|Hypophosphataemia in malnutrition|
|Treatment of Hypophosphatemia||David Brewster||25.02.2000|
|hypophosphataemia in malnutrition||Michael Golden||25.02.2000|
Subject: Treatment of Hypophosphatemia
Date: Fri, 25 Feb 2000 07:21:46 +0930
Malnourished children often have low serum phosphate levels, and reports by Waterlow, Manary and others have generally found it has prognostic value.
Aboriginal children in northern Australia sometimes have hypophosphatemia, but it seems to be more related to osmotic diarrhoea than severe malnutrition.
My question is at what serum level should treatment be instituted, and what dose of phosphate should be used in children? I cannot get clear indications from the usual sources, so would welcome other's experience and advice.
(An unrelated question: In calculating weight gain in kwashiorkor, I have always subtracted the discharge weight from the lowest weight (after loss of oedema) in grams/ divided by the lowest weight in kg and/ divided again by the length of hospital stay. This is expressed as g/kg/day. Is this other people's understanding. It has been suggested to me that the middle /kg/ should be the discharge weight rather than the lowest weight. Which is correct?) (see here / voir ici)
NT Clinical School, Darwin, Australia
Date: Fri, 25 Feb 2000 17:57:16 +0000
From: Michael Golden <m.goldenatabdn.ac.uk>
Subject: hypophosphataemia in malnutrition.
Your question about hypophosphataemia is critically important from a large number of points of view.
I take the liberty of answering you at length (sorry to readers who are not interested in phosphate).
Low plasma phosphate is strongly associated with mortality, and occurs in gastroenteritis as well as malnutrition!
(Friman "serum Phosphorus in protein energy malnutrition" J paed Gast Nutr 1:547-550;1982 for example where normal PO4 was 1.8mmol/l, gastro -1.3, kwash 1.1, kwash+gastro 0.7mmol/l - 9/10 with low PO4 died, and the report from Malawi: Manary, J pediatr 133;789-791;1998 68%motality with hypophosphataemia and 22% without).
Large amounts can be lost in the stool in diarrhoea, in the urine in acidosis and from the skin in those with open lesions.
However, PO4 is predominantly an intracellular ion and the plasma levels are not a good guide to status (as with all the type II nutrients).
Jeejeebhoy has done some very elegant experiments with in-vivo PO4 NMR that show how critical PO4 can be.
The early balance studies show that PO4 is retained avidly during recovery, that the depletion of PO4 is greater than that of nitrogen, that the intake needed for balance in malnutrition is about 0.82mmol/kg/d, and that repletion of the tissues takes about 3 weeks treatment with a milk-based diet. (Waterlow JC, Wills VG. "Balance studies in malnourished Jamaican infants: 1.Absorption and retention of nitrogen and phosphorus". Br.J.Nutr. 1960;14:183-183. Waterlow JC, et al. "Balance studies in malnourished Jamaican infants 2. Comparison of absorption and retention of nitrogen and phosphorus from human milk and cow's milk mixture". Br.J.Nutr. 1960;14:199-205. Holeman K, Lambrechts A "Calcium and phosphorus balances in African Children" J. Trop. Pediatr. 43-49; 1958. Holeman K, Lambrechts A "Calcium and phosphorus metabolism in malnutrition and kwashiorkor" J Trop Pediatr. 129-132;1959)
Depletion should be suspected in all "floppy" children who have a reduced muscle tone.
There are similar glucose and fructose intolerances in malnutrition (clearance rate half normal) - this is not due to hormonal abnormalities as fructose does not need insulin. The most likely explanation is a lack of ability to covert fructose into fructose-1-phosphate or glucose into glucose-6-phosphate and then to 1-6 biphosphate for metabolism - with low intracellular PO4 there will be a block to energy metabolism.
Large amounts of fructose, which is phosphorylated 10 times more quickly than glucose, can cause lactic acidosis (and hyperuricaemia) in normal people and a fall in blood glucose - this is because of the sudden consumption of tissue high-energy phosphate. (review: Gitzelmann R In: Scriver et al (Eds), The Metabolic Basis of Inherited Disease, vol 1, 6th ed 1989). Patients with congenital enzyme defects who are given fructose, sucrose or sorbitol get major hepatotoxicity, hyper and then hypokalaemia, hypoglycaemia (fructose stops glucose release from the liver, reduces gluconeogenesis and blocks glycogenolysis - hypoglycaemia is prevented by galactose, but not by PO4), hemorrhage in the intestinal mucosa, shock and an encephalopathy. These changes are due to the sudden depletion of high-energy phosphate. Many of the changes are similar to those found in very severe kwashiorkor. With the reduced levels of hepatic enzymes in kwash (the ones in this pathway have not been measured) and a low PO4, there could easily be a situation where even giving sugar to quickly could cause fatal liver damage because of if there is a lack of available PO4!
Certainly, a high carbohydrate load will further lower plasma phosphate.
This is one of the reasons why lactose (galactose) containing foods (milk) should be given along with the high fructose (sucrose) diets in the prevention of hypoglycaemia.
There is quite a large literature from parenteral feeding on diet and refeeding induced hypophosphataemia sometimes fatal. PO4 is now routinely added to parenteral feeding mixtures (perhaps some of these experts could comment further on this) - and also on the safety and amounts that are added. This is one source of guidance for what we should be doing in formulating our diets. There is a good review of some of these aspects by Peppers MP et al "Endocrine crises. Hypophosphatemia and hyperphosphatemia" Critical Care Clinics 1991;7:201-214.
