Abnormal electrolyte and water metabolism in acute intermittent porphyria

Clinical

Studies

Abnormal Electrolyte and Water Metabolism in Acute Intermittent Porphyria* The Transient Ina@ropriate EMANUEL S.

Secretion of Antidiuretic Hormone

HELLMAN, M.D.,? DONALD P. TSCHUDY, M.D. and FREDERIC C. BARTTER, M.D. Bethesda, Maryland Her past history was pertinent only in that acute urinary retention requiring catheterization had occurred during her first two pregnancies, and was followed by symptoms of urinary tract infection. There was no familial history of porphyria. Physical examination revealed a lethargic, debilitated, normally hydrated, afebrile, slender woman complaining of diffuse pain in the lower part of the abdomen. The pulse was regular at 142 per minute and blood pressure was 120/85 mm. Hg with the patient supine. The abdomen was visibly asym-

T

HE occurrence of hypochloremia and/or hyponatremia in symptomatic acute intermittent porphyria has been reported frequently since the first observation by Roth in 1935 [I]Various speculations have been advanced as to the etiology of these serum electrolyte abnormalities. In this paper a possible mechanism is proposed on the basis of studies in two patients with acute intermittent porphyria. It is suggested that they manifested a transient inappropriate secretion of antidiuretic hormone. One of them had, in addition, an episode of hypoma~esemia and hypocalcemia, with concomitant tetany, during a clinically symptomatic period.

metrical, with a multinodular,irregular,firm, slightly tender mass about 20 cm. in diameter in the lower right quadrant. Peristalsis was hypoactive. The liver was slightly tender and minimally enlarged. Detailed neurologic examination was within normal limits. Hemoglobin, white blood ceil count and differential were normal. A morning urine specimen was reddish brown, with a pH of 5.0, specific gravity of 1.020, trace proteinuria, a strongly positive test result for porphobilinogen and a negative test result for myoglobin. The spun sediment showed a few red blood cells and numerous white blood cells. Escherichia coli was cultured in colony count greater than IO6 per cc. of urine. The blood urea nitrogen was 45 mg, per cent, fasting blood sugar 116 mg. per cent, bromsulfalein retention 8 per cent after 45 minutes, serum glutamic-oxalacetic transaminase 22 units, serum albumin and globulin 3.3 and 4.0 gm. per cent, respectiveiy, erythrocyte sedimentation rate 37 mm. per hour, serum total biiirubin 0.2 mg. per cent with 0.11 mg. per cent as direct reacting component, and alkaline phosphatase 14 King-Armstrong units. An electrocardiogram demonstrated sinus tachycardia and wide angle between QRS and T vectors consistent with left ventricular ischemia. The chest roentgenogram was within normal limits, Roentgeno-

CASE REPORTS

R. N. A., a thirty-five year old white housewife (gravida III, para III), was admitted to the Clinical Center of the National Institutes of Health on April 27, 1960. During the twenty months prior to admission she had experienced recurrent episodes of pain in the lower part of the abdomen of ,several days’ duration; they subsided spontaneously. Recently she had noted the passage of reddish brown urine that darkened to a deep brownish black on exposure to sunfight. The diagnosis of acute intermittent porphyria was established by the demonstration of porphobilinogenuria nine months prior to admission. One month prior to admission she delivered a full term normal infant. She received ergotamine as an oxytocic, but no barbiturates. Two weeks later, severe cramping pain in the lower part of the abdomen recurred, with anorexia, constipation, insomnia, emotional lability and progressive malaise and fatigue.

Service, National Cancer Institute and the Clinical Endocrinology Branch, National Heart Institute, Bethesda, Maryland. Manuscript received July 13, ‘1961. +fpresent address: Department of Cardiology, Georgetown University Hospital, Washington, D. C.

