Louis Flancbaum, M.D., FACS, FCCM, FCCP

• Associate Professor of Surgery, Anesthesiology,
• and Human Nutrition
• The Ohio State University Hospitals
• Columbus, OH

These tumors are usually associated with pleural effusions metabolic disease what is it januvia 100 mg order fast delivery, which contain floating tumor cells diabetes type 1 or 2 worse januvia 100 mg order with amex. The diagnosis can be made by submitting a sample of pleural fluid for cytologic examination diabetes symptoms explained cheap januvia amex. Compare the infections of the upper respiratory system with those of the so-called middle respiratory system diabetes diet while pregnant generic 100 mg januvia with mastercard. List the most common causes of pneumonia diabetes urine test fasting order januvia 100 mg line, and give specific characteristics about each of these forms of lung infection. Explain the concept of atypical pneumonia, and give specific examples of this clinicopathologic entity. List four main pathogenetic mechanisms of ventilatory failure, and explain how they affect respiration. Describe the pathology of acute respiratory distress syndrome and explain its pathogenesis. Correlate the pathology of carcinomas of the larynx with clinical findings and prognosis of the disease. Discuss the possible causes of aplastic anemia and the associated bone marrow biopsy findings. Describe the causes and typical findings of iron deficiency and pernicious anemia. Compare hemolytic anemias caused by intrinsic and extrinsic red blood cell defects. Define leukocytosis-leukopenia and lymphocytosis-lymphopenia, and list the possible causes of these conditions. List the common pathologic findings of leukemia and lymphoma, and relate them to clinical symptoms. Define multiple myeloma, list the most common sites involved in this disease, and list three laboratory findings. It is routinely performed on most, if not all, hospitalized patients and many of those seen in ambulatory health care facilities. General medical practitioners, highly specialized physicians, nurses, and many allied health professionals deal with hematologic data daily and are trained to interpret such findings. The clinicians treating disorders of blood cells and coagulation factors are called hematologists and hematopathologists. Expert hematologists are called on as consultants in complicated cases and for those patients who do not respond to standard therapy. Hematologists also treat patients with neoplastic diseases of blood-forming tissues, such as leukemia; primary deficiencies of the bone marrow, such as aplastic anemia; and bleeding disorders, such as hemophilia. Hematopathologists supervise blood banks and prepare blood and blood components for transfusion, although in major medical centers there are also specialists of transfusion medicine. Plasma is the protein-rich fluid component of the blood, which contains not only albumin and globulins but also all the clotting factors. Granulocytes are divided on the basis of their cytoplasmic granules into neutrophils, eosinophils, and basophils. Monocytes and lymphocytes are also known as agranular leukocytes because they do not contain cytoplasmic granules. From the yolk sac, the hematopoietic stem cells migrate to the liver and then to the bone marrow and, to some extent, to the spleen, lymph nodes, and thymus. Extramedullary hematopoiesis in the liver and the spleen subsides after birth, and the bone marrow remains the primary blood-forming organ. As the organism matures, the red bone marrow of the long bones is replaced by fat. The thymus and lymph nodes remain sites of lymphocytopoiesis in infancy and adolescence, but the thymus usually involutes after puberty. Lymph nodes form lymphocytes, but in adults these organs do not produce red blood cells or granulocytic leukocytes. However, if the hematopoietic bone marrow is destroyed, extramedullary hematopoiesis may resume in the spleen, liver, and lymph nodes. The mature blood cells are descendants of developmentally pluripotent hematopoietic stem cells. The term pluripotent means that these cells can differentiate and develop into more than one mature cell type. The mother stem cell differentiates into several developmentally committed stem cells, which are the precursors of distinct cell lineages, the ultimate product of which are the mature blood cells. The lymphoid stem cell gives rise to B-cells, which finally mature into immunoglobulin-secreting plasma cells, and T-cells, most of which assume their function in mediating cell-mediated immune reactions after they have passed through the thymus (T-thymus! The myeloid stem cell, also known as the trilineage-myeloid stem cell, gives rise to three subsets of stem cells, which are the precursors of mature erythrocytes, megakaryocytes, and nonlymphoid white blood cells such as neutrophils, monocytes, eosinophils, and basophils. The stem cells of various cell lineages are small, undifferentiated cells that are indistinguishable from one another; however, they differ with regard to their development potential. Many other growth factors, such as interleukins produced by macrophages and T-lymphocytes, also stimulate blood cell formation. Only the growth factor for the erythroid cell lineages-erythropoietin-is produced outside of the bone marrow (in the kidney). Taller men have more blood than shorter men, and females typically have less blood than males. Blood cells can be separated from the plasma by allowing the formed elements to form sediment over a period of several hours at the bottom of a tube coated with anticoagulant. This can be achieved much faster by centrifuging the blood at high speed for 2 to 3 minutes. The volume of packed red blood cells, expressed as a percentage of the total peripheral blood, is called the hematocrit. In healthy adults, formed blood cell elements constitute 40% to 45% of the total blood volume, whereas the plasma accounts for 55% to 60%. Isolation of the genes for erythropoietin and other hematopoietic growth factors made it possible to produce them commercially using recombinant gene methodology. Anemic patients who do not have endogenous erythropoietin, because their kidneys have been destroyed by disease, can be treated successfully with recombinant erythropoietin. Most of this second phase consists of red blood cells, except for the top layer, called the buffy coat, which contains leukocytes and platelets. The coagulation proteins are consumed in this process, which leads to transformation of plasma into serum. It contains all the proteins except fibrinogen, prothrombin, and other coagulation factors. Some blood tests can be performed only on plasma, whereas others can be performed on serum. By contrast, blood collected in "red top" tubes, which do not contain anticoagulants, will coagulate and