Susan Stegman, MD Medical Director AXA Equitable Life May 3, 2016
Underwriting impact Anemia overview Classification of anemia Specific anemia topics Iron deficiency anemia Thalassemia Megaloblastic anemia Mixed anemias Myelodysplasia Case studies Conclusion
Mortality risk based on: Type and severity of anemia Speed of onset Acute vs chronic anemia Other impairments contributing to anemia Appropriate evaluation, treatment and follow-up Compliance with treatment Risk of recurrence Note if any co-morbid conditions aggravated by anemia and those that exacerbate anemia Most anemias detected in aps information CBC done only on fresh blood, not useful on insurance applicants except for Hb level
Definition: Reduction in red blood cell mass causes decreased RBC oxygen-carrying capacity Hemoglobin <13g/dL in men, <12g/dL in women Exceptions Baseline decreased hemoglobin: Pregnancy Heavy menses Baseline increased hemoglobin: High altitude Heavy smoker Polycythemia vera
Epidemiology: Broad range of demographics Incidence depends on type of anemia Diverse group of diseases Genetic causes occur among certain ethnic groups and in specific geographic areas Nutritional causes often occur with lower socioeconomic status, common in third-world countries
Normal RBC microanatomy: Biconcave disc with no nucleus Flexible to fit easily through capillaries Filled with iron-containing protein hemoglobin Normal RBC physiology: RBC production stimulated by erythropoietin released by kidney Bone marrow produces RBCs 2.4 million new erythrocytes produced per second Each RBC circulates for 100-120 days 25% of cells in human body are RBCs Nearly 40-45% of human blood volume consists of red blood cells
Normal RBC morphology
Genetic/inherited anemias Sickle cell anemia Thalassemia Hereditary spherocytosis G6PD deficiency Acquired due to nutritional/dietary factors Folate, iron, thiamine, B-12 deficiency Alcoholism Acquired due to underlying medical conditions Malignancy Renal disease GI/uterine bleeding Hematologic disorders Anemia of chronic disease
Based on mechanism of decreased hemoglobin 1. Blood loss (acute or chronic): COMMON 2. Decreased/defective RBC production: COMMON 3. Increased RBC destruction: UNCOMMON Based on color/hemoglobin content 1. hypochromic (pale color due to low Hb content) 2. normochromic (normal color with Hb content) Based on mean corpuscular volume (MCV) 1. microcytic: small RBCs due to decreased MCV 2. normocytic: normal RBC size and MCV 3. macrocytic: large RBCs due to increased MCV
MCV: average volume of each red blood cell determined by: 1. Iron stores/ferritin: deficiency causes decreased hemoglobin production => decreased cytoplasm => smaller than normal RBCs => low MCV 2. B-12 and folate: low levels cause impaired DNA synthesis => no signal to progress from G2 growth stage to mitosis = cell growth without division => increased cytoplasm => larger than normal RBCs => elevated MCV
Red cell distribution width (RDW) Reported on all CBCs Measures the range of RBC volume variation Normal RDW 11-15% Distinguishes different types of anemias with same MCV High RDW reflects wide range of RBC sizes
Normal RDW Heterozygous beta thalassemia (beta thalassemia minor or trait) Anemia of chronic disease Elevated RDW Iron deficiency anemia Sickle thalassemia cell disease Thalassemia intermedia Alpha and beta thalassemia major
Normal RDW Aplastic anemia Chronic liver disease Chemotherapy Antiviral medications Alcohol dependence (formerly alcoholism) Elevated RDW Folate or B-12 deficiency Immune hemolytic anemia Cytotoxic chemotherapy Chronic liver disease Myelodysplastic syndrome
Elevated RDW/normal MCV: EARLY iron, vitamin B-12 or folate deficiency Dimorphic anemia (concurrent iron AND folate deficiency) Sickle cell disease Chronic liver disease
Focus on anemias that: 1. frequently seen in underwriting 2. not an outright decline 3. severity may warrant postpone or ratings 4. can have wide range of presentations and mortality risks
3 million cases in US annually Caused by decreased iron intake or absorption and/or chronic blood loss Not seen with acute blood loss (takes time to deplete iron stores from bone marrow) Affects nearly 1 billion persons worldwide 600 million cases of moderate IDA worldwide (8.8% of world population) 375 million more with mild IDA Causes 50% of anemia cases worldwide Leading cause is parasitosis