* From the Metabolism

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Porphyria-Hellman logic examination of the abdomen demonstrated considerable fecal material in the ascending colon. On an ad Eibitum but measured diet the patient’s food intake averaged about 375 calories per day over the first five days. She received phenothiazines and meperidine for abdominal pain. The administration of saline and oil cathartics, oil retention and saline enemas, and Prostigmine* resolved the mass in the lower right quadrant (apparently a fecai impaction) within seventy-two hours, with concomitant disappearance of abdominal pain and general improvement in physical condition. Figure IA is a construction from available data describing electrolyte and water metabolism over the initial period of hospitaiization. On the second hospital day the patient received 3,365 ml. of water (2,000 ml. of which was given intravenously as 5 per cent dextrose and water), and on the third hospital day 2,950 ml. (1,000 ml. given intravenously as normal saline solution). During this period she gained 1.6 kg. On the morning of the third hospital day the blood urea nitrogen had fallen to 21 mg. per cent, sernm sodium 121 mEq. per L., and bicarbonate 25 mEq. per L. The serum calcium was 8.8 mg. per cent and serum phosphorus 2.2 mg. per cent. “Fingerprinting” of the patient’s skin was observed on digital pressure, suggesting cellular overhydration. On the morning of the fourth hospital day diplopia due to left lateral rectus weakness and mild generalized weakness of the major muscle groups of all four extremities developed. The patient complained of paresthesias of the fingers and toes but had no objective cutaneous sensory deficit. She was unaware of a distended bladder, and 1,100 ml. of urine was removed by catheterization. By the morning of the fifth hospitaf day moderate generalized weakness of somatic and bulbar musculature had developed. Deep tendon reflexes were absent in the legs and reduced in the right arm. The plantar response was extensor on the left; palmomental response was strongly positive on the right, and a positive snout reflex was observed. Pain and touch sensation were decreased in the right arm and hand; vibratory and touch sensations were absent in both feet. Tachycardia, pupillary dilation, irregular dermal vasoconstriction, profuse diaphoresis, and enteric and bladder dysfunction indicated autonomic involvement. Tachypnea (36 per minute) was present. Synergistic motor action was defective. The patient was oriented and somnolent, but higher mental functions were deficient. Serum electrolytes at this time were: sodium 111 mEq. per L., potassium 3.7 mEq. per L., chloride 71 mEq. per L., and bicarbonate 23 mEq. per L. The sodium concentration was 106 mEq. per L. in a singie specimen of urine analyzed before infusion of saline solution. The urinary pH was 5.0. Sodium chloride (1,361 mEq.; average concentration 180 mEq. per L.) was given VOL. 32,

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intravenously during the following forty-eight hours, elevating the serum sodium to 138 mEq. per L., and the chloride to 101 mEq. per L. During the fifth and sixth hospital days the patient’s condition deteriorated rapidly. A flaccid quadriplegia developed, and she became more obtunded and finally comatose. On the sixth hospital day persistent spontaneous twitching of the extremities appeared and a bilaterally positive Chvostek sign was elicited. The serum calcium was 7.6 mg. per cent, the serum phosphorus 2.2 mg. per cent that morning. The serum total protein was 6.2 gm. per cent with albumin 2.6 and globulin 3.6 gm. per cent. One gram of calcium gluconate (93 mg. ionic calcium) was given intravenously on two separate occasions without relieving the tetany. The serum magnesium was then found to be 0.9 mg. per cent.* Individual intramuscular injections of 1 gm. of magnesium sulphate diminished tetany transiently, and tetany disappeared following the administration of 6 gm. magnesium sulphate (1.2 gm. ionic magnesium) and 4 gm. calcium gluconate (372 mg. ionic calcium) over a period of eighteen hours. The serum magnesium had reached the normal range by the seventh, the serum calcium by the eighth hospital day. By the seventh hospital day the patient was alert and responsive, and taking fluids orally. Her course fluctuated through the ninth hospital day with intermittent disorientation, varying degrees of the neurologic deficits mentioned, and transient hypotension requiring treatment with intravenously administered metaraminot. On the eighteenth hospital day, a metabolic balance study was begun. From this point to the time of discharge on the seventieth hospital day the patient showed progressive recovery of neuromuscular function to the point where she was ambulatory without assistance. Therapeutic measures other than those related to water and electrolyte metabolism will not be discussed further. They were employed after the development of the electrolyte abnormalities and discontinued before the balance study was undertaken. Although moderate weakness of the lower extremities persisted, motor strength in the arms was normal, and there were no bulbar, cerebellar or cortical signs. Pyuria and bacilIuria cfeared short@ after the administration of tetracycline and streptomycin, and subsequent urine cultures demonstrated no pathogenic organisms. Additional pertinent laboratory examinations performed during hospitalization included: serum creatinine 0.5 to 0.8 mg. per cent; creatinine clearance 69 to 88 ml. per minute (82 to 105 ml. per minute * Serum and urinary ma~esium determinations were by a calorimetric method utilizing titan

performed

yellow 121, modified by Basinski and Rakes [3], as presented at the eleventh annual meeting df the American Association of Clinical Chemists, August 21-29, Cleveland, Ohio.

