Archives of Disease in Childhood, 1975, 50, 351.

Malabsorption syndrome with cow's milk intolerance

Clinical findings and course in 54 cases
P. KUITUNEN, J. K. VISAKORPI, E. SAVILAHTI, and P. PELKONEN
From the Children's Hospital, University of Helsinki, Finland

Kuitunen, P., Visakorpi, J. K., Savilahti, E., and Pelkonen, P. (1975).

Archives of Disease in Childhood, 50, 351. Malabsorption syndrome with cow's
milk intolerance: clinical findings and course in 54 cases. Fifty-four infants
with the malabsorption syndrome and cow's milk intolerance seen during 1962-1971
were investigated. All had diarrhoea and failed to thrive. Most had vomiting and
about 20% had atopic eczema and recurrent respiratory infections. Laboratory
investigations revealed malabsorption, raised serum IgA, and precipitins to cow's
milk. Biopsies showed that the jejunal mucosa was damaged, and in about half the
cases was flat. The patients did well on human milk but reacted clinically to cow's
milk challenge, either in a few hours or gradually during 3-4 weeks. Some patients
showed first a quick, but later a slow, reaction. Clinical symptoms of cow's milk
intolerance disappeared at the age of about one year. At that time 81 % had normal
faecal fat, but only 29% had a normal proximal jejunal mucosa. Many of the patients
developed intolerances to other food proteins, such as soya and wheat, if these were
given during the sensitive period. Forty-two patients have been followed up for
2 years on a normal gluten-containing diet. Of these, 37 have a normal or nearly
normal jejunal mucosa and 5 (12%) have subtotal villous atrophy indicative of coeliac
disease.
It is concluded that the malabsorption syndrome with cow's milk intolerance is a
clear-cut clinical entity. However, the symptomatology, results of laboratory tests,
and jejunal biopsy findings closely resemble those of other entities where damage to
the intestinal mucosa causes a malabsorption syndrome. Follow-up studies showed
that the disease is transient, but about 10% of the patients have coeliac disease,
regarded in such cases as the primary disorder.

Cow's milk allergy or 'illness induced by cow's Hospital, University of Helsinki, during 1962-1971
milk' leads to a variety of clinical symptoms, respira- (Table I), who fulfilled the following diagnostic criteria.
tory, cutaneous, or gastrointestinal (Gerrard et al., (1) Prolonged gastrointestinal symptoms and malabsorp-
1973; Gryboski, 1967; Freier, 1973). During the tion verified by absorption tests (faecal fat >3 g/d
past decade we have studied the condition in which and/or urinary D-xylose excretion < 15%). (2) Dis-
appearance of symptoms after elimination of cow's milk.
chronic diarrhoea and the malabsorption syndrome (3) Reaction to cow's milk challenge with gastrointestinal
with jejunal mucosal changes are apparently caused symptoms and/or poor weight gain. 27 children had
by cow's milk proteins (Kuitunen, Visakorpi, and never eaten gluten; 27 had done so, 11 not until the
Hallman, 1965; Kuitunen, 1966; Kuitunen et al., onset of gastrointestinal symptoms and 16 before onset.
1973). Particular attention was paid to the clinical
course of the disease and to the late prognosis. Elimination and provocation. Treatment was
started by eliminating cow's milk, and feeding human
milk. Clear clinical improvement resulted, usually in a
Material and methods few days. In some patients, however, the diarrhoea
Patients. The series consisted of 54 consecutive continued, apparently due to secondary lactose mal-
patients with this syndrome seen at the Children's absorption. Some even had to be given parenteral
nutrition initially, followed by gradually increasing feeds
Received 9 October 1974. of human milk. When the clinical condition was
351
352 Kuitunen, Visakorpi, Savilahti, and Pelkonen
TABLE I
Details of 54 patients with malabsorption syndrome and cow's milk intolerance

N.o l Bos Mean age Mean duratio|i

paino. ofiBoys No. of Boys/ Matnse
aymtonseto
of cow's milk
feeding before
Mean age
on admiission
patients girls
patlents
sYmtf(range
glrls(range)
onset of symptoms
(range)
(range)

