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Low Specific Gravity Syndrome H. W. Gillen and C. E. Pippinger Data strongly suggestthat the longer patients have been treated in New Castle State Hospital, the higher the probability that they will demonstrate the low specific gravity syndrome. It is believed that a probably unrecognized alteration in human water metabolism among institutionalized patients who have chronic, severe epilepsy and who have been administered anticonvulsant drugs for many years has been documented. The drugs most commonly used within this population are diphenyihydantoin and phenobarbital. Each compound is reported to affect (albeit oppositely) the release of ADH, and both affect cellular enzyme systems related to water and/or electrolyte metabolism. PATIENTS WITH CHRONIC NEUROLOGIC DISEASE present an opportunity for study of long-range alterations in biochemical and physiologic phenomena. If these same patients have also received various pharmacologic agents for many years, a second opportunity exists to study minor toxic effects on human function. At New Castle State Hospital (NCSH), a hospital for patients with chronic epilepsy, both conditions exist within the patient population. For these reasons tile biochemical researcim laboratory of the hospital began a systematic screening program, searching for biochemical evidence of altered function that, if identified, might then be correlated with either some aspect of tile neurologic disease or some feature of time prolonged adnministration of pharmacologic agents (mostly anticonvulsants and tranquilizers). Tile first phase of time screening program consisted of examination of the voided morning urine specimens collected over a 3-month period from the entire hospital population (N = 793). The screening tests, performed by classiclaboratory technics,are: From the lad. 46202; Castle, md. Supported Department and the of Neurology, Biochemical in part by U. S. Public in at the Symposium Laboratory, Oak Tn(l,amIa University Laboratory, Reseai-eh Health Service Grants School of New Castle NIl Medicine, State 05021-12, Indianapolis, Hospital, New FR-00057-05, and 1IE-10401. Presented Oak Ridge part National on Ridge, Urinary Tena., 403 Constituemits Nov. 30-Dec. of Low 1, 1967. Molecular Weight, 404 6ILLEN & PIPPINGER 1)imiitmoplienylhydrazinc Iiidoxyl sulfate I midolic acid spot test Chemistry Watson-Schwartz: chloroform extinction Watson.Sehwai-tz : butanol extractioti M eta elmroisma tie sta iii (mmcina my sed iiii it) Plmenistix lienesliet’s Clinitest Specific gravity Omie-diniClmsiollal chromatography Pi-ohi 1)11 paper for Clinical amino ii test ( ahlomamin ) acids Initial examination of time data revealed a large skew in time distribution of the urine specific gravities (1) as seen in Tal)le 1. This was originally suspect, but repeated tests Oil specimenS from the same patients at different meteorologic seasons, including S or more consecutive daily collections,confirmed without doubt that the observations were not spurious. State hospitals, regardless of their purpose, often have similarities not suspected at first because of the inadequate number of personnel available and fiscal limitations on diets and drug sources. Five hospitals of time State of Indiana Department of Mental Health cooperated with mis amid provided, each data from time routine morning urinalysis from 500 consecutive patients. These data failed to (lemonstrate the skew seen originally. Two community hospitals also assisted us, and analysis of their data confirmed our suspicion that our patient population was unique. One of the community hospitals was in the immediate vicinity and therefore served as a control for nmeteorologic and geographic features. NCSH has its own water supply system, independent of time local community, and this feature of geographic control has not yet 1)een studied. Because of the possibility that chronic drug effects produced the low urine specific gravities of our patients, we searched for evidence that patients in other state hospitals on similar drugs may have similar changes. We therefore obtained the assistance of the Director of Laboratories at time Craig Colony and School, Sonyea, N. Y., where the patient population is almost identical (chronic, severe epilepsy) and the drugs used are very similar. The 500 urinalysis reports from Craig Colony were not