Erythron pathophysiology- what does it really mean?

ABSTRACT

AIM: To identify the meaning of erythron Pathophysiology and its relationship in the diagnosis of anaemia.

METHODS: Relevant information were consulted in various papers in an attempt to identify the issues on erythron Pathophysiology.

CONCLUSION: The conclusion was that when we talk about erythron Pathophysiology, it means the disorder of erythrocytes or red blood cells that can be seen in clinical practice and this can be manifested in many forms.

KEYWORDS: Erythron, Pathophysiology, Anaemia

Corresponding Author: Peter Ubah Okeke

Student, School of Science & Engineering,

Atlantic International University, Honolulu- Hawaii

www.aiu.edu

Term paper

INTRODUCTION

Erythron is the name given to the collection of all stages of erythrocytes throughout the body and this includes the developing precursors in bone marrow and the circulating mature erythrocytes in the peripheral blood, therefore erythron is the entirety of erythroid cells in the body. However, pathophysiology refers to the manner in which a disorder (in this case erythrocytes) translates into clinical symptoms. For the purpose of this assignment we concentrate on disorders of iron and heme metabolism and under this heading, general concepts in anemia and iron deficiency anemia will be discussed.

General concepts in anemia

Anemia may result whenever red blood cell (RBC) production is impaired, RBC life span is shortened or there is frank loss of cells. The anemias associated with iron typically are categorized as anemias of impaired production. The formation of RBCs requires many constituents, chief among them being the components for the production of hemoglobin (Hb): iron, heme and globin. Depending on the cause, lack of available iron results in iron deficiency anemia or the anemia of chronic inflammation. Inadequate availability of heme results in a relative excess manifested in sideroblastic anemias, while inadequate globin production results in the thalassemias. Iron is absorbed from the diet in the small intestine, carried by transferrin to a cell in need, and incorporated into the muscles where it is held as ferritin until incorporated into its final functional molecule.

That functional molecule may be a heme-based cytochrome, muscle myoglobin or developing RBCs (Hb), iron may be unavailable for incorporation into heme because of inadequate stores of body iron or merely because of impaired mobilization. The anemia associated with inadequate stores is termed iron deficiency, whereas the anemia resulting from impaired mobilization is anemia of chronic inflammation due to its association with chronic inflammatory conditions, such as rheumatoid arthritis. When the iron supply is adequate and mobilization is unimpaired, but an intrinsic RBC defect prevents incorporation of iron into heme, the resulting anemia is termed sideroblastic, referring to the presence of iron in the developing RBCs.

Iron deficiency Anemia

Iron deficiency anemia develops when the intake of iron is inadequate to meet a standard level of demand when the need for iron expands or when there is chronic loss of Hb from the body.

Inadequate intake

Iron deficiency anemia can develop as the erythron is slowly starved for iron. Each day, approximately l mg of iron is lost from the body mainly in the mitochondria of desquamated skin and sloughed intestinal epithelium Hallberg (1981). When the diet is consistently inadequate in iron, over time the body`s stores of iron become depleted. Ultimately, RBC production slows as a result of the inability to produce Hb. With approximately 1% of cells naturally dying each day, the anemia becomes apparent when the production rate cannot replace lost cells.

Increased need

Iron deficiency also can develop when the level of iron intake becomes inadequate to meet the needs of an expanding erythron. This is the case in periods of rapid growth such as infancy, childhood and adolescence. Pregnancy and nursing place similar demands on the mother"s body to provide iron for the developing fetus or nursing infants and herself. In each of these instances, what had previously been an adequate intake of iron for the individual becomes inadequate as the need for iron increases.

Chronic blood loss

A third way iron deficiency develops is with excessive loss of Hb from the body. This loss occurs with slow hemorrhage or hemolysis. Any condition in which there is a slow low-level loss of RBCs may result in iron deficiency.

For women, heavy menstrual bleeding can constitute a chronic loss of blood leading to iron deficiency as can bleeding associated with fibroid tumors. For women or men gastro intestinal bleeding from ulcers or tumors, loss of blood via the urinary tract with kidney stones or tumors also can lead to iron deficiency. Persons with chronic intravascular hemolysis such as paroxysmal nocturnal hemoglobinuria, can lead to iron deficiency due to the loss of iron in Hb passed into the urine.

