Digestion 1998;59:530–546

Julio C. Bai
Malabsorption Syndromes
Universidad del Salvador, and Hospital de
Gastroenterologı́a ‘Dr. Carlos Bonorino
Udaondo’, Buenos Aires, Argentina

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Key Words Abstract

Malabsorption Background/Aims: Malabsorption syndromes commonly result from a
Pathophysiology pathological interference of the normal digestive process. There have been
Absorption major advances in the last 4 years. The purpose of this review is to highlight in
Celiac disease the form of a brief summary the most outstanding information available.
Whipple’s disease Methods: The review was performed based on a medical literature search
using MEDLINE (1993–1997), bibliographic reviews of book chapters and
review articles. As a consequence of the extensive information incorporated in
the period and the limited scope of this review, the review will focus in three
aspects: (1) an overview on some clinical aspects of malabsorption; (2) dis-
eases in which predominates the disturbed mucosal phase of the digestive pro-
cess, and (3) providing information on diagnostic testing regarding malabsorp-
tion. Results: Major advances on celiac disease, Whipple’s disease, giardiasis,
tropical sprue, malabsorption of oligo- and disaccharides, vitamin B12 and bile
salts are discussed. New aspects on diagnostic procedures for malabsorption
are also presented. Conclusion: Although major advances have given a great
support to the investigation of malabsorption, yet the syndrome remains a
major diagnostic dilemma. Based on the limited availability of most diagnos-
tic tests, a simple and practical diagnostic algorithm is presented.
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Introduction tive assimilation of many nutrients resulting in classical

In general, malabsorption constitutes the pathological
interference with the normal physiological sequence of
digestion (intraluminal process), absorption (mucosal
process) and transport (postmucosal events) of nutrients.
A general consensus considers the term malabsorption to
refer to defective mucosal absorption, while maldigestion
denotes impaired intraluminal nutrient metabolism.
Most diseases producing malabsorption generate defec-
overt malabsorptive symptoms. On the contrary, some
rare diseases selectively affect one nutrient resulting in a
disorder with a paucity of symptoms. Many features of
patients with malabsorption are familiar to gastroenterol-
ogists; however, the etiology is often puzzling. Several
studies published in the last four years have modified
some concepts, changed criteria and generated new ap-
proaches to this important problem.
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© 1998 S. Karger AG, Basel Julio C. Bai, MD

ABC
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0012–2823/98/0595–0530$15.00/0 Hospital de Gastroenterologı́a, Caseros 2061

Fax + 41 61 306 12 34 (1264) Buenos Aires (Argentina)
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 The present review will provide a brief state of the art
of the most relevant advances of the last 4 years among
some disorders impairing the digestive process. In order
to better define new advances in diseases producing mal-
absorption we will arbitrarily segregate the events of
digestion and absorption into the three components of the
digestive process: intraluminal, mucosal and postmucosal
phases. However, because the extensive information in-
corporated in the last years and the limited scope of this
review, we will focus on diseases in which predominate
the disturbed mucosal process. We will give an overview
of some clinical aspects of malabsorption and finally, we
will suggest a diagnostic approach to malabsorption as it
must be considered at the end of this century.
Clinical Aspects of Malabsorption
A wide range of clinical features are result from the
malabsorptive process and may be clues to its etiological
diagnosis. According to the intensity of these symptoms,
clinical features have been arbitrarily segregated in:
(1) clear features of overt malabsorption (usually in pa-
tients with severe and long-standing malabsorption);
(2) evidence of subclinical malabsorption (minor symp-
toms and signs are present, mostly extraintestinal fea-
tures); and (3) circumstances in which classical malab-
sorption diseases can be present in cases with an asymp-
tomatic clinical course and normal physical examination.
Others prefer to classify clinical malabsorption into three
basic categories: (1) selective, as seen in lactose malab-
sorption; (2) partial, as observed in a-ß-lipoproteinemia,
and (3) total as in celiac disease [1]. Clinical practice has
shown that both clinical classifications can be associated.
Classical Overt Malabsorption
Patients complain of symptoms that can be divided
into two areas: intestinal and extraintestinal manifesta-
tions. Usually, intestinal features are dominant in this
type of clinical expression of severe malabsorption.
Chronic diarrhea is a highly subjective symptom. Some-
times, a clear perception is not obtained, especially in
patients with chronic symptoms. Watery, diurnal and
nocturnal, bulky, frequent stools are the clinical hallmark
of overt malabsorption, although not always present.
Stool color can be influenced by fat content. Patients with
steatorrhea present pale, yellow, floating, spongish stools.
This subjective impression must be confirmed by an
adequate examination of feces. This examination must
include fecal weight, number of stools, and color assess-
ment. Other gastrointestinal features are anorexia, hyper-
phagia, nausea, vomiting, abdominal distention, borbo-
Malabsorption Syndromes
rygmis, excessive flatus, etc. Although abdominal discom-
fort is common, abdominal pain is unusual. The cramping
pain suggests the presence of obstructed intestinal seg-
ments (Crohn’s disease, malignancies, etc.) especially if it
persists after defecation. In some wasted patients occa-
sionally there may be visible peristalsis. It is important to
remember that many patients with malabsorption present
with subtle gastrointestinal symptoms with only minor or
no changes in stool frequency, color, or consistency.
Subclinical malabsorption is well recognized, especial-
ly in celiac disease. Patients do not present gastrointesti-
nal symptoms, rather they exhibit long-lasting and fre-
quently missed extraintestinal features that are rarely
associated with intestinal problems (short stature, infertil-
ity, bone disease, hematological problems, etc.) [2]. Once
again, an asymptomatic course can be observed among
relatives of celiac disease patients who present with small
bowel mucosal atrophy [3].
Extraintestinal manifestations comprise a wide range
of symptoms involving most systems. The description of
the spectrum of extraintestinal symptoms exceeds the
scope of this review and interested readers are encouraged
to read very excellent recent clinical updates [4].
Global Malabsorption
Giardiasis
Giardia Intestinalis is a protozoan parasite that over
the last years has been recognized as an important patho-
gen for human beings with a worldwide distribution. The
parasite invades the upper gastrointestinal tract and gall-
bladder. Giardiasis is the human infection produced by
the parasite that may lead to different clinical situations.
Most patients are asymptomatic, but other can express
acute or more frequently chronic diarrhea, malnutrition
and growth retardation in children. However, despite pro-
gress in understanding the biology of Giardia many
researchers believe that, at least in highly endemic tropi-
cal areas, its pathogenic role must be questioned. An
asymptomatic clinical course can be related to either the
pathogen (phenotypic and genotypic diversity, and pres-
ence of virulent factors) [5], to the severity of the infection
(determined by parasite load) and to host factors (e.g.
hypogammaglobulinemia). Giardiasis is associated with a
wide repertoire of small intestinal mucosal abnormalities
ranging from normal appearance at light microscopy
(96% of cases) to subtotal villous atrophy with crypt
hyperplasia and intraepithelial lymphocyte infiltration
[6]. Two recent experimental studies have suggested that
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Giardia-induced enteropathy could be associated with the
stimulation of the enzyme ornithine decarboxylase, a rate-
limiting factor in cell proliferation [7, 8]. A study from
England has shown that small intestinal architecture, disac-
charidase activity and absorption of fluid electrolytes in
neonatal rat intestine were related to the Giardia strain
infection [9]. There is evidence that the presence of malab-
sorption syndrome in giardasisis is closely related to the
degree of enteropathy, however, Giardia also promotes
changes in a variety of luminal factors (bacterial over-
growth, bile salt deconjugation and uptake by the parasite,
inhibition of host enzymes, etc.) that can participate as sec-
ondary factors to the morphological abnormalities [10].
