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Metabolic alkalosis with diarrhea and chloride-free urine
T h e ] o u r n a l of P E D I A T R I C S
849
Metabolic alkalosis witb diarrhea and chloride-free urine The virtual absence of chloride in the urine and a concentration o[ chloride in [eces which exceeds that o[ sodium are unique [eatures o[ congenital a[kalosis with diarrhea. Five patients with this disorder have been described and the available evidence is interpreted to indicate that the [undamentaI derangement is excessive loss o[ chloride in [eces. The subject o[ the present report has deficient intestinal disaccharidase activity, probably secondary to the chronic diarrheal disorder. In all probability a number o[ associated primary or secondary metabolic disorders will be found in children with this condition.
George M . O w e n , M . D . ~ IOWA
CIT Y~ I O W A
I zq 1945, G a m b l e a n d associates1 a n d D a r row 2 each described an infant with metabolic alkalosis a n d a history of d i a r r h e a since birth, v i r t u a l absence of chloride in the urine, a n d a c o n c e n t r a t i o n of chloride in the feces exceeding t h a t of sodium. T h r e e a d d i tional cases have been d e s c r i b e d ? -~ G a m b l e ' s p a t i e n t died a t 26 m o n t h s of age after e x p l o r a t o r y l a p a r o t o m y . Findings at the time of o p e r a t i o n a n d necropsy did not e x p l a i n the clinical manifestations or biochemical alterations. D a r r o w ' s p a t i e n t is now 22 years of age a n d continues to m a n i fest the same m e t a b o l i c d e r a n g e m e n t s origin a l l y r e p o r t e d 2 T h e subject of this r e p o r t presented a similar clinical picture, a p p e a r e d to have recovered f r o m the disorder at 2 ~ years of age, b u t subsequently d e m o n s t r a t e d
From the Department o[ Pediatrics, State University o[ Iowa. ~'Address, Department ol Pediatrics, State University o] Iowa, lowa city, Iowa,
clinical a n d biochemical evidence of abnormality. CASE
REPORT
Patient R. F. was born Nov. 10, 1959, after a normal pregnancy, labor, and delivery. The birth weight was 2,400 grams and the immediate neonatal course was uncomplicated, although the stools were said to be loose from the time of birth. There was no family history of chronic or recurrent diarrhea. He was breast-fed for 3 months, received a prepared infant formula the succeeding 3 months and, thereafter, whole cow's milk. A nearly unrestricted selection of infant strained foods was permitted after the third month. His parents believed that at 6 months of age his weight was approximately 6,000 grams. He was admitted to a hospital near his home in July, 1960, because of diarrhea, and symptomatic treatment resulted in little change in the clinical course. Fever and increasingly severe diarrhea and vomiting leading to moderate dehydration prompted admission to the University Hospitals in August, 1960, when the child was 9 rnonths of age.
8 50
December 1964
Owen
Table I. Summary of biochemical findings of blood, serum, and urine and of medical treatment of
I
Blood
i
Date
i*
8-23-60" 9-5-60 9-20-60 9-30,-60 10'-18-6'0 11-11-6'0
pH
. CO~ (mM./L.)
Na (mEq./L.)
39t 33 38 22 25 17
132 132
___ ___ 7.3,7 7.52 7.44
4-20-61 4-26-61" 5-25-61" 9-26-61 6-13~62 10,-5-62 4-3-63 7-24-63 81-9-63" 10-9-63" 12-11-63"
7.39 7.48 7.50 7.43 ___
Serum K (mEq./L.)
Cl (mEq,/L.)
2.9 4.0 __ 3.9 3.9 3.3
82 76 73 96 85 ---
3.5 4.4 5.4 5.0 4.3' 2.9 3.7 4.9 4.4
97 86 10'4 102 104 90
140 140 141
21 19 2'3 21 18 33 30 27 21 21
7.40 7.35 7.47
1 I
144 137 142 150 i43 ___ 143 137
103 100
eAdmlssion to hospital. "~Normal range 18 to 23 mM. per liter.
190
15
~ k
170
_
Glucose (Dec'63)
~
150
/\
, %.-" i
II
.t
~
.
.,.%
'.X I :"
I
,/
\
130
95
\%
\
\
.
a =:-Ga]actose (Jan'64)
I10
-
I.:
-
#s !g
90
.Lactose (Aug'63)
\
It % % ~%
90
~85
70
~. 8 0
75
50
7o I
2
3
4
I 0
I 50 TIME
AGE
(YEARS)
Fig. 1. G r o w t h curve of Patient R. F. (plotted on Iowa Growth Charts).
I 60
I 90
I 120
F 150
(MINUTES)
Fig. 2. C o n c e n t r a t i o n of total reducing substance in capillary blood after oral administration of various sugars to Patient R. F.
Volume 65
Number 6 part 1
Alkalosis with diarrhea and chlorine-free urine
85 1
Patient R. F.