different from normal, reconfirming our initial conTable Specific 1. SPECIFIC GRAVITY DETERMINATIONS Variation from expected distribution = 793) No. gravity 207* 275* 136 9S 49 24 4 1.000-1.005 L006-1.OlO 1.011-1.015 1.016-1.020 1.021-1.025 1.026-1.030 1.031-1.035 * (N by more than 3 S.D. Vol. 14, No. 5, 1968 405 LOW SPECIFIC GRAVITY SYNDROME elusion that the population of our hospital appeared to be unique, for reasons unknown (Table 2). When the problem of low urinary specificgravity is approached symptomatically, the differential diagnosis lies essentially between diabetes insipidus due to various mechanisms and primary renal disease. Since niany of time patients have considerable brain damage, it is also possible that various conipulsive behaviorial patterns have developed includimig “psychogenic diabetes insipidus.” However, time size of the population seemed too large, especially when compared with other institutionalized populations of brain-damaged patients (the mentally retarded). Time diversity of causes of chronic epilepsy requiring institutionalization almost preclude a common endocrinologic mechanism and would negate time probal)illty of common renal pathologic processes accounting for time low urinary specific gravity (or, thin urine). However, proloimged administration of anticoiivulsantdrugs is associated with cytologic changes that might be related to water amid/or electrolyte metabolism, and is associated w-itim changes in hepatic and endocrine function (2). We therefore began preliniinary studies of fluid balance to determine if the patients had enlarged or excessive intakes related to their unconcentrated urine. Once the range of the individual water balance was established, fluid intake restriction was imposed to determine if the patients had the ability to concentrate their urine. The initial studies were uiisatisfactorv but did indicate that some patients could concentrate tlmeir urine if intake was sufficiently reduced. The investigation was transferred to time Clinical Research Center at Indiana Fniversity Table 2. MEANS OF 500 URINESPECIFIC FROM 9 DIFFERENT GRAVITY DETERMINATIONS HOSPITALS Nov pilal.’ Name State hospitals New Ca.stle State Hospital Beatty State Hospital Richmond State Hospital Evansville State Hospital Fort Wayne State Hospital Muscatatuck State Hospital Craig Colony & Sehool (Somlyea, Special County Mean Epilepsy NY) General communils hospital.sMiami Valley Hospital Henry functiov retardation retardation 1 014 1 .015 - = is vienifieantl <.001. (lifferent graviiy 1.012* 1 .014 1 .016 1 .015 1 .019 1.020 1 .016 - Hospital * New Castle State Hospital mean lmsespita!s, According to the (test, p Mental Mental Epilepsy opecific from means of each and all other - 4O GILLEN Medical Center. Four patients a preliminary report of these & PIPPINGER have been observations. Clinical studied to date. This Chemistry iaier is Methods Patients were selected from the NCSH population on the basis of timeir low urinary specific gravity, absence of recognized renal disease, and freedom from gross disturbances of behavior. The daily fluid intake and output were measured during the entire hospitalization, as were the body weight, urine specific gravity and osmolality, and usually the plasma osmolality. Serum was analyzed for sodium, potassium, chloride, calcium, phosphorus, urea, creatinilme, uric acid, cholesterol, protein-bound iodine, proteiim electrophoresis, total carbon dioxide, protimrombin time, SGOT, SGPT, alkaline phospimatase, and fasting blood sugar. The 24-hr. urine collections were analyzed for sodium, potassium, calcium, chloride, phosphorus, uric acid, urea, creatinine, 17-hydroxycorticosteroids, 17 ketosteroids, total amino acids (ninhydrin), and by chromatography for amino acids and mucopolysaccharides. Multiple 24-hr. urine specimens, with matched serum samples, were serially studied before and during fluid intake restriction for sodium, potassium, calcium, chloride, urea, creatinine, and phosphorus. All biochemical determinations were made by classic methods. The following functional studies were done: intravenous excretory pyelogram, T-3 resin uptake, urea clearance, creatinine clearance, electrocardiogram, and electroencephalogram. The whole blood volumes were determined isotopically. Classic hematologic studies were made, and time mean corpuscular volumes and mean corpuscular henioglobiii contents