on centrifugation will yield serum. In general, clinical laboratories specify the requirements for each test, and one must check the hospital manual before drawing blood for a specific test. Overview of Major Diseases Hematologic diseases occur as a result of abnormal formation, increased destruction, or abnormal structure and function of blood cells. Principal hematologic diseases include the following: · Anemia · Leukemia · Lymphoma · Bleeding disorders Several facts important to an understanding of the hematopoietic system are presented here, before a discussion of specific pathologic entities: 1. Erythrocytes are ideally suited for their primary function: transport of oxygen from the lungs to the peripheral tissues. The red color is derived from hemoglobin, an iron-containing pigment that constitutes 90% of the dry weight of each normal, mature erythrocyte. In peripheral blood smears, the thinner central portion, spanning half the cell diameter, appears paler than the peripheral part. The erythrocytes are round but can easily be deformed while passing through small capillaries and other small vessels. Erythrocytes do not have nuclei or organelles that would interfere with their transport function. Because of their biconcave shape, they have a large surface that allows easy diffusion of gases. Hemoglobin is a complex molecule that consists of four heme groups and four globins. Heme is composed of four pyrrole rings held together with a centrally placed iron in ferrous form (Fe2+). The globin part of hemoglobin consists of four polypeptide chains designated by the Greek letters alpha, beta, gamma, and delta. Mutations of these genes cause hemoglobinopathies and are marked by abnormal hemoglobins; for example, sickle cell anemia is characterized by an abnormal B chain, and the hemoglobin is known as hemoglobin S (HbS). Deficiency or malabsorption of these nutrients also results in anemia; anemia may develop because the nutrient is not available in food, because it cannot be absorbed, or because the loss exceeds the intake. The aging cells are sequestered in the spleen, which removes the old and defective red blood cells from circulation and serves as their primary "graveyard. The remainder is excreted in the form of urobilinogen and stercobilinogen in urine and feces. Normal synthesis of hemoglobin occurs only in the presence of nutrients, iron, vitaminB12,andfolicacid. Objective measurements of red blood cell parameters are done with instruments that estimate the mean size of red blood cells and their hemoglobin content. Analysis of blood has become highly automated and is performed with sophisticated instruments. Low values (<80 fL) indicate microcytic anemia, whereas high values (>100 fL) indicate macrocytic anemia. Neutrophils are the most abundant white blood cells in the blood, accounting for 60% to 70% of all nucleated cells. The main function of neutrophils is to defend the body against bacterial infections. Neutrophils are most qualified for this job, because they have remarkable mobility. Eosinophils account for 1% to 3%, and basophils for less than 1%, of all white blood cells in the blood. The release of these substances causes blood vessels to dilate and increases their permeability. Neutrophils are short-lived cells that survive no more than 4 days in the peripheral circulation. Therefore, these cells must be replaced constantly, and the bone marrow produces new neutrophils at a very fast pace. Because the life span of neutrophils is about 300 times shorter than the life span of erythrocytes, the bone marrow contains three times more white blood cell precursors than erythroid precursors. The abundant cytoplasm of megakaryocytes forms buds, which are released into the circulation as platelets. Platelets do not have nuclei; however, they survive 8 to 10 days in the circulation. Malignant transformation of hematopoietic cells may result in solid tumors or leukemia. Lymphomas, resulting from malignant transformation of lymphoid cells, occur most often in lymph nodes. These malignant cells may remain localized to their site of origin, extend into the adjacent tissues, or enter the circulation. Because of the white color of blood that contains large numbers of malignant leukocytes, the malignancy of circulating white blood cells is called leukemia. This may be associated with the following: · Appearance of abnormal hemoglobins · Reduced number of red blood cells · Structural abnormalities of red blood cells Because of the reduction of hemoglobin in the circulating blood, the tissues do not receive enough oxygen, and symptoms of hypoxia develop. These symptoms vary, because no organs are equally susceptible to oxygen deprivation. In principle, all organs show signs of slower metabolism and a reduced capacity to respond to increased demand for action. For example, hypoxia of the brain causes somnolence, and cardiorespiratory hypoxia causes shortness of breath and easy fatigability. Paleness of the skin and mucosae is a common feature of anemia, but it has almost no functional consequences. Etiology and Pathogenesis Anemia may be a consequence of the following: · Decreased hematopoiesis · Abnormal hematopoiesis · Increased loss or destruction of red blood cells Each of these categories includes several distinct diseases, the most important of which are listed in Box 9-2. Decreased hematopoiesis Decreased hematopoiesis may be a consequence of bone marrow failure or a deficiency of essential nutrients. The stem cells disappear from the bone marrow with consequent pancytopenia (lack of all blood cells) in the peripheral blood. Bone marrow stem cells may be damaged or replaced by infiltrates of metastatic tumor cells. Similar bone marrow destruction occurs in various forms of leukemia, in which the leukemic cells infiltrate the bone marrow, replacing all normal cell components. Anemia, and even pancytopenia, are typical features of malnutrition and starvation. Intestinal malnutrition syndromes impair absorption of iron as well, thus contributing to iron deficiency anemia. Abnormal hematopoiesis Abnormal hematopoiesis is usually a consequence of genetic abnormalities. These can be inherited as Mendelian traits that affect families, but they may also occur as point mutations in individuals without a previous family history of such a disease. The best known among these is sickle cell anemia, caused by a gene mutation that substitutes a valine for the glutamic acid at position 6 of the beta chain of hemoglobin. Erythrocytes that contain abnormal hemoglobin (or are abnormally shaped) cannot function properly, and affected patients suffer from chronic hypoxia. Furthermore, the abnormal hemoglobin reduces the life span of erythrocytes, which are destroyed at an increased rate in the spleen and within the blood vessels.

