Hereditary Hemochromatosis
Our Patient
• 55 year old white male
• Chief complaint: “Really tired all the time.”
History and Physical
• Pt complains of extreme fatigue for the past six months.
• Pt has less endurance for his favorite activities.
• Pt feels that his exercise tolerance is decreased – he gets
short of breath easily.
• Pt cannot identify exacerbating or relieving factors.
• Associated symptoms:
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Abdominal fullness.
Severe joint pains.
Frequent urination.
Thinks he may get occasional leg edema, but isn’t sure.
Occasional heart palpitations.
No fevers.
Differential Diagnosis of Subacute
Fatigue
• Broad differential diagnosis!
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Cardiac disease
Renal failure
Liver failure
Endocrine disease
• Thyroid?
• Adrenal?
• HPA axis?
– Autoimmune disease
– Chronic infection
• Bacterial?
• Viral?
• Fungal?
– Depression
– Cancer
• What do you want to do for this patient?
History and Physical, Continued.
• PMH:
– Hypertension, past 5 years. Well controlled on
thiazide.
– Arthritis, past 15 years in hips, knees, hands.
– Low testosterone, past 5 years.
• PSH:
– None.
History and Physical, Continued.
• FH:
– Mother is alive at 80; has mild hypertension and
Alzheimer dementia.
– Father died of congestive heart failure at 59. Had
hypertension, diabetes mellitus, and severe arthritis.
– Siblings:
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Sister, 60, recently diagnosed with diabetes mellitus.
Brother, 57, healthy.
Brother, 52, advanced alcoholic cirrhosis.
Sister, 49 and healthy.
– Pt has two healthy children, ages 22 and 24.
History and Physical, Continued.
• Social History. Pt is married. Nonsmoker and
nondrinker. Worked as a business executive until he
retired this year due to symptoms.
• Review of systems, significant points.
– Skin: Increased pigmentation; denies sun exposure. Pt
notices that his breast tissue has grown.
– Cardiovascular: Worsening exertional dyspnea over the
past three years. Can climb 2 flights of stairs. Has had 2pillow orthopnea for the past 6 months. No syncope or
palpitations.
– Hematologic: Pt notices that he bruises more easily.
– Endocrine: Decreased sexual drive.
– Musculoskeletal: Worsening arthritis.
Initial Labs
– Chem 10
• Na+, K+, HCO-3, Cl-, BUN, Creatinine, Glucose, Ca++,
Mg++, PO4.
– CBC with differential
– Serum liver enzymes (AST, ALT, Alk Phos)
– Serum B-type Natriuretic Peptide
– Serum TSH and total T4.
– Serum Iron studies
Lab Results:
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WHICH OF THESE ARE ABNORMAL?
Na+: 140 mEq/L
K+: 4.0 mEq/L
Cl-: 100 mEq/L
HCO3: 24 mEq/L
BUN: 30 mg/dL
Cr: 1.0 mg/dL
Glucose: 240 mg/dL
Ca++: 9.8 mg/dL
Mg++: 2.0 mg/dL
PO4: 3.0 mg/dL
Lab Results:
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WHICH OF THESE ARE ABNORMAL? (Abnormals are in red).
Na+: 140 mEq/L (normal ≈ 137-145 mEq/L)
K+: 4.0 mEq/L (normal ≈ 3.5-5.0 mEq/L )
Cl-: 100 mEq/L (normal ≈ 98-110 mEq/L )
HCO3: 24 mEq/L (normal ≈ 22-26 mEq/L )
BUN: 18 mg/dL (normal ≈ 7-21 mg/dL )
Cr: 1.0 mg/dL (normal ≈ 0.5-1.4 mg/dL )
Glucose: 240 mg/dL random fasting  Abnormal. (Normal ≈ 65110mg/dL)
• Ca++: 9.8 mg/dL (normal ≈ 8.5-10.4 mg/dL )
• Mg++: 2.0 mg/dL (normal ≈ 1.5-2.5 mg/dL )
• PO4: 3.0 mg/dL (normal ≈ 2.5-4.5 mg/dL )
Lab Results:
• Which of these is abnormal?
• CBC with differential:
– Hemoglobin: 15 g/dL
– Hematocrit: 45%
– Plt: 357,000/μL
– WBC: 8,500/μL; 74% Neutrophils, 24% Lymphs,
1% Eosinophils, 1% Basophils
Lab Results:
• Which of these is abnormal?
• Answer: None. All are OK.
• CBC with differential:
– Hemoglobin: 15 g/dL (Normal male ≈ 13.2-16.2 g/dL)
– Hematocrit: 45% (Normal male ≈ 40-52%)
– Plt: 357,000/μL (Normal ≈ 140,000-350,000/µL)
– WBC: 8,500/μL; 70% Neutrophils, 24% Lymphs,
4% Monocytes; 1% Eosinophils, 1% Basophils
(Normal ≈ 4,100-10,900 WBC; Neutrophils 35-80%; Lymphocytes 2050%; Monocytes 2-12%; Eosinophils 0-7%; Basophils 0-2%)
Lab Results
• Which of these are abnormal?
