Question 1: In daily clinical usage the terms maldigestion, malabsorption, and malassimilation
are not always clearly separated. What are the exact definitions as a basis for understanding
as well as regarding reasonable differential diagnostics?
Dietrich: Malassimilation is the umbrella term for a deficit of nutrients and includes
maldigestion (failure of enzymatic intraluminal extraction of chyme) and malabsorption
(failure of taking up the extracted nutrients by the intestinal epithelium).
Question 2: You see a patient for the first time. In your opinion, which symptoms
and clinical signs are potentially indicating malabsorption? In this situation, which
basic laboratory findings do you deem necessary in order to confirm your suspicion
of malabsorption?
Al-Taie: Patients suffering from malabsorption can present with a broad spectrum of
often non-specific symptoms such as bloating, flatulence, and diarrhea or fatty stools.
In addition, weight loss, fatigue, ataxia, tetany, skeletal pain, and amenorrhea can
also be caused by malabsorption.
In cases of mild malabsorption, no specific signs can be detected on examination.
However, kachexia, hypoproteinamic edema, paleness, nail and hair dystrophy and ecchymosis,
disturbances of deep sensibility, and osteoporotic fractures can indicate severe global
or specific malabsorption.
Basic laboratory tests to confirm malabsorption include different blood tests such
as complete blood count, iron, ferritin, C-reactive protein, ALT, AST, albumin, creatinine,
cholesterol, calcium and potassium, and international normalized ratio (INR). Depending
on the suspected underlying disease, extended laboratory examinations comprise serum
25-hydroxyvitamin D, vitamin B12, folic acid, tissue transglutaminase antibodies,
serum electrophoresis, gastrin, vasoactive intestinal polypeptide (VIP), fecal elastase,
and fecal calprotectin.
Dietrich: Malabsorption is marked by unspecific symptoms such as diarrhea, underweight,
paleness, and wasting of muscles, in severe cases also by the presence of ascites.
Determination of albumin, total protein, prothrombin time, cholesterol, electrolytes,
and ferritin may contribute to a confirmation of this clinical impression.
Schütte: The spectrum of symptoms seen in global malabsorption is broad. Weight loss
despite adequate food intake, diarrhea with voluminous and foul-smelling stools, and
edema secondary to hypoalbuminemia are the classic clinical signs. While some patients
may even be asymptomatic, the majority present with rather mild gastrointestinal symptoms
like abdominal distension and flatulence. Malabsorption of specific nutrients results
in more specific symptoms, e.g. vitamin B12 deficiency resulting in polyneuropathy
or pernicious anemia.
A diagnosis of malabsorption cannot be established on the basis of blood tests alone.
A diligent medical history frequently leads to the suspicion of malabsorption followed
by a further work-up. Laboratory tests including assessments of differential blood
count and of concentrations of protein, albumin, folate, vitamin B12, ferritin, total
iron-binding capacity, coagulation status, calcium, vitamin D, and alkaline phosphatase
(AP) are a good start. Further diagnostic tests should be chosen dependent on the
individual patient and his signs and symptoms with tests for fat malabsorption (e.g.
fecal fat determination) and carbohydrate malabsorption (e.g. D-xylose test and specific
breath tests (amongst others lactose, fructose, sorbitol)) in addition to ultrasound
with the assessment of the small bowel, esophagogastroduodenoscopy with duodenal biopsies,
and ileocolonoscopy with biopsies being important parts of the diagnostic cascade.
Schumann: I feel that zinc is a good additional marker for measuring small intestinal
absorption. If its level is found to be reduced, it is also worthwhile to substitute
zinc, since a number of complications the patient experiences in daily life might
improve with a normalization of zinc levels (i.e. dermatitis, glossitis, hair loss,
nail dystrophy, recurrent infectious complications). Similarly, magnesium might be
helpful [1].
Question 3: Disturbances of biliary secretion may cause malabsorption. For clinical
practice, which hepatobiliary disorders have to be evaluated in differential diagnosis?
Which diagnostic procedures do you recommend? What are the therapeutic options?
Dietrich: Cholestasis, regardless of its origin (intrahepatic or posthepatic), leads
to a lack of micelles in the small intestine [2]. Since the presence of micelles is
a prerequisite for absorption of lipophilic compounds in the intestinal lumen, this
condition leads to malabsorption of these compounds, especially of the fat-soluble
vitamins A, D, E, and K. In general, the presence of any liver disease can be diagnosed
by the simple determination of the classic liver enzymes GOT (AST), GPT (ALT), gamma-glutamyl
transferase (γ-GT), and AP, and bilirubin [3]. In rare cases of cirrhosis, these values
are normal despite the presence of a liver disease and require further investigations
(e.g. ultrasound, serum protein electrophoresis).
