Atlas of Genetic Diagnosis and Counseling || Hereditary Hemochromatosis

Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC; HFE 1) is a com-

mon hereditary disorder of iron metabolism and the

most common inherited autosomal recessive disorder

in Caucasians with a prevalence of 1 in 300 to 1 in 500

individuals. It is characterized by inappropriately high

iron absorption resulting in progressive iron overload.

Synonyms and Related Disorders

Hemochromatosis

Genetics/Basic Defects

1. Inheritance: autosomal recessive

2. Cause: result of a single faulty HFE gene on

chromosome 6p21.3 near the HLA complex that

codes for a glycoprotein called HFE, which binds

to the transferrin receptor and reduces its affinity for

iron-bound transferrin, allowing cellular uptake of

iron-based transferrin

3. Two common mutations (missense)

a. C282Y.

i. Accounts for most cases of HHC

ii. Homozygotes for C282Y mutation (>80%

cases world-wide) are at high risk for HHC.

iii. Heterozygote for C282Y mutation.

a) Have increased levels of transferrin

saturation

b) Rarely have organ damage

b. H63D: Homozygotes for H63D (often

has a potentiator, such as hepatitis C infection,

b-thalassemia trait) are unlikely to develop HHC.

c. C282Y/H63D (11% present phenotypically):

Compound heterozygotes for C282Y/H63D have

a milder form of HHC than C282Y homozygotes.

4. Other HFE mutations

a. Missense mutations

i. S65C: the third most common mutation

ii. G93R

iii. I105T

iv. Q127H

v. R330M

b. Frameshift mutations

i. P160DCii. V68DT

c. Nonsense mutations

d. Spice site mutation

5. Clinical expression of the disease

a. Homozygotes: affected clinically

b. Heterozygotes

i. Can have minor abnormalities of the param-

eters that reflect body iron status

ii. Can develop significant iron overload

only when other diseases that affect iron

metabolism coexist, such as:

a) Heterozygous b-thalassemia

b) Hereditary spherocytosis

c) Sporadic porphyria cutanea tarda

6. Hereditary hemochromatosis not attributable to

mutations in HFEa. A subgroup of hereditary hemochromatosis

indistinguishable from HFE-associated HHC

b. Does not have mutations in HFE.c. The disease does not appear to be linked to the

HLA complex.

d. The genetic basis has not been defined.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_116,# Springer Science+Business Media, LLC 2012

1025

7. Pathophysiology (Whittington and Kowdley, 2002)

a. Inappropriately high intestinal iron absorption:

the most important pathophysiological step in

body iron loading

b. Effects of mutations on iron absorption: central

to the understanding of the pathological basis of

hereditary hemochromatosis

Clinical Features

1. Variable clinical presentation

2. Median age at presentation of symptoms

a. Fifty one years in males

b. Female homozygotes

i. Less likely to develop symptomatic disease

ii. Median age: age 50

3. Asymptomatic: abnormal serum iron studies on

routine screening

4. Early manifestations

a. Often subtle

b. Vague arthralgias

c. Fatigue

d. Lethargy

e. Apathy

f. Weight loss

5. Later manifestations as tissue iron progressively

accumulates

a. Discoloration of the skin

b. Arthropathy

i. Due to iron accumulation in joint tissues.

ii. Arthritis with joint swelling most com-

monly involves:

a) Metacarpophalangeal (MCP) joints

b) Proximal interphalangeal joints

c) Knees

d) Feet

e) Wrists

f) Back

g) Neck

iii. Chondrocalcinosis.

a) Involves the knees and wrists

b) May be asymptomatic

iv. Symptoms usually do not respond to iron

removal.

c. Liver involvement

i. Abdominal pain associated with

hepatomegaly

ii. Hepatomegaly, the most common physical

abnormality

iii. Splenomegaly

iv. Cirrhosis

v. Portal hypertension

a) Ascites

b) Encephalopathy

vi. Hepatocellular carcinoma in about 30% of

cases

d. Cardiac involvement

i. Dilated cardiomyopathy

ii. Arrhythmias

iii. Cardiac failure

e. Endocrine abnormalities

i. Diabetes mellitus

ii. Pituitary hypogonadism

a) Decreased libido and impotence (tes-

ticular atrophy) in men

b) Amenorrhea in women

iii. Hypothyroidism

6. Suspect diagnosis from characteristic clinical

manifestations

a. Classical clinical triad of “bronzed cirrhosis

with diabetes” in a middle-aged man:

i. Diffuse hyperpigmentation (melanodermia),

often with a metallic gray or “bronze” rather

than a brown discoloration

ii. Hepatomegaly, with the liver markedly

enlarged, firm and sharp to palpation but

without signs of hepatocellular insuffi-

ciency (no palmar erythema, no spider

nevi, no bruises, normal prothrombin time)

or of portal hypertension

iii. Diabetes mellitus, often requiring insulin

b. Presence of cardiomyopathy

c. Diagnosis at this late stage: considered a

diagnostic failure

7. Suspect diagnosis from earlier signs and

symptoms

a. Sex and age: Both young adults and older women

are at risk.

b. “Rule of three A’s”

i. Asthenia: unexplained chronic fatigue

ii. Arthralgia

a) A “painful” handshake: resulting from

chronic arthritis of the second and third

MCP joints.

b) Other joints affected especially the

knees and wrists.

