The subtle and variable clinical expressions of gluten-induced enteropathy (adult celiac disease, nontropical sprue)

The Subtle and Variable Clinical Expressions of Gluten-Induced Enteropathy (Adult Celiac Disease, Nontropical Sprue)* An Analysis

of Twenty-One

JAMES G. MANN, M.D. WILLIAM R. BROWN, M.D. FRED KERN, JR., M.D. Denver, Colorado

Consecutive

Cases

Study of twenty-one cases of gluten-induced enteropathy emphasized that the clinical expressions are highly variable and may be subtle or occult. The classic features of diarrhea, weight loss, steatorrhea and malnutrition were the predominant features in only eight patients (38 per cent). Other presenting problems included thrombophlebitis, megaloblastic anemia of pregnancy, edema, tetany, nonspecific gastrointestinal symptoms, bone pain and diarrhea associated with diabetes or occurring after abdominal surgery. laboratory abnormalities were often minimal or mild. Steatorrhea was present in only thirteen of twenty patients (65 per cent). Intestinal disaccharidase activities were low in twelve untreated patients. The mean serum immunoglobulin M (IgM) level was significantly diminished in twelve patients studied. One patient had a selected serum and exocrine IgA deficiency. In three patients a roentgenographic malabsorption pattern was the initial clue to the diagnosis. The classic clinical features of gluten-induced enteropathy (nontropical sprue, adult celiac disease) are steatorrhea, diarrhea, weight loss and malnutrition [l-3]. When these features are present the diagnosis may be made promptly. These features may, however, be mild or absent [4-81,

and selected nutritional deficiencies, e.g., iron deficiency [9], osteomalacia [lo], hypoprothrombinemia [5,7] or anemia [ll] may obscure the underlying disorder. The variable clinical expressions of gluten-induced enteropathy, although emphasized in some series [4-71, often are the subject of individual case reports [8-111, thereby suggesting that nonclassic presentations are exceptional. This review of twenty-one consecutive cases of gluten-induced enteropathy seen at the University of Colorado Medical Center from 1961 to 1968 reveals that (1) commonly the gastrointestinal symptoms are mild or nonspecific and classic features may be absent; (2) secondary nutritional manifestations may predominate; (3) minimal symptomatic, laboratory and roentgenographic clues to the diagnosis must be heeded; and (4) coexisting alternative explanations for malabsorption may obscure the diagnosis. These subtle and variable characteristics of gluten-induced enteropathy often cause confusion, delay and error in diagnosis and treatment.

PATIENTS * From the Divlrion of Gaotroenterology, Department of Medicine, University of Colorado Medical Center, Denver, Colorado 80220. This work was supported in part by NIH Training Grant in Gastroenterology No. AM.5122 and an NIH Clinical Research Grant No. FR-00051. Requests for reprints should be addressed to Dr. Fred Kern, Jr., University of Colorado Medical Center, 4200 E. Ninth Avenue, Denver. Colorado 80220. Manuscript received May 2. 1969. Volume 48, March

1970

AND METHODS

The diagnosis in all patients was established by the presence of a flat mucosal surface of the jejunal biopsy specimen and, in all cases in which treatment could be assessed, a favorable symptomatic, chemical and histologic response to a gluten-free diet. Mucosal biopsy specimens were taken at or near the duodenojejunal junction under fluoroscopic observation using the multipurpose tube [12] or Carey capsule [13]. Five-hour D-xylose urinary excretion was estimated after a 25 gm oral dose [14]. Fecal fat content of seventy-two hour collections was determined by the method of van de Kamer et al. [15] as modified by Anderson et al. [16]. Patients were given a 100 gm fat diet during 357

40, I= 65, F

55, F 60, F 30, F

79, F

45, M 75, M

46, M 40, F

55, F

65, M

36, M

21, M 57, F

3 4

5 6 7

8

9 10

11 12

13

14

15

16 17

Edema and diarrhea Edema, tetany, diarrhea, diabetes Diarrhea and weight loss Diarrhea, weight loss and edema Bone pain and tetany “Gas” and bloating Diabetes and peptic symptoms Diarrhea, weight loss and diabetes Peptic symptoms Weakness, weight loss, edema and thrombophlebitis Diarrhea and weight loss Postpartum diarrhea and weight loss Diarrhea, weight loss and thrombophlebitis Diarrhea, weight loss, weakness, neuropathy Diarrhea, edema and weight loss following pancreatic trauma Large, bulky stools Diarrhea after vagotomy and pyloroplasty Diarrhea and weight loss Diarrhea, peptic symptoms and diabetes Megaloblastic anemia of pregnancy Diarrhea and edema following antrectomy and gastrojejunostomy

Normal values

60, M

23, F

50, M 58, M

40, t=

58, M

4.8

42

16

39

31 M47+5 F 4211~5

<5

4.9

2.2

11.0 34

34 51

20

24-59 9.1

17

37 46

51

35

43

41 32

... 28

31 43

4.4 2.9

14 8.2 3.2

37 36 40

45 50

20-55 2.8

36

Stool Fat Excretion (gm/24 hr)

30 lob150

1.5

10

...

37 ...

14 ...

13

5

11

... 3

... 167

66

42 19 35

... 19

7

Serum Carotene (pg/lOO ml)

3.6-4.5

...

...

...

4.4 ...

4.4 ...

3.4

4.3

4.1

4.5 ...

... ...

4.2

1.7 4.7 ...

4.3 4.9

3.0

Serum Potassium (mEq/Lj

Enteropathy

>4.5

4.1

1.0

2.9 1.7

4.4 4.6

0.1

1.2

2.7

1.1 0.25

3.6 1.9

1.6

O.&o.3 1.5 1.1

0.64 0.3

1.0

D-Xylose Excretion (gm/24 hr)

Patients with Gluten-Induced

35 43

45

(%I

Hematocrit

Data of Twenty-one

Presenting Signs and Symptoms

Clinical and Laboratory

Age (yr), Sex

1

1 2

Case No.

