PLE = Protein-losing enteropathies
Diagnosis and management
Stanley L. Marks
BVSc, PhD, Dipl ACVIM (Internal Medicine, Oncology), Dipl ACVN, Professor California, USA
| Protein-losing enteropathy (PLE) is a syndrome caused by|
a variety of gastrointestinal diseases causing the enteric loss
of albumin and globulin.1,2 Intestinal inflammation, infiltration,
ulceration, blood loss, and primary or secondary lymphangiectasia
are well documented causes of PLE (Table 1).
If left untreated, the final outcome of PLE is panhypoproteinemia
with decreased intravascular oncotic pressure and
the development of abdominal and pleural effusion, peripheral
oedema, and death. An important sequel to PLE
includes thromboembolic disease secondary to the loss of
antithrombin. Protein-losing enteropathy is uncommon in
cats, and most cats with PLE are diagnosed with intestinal
lymphoma or severe IBD.
| DIAGNOSTIC APPROACH|
In some animals, weight loss is the only initial symptom
of PLE because the syndrome can also occur in dogs without
clinical signs of gastrointestinal disease.1 The signalment
of the animal is important as certain breeds such as the Yorkshire
Terrier, Soft-Coated Wheaton Terrier, Norwegian Lundehund,
and Basenji are predisposed to PLE. Standard laboratory
investigations include a complete blood count
(CBC), serum biochemistry profile, and urinalysis. Lymphopenia
is often associated with PLE secondary to lymphangiectasia.
Serum albumin and total protein should be
carefully evaluated in all patients with a history of weight
Table 1 - Causes of Protein-Losing-Enteropathy (PLE)
A. Diseases affecting intestinal lymphatic drainage
• Congenital or idiopathic acquired
• Breed predisposition
• Congestion secondary to right-sided heart failure or portal hypertension
B. Acute or chronic inflammatory diseases that result in increased mucosal permeability to protein
• Inflammatory bowel disease (eosinophilic or lymphoplasmacytic enteritis)
• Granulomatous enteritis (histoplasmosis, Pythiosis)
• Intestinal neoplasia, (lymphoma, carcinoma)
• Immunoproliferative enteropathy of Basenjis
• Parasitic enteritis in young animals
• Villous atrophy, gluten enteropathy, certain viral and bacterial enteritides
• Chronic obstruction or intussusception
C. Gastrointestinal Blood Loss
• Bleeding tumors
• Intestinal parasites (Hookworms)
• Soft Coated Wheaton Terriers develop PLE and PLN (protein-losing nephropathy).
| loss, anorexia, vomiting or diarrhoea. Although PLE is typically|
associated with panhypoproteinemia, the absence of
hypoglobulinemia does not preclude a diagnosis of PLE
because there are numerous reasons for increased production
of globulin in dogs (e.g., intestinal histoplasmosis or pythiosis).
Additional abnormalities found on the serum biochemistry
profile in association with PLE include hypocholesterolemia
(secondary to malabsorption) and hypocalcemia.
The causes for the hypocalcemia are multifactorial and
include hypoalbuminemia (affects total calcium), decreased
absorption of vitamin D, and malabsorption of magnesium.
Magnesium has been shown to be pivotal for the activation
of PTH in the parathyroid gland, increasing the renal and
skeletal tissue responsiveness to PTH, and activation of vitamin
D.3 Yorkshire terriers with PLE are apparently 9.2 X
more likely to develop hypomagnasemia and hypovitaminosis
D compared to other canine breeds.3 Measurement
of total and ionized serum magnesium is recommended in
animals with gastrointestinal disease and hypocalcemia. A
faecal flotation should be routinely performed in all diarrheic
animals to help rule out intestinal parasites (e.g., Hookworms)
which may contribute to the loss of protein.
Once hypoalbuminemia has been documented, the cause
must be identified. Important considerations for hypoalbuminemia
include protein-losing enteropathy, hepatic insufficiency,
protein-losing nephropathy (PLN), vasculitis, exudative
skin lesions, exocrine pancreatic insufficiency (EPI),
and Addisons disease. Dogs with concurrent liver disease
and intestinal disease can prove challenging, in that disorders
of both organs can be associated with hypoalbuminemia.
Protein-losing nephropathy can be easily eliminated
from the differential list by performing a urinalysis and
determining the urine protein:creatinine ratio if the animal
is proteinuric. Caution should be heeded in the interpretation
of mild increases in the UPC ratio, as animals with
active urine sediment can also have a mild increase in the
UPC ratio in the absence of glomerular disease. In addition,
most patients with proteinuria tend to exhibit hypoalbuminemia
in the presence of normo-or mild hyperglobulinemia.