54 25/29 9w 4w 15w
(ld-22w) (1d-18w) (4d-44w)

satisfactory, a provocation test was made with an un- hour urine after a single L-histidine load (350 mg/kg).
adapted cow's milk formula (100 ml contains 2 2 g Urinary and faecal sugars were measured by thin-layer
protein, 2-2 g fat, 0-26 g sucrose, and 7-28 g lactose) chromatography. In some patients, in addition, the
made from powdered cow's milk. Starting with a single stools were studied by the Clinitest method. Immuno-
oral dose of 5 ml, if no clinical reaction was observed, logical tests were performed as described by Immonen
10 ml was given with every meal and the dose was then (1967). Other laboratory tests were performed by
gradually increased daily. Within a week the child routine methods. The proximal jejunal biopsy speci-
was put on cow's milk formula alone if there was no men was taken with the Crosby-Kugler capsule of
reaction. If gastrointestinal symptoms (vomiting and/or paediatric size near the ligamentum of Treitz and
diarrhoea) occurred within one day the reaction was examined under a dissecting microscope (Booth et al.,
called rapid. If the reaction set in later on, it was called 1963) and by light microscopy (Kuitunen, 1966).
slow. If no reaction was observed within 4 weeks, the
result of the challenge was considered to be negative. Results
In addition, 8 patients were tested with isolated cow's
milk protein fractions and 19 with wheat (Tables V and Symptoms and signs (Tables I and II). The
VI) when still intolerant to cow's milk. Other food malabsorption syndrome with cow's milk intolerance
intolerances were observed when these foods were is a disease of early infancy. The gastrointestinal
introduced into the diet. After 2-4 months human milk symptoms appear on average at 2 months, and after
was replaced by soya milk or Nutramigen and the child about 1 month's cow's milk feeding. Vomiting is
was sent home on this diet. This elimination diet was
often accompanied by prolonged diarrhoea and
also gluten-free. The patients were readmitted at the
age of 6-14 months to test whether they could now failure to gain weight. 14 infants (26%) were
tolerate cow's milk. Cow's milk elimination was severely dehydrated on admission and required
discontinued as soon as possible. Gluten-containing intravenous fluids. 3 of these were fed parenterally
food was allowed, usually about 5-6 months after cow's for 40 days, 4 months, and 7j months, respectively.
milk had been reintroduced, without preliminary testing, On admission 4 infants were suspected to have ileus
but usually not before the intestinal mucosa was clearly and 2 even underwent laparotomy. Recurrent
improved. Follow-up examinations were done when respiratory infections and eczema were common.
the child had been on a normal diet for 1 and 2 years. 4 infants had Down's syndrome.
Methods. Faecal fat was measured by the method of
van de Kamer et al. (1949) in a 3-day sample. The Initial laboratory and biopsy findings.
D-xylose excretion test was performed with a 5-hour Absorption tests indicated malabsorption, this being
sample of urine after the ingestion of 350 mg D-xylose/ a condition for the diagnosis (Table III). Lactose
kg body weight. Urinary FIGLU was measured by absorption was not studied systematically but
high-voltage electrophoresis (Knowles, 1962) from 12- lactosuria was found in 18 out of 33 patients and

