Charles Steenbergen, Jr, M.D., Ph.D.

• Professor of Pathology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0021100/charles-steenbergen

He assumed that all species are subject to natural selection and that therefore for each species there is an age beyond which extrinsic limitations would so dominate that intrinsic limitations would have no effect prehypertension 135 purchase lopressor online. He explicitly assumed that an older immortal organism would be functionally identical to its younger self and therefore have identical fitness blood pressure chart time of day cheap generic lopressor uk. The difference between older and younger immortal organisms is that there are fewer of them because of extrinsic causes of mortality blood pressure guidelines 2013 generic lopressor 25mg with mastercard. Kirkwood) subsequently proposed (dotted line arteria descendens genus cheap lopressor 50mg mastercard, concept 3) that the evolutionary value of additional lifespan free of the deleterious effects of aging declines but never declines to exactly zero blood pressure regular buy lopressor on line amex. In addition arrhythmia echocardiogram purchase 25 mg lopressor with visa, aging causes degradation at relatively young ages and this degradation has obvious negative effects on survival potential. These theorists therefore propose that aging must be an unavoidable adverse side-effect that is coincidentally rigidly linked to some beneficial design property. Because the evolutionary benefit of life declines once an organism has had some opportunity to reproduce, the ultimately catastrophic disadvantage of aging could be outweighed by a relatively smaller 59 the Evolution of Aging compensating advantage to younger animals. The assumed rigid linkage prevents the evolution process from producing a design that accomplishes the benefit without the adverse side-effect. The rigid linkage concept is itself subject to counter-argument as described in Chapter 7. The net evolutionary effect of aging is effectively zero if we sum the minor negative effect of not living longer (curve 3) and the positive effects of the assumed linked properties. If we look at lifespans of thousands of different species it is obvious that a species can evolve whatever lifespan it needs from an evolutionary standpoint. Therefore if the net value of living longer and reproducing more at some age were even slightly positive it is assumed that the organism would have evolved a longer life. We all have eyebrows therefore we infer that eyebrows must convey some tiny evolutionary advantage. All of the above concepts are compatible with traditional (c ~1950) evolutionary mechanics theory, which requires evolved traits to increase the ability of individual organisms to survive or reproduce. Concepts 2 and 3 provide a much better fit to multi-species lifespan observations than concept 1. Finally, advocates of purposely programmed or adaptive aging such as Weismann and subsequent current proponents (dashed line, concept 4) contend that beyond some speciesspecific lifespan, also dependent on age of reproductive maturity, additional lifespan creates an evolutionary disadvantage and that therefore organisms evolved mechanisms for proactively limiting their lifespans to achieve an optimum lifespan. In this case there would be evolutionary force (f) to both achieve the species-specific optimum lifespan by means of myriad complex evolved survival characteristics and also to avoid exceeding it by means of an evolved lifespan limiting mechanism. Because, unlike the other concepts, there is evolutionary force toward limiting lifespan, there is an evolutionary rationale for the development of a complex mechanism to accomplish the limiting function. Instead of proposing that at some age the net value of further survival and reproduction declines to zero it proposes that at some age the net value of surviving and reproducing becomes at least slightly negative. Programmed theories of aging (complex lifespan regulation) based on life-value concept 4 also fit the multi-species lifespan observations (see following table) and, in addition, provide a better fit to many other observations including the following: -Caloric restriction effect toward increasing lifespan -Stress effects toward increasing lifespan -Progeria and Werner syndrome -Aging genes produce aging with no known traditional (individual) benefit -Negligible senescence, apparently non-aging organisms -Observed lifespan regulation in simple organisms (Kenyon, et al) -Octopus suicide mechanism (Wodinsky, 1977) -Similarity in aging symptoms between short and long-lived species 60 the Evolution of Aging Because the assumed beneficial effects of limiting lifespan could trade off against the presumed residual beneficial effect of living longer shown in curve 3, programmed aging theories do not have to assume the existence of rigid linkages that improbably only affect aging. If some ancestor species evolved a long lifespan, would this mean that all of its descendent species would have a lifespan at least as longfi Since programmed theories assume evolutionary force toward both achieving the target lifespan and not exceeding it, they do not have this problem. Some theorists contend that for animals that nurture their young, the value of life varies between conception and reproductive maturity. I have not attempted to