Iron Overload and Deficiency anemia hematology

Iron Overload and Deficiency

1. IRON DEFICIENCY ANEMIA

2. Objectives
•1. To discuss the essentials of diagnosis of Iron Overload and Iron
Deficiency
•2. To enumerate laboratory findings in Iron Deficiency and Overload

3. Reference
•Greer JP,Arber DA,Glader B, et al.Wintrobe’s Clinical
Hematology. 13th ed. Philadelphia, PA: Wolters Kluwer Health |
Lippincott Williams & Wilkins;2014.

4. References
•Auerbach M et al. Single-dose intravenous iron for iron deficiency: a
new paradigm. Hematology Am SocHematolEducProgram. 2016 Dec
2;2016(1):57–66. [PMID: 27913463]
•Auerbach M et al. How we diagnose and treat iron deficiency anemia.
Am J Hematol. 2016 Jan;91(1):31–8. [PMID: 26408108]

5. References
•CamaschellaC. Iron-deficiency anemia. N EnglJ Med. 2015 May
7;372(19):1832–43. [PMID: 25946282]
•HempelEV et al. The evidence-based evaluation of iron deficiency
anemia. Med Clin North Am. 2016 Sep;100(5):1065–75. [PMID:
27542426]

6. ESSENTIALS OF DIAGNOSIS
•Iron deficiency: serum ferritin is less than 12 ng/mL (27 pmol/L) or
less than 30 ng/mL (67 pmol/L) if also anemic.
•Caused by bleeding unless proved otherwise
•Responds to iron therapy.

7. General Considerations
•Iron deficiency is the most common cause of anemia worldwide.
Aside from circulating red blood cells, the major location of iron in the
body is the storage pool as ferritin or as hemosiderinin macrophages.

9. Iron Deficiency Anemia
•In general, iron metabolism is balanced between absorption of 1
mg/day and loss of 1 mg/day. Pregnancy and lactation upset the iron
balance, since requirements increase to 2–5 mg of iron per day.
Normal dietary iron cannot supply these requirements, and medicinal
iron is needed during pregnancy and lactation.

10. Iron Deficiency Anemia
•Decreased iron absorption can also cause iron deficiency, such as in
people affected by celiac disease (gluten enteropathy), and it also
commonly occurs after gastric resection or jejunal bypass surgery.

11. Iron Deficiency Anemia
•The most important cause of iron deficiency anemia in adults is
chronic blood loss, especially menstrual and gastrointestinal blood
loss. Iron deficiency demands a search for a source of gastrointestinal
bleeding if other sites of blood loss (menorrhagia, other uterine
bleeding, and repeated blood donations) are excluded.

12. Iron Deficiency Anemia
•Prolonged aspirin or nonsteroidal anti-inflammatory drug use may
cause it even without a documented structural lesion. Celiac disease,
even when asymptomatic, can cause iron deficiency through poor
absorption in the gastrointestinal tract. Zinc deficiency is another
cause of poor iron absorption. Chronic hemoglobinuria may lead to
iron deficiency, but this is uncommon.

13. Iron Deficiency Anemia
•Traumatic hemolysis due to a prosthetic cardiac valve and other
causes of intravascular hemolysis (eg, paroxysmal nocturnal
hemoglobinuria) should also be considered. The cause of iron
deficiency is not found in up to 5% of cases.

14. Iron Deficiency Anemia
•Pure iron deficiency might prove refractory to oral iron replacement.
Refractoriness is defined as a hemoglobin increment of less than 1
g/dL (10 g/L) after 4–6 weeks of 100 mg/day of elemental oral iron.

15. Iron Deficiency Anemia
•The differential diagnosis in these cases (Table 13–3) includes
malabsorption from autoimmune gastritis, Helicobacter pylori gastric
infection, celiac disease, and hereditary iron-refractory iron deficiency
anemia

16. Iron Deficiency Anemia
•Iron-refractory iron deficiency anemia is a rare autosomal recessive
disorder due to mutations in the transmembrane serine protease 6
(TMPRSS6) gene, which normally down-regulates hepcidin. In iron-
refractory iron deficiency anemia, hepcidin levels are normal to high
and ferritin levels are high despite the iron deficiency.

