Accepted Manuscript

Title: Diabetes and Anemia: International Diabetes Federation

(IDF) – Southeast Asian Region (SEAR) position statement

Authors: Manisha Sahay, Sanjay Kalra, Rajesh Badani,

Ganapathi Bantwal, Anil Bhoraskar, A.K. Das, Bharati
Dhorepatil, Sujoy Ghosh, Tarun Jeloka, Deepak Khandelwal,
Zafar Ahmed Latif, Milind Nadkar, Md. Faruque Pathan,
Banshi Saboo, Rakesh Sahay, Suleiman Shimjee, Dina
Shrestha, Ali Siyan, Shamim Hayder Talukdar, Mangesh
Tiwaskar, A.G. Unnikrishnan

PII: S1871-4021(17)30116-9
DOI: http://dx.doi.org/doi:10.1016/j.dsx.2017.04.026
Reference: DSX 780

To appear in: Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Please cite this article as: Sahay Manisha, Kalra Sanjay, Badani Rajesh, Bantwal
Ganapathi, Bhoraskar Anil, Das AK, Dhorepatil Bharati, Ghosh Sujoy, Jeloka
Tarun, Khandelwal Deepak, Latif Zafar Ahmed, Nadkar Milind, Pathan Md
Faruque, Saboo Banshi, Sahay Rakesh, Shimjee Suleiman, Shrestha Dina, Siyan
Ali, Talukdar Shamim Hayder, Tiwaskar Mangesh, Unnikrishnan A.G.Diabetes and
Anemia: International Diabetes Federation (IDF) – Southeast Asian Region (SEAR)
position statement.Diabetes and Metabolic Syndrome: Clinical Research and Reviews
http://dx.doi.org/10.1016/j.dsx.2017.04.026

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 Diabetes and Anemia: International Diabetes Federation (IDF) - Southeast Asian Region

(SEAR) position statement

Manisha Sahay1, Sanjay Kalra2*, Rajesh Badani3, Ganapathi Bantwal4, Anil Bhoraskar5, A. K.

Das6, Bharati Dhorepatil7, Sujoy Ghosh8, Tarun Jeloka9, Deepak Khandelwal10, Zafar Ahmed

Latif11, Milind Nadkar12, Md. Faruque Pathan11, Banshi Saboo13, Rakesh Sahay1, Suleiman

Shimjee14, Dina Shrestha15, Ali Siyan16, Shamim Hayder Talukdar17, Mangesh Tiwaskar18, A. G.

Unnikrishnan19

1
Osmania Medical college, Hyderabad, India; 2Bharti Research Institute of Diabetes &

Endocrinology (BRIDE), Karnal, Haryana, India; 3Aditya Birla Memorial Hospital, Pune, India; 4

St Johns Medical College & Hospital, Bengaluru; 5Asian Heart Institute, Mumbai, Maharashtra,

India; 6Pondicherry Institute of Medical Sciences, Puducherry; 7Shree Hospital, Pune, India;
8
IGPGMER, Kolkata, India; 9Aditya Birla Memorial Hospital, Pune, India; 10Maharaja Agrasen

Hospital, Punjabi Bagh, Delhi; 11BIRDEM Academy, Dhaka, Bangladesh; 12Seth G.S. Medical

College & KEM Hospital, Mumbai, India; 13Dia Care - Diabetes Care and Hormone Clinic,

Ambawadi, Ahmedabad, India; 14Apollo Bramwell Hospital, Port Louis, Mauritius; 15Norwic

International Hospital, Kathmandu, Nepal; 16Maldivian Diabetes Society , Male, Maldives;

17
Eminence, Dhaka, Bangladesh; 18Asian Heart Institute & Research Centre, Mumbai, India;
19
Chellaram Diabetes Institute, Pune, India.

1
*Corresponding author:

Dr. Sanjay Kalra,

Bharti Research Institute of Diabetes & Endocrinology (BRIDE),

Kunjpura Road, Karnal,

Haryana, India.

E-mail: brideknl@gmail.com

Article type: Review

Short title: Diabetes and Anemia – Position Statement Article

2
Abstract

Anemia is often associated with diabetes mellitus and is known to intensify the risk of

developing diabetes-related microvascular and macrovascular complications. There is paucity in

understanding of co-existence of these conditions, especially in Southeast Asian countries. Iron

and/or erythropoietin deficiencies are the major causes of anemia in diabetes, and diabetic

kidney disease plays a key role. Patients with diabetes need to be screened for anemia along

with other risk factors and anemia should be corrected appropriately to improve overall clinical

outcomes. This position statement aims to provide a comprehensive overview and an algorithm

for appropriate management of anemia in patients with diabetes.

Key words (4): Anemia; diabetes mellitus; erythropoietin; iron.

3
Introduction

The co-existence of anemia and diabetes is being increasingly explored as it has a major impact

on the overall health status of the patients (1-3). The prevalence of concurrent anemia and

diabetes mellitus (both type 1 and type 2) ranges from 14% to 45% in different ethnic

populations worldwide (4-7). Although anemia and diabetes mellitus are increasingly recognized

as a major health conditions,(8-10) little is known about the co-existence of these conditions in

south-east Asian countries like India, Sri Lanka, Bangladesh, Nepal, Mauritius and Maldives. In

India, the prevalence of anemia in patients with diabetes was estimated to be approximately

18% (11, 12) .

The risk of anemia in patients with diabetes is estimated to be two- to three-times higher than

that of patients without diabetes (5, 13). Early evidences indicate that the incidence of anemia in

patients with diabetes mellitus is typically associated with presence of kidney disease (13, 14).

The risk of developing anemia in patients with diabetes mellitus associated with kidney disease

is greater than in those patients having kidney disease of other causes (14). Nonetheless, the

early occurrence of anemia in patients without kidney disease suggests existence of some other

causes of anemia in these patients (5). Patients with poor glycemic control are at a higher risk of

developing anemia than patients having good glycemic control; and the risk further increases

with onset of kidney disease (15).

Chronic anemia in diabetes mellitus predicts the progression of macrovascular complications

such as cardiovascular disease and stroke as well as microvascular complications such as

nephropathy and retinopathy (16). Indeed, the constellation of these modifiable risk factors is

often overlooked and if untreated, it is associated with poor outcomes, including impaired quality

of life, increased hospitalization and all-cause mortality (3, 17). Therefore, appropriate

screening, prompt detection and correction of anemia are crucial to improve the clinical

4
outcomes in patients with diabetes mellitus. The purpose of this International Diabetes

Federation (IDF) - Southeast Asian Region (SEAR) position statement is to provide a

comprehensive overview and evidence-based recommendations for the management of anemia

in patients with diabetes mellitus.

Pathophysiology of anemia in diabetes: Multifactorial mechanism

The etiology and pathophysiology of anemia in both type 1 and type 2 diabetes mellitus is

considered to be multifactorial.

Type 1 diabetes mellitus

Anemia in type 1 diabetes mellitus is mostly attributable to autoimmune causes, mainly

autoimmune gastritis and pernicious anemia. Patients having autoimmune gastritis are

frequently diagnosed with iron deficiency anemia that may precede pernicious anemia; or both

conditions may coexist occasionally. Iron deficiency anemia is observed in 20–40% of patients

with autoimmune gastritis; while pernicious anemia can be identified in up to 15–25% of patients

(18). Decreased gastric acidity or hypo/achlorhydria in autoimmune gastritis, due to destruction

of H+/K+ATPase-containing parietal cells, reduce the availability of iron for absorption and may

lead to iron deficiency anemia (18). Pernicious anemia, which is considered as an end stage of

autoimmune gastritis, is a consequence of altered absorption of vitamin B12. The progressive

loss of parietal cells in autoimmune gastritis leads to failure of intrinsic factor production and

prevention of vitamin B12-intrinsic factor complex formation, resulting in malabsorption of

vitamin B12 (18).