portray this in the diagram because it is not germane to the aging and lifespan issue. There are a number of important points to note regarding the value-of-life controversy: 1. The four concepts span all of the possibilities regarding evolutionary value of life vs. Despite 150 years of effort we have been unable to definitively narrow the possibilities. Theories of biological aging are essentially dictated by the value of life issue and each concept has its own dependent set of biological aging theories. These arguments tend to resemble arguments as to how many angels can fit on the head of a pin! They therefore logically tend to believe in fundamental limitation 61 the Evolution of Aging theories, which in turn suggest that aging is an unalterable property of life and that consequently our ability to prevent or treat massively age-related diseases may be severely limited. If one believes in, say, concept 2 for mammals, there is no obvious reason for believing in a different lifevalue concept in connection with birds or perhaps even plants. However, those proposing dependent mammal aging theories often want to consider only mammals while excluding and ignoring any contrary evidence derived from non-mammal species. All of the evolutionary programmed and non-programmed aging concepts (curves 2, 3, and 4) agree that at some species-specific age the net evolutionary value of surviving and reproducing must be effectively zero. To illustrate, imagine an experiment to determine if some agent extends lives of rats. We compare the lifespans of a group of treated rats to a control group of untreated animals. A false 62 the Evolution of Aging positive result could obviously be obtained merely by excluding some of the negative data points. Good science demands extremely careful consideration of the validity of each exclusion. People discussing human aging theories based on wear and tear or other generic or even universal damage mechanism. It might seem perfectly reasonable that an article about a human aging theory, written by someone only interested in human aging, for an audience that was primarily or exclusively interested in humans. One can certainly understand that humans are very different from, say, the tiny roundworm C. Maybe this difference justifies exclusion of roundworm data from mammal aging theoriesfi The problem with this is that all of the nonprogrammed aging theories are based on concepts that are extremely widely applicable to living organisms. Traditional evolutionary mechanics is specifically proposed as applying to all organisms. The value-of-life concepts are also apparently applicable to at least all sexually reproducing organisms having specific lifespans. Therefore, neither evolutionary mechanics nor the valueof-life concepts provide a rationale for excluding roundworm or other non-human data from an aging theory. Good science would demand that the theorist identify the specific rationale used in excluding each item of contrary data. Advice to reader: When reading papers about aging theory, consider carefully what empirical evidence (see chapter 6) is being excluded and the rationale (if any) presented for the exclusion. Digital Genetics and Evolution Theory Our knowledge of the mechanics of inheritance has increased enormously since the time of Darwin or even the time of Medawar. This chapter is intended to provide only a brief summary of the aspects of modern genetics that are relevant to discriminating between various theories of evolutionary mechanics and dependent theories of aging. Since evolution involves the modification and propagation of heritable information that directs the design characteristics of organisms, an understanding of the mechanics of inheritance is critical to understanding evolution. Early scientists thought that sexual reproduction involved transmission of a miniature microscopic animal. Another early theory had it that the miniature animals were nested such that the outermost animal grew larger and then transmitted the remaining nested microscopic animals during reproduction. This scheme would apparently be limited in the total number of consecutive reproductions and did not explain why animals shared characteristics of both parents. The information was somehow stored in the organism during its life and then transmitted to descendants during reproduction. If a giraffe stretched its neck reaching for food its descendants would have longer necks. If a blacksmith developed enlarged arm muscles as a result of his profession, his sons would be more likely to have larger arms. This idea, that events that happened during the life of an organism could affect and modify the stored information in a structured way has been subsequently disproved. Therefore, sexual reproduction involves the copying and transmission of genetic information as well as the structured merging of information from two parents to direct the design of the descendent organism. Growth of an organism involves reading and interpreting the information and constructing an organism whose design is specified by the plan conveyed by the transmitted information. Finally, the design of all organisms provides some mechanism for storing the genetic information so that it is available for subsequent reproduction. Evolution theory tells us that species evolved from other species so it is obvious that some mechanism must