Curs 6: Explorarea metabolismului fierului, hemului i cuprului2012-2013

Coninutul cursului 6:Explorarea metabolismului fieruluiDistribuia i circuitul fiierului n organismTeste de laborator utile n explorarea metabolismului fierului. Deficiena de fier: aspecte clinice, cauze, modificarea parametrilor de laboratorSuprancrcarea cu fier: aspecte clinice, cauze. Modificarea parametrilor de laborator.Porfiria. Intoxicaia cu Pb.Distribuia i circuitul curului n organism.Deficiena i suprancrcarea de fier: aspecte clinice, cauze, modificri ale parametrilor de laborator.

2012-2013I. Explorarea metabolismului fierului

Distribuia fieruluiDistribuia fierului la adult: 4 g: 3g: hemoglobin, mioglobin, enzime; 1g: depozitat n feritin, hemosiderin.

Aport zilnic: 4 mg.Fierul liber este toxic

Distribuia fierului:n snge fierul este legat de o protein = transferinFierul este depozitat n feritin i hemosiderin

Surse alimentare de fier: carne, organe, pete, albu, piper, spanac, nuci. 7 mg Fe/ 1000 kcal diet;

Hemoproteine:

HemoglobinaMioglobinaLeag oxigenul mai rapid dect Hb.Coninutul de mioglobin crete odat cu efortul fizic i scade n atrofia muscular. Leziunile musculare elibereaz mioglobina prin rhabdomioliz,sau prin sindrom de strivire, infarct miocardic.

Heminele celulare (Fe3+) citocromi, citocromoxidaze n mitocondrii, rol n respiraia celular. Inactivarea cu cianuri sau oxid de carbon duce la consecine letale. Citocromii P450, P448 (localizai n microzomi) rol n hidroxilarea unor medicaments, detoxificare i biotransformare.

Absorbia fierului la nivel intestinal asigur un necesar de 4 mg Fe/ziFierul Heminic (Fe2+, prezent n carne) este absorbit mai bine dect fierul nonheminic (Fe3+, prezent n vegetale). Fosfaii din produsele lactate, oxalaii din vegetale verzi reduc absorbia fierului. Vitamina C transform Fe3+ in Fe2+, favoriznd absorbia.

Proteine secifice implicate n transportul fierului la nivel intestinal = transferina intestinal: scderea fierului induce creteri ale transferinei intestinale i transport al fierului n plasm. Creterea Fe duce la scderea transferinei intestinale, crescnd apoferitina care va lega fierul n forme non-absorbabile.

Transportul fieruluiTransferina transport fierul extracelular (Fe + Siderofilina). Siderofilina este o beta-globulin. Transferina poate conine 1-2-3 atomi de Fe3+.

Receptorii pentru transferin sunt bine reprezentai la nivelul unor organe: ficat, placent, eritroblati/ reticulocite.

Receptorii pentru transferin cresc n deficienele de fier i scad n suprancrcarea cu fier.

Depozitarea fierului: n ficat, mduv, splin60% - Feritin grup de proteine hidrosolubile, de form sferic, cu un miez plin de incluziuni cu fier. scade prima n deficienele de fier, crete n suprancrcarea cu fier, n procese inflamatorii asociate cu leziuni hepatice).Apoferitina feritin fr incluzii cu fier

30% - Hemosiderin condensri de complexe fier-protein, insolubile. Creterea hemosiderinei este asociat cu suprancrcarea cu fier ( coloraia Pearls sau cu albastru de Prusia).

Reglarea metabolismului fieruluiHepcidina peptide format din 25-amino acizi; este reglatorul principal al metabolismului fierului n organism. Este sintetizat n ficat (d) i eliberat n plasm; se leag de un canal transportator celular de fier feroportina cauznd internalizarea i degradarea lui, scznd efluxul de fier din enterocite (a) i din macrofage (c) n plasm.

A. Rolul hepcidinei n homeostazia fieruluiO cretere a fierului n plasm cauzeaz o cretere a produciei de hepcidin (sgeata galben).