5
Type 1 diabetes is also associated with malabsorption disorder such as celiac disease – a

chronic immune-mediated enteropathy, triggered in genetically susceptible patients due to

intake of gluten protein. Iron deficiency anemia is frequently reported in this condition due to

impaired absorption of iron and vitamin B12, which is caused by villous atrophy in intestinal

mucosa. Another common cause of anemia in type 1 diabetes patients is hypothyroidism – with

an estimated prevalence of 20-30% in such patients. The most frequent type of anemia reported

in hypothyroidism is normochromic normocytic followed by microcytic hypochromic or

macrocytic. In hypothyroid state, there is a reduced synthesis of erythropoietin due to reduction

in the need of oxygen, which may subsequently lead to bone marrow repression. Although,

erythrocyte life cycle is normal in hypothyroidism, hypoproliferative erythropoiesis leads to

normochromic normocytic anemia.

Type 2 diabetes mellitus

There are several mechanism explained regarding the development of anemia in patients

having type 2 diabetes mellitus (Fig. 1). Iron and erythropoietin deficiency, and

hyporesponsiveness to erythropoietin are plausible causes of anemia in diabetes patients

having kidney disease or even with relatively normal glomerular filtration rates (19, 20). The

production of erythropoietin is modulated by sympathetic nervous system. Thus, in patients with

diabetes, sympathetic denervation of kidney due to autonomic neuropathy might create a

hypoxic environment in the renal interstitium causing impaired production of erythropoietin by

the peritubular fibroblasts (19). Chronic hyperglycemia could also potentially lead to increased

apoptosis of renal tubular cells and tubular ischemia (20). In addition, hyperglycemia worsens

the function of hypoxia-inducible factor 1 (HIF-1), resulting in interstitial fibrosis as well as

disruption of interstitial and vascular architecture, which ultimately impairs erythropoietin

6
synthesis (21). Several other factors contributing to the chronic hypoxic environment that

promotes erythropoietin stress include: diabetic nephropathy, chronic inflammation, abnormal

red blood cells (RBCs), increased levels of advanced glycation end products, nutritional

deficiency of iron, folate and vitamin B12 and low testosterone levels (20).

Decreased erythropoietin response in diabetes mellitus is also attributed due to increased

glycosylation, low levels of erythropoietin, reduced functional erythropoietin; and erythropoietin

resistance due to glycation of erythropoietin receptors (20, 22, 23). Chronic inflammatory state

in diabetes mellitus is characterized by increased circulating concentrations of proinflammatory

cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF-α), transforming growth

factor (TGF-β) and interferons (IFNs). These inflammatory cytokines are thought to be involved

in apoptosis of erythroid progenitor cells. Additionally, chronic hyperglycemia and advanced

glycation end products potentiating oxidative stress by increasing the production of free oxygen

radicals, which cause impaired deformability and reduced lifespan of RBCs leading to a

reduction in circulating haemoglobin (20, 22).

Nonetheless, hyporeninemia and urinary loss of erythropoietin have also been hypothesized as

possible mechanisms involved in anemia in diabetes mellitus. Recently, dipeptylpeptidase-4

(DPP-4) has also been found to play an important role in hematopoiesis, by affecting

hematopoietic stem cells and hematopoietic progenitor cells (24). It has been hypothesized that

in presence of a disease state or altered physiological homeostasis, modification in the

regulatory proteins by DPP-4 may alter the process of hematopoiesis at various levels (24, 25).

In patients with diabetic kidney disease, there is a decrease in erythropoietin production from

the peritubular fibroblasts. Additionally, in these patients iron deficiency anemia may result from

(1) reduced dietary iron intake due to diet restriction, (2) impaired dietary iron absorption and (3)

increased blood loss due to hemodialysis procedure, uremia or ulcer related gastrointestinal

7
bleeding (26). Impaired iron absorption is probably a consequence of increased levels of

hepcidin, a negative regulator of iron absorption and medications like proton pump inhibitors

and phosphate binders.

Treatments leading to anemia

Medications

Patients with diabetes mellitus are treated with antihyperglycemic agents (AHAs) along with

multiple medications for accompanying comorbid conditions. Metformin, often used as a first line

treatment for diabetes mellitus, has been potentially associated with vitamin B12 deficiency due

to malabsorption of vitamin B12, contributing to megaloblastic anemia (27). Reduction in

absorption of vitamin B12 may typically begin as early as four months after initiation of the drug;

however the clinical features may manifest after 5-10 years due to vitamin B12 stores in the liver

(28, 29). Evidence has shown that approximately 10%–30% of patients on long-term metformin

therapy tend to experience vitamin B12 malabsorption (30). Increasing age, dose and duration

of metformin influences the risk of developing vitamin B12 deficiency (27, 31). Patients using

metformin for ≥3 years are at nearly double the risk of developing vitamin B12 deficiency than

those patients receiving metformin for ≤3 years (27). Use of thiazolidinediones may also induce

anemia, probably because of expansion of body fluid volume and impaired hematopoiesis due

to fat accumulation in bone marrow.(32) Reduction in hemoglobin levels (to ~10 g/L) and fall in

hematocrit levels (up to 3.3%) have been reported with use of pioglitazone in clinical studies

(33, 34). Treatment with antihypertensive medications such as angiotensin converting enzyme

(ACE) inhibitors or angiotensin receptor blockers (ARB) are also known to be associated with

anemia development (35, 36). Angiotensin II is a key regulator of erythropoiesis and also an

8
important factor for growth of erythroid precursors. The use of ACE inhibits or ARB influences

the erythropoietin action of angiotensin and contributes to the development of anemia (37).

On the contrary, AHAs like DPP-4 inhibitors and sodium glucose co-transporter type 2 (SGLT2)

inhibitors have shown favorable outcomes in patients with anemia (38-40). The DPP4 inhibitors

may improve the erythropoietin production by inhibiting the altered action of DPP4 enzyme on

certain interleukins, chemokines and erythropoietin. Recently, DPP-4 inhibitors have shown to

reduce the erythropoietin stimulating agents (ESA) dose requirement in patients with diabetes

undergoing hemodialysis (39). The SGLT2 inhibitors have also shown to improve erythropoietin

level through its renoprotective action by inhibiting tubulointerstitial hypoxia and oxidative stress

and it is associated with improvement in the hematocrit and hemoglobin levels (38).

Bariatric Surgery

Bariatric surgery is generally indicated in patients with BMI ≥40 kg/m2 or ≥35 kg/m2 with obesity-

related metabolic complications (41). The most commonly performed procedures are Roux-en Y

gastric bypass, biliopancreatic diversion with or without duodenal switch, adjustable gastric

banding and sleeve gastrectomy (42). These procedures may often result in reduced absorption

of micronutrients, intestinal bleeding due to ulcers or reduced gastric acid secretion that may

lead to iron deficiency and iron deficiency anemia (43). The incidence of iron deficiency in

patients undergoing these procedures ranges from 12% to 47% (44). Studies have also shown

that these patients prior to the surgery are at higher risk of iron deficiency and it can further

intensify the risk of complications (45).

9
Iron overload and risk of diabetes mellitus

Iron overload status or hemochromatosis can be distinguished as primary or secondary. The

primary form of hemochromatosis (also known as hereditary hemochromatosis) is a genetic

condition characterized by iron deposition in the parenchymal cells. It usually results from

mutations in the genes encoding proteins that are involved in iron homeostasis. Secondary

hemochromatosis occurs in conditions where excess iron is secondary to other disease states

(eg. multiple transfusions in β thalassemia major) and iron is primarily deposited in the reticulo

endothelial system. Other causes of secondary hemochromatosis include, but are not limited to,

dysmetabolic iron overload syndrome (DIOS), hepatitis C infection, porphyria cutanea tarda and

increased iron intake (Table 1). Evidence of systemic iron overload contributing to abnormal

glucose metabolism was first identified based on increased frequency of diabetes mellitus

observed in patients with classic hereditary hemochromatosis or β thalassemia major (46).

However, from the recent evidences, it is confirmed that iron overload, irrespective of the cause

or the genetic factor involved, is correlated with an increased incidence of type 2 diabetes

mellitus. Recently, increased dietary intake of iron, particularly consumption of red meat and

resultant increase in body iron stores is found to be associated with development of diabetes

mellitus. The possible mechanisms involved in the iron-induced diabetes are (1) decrease in

insulin secretion due to oxidative stress mediated apoptosis of pancreatic islets and (2) insulin

resistance with or without involvement of hepatic dysfunction (47).

