Week 1 HEME/ONCOLOGY
Jan 6: Heme Metabolism and Porphyrias
Importance of Heme
- Heme is essential as a prosthetic group in many proteins involved in oxygen transport and oxidation processes. Heme
is a porphyrin that is bound to iron(II- ferrous)
- Key hemoproteins include hemoglobin, cytochromes, catalase, and peroxidase
- Synthesis occurs in all mammalian cells, primarily in erythropoietic tissue and liver
- When hemoproteins turn over, heme must be degraded and newly synthesized
Heme Synthesis and Regulation
- Protoporphyrin IX + Fe = Heme
- First step is the RATE-LIMITING STEP, occurs in mitochondria
- Succinyl CoA + Glycine → δ-ALA using the enzyme δ-ALA synthase
- Requires vitamin B6 as cofactor
- Regulated through:
1. RLS Enzyme control (repressed by heme, stimulated by steroids and barbiturates)
2. Feedback inhibition by heme
Heme Degradation
- Degraded in the spleen and excreted into the urine, iron conserved
- Causes of hemolysis: erythrocyte fragility, burns, erythroblastosis fetalis
- If hemolysis occurs, Hgb with its iron is released into plasma
- Bruising: Heme = (red/purple), Biliverdin = (yellow/green), Bilirubin = (red/orange)
Bilirubin
- Lipid soluble, transported into the blood via carrier(Albumin)
- in the liver, UDP-glucuronyl transferase transfers 2x UDP to convert it into soluble Bili diglucuronide
- Bilirubin diglucuronide is then excreted in the bile
Lead Poisoning
- Inhibits ALA dehydratase(step 2) and ferrochelatase (last step), Elevated ALA
- Characterized by Microcytic anemia, everything else normal, basophilic stippling on blood smear
- Symptoms: Neurologic, GI, and Hematologic (a/w construction work)
- Complications: developmental disabilities, hearing loss, behavior, kidney damage, reduced IQ, slowed growth
- Treatment involves chelation therapy using EDTA, dimercaprol, or dimercaptosuccinic acid
*renal toxicity with EDTA*
Porphyrias
Types and Classifications
1. Erythropoietic porphyria: defect in porphyrin metabolism in blood-producing tissues
,2. Hepatic porphyria: defect in porphyrin metabolism in the liver
a) Hereditary or acquired
3. Cutaneous porphyrias: defect in porphyrin metabolism in the skin, causes photosensitivity
4. Acute porphyrias: impaired L-Trp catabolism → decreased serotonin → neurological symptoms
Key Examples
Acute Intermittent Porphyria
- Defect in porphobilinogen deaminase, causes PPGN accumulates in liver, excreted in urine
- 1/20,000 frequency, autosomal dominant
- Symptoms: neurological issues, abdominal pain, red urine, tachycardia, HTN
- Treatment: glucose(dec. biosynthesis) and hematin(ALA synthase inhibitor)
Porphyria Cutanea Tarda
- Defect in uroporphyrinogen decarboxylase
- 1:10,000 frequency
- Caused by iron, alcohol, hepatitis C, HIV, estrogen
- Symptoms: photosensitivity, skin changes, excess hair growth, liver problems
- Treatment: phlebotomy, chloroquine
Jan 6: Iron Metabolism
Iron Properties and Functions
- Functions in electron transport, O2 transport, Antioxidant
- Heme-containing: (Hgb, myglobin, cytochrome, COX),
- Non- Heme: (Fe-S clusters, ribonucleotide reductase)
- Redox reactions between ferric (Fe3+) and ferrous (Fe2+) forms
- Free iron caused by heme breakdown/injury can generate harmful free radicals (ROS)
Iron Transport and Storage
- Absorbed in duodenum, mostly incorporated into Hgb, some in muscle/other tissue
- Transported in plasma by Transferrin
- Transferrin receptor: TfR1, TfR2
- Stored in parenchymal cells of liver and reticuloendothelial macrophages bound to Ferritin in cytosol
- Hemosiderin: insoluble derivative of ferritin released in tissue injury
1. In the stomach, Fe3+ is reduced to Fe2+ by Ferric reductase, oxidized, and then reduced again
2. Transported into the apical border of intestine by DMT1 (cotransport with H+)
Key Proteins Involved