TABLE II
Symptoms and signs in 54 patients with malabsorption syndrome and cow's milk intolerance
Macroscopical Severely Mean weight Recurrent
Diarrhoea Vomiting blood in dehydrated on admission* Eczema respiratory Down's
Stools on admission (-SD) infections syndrome
54/54 36/54 6/54 14/54 -3-3 12/54 13/54 4/54
(-*n1- -5d85)
*Stadard deviauion calculated from the normal weight tablea of Finnish children.
 Malabsorption syndrome with cow's milk intolerance 353
TABLE III Reactions to provocation. In 28 infants the
Initial laboratory and biopsy findings in 54 patients first reaction to cow's milk was rapid and in 26 it was
with malabsorption syndrome and cow's milk slow. In some patients an initial rapid and later
a slow reaction were discernible. This may explain
intolerance
why the mean age of the patients who reacted
Laboratory findings
rapidly was lower (Table IV). Reactions to some
Faecal fat excretion > 3 g/d 42/51 cow's milk protein fractions are summarized in
D-xylose excretion 15 %
< 38/53 Table V. Positive reactions were most frequent
Positive urinary FIGLU test 40/50 with (3-lactoglobulin and casein. Reactions to some
Haemoglobin < 10 g/dl 11/53
Eosinophils in blood >4% 17/52 other foods can be seen in Table VI. In addition,
Serum alkaline phosphatase activity > 10 B-L units 5/49 2 patients reacted to bananas, 2 to eggs, and one to
Prothrombin <80% 26/52
Serum total protein <5-5 g/100 ml 14/45 beef. All the challenges were performed when the
Increased serum IgA ( = > + 2SD)
Precipitins to cow's milk
37/50 patients were still intolerant to cow's milk. Thus
32/49 these patients readily develop sensitivities to other
Precipitins to gluten 6/49
Generalized aminoaciduria 10/24 foods besides cow's milk, if exposed to them early.
Stool culture:
Staphylococcus aureus
Staphylococcus albus
Pseudomonas aeruginosa
Recovery from cow's milk intolerance.
Enteropathogenic Esch. coli Because challenges could not be repeated systema-
tically, it was impossible to determine the exact age
Proximal jejunal biopsy findings at which clinical cow's milk intolerance disappeared.
Normal villous structure (finger- and leaf-shaped villi)
Slight villous changes (high ridges) The age at the latest positive challenge, and the
Partial villous atrophy (convoluted mucosa) point at which the patients no longer reacted to
Subtotal villous atrophy (flat mucosa)
cow's milk, suggest that tolerance develops between
about 31 and 58 weeks (Table IV).
increased amounts of lactose in the stools in 12 out of Recovery from the disease. The results of
23 patients. In addition, Clinitest was clearly investigations made at the time of reintroduction of
positive in 4 out of 7 patients. All these tests cow's milk and reintroduction of gluten into the
indicated lactose malabsorption in about half the diet showed that gradual improvement occurred
patients. Immunological studies showed increased (Table VII). In most patients malabsorption
serum IgA content and precipitins to cow's milk, could no longer be detected at ages of 1-1l years,
but precipitins to gluten were rare. In most infants but the proximal jejunal mucosa was often still
no pathogenic organisms were found. The patho- abnormal. The histological structure of the surface
genic roles of Staph. aureus and albus are not clear. epithelium improved considerably within a month
Tests for Giardia lamblia were not systematically on breast milk.
carried out. Jejunal biopsy often revealed severe
mucosal damage of the type seen in coeliac disease. Late prognosis. Results of follow-up biopsies
In one infant villous structure was normal, but the of the proximal jejunal mucosa are presented in
villous epithelium had a slight intraepithelial Table VIII. We were able to re-examine 42
round-cell infiltration, andthe nuclei were somewhat patients who had been on a gluten-containing diet
disorientated. for 2 years or more. In 33 of these the proximal

TABLE IV
Challenges with cow's milk in 54 patients with malabsorption syndrome and cow's milk intolerance

Mean age (and range) at Mean age (and range) Mean age (and
latesiage
time of first challenge M a nge range) at time
pstiveo
chlatestpsiie
challengeto
when patients
no longer reacted
challenge
Rapid reaction Slow reaction
(28 patients) (26 patients)
16w 26w 29w 55w
(8w-52w) (1 lw-53w) (13w-73w) (22w-108w)
354 Kuitunen, Visakorpi, Savilahti, and Pelkonen
TABLE V
Reactions to some cow's milk protein fractions in 8 patients with malabsorption syndrome and cow's milk
intolerance
Proteins used in provocations*
Case no. Bovine
Bvn Bovine
CaseinLct -aco Bvn
(2800emg
(2800
mg) albumin
(100 mg)
globulin
(320 mg)
albumn
(4lbumi) Y-globulin
(80 mg)

it + _ + .
2t +_
3t +-
4jt + + +
5 +
6 + -+
7 -+ +-
8 + +
5/6 1/4 6/7 1/7 1/5

*Casein obtained from Hoffman-La Roche; lactalbumin and 3-lactoglobulin from Nutritional Biochemicals Co.; bovine albumin powder
and bovine y-globulin from Armour Pharmaceutical Company Ltd. The doses correspond roughly to the content of protein in 100 g whole
milk.
tData concerning these patients have been published (Visakorpi and Immonen, 1967).

