defecation becomes difficult, constipation is present. If constipation is a continuing problem, a physician can help record the movement of materials through the large intestine via several tests. The patient swallows about 20 small markers that will show up on an X ray. At intervals during the following week, X rays are taken, and the number and locations of the markers are noted. If muscle contraction of the intestinal wall is insufficient, the markers move slowly along their course. Injured nerves, certain drugs, dehydration, and prolonged overuse of stimulatory laxatives can bring about this difficulty. Some or all of these problems frequently occur in the elderly. On the other hand, markers may move normally at first and then slow down considerably in the descending colon and rectum. Habitual disregard of the defecatory urge may have caused this problem, or a cancerous polyp might be obstructing normal movement. If the former is the case, it is possible to retrain the rectum to work properly. Sitting on the toilet for about 20 minutes each morning can encourage a return of the reflexes that have disappeared, but straining is not recommended. Temporary constipation due to traveling, pregnancy, or medication can sometimes be relieved by increasing dietary fiber, drinking plenty of water, and getting moderate amounts of exercise. The use of oral laxatives (agents that aid emptying of the intestine) is a last resort. Bulk-forming laxatives, such as those that contain bran, psyllium, and methyl cellulose, are considered best because they promote the defecation reflex. Laxatives that contain osmotic agents, such as carbohydrates or salts (lactulose, milk of magnesia, or Epsom salts), cause water to move into rather than out of the colon. Stool softeners (mineral oil or those that contain docusate) should be used sparingly. Mineral oil reduces the absorption of fat-soluble vitamins, and docusate can cause liver damage. Laxatives that contain chemical stimulants (such as phenolphthalein in Ex-Lax and Feen-A-Mint) can damage the defecation reflex and lead to a dependence on their use. Aside from laxatives, rectal suppositories are sometimes helpful in providing lubrication and stimulating the defecation reflex. Enemas introduce water into the colon and, therefore, also help stimulate defecation.

Diarrhea can result when intestinal chloride secretion is stimulated excessively, and the resulting luminal fluid load exceeds the absorptive capacity of the small and large intestines (Figure 52–3). The prototypic disease state in which this occurs is cholera, in which Vibrio cholerae bacteria in the intestinal lumen secrete a toxin. The active subunit of this toxin translocates to the basolateral membrane of intestinal epithelial cells where it irreversibly activates the stimulatory Gs G-protein, resulting in a massive accumulation of cAMP and stimulation of downstream signaling pathways. This produces uncontrolled and sustained chloride secretion, inhibition of electroneutral NaCl absorption, and an outpouring of fluid into the lumen. Stool volumes of up to 20 L per day are not uncommon in this disorder, which can rapidly lead to death due to the complications of dehydration if left untreated. Active intestinal secretion may also underlie diarrhea caused by a number of other enteric pathogens, including rotavirus and Salmonella. Clostridium difficile is a pathogen that is often acquired in hospital settings, particularly in patients whose normal enteric flora has been disrupted by the administration of antibiotics. It secretes toxins that provoke chloride secretion via calcium-dependent pathways in addition to damaging the barrier function of the epithelium. Finally, the endogenous peptide regulator of chloride secretion, guanylin, shows homology to a heatstable toxin produced by certain strains of pathogenic E. coli, which is the major cause of traveler’s diarrhea. Secretory diarrhea can also occur in noninfectious settings. In particular, when the epithelium is exposed to a barrage of immune and inflammatory mediators, such as in the inflammatory bowel diseases of Crohn’s disease and ulcerative colitis, there is both a stimulation of chloride secretion and an inhibition of sodium and chloride absorption, seen clinically as diarrhea, which is the most frequent symptom of these conditions. Diarrheal diseases continue to represent a major public health problem, particularly in developing countries where sanitation is inadequate and represent an important cause of infant mortality in such countries, second only to respiratory infections. Diarrheal diseases also have a major impact in developed countries, though more frequently in terms of discomfort, inconvenience, and lost productivity than mortality. Nevertheless, thousands of deaths from diarrheal diseases occur each year even in the United States, and many of these take place even after the patient has reached a health facility due to an under appreciation of how rapidly diarrhea can cause dehydration and metabolic disturbances.