Recent studies have explored the value of immunoas-
says, immunofluorescence microscopy, conventional mi-
croscopy and flow cytometry for detection of G. intestina-
lis. Sensitivity, specificity and predictive values are in
favor of those immunologic tests [11–13].
Celiac Disease
Several hundred important communications have
been published in the medical literature on all facets of
celiac disease during the past four years. Because of the
limited space, this review will only focus on aspects relat-
ed to advances in: the epidemiology of celiac disease,
some clinical aspects, the role of antibodies in the screen-
ing and diagnosis, some metabolic sequelae such as bone
disorders and the relationship with some associated con-
ditions. For more detail, readers are encourage to read
more complete recent reviews [14, 15].
Earlier studies suggested that celiac disease was a rela-
tively rare disorder in populations of western Europe with
a wide range of general prevalence between 1 in 1,000 and
1 in 5,000 individuals. However, a greater prevalence had
been detected in Great Britain. Recent screening studies
have found a greater prevalence of one in 200 in almost
every region of the western Europe where it has been
explored (e.g. in school children all along Italy or Swedish
adult blood donors) [16, 17]. During the 1980s several
groups had reported that the incidence and prevalence of
celiac disease were declining. However, this impression
changed at the end of that decade with the identification
of greater number of cases with some different clinical
characteristics. This change seems to be produced by sev-
eral factors: underdiagnosis in the past, the recognition of
cases with milder clinical expression, an improved medi-
cal attention by physicians alert to the different clinical
features, improved surveillance techniques and the wider
use of endoscopy are, among other factors, responsible for
that increased incidence [18, 19].
532 Digestion 1998;59:530–546
It is commonly assumed that chronic diarrhea and
overt malabsorption are the classical clinical features of
celiac disease. During the 1980s and part of this decade,
several studies have demonstrated that most of the new
cases are now individuals with milder gastrointestinal
symptoms, features related to extraintestinal manifesta-
tions [20], or patients in whom the primary diagnosis is an
autoimmune disorder such as primary biliary cirrhosis
[21], thyroid diseases [22], insulin-dependent diabetes
mellitus [23, 24], etc. A very high prevalence of celiac dis-
ease among subjects with Down’s syndrome [25] and neu-
rological disorders [26] was recently observed. Despite
manifestations of intestinal mucosal atrophy, the disease
can be clinically asymptomatic as was observed among
first-degree relatives [3]. The term latent celiac disease
has generated some confusion. It refers to subjects who
present with minor features of gluten sensitivity but who
can develop overt celiac disease [27]. By contrast, others
refer to ‘latent’ cases who are non-atrophic on a gluten-
containing diet, but who in the past had a flat mucosa that
has responded to a gluten-free diet [28].
Although research has continued in the last four years,
exploration of celiac disease-related serology has permit-
ted some few advances. An alternative substrate with
human umbilical cord has been developed recently for
antiendomysium antibodies [29]. There is a consensus
that the EmA test presents a similar screening value no
matter the substrate. A recent study among three universi-
ty groups has observed that antigliadin antibodies cross-
react with human enterocytes and calreticulin, an intra-
cellular enzyme involved in calcium metabolism [30].
These authors suggest that antigliadin antibodies can play
a pathogenic role in celiac disease and we can infer that
further studies must explore a pathogenic role in calcium
malabsorption. Recently, Dieterich et al. [31] have identi-
fied tissue transglutaminase as the autoantigen for pro-
duction of antireticulin/antiendomysial antibodies. How-
ever, there is some controversy about the importance of
this finding [32].
The association between celiac disease and gynecologi-
cal and obstetric disorders has been recently received
attention [33]. A case control study noted that in un-
treated subjects there was a delayed menarche, earlier
menopause, increased secondary amenorrhea and sponta-
neous abortions and that a high proportion of cases first
became symptomatic during pregnancy or puerperium.
Celiac disease is strongly associated with bone disorders
such as osteopenia, osteoporosis and osteomalacia [34].
Bone involvement has been observed in patients with
either symptomatic untreated disease [35] or those with
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an asymptomatic clinical course [36]. Treatment with a
gluten-free diet produces a significant improvement in
bone density as has been demonstrated by several studies
[37–39]; however, a complete bone recovery is infre-
quent.
Whipple’s Disease
Whipple’s disease is a chronic systemic disorder that
has been suspected to be of infectious origin since its first
description [40]. The disease is characterized by multior-
gan involvement with prominent compromise of the gas-
trointestinal tract, lymph nodes, endocardium, central
nervous system, and several other organs. The disease is
also characterized by the presence of foamy, large macro-
phages containing periodic acid-Schiff-positive diastase-
resistant inclusions (PAS), with a typical rod shape. The
suspected microorganism is mainly lodged in macro-
phages with very few in the extracellular compartment.
The main and distinctive characteristic of the suspected
bacterium was the trilaminar cellular wall demonstrated
by electron microscopy. Despite multiple attempts at cul-
ture, the putative infectious agent was unknown until
recent years. Therefore, treatment remains based on
empirical clinical grounds. By taking advantage of new
molecular biology technology, amplification of genetical
material from infected clinical specimens allowed identi-
fication of the previously uncharacterized microbial
pathogen. The development of a polymerase chain reac-
tion (PCR)-based test for this agent has generated a funda-
mental change in the approach to microbial identifica-
tion, diagnosis and taxonomic classification of the bacil-
lus. [41, 42]. The phylogenetic analysis of the rDNA
sequence suggested that the Whipple bacillus is an actino-
mycete and promoted the proposal of a new taxon, Tro-
pheryma whippelii. After that, several studies have al-
lowed identification of the putative bacillus in several
cohorts of patients either with intestinal involvement or
with extraintestinal manifestations such as uveitis [43],
neurologic involvement [44], etc. The identification of
T. whippelii was facilitated by a modified PCR-based
assay. However, conversion of biological samples to nega-
tive PCR assay did not preclude extraintestinal relapses
[45].
Another important pathogenic factor associated with
Whipple disease is related to ill-defined host susceptibili-
ty. From the histological point of view, T. Whippelii accu-
mulates, is active and reproduces in the cellular milieu of
macrophages. This evidence suggests, macrophage dys-
function with normal phagocytosis but abnormal lysis
[46, 47]. These cellular immune deficiencies were only
Malabsorption Syndromes
demonstrated on nonspecific antigens. Recently, the in
vitro production of cytokines from purified macrophage
precursors and cytokine expression on duodenal biopsy
specimens were tested. Monocytes and biopsy samples of
patients with Whipple disease express a reduced produc-
tion and expression of IL-12 and interferon-gamma [48].
Although the study suggests a genetic basis for these
defects, it cannot define whether this macrophage dys-
function is the cause or the result of a previous T-cell
defect.