• Liver Enzymes
– AST: 201 U/L
– ALT: 186 U/L
– Alk Phos: 314 U/L
• B-type Natriuretic Peptide: 450 pg/mL
• Endocrine
– TSH: 0.1µU/mL
– Total T4: 1.0 mg/dL
– Free T4 0.2 mg/dL
Lab Results?
• Which of these are abnormal?
• Liver Enzymes
– AST: 150 U/L (Normal ≈ 5-35 U/L)
– ALT: 107 U/L (Normal ≈ 7-56 U/L)
– Alk Phos: 214 U/L (Normal ≈ 38-126 U/L)
• B-type Natriuretic Peptide: 450 pg/mL (< 100pg/mL is normal;
100-300pg/mL suggests CHF; 300-600pg/mL indicates mild CHF)
• Endocrine
– TSH: 0.1 µU/mL (Normal ≈ 0.4-4.0µU/mL)
– Total T4 1.0 mg/dL (Normal ≈ 4.5-11.5 mg/dL)
– Free T4 0.2 mg/dL (Normal ≈ 0.7-2.0 mg/dL)
Lab Results
• Which of these are abnormal?
• Iron Studies
– Serum Iron Concentration: 250µg/dL
– Serum Ferritin: 3,000ng/mL
– Transferrin Saturation: 80%
– Total Iron Binding Capacity: 200µg/dL
Lab Results
• Which of these are abnormal?
• Iron Studies
– Serum Iron Concentration: 250µg/dL
• (Normal male ≈ 50-150 µg/dL)
– Serum Ferritin: 3,000ng/mL
• (Normal male ≈ 20-300ng/mL)
– Transferrin Saturation: 80%
• (Normal ≈ 14-50%)
– Total Iron Binding Capacity: 200µg/dL
• (Normal ≈ 250-450 µg/dL)
Lab Results Recap
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Elevated Liver Enzymes
Hypothyroidism (low TSH and T4)
Mild Congestive Heart Failure
Elevated Blood Glucose
Serum Iron Studies suggest Iron Overload.
What will we do to confirm the suspected
diagnosis?
• What other tests do we want?
Next Steps?
• Liver
– Biopsy
• Cardiac Evaluation
– Cardiac Imaging Options
– Electrocardiogram
– Biopsy?
Liver Biopsy Results
No cirrhosis
noted.
Hemosiderin granules inside hepatocytes.
Note the bright staining with Prussian
Blue.
Hemosiderin granules at
lower-power magnification,
without Prussian blue stain.
Cardiac Studies
• Echocardiogram – shows biventricular
diastolic dysfunction.
• Holter EKG – shows atrial tachyarrhythmias.
• Myocardial biopsy – shows hemosiderosis
(intracellular iron).
Surviving myocytes
Hereditary Hemochromatosis
• Autosomal Recessive
• Associated with mutations in the HFE gene, whose protein product
modulates iron transport from duodenal enterocytes into the
bloodstream.
• Affects 8/1000 of people of Northern European descent; as many as
10% of U.S. whites may be carriers.
• 50% of affected males and 25% of affected females suffer serious
complications.
• The most common disease-associated allele is the C282Y mutation;
an H63D mutation is also reported. Compound heterozygotes may
display a disease phenotype.
• Treatment is therapeutic serial phlebotomy. Even if instituted late,
this can improve patient symptoms, most notably cardiac ones.
Pathophysiology
– With insufficient HFE function, inappropriate
amounts of iron accumulate in the body.
– When found intracellularly, this iron is referred to
as “hemosiderin.”
At left, panels A-D, hemosiderin
granules in liver tissue.
Prussian blue stain
Note the intracellular
location of the granules.
Pathophysiology, Continued
– Hemosiderin deposition is thought to cause tissue
damage by generating free radicals.
– Hemosiderin may deposit in the anterior pituitary.
– Hemosiderin may deposit in the liver.
– Hemosiderin may deposit in the pancreas.
– Hemosiderin may deposit in the myocardium.
– Hemosiderin may deposit in joints.
• May present as severe, diffuse osteoarthritis.
– Hemosiderin may deposit in the skin.
• Patients, who are often naturally light-skinned, may
experience an unexplained darkening of their skin.
Hereditary Hemochromatosis – Clinical
Features
• Affected males – symptoms usually manifest after age 40.
• Affected females – symptoms usually manifest several
years after menopause.
• This disparity is thought to be related to females’ tendency
to lose iron through menses and in childbearing.
• The “classic” presentation is that of “bronze diabetes”, or a
constellation of symptoms including skin
hyperpigmentation and diabetes mellitus; this represents a
very late stage of the disease.
• Today, it tends to present earlier; the most common
presenting symptoms are nonspecific, and include fatigue,
abdominal pain, and arthritis.
