III.
Infantile
Diarrhea
Associated
with
Intolerance
to
Disaccharides
Philip Sunshine, M.D., and Norman Kretchmer, M.D., Ph.D.
Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California
(Submitted Deceniber 26, 1963; accepted for publication February 7, 1964.)
Presented in part at the 73rd Annual Meeting, American Pediatric Society, Atlantic City, May, 1963. This investigation was supported in part by a grant-in-aid from the John A. Hartford Foundation and by a Public Health Service Research Grant AM-03501 from the National Institute of Arthritis and Metabolic Diseases, Public Health Service.
During this study the author (P.S.) was a postdoctoral Fellow of a Training Grant #5T1AM-5229 from the National Institute of Arthritis and Metabolic Diseases, Public Health Service; then a Fellow of the National Foundation.
ADDRESS: 300 Pasteur Drive, Palo Alto, California.
STUDIES
OF
SMALL
INTESTINE
DURING
DEVELOPMENT
38
PEDIATRICS, July 1964
I
N THE practice of pediatrics it is anestabiished fact that some infants may
have an intolerance to various complex
car-bohydrates, associated with or followed by
episodes of diarrhea. If these patients are
maintained on a diet with a high
concentra-tion of carbohydrates, their symptoms
per-sist or are aggravated. When carbohydrates
are removed from their diets, the infants
gain weight and thrive.19
Sixty years ago, Finkelstein and Meyer
advocated the feeding of milk with a high
protein content, “Eiweissmilch,” to infants
with gastrointestinal disturbances. Initially,
these authors believed that the whey
por-tion of the milk was the substance
responsi-ble for the gastrointestinal symptoms
dem-onstrated by dystrophic infants. Later, they
stated tilat not only was diminution of the
whey fraction of milk necessary, but also a
reduction of milk sugars was required for
complete remission of diarrhea.13
In 1921 Howland,bo in his presidential
address before the American Pediatric
So-ciety, lucidly described congenital
intoler-ances to carbohydrates, temporary
intoler-ance following acute episodes of diarrhea,
and prolonged intolerance associated with
chronic intestinal indigestion. He, as well
as others, advocated removal of
carbo-hydrates from diets of infants with either
prolonged or severe diarrhea.
There were few subsequent studies
pub-lished until 1958 when Durand described
an infant who was born of consanguineous
parents, and who had severe diarrhea,
wasting, renal acidosis, and lactosuria.11 In
1959 Holzel and coworkersI2 described two
siblings with diarrhea and with vllat
ap-peared to be congenital absence of
intesti-nal lactase. This disorder was characterized
by little or 110 elevation in blood glucose
following ingestion of lactose. These infants
recovered from their severe diarrhea when
foods containing lactose were withheld.
This report stimulated further
investiga-tion concerning the possibility that in some
infants, chronic diarrhea, malabsorption
syndrome, and failure to thrive were
re-lated to inactivity of intestinal
disaccha-ridases. Since that time, no fewer than 35
patients with what is now termed
heredi-tary disaccharide intolerance have been
de-scribed.I233 Most of these patients have
had intolerance to lactose, a few have had
intolerance to sucrose, and recently 8
pa-tients with intolerance to both sucrose and
isomaltose have been described.27,IS,29
Weij-ers and his co-workers described one pa-tient with a presumptive intolerance to su-crose and maltose.19
Since many of the patients described
were siblings, and a family history of other
infants with gastrointestinal disturbances
was often elicited,lI,18,27 the disorder was
considered as hereditary and congenital.
Weijers24 proposed that a secondary
encoun-tered in association with any process which
damaged intestinal cells such as acute or
chronic enteritis. Haworth also
demon-strated a lack of elevation of blood glucose
following ingestion of lactose by patients
with acute enteritis.33
We have studied six infants over the past
two and one-half years, who have ranged
in age from 5 weeks to 12 months and
who demonstrated chronic fermentative diarrhea, excessive flatus, poor weight gain,
and intolerance to one or two disaccharides.
One infant could hydrolyze neither lactose
nor sucrose, 2 could not hydrolyze lactose,
and 3 infants could not hydrolyze sucrose.
All infants had stools with acid pH, and 5
of the 6 excreted large amounts of the
in-volved disaccharide into their urines. Only
2 infants had pathogenic stool bacteria.
Viral isolation was not attempted in tlliS
study. After these patients were placed on
a diet which eliminated the offending
di-saccharide or disaccharides, their diarrhea
ceased and they gained weight. After this
dietary regiment was used from 1 to 8
months, the patients were re-examined and
were found to tolerate all carbohydrates
normally.