Urine pH
C1 (mEq./L.)
7.0 7.0 7.5
Urine specific gravity 1.027
--__-
----
0
7.5
0
_--
0
8.3 7.5
0 0
7.5 8.0 6.1
240 142 1 15 141 ___ 105
7.0 7.0 6.0
Comment
Treatment KC1 20 mEq. daily KC1 35 mEq. daily NaCI 15 mEq. subcutaneously Acetazolamide, 25 to 50 mg., and KC1, 20 to 35 mEq., until April, and August, 1961, respectively
None None None KC1 40 mEq. daily by mouth None None None KC1 30 mEq. daily
Urine solutes 835 mOsm. per liter Urine specific gravity 1.021
Pneumonia
Rubeola 9-23-63 Urine solutes 985 mOsm. per liter
T a b l e I I . U r i n a r y a n d f e c a l e x c r e t i o n s of e l e c t r o l y t e s of P a t i e n t R . F. in relation to intake
Intake
I
Feces
Vol.
Na
I K
cl
( Vol. I
No NaC1 1,385 NaC1 1,100 added
17 94
25 20
17 94
128 376
Excretion ,I-
cl
LVol.
20 60
72'0 138
Urine
~
I K
Cl
[(ml./ (mEq./ (mEq./ (mEq./ (ml./ (mEq./ (mEq./ (mEq./ (m[./ (mEq./ (mEq,/ (mEq./ day) day) day) day) day) Formula J day) day) day) , day) Iday) t day) I day)
Physical examination. W h e n he was a d m i t t e d to the University Hospitals, his body length of 69 cm. was slightly below the sixteenth percentile of the Iowa G r o w t h C h a r t for infants 9 months of age, the weight of 6,425 grams was m a r k e d l y below the sixteenth percentile (Fig. 1). T h e r e was evidence of mild d e h y d r a t i o n b u t no distress, H e was able to sit alone (since the age of 7 m o n t h s ) and would pull himself to a standing position if helped but was unable to crawl and was somewhat less socially responsive t h a n most children his age. Muscle mass a n d muscle tone were below n o r m a l for age. T h e m e a n blood pressure was 90 mm. H g as determ i n e d by the flush method. L a b o r a t o r y examinations. Urinalyses, hemograms, and the erythrocyte sedimentation rate
8 49
12 12
ll 24
4 5
0 0
were normal. T h e concentration of urea n i t r o g e n in the serum was 28 mg. p e r 100 ml. at the time of admission b u t subsequently was n o r m a l on several occasions. Some degree of metabolic alkalosis was present ( T a b l e I ) . E x a m i n a t i o n s a n d
T a b l e I I I . Assays of d i s a c c h a r i d a s e a c t i v i t y ~
Substance 1
Test'~
l
Normal rangeg(
Lactase .25 1.5 to 5.0 Invertase 3.85 6.0 to 14.0 Isomaltase 3.92 6.0 to 12.0 Maltase 7.75 20.0 to 40.0 ~Courtesy of Dr. Gordon Forstner, Department of Biochemistry, Chicago Medical School Institute for Medical Research. -~Expressed as jzmoles dlsaccharide hydrolyzed per minute per gram wet weight o[ tissue.
C~
C~
Volume 65 Number 6 part 1
Alkalosis with diarrhea and chIorine-[ree urine
853
C
LINE OF ORIGIN
D Fig. 3. Paper chromatograms showing lack of hydrolysis of lactose by homogenates of duodenal mucosa.
854
December 1964
Owen
T a b l e I V . D a i l y intake a n d excretion of w a t e r a n d electrolytes in cases of congenital alkalosis witk Intake Oral or parenteral or both Patient
Age (too.)
Weight (Kg.)
Water (ml.)
Na (mEq.)
K (mEq.)
C1 (mEq.)
O. C. ~
15
9.
1,270
94
53
109
R. A. 2
24
8.5
880
53
14
51
W.K. a
6
4.
34
60
31
D. V. 4
24
-
1,050
14
76
75
R.F.
17
8.1
1,100
94
20
94
V. T. 5
13
7.2
1,071
31
51
57
NormaV
15
11.5
eFigures in parentheses are per cent of intake.
