Jayanth Radhamohan Doss, MD
- Assistant Professor of Medicine
https://medicine.duke.edu/faculty/jayanth-radhamohan-doss-md
On top of this genetic predisposition treatment h pylori buy cheap aricept 10 mg on line, an environmental insult is likely to be required for the development of diabetes medications you can take while nursing order 5 mg aricept mastercard. The environmental factors are quite varied and we are only now beginning to isolate some of them medications versed order cheap aricept. Congenital rubella cases provide compelling evidence that some of these environmental triggers are viral proteins treatment xdr tb guidelines purchase aricept 10mg overnight delivery. Approximately 20 percent of babies with congenital rubella will develop type 1 diabetes mellitus medications given during labor order aricept 10 mg with amex. Other viruses such as Coxsackie virus treatment quad tendonitis purchase 5mg aricept fast delivery, cytomegalovirus, and hepatitis viruses have been implicated. Polyuria, polydipsia, weight loss, fatigue, polyphagia, anorexia, deteriorating school performance, failure to thrive, and nocturnal enuresis can occur. Clinical symptoms become apparent when the blood sugar rises above the renal threshold and glycosuria induces an Page 515 osmotic diuresis. Insulinopenia allows hormone sensitive lipase to cut long fatty-acid chains into two carbon acetate fragments which are converted to ketoacids. Patients will present in varying degrees of decompensation as the serum pH decreases and as the dehydration progresses. New onset type 1 diabetes will frequently present with diabetic ketoacidosis of varying severity. Secondary enuresis, unexplained weight loss, and polyuria should raise suspicions about diabetes. A random glucose of >200 mg/dl and elevated ketones in the urine or serum in the presence of classic symptoms of diabetes strongly supports the diagnosis of diabetes. There is no single test that will definitively differentiate between type 1 and type 2 diabetes. In the case of type 1 diabetes, the capacity to make insulin will decrease over the course of several months as islet cell destruction advances. In type 2 diabetes, the beta cell function is lost over the course of years to even decades. Despite hyperglycemia, glucose cannot be transported into many cells in the absence of insulin. Therefore, cellular energy metabolism utilizes lipolysis with resultant organic acid, ketone formation. Patients classically present with severe dehydration, vomiting, deep respirations (respiratory compensation for metabolic acidosis) and a ketotic odor to the breath. Complications such as cerebral edema may occur, the etiology of which is not fully understood. However, severely dehydrated or patients in shock will need more aggressive fluid administration rates. Cerebral edema occurs because the high extracellular glucose levels result in osmotic gradients which pull water from the cells creating cellular dehydration (similar to how a grape changes into a raisin). The hyperosmolar non-ketotic state has a substantial mortality rate in the 25% range especially if the patient presents in coma, because cerebral cells are subjected to greater degrees of cellular dehydration and a higher risk of irreversible injury. The answer is uncertain, but it may have something to do with differences in lipid metabolism between individuals. Once patients are stabilized on the hospital floor, subcutaneous insulin is currently the standard treatment. The back-up system for the pump, however, is injections so everyone should learn the basics of subcutaneous insulin injections. The key to managing diabetes is to balance the factors that increase the blood sugar with the factors that decrease the blood sugar. Parents of children with diabetes need to learn enough about diabetes to take care of their children at home. At the very least, they will need to learn about: insulin injections, the types of insulin, blood glucose monitoring, the influences of diet on blood sugar, the influence of exercise on blood sugar, the influence of illnesses on blood sugar, symptoms of hypoglycemia, and the proper response to high and low blood sugars. Several education sessions are usually needed to cover the large amount of information. With so many important aspects to the treatment of diabetes, a team approach that includes dietitians, counselors, diabetes educators, and doctors usually works best. The sophistication of the family and the ability of the child to give themselves their own shots are important considerations. Two common insulin programs include the mixed-split program and the multiple daily injection program. In the mixed split program, two insulin types are mixed together and given in two injections. Each shot is supposed to take care of two different meals so the morning shot will take care of breakfast and lunch. This program is fairly flexible and usually leads to better control of the blood sugars. Careful monitoring of the glucose levels is required to adjust the doses on a daily basis while they are in the hospital. Because the insulin shots are not physiologic, we may need to tolerate a high post-prandial sugar in some patients. Some children and infants are continuously post-prandial so their blood sugar control is often quite complex. Aiming for excessively tight blood sugar control with a complex insulin program will likely fail in children with complex social issues at home. With this in mind long-term management would include getting as many blood sugar levels into a "goal range" as reasonably feasible. Goals for the hemoglobin A1C values should also be tailored to meet the needs of the family and the patient. In general, lower hemoglobin A1C values are desirable, but the incidence of hypoglycemia is important. Hemoglobin A1C values that are less than 8 are often attainable in elementary school children. To achieve these lower hemoglobin A1 C values, adjusting the insulin doses are mandatory. Most families can learn enough about diabetes to adjust the insulin doses themselves. A consistently high pre-lunch blood sugar, for instance, would imply Page 516 that the breakfast insulin should be increased. The insulin dose should be increased if the meal was not excessive and if the patient was not particularly active. There is some debate about whether insulin resistance or decreased insulin release is the initial problem. Both of these problems occur and the effects of the relative insulinopenia can be found in utero. Adults with type 2 diabetes are much more likely to have had an intrauterine growth retardation than the adults without type 2 diabetes. The early stages of type 2 diabetes are characterized by relatively normal fasting glucose levels but elevated post-prandial blood sugars. This occurs since the insulin that is available can eventually lower the blood sugar levels but cannot take care of the glucose load soon after a meal. As the disease progresses, islet cell function slowly declines in type 2 diabetes and the fasting blood sugars will rise as well. The same insulin program with the same adjustment strategies will work very well in even the early phases of type 2 diabetes. When type 2 diabetes, as patients slowly lose their ability to make insulin, they will more closely resemble people with type 1 diabetes and insulin becomes a necessity. Theoretically, sulfonylureas, biguanides, and thiazolidinediones can be