Pathoma_Husain

Pathoma_Husain. Total iron-binding capacity (TIBC)-measure of transferrin molecules in the blood 3. % saturation-percentage of transferrin molecules that are bound by iron (normal is 33%) 4. Serum ferritin-reflects iron stores in macrophages and the liver E. Iron deficiency is usually caused by dietary lack or blood loss. 1. Infants-breast-feeding (human milk is low in iron) 2. 3. 4. Elderly-colon polyps/carcinoma in the Western world; hookworm (Ancylostoma duodenale and Necator americanus) in the developing world 5. Other causes include malnutrition, malabsorption, and gastrectomy (acid aids iron absorption by maintaining the Fe2+ state, which is more readily absorbed than Fe3+). F. Stages of iron deficiency 1. Storage iron is depleted--J.. ferritin; t TIBC 2. Serum iron is depleted--J.. serum iron; -J.. % saturation 3. Normocytic anemia-Bone marrow makes fewer, but normal-sized, RBCs. 4. Microcytic, hypochromic anemia-Bone marrow makes smaller and fewer RBCs.


Pathoma_Husain

Pathoma_Husain. Normocytic anemia-Bone marrow makes fewer, but normal-sized, RBCs. 4. Microcytic, hypochromic anemia-Bone marrow makes smaller and fewer RBCs. G. Clinical features of iron deficiency include anemia, koilonychia, and pica. H. Laboratory findings include 1. Microcytic, hypochromic RBCs with t red cell distribution width (RDW, Fig. 5.1) 2. -J.. ferritin; t TIBC; -J.. serum iron; -J.. % saturation 3. I. Treatment involves supplemental iron (ferrous sulfate). J. Plummer-Vinson syndrome is iron deficiency anemia with esophageal web and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue III. ANEMIA OF CHRONIC DISEASE A. Anemia associated with chronic inflammation (e.g., endocarditis or autoimmune conditions) or cancer; most common type of anemia in hospitalized patients B. Chronic disease results in production of acute phase reactants from the liver, including hepcidin.


Pathoma_Husain

Pathoma_Husain. B. Chronic disease results in production of acute phase reactants from the liver, including hepcidin. 1. Hepcidin sequesters iron in storage sites by (1) limiting iron transfer from macrophages to erythroid precursors and (2) suppressing erythropoietin (EPO) Fig. 5.1 Microcytic, hypochromic RBCs of iron Fig. 5.2 Ringed sideroblasts (Prussian blue stain). deficiency anemia. production; aim is to prevent bacteria from accessing iron, which is necessary for their survival. 2. ..l.-available iron ➔ ..l.-heme ➔ ..l.-hemoglobin ➔ microcytic anemia C. Laboratory findings include 1. t ferritin, ..l.-TIBC, ..l.-serum iron, and ..l.-% saturation 2. D. Treatment involves addressing the underlying cause. IV. A. Anemia due to defective protoporphyrin synthesis 1. ..l.-protoporphyrin ➔ ..l.-heme ➔ ..l.-hemoglobin ➔ microcytic anemia B. Protoporphyrin is synthesized via a series of reactions. 1.


Pathoma_Husain

Pathoma_Husain. IV. A. Anemia due to defective protoporphyrin synthesis 1. ..l.-protoporphyrin ➔ ..l.-heme ➔ ..l.-hemoglobin ➔ microcytic anemia B. Protoporphyrin is synthesized via a series of reactions. 1. Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using vitamin B6 as a cofactor (rate-limiting step). 2. Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen. 3. Additional reactions convert porphobilinogen to protoporphyrin. 4. Ferrochelatase attaches protoporphyrin to iron to make heme (final reaction; occurs in the mitochondria). C. Iron is transferred to erythroid precursors and enters the mitochondria to form heme. If protoporphyrin is deficient, iron remains trapped in mitochondria. 1. Iron-laden mitochondria form a ring around the nucleus of erythroid precursors; these cells are called ringed sideroblasts (hence, the term sideroblastic anemia, Fig. 5.2). D. Sideroblastic anemia can be congenital or acquired. 1.


Pathoma_Husain

Pathoma_Husain. D. Sideroblastic anemia can be congenital or acquired. 1. Congenital defect most commonly involves ALAS (rate-limiting enzyme). 2. 1. Alcoholism-mitochondrial poison ii. Lead poisoning-inhibits ALAD and ferrochelatase iii. Vitamin B6 deficiency-required cofactor for ALAS; most commonly seen as a side effect of isoniazid treatment for tuberculosis E. Laboratory findings include t ferritin, -1, TIBC, t serum iron, and t % saturation (iron-overloaded state). V. A. Anemia due to decreased synthesis of the globin chains of hemoglobin 1. -1, globin ➔ -1, hemoglobin ➔ microcytic anemia B. Inherited mutation; carriers are protected against Plasmodium falciparum malaria. C. Divided into a-and P-thalassemia based on decreased production of alpha or beta globin chains. 1. Normal types of hemoglobin are HbF (a2y), HbA (a2p), and HbA2 (a/\). Table 5.1: Laboratory Findings in Microcytic Anemia Anemia of Chronic Disease High Low Low Low D. E.


Pathoma_Husain

Pathoma_Husain. 1. Normal types of hemoglobin are HbF (a2y), HbA (a2p), and HbA2 (a/\). Table 5.1: Laboratory Findings in Microcytic Anemia Anemia of Chronic Disease High Low Low Low D. E. a-Thalassemia is usually due to gene deletion; normally, 4 alpha genes are present on chromosome 16. 1. 2. Two genes deleted-mild anemia with t RBC count; cis deletion is associated with an increased risk of severe thalassemia in offspring. i. Cis deletion is when both deletions occur on the same chromosome; seen in Asians ii. Trans deletion is when one deletion occurs on each chromosome; seen in Africans, including African Americans 3. Three genes deleted-severe anemia; p chains form tetramers (HbH) that damage RBCs; HbH is seen on electrophoresis. 4. (Hb Barts) that damage RBCs; Hb Barts is seen on electrophoresis. P-Thalassemia is usually due to gene mutations (point mutations in promoter or splicing sites); seen in individuals of African and Mediterranean descent 1.


Pathoma_Husain

Pathoma_Husain. Two p genes are present on chromosome 11; mutations result in absent (P0) or diminished (p+) production of the p-globin chain. 2. P-Thalassemia minor (PIP+) is the mildest form of disease and is usually asymptomatic with an increased RBC count. i. Microcytic, hypochromic RBCs and target cells are seen on blood smear (Fig. 5.3). ii. Hemoglobin electrophoresis shows slightly decreased HbA with increased HbA (5%, normal 2.5%) and HbF (2%, normal 1%). 3. P-Thalassemia major (P 0!pa) is the most severe form of disease and presents with severe anemia a few months after birth; high HbF (a2y) at birth is temporarily protective. i. Unpaired a chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by the spleen).


Pathoma_Husain

Pathoma_Husain. i. Unpaired a chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by the spleen). ii. Massive erythroid hyperplasia ensues resulting in (1) expansion of hematopoiesis into the skull (reactive bone formation leads to 'crewcut' appearance on x-ray, Fig. 5.4) and facial bones ('chipmunk facies'), (2) extramedullary hematopoiesis with hepatosplenomegaly, and (3) risk of aplastic crisis with parvovirus Bl9 infection of erythroid precursors. iii. Chronic transfusions are often necessary; leads to risk for secondary hemochromatosis iv. Smear shows microcytic, hypochromic RBCs with target cells and nucleated red blood cells. v. Electrophoresis shows HbA and HbF with little or no HbA. Fig. 5.3 Target cells. Fig. 5.4 'Crewcut' appearance. (Reproduced with Fig. 5.5 Hypersegmented neutrophil in permission, www.orthopaedia.com/x/xgGvAQ) macrocytic anemia. I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. Fig. 5.3 Target cells. Fig. 5.4 'Crewcut' appearance. (Reproduced with Fig. 5.5 Hypersegmented neutrophil in permission, www.orthopaedia.com/x/xgGvAQ) macrocytic anemia. I. BASIC PRINCIPLES A. Anemia with MCV > 100 µm3; most commonly due to folate or vitamin Bl2 deficiency (megaloblastic anemia) B. Folate and vitamin Bl2 are necessary for synthesis of DNA precursors. 1. Folate circulates in the serum as methyltetrahydrofolate (methyl THF); removal of the methyl group allows for participation in the synthesis of DNA precursors. 2. Methyl group is transferred to vitamin Bl2 (cobalamin). 3. Vitamin Bl2 then transfers it to homocysteine, producing methionine. C. Lack of folate or vitamin Bl2 impairs synthesis of DNA precursors. 1. Impaired division and enlargement of RBC precursors leads to megaloblastic anemia. 2. Impaired division of granulocytic precursors leads to hypersegmented neutrophils. 3.


Pathoma_Husain

Pathoma_Husain. 1. Impaired division and enlargement of RBC precursors leads to megaloblastic anemia. 2. Impaired division of granulocytic precursors leads to hypersegmented neutrophils. 3. Megaloblastic change is also seen in rapidly-dividing (e.g., intestinal) epithelial cells. D. Other causes of macrocytic anemia (without megaloblastic change) include alcoholism, liver disease, and drugs (e.g., 5-FU). II. FOLATE DEFICIENCY A. Dietary folate is obtained from green vegetables and some fruits. 1. Absorbed in the jejunum B. Folate deficiency develops within months, as body stores are minimal. C. Causes include poor diet (e.g., alcoholics and elderly), increased demand (e.g., pregnancy, cancer, and hemolytic anemia), and folate antagonists (e.g., methotrexate, which inhibits dihydrofolate reductase). D. Clinical and laboratory findings include 1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes, Fig. 5.5) 2. 3. .,J., serum folate 4. 5. Ill. VITAMIN Bl2 DEFICIENCY


Pathoma_Husain

Pathoma_Husain. D. Clinical and laboratory findings include 1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes, Fig. 5.5) 2. 3. .,J., serum folate 4. 5. Ill. VITAMIN Bl2 DEFICIENCY A. Dietary vitamin Bl2 is complexed to animal-derived proteins. 1. Salivary gland enzymes (e.g., amylase) liberate vitamin Bl 2, which is then bound by R-binder (also from the salivary gland) and carried through the stomach. 2. Pancreatic proteases in the duodenum detach vitamin Bl2 from R-binder. 3. Vitamin Bl2 binds intrinsic factor (made by gastric parietal cells) in the small bowel; the intrinsic factor-vitamin Bl2 complex is absorbed in the ileum. B. Vitamin Bl2 deficiency is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin Bl 2. C. Pernicious anemia is the most common cause of vitamin Bl2 deficiency. 1. Autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency


Pathoma_Husain

Pathoma_Husain. C. Pernicious anemia is the most common cause of vitamin Bl2 deficiency. 1. Autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency D. Other causes of vitamin Bl2 deficiency include pancreatic insufficiency and damage to the terminal ileum (e.g., Crohn disease or Diphyllobothrium latum [fish tapeworm]); dietary deficiency is rare, except in vegans. E. Clinical and laboratory findings include 1. Macrocytic RBCs with hypersegmented neutrophils 2. 3. Subacute combined degeneration of the spinal cord i. Vitamin B12 is a cofactor for the conversion of methylmalonic acid to succinyl CoA (important in fatty acid metabolism). ii. Vitamin B12 deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization. iii. Damage results in poor proprioception and vibratory sensation (posterior column) and spastic paresis (lateral corticospinal tract). 4. -.J, serum vitamin B12 5.


Pathoma_Husain

Pathoma_Husain. iii. Damage results in poor proprioception and vibratory sensation (posterior column) and spastic paresis (lateral corticospinal tract). 4. -.J, serum vitamin B12 5. t serum homocysteine (similar to folate deficiency), which increases risk for thrombosis 6. I. BASIC PRINCIPLES A. Anemia with normal-sized RBCs (MCV = 80-100 µm3) B. Due to increased peripheral destruction or underproduction 1. Reticulocyte count helps to distinguish between these two etiologies. II. RETICULOCYTES A. Young RBCs released from the bone marrow 1. Identified on blood smear as larger cells with bluish cytoplasm (due to residual RNA, Fig. 5.6) B. Normal reticulocyte count (RC) is 1-2%. 1. RBC lifespan is 120 days; each day roughly 1-2% ofRBCs are removed from circulation and replaced by reticulocytes. C. A properly functioning marrow responds to anemia by increasing the RC to > 3%. D. RC, however, is falsely elevated in anemia.


