Exam 2: Lecture 37a

Question 1

Describe the make-up of Hb

Answer 1

• 2 alpha globin chains
• 2 beta- globin chains
• 4 heme

Question 2

Where is heme produced?

Answer 2

• mitochondria and cytoplasm
• primarily in the BM and liver
• heme is needed to make cytochrome P450 enzymes in the liver
• regulated by ALAS1 gene in liver and ALAS2 gene in the BM

Question 3

Describe iron metabolism

Answer 3

1) iron is absorbed via duodenum and proximal jejunum via DMT
2) basolateral side–> iron leaves the enterocyte to enter the blood via ferroportin
3) in circulation, Fe is with transferrin
4) option 1: Fe is transported to erythroid precursors in the BM via transferrin receptors
5) option 2: Fe to reticuloendothelial system to macrophages via spleen, BM, and liver (enters via ferroportin– on RES cells )

• 2/3 Fe stored in RBC

Question 4

What is hepcidin’s role in iron metabolism?

Answer 4

• with chronic disease/ inflammatory anemias due to upregulated cytokines , hepcidin will cause the release of acute phase proteins
• hepcidin binds to ferroportin and causes the internalization and degradation of Fe
• result in the sequestration of iron in storage sites
• decrease Fe absorption from gut (rate of absorption increases by low stores, anemia, and hypoxia)

Question 5

No physiologic process exists to get rid of excess iron

Question 6

Define anemia

Answer 6

• a decrease in the total amount of RBC and hemoglobin in the blood
• anemia results in a reduced ability of the blood to carry oxygen

Question 7

HCT and Hb

Answer 7

• volume of RBC in relation to total blood volume ( >40% mem; > 36% women )
• HCT is usually 3x Hb value
• HBL; M >13; 12 g/dL> F

Question 8

What are some of the causes of anemia?

Answer 8

• decreased production of RBC
• blood loss
• decreases life span of RBC (hemolysis)

Question 9

Anemia symptoms

Answer 9

• body very adaptable to gradual decreases in Hgb
• Weakness, fatigue, light-headedness
• dyspnea
• angina
• headache
• cold- tolerance
• irritability and growth delay in children
• iron deficiency–> Pica: likes to eat ice, baking powder, clay, chalk, sand
• restless legs

Question 10

What are some physical findings of anemia? general anemias and nutritional anemias

Answer 10

• tachycardia
• Pallor (pale conjunctiva, and pale skin creases)

Nutritional anemias:
- angular cheilitis (painful cracks at the corner of lips)
- atrophic glossitis (smooth, glossy tongue)
- Koilonychia (nail spooning)

Question 11

How to evaluate anemia?

Answer 11

1) look at CBC (complete blood count) –> distinguish between isolated anemia and bicytopenia/pancytopenia

2) MCV- mean corpuscular volume (size difference of RBC)–> microcytic anemia, normocytic anemia, macrocytic anemia

3) Peripheral blood smear–> are they the same size as the lymphocyte nucleus? is the central pallor 1/3 of RBC diameter? is it uniform size?

4) Reticulocyte count–> stains slightly blue, larger than RBC; increased amount of reticulocytes is termed polychromasia; elevated retic count–> indicative of increased red cell turnover/ production die to acute blood loss or hemolysis )>100, 000
- will be low or normal in most other causes of anemia

5) remainder of blood work
- look at Hb trend ( developed anemia over 2 weeks of years?
- creatinine –> CKD or end stage renal disease can cause anemia
- microcytic–> order iron studies
- if iron levels are normal, do hemoglobin electrophoresis
- if retic count elevated–> hemolytic work up to exclude bleeding ( LDH elevated, indirect bilirubin elevated, haptoglobin suppressed)
- if macrocytic–> liver function test, TSH, folate, B 12

Question 12

What are microcytic anemias

Answer 12

• thalassemia (alpha or beta globin mutation; defective globin synthesis)
• sickle cell anemia
• iron deficiency –> could be heme, iron
• sideroblastic anemia–> defective protoporphyrin synthesis resulting in excessive iron storage in mito —> X linked do to ALAS ( rate limiting); acquired…. alcohol, lead, and meds (isoniazid), MDS with rings of sideroblast
• anemia of chronic disease

Question 13

What are normocytic anemias

Answer 13

• Anemia of chronic disease
  -Chronic kidney disease
• Blood loss
• hemolysis
• bone marrow disease
• mixed etiologies (could be micro and macro mixed equating to normal)

Question 14

What are macrocytic anemias?

