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Israel Journal of Veterinary Medicine  Vol. 70 (3)  September 2015 17 Protein Losing Enteropathies
Canine Protein Losing Enteropathies
Willard, M.
Texas A&M University, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas, USA.
*
Corresponding Author: Dr. Michael Willard, DVM, DACVIM. College of Veterinary Medicine, Department of Small Animal Clinical Sciences, TAMU-
4474, Texas A&M University, College Station, TX 77843-4474, USA. Email: mwillard@cvm.tamu.edu
ABSTRACT
Protein-losing enteropathies are traditionally thought of as being diseases with a very poor prognosis. While
this is often true, there are subsets of these patients which, if diagnosed in a timely fashion, may often have a
relatively good prognosis. Lymphangiectasia in particular is a disease that is often misdiagnosed or diagnosed
so late that it is no longer treatable. Clinicians should actively seek for evidence of lymphangiectasia in dogs
with protein-losing enteropathies as this can be a disease that they may be able to control for years, at least
in some cases.
Keywords: Canine; Lymphangiectasia; Hypoalbuminemia; Diagnosis
REVIEW
While relatively uncommon in human medicine, protein-
losing enteropathies (PLE) are actually relatively common in
dogs (1). Historically, they have tended to be associated with
severe diseases, and were considered to have a poor prognosis.
(2) However, new data suggests that there is a subset of these
animals that can actually respond reasonably well to therapy
and consequently enjoy a near normal life.
Anytime the clinician is confronted with a hypoprotein-
emic dog, the frst step is to measure the serum albumin con-
centration as opposed to being satisfed with the serum total
protein concentration. It is important not to use a human
clinical pathology laboratory for this measurement as their
technology may or may not detect canine albumin. Normal
dogs can have measured serum albumin concentrations of 1.5
gm/dl because of methodological problems with the human
technology when trying to measure canine albumin. In ad-
dition, serum albumin is a bit of a “delicate” test to run. It is
clearly best to have the same veterinary laboratory measure
the serum albumin each time so that one can accurately
compare values run on diferent days.
Panhypoproteinemia is not a very reliable indicator
of PLE. Dogs with PLE that initially were hyperglobulinemic
may lose over half of their plasma proteins and consequently
have normal serum globulin concentrations. Conversely,
occasional panhypoproteinemic dogs have hepatic disease
or glomerular disease as the major source of protein loss,
for reasons which are not clear. Terefore, the work up for
hypoalbuminemic dogs is the same regardless of whether or
not they are panhypoproteinemic.
For the patient with a serum albumin < 2 gm/dl, the
frst step is to examine the skin for obvious lesions which
could cause protein loss. Cutaneous lesions sufcient to cause
such hypoalbuminemia should be very obvious. Te clinician
should be able to simply examine the patient and quickly
ascertain whether or not the skin is the reason for the hypo-
albuminemia. Following this, hepatic function testing (e.g.,
resting and post-prandial serum bile acid concentrations) and
a urinalysis are indicated. If there is any doubt concerning
the urinalysis results, then a urine protein:creatinine ratio
will quantify the magnitude of urinary protein loss. Severe
hypoalbuminemia (i.e., < 2 gm/dl) in a dog with diarrhea
suggests a PLE; however, diarrhea (even severe diarrhea)
can be due to primary hepatic disease. Many dogs and cats
with PLE do not have vomiting or diarrhea, and some dogs
with PLE present with only ascites. In fact, some dogs with
Israel Journal of Veterinary Medicine  Vol. 70 (3)  September 2015 Willard, M. 18
PLE will be fortuitously diagnosed when the dog comes in
for a routine yearly wellness check and has routine blood
examination.
Te serum cholesterol concentration can help the
clinician determine the cause of the hypoalbuminemia.
Hypocholesterolemia concurrent with hypoalbumin-
emia suggests either PLE or hepatic insufciency.
Hypercholesterolemia occurring along with hypoalbumin-
emia is more suggestive of a protein-losing nephropathy.
After severe, exudative cutaneous disease, protein-losing
nephropathy, and hepatic insufciency are eliminated, then
PLE is a reasonable tentative diagnosis of exclusion in pa-
tients with a serum albumin < 2.0 gm/dl. Fecal concentra-
tions of alpha-1 protease inhibitor can be measured to try
to confrm PLE if there is confusion because of concurrent
hepatic or renal disease; however, this is not always an easy
test to run or interpret (3, 4). Te major use for this test in
clinical medicine seems to be the hypoalbuminemic patient in
which one strongly suspects PLE (e.g., based upon it having
severe diarrhea or having hypocholesterolemia), but which
also has a protein-losing nephropathy and/or hepatic disease.
Tere are several nuances about this test, especially collecting
samples that make it potentially difcult to interpret. Tis test
is seldom needed in clinical practice.
