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STUDENT DIGITAL NEWSLETTER ALAGAPPA INSTITUTIONS |
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Brindusa Truta, M.A.S., M.D.
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Women receiving warfarin should be advised against pregnancy because of this risk blood sugar 400 and above buy 500 mg metformin fast delivery. If pregnancy develops diabetes diet related quality of life generic metformin 850 mg with mastercard, full-dose subcutaneous heparin should be substituted for warfarin diabetic diet and oatmeal order metformin 850mg otc. Poisoning with warfarin has occurred in children ingesting coumarin-type rat poisons diabetes symptoms upset stomach buy metformin 500 mg without a prescription. Rarely diabetes mellitus and infection metformin 850mg, areas of skin necrosis are seen diabetic diet low carb high protein generic 500mg metformin with visa, particularly after large loading doses of warfarin; these lesions are associated with thrombi in the microcirculation. In a proportion of these patients, early depletion of protein C and protein S by warfarin in the absence of heparin coverage may explain this thrombotic complication. Reviews heparin and low-molecular-weight heparin mechanisms of action and current therapeutic use. Combining aspirin with warfarin reduces thromboembolic events more effectively than warfarin alone, without significantly increasing bleeding complications in patients with mechanical valves. Cancer describes a class of diseases characterized by the uncontrolled growth of aberrant cells. Cancers kill by the destructive invasion of normal organs through direct extension and spread to distant sites through the blood, lymph, or serosal surfaces. The abnormal clinical behavior of cancer cells is often mirrored by biologic aberrations such as genetic mutations, chromosomal translocations, expression of fetal or other discordant ontologic characteristics, and the inappropriate secretion of hormones or enzymes. All cancers invade or metastasize, but each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment, and study. Cancer is the second most deadly disease and is expected to surpass heart disease early in the 21st century to top that nefarious list (see Chapter 193). Over the past half century, the frequency of most cancers has been stable, but some dramatic changes have taken place. Steady declines in stomach and uterine cancer have occurred, the latter undoubtedly due to routine cytologic screening for cervical cancer. The cause of the decline in stomach cancer is unclear but may in part relate to increased use of antibiotics and their effect on chronic Helicobacter pylori infection. The most striking change has been the increases in lung cancer in both men and women, undoubtedly related to smoking. The overall mortality, particularly for those younger than age 65, has declined, primarily due to more effective therapy for cancers of fetal and hematopoietic origin that occur in the younger population. A broad array of agents can cause or directly contribute to a sequence of events or sensitize cells in such a way that cancer develops (see Chapter 190). The final common pathway in virtually every instance is a cellular genetic mutation that converts a well-behaved cellular citizen of the body into a destructive renegade that is unresponsive to the ordinary checks and balances of a normal community of cells. Promoters (oncogenes) and suppressors (like the retinoblastoma or p53 gene) play a central role in many cases (see Chapter 191). Chemicals such as benzene and nitrosamines, physical agents such as gamma and ultraviolet radiation, and biologic agents such as the Epstein-Barr and hepatitis viruses contribute to carcinogenesis under certain circumstances. Evidence exists to link dietary factors to carcinogenesis; although not as clear as one would like, the evidence is strong enough to recommend diets low in fat and high in fiber. A sensible diet is based on grains, vegetables, and fruits, with smaller than the current average proportions of fat. Inherited susceptibilities are becoming more evident and probably play a key role in a significant number of cancers of the breast and colon. Down syndrome and the Li-Fraumeni syndrome are well-known harbingers of a substantial risk for developing cancer. The single most important carcinogen in the United States and Europe is tobacco (see Chapter 13), because it causes or contributes to the development of about one third of all cancers: primarily lung, esophageal, head and neck, and bladder. Less well appreciated is the contribution tobacco may make to causing breast, colon, and gastric cancer. Tobacco-related cancer is also important because it is preventable by the obvious, inexpensive, and 100% effective means of abstention. Although the total number of smokers in the United States has declined, women smoke more than ever, adolescents continue to view smoking as socially chic, and the number of smokers in Asia and developing countries is growing at an alarming rate. When prevention of cancer is not possible because effective means are lacking, early detection is the next best strategy to reduce cancer mortality. As a general rule, the smaller and more confined the tumor, the more likely therapy will result in permanent cure. This approach has been most successful for directly accessible tumors that have an early malignant or premalignant state. Examples include Papanicolaou smears and surgical conization for cancer of the uterine cervix, physical removal of early skin cancer, and colonoscopic removal of colorectal polyps. However, it is not clear that all in situ breast and prostate cancers will become invasive and fatal, so there is some risk of overtreatment, particularly for prostate cancer. An even more exciting development in this effort has been the emergence of genetic screening and counseling of families at high risk for developing cancer. Individuals at risk are identified largely by analysis of family pedigrees, and the increasing availability of the revolutionary tools of molecular biology can identify specific genetic mutations (see Chapter 191). It is certain that many such genes will be identified, focusing the cancer screening and early detection efforts more efficiently and productively on high-risk populations (see Chapter 190). Although it is impossible to know the specific details of early in vivo tumor growth and the efficiency of tumor cell renewal of human cancer, clinical and laboratory observations have provided a reasonable conceptual framework. This framework should be used with caution, however, because it is certain that the intrinsic factors that control tumor growth and propagation are far more complex, episodic, and heterogeneous than currently known, even within a single tumor mass. Furthermore, the stromal environment and neovascularization of tumors have become more central to our understanding of this process than heretofore. A tumor reaches the size of clinical detectability when it contains about 109 cells, weighing about 1 g and occupying a volume of about 1 mL. Below 109 cells, the tumor is usually undetectable, but it has already undergone at least 30 doublings, and only 10 further doublings will produce the 1 kg of tumor. This exercise illustrates how much has already occurred, with all the opportunities for the cancer to undergo advantageous mutation and metastasis, before clinical detection. Once the tumor has grown into the clinically evident range, it tends to grow progressively slower with increasing size. This deceleration of growth probably occurs because the tumor outgrows its blood supply, reaches anatomic Figure 189-1 A schematic representation of the phases of growth of a cancer. After a period of inapparency (lag phase), growth tends to be logarithmic, followed by deceleration due to inadequate nutrients, competitive inhibition among cells, or a lack of neovascularization. Thus, cancers probably grow much like bacteria after inoculation into a favorable medium. Growth then slows when new cell production and cell death are nearly equal, with the latter phase in culture due to crowding and inadequate nutrients. Of course, in bacteria as well as cancers, the specific growth characteristics differ among types as well as within types that have developed subpopulations of mutant clones. Also, after gross surgical removal, residual cancer cells may grow more rapidly and be more sensitive to subsequent ("adjuvant") chemotherapy. The sensitivity or resistance to chemotherapy or irradiation, however, probably has as much or more to do with the specific biochemical and metabolic features of the cancer cell as with its growth characteristics (see Chapter 198). From a diverse set of orphan diseases usually managed by surgeons alone and viewed with despair by most physicians, it has become a complex and exciting discipline that draws its strength from the essential partnership of specialists in medicine, surgery, pediatrics, pathology, radiation oncology, diagnostic imaging, psychiatry, and others. This remarkable evolution can be credited to therapeutic successes and biologic advances that could not be imagined in the early 1950s. Oncology has pointed the way to an understanding of the biologic variability of cancer and the success that is possible with a coordinated multimodal approach to therapy. Any physician who seriously and expertly assumes responsibility for the management of patients with cancer should have three sets of goals: therapeutic, human, and scientific. The initial therapeutic goal is to cure patients and return them to a normal place in society. This goal, which should be attempted in virtually all cancers, even when the likelihood of cure is small, requires an attitude of reasonable hope and determination as well as a willingness to attempt difficult, dangerous, and sometimes daring approaches to fundamentally resistant diseases. If, after a reasonable attempt, permanent cure is not possible, the physician must not abandon the patient but rather should aim for a secondary goal-a long, qualitatively satisfactory remission. If and when this second goal is no longer possible, the tertiary level of therapeutic intent is to obtain a remission of any kind and duration; however, at this stage and later, one is less willing to expose the patient to the possibility of serious side effects or long hospitalization. When the possibility of remission of any type becomes remote, the fourth goal is to control the disease and symptoms by the judicious use of palliative therapeutic measures. The objective in this final stage is terminal comfort care, which is always difficult because it requires the admission that specific therapy is no longer of any value. Instead of blood transfusions, antibiotics, or chemotherapeutic agents, the physician must use pain medications, sedation, psychosocial support, and other comfort measures with the thought of returning the patient to the home or another appropriate setting and to the support of family. The human goals in oncology are inextricably linked with the therapeutic and scientific goals. Physicians, nurses, and other health care providers must be sensitive to the particular needs of the patient and family