exist for modifying genetic information. Evolution theory says that species could build upon and extend the characteristics of ancestor species so that it is clear that the modifications are progressive and cumulative. We now know that evolution of life on Earth has been progressing for about four billion years. The mechanisms that are being used by nature to copy and store genetic information are apparently capable of such high fidelity that such a progression is possible. If there is some limit to the ultimate extent to which evolution can progress, we have apparently not yet reached it. These two modes for transmission, storage, and copying of information have very different properties. An understanding of these properties is critical to understanding genetics issues in evolution and aging theories. The displacement and path of the resulting track was continuously variable in response to the sound pressure. The phonograph was an instrument for storing and reproducing information in analog form. The information stored in such a recording could be copied to make thousands of duplicate recordings that could be transmitted far and wide. The operator converted written characters into a code consisting of long or short marks separated by spaces. Since the signal (the desired, information) is continuously variable, any disturbance introduces an error or discrepancy from the original signal that cannot be removed because it is indistinguishable from the signal. This is an especially severe problem when consecutive copies of information are made. Edison could make thousands of copies of an original because each copy was a copy of the original, that is, there was only one generation. If we needed to make a copy of a copy of a copy of a copy the cumulative noise buildup would be very severe. That is, we could convert the 27 possible English symbols to 27 possible combinations of five binary digits. This scheme was used in the Baudot code (invented in 1870 by Emile Baudot) used for early automated telegraph (teletype) machines. Suppose we had some automated weather stations and wanted to send a digital message from each station to our central location several times per hour. Suppose further that our system works by sequentially sending any of four possible symbols denoted A, B, C, and D. We could devise a message format or code as follows: 65 the Evolution of Aging Symbols would be sent in order reading from left to right.

Symptoms and Signs mine receptors and may be particularly useful in chronic urticaria arrhythmia 2014 ascoms purchase lopressor mastercard, although its use may be limited by the sedating the symptoms and signs of anaphylaxis or anaphylactoid side effect arrhythmia hyperkalemia best 50mg lopressor. Common causes of systemic Tryptase released by mast cells can be measured in the serum allergic and pseudoallergic reactions blood pressure 7843 purchase cheap lopressor line. The blood sample should be obtained within 3 Drugs hours of onset of the reaction hypertension young age buy lopressor with visa, although tryptase levels are Antibiotics often normal heart attack troublemaker order lopressor on line amex, particularly in individuals with food-induced Anesthetic agents anaphylaxis heart attack low vs diamond purchase lopressor mastercard. The complete blood count may show an eleFoods vated hematocrit due to hemoconcentration. Elevation of Peanuts, tree nuts, shellfish, and others serum creatine kinase, aspartate aminotransferase, and lactic Biologicals Latex dehydrogenase may be seen with myocardial involvement. Antisera Arterial blood gases may show hypoxemia, hypercapnia, and Blood products acidosis. Enzymes Monoclonal antibodies (eg omalizumab) Insect venoms Differential Diagnosis Causes of anaphylactoid reactions Although shock may be the only sign of anaphylaxis, other Radiocontrast media Aspirin and other nonsteroidal anti-inflammatory drugs diagnoses should be considered, especially in the setting of Anesthetic agents sudden collapse without typical allergic findings. Anaphylaxis is highly likely when any one of the following Mastocytosis, hereditary angioedema, scombroid poisoning, three criteria are fulfilled: vasovagal reactions, vocal cord dysfunction, and anxiety 1. Acute onset of an illness (minutes to several hours) with attacks may cause symptoms mistaken for anaphylaxis. Respiratory compromise (eg, dyspnea, wheeze-bronreaction, complications may vary from none to aspiration chospasm, stridor, reduced peak expiratory flow, pneumonitis, acute tubular necrosis, bleeding diathesis, or hypoxemia) sloughing of the intestinal mucosa. Reduced blood pressure or associated symptoms of heart and brain damage can be terminal. Risk factors for end-organ dysfunction (eg, hypotonia [collapse], synfatal or near-fatal anaphylaxis include age (adolescents and cope, incontinence) young adults), reactions to peanut or tree nuts, associated 2. Two or more of the following that occur rapidly after asthma, strenuous exercise, and ingestion of medications exposure to a likely allergen for that patient (minutes to such as fi-blockers. Involvement of the skin-mucosal tissue (eg, generalPrevention ized urticaria, itch-flush, swollen lips-tongue-uvula) Strict avoidance of the causative agent is extremely imporb. Reduced blood pressure or associated symptoms (eg, temporal relationship between exposure and