T. Brenton. University of Saint Thomas, Saint Paul.

Observer bias Observerbias is the conscious or unconscious distortion in perception of report- ing the measurement by an observer order generic fosamax from india. It may occur when physicians treat patients differently because of the group to which they are assigned order fosamax 70 mg without prescription. Physicians in a study may give more intensive adjunctive treatment to the patients who are assigned to the intervention group rather than to the placebo or comparison group purchase 70mg fosamax with visa. They may interpret the answers to questions on a survey differently in patients known to be in the active treatment rather than control group fosamax 35mg low cost. An observer not blinded to patient selection may report the results of one group of patients differently from those of the other group. One form of this bias occurs when patients who are the sickest may be either preferentially included or excluded from the sample because of bias on the part of the observer making the assignment to each group. Data collected retrospectively by reviewing the medical records may have poor data quality. The records used to collect data may contain inadequate detail and possess questionable reliability. They may also use varying and sub- jective standards to judge symptoms, signs of disease severity, or outcomes. The implicit review of charts introduces the researcher’s bias in interpreting both measurements and outcomes. If there are no objective and explicit criteria for evaluating the medical records, the infor- mation contained in them is open to misinterpretation from the observer. It has been shown that when performing implicit chart reviews, researchers subcon- sciously fit the response that best matched their hypothesis. Researchers came up with different results if they performed a blinded chart review as opposed to an unblinded review. Explicit reviews are better and can occur when only clearly objective outcome measures are reviewed. Even when the outcomes are more objective it is better to have the chart material reviewed in a blinded manner. The Hawthorne effect was first noticed during a study of work habits of employees in a light bulb factory in Illinois during the 1920s. It occurs because being observed during the process of making measurements changes the behav- ior of the subject. In the physical sciences, this is known as the Heisenberg Uncer- tainty Principle. If subjects change their behavior when being observed, the out- come will be biased. One study was done to see if physicians would prescribe less expensive antibiotics more often than expensive new ones for strep throat. In this case, the physicians knew that they were being studied and in fact, they prescribed many more of the low-price antibiotics during the course of the study. After the study was over, their behavior returned to baseline, thus they acted differently and changed their clinical practices when being observed. This and other observer biases can be prevented through the use of unobtrusive, blinded, or objective measurements. Misclassification bias Misclassification bias occurs when the status of patients or their outcomes is incorrectly classified. If a subject is given an inaccurate diagnosis, they will be counted with the wrong group, and may even be treated inappropriately due to their misclassifaction. For instance, in a study of antibiotic treatment of pneumonia, patients with bronchi- tis were misclassified as having pneumonia. Those patients were more likely to get better with or without antibiotics, making it harder to find a difference in the outcomes of the two treatment groups. Patients may also change their behaviors or risk factors after the initial grouping of subjects, resulting in misclassification bias on the basis of exposure. Misclassification of outcomes in case control studies can result in failure to correctly distinguish cases from controls and lead to a biased conclusion. One must know how accurately the cases and controls are being identified in order to avoid this bias. If the disorder is relatively common, some of the control patients may be affected but not have the symptoms yet. One way of compensating for Sources of bias 87 this bias is to dilute the control group with extra patients. This will reduce the extent to which misclassification of cases incorrectly counted as controls will affect the data. Let’s say that a researcher wanted to find out if people who killed themselves by playing Russian Roulette were more likely to have used alcohol than those who committed suicide by shooting themselves in the head. The researcher would look at death investigations and find those that were classified as suicides and those that were classified as Russian Roulette. However, the researcher suspects that some of the Russian Roulette cases may have been misclassified as suicides to “protect the victim. Obviously if Russian Roulette deaths are routinely misclassified, this strategy will not result in any change in the bias. Outcome classification based upon subjec- tive data including death certificates, is more likely to exhibit this misclassifica- tion. This will most likely result in an outcome that is of smaller size than the actual effect. This bias can be prevented with objective standards for classifica- tion of patients, which should be clearly outlined in the methods section of a study. Miscellaneous sources of bias Confounding Confounding refers to the presence of several variables that could explain the apparent connection between the cause and effect. If a particular variable is present more often in one group of patients than in another, it may be respon- sible for causing