and understand the social environment from which they came and to which they must return. The physician must help patients maintain their dignity, understand their weaknesses, and refuse to allow any frustration, animosity, or excessive friendship to develop and threaten good judgment and the best interests of the patient. The use of scientific methods in oncology is only in its adolescence, and definitive treatment has been established for only a small proportion of the circumstances and types of cancers that can arise. Systematic protocol studies yield useful information about a new drug, a novel regimen, or a biologic feature. Physicians who manage a small number of patients per year cannot possibly have the background and support necessary to treat these complex diseases adequately. This task is best left to specialists who participate in active scientific programs and have the resources to deliver optimal clinical care. It is also important to understand the limitations of science; at times, the best option is no specific anticancer treatment at all. The first diagnostic principle is that adequate tissue must be obtained from the tumor to establish the specific diagnosis and subtype of cancer. The rare exceptions are instances in which a biopsy might be life threatening and the anatomic location is virtually pathognomonic of a specific histology; two notable examples are brain tumors and anterior mediastinal tumors that compress the trachea and blood vessels. In the latter situation, often due to a lymphoma, corticosteroids may reduce the tumor size and relieve symptoms before a biopsy is attempted. More often, an adequate sample must be obtained before therapy is started unless complete surgical excision is definitively diagnostic and therapeutic. Because management of each type and subtype of cancer is often distinctive, every effort must be made to obtain appropriate samples, even if therapy is delayed for a short time. A specific diagnosis is seldom a problem in the leukemias because bone marrow aspiration usually affords a ready answer; solid tumors may present greater difficulty. Cancer diagnosis also requires an understanding of paraneoplastic syndromes (see Chapter 195), endocrine (see Chapter 194) and cutaneous manifestations of cancer (see Chapter 196), and oncologic emergencies (see Chapter 199). In the leukemias, this goal can be accomplished readily by physical examination, routine laboratory tests, chest roentgenography, and examination of cerebrospinal fluid. With solid tumors, determination of the extent of the disease, that is, the stage of the tumor, often involves major surgery and an extensive examination that includes diagnostic imaging. A coordinated approach involving the surgeon and pathologist is crucial to determine the extent of tumor invasion; without this approach, one may lack essential information for planning treatment and for judging its success. Failure to detect a tumor that has extended to regional lymph nodes can lead to undertreatment and a false impression that the local treatment, whether surgery or radiation therapy, was adequate. Generic staging systems (Table 189-2) can be supplemented by detailed and specific staging systems that have been developed for most cancers to recognize peculiar pathogenetic features, modes of spread, and potential curability. In addition, modern oncology demands an extensive biologic classification of leukemias and solid tumors, often requiring sophisticated scientific approaches not available a few years ago: monoclonal antibodies to determine the phenotype of lymphomas and leukemias; light and electron microscopy with special stains to determine the presence of glycogen, enzymes, or other substances that help to classify solid tumors; chromosomal analysis and modern molecular probes that identify unique characteristics of a disease; and responsible oncogenes, suppressor genes, and familial genes (see Chapter 191). Has extended beyond regional site of origin, crossing several tissue planes or extending more distantly via lymphatics or blood. Also may be 3 confined to an organ or region, but be unresectable because of anatomic extent or location. This stage is used rather than stage 2 or stage 4 depending on the usefulness of local and systemic treatment modalities and the likelihood of cure for that specific cancer. All pertinent information-medical, developmental, and social-must be sought before treatment is planned. The second step is to know the tumor: its usual behavior, usual rate of growth, mode of spread, whether it is local or systemic, and any features that may provide prognostic or therapeutic leads. Third, the physician must know the available therapies: not only the therapeutic modalities such as chemotherapy, radiation therapy, and surgery, but also the skills and limitations of colleagues. Finally, the physician must know his or her own skills, experience, objectivity, and limitations. Caring for patients with cancer is not easy; the physician must be prepared for disappointment as well as success. Clarity of intent-whether curative, palliative, or supportive-will avoid confusion of approach and method. Treatment protocols, either research or "standard of care" regimens, are important tools that allow strategies to be planned before immediate decisions become necessary. Protocols are also more likely to provide useful conclusions from a study or experience, because a scientific question or a uniform approach has been formulated and data have been collected in a systematic manner. The planned therapy may require adjustment if complications develop after treatment has begun. Although many of these adjustments can be anticipated and specified in the protocol, not every circumstance can be foreseen. A protocol also is intended to provide practical information that will lead to improved treatment of subsequent patients.
Imaging studies may also detect space-occupying lesions or occlusion of major blood vessels blood sugar 10 quality 850 mg metformin. Blood serology and toxicologic screens are helpful in identifying patients with suspected viral hepatitis or poisoning ketonuria diabetes mellitus type 2 discount 500 mg metformin otc. Liver biopsy may be necessary to document the characteristic histologic patterns in patients with vaso-occlusive diseases diabetes insipidus research generic 850mg metformin with visa, graft-versus-host disease diabetes signs early buy metformin 850mg, and other less common causes of acute liver failure diabetic diet breakdown trusted 500 mg metformin. However blood glucose jobs buy metformin 850mg low price, biopsy is very risky in patients with acute liver failure because they generally have a serious coagulopathy. Patients with acute liver failure usually require care in an intensive-care unit, especially when they develop stage 2 to 3 hepatic encephalopathy, serious bleeding, sepsis, or recurrent bouts of hypoglycemia; most such patients require a central venous pressure monitor, arterial line, urinary catheter, and nasogastric tube. It is excreted in the urine, so urine output and plasma osmolality must be monitored carefully. Regular determination of peripheral blood glucose (every 4-6 hours) is recommended. Coagulopathy is common in patients with acute liver failure due to decreased platelet count and inadequate synthesis of clotting factors. Patients with clinically significant bleeding and those who need invasive procedures. Orthotopic liver transplantation (see Chapter 155) offers a definitive treatment for acute liver failure. However, this surgery is an option only for highly selected patients with hepatic failure (Table 154-2). Despite advances in medical therapy and intensive care, the survival rate of patients whose acute liver failure progresses to stages 3 to 4 of hepatic encephalopathy is still poor (10-40%). Survival depends on the age, time between the onset of hepatic failure and development of hepatic encephalopathy, the prothrombin time, and, most importantly, the cause of acute liver failure. With the introduction of orthotopic liver transplantation, survival rates have increased to 60 to 80%. Chronic liver failure, which is a progressive decline of multiple liver functions in patients with established chronic liver disease, is frequently associated with intermittent episodes of hepatic encephalopathy. Hepatic encephalopathy can occur in cirrhosis of any cause and typically signifies significant portal hypertension and end stage of chronic liver disease. It is important to distinguish reversible precipitating factors from the inexorable progression of chronic liver disease. The exact prevalence of chronic liver failure is unknown, but chronic liver failure is much more common than acute liver failure and probably accounts for most liver-related deaths. Loss of more than 70% of functioning liver cells results in the covert redistribution of splanchnic blood flow, an energy-deficient state, and the failure of multiple secondary organs. Chronic liver injury eventually results in the death of hepatocytes followed by the accumulation of fibrous tissue. The fibrous tissue distorts the architecture of the organ, causing portal hypertension and the development of portosystemic shunting. Clinical manifestations of chronic liver failure evolve over many months to years and eventually include recurrent episodes of hepatic encephalopathy, progressive metabolic derangements (hypoalbuminemia, osteodystrophy, hyponatremia, acidosis, hyperbilirubinemia, glucose intolerance, and hypoglycemia), worsening of portal hypertension and its life-threatening complications (variceal bleeding, ascites, spontaneous bacterial peritonitis), severe pruritus, hematologic abnormalities (coagulopathy, leukopenia, thrombocytopenia, anemia, folate deficiency, hemoptysis), altered metabolism of endogenous hormones and drugs, and the development of functional renal failure. The Child-Pugh classification, which was developed to assess the severity of chronic liver failure, is based on five equally weighted clinical-laboratory parameters (encephalopathy, ascites, serum albumin, serum bilirubin, nutritional status) with a maximal possible score of 15 (Table 154-3). Patients with compensated chronic liver failure are Child-Pugh A (score 1-5), whereas those with advanced cirrhosis are Child-Pugh C (score 11-15). Treatment of chronic liver failure includes identification and correction of potentially reversible factors that may precipitate liver failure in patients with chronic liver disease, such as sepsis, gastrointestinal bleeding, heavy loads of dietary protein, and un-necessary medications. Hepatic encephalopathy (see earlier) and other complications of portal hypertension (see Chapter 153) must be treated appropriately, and orthotopic liver transplantation should be considered (see Chapter 155). Patients with recurrent hepatic encephalopathy, refractory ascites, hepatorenal syndrome, and/or recurrent variceal bleeding should be considered for possible liver transplantation (see Chapter 155). Currently, absolute contraindications for orthotopic liver transplantation include extrahepatic hepatobiliary malignancy, active sepsis outside the hepatobiliary system, and cardiopulmonary failure. Six-month survival after