TABLE

7 15

...

...

...

11.8 ...

2.0 ...

0.2

1.2

0.4

... ...

... ...

...

1.8 12.2 ...

5 3.3

...

Cofio-B,2 Excretion (% in 24 hr)

>50

...

20

100

100 100

...

...

47

...

52

...

70

...

100

...

37 24 52

56 85

58

(%)

Prothrombin Time

8.8 10.5

7.5

7.1

10.3

7.5 10.7

...

8.3

8.6

5.7

9.1

7.2 8.5

9.6 10.1

8.6

3.8 7.6 9.6

7.1 9.2

7.2

Serum Calcium (mg,‘lOO ml)

2.2-4.4

3.0

3.1

4.2

3.9 4.0

3.5 ..

2.8

2.6

3.6

3.6 2.7

3.0 3.4

3.8

1.4 3.0 4.5

0.08 4.1

2.1

Serum Phosphorus (mg ‘100 ml)

Serum

2.7 3.6

4.2

3.1

1.2

3.1

1.6 3.2

3.5 4.4

3.1

2.3 ...

1.7

2.4 3.2

2.4

Albumin (gm 100 ml)

?

1

F 5

I

?! ;;I : 2 2 <

GLUTEN-INDUCED

the

collection

testinal

The disaccharidase

periods.

biopsy

specimens

was measured

activity

by the

of

in-

method

of

TABLE II

Dahlqvist [17]. Vitamin Bls absorption was determined by the Schilling test [18]. Serum immunoglobulin levels were determined by a modified Oudin method [19].

Group

RESULTS

I

Clinical and laboratory data of the twenty-one patients are summarized in Table I. Clinical Features. There were ten male and eleven female patients, aged twenty-one to seventy-nine years. Fourteen patients (66 per cent) complained of diarrhea, ten (48 per cent) of weight loss, six (29 per cent) of edema, six (29 per cent) of abdominal pain and two (10 per cent) of tetany. The patients were classified in five groups according to the predominant presenting features and associated disorders (Table II). The classic features of nontropical sprue were predominant in only eight patients (38 per cent). In the other thirteen (62 per cent), diarrhea, steatorrhea and weight loss were either very mild or absent or were less significant than other complaints. Patients representing each of the five groups are discussed.

Classification According

ENTEROPATHY

of Patients

to Clinical

-

with

MANN

ET

Nontropical

AL.

Sprue

Presentation No. of Cases

Classic Diarrhea,

a weight

loss, steatorrhea

II

Diabetes

III

Postoperative diarrhea Vagotomy and pyloroplasty .............. Antrectomy and gastrojejunostomy ...... Pancreatic laceration . . . . . . . . . . . . . . . . . . . . .

with diarrhea

3

IV

Mild and nonspecific

V

Selected nutritional deficiencies Hypoalbuminemia and edema complicated by thrombophlebitis . . . . . . . . . . . . . . . . . . . . ..,... Megaloblastic anemia of pregnancy Bone pain and hypocalcemia without diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

gastrointestinal

3 1 1 1

complaints

4 3

1 1 1

Case 4. This sixty-five year old white woman was first seen in April 1966. After an episode of “Asiatic flu” in 1964 she had persistent watery diarrhea and lost 36 pounds. One month before hospitalization hypoproteinemia, hypocalcemia, hypokalemia and hypoprothrombinemia were discovered. She was treated effectively for her diarrhea with low doses of steroids and diphenoxylate hydrochloride (LomotilQ. She was found to be hypotensive, thin and very weak. Increased cutaneous pigmentation, abdominal distention, edema and hypoactive tendon reflexes were present. The hematocrit was 37 per cent and the white blood cell count 13,200 per cu mm, with a normal differential count.

The erythrocytes appeared macrocytic. The serum potassium was 1.7 mEq per L, calcium 3.8 mg per 100 ml, serum carotene 42 pg per 100 ml, prothrombin content 37 per cent: D-xylose excretion 0.8 and 0.3 gm per five hours on two occasions, and stool fat excretion 14.0 gm per twenty-four hours. The x-ray study of the small intestine (Fig. 1A) s.howed a malabsorption pattern. Her bones were markedly osteoporotic. The biopsy specimen of the small bowel (Fig. 1B) demonstrated a flat mucosa. Intestinal disaccharadase activity was very low (Table IV). The patient responded promptly to a gluten-free diet. In a biopsy specimen of the small bowel obtained seven months later, intestinal villi had returned, although they were short and blunt. Twenty-six months later the patient was totally asymptomatic. The serum carotene was 193 fg per 100 ml and calcium 8.6 mg per 100 ml.

Fig.

no

Group I. Classic Presentation

1.

Case

demonstrating specimen

Volume

of

48,

4.

A,

x-ray

dilatation small

March

study

of

of intestinal

intestine.

1970

(Eight

Original

small loops

Patients)

intestine and

of

coarse

magnification

patient

folds. X

80.

E.

S.

B, biopsy There

villi.

present

The

surface

in the

lamina

epithelium propria

is grossly in

increased

abnormal.

Round

cells

are

numbers.

are

359

GLUTEN-INDUCED

ENTEROPATHY

-

MANN

ET AL.

165

l ----___ ---/ -8 /

160

/

155 I

/

I’

150

c

145

-_

* 0 z

140

; a

135

-_

Z F

130

3 l” t

125

120

115

110

105

100 JAN

FEB

MAR

APR

MAY

JUNE

JULY

AUG

SEPT

OCT

NOV

DEC

JAN

FEB

MAY

JUNE

JULY

.