were calculated. The total white blood cell count was done and the distribution of cell types was counted. After 3-5 days of observation without restriction of fluid intake, a slow, progressive restriction was imposed at 2-day intervals. ITrine amid serum analyses continued during this period. Wimen the patient could be maintained with a fluid output of less than 2 liters, time plasma antidiuretic hormone (ADH) content was assayed (3)* At this time the whole blood volume was redetermined. The patient was then allowed fluid intake and 24-hr. urine specimens were again collected. Results Several attempts the control, without *Tlmese assays University School were of to restrict restraining performed Medicine. fluid intake the patient, by Di-. Ward W. Moore, were made at NCSH, hut was difficult. On occasion, T)ep:irtnieiit of Physiology, lioliasia Vol. 14, No. 5, 1968 LOW SPECIFIC GRAVITY SYNDROME 407 the logistics of this program exceeded the personnel available. Changes in body weight each morning were used as an index of the efficacy of fluid restriction, which, by this criterion, was unsatisfactory. The patients, during the periods of observation, often excreted more than the recorded intake. This could be accepted if one assumed the patients carried an excess water load. The diuresis would be “proportional” to the plasma osnmolality, if renal function and Al)H secretion were normal. This appeared to occur wimen fluid intake control was “lost.” Quantitative fluid and electrolyte balance studies have not yet been performed. Four patients have been studied; their abbreviated clinical sum- maries are in the Appendix. The first 3 patients were selected because of their persistently low urine specific gravity. The fourth patient was selected because it appeared that after only 2 months of hospitalization her urine specific gravity had decreased from time normal values originally measured at the time of her admission to NCSH. The initial blood and urine studies of constituents that changed duritmg fluid restriction are found in Tables 3 amid 4. The serum amid urine biochemical values from the first 3 patients after significant fluid restriction, when the plasma ADH was assayed are given in Tables 5 and 6. All patients had daily, 24-hr. excretions of sodium, calcium, and chloride that were low to low-normal, according to our laboratory Table 3. SERUM Patient Na D.W. D.B. N.D. AW. 135 137 140 140 * CONSTITUENTS IN PATIENTS C! 4.1 4.0 43 4.3 Creatininet 102 102 102 103 Fiuw WITH UNLIMITED Caiciumt Ureaf 9.5 9.3 8.9 9.5 7 It) 9 S 0.85 0.81 0.62 060 INTAKE Ovmolality (mosm./kg.) 284 291 292 275 Intake (L.) 6.6 6.9 4.9 3.25 in mEq./L. tin mg./l00 Table ml. 4. URINE CONSTITuENTS IN PATIENTS WITH UNLIMITED Fi,umn iNTAKE Ormol‘ii its’ K C1 112 82.6 112 1.2 0.3 110 152 130 71.5 62.0 499 110 154 137 1.57 0.96 1.12 0.28 Patient Na D.W. D.B. N.1). A.W. * In mEq./24 hr. tin gm./24 hr. Urine/serum osmolality. Creatininef Csilciumt - 0.04 Uresmt - 9.588 8.45 9.05 (moon,./ kg.) Output (L.( Specific gravity 182 6.7 1.002 180 218 750 7.7 4.6 3.9 1.004 1.003 1.020 i/NI 064 0.62 0.75 2.87 408 GILLEN Table 5. SERUM & PIPPINGER Clinical AFTER FLUID CONCENTRATIONS Chemistry RESTRICTION Damp!ality (mosm./ CressPatient Na’ K’ (‘1’ D.W. D.B. N.D. 150 139 142 4.7 4.2 4.3 102 102 106 ti,sinet Cahiumt 0.86 0.58 0.66 11 II 11 - 9.6 5.8 intake (pu. kg.) (L.) ml.) 257 255 307 2.3 2.6 2.9 2.2 4.3 0.9 Ice,t In mEqJL. * tlmmm ./lOOml Table 6. URINE CONCENTRATIONS AFTER FLUID RESTRICTION Oumolality Patient .‘sa’ K’ Cl’ Creatini net 1).W. D.B. N.1). 184 235 62.8 78 67.2 59.9 198 280 62.4 L66 0.89 1.15 In mEq./24 * Caiciumt (movm./ kg.) Ureat - - 0.16 0.02 9.43 4.95 548 352 312 Output (L.) Specific 1.7 1.8 7.1 gravity 1 81 1.010 1.005 1.012 L91 1.22 1.02 hr. tIn mg./24 hr. osmolality. Urine/serum standards. The urine osniolality was often low on admission with unfluid intake. With fluids administered ad lib,the patients consumed betweeim 5 and 12 L./day and excreted similar volumes. The fourth patient, who appeared to be starting this abnormality, after continued observation, had relatively normal rellal functioim and water restriction was miot mitiated at this time. restricted Fluid restriction was imposed after time urea and creatrnnie clearance studies were completed (Table 7) ammdthe initial whole blood volumes determined. Although intake control was attempted rigorously, output