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Etiology and Pathogenesis the events leading to the formation of lung carcinoma are not fully understood blood sugar fasting 100 mg januvia order overnight delivery. Tobacco smoke contains many potentially harmful substances diabetes type 2 what not to eat list buy januvia 100 mg cheap, the most important of which are chemically classified as polycyclic hydrocarbons diabetes mellitus y sus sintomas cheap januvia 100 mg on line. Like the polycyclic hydrocarbons derived from tar diabetes insipidus ketones trusted januvia 100 mg, those in cigarette smoke are also mutagenic to bacteria in vitro in an Ames test diabetes medications and pancreatitis order januvia visa. In tissue culture, these chemicals can initiate and promote malignant transformation of normal mammalian cells. It is assumed that the exposure to carcinogens in smoke initiates malignant transformation of bronchial cells and promotes their progression into invasive cancer. Inhaled procarcinogens (incomplete carcinogens) are transformed into carcinogens through the action of cytoplasmic enzymes in bronchial cells exposed to smoke. Inducibility of these enzymes, which are potentially important for carcinogenesis, is genetically determined. These genetic differences could account for the fact that not all smokers develop lung cancer and for the fact that increased predisposition to lung cancer has been noted in some families. The chemicals inhaled from tobacco smoke contain several proven carcinogens and also various irritants that could act as promoters of incipient neoplasia. Histologic studies of respiratory epithelia in smokers indicate that in most cases bronchial cancer is associated with a variety of preneoplastic lesions that are most likely caused by the combined action of carcinogens and irritants. It has been proposed that the sequence of events begins with metaplasia of the bronchial epithelium. If smoking is discontinued, the lesion will disappear and the normal structure of bronchial epithelium will be restored. If the carcinogenic stimuli persist, metaplasia will progress into carcinoma in situ, and this will give rise to invasive carcinoma, most of which will be of the squamous type. Initial squamous metaplasia explains the paradoxical appearance of a squamous cell carcinoma in an epithelium not normally composed of squamous cells. If the transformed stem cells progress and become more anaplastic, the tumor will be histologically classified as an undifferentiated large-cell carcinoma. In some bronchial carcinomas the malignant transformation will primarily involve the neuroendocrine cells, which are normally present in the bronchial mucosa. Highly malignant neuroendocrine carcinomas are called small-cell carcinomas (also known as oat-cell carcinomas). Finally, some bronchial tumors will be composed of cylindrical cells, resembling the normal cells of the bronchus. It is worth mentioning that lung tumors may be also benign, but such benign neoplasms are rare and outnumbered by malignancies. We should also mention the lowgrade malignant tumor composed of neuroendocrine cells, called a carcinoid tumor. In contrast to small-cell carcinomas, the high-grade neuroendocrine tumors, which are in 99% of cases found in smokers, carcinoids can occur in nonsmokers as well and are linked to smoking only in about 40% of all cases. Macroscopic Pathology Most tumors encountered in clinical practice by surgeons or pathologists are grossly visible masses that can be classified according to their location as hilar (central) or peripheral (subpleural). Despite overwhelming scientific evidence linking lung carcinoma to smoking, many people continue to smoke cigarettes, and the tobacco industry is making higher profits than ever. It was only in 1998 that the tobacco industry finally agreed to pay for some of the health care costs caused by smoking. Those that protrude into the bronchi and those that cause ulceration of the overlying bronchial mucosa can be recognized by bronchoscopy. Some tumors arising from cells in the terminal bronchioli tend to grow inside the alveoli and were previously called bronchioloalveolar carcinomas. Fortunately, they can be recognized by x-ray, because they cause a localized consolidation that resembles pneumonia, suspiciously do not heal, and tend to enlarge. Locally, these tumors extend into the mediastinum and often spread into the pleural cavity. At the time of diagnosis, more than 70% of patients already have metastases that are apparent, and many more probably have microscopic metastases that are clinically unapparent. Approximately one half of those with tumors extending beyond the lung parenchyma have metastases to the local lymph nodes. Lung cancer also has a tendency to metastasize to bones, kidneys, and, for some peculiar reason, the adrenals. Microscopic Pathology Lung tumors can be classified microscopically into several groups: · Adenocarcinoma (40%) · Squamous cell carcinoma (30%) · Large-cell undifferentiated carcinoma (10%) · Small-cell carcinoma (15%) · Carcinoids (1% to 5%) Each of these tumor types has unique histologic features, although there is some overlap between certain tumor forms. In approximately 10% of cases, tumors have more than one pattern and thus have a mixed histologic appearance. Squamous cell carcinomas of the lung have the same histologic features as squamous cell carcinomas of other sites. Small-cell carcinomas are treated primarily by chemotherapy and are not removed surgically. These tumors are composed of uniform cells and have a tendency to invade locally and grow slowly. They do not metastasize to distant places, and local resection is the treatment of choice, with a cure rate of 85%. Clinical Features Symptoms of lung cancer can be classified as being related to the following: · Bronchial irritation or obstruction · Local extension into the mediastinum or pleural cavity · Distant metastases · Systemic effects of neoplasia Approximately 10% to 15% of patients with lung cancer have no obvious symptoms, and the tumor is discovered incidentally during routine chest x-ray examination. Among the patients who are symptomatic, approximately one third will report to the physician with symptoms pertaining to local effects of the tumor in the chest, one third will present with symptoms pertaining to distant metastases, and one third will present with nonspecific systemic complaints and no localizing symptoms. Bronchial irritation most often causes coughing; less commonly, it causes respiratory wheezing, dyspnea, and other respiratory symptoms. Local extension of the tumor into the pulmonary parenchyma tends to obstruct bronchi, cause atelectasis, and predispose the individual to lung infection. Extension to the pleural surface is typically associated with pleural effusion and progressive dyspnea secondary to lung compression. Ingrowth of the tumor into the mediastinal nerves causes pain or paralysis of the muscles of the diaphragm or vocal cords. Brain metastases result in neurologic symptoms and are associated with high mortality. The systemic symptoms of lung cancer do not differ significantly from symptoms produced by