Valori crescute ale hepcidinei inhib eliberarea fierului n plasm dinspre macrofage, hepatocit i duoden.

Pe msur ce fierul este consumat din plasm, pentru sinteza de hemoglobin, nivelele de fier se reduc i producia de hepcidin va scdea (mecanism de feedback).

B. Rolul hepcidinei n anemia din inflamaieIL-6 i alte citokine stimuleaz sinteza de hepcidin (sgeata galben), ducnd la creteri ale hepcidinei n plasm.

Concentraii crescute ale hepcidinei vor inhiba efluxul de fier din macrofage, ficat i duoden.

Scderea fierului plasmatic va fi cauza eritropoezei deficitare, pe seama deficitului de fier.

C. Rolul hepcidinei n hemocromatoza ereditarHemocromatoza este cauzat de deficiena de hepcidin sau rezistena la hepcidin.

Deficiena de Hepcidin este cauzat de mutaii n gena hepcidinei sau a unor gene reglatoare ale reglatorilor hepcidinei. Rezistena la Hepcidin este o form rar de hemocromatoz i rezultatul unor mutaii n receptorii pentru hepcidin sau n proteina transportatoare - canal feroportina.

Valori sczute ale hepcdinei sau absena efectului hepcidinei datorat rezistenei, permite absorbia necontrolat a fierului, ducnd la valori crescute ale fierului seric, saturaie crescut a transferinei i acumulare de fier nelegat de transferin. Excesul de fier se depune pe organele vitale, cauznd leziuni organice.

Eliminarea fierului:

1 mg Fe se pierde zilnic la nivel intestinal, datorit proceselor fiziologice descuamri la nivel intestinal, excreia biliar, hemoragii oculte.

Femeile (18-55 ani) pierd 25 mg Fe cu 50 ml snge, lunar.

Explorri de laborator ale metabolismului fierului1. Fierul seric i urinar:Fe seric: 50-150 microgram/dl. Fe seric reprezint Fe legat la transferin.Fe urinar: pentru diagnosticul suprancrcrii cu fier sau pentru monitorizarea tratamentului cu deferoxamin (Desferal) fierul urinar crete dup administrare.Scderi: anemia feripriv Creteri: anemia hemolitic, suprancrcarea cu fier.

2. Feritina util pentru a explora depozitele solubile de fier. Feritina sub 20 g/l indic o deficien naintea instalrii anemiei feriprive.Suprancrcarea cu fier: >500 g/l talasemii, leucemii.3. Transferina crescut fiziologic la copii i gravide (trim 3).

4. Capacitatea Total de Legare a Fierului reflect coninutul de transferin n serCreteri: Deficiena de fier- graviditate, anemia feripriv Hemoragii PolicitemiiScderi: n excesul de fier, boli inflamatorii cronice Talasemii Cancer, boli hepatice, artrit reumatoid

Creteri FALSE: administrare de cloramfenicol, fluoruri.

Modificari ale metabolismului fierului

Deficiena de fierDeficiena dobndit de transferin: atransferinemia congenitalSuprancrcarea cu fierHemosiderozaHemocromatoza

Deficiena de fierCauze:-Diet inadecvat (finoase)-Absorbie deficitar: rezecie gastric, rezecie intestin subire, diaree cronic, malabsorbieaclorhidria= factor de risc pentru malabsorbioa fierului

Anemia feripriv i deficiena de fier:Anemia feripriv: hematii hipocrome, microcite, anulocite (n stadii avansate de deficien de fier). nainte de a scdea Hb, fierul este utilizat pentru sinteza Hb.- Deficiena de fier---afecteaz enzimele celulare care conin fier:mitochondrial alfa-glicerofosfat oxidase: deficiena lor duce la creterea acidului lactic n muchi---senzaie de oboseal muscular.monoaminoxidase (MAO) explic scderea catabolismului catecolaminelor. Acumularea lor duce la iritabilitate.- Deficiena de fier i expunerea la frig: hormonii tiroidieni nu vor crete corespunztor, ducnd la o termogenez deficitar (senzaie permanent de frig)- Deficiena prelungit de fier---anemie microcitar---atropia mucoasei digestive: lingual, faringian, esofagian---disfagie sideropenic = senzaie de arsur + jen la deglutiie. (Sdr Plummer-Vinson). Aclorhidria mucoasei gastrice cedeaz la tratamentul cu Fe.