orthotopic liver transplantation in clinically stable patients with chronic liver failure is as high as 90%; for patients in intensive-care units at the time of transplantation, however, 6-month survival is only about 65%. Widespread administration of hepatitis B vaccine will significantly decrease the incidence of hepatitis B, which is one of the major causes of chronic liver failure worldwide. New therapeutic regimens for the hepatitis C virus may significantly retard development of end-stage liver disease. A review of the main principles of treatment and therapy of specific types of hepatic encephalopathy. Roberts In the last 30 years, liver transplantation has moved from an experimental procedure to accepted medical therapy for patients with acute or chronic liver failure. About 4500 liver transplantations are performed annually in the United States, and the 1-year survival rate following liver transplantation is now 85 to 90% or better. The procedure is currently underwritten by most states, private insurance companies, and Medicare. Although liver transplantation is still an expensive procedure, the cost has decreased such that it now offers a better outcome and lower cost than many treatments for acute and chronic liver failure. The improvement in patient and graft survival following liver transplantation has resulted from changes in patient selection, operative techniques, and immunosuppressive regimens. As newer immnosuppressive medications become available, it appears likely that the morbidity and mortality rates and costs of liver transplantation will continue to decrease. With improvement in survival rate and with more patients undergoing liver transplantation, availability of donor organs has become the rate-limiting factor. For example, an episode of spontaneous bacterial peritonitis suggests a 1-year survival rate of approximately 50%. It is also apparent that patients with stable cirrhosis, without decompensation or complications, are probably not well served by transplantation. Liver transplantation has also altered the use of many of the procedures previously performed for complications of chronic liver disease, such as portal-systemic shunting for recurrent variceal hemorrhage, peritineovenous shunting for intractable ascites, and radical biliary tract surgery for patients with sclerosing cholangitis. These operations, which were once the only option for the patient with liver disease, are now assuming a secondary role. For example, portosystemic shunting has a poor outcome in patients with severe liver dysfunction, but these same patients can do well after liver transplantation. Viral hepatitis is the most common cause of fulminant liver failure; other causes include toxins. These patients are at high risk for development of cerebral edema followed by brain herniation if not properly managed. Pre-transplantation management includes elevation of the head, careful monitoring of intracranial pressure, and aggressive therapy using mannitol, and sometimes even hyperventilation with barbiturate coma for increased intracranial pressure. Transplantation is performed for a wide variety of causes of liver failure, with hepatitis C now the most common indication (Table 155-1). Contraindications to liver transplantation include systemic sepsis, active substance abuse (including ethanol), extrahepatic malignant disease, and advanced cardiopulmonary disease. Transplantation is generally not performed for cholangiocarcinoma because the survival rate of these patients following transplantation is poor. The fibrolamellar variant of hepatocellular carcinoma carries a much better prognosis, and patients with cirrhosis and small hepatomas (3 to 5 cm) may have a survival rate similar to that of patients without hepatoma. Transplantation may be preferred to resection in these patients because of the high rate of recurrence and liver failure with resection. End-stage liver disease caused by chronic ethanol abuse has been increasingly recognized as an appropriate indication for transplantation; results in these patients are the same as those for patients with chronic liver failure of other causes. Recidivism following transplantation is a significant problem in these patients in the long term. To justify the use of organs in these patients, better criteria must be found to predict recidivism. The transplantation of patients with hepatitis B, initially complicated by the recurrence of the viral infection with a high rate of graft failure and death, now has much better outcome because antiviral strategies, such as lamivudine and the hepatitis B immune globulin, have markedly decreased the risk of recurrent disease. Transplantation for hepatitis C is also complicated by recurrent viral infection; the 5-year survival rate in these patients does not appear to be significantly altered, but the long-term outlook is unclear. In general, donors for large non-O recipients tend to be more available than for small O recipients. This discrepancy reflects a higher accident rate for young adult males and the use of type O livers in recipients of other blood types. Priority for recipients is based on criteria that include the level of care that potential recipients currently require. Those in intensive care are assigned the highest priority; those at home, the lowest. Because of the continuing shortage of organs for transplantation, there has been an interest in using portions of the liver from living donors and dividing cadaveric organs between two recipients. Living donor transplantation was first used in the situation in which a parent would donate the left lateral segment of the liver to a child. With the rapid acceptance of this technique for pediatric transplantation, interest turned to living-related transplantations between adults. Although these programs are in the early stages of development, it appears either the full left lobe or the full right lobe can provide adequate liver volume to the recipient. The division of a donor liver between the two recipients (split liver transplantation) has a similar rationale. In auxiliary liver transplantation, the left lateral segment of the donor liver replaces the native left lateral segment, leaving the bulk of the native liver in place. This procedure is usually used in situations in which the recipient liver may be expected to recover, such as fulminant hepatic failure related to a toxin; the donor liver segment serves as a bridge until the patient recovers. Early post-operative hepatic artery thrombosis requires re-transplantation because it usually results in necrosis of the liver and/or biliary tree. Portal vein thrombosis can be asymptomatic or can present clinically as portal hypertension. Biliary tract complications usually appear as strictures within the biliary tree or as bile leaking from the biliary reconstruction. In the post-transplantation period, renal failure may result from preexisting renal dysfunction, intraoperative renal ischemia, postoperative cyclosporine toxicity, or a combination of these factors. The average patient experiences at least one episode of bacterial infection and has a 40 to 50% chance of development of a fungal or viral infection following liver transplantation. As one of the major complications of immunosuppression is infections, use of prophylactic anti-infective agents improves the therapeutic index of the immunosuppressive agents. Bacterial infections in the early post-transplantation period include biliary infections, intra-abdominal abscesses, pneumonia, or infections related to central venous catheters. Fungal infections, including systemic candidiasis (see Chapter 400), usually occur during the early transplantation period and are related to intravascular catheters or intra-abdominal candidal abscesses. Later, other opportunistic fungal infections, such as aspergillosis (see Chapter 401), predominate. Viral infections following liver transplantation are most often caused by herpesviruses (Chapter 385). Mucocutaneous herpes simplex and varicella-zoster infections can follow transplantation, and prophylactic or therapeutic acyclovir is effective in preventing or treating these infections. Pneumocystis carinii infection (Chapter 402) was previously a problem in all forms of solid organ transplantation, but with prophylactic use of trimethoprim-sulfamethoxazole, morbidity and mortality rates related to this agent have been eliminated in transplantation recipients. Both drugs are usually started in the early post-transplantation period and are continued indefinitely. Both are metabolized by the cytochrome P-450-dependent mono-oxygenases, and therefore systemic levels can be decreased by drugs that induce this pathway, such as rifampin, barbiturates, or phenytoin. Both drugs appear to increase the risk of post-transplantation lymphoproliferative disorders. Prednisone is generally used in combination with cyclosporine or tacrolimus to prevent rejection. In the liver transplantation recipient, a major issue is the exacerbation of the pre-transplantation bone loss that is associated with cholestatic liver disease by post-transplantation corticosteroids; significant disability may occur in the early post-transplantation period. Bisphosphonates may prove to be helpful in preventing steroid-induced bone disease in the transplantation recipient (Chapter 257). Azathioprine, a third agent used for post-transplantation immunosuppression, blocks proliferation of white blood cells and thereby decreases the proliferative or amplification response of the rejection process. Azathioprine likely will be replaced with the more powerful immunosuppressive agent mycophenolate mofetil, which inhibits synthesis of guanine nucleotides and appears to be more selective for lymphocytes. Randomized trials of mycophenolate mofetil have resulted in a 50% reduction in the incidence of acute rejection in recipients of renal transplantation; a similar reduction may be expected in liver transplantation recipients. Studies in the renal transplantation population have demonstrated a 50% decrease in the rate of acute rejection with minimal toxicity. The best long-term immunosuppressive regimen for the liver transplantation patient is unclear. With careful monitoring, prednisone 819 probably can be safely withdrawn in most patients in the first year. Histologic features include periportal infiltrate, bile duct epithelial damage, and endotheliitis. Treatment for rejection includes use of additional steroids or antilymphocyte preparations. A change from cyclosporine- to tacrolimus-based immunosuppression may result in an improved rate of salvage from ongoing rejection. This report describes the appropriateness of listing patients for transplantation on the basis of current knowledge of the natural-history of liver disease. The appropriate diagnostic possibilities are best considered by determining the clinical setting in which the tumor is discovered (Table 156-1). Benign tumors are frequently found incidentally or present with local symptoms due to mass effect and may be influenced by gender and the use of oral contraceptives. Primary malignant tumors of the liver usually present in the setting of known chronic liver disease and may be associated with a deterioration in hepatic function.