a significant effect. For example, a study was done to look for the effect of antioxidant vitamin E intake on the outcome of cardiovascular dis- ease. It turned out that the group with high vitamin E intake also had a lower rate of smoking, a higher socioeconomic status, and higher educational level than the groups with lower vitamin E intake. It is much more likely that those other variables are responsible for all or part of the decrease in observed cases of car- diovascular disease. There are statistical ways of dealing with confounding vari- ables called multivariate analyses. The rules governing the application of these types of analyses are somewhat complex and will be discussed in greater detail in Chapter 14. When looking at studies always look for the potential presence of confounding variables and at least make certain that the authors have adjusted for those variables. However, no matter how well the authors have adjusted, it can be very difficult to completely remove the effects of confounding from a study. Contimination is more commonly seen in randomized clin- ical trials, but can also exist in observational studies. In an observational study, it occurs if the control group is exposed to the same risk factor as the study group. However, there may be an environmental situation by which those classi- fied as not exposed to the risk factor are actually exposed. For example, a study is done to look at the effect of living near high-tension wires on the incidence of leukemia. Those patients who live within 30 miles of a high-tension wire are considered the exposed group and those who live more than 30 miles away are considered the unexposed control group. Those people who live 30 to 35 miles from high-tension wires could be misclassified as unexposed although they may truly have a similar degree of exposure as those within 30 miles. In fact, families living 60 miles from the wires may be equally affected by the electrical field if the wires have four times the amount of current. Cointervention occurs when one group or the other receives different medical care based partly or totally upon their group assignment. This occurs more often in randomized trials, but could be present in an observational study when the group exposed to one particular treatment also receives different therapy than the unexposed group. This can easily occur in studies with historical controls, since patients in the past may not have had access to the same advances in med- ical care as the patients who are currently being treated. The end results of the historical comparison would be different if both groups had received the same level of medical care.

Medical science amasses tens of thousands of papers annually cheap 35 mg fosamax with mastercard, each representing a tiny fragment of the whole picture order fosamax mastercard. To look at only one piece and try to understand the benefits and risks is like standing an inch away from an elephant and trying to describe everything about it discount fosamax 35 mg free shipping. Each specialty order fosamax 35mg free shipping, each division of medicine keeps its own records and data on morbidity and mortality. We have now completed the painstaking work of reviewing thousands of studies and putting pieces of the puzzle together. Because of the extraordinarily narrow, technologically driven context in which contemporary medicine examines the human condition, we are completely missing the larger picture. Medicine is not taking into consideration the following critically important aspects of a healthy human organism: (a) stress and how it adversely affects the immune system and life processes; (b) insufficient exercise; (c) excessive caloric intake; (d) highly processed and denatured foods grown in denatured and chemically damaged soil; and (e) exposure to tens of thousands of environmental toxins. Instead of minimizing these disease-causing factors, we cause more illness through medical technology, diagnostic testing, overuse of medical and surgical procedures, and overuse of pharmaceutical drugs. The huge disservice of this therapeutic strategy is the result of little effort or money being spent on preventing disease. Underreporting of Iatrogenic Events As few as 5% and no more than 20% of iatrogenic acts are ever reported. In 1994, Leape said his figure of 180,000 medical mistakes resulting in death annually was equivalent to three jumbo-jet crashes every two days. What we must deduce from this report is that medicine is in need of complete and total reform—from the curriculum in medical schools to protecting patients from excessive medical intervention. It is obvious that we cannot change anything if we are not honest about what needs to be changed. We are fully aware of what stands in the way of change: powerful pharmaceutical and medical technology companies, along with other powerful groups with enormous vested interests in the business of medicine. They fund medical research, support medical schools and hospitals, and advertise in medical journals. Such funding can sway the balance of opinion from professional caution to uncritical acceptance of new therapies and drugs. You have only to look at the people who make up the hospital, medical, and government health advisory boards to see conflicts of interest. Erik Campbell, the lead author, said, "Our previous research with faculty has shown us that ties to industry can affect scientific behavior, leading to such things as trade secrecy and delays in publishing research. Marcia Angell struggled to bring greater attention to the problem of commercializing scientific research. In June 2002, the New England Journal of Medicine announced that it would accept journalists who