Oral iron

Oral iron is usually recommended as first-line therapy, as it is a cost-effective strategy to restore iron balance. Both ferrous and ferric forms are available, but only the ferrous form is recommended due to superior absorption. Ferrous sulfate is used most frequently, but ferrous gluconate and fumarate can also be used.^1,2,3

Shortcomings of oral iron supplementation are: (1) Poor iron absorption (10–15%), (2) iron loss or iron requirements in excess of the absorbed dose, (3) low bioavailability, (4) poor tolerability, (5) leading to noncompliance. Iron absorption can be lowered by concomitant intake of iron absorption inhibitors like phosphates, phytates, and tanates in food and certain digestive disorders. Certain side effects like abdominal discomfort, nausea/vomiting, diarrhea, and/or constipation are directly related to the amount of elemental iron ingested.^1,4,5,6

Fig. 2: Liposomal iron absorption

ORAL LIPOSOMAL IRON

Iron salts like ferrous pyrophosphate are covered with liposome, a spherical structure of a phospholipidic nature that is similar to those human cell membranes. This preparation crosses the gastric acid barrier and reaches the small intestine intact. In the intestine, the M cells due to their low lysozyme content integrally absorb liposomal iron without the need for specific transporters (Fig. 2).

Subsequently, the liposome is incorporated by endo-cytosis from macrophages and through the lymphatic stream it reaches, intact, the hepatocytes. The liposomal protection allows the iron to overcome the free gastric environment, preventing early degradation of the sub-stance and/or its inactivation and to be absorbed directly. This mechanism provides liposomal iron a greater avail-ability, reduces gastrointestinal side effects, and prevents iron instability in the gastrointestinal tract to be directly absorbed into the intestine and directly liberated into the liver.^7-9

Consequently, this method of iron supplementation is associated with high gastrointestinal absorption, high bioavailability, and a low incidence of side effects.¹⁰ The absorption or bioavailability of liposomal pyrophosphate iron is 3.5 times greater than the free pyrophosphate iron, 2.7 times higher than iron sulfate, and 4.1 times higher compared with iron gluconate. In addition, the plasma concentration of liposomal iron was maximum after 2 hours from the assumption, which guarantees greater bioavailability of the element for all metabolic processes.⁷

CLINICAL USES

Chemotherapy-related Anemia

Anemia in cancer patients is common due to pathologic deficiency in the amount of oxygen-carrying Hb in red blood cells. Current treatment for chemotherapy- associated anemia often relies on the use of erythropoietic-stimulating agents. In one of the recent studies by Mafodda et al,¹¹ a comparison between oral liposomal iron vs IV iron in anemic cancer patients receiving chemotherapy was made. Liposomal oral iron provided similar increase in Hb levels and Hb response, with higher tolerability without the risks or side effects of IV iron. Similarly, from baseline to study end, a mean increase in Hb levels of 2.2 gm/dL and improvement in quality of life (QoL) parameters was noted with liposomal iron in patients with chemotherapy-related anemia.¹² Barni et al¹³ suggest that liposomal iron could be considered as a prophylactic measure to prevent transfusions/erythropoiesis-stimulating agents (ESAs) in cancer patients treated with chemotherapy and preexisting mild anemia.

Liposomal iron can be used as supportive therapy to reduce fatigue and improve QoL in patients with advanced prostate cancer and bone metastasis treated with monthly IV injections. It is also suggested that liposomal iron could be considered for its prophylactic use to prevent transfusion/ESAs in patients with preexisting mild anemia and to improve compliance at treatment with monthly IV injections of Radium-233 dichloride.^14,15 In young advanced-stage Hodgkin lymphoma patients, supplementation of oral liposomal iron was well tolerated and maintained Hb above levels, requiring further supportive therapy.¹⁶

Iron Deficiency Anemia and Inflammatory Bowel Disease

A preliminary study showed that IDA and IBD patients on liposomal iron (10.5–12.4 gm/dL) had better increase in Hb levels as compared with patients on ferrous sulfate (10.8–11.7 gm/dL) or no iron supplement (11.3–11.9 gm/dL).  An increase of Hb >2 gm/dL was more frequent in patients treated with liposomal iron than in patients with no iron supplement. Liposomal iron was well tolerated in both IDA and IBD patients.¹⁷ In a similar study, one-third of the IBD patients treated with liposomal iron were normalized in 12 weeks, with an average Hb increase of 11.1 to 11.8 gm/dL (p = 0.0023). Furthermore, the average rating in the questionnaire on QoL of IBD (CCVVEII-9) improved from 61.2 to 66.8 points on the final visit. An adherence of >90% and acceptance of >80% was noted. Therefore, liposomal iron can be helpful in those patients who do not tolerate classic prepared doses of oral iron.¹⁸ In refractory anemia, oral liposomal iron is found to safe, effective, and has demonstrated noninferiority over IV iron.^19,20 Compared with conventional iron supplements like ferric ammonium citrate and heme iron, liposomal iron increased iron levels and HB concentrations so as to alleviate the anemia in murine models of sports anemia and anemia of inflammation.²¹ Liposomal iron was also effective in elderly patients, well tolerated, and produced a great improvement in the anemia condition without side effects, which helped in improving QoL.²² Liposomal iron was found to be more effective than iron sulfate in increasing Hb levels and to reduce inflammatory markers in correction of anemia of chronic inflammatory disease.²³ The IBD patients are usually more frequently resistant to oral therapy and they show low compliance. Liposomal iron showed excellent compliance and treatment adherence.²⁴