METHODS
Concentration of glucose in blood was
always measured in two separate samples
using 0.1 ml of blood pipetted directly into
1.9 ml of cold water and immediately
pre-cipitated with 1.8% barium hydroxide and
2% zinc sulfate. The filtrate was assayed for
true blood glucose with special Glucostat
obtained from Worthington Laboratories of
New Jersey. The pH of stool was estimated
with nitrazine paper by nursing personnel.
Sweat sodium was obtained by the
ionto-phoretic method of Gibson and Cooke36 and
measured with a Baird flame photometer.
Chromatography for urinary sugars was
performed with Whatman No. 1 paper
using the descending technique with
iso-propanol:water (4:1) as moving solvent.
Fifty lambda of urine was pipetted directly
on the paper. Dried papers were dipped in
benzidine reagent and heated to 100 to
110#{176}C. Glucose, sucrose, and lactose
ap-peared as brownish spots and fructose as a
yellow spot on a white background.
D-xylose was measured in a 5-hour urine
sample by a modified method of Roe and
Rice.35 Total lipid in a 72-hour stool
speci-men was measured by the Selvey
Labora-tories of South San Francisco with the
method described by Williams.3’ Bacterial
cultures were done by the Division of
In-fectious Disease under the supervision of
Dr. Lowell A. Rantz.
Tolerance tests for monosaccharides and
disaccharides were performed on patients
when they were free of acute diarrhea and
other gastrointestinal symptoms. The tests
were usually spaced at least tllree days
apart and each abnormal test was repeated
at least once. Monosaccharides were given
in the amount of 2.0 gm/kg body weight
and disaccharides were given in the amount
of 2.5 to 3.5 gm/kg body weight. A
toler-ance test for maltose was performed
in-itially on all patients; however, the maltose,
despite being certified pure, contained free
glucose and reacted with glucose oxidase
to yield very high blanks and falsely
ele-vated values for blood glucose.
CASE REPORTS AND
RESULTS
Case 1, P.N. #9-34-3
This was the third infant of a 19-year-old mother who had an uncomplicated pregnancy,
labor, and delivery. The infant, a girl, weighed
3.3. kg at birth and was fed a formula of evapo-rated milk. On her third day of life she began to vomit and continued to have intermittent projectile
vomiting until she was 10 days old. Frothy diar-rhea began on the fourth day and continued inter-mittently despite frequent changes of formula. At 5 weeks of age she was admitted to another hospital and rapid clearing of symptoms occurred
when she was placed on intravenous therapy. An upper gastrointestinal examination was normal.
When she was fed milk again, her diarrhea and
vomiting recurred. She was referred at 2 months
of age to the Stanford Medical Center. There was no family history of any gastrointestinal
disturb-ances.
The patient was a thin, white female who had a marked ioss of subcutaneous fat, but who was in no acute distress. Her weight was 3,500 gm,
P.N. 9 34 73
Age 2 mo
WI. 3.5 kg.
Age 12 mo o-o sucrose
WI. 9.1 kg. -K I aclose
- - -0.,
60 90
Time (mins.)
30
8
5 6
0
(1)
4
60
Time
90
(mins.)
20
-FIG. 1. Patient P.N.:
8 16 24 32 40 8 16 24 32 40
Time (hrs.) T Ime (hrs.)
a b
Glucose in blood and pH of stool after ingestion of disaccharides (2.5 g/kg). (a) During active stage of disease. (b) During remission.
32/ruin. Except for severe excoriation of the
but-tocks, no other physical abnormalities were noted.
Hemoglobin was 10.2 gm/100 ml; WBC 15,800
cells/mm2 with polymorphonuclear leucocytosis.
The CO2 was 14.6 mM/i but the other electro-lytes were within normal limits. There were usual
fecai flora; sweat sodium was 10 mEq/l and stool pH was 4.5.
Because the stools were consistently acid, di-saccharide tolerance tests were performed. These results (Fig. la) demonstrate a normal rise in blood sugar following administration of sucrose, but essentially no elevation after ingestion of lactose. The pH of stools was acid and diarrhea resulted after ingestion of lactose.