other tumors and include weight loss and cachexia, anorexia, and general malaise. The only patients who can be effectively cured are those whose tumors are clinically inapparent and were discovered by chance on cytologic examination or bronchoscopy and those with most typical carcinoid tumors. Because a large amount of blood circulates through the lungs, any tumor cell floating in the blood could be filtered out while passing through the pulmonary capillaries. Furthermore, the thoracic duct (the main lymphatic vessel) is confluent with the superior vena cava; thus, the tumor cells transported in the lymph will also lodge in the lungs. Pulmonary metastases may present as the following: · Solitary lesions · Multiple lesions · Diffuse lesions replacing large parts of the lung or diffusely covering the pleural surface Solitary metastases may be resected. If the patient has no other evidence of tumor, such treatment may be beneficial and prolong life. This typically occurs after stab wounds of the chest wall or rupture of emphysematous lung tissue. Pleural Diseases the pleura forms the outer covering of the lung (visceral pleura) and the inner covering of the chest cage (parietal pleura). It is a virtual space because the two layers of the pleura are tightly opposed to one another and are separated only by a thin film of fluid that keeps the surfaces moist, allowing movement of the lungs during respiration. If the traction of this negative pressure is Pleural Effusions Accumulation of fluid in the pleural cavity is called hydrothorax or pleural effusion. Transudate is formed as a result of increased hydrostatic pressure in the pulmonary system in patients with congestive left ventricular failure and heart failure. Pleuritis most often results from the extension of bacterial pneumonia to the pleural cavity. Fibrinous or fibrinopurulent pleuritis, especially if associated with inflammation of the pleura or tissue destruction, stimulates the ingrowth of granulation tissue into the pleural cavity. This leads to obliteration of the cavity and the formation of fibrous adhesions between the visceral and parietal pleura, called fibrothorax. Partial fibrotic obliteration of the pleural cavity filled with pus results in empyema. Empyema resembles an abscess in which the pus may remain for extended periods unless surgically removed. Pleural Tumors Tumors of the pleura may be primary or secondary, benign or malignant. Microscopically it is composed of fibroblastic cells arranged without any distinct pattern ("patternless tumor"). It accounts for less than 2% of all malignant tumors in men and even fewer in women. These tumors are locally invasive into the lung and the chest wall and are often accompanied by pleural effusion. They do not metastasize outside the thorax until late in the course of the disease. Microscopically they may be classified as epithelioid (60%), sarcomatoid (20%), or mixed (20%). Clinical symptoms related to the compression of the lung include dyspnea, coughing, and chest pain. Secondary tumors are either pulmonary primaries extending to the pleura or metastases from distant sites. Increased loss and destruction of red blood cells Various conditions may cause increased loss or destruction of red blood cells, including bleeding, intrasplenic sequestration, immune hemolysis, and infections. To compensate for the loss of blood and maintain a constant volume of circulating blood, the body mobilizes fluid from the interstitial spaces into the circulation. This restores the volume of blood but dilutes it, thereby changing the ratio of blood cells to fluid. This temporary dilutional anemia is usually corrected spontaneously within a few weeks by replenishment of the blood cells from the bone marrow. However, if the bleeding persists, as in patients with a bleeding peptic ulcer, chronic anemia will develop. Normally, old red blood cells are removed from the circulation during their passage through the spleen. The removal of red blood cells may be accelerated in some pathologically altered and enlarged spleens. This disease of unknown etiology is marked by splenomegaly (an enlargement of the spleen) and increased destruction of red blood cells and suppression of hematopoiesis in the bone marrow. An important form of red blood cell destruction occurs in various autoimmune disorders and hemolytic anemias. Common to these disorders is an antibody-mediated injury of red blood cell membranes, which leads to their rupture (hemolysis) and the release of hemoglobin. It is caused by an infection with the parasite Plasmodium, which invades the red blood cells and causes their lysis. Millions of people are infected with malaria worldwide, but in North America and Europe the disease is not common. Morphology of Anemia Morphologic and biochemical classifications of anemias are based on the study of peripheral blood smears, measurement of hemoglobin content, and chemical analysis of hemoglobin. The blood smears provide a quick and simple approach to evaluating red blood cell size, shape, and hemoglobin content. Small red blood cells are called microcytic, whereas the large ones are called macrocytic. The variation in size of erythrocytes is called anisocytosis, whereas the variation in shape is termed poikilocytosis. Typically this type of anemia occurs after a massive blood loss ("dilutional anemia"). It is also seen in thalassemia, a hereditary defect affecting the synthesis of hemoglobin. Typically, this is caused by a deficiency of vitamin B12 and/or folic acid, but it can also occur in chronic liver disease. These anemias are descriptively called by the predominant cell shape seen in peripheral smears and include entities, such as elliptocytosis and spherocytosis. The prototype of this form of anemia is sickle cell anemia, a disease characterized by the appearance of sickleshaped erythrocytes. Morphologic classification of anemias is usually supplemented these days by biochemical data. For example, some microcytic anemias are caused by an iron deficiency, whereas others are a symptom of a genetic disorder of globin, the gene defect that causes thalassemia. To establish the cause of a microcytic hypochromic anemia, one would first have to exclude iron deficiency by measuring the blood iron and estimating the iron stores in the body. Thalassemia, the other cause of microcytic hypochromic anemia, can be diagnosed by demonstrating the abnormal hemoglobin levels typical of this disease. In most cases the morphologic-biochemical classification of anemia will point to the cause of the anemia, which then can be assigned to one of the categories within the etiologicpathogenetic classification system. Once the cause of an anemia is identified, one should try to eliminate the adverse influences or provide substitutional therapy to correct the deficiency. Many of these secondary aplastic anemias are reversible, and elimination of the causative agent often allows the bone marrow to recover. The prognosis for recovery in patients with idiopathic aplastic anemia is less favorable. Pathology the bone marrow is typically depleted of hematopoietic cells and consists only of fibroblasts, fat cells, and scattered lymphocytes.

