Acta Med Scand 204: 93-96, 1978

Mild Phosphate Diabetes in Adults

Erik Lundberg, Harald Bergengren and Bengt Lindqvist

From the Departments i f Rheumatology, Pathology and Medicine, Umed University, Umed. Sweden

ABSTRACT. Phosphate diabetes has been consid- ered 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 1G51). The diagnoses were myalgia, dorsalgia (n = 7), papillitis calcificans (n = S), prostatitis or prostate accretions (n = 4), dizzi- ness (n=2), kidney stones, tubular defect, interstitial nephritis, medullary sponge kidney (1 case each), two patients had transplanted kidneys. Asthenia was a common additional diagnosis. The patients’ com- plaints have been pain in the muscles, joints, bones (18 cases), tiredness (10 cases), dizziness (8 cases), shakyness, numbness, 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 hy- pophosphataemia and hyperphosphaturia, were high pH in the urine, hyperaminoaciduria, and phos- phate crystals in dried urine.

Phosphate diabetes can be defined as hy- perphosphaturia, 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 para- thyroid hormone (l) , to induce hyperphospha- tuna. The excretion of phosphates in the urine is re-

duced by 1,25-dihydroxy-vitamin D, and I-a- hydroxy-vitamin D, (12).

Phosphate diabetes has been diagnosed consider- ably 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 consider- ably more vague. We have not found any general review of the patients’ difficulties in mild cases of phosphate diabetes. Case histories record com- plaints 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 concern- ing its frequency. However, this will depend on how phosphate diabetes is defined, that is to say, on the values for hyperphosphaturia and hypophos- phataemia, 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 De- partments 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 s0 .8 mmol/l has been established, and for the diagnosis of hyperphosphaturia a urinary ex- cretion of at least 25 mmo1/24 hours or a phosphate clear-

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94 E. Lundberg et al.

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

No. of pats.

Diagnoses Myalgia, dorsalgia or arthralgia Papillitis calcificans Prostatitis or prostate stone(s) Transplanted kidney Vertigo Kidney stones Tubular defect Interstitial nephritis Medullary sponge kidney

Complaints Pain in the muscles, joints, bones Tiredness Dizziness Shakyness, numbness, burning sensation Tenderness in muscles and bones Feeling of pressure on the bladder

Findings Calf tenderness Reduced manual power Slight dizziness with Romberg’s Slight muscle atrophy Waddling gait

test

7 S 4

I 1

18 10 8 7 7 6

13 8 3 2 2

ance in excess of 15 ml/min/1.73 mr BSA. We have not introduced dietetic restrictions in regard to phosphate-rich food as we wanted to detect individuals with hyperphos- phaturia and hypophosphataemia. With a phosphate-poor diet the frequency of hyperphosphaturia, of course, de- creases, while the frequency of hypophosphataemia in- creases. Our main interest has been to ascertain how many patients on a normal diet have a phosphate-rich uri- nary excretion in spite of a low phosphate level in serum. Urinary phosphate excretion investigations have been discussed by, among others, Nordin and Fraser (15).

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 helshe 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). ?%e mean serum pikosphorus concentration was 0.7 mmol/l (range 0.5-0.8). Mean phosphate clearance was 31 ml/min/1.73 ma (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 I-a- hydroxy-vitamin D1, 0.5-1 .O pg daily (supplied by Lowens 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 under- gone 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, in- termittent swellings, pain in the loin and flank. Sometimes also tiredness, dizziness, tenderness in bones and mus- cles. Serum phosphate 0.6 mmol/l, phosphate clearance 41 ml/min. Abundance of phosphate crystals in dried urine. Slight bone tenderness. Treated with phosphate and 1-a-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/l, phosphate clearance 36 ml/min. Good manual capacity, no bone tenderness. Abundant phosphate crys- tals in dried urine. Her complaints disappeared after 4 months of phosphate treatment.

Case 3. Male, 50 years. Long-standing back pain, in- creasing pain in all joints, muscle cramp, walking difficul- ty, swaying walk. Fatigue, dizziness, pressure on the chest. In 1%9 papillitis calcificans with mild azotae- mia. Serum creatinine level at present 240 pmol/l. Aminoaciduria. Serum phosphate 0.7 mmol/l, phosphate clearance 33 ml/min. Manual capacity somewhat reduced, pain threshold in the calves at 80 mmHg, low. Treated with phosphate tablets and I-a-vitamin D,. His troubles have diminished somewhat.

