Question

A 54-year-old man is evaluated in the clinic due to generalized weakness and lethargy for the past 5 years. He has no history of hypothyroidism or depression. The patient uses acetaminophen intermittently for joint pains that he attributes to "old age." He drinks alcohol occasionally but does not use tobacco or illicit drugs. His older brother died of liver cirrhosis. Laboratory tests show a serum ferritin level of 1800 µg/L. If this patient's disorder is hereditary, which of the following processes most likely affects the genetic defect responsible for his condition?

A. Blood iron transport

B. Hemoglobin synthesis

C. Hepatic iron excretion

D.Intestinal iron absorption

E. Renal iron excretion

Correct Answer: D. Intestinal Iron Absorption

Problem-Solving Skill

🧠 Key Symptoms

Generalized weakness and lethargy
⬇
Consider metabolic or systemic issues (e.g., iron overload, endocrine dysfunction, chronic disease).

🧠 Family History

Brother with liver cirrhosis
⬇
Think of hereditary conditions (e.g., hemochromatosis, Wilson disease).

🧠 Laboratory Findings

↑ Ferritin (1800 µg/L)

↑ Serum iron

↓ TIBC (transferrin saturation is high)
⬇
Interpret as iron overload—narrow differentials to disorders causing iron accumulation.

🧠 Differentiating Causes of Iron Overload

• Hereditary hemochromatosis: Mutations in HFE gene → ↑ intestinal iron absorption.

• Secondary hemochromatosis: Chronic transfusions, hemolytic anemia.

• Wilson disease: Copper overload, not iron.
  ⬇
  Clinical context (age, labs, history) strongly favors hereditary hemochromatosis.

Concept

🧠 Genetic Mutation
HFE gene mutation (C282Y or H63D)
⬇
🧠 Pathophysiological Mechanism
↓ Hepcidin production
⬇
Unregulated ferroportin activity
⬇
↑ Intestinal iron absorption
⬇
🧠 Iron Overload
↑ Iron in blood and tissues
⬇
🧠 Laboratory Findings
↑ Serum ferritin (storage overload)
⬆ Serum iron (excess circulating iron)
⬆ Transferrin saturation (more iron bound to transferrin)
⬇️ TIBC (binding capacity reduced due to saturation)
⬇
🧠 Clinical Manifestations

• Liver:
  ⬆ Iron deposition → Hepatomegaly, Cirrhosis → ↑ Risk of hepatocellular carcinoma
  ⬇ Liver function → Fatigue, Lethargy

• Pancreas:
  ⬆ Iron deposition → β-cell damage → ↓ Insulin production → Diabetes mellitus ("bronze diabetes")

• Heart:
  ⬆ Iron deposition → Cardiomyopathy & Arrhythmias → Dyspnea, Palpitations

• Skin:
  ⬆ Iron deposition → Melanin production stimulation → Hyperpigmentation ("bronze skin")

• Joints:
  ⬆ Iron deposition → Arthropathy → Chronic joint pain, Stiffness

  
  ⬇
  🧠 Diagnostic Confirmation
  Genetic testing for HFE mutations (C282Y or H63D)

Explanation of Other Answers

A. Blood Iron Transport:
🧠 No defect in transferrin or blood iron transport → Ruled out.

B. Hemoglobin Synthesis:
🧠 No anemia or microcytosis seen → Hemoglobin synthesis unaffected.

C. Hepatic Iron Excretion:
🧠 Liver stores excess iron but does not excrete iron → Incorrect.

E. Renal Iron Excretion:
🧠 Kidneys play a minimal role in systemic iron regulation → Not relevant.

Flashcards

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Dr. Shoaib Ahmad