New technological approaches to culture intracellular
macrophages were recently applied to survival and grow
of intracellular pathogens in human phagocytes [49]. This
novel strategy consists in the inoculation of Whipple dis-
ease infected tissue into human phagocytes deactivated
with interleukin-4, interleukin-10 and dexametasone. The
cultured bacteria was identified as T. whippelii based on
PAS positive staining, electron microscopy and molecular
analyses and studies confirm bacterial growth and multi-
plication. The most effective deactivating factor was in-
terleukin-4. The last 4 years have increased our knowl-
edge of Whipple disease; firstly, the putative microorgan-
ism causing the disease was recognized and secondly,
T. whippelii was recently cultured in an immunodeficient
cellular habitat. Several issues need to be addressed in the
near future. Perhaps the most important aspect to be eval-
uated is the defect involved in host susceptibility. Other
aspects are related to microbial susceptibility and protec-
tion for susceptible hosts or supplementation for antibiot-
ic-resistant subjects.
Tropical Sprue
There are a series of specific causes of chronic diarrhea
and malabsorption that mostly affect populations of trop-
ical and subtropical areas; these include intestinal tuber-
culosis, Mediterranean lymphomas, severe malnutrition,
etc. Tropical sprue is a syndrome of unknown etiology
that should not be considered a single entity. Patients
must be suspected of tropical sprue if they are resident in
or were visitors to tropical or subtropical areas and have
chronic diarrhea and malabsorption of two unrelated sub-
stances such as xylose and vitamin B12. Although the
small intestinal biopsy is not characteristic (tropical enter-
opathy: villous enfacement, inflammatory infiltration of
lamina propria and epithelium, minor enterocyte dam-
age), it is useful to differentiate from other disorders
where biopsy can be diagnostic (Whipple’s disease, stron-
gyloidiasis, etc.). From a clinical point of view, there is a
wide variety of possibilities ranging from asymptomatic
structural and/or functional abnormalities to an overt
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malabsorption state responding to folate and broad spec-
trum antibiotic treatment [50]. There is evidence support-
ing an infectious cause, however, the exact nature of the
infection is unknown [51]. Intestinal colonization with
mixed fecal flora has been demonstrated by several stud-
ies, however, the possible role of protozoan parasites is
increasingly demonstrated (Cryptosporidium parvus, Iso-
spora belli, Cyclospora cayetanensis, etc.) [51, 52].
Despite these and other studies, further research is nec-
essary in order to clarify several obscure aspects of tropi-
cal sprue.
Aging and Malabsorption
In western countries the proportion of population with
age older than 60 years old is increasing. Scientists are
giving more and more attention to this trend in order to
understand aging processes and diseases that are ex-
pressed in a higher prevalence with advancing age. Most
functions, including gastrointestinal physiology, exhibit a
low degree of decline as a result of old age itself. Thus,
there is little clinical evidence of digestive problems as a
consequence of age. Malabsorption is not a common find-
ing in elderly and when it is present oftenly results as con-
sequence of concomitant disorders. The small bowel has a
very extensive absorptive capacity that it is not complete-
ly used under common circumstance. This capacity is
known as functional reserve and is only activated in
pathological circumstances. It seems possible that gas-
trointestinal reserve might be reduced in older people
making them more susceptible to insults and with conse-
quent rapid decompensation [53]. Malnutrition and ca-
chexia in the elderly can be associated with several gas-
trointestinal and extraintestinal disorders. They can con-
tribute to morbility and mortality of elderly people.
Weight loss can be secondary to altered appetite, malab-
sorption or increased catabolism. Malabsorption can be
produced by gastric hypochlorhydria (and subsequent
small bowel bacterial overgrowth), dysmotility or chronic
intestinal ischemia [54]. A recent study in patients with
cachexia secondary to chronic congestive heart failure has
shown fat malabsorption as it was assessed by triolein
breath test [55]. However, in this opportunity, malabsorp-
tion was not associated with small bowel bacterial over-
growth. A recent study of Majumdar et al. [56] inferred
that a slow cell turnover and continual cell renewal can
produce a major impact in cell proliferation and are the
more frequently age-related phenomena. They may result
in the induction of malnutrition and malabsorption.
Recently, a survey from Canada detected that despite
adequate daily dietary intake of folate and vitamin B12
534 Digestion 1998;59:530–546
(according to the recommended requirements) an in-
creased risk of deficiency of both hematopoietic factors is
present in patients older than 65 years [57].
Miscellaneous Disorders
Radiation enteritis can be rarely observed among pa-
tients with malignancies. Symptoms can be masked by the
primary pathological process. A very interesting study
from Australia has shown that during pelvic radiation,
patients have significantly increased stool frequency asso-
ciated with malabsorption of bile acids, vitamin B12, lac-
tose and also steatorrhea compared to baseline studies.
One to two years after irradiation, the great majority of
patients had significantly lower bile acid absorption or
other abnormal absorption tests [58]. A recent study from
Germany has successfully used hyperbaric oxygen to treat
a patient with malabsorption due to radiation enteritis
[59]. Although hyperbaric oxygen has been effectively
employed in radiation proctitis or perineal Crohn’s dis-
ease based on their ischemic pathogenesis, the routine use
in malabsorption induced by the radiation injury requires
further investigation.
Most patients with malignancies present with nutri-
tional deficiencies and this circumstance can contribute
to the morbility and mortality. Chemotherapy can con-
tribute to this risk by inducing malabsorption of nutrients
such as lactose [60]. D-Xylose malabsorption may be
related to a morphological impairment in the proximal
small intestine [61]. A study from Japan has shown that
the coadministration of methotrexate and vitamin A to
rats can prevent morphological and functional abnormali-
ties of the small intestine [62].
Malabsorption of Single Nutrients
Malabsorption of Oligosaccharides and
Monosaccharides
The integrated process of digestion and absorption of
carbohydrates includes a luminal phase producing oligo-
saccharides which require further hydrolysis to monosac-
charides that are then absorbed across the mucosal micro-
villous membrane. The enzymes which hydrolyze these
products, disaccharidases, are produced by the epithelial
cells and are localized in the brush border. Deficiency of
these hydrolases may be either primary or secondary to
diseases of the small intestinal mucosa (acute gastroenter-
itis, celiac sprue, alcoholism, malnutrition, etc.).
The most common and well known hydrolase defect is
lactase deficiency inducing lactose intolerance. There are
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three forms of lactase deficiency: constitutional, second-
ary and a very rare congenital disorder. New evidence
suggests that women with lactase deficiency can tolerate
increased amounts of lactose during late pregnancy [63].
Suarez et al. [64] have studied people who identify them-
selves as severely lactose-intolerant. They have observed
that abdominal symptoms attributed to lactose intoler-
ance were not resolved by a lactose-hydrolyzed milk. Lac-
tose intolerance can be masked by other diseases. In a
study from the Netherlands, a substantial number of
patients diagnosed with irritable bowel syndrome (24%)
showed evidence of lactose malabsorption as detected by
the hydrogen breath test [65]. Furthermore, based on clin-
ical findings, the authors could not discriminate who
would require a lactose-restricted diet. Lactose intoler-
ance has been observed in up to 70% of adult HIV-
infected patients; this was particularly more severe in
those with advanced disease [66]. The hereditary lactase
deficiency is inherited as autosomal-recessive.
