Margaret L. Godley, PhD, CBiol, MIBiol

• Clinical Scientist, Honorary Fellow in Pediatric Urology,
• Institute of Child Health, University College London and
• Great Ormond Street Hospital for Children, London, United
• Kingdom

The thyroid also contains lymphoid follicles birth control pills walmart cheap 3.03 mg yasmin with amex, which are yet another sign that this disease is immune mediated birth control knee pain generic yasmin 3.03 mg on line. Surgical removal of the nodular gland usually results in the normalization of hyperfunction of the thyroid birth control for women day order yasmin, and may actually induce hypothyroidism requiring hormonal replacement therapy birth control 5 year implant discount 3.03mg yasmin visa. Such tumors appear as solitary nodules that concentrate radioactive iodine and are diagnosed as "hot nodules" on radioactive scanning birth control pills youtube generic yasmin 3.03mg without prescription. Clinical Features the symptoms of hyperthyroidism result from an excess of thyroid hormones and include restlessness birth control pills with iron cheap 3.03mg yasmin free shipping, nervousness, emotional lability, sweating, and tachycardia. The cause of exophthalmos is not known, but it is thought to be related to the systemic immune disorder that causes thyroid hyperfunction. In a minority of cases, there is also localized infiltrative dermatopathy presenting as scaling, thickening, and induration of the skin overlying the shins. Hyperthyroidism caused by nodular goiter or thyroid adenoma is not associated with exophthalmos and pretibial myxedema. The best results are achieved in patients with solitary hyperfunctioning nodules that can be removed surgically. The human body requires iodine, and if the food and water consumed do not contain adequate amounts, as occurs in some parts of the world. Deficiency of iodine in food and water is worldwide still the most common cause of hypothyroidism. Iodine is preventively added to the salt in most Western countries; thus iodine deficiency is rare in the United States and Canada. Such iatrogenic hypothyroidism typically evolves postoperatively after resection of a thyroid that has been infiltrated by tumor. Deficiency of thyroid hormones affects essentially all organs in the body, slowing their function. The heart beats slowly (bradycardia); the intestines lose mobility (constipation); and the skeletal muscles are weak, stiff, and aching. The diagnosis of hypothyroidism is based on biochemical measurements of thyroid hormones in circulation. Nodular Goiter Enlargement of the thyroid is called nodular goiter or thyroid struma. The term nodular goiter is noncommittal, and a pathologic examination must be performed to exclude tumors. Nodular goiter may result from iodine deficiency but most often the cause is not known, and it is thus considered to be idiopathic. Children with genetic defects may show signs of so called dyshormonogenetic goiter. Histologically, such a gland is infiltrated with lymphocytes that destroy thyroid follicles. Deficiency of iodine in food and water is usually associated with nodular enlargement of the thyroid (nodular goiter). Because the thyroid cannot synthesize enough T3 and T4, its follicles undergo compensatory hyperplasia in an attempt to increase the production of hormones. In many cases this compensatory mechanism is not sufficient, and the serum levels of T3 and T4 are low. Histologically, these nodules consist of thyroid follicles that vary in size and shape and are usually filled with colloid. Between the nodules, the struma consists of vessels and collagen fibers infiltrated with lymphocytes and macrophages. Secondary changes, such as calcification, hemorrhage, and atrophy of the compressed follicles in the surrounding parenchyma, are common. Clinical Features Most goiters are euthyroid, that is, they do not cause either hyperthyroidism or hypothyroidism. In children the deficiency of thyroid hormones affects the growth of the entire body and, most specifically, development of the central nervous system. The treatment of goiter includes resection of the enlarged portions of the thyroid. Although they are found in 3% to 4% of all adults, they are of limited clinical significance, primarily because such tumors are small. Malignant thyroid tumors are rare and are outnumbered by benign tumors in a ratio of 10: 1. Thyroid tumors are more common in women than in men, and thus every year there are only some 15 malignant tumor diagnosed in 100 000 women and 5 per 100 000 men. Other tumors are composed of nonfunctional thyroid cells that form so-called cold nodules, which are unable to concentrate radioactive iodine. In this respect, such cold nodules resemble carcinomas, many of which cannot concentrate iodine either. The final diagnosis can be made only by microscopic examination of biopsy material. Thyroid adenomas are not premalignant; thus, most small nodules do not require any treatment. Larger tumors are usually removed for cosmetic reasons to correct the deformity in the contour of the neck. All these tumors, except medullary carcinomas, originate from follicular cells; medullary carcinomas originate from C cells. Among the risk factors for developing thyroid tumors, the best documented are the effects of nuclear irradiation. After the explosion of the atomic bomb in Japan in 1945, and after the nuclear plant accident in Chernobyl in Ukraine in the 1980s, epidemiologists noticed an increase in the incidence of thyroid cancer. It is a low-grade, hormonally inactive Adenomas Follicular adenoma of the thyroid is the most common benign tumor. Most adenomas are small, well encapsulated with fibrous tissue, and composed of thyroid follicles. Typically, adenomas comprise cells that do not take up radioactive iodine more avidly than does the normal thyroid. The tumor tends to metastasize to the local lymph nodes; distant metastases are rarely found and usually only late in the course of the disease. It occurs relatively early in life and has a peak incidence in the third to fifth decade. This tumor has a most favorable prognosis; indeed, 80% of patients are alive 10 years after diagnosis. Follicular carcinoma is much less common than papillary carcinoma, accounting for only 15% of malignant thyroid diseases. The tumor grows more aggressively than papillary carcinoma but still has a good prognosis. Most of these tumors do not concentrate radioactive iodine (cold nodules), but some of them take up radioactive iodine and produce thyroid hormones (hot nodules). Those tumors that do concentrate iodine can be treated with radioactive iodine, because accumulated radioactive iodine is a strong source of internal radiation, and it kills cells. This treatment is especially