The patient was fed Nutramigen and gained weight. She was discharged and maintained on the same diet until she was 5 months old, and then she was placed on a regular diet without
sequel-lae. At 12 months of age she was readmitted for re-evaluation. Her weight was 9.1 kg and her
length was 72.5 cm. Disaccharide tolerance tests
were normal (Fig. ib). The stool pH’s were
alka-line, and there was no diarrhea. Lactosuria was
demonstrated during her first admission in
associa-tion with administration of lactose but was not observed during her second admission (Fig. 7). The patient has continued to gain weight and
thrive on a regular diet.
0 0 .0
E 0
0
0) U, 0 U
0’
E
0’
E
Case 2, D.L. #1O57l7*
This infant aS the product of a full-term,
normal pregnancy and weighed 3,050 gm at birth. Because a 2-year-old sibling had a rash and colic associated with ingestion of cow’s milk, this infant
‘as started on Sobee formula for the first 6
months of life. She had intermittent episodes of
vomiting associated with loose stools, but thrived and doubled her birth weight at 5 months of age.
\Vhen she was 1 1 months old she began to have severe diarrhea and mild jaundice was noted. She
was hospitalized for malabsorption syndrome and
treated with a gluten-free diet. Since she did not
respond to therapy, she was referred to the Stan-ford Medical Center. The patient’s sister was the only other member of the family with any gastro-intestinal symptoms.
PHYSICAL EXAMINATION: The patient had a pro-tuberant abdomen and severe excoriation in the diaper area. She weighed 7.9 kg; was 72 cm long
and had a blood pressure of 75/55 mm; pulse 100/mm; and respirations of 28/mm. Her physical examination was otherwise normal. Laboratory examination disclosed: Hemoglobin 11.3 gm/100
ml; normal WBC and a normal differential.
D.L. 0 57 17 Age IS mo. .-o sucrose
g
Age 2 mo. WI. 9.5 kg. s- lactoseL Wt. 7.9 kg.
E 25
50L
0’
E
8
7
I
3-- 6
0 0
i;:; 5
4
30 60 90 120
Time (mins.)
“OOO, o--o- - - -o
0 000
O----oO-O.--’”S..
8 I6 24 32 40 8 16 24
Time (hrs.) Time (hrs.)
a b
32 40
Fie. 2. Patient DL.: Glucose in blood and pH of stool after ingestion of disaccharides (2.5 g/kg). (a) During acute stage of disease. (b) During remission.
I I
30 60 90 20
Time (mins.)
41
nalysis was normal. Heterophile and liver function
studies were normal. (SCOT -37 units, alkaline
hosphatase 6.2 B.L. units, ceph. floe. 1+.)
Absorption of D-xylose was 17%. The 72-hour stool fat and an examination of the upper
gastro-intestinal tract were normal. Tolerance tests using
glucose and lactose were normal. There was no
rise in blood glucose noted after ingestion of sucrose (Fig. 2a). Stool pH’s were acid after
sucrose ingestion, but alkaline following
adminis-tnation of lactose and glucose. This patient was
placed on a sucrose-free diet and her diarrheal symptoms disappeared. Subsequently, she gained weight and thrived.
She was readmitted at the age of 15 months and weighed 9.5 kg. Repeated sucrose tolerance
tests were normal and lien stools remained alkaline
(Fig. 2b). Sucrosunia had been observed during her initial hospitalization, but there was no
mdli-tuna at the time of her revisit (Fig. 7). The patient
is now on a regular diet and continues to gain
weight.
Case 3, T.H. #10-44-41
T.H. was the product of the first pregnancy of
a 16-year-old mother who had “flu-like” illness during her first month of pregnancy. The mother also had hyperemesis and was treated with Tigan and Compazine. She delivered a 2.0 kg
female infant who had phocomelia, bilateral
talipes equinovarus, a shortened left femur, and bilateral congenital dysplasia of the hip. The infant began to vomit and have diarrhea at 2 days of age. She was hospitalized 3 times for therapy of the diarrhea, and changed from formula to formula without relief. Roentgenographic examina-tions of the gastrointestinal and urinary tracts were normal. She was referred to Stanford at age
234 months for evaluation. Her family history was
unremarkable.
PHYSmAL EXAMINATION: On admission the
pa-tient was noted to be a thin, wasted, white, female with many anatomic abnormalities. Her blood pressure was 90 mm by the flush technique; pulse
152/mm; respirations 36/mm; temperature 37.6#{176}; weight 2.7 kg; and length 45 cm. She had a high-arched palate, scoliosis, and a blowing grade 11/6 systolic murmur which was detected over the entire precordium. Her hemoglobin was 8.6
gm/100 ml and the WBC was 25,900 cell/mm3 with a polymorphonuclear leucocytosis. Electro-lytes, urinalysis, and urine cultures were normal. Stool fat was 16.5 gm/72 hr. Stool cultures re-vealed pathogenic E. coil, type 0111.