accept money from drug companies because it was too difficult to find ones who have no ties. Jerome Kassirer, said that was not the case and that plenty of researchers are available who do not work for drug companies. Cynthia Crossen, a staffer for the Wall Street Journal, i n 1996 published Tainted Truth : The Manipulation of Fact in America , a book about the widespread practice of lying with statistics. In 1981 Steel reported that 36% of hospitalized patients experienced iatrogenesis with a 25% fatality rate, and adverse drug reactions were involved in 50% of the injuries. In 1991, Bedell reported that 64% of acute heart attacks in one hospital were preventable and were mostly due to adverse drug reactions. Leape focused on the “Harvard Medical Practice Study” published in 1991, (16a) which found a 4% iatrogenic injury rate for patients, with a 14% fatality rate, in 1984 in New York State. From the 98,609 patients injured and the 14% fatality rate, he estimated that in the entire U. Why Leape chose to use the much lower figure of 4% injury for his analysis remains in question. Using instead the average of the rates found in the three studies he cites (36%, 20%, and 4%) would have produced a 20% medical error rate. The number of iatrogenic deaths using an average rate of injury and his 14% fatality rate would be 1,189,576. Leape acknowledged that the literature on medical errors is sparse and represents only the tip of the iceberg, noting that when errors are specifically sought out, reported rates are “distressingly high. First, he found that each patient had an average of 178 “activities” (staff/procedure/medical interactions) a day, of which 1. This may not seem like much, but Leape cited industry standards showing that in aviation, a 0. In trying to determine why there are so many medical errors, Leape acknowledged the lack of reporting of medical errors. Medical errors occur in thousands of different locations and are perceived as isolated and unusual events. But the most important reason that the problem of medical errors is unrecognized and growing, according to Leape, is that doctors and nurses are unequipped to deal with human error because of the culture of medical training and practice. Medical mistakes are therefore viewed as a failure of character and any error equals negligence. Leape cites McIntyre and Popper, who said the “infallibility model” of medicine leads to intellectual dishonesty with a need to cover up mistakes rather than admit them. There are no Grand Rounds on medical errors, no sharing of failures among doctors, and no one to support them emotionally when their error harms a patient. Leape hoped his paper would encourage medical practitioners “to fundamentally change the way they think about errors and why they occur. Therefore, the iatrogenic death rate dwarfs the annual automobile accident mortality rate of 45,000 and accounts for more deaths than all other accidents combined. The survey found that more than 100 million Americans have been affected directly or indirectly by a medical mistake. Forty-two percent were affected directly and 84% personally knew of someone who had experienced a medical mistake. Leape used a 14% fatality rate to determine a medical error death rate of 180,000 in 1994. The authors learned that the American College of Surgeons estimates that surgical incident reports routinely capture only 5- 30% of adverse events. In one study, only 20% of surgical complications resulted in discussion at morbidity and mortality rounds. They also suggest that our statistics concerning mortality resulting from medical errors may be in fact be conservative figures. An article in Psychiatric Times (April 2000) outlines the stakes involved in reporting medical errors. General Accounting Office responsible for health financing and public health issues, testified before a House subcommittee hearing on medical errors that "the full magnitude of their threat to the American public is unknown” and "gathering valid and useful information about adverse events is extremely difficult. A survey of nurses found that they also fail to report medical mistakes for fear of retaliation. Pharmacology texts also will tell doctors how hard it is to separate drug side effects from disease symptoms. Treatment failure is most often attributed to the disease and not the drug or doctor. Doctors are warned, “Probably nowhere else in professional life are mistakes so easily hidden, even from ourselves. Jay Cohen, who has extensively researched adverse drug reactions, notes that because only 5% of adverse drug reactions are reported, there are in fact 5 million medication reactions each year. Dorothea Wild surveyed medical residents at a community hospital in Connecticut and found that only half were aware that the hospital had a medical error-reporting system, and that the vast majority did not use it at all. Wild adds that error reporting is the first step in locating the gaps in the medical system and fixing them. With the discovery of the “germ theory,” medical scientists convinced the public that infectious organisms were the cause of illness. Medication Errors A survey of a 1992 national pharmacy database found a total of 429,827 medication errors from 1,081 hospitals. The error rate intercepted by pharmacists in this study was 24%, making the potential minimum number of patients harmed by prescription drugs 417,908. A 2003 study followed 400 patients after discharge from a tertiary care hospital setting (requiring highly specialized skills, technology, or support services). Reuters also reported that prior research has suggested that nearly 5% of hospital admissions (over 1 million per year) are the result of drug side effects.

