ON HOMEOSTASIS DISORDERS

1. IRON HOMEOSTASIS
DISORDERS

2. Iron Deficiency
• The clinical manifestation of iron deficiency is anemia
• The health consequences of anemia are:
• Increased risk of maternal and child mortality
• Impaired cognitive and physical development in children
• Reduced physical performance and work productivity in adults
• Cognitive decline in the elderly
• Patients with CKD, anemia is associated with a lower quality of life and a
higher risk of numerous adverse outcomes

3. Causes Iron Deficiency
⁻ Insufficient dietary iron absorption
⁻ Increased iron requirements during pregnancy and rapid growth in
children
⁻ increased blood loss or decreased release from ferritin
⁻ Increased iron utilization induced by erythropoiesis stimulating agents
⁻ Increased blood losses from hemodialysis, frequent phlebotomy, and
uremic platelet dysfunction
⁻ Mutations in genes involved in duodenal iron uptake, iron
mobilization from body stores

4. Iron Overload
• Major causes of systemic iron overload are hereditary
hemochromatosis, iron loading anemias, and transfusional or other
secondary forms of iron overload
• Hereditary hemochromatosis is a single-gene homozygous recessive
disorder leading to abnormally high Fe absorption
• Mutations affect the genes encoding hepcidin or the genes that induce of
hepcidin expression in response to iron
• Iron loading anemias can come as a result of conditions like
thalassemias, congenital dyserythropoietic anemias

5. Iron Overload
• Secondary iron overload can come from
• Excessive dietary, medicinal, or transfusional Fe intake or be due to metabolic
dysfunction
• Hemosiderosis is an iron overload that shows an increased serum iron
and total iron binding capacity (TIBC) or transferrin, but without
demonstrable tissue damage
• In iron overload, the excess iron causes oxidative damage and organ
dysfunction which can lead to conditions like
• Cirrhosis, cardiomyopathy, diabetes mellitus, and other endocrinopathies.

6. Iron and Diabetes Mellitus
• Diabetes mellitus is a common complication of iron overload
disorders
• Increased dietary heme iron and high body iron stores are associated
with an increased risk of type 2 diabetes and other insulin resistance
states
• The mechanisms by which iron contribute to diabetes pathogenesis
are still not fully understood, but appear to be multifactorial.

7. Iron and Cardiovascular Disease
• The heart is a major organ where iron accumulates in hereditary
hemochromatosis and β-thalassemia.
• Iron accumulation is associated with cardiomyopathy, which is a
major cause of morbidity and mortality in these patients
• The pathophysiology of iron-overload cardiomyopathy is
multifactorial including
• Oxidant-mediated injury, interference with cardiac electrical function, and
promotion of fibrosis

8. Iron and Neurodegenerative Diseases
• Iron deficiency impairs brain development and cognition
• Iron overload in the brain associates with many neurodegenerative
disorders
• Certain areas of the brain like basal ganglia, tend to be impacted most and
lead to a group of disorders known as neurodegeneration with brain iron
accumulation (NBIA) diseases

9. Iron and Cancer
• Iron overload is associated with an increased risk of hepatocellular
carcinoma and possibly other cancers in patients with hereditary
hemochromatosis and β-thalassemia.
• Iron excess can contribute to cancer development by two main
mechanisms
• The pro-oxidant effects of iron can damage DNA and thereby promote
oncogenesis.
• Cancer cells have an enhanced dependence on iron to maintain their rapid
growth rate

10. Iron and Kidney Disease
• Iron and iron-induced reactive oxygen species involve in the
pathogenesis of multiple models of acute kidney injury (AKI).
• Kidney iron accumulation has also causes CKD models.
• Ischemic or toxic insults to the kidney increase the intracellular
release of labile iron (catalytic iron) that result in oxidative damage

11. Iron and Mineral and Bone Disorders
• Osteoporosis is prevalent in patients with hemochromatosis and β-
thalassemia.
• The etiology is multifactorial, but there is an evidence that iron
deposits in bone and can directly impair bone formation or
remodeling
• Iron deficiency induces production of the bone-derived hormone
fibroblast growth factor 23 (FGF23) that regulates phosphorous and
vitamin D homeostasis
• FGF23 acts on the kidneys to reduce the reabsorption of phosphorus
and increase the production of 1,25-dihydroxyvitamin D.

12. Iron and Mineral and Bone Disorders
• In normal patients, the increased FGF23 production is coupled with
an increase in cleavage so that there is minimal change in bioactive
intact FGF23 levels.
• Iron deficiency increases intact FGF23 levels and exacerbates clinical
manifestations of renal phosphate wasting, inappropriately low
vitamin D levels, and rickets/osteomalacia

13. Iron and Infection
• Pathogenic microorganisms, like humans, require iron for survival and
proliferation
• Pathogenic microorganisms obtain iron from their human hosts
• Hepcidin-ferroportin system in humans restricts iron availability
during infection, thus reducing the availability of iron by the
Pathogenic microorganisms