Dogs with Cushings disease or dogs receiving exogenous
steroids can also have abnormal UPC ratios. Once PLN
has been ruled out based on the urinalysis, further evaluation
of hepatic function should be determined to help rule out
hepatic insufficiency as the cause for the hypoalbuminemia.
Careful evaluation of hepatocellular function parameters
(BUN, cholesterol, glucose, albumin, and bilirubin) on the
chemistry panel should be performed before measurement of
serum bile acids. Interpretation of liver enzyme values
(ALT, AST, GGT, and ALP) should be done with caution as
many dogs with severe liver disease do not have marked elevations
in hepatocellular enzymes. Elevations in serum bile
acid concentrations are not pathognomonic for hepatic insufficiency,
as nonhepatic diseases are well documented at
increasing serum bile acids (intestinal disease, pancreatitis,
anemia, diabetes mellitus, etc). Occasionally, biopsy of the
liver and intestinal tract is required to differentiate primary
liver disease from reactive hepatopathies. Laboratory assessment
of EPI can be performed by measuring concentrations
of canine tryspinogen-like immunoreactivity (cTLI), and
evaluation of the small intestinal absorptive function can be
evaluated by measuring concentrations of serum cobalamin
|evaluated by measuring concentrations of serum cobalamin|
and folate. Dogs that are severely hypocalcemic should be
further evaluated to determine the cause for the low calcium.
Measurement of faecal _1-proteinase inhibitor (_1-PI)
can be used to further support a diagnosis of PLE in animals
with concurrent liver disease or PLN, although this test is
limited by logistical constraints in that samples must be
shipped frozen, and there is currently only one laboratory
that performs the ELISA at Texas A & M University.4 _1-
proteinase inhibitor is the same size as albumin and is lost in
the intestinal tract and excreted via the feces where it can be
measured as a marker for PLE. Three separate voided faecal
specimens are collected into special volume-calibrated cups
available from the laboratory. It is important that the faecal
specimens be naturally voided as digital extraction of the
faecal specimen can result in microscopic blood loss and
false elevations in faecal _1-PI. The faecal specimens should
be immediately frozen after collection and shipped on ice
via overnight mail to the laboratory.
Abdominal imaging via ultrasonography can be particularly
helpful to further elucidate the cause of PLE, as many
dogs with intestinal lymphangiectasia show evidence of
hyperechoic mucosal striations secondary to lacteal dilation.5
In addition, abdominal ultrasonography can be helpful for
aspirating abdominal fluid for cytological characterization.
Most dogs with PLE require intestinal biopsies to confirm
the diagnosis, and empiric dietary and medical trials
that are commonly utilized for dogs with no evidence of panhypoproteinemia
are typically avoided in an effort to procure
a specific diagnosis as soon as possible. Gastroduodenoscopy
and biopsy can be used to diagnose lymphangiectasia
in most patients if appropriate biopsy technique is
utilized and biopsies of the duodenum and ileum are
obtained. Gastroduodenoscopy also affords one the opportunity
to evaluate the intestinal mucosa for erythema and dilated
lacteals that are filled with chyle. Occasionally the dilated
lymphatics are located below the mucosal layer and can
be missed endoscopically despite the implementation of
appropriate biopsy technique. Exploratory laparotomy and
biopsy affords one the luxury of full-thickness biopsies that
are usually easier for pathologists to interpret; however, the
disease can be patchy or multifocal underscoring the importance
of obtaining multiple full-thickness biopsies from the
duodenum, jejunum, and ileum. Lipogranulomas are commonly
seen on the serosal aspect of the intestine in dogs with
lymphangiectasia. Caution should be heeded when performing
full-thickness biopsies in animals that are hypoproteinemic
with ascites. These patients are at increased risk for
dehiscence, and implementation of nonabsorbable or poorly
absorbable suture should limit the risk of suture line leakage.
MANAGEMENT OF PLE
The goal of therapy for intestinal lymphangiectasia is to
decrease the enteric loss of plasma protein, resolve associated
intestinal or lymphatic inflammation, and control effusion
or oedema. The prognosis for PLE is guarded because of the
variable underlying causes and severity of the disease when
| Medical Management|
Parenteral fluid therapy: Administration of colloids such
as Dextran 70 or Hetastarch can be used to increase the plasma
oncotic pressure in animals that are severely hypoalbuminemic.
This is typically administered prior to surgery in
an effort to minimize complications associated with low
plasma colloidal oncotic pressure. The administration of
fresh frozen plasma is an expensive and less efficient means
of increasing the COP in dogs that are severely hypoalbuminemic.