Hereditary hemochromatosis

Hereditary hemochromatosis (type 1) predominantly occurs due to homozygous C282Y or

H63D mutation or compound heterozygous C282Y/H63D mutation in the HFE gene.(48-50)

Other causes of hemochromatosis are mutations in the hepcidin regulators hemojuvelin (HFE2;

10
type IIA hemochromatosis), hepcidin gene (HAMP; type IIB hemochromatosis), transferrin

receptor 2 (TFR2; type III hemochromatosis) or ferroportin 1 (SLC40A1; type IV

hemochromatosis) (51). All these mutations may lead to reduced production of hepcidin,

resulting in failure in regulation of iron entry into the circulation and which may culminate in

elevated iron stores (51). Patients with hereditary hemochromatosis, mostly C282Y

homozygote, are observed to have abnormally high levels of serum ferritin and transferrin

saturation (TSAT) (52). This genetic predisposition to iron overload, if left untreated, may further

lead to several complications such as diabetes mellitus, hepatic cirrhosis, cardiovascular

disease or heart failure, arthritis and hypogonadism (53).

In hereditary hemochromatosis, up to 60% of patients develop diabetes mellitus due to

increased iron levels (47, 54). The main cause of diabetes mellitus in these patients is insulin

deficiency, resulting from damage of insulin-secreting β cells due to iron accumulation, followed

by insulin resistance, occurring either directly or mediated by hepatic dysfunction (47). Several

studies have shown a positive correlation between elevated levels of ferritin and risk of

developing diabetes mellitus (55-57). In a prospective study, serum ferritin and transferrin

saturation were associated with the onset of abnormalities in glucose metabolism, which

suggests the causative role of dysregulated iron metabolism in the onset of insulin resistance in

type 2 diabetes (57).

β thalassemia

The hereditary hemolytic anemia (β thalassemia) characterized by reduced production of β

globin subunit of hemoglobin often necessitates multiple blood transfusions in the patients in

order to maintain adequate erythrocyte levels (46). Owing to repeated transfusion and increased

iron absorption, β thalassemia patients often become iron overloaded and may eventually

11
develop diabetes mellitus (47). The prevalence of diabetes mellitus in these patients is

estimated to range from 6%–14% (58). In transfusion overload, insulin resistance appears to

occur first, followed by insulin deficiency, which is contrary to pathogenesis of diabetes in

hereditary hemochromatosis (51, 59). This can be probably explained by the excess iron

accumulation in conditions of low hepcidin (in hereditary hemochromatosis) versus high

hepcidin in β thalassemia patients with iron overload (46).

Dysmetabolic iron overload syndrome

Dysmetabolic iron overload syndrome (DIOS) is a specific form of iron loading disorder, unlike

classic hemochromatosis, and it is mainly characterized by hyperferritinemia and normal

transferrin saturation (60). This condition is commonly associated with insulin-resistant

conditions such as metabolic syndrome or non-alcoholic fatty liver disease (NAFLD), affecting

approximately up to one-third of patients (61, 62). The exact mechanism of iron overload in

DIOS is still unclear; however, it is postulated that in the liver, the iron is mainly accumulated in

Kupffer cells because of impaired iron export resulting from downregulation of liver iron exporter

ferroportin-1. This downregulation occurs as a result of systemic and hepatic inflammation.

Besides that, low copper bioavailability further impairs the iron mobilization from liver. As a

result, hepcidin production in liver is increased, causing decreased absorption of iron from the

duodenum. High levels of urinary, serum and liver hepcidin were observed in patients with DIOS

than control or patients with hemochromatosis (63, 64). In this condition, although there is an

elevated hepcidin concentration, it is relatively low for the amount of iron overload, indicating the

ineffective response of hepcidin (65). Additionally, hepcidin, proinflammatory cytokines (TNF-α)

and adipokines (leptin and resistin) produced from adipose tissue were found to influence iron

homeostasis in the liver and also dysregulate glucose and lipid metabolism.

12
Anemia and Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is known to affect up to 28% pregnant women worldwide

(66) and the rates across several states in India range from 3.8% to 17.8%.(67) The potential

risks associated with GDM include fetal loss, preeclampsia and other obstetric complications,

increased long-term risks of type 2 diabetes mellitus and cardiovascular diseases and an

impending adverse metabolic impact on the offspring (68). The commonly recognized

determinants of GDM include obesity, excessive pregnancy weight gain, familial history of

diabetes, age at pregnancy >25 years, co-existence of essential hypertension or polycystic

ovarian syndrome (69, 70). Currently, iron disorder is also considered to be one of the

determinants of GDM. Although several studies report associations between abnormal

hemoglobin levels and adverse outcomes in pregnancy, fewer studies have explored

associations between anemia and GDM. In a retrospective case control study, it was observed

that pregnant women with iron deficiency anemia had reduced likelihood of developing GDM

(71). The study also suggested a significant inverse correlation between prevalence of GDM

and severity and duration of anemia.

The association of iron status and risk of GDM using biomarkers like serum iron, ferritin and

hepcidin was evaluated in various studies (72, 73). A high serum iron and ferritin was positively

correlated with higher risk of GDM; however the correlation for high serum iron was found to be

inconsistent (74-76). Serum hepcidin levels were found to be elevated in GDM patients. Further,

it was postulated that higher levels of hemoglobin, which can be linked with increased iron

intake during pregnancy, were positively related to the risk of GDM (73). Hemoglobin (>130 g/l)

in early pregnancy has been demonstrated to be an independent risk factor of GDM.(71)

Moreover, it has been found that for every 1 mg of heme iron, there is a 51% increase in

adjusted odds of gestational diabetes (77). High heme iron intake particularly in pregnant

women who are not anemic and have other underlying risk factors further increases the risk of

13
developing GDM. The excess iron in the placenta has been primarily associated with oxidative

stress during pregnancy. The role of increased oxidative stress and the property of excess iron

in generating reactive free radicals have been postulated to contribute to the risk of diabetes

mellitus during pregnancy. The high susceptibility of pancreatic β-cells to oxidative stress leads

to impaired insulin synthesis and secretion. In addition, excess iron disrupts insulin action and

causes increased lipolysis in adipose tissue, decreased glucose utilization in muscles and

increased gluconeogenesis in liver (78).

Anemia - role in complications of diabetes

Diabetic kidney disease

Diabetic nephropathy is a common consequence of type 2 diabetes mellitus and it is observed

in almost 5% of newly diagnosed diabetes patients (79). Further, within 10 years of diagnosis,

nearly 30% to 40% of patients may progress to diabetic nephropathy (79). In these patients,

anemia is a common manifestation and can be observed even before any demonstrable

changes in renal function (80, 81). The risk of anemia in patients with diabetes having kidney

disease is 2 to 10-fold greater than in patients without diabetes but with a similar degree of renal

dysfunction (13, 14). Anemia occurs at early stage in patients with diabetes and kidney disease

and it is usually more severe compared with non-diabetes patients with similar renal impairment

(19, 82). On the other hand, anemia may also contribute to the progression of kidney disease in

patients having diabetes; which can further aggravate anemia, completing the vicious cycle.

Although anemia per se is not known to result in microvascular damage or cause end-stage

renal disease; however, it may influence the pathways that may lead to the progression of

kidney damage in diabetes (80). Renal hypoxia, oxidative stress and functional erythropoietin

deficiency together may contribute to progressive renal damage in diabetic kidney disease (80).

14
Anemia may accelerate progression of kidney disease by increasing the glomerular pressure

and proteinuria due to increased renal sympathetic nerve activity (83). Further, the combination

of anemia, diabetes mellitus and chronic kidney disease (CKD) compounds the risk of

cardiovascular disease, stroke, increased hospitalization and mortality (84-86).

