Heavy metals (IRON) Dr. Asmaa Fady Ph D., MSC., M.B, B.Ch اسم ورقم المقرر – Course Name and No. 7/1/2019

Learning objectives By the end of the lecture, the student should: Circumstances & toxic dose of iron poisoning. Pathophysiology and mechanism toxicity of iron. Clinical presentation of acute IRON toxicity. Clinical presentation of chronic IRON toxicity. Diagnosis & treatment of Iron Toxicity. اسم ورقم المقرر – Course Name and No. 7/1/2019

Circumstances of poisoning Common & serious accidental poisoning in children under 6 years (Many preparations & easy accessible) Attractive preparations use during pregnancy & postpartum period. Serious iron ingestions in adults are usually associated with suicidal attempts. اسم ورقم المقرر – Course Name and No. 7/1/2019

Toxic dose of Iron: Ingestions of less than 20 mg/kg of elemental iron usually cause no symptoms. Ingestion of 20 to 60 mg/kg results in mild to moderate symptoms ingestion of more than 60 mg/kg may lead to severe morbidity. اسم ورقم المقرر – Course Name and No. 7/1/2019

IRON Toxicokinetics: Absorption: Iron is absorbed in intestine. Ferrous (Fe+2) form is more readily absorbed than ferric (Fe+3) iron. Iron is absorbed in ferrous form and is oxidized to ferric form within cells. Distribution: It is transported in blood bound to a protein called transferrin. The iron binding capacity (transferrin level) is usually 300-500 ug/dl (TIBC) & normal serum iron level is 50-150 ug/dl. So, there is usually no free iron circulating in blood. Citrate & ascorbate (in citrus fruits) can form complexes with iron that ↑ absorption, while tannates in tea can ↓ absorption. اسم ورقم المقرر – Course Name and No. 7/1/2019

Pathophysiology of iron toxicity Two distinct toxic effects: (1) it causes direct caustic injury to the gastrointestinal mucosa (2) it impairs cellular metabolism, primarily of the heart, liver, and central nervous system (CNS). The caustic effects of iron on the gut cause the initial symptoms of vomiting, diarrhea, and abdominal pain. Hemorrhagic necrosis of gastric or intestinal mucosa can lead to bleeding, perforation, and peritonitis. Zohair Al Aseri MD,FRCPC EM & CCM

Pathophysiology of iron toxicity Unbound (free) iron moves into cells and localizes near the mitochondrial cristae, resulting in uncoupling of oxidative phosphorylation and impairment of adenosine triphosphate synthesis. Cell membranes are injured by free radical-mediated lipid peroxidation. Zohair Al Aseri MD,FRCPC EM & CCM

Pathophysiology of iron toxicity Iron increases capillary permeability and induces both arteriolar and venodilation. Myocardial toxicity decreases cardiac output. Hydration of the iron molecule creates an excess of unbuffered protons, worsening metabolic acidosis. This multitude of effects, combined with severe gastrointestinal fluid losses, can lead to the development of shock, cardiovascular collapse, and death. Zohair Al Aseri MD,FRCPC EM & CCM

Mechanism of Iron toxicity: Systems affected: GIT. Liver is target organ: portal vein transports iron to liver: Iron exits and comes into contact with hepatocytes  immediate damage of hepatocytes, periportal injury & necrosis  complete necrosis  hepatic failure. lipid peroxidation & destruction of hepatic mitochondria. metabolic acidosis. Cardiovascular System. اسم ورقم المقرر – Course Name and No. 7/1/2019

Mechanism of IRON cardiotoxicity: Cardiovascular System: Shock : Vasodilatation: Iron is potent VD so Free circulating iron  damage of BV  release of histamine & serotonin  PVD  venous pooling. Coagulation defects caused by hepatic dysfunction bleeding tendency & Direct effects of iron on clotting factors (iron inhibits thrombin). Hemorrhagic gastroenteritis. Free iron cause direct damage to heart → ↓ myocardial contractility (negative inotropic effect on myocardium). اسم ورقم المقرر – Course Name and No. 7/1/2019

Clinical presentation of acute IRON toxicity First stage: within 6 hrs: Mild & moderate toxicity: (GIT): hemorrhagic gastroenteritis. Absence of vomiting within the first 6hrs excludes serious toxicity Severe toxicity: (poor prognosis): Shock + metabolic acidosis. Second stage: 6-24 hrs "honeymoon phase”: Latent period of apparent improvement. (GIT symptoms only). Redistribution of free circulating iron from intravascular space into reticuloendothelial cells & intracellular compartment cellular toxicity. اسم ورقم المقرر – Course Name and No. 7/1/2019

Clinical presentation of acute IRON toxicity Third stage: 24-48 hrs (multisystem failure/ shock stage) (poor tissue perfusion, metabolic acidosis, oxidative damage) Worsening of GI hge. coma Renal insufficiency Liver insufficiency: jaundice, coagulation defects. Progressive pulmonary dysfunction Pancreatic & hepatic injury → hyperglycemia Note: serum iron may be normal Fourth stage 2-3 days: hepatic failure Fifth stage: 2-8 weeks (later on): liver cirrhosis, gastric scaring & pyloric stricture اسم ورقم المقرر – Course Name and No. 7/1/2019