used in children as they can in adults. Studies that show efficacy and safety in children are not yet available so they must be used with caution. The identical twin of a patient with type 1 diabetes has what risk for developing type 1 diabetes Pediatric Endocrinology: Physiology, Pathophysiology, and Clinical Aspects, 2nd edition. It is elevated when the glucose levels are high and it is a good marker for diabetes control. Her family history is significant for a grandmother and aunt with Hashimoto thyroiditis. Clinically, there is resolution of her tachycardia, weight loss, and fatigue, and her goiter decreases in size. The hypothalamic-pituitary-thyroid axis regulates production and maintains peripheral concentrations of the biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). It is synthesized as a component of the large (660-kD) precursor thyroglobulin molecule. Iodine is the rate-limiting substrate, which must be actively transported in to the thyroid follicular cell by a plasma membrane sodium/iodide pump. Thyroid hormones also bind to albumin and lipoproteins with lesser affinity (1,2). T4 serves largely as a prohormone and is deiodinated in peripheral tissues by several iodothyronine monodeiodinase enzymes to active T3 or biologically inactive reverse T3 (rT3). The major source of circulating T3 is peripheral conversion from T4, largely by the liver. Only small amounts of T3 are secreted Page 517 by the thyroid gland in euthyroid subjects ingesting adequate iodine. The T3 mediates the predominant effects of thyroid hormones via binding to the 50-kD nuclear protein receptors, which function as transcription factors modulating thyroid hormone-dependent gene expression (1,2). During the first trimester of gestation, the thyroid gland arises from the foramen caecum at the base of the tongue and migrates caudally to the neck site. The placenta is permeable to thionamide drugs used to treat maternal hyperthyroidism, which could result in fetal and early postnatal hypothyroidism. T3 and T4 concentrations increase 2 to 6 fold, peaking at 24 to 36 hours after birth and gradually declining to levels characteristic of infancy over the first 4-5 weeks of life. Transient (transplacental passage of antithyroid drugs, maternal transfer of antibodies) Secondary hypothyroidism: 1. Euthyroid Sick Syndrome Congenital hypothyroidism (3) is an important cause of mental retardation that can be prevented with early identification and treatment. Newborn screening for congenital hypothyroidism is now routine in most industrialized societies. Screening tests are usually carried out with dried blood spot samples collected via skin puncture. Thyroid dysgenesis describes infants with ectopic or hypoplastic thyroid glands as well as those with total thyroid agenesis. Ectopic glands may be located anywhere from the base of the tongue, along the thyroglossal duct, laterally, or as distant as the myocardium. A normal or near normal circulating level of T3 in the presence of low T4 suggests the presence of residual thyroid tissue, and this can be confirmed by a thyroid scan. A measurable level of serum thyroglobulin indicates the presence of some thyroid tissue; athyroid infants have no circulating thyroglobulin. Dyshormonogenesis, or the inborn errors of thyroid hormone synthesis, secretion, and utilization, follows an autosomal recessive pattern of inheritance. The most common defect involves deficiency of thyroperoxidase enzyme, which is responsible for organification of iodide. Other defects may involve iodide trapping, coupling of tyrosyl rings, abnormal thyroglobulin synthesis, or deiodination of iodothyronines. The presence of a goiter in an infant is supportive evidence of antithyroid drug or goitrogen induced transient hypothyroidism. Physical examination may reveal one of several early and subtle manifestations of hypothyroidism, including a large posterior fontanelle, prolonged jaundice, macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia or goiter. Fewer than 5% of infants are diagnosed on clinical grounds before the screening report, but 15-20% of infants have suggestive signs when carefully examined at age 4-6 weeks, after the screening results have been reported. For infants with congenital hypothyroidism, prompt initiation of levo-thyroxine (75-100-ug/m2/d) treatment is essential. Page 518 Hashimoto thyroiditis (autoimmune hypothyroidism, chronic lymphocytic thyroiditis) is an autoimmune, inflammatory process causing 55-65% of all euthyroid goiters and nearly all cases of hypothyroidism in childhood and adolescence (5,6). The specific mode of inheritance is not known, but there is a high familial incidence. Thyroid inflammation and damage result from self-directed humoral and cell-mediated immunity. Antibody markers of the destructive process include anti-thyroglobulin and anti-thyroperoxidase antibodies. The initial presentation of Hashimoto thyroiditis can usually be categorized as thyromegaly with euthyroidism, toxic thyroiditis, or hypothyroidism with or without thyromegaly. The majority of patients are asymptomatic and present with an enlarged thyroid gland. The gland may be symmetrically or asymmetrically enlarged with a bosselated (cobblestone) texture. Toxic thyroiditis (Hashitoxicosis) is a transient, self-limited form of hyperthyroidism occurring in less than 5% of patients. If hypothyroidism is present, there may be a history of poor growth, fatigue, constipation, mild weight gain, dry skin and cold intolerance. In addition, serum T3 concentration should be determined if the patient appears to have hyperthyroidism. Long-term follow-up studies indicated that chronic lymphocytic thyroiditis resolves in 50% of children. Replacement therapy should continue until the patient has achieved final adult height. If a child has positive antibodies but is euthyroid, replacement therapy is not necessary, however thyroid function should be monitored regularly.
In general symptoms pulmonary embolism buy aricept 10 mg without a prescription, the risk of infection can be related to the bone marrow reserve and overall immune competence of patients with neutropenia symptoms 5th disease order cheap aricept on line. Careful consideration of the overall risk of infection needs to be utilized to determine the appropriate management of these children treatment algorithm aricept 5mg discount. Inadequate treatment or follow-up of children with neutropenia and a high risk of infection can be fatal symptoms kidney pain buy generic aricept 10 mg on line, while over aggressive treatment of a child with a benign neutropenia may result in inappropriate medical care and unnecessary morbidity medications used to treat anxiety purchase line aricept. These guidelines can be used in the evaluation and management of the child with neutropenia: 1 treatment bronchitis purchase 10mg aricept visa. Empiric parenteral antibiotic therapy (consider ceftazidime, vancomycin, or meropenem) to cover S. Consider outpatient management with a parenteral broad spectrum antibiotic (ceftriaxone) if the child is non-toxic, the family and follow up are reliable, and the child has none of the signs of more serious neutropenia syndromes. If any of these danger signs are present, patients should have more extensive evaluations and a hematology consultation. If no danger signs present themselves, no further testing is needed and parents should be reassured. Routine use