Pathoma_Husain

Pathoma_Husain. C. A properly functioning marrow responds to anemia by increasing the RC to > 3%. D. RC, however, is falsely elevated in anemia. 1. RC is measured as percentage of total RBCs; decrease in total RBCs falsely elevates percentage of reticulocytes. E. RC is corrected by multiplying reticulocyte count by Hct/45. 1. Corrected count > 3% indicates good marrow response and suggests peripheral destruction. 2. Corrected count < 3% indicates poor marrow response and suggests underproduction. III. PERIPHERAL RBC DESTRUCTION (HEMOLYSIS) A. Divided into extravascular and intravascular hemolysis; both result in anemia with a good marrow response. B. Extravascular hemolysis involves RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes). Fig. 5.6 Reticulocyte. Fig. 5.7 Spherocytes. 1. Macrophages consume RBCs and break down hemoglobin. i. Globin is broken down into amino acids.


Pathoma_Husain

Pathoma_Husain. Fig. 5.6 Reticulocyte. Fig. 5.7 Spherocytes. 1. Macrophages consume RBCs and break down hemoglobin. i. Globin is broken down into amino acids. ii. Heme is broken down into iron and protoporphyrin; iron is recycled. 111. Protoporphyrin is broken down into unconjugated bilirubin, which is bound to serum albumin and delivered to the liver for conjugation and excretion into bile. 2. Clinical and laboratory findings include i. Anemia with splenomegaly, jaundice due to unconjugated bilirubin, and increased risk for bilirubin gallstones ii. Marrow hyperplasia with corrected reticulocyte count> 3% C. Intravascular hemolysis involves destruction of RBCs within vessels. 1. Clinical and laboratory findings include 1. Hemoglobinemia 11. Hemoglobinuria iii. Hemosiderinuria-Renal tubular cells pick up some of the hemoglobin that is filtered into the urine and break it down into iron, which accumulates as hemosiderin; tubular cells are eventually shed resulting in hemosiderinuria.


Pathoma_Husain

Pathoma_Husain. iv. Decreased serum haptoglobin I. HEREDITARY SPHEROCYTOSIS A. Inherited defect ofRBC cytoskeleton-membrane tethering proteins 1. Most commonly involves ankyrin, spectrin, or band 3 B. Membrane blebs are formed and lost over time. 1. Loss of membrane renders cells round (spherocytes) instead of disc-shaped. 2. Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia. C. Clinical and laboratory findings include 1. Spherocytes with loss of central pallor (Fig. 5.7) 2. 3. Splenomegaly, jaundice with unconjugated bilirubin, and increased risk for bilirubin gallstones (extravascular hemolysis) 4. Increased risk for a plastic crisis with parvovirus Bl9 infection of erythroid precursors D. Diagnosed by osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution


Pathoma_Husain

Pathoma_Husain. Increased risk for a plastic crisis with parvovirus Bl9 infection of erythroid precursors D. Diagnosed by osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution E. Treatment is splenectomy; anemia resolves, but spherocytes persist and Howell-Jolly bodies (fragments of nuclear material in RBCs) emerge on blood smear (Fig. 5.8). II. SICKLE CELL ANEMIA A. Autosomal recessive mutation in~ chain of hemoglobin; a single amino acid change replaces normal glutamic acid (hydrophilic) with valine (hydrophobic). B. Gene is carried by 10% of individuals of African descent, likely due to protective role against falciparum malaria. C. Sickle cell disease arises when two abnormal ~ genes are present; results in >90% HbS in RBCs D. HbS polymerizes when deoxygenated; polymers aggregate into needle-like structures, resulting in sickle cells (Fig. 5.9). 1. Increased risk of sickling occurs with hypoxemia, dehydration, and acidosis. 2.


Pathoma_Husain

Pathoma_Husain. 1. Increased risk of sickling occurs with hypoxemia, dehydration, and acidosis. 2. HbF protects against sickling; high HbF at birth is protective for the first few months of life. Treatment with hydroxyurea increases levels ofHbF. E. F. G. H. Cells continuously sickle and de-sickle while passing through the microcirculation, resulting in complications related to RBC membrane damage. 1. Extravascular hemolysis-Reticuloendothelial system removes RBCs with damaged membranes, leading to anemia, jaundice with unconjugated hyperbilirubinemia, and increased risk for bilirubin gallstones. 2. Intravascular hemolysis-RBCs with damaged membranes dehydrate, leading to hemolysis with decreased haptoglobin and target cells on blood smear. 3.


Pathoma_Husain

Pathoma_Husain. 2. Intravascular hemolysis-RBCs with damaged membranes dehydrate, leading to hemolysis with decreased haptoglobin and target cells on blood smear. 3. i. Expansion of hematopoiesis into the skull ('crewcut' appearance on x-ray) and facia l bones ('chipmunk facies') 11. Extramedullary hematopoiesis with hepatomegaly iii. Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors Extensive sickling leads to complications of vaso-occlusion. 1. Dactylitis-swollen hands and feet due to vaso-occlusive infarcts in bones; common presenting sign in infants 2. Autosplenectomy-shrunken, fibrotic spleen. Consequences include i. Increased risk of infection with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae (most common cause of death in children); affected children should be vaccinated by 5 years of age. ii. Increased risk of Salmonella paratyphi osteomyelitis iii. Howell-Jolly bodies on blood smear 3.


Pathoma_Husain

Pathoma_Husain. ii. Increased risk of Salmonella paratyphi osteomyelitis iii. Howell-Jolly bodies on blood smear 3. i. Presents with chest pain, shortness of breath, and lung infiltrates ii. Often precipitated by pneumonia iii. Most common cause of death in adult patients 4. 5. Renal papillary necrosis-results in gross hematuria and proteinuria Sickle cell trait is the presence of one mutated and one normal pchain; results in < 50% HbS in RBCs (HbA is slightly more efficiently produced than HbS) 1. Generally asymptomatic with no anemia; RBCs with < 50% HbS do not sickle in vivo except in the renal medulla. 1. Extreme hypoxia and hypertonicity of the medulla cause sickling, which results in microinfarctions leading to microscopic hematuria and, eventually, decreased ability to concentrate urine. 1. Sickle cells and target cells are seen on blood smear in sickle cell disease, but not in sickle cell trait. 2.


Pathoma_Husain

Pathoma_Husain. 1. Sickle cells and target cells are seen on blood smear in sickle cell disease, but not in sickle cell trait. 2. Metabisulfite screen causes cells with any amount of HbS to sickle; positive in both disease and trait 3. Hb electrophoresis confirms the presence and amount ofHbS. Fig. 5.8 Fragment of nuclear remnant (HowellFig. 5.9 Sickle cell disease. Fig. 5.10 Hemoglobin C crystal. Jolly body) within RBC. Red Blood Cell Disorders _,... i. Disease-90% HbS, 8% HbF, 2% HbA (no HbA) ii. Trait-55% HbA, 43% HbS, 2% HbA2 III. HEMOGLOBIN C A. Autosomal recessive mutation in ~ chain of hemoglobin 1. Normal glutamic acid is replaced by lysine. 2. B. Presents with mild anemia due to extravascular hemolysis C. Characteristic HbC crystals are seen in RBCs on blood smear (Fig. 5.10). I. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) A. Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction by complement 1.


Pathoma_Husain

Pathoma_Husain. A. Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction by complement 1. Blood cells coexist with complement. 2. Decay accelerating factor (DAF) on the surface of blood cells protects against complement-mediated damage by inhibiting C3 convertase. 3. DAF is secured to the cell membrane by GPI (an anchoring glycolipid). 4. Absence of GPI leads to absence of DAF, rendering cells susceptible to complement-mediated damage. B. Intravascular hemolysis occurs episodically, often at night during sleep. 1. Mild respiratory acidosis develops with shallow breathing during sleep and activates complement. 2. RBCs, WBCs, and platelets are lysed. 3. Intravascular hemolysis leads to hemoglobinemia and hemoglobinuria (especially in the morning); hemosiderinuria is seen days after hemolysis.


Pathoma_Husain

Pathoma_Husain. 2. RBCs, WBCs, and platelets are lysed. 3. Intravascular hemolysis leads to hemoglobinemia and hemoglobinuria (especially in the morning); hemosiderinuria is seen days after hemolysis. C. Sucrose test is used to screen for disease; confirmatory test is the acidified serum test or flow cytometry to detect lack of CDSS (DAF) on blood cells. D. Main cause of death is thrombosis of the hepatic, portal, or cerebral veins. 1. Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis. E. Complications include iron deficiency anemia (due to chronic loss of hemoglobin in the urine) and acute myeloid leukemia (AML), which develops in 10% of patients. II. GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY A. X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress 1. RBCs are normally exposed to oxidative stress, in particular H20 2• 2.


Pathoma_Husain

Pathoma_Husain. A. X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress 1. RBCs are normally exposed to oxidative stress, in particular H20 2• 2. Glutathione (an antioxidant) neutralizes H 0 , but becomes oxidized in the process. 3. NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione. 4. ,J, G6PD ➔ ,J, NADPH ➔ ,J, reduced glutathione ➔ oxidative injury by H20 2 ➔ intravascular hemolysis B. G6PD deficiency has two major variants. 1. African variant-mildly reduced half-life of G6PD leading to mild intravascular hemolysis with oxidative stress 2. Mediterranean variant-markedly reduced half-life of G6PD leading to marked intravascular hemolysis with oxidative stress 3. High carrier frequency in both populations is likely due to protective role against falciparum malaria. C. Oxidative stress precipitates Hb as Heinz bodies. 1.


Pathoma_Husain

Pathoma_Husain. High carrier frequency in both populations is likely due to protective role against falciparum malaria. C. Oxidative stress precipitates Hb as Heinz bodies. 1. Causes of oxidative stress include infections, drugs (e.g., primaquine, sulfa drugs, and dapsone), and fava beans. 2. Heinz bodies are removed from RBCs by splenic macrophages, resulting in bite cells (Fig. 5.11). 3. Leads to predominantly intravascular hemolysis D. Presents with hemoglobinuria and back pain hours after exposure to oxidative stress E. Heinz preparation is used to screen for disease (precipitated hemoglobin can only be seen with a special Heinz stain, Fig. 5.12); enzyme studies confirm deficiency (performed weeks after hemolytic episode resolves). III. IMMUNE HEMOLYTIC ANEMIA (IHA) A. Antibody-mediated (IgG or IgM) destruction ofRBCs B. IgG-mediated disease usually involves extravascular hemolysis. 1.


Pathoma_Husain

Pathoma_Husain. III. IMMUNE HEMOLYTIC ANEMIA (IHA) A. Antibody-mediated (IgG or IgM) destruction ofRBCs B. IgG-mediated disease usually involves extravascular hemolysis. 1. IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin); membrane of antibody-coated RBC is consumed by splenic macrophages, resulting in spherocytes. 2. Associated with SLE (most common cause), CLL, and certain drugs (classically, penicillin and cephalosporins) i. Drug may attach to RBC membrane (e.g., penicillin) with subsequent binding of antibody to drug-membrane complex ii. Drug may induce production of autoantibodies (e.g., a-methyldopa) that bind self antigens on RBCs 3. Treatment involves cessation of the offending drug, steroids, IVIG, and, if necessary, splenectomy. C. IgM-mediated disease can lead to intravascular hemolysis. 1. IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities (cold agglutinin). 2.