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BODY WT. K9. 2ooo

WATER BAL. mk/d

+O 2000 4Ow 140

SERUM No mEq9 L. 120

100

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800. 600

URINARY OSM. 24.hr. pool mOsmVKg=

1

600

.

400

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SERUM Mg mgffO0 ml.

SERUM Co mgJl00ml.

co EKE

8. 500

rng&i~o 500 EXCRETION (urinary) 1000 .

PATIENT

.

PATIENT

R.N.A.

1A

B.L.W.

1B

FIG. 1. A, patient R. N. A. B, patient B. L. W. Electrolyte and water metabolism over initial periods of hospitalization. See legend to Figure 2.

AMERICAN

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Porphyria-Hellman per 1.73 sq. M. body surface area); phenolsulphonphthalein excretion 15 minutes 14 per cent, 120 minutes 41 per cent; intravenous pyelogram prompt bilateral excretion and good concentration of dye with no structural abnormalities demonstrable; twenty-four hour urinary 17-ketosteroids 2.3, 3.1 hour urinary 17-hydroxymg. ; and twenty-four corticosteroids 3.2, 5.1 mg. B. L. W., a thirty-one year old white housewife (gravida III, para III), had been in excellent general health with no antecedent history of cardiovascular, renal, endocrinologic, hepatic or neurologic disease. There was no known familial history of porphyria. In November 1959 the patient had a partial dental extraction under sodium pentothal general anesthesia, and the evening following this procedure noted “nervousness,” irritability, shaking chills and aching pain in the lower part of the abdomen. During the subsequent five weeks these symptoms persisted, and she noted constipation and transient migratory paresthesias in the extremities and progressive development of a flaccid quadri- and bulbar paresis. The diagnosis of acute intermittent porphyria was established by the demonstration of porphobilinogenuria, and she was admitted to the National Institute of Neurological Diseases and Blindness in December 1959. Her course over the next six months was one of progressive and sustained improvement and by June 1960 she was ambulatory and managing her household without assistance. Moderate weakness of the extensor groups of the upper extremities persisted, but motor function in the lower extremities and of the bulbar musculature was normal. She had, however, lost about 30 kg. from a weight of 70.5 kg. before the illness and complained of emotional lability, anxiety and insomnia. On June 2, 1960, she experienced her first normal menses since the onset of her illness. On June 23, she noted the passage of small amounts of dark blood per vaginam, with cramping pain in the lower part of the abdomen, anorexia and constipation. She was re-admitted to the Clinical Center on July 1, 1960. Physical examination revealed a poorly nourished, normally hydrated, lethargic, uncomfortable woman. The pulse was regular at 140 per minute. Blood pressure was 140/100 mm. Hg with the patient supine. A large fecal impaction was palpable in the right colon. Neurologic examination revealed the abnormalities previously noted, with no recent changes. The hemoglobin was 13.7 gm. per cent, white blood cells 10,300 per cu. mm., with normal differential count. The urine was normal in appearance, pH 5.0, specific gravity 1.012; results of tests for protein, sugar and acetone were negative. The test result for porphobilinogen was strongly positive. The spun sediment demonstrated no formed elements. The blood urea nitrogen was 26 mg. per cent, fasting VOL.