Patients with inactive/mildly active inflammatory bowel disease were screened for anemia in the interventional pilot study conducted from November 2016 to March 2018. Patients with mild anemia were treated with oral liposomal iron for 8 weeks. Conclusion: Treatment with oral liposomal iron is effective in improving mild iron deficiency anemia and quality of life, as well as in decreasing fatigue in patients with inactive or mildly active inflammatory bowel disease.²⁵

Chronic Kidney Disease-related Anemia  

In the preliminary study, 21 patients with CKD-related anemia were analyzed, 14 of whom were treated with oral liposomal iron and 7 with IV iron. The observed increase of Hb at 8 weeks compared with baseline was similar in both groups, but was significant in the liposomal group only.⁷ Data show that oral iron administration compared with the IV iron therapy showed a significant increase in terms of Hb concentration and transferrin saturation and a significant decrease regarding C-reactive protein values and weekly consumption of erythropoietin. In conclusion liposomal iron seems to be a valid alternative to IV iron therapy in CKD patients.²⁶ A recent study by Pisani et al²⁷ showed that oral liposomal iron was a safe and efficacious alternative to IV iron gluconate to correct IDA in nondialysis CKD patients. Oral liposomal iron was also effective in improving and or/maintaining Hb values in hemodialysis patients, normalizing ferritin values and significantly decreasing erythropoietin consumption.²⁸ According to Griveas,²⁹ oral liposomal iron seems to be a safe and efficacious alternative in managing CKD patients with anemia.¹⁵

Other researchers suggest that therapy with two capsules of liposomal iron daily could be an alternative therapy in hemodialysis patients with iron deficiency.³⁰ Arenas et al³¹ showed that liposomal iron was effica-cious, well tolerated, and with an excellent therapeutic adherence treatment option for patients with nondialysis CKD. It is documented in one of the studies that addition of liposomal iron to the 12-week standard regimen with subcutaneous erythropoietin is effective in improving hematological parameters but also, more importantly, the QoL with no side effects and excellent tolerability in elderly anemic patients with no end-stage CKD.³² In anemic CKD patients at stages III to IV, supplementation with liposomal iron was associated with reduced activation of the inflammatory state, as assessed by reduction of erythrocyte sedimentation rate.³³ It is demonstrated that liposomal iron was safe and efficacious in maintaining transferrin saturation levels in peritoneal dialysis patients. Although ferritin levels decreased, they remained within therapeutic range. No gastrointestinal adverse effects were reported.³⁴

Celiac Disease

Patients with celiac disease (CD) frequently suffer from IDA and may benefit from iron supplementation. After a follow-up of 90 days, CD and IDA patients in both liposomal and sulfate groups showed an increase in Hb levels compared with baseline (+10.1 and +16.2% for liposomal and sulfate groups respectively), and a significant improvement in all iron parameters, with no statistical difference between the two groups. Therefore, liposomal iron can be effective in providing iron supplementation in difficult-to-treat populations.³⁵

pregnant women with iron deficiency

This study aimed to determine the effects of liposomal iron pyrophosphate/ascorbic acid on clinical and psychological outcomes in pregnant women. Women at the 11th–13th weeks of gestation with iron deficiency anaemia assuming Sideremil™ from April 2018 to May 2019 were recruited. Haematochemical, obstetric, neonatal and psychological outcomes were investigated at the enrolment, 21–23 weeks of gestation, 30–32 weeks of gestation and after 6 weeks from childbirth. Results showed significant positive effects on haemoglobin, ferritin, sideremia and transferrin levels, compared to baseline data. A significant improvement of anxiety and depression levels was also observed. Regarding the quality of life, all the domains significantly improved, especially the Physical Role domain. Our results indicate that Sideremil^™ may be a valid treatment for iron deficiency anaemia in pregnant women, since it significantly improves haematological and mental health outcomes. However, further studies are needed to confirm these results.³⁶

Other Conditions

It was demonstrated that liposomal iron was effective in replenishing iron storage in cirrhotic patients and despite the use of a high dose, it is well tolerated.³⁷ In diabetic patients with IDA supported with liposomal iron, the need for median lispro insulin was lower than that of he patients supported with IV sodium ferrigluconate.²³ Similarly, liposomal iron was found to be safe and cost-effective in hepatitis C virus patients with type II diabetes and anemia due to esophageal or gastric bleeding.³⁸ In diabetic patients with IDA supported with liposomal iron, the median lispro insulin need appears to be lower than that of the patients supported with IV sodium ferrigluconate. However, the study needs confirmation on a larger cohort of patients.³⁸

Researchers assessed the effect of switching to oral liposomal iron in patients receiving IV iron supplementation after bariatric surgery, which currently requires parenteral iron therapy due to intolerance to existing oral products or therapeutic failure. Oral liposomal iron was found be an excellent alternative to IV iron for maintenance treatment in bariatric surgery patients with iron deficiency. It might help to reduce health care costs and improve the QoL of these patients.^15,39 Liposomal iron was found to be more effective and well tolerated than iron sulfate for correction of anemia in systemic sclerosis patients who have both chronic inflammation and gastro-intestinal malabsorption issues.⁴⁰ Liposomal iron therapy was found to be safe, well tolerated, and effective at least as a standard ferrous salt therapy in patients undergoing cytoreductive surgery with intraperitoneal hyperthermic chemotherapy.⁴¹

References

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