Answer 14

• megaloblastic
• liver disease
• hypothyroidism
• meds (chemotherapy)
• bone marrow disease
  red cell agglutination

Question 15

What are the causes of blood loss that lead to iron deficiency anemia?

Answer 15

• menorrhagia and fibroids
• occult GI blood loss common in males and post- menopausal females
• peptic ulcer disease
• polyps/cancers
• Inflammatory bowel disease
• angiodysplasia/ avms –> hereditary hemorrhagic telangiectasia ( Osler- Weber- Rendu disease)
• plummer- Vinson Syndrome: triad of esophageal webs, dysphagia, and iron deficiency

Question 16

How can you get iron deficiency due to diet?

Answer 16

• decreased intake of iron
• breast milk does not have much iron –> baby formula milk is enriched with iron
• malnutrition
• vegetarians
• could be decreased absorption of FE–> anything that effects the acidic environment if the duodenum –> ex. gastric bypass, Crohn’s disease (inflammatory bowel disease), celiac sprue, helminthic infections, H Pylori infection
• increased utilization of Fe in pregnancy

Question 17

What is RDW? Describe it in relation to anemia

Answer 17

• red cell distribution width (RDW)
• measure the variation of size of the RBC –> RDW
• increased in iron deficiency (RDW)
• in iron deficiency–> as Fe deficiency develops, RBC becomes smaller and smaller… leads to a great variation in size (RDW)
• thrombocytosis ( high platelets)

Question 18

Labs for iron deficiency anemia and peripheral blood smear pattern

Answer 18

• elevated RDW
• Thrombocytosis (high platelets)
• decreases Hb
• low ferritin
• low serum iron
• high TIBC
• % saturation (transferrin saturation)
• hypochromic –> increased central pallor (low MCH or MCHC)
• anisocytosis (variable size - increased RDW) and poikilocytosis (variable shape)

Question 19

How do you treat iron deficiency anemia?

Answer 19

• find and fix the underlying cause
• blood transfusion
• iron–>oral preparations better than dietary intake because it’s enough to replace [FERROUS SULFATE]
• side effects –. black stool, nausea, constipation, and dyspepsia
• take it with food; it is better absorbed with empty stomach
• antacids and calcium can decrease absorption
• gastric acidity increased absorption (orange juice, ascorbic acid)

Question 20

What should you expect following iron replacement?

Answer 20

• reticulocytosis in 4-7 days
• Hb response in 1-2 weeks
• resolution of anemia in 4-6 weeks

Question 21

What can cause anemia chronic disease?

Answer 21

• autoimmune (RA, SLE)
• Chronic infections–> HIV, endocarditis, osteomyelitis, TB, chronic active hepatitis
• sepsis/infection in hospitalized patients–> common cause of anemia in the hospital
• malignancy –> advanced and metastasis

Question 22

what is the pathophysiology and anemia of chronic disease?

Answer 22

• increased production of cytokines: IL-6, TNF- beta, IL-1, IFN–> leads to the release of acute phase proteins
• increased hepatic production of hepcidin –> prevents bacteria from accessing needed iron for growth
• decreased production of transferrin
• poor utilization of iron stores

Question 23

How do you diagnose anemia of chronic disease? - including iron labs

Answer 23

• retic count will be low
• normocytic anemia, but can be microcytic if advanced
• clinical situation; underlying inflammation
• exclusion of other apparent causes
• low serum iron
• low TIBC
• low transferrin saturation
• normal or elevated ferritin
• elevated hepcidin

Question 24

How can you treat anemia of chronic disease treatment?