17. Symptoms and Signs
•The primary symptoms of iron deficiency anemia are those of the
anemia itself (easy fatigability, tachycardia, palpitations, and dyspnea
on exertion). Severe deficiency causes skin and mucosal changes,
including a smooth tongue, brittle nails, spooning of nails
(koilonychia), and cheilosis.

18. Symptoms and Signs
•Dysphagia due to the formation of esophageal webs (Plummer-
Vinson syndrome) may occur in severe iron deficiency. Many iron-
deficient patients develop pica, craving for specific foods (ice chips,
etc) often not rich in iron.

19. Laboratory Findings
•Iron deficiency develops in stages. The first is depletion of iron stores
without anemia followed by anemia with a normal red blood cell size
(normal MCV) followed by anemia with reduced red blood cell size
(low MCV). The reticulocyte count is low or inappropriately normal.
Ferritin is a measure of total body iron stores.

20. Laboratory Findings
•A ferritin value less than 12 ng/mL (27 pmol/L) (in the absence of
scurvy) is a highly reliable indicator of reduced iron stores. Note that
the lower limit of normal for ferritin generally is below 12 ng/mL (27
pmol/L) in women due to the fact that the normal ferritin range is
generated by including healthy menstruating women who are iron
deficient but not anemic.

21. Laboratory Findings
•However, because serum ferritin levels may rise in response to
inflammation or other stimuli, a normal or elevated ferritin level does
not exclude a diagnosis of iron deficiency.

22. Laboratory Findings
•A ferritin level less than 30 ng/mL (67 pmol/L) almost always indicates
iron deficiency in anyone who is anemic. As iron deficiency
progresses, serum iron values decline to less than 30 mcg/dL (67
pmol/L) and transferrin (the iron transport protein) levels rise to
compensate, leading to transferrin saturations of less than 15%.

23. Laboratory Findings
•Low transferrin saturation is also seen in anemia of inflammation, so
caution in the interpretation of this test is warranted. Isolated iron
deficiency anemia has a low hepcidin level, not yet a clinically
available test. As the MCV falls (ie, microcytosis), the blood smear
shows hypochromic microcytic cells.

24. Laboratory Findings
•With further progression, anisocytosis (variations in red blood cell
size) and poikilocytosis (variation in shape of red cells) develop.
Severe iron deficiency will produce a bizarre peripheral blood smear,
with severely hypochromic cells, target cells, and pencil-shaped or
cigar-shaped cells.

25. Laboratory Findings
•Bone marrow biopsy for evaluation of iron stores is rarely performed.
If the biopsy is done, it shows the absence of iron in erythroid
progenitor cells by Prussian blue staining. The platelet count is
commonly increased, but it usually remains under800,000/mcL (800 ×
109/L).

26. Differential Diagnosis
•Other causes of microcytic anemia include anemia of chronic disease
(specifically, anemia of inflammation), thalassemia, lead poisoning,
and congenital X-linked sideroblasticanemia. Anemia of chronic
disease is characterized by normal or increased iron stores in bone
marrow macrophages and a normal or elevated ferritin level; the
serum iron and transferrin saturation are low, often drastically so, and

27. Differential Diagnosis
•the total iron-binding capacity (TIBC) (the blood’s capacity for iron to
bind to transferrin) and transferrin are either normal or low.
•Thalassemia produces a greater degree of microcytosisfor any given
level of anemia than does iron deficiency and, unlike every other
cause of anemia, has a normal or elevated red blood cell count as
well as a reticulocytosis.

28. Treatment
•The diagnosis of iron deficiency anemia can be made either by the
laboratory demonstration of an iron-deficient state or by evaluating
the response to a therapeutic trial of iron replacement. Since the
anemia itself is rarely life-threatening, the most important part of
management is identification of the cause—especially a source of
occult blood loss.

29. A. Oral Iron
•Ferrous sulfate, 325 mg once daily or every other day on an empty
stomach, is a standard approach for replenishing iron stores. As oral
iron stimulates hepcidin production, once daily or every other day
dosing maximizes iron absorption compared to multiple doses per
day, and with fewer side effects.