T a b l e V. I n t a k e and excretion of w a t e r a n d electrolytes m congenital alkalosis with diarrhe Intake
Patient
Body sur/ace area (M. e)
O. C. 1 R. A.2 W. K. 3 D. V. 4 R.F. R.F. V.T.~ Normal 7
0.4 0.45 0..23 0.46 0.36 0.36 0.36 0.50
I Water (ml.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
3,180 1,960 __ 2,280 3,060 3,840 2,980
236 118 148 30 262 47 86
133 31 260 166 56 69 142
273 113 135 163 262 47 159
1,800 840 735 654 1,045 356 1,450 600
cultures of blood, pharyngeal secretions, stools, cerebrospinal fluid, and urine gave no evidence of infection. Roentgenograms of the chest did not demonstrate abnormality, and the esophagus, stomach, duodenum, small intestine, large intestine, and urinary tract appeared normal as visualized with the aid of radiopaque contrast material. No abnormality was detected by electrocardiography. Renal clearances of inulin, mannitol, and urea (118, 94, and 60 ml. per 1.73 M. 2 per minute, respectively) were within normal limits although clearance of para-aminohippurate (393 ml. per 1.73 M. 2 per minute) was below the normal range. Three hours after administration of 9.7 mEq. of sodium bromide by garage, the concentration of bromide in the serum was approximately 3 mEq. per liter, sug-
gesting normal intestinal absorption of bromide and, therefore, presumably, of chloride. U r i n a r y a n d fecal excretions of electrolytes were d e t e r m i n e d on two occasions in 1961 with an interval of one m o n t h between studies. F o r several weeks before each study, the infant received Similac (67 calories p e r 100 ml.) a d libitum, acetazolamide, 25 mg. daily (before only first s t u d y ) , a n d potassium chloride, 25 m E q . daily. T w e n t y - f o u r hours before the first s t u d y a n d four days before the second study, an e x p e r i m e n t a l f o r m u l a low in electrolyte c o n t e n t was given w i t h a d d e d sodium chloride. D u r i n g the second study no sodium chloride was a d d e d to the formula. D a t a on u r i n a r y a n d fecal
Volume 65 Number 6 part 1
AIkalosis with diarrhea and chIorine-[ree urine
855
diarrhea Excretion Feces
Urine
Water (ral.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
K (mEq.)
348 (27)
Na (mEq.) 60 (64)
720 (57)*
51 (54)
24 (45)
103 (94)
378 (36)
27 (51)
9 (65)
169
13 (39)
300 (29)
Cl (mEq.)
24 (45)
0
53 (104)
187 (21)
20 (38)
17 (120,)
0
8 (13)
28 (89)
168
4 (11)
18 (30)
0
12 (86)
27 (35)
45 (60)
300 (29)
13 (93)
33 (43)
0
376 (34)
49 (52)
12 (60)
6~0 (63)
138~ (13)
24 .(26)
5 (25)
0
521 (49)
27 (89)
30 (59.)
51 (89)
179 (17)
5 (I6)
12, (23)
0
300
18
10
12
110
7
15
11
(expressed as milliliters or milliequivalents per square meter per day) Excretion Feces
Urine
Na ( mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
128 60 57 26 136 22 75 34
60 20 35 59 14 10 83 16
258 118 122 98 167 55 142 20
855 415 730 654 384 2,000 497 220
150 44 17 28 67 31 14 16
60 38 78 72 33 33 33 34
0 0 0 0 0 0 0 26
excretions of water, sodium, potassium, and chloride are presented in relation to intake in Table II. In August, 1963, a 24 hour specimen of urine contained 2.4 mg. of 17-ketosteroids and 2.7 nag. of 17-hydroxycorticosteroids. Xylose, administered orally, was found to be absorbed normally, 20 per cent of an administered dose being recovered in the urine in 8 hours. The concentration of xylose in the blood 3 hours after ingestion was 6.3 mg. per 100 ml. The concentration of total reducing substance in the capillary blood was determined at periodic intervals after oral administration of a standard dosage of various sugars
(Fig. 2). Lactose was administered on two occasions, first in August, 1963, and again in December, 1963. A glucose tolerance test performed in December, 1963, and a galactose tolerance test in January, 1964, appeared to be normal (Fig. 2). The fact that xylose, glucose, and galactose were normally absorbed and that there was little or no increase in concentration of reducing substances in the blood after administration of lactose by mouth suggested that the activity of intestinal lactase was deficient. Intestinal mucosa obtained Jan. 23, 1964, by transoral biopsy ~ with a Ruben tube was eBy Dr. James Chrlstensen, Department of Internal Medicine, State University of Iowa.
