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
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
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
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?