The onset of the morphologic features directly correlates with the timeframe of initiation of drug use or toxin exposure and the onset of clinical symptoms and liver test abnormalities diabetic diet juice cheap januvia 100 mg without prescription, beginning within a few days or less after exposure diabetes signs and symptoms in hindi buy januvia now. The Acute Hepatocellular Necroinflammatory Change 219 liver cells appear eosinophilic with the nuclei pyknotic and karyorrhectic in the very early stages diabetes test pregnancy glucose test discount januvia 100 mg amex, with rapid onset of nuclear loss melatonin and diabetes medications order cheap januvia online, shrinkage of the cytoplasm managing diabetes naturally purchase januvia 100 mg visa, and eventual liver cell dropout with collapse of the lobular reticulin framework. In most cases the perivenular (zone 3 of Rappaport) region is involved, in large part due to the hepatocytes in this zone most active in physiologic drug metabolism; however, infrequently the periportal zone may show injury such as seen in ferrous sulfate and phosphorus-induced necrosis. There are most often sharp demarcations of the areas of necrosis and the adjacent viable hepatocytes; however, in the most severe cases the perivenular and midzones and sometimes all zones (panlobular) can be involved by severe confluent necrosis. All lobules throughout the liver are equally affected, as opposed to coagulative necrosis secondary to ischemia (acute heart failure) where the degree of damage may somewhat vary from one hepatic lobule to another dependent of the specific arterial blood flow to each particular functional region. Usually there are no inflammatory infiltrates in the areas of necrosis, although eventually a histiocytic and Kupffer cell reaction to clear the liver of the necrotic hepatocytes occurs. Interestingly a neutrophilic infiltrate that is common in ischemic necrosis due to poor vascular perfusion (hypotension) is less frequent in direct drug-induced injury. The adjacent hepatocytes often show a hydropic change due to liver cell regeneration. In addition, if there is impediment to bile flow from the necrosis, cholestasis may also be seen in the viable hepatic parenchyma. The portal tracts in almost all instances are not affected, with no fibrosis, little if any portal inflammatory infiltrates, and normal bile ducts; however, in periportal or panlobular necrosis a prominent bile ductular reaction originating from facultative stem cell activation is not uncommon. The perivenular and midzonal hepatocytes show a coagulative necrosis without an inflammatory reaction, with the adjacent viable periportal hepatocytes unremarkable. Acute Hepatocellular Necroinflammatory Change Liver injury associated with portal and lobular inflammation is characteristic of idiosyncratic hypersensitivity reactions and may present clinically as an acute hepatitis or occur in an otherwise asymptomatic patient with transaminitis. The portal tracts are normal although at times a minimal lymphocytic infiltrate can occur. The inflammation can be patchy, with variable liver cell necrosis, apoptosis, and hydropic or ballooning changes of the hepatocytes, or the injury can be diffuse. At times a sinusoidal lymphocytosis can also occur and mimic the features seen in acute Epstein­Barr virus and cytomegalovirus-induced hepatitis ("mononucleosis-type pattern"), an example being phenytoin-associated injury. Additionally at times the necroinflammatory change can form small aggregates of lymphocytes and histiocytes and mimic small granulomas ("granulomatous necrosis"). The portal tracts usually show a lymphocytic infiltrate that at times can be prominent, although in drug-induced injury the degree of portal inflammation is usually not as striking as in acute or chronic viral hepatitis. Although portal infiltration by eosinophils can occur and is helpful in the diagnosis of a hypersensitivity reaction, oftentimes eosinophils are few or even absent. Scattered portal neutrophils can also occur, but are not oriented towards any particular portal structures. A periportal interface inflammatory activity is usually not a feature except in the chronic hepatitic reactions. In the more severe cases associated with jaundice and markedly elevated transaminases, a confluent necrosis with extensive liver cell injury and dropout can also ensue, and although the perivenular zone is initially affected, all zones can be involved in severe fulminant hepatitis. The necrosis can be highlighted by the reticulin stain which shows collapse of the reticulin framework. A variable and sometimes prominent lobular inflammation by predominantly lymphocytes is also seen in the viable areas. When there also are areas of spared hepatocytes, the injury is termed submassive hepatic necrosis, while involvement of all hepatocytes in all lobules (panacinar) is termed massive hepatic necrosis. The portal tract exhibits a prominent mixed inflammatory infiltrate including numerous eosinophils. Extensive confluent necrosis and necroinflammatory change is seen involving the perivenular and midzonal hepatocytes. Diffuse moderate lobular necroinflammatory change is seen, the inflammatory cells chiefly lymphocytes. Severe confluent hepatic necrosis with a predominantly lymphocytic inflammatory infiltrate is present. Chronic Hepatocellular Necroinflammatory Change Although most cases of drug-induced hepatocellular injury recover when the drug is discontinued, ongoing necroinflammatory changes over time may lead to a chronic hepatitis that may persist even when the drug is no longer being administered. Diffuse lobular necroinflammatory change is seen, the inflammatory cells predominantly lymphocytes. The portal tracts usually show a variable predominantly lymphocytic infiltrate