PO4 is also essential to excrete acid in the kidney. (Kohaut EC et al "Reduced renal acid excretion in malnutrition: a result of phosphate depletion". Am.J.Clin.Nutr. 1977;30:861-867). Indeed, this may be part of the problem in gastroenteritis (both getting acidotic because of PO4 depletion and also the acidosis depleting PO4).
It was this aspect that I was investigating in Jamaica - the children got profoundly acidotic and could not excrete acid equivalents, some died, (we later found the acidosis was due to giving magnesium chloride supplements without sufficient base). They did not get acidotic later when they were receiving our high energy cow's-milk based formula diet even though, at that time we were continuing to give magnesium chloride. This was because the rapid-growth milk diet had sufficient PO4 to allow excretion of the acid burden. After this experience I designed an experiment to give oral PO4 to the children and examine its effects on acid base/electrolyte metabolism - Pr of Alan Jackson was the independent physician assessing the conduct of the study with complete authority to change or abort the study.
I gave the oral PO4 to 3 children. Alan stopped the study because he had the clinical impression that they became less well over 24 h after the PO4.
There were no plasma electrolyte changes, and there was no definite clinical syndrome. However, one of the children had haemodynamic instability which was very worrying (they recovered uneventfully). I have not given PO4 to such children since that time, and this experience effectively stopped the work on PO4 in Jamaica. Acute changes in calcium homeostasis are, in my opinion a strong possibility that should be investigated as the diet we used had very little Ca in it (PO4 may be safe if given along with Ca). PO4 infusion can also cause hypokalaemia if insufficient K is in the diet, but this was not the case in our patients.
The problems that we experienced were not unlike those seen in neonates that are given diets with a high PO4:Ca ratio (perhaps the neonatologists could comment). However, it is quite possible that these already desperately sick children clinically deteriorated for other reasons. A note about this experience has been put into several publications concerning PO4 in malnutrition. The problems with PO4 are too important not to be seriously investigated and the situation cannot be left like this.
I consider that PO4 is one of the reasons why milk based diets have been so successful in the treatment of severe malnutrition. PO4 has been left out of the mineral mix because there is abundant PO4 in cow's milk and additional PO4 was not added partly because of the experience cited above, and partly because it is designed ONLY for use with a cow's milk based diet.
When designing F75, however, the low PO4 was one of the factors that I considered carefully.
The DSM content is reduced to minimize the sodium load and not to give excess protein - but this also means that the PO4 content is reduced, and there is none in the mineral mix (there is citrate to balance the magnesium chloride).
F75 has more DSM and PO4 than the diet (called mixPG) that we were using in Jamaica when I was doing the studies of acid excretion (it had 0.7mmolPO4/100kcal). The main reason for increasing the DSM in F75 over the diet we used successfully in Jamaica, was to allow the resynthsis of albumin (which did not occur with the more restricted diet) and as importantly to try and increase the PO4 intake. This was the compromise -having enough PO4 without too much Na. But it should clearly have more than the balance point (0.8mmol/kg) to allow for the high carbohydrate intake and the depletion. F75 now has 1.04mmolP/100kcal. In contrast F100 has 2.46mmolP/100kcal, we are fairly sure is sufficient because it allows for a reasonable renal PO4 excretion (important for acid-base balance).
I have also been concerned about the effects of carbohydrate loads (sucrose in particular) in treatment of patients with already critical hypophosphataemia. Indeed, it is this aspect of treatment, where we attempt to prevent hypoglycaemia with what is thought to be innocuous carbohydrate, that theoretically be the reason for the high morality in the phosphate depleted patients reported by Manary and Frieman? Certainly in parenteral feeding carbohydrate loading can lead to fatal hypophosphataemia in the depleted patient. This is one of several reasons why I was so keen to have a starch-based F75, rather than a sucrose (fructose) based F75t, for treatment at the critical phase of children with critical liver function (the other being the very high osmolality of sucrose based F75 and of F100, in terms of giving an osmotic diarrhoea) .
It may be that F75 should have a small supplement of PO4 to increase the level to somewhere between 1 and 2.4 mmol/100kcal( between F75 and F100) and also that calcium should be added to prevent a gross Ca: PO4 ratio change. But this has not been done and there is no experimental work to justify its inclusion: the experience with the 3 children to whom we gave PO4 makes it mandatory to have a properly controlled trial in facilities that can do all the appropriate measurements and monitoring before such a change is made to F75. I speculate that this would be an important improvement and would reduce the mortality. However, such studies would need be done somewhere by clinical physiologists with the facilities and a full understanding of calcium, phosphorus, electrolyte, energy, renal and hepatic metabolism in malnutrition - I do not know of such a facility in the developing world.
These factors are all important to all those who are using diets made from local foods for the treatment of kwashiorkor in its early stages. The children are as metabolically "brittle" as someone with diabetic ketoacidosis, there are a great many interactions and considerations in getting exactly the right balance of nutrients. At this stage the diet is the medicine and we should take as much or more care with it than with and other pharmaceutical product. Later when the metabolic changes are reversed and it is weight gain that is needed the situation is entirely different.
Phosphorus is unavailable from most plant based foods (soya, cereal etc) and will potentially make any hypophosphataemia much worse. Because the mineral mix for F100 is designed to be added to a cow's milk based diet (with Ca and PO4 already in the ingredients), it is not suitable for addition to porridges and other foods (without modification) or for other purposes.
David, there is a great deal of work to be done with phosphorus until we can answer your questions properly. It is tragic that this work does not seem to be going on.
Prof. Michael H.N.Golden
Dept of Medicine and Therapeutics, Univ of Aberdeen, Foresterhill, AB9 2ZD. Scotland, (UK)
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