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19
Том 20. N 3-4 2016 р.
КЛ1Н1ЧНА МЕДИЦИНА
© Nedoborenko V.M., Kaidashev I.P. UDK 616.155.194.8-056.52
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THE PATHOGENESIS OF IRON DEFICIENCY ANEMIA IN OBESITY*
Nedoborenko V.M., Kaidashev I.P.
Higher State Educational Establishment of Ukraine "Ukrainian Medical Stomatological Academy"
Зал1зодефцитна анем1я та ожирння стали глобальними проблемами, як стосуються не тльки кран з високим piB-нем якост.i життя, але й кран, що розвиваються. Експериментальн'1 та клнмн1 дослдження вказують на те, що сс-нуе взаемозв'язок мж метабол1змом мкроелемента зал1за та надм1рним накопиченням бло.ï жировоï тканини. Ожир i ння пов'язане з низько нтенсивним хрон ¡чним запаленням та збльшеним р! внем концентраци гепсидину в кров1. Гепсидин е ключовим регулятором системного гомеостазу мкроелемента залза. У цьому огляд1 узагальнено сучасн i уявлення про зм ¡ни гомеостазу зал ¡за при ожир1нн1 та наведено припущення щодо л ¡кування.
Ключовi слова: ожирЫня, низько Ытенсивне хрошчне запалення, гепсидин, залiзодефiцитна анемля.
Introduction
Iron deficiency anemia and obesity are global health problems that occur in everyday activities of various medical practices. They affect not only medical aspects but also social - economic aspects and disrupt the quality of life of these patients.
Iron deficiency anemia is the leading cause of anemia and is found in more than 2 billion people around the world. This statistic was confirmed by analyzing a large number of reports from 187 countries from 1990 to 2010[1] and showed a decrease in quality of life, low productivity, difficulty concentrating, decreased cognitive functions, weakness and fatigue.
Obesity is a common metabolic disease and is characterized by excessive accumulation of white adipose tissue due to increased food intake and lifestyle changes.
[2] As of 2014 more than 1.9 billion people aged 18 and older are overweight and 600 million are clinically obese;
[3] this puts them at risk of many diseases including metabolic syndrome, diabetes, cardiovascular disease and cancer.
There is a standing close relationship between the metabolism of iron and obesity due to immunological abnormalities in molecular - biological level.
Unfortunately, there are still unanswered questions about the prognosis and treatment of obesity in combination with iron deficiency anemia and the effects on the common pathogenetic links of these diseases.
Hypotheses of hypoferremia in obesity
Wenzel et al (1962) first reported on the link between the iron metabolism and obesity. They found lower concentrations of iron in the blood serum in adolescents with
obesity compared to individuals who had normal weight. These findings were confirmed by subsequent studies.
In recent decades, formed three main hypotheses of hypoferremia obesity have been suggested:
- Nutritional hypothesis, which establishes iron deficiency as comorbidity obesity in different age groups, irrespective of its consumption.^
- The blood volume hypothesis to increase blood volume in patients with obesity due to weight gain, which was confirmed only in experiments. [5]
- The inflammatory hypothesis [6] is based on the participation of systemic inflammation in violation disruption of the iron metabolism in obesity. This hypothesis is the most reasonable and is logically combined with previous research on low-grade systemic inflammation as a new model of the pathological process.
Revealing the essence of this hypothesis is in the should pay attention to two key components: low-grade systemic inflammation and dysregulation of iron metabolism involving hepcidin - a peptide hormone that is the primary regulator of systemic iron metabolism protein, mediated immune defense and inflammation. [7]
One of the definitions of "inflammation" is a series of cellular and humoral responses aimed at protecting the body from various injuries, including infection and eventually leads to the restoration of functional and morphological integrity of the affected tissue; [8] it is generally characterized by increased local and systemic cytokine levels, with increasing numbers of immune cells (primarily neutrophils) that enter the site of inflammation, dominating mainly in the acute phases and macrophages in more chronic conditions. [9] Chronic systemic inflammation is characterized by increased cytokines by 3-5 times, but remains consistently high. [10]
* To cite this English version: Nedoborenko V.M., Kaidashev I.P. The Pathogenesis of Iron Deficiency Anemia in Obesity // Problemy ekologii ta medytsyny. 2016. - Vol 20, № 3-4. - P. 13-15.
TOM 20. N 3-4 2016 P.