Parenteral fluid therapy can be discontinued when
the albumin is > 1.5 g/dl and any ascites or peripheral oedema
has resolved. Loop diuretics such as furosemide (1-2
mg/kg, SC or PO) can be used to decrease abdominal or
pleural effusions, although caution should be heeded in
monitoring the patient’s hydration status and serum potassium
concentrations. Potassium sparing diuretics such as
spironolactone (2-4 mg/kg PO or IV) can be used together
with furosemide to decrease the likelihood of hypokalemia
Most dogs with lymphangiectasia do not warrant antiinflammatory
therapy, unless the intestinal biopsies show
evidence of moderate to severe intestinal inflammation with
the lymphangiectasia. In these animals a tapering dose of
prednisone or prednisolone can be administered starting at
1-2 mg/kg BID with a gradual taper over the ensuing 8-12
weeks. Large-breed dogs can be started on azathioprine
concurrent with the prednisone in an effort to reduce the
amount of steroid administered and decrease adverse effects.
Azathioprine is administered to dogs at a dosage of 1-2
mg/kg SID for 10-14 days, followed by 1-2 mg/kg every second
day. Prednisone dosage is typically reduced by 50% if
administered concurrently with azathioprine. In dogs with
severe malasimmilation, orally administered prednisone is
unlikely to be absorbed properly, and one should administer
the prednisone parenterally for the first week before switching
to oral administration. A recently published study documented
the therapeutic benefit of cyclosporine (5 mg/kg
SID for dogs with IBD refractory to prednisone therapy.6
Cobalamin (vitamin B12) should be administered parenterally
in all dogs with subnormal serum cobalamin concentrations.
The author administers cobalamin at a dose of 500 to
1000 _g per dog SC once weekly for 6 weeks. Readministration
of cobalamin should be based on reevaluation of
serum cobalamin concentrations and resolution of clinical
signs. Patients that are severely hypocalcemic (despite
attempted correction for the hypoalbuminemia) should be
considered for parenteral magnesium supplementation in the
form of magnesium sulphate at 1 mEq/kg/day. Magnesium
can also be supplemented orally as magnesium hydroxide
(milk of magnesia) at a dosage of 5-15 ml per dog/24 hrs.
Antibiotics such as metronidazole (10 mg/kg BID) or
tylosin (20 mg/kg BID) both for 3 weeks are often administered
to dogs with IBD.
| Dietary Management|
Severe dietary fat restriction is one of the most important
aspects in the management of dogs with intestinal lymphangiectasia.
Diets that are highly digestible and that contain
< 20% fat calories on an ME basis are recommended.7
The author recommends the feeding of a premium commercial-
based diet if possible; however, there are a small number
of dogs with severe lymphangiectasia that will need further
fat restriction than that provided in commercial diets,
and home-cooked diets are warranted. These home-cooked
diets should be made up by a veterinary nutritionist to
ensure that the diets are complete and balanced. Dogs with
concurrent IBD and lymphangiectasia are more challenging
to manage from a dietary perspective, because these animals
need a novel, select protein source diet that is also
markedly fat restricted and virtually all commercial diets do
not fit these criteria. An alternative to consider is the use of
hypoallergenic diets containing hydrolyzed protein sources
and moderate amounts of dietary fat. Failure to respond
favorably to these diets warrants a home-cooked diet that is
more fat-restricted and contains a novel, select protein
source. Administration of medium chain triglycerides
(MCT’s) to enhance the caloric density of the diet are not
recommended due to their unpleasant taste and potential for
inducing diarrhoea. Recent evidence also suggests that
MCT’s are not transported entirely via the portal circulation
to the liver, and can exacerbate the lymphangiectasia. Total
parenteral nutrition can be administered to cachectic animals
with severe hypoalbuminemia and intractable vomiting
1. Petersen PB, Willard MD. Vet Clin Am Small Anim Pract 2003;
2. Kull PA, et al. J Am Vet Med Assoc 2001; 15; 219(2):197-202.
3. Kimmel SE, Waddell LS, Michel KE. J Am Vet Med Assoc 2000;
4. Murphy KF, et al. Vet Clin Pathol 2003; 32(2):67-72.
5. Sutherland-Smith J, et al. 2007; 48(1):51-7.
6. Allenspach K, et al. J Vet Intern Med 2006; 20(2):239-44.
7. Marks SL, Fascetti AJ. Nutritional management of diarrhoeal disease.
In: Kirk’s Current Veterinary Therapy XIII. Editors, Bonagura
J.D; 2000; 653-658.