Pathogenesis

Iron deficiency anemia develops slowly, progressing through stages that physiologically blend one into the other but are useful delineations for understanding disease progression Suominem et al (1998).

Iron is distributed among three compartments:

• 1. The storage compartment, principally as ferritin in the bone marrow, macrophages and liver cells.

• 2. The transport compartment of serum transferrin.

• 3. The functional compartment of Hb, myoglobin, and cytochromes. Hb and intra cellular ferritin constitute nearly 95% of the total distribution of iron Andrews (2003).

For a period of time as iron intake lag behind loss, essentially normal iron status continues. Absorption of iron through the intestine is accelerated in an attempt to meet the relative increased demand for iron, but this is not apparent in laboratory tests or patient symptoms. The person appears apparently healthy but as the negative iron balance continues however, a stage of iron depletion develop.

Stage 1

This is characterized by a progressive loss of storage iron. The body"s reserve of iron is sufficient to maintain the transport and functional compartments through this phase. So RBC development is normal. There is no evidence of iron deficiency in the peripheral blood picture and the patient experiences no symptoms of anemia. If ferritin levels are measured, they are low, indicating the decline in stored iron, which also could be detected in an iron stain of the marrow. Without evidence of anemia, neither of these tests would be performed and individuals appear healthy. Dallman et al (1980) estimated that nearly 50% of U.S. infants are in this phase of iron deficiency.

Stage 2

This stage two of iron deficiency is defined by the exhaustion of the storage pool of iron. For a time RBC production continues as normal, relying on the iron available in the transport compartment. Anemia as measured relative to the reference range of Hb, is still not evident, although an individual"s Hb may begin dropping. Other iron-dependent tissues such as muscles may begin to be affected, but the symptoms may be nonspecific. Ferritin estimation and serum iron are still low. Whereas total iron binding capacity (TIBC) (that is transferin) increases. Free erythrocytes protoporphyrin (FEP), the porphyrin into which iron is inserted to form heme, begins to accumulate. Transferrin receptors increase on the surface of iron-starved cells as they are trying to capture as much available iron as possible.

Stage 3

Iron deficiency in this stage is frank anemia. The Hb and hematocrit (HCT) are low relative to the reference ranges having thoroughly depleted storage iron and diminshed transport iron, developing RBCs are unable to develop normally. The number of cell divisions per precursor increases because hemoglobin accumulation in the developing cells is slowed allowing more time for cell divisions. The result is first smaller cells with adequate Hb concentration, although ultimately even these cannot be filled with Hb. These cells become microcytic and hypochronic.

Ferritin levels are exceedingly low. Other iron studies also are abnormal and the FEP and transferrin receptors levels increase. In this phase, the patient experiences the nonspecific symptoms of anemia, typically fatigue and weakness especially with exertion. Pallor is evident, sore tongue (glossitis) and angular chelosis are seen. Koilonychia may also be seen if the deficiency is long standing, patient may also experience cravings for non food items called pica. The cravings may include things such as dirt, clay, laundry starch or most commonly ice specifically called pagophagia.

Epidemiology

Menstruating women are at especially high risk. If women of childbearing age are not properly supplemented, pregnancy and nursing can lead to a loss of nearly 900 mg of iron. Succeeding pregnancies can exacerbate the problem leading to iron deficient fetuses Green et al (1968). Growing children also are at high risk. Cow"s milk is not a good source of iron and infants need to be placed on supplemented formular by about age 6 months when their fetal stores of iron become depleted. This assumes infants were able to establish adequate stores from their mothers in utero. Even though breast milk is a better source of iron than cow"s milk, Saarinen et al (1977), it is not a consistent source Siimes et al (1979). Iron supplementation also is recommended for breast fed infants after 6 months of age.

Iron deficiency is relatively rare in men and postmenopausal women because the body conserves iron so tenaciously and these individuals lose only about 1 mg/dl.

Gastro intestinal disease, such as ulcers, tumors hemorrhoids, should be suspected for iron deficient patient in either of these groups if the diet is known to be adequate in iron.