Laboratory findings Low serum iron, ferritin and MCV Elevated TIBC, transferrin and RDW Secondary thrombocytosis Peripheral blood smear: Hypochromia Microcytosis Poikilocytosis (variation in shape) Anisocytosis (variation in size causing elevated RDW) Nucleated RBCs Diagnosis often made based on laboratory findings, rarely BM biopsy with iron staining
Causes: Blood loss Decreased iron absorption Decreased iron intake Treatment Iron supplementation to correct depleted bone marrow ferritin stores Oral iron first-line IV iron when impaired iron absorption or when rapid supplementation needed Dietary adjustments to increase intake of heme iron (meat, eggs)
Mortality risk Lower in pregnancy and women of child-bearing ages unless Hb <9.5 Normal Hb levels can be of concern in those with baseline elevated Hb GI blood loss always a concern for underlying malignancy especially if age >50 Potentially higher risk in cases of: Young males Older men and post-menopausal women New-onset without apparent cause Hx anemia with marked decrease from usual Hb level
Microcytic, hypochromic anemia Autosomal recessive disorder that leads to deleted or dysfunctional hemoglobin Defective hemoglobin production leads to microcytosis Resultant improper O2 transport and destruction of RBCs (hemolysis) Decreased number of intact circulating RBCs leads to anemia
Why is this disorder so confusing? Need to understand basics of hemoglobin structure Protoporphyrin ring with iron in the center and 4 globin chains 2 alpha globin chains with 4 genes each 2 beta globin chains with 2 genes each Thalassemia occurs with either alpha gene deletions or beta gene defects MCV disproportionately low compared to degree of anemia (MCV in 60s)
Alpha thalassemia (αα/αα) Deletion of one or more of the 4 globin chain genes 1 deletion = silent carrier normal labs 2 deletions = alpha thalassemia trait/minor mild microcytosis and hypochromia with no anemia 3 deletions = alpha thalassemia intermedia/hb H disease compensated hemolytic state, transfusions needed 4 deletions = hydrops fetalis (Hb Barts) decompensated hemolytic state uniformly fatal
Beta thalassemia (ββ) Defect in one or both β globin chain genes 1 defect = heterozygous beta thalassemia SAME AS beta thalassemia trait SAME AS beta thalassemia minor 2 defects = homozygous beta thalassemia SAME AS beta thalassemia major SAME AS Cooley s anemia: most severe type of congenital hemolytic anemia 2 partial defects Beta thalassemia intermedia: less severe form than homozygous beta thalassemia can survive into adulthood without treatment
Treatment Alpha thalassemia Silent carrier: none Trait: none Hb H disease: periodic transfusions for severe (<7g/dL) or symptomatic anemia, chelation therapy for iron overload from transfusions Hydrops fetalis: supportive, uniformly fatal Beta thalassemia Minor/heterozygous/trait: none Intermedia: ranges from none to transfusion-dependent Major: transfusion therapy due to chronic hemolysis Splenectomy due to splenic sequestration Chelation therapy for transfusion iron overload BM transplantation
Increased mortality risk: Transfusion-dependent beta thalassemia Iron overload from chronic transfusion Progression of anemia from chronic hemolysis Alpha thalassemia intermedia/hb H Beta thalassemia intermedia No increased mortality risk: Alpha thalassemia silent carrier or trait/minor Beta thalassemia trait/minor
Due to vitamin B-12 or folate deficiency from inadequate intake or poor GI absorption B-12 deficiency Gastrectomy/gastric bypass surgery/pernicious anemia Ileal resection or bypass Malabsorption Chronic pancreatitis Fish tapeworm infection Crohn s disease involving terminal ileum Folate deficiency Alcoholism Pregnancy (increased demand for neural tube formation) Cirrhosis malabsorption
Laboratory: Low Hb Elevated MCV >99 Peripheral blood smear Oval-shaped macrocytic RBCs Anisocytosis Poikilocytosis Hypersegmented neutrophils Treatment Oral folate and/or IM B-12 injections Correct underlying cause(s) of deficiency
Normal neutrophils Hypersegmented neutrophils