For the majority of patients with solid tumors diabetes mellitus type 2 drugs generic metformin 850mg fast delivery, spinal cord compression can be palliated diabetes mellitus nursing interventions buy metformin 850mg low cost, but curative therapy is not available (exceptions are patients with lymphoma or testicular cancer) nephrogenic diabetes insipidus quizlet metformin 850 mg with visa. Headache diabetes diet log book purchase metformin 500 mg visa, altered mental status diabetes type 2 family history 500 mg metformin amex, seizures diabetes type 2 vegetables buy metformin 850mg online, or a focal neurologic examination in cancer patients may signal intracranial metastases (most commonly melanoma and cancers of the lung and breast). A careful history and physical examination and laboratory evaluation are critical and should guide decisions for further evaluation. If no mass lesion is demonstrable, leptomeningeal carcinomatosis should be considered as the cause of neurologic signs and symptoms and sought by examination of cerebrospinal fluid. If signs of increased intracranial pressure exist with or without impending herniation, intravenous dexamethasone (16 mg every 6 hours) should be administered to lessen cerebral edema. Status epilepticus requires immediate-acting drugs, such as benzodiazepines, and close attention to respiratory status. Seizures, other than status epilepticus, caused by intracranial metastasis are managed by phenytoin (oral loading dose 1 g in divided doses followed by 300 mg/day). Drug levels should be monitored, especially because accompanying dexamethasone therapy can accelerate the metabolism of phenytoin. Other than for seizures, the routine use of prophylactic phenytoin is not recommended for patients with intracranial metastases. For patients with controlled or no systemic disease and a solitary intracranial metastasis in a site not amenable to surgery, radiation to the site of disease at higher doses (4000-5000 cGy) is justified. By and large, a surgically accessible solitary lesion in a patient with controlled systemic disease merits surgical removal followed by postoperative radiation therapy. Patients with solid malignancies who present with brain metastases have limited life expectancies (median survival in the range of 6-12 months), but there is considerable variation among patients. Symptoms, which frequently worsen when the patient lies down or leans forward, may include fullness or stuffiness in the ears or nose, visual disturbances, facial swelling, shortness of breath, cough, chest pain, voice changes (hoarseness), dysphagia, headache, stupor, seizures, and syncope. Back pain may herald simultaneous spinal cord compression by a contiguously extending tumor. Immediate therapy is indicated for impending airway obstruction (stridor) or increased intracranial pressure (stupor, seizure), particularly in a thrombocytopenic patient. Sputum cytology, bone marrow, lymph node biopsy, thoracentesis, bronchoscopy, and thoracotomy may confirm the diagnosis. In most cases, radiation therapy remains the primary treatment, commonly using doses of 150 to 300 cGy per fraction to a total dose of 3000 to 5000 cGy. Cardiac tamponade in a cancer patient may have a non-cancerous cause, may be the first manifestation of malignancy, or may signify disease progression. Prompt diagnosis is necessary because tamponade is life threatening, but successful treatment improves survival. When fluid pressure within the pericardial sac approaches right atrial and ventricular diastolic pressure, cardiac tamponade occurs. As intrapericardial pressure increases, heart rate, myocardial contractility, and systemic resistance increases. If intrapericardial pressure increases rapidly, between 150 to 250 mL of fluid (normal volume <50 mL) may cause tamponade; if fluid accumulates slowly, however, more than 1 L may be accommodated without producing decompensation. Symptoms are non-specific and include shortness of breath, chest pain, cough, hoarseness, nausea, abdominal pain, hiccoughs, and anxiety. The chest radiograph may show an enlarged globular (water bottle) heart and possibly pleural effusions. Two-dimensional echocardiography (see Chapters 43 and 65) is the non-invasive, preferred diagnostic study that provides both anatomic and physiologic information. Pericardiocentesis is lifesaving: it provides fluid for diagnosis; and with insertion of a pigtail catheter, it permits measurement of the rate of fluid reaccumulation and the instillation of drugs for sclerosis. If fluid is hemorrhagic, a hematocrit lower than systemic and the absence of clot weigh against the fluid resulting from puncture of the myocardium. Once a malignancy has been established and intrapericardial pressures are reduced, there are several treatments available. Radiation therapy up to 40 Gy is highly successful (approaching 100%) in treating effusion caused by leukemias or lymphomas; however, radiation is not the preferred course of treatment for these patients because of the potential cardiac toxicity, and systemic chemotherapy is often preferred. The most common surgical approach 1077 Figure 199-2 Flow diagram for evaluation of cardiac tamponade in the cancer patient. However, patients with malignant pericardial tamponade (especially those with solid tumors) often have such a poor prognosis that surgical approaches are not pursued. After placement of a pigtail catheter, sclerosis of the pericardial space may be considered with various chemotherapeutic agents, radioisotopes, or doxycycline. Doxycycline is highly effective in sclerosing the pericardial space and eliminating fluid recurrence, but patients should be monitored during and immediately after sclerosis because many develop transient fevers, arrhythmias, or chest pain after treatment. The most common causes (bronchitis, tuberculosis, fungal infections, lung abscess, bronchiectasis, and bronchial adenoma) of hemoptysis are not neoplastic; however, malignancies, especially of bronchogenic origin, are most common among older patients. Hemoptysis associated with respiratory compromise, major hemoptysis (200 mL in 24 hours) or massive hemoptysis (1000 mL in 24 hours) should be considered an emergency. The tempo of the bleeding should dictate the pace and aggressiveness of the intervention. The first intervention is to place the patient on his or her side with the bleeding lung down. Correction of coagulopathy and thrombocytopenia, repletion of blood volume, and determination of the site and cause of bleeding are undertaken simultaneously. Flexible bronchoscopy allows for better visualization and is the diagnostic procedure of choice to determine the site and cause of bleeding and to provide direct therapeutic intervention. Endobronchial tamponade using an 8-French Fogarty catheter is a temporizing procedure. In terms of definitive therapy, surgical resection should be considered if the patient can tolerate the procedure and if the site can be localized. For non-massive bleeding, radiation therapy can be delivered to sites of hemoptysis and is effective in up to 80% of patients. Airway obstruction by an intrinsic or extrinsic malignancy is an emergency, and management depends on the tempo of narrowing, its location, previous treatment, and the type of tumor (most commonly lung cancer). Corticosteroids should be given to lessen edema and, in the case of lymphomas, to begin treatment. Obstruction at or above the larynx and high tracheal region should first be relieved by tracheostomy with