TABLE VI TABLE VIII

Clinical intolerance to soya, wheat, and Nutramigen Proximal jejunal biopsy findings at follow-up for more
in patients with the malabsorption syndrome and cow's than 2 years* in 42 patients with the malabsorption
milk intolerance syndrome and cow's milk intolerance
Soya Wheat Nutramigen Appearance of proximal jejunal mucosa
Normal 33
4/35 7/19 3/17 Slight mucosal changes 4
Subtotal villous atrophy 5
1 1~~~~~~~~~~~~~~~~~~~
Total 42
* Of the whole 1962-1971 series of 54 patients, 7 were followed
jejunal mucosa was completely normal; 4 had for less than 2 years, and 5 were not followed up.
slight mucosal changes in the surface epithelium of
the vili, but the villous structure looked normal atrophy (flat mucosa) of the type seen in untreated
both under the dissecting microscope and on histo- coeliac disease. Those 7 patients who were follow-
logical section. 5 patients had subtotal villous ed up for less than 2 years on a gluten-containing
TABLE VII
Laboratory and biopsy findings at the time of reintroduction of cow's milk and gluten into the diet
Results at time of Results at time of
reintroduction of reintroduction of
cow's milk gluten
Age of patients
(mean) 55w 78w
(range) 23w-114w 29w-261w
Faecal fat excretion > 4 g/d 4/41 2/29
D-xylose excretion < 15 % 11/41 4/32
Positive urinary FIGLU test 9/33 5/7
Increased serum IgA (> + 2SD) 4/42 3/36
Precipitins to cow's milk 16/37 26/37
Precipitins to gluten 0/37 0/37
Normal proximal jejunal mucosa 10/35 18/35
Abnormal proximal jejunal mucosa 25/35 17/35
Slight mucosal changes 8/35 8/35
Partial villous atrophy 14/35 6/35
Subtotal villous atrophy 3/35 3l35
 Malabsorption syndrome with cow's milk intolerance 355
diet had a completely normal proximal jejunal in addition to cow's milk protein. As challenges
mucosa. with milk protein fractions have shown, intolerance
Comparing the 5 patients who had a flat mucosa to cow's milk is based on a complex sensitivity to
with the others the following points emerged. many fractions, though 3-lactoglobulin seemed to
Their average age at onset of symptoms and the be the most common sensitizing agent in our series,
average age on admission were higher. At the as in those of others (Freier et al., 1969; Ratner
initial biopsy the proximal jejunal mucosa was flat in et al., 1958). However, it is difficult to say how
each of the 5, and recovery was slow. In 2 patients often the patients may develop other sensitivities,
full normalization of the proximal jejunal mucosa because in the beginning, during the most sensitive
on the gluten-free diet took 2 years and 4j years, period, all our patients were fed with human milk
and in 2 other patients only partial recovery was only. If all infants were fed from the outset with,
attained in 2i years and 5 years, respectively. In say, soya milk, the incidence of soya sensitivity
the fifth patient normalization of the proximal je- would doubtless increase considerably. With the
junal mucosa did not occur because she did not elimination diet the clinical course was usually
keep to the gluten-free diet prescribed. favourable, resembling the improvement seen in
Provocation with gluten in the 4 patients with coeliac disease treated with a gluten-free diet. At
completely or partially normalized mucosa resulted first the clinical symptoms disappear, then absorp-
in clear deterioration of the structure of the proximal tive function normalizes, and finally, 1-1j years
jejunal mucosa. So we consider that at least these after the start of treatment the intestinal mucosa
4, and presumably also the fifth patient with a per- becomes completely normal. Clinical sensitivity
sistently flat mucosa, suffer from coeliac disease. to cow's milk disappears at the age of about 1 year,
and often before complete recovery of the intestinal
Discussion mucosa. Mucosal healing continued even when the
This report summarizes the clinical data collected patients were fed on cow's milk once they were able
by us during the past 10 years in connexion with to tolerate it clinically.
our study of the malabsorption syndrome with Follow-up studies clearly show that this disease
cow's milk intolerance. Our findings concerning is transient and complete recovery follows. It was
the clinical picture of the disease and the initial suggested earlier by us (Visakorpi and Immonen,
laboratory findings are fairly consistent with the 1967) that cow's milk intolerance may 'pave the
data presented in many other papers (Fallstr6m, way' to permanent gluten intolerance, i.e. to coeliac
Winberg, and Andersen, 1965; Lamy et al., 1963; disease. The present series included 5 coeliac