Pathoma_Husain

Pathoma_Husain. C. IgM-mediated disease can lead to intravascular hemolysis. 1. IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities (cold agglutinin). 2. RBCs inactivate complement, but residual C3b serves as an opsonin for splenic macrophages resulting in spherocytes; extreme activation of complement can lead to intravascular hemolysis. 3. Associated with Mycoplasma pneumoniae and infectious mononucleosis. D. Coombs test is used to diagnose IHA; testing can be direct or indirect. 1. Direct Coombs test confirms the presence of antibody-or complement-coated RBCs. When anti-IgG/complement is added to patient RBCs, agglutination occurs if RBCs are already coated with IgG or complement. This is the most important test for IHA. 2. Indirect Coombs test confirms the presence of antibodies in patient serum. AntiIgG and test RBCs are mixed with the patient serum; agglutination occurs if serum antibodies are present.


Pathoma_Husain

Pathoma_Husain. 2. Indirect Coombs test confirms the presence of antibodies in patient serum. AntiIgG and test RBCs are mixed with the patient serum; agglutination occurs if serum antibodies are present. Fig. 5.11 Bite cell. Fig. 5.12 Heinz bodies (Heinz preparation). Fig. 5.13 Schistocyte. IV. A. Intravascular hemolysis that results from vascular pathology; RBCs are destroyed as they pass through the circulation. 1. Iron deficiency anemia occurs with chronic hemolysis. B. Occurs with microthrombi (TTP-HUS, DIC, HELLP), prosthetic heart valves, and aortic stenosis; when present, microthrombi produce schistocytes on blood smear (Fig. 5.13). V. A. Infection ofRBCs and liver with Plasmodium (Fig. 5.14); transmitted by the female Anopheles mosquito B. RBCs rupture as a part of the Plasm odium life cycle, resulting in intravascular hemolysis and cyclical fever. 1. 2. C. Spleen also consumes some infected RBCs; results in mild extravascular hemolysis with splenomegaly I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. 1. 2. C. Spleen also consumes some infected RBCs; results in mild extravascular hemolysis with splenomegaly I. BASIC PRINCIPLES A. Decreased production of RBCs by bone marrow; characterized by low corrected reticulocyte count B. Etiologies include 1. Causes of microcytic and macrocytic anemia 2. Renal failure-decreased production of EPO by peritubular interstitial cells 3. Damage to bone marrow precursor cells (may result in anemia or pancytopenia) II. PARVOVIRUS Bl9 A. Infects progenitor red cells and temporarily halts erythropoiesis; leads to significant anemia in the setting of preexisting marrow stress (e.g., sickle cell anemia). B. Treatment is supportive (infection is self-limited). III. APLASTIC ANEMIA A. Damage to hematopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count B. Etiologies include drugs or chemicals, viral infections, and autoimmune damage.


Pathoma_Husain

Pathoma_Husain. B. Etiologies include drugs or chemicals, viral infections, and autoimmune damage. C. Biopsy reveals an empty, fatty marrow (Fig. 5.15). Fig. 5.14 Erythrocytes infected with P falciparum. Fig. 5.15 Aplastic anemia. (Courtesy of Paulo Mourao, MD) D. Treatment includes cessation of any causative drugs and supportive care with transfusions and marrow-stimulating factors (e.g., erythropoietin, GM-CSF, and G-CSF). 1. Immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines. 2. May require bone marrow transplantation as a last resort IV. MYELOPHTHISIC PROCESS A. Pathologic process (e.g., metastatic cancer) that replaces bone marrow; hematopoiesis is impaired, resulting in pancytopenia. I. BASIC PRINCIPLES A. Hematopoiesis occurs via a stepwise maturation of CD34+ hematopoietic stem cells (Fig. 6.1). B. Cells mature and are released from the bone marrow into the blood.


Pathoma_Husain

Pathoma_Husain. I. BASIC PRINCIPLES A. Hematopoiesis occurs via a stepwise maturation of CD34+ hematopoietic stem cells (Fig. 6.1). B. Cells mature and are released from the bone marrow into the blood. C. A normal white blood cell (WBC) count is approximately 5-10 K/µL. l. A low WBC count(< 5 K) is called leukopenia. 2. A high WBC count(> 10 K) is called leukocytosis. 3. A low or high WBC count is usually due to a decrease or increase in one particular cell lineage. II. LEUKOPENIA A. Neutropenia refers to a decreased number of circulating neutrophils. Causes include l. Drug toxicity (e.g., chemotherapy with alkylating agents)-Damage to stem cells results in decreased production of WBCs, especially neutrophils. 2. Severe infection (e.g., gram-negative sepsis)-Increased movement of neutrophils into tissues results in decreased circulating neutrophils. 3.


Pathoma_Husain

Pathoma_Husain. 2. Severe infection (e.g., gram-negative sepsis)-Increased movement of neutrophils into tissues results in decreased circulating neutrophils. 3. As a treatment, GM-CSF or G-CSF may be used to boost granulocyte production, thereby decreasing risk of infection in neutropenic patients. B. Lymphopenia refers to a decreased number of circulating lymphocytes. Causes include l. Immunodeficiency (e.g., Di George syndrome or HIV) 2. High cortisol state (e.g., exogenous corticosteroids or Cushing syndrome)induces apoptosis of lymphocytes 3. Autoimmune destruction (e.g., systemic lupus erythematosus) 4. Whole body radiation-Lymphocytes are highly sensitive to radiation; lymphopenia is the earliest change to emerge after whole body radiation. III. LEUKOCYTOSIS


Pathoma_Husain

Pathoma_Husain. Whole body radiation-Lymphocytes are highly sensitive to radiation; lymphopenia is the earliest change to emerge after whole body radiation. III. LEUKOCYTOSIS A. Neutrophilic leukocytosis refers to increased circulating neutrophils. Causes include l. Bacterial infection or tissue necrosis-induces release of marginated pool and bone marrow neutrophils, including immature forms (left shift); immature cells are characterized by decreased Fe receptors (CD16). Fig. 6.1 Hematopoiesis. pathoma.com 2. High cortisol state-impairs leukocyte adhesion, leading to release of marginated pool of neutrophils B. Monocytosis refers to increased circulating monocytes. Causes include chronic inflammatory states (e.g., autoimmune and infectious) and malignancy. C. Eosinophilia refers to increased circulating eosinophils. Causes include allergic reactions (type I hypersensitivity), parasitic infections, and Hodgkin lymphoma. Eosinophilia is driven by increased eosinophil chemotactic factor.


Pathoma_Husain

Pathoma_Husain. D. Basophilia refers to increased circulating basophils; classically seen in chronic myeloid leukemia E. Lymphocytic leukocytosis refers to increased circulating lymphocytes. Causes include 1. Viral infections-T lymphocytes undergo hyperplasia in response to virally infected cells. 2. Bordetella pertussis infection-Bacteria produce lymphocytosis-promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node. IV. INFECTIOUS MONONUCLEOSIS (IM) A. EBV infection that results in a lymphocytic leukocytosis comprised of reactive CDs+ T cells; CMV is a less common cause. 1. EBV is transmitted by saliva ("kissing disease"); classically affects teenagers B. EBV primarily infects 1. Oropharynx, resulting in pharyngitis 2. Liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes 3. C. CDs+ T-cell response leads to 1. Generalized lymphadenopathy (LAD) due to T-cell hyperplasia in the lymph node paracortex 2.


Pathoma_Husain

Pathoma_Husain. C. CDs+ T-cell response leads to 1. Generalized lymphadenopathy (LAD) due to T-cell hyperplasia in the lymph node paracortex 2. Splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath (PALS) 3. High WBC count with atypical lymphocytes (reactive CDs+ T cells) in the blood (Fig. 6.2) D. The monospot test is used for screening. 1. Detects IgM antibodies that cross-react with horse or sheep red blood cells (heterophile antibodies) 2. 3. A negative monospot test suggests CMV as a possible cause of IM. 4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen. Fig. 6.2 Atypical lymphocyte, infectious Fig. 6.3 Splenic rupture. (Courtesy of K.V. mononucleosis. Santosh, MD) E. Complications 1. Increased risk for splenic rupture (Fig. 6.3); patients are generally advised to avoid contact sports for one month. 2. Rash if exposed to ampicillin 3.


Pathoma_Husain

Pathoma_Husain. E. Complications 1. Increased risk for splenic rupture (Fig. 6.3); patients are generally advised to avoid contact sports for one month. 2. Rash if exposed to ampicillin 3. Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops. I. BASIC PRINCIPLES A. Neoplastic proliferation of blasts; defined as the accumulation of > 20% blasts in the bone marrow. B. Increased blasts "crowd-out" normal hematopoiesis, resulting in an "acute" presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropenia (infection). C. Blasts usually enter the blood stream, resulting in a high WBC count. 1. Blasts are large, immature cells, often with punched out nucleoli (Fig. 6.4). D. Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts. II. ACUTE LYMPHOBLASTIC LEUKEMIA


Pathoma_Husain

Pathoma_Husain. D. Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts. II. ACUTE LYMPHOBLASTIC LEUKEMIA A. Neoplastic accumulation oflymphoblasts (> 20%) in the bone marrow 1. Lymphoblasts are characterized by positive nuclear staining for TdT, a DNA polymerase. 2. TdT is absent in myeloid blasts and mature lymphocytes. B. Most commonly arises in children; associated with Down syndrome (usually arises after the age of 5 years) C. Subclassified into B-ALL and T-ALL based on surface markers D. B-ALL is the most common type of ALL. 1. Usually characterized by lymphoblasts (TdT+) that express CDlO, CD19, and CD20. 2. Excellent response to chemotherapy; requires prophylaxis to scrotum and CSF (Fig. 6.5) 3. Prognosis is based on cytogenetic abnormalities. i. t(l2;21) has a good prognosis; more commonly seen in children ii. t(9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+ ALL)


Pathoma_Husain

Pathoma_Husain. Prognosis is based on cytogenetic abnormalities. i. t(l2;21) has a good prognosis; more commonly seen in children ii. t(9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+ ALL) E. T-ALL is characterized by lymphoblasts (TdT+) that express markers ranging from CD2 to CDS (e.g., CD3, CD4, CD7). The blasts do not express CDlO. Fig. 6.4 Blasts of acute leukemia. Fig. 6.5 Acute lymphoblastic leukemia involving meninges. 1. Usually presents in teenagers as a mediastinal (thymic) mass (called acute lymphoblastic lymphoma because the malignant cells form a mass) III. ACUTE MYELOID LEUKEMIA A. Neoplastic accumulation of immature myeloid cells (> 20%) in the bone marrow B. Myeloblasts are usually characterized by positive cytoplasmic staining for myeloperoxidase (MPO). 1. Crystal aggregates of MPO may be seen as Auer rods (Fig. 6.6). C. Most commonly arises in older adults (average age is 50-60 years)


Pathoma_Husain

Pathoma_Husain. 1. Crystal aggregates of MPO may be seen as Auer rods (Fig. 6.6). C. Most commonly arises in older adults (average age is 50-60 years) D. Subclassification based on cytogenetic abnormalities, lineage of immature myeloid cells, and surface markers. High-yield subtypes include 1. Acute promyelocytic leukemia (APL) i. Characterized by t(l5;17), which involves translocation of the retinoic acid receptor (RAR) on chromosome 17 to chromosome 15; RAR disruption blocks maturation and promyelocytes (blasts) accumulate. ii. Abnormal promyelocytes contain numerous primary granules that increase the risk for DIC. iii. Treatment is with all-trans-retinoic acid (ATRA, a vitamin A derivative), which binds the altered receptor and causes the blasts to mature (and eventually die). 2. Acute monocytic leukemia i. Proliferation of monoblasts; usually lack MPO ii. Blasts characteristically infiltrate gums (Fig. 6.7).