measurements were mucim more likely to be correct and daily body weights frequently failed to correlate w-iththe recorded fluidbalance sheets per 24 -hr. period. Table 7. UREA AND CREATININE Jiefore CI.E.’SRANCES AND WHOLE Clessr,s ore iI’hoic Whole Putie,st (‘ 1).W. D.B. N.D. A.W. * Urea normal) 99.9 99.0 112.0 133() l’mom mmomogram. BLOOD (.reats,a,,,e (ml. mm.) 171.0 89.6 l49.t) 170.0 \OLUMES revtriction blood volume (‘vi.) blood coin me (ml.) after re.vtrjctjon -- Calculated 5040 4534 4342 4400 Expected’ 3700 4231 3348 4205 Calculated Expected#{176} 4200 3700 4332 4085 3406 3348 No restriction Vol. 14, No. 5, 1968 409 LOW SPECIFIC GRAVITY SYNDROME Discussion In all patients, the urinary constituents per 24 hr. were less thami expected; timis was especiallyso for the chloride. The sodium was almost always at the lower end of the expected rammge. If this constitutes a signiflcaimt discrepancy from time normal is not yet determined. Cross checks were made in two separate laboratories, and we therefore believe that this population may represent several unexpected problenms, as yet unsolved. \Vhen water restriction imposed, only 1 of the 3 1)atielltS ever had an elevated urine osmolalitv al)ove 400 mosm./kg., or aim increased urnme specific gravity above 1.012. Time urine-to-osmolality ratio failed to differentiate ADH-deficiellcv diabetes insipidus after water deprivalion as predicted by Frasier et at. (1) Only 1 of time 3 patients fulfilled the criteria, ojyn that were used to in(licate a normal ability to form a concentrated urine. This was iii spite of the normal venous A1)H levels. Other criteria of renal function were all within normal limits. This . particular literature disorder of renal fuiictiomm has to time best of our knowledge. not been described in the Time inflimence of time anticollvulsant drugs on renal function without time development of systemic lupus erythematosis syndrome is poorly documented. Lee et at. (:l) reported that intravenous dipimenyhimydantoin HCI, 250 mg., produced a prompt increase in free water clearance. Diphenylhydaiitoin is reported to inhibit ADH release which should enhance water excretion, while according to Kleenman amid Fichman (6), phenobarbital is considered a potent stimulus to AT)H release. Some of time alterations iii hepatic enzymatic activity imave l)een recently described by Zeidenberg et a!. (7). induction of increased activity rates of enzymatic systems is now an accepted concept and has occasionally been demonstrated using some of the anticonvulsarit drugs (8). How this may be related to our observation of a large number of patients who do not normally concentrate their urine remains to be determined. Appendix Patient D.W. (IUMC 424216) was a 35-year-old Caucasian male who had been well until age 7, at which time generalized seizuresbegan without obvious cause. He has 1 feeble-minded sibling.In retrospectit is now believedthat his growth and development may have been retarded before the onset of the epilepsy; he is now moderately mentally retarded (IQ estimated at 70). He was admitted to NCSH in 1941. He has about 2 seizures (major) a year and takes diphenylhydantoin (100 mug. h.i.d.),phenoharbital (100 ng. t.i.d.), and chlorpromazine hydrochloride (50 mg. q.i.d.). The general and neurologic examinations were within normal limits.Serology, hemograms, routine urinalysis. 410 GILLEN & PIPPINGER Clinical Chemistry and X-rays of the chest and skull were all normal except for the low urine specific gravity and an increased MCV (115). Patient D.B. (TUMC 424286) was a 56-year-old Caucasian male who had been well until age 12, at which time generalized seizures began for no apparent reason. The family history is negative fornervous system disease. He was adlnitted to NCSH in 1931 and is now considered moderately retarded mentally. For the past 2 years he has had very rare seizures while taking the following medications: diphenylhydantoin (100 mg. t.i.d.), phenobarbital (100 mg. q.i.d.), and chlorpromazine hydrochloride (50 111g. t.i.d. and h.s.). He has been on a 1500-cal., salt-free diet for the past 2 years. The general and neurologic examinations were within normal limits (IQ estimated at 85). Serology, heniograms, X-rays of the chest and skull, and routine urine analysis were normal except for the low urine specific gravity. Patient N.D. (IUMC 426304), a 32-year-old Caucasian female, was