hereditary hemochromatosis

1. Hereditary (primary)
hemochromatosis (HHC)

2. Introduction
 Hereditary hemochromatosis is an inherited predisposition to absorb excess
iron (Fe) from the diet
 Total body iron may reach up to 20-60g, normal body iron is 3-4g
 Mutations in the HFE gene are the most common cause of adult onset iron
overload
 In some predisposed individuals, excessive iron absorption and subsequent
storage in various organs (i.e. liver, pancreas, heart, joints and pituitary)
eventually lead to cellular injury
 If untreated, over time this can cause irreversible tissue/organ damage and
shorten life expectancy

3. Prevalence and incidence
 Autosomal recessive inheritance
 HFE– associated Hemochromatosis accounts for > 90% of cases and is the most
common adult onset form:
 Single point gene mutation C282Y and H63D can occur
 Cystine to tyrosine substitution (C282Y)
 Histadine to aspartic acid (H63D)
 Carrier rate 1 in 7 - 10 Caucasians
 Incidence 1 in 200 - 400

4. Autosomal Recessive Inheritance

5. HFE gene
 HFE gene on chromosome 6
 Involved in iron homeostasis by interacting with transferrin receptor in
basolateral membrane of intestinal epithelial cells
 HFE protein normally limits amount of iron uptake by gut and regulates
amount of iron stored in the tissues
 A defect in uptake of transferrin associated iron may lead to up regulation of
enterocyte iron specific divalent metal transporters and excessive iron
absorption

6. Hepcidin model in HFE mutation

7. Clinical manifestations
Influenced by
 Age
 Sex
 Dietary iron
 Alcohol
 Blood loss in menstruation and pregnancy
 Unknown factors
 Alcohol abuse and Hepatitis C accelerate
 Classic description: cutaneous hyperpigmentation and diabetes in a
patient with cirrhosis
Typically, symptoms of hereditary hemochromatosis present in men aged 40-60
and in post-menopausal women; however, onset is variable and can occur much
earlier or much later.

8. Clinical manifestations
Symptoms are nonspecific and include:
 weakness, lethargy
 skin discoloration (bronze or grey)
 abdominal pain with or without hepatomegaly
 joint pain and/or stiffness, arthritis
 diabetes
 cardiomyopathy
 cirrhosis
 hepatocellular carcinoma
 testicular atrophy, erectile dysfunction
 menstrual irregularity

9. Clinical manifestations

10. Diagnostic testing for HH
 Transferrin saturation:
 >45% indicates significant Fe accumulation
 Serum ferritin - levels indicating significant iron accumulation:
1. >200 mcg/L pre-menopausal women
2. >300 mcg/L post-menopausal women
3. >300 mcg/L for men
 CT may show features suggesting excess hepatic iron
 Liver biopsy if ferritin >1000 to assess damage
 Consider genetic testing – DNA testing for common mutations (C282Y, H63D)

11. Genetic Testing for HH should be offered
to patients with following
 Appropriate clinical presentation
 Any adult with biochemical evidence of iron overload
 >45% transferrin saturation (TS) and >300mg/L serum ferritin (SF) in men and
post-menopausal women or >200mg/L SF in pre-menopausal women
 Unexplained chronic liver disease and increased TS
 An adult with a first-degree relative (sibling, parent or child) with one of the
following genetic test results:
1. C282Y/C282Y (homozygote)
2. C282Y/H63D (compound heterozygote)
3. C282Y/S65C (compound heterozygote)
4. C282Y heterozygote (carrier)
 Liver biopsy suggestive of iron overload

12. What is the value of genetic testing?
 To confirm diagnosis
 Sequential screening of family members
 Family members with identified mutations can be offered:
 Screening plan to monitor for iron overload.
 Normal life expectancy if diagnosed before DM or cirrhosis
 Treatment plan to prevent further organ damage, morbidity & mortality.
 Prolonged survival with serial phlebotomy
 Goal of ferritin <50 may take > 1 year
 Environmental modification
 Diet, alcohol, viral hepatitis A/B immunization

13. Treatment
Reserved for evidence of iron overload/complications
 Venesection
 Deferoxamine (DFO)
 Avoid iron supplements, red meat
 Avoid alcohol and tobacco

14. Venesection
 Removal of 500 ml of blood
 Removes 250 mg iron
Do weekly until iron depletion
1. Hgb < 12
2. Ferritin < 50
3. Transferritin saturation < 50%
4. 2-3 years may be required to remove >20g
 Long term maintenance about once every 3 months

15. Deferoxamine chelation
 The greatest challenge with DFO is patients’ adherence to therapy
 Poor oral bioavailability
 Short plasma half-life
 Slow subcutaneous administration over 8–12 hours, 5–7 days/week
 Poor compliance

16. Prognosis
 Pre cirrhotic patients with HHC have a normal life expectancy
 Cirrhotic patients have a relatively good prognosis as compared to other forms
of cirrhosis
 Screening for hepatocellular carcinoma is mandatory as it is the main cause
of death affecting 1/3 of patients with cirrhosis

17. Case
 60 years old male
 3 month history of fatigue & joint pain
 drinks 2 beers/day
 brother with type 2 diabetes
Physical exam:
 hepatomegaly
 enlarged and tender knuckles
 several tattoos

18. Case
Routine blood work:
 Fasting glucose - normal
 Bilirubin - normal
 ALT 67 U/L
(reference range 0-40)
 AST 73 U/L
(reference range 0-37)
 GGT 92 U/L
(reference range 5-35)
Patient stops drinking
 6 weeks later:
 ALT & AST levels are
unchanged
 GGT - normal
 Hepatitis A & B serology
negative
What next?

19. Case
Further blood work:
 Ferritin 640 mcg/L(reference range <300mcg/L)
 Transferrin saturation 60% (reference range <45%)
What is the diagnosis?

20. Thank you