1026 Hereditary Hemochromatosis

c) Can also suffer from pseudogout (pyro-

phosphate arthropathy).

d) Arthritis greatly diminishes the quality

of life.

iii. Aminotransferase (transaminases) elevation

8. Cause of death

a. Liver failure

b. Cancer

c. Congestive heart failure

d. Arrhythmia

9. Other conditions associated with significant iron

overload

a. Non-HFE hereditary hemochromatosis

(Pietrangelo, 2010)

i. Transferrin receptor 2 gene (TFR2, on 7q22)hemochromatosis

a) Caucasian or non-Caucasian

b) Male or female

c) Thirty to forty years

d) Cardiomyopathy

e) Endocrinopathy

f ) Liver disease

g) Elevated transferrin saturation (TS) and

serum ferritin (SF)

ii. Hemojuvelin (HJV on 1q21) or hepcidin

gene (HAMP, on 19q13) juvenile

hemochromatosis


b) Male or female

c) Fifteen to twenty years

d) Impotence/amenorrhea and/or

cardiomegaly

e) High TS and SF

iii. Ferroportin disease (SLC40A1, on 2q32)


b) Male or female

c) Ten to eighty years

d) One patient with unexplained

hyperferritinemia

e) Unexplained elevation of SF and normal

TS

b. Secondary iron overload

i. Iron-loading anemias (ineffective erythropoi-

esis, increased iron absorption, blood

transfusions)

a) b-thalassemia

b) Congenital dyserythropoietic anemias

c) Sideroblastic anemia

d) Pyridoxine-responsive anemia

ii. Hypoplastic anemias (blood transfusions)

a) Aplastic anemia

b) Myelodysplastic syndromes

c) Pure red cell aplasia

iii. Chronic hemolytic anemias (increased iron

absorption)

a) Spherocytosis

b) Sickle cell anemia

c) Pyruvate kinase deficiency

iv. Parental iron overload

a) Red blood cell transfusion

b) Iron dextran injections

c) Long-term hemolysis

v. Neonatal hemochromatosis

vi. Ceruloplasmin deficiency (acerulo-

plasminemia) (decreased ferroxidase

activity)

vii. Sub-Saharan iron overload (increased die-

tary iron, increased iron absorption)

viii. Porphyria cutanea tarda (increased iron

absorption)

ix. Hepatic disorders

a) Chronic viral hepatitis

b) Alcoholic cirrhosis

c) Portacaval shunts (increased iron

absorption)

Diagnostic Investigations

1. Biochemical testing

a. High serum ferritin levels

b. High transferrin-iron saturation value: an early

and reliable indicator for risk of iron overload/

HFE-HHC

i. A fasting transferrin-iron saturation of�60%

for men and�50% for women on at least two

occasions, in the absence of other known

causes of elevated transferrin-iron saturation,

is observed in about 80% of individuals with

HFE-HHC and is considered suggestive of

HFE-HHC.

ii. A threshold transferrin-iron saturation

of 45% is more sensitive for detecting

HFE-HHC suggested by recent studies.

iii. Some overlap occurs in serum transferrin-iron

saturation among homozygotes and

heterozygotes.

Hereditary Hemochromatosis 1027

2. Radiography

a. Arthropathy

i. Squared-off bone ends and hook-like

osteophytes in the MCP joints, particularly

in the second and third MCP joints

ii. Subchondral arthropathy

iii. Chondrocalcinosis

3. MRI of the liver

a. The most promising noninvasive technique for

identification of HHC. High hepatic iron content

causes:

i. A decrease in signal intensity of the liver

ii. A marked decrease in transverse (T2) relaxa-

tion time

4. Liver biopsy to assess histologic hepatic iron stores

a. Usually not indicated for diagnostic purposes in

HFE-HHC.

b. Recommended to C282Y homozygotes with

a serum ferritin concentration of >1,000 ng/mL

to determine if cirrhosis is present; those with

a serum ferritin concentration <1,000 ng/mL

need not undergo biopsy.

c. Useful to determine hepatic iron overload, par-

ticularly in patients with presumed hemochro-

matosis who lack the common HFE mutations

associated with HFE-HHC.