onset of symphypotonia [collapse], syncope, incontinence) toms. Persistent gastrointestinal symptoms (eg, crampy abor skin testing may be indicated. With exercise-induced dominal pain, vomiting) anaphylaxis, patients should be instructed to exercise with 3. Reduced blood pressure after exposure to a known alleranother person and to stop exercising at the first sign of gen for that patient (minutes to several hours) symptoms. Low systolic blood pressure in children, defined as less laxis should carry epinephrine for self-administration (eg, than 70 mm Hg in those aged from 1 month to 1 year, EpiPen or Twinject in 0. Patients with idioIntravenous methylxanthines are generally not recompathic anaphylaxis may require prolonged treatment with mended because they provide little benefit over inhaled fi2oral corticosteroids. Corticosteroids Treatment Although corticosteroids do not provide immediate benefit, when given early they may prevent protracted or biphasic A. Exposure to the triggering agent prednisone, 1 mg/kg up to 50 mg, might be sufficient for less should be discontinued. Oxygen Hypotension refractory to epinephrine and fluids should be should be delivered by mask or nasal cannula with pulse treated with intravenous vasopressors such as noradrenaline, oximetry monitoring. Epinephrine the patient should be monitored after the initial symptoms Epinephrine is the treatment of choice for anaphylaxis. Epihave subsided, because biphasic or protracted anaphylaxis nephrine 1:1000, 0. In two reports describing children, adolescents, and adults who died from foodC. Addition of ranititoms are recognized promptly and treated aggressively, dine, an H2-blocker, 1 mg/kg up to 50 mg intravenously, may and the offending agent is subsequently avoided. Exercisebe more effective than an H1-blocker alone, especially for induced and idiopathic anaphylaxis may be recurrent. Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. In the presence of serum complement, the Most adverse drug reactions are not allergic although antibody-coated cell is either cleared or destroyed, causing patients or caregivers often report them as a drug drug-induced hemolytic anemia or thrombocytopenia. Sensitization usually occurs via cally mediated and may be due to idiosyncratic reactions, the topical route of administration. Stevens-Johnson syndrome, exfoliative dermatitis, and the Patients or caregivers often describe an adverse drug maculopapular rash associated with penicillin or ampicillin. Adverse drug reactions are any undesirHowever, patients given ampicillin during Epstein-Barr able and unintended response elicited by a drug. They may result from an inherited propensity for hepatic biotransformation of drug into toxic 1. The Clinical Findings penicillins and other fi-lactam antibiotics, including cephaA. Symptoms and Signs losporins, carbacephems, carbapenems, and monobactams, Allergic reactions can result in pruritus, urticaria, angioshare a common fi-lactam ring structure and a marked edema, or anaphylaxis. The other penicillin metabolites are present in associated with the underlying anemia or thrombocytopenia. Sulfonamide reactions are mediated presumably by a reactive metabolite (hydroxylamine) produced by cytoB. Atopy does not predispose to development of difficult, however, because many immunologic reactions are a reaction, but atopic individuals have more severe reactions. In the case of However, another study suggested that although only 2% of contact sensitivity reactions to topical antibiotics, a 48-hour penicillin-allergic patients would react to a cephalosporin, patch test can be useful. Solid-phase in-vitro immunoassays for IgE to penicillins Carbacephems (loracarbef) are similar to cephalosporins, are available for identification of IgE to penicilloyl but are although the degree of cross-reactivity is undetermined. Assays for specific IgG and IgM have been lactam antibiotics with a bicyclic nucleus and a high degree shown to correlate with a drug reaction in immune cytopeof cross-reactivity with penicillin. In contrast, monobactams nias, but in most other instances such assays are not clinically (aztreonam) contain a monocyclic rather than bicyclic ring useful. Skin testing for immediate hypersensitivity is helpful structure, and limited data suggest that aztreonam can be only in predicting reactions caused by IgE antibodies. Penicillin therapy in patients with a history of an immediate hypersensitivity Treatment reaction to penicillin, but with negative skin tests to both A. In contrast, the such as anaphylaxis, urticaria, and angioedema are treated predictive value of a positive skin test is approximately 60%. Not using the minor determinant mixture in skin be managed by withdrawal of the offending agent or reductesting can result in failure to predict potential anaphylactic tion in dose. Unfortunately the minor determinant mixture is pressed by drug withdrawal, antihistamines, and corticosterstill not commercially available, although most academic oids. Approximately 4% of subtreatment with antihistamines and topical corticosteroids. If possible, subsequent therapy should be with an alternative the degree of cross-reactivity of determinants formed drug that has therapeutic actions similar to the drug in from cephalosporins with IgE to other fi-lactam drugs question but with no immunologic cross-reactivity. Desensitization