..s.

A”-

1968

1967 Fig. 2. Case 15. The clinical course of patient S. D. The abrupt loss of weight after the start of radiation therapy, the poor response to

pancreatic instituting

Comment: Patients in this group complained primarily of gastrointestinal symptoms suggesting a malabsorptive state. Although symptoms varied in intensity and duration (many years in some cases), all patients had diarrhea, steatorrhea and weight loss. Steatorrhea was minimal in some cases. One patient (Case 14) also had a severe peripheral neuropathy. Addisonian pernicious anemia, although suspected, was excluded; the serum vitamin B, level was normal. Even though the patient adhered to a strict gluten-free diet for seventeen months, during which time marked clinical, chemical and mucosal histologic improvement occurred, the neuropathy did not change.

She was pale and appeared chronically ill. Her abdomen was distended; the bowel sounds were hyperactive. Her legs and thighs were edematous. The hematocrit was 35 per cent, serum calcium 7.1 mg per 100 ml, prothrombin content 56 per cent, D-xylose excretion 0.64 gm per five hours, daily fecal fat excretion 20, 55 and 45 gm (three seventy-two hour collections). The &hilling test was abnormal. An oral glucose tolerance test curve was flat. The biopsy specimen of the small intestine had a flat mucosal surface. A gluten-free diet was instituted, and the patient’s condition promptly improved. One and a half months later the stool fat excretion had decreased to 14.0 gm per twenty four hours, whereas D-xylose excretion remained low at 0.44

Group

II. Diabetes

with

Diarrhea

(Three

Patients)

Case 2. This forty year old diabetic woman was admitted in October 1961 because of diarrhea and tetany. In early 1961 watery diarrhea associated with weakness, fatigue and cramping abdominal pain began. In July 1961 a very low serum calcium level and tetany were noted. The diagnosis of hypopituitarism was made. Her diarrhea diminished after steroid therapy, but the stools were bulky, yellow and foul-smelling. Her daily insulin requirement decreased from 50 units to 15 units, and she experienced several episodes of hypoglycemia. She lost 50 pounds. 360

enzyme replacement. and the dramatic a gluten-free diet are demonstrated.

weight gain after

gm per five hours. The serum ml and prothrombin

content

calcium was 9.0 mg per 100 100 per cent.

Comment: Initially hypopituitarism was incorrectly diagnosed, and the diarrhea was attributed to visceral neuropathy. During the uncontrolled period of this patient’s illness the diabetes became less severe, and the oral glucose tolerance test curve was flat. Following gluten withdrawal, as glucose absorption improved, her insulin requirement again increased. In the two other diabetic subjects of this group (Cases 8 and 19) diarrhea also was initially attributed to visThe American

Journal of Medlclne

GLUTEN-INDUCED

Fig.

3.

showing small

Case

15.

intestinal intestine.

A,

barium

dilatation Original

study and

magnification

ceral neuropathy, causing the correct diagnosis. Group

111. Postoperative

of

coarse

small folds. X

considerable

Diarrhea

(Three

bowel B, 80.

of

biopsy Note

delay

patient

S.

specimen total

D.

atrophy

of

There

villous

in making

48,

March

1970

an

abnormal increased

surface number

epithelium of

mitoses,

-

and but

MANN

elongated the

crypt

ET

AL.

crypts. cells

are

normal.

and daily fecal fat content 8.7 gm. The small bowel mucosa showed improvement. The patient has remained well while adhering to a gluten-free diet and has gained 50 pounds.

Patients)

In January 1967 this thirty-six year old SpanishCase 15. American man sustained blunt trauma to his abdomen in an automobile accident. At laparotomy a laceration of the pancreas was repaired. Subsequently a cutaneous pancreatic fistula developed which failed to close; this was treated with irradiation (2,400 r delivered over an eighteen day period, directed to ths pancreas via an 8 by 14 cm port). In May 1967 the patient complained of nausea, vomiting, abdominal pain and severe diarrhea. An x-ray study of the upper gastrointestinal tract suggested a pancreatic cyst. A partial pancreatectomy, splenectomy and pancreaticojejunostomy were performed. The patient was given pancreatic enzyme therapy (Viokasea) but, after an initial weight gain, lost weight, and the diarrhea persisted. In September his daily fecal fat excretion was 24 gm and D-xylose excretion 4.4 gm per five hours. An oral glucose tolerance test curve was flat but the intravenous glucose tolerance test was normal. Pancreatic enzymes (CotazymeB, 2 capsules every hour) were administered, but his symptoms and steatorrhea were unchanged. He lost 37 pounds. His clinical course is summarized in Figure 2. Fourteen years earlier he had had a ten week episode of diarrhea with frequent, bulky, foul-smelling stools and a 20 pound weight loss. When evaluated in October 1967 he appeared chronically ill and wasted. Shotty generalized adenopathy, abdominal distention and hyperactive bowel sounds were present. The hematocrit was 37 per cent, serum carotene 14 pg per 100 ml, Schilling test abnormal and stool fat excretion 59.1 gm per twenty-four hours. An x-ray series of the small bowel revealed a malabsorption pattern and the jejunal mucosal biopsy specimen was typical of nontropical sprue (Fig. 3). Dietary gluten restriction was instituted and pancreatic enzyme replacement stopped. Within three weeks he had gained 27 pounds. Three months later the D-xylose excretion was 4.2 gm per five hours, serum carotene 93 pg per 100 ml Volume