Pathoma_Husain

Pathoma_Husain. 2. Acute monocytic leukemia i. Proliferation of monoblasts; usually lack MPO ii. Blasts characteristically infiltrate gums (Fig. 6.7). 3. Acute megakaryoblastic leukemia i. Proliferation of megakaryoblasts; lack MPO ii. Associated with Down syndrome (usually arises before the age of 5) E. AML may also arise from pre-existing dysplasia (myelodysplastic syndromes), especially with prior exposure to alkylating agents or radiotherapy. 1. Myelodysplastic syndromes usually present with cytopenias, hypercellular bone marrow, abnormal maturation ofcells, and increased blasts(< 20%). 2. Most patients die from infection or bleeding, though some progress to acute leukemia. I. BASIC PRINCIPLES A. Neoplastic proliferation of mature circulating lymphocytes; characterized by a high WBC count B. Usually insidious in onset and seen in older adults II. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) A. Neoplastic proliferation of naive B cells that co-express CDS and CD20; most common leukemia overall


Pathoma_Husain

Pathoma_Husain. II. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) A. Neoplastic proliferation of naive B cells that co-express CDS and CD20; most common leukemia overall B. Increased lymphocytes and smudge cells are seen on blood smear (Fig. 6.8). C. Involvement of lymph nodes leads to generalized lymphadenopathy and is called small lymphocytic lymphoma. D. Complications include 1. Hypogammaglobulinemia-Infection is the most common cause of death in CLL. 2. 3. Transformation to diffuse large B-cell lymphoma (Richter transformation)marked clinically by an enlarging lymph node or spleen III. HAIRY CELL LEUKEMIA A. Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes (Fig. 6.9) B. Cells are positive for tartrate-resistant acid phosphatase (TRAP). C. Clinical features include splenomegaly (due to accumulation of hairy cells in red pulp) and "dry tap" on bone marrow aspiration (due to marrow fibrosis). Lymphadenopathy is usually absent.


Pathoma_Husain

Pathoma_Husain. C. Clinical features include splenomegaly (due to accumulation of hairy cells in red pulp) and "dry tap" on bone marrow aspiration (due to marrow fibrosis). Lymphadenopathy is usually absent. D. Excellent response to 2-CDA (cladribine), an adenosine deaminase inhibitor; adenosine accumulates to toxic levels in neoplastic B cells. IV. A. Neoplastic proliferation of mature CD4+ T cells B. Associated with HTLV-1; most commonly seen in Japan and the Caribbean C. Clinical features include rash (skin infiltration), generalized lymphadenopathy with hepatosplenomegaly, and lytic (punched-out) bone lesions with hypercalcemia. V. A. Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing localized skin rash, plaques, and nodules. Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses. B. Cells can spread to involve the blood, producing Sezary syndrome.


Pathoma_Husain

Pathoma_Husain. B. Cells can spread to involve the blood, producing Sezary syndrome. 1. Characteristic lymphocytes with cerebriform nuclei (Sezary cells) are seen on blood smear (Fig. 6.10). Fig. 6.9 Hairy cell leukemia. (Courtesy of Paulo Fig. 6.10 Sezary cells. (Courtesy of Paulo Mourao, Mourao, MD) MD) I. BASIC PRINCIPLES A. Neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood (average age is 50-60 years) B. Results in high WBC count with hypercellular bone marrow 1. Cells of all myeloid lineages are increased; classified based on the dominant myeloid cell produced C. Complications include 1. Increased risk for hyperuricemia and gout due to high turnover of cells 2. Progression to marrow fibrosis or transformation to acute leukemia II. CHRONIC MYELOID LEUKEMIA (CML) A. Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors; basophils are characteristically increased (Fig. 6.11).


Pathoma_Husain

Pathoma_Husain. II. CHRONIC MYELOID LEUKEMIA (CML) A. Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors; basophils are characteristically increased (Fig. 6.11). B. Driven by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion protein with increased tyrosine kinase activity. 1. First line treatment is imatinib, which blocks tyrosine kinase activity. C. Splenomegaly is common. Enlarging spleen suggests progression to accelerated phase of disease; transformation to acute leukemia usually follows shortly thereafter. 1. Can transform to AML (2/3 of cases) or ALL (1/3 of cases) since mutation is in a pluripotent stem cell. D. CML is distinguished from a leukemoid reaction (reactive neutrophilic leukocytosis) by 1. Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive) 2. Increased basophils (absent with leukemoid reaction) 3. III. POLYCYTHEMIA VERA (PV)


Pathoma_Husain

Pathoma_Husain. Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive) 2. Increased basophils (absent with leukemoid reaction) 3. III. POLYCYTHEMIA VERA (PV) A. Neoplastic proliferation of mature myeloid cells, especially RBCs 1. Granulocytes and platelets are also increased. B. Associated with JAK2 kinase mutation C. Clinical symptoms are mostly due to hyperviscosity of blood. 1. 2. Increased risk of venous thrombosis (e.g., hepatic vein, portal vein, and dural sinus) 3. Flushed face due to congestion (plethora) 4. Itching, especially after bathing (due to histamine release from increased mast cells) D. Treatment is phlebotomy; second-line therapy is hydroxyurea. Fig. 6.11 Chronic myelogenous leukemia. Fig. 6.12 Essential thrombocythemia. 1. Without treatment, death usually occurs within one year. E. PV must be distinguished from reactive polycythemia. 1. In PV, erythropoietin (EPO) levels are decreased, and Sao is normal. 2.


Pathoma_Husain

Pathoma_Husain. 1. Without treatment, death usually occurs within one year. E. PV must be distinguished from reactive polycythemia. 1. In PV, erythropoietin (EPO) levels are decreased, and Sao is normal. 2. In reactive polycythemia due to high altitude or lung disease, Sao2 is low, and EPO is increased. 3. In reactive polycythemia due to ectopic EPO production from renal cell carcinoma, EPO is high, and Sao2 is normal. IV. A. Neoplastic proliferation of mature myeloid cells, especially platelets (Fig. 6.12) 1. RBCs and granulocytes are also increased. B. Associated with JAK2 kinase mutation C. Symptoms are related to an increased risk of bleeding and/or thrombosis. 1. Rarely progresses to marrow fibrosis or acute leukemia 2. V. A. Neoplastic proliferation of mature myeloid cells, especially megakaryocytes 1. Associated with JAK2 kinase mutation (50% of cases) B. Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis (Fig. 6.13).


Pathoma_Husain

Pathoma_Husain. B. Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis (Fig. 6.13). C. Clinical features include 1. Splenomegaly due to extramedullary hematopoiesis 2. Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes, Fig. 6.14) 3. Increased risk of infection, thrombosis, and bleeding I. BASIC PRINCIPLES A. LAD refers to enlarged lymph nodes. 1. Painful LAD is usually seen in lymph nodes that are draining a region of acute infection (acute lymphadenitis). 2. Painless LAD can be seen with chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or lymphoma. B. In inflammation, lymph node enlargement is due to hyperplasia of particular regions of the lymph node (Fig. 6.15). 1. Follicular hyperplasia (B-cell region) is seen with rheumatoid arthritis and early stages of HIV infection, for example. Fig. 6.13 Myelofibrosis. Fig. 6.14 Tear-drop RBC. Fig. 6.15 Normal lymph node. 2.


Pathoma_Husain

Pathoma_Husain. Fig. 6.13 Myelofibrosis. Fig. 6.14 Tear-drop RBC. Fig. 6.15 Normal lymph node. 2. Paracortex hyperplasia (T-cell region) is seen with viral infections (e.g., infectious mononucleosis). 3. Hyperplasia of sinus histiocytes is seen in lymph nodes that are draining a tissue with cancer. I. BASIC PRINCIPLES A. Neoplastic proliferation oflymphoid cells that forms a mass; may arise in a lymph node or in extranodal tissue B. Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin lymphoma (HL, 40%) (Table 6.1) C. NHL is further classified based on cell type (e.g., B versus T), cell size, pattern of cell growth, expression of surface markers, and cytogenetic translocations. 1. Small B cells-follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma (i.e., CLL cells that involve tissue) 2. 3. Table 6.1: Differences Between Non-Hodgkin Lymphoma and Hodgkin Lymphoma Composition of mass Lymphoid cells Painless lymphadenopathy, usually arises


Pathoma_Husain

Pathoma_Husain. 3. Table 6.1: Differences Between Non-Hodgkin Lymphoma and Hodgkin Lymphoma Composition of mass Lymphoid cells Painless lymphadenopathy, usually arises Clinical with 'B' symptoms, usually arises in young Guides therapy; radiation is the mainstay of treatment. Fig. 6.16 Follicular lymphoma. A, Disruption of normal lymph node architecture by neoplastic follicles. B, Neoplastic follicles lacking tingible body macrophages. C, Reactive follicular hyperplasia with tingible body macrophages for comparison. II. FOLLICULAR LYMPHOMA A. Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules (Fig. 6.16A) B. Presents in late adulthood with painless lymphadenopathy C. Driven by t(l4;18) l. BCL2 on chromosome 18 translocates to the lg heavy chain locus on chromosome 14. 2. Results in overexpression of Bcl2, which inhibits apoptosis D. Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody).


Pathoma_Husain

Pathoma_Husain. 2. Results in overexpression of Bcl2, which inhibits apoptosis D. Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody). E. Progression to diffuse large B-cell lymphoma is an important complication; presents as an enlarging lymph node F. Follicular lymphoma is distinguished from reactive follicular hyperplasia by 1. Disruption of normal lymph node architecture (maintained in follicular hyperplasia) 2. Lack of tingible body macrophages in germinal centers (tingible body macrophages are present in follicular hyperplasia, Fig. 6.16B,C) 3. 4. Monoclonality (follicular hyperplasia is polyclonal) III. MANTLE CELL LYMPHOMA A. Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone B. Presents in late adulthood with painless lymphadenopathy C. Driven by t(ll;l4) 1. Cyclin Dl gene on chromosome 11 translocates to lg heavy chain locus on chromosome 14. 2.


Pathoma_Husain

Pathoma_Husain. B. Presents in late adulthood with painless lymphadenopathy C. Driven by t(ll;l4) 1. Cyclin Dl gene on chromosome 11 translocates to lg heavy chain locus on chromosome 14. 2. Overexpression of cyclin Dl promotes Gl/S transition in the cell cycle, facilitating neoplastic proliferation. IV. A. Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone B. Associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis 1. The marginal zone is formed by post-germinal center B cells. C. MALToma is marginal zone lymphoma in mucosal sites. 1. Gastric MALToma may regress with treatment of H Pylori. V. A. Neoplastic proliferation of intermediate-sized B cells (CD20+); associated with EBV B. Classically presents as an extranodal mass in a child or young adult Fig. 6.17 Burkitt lymphoma. A, Involvement of jaw. B, 'Starry-sky' appearance. (A, Courtesy Mike Blyth) 1.


Pathoma_Husain

Pathoma_Husain. B. Classically presents as an extranodal mass in a child or young adult Fig. 6.17 Burkitt lymphoma. A, Involvement of jaw. B, 'Starry-sky' appearance. (A, Courtesy Mike Blyth) 1. African form usually involves the jaw (Fig. 6.17A). 2. Sporadic form usually involves the abdomen. C. Driven by translocations of c-myc (chromosome 8) 1. t(8;14) is most common, resulting in translocation of c-myc to the lg heavy chain locus on chromosome 14. 2. Overexpression of c-myc oncogene promotes cell growth. D. Characterized by high mitotic index and 'starry-sky' appearance on microscopy (Fig. 6.17B) VI. DIFFUSE LARGE B-CELL LYMPHOMA A. Neoplastic proliferation oflarge B cells (CD20+) that grow diffusely in sheets 1. Most common form of NHL 2. B. Arises sporadically or from transformation of a low-grade lymphoma (e.g., follicular lymphoma) 1. Presents in late adulthood as an enlarging lymph node or an extranodal mass I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. B. Arises sporadically or from transformation of a low-grade lymphoma (e.g., follicular lymphoma) 1. Presents in late adulthood as an enlarging lymph node or an extranodal mass I. BASIC PRINCIPLES A. Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and prominent nucleoli ('owl-eyed nuclei', Fig. 6.18); classically positive for CD15 and CD30 B. RS cells secrete cytokines. 1. Occasionally results in 'B' symptoms (fever, chills, weight loss, and night sweats) 2. Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils 3. May lead to fibrosis C. Reactive inflammatory cells make up a bulk of the tumor and form the basis for classification of HL. Subtypes include 1. 2. 3. 4. D. Nodular sclerosis is the most common subtype of HL (70% of all cases). 1. Classic presentation is an enlarging cervical or mediastinal lymph node in a young adult, usually female. 2.