- DMT1/DCT1 (apical transport): transports Fe2+ into intestine
- Ferroportin (basolateral transport): transports Fe to plasma and requires Hephastin
- Hephaestin (ferroxidase in intestines): oxidation to form Fe3+, Fe transfer to plasma
- Ceruloplasmin (ferroxidase in other cells)
Regulation of Iron Homeostasis
,- Hepcidin: 25 amino acid peptide hormone from liver, decreases iron absorption
Hepcidin → Ferroportin degraded → reduced iron export from tissues → decreased iron absorption into intestines →
decreased iron in blood/tissues
- Minihepcidins: potential treatment for iron overload, can possibly treat HH
- Hepcidin agonist: antibody that blocks hepcidin from binding, lowers hepcidin levels, treatment for anemia
Iron Disorders
Iron Deficiency Anemia
- Initially depletes reserves without symptoms
- Diagnosed: transferrin saturation levels (<20%), normal~30%
- Treated with ferrous sulfate or blood transfusions, need to r/o blood loss
Hereditary Hemochromatosis(HH)
- Most common genetic defect in Caucasians (1/400)
- Caused by mutations in HFE gene (ΔTfR2, Δhemojuvelin, Δhepcidin)
- Results in excessive iron absorption and storage
- Affects multiple organs including liver, heart, and pancreas
- cirrhosis, cardiomyopathy, DM, pigmentation, joints, hypogonadism
- Treated through phlebotomy and chelators
Anemia of Chronic Disease(ACD)
- Caused by impaired iron utilization
- Associated w/ inflammatory conditions, chronic infections, IBD, autoimmune, neoplasia
- Inflammatory cytokines→increase Hepcidin → decreased iron absorption and release
- Treatment focuses on underlying condition
ACD HH
Hepcidin Levels High Low
Fe Absorption Low High
RE macrophage stores High Low
Circulating Fe Low High
Iron Overload
- Can be caused by:
- Acute poisoning: induces hypotension, metabolic acidosis, and coma
- Chronic overload: in patients who receive multiple transfusions
- Hereditary Hemochromatosis
- Reduced erythropoiesis: certain anemias cause destruction of erythroid cells in the marrow
- i.e. Thalassemias, Sideroblastic Anemias
Lab Testing for Iron
- Serum iron, serum iron binding capacity, serum ferritin, serum transferrin sats, CBC, BM/liver biopsy
, Total Iron Binding Capacity(TIBC) = Unsaturated Iron Binding Capacity(UIBC) + Serum Iron
Transferrin-Iron Binding Capacity (TIBC)
Jan 6: Malaria
Types and Characteristics
- Plasmodium vivax: Common, has latent form with relapse potential
- Plasmodium ovale: Features latent form with relapse potential
- Plasmodium malariae: 72-hour cycle (vs standard 48 hours)
- Plasmodium knowlesi: 24-hour cycle
- Plasmodium falciparum: Most common and serious form
- Causes higher RBC infection leading to capillary occlusion
- Associated with hemorrhage and necrosis
- Known for drug resistance
Epidemiology and Transmission
- Transmitted by Anopheles mosquito
- 90% of cases occur in Africa
- Highest risk groups: young children and pregnant individuals
Clinical Features
- Initial symptoms typically appear within one month of exposure
- Common symptoms: fever, fatigue, myalgias, headache
- Later stage: periodic fevers
- Complications vary by type:
- P. falciparum: cerebral malaria, jaundice, edema, severe anemia
- P. malariae: nephrotic syndrome
- P. knowlesi: respiratory distress, renal failure
- P. vivax and P. ovale: recurrent illness every 6-8 weeks
Diagnosis and Treatment
- Blood films:
- “ring shaped erythrocyte inclusions” in Malaria
- “Ring shaped and cross shaped erythrocyte inclusions” in Babesiosis(Borrelia burgdorferi- same as lyme)
- Rapid tests detecting malarial antigen
- Treatment options:
- Vector control
- Chloroquine (first-line)
- Artemisinin for chloroquine-resistant cases
- IV artesunate or quinine for severe cases
- Prevention:
- RTS/S vaccine shows 40-50% efficacy
- Targets malarial protein necessary for hepatocyte infection