85 6
Omen
frozen promptly and maintained in the frozen state until assays of disaccharidase activity could be performed. Results of enzyme assays are shown in Table III and Fig. 3. Subsequent course. From November, 1960, until April, 1961, the parents were instructed to add potassium chloride, 20 to 35 mEq. daiIy, to the formula and to give acetazolamide in dosage of 25 to 50 mg. daily. It is presumed that the child received the prescribed medications during this interval although all observers questioned the reliability of the parents. Administration of acetazolamide was terminated in April, and that of supplementary potassium chloride in August, 1961. The concentrations of electrolytes in the blood remained within nmTnal limits (Table I) although diarrhea persisted. In June, 1962, chloride was detected in the urine for the first time although approximately 20 determinations had been made during the preceding 20 months. In 1963, the parents believed there was some association between ingestion of whole cow!s milk or ice cream and recurrence of diarrhea which generally lasted a day or so. During the more recent admissions to the hospital, it was noted that he generally declined milk offered at mealtime or snacks. Several physical examinations after November, 1960, did not disclose any abnormality other than small size; there was notable improvement in muscle strength. The neurologic examination was considered normal. Psychologic testing was performed in April, 1963; the intelligence quotient was estimated to be 84. A younger brother, born at University Hospital in August, 1962, has grown and developed normally. COMMENT
Virtual absence of chloride in the urine and a concentration of chloride in the feces exceeding that of sodium are unique features of congenital alkalosis with diarrhea. Data pertaining to intakes and excretions of water and eIectrolytes in children with this disorder are shown in Table IV. With the possible exception of Patient V. T., the funda-
December t964
mental disorder in children with alkalosis and diarrhea appears to be excessive loss of chloride in feces. A continuing loss of potassium in urine and feces undoubtedly contributes to the rapidity of development and severity of metabolic alkalosis. In view of a normal absorption of bromide from the intestine of Patient R. F., it seemed reasonable to assume that children with this condition have normal intestinal absorption of orally administered chloride. It is important to note that concentration of chloride in fecal water was virtually identical in Patient R. F. (Tables II and V) whether intake of chloride was high or low. Therefore, in association with the high intake of sodium chloride, the volume of fecal water increased proportionately. The apparent close relationship between chloride intake (oral or parentera?) and fecal losses of chloride and secondarily of water, suggests that failure of normal reabsorption of chloride in the distal intestine is the primary disorder in metabolic alkalosis with diarrhea and chloride-free urine. Metabolism of water appears to be normal as suggested by the study of Patient R. F. (Table V) when he received a relatively low sodium chloride intake and a relatively large (3,840 ml. per square meter per day) intake of water. Intestinal deficiency of lactase with faulty digestion of lactose and consequent chronic diarrhea, potassium depletion, and hypochloremic alkalosis has been suggested ~ as the cause of congenital alkalosis with diarrhea in Patient V. T. (Table IV). The concentration of chloride in the feces of this child was relatively low and the abnormality appeared to be similar to that of adult subjects with hypochloremic alkalosis and diarrhea in association with primary aldosteronism, ulcerative colitis, pancreatic tumors, or prolonged use of laxatives. ~ These individuals have relatively tow concentrations of chloride in the feces and do not manifest a direct relation between intake of sodium chloride and fecal loss of water and sodium
~PersonaI communication from Dr. Tucker.
Volume 65 Number 6 part 1
Alkalosis with diarrhea and chIorine-[ree urine
chloride as was true of children with alkalosis and diarrhea. T h e subject of the present report was stated to have been healthy and growing rapidly during the first 6 months of life, m u c h in contrast to other patients with congenital alkalosis with diarrhea. H e appeared to have recovered by 2 ~ years of age, although he continued to have recurrent diarrhea. Chloride was excreted in the urine, and administration of potassium chloride no longer appeared to be necessary; the carbon dioxide content of the blood and the concentrations of electrolytes in the serum were within normal ranges. T h e r e is sufficient evidence to indicate that Patient R. F. has lactase deficiency and probably some abnormality in activity of sucrase and perhaps of maltase and isomaltase. I t seems less likely that the deficiency is primary than that it is secondary to the long-standing diarrheal disorder. However, the present clinical course, with intermittent exacerbations with diarrhea and apparent alterations in water and electrolyte metabo-
85 7
lism, m a y reflect some relationship of diet and disaccharidase deficiency.
REFERENCES
1. Gamble, J. L., Fahey, K. R., Appleton, J. E., and MacLachlen, E. A." Congenital alkalosis with diarrhea, J. P~D~T. 26: 509, 1945. 2. Darrow, D. C.: Congenital alkalosis with diarrhea, J. PEDIAT. 26: 519, 1945. 3. Kelsey, W. M.: Congenital alkalosis with diarrhea, A. M. A. Am. J. Dis. Child. 88: 344, 1954. 4. Duyck, E. M., and Vink, C. L. J.: Quelques resultats de bilans m6taboliques dans un cas d'alcalose cong6nitale avec diarrh6e, Helvet. paediat, acta 10: 189, 1955. 5. Tucker, V., Wilmore, D., and Lauer, R.: Chronic diarrhea and alkalosis, Pediatrics (in press). 6. Levitin, H.: Personal communication, Yale University School of Medicine. 7. Bruck, E., Aceto, T., Jr., and Lowe, C. U.: Intravenous fluid therapy for infants and children, Pediatrics 25: 496, 1960. 8. Schwartz, W. B., and Relman, A. S.: Metabolic and renal studies in chronic potassium depletion resulting from overuse of laxatives, J. Clin. Invest. 32: 258, 1953.
Erratum. In the article by P. M. Smythe, "The problem of detubating an infant with a tracheostomy," in the September, 1964, issue of the JOURNAL,Fig. 5 on page 451 is upside down and should be turned for the proper view.