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blood sugar 102 mg. per cent, serum sodium 134 mEq. per L., potassium 4.1 mEq. per L., chloride 94 mEq. per L., bicarbonate 26 mEq. per L., calcium 10.5 mg. per cent, magnesium 1.8 mg. per cent, bromsulfalein 19 per cent retention in forty-five minutes, serum glutamic-oxalacetic transaminase 20 units, serum albumin and globulin 3.7 and 3.8 gm. per cent, respectively, erythrocyte sedmentation rate 15 mm. per hour, serum total bilirubin 0.4 mg. per cent, with 0.13 mg. per cent as direct reacting component, thymol turbidity 1 unit, cephalin flocculation negative, and alkaline phosphatase 11 KingArmstrong units. The creatinine clearance was 110 ml. per minute. Phenolsulfonthalein excretion was 33 per cent in fifteen minutes and 70 per cent in 120 minutes. An eIectrocardiogram showed sinus tachycardia. An intravenous pyelogram demonstrated prompt excretion bilaterally with definition of normal structures. Roentgenologic examination of the chest was within normal limits. During the first twelve hospital days the patient’s condition remained unchanged. Abdominal pain, tachycardia and hypertension persisted. Delusions, bizarre dreams, periods of amnesia, anxiety and emotional lability occurred frequently. Figure 1B describes body weight, water balance, serum sodium and urinary osmolality from the second through the thirteenth hospital days. On the seventh hospital day the patient excreted 177 mEq. of sodium in the urine, resulting in a markedly negative sodium balance on that day. We have no explanation for this. On the eighth and ninth hospital days she demonstrated oliguria, her body weight increased acutely by 1.13 kg., and her serum sodium decreased to 124 mEq. per L. On the eighth hospital day the osmolality of her twenty-four hour urine pool was 604 mOsm. per kg. During the following three days water intake was limited to approximately 1,400 ml. per twenty-four hours and the sodium offered in the diet was kept at 80 mEq. per twenty-four hours. A diuresis ensued, the body weight decreased rapidly by 1.80 kg. and the serum sodium rose to 139 mEq. per L. Beginning on the twelfth hospital day the patient’s condition gradually and spontaneously improved. Appetite increased, constipation was no longer a problem, and abdominal pain, vaginal bleeding and psychiatric symptoms remitted. The pulse rate fell to the range of 90 to 100 and the blood pressure to a low normal range. She was discharged on the twenty-ninth hospital day. METHODS

On the eighteenth and subsequent hospital days, patient R. N. A. was on a metabolic balance regimen. The results are shown in Figure 2. Intake of sodium, calcium and phosphorus were determined by analysis [4-6] of standard diets. Twenty-four hour urine pools were analyzed for sodium, calcium and phosphorus,

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WATER BALANCE ml

DAYS

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SUOIUM mEq/liter

suoluM BALANCE mEq

:::piJ

5o 0 50 100

CALCIUM BALANCE gm

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FIG. 2. Patient R. N. A. kktabolic babrxe study. Intakes am plotted dowawards from zero lines, and urinary WtpUtS (shaded) upwards. “Inswsible” water loss is shown as clear arests below urinary volumes; fecal calcium and phosphants are shown 23.~ clear areas b&w urinary values.

Porphyria-Hellman and four day fecal pools were analyzed for calcium and phosphorus by the same methods. Fecal sodium

was estimated to be 2 per cent of intake. Daily water intake, as charted, is composed of measured distilled water, water content of foods and metabolic water calculated from the weights of protein, carbohydrate and fat ingested. “Insensible water loss,” as charted, represents dermal and pulmonary loss and the water content of stools, and was calculated from the following expression: (insensible water loss) = (water intake) - (urine volume) - (estimated net change in body water*) Body water was measured by determining the dilution of a weighed amount of tritiated water in the “exchangeable” body water [7]. Serum and urine osmolalities were determined by freezing point depression [8]. RESULTS

Metabolic Balance Study Patient R. A? A. Efect of variations in water and electrolyte intake on water, and phosphorus balance, serum sodium, calcium, sodium, and urinary osmolality (Fig. 2): During the first sixteen days of the balance study the patient lost 3.24 kg. of body weight as a consequence of neuropathic muscular atrophy and immobilization. There was an over-all negative calcium and phosphorus balance of 4.97 gm. and 7.57 gm., respectively, implying a net tissue loss of 2.52 kg., not including bone [9]. Over the last twelve days of the study she gained 0.42 kg., roughly coincident with the onset of her slowly progressive increase in motor function. Over this period there was an over-all negative calcium and phosphorus balance of 4.50 gm. and 0.26 gm., respectively. This implied a net soft tissue gain of 0.83 kg., despite continued bone resorption. Acute changes in body weight resulting from alterations in fluid balance are superimposed upon these long-term trends. During the first seventeen days the intake of sodium, potassium, phosphorus and calcium was kept constant at 101 mEq. per twenty-four hours, 47 mEq. per twenty-four hours, 1.14 gm. per twenty-four hours, and 0.770 gm. per twenty-four hours, respectively. During the first four days the water intake was less than * The estimated net change in body water was derived by subtracting the estimated change in “dry body mass” from the total body weight change over a twenty-four hour period. Change in “dry body mass” was calculated by multiplying the average daily weight change over long term trends (days 1 through 16, and days 17 through 28) by the fraction of the body composed of dry mass as obtained from body water determinatiops. VOL.