Retinopathy

Low levels of hemoglobin, hematocrit and RBC count increases the risk of diabetic retinopathy,

affecting almost 28% of patients.(87) A hemoglobin level of <12 g/dl doubles the risk of

developing retinopathy in patients with diabetes; and the risk multiplies with an increase in

severity of anemia, especially when the hemoglobin level is less than 6 g/dl (88). Patients with

diabetes having hemoglobin <12 g/dl also have a 5-fold increase in the risk of pre-proliferative

or proliferative retinopathy compared with those with normal hemoglobin levels (89). Retinal

hypoxia is the key component of diabetic retinopathy and it is linked to decreased blood

capillary blood flow or occlusion of retinal capillaries due to increased blood viscosity and

deformation of RBCs. It is hypothesized that retinal hypoxia, increases the production of

vascular endothelial growth factor (VEGF) and causes retinal neovascularization and

proliferation (80).

Cardiovascular diseases

Anemia is considered to be an independent risk factor for cardiovascular morbidity and mortality

(90). The prevalence of anemia among patients with diabetes having chronic kidney disease

and heart failure is 10-fold greater than in general population (91, 92). Left ventricular

hypertrophy and heart failure are commonly observed cardiac complications in patients with

anemia and diabetes and there are several mechanisms involved (93). Anemia causes

15
worsening of tissue hypoxia, increased blood viscosity and release of nitrous oxide, leading to

peripheral vasodilation and fall in blood pressure, which further causes activation of sympathetic

nervous system and reduced renal function. This in turn leads to activation of renin angiotensin

aldosterone system and vasopressin, causing increase in sodium/fluid retention, plasma volume

expansion and ultimately left ventricular hypertrophy and dilatation as well as stress on the

myocardium. Moreover, erythropoietin deficiency may cause defects in cardiac remodeling,

contributing to cardiac dysfunction (93, 94).

Diabetic foot ulcers

The prevalence of anemia in patients with diabetic foot ulcer ranges from 49% to 62% in

developing countries (95, 96). Anemia is frequently associated with lower extremity

amputations, increased hospitalization and mortality in patients with diabetic foot ulcers;

however, it is not fully understood whether anemia is an independent predictor of adverse

outcomes in this condition (96, 97). Reduced cutaneous oxygenation due to low hemoglobin

levels and reduced capillary blood flow has been suggested to aggravate lower limb ischemia.

Additionally, anemia may impair diabetic wound healing through reduced action of HIF, causing

decreased oxygen availability and impaired cellular metabolism (98). Furthermore, reduced

wound healing has been linked to increased blood viscosity and reduced peripheral perfusion

(95).

Anemia and tests for diagnosis and monitoring of diabetes

The glycated hemoglobin (HbA1c) measurement is almost a gold standard for monitoring

glycemic control and diagnosis of diabetes mellitus. However, it is noteworthy that there are

16
several genetic, hematologic and disease conditions that might influence the HbA1c estimation,

thus HbA1c does not reflect the actual values of average glycemia (99). Typically, conditions

that increase the life of erythrocytes or associated with decreased turnover rate of RBCs

prolong the exposure of cells to glucose and result in elevated HbA1c levels. For example, iron

deficiency anemia, vitamin B12 and folate deficiency are associated with spuriously elevated

HbA1c levels in patients with or without diabetes (100, 101).

Likewise, conditions that reduce the survival of erythrocytes or are associated with increased

red cell turnover reduce the glycation and result in lower HbA1c levels. Acute or chronic blood

loss, hemolytic anemia, end-stage renal disease and splenomegaly are the conditions

associated with spuriously lower HbA1c levels (101, 102). Even during pregnancy, the HbA1c

levels are artificially low because of decreased lifespan of RBCs and therefore it may not be an

appropriate tool for diagnosing gestational diabetes (103).

Hemoglobin variants, otherwise known as hemoglobinopathies, are also known to interfere with

HbA1c tests. In these variants, mutations occur in the globin genes resulting in alterations in the

amino acids of the globin protein (104, 105). There are several variants identified; however only

few are common and have clinical relevance. Depending upon the assay method used, patients

with hemoglobinopathies may show falsely elevated or decreased HbA1c levels. In general,

patients with HbSS (sickle cell trait), HbCC, or HbSC, the HbA1c measurement may be

unreliable (105). Besides an interference with the assay methods, these patients may also have

anemia, increased RBC turnover and transfusion requirements, which can influence the HbA1C

levels. The HbE variant, which is common in south-east Asian regions, is known to interfere with

A1c measurement, depending upon the assay method used (106).

Therefore, in these situations, use of alternate markers of glycemia such as fructosamine,

glycated albumin, 1,5-anhydroglucitrol (1,5-AG), and glucose self-monitoring can be more useful

17
in the management of diabetes mellitus. High fructosamine (268-870 mmol/L) or glycated

albumin (>20%), in addition to self-monitored blood glucose measures and/or fasting or random

blood glucose measures may indicate hyperglycemia over 2 to 3 weeks. Low 1,5-AG level

(reference range: 6.8-29.3 mcg/mL in women and 10.7-32.0 mcg/mL in men) indicates

hyperglycemia over 24 hours, which can be used in adjunct to glucose self-monitoring to

measure daily changes in glycemic levels. The interpretation of fructosamine and glycated

albumin should be made with caution in patients with renal disease, hyperthyroidism,

nonalcoholic fatty liver disease and other liver disease. Similarly, interpretation of 1,5 AG may

be limited in renal disease and gestational diabetes. HbA1c estimation by thiobarbituric acid

method may be useful in CKD. Standard screening or diagnostic criteria based on 75 g or 100 g

oral glucose tolerance test (OGTT) can be considered for gestation diabetes (107).

Screening of anemia

According to the World Health Organization (WHO), anemia is defined as level of hemoglobin

<13 g/dL in men, <12 g/dL in normal women and <11 g/dL in pregnant women (108). Evaluation

of mean corpuscular hemoglobin (MCH) or mean corpuscular volume (MCV) can distinguish

macrocytic anemia (vitamin B12 or folate deficiency) from microcytic or normocytic (109).

Vitamin B12 or folate deficiency can be further confirmed based on the serum levels (110). Iron

status can be clinically assessed by measuring serum ferritin concentrations and TSAT (111).

These serum markers of iron can be used to differentiate iron deficiency anemia and anemia

due to chronic disease (112). Ferritin level below 30 ng/mL and TSAT below 20% are indicative

of iron deficiency anemia. In presence of inflammatory or chronic disease conditions like CKD or

chronic heart failure, iron deficiency anemia can be diagnosed if ferritin level is between 30

ng/mL and 100 ng/mL and TSAT is <20%.

18
In patients with CKD, it is important to distinguish the absolute versus functional iron deficiency.

In absolute iron deficiency, because of the depleted iron state, there is an insufficiency of iron

for hemoglobin production. Whereas, in functional iron deficiency, in spite of adequate iron

stores, there is a poor availability of iron for the erythropoiesis. A serum ferritin >100 ng/mL and

TSAT <20% can indicate functional iron deficiency. Anemia of chronic disease can be

diagnosed if serum ferritin is >100 ng/mL and TSAT is >20% and can be confirmed with a

soluble transferrin receptor (sTfR)/log ferritin index (113). A value of <1 may indicate anemia of

chronic disease without iron deficiency anemia, whereas a value above 2 may suggest

presence of iron deficiency anemia with or without anemia of chronic disease (Fig. 2).

Following the diagnosis of anemia, it is imperative to identify the underlying cause that may

require immediate management. The iron deficiency anemia could be due to poor nutritional

intake, poor iron absorption or chronic blood loss. Evaluation of urine or stool examination,

colonoscopy or upper endoscopy can be considered to rule out blood loss from gastrointestinal

or genitourinary tract. A noninvasive screening for atrophic gastritis, celiac disease, and

Helicobacter Pylori infections can also be included to confirm the iron, vitamin B12 or folate

malabsorption or refractory iron deficiency anemia. Use of proton pump inhibitors, antacids,

metformin or any other medications that impairs the absorption of micronutrients should be

evaluated. In patients with normal or low MCV, an Hb electrophoresis could be performed to

exclude sickle cell disease or thalassemia. Anemia of chronic disease is usually related to

underlying inflammatory conditions, such as diabetes, CKD or heart failure.