849
Metabolic alkalosis witb diarrhea and chloride-free urine The virtual absence of chloride in the urine and a concentration o[ chloride in [eces which exceeds that o[ sodium are unique [eatures o[ congenital a[kalosis with diarrhea. Five patients with this disorder have been described and the available evidence is interpreted to indicate that the [undamentaI derangement is excessive loss o[ chloride in [eces. The subject o[ the present report has deficient intestinal disaccharidase activity, probably secondary to the chronic diarrheal disorder. In all probability a number o[ associated primary or secondary metabolic disorders will be found in children with this condition.
George M . O w e n , M . D . ~ IOWA
CIT Y~ I O W A
I zq 1945, G a m b l e a n d associates1 a n d D a r row 2 each described an infant with metabolic alkalosis a n d a history of d i a r r h e a since birth, v i r t u a l absence of chloride in the urine, a n d a c o n c e n t r a t i o n of chloride in the feces exceeding t h a t of sodium. T h r e e a d d i tional cases have been d e s c r i b e d ? -~ G a m b l e ' s p a t i e n t died a t 26 m o n t h s of age after e x p l o r a t o r y l a p a r o t o m y . Findings at the time of o p e r a t i o n a n d necropsy did not e x p l a i n the clinical manifestations or biochemical alterations. D a r r o w ' s p a t i e n t is now 22 years of age a n d continues to m a n i fest the same m e t a b o l i c d e r a n g e m e n t s origin a l l y r e p o r t e d 2 T h e subject of this r e p o r t presented a similar clinical picture, a p p e a r e d to have recovered f r o m the disorder at 2 ~ years of age, b u t subsequently d e m o n s t r a t e d
From the Department o[ Pediatrics, State University o[ Iowa. ~'Address, Department ol Pediatrics, State University o] Iowa, lowa city, Iowa,
clinical a n d biochemical evidence of abnormality. CASE
REPORT
Patient R. F. was born Nov. 10, 1959, after a normal pregnancy, labor, and delivery. The birth weight was 2,400 grams and the immediate neonatal course was uncomplicated, although the stools were said to be loose from the time of birth. There was no family history of chronic or recurrent diarrhea. He was breast-fed for 3 months, received a prepared infant formula the succeeding 3 months and, thereafter, whole cow's milk. A nearly unrestricted selection of infant strained foods was permitted after the third month. His parents believed that at 6 months of age his weight was approximately 6,000 grams. He was admitted to a hospital near his home in July, 1960, because of diarrhea, and symptomatic treatment resulted in little change in the clinical course. Fever and increasingly severe diarrhea and vomiting leading to moderate dehydration prompted admission to the University Hospitals in August, 1960, when the child was 9 rnonths of age.
8 50
December 1964
Owen
Table I. Summary of biochemical findings of blood, serum, and urine and of medical treatment of
I
Blood
i
Date
i*
8-23-60" 9-5-60 9-20-60 9-30,-60 10'-18-6'0 11-11-6'0
pH
. CO~ (mM./L.)
Na (mEq./L.)
39t 33 38 22 25 17
132 132
___ ___ 7.3,7 7.52 7.44
4-20-61 4-26-61" 5-25-61" 9-26-61 6-13~62 10,-5-62 4-3-63 7-24-63 81-9-63" 10-9-63" 12-11-63"
7.39 7.48 7.50 7.43 ___
Serum K (mEq./L.)
Cl (mEq,/L.)
2.9 4.0 __ 3.9 3.9 3.3
82 76 73 96 85 ---
3.5 4.4 5.4 5.0 4.3' 2.9 3.7 4.9 4.4
97 86 10'4 102 104 90
140 140 141
21 19 2'3 21 18 33 30 27 21 21
7.40 7.35 7.47
1 I
144 137 142 150 i43 ___ 143 137
103 100
eAdmlssion to hospital. "~Normal range 18 to 23 mM. per liter.
190
15
~ k
170
_
Glucose (Dec'63)
~
150
/\
, %.-" i
II
.t
~
.
.,.%
'.X I :"
I
,/
\
130
95
\%
\
\
.
a =:-Ga]actose (Jan'64)
I10
-
I.:
-
#s !g
90
.Lactose (Aug'63)
\
It % % ~%
90
~85
70
~. 8 0
75
50
7o I
2
3
4
I 0
I 50 TIME
AGE
(YEARS)
Fig. 1. G r o w t h curve of Patient R. F. (plotted on Iowa Growth Charts).
I 60
I 90
I 120
F 150
(MINUTES)
Fig. 2. C o n c e n t r a t i o n of total reducing substance in capillary blood after oral administration of various sugars to Patient R. F.
Volume 65
Number 6 part 1
Alkalosis with diarrhea and chlorine-free urine
85 1
Patient R. F.
Urine pH
C1 (mEq./L.)
