Transcript Document

Hereditary Hemochromatosis
Developed by Dr. Judith Allanson, Ms. Shawna Morrison and Dr. June Carroll
Last updated April 2014
Disclaimer
• This presentation is for educational purposes only and should
not be used as a substitute for clinical judgement. GEC-KO
aims to aid the practicing clinician by providing informed
opinions regarding genetic services that have been developed
in a rigorous and evidence-based manner. Physicians must use
their own clinical judgement in addition to published articles
and the information presented herein. GEC-KO assumes no
responsibility or liability resulting from the use of information
contained herein.
Objectives
• Following this session the learner will be able to:
– Refer to their local genetics centre and/or order genetic
testing for hereditary hemochromatosis
– Discuss and address patient concerns regarding family
history of hereditary hemochromatosis
– Find high quality genomics educational resources
appropriate for primary care
Case
• Michael is a 49-year-old male of Northern European descent
with complaints of joint pain in his knees and hands. He is
having a difficult time because his brother recently passed
away at a young age.
• Past Medical History:
– Numerous office visits over 3–4 years for fatigue, weakness, and pain
• Family History:
–
–
–
–
–
–
Michael is married with two healthy teenage sons (16, 14)
Father died at age 55 from myocardial infarction (MI)
Mother, 76, alive and well
Brother died at age 53 of esophageal varices
Sister, 55, has type II diabetes
Brother, 43, and sister, 40, alive and well
CDC- NCBDDD http://www.cdc.gov/ncbddd/hemochromatosis/index.html
Family history
55
MI
49
Joint pain – knees
and hand
HPI fatigue, pain &
weakness
16
14
75
A&W
d.53
Esophageal varices
55
Type II diabetes
43
A&W
40
A&W
Case
• Social History:
– Drinks "a couple of beers a week”, no tobacco or recreational drug use
– No multivitamin use
• Physical Exam:
– Mild hepatomegaly
– Modest enlargement of the second and third MCP joints
What is Hereditary Hemochromatosis?
• Hereditary hemochromatosis is an inherited predisposition to
absorb excess iron (Fe) from the diet
• 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) eventually lead to cellular injury
• If untreated, over time this can cause irreversible tissue/organ
damage and shorten life expectancy
• With early identification of at-risk individuals, surveillance of
iron indices, and treatment when necessary, complications
can be avoided
What is Hereditary Hemochromatosis?
• 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.
• Symptoms are nonspecific and include:
– weakness, lethargy
– skin discoloration (bronze or grey)
– abdominal pain with or without hepatomegaly
– joint pain and/or stiffness, arthritis
While any of these health
– diabetes
concerns can be caused by
– cardiomyopathy
hereditary hemochromatosis,
– cirrhosis
the presence of two or more
should greatly increase
– hepatocellular carcinoma
suspicion that the condition is
– testicular atrophy, erectile dysfunction
present
– menstrual irregularity
What do I need to know about the genetics
of Hereditary Hemochromatosis?
• Autosomal recessive, with reduced penetrance
• Caused by mutations in the HFE gene located on chromosome 6
• Standard testing by North American molecular genetics laboratories
is targeted mutation analysis
– Looks specifically for the two most common HFE mutations, C282Y and
H63D
– These account for over 90% of hereditary hemochromatosis
• About 1 in 3 individuals of Northern European ancestry are carriers
(heterozygotes) of the C282Y or H63D HFE gene mutations
• About 1 in 260 individuals have two copies of (are homozygous for)
the C282Y HFE gene mutation (genotype C282Y/C282Y)
Autosomal Recessive Inheritance Refresher
H/ H
No HFE gene mutation
¼ - 25%
C282Y carrier
C282Y carrier
C282Y / H
C282Y / H
C282Y/ H
H / C282Y
C282Y carrier
C282Y carrier
½ - 50%
C282Y/ C282Y
Homozygous for C282Y
¼ - 25%
At risk for iron overload
Actual risk depends on other
genetic and non-genetic factors
Autosomal Recessive Inheritance Refresher
Homozygous for C282Y
C282Y / C282Y
C282Y/ H
C282Y/ H
No HFE mutation
H/H
C282Y / H
100% will be heterozygous for C282Y HFE
mutation
*can reveal non-paternity
C282Y/ H
Who should be offered biochemical testing
for iron overload?
• If your patient has suggestive symptoms, physical findings or a family
history of Hereditary Hemochromatosis, transferrin saturation and serum
ferritin are ideally ordered together to determine the likelihood of iron
overload
• Transferrin saturation (TS)
– TS is a reliable screen for iron overload
– Fasting TS of >45% is considered a sensitive but not specific threshold for identifying
individuals who may have iron overload
• Serum ferritin (SF)
– In combination with persistent elevation of fasting TS, elevated ferritin is suspicious for
iron overload
– Remember that SF is an acute phase reactant that can be elevated by other
inflammatory processes. Therefore an elevated SF does not necessarily
imply iron overload and is not a reliable first or only screen
Who should be offered genetic testing?
