Learning Objectives
1) Explain the epidemiology and prevalence of Hereditary Hemochromatosis (HH)
2) Describe the typical presentation of HH
3) Describe the prognosis and treatment for HH
4) Name the genes involved and mode of inheritance for HH
5) Name and describe the variations of HH
6) Create a genetic counseling plan for a patient and the family members of
a person with HH
Pretest Questions
1) Of which of the following ages do the majority of male patients with Hereditary
Hemochromatosis present?
a.) 20-30
b.) 10-20
c.) 30-40
d.) 40-50
e.) 60-70
2) The majority of patients with Hereditary Hemochromatosis first present
with which of the following symptoms?
a) chronic hepatitis
b) fatigue
c) fulminant hepatic failure
d) cardiac arythmia
e) Arthropathy
3) Through what mode of inheritance is Hereditary Hemochromatosis acquired?
a) autosomal dominant
b) autosomal recessive
c) x-linked
d) incomplete penetrance
e) multivariant inheritance
4) Hereditary Hemochromatosis places individuals at increased risk for which
of the following diseases?
a) Diabetes Mellitus
b) liver cirrhosis
c) dilated cardiomyopathy
d) Arthropathy
e) Hypogonadism
f) all of the above
5. Which of the following genes plays a role in the development of Hereditary
Hemochromatosis?
a) ApoA2
b) BA4
c) ApoE4
d) ATP7B
e) HFE
Answers: 1) d 2) b 3) b 4) f 5) e
Case Study
A 42 year old male is referred for evaluation of increased serum glucose and
iron levels. The patient reports only an increase in fatigue over the last
two year, which he attributed to growing older. The patient denies fever, chills,
nausea, vomiting, gastro-esophageal reflux, hematemesis, melena, weight loss,
diarrhea, constipation, change in bowel habits, or any recent infection. The
patient denies drinking alcohol or illicit drug use. Family history is non-contributory.
Physical is unremarkable.
Explain the epidemiology and prevalence of Hereditary Hemochromatosis:
Approximately 10% of United States and Western European Caucasians
have the heterozygous mutation causing the disease. Approximately 5% of that
same population possesses the homozygous mutation. However, only an estimated
10% of heterozygous mutations result in patients ever becoming symptomatic.
What is the typical clinical presentation of Hereditary Hemochromatosis?
Clinical symptoms of this disease are caused from an increased
intestinal absorption of iron that results in iron overload of the liver, heart,
pancreas, and pituitary. Normally, both heme and non-heme iron stores are absorbed
in inverse proportion to the body’s iron stores. Individuals lose iron
through skin cells, sweat, the GI tract, and for women, through menses. These
losses are reacquired through absorbing approximately 10% of iron ingested
through diet. In patients with Hemochromatosis, the body’s iron stores
fail to regulate the amount of heme iron absorbed. The average age where enough
iron has been absorbed to cause symptoms is 40-50 years old for males and a
few years older in females. The following are symptoms of individuals
with the disease:
1)
weakness, lethargy, extreme fatigue (76%)
2)
arthralgia (44%)
3)
loss of libido (26%), impotence in males (45%)
4)
liver function abnormalities (75%)
5) diabetes
mellitus (48%)
6)
EKG abnormalities (31%)
***The Classic Triad of: diabetes,
skin pigmentation (bronze diabetes), and liver cirrhosis
does not occur until late in the disease***
Also, the majority of patients are
now originally diagnosed after further investigation of increased serum iron levels or from screening
after a relative is diagnosed with Hemochromatosis.
What diseases or medical problems does Hereditary Hemochromatosis
place a patient at increased risk?
- Liver Disease- Increased iron accumulation leads
to increased hepatic enzymes, hepatomegaly, and eventual development of cirrhosis.
If the disease is caught early and immediately treated, reversal of these
symptoms is often achieved.
- Hepatocellular carcinoma- studies show a range of increased
risk from 20-200 times the normal population
- Diabetes Mellitus- Approximately 50% of patients develops
Type 1 or Type 2 diabetes as a result of copper accumulating in the pancreas.
The risk for Type 2 diabetes is 6 times the normal population and the risk
for Type 1 diabetes is 5 times the general population
- Arthopathy- usually exhibits calcium pyrophosphate crystal
deposition
- Heart Disease- increased risk of dilated cardiomyopathy,
conduction disturbances (sick sinus syndrome), and heart failure
- Hypothyroidism
- Hypogonadism- secondary hypogonadism is the most commonly
observed endocrine abnormality seen in Hemachromatosis patients. Iron accumulates
in the pituitary glands, reducing trophic hormone secretion.
- Infections-such as Listeria, Yersinia enterocolitica,
and Vibrio vulnificus-seen in iron overloaded and dialysis patients
Hereditary Hemochromatosis is Diagnosed by:
In order to diagnose individuals who exhibit clinical signs
of Hemochromatosis, screening tests measuring serum ferritin concentrations
and transferrin-iron saturations are conducted. A fasting transferring-iron
saturation of over 50% in women and over 60% in men are considered positive
tests for Hemochromatosis. The diagnosis can be confirmed through genetic testing
listed below.