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2,400 ml. per twenty-four hours. There was an over-all negative balance of sodium, phosphorus and water, consistent with the progressive loss of body tissue. Serum sodium remained within the normal range. From day 5 through day 8, the water intake was increased to 3,400 ml. per twenty-four hours. Water retention occurred on days 5 through 7, and a diuresis on day 8. The sodium balance was negative by 93 mEq. during these four days. Serum sodium fell precipitously, reaching 126 mEq. per L. on the morning of the seventh day, and rising subsequently as the patient went into negative water balance on the last day of water loading. The patient gained 0.22 kg. during the first three days of increased water intake. (This figure clearly underestimates the net gain in body water, as she was losing tissue throughout this period.) Total body water, as measured with tritiated water, increased by 0.92 kg. over this period. Despite hyponatremia, the urine remained hypertonic to serum throughout the period of water loading. Water intake was reduced to 1,650 ml. per twenty-four hours on day 9. The sodium balance became positive and the serum sodium rose to normal. From the fourteenth through the seventeenth balance days the patient’s daily intake contained 2,104 ml. of water, 101 mEq. of sodium and 47 mEq. of potassium. On day 18 the sodium intake was lowered to 10 mEq. per twenty-four hours, while the water intake remained essentially unchanged (2,178 ml. per twenty-four hours). Although the sodium balance was negative on the first day of this regimen, as might have been expected, there was a slight gain in weight, presumably as a result of water retention. After the first day, the sodium output was essentially equal to the intake. On the twenty-third day the water intake was raised to 3,900 ml. per twenty-four hours. Water retention occurred without change in sodium balance. The serum sodium fell to 124 mEq. per L. and the patient gained 1.4 kg. (This latter figure overestimates the net gain in body water as she was now gaining tissue.) Total body water, as measured with tritiated water, increased by 0.83 kg. over this period. Urine osmolality became lower than that observed during the previous period of water loading but remained considerably above that observed normally during maximal water diuresis.

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Sequential Water Loading Tests Patient B. L. W. Effects of ethanol and desoxycorticosterone on the response to a water load (Fig. 3): On July 13, 15, 18 and 20, while the patient was on a constant metabolic diet, water loading tests were performed as follows: From 12:Ol A.M. to the termination of each individual study at 1:30 P.M., the patient received nothing orally and remained in the recumbent position except for brief periods during micturition. At 8:30 A.M. of the test day, blood was drawn, the patient emptied her bladder and 1,000 ml. of 5 per cent dextrose and water was administered intravenously over the subsequent one hour period. During the five hours from the start of the infusion, blood was drawn at specified intervals for serum osmolality, sodium and creatinine. The patient voided at specified times, and urinary osmolality, volume, creatinine and sodium concentrations were determined. Creatinine clearances were calculated. On July 15, 32.5 ml. of absolute ethanol was added to the infusion. On July 18, desoxycorticosterone acetate (DOCA) 3 mg. in oil was administered at 7:30 A.M. On July 20, the procedure of July 13 was repeated as a control study. Results are shown in Figure 3. On July 13 the patient had a grossly abnormal response to a water loading test, By the end of five hours she had excreted only 215 ml. and maximal urine flow was only 2 ml. per minute. While serum osmolality had fallen from 298 to 278 mOsm. per kg. two hours after the start of the infusion, the maximal dilution of urine was only to 639 mOsm. per kg. Two days later, when the study was repeated with ethanol, cumulative excretion of water, maximal urine flow, fall in serum osmolality and maximal dilution of urine were comparable. Three days later, when the study was repeated with DOCA, the five hour cumulative excretion of water had risen to 620 ml., maximal urine flow was 3 ml. per minute, and maximal dilution of urine was to 281 mOsm. per kg. The subsequent control study, seven days following the initial one, showed a normal response to a water load. The five hours cumulative excretion of water was 726 ml., maximal urine flow was 5 ml. per minute and maximal dilution of urine was to 59 mOsm. per kg. Creatinine clearances during these four experimental periods were comparable. Table I describes total sodium, potassium and osmolal excretion during each of the five hour periods.

et al. TABLE

PATIBNT

B.

EXCRETION

L.

W.

