Iron infusions commonly cause low phosphate

While this pitfall affects one of the most popular types of IV iron therapy, there are some simple steps to managing patients.

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Watch for hypophosphataemia in patients following an intravenous iron infusion, particularly if the patient has had repeated infusions, a leading endocrinologist has urged GPs. 

Iron deficiency affects more than 15% of the world’s population, most commonly women, and it’s increasingly treated with intravenous iron.

But anywhere from 46% to 75% of patients who are treated with ferric carboxymaltose infusion, the most frequently used formulation, will develop hypophosphataemia, Melbourne endocrinologist Professor Peter Ebeling AO told the audience at the Healthed Annual Women’s and Children’s Health Update in Sydney this month.

Hypophosphataemia occurs when serum phosphate levels fall to less than 0.8mmol/L, and it can lead to osteomalacia. The condition is more common after more than one treatment, so patients such as those with chronic anaemia are most at risk.

The main symptoms of hypophosphataemia are ongoing fatigue, muscle weakness and bone pain, which can look like iron deficiency.

“People can have proximal muscle weakness and bone pain around the wrists. And they can develop stress fractures in the bones called Looser’s Zones [indicating osteomalacia]. These are commonly seen in the medial aspect of the femur but they can also occur in other bones,” Professor Ebeling said.

Hypophosphataemia post-infusion tends to resolve spontaneously but can persist for five weeks in about half of those who have it, and for six months in about one in 20 affected people.

In 11% of patients, the low phosphate levels can be very severe, with serum phosphate falling to less than 0.35mmol/L.

“That can really affect muscle function and myocardial function,” Professor Ebeling said.

“The problem is that some of the symptoms of iron deficiency overlap with the symptoms of having a low phosphate level.

“Patients with iron deficiency will feel tired and possibly have a headache. They’ll have thinning hair. They can have angular cheilitis and pale skin, nail changes and restless leg syndrome.

“But if you have a low phosphate level you can also feel tired, have nausea and vomiting and diarrhoea.”

The reason it happened came down to a series of interactions between hormones, Professor Ebeling said.

Fibroblast growth factor-23 (FGF-23), produced by bones, controls how the body excretes phosphate from the kidney. Ferric carboxymaltose stimulates the production of intact FGF-23 osteocytes, as does the iron deficiency itself.

“That acts on the kidney to reduce the active form of vitamin D,” Professor Ebeling said.

“That inhibits the sodium phosphate and calcitriol levels in the kidney, and you get a high level of phosphate excretion in urine. There’s also a reduction in phosphate and calcium absorption from the intestine, and a secondary increase in parathyroid hormone production.

Making the connection between iron infusions and bone symptoms could also save patients unnecessary worry, Professor Ebeling said.

“I’m sure you’ve all seen patients with a stress fracture in the metatarsal,” he said.

“I was referred a patient who had been having multiple infusions by their haematologist for undiagnosed anaemia.

“When they did a bone scan, they had multiple hotspots on the bone scan and the patient thought they had metastatic bone cancer. The haematologist referred the patient to an oncologist. They had a bone biopsy and it turned out to be osteomalacia,” he said.

Look out for these signs

There are several clues that can lead to a diagnosis of hypophosphataemia, Professor Ebeling said.

“If you have patients who are having multiple iron infusions and they have symptoms of worsening fatigue, pain and muscular weakness, measure their serum phosphate,” he said.

A decrease in serum phosphate can occur as early as one week after an infusion, he said. Parathyroid hormone and alkaline phosphatase levels are often elevated, and patients with persistent hypophosphataemia may have a low level of active vitamin D.

“It’s probably worth measuring calcium and alkaline phosphatase, the PTH and vitamin D, and maybe even the active form of vitamin D, though you won’t get that result back for weeks and it will cost the patient quite a bit of money.”

