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(1)

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 an

estabiished 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

(2)

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,

(3)

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.

(4)

D.L. 0 57 17 Age IS mo. .-o sucrose

g

Age 2 mo. WI. 9.5 kg. s- lactose

L 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

(5)

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

(6)

75.

50

-25

P.L. 6 77 21

Age 5 wks.

WI. 4.2 kg.

Age 7

/2

wks

WI. 5.1 kg.

-- sucrose *- lactose 0

0

0 .3

E

0

0

6)

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 after

g/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

(7)

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 lactose

0

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

(8)

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,

(9)

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

(10)

clini-lactose

blood

H

GTT

lactosemia

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

(11)

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

(12)

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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(13)

Disaccha-ride intolerance. Ilelv. Pediat. Acta, 17:395,

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Acknowledgment

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1964;34;38

Pediatrics

Philip Sunshine and Norman Kretchmer

Diarrhea Associated with Intolerance to Disaccharides

STUDIES OF SMALL INTESTINE DURING DEVELOPMENT: III. Infantile

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1964;34;38

Pediatrics

Philip Sunshine and Norman Kretchmer

Diarrhea Associated with Intolerance to Disaccharides

STUDIES OF SMALL INTESTINE DURING DEVELOPMENT: III. Infantile

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