otherwise

with is

ENTEROPATHY

This patient’s malabsorption was initially Comment: attributed to a very likely cause, pancreatic insufficiency. The nearly normal D-xylose test was consistent with this diagnosis. When pancreatic replacement therapy failed to reduce the steatorrhea, a small bowel biopsy was performed and the diagnosis of gluten-induced enteropathy was made. Correction of the malabsorption by glutenfree diet alone is evidence that gluten-induced enteropathy, not pancreatic insufficiency, had caused the malabsorption state. Except for the episode of diarrhea fourteen years earlier, this patient had no preoperative symptoms of malabsorption. His severe diarrhea and weight loss began soon after the start of radiation therapy, raising the question of whether radiation played an etiologic role. The intestinal abnormality was typical of gluten enteropathy and not radiation damage [20,21], and dramatic clinical recovery began soon after the start of gluten restriction. Thus the mucosal injury probably did not result primarily from radiation exposure. In two other patients of this group the diagnosis of nontropical sprue was made after abdominal surgery. A fifty-seven year old woman (Case 17) suffered from persistent diarrhea, nausea, vomiting and epigastric pain a few days after a cholecystectomy, vagotomy and pyloroplasty had been performed for a suspected duodenal ulcer and chronic cholecystitis. After a roentgenogram of the small bowel demonstrated a malabsorption pattern, a jejunal biopsy was performed, revealing a flat mucosal surface. In a sixty year old man (Case 21) adult celiac disease became manifest following an antrectomy and gastrojejunostomy which had been performed for a duodenal ulcer. Neither of these two patients had diarrhea preoperatively; both responded dramatically to gluten withdrawal. 361

GLUTEN-INDUCED

ENTEROPATHY

-

MANN

ET

AL.

Fig.

4.

tient

Case H.

second

and

biopsy 80.

Note C, gluten

cation

X

columnar villi

Group IV. Patients)

Nonspeofic

Gastrointestinal

Complaints

(Four

Case 6. This sixty year old white woman was seen in July 1966 because of an “abnormal small intestine.” Thirty years earlier the diagnosis of amebic dysentery had been made. Since then she had had episodic diarrhea and bloating. Three months before admission constipation, abdominal distention and vomiting abruptly began. Despite these symptoms the patient gained 12 pounds. She was obese and anxious. The abdomen was distended but not tender; the bowel sounds were normal. No enlarged organs were felt, but there was a suggestion of fullness in the left upper abdominal quadrant. The hematocrit was 40 per cent. The serum carotene was 35 pg per 100 ml and D-xylose excretion 1.1 gm per five hours. The oral glucose tolerance test curve was diabetic. Serum immunoglobulin A (IgA) was totally absent and IgM was mildly decreased (73 mg per 100 ml). The x-ray pattern of the small intestine was consistent with a malabsorption

of

are

the

study a

of

small

restriction

for

nine

115.

The

surface

cells

now

present.

present,

though

still

of of

Original

of

months. The

intestinal

Original is

nuclei

B,

surface the

intestine

epithelium

the

barium.

abnormal

small

pa-

of

magnification

infiltration of

of

pattern

atrophy, cell

specimen

intestine

dilatation

intestine.

round

biopsy

small

segmentation

villous

and

of

“moulage”

duodenum, and

subtotal

cells

propria.

barium

flocculation

specimen

epithelial after

6. A,

demonstrating

portion

loops X

E.

lamina obtained magnifi-

normal

are

basal

with and

blunted.

state, and a small bowel biopsy revealed total villous atrophy (Fig. 4). lmmunofluorescent staining of the biopsy specimen revealed absence of IgA-containing plasma cells in the lamina propria, but abundant IgG and IgM cells. IgA was absent from tears, saliva and duodenal juice. After a gluten-free diet was instituted she gained weight rapidly. Her diabetes became worse and oral hypoglycemic agents were prescribed. The bloating and abdominal distention subsided somewhat and diarrhea ceased. After eight months of diet therapy the serum carotene had increased to 78 fig per 100 ml, the D-xylose excretion was 5.7 gm per five hours, and the intestinal histologic abnormalities had diminished (Fig. 4C). A definite mass in the left upper quadrant became palpable, and laparotomy was performed. A rubbery, lobulated indurated mass histologically typical of retractile mesenteritis was found.

Comment:

For

many

years

this The

patient American

had Journal

symptoms of

Medicine

GLUTEN-INDUCED

Fig.

5.

tient

M.

barium

Case L. and

20.

A,

roentgenogram

demonstrating irregular

folds.

mild 6,

of intestinal

original

gastrointestinal

tract

dilatation, magnification

of

pa-

flocculation X

80.

of

A dense

suggestive of the “irritable colon” syndrome. She was constipated and obese. Only after the roentgenographic malabsorption pattern was noted were absorption studies conducted and the correct diagnosis made. She became overtly diabetic after the institution of gluten restriction, and intestinal absorption improved. We have not seen retractile mesenteritis in other patients with gluten4nduced enteropathy and know of no reports of the two conditions coexisting. Two other patients in this group (Cases 7 and 9) had symptoms suggesting peptic ulcer or hiatal hernia. Neither had diarrhea or weight loss. In both the clue to the correct diagnosis was an abnormal roentgenographic small bowel pattern. A fourth patient (Case 16) complained only of passing a single, large stool daily which frequently clogged the toilet. Group V. Selected Nutritional

Deficiencies

(Four

Patients)