Low-grade systemic inflammation transforms abnormal external and internal stimuli to disrupt intracellular metabolism; this leads to chronic internal diseases. The effect of it in the hyperactivation of the immune system is caused by the disruption of the normal human biology. [11]
Although, in many ways, obesity resembles the immune inflammation in its classical form, the difference is that this low intensity inflammation produces lower levels of circulating cytokines, such as C-reactive protein (CRP) and interleukin -6 (IL-6), and absent of clinical signs of inflammation. [12] In addition, it is believed that this chronic inflammation requires a relatively longer period of treatment (> 8 weeks in animal models) before there are noticeable changes in adipose tissue. [13]
A potential basis for the initiation of inflammation in obesity is endoplasmic reticulum (ER) stress, mainly in the liver and adipose tissue due to excess lipid accumulation and a disturbed energy metabolism. ER stress activates a stress response signaling network - "unfolded protein response" (UPR) that drives protective but also apoptotic and, particularly, inflammatory reactions. During ER stress, activated transmembrane protein, including protein kinase/endoribonuclease IRE1, which induces inflammatory signaling cascade by activating IKK, MAPKs p38 and JNK, and finally the main inflammatory transcription factor NF-KB, [14] which is a central integrator of pro-inflammatory signals and the main regulator of genes involved in inflammation, innate and adaptive immunity and apoptosis. [15]
Adipose tissue is infiltrated many immune cells, especially macrophages, which make up 40% of the fat cells, [13] which is a major source of inflammatory mediators in adipose tissue of mice and humans. Inflammatory cytokines affect intracellular pathways that regulate inflammation by activating nuclear transcription factors.
Hepcidin as the second part of the hypothesis was found by Krause et al (2000-2001) by ultrafiltration of
blood. This peptide is composed of 25 amino acids with antimicrobial activity was called LEAP-1 (antimicrobial peptide - 1 expressed by the liver). In the same period, Pigeon et al. (2001) identified the gene (HAMP), which regulates the metabolism of iron and encodes for the LEAP-1 high expression from the liver, and significantly lower expression in the kidney, adipose tissue, heart, brain, calling it hepcidin (hep - liver and cidin - bactericidal protein). [16]
The action of hepcidin on cellular iron homeostasis is detected by binding to the only known exporter of iron, protein ferroportin that leads to its internalization and degradation. [17] As a result of this interaction, the absorption of iron from food is reduced due to reduction hepcidin - mediated expression ferroportin enterocytes, which leads to lower circulating levels of iron, with it increases the inhibition of macrophage iron export by the same mechanism. [18]
This regulatory peptide can be synthesized in response to inflammatory stimuli in quantitative terms the liver to a lesser extent, other tissues and cells, heart, kidney, adipose tissue, spinal cord, myeloid cells, alveolar macrophages and monocytes. [19]
Bekri et al (2006) provided the assumptions that hepcidin is synthesised not only in the liver but also in adipose tissue. This research demonstrated the increased content of mRNA hepcidin in the adipose tissue of patients suffering from obesity. The level of mRNA positively correlated with markers of inflammation (IL-6, CRP) and body mass index. In contrast, HAMP expression in the liver was not related to CRP; however, liver HAMP was positively correlated with serum transferrin saturation. Also, results showed that in obese patients, 68% had a low ratio of transferrin saturation and 24% had anemia. [20]
J - Ferroportin
- Hemojuvelin Y - Transferrin
Figure 1. The pathogenesis of hypoferremia in obesity
In this regard, it is believed that adipose tissue can make a significant contribution to circulating levels of hepcidin. This assumption is confirmed by the presence of a significant direct relationship between the level of hepcidin and the degree of obesity. [21]
In recent years, studies have shown a link between hepcidin, chronic inflammation and a low concentration of iron in patients with obesity, with the possible emergence of hypoferremia determination mechanism. But despite
npoSAeMH eKOAoriï Ta MeanuHHH
the large number of studies clearly defined impact adipose tissue on levels hepcidin not fully understood.
There are assumptions that in obesity chronic inflammation leads to real iron deficiency as a result of long-term decreased iron absorption and unregulated iron loss. [22] The qualifiers for iron deficiency in obese individuals may therefore be similar to those seen in anemia of chronic disease coexisting with real iron deficiency. However, this definition of iron deficiency has not always been the case in studies measuring iron status in obese populations, and further research is needed.