Liu et al., 1968). The onset of this disease seems patients, but we believe that these patients initially
to be limited to early infancy, and thus may lead had coeliac disease, which was then complicated by
to severe dehydration and a dangerous situation, cow's milk intolerance. The misconception that
sometimes necessitating parenteral nutrition. cow's milk intolerance may induce coeliac disease
Classic allergic phenomena like eczema and was due to the fact that it may be accompanied by
eosinophilia are often associated with this disease. 'transient gluten intolerance' as well as by intoler-
Laboratory tests in general give results similar to ances to other food proteins. If this transient
those found in other malabsorptive diseases, intolerance to gluten is unrelated to coeliac disease,
so that even with jejunal biopsy these tests fail to as we now believe, does that also mean that coeliac
provide criteria for differentiating this disease, and disease in early infancy is often associated with
clinical challenge becomes crucial for diagnosis. cow's milk intolerance? If we add these 5 patients
A rapid, even anaphylactic, reaction is the typical with cow's milk intolerance to our whole series of
response to challenge with cow's milk, but a infants with confirmed coeliac disease (82 infants)
different and slower response is also quite common, we find a high incidence of cow's milk intolerance
anorexia, bulky stools, and poor weight gain ap- in coeliac disease. If we count only the coeliac
pearing within 3-4 weeks. This 'slow' reaction patients in whom the disease set in before 6 months
closely resembles that seen in coeliac disease after of age, the incidence is higher still. For practical
challenge with gluten. In the initial stages of the reasons a differential diagnosis between coeliac
disease, when the process is very active, the reaction disease and the malabsorption syndrome with
to challenge is rapid, but later becomes slower. cow's milk intolerance should be made as early as
Finally, asymptomatic reactions may occur, as possible. In our experience, however, this is
suggested by Savilahti (1973). difficult. If the patient has never received gluten
A significant observation is that these patients and the biopsy reveals only minor changes, coeliac
tend to develop sensitivities to other food proteins disease can be excluded. But if the dietary history
3
356 Kuitunen, Visakorpi, Savilahti, and Pelkonen
is uncertain and laboratory tests as well as biopsy and manifestations in an unselected series of newborns. Acta
Paediatrica Scandinavica, Suppl., 234.
show severe malabsorption and intestinal damage, Gryboski, J. D. (1967). Gastrointestinal milk allergy in infants.
the diagnosis can be verified only by clinical ob- Pediatrics, 40, 354.
servation with biopsies over a period of several Immonen, P. (1967). Levels of the serum immunoglobulins yA,
yG and yM in the malabsorption syndrome in children.
years. Annales Paediatriae Fenniae, 13, 115.
The aetiology and pathogenesis of this disease Kamer, J. H. van de, Huinink, H., Ten, B., and Weyers, H. A,
(1949). Rapid method for the determination of fat in feces.
are beyond the scope of this study. We have Journal of Biological Chemistry, 177, 347.
found that cow's milk (probably cow's milk proteins) Knowles, J. P. (1962). Excretion of formiminoglutamic acid in
steatorrhoea. Gut, 3, 42.
exert a deleterious effect on the intestinal mucosa Kuitunen, P. (1966). Duodeno-jejunal histology in malabsorption
in these patients (Kuitunen et al., 1973). It is syndrome in infants. Annales Paediatriae Fenniae, 12, 101.
evident that immunological mechanisms are in- Kuitunen, P., Visakorpi, J. K., and Hallman, N. (1965). Histo-
pathology of duodenal mucosa in malabsorption syndrome in-
volved (Savilahti, 1973), but observed changes in duced by cow's milk. Annales Paediatrici, 205, 54.
local mucosal immunoglobulin production are Kuitunen, P., Rapola, J., Savilahti, E., and Visakorpi, J. K. (1973).
Response of the jejunal mucosa to cow's milk in the malabsorp-
transient. In spite of the high frequency of atopic tion syndrome with cow's milk intolerance. A light- and
phenomena like eczema and eosinophilia, the reac- electron-microscopic study. Acta Paediatrica Scandinavica,
62, 585.
tion in the intestine seemed not to be mediated by Lamy, M., Nezelof, C., Jos, J., Fr6zal, J., and Rey, J. (1963).
IgE. Biopsy of intestinal mucosa in children. First results of study
of malabsorption syndromes. Presse Midicale, 71, 1267.
Liu, H. Y., Tsao, M. U., Moore, B., and Giday, Z. (1968). Bovine
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