Evoluia anemiei feriprive:Scderea FeritineiScderea Fe sericCrete CTLF= capacitatea total de legare a FeAnemia scderea hemoglobineiHematii hipocrome, microcitoz

Tratament: Fe oral, iv (n malabsorbie).

Deficiena de transferin atransferinemia congenital= anemia hipocrom, microcitoz cu valori foarte sczute ale transferinei (0-40 mg/dl n comparaie cu 200-400 mg/dl la grupul de control).

Este rezistent la terapia cu fier. Remediu dup perfuzii cu plasm sau cu transferin purificat.Au fost identificai i i Ac anti transferin.

Suprancrcarea cu fierHEMOSIDEROZA apare la pacieni politransfuzai, sau n infecii cronice. Fierul este incorporat n macrofage.

HEMOCROMATOZA fierul este internalizat n macrofage i depozitat n ficat, pancreas, glande endocrine.Leziunile oxidative ale proteinelor membranare vor duce la slerozarea organelor suprancrcate cu fier.Cauza: absorbie excesiv de fier, necontrolat, de cauze genetice.ACERULOPLASMINEMIA deficiena (AR) a ceruloplasminei.

II. Porfiria

Porfiria= grup de boli dobndite sau motenite cauzate de deficiena unor enzime implicate n biosinteza hemului (also called porphyrin pathway)

Majoritatea porfiriilor sunt transmise AD; din aceast cauz nivelul enzimelor este redus la 50% fa de normal.

Tratamentul const n administrarea de hemin, producndu-se un feedback negativ pentru sinteza hemului.

Clasificare: - n funcie de locul supraproduciei i acumulrii de intermediari de sintez ai hemului:- Porfitii acute (hepatice)- Porfirii cutanate (eritropoetice)

Manifestri clinice: neurologice i/sau cutanate

Biosinteza hemului

EMBED ChemDraw.Document.4.5

Heme c

_1023309912.cdx

_1023310680.cdx

Fe2+ este adugat la protoporfirina IX via ferocheletazei, rezultnd hemul.

EMBED ChemDraw.Document.6.0

Ferrochelatase

protoporphyrin IX heme

2H+

Fe++

_1038859414.cdx

_1039979791.cdx

_1039980880.cdx

_1041850706.unknown

_1039980348.cdx

_1038859950.cdx

_1038858807.cdx

Sinteza hemului n seria eritrocitar85% din sinteza hemului are loc n eritroblatiEste finalizat n reticulocite i hematiiReglarea sintezei Fe la nivelul enzimelor -FEROCHELATAZA i PORFOBILINOGEN DEAMINAZA

Sinteza hemului n FICATFicatul este sursa major extra-eritrocitar de sintez a hemului

In ficat hemul este sintetizat pentru a fi utilizat la sinteza citochromului -P450, implicat n detoxificarea (medicamentelor, toxinelor, etc).

Reglarea sintezei - la nivelul ALA sintetazei, respectiv formarea 5-ALA (acidului 5 aminolevulinic), care este factorul limitativ n sinteza hemului la nivel hepatic.

Porfiria acut

-cauzat de deficiena enzimei porfobilinogen deaminaza, implicat n conversia porfobilinogenului n uroporfirinogen III.

PBG i 5-ALA cresc n plasm i n urin.ALA sintetaza este crescut datorit faptului c datorit deficienei enzimei (PBG deaminaza), sinteza nu e urmat de o cretere a produciei de hem, care s inhibe sinteza hemului la nivelul ALA sintetatazei. Rezultat: cretere masiv a produilor intermediari/ precursori ai hemului (porfirine).