subsequent radiation therapy or surgery performed in a non-emergency setting. More distal obstructions can be treated with surgery, the placement of an expandable stent, and/or radiation therapy (external and/or brachytherapy). A stent placed under fluoroscopic guidance has become a preferred method of palliation. Restrictions to its use include lobar or segmental level lesions, extraluminal compression, total luminal obstruction, upper lobe lesions, and the presence of a tracheoesophageal fistula. Lung, particularly squamous cell, and breast cancers account for 40 to 60% of all cases. Malignancy-associated hypercalcemia is often caused by tumors that secrete a parathyroid-related protein that causes increased osteoclastic activity and results in increased bone and renal tubular calcium reabsorption (see Chapter 194). Likewise, osteolytic metastases can act directly on bone to cause calcium resorption or can secrete factors that result in bone resorption or activation of osteoclasts. Approximately 45% of calcium is ionized (non-protein bound), and total calcium levels must be corrected for changes in serum albumin concentration. In patients with symptomatic hypercalcemia, laboratory values usually show an elevated serum calcium, commonly above 12 mg/dL. The clinical manifestations may be non-specific and depend in part on the general metabolic condition and associated illnesses of the patient, as well as on the degree and rapidity of calcium elevation. Symptoms include polyuria, nocturia, polydipsia, anorexia, nausea, vomiting, abdominal pain, constipation, fatigue, lethargy, confusion, psychosis, agitation, stupor, obtundation, and coma. For patients who are symptomatic or have serum calcium levels above 13 mg/dL, treatment should be immediate and aggressive. Because of the reversible defects of renal tubular absorption and subsequent fluid loss coupled with decreased oral intake, the patient is invariably volume depleted. Volume repletion with normal saline at a rate of 200 to 300 mL/hour will result in calciuresis. Once rehydration is accomplished, urinary output should be maintained at 100 to 200 mL/hour. Electrolytes, including magnesium, should be checked frequently and, when necessary, repleted. Once the patient is initially stabilized, the optimal treatment becomes therapy for the underlying malignancy. Steroids can be effective in reducing hypercalcemia in multiple myeloma, lymphoma, and occasionally breast cancer. The bisphosphonates, the most commonly used agents, bind to hydroxyapatite crystals and inhibit their dissolution. These drugs should be administered only after the patient has been hydrated and adequate urine output has been established. Two bisphosphonates, etidronate and pamidronate, are now available and are the treatments of choice for malignancy-associated hypercalcemia in the United States. Pamidronate is administered in a single dose of 60 to 90 mg by slow intravenous infusion over 24 hours. The bisphosphonates will reduce serum calcium levels to the normal range in at least 60% of patients. These compounds are very well tolerated, although a transient temperature elevation may be observed 24 to 48 hours after administration. Caution should be exercised if administration is planned for patients with renal insufficiency. Intravenous plicamycin (previously known as mithramycin) (10 to 25 mug/kg over a period of 4-6 hours) may be given every 48 hours for up to three doses. After the initial course, plicamycin may be administered up to twice weekly to maintain normocalcemia. The use of plicamycin to treat hypercalcemia has declined because of concern over toxicities that include hypotension, hepatic and renal dysfunction, and bone marrow suppression, especially thrombocytopenia. Patients being treated with any of these agents should be observed closely for the development of hypocalcemia. Tumor lysis syndrome is a metabolic emergency that can be anticipated and prevented. Rapid tumor lysis is usually encountered after initiation of chemotherapy for rapidly proliferating malignancies such as high-grade lymphomas or acute leukemias. The syndrome can occur within 48 hours after arterial embolization of large tumors within the liver. Tumor lysis syndrome causes rapid and severe metabolic changes, including hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia. Hyperuricemia or hyperphosphatemia can cause renal failure secondary to uric acid or calcium phosphate crystallization in the tubules. Hypocalcemia caused by precipitation of calcium phosphate and lowered calcitriol levels can result in neuromuscular irritability, tetany, and obtundation. Hyperkalemia can be sufficiently severe to cause cardiac arrhythmias and sudden death. Treatment begins with identification of the patient at risk and prevention of the metabolic and end-organ changes. If a patient is likely to develop rapid tumor lysis associated with chemotherapy, hospital admission and initiation of measures to circumvent the syndrome are necessary. Volume status should be assessed and electrolytes, blood urea nitrogen, creatinine, uric acid, phosphorus, and calcium serum levels should be obtained before beginning chemotherapy. If possible, intravenous hydration should begin before the administration of chemotherapy. If patients present with evidence of tumor lysis syndrome before chemotherapy, every effort should be made to correct the metabolic abnormalities before starting the drugs. It is not always possible to postpone chemotherapy, however, and in such a setting, hemodialysis may be necessary. To avoid uric acid precipitation in the renal tubules, the urine should be alkalinized with 0. Urinary output between 100 to 200 mL/hour should be maintained; loop diuretics (furosemide) may be necessary to maintain urine flow. Allopurinol should be administered before chemotherapy (500 mg/m2 by mouth on day one and 300 mg on subsequent days) because it decreases uric acid production by inhibiting xanthine oxidase. It should be noted that calcium phosphate crystal formation theoretically can be increased by alkalinization of the urine (pH >8). However, practical considerations would dictate that excretion of uric acid is of primary importance and high volume urinary output, even when alkaline, will dilute calcium phosphate in the urine and lessen the danger of phosphate crystalluria. Rarely, calcitriol replacement will be necessary to obviate persistent hypocalcemia caused by low calcitriol levels. Hemodialysis should be initiated when volume status, urinary output, acid-base status, and electrolyte changes signal its necessity. Patients who have received or are receiving cyclophosphamide or ifosfamide may develop a life-threatening urologic emergency, hemorrhagic cystitis, caused by metabolites (chlorethylazeridine, chloroacetic acid, and acrolein) of either chemotherapy agent. Because metabolites are excreted by the kidneys, high concentrations can accumulate in the bladder. The bladder grossly appears hyperemic and edematous with areas of punctate hemorrhage; mucosal erosions and sloughing are common. The best management entails prevention by maintaining a high urinary output to decrease the concentration of metabolites in the bladder and by correcting any coagulation defect. Systemic use of sodium 2-mercaptoethanesulfonate (mesna) prevents mucosal irritation by detoxifying the metabolites within the bladder. Once hemorrhagic cystitis occurs, conservative management with care to ensure excellent urinary output is often adequate.
