Acta Med Scand 204: 93-96, 1978

Mild Phosphate Diabetes in Adults

Erik Lundberg, Harald Bergengren and Bengt Lindqvist
From the Departments of Rheumatology, Pathology and Medicine, Umeå University, Umeå, Sweden

ABSTRACT.

Phosphate diabetes has been considered as rare and to occur almost exclusively in children. Upon examination of adult patients with rheumatic or kidney diseases it has, however, been found that the combination of hypophosphataemia and hyperphosphaturia is not so rare. This paper deals with 24 adult patients of this type, whom we have found during 6 months. Their mean serum phosphorus concentration was 0.7 mmol/l (range 0.5-0.8). Mean phosphate clearance was 31 ml/ min/1.73 m2 (range 16-51). The diagnoses were myalgia, dorsalgia (n=7), papillitis calcificans (n= 5), prostatitis or prostate accretions (n=4), dizziness (n=2), kidney stones, tubuar defect, interstitial nephritis, medullary sponge kidney (1 case each), two patients had transplanted kidneys. Asthenia was a common additional diagnosis. The patients’ complaints have been pain in the muscles, joints, bones (18 cases), tiredness (10 cases), dizziness (8 cases), shakyness, nunbness, burning sensation (7 cases), tenderness in the muscles and bones (“the princess-on-the-pea syndrome”) (7 cases). The most common findings upon examination were bone tenderness (13 cases), reduced manual power (8 cases), positive Romberg test (3 cases), slight muscle atrophy (2 cases), waddling gait (2 cases). The most common findings encountered in the laboratory, besides hypophosphataemia and hyperphosphaturia, were high pH in the urine, hyperaminoaciduria, and phosphate crystals in dried urine.

Phosphate diabetes can be defined as hyperphosphaturia, in spite of hypophosphataemia, with a normal urinary calcium level and normal serum concentrations of calcium and parathyroid hormone. The condition has been described in cases of primary renal hyperphosphaturia, vitamin D resistant rachitis, distal renal tubular acidosis and other tubular defects, after kidney transplantation, in association with various bone tumours, so-called sclerotising bone angiopericytoma, and during cortisone treatment of chronic joint diseases (3, 5, 9, 13, 16). Calcitonin has been shown, like parathyroid hormone (1), to induce hyperphosphaturia. The excretion of phosphates in the urine is reduced by 1,25-dihydroxy-vitamin D3 and 1-α-hydroxy-vitamin D3, (12).
Phosphate diabetes has been diagnosed considerably more often in children than in adults. Falkson and Frame (5) found 150 cases described in the literature but only 8 % were adults. Adult phosphate diabetes has also been described by Nagant and Krane (14). Phosphate diabetes gives rise to osteomalacia in children (5). In adults, severe phosphate diabetes can likewise give rise to osteomalacia (6, 17). In milder cases of earlier stages the patients’ complaints are considerably more vague. We have not found any general review of the patients’ difficulties in mild cases of phosphate diabetes. Case histories record complaints as: bone tenderness, pain in the bones, back pain, moderate muscle weakness, pain in the soles of the feet, diarrhoea and thin urine. The patient’s general condition is usually good. Mild phosphate diabetes is probably a common condition. We have not found any information in the literature concerning its frequency. However, this will depend on how phosphate diabetes is defined, that is to say, on the values for hyperphosphaturia and hypophosphataemia, that are considered to permit such a diagnosis. Phosphate diabetes can have clinical significance only if the patient is troubled by the condition.
Over a period of six months we have met 24 patients with mild phosphate diabetes in the Departments of Rheumatology and Nephrology. Treatment of the condition has attracted increased interest in that one now has access to less irritating phosphate tablets than previously, as well as new, active vitamin D preparations.

METHOD

Phosphate level was estimated according to the ACU-Chem method, a modification of the Certific Chem method (4). For the diagnosis of hypophosphataemia a serum concentration of ≤0.8 mmol/l has been established, and for the diagnosis of hypephosphaturia a urinary excretion of at least 25 mmol/24 hours or a phosphate clear ance in excess of 15 ml/min/1.73 m2 BSA. We have not introduced dietetic restrictions in regard to phosphate-rich food as we wanted to detect individuals with hyperphosphaturia and hypophosphataemia. With a phosphate-poor diet the frequency of hyperphosphaturia, of course, decreases, while the frequency of hypophosphataemia increases. Our main interest has been to ascertain how many patients on a normal diet have a phosphate-rich urinary excretion in spite of a low phosphate level in serum. Urinary phosphate excretion investigations have been discussed by, among others, Nordin and Fraser(15).

