Anemia I - Microcytic Anemias, Hemochromatosis, and Porphyrias Flashcards
Where does heme biosynthesis take place and how many hemes are there per HgA?
HgA is a tetramer of two alpha and two beta globulins = 4 hemes per HgA
ALA synthase is first and rate-limiting step, in mitochondria
Most other enzymes occur in cytoplasm
Iron is put into protoporphyrin 9 of hemoglobin via ferrochelatase, again in mitochondria
What is the definition of anemia for men / women?
Decrease in hemoglobin in the blood
Men: Hgb < 13 g/dL or <40% hematocrit
Women: HgB <12 g/dL or <36% hematocrit
Hct is typically 3x the Hgb
What are the three broad causes of anemia?
- Decreased production of RBCs - most common
- Blood loss (hemorrhage)
- Decreased lifespan of RBCs - hemolysis
What is the first step of evaluating a patient with anemia?
Look at the rest of the CBC - see if WBC differential and platelets are out of whack
What is the differential diagnosis for microcytic anemias?
- Iron deficiency anemia
- Anemic of chronic disease (if bad)
- Thalassemias
- Sideroblastic anemias
What is the DDx of normocytic anemias?
Anemia of chronic disease - most common Chronic kidney disease - loss of EPO Blood loss Hemolysis Mixed etiologies, i.e. genetic Bone marrow disease
What is the ddx of macrocytic anemias?
Megaloblastic (b9/b12 deficiencies) Liver disease Hypothyroidism Bone marrow disease Meds (i.e. 5-FU) Rouleaux formation - inflated MCV due to agglutination, as in multiple myeloma
How do normocytic and normochromic RBCs appear on peripheral blood smear?
Normocytic - size is about the same as a lymphocyte nucleus
Normochromic - central pallor is about 1/3 of RBC diameter
What is polychromasia and in what causes of anemia does it happen? What count is indicative of increased RBC turnover?
Increased reticulocytes (100,000 = absolute count showing increased turnover) on blood smear (stain blue due to residual DNA in cytoplasm, and are larger than normal RBC)
Happens in anemia due to acute blood loss or hemolysis -> more erythropoesis
What are some other important studies in the workup of anemia?
- Hemoglobin trend
- Creatinine
- Iron studies
- Hemolytic workup - reticulocyte count, LDH, bilirubin, haptoglobin
- Liver function tests
- TSH
When would LFTs / TSH need to be ordered?
Workup of macrocytic anemia -> liver disease and hypothyroidism can be causes of non-megaloblastic macrocytic anemia
Why do we need to measure Hgb trend and creatinine levels?
Hgb trend - see if the Hgb has been chronically low or if this anemia is more acute
Creatinine - check for chronic kidney disease -> can decrease EPO and cause anemia
What is the relative bioavailability of the three forms of iron?
Heme > ferrous (Fe+2) > ferric (Fe+3)
Where is iron absorbed, and how does the stomach play a role?
Acidification via the stomach reduces the iron and makes it more readily absorbable
Absorbed in duodenum
What are the major storage and carrier proteins for iron?
Storage - ferritin, within reticuloendothelial cystem
Carrier - Transferrin - delivers iron to macrophages in RES and developing erythrocytes in bone marrow via transferrin receptor
What is ferroportin? What controls its activity?
Transporter on basolateral surface of mucosal enterocytes which controls export of iron from these cells
Activity is decreased by hepcidin - a positive acute phase protein which is designed to sequester iron from microbes in inflammatory states
What is the mechanism of action of hepcidin?
Sequesters iron in storage sites by modulating the internalization and degradation of ferroportin
Also decreases iron absorption in gut (in times of iron deficiency, absorption can be increased up to 5-fold)
What holds most of our iron at any given time and how do we lose it?
Mostly held by erythrocytes (2/3), rest is held by reticuloendothelial system and in some part by cytochromes, myoglobins, etc
Lost via desquamation of skin (no physiological mechanism for removal)
What causes sideroblastic anemia and thalassemia?
Sideroblastic - due to defective protoporphyrin synthesis resulting in excess trapping of iron in mitochondria
Thalassemia - due to defective globin synthesis
What are the congenital and acquired causes of sideroblastic anemia?