with occasional macrophages and sometimes plasma cells and eosinophils, with the bile ducts usually not involved. Periportal interface inflammatory activity, a hallmark of active chronic hepatitis, is also apparent to variable degrees. In some instances of chronic hepatitis, portal, periportal, and intrasinusoidal collagen deposition can occur which can lead to cirrhosis with time if the drug is not discontinued. Activation of hepatic stellate (fat-storing) cells leading to laydown of extracellular sinusoidal collagen is one mechanism, alcohol-related fibrosis an excellent example. When also associated with bile duct injury, a "biliary" fibrosis with duct loss and cirrhosis can occur. Portal fibrosis with prominent periportal interface inflammatory activity is seen. Some of the patients who develop autoimmune hepatitis induced by drugs may have a history of other autoimmune disorders as well. Additionally the lack of recurrence of the autoimmune hepatitis after the drug withdrawal supports that the autoimmune disease was indeed drug induced. Of note is that oftentimes the hepatitis presents as an acute event with portal fibrosis initially minimal to absent; however progression of the disease with accompanying fibrosis over time when the drug is not discontinued can occur. Although halting the drug use can prevent further development of fibrosis, when there is cirrhosis reversibility virtually does not occur (rare exceptions). Therefore since the vast majority of drugs associated with the risk of developing cirrhosis are known. Screening with biopsy is often critical, as not infrequently the liver tests can be normal or show only minimally elevated transaminases with even a normal albumin yet fibrosis can be present and progress. A well-established cirrhosis is present from this patient with a long history of alcohol abuse with recent abstinence (absence of steatosis, ballooning change, Mallory-Denk bodies). Portal fibrosis with periportal interface inflammatory activity is seen, the inflammatory cells consisting of lymphocytes with increased numbers of plasma cells, the latter often arranged in small clusters. Lymphocytes can be seen hugging up against the terminal hepatic venular endothelium (endothelialitis), a feature that can sometimes occur in autoimmune hepatitis. Therefore it is often problematic in assessing whether the steatosis is all or part drug induced. The fat can be macrovesicular (large droplet fat globules equal to or greater than the size of the nucleus), microvesicular (small droplet fat smaller than the nucleus) or mixed. In some instances the fat globules can be so small ("foamy") that they cannot be appreciated on routine H&E stain, necessitating performance of a stain for neutral triglycerides (Oil Red O) on frozen sections from fresh or formalin fixed liver tissue. Fat can also be seen from normally processed tissue with immunoperoxidase stains using perilipin and adipophilin markers, two proteins that play a role in lipid metabolism, with positive staining appearing at the rim of the lipid droplets. The fat can also be patchy throughout the lobules, have a zonal accentuation, or be diffusely distributed in virtually all of the hepatocytes. In addition small fat droplets can be present within portal macrophages, in lipogranulomas, and in the subendothelial fat storing (Ito, stellate) cells. Steatosis that is mainly macrovesicular can occur without associated inflammation on biopsy, even when mild transaminitis is present; however, in drug-induced steatosis usually some other histologic features such as portal inflammation and patchy lobular inflammation 224 11 Drug- and Toxin-Induced Liver Diseases are also apparent. Although fatty change with any inflammation can loosely be referred to as steatohepatitis, that term is more often applied to the additional presence of varying sinusoidal fibrosis, which may in the more active stages also show liver cell ballooning and Mallory­Denk bodies. These additional features at times make drug-induced injury difficult to distinguish from alcoholic hepatitis or active non-alcoholic steatohepatitis. In addition, foamy lipid deposits can occur within the lysosomes of hepatocytes due to the inhibition of phospholipase A from lipid hydrolysis (phospholipidosis), and can be induced by various drugs. Histologically not only fatty change but also sinusoidal fibrosis and Mallory­Denk body formation can also occur in this subgroup. Small droplet fat is seen in the hyperplastic stellate (Ito, fat-storing) cells that lie just beneath the sinusoidal endothelial cells. Macrovesicular fat with accompanying mild lobular necroinflammatory change is seen. Mallory­Denk Bodies 225 abnormalities, immune-mediated reactions, certain neoplasms, and various miscellaneous conditions (see Table 6. Granulomas secondary to drug-induced reactions are also well documented and are felt to be secondary to a cellular immune-mediated reaction to the drug or its metabolites. These granulomas can be well (epithelioid type) or poorly (inflammatory type) demarcated. The former usually contain epithelioid histiocytes with scattered lymphocytes and sometimes multinucleated giant cells, while the latter consist of macrophages, eosinophils, plasma cells and neutrophils to various degrees, infrequently associated with multinucleated giant cells. The inflammatory granulomas also can be quite small and consist of only a small cluster of mixed inflammatory cells ("micro-granulomas"). Central necrosis with or without fibrin deposition within the granulomas is infrequent but can occur in drug-induced injury. Since these granulomas very much mimic those seen in other necroinflammatory processes, especially infections, the use of special stains, serologies, and cultures of tissue and various body fluids is