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Estrogen replacement therapy and coronary heart disease: a quantitative assess- ment of the epidemiologic evidence fosamax 35mg free shipping. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized con- trolled trial 70 mg fosamax sale. The risk factor values were assigned using log–normal distributions of the reported mean and standard deviation for each risk factor fosamax 35 mg generic. Correlations between risk factor distributions were based on information from the Asia-Pacific cohort cheap fosamax line. These relative risk estimates were applied to the hypothetical cohort to determine the relative risk of each individual in the cohort. Absolute risk of a cardiovascular event was determined by scaling individual relative risk to popula- tion incidence rates of cardiovascular disease (ischaemic heart disease and stroke), estimated from the Global Burden of Disease Study. The mean absolute risk for various combinations of risk factor levels was then calcu- lated and tabulated. Primary and subsequent coronary risk appraisal: new results from The Framingham Study. Estimates of global and regional potential health gains from reducing multiple major risk factors. Comparative Quantification of Health Risks: Global and Regional Burden of Diseases Attributable to Selected Major Risk Factors. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Univeristy of Münster, Münster, Germany Dr Stephen Lim, University of Queensland, School of Population Health, Herston, Australia Dr Lars H. Milan, Italy Dr Alberto Morganti, San Paolo Hospital, Milan, Italy Dr Judith Whitworth, John Curtin School of Medical Research, Canberra, Australia Other external experts Dr Aloyzio Achutti, Porto Alegre, Brazil Dr Antonio Bayés de Luna, Catalonia Institute of Cardiovascular Sciences, Barcelona, Spain Dr Pascal Bovet, University Institute of Social and Preventive Medicine, Lausanne, Switzerland Dr Flavio Burgarella, Cardiac Rehabilitation Centre, Bergamo, Italy Dr John Chalmers, University of Sydney, New South Wales, Australia Dr Guy G. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This report was produced under the overall direction of Catherine Le Galès-Camus (Assistant Director-General, Noncommunicable Diseases and Mental Health), Robert Beaglehole (Editor-in-Chief) and JoAnne Epping-Jordan (Managing Editor). The core contributors were Dele Abegunde, Robert Beaglehole, Stéfanie Durivage, JoAnne Epping-Jordan, Colin Mathers, Bakuti Shengelia, Kate Strong, Colin Tukuitonga and Nigel Unwin. Guidance was offered throughout the production of the report by an Advisory Group: Catherine Le Galès-Camus, Andres de Francisco, Stephen Matlin, Jane McElligott, Christine McNab, Isabel Mortara, Margaret Peden, Thomson Prentice, Laura Sminkey, Ian Smith, Nigel Unwin and Janet Voûte. External expert review was provided by: Olusoji Adeyi, Julien Bogousslavsky, Debbie Bradshaw, Jonathan Betz Brown, Robert Burton, Catherine Coleman, Ronald Dahl, Michael Engelgau, Majid Ezzati, Valentin Fuster, Pablo Gottret, Kei Kawabata, Steven Leeder, Pierre Lefèbvre, Karen Lock, James Mann, Mario Maranhão, Stephen Matlin, Martin McKee, Isabel Mortara, Thomas Pearson, Maryse Pierre-Louis, G. Ramana, Anthony Rodgers, Inés Salas, George Schieber, Linda Siminerio, Colin Sindall, Krisela Steyn, Boyd Swinburn, Michael Thiede, Theo Vos, Janet Voûte, Derek Yach and Ping Zhang. Report development and production were coordinated by Robert Beaglehole, JoAnne Epping-Jordan, Stéfanie Durivage, Amanda Marlin, Karen McCaffrey, Alexandra Munro, Caroline Savitzky, Kristin Thompson, with the administrative and secretarial support of Elmira Adenova, Virgie Largado-Ferri and Rachel Pedersen. The web site and other electronic media were organized by Elmira Adenova, Catherine Needham and Andy Pattison. Four out of five chronic disease deaths today are in low and middle income countries. People in these countries tend to develop diseases at younger ages, suffer longer – often with preventable complications – and die sooner than those in high income countries. Globally, of the 58 million deaths in 2005, approximately 35 million will be as a result