Portal hypertension refers to conditions where the resistance to blood flow through the liver is increased, which can have several causes and results in a variety of problems. As we have already discussed, the liver has a very low resistance vasculature in health, and pressures increase little as flow increases since additional sinusoids can be recruited. However, in several liver diseases, inflammatory responses trigger hepatic stellate cells to increase collagen production, reducing permeability across the sinusoidal endothelium and space of Disse and impairing liver function due to the associated fibrosis. The hardening of the liver impedes flow through the sinusoids. Some of the sinusoids and liver parenchyma may also be destroyed and replaced by fibrous tissue, further impairing liver function. The most obvious clinical consequence of portal hypertension is a condition known as ascites. Because the hepatic sinusoids and space of Disse are very permeable and allow albumin to pass, large quantities of lymph are produced by the liver even in health, and are collected by a series of lymph ducts that eventually return the fluid to the blood via the thoracic duct. However, when portal hypertension develops, plasma transudation increases and overwhelms the hepatic lymphatics, which may themselves be compromised by liver fibrosis. The resulting fluid, which contains almost as much albumin as the plasma, weeps from the surface of the liver and accumulates in the peritoneal cavity. In advanced liver disease, many liters of fluid may be found. Another consequence of portal hypertension is the development of collateral blood vessels to surrounding structures. These form in an attempt to bypass the blockage to portal flow posed by the hardened liver, and reconnect to the systemic circulation. If the collateral vessels link to the esophagus, they are referred to as esophageal varices and are vulnerable to erosion and rupture, particularly if their internal pressure is high. Rupture of such varices represents a major medical emergency due to the challenges involved in reestablishing hemostasis. Ruptured varices are also at high risk for rebleeding. Variceal pressures can be reduced by constructing a surgical shunt between the portal vein and the systemic circulation, although doing so diverts portal blood from any remaining functional liver parenchyma, and thus increases complications associated with the loss of the detoxifying functions of hepatocytes. Portal hypertension refers to conditions where the resistance to blood flow through the liver is increased, which can have several causes and results in a variety of problems. As we have already discussed, the liver has a very low resistance vasculature in health, and pressures increase little as flow increases since additional sinusoids can be recruited. However, in several liver diseases, inflammatory responses trigger hepatic stellate cells to increase collagen production, reducing permeability across the sinusoidal endothelium and space of Disse and impairing liver function due to the associated fibrosis. The hardening of the liver impedes flow through the sinusoids. Some of the sinusoids and liver parenchyma may also be destroyed and replaced by fibrous tissue, further impairing liver function. The most obvious clinical consequence of portal hypertension is a condition known as ascites. Because the hepatic sinusoids and space of Disse are very permeable and allow albumin to pass, large quantities of lymph are produced by the liver even in health, and are collected by a series of lymph ducts that eventually return the fluid to the blood via the thoracic duct. However, when portal hypertension develops, plasma transudation increases and overwhelms the hepatic lymphatics, which may themselves be compromised by liver fibrosis. The resulting fluid, which contains almost as much albumin as the plasma, weeps from the surface of the liver and accumulates in the peritoneal cavity. In advanced liver disease, many liters of fluid may be found. Another consequence of portal hypertension is the development of collateral blood vessels to surrounding structures. These form in an attempt to bypass the blockage to portal flow posed by the hardened liver, and reconnect to the systemic circulation. If the collateral vessels link to the esophagus, they are referred to as esophageal varices and are vulnerable to erosion and rupture, particularly if their internal pressure is high. Rupture of such varices represents a major medical emergency due to the challenges involved in reestablishing hemostasis. Ruptured varices are also at high risk for rebleeding. Variceal pressures can be reduced by constructing a surgical shunt between the portal vein and the systemic circulation, although doing so diverts portal blood from any remaining functional liver parenchyma, and thus increases complications associated with the loss of the detoxifying functions of hepatocytes.