of granulocyte-colony stimulating factor to increase bone marrow production of neutrophils is not indicated for most acquired neutropenias and should be limited to specific disorders where the neutropenia is due to inadequacy of the marrow reserve pool. Children with neutrophil dysfunction must be suspected on clinical grounds, keeping in mind that even the most common primary neutrophil dysfunction syndrome is extremely rare. Children with primary neutrophil function defects usually present with low-grade chronic bacterial or fungal infections. Skin and mucosal infections, lymphadenitis, and abscesses are among those infections commonly seen. These infections tend to be persistent and difficult to resolve with standard treatment. Children with suspected immunodeficiency should be screened for humoral, cellular, and complement mediated immunity prior to neutrophil function assays. Once a neutrophil defect is suspected and other causes of primary immunodeficiency are ruled out, referral to a specialist familiar with the evaluation of primary neutrophil defects should be made. Anticoagulated samples (usually sodium heparin) should be freshly drawn and transported as quickly as possible to a neutrophil or immunology laboratory. Control samples and parental blood samples are often requested for comparison purposes. Neutrophil function tests generally need to be performed at research laboratories experienced with the assays. Chediak-Higashi syndrome: Pathophysiology is decreased degranulation, chemotaxis and granulopoiesis; inheritance autosomal recessive; rare with 200 cases reported; multisystem disorder with clinical characteristics that include mild coagulopathy, peripheral and cranial neuropathy, hepatosplenomegaly, pancytopenia, partial oculocutaneous albinism, frequent bacterial infections (usually S. Children with neutrophil functional defects rarely present with overwhelming bacterial or fungal infections, but more commonly suffer from low grade, chronic infections that may become indolent and impossible to effectively treat. Chronic infection and inflammation associated with deep seated infections leads to a high rate of morbidity and shortened survival. Low grade infections that are neglected can evolve into serious disseminated infections without the appropriate, timely administration of antibiotics or antifungal agents. Adding to this difficulty in clinical monitoring, is an attenuated inflammatory response that often masks serious infection. Referral to subspecialists experienced in the management of children with immunodeficiencies or neutrophil disorders is critical to minimize morbidity and mortality for this population. Infections in children with defects in neutrophil function are characterized by: a. Leukocyte disorders: quantitative and qualitative disorders of the neutrophil, Part 1. He is now brought in because his mother notes a decrease in energy, pallor, and easy bruising in his extremities. He complains of leg and arm pains over the last 2 weeks that seem to be aggravated by exercise. The tip of his spleen is 2 cm below the left costal margin and his liver is 3 cm below the right costal margin. His skin shows bruises over the anterior tibial regions and five bruises over the left knee. He is treated with a four drug induction chemotherapy which achieves initial remission. Although only 1% of all cancers occur in children (<19 years of age), it is the second leading cause of childhood death. Early detection and prompt therapy have the potential to prolong survival and frequently cure the disease. A team of experts (nurses, social workers, oncologists, surgeons, pathologists, psychologists) tries to meet the complexities of giving the children the most intense course of therapy possible, while not depriving them from having some level of normalcy (going to school, playing with friends). Surgery, the oldest treatment, provides the best chance of a cure for a localized tumor. It also plays a major role in other aspects of management, including diagnosis, staging, relieving symptoms, reconstruction, and prevention. It is used to treat the primary lesion, shrink a tumor prior to surgery, or palliatively relieve painful symptoms of bone metastasis. Radiation targets rapidly dividing cells, which includes cancer cells and normally dividing cells of the skin, hair, gastrointestinal mucosa, bone marrow, reproductive tissues, sweat glands, and lungs. Some examples are: asymmetry of the irradiated extremity, hypothyroidism, neurological dysfunction, growth retardation, and development of a secondary tumor. It was introduced in the 1940s when Goodman and Gilman first administered nitrogen mustard to patients with lymphoma. Nitrogen mustard, the first alkylating agent used, produced partial remission with considerable toxicity. The era of modern chemotherapy has since evolved to include several other classes of drugs: hormones (prednisone), antimetabolites (methotrexate, 5-fluorouracil), plant alkaloids (etoposide, vincristine, paclitaxel), and antibiotics (doxorubicin, bleomycin). Though chemotherapy has limited use for localized tumors, it is often the most effective agent for the management of disseminated or systemic cancer. These include the hematological malignancies (leukemias, lymphomas), metastasis of the primary solid tumor, and potential micro-metastasis after surgery or radiation. Unfortunately, their utility is limited by the various acute and chronic complications involved with their use. Frequent side effects of chemotherapy include vomiting, diarrhea, cachexia, bone marrow suppression, and immunosuppression. Bone marrow suppression leads to anemia, thrombocytopenia, neutropenia, and hyper-leukocytosis (this is an abnormal increase of white blood cells while the others are an abnormal decrease of different blood precursor cells). In addition, the substantial break down of tumor cells by chemotherapy can lead to tumor lysis syndrome, in which a large amount of phosphate, potassium, and uric acids are released into the circulation, when large number of cancer cells are killed. Patients undergoing chemotherapy often have a decreased appetite and consequently are malnourished. Enteral tube feeding and parenteral hyperalimentation may become necessary when oral intake is severely inadequate. In situations of continual febrile illness for more than 1 week, fungal and viral infections must be considered. Common opportunistic infections include candidiasis, aspergillosis, and Pneumocystis carinii. Temporary prophylactic treatment with trimethoprim/sulfamethoxazole is often prescribed in anticipated bone marrow suppression. Children on chemotherapeutic protocols are prone to complications from disseminated viral infections. They should not be given live attenuated vaccines, since these attenuated organisms may still cause disseminated disease in immunocompromised hosts. Although the acute complications of chemotherapy are relatively manageable, some of its long-term consequences are devastating and often cause significant morbidity and mortality. Irreversible complications include leukoencephalopathy following high-dose intrathecal methotrexate, infertility in male patients treated with cyclophosphamide, myocardial damage from anthracyclines, pulmonary fibrosis after bleomycin, pancreatitis after asparaginase, and hearing loss associated with cisplatin. It is strongly recommended that children be checked