Pathoma_Husain

Pathoma_Husain. 3. 4. D. Nodular sclerosis is the most common subtype of HL (70% of all cases). 1. Classic presentation is an enlarging cervical or mediastinal lymph node in a young adult, usually female. 2. Lymph node is divided by bands of sclerosis (Fig. 6.19A); RS cells are present in lake-like spaces (lacunar cells, Fig. 6.19B). E. Important considerations regarding other subtypes of HL 1. Lymphocyte-rich has the best prognosis of all types. Fig. 6.18 Reed-Sternberg cell. Fig. 6.19 Hodgkin lymphoma, nodular sclerosis type. A, Sclerosis of lymph node. B, Reed-Sternberg cells in lacunar spaces. 2. Mixed cellularity is often associated with abundant eosinophils (RS cells produce IL-5). 3. Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly and HIV-positive individuals I. MULTIPLE MYELOMA A. Malignant proliferation of plasma cells in the bone marrow 1.


Pathoma_Husain

Pathoma_Husain. I. MULTIPLE MYELOMA A. Malignant proliferation of plasma cells in the bone marrow 1. Most common primary malignancy of bone; metastatic cancer, however, is the most common malignant lesion of bone overall. 2. B. Clinical features include 1. Bone pain with hypercalcemia-Neoplastic plasma cells activate the RANK receptor on osteoclasts, leading to bone destruction. Lytic, 'punched-out' skeletal lesions are seen on x-ray (Fig. 6.20A), especially in the vertebrae and skull; increased risk for fracture 2. Elevated serum protein-Neoplastic plasma cells produce immunoglobulin; M spike is present on serum protein electrophoresis (SPEP), most commonly due to monoclonal IgG or IgA. 3. Increased risk of infection-Monoclonal antibody lacks antigenic diversity; infection is the most common cause of death in multiple myeloma. 4. Rouleaux formation ofRBCs on blood smear-Increased serum protein decreases charge between RBCs (Fig. 6.20B). 5.


Pathoma_Husain

Pathoma_Husain. 4. Rouleaux formation ofRBCs on blood smear-Increased serum protein decreases charge between RBCs (Fig. 6.20B). 5. Primary AL amyloidosis-Free light chains circulate in serum and deposit in tissues. 6. Proteinuria-Free light chain is excreted in the urine as Bence Jones protein; deposition in kidney tubules leads to risk for renal failure (myeloma kidney). II. MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) A. Increased serum protein with M spike on SPEP; other features of multiple myeloma are absent (e.g., no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria). B. Common in elderly (seen in 5% of 70-year-old individuals); 1 % of patients with MGUS develop multiple myeloma each year. III. WALDENSTROM MACROGLOBULINEMIA A. B-cell lymphoma with monoclonal IgM production B. Clinical features include


Pathoma_Husain

Pathoma_Husain. III. WALDENSTROM MACROGLOBULINEMIA A. B-cell lymphoma with monoclonal IgM production B. Clinical features include Fig. 6.20 Multiple myeloma. A, 'Punched-out' lesions involving skull, x-ray. B, Rouleaux formation of Fig. 6.21 Birbeck granule, electron microscopy. RBCs. (Courtesy of humpath.com) 1. Generalized lymphadenopathy; lytic bone lesions are absent. 2. Increased serum protein with M spike (comprised oflgM) 3. Visual and neurologic deficits (e.g., retinal hemorrhage or stroke)-IgM (large pentamer) causes serum hyperviscosity. 4. Bleeding-Viscous serum results in defective platelet aggregation. C. Acute complications are treated with plasmapheresis, which removes IgM from the serum. I. BASIC PRINCIPLES A. Langerhans cells are specialized dendritic cells found predominantly in the skin. 1. 2. Present antigen to nai:ve T cells B. Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells.


Pathoma_Husain

Pathoma_Husain. 1. 2. Present antigen to nai:ve T cells B. Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells. 1. Characteristic Birbeck (tennis racket) granules are seen on electron microscopy (Fig. 6.21); cells are CDla+ and S-100+ by immunohistochemistry. II. LETTERER-SIWE DISEASE A. Malignant proliferation of Langerhans cells B. Classic presentation is skin rash and cystic skeletal defects in an infant(< 2 years old). C. Multiple organs may be involved; rapidly fatal III. EOSINOPHILIC GRANULOMA A. Benign proliferation of Langerhans cells in bone B. Classic presentation is pathologic fracture in an adolescent; skin is not involved. C. Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous eosinophils. IV. HAND-SCHULLER-CHRISTIAN DISEASE A. Malignant proliferation of Langerhans cells B. Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child. I. BASIC PRINCIPLES


Pathoma_Husain

Pathoma_Husain. A. Malignant proliferation of Langerhans cells B. Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child. I. BASIC PRINCIPLES A. Inflammation of the blood vessel wall 1. Arterial wall is comprised of three layers: endothelial intima, smooth muscle media, and connective tissue adventitia (Fig. 7.1). B. Etiology is usually unknown; most cases are not infectious. C. Clinical features include 1. Nonspecific symptoms of inflammation (e.g., fever, fatigue, weight loss, and myalgias) 2. Symptoms of organ ischemia-due to luminal narrowing or thrombosis of the inflamed vessels D. Divided into large-, medium-, and small-vessel vasculitides 1. Large-vessel vasculitis involves the aorta and its major branches. 2. Medium-vessel vasculitis involves muscular arteries that supply organs. 3. Small-vessel vasculitis involves arterioles, capillaries, and venules. II. LARGE-VESSEL VASCULITIS A. Temporal (Giant Cell) Arteritis 1.


Pathoma_Husain

Pathoma_Husain. 3. Small-vessel vasculitis involves arterioles, capillaries, and venules. II. LARGE-VESSEL VASCULITIS A. Temporal (Giant Cell) Arteritis 1. Granulomatous vasculitis that classically involves branches of the carotid artery 2. 3. Presents as headache (temporal artery involvement), visual disturbances (ophthalmic artery involvement), and jaw claudication. Flu-like symptoms with joint and muscle pain (polymyalgia rheumatica) are often present. ESR is elevated. 4. Biopsy reveals inflamed vessel wall with giant cells and intimal fibrosis (Fig. 7.2). i. Lesions are segmental; diagnosis requires biopsy of a long segment of vessel, and a negative biopsy does not exclude disease. 5. Treatment is corticosteroids; high risk of blindness without treatment B. Takayasu Arteritis 1. Granulomatous vasculitis that classically involves the aortic arch at branch points 2.


Pathoma_Husain

Pathoma_Husain. 5. Treatment is corticosteroids; high risk of blindness without treatment B. Takayasu Arteritis 1. Granulomatous vasculitis that classically involves the aortic arch at branch points 2. Presents in adults < 50 years old (classically, young Asian females) as visual and neurologic symptoms with a weak or absent pulse in the upper extremity ('pulseless disease'). ESR is elevated. 3. Treatment is corticosteroids. III. MEDIUM-VESSEL VASCULITIS A. Polyarteritis Nodosa 1. Necrotizing vasculitis involving multiple organs; lungs are spared. 2. Classically presents in young adults as hypertension (renal artery involvement), abdominal pain with melena (mesenteric artery involvement), neurologic disturbances, and skin lesions. Associated with serum HBsAg pathoma.com 3. Lesions of varying stages are present. Early lesion consists of transmural inflammation with fibrinoid necrosis (Fig. 7.3); eventually heals with fibrosis, producing a 'string-of-pearls' appearance on imaging 4.


Pathoma_Husain

Pathoma_Husain. Treatment is corticosteroids and cyclophosphamide; fatal if not treated B. Kawasaki Disease 1. 2. Presents with nonspecific signs including fever, conjunctivitis, erythematous rash of palms and soles, and enlarged cervical lymph nodes 3. Coronary artery involvement is common and leads to risk for (1) thrombosis with myocardial infarction and (2) aneurysm with rupture. 4. Treatment is aspirin and IVIG; disease is self-limited. C. Buerger Disease 1. 2. Presents with ulceration, gangrene, and autoamputation of fingers and toes; Raynaud phenomenon is often present. 3. Highly associated with heavy smoking; treatment is smoking cessation. IV. SMALL-VESSEL VASCULITIS A. Wegener Granulomatosis 1. Necrotizing granulomatous vasculitis involving nasopharynx, lungs, and kidneys 2. Classic presentation is a middle-aged male with sinusitis or nasopharyngeal ulceration, hemoptysis with bilateral nodular lung infiltrates, and hematuria due to rapidly progressive glomerulonephritis.


Pathoma_Husain

Pathoma_Husain. 3. Serum c-ANCA levels correlate with disease activity. 4. Biopsy reveals large necrotizing granulomas with adjacent necrotizing vasculitis (Fig. 7.4). 5. Treatment is cyclophosphamide and steroids; relapses are common. B. Microscopic Polyangiitis 1. Necrotizing vasculitis involving multiple organs, especially lung and kidney 2. Presentation is similar to Wegener granulomatosis, but nasopharyngeal involvement and granulomas are absent. 3. Serum p-ANCA levels correlate with disease activity. 4. Treatment is corticosteroids and cyclophosphamide; relapses are common. C. Churg-Strauss Syndrome 1. Necrotizing granulomatous inflammation with eosinophils involving multiple organs, especially lungs and heart 2. Asthma and peripheral eosinophilia are often present. 3. Serum p-ANCA levels correlate with disease activity. Fig. 7.1 Normal muscular artery. Fig. 7.2 Temporal (giant cell) arteritis. Fig. 7.3 Fibrinoid necrosis, polyarteritis nodosa. D. Henoch-Schonlein Purpura 1.


Pathoma_Husain

Pathoma_Husain. Fig. 7.1 Normal muscular artery. Fig. 7.2 Temporal (giant cell) arteritis. Fig. 7.3 Fibrinoid necrosis, polyarteritis nodosa. D. Henoch-Schonlein Purpura 1. Vasculitis due to IgA immune complex deposition; most common vasculitis in children 2. Presents with palpable purpura on buttocks and legs, GI pain and bleeding, and hematuria (IgA nephropathy); usually occurs following an upper respiratory tract infection 3. Disease is self-limited, but may recur; treated with steroids, if severe I. BASIC PRINCIPLES A. Increased blood pressure; may involve pulmonary (see chapter 9) or systemic circulation B. Systemic HTN is defined as pressure :2'. 140/90 mm Hg (normal ~ 120/80 mm Hg); divided into primary or secondary types based on etiology II. PRIMARY HTN A. HTN of unknown etiology (95% of cases) B. Risk factors include age, race (increased risk in African Americans, decreased risk in Asians), obesity, stress, lack of physical activity, and high-salt diet. III. SECONDARY HTN


Pathoma_Husain

Pathoma_Husain. B. Risk factors include age, race (increased risk in African Americans, decreased risk in Asians), obesity, stress, lack of physical activity, and high-salt diet. III. SECONDARY HTN A. HTN due to an identifiable etiology (5% ofcases) B. Renal artery stenosis is a common cause (renovascular hypertension). 1. Stenosis decreases blood flow to glomerulus. 2. Juxtaglomerular apparatus (JGA) responds by secreting renin, which converts angiotensinogen to angiotensin I. 3. Angiotensin I is converted to angiotensin II (ATII) by angiotensin converting enzyme (ACE). 4. ATII raises blood pressure by (1) contracting arteriolar smooth muscle, increasing total peripheral resistance and (2) promoting adrenal release of aldosterone, which increases resorption of sodium in the distal convoluted tubule (expanding plasma volume). 5. Leads to HTN with increased plasma renin and unilateral atrophy (due to low blood flow) of the affected kidney; neither feature is seen in primary hypertension.


Pathoma_Husain

Pathoma_Husain. 5. Leads to HTN with increased plasma renin and unilateral atrophy (due to low blood flow) of the affected kidney; neither feature is seen in primary hypertension. C. Important causes of stenosis include atherosclerosis (elderly males) and fibromuscular dysplasia (young females). Fig. 7.4 Wegener granulomatosis. A, Necrotizing granuloma. B, Giant cells at edge of granuloma. Fig. 7.5 Atherosclerosis. 1. Fibromuscular dysplasia is a developmental defect of the blood vessel wall, resulting in irregular thickening of large-and medium-sized arteries, especially the renal artery. IV. BENIGN AND MALIGNANT HTN A. HTN can also be classified as benign or malignant. B. Benign HTN is a mild or moderate elevation in blood pressure; most cases of HTN are benign. 1. Clinically silent; vessels and organs are damaged slowly over time. C. Malignant HTN is severe elevation in blood pressure (> 180/120 mm Hg); comprises < 5% of cases 1. 2.