A number of other rare defects of brush border mem-
brane hydrolase activity occur as inherited or secondary
disorders. Symptoms are related to ingestion of the spe-
cific carbohydrate. A recent study by Ziambaras et al. [67]
showed evidence that excessive production of cytokines
(IL-6) in the inflamed intestine of Crohn’s disease induces
downregulation of the expression of sucrase-isomaltase
with the consequent defective hydrolysis. Congenital su-
crase-isomaltase deficiency is a rare disorder in which
mutant phenotypes generate transport-incompetent mole-
cules. The enzyme is produced into the cell but is not
transported to the brush border due to a Q1098P muta-
tion [68]. Isolated fructose malabsorption, a very rare con-
genital disorder, was not associated with mutations in the
gene encoding the facilitative hexose transporter GLUT5
[69].
Bile Acid Malabsorption
Bile acids are necessary for the absorption of dietary
fats and sterols from the intestine. They are synthesized in
the liver. The gall bladder stores bile between meals that is
excreted into the intestine during digestion. More than
90% of bile acids are reabsorbed from distal intestine in
the enterohepatic recirculation; most importantly, in the
distal 100 cm of ileum there is an active uptake step. Mal-
absorption of bile acids can produce diarrhea with some
special characteristics. It involves an active secretory pro-
cess which tends to be reduced by fast. If bile acids are not
recovered by the ileum, they are transformed into very
active metabolites. A high concentration of bile acids in
the colon (13 mmol/l) may induce diarrhea as a conse-
Malabsorption Syndromes
quence of a number of factors operating synergistically.
These can be classified as [70] primary or secondary bile
acid malabsorption. Primary malabsorption is also
known as idiopathic diarrhea [71]. Secondary bile acid
malabsorption is associated with intestinal resection [72],
disease of the distal ileum or other clinical conditions
such as postcholecystectomy [73] and post vagotomy.
Recently, bile acid malabsorption was also demonstrated
in some patients with AIDS and chronic diarrhea. Two
recent studies showed a significant improvement of symp-
toms (diarrhea) in AIDS patients in response to treatment
with a bile sequestering agent [74, 75]. As was previously
suspected, bile acid malabsorption might also play an
important pathogenic role in patients with Crohn’s dis-
ease in which chronic diarrhea remained unresponsive to
standard anti-inflammatory treatment. According to a
recent publication, the integrity of the enterohepatic cir-
culation was significant impaired in patients with Crohn’s
disease irrespective of small bowel resections (19% of
patients without resection and 28% of those with resec-
tion had altered enterohepatic recirculation) [76].
Postinfective bowel dysfunction was associated with
chronic bile acid malabsorption in a dual fashion. Firstly,
Niaz et al. [77] have demonstrated a clear history of acute
gastroenteritis as an initial event in a group of patients
with well-defined bile acid malabsorption. This has been
evident in 16/29 patients with no other identifiable causes
of bile acid loss. On the other hand, bile acid malabsorp-
tion has been identified as the most probable cause of
chronic diarrhea after acute infectious diarrhea in a rela-
tively high proportion of patients diagnosed with this dis-
order [78, 79].
Various studies have emphasized the high prevalence
of bile acid malabsorption in chronic diarrhea of un-
known origin [80, 81]. Thus, bile acid metabolism assess-
ment should be routinely performed in patients for which
the cause of diarrhea is not obvious after full investiga-
tion. If this disorder is confirmed, therapeutic strategy
should include the use of bile acid chelators [82]. Recent
contributions were made to the understanding of the fac-
tors involved. Mutations in the active bile acid transport-
er gene (SLC1012) was postulated as a pathogenic mecha-
nism by Oelkers et al. [83]. On the other hand, specific
morphological abnormalities of ileal mucosa were not
detected in a group of patients suffering primary bile acid
malabsorption [84], as has been previously reported [85].
Vitamin B12 Malabsorption
Often, macrocytic anemia is present in patients with
primary gastrointestinal alterations. In such circum-
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stances, the most likely reason is defective absorption of
essential hematopoietic factors such as folic acid and vita-
min B12. Vitamin B12 has a complex intraluminal meta-
bolic process starting with the salivary excretion (protein
R) and including the participation of gastric secretion (in-
trinsic factor), a pancreatic factor (proteases) and an
active uptake in the terminal ileum. Several gastrointesti-
nal conditions can be associated with malabsorption of
vitamin B12. Among others, small bowel bacterial over-
growth, tropical sprue, celiac disease, Crohn’s disease,
Whipple’s disease are the most relevant gastrointestinal
conditions associated with clinical evidences of vitamin
deficiency.
Approximately 2–4% of laboratory samples have evi-
dence of macrocytosis [86]. In spite of vitamin B12 defi-
ciency appearing to have a worldwide distribution, its
occurrence is more common in pregnant and lactating
women and their young children in developing countries.
This disorder may be primarily due to malabsorption but
it is possibly exacerbated by low dietary intake and, for
young children, by maternal depletion of the vitamin.
Thus, prevalence of deficient and low plasma vitamin B12
concentrations were 8 and 33% in a group of 219 rural
Mexican children. [87]. The same report provided infor-
mation about vitamin B12 status in adults, including preg-
nant and lactating women in whom a high prevalence of
low plasma vitamin B12 values (19–41%) and of low
breast milk concentrations (62% of the population) were
found. The importance of these findings is due to the
potential impact on infant neurological development and
the relatively easy replacement provided by supplements
of the vitamin [88].
Imerslund-Najman-Grasbeck disease (IGS) is a rare
inherited disorder characterized by a megaloblastic
anaemia due to specific malabsorption of vitamin B12 by
ileal enterocytes. Less than 200 cases have been described
in the literature, including 36 new patients reported by a
group from Turkey [89]. Recurrent infections, pallor, gas-
trointestinal complaints or failure to thrive are presenting
symptoms at diagnosis [90, 91]. Some patients exhibit
neurologic symptoms and a rare pigmentary disorder
unresponsive to vitamin B12 therapy was also described
[92]. The diagnosis of the disorder is based on the associa-
tion of megaloblastic anemia, low serum vitamin B12 lev-
els and abnormal Schilling urinary excretion test results
with mild proteinuria [93]. Loss of urinary protein, a fre-
quent feature of this disease, was detected in 78% of the
pool of Turkish patients. Folate or intrinsic factor defi-
ciencies and anti-intrinsic factor antibodies are common-
ly found. In spite of its obscure pathogenesis, Gueant et al.
536 Digestion 1998;59:530–546
[94] suggested that the decreased intrinsic factor-receptor
activity in ileal mucosa constitutes an important patho-
genic mechanism. Moreover, these authors proposed the
measurement of urinary receptor activity by a radioiso-
tope assay as a useful tool for diagnosis. Finally, perma-
nent parenteral vitamin B12 therapy usually results in a
favorable outcome of the disease. However, efficacy of
oral treatment with megadose vitamin B12 was recently
showed in a patient treated by the Turkish group [95].
Juvenile megaloblastic anemia caused by selective in-
testinal malabsorption of vitamin B12 has been considered
a distinct condition displaying autosomal-recessive inher-
itance. Aminoff et al. [96] reported linkage studies assign-
ing a recessive-gene locus for the disease to chromosome
10 in previously diagnosed multiplex families from Fin-
land and Norway, proving the Mendelian mode of inheri-
tance. The locus was tentatively assigned to the 6-cM
interval between markers D10S548 and D10S466.
