Heme Pathology Flashcards
Anemia
P: signs/symptoms of hypoxia Weakness, fatigue, dyspnea Pale conjunctiva, skin Headache and lightheaded Angina (prexisting CAD)
Hb, Hct and RBC count as surrogates
Hb < 13.5 in males, <12.5 in females
Microcytic Anemia
MCV < 80
Decreased in production of hemoglobin (defective heme or globin synthesis)
heme = iron + protoporphyrin
Iron deficiency, anemia of chronic disease, sideroblastic anemia, thalassemia
Iron deficiency anemia and Causes
Cause: decrease iron -> decrease hemoglobin synthesis
Most common type of anemia (most common nutritional deficiency)
Deficiency from dietary lack/blood loss
Infants - breast-feeding
Children - poor diet
Adults - peptic ulcer; menorrhagia/pregnancy
Elderly - colon polyps/carcinoma; hookworm (Ancylostoma duodenale/Necator americanus)
Other causes: malnutrition, malabsorption, gastrectomy (acid aids iron absorption by maintaining Fe2+ state)
Iron absorption and transport
Absorption in duodenum
Enterocytes have heme/non-heme (DMT1) transporters
Enterocytes transport iron across cell membrane through ferroportin
Transferrin transports iron in bood and delivers to liver/bone marrow macrophages for storage
Intracellular iron bound to ferritin (prevent fenton reaction - free radical)
Lab Measurements of iron status: Serum iron Total iron-binding capacity % Saturation Serum ferritin
Serum iron: iron in blood
Total iron-binding capacity: transferrin
% Sat: % transferrin bound to iron
Serum ferritin: iron stored in liver/macrophages
Iron deficiency: Stages and Histology
deplete storage iron (decrease ferritin, increase TIBC) -> deplete serum iron (decrease serum iron, decrease %sat) -> normocytic anemia (make fewer, but normal RBC) -> microcytic, hypochromic anemia (smaller and fewer cells)
P: anemia, koilonychia (spoon-shaped nails), pica
Lab: microcytic, hypochromic RBC with increased red cell distribution width
Decreased ferritin, increased TIBC; decreased serum iron and % saturation
Tx: supplemental iron (ferrous sulfate)
Plummer-Vinson syndrome
Iron deficiency anemia with esophageal web and atrophic glossitis
Anemia, dysphagia, beefy-red tongue
Anemia of Chronic Disease
Anemia assoc. with chronic inflammation (endocarditis, autoimmune conditions) or cancer; most common anemia in hospitalized patients
initially normocytic -> progress to microcytic, hypochromic
Increased production of acute phase reactants from liver (hepcidin)
Lab: high ferritin, low TIBC, low serum iron, low % saturation
increased free erythrocyte proptoporphyrin (FEP)
Tx: underlying cause; exogenous EPO (cancer patients)
Role of Hepcidin
1) Limits iron transfer from macrophages to erythroid precursors
2) Supresses erythropoietin (EPO) production
3) binds ferroportin on intestinal mucosal
Prevent bacteria from accessing iron (necessary for their survival)
Heme synthesis pathway
(Mitochondria) Rate limiting step
1) glycine + succinyl coA + B6 -> delta-aminolevulinic acid (ALA Synthase) inhibited by glucose, heme
(Cytoplasm)
2) ALA is converted to porphobilinogen (ALA Dehydratase)
3) Porphobilinogen -> hydroxymethylbilane (Porphobilinogen deaminase)
4) Hydroxymethylbilane -> Uroporphyrinogen III
5) Uroporphyrinogen III -> Coproporphyrinogen III (Uroporphyrinogen decarboxylase)
(Mitochondria)
6) Protoporphyrin + Fe2+ -> Heme (Ferrochelatase)
Iron is transferred to erythroid precursors and enters mitochondria from heme. If protoporphyrin is deficient, iron remains trapped - ringed sideroblasts
Lead poisoning
P: Child exposed to lead paint - mental retardation
Adults - battery/ammunition/radiator factory - headache, memory loss, demyelination
lead lines on gingivae (burton’s lines) and on metaphyses of long bones on x-ray; encephalopathy; abdominal colic; wrist/foot drop
Microcytic anemia, GI, kidney disease
Inhibits ALAD and ferrochelatase; inhibits rRNA degradation, causing RBC to retain aggregates of rRNA (basophilic stippling)
Increased ALA, protoporphyrin in blood
Tx: Dimercaprol and EDTA; Succimer for chelation for kids
Acute intermittent porphyria
Defective porphobilinogen deaminase