of chronic diseases. They are currently the major cause of death among adults in almost all countries and the toll is projected to increase by a further 17% in the next 10 years. At the same time, child overweight and obesity are increasing worldwide, and incidence of type 2 diabetes is growing. This is a very serious situation, both for public health and for the societies and economies affected. Until recently, the impact and profile of chronic disease has generally been insuf- ficiently appreciated. This ground-breaking report presents the most recent data, making clear the actual scale and severity of the problem and the urgent need for action. The means of preventing and controlling most chronic diseases are already well- established. It is vital that countries review and implement the interventions described, taking a comprehensive and integrated public health approach. Through investing in vigorous and well- targeted prevention and control now, there is a real opportunity to make significant progress and improve the lives of populations across the globe. I have looked at the facts contained in this report and I can see that to meet these challenges I will have to address chronic diseases. But it is less well understood that diseases such as heart disease, stroke, cancer and diabetes already have a significant impact and that, by 2015, chronic diseases will be a leading cause of death in Nigeria. In the majority of cases these are preventable, premature deaths and they are undermining our efforts to increase life expectancy and the economic growth of our country. If we wait even 10 years, we will find that the problem is even larger and more expensive to address. Prosperity is bringing to our nation many benefits, but there are some changes that are not positive. As our diets and hab- its are changing, so are our waist- viii Supporting statements lines. Already, more than 35% of women in Nigeria are overweight; by 2010 this number will rise to 44%. We do not need to say, “we are a poor nation, we cannot afford to deal with chronic diseases”. As this report points out, there are low-cost, effective measures that any country can take. Governments have a responsibility to support their citizens in their pursuit of a healthy, long life. It is not enough to say, “we have told them not to smoke, we have told them to eat fruit and vegetables, we have told them to take regular exercise”. We must create com- munities, schools, workplaces and markets that make these healthy choices possible. I believe, and the evidence supports me, that there are clear links between health, economic development and poverty alleviation. If my government and I are to build a strong Nigeria, and if my brothers and sisters throughout Africa are to create a strong continent, then we must include chronic diseases in our thinking. If we take action now, it could be that the predictions outlined in these analyses never come true. I will join with the World Health Organization to implement the changes necessary in Nigeria, in the hope that we, too, can contribute towards achieving the global goal of reducing chronic disease death rates by 2% per year over the next 10 years, saving 36 million lives by 2015. However, we now have major public health issues due to chronic diseases that need to be addressed with equal energy and focus. This World Health Organization report, Preventing chronic diseases: a vital investment, is of relevance to me, as Indian Minister for Health, as my country tackles the increasing number of issues relating to chronic disease. The scale of the problem we face is clear with the projected number of deaths attributable to x Supporting statements chronic diseases rising from 3. A number of my fellow citizens are featured within this report, as Faces of Chronic Disease. Sridhar Reddy, who, like a huge proportion of Indians, consumed tobacco and bat- tled both serious cancer and associated financial debts. His story is all too familiar in a country which is the world’s second largest producer, as well as consumer, of tobacco, where we consequently experience huge rates of cancer, including the largest numbers of oral cancer in the world.