In spite of prolonged omeprazole therapy associated
with cobalamin deficiency due to protein-bound vitamin
B12 malabsorption having been previously described [97],
the first case of megaloblastic anemia secondary to vita-
min B12 deficiency was only recently reported by Bellou et
al. [98] in a patient taking 40–60 mg for 4 years. Omepra-
zol administration during 4 weeks was also related to a
higher incidence of gastric and duodenal bacterial over-
growth secondary to a decreased acid secretion when
compared to that observed in a group treated with cimeti-
dine (53 vs. 17%, respectively). However, these authors
were not able to find any signs of malabsorption following
administration of both drugs [99]. On the contrary, a
study including 10 healthy volunteers showed that ome-
prazol intake was associated with a significantly acute
decreased cyanocobalamin absorption after 2 weeks of 20
or 40 mg of omeprazole daily and that this effect was
dose-dependent [100].
Ileal damage secondary to radiation side effects was also
demonstrated as a cause of vitamin B12 malabsorption. A
group from the Netherlands reported low levels of vitamin
B12 in 10/44 (23%) women who had previously received
pelvic radiation for gynecological tumors [101]. Behrend et
al. studied the impact of ileorectal anastomosis on vitamin
B12 absorption in a cohort of 82 patients with Crohn’s dis-
ease. Absorption of vitamin B12, tested by the Schilling
test, was impaired in most Crohn’s disease patients. Sub-
jects with more than 60 cm of ileal resection all had vita-
min B12 malabsorption. Resections of less than 60 cm were
associated with a high risk of vitamin B12 malabsorption
[102]. Similar findings were observed in patients with
Crohn’s disease and no intestinal resection [103].
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 Bjarnason et al. [104] recently reported that 13 HIV-
seropositive male homosexuals exhibited a significant
reduction in absorption of cobalt-58 labelled cyanocobal-
amine when compared to healthy controls and this effect
was mainly shown in patients with AIDS diarrhea and
was independent of ileal morphologic changes. Addition-
ally, Lambl et al. [105], who studied 19 HIV-positive
patients with chronic diarrhea, demonstrated that asso-
ciation with either microsporidia or no identified patho-
gen increased the risk of developing severe vitamin B12
malabsorption. Finally, a recent Canadian study has
shown that vitamin B12 malabsorption can also be associ-
ated with either advanced disease or antiviral therapy
effects [106].
Diagnostic Procedures
Tests for Detecting Functional Abnormalities
Fat Malabsorption Studies
The quantitative determination of fecal fat has been
classically used as the method for documenting fat excre-
tion. In normal conditions, fecal fat content must not
exceed 7 g/day and it remains constant despite the fat
intake. In malabsorption states which compromise fat
absorption, fecal fat output increases generating the char-
acteristic features of steatorrhea. Fat excretion may be
normal in malabsorption conditions which compromise
other nutrients or in situations of small intestinal mucosal
damage where the functional reserve capacity produces
compensation of lacking functions. Several methods
(gravimetric, titrimetric, staining, radioisotopic, spectro-
photometric, nuclear magnetic resonance, etc.) have been
employed for determination of fecal fat. The titrimetric
method of Van de Kamer et al. [107] was considered the
gold standard for detecting fecal fat. However, the meth-
od is cumbersome and with a lot of practical difficulties
such as: is time-consuming for the patient requiring a 5- to
6-day high intake of dietary fats and a 3-day complete col-
lection of feces, and personnel adapted to fecal tests. On
the other hand, the method cannot detect sterols and
medium and short chain fatty acids. For these reasons, the
method is not routine practice in general hospitals nowa-
days. By contrast, a simple microscopic tests has gained
favor among specialists. The Sudan stain using a saturat-
ed Sudan III solution is a practical screening method
[108]. However, the main drawbacks of the test are its
poor reproducibility and very low degree of sensitivity for
mild to moderate steatorrhea [109]. The 14C-triolein and
Malabsorption Syndromes
13C-triglyceride breath tests have recently been employed
in the detection of fat malabsorption by impaired lypolisis
[110]. They were reported to have 100% sensitivity and
96% specificity, but radioisotopes or nonradioactive iso-
topes and facilities for their determination are not avail-
able in most laboratories and the results are very expen-
sive. Recently, near infrared spectrometry and NRM
spectrometry were shown to be very sensitive and specific
methods to determine the amount of fat in feces [111].
The steatocrit is a very interesting, simple, inexpensive,
rapid, semiquantitative micromethod that uses an aliquot
of homogeinized stool and centrifugation of the sample to
determine the percentage of fat in the specimen [109].
The method has been shown to be sensitive (87%) and
specific (97%). Since separation of different phases in
fecal homogenate (fat, liquid and nonfat solids) is pH-
dependent, fecal acidification was suggested as a tool for
improving the accuracy of the method [112].
Tests for Carbohydrate Malabsorption
Carbohydrate malabsorption occurs either as part of a
generalized malabsorption process or as a selective defect
localized in the epithelial cell. Both circumstances pro-
duce a characteristic voluminous, watery, acidic diarrhea
(pH ! 5.5) with increased concentration of organic an-
ions. When the malabsorption of carbohydrates is sus-
pected in a scenario of global malabsorption, its investiga-
tion loss importance. On the contrary, when evidence sug-
gests that symptoms are related to a specific moiety,
investigation of the causal factor is necessary. Established
methods for quantitative analysis of fecal carbohydrates
are rarely performed because they generate several prob-
lems. A recent study from Germany has shown that
near-infrared reflectance analysis of feces is a reliable and
accurate test for carbohydrate malabsorption [113]. Oral
tolerance tests are the most simple tool to detect specific
disacharidase deficiencies. Thus, lactase, sucrase-isomal-
tase and and trehalase deficiency were extensively ex-
plored using the tolerance tests for the respective sugars.
However, nowadays these tests have been replaced by
breath tests employing the putative substrate. These sub-
strates can be marked by radioisotopes (14C) or by nonra-
dioactive isotopes (13C). On the other hand, it has been
shown simpler, cheaper and accurate to detect the end-
expiratory hydrogen production after ingestion of sugars
(hydrogen breath tests). A study from Denmark suggests
that the status of methane production should be known
(simultaneous assessment of hydrogen and methane pro-
duction by intestinal flora) to interpret breath tests for
carbohydrate malabsorption [114]. A similar conclusion
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was obtained in an Italian study [115]. Direct assay of
mono- or disaccharides is not used in clinical practice.
The D-xylose test has been used widely to assess the
functional absorptive capacity of the proximal small in-
testine. The pentose is absorbed by facilitated diffusion
using a sodium-hexose cotransporter. The test is easy to
perform and the absorbed monosaccharide can be de-
tected either in plasma or urine. Both types of determina-
tions have similar sensitivity and specificity. In recent
years, the xylose test has been the subject of numerous
revisions which question its utility. The test has been
employed in the screening for celiac disease. In this sense,
sensitivity and specificity of celiac disease-related serolo-
gy have given better performance than the D-xylose test.
Tests for Protein Malabsorption and Protein Losing
Enteropathy
Hypoproteinemia and hypoalbuminemia may fre-
quently accompany malabsorption disorders. Protein
malabsorption is difficult to assess because tests are diffi-
cult to interpret and require balance studies. Protein los-
ing enteropathy can be the sole cause or an important con-
tributing factor for the development of low serum protein.