often essential in arriving at the correct diagnosis. The parenchyma shows a small well-demarcated collection of lymphocytes and macrophages. Mallory­Denk Bodies Mallory­Denk bodies are eosinophilic irregular ropey intracytoplasmic inclusions in the hepatocyte and are associated with various hepatic disorders, in particular the fatty liver diseases. On electron microscopy these inclusions consist of filamentous randomly oriented intracytoplasmic processes composed of various cytokeratins, ubiquitin-binding protein p62, and other peptides. Mallory­Denk bodies can also occur in other liver diseases such as chronic biliary tract disorders. The Mallory­Denk bodies associated with both alcoholic hepatitis and non-alcoholic steatohepatitis are accentuated in the perivenular zone, although in severe cases the midzones and in the more severe cases all zones may be involved, while in amiodarone hepatotoxicity the periportal hepatocytes are most often affected. A portal tract shows a well-circumscribed granuloma composed of lymphocytes and epithelioid histiocytes. Acute Cholestatic Liver Injury Cholestasis associated with an absence of lobular or portal inflammation and without interlobular bile duct injury is termed simple cholestasis and can occur from various drugs and toxins. The bile is usually seen in the perivenular zone and can occur within the liver cell cytoplasm, within dilated canaliculi, or both. At times the bile can be diffuse and involve all zones, and when the periportal zone is involved the bile can at times be seen within dilated cholangioles located at the border of the portal tracts and parenchyma, sometimes associated with a mild predominantly neutrophilic infiltrate (acute cholangiolitis). Intracellular bile is a clumped green to yellow-green pigment that stains positively on Hall stain. Cholestatic hepatitis refers to liver damage associated with not only cholestasis but also variable portal and lobular inflammation and can occur secondary to drug- or toxin-induced injury. The cholestasis is usually accentuated within the perivenular zone and is associated with usually a lymphocytic infiltrate with variable Kupffer cell hyperplasia. Variable swelling and hydropic changes of the hepatocytes containing the bile may occur. The portal inflammation is usually lymphocytic with occasional neutrophils, plasma cells, and eosinophils. The degree of portal inflammation can vary but is seldom present to the extent seen in viral hepatitis. In addition the degree of intracellular and intracanalicular bile can be striking and outweigh the only mild portal and lobular inflammation. Periportal interface inflammatory activity is usually not a feature, and the interlobular bile ducts are usually normal, although as in simple cholestasis there can be cholangiolar proliferation when the cholestasis also involves the periportal zones. Intracanalicular and intracytoplasmic bile is seen along with mild lobular necroinflammatory change. The interlobular bile duct shows considerable cytologic atypia and is surrounded and focally infiltrated by lymphocytes. Chronic Cholestatic Liver Injury Although the interlobular bile ducts are not primarily affected in most cases of cholestatic-induced liver injury, in some instances of cholestatic hepatitis the bile ducts can also be damaged (chronic cholestatic pattern). When neutrophils are involved the features can mimic the acute cholangitis seen in bile duct obstruction; however the damaged ducts do not show the proliferation and ectasia seen in bile duct obstruction. Lymphocytes can also be the inflammatory cell targeting the interlobular bile ducts (non-suppurative duct damage) and with time the duct injury can eventually lead to interlobular bile duct loss, features similar to those seen in primary biliary cirrhosis and autoimmune hepatitis with duct damage (autoimmune cholangitis). Very rarely periductal fibrosis similar to that seen in long-term bile duct obstruction and primary sclerosing cholangitis can occur, an example being injury due to floxuridine in the therapy of hepatic tumors. Regardless of the type of duct damage, the parenchyma oftentimes usually shows a mild lobular inflammation and variable degrees of cholestasis that at times can be quite minimal or absent. In addition, with time portal fibrosis of a biliary type can occur and uncommonly even a biliary cirrhosis can be the unfortunate outcome. Vascular Injury Damage to the sinusoids and outflow vessels can occur secondary to drug- and toxin-induced damage. The portal tracts show a prominent mixed inflammatory infiltrate including eosinophils. In addition, certain drugs, in particular the Senecio alkaloids, can also cause endothelial inflammation, sloughing of the endothelial cells, and eventual endothelial loss (sinusoidal obstruction syndrome, veno-occlusive disease) which can sometimes spread out and involve the zone 3 endothelial cells and sinusoids as well. Rarely sinusoidal dilatation, usually involving the midzonal hepatocytes, can be seen associated with oral contraceptive usage. The sinusoids can also be focally damaged and weakened, causing focal sinusoidal dilatation with small intralobular micro-cyst formation (peliosis hepatis) usually filled with red blood cells. At times these peliotic lesions can enlarge to the degree of being discernible by imaging. The larger outflow vessels (sublobular and hepatic veins) can also undergo thrombosis and occlusion by certain drugs, in particular alcohol but also oral contraceptives. Inflammation of the hepatic arteries can also occur, and more often involve the medium-sized arteries, causing a vasculitis. Neoplasms and Related Lesions Certain drugs and toxins may with time lead to the formation of both benign and malignant hepatic neoplasms and space-occupying related lesions.

