Week 3 Narrative Part 1

Pathogenesis and Pathophysiology of the common, recurrent Illnesses and Diseases present in Kevadiya Colony and the Surrounding Tribal Villages

It is important to realize that the majority of the inhabitants found in Kevadiya Colony and the surrounding tribal villages of the Satpuda region live at or below the poverty line.* As a result the most prevalent diseases and illnesses that burden these populations manifest in the forms of malnutritional disorders. Prevalent malnutritional disorders found in the Satpuda region include: (1) general malnutrition (and protein-energy-malnutrition), (2) iron deficiency (and iron deficiency anemia—IDA), (3) vitamin A deficiency (and its associated conditions of xerophthalmia and nyctalopia—night blindness as well as increased susceptibility to measles, malaria, and diarrhea), (4) iodine deficiency (and associated physical manifestations of goiter or cretinism), (5) zinc deficiency (with a greater predisposition to diarrhea, pneumonia, and malarial infections), (6) riboflavin deficiency (and dermatitis), (7) folic acid deficiency (and its associated condition of megaloblastic anemia in elders and neural tube defects in infants—i.e. anencephaly and spina bifida), (8) and vitamin D and calcium deficiencies (and its associated conditions of rickets and osteoporosis). As a result of poor nutritional status, lowered immunity status due to various micronutrient deficiencies, and inadequate daily hygienic practices, these villagers are also burdened with parasitic and opportunistic infections. Such infections include: (9) scabies, (10) parasitic worm infections (including roundworms, hookworms, tapeworms, ring worms, and Echinococcus Granulosus infections), (11) lice and nits, (12) fungal infections (and resulting skin infections and dermatitis), and (13) malarial infections (especially during the monsoon season).

Please note that due to time constraints, the pathogenesis and pathophysiology of the following two conditions: (1) iron deficiency (and iron deficiency anemia) and (2) vitamin A deficiency (and its associated conditions of xerophthalmia and nyctalopia) will be covered in detail in Week 3. If there is an interest in any of the other micronutrient deficiencies or parasitic or opportunistic infections that were mentioned above, then the pathogenesis and pathophysiology of these conditions can be discussed in greater detail UPON REQUEST after all other topics and dimensions of Project ASHA have been explored and discussed—after Week 9.

* NOTE: Although poverty has a major impact on the burden of disease in the villages of the Satpuda region; poverty alone does not predispose the villagers of Kevadiya Colony and the surrounding villages to both malnutritional disorders and parasitic and opportunistic infections. The various factors that influence a villager’s susceptibility and predisposition to disease and illness will be covered in next week’s—Week 4—material.

Malnutritional Disorder: Iron Deficiency Anemia (IDA)

General Overview—Hemoglobin (HB) performs the primary function within a mature erythrocyte (RBC) by binding to and carrying molecules of oxygen. The amount of hemoglobin is determined by three integral and coordinated processes: (1) the production of the α- and β-globin proteins, (2) the biosynthesis of the heme porphyrin ring, and (3) the availability of iron. Deficiencies in any of the three processes to produce mature hemoglobin molecules can result in hypochromic and microcytic anemia. Microcytic anemia can typically be identified by automated RBC indices and hypochromic microcytic anemia can be validated via a peripheral blood smear.

Figure 1—Peripheral blood smear of a patient with normal erythrocytes (RBCs): Notice that the RBCs are nearly the same size as the darkly stained lymphocyte nucleus and are hence normocytic. Also notice that the central pallor (the pale, central portions) of the RBC are less than or equal to half the diameter of the respective cells and are hence normochromic. Thus normal erythrocytes are classified as normocytic and normochromic.

Figure 2—Peripheral blood smear of a patient with Iron Deficiency Anemia (IDA): Notice that the RBCs have a smaller diameter than the normal, darkly stained lymphocyte nucleus and are hence microcytic. Also notice that the pale, central portions of the RBCs exceed more than half the diameter of the respective cells and are hence hypochromic. Thus IDA is characterized as a microcytic hypochromic anemia.

Epidemiology—Iron deficiency is the most common cause of anemia at the global level. The worldwide prevalence of IDA is estimated to burden up to 10% of the world population or affect more than 500 million people. The prevalence rates are critically high in developing nations where both dietary insufficiency/malnutrition and intestinal parasites are prevalent (Ginder, 2012). Within Kevadiya Colony and the surrounding tribal villages, IDA is especially prevalent in both pregnant and non-pregnant women  as well as their new born children. As a result, child mortality is high within the Satpuda Region and is a major health issue within Narmada District, Gujarat, India.

