Hereditary Hemochromatosis: Rapid Evidence Review

 

Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload. It is the most common inherited disorder among people of northern European ancestry. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease. The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. Women are often diagnosed later than men, likely because of menstrual blood loss. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. A common initial presentation is an asymptomatic patient with mildly elevated liver enzymes who is subsequently found to have elevated serum ferritin and transferrin saturation. Ferritin levels greater than 300 ng per mL for men and 200 ng per mL for women and transferrin saturations greater than 45% are highly suggestive of hereditary hemochromatosis. Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications. Liver transplantation may be considered in select patients. Individuals with hereditary hemochromatosis have an increased risk of hepatocellular carcinoma and colorectal and breast cancers. Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition.

Hereditary hemochromatosis is an autosomal recessive condition that results in systemic iron overload due to a deficiency in hepcidin, an iron regulatory protein.1,2 The body's iron stores are primarily regulated by controlling intestinal absorption. Other than menses and shedding of senescent cells, there are no physiologic mechanisms of iron excretion. Deposition of excess iron into parenchymal cells leads to tissue damage and ultimately organ failure. The liver, pancreas, joints, heart, skin, and pituitary glands are the most commonly involved organs.3,4 This article summarizes the best available patient-oriented evidence regarding hereditary hemochromatosis.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

First-degree relatives of patients with hereditary hemochromatosis should be screened for the disease.1,3

C

American College of Gastroenterology expert consensus guideline

Hereditary hemochromatosis should be considered in the differential diagnosis of patients with elevated liver enzymes and abnormal iron study results.24,11

C

Expert consensus and narrative reviews

Aside from alcohol cessation, dietary modifications have minimal impact on iron overload and are generally not recommended in patients with hereditary hemochromatosis.1,8

C

American College of Gastroenterology expert consensus guideline

Lifelong phlebotomy is the mainstay of treatment to maintain a goal serum ferritin level of around 50 ng per mL (50 mcg per L).1,22,23,30,31

C

Expert opinion (serum ferritin goal varies based on recommending organization)


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

First-degree relatives of patients with hereditary hemochromatosis should be screened for the disease.1,3

C

American College of Gastroenterology expert consensus guideline

Hereditary hemochromatosis should be considered in the differential diagnosis of patients with elevated liver enzymes and abnormal iron study results.24,11

C

Expert consensus and narrative reviews

Aside from alcohol cessation, dietary modifications have minimal impact on iron overload and are generally not recommended in patients with hereditary hemochromatosis.1,8

C

American College of Gastroenterology expert consensus guideline

Lifelong phlebotomy is the mainstay of treatment to maintain a goal serum ferritin level of around 50 ng per mL (50 mcg per L).1,22,23,30,31

C

Expert opinion (serum ferritin goal varies based on recommending organization)


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

The Authors

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SHAWN F. KANE, MD, FAAFP, FACSM, is an associate professor in the Department of Family Medicine at the University of North Carolina in Chapel Hill....

CAROLINE ROBERTS, MD, is assistant residency director and an assistant professor in the Department of Family Medicine at the University of North Carolina.

RYAN PAULUS, DO, is a resident in the Department of Family Medicine at the University of North Carolina.

Address correspondence to Shawn F. Kane, MD, FAAFP, FACSM, University of North Carolina, 590 Manning Dr., Chapel Hill, NC 27599 (email: shkane@email.unc.edu). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

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