Many dogs with PLE have relatively severe alimen-
tary tract disease (or at least alimentary tract disease that
can become life-threatening) which should be diagnosed
promptly to maximize the chance for successful therapy.
Hence, aggressive diagnostics are typically an appropriate
recommendation. Although therapeutic trials can be chosen
in place of classic diagnostic tests in many of the more com-
mon alimentary tract diseases (e.g., dietary allergy, dietary
intolerance, antibiotic-responsive enteropathy, parasites), such
an approach is generally ill-advised if the serum albumin
concentration is less than 2.0 g/dl. Tis is true because it
may be necessary to perform an antibiotic and/or dietary
therapeutic trial for 3-6 weeks in order to ascertain if it is
being efective, and a patient with severe PLE can markedly
deteriorate during this time, especially if the serum albumin
concentration is falling rapidly.
Any GI disease can cause PLE if it is severe enough.
Many acute gastrointestinal (GI) diseases cause PLE (e.g.,
parvoviral enteritis); however, these diseases typically are
comparatively easier to treat than the chronic GI disease
causing PLE. Te major causes of PLE in adult dogs tend to
be intestinal lymphangiectasia, alimentary tract lymphoma
(LSA), fungal infections (i.e., histoplasmosis and pythiosis),
and then infammatory bowel disease (IBD) (1). Other
causes may include alimentary tract ulceration/erosion,
severe disease of intestinal crypts, antibiotic-responsive en-
teropathy, and parasites. Te major causes of PLE in juvenile
dogs tend to be parastic and chronic intussusception. Cats
with PLE usually have IBD or alimentary tract lymphoma.
Once PLE has been diagnosed, intestinal biopsy is usually
the best and more reliable means of determining the cause.
Biopsy can be performed via laparotomy, laparoscopy, or
endoscopy. Feeding a small, fatty meal (use canned food,
not dry, and add in cream or corn oil) the night before the
procedure might make it easier to diagnose lymphangiectasia
on histopathology (5). Flexible endoscopy, when done by
someone well trained in taking and submitting diagnostic
tissue samples is usually more than adequate to obtain a solid
diagnosis.
However, it is preferable to image the dog before biopsy.
Radiographs and barium series are seldom useful. Abdominal
ultrasound is appropriate to make sure that there are no focal
infltrates that are out of reach of the endoscope, or which
might be more easily diagnosed by ultrasound-guided fne
needle aspiration. Furthermore, there are ultrasonographic
changes (i.e., hyperechoic streaks in the submucosa) that can
be diagnostic of lymphangiectasia (and thus eliminate the
need for biopsy) (6). Feeding fat the night before the ultra-
sound can enhance the chances of ultrasound fnding dilated
lymphatics in the submucosa, a fnding that is considered vir-
tually diagnostic of lymphangiectasia. (7) Lymphangiectasia
can be relatively localized in one segment of the intestines. In
many cases, lymphangiectasia, IBD or LSA may be obvious
in the ileum but not in the duodenum. Terefore, if fexible
endoscopy will be done, it is important to biopsy both the
duodenum and ileum (8, 9). It is not necessary to enter the
ileum with the endoscope to obtain a good tissue sample of
the ileal mucosa. One can blindly pass the biopsy forceps
through the ileocolic valve and typically obtain high quality
mucosal biopsies of the ileum.
While histopathology is obviously the desired means of
diagnosis, surgeons can sometimes make a tentative diagnosis
of lymphangiectasia based upon grossly visible endoscopic
fndings (i.e., numerous, erratic, grossly engorged lacteals
seen as large white blebs on the mucosa) (10). However,
these lesions are “fragile” and apparently may be destroyed
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Israel Journal of Veterinary Medicine  Vol. 70 (3)  September 2015 19 Protein Losing Enteropathies
during biopsy if the endoscopist or surgeon is not careful.
Furthermore, if one biopsies the intestines and cannot fnd a
cause of PLE, sometimes lymphangiectasia can be tentatively
diagnosed by the process of eliminating all the other causes
(e.g., IBD, lymphoma, parasites, intussusception, fungal
infections, ulcers).
Laparotomy and laparoscopy are both profcient meth-
ods to obtain diagnostic samples, but it is surprisingly easy
to procure non-diagnostic samples with both techniques.
Te phrase “full-thickness sample” is not synonymous with
“diagnostic sample”. Endoscopy does have the advantage of
allowing one to visualize mucosal lesions that are “invisible”
when looking at the serosa. Feeding fat the night before the
procedure might make it easier to fnd diagnostic lesions
(5). In some cases, the diagnosis can only be obtained by
biopsying these focal lesions. If full-thickness biopsies are
obtained in severely hypoalbuminemic animals, then serosal
patch grafting will minimize the risk of suture line leakage.
A nonabsorbable or a poorly absorbable suture (PDS) may
also be used to lessen the likelihood of complications.