degree of clinical cross-reactivity is much lower than the invitro cross-reactivity. Antibodies to the secondand be considered if alternative therapy is not acceptable. This third-generation cephalosporins appear to be directed at the should be done only by a physician familiar with desensitizaunique side chains rather than at the common ring structure. Of note, desensitithe present literature suggests that a positive skin test to a zation is only effective for the course of therapy for which the cephalosporin used at a concentration of 1 mg/mL would patient was desensitized, unless maintained on a chronic place the patient at increased risk for an allergic reaction to prophylactic dose of the medication as patients revert from a that antibiotic. However, a negative skin test would not desensitized to allergic state after the drug is discontinued. Patients with Stevens-Johnson synallergy to secondand third-generation cephalosporins in drome should not be desensitized because of the high morpatients with penicillin allergy and that penicillin skin testing tality rate. Stevens-Johnson syndrome and toxic sources of latex allergen, although these products are molded epidermal necrolysis may be associated with a high mortality rather than dipped, and allergic reactions to molded products rate. Latex-allergic patients and their caregivers must be continuously vigilant for hidden sources of exposure. Latex Allergy General Considerations Clinical Findings Allergic reactions to latex and rubber products have become A. Symptoms and Signs increasingly common since the institution of universal prethe clinical manifestations of IgE-mediated reactions to cautions for exposure to bodily fluids. Children with spina latex can involve the full spectrum of symptoms associated bifida appear to have a unique sensitivity to latex, perhaps with mast cell degranulation. Localized pruritus and urtibecause of early and frequent latex exposure as well as altered caria occur after cutaneous contact; conjunctivitis and rhinineuroimmune interactions. Finally, vascular colrecurrent exposure to latex such as urogenital anomalies and lapse and shock leading to fatal cardiovascular events may ventriculoperitoneal shunt have also been associated with occur. The primary allergens Latex is the milky fluid obtained by tapping the cultivated include accelerators and antioxidants used in the manufacrubber tree, Hevea brasiliensis. Laboratory Findings excess proteins, then dry-lubricated with a powder such as corn starch. Epicutaneous prick testing is a rapid, inexpensive, and sensiLatex is a complex biologic mixture composed of rubber tive test that detects the presence of latex-specific IgE on skin particles in a phospholipoprotein envelope and a serum mast cells. Obstacles to its use include lack of a standardized containing sugars, lipids, nucleic acids, minerals, and various antigen. The protein component is thought to contain the been associated with skin testing to latex, and intradermal allergenic properties. IgE from latex-sensitized individuals reacts with Immunoassay testing involves the in-vitro measurement different protein components, supporting the notion that of specific IgE, which binds latex antigens. New used for testing have included native plant extracts, raw allergenic epitopes are generated during the manufacturing latex, and finished products. Thus, polypeptides from latex glove extracts vary of latex-induced symptoms or positive skin tests, the sensiboth quantitatively and qualitatively with different brands tivity of immunoassays testing for latex antigens ranges from and lots of gloves. These important because it may be possible to alter the manufacbroad ranges may reflect the patient population studied and turing process to reduce the final allergen content. A Latex is ubiquitous in medical settings, and many sources positive immunoassay test to latex in the presence of a highly may be inconspicuous. The use of powder-free latex gloves is and chestnut have been found to be antigenically similar to an important control measure for airborne latex allergen. Insulin Complications may be similar to those caused by other Approximately 50% of patients receiving insulin have posiallergens. Prolonged exposure to aerosolized latex may lead tive skin tests, but IgE-mediated reactions occur rarely. If less than 24 hours has especially on the hands, can lead to functional disability. Skin testing and desensiAvoidance remains the cornerstone of treatment for latex tization are necessary if the interval between the allergic allergy. Prevention and supportive therapy are the most reaction and subsequent dose is greater than 24 hours. Local Anesthetics supply of vinyl or latex-free gloves for use when visiting a Less than 1% of reactions to local anesthetics are IgEphysician or dentist. Management involves selecting a local anesthetic classified with respect to their ability to induce IgE-mediated from another class. Gloves made from synthetic materials include pected agent, followed by a provocative challenge. To rule Neolon (Becton-Dickinson), Tactyl 1 (Smart Practice), and out paraben sensitivity, skin testing can be done with 1% Elastyren (Hermal). Aspirin & Other Nonsteroidal Prophylactic premedication of latex-allergic individuals has been used in some surgical patients at high risk for latex Anti-Inflammatory Drugs allergy.