Pathoma_Husain

Pathoma_Husain. 1. Clinically silent; vessels and organs are damaged slowly over time. C. Malignant HTN is severe elevation in blood pressure (> 180/120 mm Hg); comprises < 5% of cases 1. 2. Presents with acute end-organ damage (e.g., acute renal failure, headache, and papilledema) and is a medical emergency I. BASIC PRINCIPLES A. Literally, "hard arteries;" due to thickening of the blood vessel wall B. Three pathologic patterns-atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis II. ATHEROSCLEROSIS A. Intimal plaque that obstructs blood flow 1. Consists of a necrotic lipid core (mostly cholesterol) with a fibromuscular cap (Fig. 7.5); often undergoes dystrophic calcification B. Involves large-and medium-sized arteries; abdominal aorta, coronary artery, popliteal artery, and internal carotid artery are commonly affected. C. Risk factors for atherosclerosis are divided into modifiable and nonmodifiable. 1.


Pathoma_Husain

Pathoma_Husain. C. Risk factors for atherosclerosis are divided into modifiable and nonmodifiable. 1. Modifiable risk factors include hypertension, hypercholesterolemia (LDL increases risk; HDL decreases risk), smoking, and diabetes. 2. Nonmodifiable risk factors include age (number and severity of lesions increase with age), gender (increased risk in males and postmenopausal females; estrogen is protective), and genetics (multifactorial, but family history is highly predictive of risk). D. Pathogenesis 1. Damage to endothelium allows lipids to leak into the intima. 2. Lipids are oxidized and then consumed by macrophages via scavenger receptors, resulting in foam cells. Fig. 7.6 Atherosclerotic em bolus. (Courtesy of Fig. 7.7 Hyaline arteriolosclerosis. Fig. 7.8 Arteriolonephrosclerosis. (Courtesy of Professor A. Garfia) Jerome Taxy, MD) 3. Inflammation and healing leads to deposition of extracellular matrix and proliferation of smooth muscle. E. Morphologic stages 1.


Pathoma_Husain

Pathoma_Husain. E. Morphologic stages 1. Begins as fatty streaks (flat yellow lesions of the intima consisting oflipid-laden macrophages); arise early in life (present in most teenagers) 2. Progresses to atherosclerotic plaque F. Complications of atherosclerosis account for > 50% of disease in Western countries. 1. Stenosis of medium-sized vessels results in impaired blood flow and ischemia leading to i. Peripheral vascular disease (lower extremity arteries, e.g., popliteal) ii. Angina (coronary arteries) iii. Ischemic bowel disease (mesenteric arteries) 2. Plaque rupture with thrombosis results in myocardial infarction (coronary arteries) and stroke (e.g., middle cerebral artery). 3. Plaque rupture with embolization results in atherosclerotic emboli, characterized by cholesterol crystals within the embolus (Fig. 7.6). 4. Weakening of vessel wall results in aneurysm (e.g., abdominal aorta). III. ARTERIOLOSCLEROSIS


Pathoma_Husain

Pathoma_Husain. 4. Weakening of vessel wall results in aneurysm (e.g., abdominal aorta). III. ARTERIOLOSCLEROSIS A. Narrowing of small arterioles; divided into hyaline and hyperplastic types B. Hyaline arteriolosclerosis is caused by proteins leaking into the vessel wall, producing vascular thickening; proteins are seen as pink hyaline on microscopy (Fig. 7.7). 1. 2. Results in reduced vessel caliber with end-organ ischemia; classically produces glomerular scarring (arteriolonephrosclerosis, Fig. 7.8) that slowly progresses to chronic renal failure C. Hyperplastic arteriolosclerosis involves thickening of vessel wall by hyperplasia of smooth muscle ('onion-skin' appearance, Fig. 7.9). 1. Consequence of malignant hypertension 2. Results in reduced vessel caliber with end-organ ischemia 3. May lead to fibrinoid necrosis of the vessel wall with hemorrhage; classically causes acute renal failure with a characteristic 'flea-bitten' appearance IV. MONCKEBERG MEDIAL CALCIFIC SCLEROSIS


Pathoma_Husain

Pathoma_Husain. May lead to fibrinoid necrosis of the vessel wall with hemorrhage; classically causes acute renal failure with a characteristic 'flea-bitten' appearance IV. MONCKEBERG MEDIAL CALCIFIC SCLEROSIS A. Calcification of the media of muscular (medium-sized) arteries; nonobstructive (Fig. 7.lOA) B. Not clinically significant; seen as an incidental finding on x-ray or mammography (Fig. 7.lOB) Fig. 7.9 Hyperplastic arteriolosclerosis. Fig. 7.10 Monckeberg medial calcific sclerosis. A, Microscopic appearance. B, Mammogram. I. AORTIC DISSECTION A. Intimal tear with dissection of blood through media of the aortic wall (Fig. 7.11) B. Occurs in the proximal 10 cm of the aorta (high stress region) with preexisting weakness of the media C. Most common cause is hypertension (older adults); also associated with inherited defects of connective tissue (younger individuals) 1. Hypertension results in hyaline arteriolosclerosis of the vasa vasorum; decreased flow causes atrophy of the media. 2.


Pathoma_Husain

Pathoma_Husain. Hypertension results in hyaline arteriolosclerosis of the vasa vasorum; decreased flow causes atrophy of the media. 2. Marfan syndrome and Ehlers-Danlos syndrome classically lead to weakness of the connective tissue in the media (cystic medial necrosis). D. Presents as sharp, tearing chest pain that radiates to the back E. Complications include pericardia! tamponade (most common cause of death), rupture with fatal hemorrhage, and obstruction of branching arteries (e.g., coronary or renal) with resultant end-organ ischemia. II. THORACIC ANEURYSM A. Balloon-like dilation of the thoracic aorta B. Due to weakness in the aortic wall. Classically seen in tertiary syphilis; endarteritis of the vasa vasorum results in luminal narrowing, decreased flow, and atrophy of the vessel wall. Results in a 'tree-bark' appearance of the aorta (Fig. 7.12) C. Major complication is dilation of the aortic valve root, resulting in aortic valve insufficiency.


Pathoma_Husain

Pathoma_Husain. C. Major complication is dilation of the aortic valve root, resulting in aortic valve insufficiency. 1. Other complications include compression of mediastinal structures (e.g., airway or esophagus) and thrombosis/embolism. III. ABDOMINAL AORTIC ANEURYSM A. Balloon-like dilation of the abdominal aorta; usually arises below the renal arteries, but above the aortic bifurcation (Fig. 7.13) B. Primarily due to atherosclerosis; classically seen in male smokers > 60 years old with hypertension 1. Atherosclerosis increases the diffusion barrier to the media, resulting in atrophy and weakness of the vessel wall. C. Presents as a pulsatile abdominal mass that grows with time D. Major complication is rupture, especially when > 5 cm in diameter; presents with triad of hypotension, pulsatile abdominal mass, and flank pain 1. Other complications include compression oflocal structures (e.g., ureter) and thrombosis/embolism.


Pathoma_Husain

Pathoma_Husain. Fig. 7.11 Aortic dissection. (Courtesy of humpath. Fig. 7.12 'Tree-bark' appearance of aorta due to Fig, 7.13 Abdominal aortic aneurysm. (Courtesy com) syphi lis. (Courtesy of Aliya Husain, MD) of Aliya Husain, MD) I. HEMANGIOMA A. Benign tumor comprised of blood vessels (Fig. 7. 14) B. Commonly present at birth; often regresses during childhood C. Most often involves skin and liver II. ANGIOSARCOMA A. Malignant proliferation of endothelial cells; highly aggressive B. Common sites include skin, breast, and liver. 1. Liver angiosarcoma is associated with exposure to polyvinyl chloride, arsenic, and Thorotrast. III. KAPOSI SARCOMA A. Low-grade malignant proliferation of endothelial cells; associated with HHV-8 B. Presents as purple patches, plaques, and nodules on the skin (Fig. 7.15); may also involve visceral organs C. Classically seen in 1. Older Eastern European males-tumor remains localized to skin; treatment involves surgical removal. 2.


Pathoma_Husain

Pathoma_Husain. C. Classically seen in 1. Older Eastern European males-tumor remains localized to skin; treatment involves surgical removal. 2. AIDS-tumor spreads early; treatment is antiretroviral agents (to boost immune system). 3. Transplant recipients-tumor spreads early; treatment involves decreasing immunosuppression. Fig. 7.14 Hemangioma. Fig. 7.15 Kaposi sarcoma. I. BASIC PRINCIPLES A. Group of syndromes related to myocardial ischemia; IHD is the leading cause of death in the US. B. Usually due to atherosclerosis of coronary arteries, which decreases blood flow to the myocardium 1. Risk factors for IHD are similar to those of atherosclerosis; incidence increases with age. II. ANGINA A. Stable angina is chest pain that arises with exertion or emotional stress. 1. Due to atherosclerosis of coronary arteries with > 70% stenosis; decreased blood flow is not able to meet the metabolic demands of the myocardium during exertion. 2.


Pathoma_Husain

Pathoma_Husain. 1. Due to atherosclerosis of coronary arteries with > 70% stenosis; decreased blood flow is not able to meet the metabolic demands of the myocardium during exertion. 2. Represents reversible injury to myocytes (no necrosis) 3. Presents as chest pain (lasting < 20 minutes) that radiates to the left arm or jaw, diaphoresis, and shortness of breath 4. EKG shows ST-segment depression due to subendocardial ischemia. 5. B. Unstable angina is chest pain that occurs at rest. 1. Usually due to rupture of an atherosclerotic plaque with thrombosis and incomplete occlusion of a coronary artery (Fig. 8.lA). 2. Represents reversible injury to myocytes (no necrosis) 3. EKG shows ST-segment depression due to subendocardial ischemia. 4. 5. High risk of progression to myocardial infarction C. Prinzmetal angina is episodic chest pain unrelated to exertion. 1. Due to coronary artery vasospasm 2. Represents reversible injury to myocytes (no necrosis) 3.


Pathoma_Husain

Pathoma_Husain. C. Prinzmetal angina is episodic chest pain unrelated to exertion. 1. Due to coronary artery vasospasm 2. Represents reversible injury to myocytes (no necrosis) 3. EKG shows ST-segment elevation due to transmural ischemia. 4. III. MYOCARDIAL INFARCTION A. Necrosis of cardiac myocytes B. Usually due to rupture of an atherosclerotic plaque with thrombosis and complete occlusion of a coronary artery (Fig. 8.lB) 1. Other causes include coronary artery vasospasm (due to Prinzmetal angina or cocaine use), emboli, and vasculitis (e.g., Kawasaki disease). C. Clinical features include severe, crushing chest pain (lasting > 20 minutes) that radiates to the left arm or jaw, diaphoresis, and dyspnea; symptoms are not relieved by nitroglycerin. D. Infarction usually involves the left ventricle (LV); right ventricle (RV) and both atria are generally spared. pathoma.com 1.


Pathoma_Husain

Pathoma_Husain. D. Infarction usually involves the left ventricle (LV); right ventricle (RV) and both atria are generally spared. pathoma.com 1. Occlusion ofleft anterior descending artery (LAD) leads to infarction of the anterior wall and anterior septum of the LV; LAD is the most commonly involved artery in MI (45% of cases). 2. Occlusion of right coronary artery (RCA) leads to infarction of the posterior wall, posterior septum, and papillary muscles of the LV; RCA is the 2nd most commonly involved artery in MI. 3. Occlusion of left circumflex artery leads to infarction of lateral wall of the L V. E. Initial phase of infarction leads to subendocardial necrosis involving < 50% of the myocardial thickness (subendocardial infarction, Fig. 8.2); EKG shows ST-segment depression. 1. Continued or severe ischemia leads to transmural necrosis involving most of the myocardial wall (transmural infarction); EKG shows ST-segment elevation. F. Laboratory tests detect elevated cardiac enzymes. 1.