Is Hemochromatosis genetic? If so what genes are involved with
inherited forms of Hemochromatosis?
Hemochromatosis disease is acquired through autosomal recessive inheritance,
causing an increase in intestinal iron absorption. The defect is localized
on the short arm of chromosome 6 and is named the HFE mutation. The mutation
is actually two missence mutations. The most common missence mutation found
in patients with the disease is a substitution of cysteine by tyrosine at the
282 amino acid site, named the C282Y mutation. An average of 83% of individuals
(range 69-100%) with hereditary hemochromatosis were found to be homozygous
for this mutation. Studies have shown that homozygosity percentages vary
according to ethnicity. While 44% of white Americans are homozygous for the
C282Y mutation, only 11% of native Americans, 3% of Hispanic Americans, and
1.4% of African Americans have a homozygous C282Y mutation. Other mutations
include:
a) heterozygous mutations containing
either C282Y or H63D mutations (3-10% of patients)
b) heterozygous mutations containing
one C282Y mutation and one H63D mutation
(4-7% of patients)
c) homozygous H63D mutations (1%
of patients)
d) neither H63D nor C282Y mutations
(5-7% of patients)
In patients with the homozygous C282Y mutation, studies suggest less than
a 1% penetrence of the disease. Previous studies show that between 75-99% of
patients will remain clinically asymptomatic despite possessing the homozygous
C282Y mutation.
What genetic counseling could you offer Hereditary Hemochromatosis patients and their family
members?
Hemochromatosis is inherited in an autosomal recessive manner.
Thus, if a parent has Hemochromatosis, the risk of offspring from this individual
is 25%. However, 11% of Western European and United States Caucasians have
two mutations. A patient’s siblings also have a 25% risk of having the
mutation. It is important to remember that because of incomplete penetrance
a parent may have the mutation but no clinical symtpoms. Similarly, not all
offspring actually develop symptoms from the inherited mutations either.
What is the prognosis and treatment for Hereditary Hemochromatosis?
The goal of therapy is to keep serum ferritin concentrations at or below 50
ng/mL through phlebotomy. Patients with homozygous mutations should be treated
by phlebotomy if any biochemical evidence of increased iron storage exists.
If total body iron is normalized through phlebotomy before liver cirrhosis
develops, life expectancy is normal for these individuals. However, many homozygous
and heterozygous individuals (due to incomplete penetrance) never develop any
end organ damage and life expectancy is normal without phlebotomy treatment.
What are the different variations of Hereditary Hemochromatosis?
- Juvenile Hemochromatosis- the mutation causing this disease
variation has been located on the long arm of chromosome 1 and is named HJV.
The gene produces the protein hemojuvelin which is expressed in skeletal
muscle, the liver, and the heart. This disease presents most commonly with
reduced glucose tolerance, cardiomyopathy, and hypogonadism rather than liver
disease. The symptoms occur at an earlier age and progress at a faster rate
than Hereditary Hemochromatosis.
- Transferrin receptor 2 mutation- this
is a rare variant of the disease developed from a mutation in the TFR 2 receptor.
It is also acquired through autosomal recessive inheritance. Clinical symptoms
are similar to Hereditary Hemochromatosis.
- Ferroportin Mutations- this
variant is acquired through autosomal dominant inheritance. It is rare, only
seen in two Australian and European families (unrelated). It occurs as a
result of a mutation in the SLC40A1 gene that encodes a basolateral membrane
protein that moves iron across the enterocytes into the blood stream.
- Hyperferritinemia
without Iron Overload- occurs in patients
who are asymptomatic despite extremely high iron levels (>1000 ng/mL)
except for an increased association with bilateral cataracts.
Hereditary Hemochromatosis Disease Patient Internet Resources:
- Patient Support Groups for Hereditary Hemochromatosis : www.questdiagnostics.com/kbase/shc/shc29hmc.htm
www.cdc.gov/genomics/training/perspectives/hemo.htm
- Hemochromatosis Patient Fact Information- www.ironoverload.org/facts.html,
www.cdc.gov/hemochromatosis/resources/index.htm
RESOURCES:
- Schrier, SL, Bacon BR. Genetics of Hereditary Hemochromatosis. Uptodate
2006. Retrieved from www.uptodate.com on
August 20, 2006
- Edwards CQ, Kushner JP. Creening for hemochromatosis. N Engl J Med 1993;
328:1616.
- Kelly AL, Rhodes DA, Roland JM. Hereditary juvenile hemochromatosis: A
genetically heterogeneous life-thretening iron-storage disease. QJM 1998;91:607
- Schrier SL, Bacon BR. Clinical manifestations of herediatary hemochromatosis.
UptoDate 2006. Retrieved from uptodate.com on August 20, 2006
|