She subsequently developed recurrent episodes of severe hypoglycaemia with few or no warning symptoms blood pressure 8660 order 100 mg lopressor free shipping. The options for managing this scenario are discussed arteria vertebralis cheap 50mg lopressor with mastercard, including increased blood glucose monitoring blood pressure monitors at walmart cheap 25mg lopressor overnight delivery, carbohydrate counting prehypertension is defined by what value purchase generic lopressor on line, education on insulin adjustment heart attack troublemaker cheap lopressor 100mg, insulin pump therapy and islet cell transplants blood pressure chart nih generic 12.5mg lopressor fast delivery. What was the rationale behind the trials Questions of repaglinide and glimepiridefi Consider which of her presentA meta-analysis of treatment with sulfonyling features are typical of type 1 diabetes ureas calculated relative risks of hypoglycaemia and type 2 diabetes respectively. However, despite their shorter duragiven a trial of a sulfonylurea, gliclazide 80 mg tion of action, the meglitinides also have a bd. She was taught home blood glucose monitorpotential risk of inducing hypoglycaemia, both as ing with a glucose meter that also allowed meamonotherapy [2] and in combination with metsurement of capilary ketones. Subsequent Course the family history of diabetes in a first-degree She developed symptomatic hypoglycaemia after relative, the pattern of adult onset diabetes on a commencing gliclazide 80 mg bd so the dose was background of a normal body habitus and the reduced to 80 mg daily and metformin was comsensitivity to sulfonylurea therapy raised the posmenced at a dose of 500 mg bd. Given ings of up to 22 mmol/l, co-existing with episodic Case 17 Hypoglycaemia Case Study 143 nocturnal hypoglycaemia. What possible reasons should be considlogue, taken with lunch and the evening meal. Risks of hypoglycaemia related to Coeliac serology and thyroid function were driving were discussed. She that her driving licence would be changed to a collapsed at work without warning and was witperiod-restricted licence. An this episode followed exercise in the form of information leafiet was provided reinforcing the swimming undertaken during the previous everecommendation to keep carbohydrate for emerning, without any adjustment to her insulin dose. She was also informed that if she had an and she was using 1 unit of insulin for 10 g of episode of hypoglycaemia behind the wheel, she carbohydrate. A corTwo months after commencing prandial insutisol day curve on 20+10 mg of hydrocortisone lin, her fasting blood glucose began to rise so she suggested that she was slightly over-replaced, commenced 6 units of a basal, long-acting insulin with cortisol peaking at 1,391 nmol/l, declining analogue and her prandial insulin doses were to 130 nmol/l by mid-afternoon and peaking at increased to 4 units at lunch and 5 units before 600 nmol/l in the early evening before becomher evening meal. It was hydrate counting was arranged 18 months after suggested that she reduce hydrocortisone to diagnosis. Her insulin requirements were still 10 mg with breakfast and 5 mg with her evelow at 1 unit of insulin for 30 g of carbohydrate ning meal with the prospect that a reduction in and a correction dose of 1 unit of insulin to reduce the peak cortisol levels should improve her gluher blood glucose by 6 mmol/l. She denied nonwas considered to have developed impaired adherence to medications. How can you assess awareness of hypoa further episode of severe hypoglycaemia at glycaemia in an individual patientfi Her capillary blood glucose, measured Various methods can be used to assess immediately after the seizure, was 11 mmol/l but awareness of hypoglycaemia [7, 8]. Her the incidence of hypoglycaemia in 29 patients insulin to carbohydrate ratio was reduced to 1 with impaired awareness was 2. By hydrocortisone dose to 20+10 mg as she was contrast, the incidence in the normal awareness concerned that the previous reduction in steroid group (n=31) was only 0. As her this heightened risk of severe hypoglycaemia Case 17 Hypoglycaemia Case Study 145 highlights the importance of identifying impaired Despite these measures and despite frequent awareness of hypoglycaemia. A hypoglycaemia-induced seizure prevalence of impaired awareness of hypoglycaein a supermarket just before lunch required the mia in that study [9] using the Clarke and Gold previous proposal to reduce her breakfast rapidmethods was similar to the prevalence observed acting insulin analogue to be reiterated, with a in