Pathoma_Husain

Pathoma_Husain. F. Laboratory tests detect elevated cardiac enzymes. 1. Troponin I is the most sensitive and specific marker (gold standard) for MI. Levels rise 2-4 hours after infarction, peak at 24 hours, and return to normal by 7-10 days. 2. CK-MB is useful for detecting reinfarction that occurs days after an initial Ml; creatine kinase MB (CK-MB) levels rise 4-6 hours after infarction, peak at 24 hours, and return to normal by 72 hours. G. Treatment includes 1. Aspirin and/or heparin-limits thrombosis 2. Supplemental 0 2-minimizes ischemia 3. 4. ~-blocker-slows heart rate, decreasing 0 demand and risk for arrhythmia 5. 6. i. Reperfusion of irreversibly-damaged cells results in calcium influx, leading to hypercontraction of myofibrils (contraction band necrosis, Fig. 8.3). ii. Return of oxygen and inflammatory cells may lead to free radical generation, further damaging myocytes (reperfusion injury).


Pathoma_Husain

Pathoma_Husain. ii. Return of oxygen and inflammatory cells may lead to free radical generation, further damaging myocytes (reperfusion injury). H. Complications of myocardial infarction are closely related to gross and microscopic changes (Table 8.1). Table 8.1: Morphologic Changes in Myocardial Infarction ~~~::c~;~N GROSS CHANGES MICROSCOPIC CHANGES COMPLICATIONS Cardiogenic shock (massive infarction), congestive heart failure, and arrhythmia Coagulative necrosis (Fig. 8.4A) Fibrinous pericarditis (Fig. 8.SA); presents as 1-3 days Yellow pallor Neutrophils (Fig. 8.4B) chest pain with friction rub Rupture of ventricular free wall (Fig. 8.SB; leads to cardiac tamponade), interventricular septum 4-7 days Yellow pallor Macrophages (leads to shunt), or papillary muscle (Fig. 8.SC; leads to mitral insufficiency) Red border emerges as Granulation tissue with 1-3 weeks granulation tissue enters plump fibroblasts, collagen, from edge of infarct. and blood vessels


Pathoma_Husain

Pathoma_Husain. Red border emerges as Granulation tissue with 1-3 weeks granulation tissue enters plump fibroblasts, collagen, from edge of infarct. and blood vessels Aneurysm (Fig. 8.7), mural thrombus, or Months White scar (Fig. 8.6A) Fibrosis (Fig. 8.6B) Fig. 8.3 Contraction band necrosis. Fig. 8.4 Myocardial infarction. A, Coagulative necrosis of myocardium. B, Neutrophilic infiltrate. Fig. 8.5 Complications of myocardial infarction. A, Fibrinous pericarditis. B, Rupture of ventricular free wall. C, Rupture of papillary muscle. (Courtesy of Aliya Husain, MD) Fig. 8.6 Myocardial scar. A, Gross appearance. B, Microscopic appearance. (A, Courtesy of Ajit Paintal, Fig. 8.7 Ventricular aneurysm. MD) IV. A. Unexpected death due to cardiac disease; occurs without symptoms or < 1 hour after symptoms arise 1. Usually due to fatal ventricular arrhythmia B. Most common etiology is acute ischemia; 90% of patients have preexisting severe atherosclerosis.


Pathoma_Husain

Pathoma_Husain. B. Most common etiology is acute ischemia; 90% of patients have preexisting severe atherosclerosis. 1. Less common causes include mitral valve prolapse, cardiomyopathy, and cocaine abuse. V. A. Poor myocardial function due to chronic ischemic damage (with or without infarction); progresses to congestive heart failure (CHF) I. BASIC PRINCIPLES A. Pump failure; divided into right-and left-sided failure II. LEFT-SIDED HEART FAILURE A. Causes include ischemia, hypertension, dilated cardiomyopathy, myocardial infarction, and restrictive cardiomyopathy. B. Clinical features are due to decreased forward perfusion and pulmonary congestion. 1. Pulmonary congestion leads to pulmonary edema.


Pathoma_Husain

Pathoma_Husain. B. Clinical features are due to decreased forward perfusion and pulmonary congestion. 1. Pulmonary congestion leads to pulmonary edema. i. Results in dyspnea, paroxysmal nocturnal dyspnea (due to increased venous return when lying flat), orthopnea, and crackles ii. Small, congested capillaries may burst, leading to intraalveolar hemorrhage; marked by hemosiderin-laden macrophages ('heart-failure' cells, Fig. 8.8) 2. Decreased flow to kidneys leads to activation of renin-angiotensin system. i. Fluid retention exacerbates CHF. C. Mainstay of treatment is ACE inhibitor. III. RIGHT-SIDED HEART FAILURE A. Most commonly due to left-sided heart failure; other important causes include leftto-right shunt and chronic lung disease (cor pulmonale). B. Clinical features are due to congestion. 1. 2. Painful hepatosplenomegaly with characteristic 'nutmeg' liver (Fig. 8.9); may lead to cardiac cirrhosis 3. Dependent pitting edema (due to increased hydrostatic pressure)


Pathoma_Husain

Pathoma_Husain. 1. 2. Painful hepatosplenomegaly with characteristic 'nutmeg' liver (Fig. 8.9); may lead to cardiac cirrhosis 3. Dependent pitting edema (due to increased hydrostatic pressure) Fig. 8.8 Hemosiderin-laden macrophages ('heart Fig. 8.9 'Nutmeg' liver, congestive heart failure. Fig. 8.10 'Boot-shaped' heart, tetralogy of Fallot. failure' cells). I. BASIC PRINCIPLES A. Arise during embryogenesis (usually weeks 3 through 8); seen in 1% of live births 1. Most defects are sporadic. B. Often result in shunting between left (systemic) and right (pulmonary) circulations. C. Defects with left-to-right shunting may be relatively asymptomatic at birth, but the shunt can eventually reverse. 1. Increased flow through the pulmonary circulation results in hypertrophy of pulmonary vessels and pulmonary hypertension. 2.


Pathoma_Husain

Pathoma_Husain. 1. Increased flow through the pulmonary circulation results in hypertrophy of pulmonary vessels and pulmonary hypertension. 2. Increased pulmonary resistance eventually results in reversal of shunt, leading to late cyanosis (Eisenmenger syndrome) with right ventricular hypertrophy, polycythemia, and clubbing. D. Defects with right-to-left shunting usually present as cyanosis shortly after birth. II. VENTRICULAR SEPT AL DEFECT (VSD) A. Defect in the septum that divides the right and left ventricles 1. 2. Associated with fetal alcohol syndrome B. Results in left-to-right shunt; size of defect determines extent of shunting and age at presentation. Small defects are often asymptomatic; large defects can lead to Eisenmenger syndrome. C. Treatment involves surgical closure; small defects may close spontaneously. III. ATRIAL SEPTAL DEFECT (ASD) A. Defect in the septum that divides right and left atria; most common type is ostium secundum (90% of cases).


Pathoma_Husain

Pathoma_Husain. III. ATRIAL SEPTAL DEFECT (ASD) A. Defect in the septum that divides right and left atria; most common type is ostium secundum (90% of cases). B. Ostium primum type is associated with Down syndrome. C. Results in left-to-right shunt and split S2 on auscultation (increased blood in right heart delays closure of pulmonary valve) D. Paradoxical emboli are an important complication. IV. A. Failure of ductus arteriosus to close; associated with congenital rubella B. Results in left-to-right shunt between the aorta and the pulmonary artery 1. During development, the ductus arteriosus normally shunts blood from the pulmonary artery to the aorta, bypassing the lungs. C. Asymptomatic at birth with continuous 'machine-like' murmur; may lead to Eisenmenger syndrome, resulting in lower extremity cyanosis D. Treatment involves indomethacin, which decreases PGE, resulting in PDA closure (PGE maintains patency of the ductus arteriosus). V.


Pathoma_Husain

Pathoma_Husain. D. Treatment involves indomethacin, which decreases PGE, resulting in PDA closure (PGE maintains patency of the ductus arteriosus). V. A. Characterized by (1) stenosis of the right ventricular outflow tract, (2) right ventricular hypertrophy, (3) VSD, and (4) an aorta that overrides the VSD B. Right-to-left shunt leads to early cyanosis; degree of stenosis determines the extent of shunting and cyanosis. C. Patients learn to squat in response to a cyanotic spell; increased arterial resistance decreases shunting and allows more blood to reach the lungs. D. 'Boot-shaped' heart on x-ray (Fig. 8.10) VI. TRANSPOSITION OF THE GREAT VESSELS A. Characterized by pulmonary artery arising from the left ventricle and aorta arising from the right ventricle B. Associated with maternal diabetes C. Presents with early cyanosis; pulmonary and systemic circuits do not mix. 1. Creation of shunt (allowing blood to mix) after birth is required for survival. 2.


Pathoma_Husain

Pathoma_Husain. C. Presents with early cyanosis; pulmonary and systemic circuits do not mix. 1. Creation of shunt (allowing blood to mix) after birth is required for survival. 2. PGE can be administered to maintain a PDA until definitive surgical repair is performed. D. Results in hypertrophy of the right ventricle and atrophy of the left ventricle VII. TRUNCUS ARTERIOSUS A. Characterized by a single large vessel arising from both ventricles 1. Truncus fails to divide. B. Presents with early cyanosis; deoxygenated blood from right ventricle mixes with oxygenated blood from left ventricle before pulmonary and aortic circulations separate. VIII. TRI CUSPID ATRESIA A. Tricuspid valve orifice fails to develop; right ventricle is hypoplastic. B. Often associated with ASD, resulting in a right-to-left shunt; presents with early cyanosis. IX. COARCTATION OF THE AORTA A. Narrowing of the aorta (Fig. 8.llA); classically divided into infantile and adult forms


Pathoma_Husain

Pathoma_Husain. IX. COARCTATION OF THE AORTA A. Narrowing of the aorta (Fig. 8.llA); classically divided into infantile and adult forms B. Infantile form is associated with a PDA; coarctation lies after (distal to) the aortic arch, but before (proximal to) the PDA. 1. Presents as lower extremity cyanosis in infants, often at birth 2. Associated with Turner syndrome C. Adult form is not associated with a PDA; coarctation lies after (distal to) the aortic arch. 1. Presents as hypertension in the upper extremities and hypotension with weak pulses in the lower extremities; classically discovered in adulthood 2. Collateral circulation develops across the intercostal arteries; engorged arteries cause 'notching' of ribs on x-ray (Fig. 8.llB), 3. Associated with bicuspid aortic valve I. BASIC PRINCIPLES A. The heart has four valves (tricuspid, pulmonary, mitral, and aortic) that prevent backflow.


Pathoma_Husain

Pathoma_Husain. Associated with bicuspid aortic valve I. BASIC PRINCIPLES A. The heart has four valves (tricuspid, pulmonary, mitral, and aortic) that prevent backflow. B. Valvular lesions generally result in stenosis (decreased caliber of the valve orifice) or regurgitation (backflow). Fig. 8.11 Coarctation of the aorta. A, Gross specimen. B, 'Notching of ribs' on x-ray. (A, Courtesy of Aliya Husain, MD. B, Courtesy of Images Paediatr Cardio/ 2009;38:7-9) II. ACUTE RHEUMATIC FEVER A. Systemic complication of pharyngitis due to group A ~-hemolytic streptococci; affects children 2-3 weeks after an episode ofstreptococcal pharyngitis ("strep throat") B. Caused by molecular mimicry; bacterial M protein resembles proteins in human tissue. C. Diagnosis is based on Jones criteria. 1. Evidence of prior group A ~-hemolytic streptococcal infection (e.g., elevated ASO or anti-DNase B titers) with the presence of major and minor criteria 2.


