DNP 604 Module 7 Genetics Case Study Example

Too Little Hepcidin: A Genetics Case Study of HFE Hemochromatosis in a Man With Aching Knuckles

Student Name

Edson College of Nursing and Health Innovation, Arizona State University

DNP 604: Advanced Human Pathophysiology Across Lifespan

Instructor Name

Month Day, Year

Too Little Hepcidin: A Genetics Case Study of HFE Hemochromatosis in a Man With Aching Knuckles

The Case

Mr. K, 52, presents with two years of fatigue and pain in the second and third knuckles of both hands. His liver enzymes are mildly elevated. Fasting transferrin saturation is 78% and ferritin is 1,450 µg/L. Genetic testing shows he is homozygous for the HFE p.Cys282Tyr (C282Y) variant. His fasting glucose is 118 mg/dL. He drinks two beers on weekends. He has two brothers and a sister.

Question 1: How is HFE hemochromatosis inherited?

HFE hemochromatosis is autosomal recessive: a person must inherit a C282Y variant from each parent. It is most common in people of Northern European ancestry. Penetrance is incomplete, meaning that many people homozygous for C282Y never develop significant iron overload or disease. Rarer forms of the disease involve other iron genes, but the shared defect is hepcidin deficiency (Alvarenga et al., 2022). Men are affected more often and earlier than women, partly because women lose iron through menstruation and pregnancy. Alcohol and other liver stressors increase the risk of liver damage.

Question 2: What is the molecular pathophysiology?

The body has no regulated way to excrete iron, so iron balance is controlled at absorption. Hepcidin, a hormone made by the liver, controls absorption by binding ferroportin, the channel that exports iron from intestinal cells and macrophages into the blood, causing it to be degraded. The HFE protein helps the liver sense iron levels and signal hepcidin production. When HFE is defective, hepcidin is inappropriately low for the body's iron load, ferroportin stays active, and the gut absorbs too much iron year after year (Gattermann et al., 2021).

Question 3: How does excess iron damage organs?

As transferrin becomes saturated, non-transferrin-bound iron appears in the blood and is taken up by the liver, pancreas, heart and joints. Free iron catalyzes the formation of reactive oxygen species, which damage lipids, proteins and DNA. In the liver, this drives fibrosis, cirrhosis and a higher risk of hepatocellular carcinoma. In the pancreas, iron injures beta cells, contributing to diabetes, which may explain his elevated fasting glucose. In joints, iron deposits typically damage the second and third knuckles of the hands, matching his knuckle pain. Cardiac iron loading can weaken the heart muscle and disturb its rhythm.

Question 4: How is the diagnosis made?

Current European guidelines state that in a person homozygous for C282Y, elevated transferrin saturation with elevated ferritin, above 50% and 300 µg/L in men, is sufficient to diagnose hemochromatosis (Zoller et al., 2022). Mr. K meets these criteria. The guidelines emphasize assessing liver fibrosis at diagnosis, because advanced fibrosis changes management and requires screening for liver cancer. A ferritin above 1,000 µg/L raises the likelihood of significant fibrosis and supports noninvasive fibrosis testing.

Question 5: How is it treated, and why does it work?

Phlebotomy removes iron in hemoglobin, and the body replaces red cells by drawing iron from stores. Each unit of blood removes about 200 to 250 mg of iron. Treatment begins with regular phlebotomy until ferritin falls to target, followed by maintenance phlebotomy to keep iron stores low (Zoller et al., 2022). Mr. K should limit alcohol and avoid iron and vitamin C supplements. Early treatment can prevent progression, although established cirrhosis and arthropathy may not fully reverse.

Question 6: What should happen with his family?

Each of his siblings has a 25% chance of being homozygous if both parents were carriers. First-degree relatives should be offered testing with iron studies and HFE genotyping, so that affected relatives can begin treatment before organ damage occurs.

References

Alvarenga, A. M., Brissot, P., & Santos, P. C. J. L. (2022). Haemochromatosis revisited. World Journal of Hepatology, 14(11), 1931-1939. https://doi.org/10.4254/wjh.v14.i11.1931

Gattermann, N., Muckenthaler, M. U., Kulozik, A. E., Metzgeroth, G., & Hastka, J. (2021). The evaluation of iron deficiency and iron overload. Deutsches Ärzteblatt International, 118(49), 847-856. https://doi.org/10.3238/arztebl.m2021.0290

Zoller, H., Schaefer, B., Vanclooster, A., Griffiths, B., Bardou-Jacquet, E., Corradini, E., Porto, G., Ryan, J., & Cornberg, M. (2022). EASL clinical practice guidelines on haemochromatosis. Journal of Hepatology, 77(2), 479-502. https://doi.org/10.1016/j.jhep.2022.03.033