Congenital - ALA synthase mutation
Acquired:
1. Alcohol - mitochondrial poison
2. Lead - inhibits ALA dehydratase and ferrochelatase
3. B6 deficiency - usually due to isoniazid therapy
What is the most common cause of iron deficiency anemia in young females? Secondarily?
Menorrhagia, most often due to uterine fibroids
Secondarily: Increased utilization due to pregnancy
What is the most common cause of iron deficiency anemia in males and post-menopausal women?
Gastrointestinal bleeds
- > peptic ulcer disease
- > cancer / polyps
- > inflammatory bowel disease
- > angiodysplasia / AV malformations
- > plummer vinson syndrom
What is the triad of Plummer Vinson syndrome?
DIE
Dysphagia
Iron deficiency
Esophageal webs
In what situations might you get iron deficiency anemia from decreased intake?
Infants - break milk is low on iron
Malnutrition
Vegetarians
What factors can lead to decreased iron absorption?
Gastric bypass Gastrectomy (low H+ states) Crohn's and Celiac disease Helminthic infections and giardiasis H. pylori infection
What are the nonspecific signs and symptoms for anemia?
Weakness, fatigue, light-headedness
Angina - decreased coronary O2
Tachycardia
Pale conjunctiva / skin creases
Cold intolerance
What are more specific signs and symptoms for iron deficiency anemia (IDA)?
Pica - wanting to eat ice, baking power, clay, chalk
Restless legs - remember, iron is used to make dopamine and low levels (Ferritin <50) can cause RLS
Koilonychia - spooning of the nails - very severe cases, most specific
How is red cell distribution width (RDW) changed in IDA?
Increased - due to a great variance in sizes of RBCs
What does TIBC measure? What does it always change oppositely to?
Total iron binding capacity - amount of transferrin storage capability in plasma
Also goes opposite the ferritin levels
-> if storage iron levels are low, liver ramps up production of transferrin
What are the findings for serum iron, TIBC, ferritin, and hepcidin in IDA?
Serum iron - decreased
TIBC - increased
Ferritin - decreased (naturally)
Hepcidin - decreased, to make way for absorption
What will blood smear show for IDA?
Microcytosis - small RBCs
Hypochromia - increased central pallor
Anisocytosis - variably sized - increases RDW
Poikilocytosis - variably shaped - PENCIL cells sometimes present
What is the treatment for IDA and what must be done to make patients take it?
Ferrous sulfate supplements TID
Can cause dyspepsia, nausea, and constipation, so it is better taken with food although it is better absorbed without food
- > take with OJ or vitamin C to increase absorption
- > do NOT take with antacids
Why might a patient be refractory to ferrous sulfate / how long should they take to improve?
RBCs start increased in 4-7 days, resolution of anemia within 4-6 weeks depending on deficiency
Refractory reasons: Noncompliance Wrong diagnosis (more than one) Not enough iron - excessive bleeding Malabsorption
What should be done for patients who are refractory to oral iron supplementation? What is the side effect of concern?
IV iron
- > more elemental iron is given at one time
- > rare: anaphylactoid reactions - more commo in iron dextran preparations)
What is the most common cause of anemia in the hospital? What are some common associated conditions?
Anemia of chronic disease (ACD)
- autoimmune - RA, SLE
- chronic infections - HIV, endocarditis, osteomyelitis, TB, hepatitis
- sepsis / infection
- malignancy
What is the pathophysiology behind ACD?
Increased production of IL-6, IL-1, TNF
- > increased hepcidin production and decreased transferrin
- > poor utilization of iron stores
What are the findings for serum iron, TIBC, ferritin, and hepcidin in ACD?
Serum iron - decreased
TIBC - decreased
Ferritin - normal / increased (stores sequestered)
Hepcidin - increased (cause)
What are the situations where exogenous erythropoietin should be given rather than just treating the underlying cause for ACD?
Malignancy
HIV
Renal failure - associated with decreased production of EPO
What is the cause of Classic hereditary hemochromatosis? What chromosome? Is it common?
Autosomal recessive HFE gene mutation on chromosome 6
-> increased intestinal absorption of iron, decreased hepcidin production, increased ferroportin transport
Most common inherited single-gene disease in US
What are secondary causes of iron overload?
Multiple blood transfusions - thalassemias, sickle cell, myelodysplastic syndromes
Ineffective erythropoesis - thalassemia intermedia or major - increases iron absorption (weird)
Chronic liver disease
Where does iron tend to accumulate in hereditary hemochromatosis?
