Chronic Disease - Iron Metabolism and Haemochromatosis

Chronic Disease - Iron Metabolism and Haemochromatosis

Contact Information

• Dr Jon Sellars
• Newcastle University
• Email: jon.sellars@newcastle.ac.uk

Learning Outcomes

Upon completion of this lecture series, students will:

• Understand the general principles of metallobiology, focusing on the types of metals and their incorporation in biological systems, and the resulting downstream effects.
• Comprehend the relationship between metals and disease, specifically Wilson’s disease (copper overload), Menkes disease (copper deficiency), and Haemochromatosis (iron overload).

Iron Deficiency: Key Facts

• Anaemia is a significant public health issue, predominantly affecting young children, pregnant and postpartum women, and menstruating adolescent girls and women.
• Low- and lower-middle-income countries experience the greatest burden of anaemia, particularly affecting populations in rural settings, poorer households, and those with no formal education.
• Globally, it's estimated that 40% of children aged 6–59 months, 37% of pregnant women, and 30% of women 15–49 years are affected by anaemia.
• In 2019, anaemia caused 50 million years of healthy life lost due to disability.
• The largest causes include dietary iron deficiency, thalassaemia and sickle cell trait, and malaria.

Iron Metabolism

Iron is crucial for various enzymes:

• Haem: Involved in oxygen transport and storage.
• Iron-Sulphur cluster: Important for electron transfer in various metabolic pathways.
• Iron Protein: Participates in a wide array of enzymatic reactions.

Key enzymes and processes involving iron:

• Ferrochelatase: Involved in the synthesis of haem.
• Ribonucleotide reductase: Uses iron to catalyze the formation of deoxyribonucleotides from ribonucleotides, essential for DNA synthesis.
• ABCE1: Involved in mRNA translation.
• Pirin: Plays a role in DNA transcription.
• DNA primase: Involved in DNA replication.

Iron is also associated with:

• DNA-repair helicases: Enzymes involved in DNA repair.
• Fe-S cluster: Important for DNA replication.

Iron Homeostasis

• Acquisition: Oxidation of ferrous iron ($Fe^{2+}$) in air forms insoluble ferric oxide-hydroxide species ($Fe^{3+}$).

• Toxicity: Iron can participate in Fenton Chemistry, generating reactive oxygen species.

  $Fe^{2+} + H<em>2O</em>2 \rightarrow Fe^{3+} + OH^- + OH^{\bullet}$

Iron Intake

• Iron is obtained from ferritin and haem.
• Ferritin: A 24-protein cage that stores iron as $Fe^{3+}$ following oxidation in the cavity.

Iron Metabolism Specifics

• Unlike copper, iron is not excreted; excess iron is stored in the liver.
• Iron uptake into the body is regulated by enterocytes.

Iron Uptake Mechanisms

Key proteins involved in iron uptake:

• Dcytb: Iron reductase that reduces $Fe^{3+}$ to $Fe^{2+}$.
• DMT1: Iron transporter that transports $Fe^{2+}$ into the enterocyte.
• HCP1: Haem transporter.
• HO1: Haem oxygenase, which degrades haem to release iron.
• FPN (Ferroportin): Iron exporter that transports iron out of the enterocyte.
• Redox processes are important for iron uptake.

Iron Delivery and Recycling

• Iron is recovered from red blood cells through:
  • Fpn (Ferroportin)
  • HO-1 (Haem oxygenase)
  • Hpx (Haemopexin)
  • Hp (Haptoglobin)
  • Cp (Ceruloplasmin)

Iron Sensing

Mechanisms for sensing iron levels:

• High concentrations of iron bind to and activate PHD enzymes.
• Degradation of Fe-S clusters occurs at high iron concentrations due to oxidative stress.
• FBXL5 is an iron oxide dimer complex that targets IRP for degradation by the proteasome

Ferroportin Regulation by Hepcidin

• The amount of iron exiting cells is proportional to the concentration of hepcidin.
• High hepcidin levels result in low concentrations of circulatory iron.

Iron Sensing Pathways

Iron Replete Conditions

• Fe-TF (Iron-Transferrin) binds to TFR1 and TFR2.
• HFE interacts with TFR1.
• BMP6 binds to BMPR, activating SMAD1,5,8.
• HJV participates in the pathway.
• ERK1,2 may be involved.
• Downstream signaling leads to hepcidin production.

Iron Deficient Conditions

• Apo-TF (Apo-Transferrin) and TFR1.
• Matriptase-2 and HJV are involved.
• BMP6 and BMPR interaction.
• ERK1,2 may be involved.
• Signaling leads to altered hepcidin production.

Visual Representation of Iron Sensing

• Diagram showing iron uptake, storage, and transport mechanisms in both iron-replete and iron-deficient states.
• Key proteins: DCYTB, DMT1, Ferritin, FPN, HP (Haptoglobin), CP (Ceruloplasmin), Apo-TF, Fe-TF, and HEPC (Hepcidin).

Haemochromatosis

• A disorder of iron absorption and storage, leading to tissue damage from excess iron deposition.
• It is the most common inherited metabolic disorder in the Western world (1 in 250 of the Northern European population).
• Clinical presentation varies beyond the classic triad of cirrhosis, diabetes, and skin pigmentation.
• Predominantly affects men (9:1 ratio) between 40 and 60 years, with symptoms like lethargy, weakness, sleep disturbance, or diabetes.
• Early symptoms are often subtle and easily overlooked.

Effects of Increased Iron Deposition

• Hepatic: Fibrosis, cirrhosis.
• Endocrine: Diabetes, hypogonadism.
• Cardiac: Myopathy, arrhythmia.
• General: Skin pigmentation, lethargy, and malaise.

Diagnosis and Treatment of Haemochromatosis

Diagnosis

• Based on excess iron stores.
• Serum ferritin concentration accurately reflects total body iron stores ( > 200 ng/ml women, > 300 ng/ml men).
• Serum iron concentration and transferrin saturation are also elevated (TSAT > 45%).
• Further assessment includes MRI of the liver, liver biopsy, and genotyping.

Treatment

• Regular phlebotomy to lower iron stores (weekly, with maintenance treatments 4-8 times a year).
• Deferoxamine as an iron chelator.

Prognosis

• Life expectancy is normal if treatment begins before diabetes or cirrhosis develops.
• Hepatic fibrosis can improve with iron removal.

Mechanism

• Hepcidin levels are low due to mutations in HFE, HJV, Hepcidin, Transferrin receptor 2, or Ferroportin.