gallstones: A 43-year-old woman who is a mother of three comes to her primary care physician complaining of sharp, colicky abdominal pain, usually when she enjoys a pepperoni pizza or other large, fatty meals. Recently, she has had pain with any meal. Her physical examination is unremarkable other than a finding that she is overweight. Nevertheless, having ruled out any cardiac disease, her physician refers her for an imaging study of her gallbladder. This reveals several stones. The patient undergoes a laparoscopic removal of her gallbladder (cholecystectomy) and her symptoms subside, other than the fact that she still cannot tolerate pepperoni pizza or fatty meals without some discomfort and bloating. The formation of stones in the gallbladder is a common disease that has afflicted humans for millennia. More than 20 million Americans have gallstones. Gallstone-related symptoms and complications are among the most common gastroenterologic disorders requiring hospitalization, at great cost to the health care system. Gallstones are of two types, related to the deposition of either cholesterol (cholesterol stones) or bilirubin (pigment stones). Cholesterol stones account for the majority of gallstones in most Western countries. Human bile is unusually rich in cholesterol. In cholesterol gallstone disease, the balance between the normal ratios of cholesterol to the other biliary lipids is disrupted, either due to cholesterol hypersecretion, relative hyposecretion of bile acids or phospholipids, or some combination of these. Obesity, the use of oral contraceptives, estrogen, old age, sudden weight loss, and genetic factors may lead to cholesterol hypersecretion. Conversely, a diminished bile acid pool can occur if the enterohepatic circulation is interrupted. In either case, patients are at risk for supersaturation of cholesterol and thus for the development of gallstones. Supersaturation is not necessarily sufficient for stone formation, however, since nucleation must also occur. Some patients may be genetically predisposed to secrete proteins that can act as nucleating agents, whereas other proteins in bile may retard nucleation. Two thirds of patients with gallstones will have no associated symptoms. Others present with episodic pain in the epigastric region. In most patients, the pain is biliary colic, thought to reflect a tonic spasm resulting from transient obstruction of the cystic duct by a stone, and sometimes precipitated by eating a large meal. Biliary colic, while severe, usually subsides within a few hours, which serves to distinguish it from acute cholecystitis, where obstruction of the cystic duct leads to inflammation of the gallbladder. In some patients, acute inflammation may progress to chronic cholecystitis, resulting in a thickened and fibrotic gallbladder. The definitive treatment for symptomatic gallstone disease is cholecystectomy, which is usually simple, safe, and curative, particularly with the advent of laparoscopic approaches .

Liver cirrhosis: A 55-year-old homeless man is brought to the emergency room by the police because he has been found unresponsive in the street. His friends state that he has been drinking heavily. On physical examination, he is found to show signs of malnutrition, and his skin and the sclera of his eyes have a yellowish coloration. His abdomen is markedly distended, and palpation shows that his liver is enlarged. Over the next hour, he regains consciousness, but still shows signs of significant confusion, and cannot supply his name, or identify the day of the week or the current President. A counselor comes to see him to discuss the likely adverse outcomes of continued alcohol ingestion, and he is referred to a shelter and a treatment program. Chronic ingestion of excessive quantities of alcohol can have insidious effects on hepatic function, as fibrotic hardening of the liver alters several aspects of structure and function. Indeed, alcohol abuse is one of the most important causes of chronic liver disease, and cirrhosis (irreversible deposition of excess collagen in the liver) accounts for the majority of all medical deaths among alcoholics. Most ingested ethanol is metabolized rapidly in the liver. Products of ethanol metabolism, most notably acetaldehyde, impair several aspects of hepatocyte metabolic function, as well as producing oxidative stress and forming protein adducts that may trigger adverse immune reactions that lead to cell death. In its initial stages, alcoholic liver disease involves the accumulation of fat in the liver. Ultimately, hepatic stellate cells are activated to produce collagen, and this occurs chronically if ingestion of excessive amounts of alcohol continues. In a subset of patients, hepatitis and fibrosis will progress to cirrhosis, characterized by fibrous bands connecting the portal triads with central veins, and small, regenerative nodules. Patients with alcoholic liver disease that has progressed at least to hepatitis and fibrosis present with a spectrum of symptoms