Hereditary Hemochromatosis

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:

– 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! – 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:

• 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 2-pillow 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: • 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: • 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 ≈ 65-110mg/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 20-50%; 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

• 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

Hemosiderin granules inside hepatocytes. Note the bright staining with Prussian Blue.

Hemosiderin granules at lower-power magnification, without Prussian blue stain.

No cirrhosis noted.

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.


• 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.


• 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.


• Pancreas– Hemosiderin deposits in the pancreas, leading to

eventual endocrine pancreatic failure. – End result is diabetes mellitus.


• 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.


• 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.


• Ophthalmologic: Angioid streaks. – 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 CorrelatesCT scan of a patient with advanced hereditary hemochromatosis.

Liver is more opaque than normal.

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

Serial hand radiographs of an HH patient.

Fairly normal radiograph. 10 years later.

Joint space narrowing.

Subchondral sclerosis (intense white band)

Note the preserved joint spaces and the relatively uniform density of the bones.

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.

Documents

Hereditary Hemochromatosis