5. Molecular genetic testing (Kowdley et al. 2006)

a. Mutation analysis for the disease-causing alleles

in the HFE gene (C282Y and H63D)

i. C282Y/C282Y homozygotes (60–90%)

ii. C282Y/H63D compound heterozygotes

(3–8%)

iii. H63D/H63D homozygote (1%)

iv. H63D/? (4%)

v. C282Y/? (1%)

vi. ?/? (6%)

b. Testing strategy for a proband

i. Mutation analysis warranted in adults with

serum transferrin-ion saturation of >45%

ii. Individuals with homozygous C282Y/

C282Y or compound heterozygous C282Y/

H63D: have genetic makeup to develop

HFC-HHC

iii. Individuals who are not C282Y homozygotes

a) Generally represent a heterogeneous

group.

b) Many have liver disease unrelated to

HFE-HHC or other metabolic syndromes.

c) Somemay have primary iron overload in

a pattern identical to HFE-HHC.

d) The next diagnostic step: perform liver

biopsy with assessment of histology

and measurement of hepatic iron

concentration

c. Carrier detection: identification of carriers and

noncarriers in at-risk family members possible

provided both HFE alleles have been identified

in the proband

6. Screening for HHC

a. HHC: a prime target for screening because of its

high prevalence, morbidity, and mortality, as

well as the benefits of early diagnosis and

treatment

b. Initial screening probe for HHC diagnosis

i. Transferrin saturation

ii. Unsaturated iron-binding capacity

Genetic Counseling

1. Recurrence risk (Kowdley et al. 2006)

a. Patient’s sib

i. Twenty-five percent if both parents are HFE-

HHC heterozygotes

ii. Fifty percent if one parent is HFE-HHC het-

erozygotes and other parent HFE-HHC

homozygote

b. Patient’s offspring: 5% risk to be affected due to

the high carrier rate forHFEmutant alleles in the

general population

i. The risk that the partner of an individual with

HFE-HHC is heterozygous for the C282Y

allele is 1/9

ii. Therefore, the risk to the offspring to be

a homozygote for C282Y allele is 1/2 �1/9 ¼ 1/18 (about 5%)

2. Prenatal diagnosis

a. Technically feasible when both parents carry

identified HFE mutations

b. Highly unusual to request prenatal diagnosis

because HHC is an adult-onset, treatable disease

3. Management (Kowdley et al. 2006)

a. Early diagnosis and treatment

i. Can completely prevent the development of

clinical complications

ii. Offer patients a normal life expectancy


b. Treatment of iron overload

i. Periodic phlebotomy

a) Goal of therapy: to achieve and maintain

a serum ferritin concentration of

�50 ng/mL

b) Usual therapy: removal of the

excess iron by weekly phlebotomy until

the serum ferritin concentration is

�50 ng/mL

ii. Dietary management

a) Avoid medicinal iron

b) Avoid mineral supplements

c) Avoid excess vitamin C which increases

intestinal absorption of inorganic iron

d) Avoid uncooked shellfish or other sea-

food which can be contaminated with V

vulnificus causing sepsis in patients with

HHC

e) Avoid alcohol consumption for patients

with liver involvement

iii. Iron chelation therapy: not recommended

unless the patient has an elevated serum ferri-

tin concentration and concomitant anemia that

makes therapeutic phlebotomy impossible

c. Conventional therapies for diabetes, hepatic fail-

ure, and cardiac failure

d. Cirrhosis: screen for hepatocellular cancer

i. Biannual abdominal ultrasound

ii. Annual serum alpha-fetoprotein testing

e. Orthotopic liver transplantation for end-stage

liver disease from decompensated cirrhosis

f. Surveillance of at-risk asymptomatic adults with

C282Y homozygotes

i. Monitor serum ferritin concentrations yearly

starting in early adulthood

ii. Initiate therapeutic phlebotomy when serum

ferritin concentrations are elevated

References

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Fig. 1 Father (40-year-old) and son (12-year-old) both carry

heterozygous C282Y mutation. H63D and S65C were not

detected. The father currently receives periodic phlebotomy

with fasting transferrin-iron saturation level of 56% (15–50)

and ferritin level of 1,238 ng/mL (20–345). The son is currently

asymptomatic. Approximately 3–5% of patients with hereditary

hemochromatosis have this genotype. The molecular results do

not rule out the possibility of disease causing mutations in other

regions of the HFE gene or in other as yet undefined genes

Temperature (°C)

48.0 50.0 52.0 54.0 56.0 58.0 60.0 62.0 64.0 66.0 68.0 70.0 72.0 74.0 76.0

10.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

−1.0

Flu

ores

cenc

e -d

(F2)

/dT

Fig. 2 Real-time PCR of HFE

gene in another patient. The

patient is homozygous for

C282Y mutation,

demonstrated by the green line

(melting point (Tm) ¼ 62.89)


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Atlas of Genetic Diagnosis and Counseling || Hereditary Hemochromatosis