The patient was started on oral dextrose solu-tions which she tolerated well. When skim milk
was added to her diet, diarrhea resulted, the pH
T.H. 104441
Age 2.5 mo.
Wt. 2.7 kg.
0- -0 sucrOse
3-K lactose
0
0 0 -3
E
0
0
0)
U,
0
U
0’
E
0’E
I
3-0 0
(I,
6 mo 3.8 kg.
0
/ \0
75
50
25
00
50
8
7
6
S
4
30 60 90 120
Time (mins.)
0 17ooc,.A5 0- -0000- -0
30 60 90 120
Time (mins.)
S
given, but her diarrhea persisted, although no
evidence of E. coil was found in stool. After her
diarrhea ceased with fluid therapy, tolerance tests
were performed. No elevation in blood glucose
was noted and the pH of her stools was acid
following administration of either sucrose or lac-tose (Fig. 3a). The patient was given Probana and soon began to gain weight. After she had been off neomycin for 7 days, tolerance tests using lactose and sucrose were still abnormal.
The patient was readmitted at the age of 6 months. Although her weight was only 3.8 kg
she had no diarrhea or other gastrointestinal symp-toms. Tolerance tests were normal and no diarrhea
resulted when either sucrose or lactose was given (Fig. 3b). The lactosuria, glucosuria, and sucro-sunia, which had originally been detected chromat-ographically had disappeared and only traces of
sucrosunia after ingestion of sucrose could be discerned (Fig. 7).
The patient received a regular diet and con-tinued to gain weight. She had no gastrointestinal symptoms, her 72-hour stool fat was 6.0 gm and
she is currently being habilitated with prosthetic
measures and orthopedic surgery.
Case 4, P.L. #6-77-21
P.L. had diarrhea since his fourth day of life
and had been placed on several different formulas
without effect. He was admitted to Stanford Medi-cal Center at 5 weeks of age. Family history was unremarkable.
He was a mildly dehydrated infant who weighed
4.2 kg (birth weight was 3.8 kg), had a length of 52 cm, a blood pressure of 100/70 mm; pulse 110/mm, and a temperature of 37#{176}.His physical examination was normal. His hemoglobin was 10.4 gm/100 ml and WBC 11,400 cells/mm3 with
poly-morphonuclear leucocytosis. The urinalysis was normal, but cultures of the stool revealed co-agulase-positive staphylococci. The patient was started on clear fluids and neomycin by mouth. He responded well to therapy, but when the pa-tient was given skim milk there was recurrence
of diarrhea with acid stools. After the patient was
asymptomatic, a glucose tolerance test was per-formed and the patient responded normally. Di-saccharide tolerance tests revealed a delayed rise in blood glucose following ingestion of lactose and essentially no elevation following ingestion of sucrose (Fig. 4a).
A Probana formula was started with no ac-companying diarrhea. At the age of 8 weeks he
was readmitted. Although, the same organism was
cultured from his stool, he had no gastrointestinal
symptoms. His weight was 5.1 kg. Disaccharide
tolerance tests were normal (Fig. 4b), and the
infant ate a regular diet without sequellae. At
1 I I
8 16 24 32 40 8 6 24 32 40
Time (hrs.) Time (hrs.)
a b
75.
50
-25
P.L. 6 77 21
Age 5 wks.
WI. 4.2 kg.
Age 7
/2
wksWI. 5.1 kg.
-- sucrose *- lactose 0
0
0 .3
E
0
06)
U, 0 U
0’
E
0’
6
I
3-0
0
(I)
00
75
50
8
7
6
5
4
0
00000- - -0-0
a
8 16 24 32 40 8 16 24
Time (hrs.) Time (hrs.)
FIG.
4. Patient P.L.: Glucose in blood and pH of stool afterg/kg). (a) During acute stage of disease. (b) During remission.
32 40
b
ARTICLES
43
30 60 90 120
Time (mins.)
I I I I
30 60 90 120
Time (mins.)
ingestion of disaccharides (2.5
the age of one year the patient weighed 13.5 kg. Although large amounts of sucrosuria and lactosunia were noted during his first admission,
only a trace of lactose was detected at
re-admis-sion (Fig. 7).