Table I. Diagnoses, complaints and findings at examination in the 24 patients with mild phosphate diabetes.

 

	No. of pats.
Diagnoses
Myalgia, dorsalgia or arthralgia	7
Papillitis calcificans	5
Prostatitis or prostate stone(s)	4
Transplanted kidney	2
Vertigo	2
Kidney stones	1
Tubilar defect	1
Interstitial nephritis	1
Medullary sponge kidney	1
Complaints
Pain in the muscles, joints, bones	18
Tiredness	10
Dizziness	8
Shakyness, numbness, burnings sensation	7
Tenderness in muscles and bones	7
Feeling of pressure on the bladder	6
Findings
Calf tenderness	13
Reduced manual power	8
Slights dizziness with Romberg´s test	3
Slight muscle atrophy	2
Waddling gait	2

 

Manual power has been measured with a balloon dynamometer. Calf tenderness has been determined by a blood pressure cuff placed round the thickest part of the calf and slowly inflated, the patient indicating when he/she begins to feel pain. Normal values are 120-180 mmHg (10).

STUDY POPULATION

We have investigated several hundred patients, mostly outpatients in the Departments of Rheumatology and Nephrology, and have found 24 patients, 14 men and 10 women, with mild phosphate diabetes. Their average age was 47 years (range 31-56). The mean serum phosphorus concentration was 0.7 mmol/1 (range 0.5-0.8). Mean phosphate clearance was 31 ml/min/ 1.73 m2 (range 16-51).
Treatment consisted in 21 cases of phosphate tablets (containing a mixture of Na-K-Mg-Ca-phosphate) in daily doses of 2-4 g (2) plus in 8 cases of 1-α-hydroxy-vitamin D3, 0.5-1.0 µg daily (supplied by Löwens Pharmaceutical, Copenhagen, Denmark).

RESULTS

In most cases the onset was unclear – the condition had existed for many years prior to diagnosis. The diagnoses are presented in Table I. The patients´complaints varied according to the basic illness (Table I). Three patients, two of whom had undergone kidney transplantation, had no or minimal trouble despite lack of phosphate. The most usual findings upon examination are also listed in Table I. Typical phosphate crystals can be seen in dried urine under the microscope (Fig.I). The urine pH was usually 6.4 – 7.4.

Six typical cases of phosphate diabetes
Case 1. Female, 47 years. Long-standing migraine, intermittent swellings, pain in the loin and flank. Sometimes also tiredness, dizziness, tenderness in bones and muscles. Serum phosphate 0.6 mmol/1, phosphate clearance 41 ml/min. Abundance of phosphate crystals in dried urine. Slight bone tenderness. Treated with phosphate and 1-α-vitamin D3. Her troubles diminished.
Case 2. Female, 39 years. Urgency of micturition for many years, feeling of pressure on the bladder. During the last year back pain, tiredness. Serum phosphate 0.4-0.8 mmol/1, phosphate clearance 36 ml/min. Good manual capacity, no bone tenderness. Abundant phosphate crystals in dried urine. Her complaints disappeared after 4 months of phosphate treatment.
Case 3. Male, 50 years. Long-standing back pain, increasing pain in all joints, muscle cramp, walking difficulty, swaying walk. Fatigue, dizziness, pressure on the chest. In 1969 papillitis calcificans with mild azotaemia. Serum creatinine level at present 240 µmol/1. Aminoaciduria. Serum phosphate 0.7 mmol/1, phosphate clearance 33 ml/min. Manual capacity somewhat reduced, pain threshold in the calves at 80 mmHg, low. Treated with phosphate tablets and I-α-vitamin D3. His troubles have diminished somewhat.
Case 4. Female, 49 years. Long-standing pain above the bladder, in the lumbar region; occasional headache. During the last year attacks of dizziness, sickness, cramp in the hands, loss of sensation in the fingers. Upon examination nystagmus was found during the attacks. Permanently tender legs. Pain in the calves at 70 mmHg, low. Good manual capacity. Serum phosphate 0.6-8, urinary phosphate 25 mmol/24 hours. Treated with phosphate tablets for more than a year, occasionally also with 1-α-vitamin D. Serum phosphate normal. Considerably improved.
Case 5. Male, 54 years. Long-standing complaint of pain in all parts of the body, stomach acidity, vomiting, trembling, sweating, staggering, uncertain gait. Mild papillitis calcificans upon urography. Serum phosphate 0.5-0.9 mmol/1. Phosphate clearance 40 ml/min. Mild aminoaciduria. Mild liver disturbance. Eosinophiluria. Treatment with phosphate tablets and 1-a-vitamin D3 discontinued after a few days for fear of complications.
Case 6. Female, 47 years. During the last 4 years pain in joints, muscles, intermittent small bleedings in the skin. Electromyography showed myopathy. Electron microscopy of muscle showed more glycogen than normal. Examination indicated muscle tenderness, muscle atrophy in the shoulder region. Serum phosphate 0.7-0.9 mmol/1. Urinary phosphate 25 mmol/24 hours, phosphate clearance 21 ml/min. Treated with phosphate tablets. Improved.