of chronic liver failure, including jaundice, nausea, and malaise. Male patients may have hypogonadism and feminization, ascribable to both the direct toxic effects of ethanol on testicular Leydig cells and effects on estrogen production and reduced estrogen breakdown. In severe cases, there can be a collection of fluid in the abdominal cavity known as ascites that may become infected (see Chapter 55), hepatic encephalopathy, renal failure, and eventually death. The primary treatment is to secure abstinence from alcohol, although some liver changes may be irreversible even after drinking has stopped. When ammonia degradation is reduced, it can accumulate in the plasma to levels that become toxic to the central nervous system. Remember that ammonia, as a small, neutral molecule, is relatively permeable across cell membranes and can easily traverse the blood–brain barrier. Patients will experience a gradual decline in mental status with confusion and dementia, followed eventually by coma if the condition is untreated. The increase in plasma ammonia in liver disease occurs by two mechanisms. First, if hepatocyte function is compromised, there is less capacity to degrade ammonia coming from the intestine and extraintestinal sites. Second, if blood flow through the liver is impaired by cirrhosis and portal hypertension has set in (see also Chapter 55), collateral blood vessels may form that shunt the portal blood flow around the liver, bypassing the residual capacity of the liver to degrade ammonia. It is likely that both mechanisms contribute to the rise in plasma ammonia in the setting of long-standing liver disease. Because the intestine supplies the largest load of ammonia to the circulation, treatments for hepatic encephalo– pathy focus primarily on reducing the delivery of ammonia into the portal circulation. A common technique is to give a sugar, lactulose, which cannot be degraded by mammalian digestive enzymes but is broken down by bacteria in the colon to form short-chain fatty acids. In turn, the pH of the colonic lumen is decreased, and more of the ammonia being formed in that site is protonated and “trapped” as ammonium ion to be lost to the stool. Similarly, patients can be given a nonabsorbable antibiotic such as neomycin that reduces the level of bacterial colonization in the intestine, thereby reducing ammonia production. Finally, patients with liver disease are often advised to follow a lowprotein diet, again in an effort to reduce ammonia production in the intestine. Ultimately, however, the only lasting treatment for hepatic encephalopathy is a liver transplant, and mental symptoms often are reversible if they have not been too long-standing. Nevertheless, transplantation remains controversial in alcoholic patients.

lactose intolerance: An 18-year-old, Asian American college freshman is living away from home for the first time. Having been brought up in a household that emphasized a traditional Chinese diet, and having been forbidden by his parents from indulging in snacks and junk food, he is particularly excited by the broad range of dishes to choose from in the cafeteria. He becomes particularly enamored of cheese pizza and chocolate ice cream. However, 2 weeks after the start of term, he comes to the student health center complaining of frequent diarrhea, gas, and bloating. A physical exam reveals that he is otherwise healthy and well nourished, and the patient denies any fever or bloody stools. Based on his history and symptoms, a diagnosis of lactose intolerance is made. A deficiency in the ability to assimilate dietary lactose is a common disorder, particularly in specific ethnic groups such as African-Americans and Asians who have not traditionally emphasized milk as a component of the adult diet. Lactose intolerance arises secondary to the normal developmental decline in lactase-phlorizin hydrolase levels that occurs after weaning, which occurs to a greater extent in some people than in others. In susceptible individuals, ingestion of lactose in dairy products overwhelms the capacity of the brush border lactase-phlorizin hydrolase to digest this disaccharide, leaving the undigested material in the small intestinal lumen from where it passes to the colon. In the colon, commensal bacteria are highly active in degrading lactose as an energy source, leading to symptoms of abdominal pain and bloating from the hydrogen and CO 2 gases that are produced. The delayed production of hydrogen (or labeled CO2) in the breath following lactose ingestion can accordingly be used as a test for the presence of lactose intolerance. Patients with lactose intolerance who wish to consume dairy products can do so without major discomfort if they also take oral supplements of a lactase enzyme derived from bacteria. This supplemental lactase is resistant to degradation by gastric acid, and thus is available in the small intestinal lumen to cleave dietary lactose into its component monosaccharides, which can then be absorbed by the small intestine.