suitable for patients who have widespread metastases. Medullary carcinoma differs from other thyroid tumors in that it is derived from C cells. Like the normal C cells, medullary carcinomas produce calcitonin, a hormone involved in regulating the homeostasis of calcium. Histologically, medullary carcinoma is composed of round or oval neuroendocrine cells arranged into groups and nests. Familial medullary carcinomas are usually discovered in early adulthood and have a good prognosis if surgically removed. Sporadic tumors, which occur at 60 years of age and older, have a less favorable prognosis, and only 50% of patients survive 5 years after diagnosis. Anaplastic (undifferentiated) carcinoma is a rare tumor, accounting for 1% to 2% of all thyroid neoplasms. It has an extremely unfavorable prognosis, and most patients die within 1 year of diagnosis. Histologically, such tumors are composed of undifferentiated large or small tumor cells that bear no resemblance to normal thyroid cells. In most instances there is a single adenoma, but in approximately 10% of these patients there are two or more adenomas. In the remaining 20% of patients who do not have adenomas, most of them have parathyroid gland hyperplasia. In less than 1% of all cases of hyperparathyroidism there is a parathyroid carcinoma. Secondary parathyroid hyperplasia occurs most often in patients who have endstage kidney disease. Hypovitaminosis D, as in osteomalacia or intestinal malabsorption syndromes, may have the same results. A Adenoma Hyperplasia B Pathology the histologic changes in the hyperplastic and neoplastic parathyroid glands are similar to one another, and thus the final pathologic diagnosis depends on the evaluation of all clinical, gross pathologic, and microscopic findings. This benign tumor is typically found in one of the four parathyroid glands, whereas the remaining three glands are of normal size. The normal gland harboring the adenoma is usually compressed by it and found at the periphery of the benign tumor. The adenoma is composed of densely packed parathyroid cells replacing the normal intraglandular fat tissue, which still can be seen in the adjacent compressed gland. In hyperplastic glands, all four glands are equally enlarged, and there is no evidence of residual or compressed normal parathyroid tissue. Microscopically, hyperplastic parathyroid glands resemble adenomas, and the pathologist cannot always distinguish these two lesions with utmost certainty. Secondary parathyroid hyperplasia is microscopically indistinguishable from primary parathyroid hyperplasia. Microscopically, they resemble adenomas, and the diagnosis is made only if the tumor cells are found invading the adjacent tissue show marked anaplasia and atypia with numerous mitoses, or have metastasized to some other site. An excess of calcium produces lethargy with "moaning," muscle weakness, and conduction defects in the heart. The time-tested student mnemonic for the four most common symptoms of hyperparathyroidism is as follows: "bones, stones, abdominal groans, and moans (with psychiatric overtones). In the bones, it stimulates osteoclasts, leading to bone resorption and the release of calcium into the circulation. Hypercalcemia and compensatory hypophosphatemia are thus the primary biochemical abnormalities detected by blood analysis. The bones show signs of decalcification, are prone to fractures, and often are quite painful. Hypercalcemia leads to deposition of calcium salts in the kidney (nephrocalcinosis) and formation of urinary the treatment of primary hyperparathyroidism includes surgical exploration of the neck and resection of the hyperfunctioning glands or the tumor. To this end the surgeons must identify all four parathyroid glands and then determine if any of them are enlarged and deserve to be removed. In most instances there is a solitary adenoma, and the resection of that tumor will cure hyperparathyroidism. If all four glands are hyperplastic and enlarged, the surgeon will typically remove 3 and leave only 1 behind. After renal transplantation, the glands may regress to normal size, and the metabolic disturbances may disappear. If renal transplantation does not normalize calcium and phosphate balance, one can assume that the hyperfunction of the parathyroid glands has apparently taken an autonomous course. Surprisingly, chromosomal analysis of the enlarged parathyroid glands of patients with tertiary hyperparathyroidism has revealed chromosomal changes identical to those seen in parathyroid adenomas. This suggests that prolonged metabolic stimulation can cause irreversible neoplastic changes in the parathyroid cells. Because tertiary hyperparathyroidism represents a form of metabolically induced neoplasia, like any other tumor, it can be cured only through surgery. This biochemical finding provides supporting evidence that the source of hyperparathyroidism has been surgically removed. Hypercortisolism may also be found in patients treated with Hypoparathyroidism Hypoparathyroidism results from parathyroid hypofunction or a complete loss of function of the parathyroid glands. Overall, it is a rare condition that most commonly occurs after inadvertent removal of all four parathyroid glands during cancer surgery of the neck. Congenital, genetic, or autoimmune causes of hypoparathyroidism are extremely rare. The most important of these is hypocalcemia, which results in changes in neuromuscular excitability and muscular contraction. The heart action becomes irregular, and in severe cases, cardiac arrest may occur. The activity of the nerves is also altered, fluctuating between hyperexcitability and depression. Each of the three zones of the adrenal cortex-zona glomerulosa, zona fasciculata, and zona reticularis-may be affected, either separately or jointly. The secretion of mineralocorticoids, glucocorticoids, or sex steroids may be altered; the excess or deficiency of these hormones will produce disturbances in the metabolism of minerals (sodium, potassium, and chloride), carbohydrate metabolism, or sexual problems. The patients appear red in the face because of a plethora of blood, hypertension, and thinning of the skin. Glucose intolerance and overt diabetes are the most common biochemical disturbances. Typically, affected patients experience fatigue and weakness and are mentally unstable. They also have numerous other minor problems, reflecting abnormal intermediate metabolism of carbohydrates. Pathology Hyperplasia of the adrenals leads to bilateral thickening of the adrenal cortex. Tumors of the adrenal appear as discrete nodules or marked irregular enlargement of the entire gland. Adenomas are usually well circumscribed, whereas carcinomas tend to extend into the adjacent tissues.