Dimorphic anemia Two distinct forms of RBCs are circulating simultaneously Examples: IDA combined with folate and/or B-12 deficiency Idiopathic acquired sideroblastic anemia with folate and/or B-12 deficiency Red blood cell transfusions Hemolytic anemias Erythropoietin therapy Alcohol dependence with GI blood loss Laboratory findings Low Hb Normal MCV (equal amounts of low and high MCV cells) Elevated RDW (wide variation in cell sizes)
Ineffective production ( dysplasia ) of all blood cells Also known as myelodysplastic syndrome (MDS) Disorder of hematopoietic stem cells Causes irreversible decrease in number and quality of blood-forming cells Incidence increasing with aging US population Often an indolent course
Median age at diagnosis 60-75 years old Rare under age 50 Males >females Causes Primary/de novo (unknown cause) Secondary or treatment-related MDS due to prior chemotherapy or radiation (younger ages) Cigarette smoke use or exposure Toxic chemical exposure (benzene) Pre-existing chromosomal abnormalities (Down Syndrome)
Laboratory findings: Anemia: high MCV and RDW hemolysis Thrombocytopenia: Platelet clumping causes spurious low count Megakaryocytes Leukopenia: Hyper-segmented and hyposegmented neutrophils on peripheral blood smear
Clinical signs: Recurrent infections Excess bleeding from unknown cause Diagnosis: High index of suspicion needed especially with mild pancytopenia Hb <13.0mg/dL males, <12.0mg/dL females Plt count <150,000 WBC <4.0mg/dL Other causes of pancytopenia need to be excluded BM biopsy required to confirm diagnosis and determined correct subtype
Treatment Tailored to patient s age, overall health, MDS subtype and prognostic score RBC transfusions to correct anemia Platelet transfusions to reduce excess bleeding Antibiotics to combat more frequent infections due to low WBC BM transplantation can be curative
Can go undetected for years in milder cases Primarily a disease of older persons Higher mortality risk with exposure to: Cigarette smoke Chemotherapy/radiation Toxic chemicals Watch for anemia of unknown cause associated with: Thrombocytopenia or normal platelet count with history of frequent bleeding Frequent infections High MCV and high RDW
37F Build 5.5.145 Long hx heavy menses takes bcp to control excessive flow APS reports usual Hb 11.0mg/dL with MCV 85, iron studies consistant with IDA Hb 3 mos ago was 9.5mg/dL with MCV 79 Diagnosis? Mortality risk?
45M Build 6.0.160 Works in sales, entertains clients, extensive domestic travel Father died from liver disease Hx GERD, takes PPI daily APS reports Hb ranging from 10.5-11.8 for the last 5 years, MCV 90, RDW 18 LFTs: AST 74 ALT 65 GGT 102 Diagnosis? Mortality risk?
69M Build 5.9.190 Hx HTN, high chol well-controlled on meds Mother died of stomach cancer at age 61 Annual Hb levels from APS records: 2011: 14.5mg/dL 2012: 14.2mg/dL 2013: 13.9mg/dL 2014: 13.3mg/dL 2015: 12.5mg/dL Diagnosis? Mortality risk?
21F Build 5.8.135 Menses very light for years Recently traveled to Greece to visit grandparents CBC done for college physical 3 yrs ago Hb 11.8mg/dL MCV 66 Repeat CBC at recent gyn exam: Hb 12.1mg/dL MCV 67 Diagnosis? Mortality risk?
72F Build 5.0.157 Hx HTN, GERD, DM, high chol Tob use ½ ppd x 40 yrs, quit 12 yrs ago Recurrent sinusitis x 5 yrs, pneumonia in 2015 Most recent labs from APS records: A1c 6.2% (baseline) WBC 3.3, Hb 9.4, MCV 108, plts 104K Normal folate and B-12 levels Normal iron studies Normal renal and hepatic functions Diagnosis? Mortality risk?
39M Lives in Colorado, very active lifestyle APS labs: 2009 Hb 17.2, MCV 94 2011 Hb 17.4, MCV 95 2014 Hb 16.5, MCV 89 Fatigue noted at OV in 3/2015 while training for a marathon Blood in stool noted 9/2015, noted hemorrhoids on exam Hb 14.8, MCV 82 Diagnosis? Mortality risk?
Anemia encompasses a broad, diverse group of disorder Always take into account WBC, plt count, MCV and RDW in any case of anemia Elderly with anemia have higher mortality risk compared to younger ages No increased mortality risk associated with: Alpha thalassemia silent carrier/minor/trait Beta thalassemia heterozygous/minor/trait Be wary of myelodysplasia when anemia occurs with: history of bleeding problems and/or frequent infections Look for alcohol abuse or dependence in any case of anemia (8% of US population)