For this reason diabetes treatment centers metformin 500mg on line, most clinicians believe that therapeutic intervention is best delayed until after this period to lessen fetal risk in a patient desirous of preserving her pregnancy diabetes in dogs food recommendations order metformin 850 mg. After the embryonic period diabetes insipidus hypertension order 500 mg metformin with visa, fetal development is focused on organ growth and maturation managing your diabetes care buy 500mg metformin with amex. Certain basic physical and metabolic capabilities appear to be required to maintain extrauterine life diabetes mellitus type 2 etiology metformin 500mg otc. Subsequent fetal morbidity and mortality are linearly correlated with gestational age (Table 252-3) diabetes test blood sugar level order metformin 500mg without a prescription. Significant literature support the concept of maximizing in utero fetal life to decrease fetal morbidity, mortality, and long-term developmental delay. Infants weighing less than 1500 g at birth appear to suffer from significant long-term deficiencies in intelligence quotient, visual motor integration, and reading performance. It is important for parents to understand the potential ramifications of early delivery on their child and realize that survival can be associated with significant long-term morbidity. The risk-benefit profiles of each modality must be carefully considered before implementation. Direct radiation damage is believed to be a relatively minor component of these detrimental effects. This leads to free radical formation with subsequent chemical intracellular reaction and damage. Because the major component of cells is water this is believed to be the major mechanism of action. In vitro studies indicate that dividing cells specifically near the mitotic phase appear to be most vulnerable. At therapeutic doses, radiation does not significantly directly damage cellular microstructures, membranes, or metabolic processes. At doses of radiation below 100 cGy cellular death results from direct inhibition of cell division and is most prevalent in cells undergoing active division. The induction of radiation-induced mutations increases as a linear function of single doses up to 400 to 600 cGy. Because of the acute toxicity to cells, radiation is considered a weak teratogen as opposed to long-term birth defects. Clinical retrospective studies suggest some association of spontaneous abortion with early fetal irradiation. The fetal effects of radiation appear to be related to the gestational age at the time of exposure, as well as total dose received. Fetal exposure to radiation between ages 11 to 16 weeks appears to result in an increased risk of microcephaly and mental retardation. Exposure in the third trimester may be associated with longer-term developmental abnormalities (Tables 252-5 and 252-6). Direct ovarian exposures of 1000 cGy are associated with permanent sterilization in more than 90% of women. Lower doses also result in sterility but appear to be dependent on patient age and menstrual and reproductive history. Estimated fetal radiation exposures for standard radiographic procedures are listed in Table 252-7. A risk-benefit assessment must be undertaken before obtaining any radiographic evaluation in pregnancy. Mammography, as noted in Table 252-7, presents essentially no risk to the developing fetus. Therefore, its use as a diagnostic modality in the patient with a clinically suspicious breast lesion is recommended. Perhaps the most commonly employed imaging procedure in the pregnant patient is real-time ultrasonography. Its use in fetal anatomic observation and age determination has been well studied and is considered safe throughout the gestational period. It can also be an important instrument for evaluation of suspected renal, abdominal, pelvic hepatic, cardiac, vascular, and breast tissues. Hepatic ultrasound evaluation can detect occult liver metastasis with a sensitivity of 76% without fetal risk. Breast ultrasonography is a useful adjunct in characterizing breast lesion architecture noted on physical examination or mammography (see section on Breast Carcinoma in Pregnancy). Depending on the specific anatomic area to be treated, the fetal exposure can range from minimal to substantial (Table 252-8). Pelvic and abdominal radical procedures can be safely undertaken if appropriate planning is used. Surgical approaches to breast, ovarian, gastrointestinal, thyroid, melanoma, neurologic, and vulvar cancer have been well described, along with a multitude of benign surgical conditions. The current anesthetic agents in common use are believed to be without risk of fetal teratogenicity, and certainly minor procedures with local or regional analgesia (epidural, spinal, nerve block) are essentially without risk. Exclusive of cesarean section, it has been estimated that approximately 35,000 pregnant women will undergo some surgical procedure per year. An issue that should be considered is the critical nature of the uteroplacental unit that is susceptible to blood pressure changes and intavascular volume depletion. Major changes in blood flow to the placenta can lead to subsequent fetal hypoxia and potential precipitate neurologic sequelae. Diagnostic procedures including fine-needle aspiration, core biopsy, and/or surgical removal of suspicious lesions should rarely, if ever, be deferred due to pregnancy. As described earlier, a surgeon and anesthesiologist with appropriate understanding of uteroplacental dynamics should be sought to provide optimal care. Equally critical is the increased thrombogenic state associated with pregnancy as brought about by decreases in plasma fibrinolytic activity, increases in coagulation factors, as well as increased pelvic and lower extremity stasis. These factors combine for a five to six times increased risk of thromboembolic phenomena in the pregnant patient, and thus appropriate thromboprophylaxis should be undertaken. Current acceptable techniques include subcutaneous heparin 5000 units three times a day, low-molecular-weight heparin (enoxaparin, 40 mg/day), or inflatable compression stockings. The potential toxicity to the developing fetus must be considered when discussing potential treatment regimens in the pregnant patient. Unfortunately, controlled data on their effects on the developing fetus are limited. Most information has come from retrospective reviews as well as laboratory experiments on gravid animals. It appears that the first trimester is the most susceptible to deleterious chemotherapy influences. Overall, it appears that approximately 20% of fetuses exposed to cytotoxic agents in the first trimester will manifest major anomalies, as compared with 3% in an unexposed population. Chemotherapeutic agents primarily act by interrupting various portions of vital cell processes. This reproductive cell cycle is divided into five phases, each with specific actions leading to cell duplication (Table 252-9). Cancer cells are thought to replicate at a higher rate and therefore should be more susceptible to the cytotoxic or cytostatic effects of chemotherapy. Specific chemotherapeutic agents are often categorized by their interaction within the cell cycle and are traditionally classified into alkylating agents, antitumor antibiotics, antimetabolites, Vinca alkaloids, biologic response modifiers, hormones, and taxanes. Specific agents and their actions are listed in Table 252-10 (see Chapter 198) the timing of chemotherapy administration in relationship to anticipated delivery must be carefully planned to avoid delivery around the time of the maternal hematopoietic nadir. Hematopoietic suppression (anemia, leukopenia, and thrombocytopenia) may occur in the fetus as a result of transplacental passage of cytotoxic agents from the mother to the fetus, and the neonatology team should be advised accordingly. To date no reasonable experience of its use in pregnancy has been reported; therefore, its use cannot be advocated. Given its activity of microtubular assembly, concern for its effect on fetal development is significant. Breast-feeding is contraindicated during chemotherapeutic administration because these systemically administered antineoplastic agents may reach significant levels in breast milk. With the expanded knowledge of the natural history of this disease, the majority of patients with early cervical carcinoma can be managed with fetal preservation (if desired) without undo maternal morbidity or mortality. A routine part of initial prenatal evaluation should include a Papanicolaou (Pap) smear. This simple, inexpensive, and extremely effective screening procedure has significantly decreased the incidence of invasive squamous cell carcinoma of the cervix in the United States. In countries where this procedure is not widely practiced, cervical cancer remains one of the leading causes of death. The purported rationale of the Pap smear is as a screening, and not a diagnostic, procedure. The success of Pap smear screening has been in its ability to diagnose dysplastic lesions, thus allowing for simple ablative and curative measures. All clinicians who practice Pap smear screening should have an understanding of the Bethesda system of Pap smear interpretation as well as diagnostic and treatment algorithms. Cytologic finding of squamous intraepithelial lesions is most commonly evaluated with cervical colposcopy. Colposcopy during pregnancy is safe and effective and in the far majority (>90%) provides adequate diagnostic information. Similar in the non-pregnant patient, any area of gross abnormality, even in the presence of a normal Pap smear, requires biopsy. Given the knowledge of the natural history of cervical dysplasia, observational strategies have been developed to allow the pregnancy to continue without need for intervention. Even in the patient with biopsy-proven carcinoma in situ, excision or cervical ablation can most commonly be deferred until after delivery. Importantly, a diagnosis of cervical dysplasia is not an indication for cesarean delivery because there has been