The prevalence rate in first-degree relatives ranges from 5 to 6% in various geographic regions birth control sugar pills discount 3.03 mg yasmin with amex. In particular birth control myths discount yasmin 3.03 mg line, smoking has been associated with increased risk and also may accelerate disease progression birth control pills how they work purchase cheapest yasmin. A past history of infection birth control you put in your arm yasmin 3.03 mg overnight delivery, in particular urinary tract infection birth control for the christian order genuine yasmin line, is also associated with increased risk birth control for women entrepreneurs purchase yasmin with visa. Pathophysiology and the Mitochondrial Antibody the section on differential diagnoses but is discussed in more detail in Chapter 7. All of these enzymes are located in the inner mitochondrial membrane and catalyze the oxidative decarboxylation of ketoacid substrates. Environmental factors including viral and bacterial infections may contribute to bile duct injury. In addition, selenium deficiency and defective sulfoxidation of bile acids and certain drugs have been speculated as possible disease mechanisms. The liver tests are otherwise normal, but liver biopsy at this time often shows characteristic pathologic changes. The asymptomatic phase is seen in patients who have abnormal liver tests but no clinical signs of disease. The symptomatic phase presents most often with fatigue and pruritus, the latter often more severe in the evenings. Splenomegaly, Primary Biliary Cirrhosis 75 spider angiomatosis, and, in the later stage disease, jaundice can occur. Steatorrhea, malabsorption, and deficiency of fat-soluble vitamins are often seen. In the more advanced disease phase, patients develop worsening jaundice, ascites, encephalopathy, bleeding esophageal varices, and eventual liver failure. When the bilirubin is greater than 6 mg/dL, the overall survival is about 2 years without liver transplantation. These overlap syndromes are discussed in detail in Chapter 7 on Autoimmune hepatitis. The small and medium-sized interlobular bile ducts are surrounded and infiltrated by lymphocytes, with cytologic atypia of the duct epithelium consisting of hydropic vacuolization of the cytoplasm, nuclear pyknosis and irregular nuclear size and distribution within the duct, and sometimes hyperplasia of the duct epithelium. The portal tract on low power shows a prominent inflammatory infiltrate consisting of lymphocytes with increased numbers of plasma cells. In addition an interlobular bile duct in the center of the field is surrounded by inflammatory cells. The interlobular bile duct shows cytologic atypia with lymphocytes surrounding and infiltrating into the duct wall. Portal fibrosis develops with atypical ductular reaction, the bile ductules at the border of the fibrous tissue and parenchyma showing flattened elongated epithelium, scanty to absent duct lumen, and proliferation with an irregular branching growth pattern. Cirrhosis is present, the regenerative nodules having a geographic jigsaw-type pattern. High power of the septa shows a moderate predominantly lymphocytic infiltrate with absence of interlobular bile ducts. Importantly, there can be considerable overlap in the histologic changes between the different stages. For example, interlobular bile duct loss can occur in portal tracts showing only mild fibrosis, and atypical ductules can be seen in the cirrhotic stage. In addition, staging and grading have been proposed looking at the different histologic variables semi-quantitatively. One in particular views the degree of (1) fibrosis, (2) duct loss, and (3) chronic cholestasis and arrives at a summary score (Nakanuma et al. The regenerative nodules are usually small (micronodular) and exhibit periseptal edema. The portal tracts show increased numbers of plasma cells that at times can be prominent. Additionally numerous eosinophils are also common, and portal lymphoid aggregates, rarely with germinal centers, can at times occur. Scattered neutrophils can sometimes be seen in and amongst the proliferating atypical ductules. In addition, infrequently neutrophils can sometimes also be seen surrounding and infiltrating into the interlobular bile ducts (acute cholangitic reaction). It is important to note that in the early-stage lesion, the duct injury is segmental and may not be seen in liver biopsy specimens, especially if there are only a few portal tracts present for evaluation. The granulomas are well demarcated, consist of numerous epithelioid histiocytes and scattered lymphocytes, with multinucleated giant cells infrequent, and central necrosis not a feature. The granulomas within the portal tracts also at times tend to abut up against and surround the interlobular bile ducts undergoing destruction. The parenchyma otherwise shows focal necroinflammatory change that is scattered within the lobules and sometimes can be quite sparse, the inflammatory cells being chiefly lymphocytes. The periportal hepatocytes often show a hydropic change and may also demonstrate intracellular bile (cholate stasis). In addition, cholestasis can also occur in end-stage disease, with the bile more concentrated in the periseptal regions. Foamy histiocytes can also at times be seen in small clusters within the parenchyma and are more common as the disease progresses. An accompanying neutrophilic infiltrate directed towards the Mallory bodies, as seen in alcoholic hepatitis, is not a feature in chronic biliary tract disorders. Primary Sclerosing Cholangitis 79 In more advanced disease, the inflammatory infiltrates consist predominantly of lymphocytes with increased numbers of plasma cells, but eosinophils are usually not prominent in this stage. Increase in portal venous and lymphatic radicals are also seen within the septa and are manifestations of portal hypertension. Most often there is a lamellar-type fibrosis with variable edema at the borders of the fibrous bands and regenerative nodules. Increase in hepatic copper and copper-binding protein can also be seen in advanced stage disease. Although increase in hepatic copper is most prominent in Wilson disease and Indian childhood cirrhosis, the increase in hepatic copper to lesser degrees also occurs due to bile retention in chronic biliary tract disorders. The copper can be visualized on biopsy specimens within predominantly the periseptal