Case 20. In September 1966, during her sixth pregnancy, this twenty-three year old woman began to note tiredness and weakness. In January 1967 a four to five day episode of intermittent epigastric pain and diarrhea occurred. In February 1967 anemia was discovered. .A bone marrow examina-. tion revealed remarkable hyperplasia of the granulocytic series with many monocy-toid forms and many giant metamyelocytes. Granulocytic leukemia was suspected. When hospitalized, the patient was febrile and had oral moniliasis. The white blood cell count was 800 per cu mm with 37 per cent granulocytes (all immature) and 64 per cent lymphocytes. The hematocrit was 20 p-r cent, platelet count less than 50,000 per cu mm and reticulocyte count 0.6 per cent. The prothrombin content was 20 per cent, serum calcium 7.1 mg per 100 ml, serum carotene 10 pg per 100 ml. The serum vitamin Bll was 389 &pg per ml (normal = 200 to 700 ppg per ml), and the serum folete level was 4.2 mpg per ml (normal = 7 to 15 mpg per ml). Examination of the bone marrow showed megaloblastic changes, neutrophilic maturation arrest and megakaryocyte hypoplasia. The patient was treated with Vitamin Bm and folic acid; her response was dramatic. The reticulocyte count inVolume

48,

March

1970

round ing

cell

the

infiltrate

crypts

abnormal.

TABLE III

Total

are

of

the

FNTEROPATHY

lamina

increased

villous

in

atrophy

Laboratory

propria number.

-

is The

MANN

seen.

Goblet

surface

ET

cells

epithelium

AL.

linis

is present.

and X-Ray Data % Abnormal

Study

100 95 93 84

X-ray study of small bowel D-xylose absorption and exretion Serum carotene Serum albumin Cobalt60 vitamin B12 absorption Stool fat Serum calcium Oral glucose tolerance (flat curve) Prothrombin activity Serum potassium

(21/21) (20/21) (14/15) (16/19)

78 ( 7/9 ) 65 (13/20) 65 (13/20) 38 ( 5/13) 28 ( 4/14) 25 ( 3/12)

creased to 16 per cent and the platelet count to l,OOO,OOO per cu mm. Improved maturation of erythrocytes and granulocytes was noted within three days. She had an uncomplicated delivery in May 1967. Her hematocrit then was 42 per cent and the white blood cell count 10,300 per cu mm,

with a normal differential count. The serum carotene value was II fig per 100 ml. Because of a persistently low serum carotene level, fur1967. No ther evaluation was conducted in September physical

abnormalities

were

found.

The

hematocrit

was

40 per cent, hemoglobin 13.3 gm per 100 ml, white blood cell count 6,800 per cu mm with a normal differential count, sedimentation rate 12 mm per hour, reticulocyte count 0.8 per cent, prothrombin content 100 per cent, serum carotene 36 fig per 100 ml, D-xylose excretion 4.1 gm per 5 hours, stool fat excretion 2.2 gm per day. The roentgenographic pattern of the small intestine and the jejunal biopsy specimen were abnormal (Fig. 5). Disaccharidase activity was abnormally low (Table IV).

Comment: The severe megaloblastic anemia in this patient resulted from folic acid deficiency which developed during a period of increased folate need and impaired absorption. Attention to laboratory abnormalities which 363

GLUTEN-INDUCED

ENTEROPATHY

-

MANN

ET

AL.

NORMAL ADULTS

SPRUE PATIENTS 5

25

z

I g c;

4

20

E

3

I

SPRUE

2 =

NORMAL

PATIENTS ADULTS

2

1

I

II P99

200 199

400 599

000 799

999 800

1000 1199

I200 1399

I599 IkoO

SPRUE PATIENTS

NORMAL ADULTS 20

4

SPRUE PATIENTS

Fig.

6.

The

distribution

immunoglobulin patients

levels

and

gluten-induced

suggested malabsorption, especially the low serum carotene value, eventually led to the correct explanation of the anemia. Gastrointestinal symptoms were minimal and neither weight lpss nor steatorrhea occurred. A second patient in this group (Case 5) had bone pain and osteomalacia for several years before gluten-sensitive enteropathy was discovered to be the cause. She had had mild gastrointestinal symptoms, but no diarrhea until a few months before the diagnosis was made. A third patient (Case 10) had thrombophlebitis corn. plicating marked peripheral edema. When hypoalbumi. nemia was noted, absorption studies were conducted, and gluten-induced enteropathy was eventually diagnosed. Roentgenographic and Laboratory Data. Roentgeno-

TABLE

Case No. 1

3 4 5 7 9 11 13 14 15 20 21

IV

Intestinal

Mucosal Disaccharidase

Lactase (Normal, 31-81 units*)

Sucrase (Normal, 48-128 units)

0.8 0 2.3 0 9.6 2.1 0.1 4.0 3.7 0 3.4 3.4

1.0 11.9 32.0 2.7 6.9 6.0 21.0 7.0 15.0 4.0 8.0 17.0

* Unit = micromole of substrate hydrolyzed gram of protein. 364

Activities Maltase (Normal, 176404 units) 10.0 41.0 98.0 13.0 8.1 29.0 96.0 20.0 86.0 20.0 43.0 47.0

per minute per

in

of

serum

in

normal

patients

with

enteropathy.

graphic and laboratory data are summarized in Tables I and III. Roentgenographic findings: The x-ray studies of the small intestine were abnormal in every patient. In three patients an abnormal pattern on the gastrointestinal study (which had been performed for symptoms other than malabsorption) led to the suspicion of adult celiac disease. Some of the studies were only minimally abnormal; in others gross abnormalities, e.g., puddling, segmentation and flocculation of the barium meal, were noted. Laboratory data: The D-xylose excretion was abnormal in twenty of twenty-one patients, the values ranging from 0.1 to 4.4 gm per five hours. In two patients the test was only minimally abnormal (4.1 and 4.4 gm excreted), but it was distinctly abnormal (less than 3 gm excreted) in seventeen of the remaining eighteen patients. Serum carotene levels ranged from 3 to 167 ,ug per 100 ml. Values were below 100 .pg per 100 ml in fourteen of fifteen patients tested, and below 50 pg per 100 ml in twelve of the fourteen. There was generally good agreement between abnormally low serum carotene levels and the amount of steatorrhea. In some patients, however, the serum carotene value was quite low in the absence of steatorrhea (Cases 20,3 and 6). The quantitative stool fat measurements varied widely, ranging from 2.2 to 59 gm per day. Seven of twenty patients studied (35 per cent) did not have steatorrhea. Diarrhea and steatorrhea did not always coexist. Two patients with dia’rrhea did not have steatorrhea, and two with steatorrhea did not have diarrhea. The serum albumin was less than 3.8 gm per 100 ml in sixteen of nineteen patients. In seven of nine patients (78 per cent) the absorption of cobaP-labelled vitamin The