7.0 7.0 7.5
Urine specific gravity 1.027
--__-
----
0
7.5
0
_--
0
8.3 7.5
0 0
7.5 8.0 6.1
240 142 1 15 141 ___ 105
7.0 7.0 6.0
Comment
Treatment KC1 20 mEq. daily KC1 35 mEq. daily NaCI 15 mEq. subcutaneously Acetazolamide, 25 to 50 mg., and KC1, 20 to 35 mEq., until April, and August, 1961, respectively
None None None KC1 40 mEq. daily by mouth None None None KC1 30 mEq. daily
Urine solutes 835 mOsm. per liter Urine specific gravity 1.021
Pneumonia
Rubeola 9-23-63 Urine solutes 985 mOsm. per liter
T a b l e I I . U r i n a r y a n d f e c a l e x c r e t i o n s of e l e c t r o l y t e s of P a t i e n t R . F. in relation to intake
Intake
I
Feces
Vol.
Na
I K
cl
( Vol. I
No NaC1 1,385 NaC1 1,100 added
17 94
25 20
17 94
128 376
Excretion ,I-
cl
LVol.
20 60
72'0 138
Urine
~
I K
Cl
[(ml./ (mEq./ (mEq./ (mEq./ (ml./ (mEq./ (mEq./ (mEq./ (m[./ (mEq./ (mEq,/ (mEq./ day) day) day) day) day) Formula J day) day) day) , day) Iday) t day) I day)
Physical examination. W h e n he was a d m i t t e d to the University Hospitals, his body length of 69 cm. was slightly below the sixteenth percentile of the Iowa G r o w t h C h a r t for infants 9 months of age, the weight of 6,425 grams was m a r k e d l y below the sixteenth percentile (Fig. 1). T h e r e was evidence of mild d e h y d r a t i o n b u t no distress, H e was able to sit alone (since the age of 7 m o n t h s ) and would pull himself to a standing position if helped but was unable to crawl and was somewhat less socially responsive t h a n most children his age. Muscle mass a n d muscle tone were below n o r m a l for age. T h e m e a n blood pressure was 90 mm. H g as determ i n e d by the flush method. L a b o r a t o r y examinations. Urinalyses, hemograms, and the erythrocyte sedimentation rate
8 49
12 12
ll 24
4 5
0 0
were normal. T h e concentration of urea n i t r o g e n in the serum was 28 mg. p e r 100 ml. at the time of admission b u t subsequently was n o r m a l on several occasions. Some degree of metabolic alkalosis was present ( T a b l e I ) . E x a m i n a t i o n s a n d
T a b l e I I I . Assays of d i s a c c h a r i d a s e a c t i v i t y ~
Substance 1
Test'~
l
Normal rangeg(
Lactase .25 1.5 to 5.0 Invertase 3.85 6.0 to 14.0 Isomaltase 3.92 6.0 to 12.0 Maltase 7.75 20.0 to 40.0 ~Courtesy of Dr. Gordon Forstner, Department of Biochemistry, Chicago Medical School Institute for Medical Research. -~Expressed as jzmoles dlsaccharide hydrolyzed per minute per gram wet weight o[ tissue.
C~
C~
Volume 65 Number 6 part 1
Alkalosis with diarrhea and chIorine-[ree urine
853
C
LINE OF ORIGIN
D Fig. 3. Paper chromatograms showing lack of hydrolysis of lactose by homogenates of duodenal mucosa.
854
December 1964
Owen
T a b l e I V . D a i l y intake a n d excretion of w a t e r a n d electrolytes in cases of congenital alkalosis witk Intake Oral or parenteral or both Patient
Age (too.)
Weight (Kg.)
Water (ml.)
Na (mEq.)
K (mEq.)
C1 (mEq.)
O. C. ~
15
9.
1,270
94
53
109
R. A. 2
24
8.5
880
53
14
51
W.K. a
6
4.
34
60
31
D. V. 4
24
-
1,050
14
76
75
R.F.
17
8.1
1,100
94
20
94
V. T. 5
13
7.2
1,071
31
51
57
NormaV
15
11.5
eFigures in parentheses are per cent of intake.