Cased . Female, 49 years. Long-standing pain above the bladder, in the lumbar region; occasional headache. Dur- ing the last year attacks of dizziness, sickness, cramp in the hands, loss of sensation in the fingers. Upon examina- tion 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 phos- phate 2s mmo1/24 hours. Treated with phosphate tablets for more than a year, occasionally also with 1-a-vitamin D3. 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 papil-

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Mild phosphate diabetes in adults 95

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, how- ever, been regarded as rare. Essentially only children with nutritional insufficiencies, or occa- sionally 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 af€lict pa- tients 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 (“varial- gia”), are to be found in most practices. Usually nothing is found upon examination. The patients are assigned the diagnosis of asthenia, neuras- thenia, myalgia, varialgia, arthralgia, etc., which make them misunderstood and unsatisfactorily treated. In this group of asthenics there are cer- tainly many cases of psychosocial insufficiency, but no doubt also unrecognized somatic illnesses. The frequency of phosphate diabetes among asthenics is unclear.

Lindqvist and Lundstrom (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 1 OOO 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 aFe 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 con- sumption of considerable quantities of food rich in phokphates 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

n

Fig. I . Triple phosphate crystals in dried urine

litis calcificans upon urography. Serum phosphate 0.5- 0.9 mmol/l. Phosphate clearance 40 ml/min. Mild aminoaciduria. Mild liver disturbance. Eosinophiluria. Treatment with phosphate tablets and I-a-vitamin D3 dis- continued 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 nor- mal. Examination indicated muscle tenderness, muscle atrophy in the shoulder region. Serum phosphate 0.7-0.9 mmol/l. Urinary phosphate 25 rnmo1/24 hours, phosphate clearance 21 ml/min. Treated with phosphate tablets. Im- proved.

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 communica- tion.

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 hyper- calcaemia, hypercalcuria and/or raised parathyroid hormone concentration in the blood. Amino- aciduria 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 cows’ muscles became

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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 dia- betes. 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 defi- ciency.

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. Esti- mation of 25-OH-vitamin D3 has not yet been shown to be of any importance.

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determining phosphate in serum with the “Certific Chem”. Clin Chem 18: 263, 1972. Falkson, G. & Frame, B.: Phosphate diabetes, a re- view. Henry Ford Hosp Med Bull 6: 244, 1958. Frame, D. & Smith, R. W.: Phosphate diabetes (A case study of osteomalacia). Am J Med 25: 771, 1958. Fuller, T. J . , Carter, N. W., Barcenas, C. & Knochel. J. P.: Reversible changes of the muscle cell in experimental phosphorus deficiency. J. Clin Invest 57: 1019, 1976. HallCn, L. G . , Lindahl, 0. & Lindqvist, B.: Enkla satt att mata handkraft hos reumatiker. Nord Med 75: 380, 1966. Hicco, D., Bordier, Ph. & Tun-Chot, S.: Phosphate et metabolisme phosphocalcique, pp. 237-247. Pub1 Hioco, D. J., Paris 1971. Lindqvist, B. & Lundstrom, J.: Enkla astenitest. Nord Med 82: 858, 1969. Lotz, M., Zisman, E. & Bartter, F. C.: Evidence for a phosphorus depletion syndrome in man. N Engl J Med 278: 409, 1968. Madsen, S. , glgaard, K. & Ladefoged, J.: 1 - Alpha-hydroxycholecalciferol-induced changes in the renal handling of phosphate and the serum para- thyroid hormone level. Acta Med Scand 200: 351, 1976. Moorhead, J. F., Willis, M. R., Ahmed, K. I., Bailled, R. A., Varghese, Z. & Tatler, G. L. W.: Hypo- phosphataemic osteomalacia after cadveric renal transplantation. Lancet 1: 694, 1974. Nagant de Deuxchaisnes, C. & Krane, S. M.: The treatment of adult phosphate diabetes and Fanconi syndrome with neutral sodium phosphate. Am J Med 43: 508. 1%7.

15. Nordin, B. D. C. & Fraser, R.: Assessment of urinary phosphate excretion. Lancet 1: 947, 1960.

16. Scriver, C. R.: Rickets and the pathogenesis of im- paired tubular transport of phosphate and other sol- utes. Am J Med 57: 43, 1974.

17. Scully, R. E., Galdabini, J. J. & McNeely, D. U.: Case report. N Engl J Med 6: 977, 1975.

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