annually post chemotherapy to detect a secondary malignancy. Page 434 Most of the chemotherapeutic complications result from their nonspecific targeting of both malignant and normally dividing cells. One of the huge advantages of newer agents is their minimal degree of dose-limiting toxicities. Stem cell transplantation has revolutionized the therapeutic options for primary bone marrow diseases and systemic neoplasms. Both autologous and allogeneic transplants have been employed successfully for a variety of hematological and oncological conditions in which chemotherapy and/or radiation have failed to induce remission. Collection of stem cells is made at various sites in the body: bone marrow, peripheral blood, and sometimes even cord blood. Its limitations still include the non availability of the "right" donors, concern about the lack of randomized comparisons to less risky chemotherapy in certain diseases where chemotherapy alone may induce remission, and chronic graft versus host disease. However, donor immunosuppression inadvertently increases the risk of infections and decreases the graft versus leukemia response that may lead to the higher relapse rate in these cases. Pain management, an essential component of oncological therapy, has recently become a focus of attention. Children were once believed to not feel as much pain because of their underdeveloped nervous system. Pain therefore should be managed in a stepwise fashion, and should be a top priority for any oncological patient, especially those needing palliative care. The major challenge in oncology treatment is to find the right combination of type and amount of chemotherapy, right amount of radiation, and the best timing of stem cell transplantation for each individual patient. In several animal models, it has been successfully proven that the immune system can be an important component in fighting off cancer. If there is some means to engraft a competent immune system to a leukemic patient, it hopefully will stimulate an immune response against leukemic cells. Hence, if it is possible to use a vector to carry the good genes to target the malignant cells, the deposit of the good genes into cancerous cells may lead to tumor regression. What are some common opportunistic infections associated with immunosuppression induced by chemotherapy Hormones (prednisone), antimetabolites (methotrexate, 5-fluorouracil), plant alkaloids (etoposide, vincristine, paclitaxel), antibiotics (doxorubicin, bleomycin), anti-angiogenesis drugs. He has some shortness of breath when he climbs stairs, but his parents deny cough, fever, nausea, emesis, bruising, headache, or visual problems. His past medical health, including birth history, immunizations, and other medical problems is unremarkable. His posterior pharynx is erythematous without lesions and no tonsillar enlargement. He has bilateral cervical nodes, posterior cervical nodes, axillary nodes, and inguinal nodes palpable (about 1-2 cm), mobile and nontender. He is admitted to the hospital and a diagnostic workup including a bone marrow aspirate and biopsy reveals acute lymphoblastic leukemia. The clinical manifestations may present insidiously or acutely, as an incidental finding on a routine complete blood count analysis or as a life-threatening infection or respiratory distress. On physical examination, there may be pallor, hepatosplenomegaly, petechiae, and/or lymphadenopathy. Because some rare cases may be difficult to diagnose even with proper diagnostic biopsies, other diagnoses should be entertained. Recommended staging studies include a careful physical examination, complete blood count, bone marrow aspirate or biopsy, lumbar puncture, and radiographic studies including possible nuclear medicine studies to assess the extent of disease. Prior to instituting specific therapy, measures should be instituted to treat emergent problems, particularly in patients with advanced disease and who may have associated airway compression or superior vena cava obstruction. Measures should also be in place to be able to monitor and intervene for treatment related problems such as tumor lysis. Tumor lysis can occur spontaneously or as a result of chemotherapy leading to serious metabolic complications such as hyperuricemia, hyperkalemia, and hyperphosphatemia. The main goal of therapy is to begin induction treatment as soon as the diagnosis is made in order to obtain remission. In general, therapy is based on cytotoxic drugs affecting the rapidly dividing cells during the cell cycle. Multiple drugs are used because each class of drugs acts on a different part of the cell cycle with the intent of interrupting cell division in the majority of malignant cells. The concept of inducing remission initially is to try and rapidly destroy the majority of malignant cells within the first 30 days of treatment. Ongoing and subsequent treatment strategies are based on the concept that malignant cells that "escaped" the induction phase will enter the cell cycle over a period of time and will then be affected by the drugs. Occasionally, emergency treatment has to be considered for life-threatening situations such as airway compression, spinal cord compression, etc. Additionally, exposure to infectious agents including live vaccines should be avoided. In general, there are clinical and laboratory findings present at the time of diagnosis which may correlate with prognosis. Other factors might include specific chromosome abnormalities, age, race, or gender. Recently, the rapidity of response to induction therapy or the presence of residual disease has been examined as a predictor of outcome. Other challenges are the result of successful treatment and related to screening and treating long term complications from therapy. Children who have received chemotherapy and/or radiation may experience delays in growth and development, therefore further testing and gathering of information should be suggested. You are the primary pediatric resident on the hematology/oncology team and covering the service over the weekend. A 6 year old was admitted on Thursday, with a history of being tired, shortness of breath, pallor and weight loss.
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It with tropical enteropathy treatment solutions purchase aricept, has been questioned is estimated that two billion individuals are iron recently (95) treatment kitty colds generic aricept 5 mg online. The possible relevance of these deficient; most of them are women or children in entities to nutritional iron deficiency is unclear developing countries symptoms graves disease order aricept canada. Finally treatment 8mm kidney stone order aricept 10mg without a prescription, surgical content of bioavailable iron are the primary cause medications names and uses buy on line aricept, procedures that alter the anatomy of the stomach but disorders that increase iron loss as a result of and duodenum may also decrease iron absorption medicine lake california discount aricept 10 mg mastercard. The most common appear to be celiac dis been reported to be a risk factor for iron defi ease (86, 87) and Helicobacter pylori infections ciency anemia in homozygous women (96). It is also impor Iron overload tant to note that inadequate absorption of multiple Iron overload is far less prevalent than iron defi nutrients associated with histological abnormali ciency. It can be considered under three