Case 5, J.B. #11-16-99
This infant weighed 2.5 kg at birth and thrived
for two weeks without difficulty on an evaporated milk formula. Diarrhea began when more Karo sugar was added to the patient’s formula. He was hospitalized at another hospital where roentgeno-graphic examinations of genitourinary system and gastrointestinal tract were normal. He was trans-ferred at 7 weeks of age to the Stanford Medical Center.
A brother died at one day of age of undeter-mined causes. Two cousins on the paternal side had severe vomiting during their infancy;
how-ever, both are now well and of normal stature.
This patient was an irritable small white male
who was dehydrated and weighed only 2.8 kg;
blood pressure 90/60 mm; pulse 144/mm;
repira-tions 36/mm. The patient had minimal periorbital edema and severe excoriation of his buttocks. Physical examination was otherwise normaL
His hemoglobin was 9.5 gm/100 ml; WBC, urinalysis and stool cultures were normal. Electro-lytes were normal except for CO2 of 14.9 mM/I.
Sweat chlorides were 20 mEq/l. Examination of
the gastrointestinal tract was normal. Attempts to feed the child evaporated milk were thwarted when diarrhea recurred. Lactose and sucrose tolerance
tests were done because the patient had persistently
acid stools. Although lactose ingestion was followed by a normal rise in blood glucose, only a minimal rise in glucose was noted following administration of sucrose (Fig. 5a). Probana was given to the in-fant with relief of gastrointestinal symptoms.
At 2.5 months of age the infant was readmitted
and weighed 5.6 kg and was 58 cm in length.
Disaccharide tolerance tests were normal and the
stool pH was 7.0 without associated diarrhea
(Fig. 5b).
This patient showed no sucrosuria or lactosuria
at any time even during the acute phase of his illness (Fig. 7). Consequently, the infant was given a regular diet, no gastrointestinal symptoms were
noted, and at 6 months of age he weighed 7.8 kg.
Case 6, J.T. #10-45-67
J.T. weighed 3.34 kg at birth. Shortly after
birth the patient began to vomit. At 24 hours of
age he was surgically explored and a volvulus was discovered. One-half of the ileum, the cecum, and one-half of the ascending colon was removed and
an end-to-end anastomosis was performed. The
dis-J.B. 1116 99 Age 7 wks.
WI. 2.8 kgs.
Age 2.5
mos.
o--o sucrose WI. 5.6 kgs. IF-k lactose0
0 0
.0
E
0 0
0) U,
0 U
DI
E
DI
E
0.
0 0
U)
FIG. 5. Patient J.B.
8 16 24 32 40 8 6 24 32 40
Time (hrs.) Time (hrs.)
a b
Glucose in blood and i.11 of stool after ingestion of disaccharides
During acute stage of diseas#{231}.(b) During remission.
DISACCHARIDE INTOLERANCE
(2.5 g/kg). (a)
lilissed from tile hospital at 2 weeks of age. At
home the baby was given Similac feeding but he had diarrhea and weight loss. He was readmitted
to the hospital aIl(l treated with intravenous fluids. As SOOfl as milk was started, the diarrhea returned.
The l)Iltient was then transferred to Stanford Medical Center. Family history as non-contribu-tor’.
PHYSICAL EXAMINATION : This baby was
cachec-tic. lie weighed 2.3 kg and was 52 cm long. His
blood pressure was 65/50 mm; pulse 140/mm;
respirations 40/mm. The baby was dehydrated,
had sunken fontanelles, a well-healed abdominal incision and markedly excoriated buttocks. His
hemoglobin was 15.5 gln/100 ml, with a WBC of
14,300 cells/mm.’ Stool culture showed normal flora. The urine had a pH of 5.0, specific gravity 1.010, and a trace of protein. Electrolytes were
normal except for a CO2 of 17.8 mM/l. The pa-tient was maintained on intravenous fluids for several days before there was a cessation of diar-rhea. Every attempt to start oral milk was compli-cated with recrudesence of diarrhea with 16 to 25
stools per (lay. Paregoric was administered with only slight improvelnent. The patient developed atelectasis of the right middle lobe and was
treated with penicillin and streptomycin. A sweat
chloride was 130 mEq/l. The patient slowly
showed signs of 1113prven1ent after he was started on a very weak Probana formula. There was no elevation of blood glucose following
administra-tion of (lisaccharides. Two veeks later these tests ‘ere repeate(l at a time when the patient was
gaining weight on a Probana formula. The blood
glucose rise following ingestion of sucrose was
normal, hut sas only 14 mgiu/100 nil after
lac-tose (Fig. 6i). After 6 weeks of hospitalization, the baby was discharged weighing 2.7 kg.
lie was readmitted at the age of 8 months
weighing 7.8 kg and was on a regular diet. The tolerance tests were repeated an(l were nonlial
(Fig. 6b). Uninar- chromatograms for sugar showed
lactosuria (luring his first admission, but there was
no mellitunia (letected on readmission (Fig. 7).