previous population studies, indicating a prevfurther reduction in her morning dose. She After a further 6 months the patient sustained was treated with glucagon by emergency paraanother episode of severe hypoglycaemia with medical staff. Specialist ther episode of severe hypoglycaemia causing review confirmed that she had little understandloss of consciousness in the cinema. Despite her ing of carbohydrate counting and had been mealtime insulin doses having been reduced, she adopting a reactive approach to her diabetes by had taken 20 units of rapid-acting analogue for a taking corrective doses in response to hyperglymeal that contained much less than 200 g of caemia rather than pre-empting the dose carbohydrate. It was apparent that attempts at required according to carbohydrate intake and re-education had not been successful. What other options could be considered she maintained that she could not comprehend to reduce the frequency of her recurrent carbohydrate counting and attempting to pursue severe hypoglycaemiafi Her weight had now almost reached her premorbid baseline at 70 kg and HbA1c was 72 mmol/mol (8. The possibility of an insulin pump was conBecause of her past experience of nocturnal sidered but discarded. While insulin pumps can hypoglycaemia she had reduced her basal insusignificantly reduce the frequency of severe lin analogue dose to just 6 units. Consequently, hypoglycaemia in individuals [14], this option fasting blood glucose readings were consiswas felt to be impractical given her inability (or tently in double figures and she was compensatreluctance) to understand and utilise carbohying by taking large doses of rapid-acting drate counting. Having had six episodes of severe analogue with her breakfast, which frequently hypoglycaemia requiring emergency medical resulted in hypoglycaemia by late morning. A programme of diabetes nurse follow-up the National Institute for Health and Clinical was instigated to titrate the dose of her basal Excellence recommends islet cell transplantation insulin and reduce the large doses of rapidas an option for patients with impaired awareness acting insulin being injected at breakfast. The of hypoglycaemia in recognition of the fact that availability of glucagon at home was discussed the procedure can significantly lower the risk of but as she lived alone she felt that this would not hypoglycaemia and may help to restore awarebe useful. In view of the initial diagagain in case this provoked another episode of nostic uncertainty, blood was taken for autoantisevere hypoglycaemia. Repeat coeliac serology and thyroid funcislet cell transplant in November 2011 with a section tests were normal. She reitconfidence to the degree that she has recomerated her previous view that she became menced swimming. Repaglinide versus glyburide: a one-year comparison Symptomatic hypoglycaemia in 411 type 1 diabetic trial. Pecher E, Ristic S, Collober-Maugeais C, Cressier F, Prevalence of impaired awareness of hypoglycaemia et al. Muhlhauser I, Heinemann L, Fritsche E, von Lennep mum doses of metformin alone: 1-year trial results. Nat Clin Pract Endocrinol Continuous subcutaneous insulin infusion for the treatMetab. Ref Type: Online Source, recovery of cognitive function following hypoglycemia London. Interventional procedure severe hypoglycemia in patients with type 1 diabetes guidance 257; 2008. Strachan Abstract Spontaneous hypoglycaemia has a very wide differential diagnosis that depends in a large part on clinical context. In the context of a patient presenting to an out-patient department with suspected hypoglycaemia, confirmation will usually require prolonged fasting. If a hypoglycaemic disorder is confirmed, measurement of serum insulin and c-peptide concentrations at the time of biochemical hypoglycaemia will help to refine the diagnostic possibilities. On some instances she has Trembling Confusion undoubtedly become muddled and on one occaWarmness Tiredness sion recently, her husband had to call an ambuAnxiety Difficulty with speaking lance because he could not rouse her from sleep. She had recovered quickly following the injection and was not taken to hospital. This fact was not appreciated by clinicians performing this test in the 1970s and 1980s and such falls in What are the questions to be askedfi She is describing sympfasting symptoms are undoubtedly more discrimitoms suggestive of hypoglycaemia, recovery folnatory for organic pathology, post-prandial hypolowing ingestion of food and there is even a glycaemia is now increasingly recognised to occur potential diagnostic