Infection of the uterine body is usually limited to the endometrium and is thus called endometritis diabetes symptoms varicose veins order januvia pills in toronto. Inflammation of the fallopian tubes is called salpingitis diabetes in dogs insulin dose discount januvia american express, and inflammation of the ovaries is termed oophoritis diabete oeil discount januvia 100 mg with visa. With regard to the duration of the disease diabetes symptoms high glucose levels discount januvia 100 mg buy line, the inflammation can be classified as acute blood glucose record purchase januvia without prescription, 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. The historic term hermaphroditism (derived from the names of two Greek gods, one male [Hermes] and one female [Aphrodite]) has been replaced by three more specific terms: · True hermaphroditism is diagnosed when the gonads are both male and female. 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. The superficial layers that do not receive enough blood become ischemic and necrotize. The functional disturbances are more common than the organic lesions, which are rare. For example, anovulation is common in pubertal girls in whom the normal cycle of the hypothalamus has not yet been established. Psychological factors, such as anxiety induced by examination or imagined pregnancy, can also cause anovulation. Anorexia nervosa and bulimia are typically associated with anovulation, and it may persist for a long time. It is important to remember that the ovary contains a finite number of oocytes, and once all the oocytes have been exhausted, at the time of menopause anovulation will ensue. Endogenous hyperestrinism reflects ovarian dysfunction or, less commonly, may be related to estrogen-producing tumors. Complex hyperplasia is classified by pathologists into two categories: complex hyperplasia without atypia (deviation from the normal state) and complex hyperplasia with atypia. Simple hyperplasia is an innocuous change, whereas the other forms of hyperplasia should be considered as possible precursors of cancer. Approximately 2% to 3% of patients with complex hyperplasia, without atypia, develop cancer. Statistics show that as many as 25% to 30% of the women who have complex hyperplasia with atypia develop endometrial adenocarcinoma. These women should be observed carefully, and those who have completed their reproductive function may choose to have their uterus removed prophylactically. Neoplasia and Related Disorders Tumors of the female tract are common and are an important cause of morbidity in women. The following facts illustrate the magnitude of this problem: · Gynecologic malignant lesions account for 15% of all malignant tumors and for 10% of all cancer deaths in women. It has been estimated that 25% of women older than 30 years have uterine leiomyomas. Ovarian cysts are found in two thirds of women of reproductive age, although most of these are nonneoplastic, small, and clinically insignificant. Carcinoma of the Vulva Carcinoma of the vulva is relatively rare, accounting for 3% of all gynecologic cancers. Patients with tumors that have spread to the lymph nodes have a less favorable prognosis. Treatment includes surgical resection of the tumor and sometimes of the entire vulva (vulvectomy), supplemented by radiation therapy and chemotherapy in advanced cases. Carcinoma of the Vagina Carcinoma of the vagina is relatively uncommon, accounting for only 2% of all gynecologic cancers. From most aspects, it resembles vulvar cancer in that it is a disease of older women and is histologically a squamous cell carcinoma. Data rounded up to the nearest hundred from the original report from the American Cancer Society, 2010. Carcinoma of the Cervix Once the most common form of gynecologic cancers, carcinoma of the cervix accounts for approximately 20% of all malignant tumors of the female reproductive tract. Nevertheless, it is still ranked as the eighth major cancer-related cause of death, and it causes more deaths than carcinoma of the body of the uterus, vagina, and vulva combined. The reduced mortality achieved over the past 50 years in North America and Europe is directly related to early detection of cervical cancer and related preneoplastic conditions by routine use of Pap smears by gynecologists. These published health data confirm that the incidence of cervical cancer has not decreased in North America and Europe, but that detection in the early stages has improved. Cervical carcinoma is most common in women with the following characteristics: · Began having sexual intercourse at an early age · Have had multiple sexual partners. Hence, it is important to perform viral studies and determine the type of virus causing the infection. Clinically, many of these precursors of cancer present as leukoplakia or erythroplakia. This vaccine can be given to both boys and girls in their teens, and scientists hope it will reduce the incidence of cervical carcinoma. As mentioned earlier, the outer surface of the cervix (exocervix) is covered with squamous epithelium, whereas the endocervical canal is lined by columnar epithelium. Most cervical carcinomas originate in this zone, which is marked by intense cell proliferation. It should be noted that this zone may widen after cervical trauma, which typically occurs during vaginal delivery of a baby when the cervix ruptures to allow birth. One could assume that women who have had numerous vaginal deliveries or those who have genitourinary infections because of promiscuity have an altered transformation zone. The transformed cells do not respond to normal regulatory stimuli operating in the tissue. They do not mature as the normal cervical cells do but remain undifferentiated and proliferate uncontrollably. The lack of normal maturation of squamous epithelium can be histologically recognized as dysplasia. Carcinoma cells may cross the basal membrane and invade the underlying connective tissue stroma. Such tumors can further spread locally or can invade lymphatic vessels and blood vessels, and metastasize to distant sites. Because the abnormal cells are shed into the vagina and can be scraped by the gynecologist, the diagnosis can also be made on the basis of cytologic studies. The diagram shows the progression from mild to severe dysplasia and to invasive cancer. Only time will show if the molecular biology test is as efficient as the Pap test. In North America the Pap test is still considered to be the most efficient way for detecting preneoplastic and neoplastic cervical lesions. Once an invasive tumor develops, it may take several forms, classified as exophytic or endophytic, depending on whether the predominant direction of growth is inside or outside the cervix. Exophytic tumors protrude into the vagina and are cauliflower-like fungating masses. Invasive tumors, called endophytic ("inside growing"), usually present as craterlike ulcerations.

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