Gastrointestinal protein loss, in the past, was measured
using radioisotopic methods. However, the methods were
not widely expanded due to several methodological limi-
tations including the lack of a proper probe, use of
radioactive markers and cost, among others. ·1-Antitryp-
sin clearance, considered a sensitive marker of gastroin-
testinal leakage of plasma proteins, has been an aid in the
management of patients with celiac disease [116], Crohn’s
disease or pouchitis [117]. Methods for determination of
·1-antitrypsin include nephelometry and radial immu-
nodiffusion with a good correlation between both tech-
niques [118]. Recently, it was also reported that patients
with a variety of HIV-related conditions exhibited an
increased fecal protein excretion, regardless of current
opportunistic enteric infection [119, 120].
Intestinal Permeability Tests
Over the past 4 years much attention has been given to
the role of intestinal permeability in various enteropa-
thies. Thus, a great number of studies have been pub-
lished exploring the use of permeability tests assessing
various aspects of gastrointestinal diseases. Moreover,
intestinal permeability has been postulated to play an
important role in the pathogenesis of several intestinal
and systemic disorders.
Methodological Aspects. An accurate intestinal perme-
ability assessment requires great attention to technical
538 Digestion 1998;59:530–546
problems such as choice of the most proper probes, test
dose composition, storage of urine specimens, etc. Of the
main markers of intestinal permeability in current use,
sugar probes or 51Cr-EDTA were the most commonly
employed. Recently, a good correlation between both
types of probes was shown [121]; however, 51Cr-EDTA
tests require a complete 24-hour urine collection and its
radioactivity makes it unattractive for repeated use, espe-
cially in children [122]. With the purpose of canceling the
influence of premucosal and postmucosal factors on intes-
tinal permeability, a dual sugar test was proposed (disac-
charide/monosaccharide) [123]. The most frequent used
combinations are differential urinary excretion of lactu-
lose/mannitol, celobiose/mannitol or disacharides com-
bined with rhamnose or raffinose. Recently, sucrose, a
very commonly used hexose, has been demonstrated to be
a suitable tool and very sensitive marker of upper gas-
trointestinal permeability [124]. It has been employed in
the detection of the NSAID-induced gastric damage
[125]. More recently, a very high sensitivity of the sucrose
test has been observed in patients with celiac disease
[126].
Localization of Intestinal Permeability Defects. Several
attempts have been developed to better define the precise
localization of intestinal permeability changes. Thus, the
jejunal and ileal contribution to intestinal permeability
derangement is insufficiently discriminated by the uri-
nary excretion of 51Cr-EDTA. Furthermore, the same
probe did not discriminate between small bowel or co-
lonic site of mucosal damage [127]. Recently, Teahon et
al. [128] were able to segregate the localization of the per-
meability defect using the ingestion of three different
markers. These authors used 51Cr-EDTA together with
3-O-methyl-D-glucose (as a marker of jejunal defect),
cobalt-57-labelled vitamin B12 (as an indicator of ileal
impairment) and sulfasalazine (colonic indicator) which
allowed a more precise differentiation of mucosal affec-
tion [128]. Sugar tests were also explored for localizing
intestinal permeability changes. As was previously men-
tioned, Meddings et al. [124] demonstrated that sucrose
may detect upper gastrointestinal permeability defects.
More recently, the same Canadian group has demon-
strated that sucralose, an artificial trichlorinated analogue
of sucrose that is not degraded by small intestinal en-
zymes or bacterial flora, is a good marker of colonic per-
meability impairment [129]. Thus, the addition of sucra-
lose to a solution of sucrose and lactulose/mannitol gives a
reliable panorama of the entire gastrointestinal tract [130,
131].
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 Uses of Intestinal Permeability Tests. Most studies
published on the clinical utility of permeability tests were
performed based on the screening capacity of diseases
such as celiac sprue [132–134]. In general, tests are based
on the fact that the mucosal damage such as that observed
in celiac disease is characterized by an increased perme-
ability for disaccharidases (cellobiose, lactulose) [135–
139], 51Cr-EDTA [140, 141] and oligosaccharides [142]
and a reduced permeability for small monosaccharides
such as mannitol [136, 139, 141], rhamnose [143] and raf-
finose. While the first reflects epithelial damage, the sec-
ond group expresses reduction in mucosal surface area.
Since celiac disease affects predominantly the jejunum
and also exhibits a well-recognized loss of disaccharidase
activity, it has been proposed recently that sucrose, a nov-
el marker to detect gastric damage [144, 145] can also be a
sensitive marker for untreated celiac disease [126]. In this
regard, with strict adherence to a gluten-free diet, sucrose
permeability has been shown to fall dramatically within
2 months [126]. A previous study suggested that increased
sucrose permeability in celiac disease could be a conse-
quence of gastric damage [146]. The authors based their
conclusions on the fact that urinary sucrose excretion par-
allels intraepithelial lymphocyte infiltration of gastric mu-
cosa. These conclusions were rejected by Cox et al. [147]
and by those results reported by Smecuol et al. [126].
Patients with Crohn’s disease frequently exhibit abnor-
mal intestinal permeability. However, conflicting results
have been reported considering permeability changes as
an objective marker of disease activity. Thus, correlation
between abnormal permeability and disease activity was
variably dependent on the study considered [148]. Inter-
estingly, some evidence has suggested that clinical re-
lapses might be preceded by a significant change in intes-
tinal permeability with increased permeation to offensive
agents [149]. Although increased permeability has been
implicated in the etiology and pathogenesis of Crohn’s
disease, up to now, there is no conclusive proof of this
hypothesis. In fact, it remains unknown whether in-
creased permeability is a primary defect or a consequence
of intestinal inflammation. Preliminary reports by Hol-
lander et al. [150] have demonstrated an increased perme-
ability of PEG 400 in first-degree relatives of patients.
This evidence raises the possibility of a genetically trans-
mitted abnormal permeability. Since this report, some
studies have provided conflicting results [151, 152]. Re-
cently, May et al. [152] were able to identify a subgroup of
individuals among first-degree relatives (approximately
10% of them) with an increased intestinal permeability
and therefore, at higher risk for development of the dis-
Malabsorption Syndromes
ease themselves [152]. The detection of this abnormality
has been demonstrated to be enhanced by agents that
damage the intestinal epithelium such as acetylsalicylic
acid [153]. Finally, permeability tests have been consid-
ered a useful tool in order to denote efficacy of different
therapeutical approach [154, 155].
Detection of Bile Acid Malabsorption
Until few years ago, direct measurement of fecal bile
acids or fecal excretion of 14C-labelled conjugated bile
acids were the most sensitive and reliable functional tests
for bile acid malabsorption. However, they are labori-
ous, need complete fecal recollection and might be diffi-
cult in patients with diarrhea. Over the last 10 years,
measurement of selenium-75-homocholic acid taurine
(75SeHCAT) has been widely employed as a useful and
appropriate tool to detect bile acid malabsorption and to
monitor response to bile acid chelators (cholestyramine or
aluminum hydroxide) in patients with various organic
and functional bowel disorders [156–158]. 75SeHCAT, a
synthetic analogue of the natural conjugated bile acid tau-
rocholic acid, is considered a good marker of active
absorption of bile salts from the terminal ileum and has
the advantage of being resistant to bacterial deconjuga-
tion when compared to the previously used 14C-glycocho-
late and 14C-taurocholate. However, interpretation of the
results may be influenced by liver disease. Furthermore,
since SeHCAT has a relatively long half-life (180 days), its
wider use should be limited. In this sense, synthesis of
gamma-emitting bile acid SeHCAT analogues with a
shorter half-life [159] and reduction of the administered
dose have been attempted [160], but their results need
further support.