A composite of the cases is shown in Table 1.
COMMENT
Dietary disaccharides are hydrolyzed to
their constituent monosaccharides by
spe-cific enzymes in the small intestine, of
which the most important disaccharidases in
human nutrition are lactase, sucrase,
mal-tase, and isomaltase.#{176} Dahlqvist4 has
J.T. 0 45 67
Age 6 wk.
wt_ 2.3 kg.
Age 8 mu.
wt. 7.75 kg.
0#{149}#{149}o sucrose
s--1 lactose
I
3-0
0
0)
8 6 24 32 40 8 6 24 32
Time (hrs.) Time (hrs.)
a 1)
FIG. 6. Patient J.T. : Glucose in blood and p1 1 of stool after ingestion of (lisIecharnl(-s (25 g/kg).
(a) l)uring acute stage of (lisease. (Ii) I)uring relnission.
40
0
0 .0
E 0
0 a)
U, I-) 0 3
E
are at least four different enzymes in man
vith maltase activity. He designated these
as nialtase Ia (isomaltase), maltase lb (su-erase), maltase II, and maltase III. \Vith the use of cytochemical methodshI and fluorescent antibody techni(fueS, lactase,
sucrase, an (1 iSolnaltase have l)een localized
PrimarilY to tllC brush border of the intesti-nal cell, although some activity can l)C (IC-tected in the succus entericus. ‘ In maii’
mammals, lactase is most active during the
perinatal 1)eriocl dIl(l then it decreases
pro-Standard RN.,9-34-73 D.L., I057-l7 T.H.,l0-44-4I RL.,6-77-2l J.B., 11-16-99 J.T., 10-45-67
(
5
S
I
#{149}
#{149}
o
a
#{149}
‘0
II
#{149}.
#{149}
L.J..
#{149}
S
#{149}. ‘
..
0
t0’ig1n !_LA R I.LA SLR A
L.
LL
R
LJ
A
LL
R
i
.!_L
A R
II
A
L
L
R
FI(;. 7. Coniposite clraving of actual chronatograIns of urinary sugars iii the six patients following ingestion of sucrose (S) and lactose (L) durilig the acute (A) and the remission (H) Pll21s(s of the disrdcr,
Data
TABLE I
CLINICAL SUMMARY OF PATIENTS WITH AN ACQUIRED INTOLERANCE TO DISACCHARIDES
PN. #934.73 D. L. 7 T. 1!. 1444l Age (mo.) Weight (kg)
1)uration of symptoms (no.)
Associated (Iefe(t1
Family history
Stool culture
Stool fat (7 hr)
Sweat chloride (mEq/l)
Gastrointestinal series
Glucose tolerance test
Lactose tolerance test
Sucrose tolerance test
Maltose tolerance test
Therapy
Age (re-exam. no)
Weight (kg)
Stool fat (7t lours)
Lactose tolerance test
Sucrose tolerance test
3.5 none negative normal flora not (lone 10 negative normal flat normal not done Nutramigen 12 9.1 not done normal normal 12 7.9 none sister with G-1 allergy normal flora 11_S gms. not done negative normal normal flat not done sucrose-free diet r15 9.5 not done normal normal 21 2.7 24 Plocomelia hip dysplasia Club feet negative E. coil pathogenic 56.1 gm. 15 negative normal flat flat not (lone Probana 6 3.5
6.0gm
low normal normal p. L. #6-77-ll 4.2 1) none negative (oagulase + staphylococcus not done 14 not (lone normal slow minimal rise flat normal Probana 2 5.l not done normal normal J_ B. #1 1-16-99 It 2.80 11 pneumonia 2 coUsins vomiting in infancy normal flora not (lone 20 negative normal Slow minimal rise flat normal Probana 2.5 5.6 not done normal normal J.T. 14 2.3 ii Cystic fibrosis Itesection of (listlil ileum negative normal flora 18.6 gms. 130 not done normal flat normal not done Nutramigen 8 7.8 not done normal normal
gressively in activity as development
pro-447 48 In rat and pig the activity of
sucrase is negligible until just prior to
weaning.41’4#{176} In contrast, in the human
both of these enzymes are active at birth.