Professor Ebeling also recommended an x-ray for painful bones and possibly a nuclear bone scan, though the result could mimic metastatic cancer. Bone density tests were not helpful, he added.

“The main thing, once hypophosphataemia is established, is not to give any further iron infusions and to treat the secondary hyperparathyroidism by giving the active form of vitamin D (calcitriol),” he said.

The other two iron infusions available in Australia, ferric derisomaltose and ferrumoxytol, result in far fewer cases of hypophosphataemia (4% and under).

Meanwhile, guidelines still recommend oral therapy as first-line treatment in most cases.

Don’t overlook the classics

Enthusiasm for intravenous iron could also mean clinicians were overlooking other practical alternatives, Canberra haematologist Dr Renee Eslick told the audience.

“I think we may be little too quick to jump to intravenous iron,” she told The Medical Republic.

“It’s good that we’re recognising iron deficiency as a problem and treating it, but IV iron has higher risks and is a significantly higher cost to the healthcare system.  I think it is worthwhile to try oral iron first,” Dr Eslick said.

People often struggled with taking oral iron supplements, but with explicit guidance on how to take it and how to manage the side effects, “you can actually push through”, she said.

Patients needed to be told specifically which iron supplement to take, Dr Eslick told the audience.

“I’ve had many women come to me with refractory iron deficiency anaemia for investigation in the haematology clinic, and so often they’re just taking an over-the-counter iron supplement that’s got very little elemental iron,” she said.

Resources for patients like the Australian Red Cross illustrated handout, Oral iron choices for adults, explained the differences clearly, she said.

“You can see that you need to take 21 of Nature’s Own Iron Plus tablets to get the same as one tablet of Ferrograd. So it just helps to put it in perspective.”

Dr Eslick said she recommended patients start with a ferrous iron supplement and then potentially they could transition to ferric iron if they were having gastrointestinal problems.

“I tend to spend the most amount of time on counselling women how to take their supplement,” she said.

“I address three key aspects. The first is to talk about compliance. The second is to talk about how to take it to make sure it’s absorbed properly. And the third thing is to tell them about the side effects in advance.”

Young women in particular needed help, especially with compliance, because they often did not think iron deficiency was important, she said.

“I usually recommend people take the iron first thing in the morning because hepcidin, the hormone that controls iron absorption, has a circadian rhythm and it’s lower in the morning. If it’s a ferrous supplement it should be taken one hour before food on an empty stomach, and you can take things to help aid absorption.”

Some things, like antacids, also reduced absorption, she said.

“There are a lot of things that will bind to the iron and limit absorption. And those are the key things that we really want to tell people about. If you’re having a bowl of cereal, which has phytates, you’re going to be having it with milk, which has lots of calcium. You might have a nice cup of tea or coffee with it.

“All of these things will bind to the ferrous iron in the diet and reduce the amount that can be absorbed.”

And when it came to side effects, constipation was the big one. One solution was dosing every second day, she said.

“We definitely know, from the bioavailability studies, that your absorption is going to be better if you take iron every second day, but it is still also true that the more iron you give, the more iron will be absorbed.

“If someone’s got iron deficiency without anaemia, or very mild anaemia, I might consider second daily dosing.”

Investigate and treat

The message underpinning this all: test and treat. 

“There are many misconceptions about the importance of iron deficiency,” Dr Eslick told TMR.

“It does cause significant symptoms and time and time again, when you make a woman iron replete, she tells you how much better she feels, what a significant difference it’s made in terms of symptoms.

“I do get a little bit annoyed when I see people out there arguing that it’s not actually a real problem, and it should be dismissed,” she said.

But this appeared to be changing, with Medicare data showing an increase in the ordering of iron studies, she said.

“If you’re looking at women at risk of iron deficiency … such as someone who’s got heavy bleeding, someone who’s vegetarian, or someone who reports symptoms, then we should be doing those tests proactively, because if we don’t pick it up, how are we ever going to be able to treat it?”