American

Journal

of

Medicine

GLUTEN-INDUCED

B,, was impaired. Serum calcium levels were low (3.8 to 8.6 mg per 100 ml) in thirteen of twenty patients (65 per cent). Hypokalemia was present in three of twelve patients; the lowest value was 1.7 mEq per L. Four of fourteen patients (28 per cent) had prothrombin activities of less than 50 per cent. An oral glucose tolerance test yielded a flat curve in five of thirteen patients (38 per cent). Intestinal disaccharidase activity was low in all twelve patients studied (Table IV). The assays were performed prior to the start of gluten restriction. Serum immunoglobulin (Ig) levels were determined in twelve patients (Fig. 6). The normal (mean i 2 standard error of the mean) serum immunoglobulin levels for adults are IgG 998 & 52 (n = 65), IgA 173 i- 17.7 (n = 63) and IgM 183 & 16.9 (n = 65). Corresponding values in patients with sprue were 834 r?rr.83, 278 i 59 and 105 + 12. Mean IgG levels in no.rmal subjects and in patients with sprue were not significantly different, but the difference between mean IgM values was highly significant (p < 0.001). Statistical significance was calculated according to the unpaired t test corrected for unequal variances [22]. The mean value of IgA was not significantly different in the two groups, but the great variability of IgA levels in the patients with sprue is evident. (Values ranged from 0 to 713 mg per 100 ml serum.) The patient (Case 6) with a complete absence of IgA, and another patient (Case l), with a decreased IgG level (246 gm per 100 ml) and IgM level (48 mg per 100 ml), have been included in this report because of their favorable response to gluten withdrawal.

COMMENTS This report emphasizes the protean clinical expressions of gluten-induced enteropathy. In most series [l-3,5,7, 231 nearly all patients have had some or all of the classic features of malabsorption (steatorrhea, diarrhea, weight loss and malnutrition), although these sometimes were minimal or absent [4,5,7,23]. Only three of eleven patients described by Brooks et al. [4] complained principally of diarrhea. The incidence of diarrhea (66 per cent) and steatorrhea (65 per cent) in our patients is lower than in other series [1,2,5-7,231, in which both were present in approximately 80 to 100 per cent of cases. Mild steatorrhea may be unaccompanied by diarrhea, as noted in two of our patients and by others [2,4, 51. Weight loss has been reported in 57 [7] to 100 per cent [5] of cases but may be mild. Only ten (47 per cent) of our patients ‘had lost weight; one was obese. Gastrointestinal symptoms may be misleading. In this series some patients’ complaints suggested peptic ulcer, hiatal hernia or irritable colon, but not malabsorption. Six patients had considerable cramping abdominal pain. Others have noted that abdominal pain [5,6] and signs suggestive of intestinal obstruction [6] may be prominent features. We and others [4,7,9] have observed that the disorder may go unrecognized or incorrectly diagnosed for many years. Considerable disparity between the intestinal histologic abnormalities and evidence of malabsorption is sometimes noted [8]. Three of our patients (Cases 8, 16 and 20) are examples of marked mucosal atrophy with minimal malabsorption. Volume

48, March

1970

ENTEROPATHY

-

MANN

ET AL.

Mild or selected chemical and roentgenographic abnormalities may suggest the diagnosis of gluten-induced enteropathy. In one of our patients (Case 20) a low serum carotene level was the principal reason for suspecting malabsorption as the cause of folic acid deficiency. The failure of intrinsic factor to improve diminished vitamin B,, absorption may be an important clue [ll]. We and others have found that D-xylose absorption [4,10] and serum carotene levels occasionally are abnormal in the absence of steatorrhea. Evidently D-xylose absorption is a reliable test in untreated patients. It was abnormally low in all forty-six patients in four series [4,5, 23,241 and in twenty of our twenty-one patients. It may, however, be only mildly abnormal when steatorrhea is marked (Case 15). Correct interpretation of the x-ray film of the small intestine is essential. In three of our patients an absorptive defect was first suggested by a “malabsorption pattern.” Marked reroentgenographic ductions in the mucosal disaccharidase activity in patients with sprue have been reported previously [25-271. Nutritional manifestations of gluten-induced enteropathy are highly variable, may be severe and may obscure the underlying disorder. In one of our patients (Case 5) bone pain was a far more significant complaint than intestinal symptoms, and steatorrhea was mild. Similar cases have been reported [5,7,10]. Significant hemorrhage due to hypoprothrombinemia has occurred commonly [2,5,6,23]. That gross bleeding did not occur in any of our patients is somewhat unusual. As in one of our patients (Case lo), edema may be a presenting symptom and may be severe [4,7]. That severe megaloblastic anemia due to folate deficiency may be associated with only minimal malabsorptive symptoms (Case 23) deserves emphasis. Severe vitamin B,, malabsorption has occurred in occult nontropical sprue [ll]. Neuropathy may be a predominant and disabling feature (our Case 14 and [6,7,28,29]) and was the major cause of death in four of sixteen patients reported by Cooke and Smith [28]. Neuropathy may antedate intestinal symptoms [2,8,29], and as in our patient (Case 14) may be uninfluenced by gluten withdrawal [28,29]. Severe hypokalemia (as in our Case 4), is not a common complication of nontropical sprue but has resulted in nephropathy [7]. A presenting complaint of two of our patients was thrombophlebitis. This may have been a complication of peripheral edema and vascular stasis. These cases illustrate that the coexistence of gluteninduced enteropathy and other disorders which may cause diarrhea and malabsorption, e.g., diabetes mellitus, pancreatic insufficiency, and gastric surgery, can result in diagnostic confusion. Malabsorption in diabetes may be due to nontropical sprue [30,31]. The presence of five diabetic patients in this series suggests that the two disorders may be commonly associated and emphasizes the importance of considering gluten-induced enteropathy in diabetic patients with gastrointestinal complaints. Diarrhea in three of the patients with diabetes was attributed initially to visceral neuropathy; all three responded well to a gluten-free diet. Diarrhea, steatorrhea and excessive weight loss after gastric surgery may be the expressions of gluten-induced enteropathy, which preoperatively had been unrecognized [32]. Quite severe malabsorption may occur after gastric resection, but one of our patients (Case 17) and those of others [32] illustrate 365