no demonstrable increased risk to mother or fetus with vaginal delivery. Locally advanced cervical carcinoma, not amenable to surgical resection, requires treatment with radical radiation therapy. The standard external high-energy teletherapy radiation often exceeds 4500 cGy and is not compatible with fetal life. Again, decision regarding fetal age, risk of early delivery versus waiting, as well as parental desires must be weighed, given the curability of this disease. With most lesions confined to the cervix, careful observation and expedited delivery after fetal maturation followed by radical treatment appears reasonable. Ovarian Carcinoma the lifetime risk of ovarian carcinoma for an American woman is approximately 1 in 70, with an age-adjusted annual incidence of approximately 13. This results in approximately 21,000 new cases of ovarian cancer and 12,500 deaths per annum. In women 40 years of age there are approximately 10 cases per 100,000, increasing to a peak incidence of approximately 45 cases per 100,000 women between the ages of 60 and 65 years. The incidence of adnexal masses associated with pregnancy has been reported to range from 1 in 81 to 1 in 2500. With the use of ultrasound for routine fetal surveillance, the detection of previously unrecognized adnexal masses in both early and late gestation is likely to increase. Of the adnexal masses noticed in pregnancy, approximately 50% will be less than 5 cm in diameter, whereas 25% are between 5 and 10 cm and 25% will be greater than 10 cm at the time of discovery. Unilateral, mobile, non-complex masses less than 5 cm, noticed in the first trimester, will resolve in greater than 90% of cases. It therefore is reasonable to observe non-suspicious neoplasms conservatively with repeat ultrasound into the second trimester (when elective surgical intervention is safest) to document spontaneous resolution. A subgroup of patients undergoing assisted reproductive therapy with various ovulation-inducing medications present a unique situation. Because of the induced ovarian hyperstimulation and increased ultrasound surveillance, these patients will commonly have ovarian cysts noted in the first trimester. Spontaneous resolution of benign-appearing ovarian cysts can be expected in greater than 90% of patients who have undergone ovulation induction. Recent reports of possible associations between ovulation induction and an increased incidence of ovarian neoplasms should, however, be kept in mind, although this is considered to most likely be a long-term effect. Adnexal masses can originate from multiple sources, and the differential diagnosis is complex, including multiple gynecologic and non-gynecologic entities. Fortunately, modern pelvic imaging, especially ultrasonography, aids greatly in differentiating the primary origins of these masses. The common types of neoplastic and non-neoplastic ovarian masses noticed during pregnancy are described in Tables 252-12 and 252-l3. Most ovarian tumors occurring during early pregnancy are benign, with the most common neoplastic ovarian mass being a benign cystic teratoma. Two to 5 per cent of adnexal masses persisting after the first trimester will be pathologically confirmed as being malignant, resulting in an overall malignancy rate of 1 in 5,000 to 18,000 live births. Other than the acute presentation of abdominal pain associated with ovarian torsion, most common between the 6th and 14th weeks of gestation, these masses often are clinically inapparent and may be accompanied only with the vague non-specific abdominal discomfort common to pregnancy. Real-time ultrasonography has revolutionized obstetrics and has become the most commonly used diagnostic tool in pregnancy. As described earlier, many of these are functional in nature (corpus luteum) and most will resolve spontaneously. Observation of non-suspicious (simple, non-complex, without excrescences, without ascites) lesions into the second trimester with repeat ultrasonographic assessment is appropriate. Pelvic Surgery in Pregnancy the timing of the surgical intervention cannot always be controlled and emergent situations occasionally arise. If laparotomy is required during the first trimester, spontaneous abortion is more likely, possibly because of disruption of the delicate corpus luteum. After 7 to 10 weeks of gestation the trophoblast is capable of supplying sufficient quantities of specific steroid hormones for the maintenance of the gestation. Should surgical extirpation of the corpus luteum be required in the first trimester, progestin support is recommended. A daily intramuscular injection of 100 mg of progesterone in oil or a 100-mg transvaginal suppository every 12 hours provides adequate progestin replacement. A mass that is first noted in the third trimester is best managed by awaiting fetal maturity if the clinical suspicion of malignancy is low.
This extensively referenced article provides information on the molecular and biochemical aspects of the glycogen storage diseases diabetes insipidus urine glucose buy metformin 850mg lowest price. An extensively referenced review that focuses on the altered metabolism diabete type 1 and 2 discount 500 mg metformin amex, treatment diabetes type 2 teaching metformin 850mg line, and outcome of the hepatic forms of glycogenesis diabetes test wikipedia purchase 850mg metformin otc. Combines the biochemical abnormalities of the glycogenoses and associated research findings with a practical guide to dietary management of children and adults diabetes symptoms thirst buy metformin 850mg low price. Greene Fructose math test diabetes joke buy 500 mg metformin mastercard, a normal dietary constituent of fruits, vegetables, honey, and the disaccharide sucrose (table sugar), is present at a level of 50 to 100 g/day in the average Western diet. The relative tolerance of dietary fructose in normal children was evaluated by feeding 31 children 2 g of fructose per kilogram of body weight. Four children developed gastrointestinal symptoms and 71% developed abnormal breath hydrogen excretion, suggesting that a significant increase in dietary fructose can result in malabsorption in some individuals. Initial metabolism of fructose primarily involves three enzymes: fructokinase, aldolase B, and triokinase. Five enzymatic defects involving fructose metabolism have been identified: (1) fructokinase deficiency, (2) aldolase A deficiency, (3) aldolase B 1089 Figure 204-1 the major pathway for fructose metabolism in the liver, showing the five defects discussed in the text. Aldolase A deficiency (2) is extremely rare and is expressed primarily during embryogenesis. The enzymatic defects in fructose metabolism are illustrated in Figure 204-1 and are discussed below. Because no pathologic condition results from this defect, the primary concern relates to the fact that fructose is a reducing sugar. Thus, a positive reaction with urinary Clinitest tablets may result in the erroneous suggestion of diabetes unless glucose oxidase is determined with a dipstick. Embryonic tissue produces aldolase A; adult liver, kidney, and intestine express aldolase B; and nervous tissue expresses aldolase C. Although all three aldolases are tetramers of identical 40-kd subunits, each is coded for different genes on different chromosomes: aldolase A on chromosome 16,16q22-q24, aldolase B on chromosome 9,9q13-q32, and aldolase C on chromosome 17,17 cen-q 21. Aldolase A deficiency may be detrimental because of its pivotal role in glycolysis. This is apparently of special relevance to the developing embryo, which expresses only aldolase A. Only a few patients with this deficit have been described, and not all symptoms are expressed to the same degree. Potential symptoms include mental retardation, short stature, hemolytic anemia, and abnormal facial appearance. Aldolase B deficiency (prevalence about 1:23,000 live births) is a potentially life-threatening autosomal-recessive disorder than can be effectively treated by eliminating dietary fructose. Symptoms become manifested only when patients ingest fructose or sorbitol-containing foods. Because lactose is the carbohydrate source in mammalian milk, infants do not develop symptoms until the introduction of dietary fruits or other fructose-containing foods or medication. The primary presentation is vomiting and other features of hypoglycemia within 20 to 30 minutes after fructose ingestion. These acute manifestations may not be apparent after lower chronic intakes, for example with fructose-containing infant formulas or sorbitol-containing gum. In these instances, failure to thrive, hepatomegaly, and cirrhosis may represent the dominant presenting features. Concomitant laboratory findings include an acute decrease in serum glucose and phosphate concentrations and an elevated uric acid concentration. With continued exposure to fructose, hyperbilirubinemia, lactic acidosis, hepatosplenomegaly, and liver failure develop in conjunction with renal tubular dysfunction (bicarbonaturia, aminoaciduria, phosphaturia). At this stage, fatty infiltration of liver, cellular necrosis, and mild bile duct proliferation with fibrosis occur. If exposure to fructose continues, progressive fibrosis, cirrhosis, and death from liver failure follow. The diagnosis is suggested by the presence of urinary reducing sugar detectable by Clinitest tablets and not by urinary dipstick, which measures glucose oxidase. Because similar clinical features may be present with galactosemia or tyrosinemia, diagnosis can be confirmed by genetic screen. Two large deletions, two four-base deletions, a single-base deletion, and a seven-base deletion/one-base insertion have been found. Regions of the enzyme where mutations have been observed recurrently are encoded by exons 5 and 9. The three most common mutations are found in these exons, making screening methods more feasible. In spite of recurrent bouts of hypoglycemia and substantial liver disease, restriction of dietary fructose usually results in almost complete recovery during a 3- to 5-week period, and affected adults have normal intelligence. Older