admitted to NCSH in 1944. The falllily history was negative for disorders of the central nervous system. Her seizures began 5 days following birth and recurred for several days. She was then seizure-free until age 3 and has had approximately 20 seizures a year since. The seizures are focal in type and start with paresthesia in the right hand, followed by tonic fiexion of the right hand and arm. A “porencephalic cyst” was demonstrated in the left cerebral centroparietal lobe by pneumoencephalography. She is mentally retarded (IQ estimated at 65) and is unable to write or read sentences. General physical examination is within normal limits. The neurologic examination reveals alternating strabisnlus, inability to optically fix on the midline when the abducting eye is positioned laterally, and hypoactive reflexes. Her present medications are: phenobarbital (100 mug. h.s.), diphenylhydantoin (100 mg. t.i.d.), and trifluoperazine (5 mg. q.i.d.). The serology and routine urinalysis were normal except for the low urine specific gravity. She has had a mild hypoehrornic, niicroeytie anemia for several years, with modest leukopenia. X-rays of the chest are normal. X-rays of the skull reveal some probable inner-table thinning over the left centroparietal lobe of the cerebrum. Patient A.W. (IUMC 428055), a 22-year-old Caucasian female, was admitted to NCSH in October 1967. She was considered to have been in normal health until age 13 at which tilne 3 types of seizures developed. These did not interfere with her schooling, and she graduated from high school in 1963 at the age of 18. Since graduation the seizures have progressed in frequency and severity, and the patient now shows evidence of deterioration of mental skills (IQ estimated at 85). Physical examination revealed an obese female with normal secondary sexual characteristics. Neurologic exanmination revealed moderate mental retardation, slurred speech, ataxic and dysmetric gait and limb movements, and moderate decrease in muscle power in her legs. The muscle stretch reflexes were hypoactive-more so in the legs. No abnormal reflexes were present. Seizure frequency now is 10 per month and she takes the following drugs for seizure control: methsuximide (300 ing. t.i.d.), phenobarbital (200 mg. h.s.), and ethosuximide (250 mg. t.i.d.). Serology, hemogram, and routine urinalysis were normal except for the low urine specific gravity. This patient has specifically been selected for study because in the 2 months following admission (average) her urine specific gravity decreased from 1.024 on 3 consecutive on 5 consecutive days. X-rays of the chest and skull were within days to 1.009 normal limits. References 1. Pippinger, C. E., Smith, A. M., Morley, anticonvulsant drugs: I. Alteration Neurology 17, 316 (1967). G. K., and Gillen, of urine specific H. W., The chronictoxicityof gravity ill epileptic patients. Vol. 14, No. 5, 1968 2. 3. 4. 5. 6. 7. 8. LOW SPECIFIC GRAVITY 411 SYNDROME Milliehap, J. G., “Anticonvulsant Drugs.” In Physiological Pharmacology, (Vol. 2, The Nervous System, Part B), Root, W. S., and Hofman, F. G., Eds., Acad. Press, New York, 1965. Rogge, J. D., Moore, W. W., Segar, W. S., and Fasola, A. F., Effect of +G. and +0, acceleration on peripheral venous ADH levels iii humans. J. Appl. Physiol. 23, 870 (1967). Frasier, S. P., Kutnik, L. A., Schmidt., B. T., and Smith, F. G., Jr., A water deprivation test for the diagnosis of diabetes insipidus in children. Am. J. Diseases Children 114, 157 (1967). Lee, W. Y., Grumer, H. A., Bronsky, D., and Waldstein, S. S., Acute water loading as a diagnostic test for the inappropriate ADH syndrome. J. Lab. Clin. Med. 58, 937 (1961). Kleeman, C. R., and Fichman, M. P., The clinical physiology of water metabolism. New En.gl. .1. Med. 277, 1300 (1967). Zeidenberg, P., Orrenius, S., and Ernster, L., Enhancement of glucuronylating enzymes and mitochondrialoxidationenzymes in liversof ratstreatedwith phenobarbitaL Trans. N. Y. Acad. Sc4., Ser. II 29, 310 (1967). Kutt, H., Winters, W., Kokenge, R., and McDowell, F., Diphenylhydantoin metabolism, blood levels, and toxicity. Neurology 11, 642 (1964). * NEW ADDRESS OF * CLINICAL CHEMISTRY EDITORIAL OFFICE Members of the American Association of Clinical Chemists and contributors to CLINICAL CHEMISTRY, please note our new address: CLINICAL CHEMISTRY P.O. 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