GLUTEN.INDUCED

that it may appear also after limited procedures, such as vagotomy and pyloroplasty. Why gluten-induced enteropathy becomes manifest in these circumstances is uncertain, but it may be due to more rapid transit of food into the gluten-sensitive bowel. The history of pancreatic trauma and surgery in one of our patients (Case 15) made pancreatic insufficiency a likely explanation for malabsorption and obscured the correct diagnosis. These cases emphasize the importance of complete evaluation of small bowel function in patients with malabsorptive disorders, especially when other apparent explanations prove unsatisfactory. The finding of abnormal serum immunoglobulin levels in several of our patients is consistent with the reported association between immunoglobulin abnormalities and malabsorptive disorders similar to nontropical sprue [4, 33-361. In agreement with others [33-351 we have found that serum IgA and IgG levels are usually not diminished. Eidelman et al. [35] have reported that serum IgA levels in patients with sprue are higher than normal. Like Hobbs et al. [33] we have found serum IgM levels in patients with sprue to be significantly lower than normal. The response to gluten restriction in dysgammaglobulinemic patients has been highly variable. In one patient (Case 1, diminished IgG and IgM) the response occurred slowly over a several month period of

very

strict

diet

deficiency) by Crabbe

therapy.

Another

is remarkably

similar

and

response

Heremans

to gluten

Although drawal

of the

many was

others

months

sometimes

for

injury

clinical

and

IgA

was

ob-

chemand

sometimes

patients

reto the

[5,6],

whereas

adverse

effects

[4-

chemical

improvement

was

histologic

improvement

was

[5,8,23].

promptly

several

Clinical,

adherence

apparent

whereas

with.

was prompt

Strict

and

delayed

often

pearance

AL.

described

study,

usually

some

it without

noted,

minimal

isolated

to gluten

recovery

[5,6,23-j.

necessary

Excellent

ET

a favorable

were confirmed.

although

abandoned

6,8].

response

improvement

[4-7,23-j,

quired

6,

including

goal of this

by others

ical and histologic dramatic

(Case

MANN

to a patient

[36],

was not a primary made

-

withdrawal.

evaluation

servations

diet

ENTEROPATHY

The

surface

reversed,

epithelial

whereas

of villi was slow and incomplete

the

reap-

[5,8,23].

ACKNOWLEDGMENT We acknowledge the assistance of Dr. Edward Chaperon, Department of Medicine, Division of Allergy and Immunology, in statistical analysis of immunoglobulin data, and Dr. John E. Struthers, Jr., for performance of some disaccharidase assays.

REFERENCES 1. Green

PA,

Wollaeger

United 2.

States.

Bossak

ET,

3.

Wang

Cl,

J

JW:

rhea.

clinical

Sinai

Observations

on

and

38:

399,

D:

Hosp the

lymph

spree

in

juice

sprue).

Observations

24:

286, of

biopsies.

of

the in

19. Claman

1957.

Brit

steator-

Med

J

2:

1318,

FP,

celiac 5.

Benson

GD,

with Buchan

DJ, J.

20.

8.

Samloff

of P,

McGuigan

JE.

AJ,

with

of

64:

adult

21.

1966.

celiac

Wiernik

G:

P,

Wuepper

Intern

Stefanyk

H.

Logan

V,

Acta LL,

suction

Carey

in

Medi-

diagnosis

Med

57:

Alvarez

S:

Med

JB:

Clin

85,

23.

1962.

Amer

J,

50:

24.

de

177: Anderson

17.

Dahlqvist

18.

Schilling

K,

347,

effect Biochem

of

of

47:

636,

iron

25. in

small

1964.

Eng

J

CE,

179

(supp

Quinton

WE:

to

26.

Med

nontropical

Bayless

TM,

ment

with

Finkel

M,

immunologic

445):

344,

pernic-

29.

small

bowel

capsule.

method

tissues. ten

J

Bokkel

for

and

Gastro-

Hunnik

determination

of

determination

Chem

Biol

H.

fat

of

173: 507, Weyers

in

feces.

J

Coeliac

dietary

A:

French

disease.

wheat

Method

7: 18, RF:

30. 31.

Gerrard

JW,

free

for

Gastrointestinal

flour. assay

JM, Lancet

of

1:

intestinal

HA:

Rapid Chem

studies

836,

33.

Weser

E,

HG.

and

the

35.

studies.

II.