Autosomal dominant
Build up of porphobilinogen, ALA, uroporphyrin
5P’s
Painful abdomen
Port wine-colored urine (turns dark upon standing)
Polyneuropathy
Psychological disturbances
Precipitated by drugs (sulfonamides, phenobarbital)
Tx: glucose and heme (inhibit ALAS)
Porphyria cutanea tarda
Defective uroporphyrinogen decarboxylase
Uroporphyrin (tea-colored urine)
Blistering cutaneous photosensitivity; most common porphyria
Sideroblastic anemia
X-linked
Defective delta-aminolevulinic acid synthase
Other causes: alcohol, lead, isoniazid, vit B6 deficiency
Lab: ringed sideroblasts with iron-laden mitochondria
High iron, high % sat, normal TIBC, high ferritin (iron overloaded state)
Tx: pyridoxine (B6 cofactor for d-ALA)
Thalassemia
Microcytic anemia
Decreased synthesis of globin chains of hemoglobin
Carriers protected against P. falciparum
Divided into alpha/beta based on decreased production of alpha/beta globin chains
Normal types of hemoglobin
HbF: alpha2 gamma 2
HbA: alpha 2 beta 2
HbA2: alpha 2 delta 2
HbH: beta 4 (seen in alpha-thalassemia -3)
Hb Barts: gamma 4 (alpha-thalassemia -4)
Alpha-thalassemia
Deletion of alpha-globin (chromosome 16)
1 deletion: asymptomatic
2 deletions: mild anemia with increased RBC count; cis deletion increases risk of severe thalassemia in offspring
Cis - Asians; Trans - Africans
3 deletions: severe anemia; HbH (beta4)
4 deletions: lethal in utero (hydrops fetalis)
HbH (gamma 4) seen on electrophoresis
Beta-thalassemia
Point mutation in splice sites/promoter sequences on chromosome 11 -> deletion (-) or reduced production (+)
African and Mediterranean descent
Beta-thalassemia minor
Mildest form: Beta/Beta+
Microcytic, hypochromic RBC and target cells
Slightly decreased HbA with increased HbA2 (>3.5%) and HbF on electrophoresis
Beta-thalassemia major
Beta(-)/Beta(-) most severe
Severe anemia a few months after birth (HbF temporarily protective)
Alpha tetramers aggregate and damage RBC -> ineffective erythropoiesis and extravascular hemolysis
Massive erythroid hyperplasia (crewcut skull, chipmunk facies)
Aplastic anemia with parvovirus B19
Little to no HbA; increased HbA2 and HbF; microcytic, hypochromic RBC with target cells and nucleated red blood cells
Tx: chronic transfusions (risk for secondary hemochromatosis)
HbS/Beta-thalassemia heterozygote: mild to moderate sickle cell depending on beta globin production
Macrocytic anemia
Anemia with MCV > 100
Most commonly due to folate or vitamin B12 deficiency (megaloblastic anemia)
Impaired synthesis of DNA precursors -> impaired division and enlargement of RBC precursors
Impaired divisions of granulocytic precursors leads to hypersegmented neutrophils (megaloblastic changes also seen in rapidly-dividing epithelial cells like intestinal)
Other causes: alcoholism, liver diseases, drugs
Folate Deficiency
Macrocytic, megaloblastic anemia
P: glossitis, decreased serum folate
Folate deficiency develops within months (minimal body storage); in green vegetables/fruits absorbed in jejunum
Causes: poor diet (alcoholics/elderly), increased demand (pregnancy, cancer, hemolytic anemia), folate antagonists (methotrexate)
Increased serum homocysteine
(THF gives methyl group to vitamin B12 -> gives to homocysteine to convert to methionine)
Normal methylmalonic acid
Vitamin B12 Absorption
1) Salivary gland enzymes (amylases) liberate B12
2) B12 binds to R-binder (from salivary gland)
3) B12 liberated from R-binder in duodenum by pancreatic proteases
4) B12 binds to intrinsic factor (from gastric parietal cells)
5) B12 and intrinsic factor absorbed in ileum
Large hepatic store of vitamin B12; from animal-derived proteins
Vitamin B12 Deficiency: Presentation and Causes
Macrocytic RBC with hypersegmented neutrophils; glossitis, subacute combined degeneration of spinal cord
Pernicious anemia (most common): autoimmune destruction of parietal cells - intrinsic factor deficiency
Other causes: pancreatic insufficiency, damage to terminal ileum (Crohn; diphyllobothrium), dietary deficiency (rare, except in vegans), proton-pump inhibitors