Clinic:- dureri abdominale- vom / constipaie- depresion- disfuncii neurologice: nevrite periferice, paralizii respiratorii, deces.

Laborator: - hiposodemie (consecina vomelor repetate, insuficien renal)Culoarea brun nchisa a urinei (urina se ntunec progresiv la lumin)

Neuro-visceralPhotosensitivityErythropoeiticErythropoeitic

Porfiria cutanat

Semne: fotosensibilitate, piele fragil, flictene, edeme, necroze, pigmentri.

Baze metabolice: fotosensibilitatea se datoreaz acumulrii porfirinelor n piele. Cauza: deficiena uroporfirinogen decarboxilaza, implicat n conversia uroporfirinogen III n coproporfirinogen III.

Laborator: Crete uroporfirinogen III n urin.

Intoxicaia cu PlumbComplicaiile intoxicaiei cu Pb: A: margine gingival; B: encefalopatie (copii) ; C: anemie (eritropoez redus i hemoliz); D: punctaii bazofile ale eritrocitelor; E: acidoz renal tubular; F: colici intestinale. G: neuropatie periferic (aduli) ;H: depozite de Pb la nivelul epifizelor (copii)

Tratament: EDTA, agent chelator, leag Pb

Intoxicaia cu PbScderea PBGPb inhib: ALA sintetaza, ferochelaza

III. Explorarea metabolismului cuprului

Deficiena de ceruloplasminaAceruloplasminemia este o afeciune dobndit autosomal recesiv (AR) cauzat de mutatii n gena ceruloplasminei.

Caracteristici: neurodegenerescen la nivelul retinei (prin depunerea de Fe la nivelul retinei), creierului.

Fe se acumuleaz n pancreas, ficat, creier.

Boala Wilson toxicitatea cauzat de suprancrcarea cu CuBoala Wilson dobndit AR caracterizat prin acumularea Cu n creier, ficat .a.Clinic: Ciroz, degenerescena ganglionilor bazali, disfuncii neuronale (micri involuntare, tremurturi, rigiditate muscular, contracii musculare spastice, disfuncii psihice, disfagie.Caracteristic: inel Kayser-Fleischer.Copiii afectai se pot nate prematur. Simptomele aprute n copilrie sunt rezultatul absorbiei intestinale anormale i deficienei secundare la nivelul unor enzime mitocondriale dependente de Cu.

Explorri de laborator n boala Wilson Defect n sinteza ceruloplasminei i/sau defect n incorporarea Cu n ceruloplasmin

Scderea Ceruloplasminei (sub 15 mg/dl)

Biopsia hepatic i dozarea Cu n esut uscat

Boala Menkes deficiena de cupruBola Menkes clinic: convulsii, temperatur anormal a corpului, aspect particular al prului (fr culoare, sau ca gri ca i oelul, friabil). Neurodegenerare a materiei cenuii din creier. Arterele din creier apar rsucite i cu perei secionai longitudinal, ce pot duce la rupturi sau blocaje ale arterelor. Osteoporoza ce poate duce la fracturi.

Determinarea raportului ntre acidul homovanillic / acidul vanillilmandelic e indicat ca metod de screening. Tratament - cupru administrat subcutanat sau intravenos.

Genetic = Mutaie n gena ATP7A cauzeaz boala Menkes. Cu se acumuleaz n unele esuturi - intestin subire, rinichi, n timp ce creierul i alte esuturi au nivele foarte sczute de cupru. Aportul sczut de Cu poate reduce activitatea unor numeroase enzime care coniin Cu necesare meninerii structurii i funciei unor organe: os, piele, vase sanguine, sistem nervos.

Boala e dobndit AR, legat de cromozomul X.

Copper transporter Ctr1Cisplatin is the queen of chemotherapy among over 700 FDA-approved drugs with applications in more than 50% of human cancers, including the lucrative non-small cell lung cancer

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).

Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Ishida,Seiko; Lee,Jaekwon; Thiele,DennisJ.; Herskowitz,Ira Proceedings of the National Academy of Science, vol. 99, Issue 22, p.14298-14302

*Iron, which is found in a large variety of foods, can be found in the diet in two forms,each having different routes of intestinal absorption. Non-heminic iron (non-heme iron orinorganic iron) is present in vegetables and dairy-based foods, while heminic iron (hemeiron) is present in foods derived from animal tissue. One of the most iron-rich food sourcesis bovine meat (beef). Iron in beef meat exists as both heme iron (HeFe), as a component ofmyoglobin in the muscle, and as non-heme Fe (nHeFe)*Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:Enterocytes in the duodenum Hepatocytes Macrophages of the reticuloendothelial system. Recent research suggests that ferroportin is inhibited by hepcidin, which therefore is the "master regulator" of human iron metabolism. Hepcidin binds to ferroportin, and results in the internalisation of ferroportin within the cell, followed by degradation by the proteasome. This results in retention of iron within the cell, and a reduction in iron levels within the plasma. This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels.*Increased iron stores and inflammation induce hepcidin synthesis, whereas suppression occurs during hypoxia, anemia and increased and/or ineffective erythropoiesis in the bone marrow (b). Furthermore, hepcidin deficiency plays a central role in the iron loading in hereditary hemochromatosis and thalassemias. Finally, hepcidin is induced under conditions of infection, decreasing the available host iron pool that is essential for survival of invading pathogens. Most of the evidence on hepcidin regulation and mode of action comes from in vitro work and mice studies that often use hepcidin mRNA as a read out. Until recently, human studies were largely impeded because suitable hepcidin assays were not available. Thus, although these discoveries on the regulation and mode of action of hepcidin have had wide reaching effects throughout the field, much work remains in defining the role of hepcidin in both healthy and diseased states. Background information Swinkels DW, Janssen MCH, Bergmans J, Marx JJM. Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clin. Chem. 2006; 52, 950-968. Ganz T. Iron homeostasis: fitting the puzzle pieces together. Cell Metab. 2008; 7, 288-290. Kemna EHJM , Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica 2008; 93,90-97. Bergmans JPH, Kemna EHJM, Janssen MCH, Jacobs EMG, Stalenhoef AFH, Marx JJM Swinkels DW. Hereditaire hemochromatose:nieuwe genen, nieuwe ziekten en hepcidine. Ned Tijdschr Geneesk (in Dutch) 2007; 151, 1121-7