Conclusions
Thus, the traditional treatment of iron deficiency anemia, which consists of adding foods with increased iron content, and giving iron supplementation, cannot be fully effective for obesity because it changes the absorption of iron and its metabolism associated with low-grade systemic inflammation.
The complex treatment of iron deficiency anemia is significantly associated with inflammation and requires pharmacological modulation of inflammatory activity aimed at the central molecular basis of systemic inflammation, such as cascade reactions associated with NF-kb.
References
1. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24.
2. Kopelman PG. Obesity as a medical problem. Nature (2000) 404:635-43.
3. http://www.who.int/mediacentre/factsheets/fs311/en/
4. Dao MC, Meydani SN (2013) Iron biology, immunology, aging, and obesity: four fields connected by the small peptide hormone hepcidin. Adv Nutr 4:602-617
5. Bertinato J, Aroche C, Plouffe LJ, Lee M, Murtaza Z, Kenney L, Lavergne C, Aziz A. Diet-induced obese rats have higher iron requirements and are more vulnerable to iron deficiency. Eur J Nutr., 2013. 6.
6. Dvoretsky L.I., Ivleva L.I., Obesity and iron deficiency. One more comorbidity? Archive of internal medicine. 2015; (5):9-16. (In Russ.)
7. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102(3):783-8.
8. Cildir G, Akincilar SC & Tergaonkar V 2013 Chronic adipose tissue inflammation: all immune cells on the stage. Trends in Molecular Medicine 19 487-500.
9. Mraz M, Haluzik M (2014) The role of adipose tissue immune cells in obesity and low-grade inflammation. J Endocrinol 222: R113-127
10. Herder C., Schneitler S., Rathmann W. et al.(2007) Low-grade inflammation, obesity, and insulin resistance in adolescents. J. Clin. Endocrinol. Metab., 92(12): 4569-4574.
11. Rasin M.S., Kajdashev I.P. (2014) The role of nuclear transcription factors in modern syntropy internal pathology (review). Ukrainian Medical Journal., № 1 (99) - I/II: 17-21
12. Medzhitov R 2008 Origin and physiological roles of inflammation. Nature 454 428-435.
13. Lee, B.-C., & Lee, J. (2014). Cellular and Molecular Players in Adipose Tissue Inflammation in the Development of Obesity-induced Insulin Resistance. Bio-chimica et Biophysica Acta, 1842(3), 446-462.
14. Zeyda M, Stulnig TM. Obesity, inflammation and insulin resistance-a mini-review. Gerontology 2009; 55:379386.
15. J. Lee. Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and Type 2 Diabetes Arch. Pharmacal Res., 36
(2013), pp. 208-222
16. Poli M, Asperti M, Ruzzenenti P, Regoni M, Arosio P
(2014) Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front Pharmacol 5(86):1-13
17. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-3
18. Nairz M, Haschka D, Demetz E, et al Iron at the interface of immunity and infection. Front Pharmacol 2014;5:152
19. Collins JF, Wessling-Resnick M, Knutson MD. Hepcidin regulation of iron transport. J Nutr. 2008 Nov;138(11):2284-8.
20. Bekri S., Gual P., Anty R., Luciani N., Dahman M., Ramesh B.,Iannelli A., Staccini-Myx A., Casanova D., Ben Amor I. et al.(2006) Increased adipose tissue expression of hepcidin insevere obesity is independent from diabetes and NASH. Gastroenterology 131: 788796.
21. Nikonorov A.A., Tinkov A.A., Popova E.V., Nemereshina O.N., Gatiatulina E.R., Skalnaya M.G., Skalny A.V. (2015) Iron in obesity: a victim or suspect. Trece elements in medicine (Moscow)., 16(2): 3-9
22. Tussing-Humphreys L, Pusatcioglu C, Nemeth E, Braunschweig C. Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin. J Acad Nutr Diet. 2012;112:391-400
Summary
Iron deficiency anemia and obesity have become a global problem affecting not only high income countries but also developing countries. Experimental and clinical studies indicate that there is a relationship between iron metabolism and weight status. Obesity is associated with low-grade systemic inflammation and elevated hepcidin concentrations. Hepcidin is the key regulator of systemic iron homeostasis. This review summarizes the current understanding of the dys-reguiation of iron homeostasis in obesity and leads assumptions about treatment.
Key Words: obesity, low-grade systemic inflammation, hepcidin, iron deficiency anemia
MaTepian HaaminoB go peaawi'i 15.11.2016