If cholestasis is present, it must be characterized as intrahepatic (cellular) or
posthepatic (obstructive). While in obstructive cholestasis due to stones or tumors
endoscopic retrograde cholangiopancreatography (ERCP) is warranted, treatment of ursodeoxycholic
acid can be helpful in intrahepatic cholestasis without cirrhosis, depending on the
diagnosis (primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC),
autoimmune cholangitis (AIC), or other diseases)). In the short term, the lack of
vitamin K is most important because it rapidly leads to impaired coagulation. To differentiate
between malabsorption and reduced liver function as a cause for clotting disturbances,
intravenous administration of vitamin K followed by the determination of prothrombin
time on the next day (Koller's test) is a useful test [4].
Question 4: Untreated celiac disease (CD) is a comparably common cause of malabsorption.
If in a patient with CD responding primarily to a gluten-free diet (GFD) signs of
malabsorption reoccur, refractory CD (RCD) has to be considered. What is the diagnostic
approach after having excluded dietary errors?
Dietrich: A new gastroscopy with duodenal biopsies should prove persistent duodenal
atrophy and exclude lymphoma. Duodenal atrophy can also be pretended by for example
collagenous sprue [5], so that differential diagnoses have to be carefully excluded
again.
Felber: Until the 20th century, CD was considered a relatively rare condition that
usually presented in childhood with symptoms of intestinal malabsorption, i.e. abdominal
distension steatorrhea, weight loss, and/or failure to thrive. Nowadays, CD is much
more common in the Western World (prevalence 1:300 in Germany), and patients with
symptoms of malabsorption constitute only the tip of the iceberg. Very often adult
CD patients present with ‘non-classical’ symptoms in their fourth or fifth decade
in life. These patients with asymptomatic or oligosymptomatic CD often present with
irritable bowel syndrome-type symptoms, abdominal discomfort, altered bowel habits,
and anemia (most commonly as iron deficiency anemia). Nevertheless, the withdrawal
of gluten from the diet leads also in these patients with ‘non-classical’ CD to a
normalization of the intestinal mucosa and the disappearance of symptoms.
If symptoms reoccur, non-compliance to a GFD must be excluded vigorously. If known
or unknown diet failures are excluded, microscopic colitis, including collagenous
and lymphocytic colitis, irritable bowel syndrome, bacterial overgrowth, lactose intolerance,
and most importantly RCD, enteropathy-associated T cell lymphoma (EATL), and ulcerative
jejunitis (UJ) must be suspected.
With a cumulative incidence of 1.5% of CD patients, RCD belongs to the family of rare
or orphan diseases. If RCD is suspected, a sequence of tests is required to rule out
or confirm the diagnosis. If RCD is confirmed, it is important to distinguish between
type I and type II RCD as prognosis and treatment differ greatly. Apart from blood
tests (ferritin, complete blood count, lactate dehydrogenase (LDH), beta-2-microglobulin,
albumin), distal duodenal biopsies have to be obtained and histological (presence
of villous atrophy; at least Marsh III), immunohistological (CD8, T cell receptor-β),
and molecular pathological (analysis of T cell receptor clonality) tests have to be
performed. Cross-sectional imaging of the abdomen is mandatory to rule out lymphadenopathy,
thickening of the small bowel wall, or atrophy of the spleen. In the case of significant
findings, a small bowel enteroscopy is required to confirm the presence of ulcerations
and to take biopsies for the confirmation of RCD, EATL, or UJ. Type II RCD is defined
by the presence of >20% aberrant intraepithelial lymphocytes (IEL; CD3- and CD8-negative)
in FACS (fluorescence-activated cell sorting) analysis and coexistence of T cell receptor
clonality. No FACS analysis is required if >50% of the IELs are CD3-and CD8-negative
in immunohistological studies.
Schütte: Small intestinal villous atrophy should be confirmed by endoscopy. Other
causes of villous atrophy (amongst others autoimmune enteropathy, tropical sprue,
Crohn's disease, combined variable immunodefiency, and eosinophilic enteritis) should
be evaluated in differential diagnosis, and EATL needs to be ruled out. Biopsies should
be taken and analyzed for abnormal intestinal lymphocytes, including immunohistochemistry
and quantification of CD3- and CD8-positive cells.
Schumann: At least 7% of CD patients do not – either primarily or secondarily – respond
to a GFD. After dietary errors have been excluded (most of the cases! Done best by
a professional nutritionist with experience in GFD), diagnostic tests have to be applied
to exclude an additional diagnosis that might be responsible for the malabsorption
syndrome (in a reasonable context of the patient's history, Crohn's disease, Whipple's
disease, giardiasis, intestinal tuberculosis, AIDS enteropathy, eosinophilic enteritis,
autoimmune enteropathy, and radiation-associated enteritis should be considered).