T a b l e V. I n t a k e and excretion of w a t e r a n d electrolytes m congenital alkalosis with diarrhe Intake
Patient
Body sur/ace area (M. e)
O. C. 1 R. A.2 W. K. 3 D. V. 4 R.F. R.F. V.T.~ Normal 7
0.4 0.45 0..23 0.46 0.36 0.36 0.36 0.50
I Water (ml.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
3,180 1,960 __ 2,280 3,060 3,840 2,980
236 118 148 30 262 47 86
133 31 260 166 56 69 142
273 113 135 163 262 47 159
1,800 840 735 654 1,045 356 1,450 600
cultures of blood, pharyngeal secretions, stools, cerebrospinal fluid, and urine gave no evidence of infection. Roentgenograms of the chest did not demonstrate abnormality, and the esophagus, stomach, duodenum, small intestine, large intestine, and urinary tract appeared normal as visualized with the aid of radiopaque contrast material. No abnormality was detected by electrocardiography. Renal clearances of inulin, mannitol, and urea (118, 94, and 60 ml. per 1.73 M. 2 per minute, respectively) were within normal limits although clearance of para-aminohippurate (393 ml. per 1.73 M. 2 per minute) was below the normal range. Three hours after administration of 9.7 mEq. of sodium bromide by garage, the concentration of bromide in the serum was approximately 3 mEq. per liter, sug-
gesting normal intestinal absorption of bromide and, therefore, presumably, of chloride. U r i n a r y a n d fecal excretions of electrolytes were d e t e r m i n e d on two occasions in 1961 with an interval of one m o n t h between studies. F o r several weeks before each study, the infant received Similac (67 calories p e r 100 ml.) a d libitum, acetazolamide, 25 mg. daily (before only first s t u d y ) , a n d potassium chloride, 25 m E q . daily. T w e n t y - f o u r hours before the first s t u d y a n d four days before the second study, an e x p e r i m e n t a l f o r m u l a low in electrolyte c o n t e n t was given w i t h a d d e d sodium chloride. D u r i n g the second study no sodium chloride was a d d e d to the formula. D a t a on u r i n a r y a n d fecal
Volume 65 Number 6 part 1
AIkalosis with diarrhea and chIorine-[ree urine
855
diarrhea Excretion Feces
Urine
Water (ral.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
K (mEq.)
348 (27)
Na (mEq.) 60 (64)
720 (57)*
51 (54)
24 (45)
103 (94)
378 (36)
27 (51)
9 (65)
169
13 (39)
300 (29)
Cl (mEq.)
24 (45)
0
53 (104)
187 (21)
20 (38)
17 (120,)
0
8 (13)
28 (89)
168
4 (11)
18 (30)
0
12 (86)
27 (35)
45 (60)
300 (29)
13 (93)
33 (43)
0
376 (34)
49 (52)
12 (60)
6~0 (63)
138~ (13)
24 .(26)
5 (25)
0
521 (49)
27 (89)
30 (59.)
51 (89)
179 (17)
5 (I6)
12, (23)
0
300
18
10
12
110
7
15
11
(expressed as milliliters or milliequivalents per square meter per day) Excretion Feces
Urine
Na ( mEq.)
K (mEq.)
Cl (mEq.)
Water (ml.)
Na (mEq.)
K (mEq.)
Cl (mEq.)
128 60 57 26 136 22 75 34
60 20 35 59 14 10 83 16
258 118 122 98 167 55 142 20
855 415 730 654 384 2,000 497 220
150 44 17 28 67 31 14 16
60 38 78 72 33 33 33 34
0 0 0 0 0 0 0 26
excretions of water, sodium, potassium, and chloride are presented in relation to intake in Table II. In August, 1963, a 24 hour specimen of urine contained 2.4 mg. of 17-ketosteroids and 2.7 nag. of 17-hydroxycorticosteroids. Xylose, administered orally, was found to be absorbed normally, 20 per cent of an administered dose being recovered in the urine in 8 hours. The concentration of xylose in the blood 3 hours after ingestion was 6.3 mg. per 100 ml. The concentration of total reducing substance in the capillary blood was determined at periodic intervals after oral administration of a standard dosage of various sugars
(Fig. 2). Lactose was administered on two occasions, first in August, 1963, and again in December, 1963. A glucose tolerance test performed in December, 1963, and a galactose tolerance test in January, 1964, appeared to be normal (Fig. 2). The fact that xylose, glucose, and galactose were normally absorbed and that there was little or no increase in concentration of reducing substances in the blood after administration of lactose by mouth suggested that the activity of intestinal lactase was deficient. Intestinal mucosa obtained Jan. 23, 1964, by transoral biopsy ~ with a Ruben tube was eBy Dr. James Chrlstensen, Department of Internal Medicine, State University of Iowa.