Attempts were performed in order to identify a meth-
od to evaluate bile acid malabsorption that does not
employ radioactive substances. Since an increased pro-
duction of bile acids can be expected in patients with sig-
nificant bile acid loss, different tests which measure the
rate of bile acid synthesis have been introduced into clini-
cal practice. Thus, recent studies have shown that plasma
7·-hydroxy-4-cholesten-3-one [161, 162] and lathosterol
[163] concentrations reflect the cholesterol 7·-hydroxy-
lase activity and bile acid production in the liver. These
studies showed a close relation between intestinal loss and
hepatic synthesis of bile acids in patients with bile acid
diarrhea. Both determinations exhibited a good perfor-
mance by comparison with the 75SeHCAT whole body
retention. This implies that these methods can be used as
convenient alternative to the most sophisticated tests.
Perhaps the most obvious advantages of the procedures
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are that they are easily performed with no radioactive
exposure.
Detection of Vitamin B12 Malabsorption
Malabsorption of vitamin B12 has been employed as a
useful method to evaluate ileal function. Measurement of
vitamin B12 excretion in dual-isotope Schilling test urine
samples is considered an accurate and useful tool in evalu-
ating vitamin B12 malabsorption. However, a recent
American multicenter study pointed out that a correct
interpretation of results is related to the quality of the clin-
ical laboratory [164]. On the other hand, since the conven-
tional Schilling test is based mainly on the absorption of
free, crystalline cobalamin, conditions such as food cobal-
amin malabsorption, in which the pathogenic mechanism
implies the inability to release cobalamin from food, are
not easily detected by this method. Thus, new tests using
cobalamin bound to protein such as eggs or to chicken
serum have been developed to gain accuracy in this com-
mon cause of cobalamin deficiency [165, 166]. In addi-
tion, another interesting modified Schilling test was re-
ported by Aimone-Gastin et al. [167], who succesfully
performed a labelled trout flesh absorption test. Measure-
ment of serum metabolite concentrations were also pro-
posed as a sensitive index of significant cobalamin defi-
ciency and its usefulness in indicating recovery after
cobalamin administration was demonstrated. Thus, 26/
35 (75%) elderly patients with low serum cobalamin levels
exhibited increased serum methylmalonic acid and/or
total homocysteine concentrations [168]. However, there
has been recent concern that the specificity of testing
serum metabolites is low. Thus, Lindgred et al. [169]
showed increased serum levels of both metabolites in
patients in whom results from the Schilling test were abso-
lutely normal and in whom no morphological basis for
cobalamin malabsorption was detected.
Tests for Detection of Abnormalities in the
Luminal Phase
Those abnormalities of the luminal phase of the diges-
tive process causing malabsorption can be explored using
a variety of tests addressing mainly detection of pancreat-
ic exocrine function and small bowel bacterial over-
growth.
Investigation of Pancreatic Insufficiency
Pancreatic abnormalities can be suspected by radio-
graphic plain films (e.g. presence of calcifications of the
540 Digestion 1998;59:530–546
pancreas). Alternative imaging studies are very useful and
more effective clues for pancreatic insufficiency (abdomi-
nal ultrasound, CT scanning, endoscopic ultrasonogra-
phy, ERCP). The quantitative pancreatic stimulation
tests are the ‘gold standards’ for assessing exocrine pan-
creatic function. They require intubation, collection of
duodenal contents, stimulation of pancreatic secretion
(using either secretin, pancreozymin, both hormones at
the same time or a test meal). The tests are cumbersome,
invasive, time consuming and expensive and are rarely
performed in clinical practice.
In order to avoid the problems of the intubation stud-
ies, some oral ‘tubeless’ tests were developed. Thus, the
bentiromide test (PABA) and the pancreolauril test were
incorporated. Both tests are based on the effect of pan-
creatic proteolytic enzymes on oral substrates and the
detection of metabolites in urine, plasma or breath. These
tests are highly sensitive and specific for detection of
moderate to severe pancreatic insufficiency. Both tests are
of limited value in the detection of mild pancreatic
impairment and once again, both require a laboratory
complexity that limits their use in clinical practice. Fecal
chymotrypsin levels in random samples of stool has been
considered a sensible marker of exocrine pancreatic func-
tion [170]. However, the sensitivity for mild to moderate
insufficiency has been questioned [171]. Fecal elastase 1
is a very interesting protease produced by the pancreas
with no intraluminal metabolism. An ELISA assay has
allowed its detection in random samples of stool [172].
Recent studies have concluded that fecal elastase concen-
tration was a reliable functional test which appeared more
sensitive and as specific as fecal chymotrypsin concentra-
tion [173]. Some data suggest that the specificity of both
tests is affected because some patients with nonpancreatic
steatorrhea (celiac disease) exhibit very low fecal enzyme
concentrations [174]. Whether these abnormal determi-
nations are a consequence of the presence of pancreatic
insufficiency in celiac disease patients or a result of other
factors still remains to be elucidated.
Investigation of Small Bowel Bacterial Overgrowth
The ‘gold standard’ test for bacterial overgrowth is the
direct quantitative bacterial count and/or culture of jeju-
nal aspirate. The test is invasive, requires trained person-
nel and radiation exposure, has many technical problems
and, nowadays, is only reserved for investigative pur-
poses. Several indirect tests were proposed based on the
noninvasive detection of metabolites produced by bacte-
ria on luminal substrates. Unfortunately, no single test is
ideal for detection of bacterial overgrowth. The most
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commonly employed indirect tests have been based on
the detection of metabolites in the expired air. Thus,
almost 30 years ago breath tests were incorporated (most
used substrates were: 14C-glycocolic acid, 14C-D-xylose,
13C-xylose) exhibiting variable sensitivity and specificity
[175]. More recently, other alternative substrates were
based on the production of H2 after glucose or lactulose
ingestion [176]. The overall sensitivity of these tests varies
from 60% to 95% and specificity approaches to 90%.
Detection of increased serum levels of unconjugated bile
salts has been evaluated but, up to now, no advantages
have been demonstrated.
Morphological Assessment of the Small Intestine
Functional tests are useful in the assessment of malab-
sorption, however, a specific diagnosis is provided in very
few conditions. On the contrary, morphological studies
are required in most cases. Anatomical characteristics
(macro- and microscopic) are explored by radiology, en-
doscopy and histology. Due to the limited scope of this
review, we will explore those recent advances provided by
the radiologic and endoscopic assessment of the small
intestine. We encourage to readers to explore very impor-
tant updates recently published on the mucosal biopsy of
the small intestine.
Small Bowel Radiology
The main aims of radiological assessment of the small
intestine are to evaluate: (1) the general structure of the
organ; (2) mucosal alterations; (3) submucosal abnormali-
ties. Additionally, barium studies can define whether the
disorder is diffuse or segmental (patchy) and the presence
of anatomical abnormalities such as strictures, diverticu-
la, etc. Classical findings in malabsorption (flocculation,
segmentation, dilation of intestinal loops) have very low
sensitivity. Disorder with extensive compromise of the
small bowel can be evaluated by a fluoroscopy based small
bowel follow-through study. Thus, Barlow et al. have
recently shown that 86% of celiac disease patients can be
detected by an abnormal fold pattern consisting of a
decreased number of jejunal folds and an increased num-
ber of ileal folds (jejunoileal fold pattern reversal) [177].