hepatocytes using the rubeanic acid (black to black-green granules) and rhodanine (red granules) stains for copper, and the orcein stain (dark brown to black granules) for copper-binding protein. The natural history follows a progressive course, with the mean survival from time of diagnosis to death in those not undergoing liver transplantation ranging from 7 to 18 years, with those who are asymptomatic at the time of diagnosis having a better outcome. The incidence varies with different geographic populations but in North America and Europe the incidence ranges from up to 0. Bacterial endotoxins are felt to play a role and have been found in the biliary epithelial cells by immunoperoxidase staining. Clinical Presentation Laboratory tests show an increase in the alkaline phosphatase activity, with mildly abnormal aminotransferases. The bilirubin is usually normal in early-stage disease but may fluctuate and becomes elevated as the disease progresses. The cystic duct and rarely the pancreatic Almost half of the patients are initially asymptomatic, with the diagnosis often occurring during workup in patients with ulcerative colitis. About a quarter of these patients usually develop symptoms within 5 years and include fatigue, pruritus, abdominal pain, and jaundice. Intermittent bouts of ascending cholangitis may occur, with patients also more susceptible for pigmented gallstones. Steatorrhea and malabsorption of fat-soluble vitamins (due to decreased availability of conjugated bile acids in the small bowel) can occur as well. Complications of dominant biliary strictures, metabolic bone disease, and advanced disease (portal hypertension, coagulopathy, liver failure) eventually may occur. Late-stage disease is also associated with an increased risk in developing cholangiocarcinoma, with reported lifetime prevalence ranging between 10 and 30%. Multifocal strictures with intervening saccular dilatation ("beads on a string" appearance) of both intrahepatic and extrahepatic bile ducts are present. Although most cases show both intra- and extrahepatic duct involvement on imaging, about a quarter have only intrahepatic involvement. Pathology the major morphologic feature involves both the intra- and extrahepatic bile ducts to variable degrees. Periductal fibrosis is present associated with focal necrosis and cytologic damage to the duct epithelium, with progressive narrowing of the duct lumen and eventual destruction and loss of the duct. Lymphocytes to varying degrees surround the ducts and may infiltrate beneath the duct basement membrane. These lesions are usually focal and can be missed in biopsies in early-stage disease. The portal tracts show a mixed inflammatory infiltrate consisting predominantly of lymphocytes with occasional plasma cells, neutrophils, and infrequently eosinophils. Variable portal edema can also be seen at the edges of the portal tracts and parenchyma, with proliferation of ductules (cholangioles) often present at the portal tract borders. These ductules are often cytologically atypical, with scanty to absent lumen and flattened duct epithelium. Cholestasis is usually present in the early stages but intermittent, the bile most concentrated within the perivenular zone. With time as the disease progresses the bile can be seen in the periportal and periseptal zones. Bile infarcts (aggregates of extracellular bile admixed with necrotic hepatocytes, fibrin, and histiocytes) also may occur but are infrequent. Variable degrees of macrovesicular steatosis may be seen, and necroinflammatory changes with apoptosis also are present but are generally mild. In some instances small fibrous nodules can be seen within these fibrotic portal tracts and fibrous septa and represent the remnants of the periductal obliterative changes of a once present interlobular bile duct. The regenerative nodules show a biliary-type pattern with perinodular lamellar fibrosis and some perinodular edema. Segmental involvement of the interlobar and segmental ducts, with only one main hepatic duct involved, may occur at times, resulting in focal liver damage (hemicirrhosis). Prominent increase in portal venous radicals is seen secondary to portal hypertension. The peribiliary glands adjacent to the hilar and extrahepatic ducts can show prominent ductular proliferation as well, sometimes these glands showing mild cytologic atypia. In the more advanced stages of the disease an increase in both copper and copper-binding protein is seen predominantly within the periseptal hepatocytes. The copper can be demonstrated by the rubeanic acid (black to black-green) and rhodanine (red) stains, with the orcein stain (dark-brown to black granules) demonstrating the increase in copper-binding protein. The common bile duct shows periductal fibrosis with a prominent lymphocytic infiltrate within the duct wall. Oftentimes the duct mucosa is damaged and sloughed, with the bile then eliciting an inflammatory reaction (bile impregnation). Imaging shows the focus of obstruction with ectasia of the biliary tract throughout the liver when the common bile duct or common hepatic duct are effected. Segmental involvement when the obstruction specifically involves the right or left hepatic ducts also may occur. Relief of the obstruction is usually associated with improvement of the liver tests and resolution of the liver pathologic findings; however, with repeated bouts of obstruction. The clinical consequences of secondary biliary cirrhosis include ascites and variceal bleeding but these complications are not as frequently seen as in cirrhosis secondary to chronic viral hepatitis or alcoholic cirrhosis. The liver on gross inspection is usually large and may be green when the cholestasis is prominent. These ectatic interlobular bile ducts eventually become tortuous, and hence on biopsy material appear to be proliferating. Within a day or two, neutrophils can be seen abutting up against the ducts (acute pericholangitis) and ductules. The dilated biliary canaliculi that contain the bile can also be surrounding by hydropic hepatocytes forming rosettes. At this stage of the disease, inflammation within the lobules is quite minimal, although if the obstruction continues a predominantly neutrophilic infiltrate can develop with eventual formation of microabscesses within the lobules. Periductal edema and duct ectasia are frequent in this early stage of bile duct obstruction.