*Atransferrinemia, also called familial hypotransferrinemia,[1] is an autosomal recessive[2] metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood.Atransferrinemia is characterized by anemia and hemosiderosis in the heart and liver. The iron damage to the heart can lead to heart failure. The anemia is typically microcytic and hypochromic (the red blood cells are abnormally small and pale). Atransferrinemia is extremely rare, with only eight cases documented worldwide.[3]Contents[hide] Symptoms Genetics Treatment References External links [edit] SymptomsSevere microcytic hypochromic anemia, growth retardation and recurrent infections are the first clinical signs of the disease. Iron overload occurs mainly in the liver, heart, pancreas, thyroid, kidney and bone joints, leading to mild to severe symptoms of liver and heart failure, arthropathy and hypothyroidism. Death may occur due to heart failure or pneumonia.[citation needed][edit] Genetics Atransferrinemia has an autosomal recessive pattern of inheritance, meaning both copies of the gene in each cell are defective.A case study was done in 1961 on a 7-year-old girl who died of heart failure with atransferrinemia. The half-normal levels of transferrin in her parents' bloodstream supported the notion that this disorder is transferred in an autosomal recessive pattern.[4] Atransferrinemia was reported in only eight patients in six families as of the year 2000. A lack of scientific data and public outreach, however, have suggested that there is a higher number of current cases. Researchers used the first known case reported in the United States[5] and identified mutations in the TF gene as a probable cause of the disorder.*Hemosiderin deposition in the lungs is often seen after , which occurs in diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and idiopathic pulmonary haemosiderosis. Mitral stenosis can also lead to pulmonary hemosiderosis. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebral arteriovenous malformations, cavernous hemangiomata. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. Hemosiderin in the kidneys have been associated with marked hemolysis and a rare blood disorder called Paroxysmal Nocturnal Hemoglobinuria.Hemosiderin may deposit in diseases associated with iron overload. These diseases are typically diseases in which chronic blood loss requires frequent blood transfusions, such as sickle cell anemia and thalassemia.*Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias, based on the site of the overproduction and accumulation of the porphyrins (or their chemical precursors). They manifest with either neurological complications or with skin problems (or occasionally both). A clinically induced and histologically identical condition is called pseudoporphyria. Pseudoporphyria is characterized by normal serum and urine porphyrin levels.The term derives from the Greek , porphyra, meaning "purple pigment". The name is likely to have been a reference to the purple discolouration of feces and urine in patients during an attack.[1] Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Dr Felix Hoppe-Seyler in 1874,[2] and acute porphyrias were described by the Dutch physician Prof B.J. Stokvis in 1889.[1][3]*The cutaneous, or erythropoietic, porphyrias primarily affect the skin, causing photosensitivity (photodermatitis), blisters, necrosis of the skin and gums, itching, and swelling, and increased hair growth on areas such as the forehead. Often there is no abdominal pain, distinguishing it from other porphyrias.In some forms of porphyria, accumulated heme precursors excreted in the urine may cause various changes in color, after exposure to sunlight, to a dark reddish or dark brown color. Even a purple hue or red urine may be seen.*Lead poisoning (also known as plumbism, colica pictonium, saturnism, Devon colic, or painter's colic) is a medical condition caused by increased levels of the heavy metal lead in the body. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems. It interferes with the development of the nervous system and is therefore particularly toxic to children, causing potentially permanent learning and behavior disorders. Symptoms include abdominal pain, headache, anemia, irritability, and in severe cases seizures, coma, and death.Routes of exposure to lead include air, water, soil, food, and consumer products. Occupational exposure is a common cause of lead poisoning in adults. One of the largest threats to children is lead paint that exists in many homes, especially older ones; thus children in older housing with chipping paint are at greater risk. Even an item as small as a paint chip can contain tens to hundreds of milligrams of lead, presenting a serious risk if ingested. Prevention of lead exposure can range from individual efforts (e.g. removing lead-containing items such as piping or blinds from the home) to nationwide policies (e.g. laws that ban lead in products or reduce allowable levels in water or soil).Elevated lead in the body can be detected by the presence of changes in blood cells visible with a microscope and dense lines in the bones of children seen on X-ray. However, the main tool