Jan 6: Heme Metabolism and Porphyrias
Importance of Heme
- Heme is essential as a prosthetic group in many proteins involved in oxygen transport and oxidation processes. Heme
is a porphyrin that is bound to iron(II- ferrous)
- Key hemoproteins include hemoglobin, cytochromes, catalase, and peroxidase
- Synthesis occurs in all mammalian cells, primarily in erythropoietic tissue and liver
- When hemoproteins turn over, heme must be degraded and newly synthesized
Heme Synthesis and Regulation
- Protoporphyrin IX + Fe = Heme
- First step is the RATE-LIMITING STEP, occurs in mitochondria
- Succinyl CoA + Glycine → δ-ALA using the enzyme δ-ALA synthase
- Requires vitamin B6 as cofactor
- Regulated through:
1. RLS Enzyme control (repressed by heme, stimulated by steroids and barbiturates)
2. Feedback inhibition by heme
Heme Degradation
- Degraded in the spleen and excreted into the urine, iron conserved
- Causes of hemolysis: erythrocyte fragility, burns, erythroblastosis fetalis
- If hemolysis occurs, Hgb with its iron is released into plasma
- Bruising: Heme = (red/purple), Biliverdin = (yellow/green), Bilirubin = (red/orange)
Bilirubin
- Lipid soluble, transported into the blood via carrier(Albumin)
- in the liver, UDP-glucuronyl transferase transfers 2x UDP to convert it into soluble Bili diglucuronide
- Bilirubin diglucuronide is then excreted in the bile
Lead Poisoning
- Inhibits ALA dehydratase(step 2) and ferrochelatase (last step), Elevated ALA
- Characterized by Microcytic anemia, everything else normal, basophilic stippling on blood smear
- Symptoms: Neurologic, GI, and Hematologic (a/w construction work)
- Complications: developmental disabilities, hearing loss, behavior, kidney damage, reduced IQ, slowed growth
- Treatment involves chelation therapy using EDTA, dimercaprol, or dimercaptosuccinic acid
*renal toxicity with EDTA*
Porphyrias
Types and Classifications
1. Erythropoietic porphyria: defect in porphyrin metabolism in blood-producing tissues
,2. Hepatic porphyria: defect in porphyrin metabolism in the liver
a) Hereditary or acquired
3. Cutaneous porphyrias: defect in porphyrin metabolism in the skin, causes photosensitivity
4. Acute porphyrias: impaired L-Trp catabolism → decreased serotonin → neurological symptoms
Key Examples
Acute Intermittent Porphyria
- Defect in porphobilinogen deaminase, causes PPGN accumulates in liver, excreted in urine
- 1/20,000 frequency, autosomal dominant
- Symptoms: neurological issues, abdominal pain, red urine, tachycardia, HTN
- Treatment: glucose(dec. biosynthesis) and hematin(ALA synthase inhibitor)
Porphyria Cutanea Tarda
- Defect in uroporphyrinogen decarboxylase
- 1:10,000 frequency
- Caused by iron, alcohol, hepatitis C, HIV, estrogen
- Symptoms: photosensitivity, skin changes, excess hair growth, liver problems
- Treatment: phlebotomy, chloroquine
Jan 6: Iron Metabolism
Iron Properties and Functions
- Functions in electron transport, O2 transport, Antioxidant
- Heme-containing: (Hgb, myglobin, cytochrome, COX),
- Non- Heme: (Fe-S clusters, ribonucleotide reductase)
- Redox reactions between ferric (Fe3+) and ferrous (Fe2+) forms
- Free iron caused by heme breakdown/injury can generate harmful free radicals (ROS)
Iron Transport and Storage
- Absorbed in duodenum, mostly incorporated into Hgb, some in muscle/other tissue
- Transported in plasma by Transferrin
- Transferrin receptor: TfR1, TfR2
- Stored in parenchymal cells of liver and reticuloendothelial macrophages bound to Ferritin in cytosol
- Hemosiderin: insoluble derivative of ferritin released in tissue injury
1. In the stomach, Fe3+ is reduced to Fe2+ by Ferric reductase, oxidized, and then reduced again
2. Transported into the apical border of intestine by DMT1 (cotransport with H+)
Key Proteins Involved