Iron deficiency is associated with infection by hookworms. The worm attaches to the intestinal wall and literally sucks blood from the gastric vessels.

Soldiers and long distance runners also can develop iron deficiency. Marching anemia develops when RBCs are hemolyzed by foot pounding trauma and iron is lost as Hb in the urine Beutler et al (1960). The amount lost in the urine can be so little that it is not apparent on visual inspection.

Laboratory Diagnosis

The tests can be grouped into three general categories:

• Screening

• Diagnostic

• Specialized

Screening test for iron deficiency anemia

When iron deficient erythropoiesis is occurring, the complete blood count begins to show evidence of microcytosis and hypochromia. Hb is decreased and RBC distribution with (RDW) greater than 15% would be expected and may precede the decrease in Hb Thompson et al (1988). For patients in high-risk groups, the elevated RDW can be an early and sensitive indicator of iron deficiency Mcclure S et al (1985).

As the Hb continues to fall, microcytosis and hypochromia become more prominent with progressively declining values for mean cell volume (MCV), mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC). The RBC count ultimately becomes decreased as does the Hematocrit.

Diagnosis of iron deficiency

Iron studies remain the back bone for diagnosis of iron deficiency. They includes assay of serum iron, total iron binding capacity(TIBC), transferring saturation and ferritin.

It is important that iron studies are drawn fasting and early in the morning. Iron shows a diurnal variation with levels dropping throughout the day Sinniah et al (1969) and iron absorbed from a meal can falsely elevate levels Crosby & O"Neil-Cutting (1984).

Specialized laboratory diagnosis

Free erythrocyte protoporphyrin (FEP) accumulates when iron is unavailable. In the absence of iron, FEP may be preferentially chelated with zinc to from zinc protoporphyrin (ZPP) Lamola et al (1975). The FEP and the Zinc chelate can be assayed fluorometrically. Serum transferrin receptors (STFR) also can be assayed using immunoassay.

Conclusion: It is very clear that erythron Pathophysiology includes anaemia and other abnormalities of erythrocytes that can be seen in clinical practice, from the formation, metabolic and the catabolic aspects of red blood cells. Specific case study could have specific clinical and laboratorial diagnosis.

References

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Beutlere et al (1960); Iron therapy in chronically fatigued non-anemia women: a double blind study. Ann intern med 52: 378-394

Croshy WH & O"Neil-Cutting MA (1984); A Small dose iron tolerance test as an indicator of mild iron deficiency. Clin invest 251: 1986-7

Dallman PR et al (1980); iron deficiency in infancy and child hood. Am J clin nutr 33:86

Green R et al (1968); Body iron excretion in man: a collaborative Study. Am J med 45; 336

Hallberg L (1981); Bioavailability of dietary iron in man. Annu Rev Nutr 1:123

Kathryn Doig (2007); Disorders of iron and heme metabolism: In Rodak BF et al edns: Hematology clinical principles & Applications. Third edn Elsevier.

Lamota AA et al (1975); Zinc protoporphyrin (ZPP): a simple, sensitive fluorometric screening test for lead poisoning. Clin chem. 21: 93 – 7

Mcclure S et al (1985); Improved detection of early iron deficiency in non anemia subjects. Jama 253: 1021

Saarinen Um et al (1977); Iron absorption in infants: High bioavailability of breast milk iron as indicated of the extrinsic tag method of iron absorption and by the concentration of serum ferritin. J pediatr 91: 36-39

Siimes MA et al (1979); Breast milk iron: a declining concentration during the course of lactation. Acta pediatr Scand 68: 29-31

Sinniah R et al (1969); Diurnal Variations of the serum iron in normal subjects and in patients with hemochromatosis. Br J Hematol 17: 351

Suominen P et al (1998); Serum transferring receptor and transferrin receptor-ferritin index identify healthy subjects with subchinical iron deficits. Blood 92: 2934

Thompson WG et al (1988); Red cell distribution width, mean corpuscular volume, and transferring saturation in the diagnosis of iron deficiency. Arch intern med 148: 2128

Autor:

Peter Ubah Okeke

2011