30. A. Oral Iron
•Extended-release ferrous sulfate with mucoprotease is a well-
tolerated oral preparation. Taking ferrous sulfate with food reduces
side effects but also its absorption. An appropriate response is a
return of the hematocrit level halfway toward normal within 3 weeks
with full return to baseline after 2 months.

31. A. Oral Iron
•Iron therapy should continue for 3–6 months after restoration of
normal hematologic values to replenish iron stores. Failure of
response to iron therapy is usually due to noncompliance, although
occasional patients may absorb iron poorly, particularly if the
stomach is achlorhydric.

32. A. Oral Iron
•Such patients may benefit from concomitant administration of oral
ascorbic acid. Other reasons for failure to respond include incorrect
diagnosis (anemia of chronic disease, thalassemia), celiac disease,
and ongoing blood loss that exceeds the rate of new erythropoiesis.
Treatment of H pylori infection, in appropriate cases, can improve oral
iron absorption.

33. B. Parenteral Iron
•The indications are intolerance of or refractoriness to oral iron
(including those with iron-refractory iron deficiency anemia),
gastrointestinal disease (usually inflammatory bowel disease)
precluding the use of oral iron, and continued blood loss that cannot
be corrected, such as chronic hemodialysis.

34. B. Parenteral Iron
•Historical parenteral iron preparations, such as high-molecular-weight
iron dextran, were problematic due to long infusion times (hours),
polyarthralgia, and hypersensitivity reactions, including anaphylaxis.

35. B. Parenteral Iron
•Current parenteral iron preparations coat the iron in protective
carbohydrate shells or contain low-molecular-weight iron dextran, are
safe, and can be administered over 15 minutes to 1 hour. Most iron
deficient patients need 1–1.5 g of parenteral iron; this dose corrects
for the iron deficit and replenishes iron stores for the future.

36. B. Parenteral Iron
•Ferric pyrophosphate citrate (Triferic) is an FDA-approved additive to
the dialysate designed to replace the 5–7 mg of iron that patients
with chronic kidney disease tend to lose during each hemodialysis
treatment.

37. B. Parenteral Iron
•Ferric pyrophosphate citrate delivers sufficient iron to the marrow to
maintain hemoglobin and not increase iron stores; it may obviate the
need for intravenous iron in hemodialysis patients.

38. When to Refer
•Patients should be referred to a hematologist if the suspected
diagnosis is not confirmed or if they are not responsive to oral iron
therapy.

39. Iron Overload

40. References
•Greer JP,Arber DA,Glader B, et al.Wintrobe’s Clinical
Hematology. 13th ed. Philadelphia, PA: Wolters Kluwer Health |
Lippincott Williams & Wilkins;2014.
•Radford-Smith DE, Powell EE, Powell LW. Haemochromatosis: a clinical
update for the practising physician.Intern Med J.2018
May;48(5):509-516.[PubMed]

41. Introduction
•Iron overload is defined as excess stores of iron in the body. Excess
iron is deposited in organs throughout the body. The most notable
organs with iron deposition are the liver, heart, and endocrine glands.
Resulting symptoms and disease are related to specific organ damage.

42. Etiology
•Primary iron overload is ofteninherited. Hereditary hemochromatosis
is the leading case of iron overload disease. In 1996, 2 gene mutations
(C282Y and H63D) of theHFEgene were discovered and linked to
primary iron overload. The most common is C282Y.

43. Etiology
•The introduction of excess ironinto the bodycauses secondary iron
overload. This occurs most commonly through blood transfusion, but
also can be due to hemolysis or excessive parenteral and/or dietary
consumption

44. Pathophysiology
•The functional changes in the human body that result from iron
overload are numerous. Excess iron deposits mainly in the liver, heart
and endocrine organs. Damage to the liver can result in chronic liver
disease, cirrhosis and lead to hepatocellular carcinoma. Damage to the
heart muscle can lead to heart failure and irregular heart rhythms

45. Pathophysiology
•Damage to the pancreas can lead to elevated blood glucose levels and
"bronze"diabetes. Hypothyroidism and hypogonadism can result in
fatigue, hair loss, infertility, and decreased libido. Joint involvement
leads to arthritis. Neurological involvement can accelerate
neurodegenerative diseases such as Alzheimer disease