The

effect

of

gastric

in

the

response

of

exposure. to

Book

of

human J Lab

human the

J Clin

Statistical

Co.,

1957,

TR:

diet.

Arch

AM,

Cohen,

in

NH0

idiopathic

lsselbacher

jejunal

mucosa

Invest

45:

of 194.

Analysis,

2nd

ed,

p 112.

Adult

celiac

Intern

disease.

Med

P-P,

Treat-

111:

(Chicago)

Janowitz

steatorrhea.

Cooke

JD,

HD:

Amer

Green

Hobbs

MH:

Intern

Long-term

J Gastroent

IE.

47:

Jr,

Wollaeger CA,

JR,

Eidelman

S,

(IgAl Crabbe rhea.

Davis

in man. PA,

Walker

A:

Intestinal

(gluten-sensitive

di-

enterop-

associated

JE

Sprague

Jr:

disease

Malabsorption

RG,

Brown

sprue.

Johnson

with

AL:

Gluten

the

507,

1962.

Diabetes

mel-

11: 388, 1962.

Diabetes

CF:

and

43:

enteropathy

Gastroenterology of

in

1967.

Gastroenterology

Deficiency Rubin

TM-globulin

Immunologic

Clin

Res

Lagunoff

D,

Rubin

Invest

syndrome.

CE:

sprue.” plasma

Heremans

A new

in

1965.

ap-

50:

796,

1966.

in

coeliac

dis-

1968.

SD,

J Clin

deficiency

571,

Neuromuscular

8: 605,

surgery.

SD,

intestinal

malab-

1966.

NM:

Gut

CS,

GW:

Davis

lactase

disorders

683,

nontropical

1: 217,

S.

89:

Spiro

EE,

gastric

Hepner

and

other

1969.

Struthers

Melnyck

Lancet

33,

mellitus.

with

after

1964.

J,

Neurological Brain

diabetes

associated

1033,

sprue

deficiency

and

48:

Anderson

223:

GE,

F

271:

celiac

steatorrhea.

Kern of

PA,

in

WT:

Solitare

sprue)

Lactosuria

DM.

disease.

with

disaccharidase

Gastroenterology

Med

Smith

HJ.

Eidelman

J Med

Eng

activity

coeliac

Vinnik,

New

disease.

Arch

Secondary (nontropical

Zschiesche

WT,

Binder

KJ:

disease

Sleisenger

between 36.

factor

Morphologic to X-ray

pogammaglobulinemic

Anal

1964.

Intrinsic

860.

immunoglobulins.

repair

Hendrix

celiac

Welsch

ease.

1952.

disaccharidases.

admin42:

1966.

JH,

celiac

pearing

Biol

Sammons

and

389,

a gluten-free

states.

32. Hedberg

1948.

34. AC,

oral Med

measurement

serum

Introduction

Yardley

GR,

litus

Photometric

F:

study

diarrhea biopsy

TH:

intestine

Gelb

patients

1, 1959.

gastrointestinal

91:

McGraw-Hill

adult

adult

1964.

Frazer

JM: of

Plotkin

athy) 28.

instrument

1949. CM.

27.

diagnostic

1966.

stomach,

Clin

1967.

adult

sprue

Addisonian

A multipurpose

esophagus, 37:

animal JH.

Occult

reference

of the

550.

the

H:

simulating

Quantitative beta.2M

damage

Bact

Massey

York,

sorption

enteropathy New

after

Lab

1964.

Browning,

W.

35,

malabsorp-

malabsorption

steatorrhea.

gastritis

Stand

EW:

for

evidence

Gluten-sensitive

Fudenberg

Med

Kamer

Smellie

JS,

Dixon

in

R:

without

special

Rubin

in

histopathoiogical

Gastroenterology Terry

but

simplified

Rice

method 16.

Celiacsprue:

with

46:

pentoses

minimal

W: C,

Severe

B~z. J

83, 1963.

Systemic

N

radioactivity

1966. 22.

1964.

steatorrhea.

biopsy A

with

R:

673,

Gastroenterology

enterology

Terry

60:

atrophic

anemia,

colon.

Trier

DA:

Radiation J Path

human

disease

diet.

of

vitamin

and

685,

saccharidase

associated

studies.

366

D,

M,

Waterhouse

Brandborg

15. Van

Adult

Problems

Ann

enteropathy.

Volwiler

1965.

ious

Roe

of

789,

gluten-free

disease.

diet.

gluten

osteomalacia

and

14.

the

of

Med

825,

11. Brown

13.

MH:

to

Celiac

in patient

Intern

absence

Moss

for

JW:

Hoffman

of sprue

272:

12.

Med

New

a gluten-free

Kelley

Ann

the

Clin

followup

I,

lesion

10.

Sleisenger

response

course

117:

1966.

tion. 9.

clinical

(Chicago)

1, 1964.

manifestations 515,

Variable

Med

OD,

Gerrard

Gibb

JJ:

Intern

upon

43:

effects

Ross

Cerda

Kowlessar

(Bait)

and 7.

KC, Arch

emphasis

cine 6.

Powell

disease.

Merrill beta-2A,

mucosa.

Brooks

excretion

radioactive

HN,

gamma-Z,

idiopathic

urinary

of

1953.

1954. 4.

on the

istration aspects

NY

the

1960.

aetiology

node

of

Clinical

(idiopathic

Mount

Jejunal

behavior

Adlersberg

syndrome

patients.

Paulley

The

Gastroenterology

malabsorption 94

EE:

JF:

cells 45:

1003,

Selective Amer

and

117,

CE:

serum

in

“hy-

1968.

The

relationship

immunoglobulin

1966. IgA

J Med

The

studies

16:

deficiency 42:

American

319,

with

steator-

1967.

Journal

of

Medicine

A