Management of Anemia

A prompt correction of anemia in patients with diabetes (with or without kidney disease) has

shown to improve the overall clinical outcome and quality of life and reduce the risk of

19
complications and mortality (114, 115). The treatment strategy must be made based on the

severity of anemia, underlying causes and comorbid conditions. Although the target for

maintaining optimal hemoglobin is still undefined, it should be individualized based on the age,

clinical status and treatment response. In patients with diabetic kidney disease, evidences have

shown that target hemoglobin level of 11-12 g/dL is adequate in order to improve the overall

outcome (86, 116). Targeting a hemoglobin level of >13 g/dL in these patients may increase the

risk of developing cardiovascular complications and mortality (117, 118).

Iron deficiency anemia

Dietary intake of iron should be optimized in patients with iron deficiency anemia. Iron (nonheme

iron) from plant sources like green leafy vegetables, legumes and dry fruits are poorly absorbed

compared to the iron obtained from meat, fish and poultry products. Consumption of vitamin-C

rich food (gooseberries, citrus, etc.) can improve the iron absorption (119).

Oral iron formulations should be considered depending upon the severity and comorbid

conditions. Oral iron is usually given to provide elemental iron of 100 to 200 mg per day to

achieve adequate repletion and smaller doses as low as 60 mg elemental iron can also be given

for better tolerability. Various oral iron formulations are available and they are composed of

ferrous iron salts (eg. ferrous ascorbate, ferrous sulphate, ferrous gluconate, ferrous fumarate)

or ferric iron salts (eg. ferric citrate) (Table 3). The absorption of ferrous form is observed to be

higher than that of ferric salts. The hemoglobin levels should be monitored during oral iron

therapy and the levels should improve within 1-2 months of treatment. In case hemoglobin

levels do not improve within the time frame (>2 g/dL), use of intravenous iron preparations

should be considered (Table 3). Intravenous iron preparations are preferred over oral depending

upon the clinical status, convenience and compliance. In clinical conditions such as celiac

20
disease, autoimmune gastritis, gastrointestinal bleeding, CKD and patients who have

undergone certain bariatric surgeries, intravenous iron therapy is preferred. Ferric

carboxymaltose, ferumoxytol and iron isomaltoside have an advantage of being administered at

higher doses and are the treatment choices when large amounts of iron are required. Vitamin

B12 and/or folate deficiency can be treated with vitamin B12 supplementation (up to 2000

mcg/day) or folic acid (5 mg/day).

Anemia of Chronic Disease

In patients with CKD, if iron deficiency anemia is present, oral or intravenous iron therapy

should be provided. Nondialysis dependent patients can receive either oral or intravenous iron

depending upon the clinical status. However, in dialysis dependent patients, intravenous iron is

preferred over oral for treating iron deficiency anemia. Intravenous ferric carboxymaltose,

ferumoxytol and iron isomaltoside can be administered at high doses and have better safety

profile in CKD patients.

The ESAs are usually initiated in iron replete patients when hemoglobin is <11 g/dL in non-

dialysis patients and <10 g/dL in dialysis patients to decrease the need for blood transfusion,

hospitalization and risk of mortality. The ESA treatment should be initiated after the correction of

iron deficiency and other inflammatory causes. Various ESAs such as recombinant human

erythropoietin, darbepoetin‑alfa and continuous erythropoietin receptor activator (CERA) are

used for management of anemia (Table 3). Generally, intravenous ESA is preferred over

subcutaneous, especially for patients on hemodialysis. The subcutaneous erythropoietin has a

greater half-life and is generally preferred in non-dialysis patients and those on peritoneal

dialysis. In addition, the ESA treatment should be individualized based on level of hemoglobin

concentration, prior response to iron therapy, the risk of blood transfusion, the risks associated

21
with ESA treatment (especially stroke or hypertension) and the presence of anemia associated

symptoms. It is required that patients are observed carefully for any side effects such as pain at

the site of injection, flu like symptoms or hypertension during ESA therapy. Patients on ESA

therapy should be monitored for hemoglobin levels every week till the hemoglobin level

becomes stable (11-12 g/dL) and thereafter every month. The dose of ESA dose should be

adjusted based on the hemoglobin concentration, rate of increase in hemoglobin level and

clinical conditions causing hyporesponsiveness (uremia, hyperparathyroidism, etc.). Treatment

with ESA should be held if there is a rapid increase in hemoglobin or if level exceeding 12 g/dL,

and resumed at lower dose when Hb reduces to <11 g/dL. A high hemoglobin level (>13 g/dL)

could increase the risk of stroke, hypertension or vascular thrombosis. Patients on ESA therapy

are recommended to maintain TSAT levels >20% and ferritin levels of >200 ng/ml in

hemodialysis dependent patients and >100 ng/ml in non‑dialysis dependent patients (117).

Conclusions

In patients with diabetes mellitus (with or without CKD), prompt detection and correction of

anemia is important to reduce the risk of adverse outcomes. Treatment with oral or intravenous

iron preparations and ESA needs to be individualized based on the patients’ clinical status and

comorbid conditions. Overcorrection of anemia with hemoglobin level exceeding 13 g/dL,

especially when treating with ESA, can be detrimental. Patients receiving treatment for anemia

should be routinely monitored along with other evaluations for diabetes-related complications.

22
References

1. Lameire N. The anaemia of silent diabetic nephropathy-prevalence, physiopathology,

and management. Acta clinica Belgica. 2003 May-Jun;58(3):159-68.

2. Thomas MC, Cooper ME, Rossing K, Parving HH. Anaemia in diabetes: Is there a

rationale to TREAT? Diabetologia. 2006 Jun;49(6):1151-7.

3. Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, et al. The risk of

developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the

RENAAL study. Kidney international. 2003 Apr;63(4):1499-507.

4. Ezenwaka CE, Jones-Lecointe A, Nwagbara E, Seales D, Okali F. Anaemia and kidney

dysfunction in Caribbean type 2 diabetic patients. Cardiovascular diabetology. 2008 Aug

27;7:25.

5. Thomas MC, MacIsaac RJ, Tsalamandris C, Power D, Jerums G. Unrecognized anemia

in patients with diabetes: a cross-sectional survey. Diabetes care. 2003 Apr;26(4):1164-9.

6. Thomas MC, Tsalamandris C, MacIsaac RJ, Jerums G. The epidemiology of hemoglobin

levels in patients with type 2 diabetes. American journal of kidney diseases : the official journal

of the National Kidney Foundation. 2006 Oct;48(4):537-45.

7. Cawood TJ, Buckley U, Murray A, Corbett M, Dillon D, Goodwin B, et al. Prevalence of

anaemia in patients with diabetes mellitus. Irish journal of medical science. 2006 Apr-

Jun;175(2):25-7.

8. WHO. The global prevalence of anaemia in 2011. 2011; Available from:

http://www.who.int/nutrition/publications/micronutrients/global_prevalence_anaemia_2011/en/.

9. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the

prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011 Dec;94(3):311-21.

23
10. IDF. IDF Diabetes Atlas. 2015; Available from:

http://www.diabetesatlas.org/resources/2015-atlas.html.

11. Gulati M, Agrawal N. Study of Prevalence of Anaemia in Patients with Type 2 Diabetes

Mellitus. Scholars Journal of Applied Medical Sciences. 2016;4(5F):1826-9.

12. Rathod G, Parmar P, Rathod S, Parikh A. Prevalence of anemiain patients with Type 2

Diabetes Mellitus at Gandhinagar, Gujarat, India. International Archives of Integrated Medicine.

2016;3(3):12-6.

13. Loutradis C, Skodra A, Georgianos P, Tolika P, Alexandrou D, Avdelidou A, et al.

Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: A

nested case-control study. World journal of nephrology. 2016 Jul 06;5(4):358-66.

14. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with

anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Archives of

internal medicine. 2002 Jun 24;162(12):1401-8.

15. Adejumo BI, Dimkpa U, Ewenighi CO, Erhabor TA, G.A. U, S.I. O, et al. The Incidence of

Anemia and the Impact of Poor Glycemic Control in Type-2 Diabetic Patients with Renal

Insufficiency. Journal of Biology, Agriculture and Healthcare. 2013;3(13):130-7.

16. Thomas MC, Viberti G, Groop PH. Screening for chronic kidney disease in patients with

diabetes: are we missing the point? Nature clinical practice Nephrology. 2008 Jan;4(1):2-3.

17. Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN, et al. Anemia

as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of

chronic kidney disease. Journal of the American Society of Nephrology : JASN. 2005

Nov;16(11):3403-10.

18. De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: a

clinically oriented review. The Journal of clinical endocrinology and metabolism. 2008

Feb;93(2):363-71.

24
19. Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ. Anemia with

erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes care. 2001

Mar;24(3):495-9.

20. Singh DK, Winocour P, Farrington K. Erythropoietic stress and anemia in diabetes

mellitus. Nat Rev Endocrinol. 2009 Apr;5(4):204-10.

21. Winkler AS, Marsden J, Chaudhuri KR, Hambley H, Watkins PJ. Erythropoietin depletion

and anaemia in diabetes mellitus. Diabet Med. 1999 Oct;16(10):813-9.

22. Craig KJ, Williams JD, Riley SG, Smith H, Owens DR, Worthing D, et al. Anemia and

Diabetes in the Absence of Nephropathy. Diabetes care. 2005;28(5):1118-23.

23. Thomas MC, Tsalamandris C, Macisaac R, Jerums G. Functional erythropoietin

deficiency in patients with Type 2 diabetes and anaemia. Diabet Med. 2006 May;23(5):502-9.

24. Ou X, O’Leary HA, Broxmeyer HE. Implications of DPP4 modification of proteins that

regulate stem/progenitor and more mature cell types. Blood. 2013;122(2):161-9.

25. Broxmeyer HE, Hoggatt J, O'Leary HA, Mantel C, Chitteti BR, Cooper S, et al.

Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress

hematopoiesis. Nature medicine. 2012 Dec;18(12):1786-96.

26. Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, et al.

Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving

Global Outcomes" (KDIGO) Controversies Conference. Kidney international. 2016 Jan;89(1):28-

39.

27. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B(12)

deficiency in patients receiving metformin. Archives of internal medicine. 2006 Oct

09;166(18):1975-9.

28. Andres E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Archives of

internal medicine. 2002 Oct 28;162(19):2251-2.

25
29. Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al.

Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate

and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Journal of

internal medicine. 2003 Nov;254(5):455-63.

30. Pierce SA, Chung AH, Black KK. Evaluation of vitamin B12 monitoring in a veteran

population on long-term, high-dose metformin therapy. The Annals of pharmacotherapy. 2012

Nov;46(11):1470-6.

31. de Jager J, Kooy A, Lehert P, Wulffele MG, van der Kolk J, Bets D, et al. Long term

treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency:

randomised placebo controlled trial. BMJ (Clinical research ed). 2010 May 20;340:c2181.

32. Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, et al. Thiazolidinediones expand

body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption.

Nature medicine. 2005 Aug;11(8):861-6.

33. Chilcott J, Tappenden P, Jones ML, Wight JP. A systematic review of the clinical

effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Clinical therapeutics.

2001 Nov;23(11):1792-823; discussion 1.

34. Berria R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, et al. Reduction in

hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II

diabetes mellitus. Clinical pharmacology and therapeutics. 2007 Sep;82(3):275-81.

35. Robles NR, Angulo E, Grois J, Barquero A. Comparative effects of fosinopril and

irbesartan on hematopoiesis in essential hypertensives. Renal failure. 2004 Jul;26(4):399-404.

36. Ishani A, Weinhandl E, Zhao Z, Gilbertson DT, Collins AJ, Yusuf S, et al. Angiotensin-

converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of

incident anemia on mortality in patients with left ventricular dysfunction. Journal of the American

College of Cardiology. 2005 Feb 01;45(3):391-9.

26
37. Vlahakos DV, Marathias KP, Madias NE. The role of the renin-angiotensin system in the

regulation of erythropoiesis. American journal of kidney diseases : the official journal of the

National Kidney Foundation. 2010 Sep;56(3):558-65.

38. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased Hematocrit During Sodium-Glucose

Cotransporter 2 Inhibitor Therapy Indicates Recovery of Tubulointerstitial Function in Diabetic

Kidneys. Journal of clinical medicine research. 2016 Dec;8(12):844-7.

39. Aono M, Sato Y. Dipeptidyl peptidase 4 inhibitor linagliptin can decrease the dosage of

erythropoiesis-stimulating agents in patients on hemodialysis. Renal Replacement Therapy.

2016;2(1):44.

40. Abe M, Higuchi T, Moriuchi M, Okamura M, Tei R, Nagura C, et al. Efficacy and safety of

saxagliptin, a dipeptidyl peptidase-4 inhibitor, in hemodialysis patients with diabetic

nephropathy: A randomized open-label prospective trial. Diabetes Res Clin Pract. 2016

Jun;116:244-52.

41. Fried M, Yumuk V, Oppert JM, Scopinaro N, Torres A, Weiner R, et al. Interdisciplinary

European guidelines on metabolic and bariatric surgery. Obesity surgery. 2014 Jan;24(1):42-55.

42. Baptista V, Wassef W. Bariatric procedures: an update on techniques, outcomes and

complications. Current opinion in gastroenterology. 2013 Nov;29(6):684-93.

43. Love AL, Billett HH. Obesity, bariatric surgery, and iron deficiency: true, true, true and

related. American journal of hematology. 2008 May;83(5):403-9.

44. Stein J, Stier C, Raab H, Weiner R. Review article: The nutritional and pharmacological

consequences of obesity surgery. Alimentary pharmacology & therapeutics. 2014

Sep;40(6):582-609.

45. Ernst B, Thurnheer M, Schmid SM, Schultes B. Evidence for the necessity to

systematically assess micronutrient status prior to bariatric surgery. Obesity surgery. 2009

Jan;19(1):66-73.

27
46. Simcox JA, McClain DA. Iron and diabetes risk. Cell metabolism. 2013 Mar

05;17(3):329-41.

47. Swaminathan S, Fonseca VA, Alam MG, Shah SV. The role of iron in diabetes and its

complications. Diabetes care. 2007 Jul;30(7):1926-33.

48. Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genetics in

medicine : official journal of the American College of Medical Genetics. 2009 May;11(5):307-13.

49. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron-

overload-related disease in HFE hereditary hemochromatosis. The New England journal of

medicine. 2008 Jan 17;358(3):221-30.

50. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel

MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature

genetics. 1996 Aug;13(4):399-408.

51. Fernandez-Real JM, Manco M. Effects of iron overload on chronic metabolic diseases.

The lancet Diabetes & endocrinology. 2014 Jun;2(6):513-26.

52. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG.

Hemochromatosis mutations in the general population: iron overload progression rate. Blood.

2004 Apr 15;103(8):2914-9.

53. Adams PC, Barton JC. Haemochromatosis. Lancet (London, England). 2007 Dec

01;370(9602):1855-60.

54. Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA. Practice guideline

development task force of the College of American Pathologists. Hereditary hemochromatosis.

Clinica chimica acta; international journal of clinical chemistry. 1996 Feb 28;245(2):139-200.

55. Acton RT, Barton JC, Passmore LV, Adams PC, Speechley MR, Dawkins FW, et al.

Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported

diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study. Diabetes care.

2006 Sep;29(9):2084-9.

28
56. Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Cross-talk between iron metabolism

and diabetes. Diabetes. 2002 Aug;51(8):2348-54.

57. Fumeron F, Pean F, Driss F, Balkau B, Tichet J, Marre M, et al. Ferritin and transferrin

are both predictive of the onset of hyperglycemia in men and women over 3 years: the data from

an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes care.

2006 Sep;29(9):2090-4.

58. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC,

et al. Survival and complications in patients with thalassemia major treated with transfusion and

deferoxamine. Haematologica. 2004 Oct;89(10):1187-93.

59. Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC. Pancreatic iron and

glucose dysregulation in thalassemia major. American journal of hematology. 2012

Feb;87(2):155-60.

60. Datz C, Felder TK, Niederseer D, Aigner E. Iron homeostasis in the metabolic syndrome.

European journal of clinical investigation. 2013 Feb;43(2):215-24.

61. Trombini P, Paolini V, Pelucchi S, Mariani R, Nemeth E, Ganz T, et al. Hepcidin

response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome.