•
Any adult with biochemical evidence of iron overload
– >45% transferrin saturation (TS) and >300mg/L serum ferritin (SF) in men and postmenopausal 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:
–
–
–
–
•
C282Y/C282Y (homozygote)
C282Y/H63D (compound heterozygote)
C282Y/S65C (compound heterozygote)
C282Y heterozygote (carrier)
Family history of iron overload, liver disease, type II diabetes, arthritis, heart
disease (relatives with symptoms of HFE-hereditary hemochromatosis)
Individuals with HFE-hereditary hemochromatosis occasionally demonstrate a normal
TS and an elevated ferritin. If clinical suspicion is high and/or the patient has a
positive family history, genetic testing is still warranted
What does the genetic test result mean?
• The actual risk to develop iron overload is dependent
on how many and which gene mutations have been
inherited, in addition to other genetic and nongenetic factors
–
–
–
–
gender
alcohol intake
use of iron and vitamin C supplements
menstrual/pregnancy-associated iron losses
What does the genetic test result mean?
• Two mutations identified in an individual with biochemical evidence of
iron overload confirm Hereditary Hemochromatosis diagnosis
• Two mutations identified in an asymptomatic individual suggest risk of
developing iron overload and yearly monitoring of iron indices is
recommended
HFE mutations
identified
C282Y/C282Y
Risk of iron overload
Highest risk of developing iron overload (38-50%)
Many of these individuals never accumulate enough iron to cause disease
(about 10-33% will develop symptoms )
C282Y/H63D
About 2% lifetime risk of developing iron overload
C282Y/S65C
Low lifetime risk of developing iron overload - similar to C282Y/H63D
H63D/H63D
About 1% lifetime risk of developing iron overload
How do I order the genetic test?
• Genetic testing is performed on a blood sample
– Will only assess risk to develop Hereditary Hemochromatosis or
confirm diagnosis in symptomatic patient
• It is important to include the following information on any requisition for
the best test interpretation:
– Indication for testing e.g. ‘symptoms of indicated disease’ or ‘abnormal iron
indices’ or ‘positive family history’
– Ethnicity e.g. Northern European
– Relevant family history e.g. parent/sibling with Hereditary Hemochromatosis
(include genetic test results of affected individual if known)
– Relevant medical history/investigations; e.g. biochemical iron overload
How will genetic testing help you and your
patient?
• If mutations are identified
– Appropriate surveillance and management of risk of iron overload
•
If no mutations are identified
– If your patient was tested because of a known family mutation, he/she
no longer needs frequent monitoring of iron indices and is not at
increased risk to develop iron overload. The test has ruled out
Hereditary Hemochromatosis
– If your patient was tested because of a reported positive family
history, more information is needed before ruling out HH in this
individual. Your patient should be encouraged to obtain confirmation
of the familial mutations and/or diagnosis
– If your patient was tested because of persistently high iron indices,
additional investigations should be considered
Are there harms or limitations of genetic
testing?
• Potential harms
– Insurance discrimination
• Genetic testing in an asymptomatic individual may affect his/her ability to
obtain life, disability, critical illness, long-term care and/or extended
health insurance
• Hereditary Hemochromatosis is a treatable condition and some insurance
companies will not deny coverage to a treated individual
– Non-paternity could be revealed
• Limitation
– Targeted mutation analysis
• Not every HFE gene mutation is looked for, however, the most common
mutations account for more than 90% of all mutations, thus fewer than
10% will be missed using current testing strategies
Case
• Blood work demonstrates biochemical evidence of
iron overload
– Ferritin >300mg/L AND TS >45%
• + suggestive family history [MI, liver disease with iron
overload, type II diabetes in first degree relatives]
• You suspect Hereditary Hemochromatosis and offer
genetic testing
• Michael accepts and the result shows he is
homozygous for C282Y HFE gene mutation
Surveillance and management
Patient identified to have two HFE
gene mutations*
Annual
monitoring
of serum
ferritin (SF)
Normal
Increased
Continue annual SF
monitoring
Refer to specialist
(e.g.
gastroenterologist,
hematologist)
Pearls
• Hereditary Hemochromatosis is a common inherited predisposition to
absorb excess iron from the diet caused by mutations in the HFE gene
• Most individuals with the predisposition do not develop clinical disease
• Hereditary Hemochromatosis has the potential to cause morbidity and
mortality. With early identification of at-risk individuals, appropriate
surveillance of iron indices, and treatment when indicated, complications
can be avoided
• Genetic testing should be considered for:
– Adults with biochemical evidence of iron overload (>45% fasting transferrin
saturation and >300mg/L serum ferritin in men and post-menopausal women
or >200mg/L SF in pre-menopausal women)
– Any adult whose first-degree relative has the C282Y HFE gene mutation
– Individuals with suggestive family histories
References
•
•
•
•
•
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of
Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by
the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 328–43
European Association for the Study of the Liver. EASL clinical practice guidelines for HFE
hemochromatosis. J Hepatol 2010; 53:3–22.
Kowdley KV, Bennett RL, Motulsky AG. HFE-Associated Hereditary Hemochromatosis. 2000
Apr 3 [Updated 2012 Apr 19]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1440/
Wallace DF, Walker AP, Pietrangelo A, Clare M, Bomford AB, Dixon JL, Powell LW,
Subramaniam VN, Dooley JS. Frequency of the S65C mutation of HFE and iron overload in
309 subjects heterozygous for C282Y. J Hepatol 2002; 36(4):474-9.
Centre for disease Control and Prevention. National Center on Birth Defects and
Developmental Disabilities. Hemochromatosis.
http://www.cdc.gov/ncbddd/hemochromatosis/index.html [Accessed September 2013]