blood test. This means we in organic disorders, such as insulinoma and folare tantalisingly close to having met all three of lowing bariatric surgery; there are even very rare the essential criteria for making a diagnosis of a cases of glucagon-like peptide 1 secreting tumours hypoglycaemic disorder, i. However, we cannot yet be certain, because we Establishing the symptom profile is also do not know what her blood glucose levels were important and patients should be asked to and, of course, capillary blood glucose test strips describe these in detail. Symptoms of are notoriously inaccurate in the hypoglycaemic hypoglycaemia can be divided into two broad range. First, it a functional basis and indeed not to be true hyposubstantially increases the likelihood of this glycaemia at all. On systems Sulfonylureas enquiry, she does say that she has lost about 6 kg Pentamidine in weight over the last 6 months and that she has Hyperinsulinaemia of infancy been experiencing some discomfort in the right High insulin and low c-peptide upper quadrant of her abdomen. Exogenous insulin Low insulin and low c-peptide Alcohol What are the signs to look forfi Patients with insulinomas invariably present Adrenocortical failure, especially in children with weight gain, because they have been eating Non-islet tumour hypoglycaemia more than normal to avoid hypoglycaemia. Inborn errors of metabolism Weight loss, in the context of a previous tumour, is not good news. If her brain is not workably unrewarding, but in this situation we need to ing properly when she first gets symptoms, she is look for signs of potential malignant disease. We need to find out urgently drug therapy is a very important precipitating what the nature was of the tumour removed 4 factor (Table 18. The other potential causes of years ago; we need to confirm the occurrence of hypoglycaemia relate to the context of the patient. She could have a malignant insulinoma, in a hospitalised patient, where liver disease and but that would mean the previous tumour is unresepsis predominate, compared with an out-patient lated. However, one would expect her to ackee fruit are common causes in some parts of be more unwell in this situation and possibly the world. Finally, she could have non-islet In this case, the patient reports that she has cell tumour hypoglycaemia. She does not sweat as nearly as much now during episodes as she did when they first started happenWhat diagnostic tests are requiredfi However, for the sake of clarity, they will be bloods for insulin and c-peptide, and possibly be presented in a logical sequence. There is no level of blood glucose which hypoglycaemic state, it is likely that you will is diagnostic of hypoglycaemia, but the lower have to try an induce an episode of hypoglycaethe glucose levels is below 3. Even, if she does more likely it is to have pathological present to an emergency department with sympsignificance. The key diagblood glucose, the lower the insulin and c-pepnostic test is the 72-h fast. As a rough rule of thumb likely that only a short period of fasting will be though, an insulinoma is likely if venous glucose required before the patient becomes hypoglycaeis <3. When insulin and come in fasting from 10 pm the night before, but c-peptide levels are both elevated, sulfonylurea that might be quite risky in this patient and she activity should be measured even in non-diabetic should be asked simply to avoid breakfast and individuals, as there are well-described instances attend at 8 am. The location for performing a of factitious or felonious administration of these 72-h fast is important. Whatever the locathe patient had a neurofibrosarcoma resected tion, it is crucial that there is a formal written pro4 years previously. During the proand for the test to be stopped when a capillary longed fast, the patient became symptomatically blood glucose reads 3. Insulin Case 18 Spontaneous Hypoglycaemia 153 the endocrinology team is then left with the difficult task of reducing or preventing hypoglycaemia. The patient should be counselled about the risks of hypoglycaemia and the potential for a further change or loss of warning symptoms.

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Diseases

• Hemifacial atrophy progressive
• Patel Bixler syndrome
• Fetal and neonatal alloimmune thrombocytopenia
• Rigid spine syndrome
• Guanidinoacetate methyltransferase deficiency
• Preaxial deficiency postaxial polydactyly hypospadia
• Horseshoe kidney
• Muscular dystrophy congenital infantile cataract hypogonadism
• Bazopoulou Kyrkanidou syndrome