Figure 3—Iron homeostasis in a normal human

(Patho-)physiology—The adult human body contains approximately 4 g of iron. The majority of the iron (~2,100 mg) is incorporated into mature hemoglobin protein in erythrocytes or (~300 mg) myoglobin found in muscle fibers. The remaining iron is largely characterized as storage iron and is stored within the hepatocytes of the liver (~1,000 mg) and within the reticuloendothelial macrophages of the bone marrow and spleen (~600 mg). A miniscule amount of iron (~3 to 7 mg) circulates in the plasma while bound to a carrier protein called transferrin. This freely circulating pool of iron is kinetically very active and has a turnover rate of 3 to 4 hours. Due to the efficiency of the iron recycling mechanism developed by the reticuloendothelial macrophage system, only 1 to 2 mg of iron is lost daily via gastrointestinal (GI) mucosal sloughing, desquamation, and menstruation—in females of reproductive age—Figure 3, above (Ginder, 2012).

Iron’s intrinsic ability to easily participate in oxidation/reduction reactions and interconvert between the ferrous (Fe²⁺) and ferric (Fe³⁺) oxidation states makes it a vital component of both the hemoglobin and myoglobin porphyrin rings that allow for the transport of oxygen molecules as well as cytochromes and various other critical enzymes. Unbound, free iron is extremely toxic because of its potential to catalyze the formation of free radicals that can produce cellular damage. Thus, iron that is not integrated into porphyrin rings is bound to carrier proteins. Transferrin is the main protein involved with circulating plasma iron while ferritin is the primary protein associated with stored intracellular iron that is found both in the mitochondria and the cytoplasm. The rate of iron loss from the human body is minimal. At the minimum, 1 to 2 mg of dietary iron is needed per day to maintain a homeostasis of iron within the body.

A major cause of iron deficiency and potential IDA is inadequate iron intake within the diet. Any diet that fails to include at least 1 to 2 mg of iron per day may fail to meet the daily iron needed to maintain a homeostasis of iron within the body. Certain diets that lack adequate sources of iron or contain organic compounds in concentrated quantities (ie. phytates from cereals or tannate from tea) will inhibit intestinal iron absorption which may ultimately result in iron deficiency and its related anemia. Iron is easily absorbed primarily in the duodenum of the GI tract; however certain pathological states can inhibit the process of absorption. Such conditions include general intestinal malabsorption and atrophic gastritis with achlorhydria (Ginder, 2012).

Clinical Manifestations—Because of the buffering capacity of iron in the stored form—iron that is bound to either to transferrin or ferritin—and remarkable compensatory physiologic mechanisms of the human body, patients burdened with a mild form of IDA may present asymptomatic in a clinical setting. In these individuals, iron deficiency may be recognized via routine laboratory and chemical analysis of their blood. To positively identify IDA via a peripheral blood smear by observing for microcytosis and hypochromia, the blood hematocrit levels must fall to approximately 30%, (NOTE: normal hematocrit level is approximately 42%). Thus in early stages of IDA, it may prove difficult to observe the clinical manifestations of IDA (Ginder, 2012).

In more advanced stages of IDA, clinical manifestations may become fairly evident. Like the other types of anemias, IDA usually presents with a set of nonspecific symptoms which can include: weakness and fatigue, pallor or paleness, dizziness, irritability, shortness of breath, and or decreased exercise or work-bearing tolerance (lack of energy). As mentioned before, iron is a critical metallic cofactor for not only hemoglobin but also the porphyrin complex found in myoglobin as well as numerous other metabolic enzymes, therefore, the resulting amount of fatigue, weakness, and exercise or work-bearing intolerance may not be proportional to the hemoglobin level. Pica is a clinical manifestation that is unique to iron deficiency and IDA. Pica is defined as an unusual craving for specific non-nutritional substances. It may manifest in several forms including: a craving for ice (known as pagophagia), a craving for clay (known as geophagia), or a craving for starch (known as amylophagia) (Ginder, 2012).

Figure 4—A condition of koilonychias

Physical signs that are associated with iron deficiency include: pale skin and eye conjunctiva (known as pallor), glossitis (swollen and or sore tongue), angular stomatitis, spooning of the fingernails (known as koilonychias)—Figure 4, and blue-tinted sclerae (Ginder, 2012), (Killip, Bennett, & Chambers 2007), and (Naqvi & Ferri, 2012).

Diagnosis—When diagnosing for IDA, the differential diagnosis may include: (1) anemia of chronic disease, (2) sideroblastic anemia, (3) thalassemia trait, and (4) lead poisoning. The diagnosis of IDA is made via laboratory testing and analysis. Initial screening consists of determining hemoglobin levels, mean corpuscular volume, RBC hemoglobin content, and reticulocyte count. Secondarily, a peripheral blood smear is performed to look for microcytosis and hypochromia of the erythrocytes (Ginder, 2012), (Killip, Bennett, & Chambers 2007), and (Naqvi & Ferri, 2012).