There is no evidence that the activity of
lactase is decreased in the adult human.#{176}
The possible fate of a dietary
disaccha-ride in the intestine is illustrated (Fig. 8)
with lactose as an example. Normally,
lac-tose is hydrolyzed by lactase to glucose and
galactose. These monosaccharides are
ac-tively transported across the intestinal cell,
and at least one eventuality is an elevation
of glucose in blood. If lactose is not
hy-drolyzed, a small amount of his sugar can
diffuse passively across the intestinal
bar-rier, but most of the sugar remains in the
intestinal lumen where it may be fermented
to lactic and other organic acids by
bac-teria located in the large intestine.
Con-sequently, there is little or no elevation of
glucose in blood.
When the activity of one or more of
these enzymes is diminished or absent in an
infant, ingestion of disaccharide will result
in a negligible rise in blood glucose,
fer-mentative diarrhea, acid stools, flatulence,
loss of weight, and on occasion vomiting.
In this case, when the constituent
mono-saccharides are administered they are
clini-lactose
blood
H
GTTlactosemia
GTT
FIG. 8. Diagram of fate of lactose in the small
intestine in presti1ct. of lactase (a) aIl(l in absence
of lactase (b).
Diarrhea may be produced if the
disac-charide is not hydrolyzed or if there is
pres-ence of excessive amounts of substrate. The
exact physiologic mechanisms for the
diar-rhea have not as yet been elucidated.
5ev-eral possibilities have been suggested: (1)
an irritative effect on the intestine of the
disaccharide or the resultant organic acids;
(2) a hydrogogue effect of a non-absorbed
substrate which increases osmotic pressure
in the lumen of the intestine; or (3) a
corn-bination of both.#{176}2
We have foundc3 that both the California
sea lion (Zalophui californianus) and the
Stellar sea lion (Eumetropias jubata), lack
intestinal lactase, sucrase, trehalase, and
cellobiase. When these animals were fed
small amounts of sucrose or lactose, they
developed severe diarrhea (scours) and had
an identical clinical picture to that
oh-served in those infants with intolerance to
disaccharides. Because of this congenital
enzymatic deficiency, these animals can be
used as a model for study of physiologic
mechanisms responsible for diarrhea
see-ondary to deficiency of disaccharidases.
In this report, 6 patients have been
de-scribed with an acquired intolerance to
di-saccharides secondary to or associated with
severe or prolonged diarrhea. These infants
had identical clinical manifestations to
those described in patients with congenital
intolerance to disaccharides. When the
in-fants were placed on a diet free of
disac-charide, their symptoms abated and they
gained weight.
Certainly, many patients lose their
ca-47
cal sequellae. Not all patients with
disac-charide intolerance have these
manifesta-tions. Many patients have a rapid and
se-vere onset of diarrhea and wasting, yet
others are detected only because their
weight gain is inadequate. This variation
of symptomatology is similar to that
ob-served in patients with gluten-induced
en-teropathy. Ingestion of negligible amounts of gluten by some patients results in severe
watery diarrhea, vomiting, abdominal
cramps, and is analogous to an
antigen-antibody anaphylactoid state.51 An
exuda-tive protein enteropathy is observed5254 in
other patients. In a third group only the
most subtle changes are recorded which
can be defined only after a careful analysis
for fat in stool.5 The clinical features of
intolerance to disaccharides are solely
de-pendent upon ingestion of disaccharides
and are not precipitated by the presence of
monosaccharides. Thus, therapy has
con-sisted of removing the offending complex
sugar from the patient’s diet. Once this
regi-men has been instituted, the gastrointestinal
symptoms disappear and the infants or
children gain weight. No other form of
ther-apy has been required.
Similar symptoms and signs may be
pro-duced by feeding large amounts of
disac-charides to patients with normal intestinal
enzymatic activity. Clinicians have long been cognizant of the practical application
of this fact. When the lactose content of a
formula was increased, the infant had more
frequent and softer stools. Talbot and Hill
reported that diarrhea resulted when there
was more than 9 to 14% of lactose in the
in-fant’s Porter and Dunn57
re-ported that infants could be fed up to 15%
lactose without evidence of intolerance.
