New Guidelines to Help You Manage Hereditary Hemochromatosis

David A. Johnson, MD


March 16, 2020

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome back to another GI Common Concerns.

This past week, I saw a patient with hemochromatosis. In preparing for my discussion with him, I had a valuable resource at hand in the recently published clinical guideline on hereditary hemochromatosis from the American College of Gastroenterology, authored by Dr Kris Kowdley and colleagues. These evidence-based recommendations give us some really interesting new messages, which I want to summarize for you here.

Genetic Causes of Hemochromatosis

The genetic abnormalities leading to hemochromatosis are driven by the C282Y gene mutation. The penetrance of the homozygous C282Y mutation in the HFE gene causes all the problems of iron overload and consequent organ damage. The prevalence of the homozygous C282Y mutation in the US population is around 0.5%; however, in Ireland and northern Scandinavian countries, it is probably between 2% and 4%. It's important to understand when you do your genetic testing that the penetrance of C282Y homozygosity is not 100% either. Instead, it's estimated to be approximately 75% in men and 50% in women.

Another genetic subtype of hemochromatosis is the H63D gene mutation, which you see on your genetic profiles. This mutation does not cause the iron overload by itself, and patients with it do not need to be monitored for primary hemochromatosis consequences. They can be somewhat subject to iron overload if it is found in combination with the C282Y mutation or if they have other consequent diseases, like alcohol abuse, hepatitis C, or nonalcoholic fatty liver disease (NAFLD). But as a general rule, the H63D gene mutation does not cause the genetic consequence of hemochromatosis.

There is also the HFE S65C gene mutation to consider. This mutation is not associated with primary tissue iron overload, but you will see it on some of the genetic profiles.

It all comes back to the homozygous C282Y mutation. Patients who are C282Y/H63D compound heterozygous do not need to be monitored for hemochromatosis consequences.

For genetic testing of the children of a proband parent with hemochromatosis, the recommendation is to test the other parent. If that parent does not have the homozygous C282Y mutation, then you do not need to further screen or test that child, as he/she is heterozygous with no consequent iron overload. If the patient is at risk because both parents are positive for the C282Y gene mutation, the guidelines recommend not to begin screening that child until the age of 18 years because the consequences of iron overload don't seem to occur prior to that point.

Counseling Patients on What to Avoid

The guidelines recommend that patients with hemochromatosis minimize vitamin C exposure, particularly supplemental vitamin C, which may accelerate iron absorption.

The recommendations do not call for avoiding red meat in patients who are undergoing phlebotomy with consequent iron depletion. However, in my mind, plenty of other good health reasons support the dietary avoidance of red meat.

Phlebotomy remains the treatment of choice, targeting an ideal plateau for iron depletion. In general, hematologists like to get the serum ferritin level to a goal of 50-100 ng/mL and routinely monitor that patients are achieving that threshold.

My patient (from this past week) specifically asked about the use of proton pump inhibitors (PPIs). Data from a prospective randomized trial showed that PPIs decrease the need for phlebotomy by a factor of 1 over the course of a year, although this was in a small cohort of patients. The guidelines recommend not placing patients on PPIs proactively as the primary treatment for hemochromatosis, but if they need PPIs for other reasons, it's certainly justifiable and can be done.

Screening Strategies

The best screening for hemochromatosis is iron saturation. An iron saturation of > 45% is virtually absolute, identifying 97%-100% of C282Y homozygotes. Ferritin is a phase reactant. Hyperferritinemia is seen in hemochromatosis. Ferritin levels > 1000 ng/mL are more predictive of advanced fibrosis and cirrhosis, so it's not such a good thing to have sky-high ferritins.

Regarding the screening for fibrosis, transient elastography is a noninvasive test that we use a lot in our patients with NAFLD. However, this imaging technique has not been validated in the population with hemochromatosis, so it's not recommended.

Clearly the new kid on the block is the MRI, specifically the T2-weighted MRI. You lose signal intensity with iron deposition in the liver, which makes T2-weighted MRI a very good noninvasive test for quantifying iron amount. The positive predictive value is not as good as the negative predictive value. The positive predictive value is around 80%-81%, whereas the negative predictive value for the absence of iron concentration is better at 83%-88%.

If there is any remaining question following MRI, a liver biopsy should be performed to quantify the iron concentration and to assess for fibrosis.

Don't forget: If there is cirrhosis in these patients, they need to be monitored for hepatocellular carcinoma. This does not stop even if they have their iron stores normalized. Surveillance should be continued as you would for any patient with cirrhosis.

Treatment Options

Although liver transplantation is not common in this indication, it remains a curative treatment for these patients who also have decompensated cirrhosis or hepatocellular carcinoma. The guideline also noted that you do not need to deplete or de-ironize these patients before you send them for transplant evaluation. Don't wait for that.

Phlebotomy does improve certain elements of consequent tissue damage and mild to moderate fibrosis, similar to what we tell our patients with NAFLD as it relates to weight reduction.

Phlebotomy may improve cardiac dysfunction, but depleting iron from the heart is a slow process. As you know, these patients can get an infiltrative disease that's restrictive or a dilated type of cardiomyopathy.

Diabetes does not improve with phlebotomy.

Arthropathy of hemochromatosis (joint damage) does not improve, but it may improve some of the arthralgias.

Lastly, the skin changes that accompany hemochromatosis do improve with phlebotomy, although extracting the iron from the skin is also a slow process.

Parting Thoughts

Here are the take-home messages I want to leave you with.

C282Y needs to be homozygous. If it is heterozygous, there really is not a concern for iron deposition in the absence of other co-mitigating disease states (eg, NAFLD, hepatitis C, alcohol abuse). Such patients don't need to be monitored in the same way.

Check the parent of a child with an identified proband. If one parent has hemochromatosis, you're looking for C282Y homozygosity in both of them. In the absence of that, the children don't need to be checked.

Don't forget that T2-weighted MRI now offers a noninvasive means of estimating hepatocellular iron concentration and is certainly better than liver biopsy.

These guidelines provide a lot of new information about hemochromatosis, which hopefully is helpful in guiding the next conversation that you have with your patients with this condition.

I'm Dr David Johnson. Thanks for listening, and I look forward to chatting with you again soon.

David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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