headings, ties of the intestinal mucosa was thought to con primary systemic iron overload, secondary iron tribute to the high prevalence of iron deficiency in overload, both of which affect several different Iron metabolism 69 Table 6. Men who are at greatest and abnormal release from stores, and organ/ risk for the disorder consume large quantities of tissue specific iron overload. However more recent stores increase in human beings with normal observations have provided strong circumstantial mucosal function is remarkable effective. In contrast to iron Dysregulation of hepcidin and abnormal deficiency, primary systemic iron overload function of its receptor Fpn, resulting in inappro appears virtually always to result from the pheno priate iron release from stores and excessive typic expression of an inherited abnormality absorption, are now considered to be the most related to the regulation of iron transport. In the important etiological factors in patients with past, sub-Saharan iron overload was considered primary systemic iron overload (Table 6. Hepcidin the initial stages and an onset in the fourth levels are inappropriately low, but not as severely or fifth decades (105). They continue to absorb Australia demonstrates that many more may have excessive quantities of iron despite increasing laboratory evidence of organ damage (108). Finch unrecognized, a small minority of individuals, proposed the existence of two regulators of iron particularly men, will develop signs and symp absorption, a stores regulator and an erythropoi toms, usually in middle age when the body iron etic regulator (119). Recent pected of being a modulator of signaling for the studies point to a common mediator, hepcidin, for iron sensor for hepcidin (22). Hepcidin production has have their clinical onset in the second or third been reported to be decreased despite elevated decades of life and present a more severe pheno serum ferritin levels (indicative of increased iron type (juvenile hereditary hemochromatosis). One, stores) in the presence of accelerated erythropoiesis type 2A, is associated with a mutation in the (120, 121), leading to continued iron accumulation. Rare cases of juvenile hereditary hemochromatosis There are several other rarer causes of iron (Type 2B) have been linked to mutations in the overload. Examples include abnormalities of ironthe phenotype associated with the gene trafficking in the mitochondrion (122) and aceru encoding TfR 2 (Type 3) occurs early in life, loplasminemia (123, 124). The function of TfR2 is unknown, although recent observations indi Anemia of inflammation cate that it also modulates hepcidin production (anemia of chronic disease) (113). The resulting production and reduced plasma iron and transfer Iron metabolism 71 rin concentrations (125). Many investigators have was well known to occur rapidly after the onset of postulated that it is a vital host response that infection or inflammation. Recent studies demon evolved to deprive pathogens of iron, and that it is strate that synthetic hepcidin administered to one of the mechanisms that constitute nutritional mice causes hypoferremia within hours of a sin immunity (126, 127). The hepcidin response past fifty years, although many questions remain to to inflammation appears to be independent of iron be answered. I have Although the former name of the anemia of provided only a brief overview of some of the inflammation, anemia of chronic disease, sug highlights that are relevant to nutrition and nutri gested slow evolution of the characteristic labora tional anemia. Donovan A, Brownlie A, Zhou Y, Shepard J, Hemosiderin: nature, formation, and significance. Pigeon C, Ilyin G, Courselaud B, Leroyer P, protein activity to inflammation: abnormal be Turlin B, Brissot P, Loreal O. Presence of the iron Transferrin receptors and iron uptake during ery exporter ferroportin at the plasma membrane of throid cell development. Influence of lactoferrin on Characterization of non-transferrin-bound iron clear iron absorption from human milk in infants. Iron in Efficient clearance of non-transferrin-bound iron by ferritin or in salts (ferrous sulfate) is equally rat liver. The uptake of hemoglobin iron by hepatic ization of ferritin from soyabeans (glycine max). Trace element Cellular and molecular mechanisms of senescent uptake and distribution in plants. The transcytosis of divalent metal Microcytic anaemia mice have a mutation in transporter 1 and apo-transferrin during iron uptake Nramp2, a candidate iron transporter gene. Cellular iron: ferroportin is the only Cloning and characterization of a mammalian proton way out. Copper repletion An iron-regulated ferric reductase associated with the enhances apical iron uptake and transepithelial iron absorption of dietary iron. Unexpected role of cerulo Range and consistency of menstrual blood loss in plasmin in intestinal iron absorption. Cellular and subcellular localization of the for vitamin A, vitamin K, arsenic, boron, chromium, Nramp2 iron transporter in the intestinal brush copper, iodine, iron, manganese, molybdenum, nick border and regulation by dietary iron. Effect of iron supplementation on the expression inversely correlates with the expression iron status of pregnant women: consequences for of duodenal iron transporters and iron absorption in newborns. Food iron mucosal uptake of iron and iron retention in idio absorption in idiopathic hemochromatosis. Comments on of iron intake on iron stores in elderly men and methods and some crucial concepts in iron nutrition. Adult coeliac disease: patterns of dietary iron overload in black South prevalence and clinical significance. Variable hematologic presentation variant associated with iron overload in African of autoimmune gastritis: age-related progression Americans. Roetto A, Daraio F, Porporato P, Caruso R, hepcidin in congenital chronic anemias. Iron traf juvenile hemochromatosis: identification of a new ficking in the mitochondrion: novel pathways mutation (C70R). He also mineral bioavailability and infant nutrition, and focuses on iron fortification and biofortification leads a postgraduate course in Nutrition and strategies. Electrolytic iron and ferric pyrophos sumers and by the presence of inhibitors or phate should be added at twice the level of ferrous enhancers of iron absorption in the meal. Addition acid and phenolic compounds, commonly present ally, specific recommendations are given detail in cereal and legume foods, are the major ing which iron compounds are most appropriate inhibitors of iron absorption, whereas ascorbic to add to the different food vehicles. Ascorbic for cereal flours and different cereal based foods, acid is commonly added to iron fortified foods to rice, milk products, cocoa products, and condi optimize iron absorption. Ferrous recently published guidelines on food fortifica bisglycinate or micronized dispersible ferric tion with micronutrients, which include recom pyrophosphate (2) are recommended for liquid mendations for iron fortification compounds and a milk products and other beverages. Recent efficacy studies, which have to a large extent fol Electrolytic iron is the only elemental iron pow lowed these guidelines, have shown good efficacy der recommended for cereal flour and breakfast of iron fortified salt, fish sauce, wheat flour and rice cereal fortification. Atomized iron and carbon diox in improving the iron status of