SODIUM,

DURINQ SERIAL

THE

WATER

I

POTASSIUM,

AND

FIVE

PERIODS

HOUR

LOADING

OSMOLAL OF

TESTS

Date

Five Hour Sodium Excretion (mEq.1

Five Hour Potassium Excretion (mJh.1

Five Hour Osmolal Excretion (mOsm. )

7/13 7/15 7/18 7/20

6.37 7.67 15.57 16.26

13.41 8.70 16.04 12.80

104 128 335 152

The increasing ability to dilute the urine is not related to increasing sodium reabsorption or dependent upon an increase of urinary solute. A shift from proximal to distal sodium reabsorption [IO] cannot be ruled out, but the constancy of the potassium excretion suggests that this did not occur. Accordingly, the results suggest decreasing secretion of antidiuretic hormone. During the eight day period of the study the patient demonstrated marked and progressive clinical improvement. There were no episodes of abdominal pain, her appetite improved and the “mean daily pulse rate” fell from about 140 to about 110 per minute. The data imply that there was also spontaneous and progressive recovery from the derangement in water and electrolyte metabolism. COMMENTS

Hypochloremia and/or hyponatremia associated with symptomatic episodes of acute intermittent porphyria have been reported frequently [ 7,71-771. Generally, when these electrolyte abnormalities have occurred, there has been clinical and occasionally histologic evidence of widespread involvement of the central nervous system, although symptoms referable to hypothalamic involvement other than acute tachycardia and hypertension have seldom been mentioned. Vomiting and diarrhea were rarely prominent symptoms in these cases and dehydration was infrequently observed. Chloruresis despite hypochloremia was documented in several instances, but the remainder of the clinical picture gave no further indication of adrenal cortical insufficiency, and urinary steroid determinations, tests of adrenal function and histologic examination of the adrenals, when performed, gave AMERICAN

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Porphyria-Hellman normal results. The reports cited do not include measurements of water and electrolyte balance, serum and urinary osmolalities, or body weights during periods of hyponatremia. While it is likely that a syndrome similar to that observed in our two patients was present, this cannot, in retrospect, be stated definitively. The patients described here manifested a similar to hyponatremia syndrome of that seen in certain patients with bronchogenie carcinoma [18-201 and disease of the central nervous system [27-231, probably the same syndrome seen also with pulmonary tuberculosis [24-261. During symptomatic episodes of porphyria water retention developed in both patients, with urinary tonicity above that normally seen with water loading, lowered serum osmolality, hyponatremia and hypochloremia, and failure of renal sodium conservation. During the balance study on patient R. N. A., an increase in water intake alone reproduced the syndrome. (Figure 2, days 5 through 8). An even greater increase in water intake during a period of sodium restriction reproduced the hyponatremia with water retention, but did not induce renal sodium loss. (Figure 2, days 23 through 26.) The effect of the low sodium diet in preventing renal sodium loss in this syndrome is comparable to that induced with DOCA or ACTH [18,27], and may result from increased secretion of aldosterone. The water loading studies in patient B. L. W. initially showed impaired ability to excrete a water load, with persistent hypertonicity of the urine. (Figure 3A.) With progressive clinical improvement, there was a normal response to the same load. (Figure 3D.) These alterations in water and electrolyte metabolism may result from endogenous inappropriate secretion of antidiuretic hormone, as they are similar to those encountered in normal subjects during persistent administration of pitressin and water [28,29]. In such subjects hyponatremia results both from water retention and from increased urinary sodium loss. Leaf et al. [27] demonstrated that increased urinary excretion of sodium followed the administration of pitressin only when there was expansion of body fluid volume, and could be prevented by limiting the fluid intake during the administration of pitressin. Even in the face of extracellular volume expansion, sodium and chloride loss could be reduced or abolished by administration of ACTH. VOL.