Liver, pancreas, skin, heart, pituitary, and joints
What is the best screening test for hereditary hemochromatosis (HH) and why?
Transferrin saturation >45%.
Ferritin will be very high as will serum iron, and transferrin will drop accordingly, saturating remaining transferrin
Family history not as good since hereditary hemochromatosis has low penetrance
How did HH used to be confirmed / how is it done now?
Used to be done by liver / heart MRI / biopsy, now done by genetic testing
What are the cardiac manifestions of HH?
Restrictive cardiomyopathy
- > eventual progression to dilated cardiomyopathy and CHF
- > arrhythmias
What are the hepatic manfestions of HH?
Hepatomegaly, fibrosis and cirrhosis, with common progression to hepatocellular carcinoma (most common cause of death)
What is the classic triad of HH?
Cirrhosis
Diabetes (due to pancreatic insufficiency)
Bronzing of the skin - hyperpigmentation
What are the joint and pituitary manifestations of HH?
Joint - arthropathy of MCP and PIP joints
Pituitary - hypogonadism
How is HH treated if ferritin is >500 or there is end-organ damage? What is the goal? What if patient has sickle cell?
Serial phlebotomies - keep ferritin to <50-100
If intolerant to phlebotomy - i.e. patient has sickle cell disease
-> Desferoxamine IV or Deferasirox PO
What are porphyrias?
Group of disorders characterized by inherited defects in heme biosynthesis pathways
-porphyrin buildup upstream causes symptoms
What are the two subdivisions of porphyrias and what types of symptoms do they cause?
Acute - neurovisceral
Chronic - cutaneous
What type of anemia do those with porphyrias get?
I tricked you, they don’t result in anemia because not enough enzyme is defective to entirely prevent biosynthesis of heme, but enough is that you get buildup of precursors which are excreted in feces / urine
What enzyme is defective in acute intermittent porphyria and what is the inheritance pattern? What builds up?
Porphobilinogen deaminase
-> build up of porphobilinogen and ALA
Inherited via autosomal dominant mechanism
What are the symptoms of acute intermittent porphyria?
NEUROVISCERAL SYMPTOMS
5 P’s of porphyria
Painful abdomen
Port-wine urine
Polyneuropathy - tingling nof limbs, respiratory failure
Psychological disturbances
Precipitated by drugs, alcohol and starvation
What enzyme is defective in porphyria cutanea tarda and what is the inheritance pattern? What builds up?
Uroporphyrinogen decarboxylase
Uroporphyrin builds up (tea-colored urine)
Autosomal dominant, but usually acquired
What are the symptoms of Porphyria cutanea tarda (PCT)?
Cutaneous symptoms and iron overload (chronic)
- > blistering photosensitivity, hypertrichosis, iron overload, and chronic liver disease (associated with alcohol consumption)
- > makes you look like a werewolf
What conditions is PCT associated with?
Hepatitis C, HIV infections, and HFE mutations (HH)
How is diagnosis of the porphyrias typically made?
Urine porphyrins, making sure to minimize light exposure which would break them down
- > best collected in acute exacerbation
- > test urine, blood, stool, then do genetic testing to confirm
How is PCT treated?
Avoid ETOH consumption (hepatic toxin), avoid sun exposure (werewolf), phlebotomy to reduce iron levels
What things precipitate AIP?
Remember the last P of porphyrias:
Precipitated
Dehydration, starvation, CYP inducers induce ALA synthase (anticonvulsants), alcohol
What is the treatment for AIP?
IV dextrose and heme to inhibit ALA synthase
Fluids and narcotics for pain
There are three alleles for the HFE gene, two of which cause some form of hereditary hemochromatosis. What combination is most likely to cause symptomatic overload.
Alleles include:
- Wild type
- C282Y
- H63D
Homozygous C282Y (C282Y/C282Y)
heterozygotes may have mild disease: C282Y / H63D
All others very unlikely to produce significant disease
What transporter moves iron from the lumen of the GI tract into the duodenal enterocyte?
DMT-1
Divalent metal cation transport-1
What is a positive hemolytic workup?
increased reticulocyte count, increased LDH, increased bilirubin, decreased haptoglobin