Regardless of how the samples will be taken, poor qual-
ity mucosal biopsies (e.g., primarily villi tips or substantial
“squash” artifact) makes it much more difcult or even impos-
sible to fnd lesions (11). If the endoscopist obtains high qual-
ity tissue samples (i.e., total length of the villi plus subvillus
mucosa down to the border of the mucosa and muscularis
mucosa), it typically takes about 6-7 tissue samples to have
90-99% confdence in fnding lymphangiectasia. However,
it can take 5-7 times as many tissue samples to have the
same assurance if the clinician is obtaining poor quality tissue
samples that primarily consist of villi tips.
Intestinal lymphangiectasia seems particularly common
in Yorkshire terriers and Soft-Coated Wheaten terriers, but
may occur in any breed (1, 12-15). Terapy for intestinal
lymphangiectasia revolves around feeding an ultra-low fat
diet (16). Anti-infammatory therapy designed to alleviate
the lipogranuloma formation that commonly occurs within
the intestinal wall and/or mesentery is typically included.
Supplementation with medium chain triglyceride oil (MCT)
used to be recommended because MCT oil supposedly by-
passes intestinal lymphatics thus preventing further rupturing
of the lacteals. Pancreatic enzymes were often added to the
diet to ensure digestion of the medium chain triglyceride oil.
MCT oil is seldom used anymore, probably because appro-
priate dietary therapy is usually more than sufcient. Feeding
homemade diets that are highly digestible and ultra-low in
fat (e.g., white turkey meat plus potato or rice) or feeding
commercial diets is often very helpful in these patients.
Commercial low fat diets can be used very successfully, but
they need to have the lowest possible fat content while at the
same time having adequate calories (i.e., reducing diets are
seldom optimal for treating lymphangiectasia). Such a diet
can be so successful that it might occasionally be appropriate
to use it as a therapeutic trial. Dogs with lymphangiectasia
often show a marked increase in serum albumin concentra-
tion within 7-14 days of starting such a diet.
Te importance of lipogranulomas in the intestinal wall
(17) and mesentery is uncertain. However, it might be that
some patients fail to respond to appropriate dietary therapy
because of formation of very large or excessive numbers of
lipogranulomas which completely obstruct the intestinal
lymphatics so that even an ultra-low fat diet cannot prevent
lacteal rupture. Terefore, once a diagnosis of lymphangiec-
tasia is made (either by histopathology, grossly at endoscopy,
or tentatively by response to an ultra-low fat diet), it seems
to be appropriate to use anti-infammatory therapy designed
to prevent granuloma formation/enlargement. Prednisolone,
azathioprine, and/or cyclosporine are commonly used for this
purpose (18). Prednisolone (2-3 mg/kg/day) is inexpensive
but has a plethora of side efects. Cyclosporine (3-6 mg/kg
bid) is often helpful, but it is expensive and it is sometimes
necessary to measure blood levels of the drug if the patient is
not responding as desired (which adds to the cost). Not only
is there a major diference between patients in how much
cyclosporine they absorb (i.e., the bioavailability), but this
aspect of pharmacokinetics may change dramatically as the
intestine heals.
Lesions of the intestinal crypts have been recognized as
being associated with PLE in dogs. Tere are two diferent
lesions of the small intestinal crypts that can cause PLE (19-
20). One type is characterized by crypts (usually duodenal)
that are flled and somewhat distended with proteinaceous
fuid and necrotic infammatory cells. While such dilated
crypts can be found in many animals (including clinically
normal dogs), fnding large numbers of them in multiple tis-
sue samples is typically associated with PLE. It is not known
whether or not this is a cause-and-efect relationship, or if the
dilated crypts are simply a marker for some other process but
are not causing the protein loss themselves. Several of these
patients have responded to therapy with elemental diets,
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Israel Journal of Veterinary Medicine  Vol. 70 (3)  September 2015 Willard, M. 20
total parenteral nutrition, prednisolone, azathioprine, and/
or metronidazole. Tis lesion can be seen in dogs with IBD
as well as lymphangiectasia (especially in Yorkshire terriers).
Chronic intussusception is a relatively important and
often missed cause of PLE in juvenile animals (21). Te
classic history is one of acute enteritis (e.g., parvoviral en-
teritis) which does not resolve as expected. Te patient feels
somewhat better, but continues to have diarrhea, and the
serum albumin concentration gradually diminishes. It can be
very hard to palpate an ileo-colic intussusception; abdominal
ultrasound is clearly the preferred way to diagnose intus-
susception. Terapy is surgical.
Although uncommon, nematodes may cause PLE in
adult animals if there are large numbers of them. Whipworms
and hookworms in particular may occasionally be responsible
for PLE in older dogs. However, giardiasis has been reported
to cause PLE in people (22).
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