However, these findings are highly controversial, espe-
cially taking into consideration that endoscopic biopsy is
mandatory and the procedure is highly available and spe-
cific with notable advantages. The small bowel follow-
through has severe limitation when the organ is explored
aiming to detect tumors, exploring unexplained gastroin-
testinal bleeding, segmental lesions, obstructions, etc. It is
in this type of patient where the enteroclisis and the dou-
Malabsorption Syndromes
ble-contrast technique (with gas or methylcellulose) have
special relevance in improving clinical yield of small bow-
el radiology [178]. Celiac disease patients require small
bowel barium studies when a complication is suspected
(malignancies, ulcerative jejunoileitis, unresponsive to
common measures, etc.). A micronodular mucosal pat-
tern can be observed in some diffuse disorders (Whipple’s
disease, macroglobulinemia, lymphangiectasia, amiloido-
sis, etc.) [178].
Endoscopy
The endoscopic examination of the small intestine has
been facilitated by the incorporation of longer instru-
ments (enteroscopes). However, these types of endoscope
are not available in most gastroenterology units. Further-
more, the procedure is invasive and most indications are
reserved for unexplained occult bleeding. Malabsorption
due to diffuse small bowel disorders also involves invaria-
bly the duodenum. Therefore, the exploration of distal
duodenun, by the most common duodenoscopy, provides
invaluable information in order to detect mucosal abnor-
malities and subsequently to obtain intestinal biopsies.
Celiac disease is the paradigm of a diffuse disorder of the
small intestine and has been a good example of how the
diagnosis can be simplified. Ten years ago, two studies
have described different endoscopic markers of sprue in
the distal duodenum. While a reduction in the number or
the absence of duodenal folds was described by Brocchi et
al. [179], the presence of scalloped folds and the mosaic
appearance of the mucosa were reported by Jabbari et al.
[180]. Furthermore, a more recent study from our labora-
tory has shown that these markers can be observed in
celiac patients with a sensitivity of 94% and a specificity
of 92% [181]. More recently, videoendoscopy has become
the standard procedure in most academic institutions.
Several studies on the prevalence of celiac disease have
shown that, nowadays, most newly-diagnosed cases are
patients with an asymptomatic or subclinical course. In
this type of patient, endoscopy of the duodenum acquires
special relevance given that they frequently undergo up-
per GI endoscopy in order to investigate nonspecific
symptoms. For clinical practice, we believe that endosco-
pists must be aware of the duodenoscopic features of
celiac disease and that this will help to ensure that most
sprue patients referred for endoscopy could be detected
and, therefore, referred for biopsy. Therefore, given the
most recent figures on the prevalence of celiac disease in
the general population, it seems very possible that endos-
copists may frequently be faced with patients referred for
upper GI endoscopy for nonspecific symptoms who will
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exhibit duodenoscopic signs indicative of mucosal atro-
phy. Therefore, much effort needs to be addressed toward
the education of endoscopists to improve diagnostic yield
and reduce disagreement in endoscopic descriptions
[182].
Practical Approach for the Assessment of Patients with
Malabsorption
Several diseases involving any of the three-stage pro-
cess of digestion-absorption can result in chronic diarrhea
and malabsorption. Our goal in evaluating a patient with
suspected malabsorption is to make a definitive diagnosis
as quickly and inexpensively as possible. This clinical
exercise deals with both diarrhea and malabsorption.
There is a key step in evaluating the patient a detailed and
complete history and careful physical examination. This
step must also include routine screening laboratory tests.
After that, malabsorption can be suspected and other
steps can be taken. Physical examination must invariably
include stool inspection by the physician and, if possible,
an approximate idea of 24-hour stool weight. There is a
general consensus that, if this step is appropriately evalu-
ated, an expert physician can correctly diagnose 70–80%
of malabsorption syndromes. If evaluation strongly sug-
gests a functional disorder (e.g. diarrhea), further studies
can be stopped and symptomatic treatment can to be
started. If symptomatic treatment is ineffective or deteri-
oration is progressive, more studies can be done.
If the exhaustive interview and physical data highly
suggest celiac disease, a diagnosis which is the most com-
mon malabsorption disorder (prevalence h1:200) in west-
ern countries, one must proceed to duodenoscopy and
small intestinal biopsy directly. If this evidence is not so
strong (chronic anemia, other autoimmune disorders,
short stature, relatives of celiac disease patients without
overt malabsorption, etc.) but suspicion still persists, a
screening test (serology) must be performed in order to
reduce the number of biopsy procedures. Less than 40%
of untreated celiac disease patients present with overt
malabsorption. This algorithm provides the most cost-
effective approach to this disorder.
When malabsorption is suspected, the next step re-
quires assessment of stools. The physical and chemical
examination of stools must include: evaluation of stool
weight and detection of steatorrhea. Some evidence sug-
gests that the assessment of plasma protein loss, although
nonspecific, could be of some additional value diagnosing
enteropathy. Most patients present with chronic diarrhea,
542 Digestion 1998;59:530–546
however, steatorrhea is less frequent. If the stool assess-
ment show normal fecal fat excretion, there may be two
different circumstances: (1) concomitant presence of in-
creased ·1-antitrypsin clearance or abnormal permeabili-
ty tests; (2) no other abnormalities. In the first setting, a
segmentary enteropathy can be suspected which would
eventually require a radiological examination, enterosco-
py, biopsy or laparotomy. In the event of chronic diar-
rhea, normal fecal fat and normal permeability, malab-
sorption of carbohydrates or bile salts must be explored. If
chronic diarrhea is associated with steatorrhea (in rare cir-
cumstances steatorrhea can be present without diarrhea),
once again plasma protein loss or permeability tests can
be very helpful. Two different possibilities can be consid-
ered: (1) if permeability tests are positive an enteropathy
(segmentary or diffuse) must be considered, and (2) on the
contrary, if there is steatorrhea but normal permeability
test is evident, an abnormal intraluminal digestive pro-
cess can be suspected. In the first circumstance the most
indicated diagnostic tests are the radiological exploration
of the small intestine, the duodenoscopic or enteroscopic
investigation with intestinal biopsy. The evaluation can
be completed with investigation of an infective cause
(parasites or bacterial infection). In the last fifteen years,
HIV infection has increased, and become part of the dif-
ferential diagnosis of enteropathy. If an intraluminal phe-
nomenon is suspected, the most adequate diagnostic tests
are: breath tests or culture of jejunal aspirates for bacterial
overgrowth (the response to antibiotic is a valid alterna-
tive when the suspicion of this entity is present and form-
er tests are not available); tests for pancreatic function
(tubeless tests; up to now, the quantification of fecal elas-
tase1 seems to be the most adequate); and the morpholog-
ical assessment of the pancreas (ultrasound, CT scan and/
or ERCP). Once again, if functional tests are not available
the response to pancreatic enzyme supplementation is a
valid alternative for detecting the pancreatic etiology of
malabsorption.
Acknowledgments
The author thanks the following medical staff for their collabora-
tion: Edgardo Smecuol, Horacio Vazquez, Sonia Niveloni, Silvia
Pedreira, Roberto Mazure and Eduardo Mauriño. The author also
thanks to Prof. Christina Surawicz, from the University of Washing-
ton, for helpful discussion and comments on the manuscript.
Bai
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