Intestinal lymphangiectasia, Inflammatory bowel disease, Protein Losing Enteropathy)
Symptoms: diarrhea (especially if it persists longer than a few days or there are repeated bouts)
vomiting/nausea (usually episodic, rather than constant)
weight loss, especially loss of muscle mass or tone.
swollen abdomen (looks pregnant) and/or swollen legs
low serum protein (sometimes that is the only sign)
Onset: any age, dogs from 6 months to 10 years have gotten it.
Cause: At this point, the cause is totally unknown. Certainly there is a genetic predisposition to the disease, and then something sets it off. Intestinal infections (viral, parasitic, and bacterial) have been implicated. Periods of stress (boarding, estrus, pregnancy, shows) seem to bring on episodes. Dr. Williams of Texas A & M's GI Lab strongly believes that there is a hypersensitivity/allergy to protein antigens (either from food or bacteria) that are in or pass through their GI tract. He feels that the normal protective mechanisms of the intestines are reduced, allowing increasing permeability in the intestinal wall so that the intestines are exposed to substances to which they would not get exposure normally.
Course of the disease: Lundehunds are born with apparently normal intestinal systems, but with time something in their system causes inflammatory cells to build up in the intestinal walls and this causes the lymphatic vessels (which normally absorb proteins from the intestines) to clog up and ooze protein/lymph into the intestines. Some dogs get the clogged up lymph vessels (lymphangiectasia) worse than others and lose protein quickly with no signs of diarrhea. Other dogs get the inflammatory build-up worse and are more prone to diarrhea than low protein. Either way, all dogs lose protein into the intestinal tract and as the inflammatory cells block up the intestinal walls, diarrhea may start, and the dog will not be able to absorb nutrients and protein from its food. Many dogs get an intestinal bacterial overgrowth and vitamin B12 deficiency, (which causes even worse diarrhea and malabsorption). This malabsorption can cause even more weight loss. In some dogs the diarrhea will be only occasional, but the loss of protein can continue insidiously. Weight loss (especially loss of muscle mass) will start, and become more and more severe as the process continues. Some dogs will improve on their own, or with treatment, and the disease will appear to go away. But actually it is only in remission. Sometime later in life, especially after periods of stress and change in the dog's life, it will usually reappear. The dog will have repeated bouts of the illness, frequently controlled with medication. Eventually, the disease process becomes resistant to medication, and the dog progressively loses weight. Once they have lost enough protein, the abdomen swells up with fluid accumulation (recall photos of malnourished children with big stomachs?) and/or the fluid will accumulate in the limbs, usually the hind legs. Sometimes the fluid may also build up inside the chest, causing breathing problems. If the dog is not euthanized, death will occur due to dehydration, extreme anemia & malnutrition, abdominal/chest fluid build-up, or they will throw a blood clot to the brain or other vital organ.
Treatment: is addressed in a separate article for veterinarians. Current treatment uses special food, (high protein, low fat), and drugs, both to reduce the cell build-up in the intestines and improve the lymphatic flow. Once fluid builds up in the abdomen or legs, there are i.v. treatments that the veterinarian can do to improve the situation in the short term.
Prognosis: can eventually be fatal, although bouts of the disease can be controlled with medication and the illness can go into remission for various periods of time, and the dog can live for many years, but the occasional dog will get a fatal case the very first time.
Incidence in the Lundehund Breed: at present is unknown, although we are trying to gather statistics. The disease can appear at a late age and some dogs get such a mild case that no one really ever diagnoses it, that it is difficult to gather firm figures. Certainly Lundehunds get this disease incredibly more often than other breeds.
Outlook: Research is being done on the treatment, diagnosis and inheritance of this disease, both here and in Norway. Researchers are looking for genetic markers and non-surgical means to find affected dogs. However, progress is very slow as this disease has multiple and variable manifestations, and therefore may not be simple to pin down.Recommendations: Do not breed highly affected dogs. Have serum protein levels done very often, at least twice a year on a healthy dog and once a month on a dog who has had an attack. Have fecal tests done every 6-12 months. If your dog has abdominal surgery for any reason, please request that your vet take an intestinal biopsy (of the proximal small intestine close to the duodenum) and submit it to the pathology lab, with the request that they look for inflammatory bowel disease and lymphangiectasia. Sometimes the signs of lymphangiectasia are visible to your vet on surgery, but other times, it requires a pathologist to make a microscopic examination. If your dog is diagnosed with the disease or has a clear biopsy, please inform your breeder.