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Thyroid autoantibodies are High titres of circulating antithyroid antibodies order 70mg fosamax otc, associ- present in patients with autoimmune disease purchase cheap fosamax line. Large goitres require subtotal thyroidectomy if causing com- Management pression of local structures such as the oesophagus or Thyroxine replacement starting with a low dose is re- trachea cheap fosamax 70mg. Treatment of elderly patients should be recurrent laryngeal nerves or parathyroids generic fosamax 70mg overnight delivery. Post-surgery undertaken with care, as any subclinical ischaemic heart or following significant thyroid destruction patients be- disease may be unmasked. Thyroxine dosing is titrated come hypothyroid requiring treatment with thyroxine according to thyroid function tests. Hashimoto’s disease (autoimmune Myxoedema coma thyroiditis) Definition Definition This is the end-stage of untreated hypothyroidism, lead- Organ-specific autoimmune disease causing thyroiditis ing to progressive weakness, hypothermia, respiratory and later hypothyroidism. Myxoedema coma may be precipitated by inter- Malignant tumours of the thyroid current illness or disorder, such as heart failure, perhaps Papillary adenocarcinoma following a myocardial infarction, stroke, pneumonia; iatrogenic causes include water overload and sedative or Definition opiate drugs. A slow-growing, well-differentiated primary thyroid tu- mour arising from the thyroid epithelium. Pathophysiology Thyroid hormones maintain many metabolic processes Incidence/prevalence in the body. Severe and chronic lack of these hormones 50% of malignant tumours of the thyroid. F > M Clinical features Clinical features There may be a history of previous thyroid disease, Presentsasasolitaryormultifocalswellingofthethyroid. The patient appears obese with may be the only sign when there is a microscopic pri- hypothermia,yellowishdryskin,thinnedhair,puffyeyes mary. Papillary tumours spread via lymphatics within and has a slow pulse, respiration and reduced reflexes. Investigations Management Patients may be identified during investigation for a soli- Myxoedema coma requires admission to intensive care. Definitive diagnosis r Respiratory failure requires support and may necessi- is by histology, although cytology from fine needle aspi- tate ventilation. Management r Corticosteroids must be given if adrenal insufficiency Total thyroidectomy with excision of involved neck is present. Radioactive iodine therapy may Chapter 11: Thyroid axis 435 be used prophylactically or as treatment for metastases. A postoperative radioisotope scan of the Prognosis skeleton and neck detects metastases as ‘hot spots’, and Tenyear survival rates of almost 90%. Plasma thyroglob- Follicular adenocarcinoma ulin levels can be monitored for recurrence. Definition Aprimary malignancy of the thyroid gland arising from Medullary carcinoma the thyroid epithelium. Definition Incidence/prevalence Tumour of the thyroid that arises from the parafollicular Approximately 20% of cases of thyroid malignancies. F > M Pathophysiology Clinical features The parafollicular cells originate from neural crest tis- Typically presents as a solitary thyroid nodule in middle- sue during embryonic life, but merge with the embry- aged patients. Parafollicular cells normally secrete calcitonin, a Investigations polypeptide, in response to small increases in calcium. Patients are investigated as for a solitary thyroid nodule The tumour cells secrete calcitonin and carcinoembry- (see page 430). Twenty per cent lymph nodes are palpable in about half of cases, but of patients have metastases in the lungs, bone or liver. Resembles a benign solitary thyroid nodule, a round encapsulated mass, but less colloid and more solid in Microscopy appearance. Histology reveals invasion of the capsule, The tumour is composed of sheets of small cells blood vessels and surrounding gland. Investigations Thyroidectomy Calcitonin levels are raised, although serum calcium lev- Hyperthyroid patients must be made euthyroid before els are normal. Calcitonin is also used for follow-up and thyroid surgery using antithyroid drugs and β-blockers for screening of relatives. The thyroid is exposed via a transverse skin-crease Management incision above the sternal notch. The lobes of the thy- Total thyroidectomy and dissection of lymph nodes in roid are supplied by the superior and inferior artery, the central neck compartment. These are dissected out, ligated and divided removing