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If forced water intake is maintained in dogs or normal human subjects receiving pitressin, the initial decrease in urine volume and excessive excretion of sodium and chloride persist for several days, and then a new equilibrium state is achieved with lower serum osmolality [30,31]. In a case of bronchogenic carcinoma with this syndrome, an “equilibrium” state was not achieved even when serum osmolality had fallen to 202 mOsm. per kg. [18]. The rise of glomerular filtration rate which regularly occurs with pitressin-induced expansion of body water [27,37] doubtless favors establishment of the new equilibrium state; the serum osmolality and sodium concentration during such a state are probably dependent both on the dosage of pitressin and on the water intake [32]. On two occasions negative sodium balance apparently preceded water retention. In patient R. N. A., abrupt reduction of sodium intake from 101 to 10 mEq. a day resulted in a negative sodium balance and was followed by two days of weight gain. (Figure 2, days 18 and 19.) As the patient was in a phase of clinical recovery, gain of dry body mass, however, accounts for a portion of this gain. In patient B. L. W., a day of marked sodium loss (Figure 1, day 7) preceded the weight gain of 1.2 kg. which followed without further sodium loss. As this patient’s condition was deteriorating clinically, loss of dry body mass may have masked water retention before day 8. Thus the figure of 1.2 kg. would underestimate the degree of water retention. Whereas changes in sodium balance are secondary to changes in water balance in patients manifesting inappropriate secretion of antidiuretic hormone, these episodes suggest also that changes in sodium balance may lead to reciprocal changes in water balance in these patients. Such a phenomenon may have been present in Case 2 of Carter and associates [23]. However, in this case conditions were chan,ged too rapidly prior to and during the first three days of the balance study to establish a “steady state” from which to estimate the effect of lowering the sodium intake on water balance. When the sodium intake in their patient was increased, a diuresis with fall of urinary osmolality did indeed occur, but on the second day of the same regimen the urine volume was lower, and urinary osmolality was higher than on the preceding ‘icontro1” days.

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Porphyria-Hellman While the final common pathway for neural or neuroendocrine control of antidiuretic hormone secretion is the supraopticohypophyseal tract, other subcortical regions appear also to be involved in the mediation of antidiuretic hormone release [33]. The clinical neurologic manifestations of acute intermittent porphyria may represent dysfunction of virtually all areas of the peripheral and central nervous system. It is of interest that in the two patients studied, in whom disordered hypothalamic or autonomic function occurred, a syndrome which probably results from transient inappropriate secretion of antidiuretic hormone was present. In one patient, (B. L. W.) the administration of alcohol, known to inhibit release of antidiuretic hormone, did not modify the manifestations of the syndrome in the manner observed after a water load. (Fig. 3.) These studies indicate that forcing of fluids during acute attacks of porphyria (as has been recommended because of oliguria, azotemia and constipation [34]), is not without hazard. Concomitant with her initial episode of water retention and hyponatremia, patient R. N. A. manifested hypomagnesemia, hypocalcemia and tetany. Hypomagnesemia, symptomatic and asymptomatic, has been reported in a growing list of clinical situations in man, and has been attributed to deficient intake, failure of gastrointestinal absorption (from the diet or from succus entericus) or urinary loss of magnesium [35-391. The total body magnesium in the average normal human subject is about 25 gm. [40]. Less than 2 per cent is in extracellular fluid, and approximately 50 per cent is in bone. Studies on magnesium kinetics have been limited to a twenty-four hour period by the short half lives of the radioactive isotopes of magnesium. The exchangeable pool at twenty-four hours appears to be only slightly greater than that quantity of magnesium contained in the extracellular fluid [47-431. This implies that acute magnesium loss of renal or gastrointestinal origin must be reflected in changes in extracellular magnesium. Symptomatic hypomagnesemia with serum levels as low as 0.4 mg. per cent (0.3 mEq. per L.) has been induced in calves in six to seven weeks by dietary deficiency of magnesium alone, occurring at a time when the concentration of intracellular magnesium was still normal. Bone magnesium concentration had fallen by 30 per cent [44], but if allowance is made for VOL.

