Haemochromatosis

Question 1

Briefly describe iron homeostasis (i.e. basic function, body iron, daily requirements and soureces)

Answer 1

• Essential for life, involved in heme proteins, drug and steroid metabolism, and immune system
• Total body iron: men 5 g, premenopausal women 3.5 g
• Iron absorption occurs mainly from red meat; daily requirements small
  Daily requirements small – replace losses
• Recommended daily intake (RDI):
  – Males and post-menopausal females 8 mg/day: absorb 10-15% (~1 mg/day)
  – Pre-menopausal females 16 mg/d, pregnant females 24 mg/d
• Richest dietary source is red meat: vegetarians are at risk of iron deficiency

Question 2

List the key proteins of fe meatbolism

Answer 2

Gene | Protein | Function |
| ———- | ———– | —————————— |
| **Ferritin | Ferritin | Iron storage protein |
| **Tf | Transferrin | Circulating iron carrier |
| **TFR | Tf receptor | Receptor for Tf |
| HJV | Hemojuvelin | Acts on neogenin |
| SLC40A1 | Ferroportin | Iron transmembrane transporter |
| **HAMP | Hepcidin | Iron regulatory hormone |

Question 3

Describe the role of hepcidin

Answer 3

• Blocks ferroportin, the cellular iron exporter
• Predominant negative regulator of iron absorption from the intestine and iron transport out of macrophages
• Synthesis stimulated by iron and inflammation

Question 4

Describe the levels of serum ferritin and transferrin significance

Answer 4

• Serum iron concentrations fluctuate; not a useful test
• Transferrin saturation is a better indicator
  
  • Normal: 20 - 44%
  • Hemochromatosis: >50%, can be >90%
  • Iron deficiency <20%

Question 5

Descrieb ferritin

Answer 5

• Tissue ferritin – high MWt iron storage protein
• Present most tissues, espec. liver, muscle, b. marrow, but…..
• …very little (3 orders of magnitude less) in serum -
  female 20-150 μg/L; male 20-350 μg/L
• Synthesis induced by iron
• Non-specifically increased or released in inflamm-
  ation, neoplasia, tissue damage (eg fatty liver)

Question 6

List som causes of raissed serum ferritin

Answer 6

• Increased body iron stores: transferrin saturation also
  increased
• Release from liver – any cause (e.g., when ALT
  increased), but ….
• …in “steady state”, most often due to alcoholic or
  non-alcoholic steatohepatitis (NASH)
• Acute phase reactant – inflammation of any cause, RA,
  lymphoma etc

Question 7

Describe hereditary haemochromatosis and the underlying genetics

Answer 7

• Single gene disorder, near HLA loci on chromosome 6p
• Autosomal recessive disorder
• Mutations in the HFE gene (C282Y, H63D) change HFE structure and function
• other variants outdated, irrelevant
• associated with iron overload: homozygous C282Y - 90% of genetic haemochromatosis in Au, compound C/H mild phenotype usually only shows up after taking excessive iron medication
  
  • homozygous H63D has no phenotype
• HFE allele frequency is 8% in caucasian –> pseudo-dominant inheritance ie one parent homozygous recessive x heterozygous
• Penetrance of HFE mutations is low (~30%)

Penetrance of Hemochromatosis

• Penetrance refers to the proportion of individuals with a disease-causing mutation who exhibit clinical effects.- thus phenotype:genotype 1:1
• Clinical penetrance of genetic hemochromatosis (GH), particularly C282Y homozygosity, is low.
  
  • Approximately 28% of males and 1.2% of females with C282Y homozygosity had iron overload-related disease.
• Factors influencing penetrance include environmental (blood donation; physiological blood loss due to pregnancy or menstruation; diet vegetarian) and genetic factors, with recent studies suggesting genetic factors are more significant.

Question 8

List and describe the complications fo longstanding iron overload

Answer 8

• Liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC- only when cirrhosis present) are complications of severe iron overload.
• Other complications include type 2 diabetes, arthritis, skin pigmentation (iron and melanin – often superimposed on hypopituarism–> slate grey or bronze colour), cardiomyopathy, primary hypogonadism, and rare endocrinopathies.
  
  • diabetes: type 2, often severe and insulin requiring. RFs include FHx, cirrhosis, obesity

Question 9

Describe haemochromatosis- linked arthritis

Answer 9

• Characteristic involvement of 2nd and 3rd metacarpo-phalyngeal joints
• Inflammatory mono-arthropathy may occur (can be pseudo-gout like), along with chondrocalcinosis
• Typically several joints symmetrically; large joints lower limb
• Arthritis may be a presenting complaint and is not related to the severity of iron overload.
  Consider haemochromatosis in unusual presentations of arthritis

Question 10

Describe the spectrum of liver disease with iron overload

Answer 10

• Minimal hepatocellular innjury or inflammation (LFT normal)
• Liver fibrosis may progress to cirrhosis, especially in the presence of excessive alcohol consumption.- LSM is an indicator
• Likelihood of cirrhosis= extent of iron overload + duration of iron overload + alcohol
• HCC second to diabetes complications as cause of death- only when cirrhosis present
• Prevention of cirrhosis is crucial in preventing liver cancer.

Question 11

How is it diagnosed?

Answer 11

• Diagnosis is based on evidence of increased body iron stores, typically indicated by raised serum ferritin and transferrin saturation.
• HFE gene testing is essential for family screening.
• Liver stiffness measurement and liver ultrasonography are performed for diagnosis and surveillance.
• Other tests not necessary eg MR quantitation of liver iron, or not done eg quantitative phlebotomy, and liver biopsy

Question 12

Describe GP management principles

Answer 12

• Early diagnosis in general practice is crucial to prevent tissue injury.
• Should be done prior to tissue injury
• Family screening and genetic testing are essential.
• Fe studies for affected person
• Venesection is recommended for patients with hemochromatosis (eg genetically proven) and evidence of iron overload (raised serum ferritin and transferrin).
• Referral to specialized services is needed for difficult cases.
• Discuss with patients the importance of alcohol and weight moderation (diabetes, cirrhosis, liver cancer)
• Specialist advice needed only in difficult cases

Question 13

Describe the relationship with comorbidities ie obesity and alcohol

Answer 13

• Excessive alcohol consumption most important factor contributing to cirrhosis
• Excessive alcohol consumption synergistically interacts with iron overload, contributing to cirrhosis. - recommend NHMRC safe drinking ([[Gastroenterology - Lecture 6]])
• Obesity and type 2 diabetes further exacerbate liver disease, diabetes risk in patients with hemochromatosis.
• Alcohol + obesity/T2D is double jeopardy
• Alcohol + obesity/T2D + iron overload is triple jeopardy
• Control of comorbidities ie alcohol and obesity is essential to prevent liver complications.

Question 14

Describe liver cancer surveillance

Answer 14

• Liver cancer screening is recommended for individuals with advanced liver fibrosis or cirrhosis.
  
  • ferritin > 1000 μg/mL, age > 40 years, unsafe alcohol consumption
• Surveillance includes liver stiffness measurement with transient elastrography; ultrasonography, and serum alpha-fetoprotein testing every six months indefinitively.
  HCC screening* highly effective and cost effective (with cirrhosis)