the desired amount of thyroid tissue. Surrounding struc- Anaplastic carcinoma tures that require identification and protection include Definition the parathyroid glands and the recurrent laryngeal This is a highly malignant tumour of the thyroid. Neuropraxia (temporary damage) of the recurrent laryngeal nerve occurs in Pathophysiology 5% of operations. The ipsilateral vocal cord becomes There is evidence that these are poorly differentiated paralysed and fixed midway between closed and open. Bilateralnerveinjuryisrarebutcausesstridorandmay They often arise in elderly patients with a long history of subsequently require laryngoplasty or permanent tra- goitre in whom the gland suddenly enlarges. Subsequent These tumours are rapidly growing and invade local hypothyroidism is treated with lifelong thyroxine structures early, most patients present with a rapidly en- supplements. This is the rate-limiting step for the pro- Resection is rarely possible, but may be carried out for duction of all the adrenocortical hormones. Radioactive io- mainly controlled in this way, aldosterone is mainly con- dine and radiotherapy are ineffective. Aldosterone is the corticosteroid with the most min- eralocorticoid activity, so-called because it controls Cortisol sodium, potassium and water balance. Its production Cortisol is the major glucocorticoid, although aldos- is stimulated mainly by the renin–angiotensin system. The glu- Renin is secreted from the juxtaglomerular apparatus in cocorticoids control glucose metabolism, for example the kidney in response to reduced renal blood flow, for gluconeogenesis, and mobilisation of fat stores (lipol- example due to hypotension. Inhibition of fibroblasts, causing reduced amounts of collagen Thinned skin, striae 6. Immunologic effects, mainly ↓ inflammation and ↑ migration of ↑ Susceptibility to inflammatory cells to areas of injury infections 8. In females 50% of the peripheral Cortisol opposes insulin, with a catabolic effect. Clinical features Common features include centripetal obesity (moon Cushing’s syndrome face, buffalo hump), plethora, osteoporosis, proximal Definition myopathy, easy bruising, striae, acne, hirsutism, poor Cushing’s syndrome is the clinical syndrome resulting wound healing and glucose intolerance. As there is a diurnal rhythm and vari- Pituitary adenoma able cortisol secretion a 24-hour urine collection or (Cushing’s disease) low-dose dexamethasone suppression test is used (see Pituitary carcinoma Fig. Radiotherapy is used in treatment of the adrenals of unresectable pituitary adenomas. Screening Tests Single dose dexamethasone given at night, plasma cortisol level taken at 9am the following day. It is familial, and associated with Pathophysiology/clinical features other organ specific autoimmune diseases, especially As for Cushing’s syndrome. Macroscopy Bilateral adrenocortical hyperplasia twice the size of Pathophysiology normal, with thickening of zona reticularis and the r The mineralocorticoids (90% activity by aldosterone, zona fasciculata. The zona glomerulosa appears normal, some by cortisol) act on the kidneys to conserve because mineralocorticoid production is controlled pri- + + sodium by increasing Na /K exchange in the dis- marily by the renin–angiotensin system. In Addison’s dis- ease, gradual loss of these hormones causes increased Microscopy sodium and water loss with a consequent decrease in The pituitary tumour is normally a microadenoma. Irradiationisusedpost-surgery,forpatientswhere cytomegalovirus complete resection was not possible. Drugs which in- Autoimmune hibit adrenal cortisol synthesis are often used as adjunc- Vascular – haemorrhage (associated with meningococcal tivetherapy,e. Their disadvantage is that they increase thrombosis Neoplastic – secondary carcinoma (e. Failure to exchange Na+ samples over a 24-hour period is used to distinguish for H+ ions can lead to a mild acidosis. Reduced cortisol may lead to symptomatic hy- Chronic adrenal insufficiency is treated with glucocor- poglycaemia. Par- pituitary, other hormones are also secreted such as enteral steroids are needed if vomiting occurs. There are often gastrointestinal com- Aetiology plaints such as anorexia, nausea, vomiting, abdominal Patients may already be diagnosed with Addison’s Dis- pain, constipation or diarrhoea. It Examination reveals weight loss, hyperpigmentation may also be caused acutely by bilateral adrenal haemor- especially in mouth, skin creases and pressure areas.

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