Diagnosis of Iron poisoning: History of exposure. Clinical picture: Hemorrhagic gastroenteritis metabolic acidosis Shock Investigations: Laboratory findings: Screening tests: Gastric fluid + H2O2 + deferoxamine → ferrioxamine (orange red color). Serum iron level: Abdominal radiographs: Reveal tablets or diffuse densities اسم ورقم المقرر – Course Name and No. 7/1/2019

Abdominal radiographs: Reveal tablets or diffuse densities اسم ورقم المقرر – Course Name and No. 7/1/2019

Diagnosis of iron poisoning: Serum Iron level The presence of gastrointestinal symptoms suggests a potentially serious ingestion, whereas their absence is reassuring. A serum iron level measured at its peak, 3 to 5 hours after ingestion, is the most useful laboratory test to evaluate the potential severity of an iron overdose. Sustained-release or enteric-coated preparations may have erratic absorption, so a second level 6 to 8 hours after ingestion should also be checked. However, Treat the patient, not the numbers. Zohair Al Aseri MD,FRCPC EM & CCM

Diagnosis of Iron poisoning: Serum iron level: 50-175 ug/dL , may reach 350 ug/dL normally. 350-500 ug/dL. Mild-to-moderate toxicity >500 ug/dL (Hepatotoxicity). 500-1000 ug/dL shock & systemic toxicity. > 1000 ug/dL (fatal). Liver function tests acid – base assessment. اسم ورقم المقرر – Course Name and No. 7/1/2019

Treatment of acute Iron toxicity: Prevent further exposure Emergency & supportive treatment. Decontamination: Syrup of ipecac is not recommended because it aggravates GI volume losses & invalidates one of the most important symptomatic monitoring parameters (vomiting). As Iron tablets clump together as their outer coatings dissolve: Gastric lavage will be of no value & AC does not bind iron well, but it can be used if there is a co-ingestion. اسم ورقم المقرر – Course Name and No. 7/1/2019

Treatment of acute Iron toxicity: Gastrotomy has been performed to remove iron from the stomach, but the success of whole-bowel irrigation generally obviates the need to consider surgery for the sole purpose of decontamination. Zohair Al Aseri MD,FRCPC EM & CCM

Treatment of acute Iron toxicity: For significant ingestions, whole-bowel irrigation with a polyethylene glycol electrolyte lavage solution (PEG- ELS) is routinely recommended. The solution is either taken orally or administered through a nasogastric tube. The usual rate of administration of PEG-ELS is 20 to 40 mL/kg/hr in young children and 1.5 to 2 L/hr for teenagers or adults, continued until the rectal effluent is clear and there is no radiographic evidence of pill fragments. Whole-bowel irrigation is contraindicated in the presence of bowel obstruction, perforation, or ileus. Zohair Al Aseri MD,FRCPC EM & CCM

Treatment of acute Iron toxicity: Enhanced elimination: Hemodialysis and hemoperfusion are not effective in removing iron due to its large volume of distribution. Exchange transfusions have been recommended for severely symptomatic patients with serum iron levels exceeding 1000 ug/dL. اسم ورقم المقرر – Course Name and No. 7/1/2019

Treatment of acute Iron toxicity: Specific antidote: Deferoxamine mesylate (desferal): Indications: repetitive vomiting metabolic acidosis mental status changes shock serum iron level > 500 ug/dL Dose: Serious toxicity / serum level: >500 ug/dL: (10-15 mg/kg/hr/ 4-12hrs IV infusion) up to 1 g/day. Mild symptoms: (90mg/kg IM) Continue treatment until clinical resolution, no urine color change or serum iron < 100 ug/dL. Ttt for more than 24 hrs. is not routinely recommended (pulmonary. Ocular, auditory toxicity) 7/1/2019

Treatment of acute Iron toxicity: Specific antidote: Deferoxamine mesylate (desferal): mechanism of action: Deferoxamine has very high and selective affinity for iron. Each molecule binds tightly to one atom of non-transferrin bound iron. + it can pass through cell walls detoxify both extracellular and intracellular labile iron pools. The presence of ferrioxamine turns the urine a “vin rose” color, which reflects the excretion of chelated iron. Deferoxamine is not affecting iron in hemoglobin, hemosiderin, ferritin. اسم ورقم المقرر – Course Name and No. 7/1/2019

Chronic iron toxicity “Hemosiderosis” Mechanism: Ferritin is iron storage proteins. When excess dietary iron is absorbed, body produces more ferritin. Ferritin is greatly abundant in heart & liver, spleen, bone marrow, so there is a large amount in these organs however, so excess iron causes tissue destruction. Iron Overload is characterized by increased levels of ferritin, haemosiderin (another storage protein that mainly the result of cell damage and is often found engulfed by macrophages that are scavenging regions of damage). اسم ورقم المقرر – Course Name and No. 7/1/2019

Chronic iron toxicity “Hemosiderosis” Causes: Repeated blood transfusion as in thalassemia major or sickle cell disease Rarely due to defect in (iron storage protein) causing excessive iron absorption. Effect: Iron deposition in parenchymal tissues  fibrotic changes & functional impairment. اسم ورقم المقرر – Course Name and No. 7/1/2019

اسم ورقم المقرر – Course Name and No. 7/1/2019