Liver international : official journal of the International Association for the Study of the Liver.

2011 Aug;31(7):994-1000.

62. Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome.

Arteriosclerosis, thrombosis, and vascular biology. 2008 Jan;28(1):27-38.

63. Aigner E, Theurl I, Theurl M, Lederer D, Haufe H, Dietze O, et al. Pathways underlying

iron accumulation in human nonalcoholic fatty liver disease. The American journal of clinical

nutrition. 2008 May;87(5):1374-83.

64. Barisani D, Pelucchi S, Mariani R, Galimberti S, Trombini P, Fumagalli D, et al. Hepcidin

and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload. Journal

of hepatology. 2008 Jul;49(1):123-33.

29
65. Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders:

diagnostic implications. Clinical chemistry. 2011 Dec;57(12):1650-69.

66. Jiwani A, Marseille E, Lohse N, Damm P, Hod M, Kahn JG. Gestational diabetes

mellitus: results from a survey of country prevalence and practices. The journal of maternal-fetal

& neonatal medicine : the official journal of the European Association of Perinatal Medicine, the

Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal

Obstet. 2012 Jun;25(6):600-10.

67. Seshiah V, Balaji V, Balaji MS, Sanjeevi CB, Green A. Gestational diabetes mellitus in

India. The Journal of the Association of Physicians of India. 2004 Sep;52:707-11.

68. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al.

Hyperglycemia and adverse pregnancy outcomes. The New England journal of medicine. 2008

May 08;358(19):1991-2002.

69. Ramos-Levi AM, Perez-Ferre N, Fernandez MD, Del Valle L, Bordiu E, Bedia AR, et al.

Risk factors for gestational diabetes mellitus in a large population of women living in Spain:

implications for preventative strategies. International journal of endocrinology.

2012;2012:312529.

70. Yang H, Wei Y, Gao X, Xu X, Fan L, He J, et al. Risk factors for gestational diabetes

mellitus in Chinese women: a prospective study of 16,286 pregnant women in China. Diabet

Med. 2009 Nov;26(11):1099-104.

71. Lao TT, Ho LF. Impact of iron deficiency anemia on prevalence of gestational diabetes

mellitus. Diabetes care. 2004 Mar;27(3):650-6.

72. Behboudi-Gandevani S, Safary K, Moghaddam-Banaem L, Lamyian M, Goshtasebi A,

Alian-Moghaddam N. The relationship between maternal serum iron and zinc levels and their

nutritional intakes in early pregnancy with gestational diabetes. Biological trace element

research. 2013 Jul;154(1):7-13.

30
73. Afkhami-Ardekani M, Rashidi M. Iron status in women with and without gestational

diabetes mellitus. Journal of diabetes and its complications. 2009 May-Jun;23(3):194-8.

74. Rajpathak S, Ma J, Manson J, Willett WC, Hu FB. Iron intake and the risk of type 2

diabetes in women: a prospective cohort study. Diabetes care. 2006 Jun;29(6):1370-6.

75. Lee DH, Folsom AR, Jacobs DR, Jr. Dietary iron intake and Type 2 diabetes incidence in

postmenopausal women: the Iowa Women's Health Study. Diabetologia. 2004 Feb;47(2):185-

94.

76. Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk

of type 2 diabetes in apparently healthy women. Jama. 2004 Feb 11;291(6):711-7.

77. Qiu C, Zhang C, Gelaye B, Enquobahrie DA, Frederick IO, Williams MA. Gestational

diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake. Diabetes

care. 2011 Jul;34(7):1564-9.

78. Zein S, Rachidi S, Hininger-Favier I. Is oxidative stress induced by iron status associated

with gestational diabetes mellitus? Journal of trace elements in medicine and biology : organ of

the Society for Minerals and Trace Elements (GMS). 2014 Jan;28(1):65-9.

79. Cooper ME, Jandeleit-Dahm K, Thomas MC. Targets to retard the progression of

diabetic nephropathy. Kidney international. 2005 Oct;68(4):1439-45.

80. Thomas MC. Anemia in diabetes: marker or mediator of microvascular disease? Nature

clinical practice Nephrology. 2007 Jan;3(1):20-30.

81. Ueda H, Ishimura E, Shoji T, Emoto M, Morioka T, Matsumoto N, et al. Factors affecting

progression of renal failure in patients with type 2 diabetes. Diabetes care. 2003

May;26(5):1530-4.

82. Ishimura E, Nishizawa Y, Okuno S, Matsumoto N, Emoto M, Inaba M, et al. Diabetes

mellitus increases the severity of anemia in non-dialyzed patients with renal failure. Journal of

nephrology. 1998 Mar-Apr;11(2):83-6.

31
83. Mohanram A, Toto RD. Outcome studies in diabetic nephropathy. Seminars in

nephrology. 2003 May;23(3):255-71.

84. Alicic RZ, Tuttle KR. Management of the diabetic patient with advanced chronic kidney

disease. Seminars in dialysis. 2010 Mar-Apr;23(2):140-7.

85. Shaheen FA, Souqiyyeh MZ, Al-Attar BA, Karkar A, Al Jazairi AM, Badawi LS, et al.

Prevalence of anemia in predialysis chronic kidney disease patients. Saudi journal of kidney

diseases and transplantation : an official publication of the Saudi Center for Organ

Transplantation, Saudi Arabia. 2011 May;22(3):456-63.

86. Choukroun G, Renou M, Lecaque C, Jaureguy M. [TREAT or not to treat: anemia in type

2 diabetes and chronic kidney disease at stages 3 and 4]. Nephrologie & therapeutique. 2011

Feb;7(1):2-9.

87. Carraro MC, Rossetti L, Gerli GC. Prevalence of retinopathy in patients with anemia or

thrombocytopenia. European journal of haematology. 2001 Oct;67(4):238-44.

88. Qiao Q, Keinanen-Kiukaanniemi S, Laara E. The relationship between hemoglobin

levels and diabetic retinopathy. Journal of clinical epidemiology. 1997 Feb;50(2):153-8.

89. Davis MD, Fisher MR, Gangnon RE, Barton F, Aiello LM, Chew EY, et al. Risk factors

for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic

Retinopathy Study Report #18. Investigative ophthalmology & visual science. 1998

Feb;39(2):233-52.

90. Sarnak MJ, Tighiouart H, Manjunath G, MacLeod B, Griffith J, Salem D, et al. Anemia as

a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC)

study. Journal of the American College of Cardiology. 2002 Jul 03;40(1):27-33.

91. Herzog C, Puumala M, Collins A. NHANES III: the distribution of Hb levels related to

chronic kidney disease (CKD), diabetes (DM), and congestive heart failure (CHF) (Abstract).

Journal of the American Society of Nephrology : JASN. 2002;13:428A.

32
92. Collins AJ, Li S, Gilbertson DT, Liu J, Chen SC, Herzog CA. Chronic kidney disease and

cardiovascular disease in the Medicare population. Kidney international Supplement. 2003

Nov(87):S24-31.

93. Gunawardena S, Dunlap ME. Anemia and iron deficiency in heart failure. Current heart

failure reports. 2012 Dec;9(4):319-27.

94. Lapice E, Masulli M, Vaccaro O. Iron deficiency and cardiovascular disease: an updated

review of the evidence. Current atherosclerosis reports. 2013 Oct;15(10):358.

95. Wright JA, Oddy MJ, Richards T. Presence and characterisation of anaemia in diabetic

foot ulceration. Anemia. 2014;2014:104214.

96. Ekpebegh CO, Iwuala SO, Fasanmade OA, Ogbera AO, Igumbor E, Ohwovoriole AE.

Diabetes foot ulceration in a Nigerian hospital: in-hospital mortality in relation to the presenting

demographic, clinical and laboratory features. International wound journal. 2009 Oct;6(5):381-5.

97. Chuan F, Zhang M, Yao Y, Tian W, He X, Zhou B. Anemia in Patients With Diabetic Foot

Ulcer: Prevalence, Clinical Characteristics, and Outcome. The international journal of lower

extremity wounds. 2016 Sep;15(3):220-6.

98. Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, et al. The Role of

Hypoxia-Inducible Factor in Wound Healing. Advances in wound care. 2014 May 01;3(5):390-9.

99. International Expert Committee report on the role of the A1C assay in the diagnosis of

diabetes. Diabetes care. 2009 Jul;32(7):1327-34.

100. Coban E, Ozdogan M, Timuragaoglu A. Effect of iron deficiency anemia on the levels of

hemoglobin A1c in nondiabetic patients. Acta haematologica. 2004;112(3):126-8.

101. Arnold JG, McGowan HJ. Delay in diagnosis of diabetes mellitus due to inaccurate use

of hemoglobin A1C levels. Journal of the American Board of Family Medicine : JABFM. 2007

Jan-Feb;20(1):93-6.

102. Nitin S. HbA1c and factors other than diabetes mellitus affecting it. Singapore medical

journal. 2010 Aug;51(8):616-22.

33
103. Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading.

Journal of general internal medicine. 2014 Feb;29(2):388-94.

104. Little RR, Roberts WL. A review of variant hemoglobins interfering with hemoglobin A1c

measurement. Journal of diabetes science and technology. 2009 May 01;3(3):446-51.

105. Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified

derivatives on assays for glycohemoglobin. Clinical chemistry. 2001 Feb;47(2):153-63.

106. Vichinsky E. Hemoglobin e syndromes. Hematology American Society of Hematology

Education Program. 2007:79-83.

107. <em>Standards of Medical Care in Diabetes—2016</em>: Summary of Revisions.

Diabetes care. 2016;39(Supplement 1):S4-S5.

108. WHO. Assessing the Iron Status of Populations. 2nd ed. Geneva, Switzerland. 2007.

109. Oustamanolakis P, Koutroubakis IE, Messaritakis I, Kefalogiannis G, Niniraki M,

Kouroumalis EA. Measurement of reticulocyte and red blood cell indices in the evaluation of

anemia in inflammatory bowel disease. Journal of Crohn's & colitis. 2011 Aug;5(4):295-300.

110. Devalia V. Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay. BMJ

(Clinical research ed). 2006 Aug 19;333(7564):385-6.

111. Locatelli F, Nissenson AR, Barrett BJ, Walker RG, Wheeler DC, Eckardt KU, et al.

Clinical practice guidelines for anemia in chronic kidney disease: problems and solutions. A

position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney

international. 2008 Nov;74(10):1237-40.

112. Cullis JO. Diagnosis and management of anaemia of chronic disease: current status.

British journal of haematology. 2011 Aug;154(3):289-300.

113. Skikne BS, Punnonen K, Caldron PH, Bennett MT, Rehu M, Gasior GH, et al. Improved

differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective

multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. American

journal of hematology. 2011 Nov;86(11):923-7.

34
114. Johansen KL, Finkelstein FO, Revicki DA, Evans C, Wan S, Gitlin M, et al. Systematic

review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients.

Nephrology, dialysis, transplantation : official publication of the European Dialysis and

Transplant Association - European Renal Association. 2012 Jun;27(6):2418-25.

115. McCullough PA, Lepor NE. The deadly triangle of anemia, renal insufficiency, and

cardiovascular disease: implications for prognosis and treatment. Reviews in cardiovascular

medicine. 2005 Winter;6(1):1-10.

116. Teehan G, Benz RL. An update on the controversies in anemia management in chronic

kidney disease: lessons learned and lost. Anemia. 2011;2011:623673.

117. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO

clinical practice guideline for anemia in chronic kidney disease. Kidney international

Supplement. 2012;2:279-335.

118. Mehdi U, Toto RD. Anemia, diabetes, and chronic kidney disease. Diabetes care. 2009

Jul;32(7):1320-6.

119. 2011. Dietary Guidelines for Indians. National Institution of Nutrtion. [01 March 2017];

Available from: ninindia.org/dietaryguidelinesforninwebsite.pdf.

35
Figure Legends

Fig. 1. Multifaceted causes of anemia in diabetes mellitus

ARB, angiotensin receptor blocker; ACEi, angiotensin converting enzyme inhibitor; DPP-4,

dipeptidyl peptidase-4; EPO, erythropoietin; RBC, red blood cells.*Malabsorptive disorders in

type 1 diabetes (autoimmune gastritis, pernicious anemia and celiac disease) causing impaired

iron/vitamin B12 absorption.

Fig. 2. Algorithm for diagnosis and management of anemia in diabetes and related disorders

*Sickle cell disease or thalassemia, if suspected can be confirmed using Hb electrophoresis

CBC, complete blood count; Hb, hemoglobin; IDA, iron deficiency anemia; MCV, mean

corpuscular volume; PPI, proton pump inhibitor; STfr log ft, soluble transferrin receptor/log

ferritin index; TSAT, transferrin saturation.

36
37
38
Table 1. Hemochromatosis and diabetes mellitus

Primary or inherited hemochromatosis

Hereditary hemochromatosis
Type I: HFE gene mutations
Type IIA: Hemojuvelin (HJV or HFE2) mutation
Type IIB: Hepcidin antimicrobial peptide (HAMP) or HFE2B mutation
Type III: Transferrin receptor 2 (TFR2 or HFE3) mutation
Type IV: ferroportin (SLC40A1) gene mutation

Secondary or acquired hemochromatosis

Transfusional iron overload due to β thalassemia
Dysmetabolic iron-overload syndrome (DIOS)
Hepatitis C infection
Porphyria cutanea tarda
Increased iron intake

39
Table 2. Comparison of findings in patients with iron disorders

Anemia Iron overload

Anemia of Dysmetabolic
chronic Hereditary iron overload
IDA disease Combined Hemochromatosis Thalassemia syndrome

Serum iron ↓ ↓ ↓ ↑ ↑ ↑

↓ Normal to ↑ ↓ to normal
Serum ferritin ↑ ↑ ↑↑
(<30 µg/l) (>100 µg/l) (30-100 µg/l)

↓ Normal ↓
TSAT ↑ ↑ Normal
(<20%) (>20%)* (<20%)

Total iron binding

↑ ↓ ↓ or Normal ↓ ↓ ↓
capacity

sTFR/log ferritin >2 <1 >2 NA NA NA

Hypochromic, Normochromic, Normochromic,

Peripheral Blood
microcytic normocytic normocytic - - -
Smear
anemia anemia anemia†
IDA, iron deficiency anemia; TSAT, Transferrin saturation.
*Functional iron deficiency may be present if TSAT<20%; †Can also be microcytic.

40
Table 3. List of preparations for management of anemia

Medications Dose

Oral iron

Ferrous Ascorbate

Ferrous sulphate

Ferrous Fumarate

Ferrous Gluconate Tablet equivalent to 200 mg of elemental iron/day

Ferrous bisglycinate

Ferrous succinate

Ferric citrate

Others

Vitamin B12 Up to 2000 mcg/day

Folic acid 5 mg tablet/day

Parenteral iron

Ferric carboxymaltose (FCM) 15 mg or 20 mg iron/kg body weight or 1000 mg of iron

(20 mL FCM) - IV administration

The maximum recommended cumulative dose of FCM:

1000 mg of iron (20 mL FCM) per week.

Iron isomaltoside 100-200 mg IV bolus injection or up to 20 mg iron/kg

infusion.

Ferumoxytol 510 mg IV over at least 15 minutes

High molecular weight iron Up to 100 mg of iron IV at ≤50 mg/min (test dose

dextran required)

Low-molecular weight iron Up to 100 mg of iron IV at ≤50 mg/min (test dose

41
 dextran required)

Sodium ferric gluconate complex 62.5-125 mg IV during dialysis or infusion over 1 hour

Iron sucrose 100-200 mg IV over 2-5 minutes

Erythropoiesis stimulating agents

Epoetin‑alfa 50 to 100 units/kg IV or subcutaneously 3 times a week

Epoetin‑beta 50 to 100 units/kg IV or subcutaneously 3 times a week

Darbepoetin‑alfa 0.45 mcg/kg/wk or 0.75 mcg/kg/fortnightly

Continuous erythropoietin 0.6 mcg/kg/fortnightly

receptor activator (CERA)

IV, intravenous

42