Hereditary Hemochromatosis – Clinical
Features
• LIVER:
– Iron overload eventually leads to hepatic
inflammation, fibrosis, and cirrhosis.
– May initially manifest as hepatomegaly or
abdominal discomfort.
– Patients frequently present with elevated liver
enzymes, or liver failure.
– Patients are more susceptible to alcoholic
cirrhosis, and should be counseled to avoid
alcohol.
Hereditary Hemochromatosis – Clinical
Features
• Hypothalamic-Pituitary Axis.
– Hemosiderin deposits in the anterior pituitary.
– In men, loss of gonadotropins may result in low
libido, testicular atrophy, and gynecomastia.
– In all patients, TSH levels may be low, resulting in
hypothyroidism.
– The thyroid gland itself may be affected by
hemosiderin deposition too; this may lead to
transient hyperthyroidism followed by
hypothyroidism.
Hereditary Hemochromatosis – Clinical
Features
• Pancreas
– Hemosiderin deposits in the pancreas, leading to
eventual endocrine pancreatic failure.
– End result is diabetes mellitus.
Hereditary Hemochromatosis – Clinical
Features
• CARDIAC
– Hemosiderin deposits in myocardial cells.
– Eventually results in diastolic dysfunction;
clinically presents as a restrictive
cardiomyopathy.
– In severe cases, clinical picture may be one of
congestive heart failure.
– Increased incidence of atrial arrhythmias in these
patients.
– Heart blocks may occur.
Hereditary Hemochromatosis – Clinical
Features
• Immunologic: Unusual infections
– Due to their high serum iron levels, hereditary
hemochromatosis patients are susceptible to severe
systemic infections by certain pathogens which can
include...
– Listeria monocytogenes – found in deli meats, cheese,
unwashed fruits.
– Vibrio vulnificus – found in raw seafood and salt water.
– Yersinia pseudotuberculosis – foodborne or zoonotic.
– Rhizopus orayzae – virulent, angioinvasive fungus.
Hereditary Hemochromatosis – Clinical
Features
• Ophthalmologic: Angioid streaks.
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Represents small breaks in Bruch’s membrane, in the choroid layer of the eye.
Found in HH as well as other metabolic diseases.
Patients are prone to developing neovascularization and retinal damage.
Patients should be advised to wear polycarbonate safety glasses.
Radiographic Correlates
Liver is more
opaque than
normal.
CT scan of a patient
with advanced
hereditary
hemochromatosis.
Enlarged spleen
suggests that this
patient has portal
hypertension
secondary to liver
damage.
Radiographic Correlates
Normal liver. Note the
uniform attenuation
pattern of the liver, and
how it has about the
same density as the
spleen.
Hemochromatosis. Note how the
liver is hyperattenuating
compared with the spleen. Also
note that the spleen is enlarged.
Hemochromatosis and Arthritis
Chondrocalcinosis, or the deposition of calcium
pyrophosphate crystals in the articular cartilage, can
occur in hereditary hemochromatosis.
Hemochromatosis and Arthritis
Subchondral
sclerosis
(intense white
band)
Joint space
narrowing.
Fairly normal radiograph.
10 years later.
Note the preserved joint
spaces and the relatively
uniform density of the bones.
Serial hand radiographs of an HH patient.
Other Histologic Findings in Hereditary
Hemochromatosis
This pancreas has extensive
deposition of hemosiderin
granules in the acinar cells.
Hereditary Hemochromatosis Treatment
• The mainstay of treatment is serial
phlebotomy.
• May prevent onset of severe symptoms in
asymptomatic patients.
• May lead to reversal of cardiomyopathy.
• Cirrhosis and pancreatic dysfunction are
irreversible.
Screening for Hereditary
Hemochromatosis
• No consensus on general population
screening.
– Serum transferrin saturation is preferred by the
AAFP, but false positives may occur in chronic
hepatitis and alcoholic liver disease.
– Ferritin is very sensitive, but extremely
nonspecific.
• Screen first-degree relatives of patients.
– HFE gene analysis is preferred, because of the
poor specificity of other noninvasive tests.
Resolution
• The patient began a regimen of serial phlebotomy, and his
serum iron levels improved.
• Patient’s liver enzyme levels returned to near normal.
Luckily, he was treated before the onset of cirrhosis.
• Patient’s cardiac function improved as well.
• Patient continued to suffer from arthritis and required
bilateral knee replacements five years later.
• Patient will require diabetes care and thyroid hormone
replacement for the rest of his life.
• Patient avoids alcohol, due to his increased risk for
cirrhosis.
• Patient avoids seafood and sea water, due to his increased
risk for Vibrio vulnificus infection.
Resolution
• Patient’s family was screened for hereditary
hemochromatosis.
– Review of patient’s father’s medical records raises
suspicion that he was affected as well.
– Pt’s older sister and younger brother were found
to have evidence of symptomatic
hemochromatosis as well.
– Pt’s son had elevated serum iron levels, and was
counseled about the need for therapeutic
phlebotomy.