Mechanical disruption of pancreatic cells has been documented in patients who develop acute pancreatitis after abdominal trauma birth control pills 7 day break buy yasmin 3.03 mg fast delivery, such as seat belt trauma in car accidents birth control pills for weight loss cheapest yasmin. Chemical injury of pancreatic cells can be induced by various toxins and drugs birth control emotional buy generic yasmin line, such as cytotoxic anticancer drugs birth control pills and menopause order 3.03 mg yasmin visa. However birth control pills zovia purchase 3.03 mg yasmin mastercard, the inflammation is usually mild birth control for women breastfeeding order yasmin 3.03mg without prescription, and drugs rarely precipitate acute pancreatic necrosis. Overstimulation of pancreatic cells by secretin could be the cause of pancreatitis in obese persons indulging in fatty foods. Acute pancreatitis is common in multiple organ failure syndromes in terminally sick patients. In most instances, acute pancreatitis is overshadowed by symptoms of failure of other major organs. Some viral infections tend to attack the pancreas specifically, as seen with the mumps virus infection. These patients have mutations in one of several genes encoding the inhibitors or stimulators of pancreatic enzyme secretion and activation and/or inactivation. For example, a mutation that results in a gain of function of the trypsinogen gene results in uncontrolled activation of this enzyme and uncontrolled proteolysis of pancreatic parenchyma. Persons born with these mutations have a 40% chance of having an acute pancreatitis attack during their lifetime. Clinically, acute pancreatitis is related to gallstones and alcohol abuse, or both, in about 80% of all cases. The cause of acute pancreatitis cannot be found in some cases, and these are considered to be idiopathic (Box 12-1). Pathology Regardless of the precipitating cause of acute pancreatitis, tissue damage occurs in a predictable manner and is always mediated by pancreatic digestive enzymes. Proteolysis caused by activation of trypsinogen, the inactive form of trypsin, leads to necrosis of tissues. The action of lipase on fat cells inside the pancreas and the peripancreatic fat tissues results in fat necrosis. Enzymatic tissue destruction is accompanied by liquefaction of the digested pancreas. These spaces are called pseudocysts because they are not lined by an internal epithelial cell layer, as are regular cysts. Necrotic tissue foci tend to attract calcium salts and undergo dystrophic calcification. Free fatty acids formed through the hydrolysis of triglycerides also bind calcium ions, thus forming calcium soaps, which can be seen as whitish specks underneath the peritoneum and wherever the fat cells have undergone enzymatic necrosis. Yellow or smudgy brownish-yellow areas of necrosis appear 2 to 3 days after the onset of the attack. The leakage of digestive enzymes into the abdominal cavity may cause peritoneal irritation, and chemical peritonitis may ensue. Areas of fat necrosis appear as grayish-yellow discolorations that gradually calcify and become whitish. By the end of the first week, pseudocysts appear as small cavities filled with liquefied tissue and pancreatic enzymes. These small cavities coalesce into larger pseudocysts, which are typically found in patients who survive the initial attack. Histologically, the hallmarks of normal pancreatic tissue are lost as a result of necrosis. The fat cells, which are normally vacuolated and filled with fat, lose their outline and transform into washed-out "ghosts" composed of collapsed cell membranes. As already mentioned, it results from the spilling of digestive enzymes from the damaged pancreas. These pseudocysts may replace large portions of the pancreatic parenchyma or may distend the pancreas, compressing and displacing the duodenum or the stomach. In contrast to pseudocysts, which contain liquefied tissue debris and enzymes, the cystic spaces within the liquefied bacterial abscess contain pus admixed to bacteria. Like the pseudocyst, pancreatic abscess will be walled off by granulation tissue, which with time becomes more and more fibrotic. Acute hyperglycemia, which is usually mild or transient, may be seen in many patients during the initial attack. Massive destruction of the islets of Langerhans, resulting in insulin dependent diabetes, is less common. Characteristic symptoms include abdominal pain and distention, nausea, and vomiting. Affected patients display apprehensiveness, are in great distress, and sweat profusely. Peritoneal rigidity signals the onset of peritonitis, which is usually accompanied by paralytic ileus. In addition to leukocytosis, which develops in response to acute inflammation, serum tests typically reveal a marked elevation in amylase and lipase levels. Biochemical signs of pancreatitis appear 24 to 72 hours after the onset of the attack. Destruction of pancreatic tissue in acute pancreatitis may result in exocrine pancreatic insufficiency, which is typically found in persons who have had recurrent bouts of the disease. It has been estimated that chronic pancreatitis develops in 20% of patients who survive acute pancreatitis. Pseudocysts that form in the pancreas after an attack of acute pancreatitis contain digestive enzymes that prevent healing of the pseudocyst. To allow tissues to heal, surgeons used to drain the pancreatic juices through a pouch made by attaching the opened pseudocyst to the external abdominal wall. The name for this procedure, marsupialization, is derived from the Latin word for "pouch. To most patients, marsupialization probably sounds less intimidating than (to invent some new words) "kangaroozation" or "possumization"! It is most puzzling that 20% of patients with chronic pancreatitis have no risk factors or preexisting disease. Some of them most likely have a genetic defect predisposing them to chronic pancreatitis, whereas in others the cause of the disease will remain unknown for the time being and such pancreatitis is characterized as idiopathic. Pathology On gross examination, the pancreas does not show typical lobulation but appears smaller, shriveled, and very firm on palpation. On cross section, white fibrous tissues may be seen replacing the grayish parenchyma and extending from the pancreas into the surrounding fat tissue. Fibrosis of the pancreas may cause distortion and the common bile duct, duodenum, or