85 6
Omen
frozen promptly and maintained in the frozen state until assays of disaccharidase activity could be performed. Results of enzyme assays are shown in Table III and Fig. 3. Subsequent course. From November, 1960, until April, 1961, the parents were instructed to add potassium chloride, 20 to 35 mEq. daiIy, to the formula and to give acetazolamide in dosage of 25 to 50 mg. daily. It is presumed that the child received the prescribed medications during this interval although all observers questioned the reliability of the parents. Administration of acetazolamide was terminated in April, and that of supplementary potassium chloride in August, 1961. The concentrations of electrolytes in the blood remained within nmTnal limits (Table I) although diarrhea persisted. In June, 1962, chloride was detected in the urine for the first time although approximately 20 determinations had been made during the preceding 20 months. In 1963, the parents believed there was some association between ingestion of whole cow!s milk or ice cream and recurrence of diarrhea which generally lasted a day or so. During the more recent admissions to the hospital, it was noted that he generally declined milk offered at mealtime or snacks. Several physical examinations after November, 1960, did not disclose any abnormality other than small size; there was notable improvement in muscle strength. The neurologic examination was considered normal. Psychologic testing was performed in April, 1963; the intelligence quotient was estimated to be 84. A younger brother, born at University Hospital in August, 1962, has grown and developed normally. COMMENT
Virtual absence of chloride in the urine and a concentration of chloride in the feces exceeding that of sodium are unique features of congenital alkalosis with diarrhea. Data pertaining to intakes and excretions of water and eIectrolytes in children with this disorder are shown in Table IV. With the possible exception of Patient V. T., the funda-
December t964
mental disorder in children with alkalosis and diarrhea appears to be excessive loss of chloride in feces. A continuing loss of potassium in urine and feces undoubtedly contributes to the rapidity of development and severity of metabolic alkalosis. In view of a normal absorption of bromide from the intestine of Patient R. F., it seemed reasonable to assume that children with this condition have normal intestinal absorption of orally administered chloride. It is important to note that concentration of chloride in fecal water was virtually identical in Patient R. F. (Tables II and V) whether intake of chloride was high or low. Therefore, in association with the high intake of sodium chloride, the volume of fecal water increased proportionately. The apparent close relationship between chloride intake (oral or parentera?) and fecal losses of chloride and secondarily of water, suggests that failure of normal reabsorption of chloride in the distal intestine is the primary disorder in metabolic alkalosis with diarrhea and chloride-free urine. Metabolism of water appears to be normal as suggested by the study of Patient R. F. (Table V) when he received a relatively low sodium chloride intake and a relatively large (3,840 ml. per square meter per day) intake of water. Intestinal deficiency of lactase with faulty digestion of lactose and consequent chronic diarrhea, potassium depletion, and hypochloremic alkalosis has been suggested ~ as the cause of congenital alkalosis with diarrhea in Patient V. T. (Table IV). The concentration of chloride in the feces of this child was relatively low and the abnormality appeared to be similar to that of adult subjects with hypochloremic alkalosis and diarrhea in association with primary aldosteronism, ulcerative colitis, pancreatic tumors, or prolonged use of laxatives. ~ These individuals have relatively tow concentrations of chloride in the feces and do not manifest a direct relation between intake of sodium chloride and fecal loss of water and sodium
~PersonaI communication from Dr. Tucker.
Volume 65 Number 6 part 1
Alkalosis with diarrhea and chIorine-[ree urine
chloride as was true of children with alkalosis and diarrhea. T h e subject of the present report was stated to have been healthy and growing rapidly during the first 6 months of life, m u c h in contrast to other patients with congenital alkalosis with diarrhea. H e appeared to have recovered by 2 ~ years of age, although he continued to have recurrent diarrhea. Chloride was excreted in the urine, and administration of potassium chloride no longer appeared to be necessary; the carbon dioxide content of the blood and the concentrations of electrolytes in the serum were within normal ranges. T h e r e is sufficient evidence to indicate that Patient R. F. has lactase deficiency and probably some abnormality in activity of sucrase and perhaps of maltase and isomaltase. I t seems less likely that the deficiency is primary than that it is secondary to the long-standing diarrheal disorder. However, the present clinical course, with intermittent exacerbations with diarrhea and apparent alterations in water and electrolyte metabo-
85 7
lism, m a y reflect some relationship of diet and disaccharidase deficiency.
REFERENCES
1. Gamble, J. L., Fahey, K. R., Appleton, J. E., and MacLachlen, E. A." Congenital alkalosis with diarrhea, J. P~D~T. 26: 509, 1945. 2. Darrow, D. C.: Congenital alkalosis with diarrhea, J. PEDIAT. 26: 519, 1945. 3. Kelsey, W. M.: Congenital alkalosis with diarrhea, A. M. A. Am. J. Dis. Child. 88: 344, 1954. 4. Duyck, E. M., and Vink, C. L. J.: Quelques resultats de bilans m6taboliques dans un cas d'alcalose cong6nitale avec diarrh6e, Helvet. paediat, acta 10: 189, 1955. 5. Tucker, V., Wilmore, D., and Lauer, R.: Chronic diarrhea and alkalosis, Pediatrics (in press). 6. Levitin, H.: Personal communication, Yale University School of Medicine. 7. Bruck, E., Aceto, T., Jr., and Lowe, C. U.: Intravenous fluid therapy for infants and children, Pediatrics 25: 496, 1960. 8. Schwartz, W. B., and Relman, A. S.: Metabolic and renal studies in chronic potassium depletion resulting from overuse of laxatives, J. Clin. Invest. 32: 258, 1953.
Erratum. In the article by P. M. Smythe, "The problem of detubating an infant with a tracheostomy," in the September, 1964, issue of the JOURNAL,Fig. 5 on page 451 is upside down and should be turned for the proper view.