• Do Proton Pump Inhibitors Reduce the Need for Phlebotomy in Patients With Hereditary Hemochromatosis?

Do Proton Pump Inhibitors Reduce the Need for Phlebotomy in Patients With Hereditary Hemochromatosis?

In certain patients with hereditary hemochromatosis (HH), treatment with proton pump inhibitors (PPIs) for 2 or more years significantly reduced the number of phlebotomies required to maintain serum levels below 100 μg/L, researchers report in the January issue of Clinical Gastroenterology and Hepatology.

HH is one of the most common chronic disorders associated with iron overload. It is characterized by excessive iron absorption from the gut caused by inappropriately low levels of hepcidin, a regulatory peptide that maintains iron homeostasis. Type 1 HH, associated with the C282Y mutation in HFE, is the most common form of iron overload among persons of Northern European descent.

Patients can develop diabetes, cirrhosis, and bronze skin pigmentation, due to excessive iron accumulation in organs including the liver, heart, and pancreas.

Phlebotomy (removal of 500 mL whole blood weekly) is the standard treatment—it reduces excess iron by removing erythrocytes. Guidelines advise to decrease the serum level of ferritin to below 50 μg/L and to maintain it at 50–100 μg/L. In untreated patients 20 to 100 phlebotomies are required to reduce the serum ferritin levels to this level, and maintenance therapy of 3 to 6 phlebotomies/year may be needed.

Although phlebotomy can decrease iron overload, the procedure is accompanied by side effects and discomfort, including fatigue, fainting, loss of appetite, bruises, and vasovagal reactions. The side effects of phlebotomy and the burden of treatment reduces patients’ productivity. Alternative or complementary, less aggressive, and noninvasive therapies are needed.

Dietary nonheme (predominantly ferric or Fe3+) iron is transported bound to transferrin (Tf) or unbound. Iron bound to Tf binds to the transferrin receptor (TfR1) and is internalized via receptor-mediated endocytosis. Fe3+ is released from Tf as a result of the decrease in endosomal pH, and 6-transmembrane epithelial antigen of the prostate 3 (STEAP3), reduces it to Fe2+. Fe2+ then is transported through the endosomal divalent metal transporter (DMT1) into the cytosol. This iron becomes part of the labile iron pool, which can be stored as a complex with ferritin or used for synthesis of Fe-containing proteins or exported out of the cell by ferroportin (FPN1). Non–Tf-bound iron is taken up by ferrireductases such as duodenal cytochrome b (DCYTB). In the presence of a proton gradient, such enzymes reduce ferric to ferrous, which are transported by the DMT1 into the enterocyte. Because a low pH and protons are needed for both extracellular and endosomal ferrireductases, PPIs reduce the absorption of iron.

Dietary nonheme (predominantly ferric or Fe3+) iron is transported bound to transferrin (Tf) or unbound. Iron bound to Tf binds to the transferrin receptor (TfR1) and is internalized via receptor-mediated endocytosis. Fe3+ is released from Tf as a result of the decrease in endosomal pH, and 6-transmembrane epithelial antigen of the prostate 3 (STEAP3), reduces it to Fe2+. Fe2+ then is transported through the endosomal divalent metal transporter (DMT1) into the cytosol. This iron becomes part of the labile iron pool, which can be stored as a complex with ferritin or used for synthesis of Fe-containing proteins or exported out of the cell by ferroportin (FPN1). Non–Tf-bound iron is taken up by ferrireductases such as duodenal cytochrome b (DCYTB). In the presence of a proton gradient, such enzymes reduce ferric to ferrous, which are transported by the DMT1 into the enterocyte. Because a low pH and protons are needed for both extracellular and endosomal ferrireductases, PPIs reduce the absorption of iron.

Previous studies of patients with HH receiving maintenance phlebotomy treatment showed that those who took PPIs for long periods of time needed fewer phlebotomies to maintain their serum level of ferritin at around 50 μg/L. Other studies have shown that absorption of non-heme iron is reduced significantly in patients taking PPIs.

René M.M. van Aerts et al therefore reviewed data from a population of patients with HH population homozygous for the C282Y mutation to determine whether chronic use of PPIs reduced the frequency of phlebotomies in the maintenance treatment phase.

In a paired group analysis of 12 patients, they compared mean serum levels of ferritin and number of phlebotomies needed each year during the periods of 3 years before and 3 years after the start of PPI therapy. They compared these results with those from a group of 9 patients who received PPIs for at least 2 years and a group of 36 patients who never received PPIs.

van Aerts et al found that before patients started taking PPIs, they underwent a median 3.16 phlebotomies each year. After they started taking PPIs, they received a median 0.50 phlebotomies each year.

Patients who received PPIs for at least 2 years needed significantly fewer phlebotomies (1.25/year) than patients in the paired group before they started taking PPIs ( 3.17/year). The number of phlebotomies in the group who never received PPIs (3.0/year) was significantly higher than in the paired group after they started taking PPIs (0.5/year).

But how do PPIs reduce iron? In an editorial that accompanies the article, Priya Handa and Kris V. Kowdley explain that because PPIs reduce gastric acid secretion, they increase duodenal pH. This inhibits conversion of ferric to ferrous iron by reducing the function of the ferrireductases, inhibiting iron uptake by DMT1 from the lumen to the enterocyte and also preventing the release of ferrous iron from the endosome into the cytoplasmic compartment, by impairing endosomal DMT1 function (see figure).

This leads to a reduction in the iron absorbed and the need for phlebotomy. Handa and Kowdley point out that attractive aspect of this strategy is that PPIs have been shown to be safe—even for long-term use.

Although van Aerts et al acknowledged that their study was small and retrospective design, they state that these promising results provide an additional therapy for patients who need phlebotomies frequently. PPIs could lead to fewer phlebotomies and thereby fewer side effects, as well as lower hospital costs, less sick leave, and greater productivity and quality of life for patients.

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