children and adults are protected from large dietary intakes of fructose by an aversion to sweets, 1090 although small amounts taken chronically may result in isolated, often reversible, somatic growth retardation. Patients usually present before age 6 months with fasting-induced lactic acidosis, hypoglycemia, and hepatomegaly. The condition is due to a defect of hepatic fructose-1,6-diphosphatase, a gluconeogenic enzyme. During fasting, urinary organic acids are similar to those of tyrosinemia type I but with an absence of succinyl acetate. The diagnosis is suspected when, after 12 to 16 hours of fasting, the blood sugar concentration falls and is not restored when glucagon is administered, and acidosis (lactate) is present. Loading tests with fructose or glycerol may be dangerous because they lead to hypoglycemia and lactic acidosis. Treatment consists of avoiding fasting and restricting dietary fructose and glycerol. The variable phenotypic expression has not been fully explained on the basis of the enzymatic defect, but all patients who show a substantial increase in D-glycerate excretion after fructose ingestion should avoid dietary fructose. A recent correlation between the genotype and phenotype of five common defects in fructose metabolism. Hillman Primary hyperoxaluria refers to two different peroxisomal enzyme deficiencies that are characterized by massive synthesis and urinary excretion of oxalic acid. Oxalate is also deposited in the heart, the eye, the skin, and other organs, leading to a variety of clinical pictures. Particularly in type I disease, the clinical manifestations present early in childhood with nephrolithiasis or nephrocalcinosis and lead to renal failure within the first decade of life. Both types are inherited as autosomal recessive traits and must be distinguished from secondary hyperoxalurias due to increased absorption of oxalate by the gut. These secondary causes include inflammatory bowel disease and fat malabsorption, which may tie up calcium and convert insoluble calcium oxalate to more absorbable salts. Although most adult patients with calcium oxalate nephrolithiasis excrete normal amounts of oxalate, it is now clear that hyperoxaluria must be considered in the differential diagnosis. Primary hyperoxaluria type I (glycolic aciduria) is caused by a defect in the peroxisomal enzyme alanine:glyoxylate aminotransferase. In its absence, glycolic acid leaves the peroxisome and is converted to oxalic acid by lactic dehydrogenase. Both glycolic and oxalic acids are excreted in large amounts, usually more than 60 mg/1. Until recently it was believed that the defect was in the enzyme D-glyceric dehydrogenase. This enzyme leads to the accumulation of hydroxypyruvic acid, which is reduced in the cytoplasm to L-glyceric acid. Recently, it was suggested that this enzyme may be the same as glyoxalate reductase, which leads to accumulation of glyoxalate and production of oxalate by lactate dehydrogenase. Asymptomatic cases or cases with only a single attack of oxaluria have been reported. Two patients in recent cases developed symptoms only after experiencing severe water deprivation (one while sailing and one while running in hot weather). Some patients with type I disease respond to large doses of pyridoxine (20 to 200 mg/day). It appears to act by stabilizing the remaining activity and is effective only in patients with some enzyme, in general the milder cases. Dilute urine should be maintained by high fluid intake, and some reports suggest that diuretics may help. Attempts to form more soluble salts of oxalate, particularly with magnesium orthophosphate and citrate, have met with some success. Renal transplants alone have failed, owing to the accumulation of oxalate produced in the liver. Other measures that maintain a dilute urine seem to be enough in the milder cases. A general review of the biochemistry of primary oxalosis and related secondary disorders. Witztum Daniel Steinberg Hyperlipidemia, abnormal elevation of plasma cholesterol and/or triglyceride levels, is one of the most common clinical problemsthat confront the physician in daily practice. Much attention has been focused on these disorders because there is a strong association of hyperlipidemia-especially hypercholesterolemia-with development of atherosclerosis, and of hypertriglyceridemia with pancreatitis. Hyperlipidemia may occur because of a primary genetic disorder or as a result of environmental influences secondary to other medical conditions, or any combination of these factors. Because lipids are transported in plasma as components of lipoprotein complexes, understanding lipoprotein physiology is necessary for informed diagnosis and therapeutic planning. The more nonpolar lipids-triglycerides and cholesteryl esters-are carried almost exclusively in the central core of the spherical lipoprotein particles. The more polar lipids (such as phospholipids and free cholesterol), together with amphipathic apolipoproteins, form a surface monolayer that serves to "solubilize" the particles and allows them to remain in stable solution in the aqueous plasma. Each lipoprotein particle contains on its surface one or more apolipoproteins that have a variety of functional and structural roles. Some apolipoproteins provide structural stability to the lipoprotein, serve as ligands for cellular lipoprotein receptors that help determine the metabolic fate of individual particles, and act as cofactors for plasma enzymes involved in plasma lipid and lipoprotein metabolism. Table 206-1 lists major apoproteins, lipoproteins on which they reside, and known or postulated functions. The most widely used classification of lipoproteins is based on their different densities, which determine their behavior during preparative equilibrium ultracentrifugation. The fact that lipoprotein particles exist as relatively discrete species when separated this way led to the currently used density classification system outlined in Table 206-2. A second classification system originally proposed many years ago assigns priority to the apoprotein content of the lipoproteins. Thus, in the future, full evaluation may include this type of analysis, but for now more research is needed to determine its clinical value. An older classification system of the lipoproteins, based on their electrophoretic patterns (lipoprotein pattern typing), while important historically for the development of our understanding of lipid transport disorders, is not used commonly today. However, for the sake of completeness, the electrophoretic mobility of each lipoprotein class is also given in Table 206-2. Between meals, free fatty acids are mobilized from the adipose tissue and serve as a major source for hepatic triglyceride synthesis. Lipogenesis, the synthesis of fatty acids de novo from carbohydrate or protein, also can occur in the liver. Fatty acids can either enter mitochondria (where beta-oxidation occurs) or they can undergo esterification to form triglycerides in the cytosol. Control of triglyceride synthesis is a complex process that appears to be regulated in part by changes in insulin and glucagon that occur with feeding. This results in a serious clinical syndrome in which patients lack any apo B-containing lipoproteins in their plasma. Apo B is found as a full-length protein termed apo B-100 (or apo B), which is made by the liver, or as a shortened form termed apo B-48, which is made in humans only by the intestine. The primary function of lipoprotein particles is to transport lipids from one site to another. This enzyme is synthesized in adipose tissue and skeletal muscle cells, secreted, and transported across the capillary endothelial cell, where it binds to glycoproteins on the endothelial luminal surface. This leads to triglyceride hydrolysis and release of fatty acids, which are then transported into the fat (or muscle) cell where they are re-esterified with glycerol and stored as intracellular triglyceride. The vast majority of triglyceride in adipose tissue is acquired by this mechanism because essentially no lipogenesis occurs de novo from glucose in human adipose tissue. Thus, after a meal, high insulin levels serve to promote storage of fatty acids in the adipocyte as triglyceride, whereas in the fasting state hydrolysis is promoted, providing fatty acids for uptake by muscle and liver. All other apolipoproteins have now been removed, together with much of the phospholipid and triglyceride and some of the cholesterol. Within the lysosome, the protein component, apo B, is degraded to amino acids or oligopeptides. The cholesteryl ester is hydrolyzed to free cholesterol, which can now leave the lysosome and is used by the cell for a variety of cellular processes, including new cell membrane synthesis, hormone synthesis (in adrenal, ovarian, or testicular cells), bile acid production (in hepatocytes), or for re-esterification to be stored as a cholesteryl-ester droplet. Thus, this efficient regulatory pathway provides a cell with sufficient cholesterol for its physiologic needs, but it prevents the overaccumulation of cholesterol, which could be toxic. It should also be appreciated that apo B-containing lipoproteins may be removed by the liver by inefficient, low-affinity pathways as well. After a triglyceride-rich meal, triglycerides and cholesterol are absorbed into the mucosal cells of the small intestine as free fatty acids and free cholesterol. There they are re-esterified to triglyceride and cholesteryl esters and incorporated into the core of a nascent lipoprotein, the chylomicron. Apo B-48 is a crucial component of chylomicrons and is a product of the same gene that codes for the intact, full-length apo B-100. Apo B-48 is so named because it is identical to the first 48% (the amino terminal portion) of apo B-100. In humans, the intact, full-length apo B-100 is made only in the liver, whereas apo B-48 is made only in the intestine. Thus, once the chylomicron has been secreted by the intestine, apo B-48 functions primarily as a structural component.
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