pylorus. Histologically, chronic pancreatitis is marked by extensive fibrosis, with scattered foci of chronic inflammation replacing the acini. The ducts and islets of Langerhans tend to persist longer, but in advanced cases they too are destroyed and obliterated by fibrosis. There is no effective treatment for acute pancreatitis; however, efforts should be directed at containing the damage and preventing the systemic consequences of shock. Elderly patients with acute respiratory failure, hypotension, and peritonitis have the highest risk of all populations, with a mortality rate near 50%. This can be prevented by removing gallstones, eliminating alcohol, and avoiding a high-fat diet. Chronic Pancreatitis Chronic pancreatitis is characterized by irregular fibrosis replacing portions of the normal pancreatic parenchyma. These changes are progressive and irreversible and produce exocrine and endocrine pancreatic insufficiency. The disease is found in 4 per 100 000 adults and is more common in males than in females; the male-to-female ratio is 3: 1. Chronic pancreatitis has an insidious onset; thus, it is very difficult to determine either its cause or pathogenesis. Because chronic alcoholism is much more widespread than chronic pancreatitis, it is difficult to explain why only some patients with chronic alcoholism develop this disease and others are spared. In some cases of chronic pancreatitis the disease is preceded by acute pancreatitis, but in most instances the onset of the disease is slow and imperceptible. In a few patients, chronic pancreatic insufficiency follows trauma or pancreatic surgery, or occurs during the course of systemic metabolic and endocrine diseases. In some patients pancreatitis is a part of the so-called IgG4 related autoimmune disease. B, Histologic examination reveals that the acini have beenreplacedbyfibroustissue(F)surroundingtheremaining ducts(D). It cannot be stopped or reversed, but some improvement may be noticed if the patient stops drinking. Malabsorption can be treated symptomatically by enzyme supplementation, but the commercial enzyme preparations are of low potency. Most patients compensate for low absorption by eating increased amounts of high-calorie food. With such adjustments quality of life may not be normal, but it is not shortened substantially. These patients tend to be at an increased risk for developing pancreatic cancer, which is approximately three times more common in this population than in age-matched controls. Pancreatic Neoplasms Neoplasms of the pancreas can be classified clinically as (1) benign or (2) malignant. On the basis of their origin, the tumors may be classified as being derived from either (1) exocrine or (2) endocrine cells. Some glycoproteins and glycolipids are shed from the tumor cells and appear in the blood. This is related to the entrapment of nerves in the fibrous tissue, which often extend into the celiac plexus. Fibrosis may cause stenosis of the duodenum, which impedes the passage of food from the stomach into the duodenum, causing pain after eating. Destruction of acinar cells reduces the capacity of the pancreas to produce digestive enzymes, which results in malabsorption and steatorrhea. Lipase deficiency accounts for the fatty stools and inappropriate absorption of fat and fat-soluble vitamins (A, D, K, and E). Signs of vitamin deficiency, such as night blindness, secondary to avitaminosis A, or a bleeding tendency, secondary to avitaminosis K, are seen in severe cases. Destruction of the islets of Langerhans occurs at a slower rate than does the loss of exocrine pancreatic cells. Nevertheless, in later stages of the disease more than 70% of patients have signs of diabetes mellitus. The diagnosis of chronic pancreatitis is based on a typical history, which usually includes alcohol abuse and the common complaints. Pain, which is usually epigastric, tends to radiate into the back and is commonly exacerbated by drinking and the ingestion of fatty meals. The workup of the patient must include abdominal x-ray studies, which will usually show numerous calcifications in the pancreas. Laboratory findings may disclose mild elevations in amylase and lipase levels in the serum, but they often yield normal values and are noncontributory. Most Adenocarcinoma of the Pancreas Adenocarcinoma of the pancreas, the most important tumor involving this organ, is the fourth major cause of cancer-related death in males and fifth in females in the United States. Approximately 37 000 new cases are recorded every year in the United States, and nearly all patients die within 12 to 24 months of diagnosis. The strongest epidemiologic association noted has been smoking, which increases the risk threefold. It has been proposed that dietary factors, such as a high-fat diet and alcohol abuse, predispose individuals to pancreatic cancer, but this hypothesis has not been definitively proven. However, this disease is relatively rare and can be implicated as a possible cause for only a minority of pancreatic carcinomas. The tumors rarely occur before the age of 40 years, but thereafter their incidence increases steadily. The incidence of tumors in males equals that in females, except in the group younger than 50 years, in which males outnumber females 3 to 1. Only 20% of affected patients have cancer that is strictly limited to the pancreas. Clinical Features Symptoms of pancreatic carcinoma depend on the location of the tumor, its size, and the extent of spread. Most often the symptoms are nonspecific and include weight loss, loss of appetite, nausea, and vomiting. Upper abdominal pain may suggest the pancreas as the cause of these cancerrelated symptoms. Tumors located in the head of the pancreas tend to obstruct the common bile duct and cause jaundice. Tumors of the body and tail of the pancreas do not cause jaundice but tend to invade the celiac plexus and cause pain. Splenomegaly may occur as a result of obstruction of the splenic Pathology Adenocarcinoma of the pancreas is an epithelial malignant lesion originating from the ducts. This is understandable because the head forms the bulk of the pancreas and contains most of the ducts. Furthermore, because these tumors of the pancreatic head tend to obstruct the bile ducts and cause jaundice, they are diagnosed more readily than are tumors of the body or the tail of the pancreas, which account for 15% of all pancreatic carcinomas.