for diagnosis is measurement of the blood lead level; different treatments are used depending on this level. The major treatments are removal of the source of lead and chelation therapy (administration of agents that bind lead so it can be excreted).Humans have been mining and using this heavy metal for thousands of years, poisoning themselves in the process. Although lead poisoning is one of the oldest known work and environmental hazards, the modern understanding of the small amount of lead necessary to cause harm did not come about until the latter half of the 20thcentury. No level of lead below which harm does not occur has been discovered. Lead poisoning can cause a variety of symptoms and signs which vary depending on the individual and the duration of lead exposure.[10][11] Symptoms are nonspecific and may be subtle, and someone with elevated lead levels may have no symptoms.[12] Symptoms usually develop over weeks to months as lead builds up in the body during a chronic exposure, but acute symptoms from brief, intense exposures also occur.[13] Symptoms from exposure to organic lead, which is probably more toxic than inorganic lead due to its lipid solubility, occur rapidly.[14] Poisoning by organic lead compounds has symptoms predominantly in the central nervous system, such as insomnia, delirium, cognitive deficits, tremor, hallucinations, and convulsions.[9]Symptoms may be different in adults and children; the main symptoms in adults are headache, abdominal pain, memory loss, kidney failure, male reproductive problems, and weakness, pain, or tingling in the extremities.[15] The classic signs and symptoms in children are loss of appetite, abdominal pain, vomiting, weight loss, constipation, anemia, kidney failure, irritability, lethargy, learning disabilities, and behavior problems.[15] Children may also experience hearing loss, delayed growth, drowsiness, clumsiness, or loss of new abilities, especially speech skills.[12] Symptoms may appear in children at lower blood lead levels than in adults.[16]Early symptoms of lead poisoning in adults are commonly nonspecific and include depression, loss of appetite, intermittent abdominal pain, nausea, diarrhea, constipation, and muscle pain.[17] Other early signs in adults include malaise, fatigue, decreased libido, and problems with sleep.[10] An unusual taste in the mouth and personality changes are also early signs.[18] In adults, symptoms can occur at levels above 40g/dL, but are more likely to occur only above 5060g/dL.[10] Symptoms begin to appear in children generally at around 60g/dL.[19] However, the lead levels at which symptoms appear vary widely depending on unknown characteristics of each individual.[20] At blood lead levels between 25 and 60g/dL, neuropsychiatric effects such as delayed reaction times, irritability, and difficulty concentrating, as well as slowed motor nerve conduction and headache can occur.[21] Anemia may appear at blood lead levels higher than 50g/dL.[17] In adults, Abdominal colic, involving paroxysms of pain, may appear at blood lead levels greater than 80g/dL.[11] Signs that occur in adults at blood lead levels exceeding 100g/dL include wrist drop and foot drop, and signs of encephalopathy (a condition characterized by brain swelling), such as those that accompany increased pressure within the skull, delirium, coma, seizures, and headache.[22] In children, signs of encephalopathy such as bizarre behavior, discoordination, and apathy occur at lead levels exceeding 70g/dL.[22] For both adults and children, it is rare to be asymptomatic if blood lead levels exceed 100g/dL.[11][edit] Acute poisoningIn acute poisoning, typical neurological signs are pain, muscle weakness, paraesthesia, and, rarely, symptoms associated with encephalitis.[15] Abdominal pain, nausea, vomiting, diarrhea, and constipation are other acute symptoms.[23] Lead's effects on the mouth include astringency and a metallic taste.[23] Gastrointestinal problems, such as constipation, diarrhea, poor appetite, or weight loss, are common in acute poisoning. Absorption of large amounts of lead over a short time can cause shock (insufficient fluid in the circulatory system) due to loss of water from the gastrointestinal tract.[23] Hemolysis (the rupture of red blood cells) due to acute poisoning can cause anemia and hemoglobin in the urine.[23] Damage to kidneys can cause changes in urination such as decreased urine output.[23] People who survive acute poisoning often go on to display symptoms of chronic poisoning.[23][edit] Chronic poisoningChronic poisoning usually presents with symptoms affecting multiple systems,[9] but is associated with three main types of symptoms: gastrointestinal, neuromuscular, and neurological.[15] Central nervous system and neuromuscular symptoms usually result from intense exposure, while gastrointestinal symptoms usually result from exposure over longer periods.[23] Signs of chronic exposure include loss of short-term memory or concentration, depression, nausea, abdominal pain, loss of coordination, and numbness and tingling in the extremities.[18] Fatigue, problems with sleep, headaches, stupor, slurred speech, and anemia are also found in chronic lead poisoning.