Fig. 1. Triple phosphate crystals in dried urine.

The short-term effect of the treatment appears to be satisfactory but not good, while the long-term effect has not yet been established. The results of treatment will be presented in another communication.
None of the patients have had skeletal changes of the osteomalacia type upon X-ray, or osteoporosis with accompanying vertebral compression. Only one patient had temporary insignificant hypercalcaemia, hypercalcuria and/or raised parathyroid hormone concentration in the blood. Aminoaciduria above normal was found in 5 of the 10 patients examined. They had a loss of chiefly glycine and glutamine but also other amino acids were sometimes excreted in increased amounts.

DISCUSSION

Bergengren (2) has described the manifestations of phosphate deficiency in cows with a high milk yield. Phosphate deficiency arises from a lack of phosphate in the feed combined with phosphate losses via the milk. The cow´s muscles became weak, they had difficulty in walking due to pain in the joints, and had tender bones (milk lameness). It has long been known that phosphate deficiency in man can lead to anorexia, muscle weakness and bone tenderness (7,11). The condition has, however, been regarded as rare. Essentially only children with nutritional insufficiencies, or occasionally a child with tubular defect, were supposed to be affected.
It appears to us, however, that the condition has been seriously neglected. Phosphate deficiency seems to be fairly frequent among adults. Even mild cases of phosphate diabetes seem to give rise to long-term complaints if the condition is disregarded for several years. The troubles which afflict patients with slight phosphate diabetes are similar to those found both in animals with nutritional phosphate deficiency and in humans with severe phosphate diabetes.
Patients with “pain all over the body”, shifting from one spot to another from day to day (“varialgia”), are to be found in most practices. Usually nothing is found upon examination. The patients are assigned the diagnosis of asthenia, neurasthenia, myalgia, varialgia, arthralgia, etc., which make them misunderstood and unsatisfactorily treated. In this group of asthenics there are certainly many cases of psychosocial insufficiency, but no doubt also unrecognized somatic illnesses. The frequency of phosphate diabetes among asthenics is unclear.
Lindqvist and Lundström (10) have described a battery of tests suitable for asthenia: manual power, pain threshold in the calf, breath-holding time and time for filling in 1000 squares. Among these tests it appears that calf pain was the most important in phosphate diabetes, followed by the manual power test (8). Ability to hold the breath appears to be normal in most cases. We are in the process of evaluating bite pressure, as some patients with phosphate diabetes complain about tender teeth.
The cause of phosphate loss in the urine can be either a tubular defect or a hormonal imbalance; possibly both factors are causative in some cases. Clinical signs of the illness may not appear unless the patient has a phosphate-deficient diet. The consumption of considerable quantities of food rich in phosphates may compensate the phosphate losses to such an extent that no appreciable phosphate deficiency occurs. Among our patients, those with kidney stone are likely to have been advised to eat calcium-deficient foods. Unfortunately, however, calcium-deficient diets are also low on phosphate, and can thus lead to phosphate deficiency (2). Many patients have, in addition, gastritis and consume large quantities of aluminium hydroxide to combat stomach acidity. In this way phosphate is removed from the intestine and the risk of phosphate defi-ciency increases in cases of mild phosphate diabetes. Finally, one can suspect that phosphate losses only gradually attain clinical significance. The body has large phosphate stores but at present it is not possible to estimate a given individual’s phosphate reserve. Serum phosphate concentration is in all probability a poor indicator of phosphate deficiency.
As we lack a method for estimating 1,25-dihydroxy-vitamin D3 in serum, it is not clear whether this is a deficient factor that may underly a large number of cases of phosphate diabetes. Estimation of 25-OH-vitamin D3 has not yet been shown to be of any importance:

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Acta Med Scand 204