- DMT1/DCT1 (apical transport): transports Fe2+ into intestine
- Ferroportin (basolateral transport): transports Fe to plasma and requires Hephastin
- Hephaestin (ferroxidase in intestines): oxidation to form Fe3+, Fe transfer to plasma
- Ceruloplasmin (ferroxidase in other cells)
Regulation of Iron Homeostasis
,- Hepcidin: 25 amino acid peptide hormone from liver, decreases iron absorption
Hepcidin → Ferroportin degraded → reduced iron export from tissues → decreased iron absorption into intestines →
decreased iron in blood/tissues
- Minihepcidins: potential treatment for iron overload, can possibly treat HH
- Hepcidin agonist: antibody that blocks hepcidin from binding, lowers hepcidin levels, treatment for anemia
Iron Disorders
Iron Deficiency Anemia
- Initially depletes reserves without symptoms
- Diagnosed: transferrin saturation levels (<20%), normal~30%
- Treated with ferrous sulfate or blood transfusions, need to r/o blood loss
Hereditary Hemochromatosis(HH)
- Most common genetic defect in Caucasians (1/400)
- Caused by mutations in HFE gene (ΔTfR2, Δhemojuvelin, Δhepcidin)
- Results in excessive iron absorption and storage
- Affects multiple organs including liver, heart, and pancreas
- cirrhosis, cardiomyopathy, DM, pigmentation, joints, hypogonadism
- Treated through phlebotomy and chelators
Anemia of Chronic Disease(ACD)
- Caused by impaired iron utilization
- Associated w/ inflammatory conditions, chronic infections, IBD, autoimmune, neoplasia
- Inflammatory cytokines→increase Hepcidin → decreased iron absorption and release
- Treatment focuses on underlying condition
ACD HH
Hepcidin Levels High Low
Fe Absorption Low High
RE macrophage stores High Low
Circulating Fe Low High
Iron Overload
- Can be caused by:
- Acute poisoning: induces hypotension, metabolic acidosis, and coma
- Chronic overload: in patients who receive multiple transfusions
- Hereditary Hemochromatosis
- Reduced erythropoiesis: certain anemias cause destruction of erythroid cells in the marrow
- i.e. Thalassemias, Sideroblastic Anemias
Lab Testing for Iron
- Serum iron, serum iron binding capacity, serum ferritin, serum transferrin sats, CBC, BM/liver biopsy
, Total Iron Binding Capacity(TIBC) = Unsaturated Iron Binding Capacity(UIBC) + Serum Iron
Transferrin-Iron Binding Capacity (TIBC)
Jan 6: Malaria
Types and Characteristics
- Plasmodium vivax: Common, has latent form with relapse potential
- Plasmodium ovale: Features latent form with relapse potential
- Plasmodium malariae: 72-hour cycle (vs standard 48 hours)
- Plasmodium knowlesi: 24-hour cycle
- Plasmodium falciparum: Most common and serious form
- Causes higher RBC infection leading to capillary occlusion
- Associated with hemorrhage and necrosis
- Known for drug resistance
Epidemiology and Transmission
- Transmitted by Anopheles mosquito
- 90% of cases occur in Africa
- Highest risk groups: young children and pregnant individuals
Clinical Features
- Initial symptoms typically appear within one month of exposure
- Common symptoms: fever, fatigue, myalgias, headache
- Later stage: periodic fevers
- Complications vary by type:
- P. falciparum: cerebral malaria, jaundice, edema, severe anemia
- P. malariae: nephrotic syndrome
- P. knowlesi: respiratory distress, renal failure
- P. vivax and P. ovale: recurrent illness every 6-8 weeks
Diagnosis and Treatment
- Blood films:
- “ring shaped erythrocyte inclusions” in Malaria
- “Ring shaped and cross shaped erythrocyte inclusions” in Babesiosis(Borrelia burgdorferi- same as lyme)
- Rapid tests detecting malarial antigen
- Treatment options:
- Vector control
- Chloroquine (first-line)
- Artemisinin for chloroquine-resistant cases
- IV artesunate or quinine for severe cases
- Prevention:
- RTS/S vaccine shows 40-50% efficacy
- Targets malarial protein necessary for hepatocyte infection