If no additional diagnosis is found, RCD must be taken into account and multiple (six)
duodenal biopsies are collected during an esophagogastroduodenoscopy, which should
show Marsh III enteropathy (i.e. villous atrophy and crypt hyperplasia) to establish
RCD diagnosis. Further work-up on the histology specimen is done by the pathologist
for RCD subtyping (i.e., if type I or type II is present), including a CD8/CD3 immunohistochemistry
(percentage of CD8-negative intraepithelial lymphocytes) and a molecular pathology
analysis (e.g. a Genescan analysis of the variable region of the T cell receptor to
look for T cell monoclonality in the small intestinal sample). RCD type II, which
is the subtype that frequently turns into an EATL, has to be considered if the CD8
portion of T cells is <50% and a monoclonality is found in the Molpath analysis. Furthermore,
additional imaging is needed. An abdominal magnetic resonance imaging (MRI) with a
specific focus on the small intestine (either done as a magnetic resonance enteroclysis
or MRI of the small intestine) can be done to identify small intestinal wall abnormalities
or irregularities of small intestinal folding and will also identify enlarged abdominal
lymph nodes. Capsule endoscopy might identify UJ, which is frequently a substrate
of RCD type II, or – if the disease has progressed – EATL. If alterations are found
in the jejunum that might be compatible with lymphoma, a single-balloon enteroscopy
can be performed to collect biopsies. As the diagnostic work-up with the histology
samples as well as the imaging work-up is best performed in centers that offer specific
expertise on RCD, the guidelines have recommended to consider transferring an RCD
patient to a center with experience in this entity [6,7,8].
Question 5: A patient with short bowel syndrome requires total parenteral nutrition.
What is the ideal management of parenteral nutrition? What does the patient need and
what is an adequate follow-up?
Dietrich: We use so-called ‘mix-bags’ with amino acids and 40% glucose for daily treatment
given via central venous line. Lipids and lipophilic vitamins can be given every other
day or three times per week. Additional micronutrients are added on clinical grounds.
Recommendations for laboratory monitoring vary; we use a panel of blood count, electrolytes,
vitamins etc. in intervals depending on the stability of the patient.
Question 6: Do intestinal infections need to be considered as a potential source of
malabsorption?
Dietrich: To my knowledge (and that of established textbooks), bacterial overgrowth,
tropical sprue, Whipple's disease, infections with Giardia lamblia, and cryptosporidiosis
can lead to malabsorption (though seldom in a severe form).
Felber: Yes, indeed; gastrointestinal infections, such as chronic G. lamblia infection
or the rare Whipple's disease caused by Tropheryma whipplei, are reasons for severe
malabsorption. Whipple's disease is characterized by arthralgia, weight loss, diarrhea,
and abdominal pain. Patients may present with neurological symptoms (e.g. cognitive
dysfunction, supranuclear ophthalmoplegia, nystagmus, myoclonus) and cardiological
complaints (e.g. dyspnoe, pericarditis, sterile endocarditis). Arthralgia may precede
the diagnosis by a number of years. Other causes are intestinal infections with Cryptosporidium
parvum, Isospora belli, Cyclospora cayetanensis, and the microsporidia.
Participants
PD Dr. Oliver Al-Taie
Medizinische Klinik
Sankt Elisabeth Hospital Gütersloh
Stadtring Kattenstroth 130, 33332 Gütersloh, Germany
oliver.al-taie@sankt-elisabeth-hospital.de
PD Dr. Christoph Dietrich
Klinik für Innere Medizin
Bethlehem Gesundheitszentrum Stolberg gGmbH
Akademisches Lehrkrankenhaus der Rheinisch-Westfälischen
Technischen Hochschule Aachen
Steinfeldstraße 5, 52222 Stolberg, Germany
dietrich@bethlehem.de
Dr. med. Jörg Felber
Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie,
Infektiologie)
Universitätsklinikum Jena
Bachstraße 18, 07743 Jena, Germany
joerg.felber@med.uni-jena.de
Dr. med. Kerstin Schütte
Klinik für Gastroenterologie, Hepatologie und Infektiologie
Universitätsklinikum Magdeburg A.ö.R.
Leipziger Straße 44, 39120 Magdeburg, Germany
kerstin.schuette@med.ovgu.de
Dr. med. Michael Schumann
Medizinische Klinik für Gastroenterologie, Infektiologie und
Rheumatologie
Campus Benjamin Franklin, Charité – Universitätsmedizin Berlin
Hindenburgdamm 30, 12200 Berlin, Germany
michael.schumann@charite.de