Answer 24

• treat the underlying cause
• exogenous erythropoietin in selected patents like malignances –> may be worse outcomes
• HIV and renal failure can get exogenous EPO

Question 25

Iron storage disease: Describe Primary

Answer 25

- Classic hereditary Hemochromatosis- usually due to HFE gene mutation - non- HFE hereditary hemochromatosis--> mutations in TFR2, hemojuvelin, hepcidin, ferroportin

Question 26

Iron overload: Describe Secondary form

Answer 26

- multiple blood transfusion --> conditions which will required multiple transfusions like thalassemia, sickle cell anemia, and MDS -conditions of ineffective erythropoiesis --> thalassemia intermediate major--> suppression of hepcidin--> increased iron absorption despite being associated with iron storage - Chronic liver disease

Question 27

Describe the HFE gene mutation

Answer 27

- on chromosome 6 - homozygous (10% Caucasians); autosomal recessive - low penetrance results in decreased hepcidin production, so excess iron and deposition in tissue --> can cause damage to the organ - increased iron absorption

Question 28

How do you diagnose hereditary hemochromatosis (HFE gene)?

Answer 28

- family history - iron studies --> elevated serum iron; transferrin sat >45%; ferritin >200 - genetic testing for HH for conformation (HFE gene mutation) - MRI- liver/cardiac to assess iron content - Liver biopsy or endomyocardial biopsy

Question 29

What is the presentation of hereditary hemochromatosis?

Answer 29

- hepatomegaly --> increased liver function test.... cirrhosis--> Hepatocellular cancer - deposits in the beta cells of the pancreas, causing insulin dependent diabetes - deposit in pituitary gland causing hypogonadism - deposit in the heart causing cardiomyopathy--> CHF and arrhythmias - skin hyperpigmentation - arthropathy in the joints (2nd/3rd MCP)

Question 30

What are the genotypes of HFE hereditary hemochromatosis?

Answer 30

- C282Y/C282Y--> primary candidates for symptomatic iron overload - C282Y/H63D--> often have increased iron stores, but less likely to have end-organ damage - C282Y/ wild-type--> much less risk

Question 31

How to remove iron?

Answer 31

- serial phlebotomies to keep ferritin <50-100 - iron chelation if intolerant to phlebotomy --> deferoxamine (IV/SQ) and Deferasirox (PO)--> thalassemia, chronic anemia, sickle cell - avoid alcohol and other hepatotoxins - avoid transfusions - screen for HCC if cirrhosis - family genetic testing

Question 32

What is porphyria?

Answer 32

- characterized by inherited defects in the heme biosynthetic pathway - build- up of heme precursors (porphyrins) proximal to enzymatic defects - excess porphyrins can then lead to symptoms

Question 33

XLSA- X LINKED SIDOERBLASTEMIA

Answer 34

- excreted in the urine or feces - clinical penetrance is low - don't typically result in anemia

Question 35

Acute intermittent porphyria (AIP)

Answer 35

- most common acute form - caused by mutations in PBG (porphobilinogen) deaminase - autosomal dominant with low penetrance - an acute porphyria with neurovisceral symptoms---. neuropathy, attacks of severe abdominal pain, port-wine urine- can progress to paresis and respiratory failure

Question 36

Porphyria cutanea tarda

Answer 36

- caused by decreased UROD (uroporphyrinogen decarboxylase) enzymatic activity (sporadic cases are most common; 20% inherited autosomal dominant) - chronic porphyria with cutaneous symptoms and iron overload --. skin blistering in sun-exposed areas - hypertrichosis--porphyria can deposit in the skin and act as a photosynthesizer - associated with liver disease (Hep C), iron overload (some have HFE mutations); HIV infections

Question 37

Diagnosis of porphyria

Answer 37

- documentation of increased porphyrins - screen urine for porphyrins - obtain specific porphyrins or metabolites in urine, blood, stool depending on which type or porphyria it is - genetic testing to confirm

Question 38

How do you treat acuet intermittent porphyria?

Answer 38

- acute attacks--> IV fluids and narcotics, IV dextrose and IV hemin ( both inhibits ALAS) - avoid precipitants that may induce ALAS --> dehydration, starvation, Oral contraceptive pills, Tobacco/alcohol, and meds (anticonvulsants)

Question 39

How to treat porphyria cutanea tarda?

Answer 39

- avoid hepatic toxins: alcohol - avoid sun exposure - phlebotomy to reduce iron levels