Pathoma_Husain

Pathoma_Husain. 1. Evidence of prior group A ~-hemolytic streptococcal infection (e.g., elevated ASO or anti-DNase B titers) with the presence of major and minor criteria 2. Minor criteria are nonspecific and include fever and elevated ESR. 3. i. Migratory polyarthritis-swelling and pain in a large joint (e.g., wrist, knees, ankles) that resolves within days and "migrates" to involve another large joint 11. Pancarditis a. Endocarditis-Mitral valve is involved more commonly than the aortic valve. Characterized by small vegetations along lines of closure that lead to regurgitation (Fig. 8.12A) b. Myocarditis with Aschoff bodies that are characterized by foci of chronic inflammation, reactive histiocytes with slender, wavy nuclei (Anitschkow cells), giant cells, and fibrinoid material (Fig. 8.12B,C); myocarditis is the most common cause of death during the acute phase. c. Pericarditis-leads to friction rub and chest pain iii. Subcutaneous nodules iv.


Pathoma_Husain

Pathoma_Husain. c. Pericarditis-leads to friction rub and chest pain iii. Subcutaneous nodules iv. Erythema marginatum-annular, nonpruritic rash with erythematous borders, commonly involving trunk and limbs v. Sydenham chorea (rapid, involuntary muscle movements) D. Acute attack usually resolves, but may progress to chronic rheumatic heart disease; repeat exposure to group A ~-hemolytic streptococci results in relapse of the acute phase and increases risk for chronic disease. III. CHRONIC RHEUMATIC HEART DISEASE A. Valve scarring that arises as a consequence of rheumatic fever B. Results in stenosis with a classic 'fish-mouth ' appearance 1. Almost always involves the mitral valve; leads to thickening of chordae tendineae and cusps 2. Occasionally involves the aortic valve; leads to fusion of the commissures (Fig. 8.13) 3. Other valves are less commonly involved. C. Complications include infectious endocarditis.


Pathoma_Husain

Pathoma_Husain. Occasionally involves the aortic valve; leads to fusion of the commissures (Fig. 8.13) 3. Other valves are less commonly involved. C. Complications include infectious endocarditis. Fig. 8.12 Acute rheumatic heart disease. A, Mitra! valve vegetations. B, Aschoff body involving myocardium. C, Anitschkow cells. (A, Courtesy of Aliya Husain, MD. B, Courtesy of Ed Uthman, MD) IV. A. Narrowing of the aortic valve orifice (Fig. 8.14) B. Usually due to fibrosis and calcification from "wear and tear" 1. 2. Bicuspid aortic valve increases risk and hastens disease onset. A normal aortic valve has three cusps; fewer cusps results in increased "wear and tear" on each cusp. C. May also arise as a consequence of chronic rheumatic valve disease; coexisting mitral stenosis and fusion of the aortic valve commissures distinguish rheumatic disease from "wear and tear."


Pathoma_Husain

Pathoma_Husain. C. May also arise as a consequence of chronic rheumatic valve disease; coexisting mitral stenosis and fusion of the aortic valve commissures distinguish rheumatic disease from "wear and tear." D. Cardiac compensation leads to a prolonged asymptomatic stage during which a systolic ejection click followed by a crescendo-decrescendo murmur is heard. E. Complications include 1. Concentric left ventricular hypertrophy-may progress to cardiac failure 2. Angina and syncope with exercise-Limited ability to increase blood flow across the stenotic valve leads to decreased perfusion of the myocardium and brain. 3. Microangiopathic hemolytic anemia-RBCs are damaged (producing schistocytes) while crossing the calcified valve. F. Treatment is valve replacement after onset of complications. V. A. Backflow of blood from the aorta into the left ventricle during diastole


Pathoma_Husain

Pathoma_Husain. F. Treatment is valve replacement after onset of complications. V. A. Backflow of blood from the aorta into the left ventricle during diastole B. Arises due to aortic root dilation (e.g., syphilitic aneurysm and aortic dissection) or valve damage (e.g., infectious endocarditis); most common cause is isolated root dilation C. Clinical features include 1. Early, blowing diastolic murmur 2. Hyperdynamic circulation due to increased pulse pressure i. Pulse pressure is the difference between systolic and diastolic pressures. ii. Diastolic pressure decreases due to regurgitation, while systolic pressure increases due to increased stroke volume. iii. Presents with bounding pulse (water-hammer pulse), pulsating nail bed (Quincke pulse), and head bobbing 3. Results in LV dilation and eccentric hypertrophy (due to volume overload) D. Treatment is valve replacement once LV dysfunction develops. VI. MITRAL VALVE PROLAPSE


Pathoma_Husain

Pathoma_Husain. Results in LV dilation and eccentric hypertrophy (due to volume overload) D. Treatment is valve replacement once LV dysfunction develops. VI. MITRAL VALVE PROLAPSE A. Ballooning of mitral valve into left atrium during systole 1. Seen in 2-3% of US adults B. Due to myxoid degeneration (accumulation of ground substance) of the valve, making it floppy (Fig. 8.15) 1. Etiology is unknown; may be seen in Marfan syndrome or Ehlers-Dantos syndrome C. Presents with an incidental mid-systolic click followed by a regurgitation murmur; usually asymptomatic 1. Click and murmur become softer with squatting (increased systemic resistance decreases left ventricular emptying). D. Complications are rare, but include infectious endocarditis, arrhythmia, and severe mitral regurgitation. E. Treatment is valve replacement. VII. MITRAL REGURGITATION A. Reflux of blood from the left ventricle into the left atrium during systole


Pathoma_Husain

Pathoma_Husain. E. Treatment is valve replacement. VII. MITRAL REGURGITATION A. Reflux of blood from the left ventricle into the left atrium during systole B. Usually arises as a complication of mitral valve prolapse; other causes include LV dilatation (e.g., left-sided cardiac failure), infective endocarditis, acute rheumatic heart disease, and papillary muscle rupture after a myocardial infarction. C. Clinical features 1. Holosystolic "blowing" murmur; louder with squatting (increased systemic resistance decreases left ventricular emptying) and expiration (increased return to left atrium) 2. VIII.MITRAL STENOSIS A. Narrowing of the mitral valve orifice 1. Usually due to chronic rheumatic valve disease B. Clinical features 1. 2.


Pathoma_Husain

Pathoma_Husain. VIII.MITRAL STENOSIS A. Narrowing of the mitral valve orifice 1. Usually due to chronic rheumatic valve disease B. Clinical features 1. 2. Volume overload leads to dilatation of the left atrium, resulting in i. Pulmonary congestion with edema and alveolar hemorrhage ii. Pulmonary hypertension and eventual right-sided heart failure iii. Atrial fibrillation with associated risk for mural thrombi (Fig. 8.16) I. BASIC PRINCIPLES A. Inflammation of endocardium that lines the surface of cardiac valves; usually due to bacterial infection B. Streptococcus viridans is the most common overall cause. It is a low-virulence organism that infects previously damaged valves (e.g., chronic rheumatic heart Fig. 8.16 Mural t hrombus involving left atrium. Fig. 8.17A Large vegetations involving tricuspid Fig. 8.17B Janeway lesions. (Courtesy of Aliya Husain, MD) valve. (Courtesy of Aliya Husain, MD) I.


Pathoma_Husain

Pathoma_Husain. Fig. 8.16 Mural t hrombus involving left atrium. Fig. 8.17A Large vegetations involving tricuspid Fig. 8.17B Janeway lesions. (Courtesy of Aliya Husain, MD) valve. (Courtesy of Aliya Husain, MD) I. disease and mitral valve prolapse). Results in small vegetations that do not destroy the valve (subacute endocarditis) 1. Damaged endocardial surface develops thrombotic vegetations (platelets and fibrin). 2. Transient bacteremia leads to trapping of bacteria in the vegetations; prophylactic antibiotics decrease risk of endocarditis. C. Staphylococcus aureus is the most common cause in IV drug abusers. 1. High-virulence organism that infects normal valves, most commonly the tricuspid. 2. Results in large vegetations that destroy the valve (acute endocarditis, Fig. 8.17A) D. Staphylococcus epidermidis is associated with endocarditis of prosthetic valves. E. Streptococcus bovis is associated with endocarditis in patients with underlying colorectal carcinoma.


Pathoma_Husain

Pathoma_Husain. D. Staphylococcus epidermidis is associated with endocarditis of prosthetic valves. E. Streptococcus bovis is associated with endocarditis in patients with underlying colorectal carcinoma. F. HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) are associated with endocarditis with negative blood cultures. G. Clinical features of bacterial endocarditis include 1. Fever-due to bacteremia 2. Murmur-due to vegetations on heart valve 3. Janeway lesions (erythematous nontender lesions on palms and soles, Fig. 8.17B), Osler nodes (tender lesions on fingers or toes), splinter hemorrhages in nail bed (Fig. 8.17C) and Roth spots (Fig. 8.17D)-due to embolization of septic vegetations 4. Anemia of chronic disease-due to chronic inflammation H. Laboratory findings 1. 2. Anemia of chronic disease(-!-Hb, -!-MCV; t ferritin,-!-TIBC,-!-serum iron, and -!-% saturation) 3. Transesophageal echocardiogram is useful for detecting lesions on valves.


Pathoma_Husain

Pathoma_Husain. 2. Anemia of chronic disease(-!-Hb, -!-MCV; t ferritin,-!-TIBC,-!-serum iron, and -!-% saturation) 3. Transesophageal echocardiogram is useful for detecting lesions on valves. I. Nonbacterial thrombotic endocarditis is due to sterile vegetations that arise in association with a hypercoagulable state or underlying adenocarcinoma. Vegetations arise on the mitral valve along lines of closure and result in mitral regurgitation. J. Libman-Sacks endocarditis is due to sterile vegetations that arise in association with SLE. Vegetations are present on the surface and undersurface of the mitral valve and result in mitral regurgitation. A. Group of myocardial diseases that result in cardiac dysfunction Fig. 8.17C Splinter hemorrhages. Fig. 8.17D Roth spots. Fig. 8.18 Dilated cardiomyopathy. (Courtesy of Jamie Steinmetz, MD) ____________c_a_r_d_i_a_c_P_a_th_o_l_o...g...y_ ---~---~----~----- II. DILATED CARDIOMYOPATHY


Pathoma_Husain

Pathoma_Husain. II. DILATED CARDIOMYOPATHY A. Dilation of all four chambers of the heart (Fig. 8.18); most common form of cardiomyopathy B. Results in systolic dysfunction (ventricles cannot pump), leading to biventricular CHF; complications include mitral and tricuspid valve regurgitation and arrhythmia. C. Most commonly idiopathic; other causes include 1. 2. Myocarditis (usually due to coxsackie A or B)-characterized by a lymphocytic infiltrate in the myocardium (Fig. 8.19); results in chest pain, arrhythmia with sudden death, or heart failure. Dilated cardiomyopathy is a late complication. 3. 4. Drugs (e.g., doxorubicin) 5. Pregnancy-seen during late pregnancy or soon (weeks to months) after childbirth 6. D. Treatment is heart transplant. III. HYPERTROPHIC CARDIOMYOPATHY A. Massive hypertrophy of the left ventricle B. Usually due to genetic mutations in sarcomere proteins; most common form is autosomal dominant. C. Clinical features include 1.


Pathoma_Husain

Pathoma_Husain. A. Massive hypertrophy of the left ventricle B. Usually due to genetic mutations in sarcomere proteins; most common form is autosomal dominant. C. Clinical features include 1. Decreased cardiac output-Left ventricular hypertrophy leads to diastolic dysfunction (ventricle cannot fill). 2. Sudden death due to ventricular arrhythmias; hypertrophic cardiomyopathy is a common cause of sudden death in young athletes. 3. Syncope with exercise-Subaortic hypertrophy of the ventricular septum results in functional aortic stenosis. D. Biopsy shows myofiber hypertrophy with disarray (Fig. 8.20). IV. RESTRICTIVE CARDIOMYOPATHY A. Decreased compliance of the ventricular endomyocardium that restricts filling during diastole B. Causes include amyloidosis, sarcoidosis, endocardial fibroelastosis (children, Fig. 8.21), and Loeffler syndrome (endomyocardial fibrosis with an eosinophilic infiltrate and eosinophilia).