metabolism conditions, there exists an overlap between nutritional anemias and those from organic and metabolic causes. (Fig. 1 & 2)


Anemia of Chronic Disease (ACD) presents as iron anemia combined with iron overload, with or without evidence of genetic hereditary forms of hemochromatosis. It’s observed to be a multi-factorial consequence of adaptive responses; some of which may be necessary and benecial.14


cause, but a symptom of the same metabolic conditions that inuence the overall regulation of inammation and biochemical events discussed here.13


(Fig. 1, 2, 3)


can be categorized into disorders that manifest as a consequence of cellular, tissue, or eventual organ hypoxia, and the adaptive burdens involved to promote molecular pump activity and mitochondrial energy production. At the cellular level, the mitochondria involved in cytochrome activity, ATP production, and electron transport become diminished in numbers and function.2


categorized into disorders that involve oxidative damage to cells, tissues, organs and consequences that result where one condition promotes the other.14


balance of homeostasis between the micronutrients zinc, copper and iron (also divalent) with respect to cellular and molecular physiology and in gene interactions that they are involved in as cofactors.4,10


Conditions involving CKD, xenobiotic exposures that impair iron metabolism, inammatory conditions that promote unregulated chronic cytokine activation or auto-


THE ORIGINAL INTERNIST MARCH 2017


Iron, a divalent cation, is involved in multiple enzyme and protein reactions in physiological functions, and is a highly oxidative and reactive micronutrient. Most notably, it is involved in transporting oxygen from blood to tissues, production of energy, DNA synthesis, and integrity of the activities of proteins that carry, transport, and store iron. It is also necessary for the function of peroxidase and cytochrome function.2


There is a narrow The latter can be


The result of the presence of these two conditions involves a paradoxical combination of iron anemia and of iron overload. The former involves impaired processes of erythropoiesis that would eventually lead to the many variations of cellular, tissue and organ system impairment once homeostatic adaptive systems have failed.13,14


These However, it is likely that it is not the


hemochromatosis condition may be stable depending on the health of the individual and adaptive capacity, or unstable and clinically evident in an individual with co- morbidities discussed in this paper. Also, the zygosity and genetic penetrance of the hereditary disorder would have an inuence on how and how much it would be expressed.6 In iron overload conditions and hemochromatosis, the iron that is not actively bioavailable becomes highly oxidative and reactive material in both its stored capacity and in its circulating state.1,2


Within the context of paradoxical iron


and HH Type 4 impairs ferroportin’s transmembrane transport role in exporting iron from cells (Ferroportin disease) in a copper-dependent coupling with hephaestin or ceruloplasmin to oxidize the iron. Type 4 HH is the next most prevalent, secondary to Type 1.1, 2


A hereditary


immunity, hepatic diseases that impair iron transport and transmembrane binding, synergistic micronutrient deciencies such as copper, excessive micronutrient competition, and dietary iron-binding interruptors ex- plain this paradoxical phenomenon. Certain immune challenges, such as bacterial, viral, fungal, and parasitic infections may also disrupt iron utilization, both as a direct effect of the pathogen’s afnity to the iron and as a consequence of the immune regulatory changes. There are also genetic variants that, individually or combined with a genetic homozygous or heterozygous hemochromatosis, can disrupt iron metabolism. The common denominator in the development of the paradoxical disorder, in the absence of nutritional deciencies, bleeding, or absolute genetic disorders, is that of liver dysfunction. Hepatic protein-binding, transport mechanisms are entirely de- pendent on the integrity of hepatic function.


It is believed that the loss of integrity of the regulation of EPO (erythropoietin) is a major “cause” of ACD in aging.19


CKD, or Chronic Kidney Disease involves impairment of erythropoietin and renal tubular dysfunction to regulate mineral balance. According to 2016 statistics from the National Institute of Diabetes and Digestive and Kidney Diseases, 14% of the general population have CKD in at least one of the ve CKD stages. The prevalence of CKD in the U.S. ranges from 1.5% to 15.6%, depending on co-morbidities and lifestyle factors.19


not usually exist in isolation and is a condition of multiple comorbidities, particularly in the context of chronic metabolic conditions and polypharmacy.18


of superimposed hereditary or genetic channelopathy variants, such as HPP (hyperkalemic periodic paralysis) where decient potassium channels are dysfunctional and potassium levels rise. These types of disorders tend to be progressive and may not be clinically evident or discovered until the “perfect storm” of inammatory events de-compensates the regulatory systems that would normally be adapting to such a variant.7,14


The paradoxical syndromes of anemia and iron overload are attributed to hepatic dysfunction, as the integrity of the formation and function of the transport and binding proteins involved in metabolism and utilization of iron depend on hepatic integrity. The inherent adaptive homeostatic feedback responses contribute signicantly to the paradoxical relationships between anemia and overload.14


Clinically, routine laboratory testing on a CBC/ differential might reveal shifts in one or a combination


29


of markers indicating iron anemia, such as low Hgb, low (Continued on next page)


In cases


chronic disease is typically as a consequence of an inammatory condition, an autoimmune or neoplastic condition, prolonged illness, trauma, chronic infection involving parasitic, fungal, bacterial, or viral loads, and, in the elderly or ill, polypharmacy. ACD may be the eventual manifestation of chronic impaired absorption of iron in the digestive tract (due to the above causes) and stored iron release and transport (molecular binding and transport functions) becomes impaired or inhibited by the exposure to chronic inammatory events. Inammation up-regulates Hepcidin, the primary hepatic iron absorp- tion regulating protein, which inhibits the activity of Ferroportin at the intestinal basolateral cell membrane to transport iron out of storage for utilization.1,2


CKD does Anemia of


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52