It is also worth remembering that the glandular epithelium of the uterus-called the endometrium- changes during the menstrual cycle birth control brand names purchase genuine yasmin on line. On the outside birth control pills blood clots purchase yasmin 3.03 mg on-line, these organs are covered with serosa birth control generic brands purchase 3.03mg yasmin, which is equivalent to the peritoneum enveloping other abdominal organs birth control question hotline order generic yasmin from india. The ovaries are almond-shaped organs composed of a connective tissue stroma birth control implant in arm buy generic yasmin 3.03 mg online, sex cord cells birth control for women 12 buy 3.03mg yasmin mastercard, and oocytes. Below the surface are oocytes surrounded by specialized sex cord cells: granulosa and theca cells that secrete female sex hormones. Oocytes and sex cords form functional units known as follicles, which enlarge under the influence of estrogens and then rupture around the fourteenth day of the menstrual cycle based on a twenty-eight day cycle. Ovarianestrogensstimulatethe proliferation of endometrium, whereas progesterone stimulates endometrial secretion and prepares the uterus for implantation of the embryo. If pregnancy does not occur, the endometrium is shed and menstrual bleeding occurs. Fertilization of the oocyte released from the ovaries at the time of ovulation takes place in the fallopian tubes. Implantation of the zygote occurs only if the uterus is properly primed by hormones. The implantation is mediated by trophoblastic cells that form the outer layer of the embryo and are the precursors of the placenta. Overview of Major Diseases the physicians treating the diseases of female reproductive organs are called gynecologists. Because of this direct contact, the female reproductive system is extremely prone to infections. The sexually active female, particularly if she has multiple partners or a single promiscuous partner, is at risk for infection. If infected, she may transmit the infection to her future sexual partners, or the infection may be spread transplacentally or vaginally during delivery of her offspring. Clearly, then, infectious diseases affect not only the health of the infected person but also that of other individuals; thus, they have major social consequences. It is estimated that 50% of infertile women have, or have had in the past, a genital infection. Abnormal secretion of estrogen and progesterone from the ovary may cause menstrual abnormalities, such as amenorrhea (no bleeding at all) or menorrhagia (profuse menstrual bleeding). Estrogen may cause endometrial hyperplasia, and it is thought to contribute to the development of endometrial cancer. Predictably, carcinomas of the fallopian tubes occur much less frequently than carcinoma of the endometrium. The causes of gynecologic tumors, like those of other organs, are not fully understood. The incidence of this cancer correlates with exposure to other sexually transmitted viruses. Carcinoma of the endometrium and many ovarian tumors appear to have a hormonal basis. Preventive screening has reduced the mortality from some forms of cancer, such as cervical carcinoma. Before the midpoint of the twentieth century, squamous carcinoma of the cervix was one of the most common fatal cancers affecting women. It is a tribute to the preventive efforts of the health care system that death secondary to cervical carcinoma is less common today. This in large part is a result of screening with the Papanicolaou test (Pap smear), which detects premalignant cervical abnormalities and allows for efficient treatment. Uterine tumors are also readily detectable, because they present as abnormal bleeding. Unfortunately, malignant diseases of the ovary are not so easily detected, and these tumors still claim many lives. New techniques of molecular biology will probably contribute even more to the fight against gynecologic cancer. Pathology of pregnancy occurs as a result of disturbances in critical events essential for the maintenance of pregnancy. Considering the complexities of human reproduction, it is a minor miracle that pregnancy occurs at all. The inability to conceive (infertility) has been recorded in every sixth couple trying to conceive a child. For example, the embryo may implant in the wrong place, such as in a fallopian tube that cannot support embryonic development (extrauterine pregnancy). The placenta may develop abnormally and give rise to hydatidiform mole and choriocarcinoma. The adverse effects of pregnancy are best exemplified by toxemia of pregnancy, a systemic disease that affects all major organs. The examiner inserts a swab or spatula and scrapes the cervix to obtain cells for cytopathologic examination. Uterus Bladder Speculum Vagina Swab or spatula Cervix Rectum However, the gonad is a testis, usually located inside the abdomen. Testes secrete male hormones, but the tissues have no receptors for testosterone and cannot respond to androgenic stimulation. For example, in congenital adrenal hyperplasia, the genetic females show virilization of the vulva. Congenital adrenal hyperplasia, the most common form of intersexualism, affects 1 in 4000 female neonates. Inflammatory Diseases Inflammatory diseases of the female genital system may be considered from several points of view and classified accordingly: 1. This classification system is based on the clinical or pathologic assessment of inflammation. The inflammation may be localized, or it may diffusely involve the entire female reproductive system and even spread to adjacent structures, such as the urethra, bladder, or rectum. Terms such as vulvitis or vaginitis are self-explanatory designations for the inflammation of these organs, although often more than one adjacent anatomic site is involved. Infection of the uterine body is usually limited to the endometrium and is thus called endometritis. Inflammation of the fallopian tubes is called salpingitis, and inflammation of the ovaries is termed oophoritis. With regard to the duration of the disease, the inflammation can be classified as acute, chronic, or recurrent. Recurrent infections may be caused by a new pathogen or represent an exacerbation of latent, clinically dormant, infections. On the basis of pathogenesis, genital infections can be classified as ascending or descending, depending on the route by which the pathogens have reached the reproductive system. For