target populations. Hydrogen lines on iron compounds, and present the method reduced (H-reduced) iron and carbonyl iron used to define the iron fortification levels. Ferrous sulfate and ferrous fumarate encap to enhance the bioavailability of fortification iron. This is needed to estimate dietary iron vides tables giving the probability of inadequacy bioavailability at 5%, 10% or 15%. In addition, it is of each target population at different iron intakes necessary to have detailed information on the iron in relation to the expected iron bioavailability intake of the target population. An abbreviated table is wide range of iron intakes within each population shown for menstruating women (Table 7. By subgroup, and the goal of the fortification program combining these values with a detailed knowl is to shift the iron intake distribution in the target edge of iron intake in the target population, it is population upwards, so that only a small proportion possible to calculate the prevalence of inadequate of that population is at risk of inadequate intake. For intakes within the population subgroup (Table most nutrients, the process is to calculate the 7. For each intake range, a prevalence of inade amount of extra daily nutrient required so that only quacy is obtained by multiplying the percentage 2. For these women, the since the iron requirements of some population sub overall prevalence of inadequacy is about 60%. Usual mean Probability of inadequacy for women consuming diets of different iron iron intake bioavailability* mg 15% 10% 5% <5 1. This amount needs to be provided by the for ranking is based either on the ability of the iron tified food vehicle. Category 1 contains iron consuming a whole grain cereal diet and, because compounds that are readily soluble in water. Because they are poorly soluble in water, these compounds cause far fewer adverse organoleptic changes than ferrous sulfate (12). A large selection of potential iron fortifi Because they are water insoluble, these com Table 7. Usual daily Probability of % prevalence of % of women iron intake inadequacy* inadequate intakes mg A B AxB <15 2 1. Relative bioavailability Compound Iron content (%) (relative to ferrous sulfate) Category 1: Water soluble Ferrous sulfate 7H2O 20 100 Ferrous sulfate, dried 33 100 Ferrous gluconate 12 89 Ferrous lactate 19 67/106* Ferric ammonium citrate 17 50-70 Category 2: Poorly water solu ble, soluble in dilute acid Ferrous fumarate 33 30/100** Ferrous succinate 33 92 Category 3: Water insoluble, poorly soluble in dilute acid Ferric pyrophosphate 25 21-75 Micronized dispersible ferric 1. It may, however, similar way as ferrous sulfate in anemic rats fed provoke fat oxidation and rancidity in cereal fortified infant formulas that had been heat flours stored for longer periods (9) and has been processed and freeze dried (28, 29). In this study, volunteer subjects were fed a sulfate is somewhat less soluble, and is preferred meal of rice and vegetable soup seasoned with to the heptahydrate form as it is less prooxidant fish sauce fortified with 57Fe-labeled ferrous (12). The authors suggested that ferrous lactate was unstable in the aqueous fish sauce and degraded in a few days to less well absorbed Ferrous gluconate ferric compounds. It is soluble in water, so would be expected infant formula and fruit flavored beverages (18) to cause similar sensory problems as ferrous sul and has been reported to be organoleptically fate. It has been less frequently used in food forti acceptable in fluid skim milk (30). Although fer fication, as it costs about five times more than fer ric ammonium citrate has been reported to be as rous sulfate. It has been used to fortify infant well absorbed as ferrous sulfate by anemic rats formula (24), grape juice and malt extract (25), (31), several studies in human volunteers have but rapidly causes fat oxidation and off colors in shown it to be less well absorbed than ferrous sul stored cereal based complementary foods (20). Using erythrocyte cious iron fortificant for whole milk powder incorporation of radioiron to measure iron reconstituted for consumption. After cluded that humans absorb pharmacological six months feeding, the prevalence of anemia doses of soluble ferrous iron about five times bet decreased from 41% to 12%, with no change in ter than soluble ferric iron (33). One would imagine that ferrous ammonium citrate was used to fortify fish sauce, fumarate could still be a useful iron compound to which was fed to volunteers with rice and vege fortify complementary foods, provided that the table soup, iron was only 50% as well absorbed as level of iron and ascorbic acid is adjusted so that the from the same meal fortified with ferrous sulfate amount of iron absorbed is sufficient to meet the (13). The reasons for lower iron absorption compared to soluble ferrous iron is presumably from ferrous fumarate than from ferrous sulfate in related to the more ready formation of insoluble, young children are unclear. In a recent stable isotope study from Mexico, iron Category 2: Poorly water soluble iron absorption from ferrous fumarate and ferrous sul compounds which are soluble in dilute acid fate were similar in women, preschool children and infants fed a maize based complementary food Ferrous fumarate (Harrington et al. Ferrous fumarate has been used mostly to fortify cereal based complementary foods for young children, but it has also been added to maize flour Ferrous succinate in Venezuela with some success (36) and to Ferrous succinate, like ferrous fumarate, is insol chocolate drinks (9). It color and may cause sensory problems in some has the advantage of being a pale brownish yel applications. Because of its insolubility in water it low color but, unlike ferrous fumarate, it has not causes fewer sensory changes than ferrous sul been widely used for food fortification. It does not cause fat oxidation during storage been suggested for fortification of infant cereals of cereal based complementary foods, but may and chocolate drinks (12, 37) and has shown cause color changes during preparation for feed equivalent bioavailability to ferrous sulfate in ing, particularly if fruits are present. When making the Ferric pyrophosphate recommendations for the choice of iron fortificant this iron compound is an off-white, water insol for infant foods, it has been assumed that ferrous uble powder which causes few if any sensory fumarate will also be as well absorbed as ferrous changes when added to different food vehicles. Two recent studies in infants and young is widely used to fortify chocolate drink powders children, however, have cast doubt on the use of and has been used extensively to fortify cereal ferrous fumarate for complementary food fortifi based complementary foods. These include the deficiency in the dewormed control children physical characteristics of the compound and the decreased from around 80% to 50%. Both can influence the lence of iron deficiency in the dewormed children dissolution of iron in the gastric juice. In addition, receiving the iron fortified rice decreased from it has been proposed that ferrous sulfate absorp 80% to 25%, significantly lower (P<0.