[15] A "lead hue" of the skin with pallor is another feature.[24] A blue line along the gum, with bluish black edging to the teeth is another indication of chronic lead poisoning.[25] Children with chronic poisoning may refuse to play or may have hyperkinetic or aggressive behavior disorders.[Lead-containing productsLead can be found in products such as kohl, a South Asian cosmetic, and from some toys.[2] In 2007, millions of toys made in China were recalled from multiple countries due to safety hazards including lead paint.[45] Vinyl mini-blinds, found especially in older housing, may contain lead.[7] Lead is commonly incorporated into herbal remedies such as Indian Ayurvedic preparations and remedies of Chinese origin.[10][5][18] There are also risks of elevated blood lead levels caused by folk remedies like azarcon and greta, which each contain about 95% lead.[10] Ingestion of metallic lead, such as small lead fishing lures, increases blood lead levels and can be fatal.[46][47][48][49] Ingestion of lead-contaminated food is also a threat. Ceramic glaze often contains lead, and dishes that have been improperly fired can leach the metal into food, potentially causing severe poisoning.[50] In some places, the solder in cans used for food contains lead.[18] People who eat animals hunted with lead bullets may be at risk for lead exposure.[51] Bullets lodged in the body rarely cause significant levels of lead poisoning,[52][53] but bullets lodged in the joints are the exception, as they deteriorate and release lead into the body over time.[54]*Distribuie: 80-120 mg n organism. Majoritatea n muchi, oase, creier, rinichi, hematiiCupremia 140 g/ dlCircuitul n organismSurse alimentare: cereale, crustacee, viscere, cacaoAportul zilnic: 2-5 mgAbsorbia se face n intestinul subire, de unde Cu este fixat labil pe albumin i transportat la ficat, unde este legat de ceruloplasmin (alfa2 globulin). Eliminarea: majoritatea se elimin prin bil. Prin urin se elimin 100 mg/zi *An epileptic seizure is a transient symptom of excessive or synchronous neuronal activity in the brain.[1] It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms (such as dj vu or jamais vu). The medical syndrome of recurrent, unprovoked seizures is termed epilepsy, but seizures can occur in people who do not have epilepsy.*Boala Menkes deficit genetic de absorbie a Cu din mucoasa digestiv*Molecular mechanisms of cisplatin and its liposomally encapsulated form, Lipoplatin. Lipoplatin as a chemotherapy and antiangiogenesis drugReview ArticleTeni Boulikas1,2,*1Regulon, Inc. 715 North Shoreline Blvd, Mountain View, California 94043, USA and 2Regulon AE, Afxentiou 7, Alimos, Athens 17455, Ellas (Greece)Cisplatin continues to be one of the cornerstone drugs in modern chemotherapy thus playing an important role among cytotoxic agents in the treatment of epithelial malignancies. Cisplatin damages, indiscriminately, cancerous and normal tissue. Its severe side effects arise from induction of apoptosis in various cell types in normal tissue in treated patients especially in peripheral nerves, renal tubules, bone marrow and gastrointestinal tract. Apoptosis may arise from the modulation of a number of signaling pathways by cisplatin including the mitochondrial pathway, the DNA damage signaling, stress-related signals, the ERK pathway and others. Patented platform technologies have been used for the liposomal encapsulation of cisplatin (Lipoplatin) into tumor targeted 110-nm in diameter nanoparticles. Based on the molecular mechanisms of cisplatin including active import / export across the cell membrane, signaling pathway modulation and DNA damage an attempt is made to speculate on the molecular mechanisms of Lipoplatin. The advantage of Lipoplatin over cisplatin is suggested to result from the ability of Lipoplatin to target primary tumors and metastases using the permeability of the vasculature of the growing tumor for its preferential extravasation and to cause a greater damage to tumor tissue compared to normal tissue as demonstrated in human studies. The nanoparticles are then avidly taken up by the tumors either via phagocytosis or by direct fusion with the cell membrane. The two mechanisms result to an overall 10 to 400-fold higher intracellular uptake of total platinum in tumor cells compared to cells in normal tissue in human studies. Animal studies shown here suggest that genes wrapped up in Lipoplatin shells target not only the tumors after systemic delivery but also their vasculature and result in the expression of a functional gene product after crossing the cell membrane barrier. It is being inferred that Lipoplatin is endowed with the properties of cisplatin plus the ability of its nanoparticles to target and kill endothelial cells of tumor vasculature suggesting that this drug has two properties, that of a chemotherapy drug and that of an antiangiogenesis agent, combined together. Lipoplatin is finishing successfully two non-inferiority phase III clinical trials as first line treatment against non-small cell lung cancer (NSCLC) and has received the orphan drug designation by EMEA against pancreatic cancer.