example, tuberculosis of the genital organs is always a descending infection secondary to a focus of primary infection elsewhere, such as the lungs. Ascending infections are acquired mostly through sexual contact and are thus classified as sexually transmitted Special Pathology Developmental Abnormalities Developmental anomalies of the female genital organs are rare, which is surprising considering the complexity of their formation during fetal life. Agenesis of the vagina or uterus, duplication of the uterus, and bicornuate uterus are mentioned here as possible, albeit rare, causes of sexual dysfunction and infertility. Discordance between the genetic sex and the phenotypic sex of an individual may result in developmental abnormalities known as hermaphroditism. Such intersexual individuals have both male and female features, or something in between. For example, one gonad may be a testis and the other an ovary, or they may be fused into an ovotestis. For example, in testicular feminization syndrome, the genetic males have a vulva, vagina, and well-developed breasts. Ascending infections are usually caused by sexual contact, pregnancy, or instrumentation. The vagina is in direct continuity with the upper genital organs; thus any microbe introduced into the vagina can ascend upstream into the uterus and the fallopian tubes. Pregnancy is yet another risk factor, and approximately 5% of all pregnancies are accompanied by endometrial infection, which may spread to the fallopian tubes. Overall, ascending infections are usually polymicrobial and are more common than descending infections. On the basis of etiology, genital tract infections may be classified as bacterial, chlamydial, viral, fungal, or protozoal. Many cases are caused by more than one pathogen and are classified as polymicrobial. Streptococcus and Staphylococcus are widespread bacteria that may cause infection of the genital organs by an ascending or descending route. Chlamydial Infections Chlamydial infections are caused by sexually transmitted Chlamydia trachomatis. Chlamydia is the most common sexually transmitted pathogen in the United States and Canada, with more than a million new cases diagnosed yearly. Estimates are that another 2 million women have chronic chlamydial genital infections. Neisseria gonorrhoeae is the cause of gonorrhea and Treponema pallidum Viral Infections Viral infections are also commonly acquired by sexual contact. The most common fungal pathogen is Candida albicans, which lives on moist surfaces. The most important pathogen is Trichomonas vaginalis, a common cause of vaginal discharge in women of reproductive age. Clinically Important Infections the most important genital infections are listed in Table 15-1. Genital herpes typically presents with grouped blisters on the vulva around the vaginal opening or on the labia and the perineal skin. The blisters usually rupture and transform into shallow oozing and painful ulcers. Crust forms on the surface of the ulcers and they heal spontaneously in 3 to 4 weeks. Following the acute stage of the infection, herpes virus migrates along the axons to the dorsal sacral root ganglions where it usually enters a latent stage. The latent virus can be reactivated migrating back along the nerves into the genital area where it again forms vesicles. The discharge may be clear or turbid and yellow and mucinous or frothy; it often has a foul smell. Infectious vaginitis can be treated with drugs; metronidazole is administered for Trichomonas, antibiotics for bacteria, and fungicides for Candida infection. The world renowned Philadelphia based Barnes Foundation art gallery, housing an invaluable collection of French Impressionist paintings, is an enduring monument to both Argyrol and its inventor. The fallopian tubes are the most susceptible to the ravages of the infection, becoming red, swollen, filled with pus, and adherent to other organs. An abscess involving the fallopian tube and ovary (tubo-ovarian abscess) may form. The patient typically has severe lower abdominal pain, fever, nausea, and vaginal discharge or bleeding. Diffuse inflammation of the peritoneum (peritonitis), a rare but very serious complication, may result from the entry of bacteria into the peritoneal cavity. As the infection progresses, other bacteria of vaginal origin may invade the fallopian tubes, which accounts for the fact that multiple bacteria can be isolated from older lesions. During the healing phase of inflammation, the fallopian tubes may become scarred and obstructed. Chlamydial Infections Chlamydial infections present as nonspecific inflammation of the vulva, internal female genital organs, and urethra. Babies born to women infected with Chlamydia are at risk for developing neonatal conjunctivitis, which must be prevented by the application of prophylactic broad spectrum antibiotic eye drops to all newborns. Infected neonates are at risk for developing neonatal pneumonia, estimated to occur in 20% of all infected newborns. It also causes urethritis (dysuria) and may even cause proctitis (infection of the rectum). Infants born to infected mothers can develop purulent conjunctivitis, which may seriously damage the eyes and cause loss of vision. Hormonally Induced Lesions the normal function of the female reproductive system depends on the proper output of ovarian hormones, which, in turn, depends on the normal function of the hypothalamicpituitary-ovarian axis. Syphilis Primary syphilis presents in females as vulvar ulcers, chancre, or cervicitis and vaginal lesions. Neonatal gonococcal conjunctivitis results from maternal infection during delivery. It was one of the major public health problems in America during the nineteenth century. Barnes, who found that silver nitrate droplets administered after birth could prevent eye infection in neonates. The pivotal moment of the normal cycle is ovulation, which occurs on the 14th day of a 28 day cycle. For all other cycle lengths, ovulation is calculated by subtracting the cycle length by 14 days, the lifespan of the corpus luteum. Examples include ovulation on day 7 for a 21 day cycle or ovulation on day 26 for a 40 day cycle. If ovulation does not occur, the proliferative phase of the menstrual cycle will continue, and the secretory phase will never be initiated. However, because the endometrium cannot proliferate indefinitely, it finally outgrows its own blood supply.

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