There have been various reports indicating
that adults would tolerate 80 to 250 gm of
dietary lactose before diarrheal symptoms
occurred.6#{176} Riggs and Beaty6’
demon-strated that a diet which contained 20%
lac-tose produced diarrhea in weaning rats
(Sprague-Dawley strain), whereas
concen-trations of 5, 10, and 15% did not. The
ani-mals receiving 20% lactose exhibited pot
bellies, slow growth, and loss of appetite.
lumen
cell
a) Iactose-. glucose +
galactose
b)
lactose-c) acetic
acid
lactic
acid
48
The clinical symptoms and signs of these
lacity to hydrolyze disaccharides during
acute eI1teritis, :o however, in a majority
of these patients, this hydrolytic ability is
regained by the time the diarrhea ceases.
\Ve lmve examined 15 infants with acute
infectious diarrhea and have found normal
stool pH and normal disaccharide tolerance tests at a time when the acute symptoms l#{236}adsul)Si(Ie(l. Ve have also studied 7 other
plltiellts vith ilitermittent or prolonged
(lidrrhea ‘ho have had a normal resioiise
following ingestion of sucrose or lactose.c4
Thus, not every patient with acute or
chronic diarrhea loses the capacity to di-gest disaccharides.
Disacchariduria was detected in 5 of the 6 j)atiellts studied during the acute phase
of their disease. This finding has been
noted in some, but not all, patients
de-scribed vith congenital absence of
intesti-iml disaccharidases . Some authors state2#{176}
that mellituria mitigates the diagnosis of
congenital absence of the disaccharidase,
lMlt rather suggests a diagnosis of a severe
sugar intolerance. The presence or absence
of niellituria probably reflects the temporal concentration of disaccharide in the
intesti-nal lumen, the greater the concentration,
the greater the potential for passive
dif-fusion across the intestinal barrier.#{176} Since
most of the absorbed disaccharides are not
metabolized by other body organs, they are
excreted unchanged in urine. We have even
noted generalized mellituria in 2 of our
pa-tients, a finding mentioned by other
ob-servers.’ Perhaps the excessive
disaccha-ride exerts a poisonOus effect on the
neph-rOIl )reCi)itating a generalized mellituria
and even an aminoaciduria.
Although we did not analyze the stool of all the patients, steatorrhea was detected in two of the infants. This abnormal excretion
of fat disappeared in one infant when she
was placed on a therapeutic diet. We have
not re-examined the stool of the second
in-fant who had cystic fibrosis and in whom
the steatorrhea could have been due to
pancreatic insufficiency.
Steatorrhea has not been commonly
ob-served in association with intolerance to
di-saccharides. KerncT noted steatorrhea in an
adult with deficiency of lactase. Cozzetto2#{176}
observed steatorrhea in his patient who
also had cystic fibrosis of the pancreas. The mechanism responsible for producing
stea-torrhea has not been defined clearly.
The familial incidence of congenital
in-tolerance to disaccharides has been cited by several authors.12, 10, 25, 27, 28 Auricchio and
co-workers recorded a family history of
in-fantile intestinal disorders in those patients
they described with sucrose and isomaltose
intolerance. This familial history was not
found in the 1)atients we described with the
acquired defect.
There appears to he two separate and
dis-tinct forms of intolerance to disaccharides.
One type is an acquired absence of the
in-testinal disaccharidase, and is a transitory defect; the other is a congenital absence of
the enzyme. Despite their etiological
dif-ferences, the clinical similarity of the two
entities is striking, and the form of therapy
is identical. Only careful observations of
these patients with frequent evaluations
will differentiate the entities and clearly
define tile syndrome.
SUMMARY
Five infants with intolerance to lactose or
sucrose and one infant with intolerance to
both lactose and sucrose have been studied.
These infants were symptomatic with
fer-mentative diarrhea, vomiting, and failure to
gain weight. Tile tolerance of these patients
to disaccharides was measured, and the
sug-ar or sugars to which they were intolerant
were removed from their diets. The infants
began to gain weight as their diarrhea
abated. After they were asymptomatic and thriving for a period of time, they were
re-examined and were found to respond
normally to the ingestion of disaccharides.
Disacchariduria was detected in 5 of the
6 infants during the acute period of their
disorders, but not at the time of their
re-examination. This finding is probably
cor-related to the amount of disaccharide
in-gested and the activity of the specific in-testinal disaccliaridase at the time of the
ARTICLES
patients with acquired intolerance to
di-saccharides were identical to those of
pa-tients with congenital absence of intestinal disaccharidases.
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Acknowledgment