A confirmatory diagnosis of IDA is made by performing tests that measure the total body iron stores. (NOTE: an absence of iron stores that can be mobilized is unique to this type of microcytic hypochromic anemia). The serum ferritin level is the most reliable, cost-effective, and noninvasive indicator that is widely available in a clinical setting. Transferrin and transferrin-bound iron levels may not be dependable gauges of iron deficiency because they are also abnormal in the anemia of chronic disease, even when there are sufficient total body iron stores (Ginder, 2012). Table 3 (below) provides laboratory results that are helpful for the differential diagnosis of IDA from various other types of anemia.

Table 3: Laboratory Results for Iron Analysis in Microcytic and Hypochromic Anemias

Anemia	Serum Iron	TIBC*	Transferrin Saturation (%)	Serum Ferritin	Serum Transferrin Receptor	Marrow RE** Iron	Marrow Ringed Siderblast
Iron Deficiency Anemia	Low	High	0 – 15	Low (<30 μg/L)	High	Absent	Absent
Anemia of Chronic Disease	Low	Normal or low	5 – 15	Normal or high	Normal	Normal or high	Absent
Sideroblastic Anemia	High	Normal	60 – 90	High	Normal or high	High	Present

*TIBC—Total Iron Binding Capacity                            **RE—Reticuloendothelial

Table adapted from Goldman L et al: Goldman’s Cecil Medicine, ed 24, Philadelphia, 2012, Saunders.

Treatment—The obvious goal of the treatment of IDA is to replenish the body’s iron stores. Another goal is to determine the underlying cause of iron deficiency. The preferred and most common route of iron administration is oral. Iron given orally is easily absorbed in the duodenum of the GI tract. Within Kevadiya Colony, iron tonic is given to children and iron folic capsules are given to adults. These patients are to take the iron supplement once daily for a period of three months. Also they are educated on the importance of eating foods that have a rich source of iron to prevent a relapse. Table 4 (below) shows how the iron supplement replenishes the body’s natural iron stores throughout the course of treatment.

Table 4: Physiological Response to Iron Supplement Therapy in Patients with IDA

Time After Iron Administration	Physiological Response
12 to 24 hours	Replacement of intracellular iron enzymes, Subjective improvement, Decreased irritability, and Increased appetite
36 to 48 hours	Initial bone marrow response and Erythroid (RBC) hyperplasia
48 to 72 hours	Reticulocytosis—peaking at around 5 to 7 days
4 to 30 days	Increase in hemoglobin level
1 to 3 months	Repletion of iron stores

Table adapted from Kliegman RM et al: Nelson Textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

Prognosis—With a majority of IDA cases, the prognosis is good. IDA can be corrected swiftly—within months—by either oral or parental iron replacement therapy. However, the long-term prognosis is contingent upon the clinical course of the underlying causative agent. It is of crucial importance to fully inspect the patient in order to determine the underlying cause of iron deficiency. Also it is imperative to fully educate the patient of the importance of eating foods that provide an adequate supply of iron (at the bare minimum 1 to 2 mg of iron daily) to prevent a relapse of the condition.

References

Ginder, G.D. (2012). 162 – Microcytic and Hypochromic Anemias. In L. Golman, & A.I. Schafer, Golman’s Cecil Medicine, 24^th ed (pp. 1039-1044). Philadelphia: Saunders, An Imprint of Elsevier. Retrieved from <http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-1604-7..00162-7&isbn=978-1-4377-1604-7&uniqId=342003605-176#4-u1.0-B978-1-4377-1604-7..00162-7>

Killip, S., Bennett, J.M., & Chambers, M.D. (2007). Iron Deficiency Anemia. American Family Physician, 75(5), 671-678. Retrieved from <http://www.mdconsult.com/das/article/body/341864719-6/jorg=journal&source=&sp=17805459&sid=0/N/575023/1.html?issn=0002-838X>

Naqvi, B.H., & Ferri, F.F.(2012). Anemia, Iron Deficiency. In F. F. Ferri, Ferri’s Clinical Advisor 2013, 1^st ed. Philadelphia: Mosby, An Imprint of Elsevier. Retrieved from <http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-0-323-08373-7..00010-8--sc29015&isbn=978-0-323-08373-7&uniqId=341864719-6#4-u1.0-B978-0-323-08373-7..00010-8--s29500>

The following figures were adapted from the following websites:

Figure 1: <http://manyp.com/profile/rbc-wbc.html>
Figure 2: <http://www.med-ed.virginia.edu/courses/path/innes/rcd/iron.cfm>
Figure 3: <http://www.cdc.gov/ncbddd/hemochromatosis/training/pathophysiology/iron_cycle_popup.htm>