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743

bone growth, this does not necessarily imply loss of magnesium from bone [45]. In normal man it is difficult to induce acute magnesium deficiency by dietary restriction alone, as renal conservation can reduce urinary loss to less than 12 mg. per day, and fecal and urinary loss combined can be less than 36 mg. per day [39,46]. Accordingly, acute magnesium deficiency in man implies excessive loss of magnesium. The loss may occur into the feces, urine or milk. Gastrointestinal loss of magnesium occurs with malabsorption resulting from functional deficiency or reduced effective area of gastrointestinal mucosa. Urinary loss of magnesium leading to hypomagnesemia may be induced by for tubular reabsorption by “competition” other divalent cations (calcium or strontium) [47,48]. In the expanded state induced by pitressin and water, a calcium diuresis occurs [49]. It is not known whether magnesium diuresis occurs by a similar mechanism, or whether the hypercalciuria induces magnesium loss by competition at tubular sites. Urinary excretion of magnesium is increased on administration of aldosterone to rats [SO], and this may explain in part the hypomagnesemia frequently seen with hyperaldosteronism. Loss of magnesium with lactation may augment losses by other routes. On the assumption that human milk contains 5 mg. of magnesium per 100 ml. [57], loss through lactation will rarely exceed 40 mg. a day. Hypomagnesemia is frequently seen during the rapid formation and calcification of bone after surgical cure of hyperparathyroidism with bone disease. Presumably, magnesium is taken up from the extracellular fluid into the bones. In patient R. N. A., anorexia over the two weeks preceding admission and through the early hospital course resulted in minimal dietary intake. Obstipation minimized fecal loss of magnesium before admission, but cathartics and saline enemas were subsequently administered frequently, and may have promoted fecal loss of magnesium. From the second through the fifth hospital days, 469 mg. of magnesium (39 mEq.) were excreted in the urine, and the serum magnesium was 0.9 mg. per cent (0.8 mEq. per L.) on the sixth hospital day. While tissue breakdown doubtless contributed to the urinary loss, the fall of serum magnesium implies a deficit in renal conservation as well. As already discussed, patient R. N. A. proba-

Porphyria-HeZlman et at. bly manifested a syndrome of inappropriate secretion of antidiuretic hormone during the period when hypomagnesemia was present. Despite the presence of hypocalcemia, the urinary excretion of calcium was high during this episode, reaching 440 mg. on one day when virtually no calcium was ingested. It is possible that the urinary loss of magnesium was promoted, directly or indirectly, by the water retention that occurs in this syndrome. The action of an excess of magnesium ion in the ambient fluids of the mammalian neuromuscular system is known to be multifocal, and may even be a summation of individual effects at any given site. Cerebral cortical activity, and neural, synaptic and muscular transmission, are consistently depressed [52-581. At certain sites the effects of hypomagnesemia have been documented [55,58-f%], while at others they must as yet be inferred to be the inverse of the effect of an excess of the magnesium [47,63]. Both of these effects may synaptic transmission. At certain of these loci an excess of calcium ion may augment these effects of hypomagnesemia [53,67,62]. Calcium infusions, in addition, may lower the serum magnesium [47,63], Both of these effects may augment the tendency to tetany seen with hypomagnesemia if calcium is admi~stered before the diagnosis is recognized. Patient R. N. A. received calcium intravenously on the sixth hospital day, before hypomagnesemia had been recognized, and according to one physician the tetany became worse at that time. Tetany disappeared for several hours after individual intramuscular injections of magnesium sulphate were given, and was absent completely in eighteen hours following the administration of a total of 6 gm. of magnesium sulphate (1.2 gm. Mg. ++), together with 4 gm. of calcium gluconate (372 mg, Ca*). Although it has been claimed that enteric secretion of magnesium does not account for significant loss by the fecal route in normal animals or in man [4??,64,65J, fecal magnesium may exceed the oral intake when dietary magnesium is very low [66]. The concentration of magnesium in the enteric secretions ranges between 1 and 3 mEq. per L. and as much as 24 mEq. per day may be secreted into the gastrointestinal .lumen, possibly more when serum magnesium concentrations are raised by parenteral administration. During a period of disordered water and electrolyte metabolism, as

observed in patient R. N. A., it would be unwarranted to make any inferences regarding gastrointestinal absorption of magnesium. Therefore the data in Figure 1A do not necessarily prove that there was a positive balance of magnesium from the sixth through thirteenth hospital days. In any event, the finding of a positive magnesium balance should not be used as an argument for a pre-existing state of magnesium deficiency. Magnesium administered parenterally to norma animals has resulted in positive magnesium balance over varying periods of time [43,66]. SUMMARY

Two patients with symptomatic acute intermittent porphyria transiently exhibited a syndrome of hyponatremia, water retention and urinary loss of electrolytes. It is suggested that this was due to inappropriate secretion of antidiuretic hormone, rendering them incapable of excreting water loads normally which, in turn, induced the observed derangements in sodium and may have contributed to metabolism, urinary loss of calcium and magnesium as well. In one patient, hypomagnesemia and hypocalcemia developed, with concomitant tetany. Excessive loss of magnesium and calcium, coupled with inadequate intake, presumably was responsible for the low serum values. REFERENCES 1. ROTH, E. Uber zwei besondere FiiLIe von chronischer

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