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, the genetic defect responsible for his condition most likely affects which of the following processes?

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, the genetic defect responsible for his condition most likely affects which of the following processes?

Quizplus · Accepted Answer

11ec160b_394b_24c6_9249_cd8bef26efc2_MD0001_00 This patient likely has hereditary hemochromatosis, an autosomal recessive disorder characterized by excessive intestinal iron absorption and accumulation within parenchymal tissues that result in end-organ damage (eg, cirrhosis, diabetes mellitus, cardiomyopathy, arthropathy). The condition is frequently caused by a missense mutation in the HFE gene (eg, C282Y), which is most commonly found in Caucasians. The HFE protein interacts with the transferrin receptor on the cell surface to facilitate endocytosis of the iron-transferrin complex. Once inside the cell, transferrin is degraded and the released iron is added to the labile iron pool. Mutation of the HFE protein leads to reduced iron uptake and causes enterocytes and hepatocytes to sense falsely low iron levels. This enhances iron accumulation in the body via 2 mechanisms: Excessive iron accumulation results in elevated levels of serum ferritin (cellular iron storage protein) and increased saturation of transferrin (major iron transporter in the plasma). (Choice A) Iron transport in the blood is not impaired in hereditary hemochromatosis as transferrin function is normal. (Choice B) Patients with severe forms of thalassemia (eg, beta thalassemia major) often have chronic hemolytic anemia and develop iron overload due to repeated blood transfusions (secondary hemochromatosis). However, hemoglobin production is normal in patients with hereditary hemochromatosis as iron transport to the bone marrow is unaffected. (Choices C and E) Total body iron levels are regulated by varying the rate of intestinal iron absorption. Although iron loss occurs through sloughing of the intestinal lining and during menstruation in women, there are no regulated mechanisms to excrete iron from the body. Educational objective: Hereditary hemochromatosis is most commonly caused by a missense mutation in the HFE gene, resulting in excessive intestinal iron absorption and organ damage (eg, cirrhosis, diabetes mellitus, cardiomyopathy, arthropathy) due to iron accumulation within parenchymal tissues. __________ References: Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. (http://www.ncbi.nlm.nih.gov/pubmed/20542038) HFE-associated hereditary hemochromatosis. (http://www.ncbi.nlm.nih.gov/pubmed/19444013)

A 54-Year-Old Man Is Evaluated in the Clinic Due to Generalized