46. History and Physical
•Patients with iron overload are asymptomatic in 3 out of 4 cases.
When signs and symptoms occur, they are generally related to specific
organ involvement. These include chronic fatigue, arthralgia,
abdominal pain, hepatomegaly, irregular heart rhythm, hypogonadism,
decreased libido, elevated blood glucose levels, hyperpigmentation
(bronze skin), and depression

47. Evaluation
•Iron overload suspected after a history and physical can generallybe
diagnosed with low costs, non-invasive blood tests. Serum iron levels
are not indicated.
•Serum ferritin greater than 300 ng/ml in males and greater than 150 to
200 ng/ml in menstruating females can be indicative of iron overload

48. Evaluation
•However, serum ferritin levels can also be elevated to a variety of
reasons, including inflammation, infection and liver disease; it is
known as an acute phase reactant. Total binding iron capacity
(TIBC)may be normalas well

49. Evaluation
•Fasting, elevated,serum transferrin saturation percentage greater than
45% can assist in further diagnosis. In classic hemochromatosis, both
serum ferritin and transferrin iron saturation percentage will most
often be elevated.

50. Evaluation
•Genetic testing is now available for theHFEgene associated with
hemochromatosis. Mutations in this gene can occur in many different
patterns. Patients with the C282Y/C282Y, H63D/H63D or
C282Y/H63D pattern are most at risk for the disease. It is estimated
that one million Caucasian Americans have the C282Y/C282Y
inheritance pattern

51. Evaluation
•Hepatic iron index on percutaneous liver biopsy can give be utilized in
difficult to diagnose cases but carries greater procedural risk than
blood testing. Liver biopsy has been the standard of diagnosis, but
with the introduction of genetic testing is reserved for more
complicated cases.

52. Evaluation
•Once the diagnosis of iron overload is established, more specific
testing is directed depending on suspected organ involvement.

53. Treatment / Management
•The treatment for iron overload is reduction therapy. This is most
commonly achieved through therapeutic phlebotomy. In patients with
an acceptable hemoglobin level, phlebotomy can initially be
prescribed every 1 to 2 weeks until serum ferritin is brought within
acceptable levels.

54. Treatment / Management
•Then a schedule of periodic phlebotomy can be maintained, generally
every 2 to 3 months, according to achieved serum ferritin levels. When
serum ferritin remains above 1000 ng/ml, the risk of liver damage and
decreased life expectancy increase dramatically.

55. Treatment / Management
•Often, patients with mildly elevated serum ferritin levels are advised
to donate blood on a regular basis. Donating more frequently than
every 8 weeks usually necessitates physician approval.

56. Treatment / Management
•In patients with hemoglobin levels that do not tolerate therapeutic
phlebotomy, iron chelation therapy becomes an option. Deferoxamine
is an iron chelation therapy currentlyin use. A conundrum occurs in
patients who must receive regular blood donations, such as the patient
with thalassemia.In these specific situations, blood transfusion must
occur but is accompanied by chelation therapy with deferasirox or
deferiprone.

57. Differential Diagnosis
•The differential diagnosis for hemochromatosis includes elevated iron
levels due to multiple transfusions, over-consumption, alcoholic liver
disease, ineffective erythropoiesis with hyperplastic erythroid marrow,
elevated iron with chronic anemia, and porphyria cutanea tarda.
Genetic testing of theHFEgene can help illuminate the diagnosis

58. Staging
•When hemochromatosis has advanced to liver cirrhosis, liver biopsy is
indicated to determine the severity of the disease. This is especially the
case if liver transplant in part of the management plan.

59. Prognosis
•The prognosis of patients with iron overload is extremelypositive
when diagnosed early and when treatment effectivelyreduces iron
levels to acceptable levels. A normal lifespan and extremely low rates
of liver damage are reported in patients who maintain serum ferritin
levels within an acceptable range.

60. Complications
•Complications of iron overload include liver damage, liver cirrhosis,
pancreatic islet cell damage, diabetes, hypothyroidism, and
hypogonadism.