Because vitamin D can be made in the skin medications via ng tube order aricept pills in toronto, it should not strictly be called a vitamin treatment definition purchase aricept 5mg, and some nutritional texts refer to the substance as a prohormone and to the two forms as cholecalciferol (D3) or ergocalciferol (D2) medications on airline flights purchase genuine aricept on line. From a nutritional perspective symptoms 32 weeks pregnant order aricept with amex, the two forms are metabolised similarly in humans medications kidney infection 5mg aricept fast delivery, are equal in potency medications zithromax discount aricept 10 mg otc, and can be considered equivalent. These functions serve 110 Chapter 8: Vitamin D the common purpose of restoring blood levels of calcium and phosphate to normal when concentrations of the two ions are low. The physiologic loop 10) starts with calcium sensing by the calcium receptor of the parathyroid gland (14). All these events raise plasma calcium levels back to normal, that in turn is sensed by the calcium receptor of the parathyroid gland. Not shown but also important is the endpoint of the physiologic action of vitamin D, namely adequate plasma calcium and phosphate ions, that provide the raw materials for bone mineralisation. Populations at risk for vitamin D deficiency Infants Infants constitute a population at risk for vitamin D deficiency because of relatively large vitamin D needs brought about by their high rate of skeletal growth. At birth, infants have acquired in utero the vitamin D stores that must carry them through the first months of life. Breast-fed infants are particularly at risk because of the low concentrations of vitamin D in human milk (16). Infants born in the autumn months at extremes of latitude are particularly at risk because they spend the first 6 months of their life indoors and therefore have little opportunity to synthesise vitamin D in their skin during this period. Consequently, although vitamin D deficiency is rare in developed countries, sporadic cases of rickets are still being reported in many northern cities but almost always in infants fed human milk (17-20). Excess production of vitamin D in the summer and early fall months is stored mainly in the adipose tissue (22) and is available to sustain high growth rates in the winter months that follow. Insufficient vitamin D stores during these periods of increased growth can lead to vitamin D insufficiency (23). Elderly Over the past 20 years, clinical research studies of the basic biochemical machinery handling vitamin D have suggested an age-related decline in many key steps of vitamin D action (24) including rate of skin synthesis, rate of hydroxylation leading to activation to the hormonal form, and response of target tissues. There is evidence that this vitamin D deficiency contributes to declining bone mass and increases the incidence of hip fractures (27). Although some of these studies may exaggerate the extent of the problem by focusing on institutionalised individuals or in-patients with decreased sun exposures, in general they have forced health professionals to re-address the intakes of this segment of society and look at potential solutions to correct the problem. These findings have led agencies and researchers to suggest an increase in recommended vitamin D intakes for the elderly from the suggested 2. The increased requirements are justified mainly on the grounds of the reduction in skin synthesis of vitamin D, a linear reduction occurring in both men and women, that begins with the thinning of the skin at age 20 years (24). Pregnancy and lactation Elucidation of the changes in calciotropic hormones occurring during pregnancy and lactation has revealed a role for vitamin D in the former but probably not the latter. The concern that modest vitamin D supplementation might be deleterious to the foetus is not justified. Furthermore, because transfer of vitamin D from mother to foetus is important for establishing the newborns growth rate, the goal of ensuring adequate vitamin D status with conventional prenatal vitamin D supplements probably should not be discouraged. Consequently, there is no great drain on maternal vitamin D reserves either to regulate calcium homeostasis or to supply the need of human milk. Because human milk is a poor source of vitamin D, rare cases of nutritional rickets are still found, but these are almost always in breast-fed babies deprived of sunlight exposure (17-20). Furthermore, there is little evidence that increasing calcium or vitamin D supplements to lactating mothers results in an increased transfer of calcium or vitamin D in milk (38). Thus, the current thinking, based on a clearer understanding of the role of vitamin D in lactation, is that there is little purpose in recommending additional vitamin D for lactating women. The goal for mothers who breast-feed their infants seems to be merely to ensure good nutrition and sunshine exposure in order to ensure normal vitamin D status during the perinatal period. Accurate food composition data are not available for vitamin D, accentuating the difficulty for estimating dietary intakes. Skin synthesis is equally difficult to estimate, being affected by such imponderables as age, season, latitude, time of day, skin exposure, sun screen use, etc. Previously, many studies had established 27 nmol/l as the lower limit of the normal range. However, a recent editorial in a prominent medical journal attacked the recommendations as being too conservative (45). This came on the heels of an article in the same journal (46) reporting the level of hypovitaminosis D to be as high as 57 percent in a population of ageing (mean 62 years) medical in-patients in the Boston area. Of course, such in-patients are by definition sick and should not be used to calculate normal intakes. Nevertheless, in lieu of additional studies of selected human populations, it would seem that the recommendations of the Food and Nutrition Board are reasonable guidelines for vitamin D intakes, at least for the near future. In most situations, approximately 30 minutes of skin exposure (without sunscreen) of the arms and face to sunlight can provide all the daily vitamin D needs of the body (24). Because not all of these problems can be solved in all geographic locations, o particularly during winter at latitudes higher than 42 where synthesis is virtually zero, it is 116 Chapter 8: Vitamin D recommended that individuals not synthesising vitamin D should correct their vitamin D status by consuming the amounts of vitamin D appropriate for their age group (Table 21). There are some suggestions in the literature that these outbreaks of idiopathic infantile hypercalcemia may have been multifactorial with genetic and dietary components and were not just due to technical problems with over-fortification as was assumed (49,50). This is all the more cause for concern because hypovitaminosis D is still a problem worldwide, particularly in developing countries at high latitudes and in countries where skin exposure to sunlight is discouraged (51). The vitamin D story: a collaborative effort of basic science and clinical medicine. Induction of monocytic differentiation and bone resorption by 1a,25 dihydroxyvitamin D3. Specific high affinity receptors for 1,25-dihydroxvitamin D3 in Human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation J. In: "High Performance Liquid Chromatography and its Application to Endocrinology". Subclinical vitamin D deficiency in neonates: definition and response to vitamin D supplements. Plasma concentrations of vitamin D metabolites at puberty: Effect of sexual maturationand implications for growth. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Vitamin D supplementation and fracture incidence in elderly persons: a randomised, placebo-controlled clinical trial. Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. In vitro metabolism of 25-hydroxycholecalciferol by isolated cells from Human decidua. Elevated parathyroid hormone related peptide associated with lactation and bone density loss. Maternal-Foetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. International Perspective: Basis, need and application of recommended dietary allowances. Williams syndrome: an historical perspective of its evolution, natural history, and etiology. Therefore, a complex antioxidant defence system normally protects cells from the injurious effects of endogenously produced free radicals as well as from species of exogenous origin such as cigarette smoke and pollutants. Should our exposure to free radicals exceed the protective capacity of the antioxidant defence system, a phenomenon often referred to as oxidative stress (2), then damage to biologic molecules may occur. There is considerable evidence that disease causes an increase in oxidative stress; therefore, consumption of foods rich in antioxidants, which are potentially able to quench or neutralise excess radicals, may play an important role in modifying the development of such diseases. Vitamin E is the major lipid-soluble antioxidant in the cell antioxidant defence system and is exclusively obtained from the diet. The term vitamin E refers to a family of eight naturally occurring homologues that are synthesised by plants from homogentisic acid. All are derivatives of 6-chromanol and differ in the number and position of methyl groups on the ring structure. The four tocopherol homologues (d-, d-, d-, and d-) have a saturated 16 carbon phytyl side chain, whereas the tocotrienols (d-, d-, d-, and d-) have three double bonds on the side chain. There is also a widely available synthetic form, dl tocopherol, prepared by coupling trimethylhydroquinone with isophytol. This consists of a mixture of eight stereoisomers in approximately equal amounts; these isomers are differentiated by rotations of the phytyl chain in various directions that do not occur naturally. Any of the synthetic all-rac-tocopherol (dl-tocopherol) should be multiplied by 0. On donating the hydrogen, the phenolic compound itself becomes a relatively unreactive free radical because the unpaired electron on the oxygen atom is usually delocalised into the aromatic ring structure thereby increasing its stability (3). Elevated levels of lipid peroxidation products are associated with numerous diseases and clinical conditions (4). Although vitamin E is primarily located in cell and organelle membranes where it can exert its maximum protective effect, its concentration may only be one molecule for every 2000 phospholipid molecules. Absorption of vitamin E from the intestine depends on adequate pancreatic function, biliary secretion, and micelle formation. Conditions for absorption are like those for dietary lipid, that is, efficient emulsification, solubilisation within mixed bile salt micelles, uptake by enterocytes, and secretion into the circulation via the lymphatic system (6). Emulsification takes place initially in the stomach and then in the small intestine in the presence of pancreatic and biliary secretions. The resulting mixed micelle aggregates the vitamin E molecules, solubilises the vitamin E, and then transports it to the brush border membrane of the enterocyte probably by passive diffusion. Within the enterocyte, tocopherol is incorporated into chylomicrons and secreted into the intracellular space and lymphatic system and subsequently into the blood stream. Tocopherol esters, present in processed foods and vitamin supplements, must be hydrolysed in the small intestine before absorption. Vitamin E is transported in the blood by the plasma lipoproteins and erythrocytes. Chylomicrons carry tocopherol from the enterocyte to the liver, where they are incorporated into parenchymal cells as chylomicron remnants. The catabolism of chylomicrons takes place in the systemic circulation through the action of cellular lipoprotein lipase. Although the process of absorption of all the tocopherol homologues in our diet is similar, the form predominates in blood and tissue. This is due to the action of binding proteins that preferentially select the form over the others. This form also accumulates in non-hepatic tissues, particularly at sites where free radical production is greatest, such as in the membranes of mitochondria and endoplasmic reticulum in the heart and lungs (10). Other proteinaceous sites with apparent tocopherol-binding abilities have been found on erythrocytes, adrenal membranes, and smooth muscle cells (12). These may serve as vitamin E receptors which orient the molecule within the membrane for optimum antioxidant function. These selective mechanisms explain why vitamin E homologues have markedly differing antioxidant abilities in biologic systems and illustrates the important distinction between the in vitro antioxidant effectiveness of a substance in the stabilisation of, for example, a food product and its in vivo potency as an antioxidant. From a nutritional perspective, the most important form of vitamin E is tocopherol; this is corroborated in animal model tests of biopotency which assess the ability of the various homologues to prevent foetal absorption and muscular dystrophies (Table 22). Kinetic studies with deuterated tocopherol (15) suggest that there is rapid equilibration of new tocopherol in erythrocytes, liver, and spleen but that turnover in other tissues such as heart, muscle, and adipose tissue is much slower. This presumably reflects an adaptive mechanism to avoid detrimental oxidative reactions in this key organ. The primary oxidation product of tocopherol is a tocopheryl quinone that can be conjugated to yield the glucuronate after prior reduction to the hydroquinone. This is excreted in the bile or further degraded in the kidneys to tocopheronic acid and hence excreted in the bile. Table 22 Approximate biological activity of naturally occurring tocopherols and tocotrienols compared with d-tocopherol Biological activity compared with Common name d-tocopherol, % d-tocopherol 100 d-tocopherol 50 d-tocopherol 10 d-tocopherol 3 d-tocotrienol 30 d-tocotrienol 5 d-tocotrienol not known d-tocotrienol not known Defining populations at risk of vitamin E deficiency There are many signs of vitamin E deficiency in animals most of which are related to damage to cell membranes and leakage of cell contents to external fluids. Muscle and neurological problems are also a consequence of human vitamin E deficiency (20). Early diagnostic signs of deficiency include leakage of muscle enzymes such as creatine kinase and pyruvate kinase into plasma, increased levels of lipid peroxidation products in plasma, and increased erythrocyte haemolysis. The assessment of the vitamin E requirement for humans is confounded by the infrequent occurrence of clinical signs of deficiency because these usually only develop in adults with fat malabsorption syndromes or liver disease, in individuals with genetic anomalies in transport or binding proteins, and possibly in premature infants (19, 21). This suggests that diets contain sufficient vitamin E to satisfy nutritional needs.