Gastroenteropathy in Norwegian...

aNorsk Kennel Klub, FCI stan-dard 265.

he Norwegian Lundehund (“puffindog”) is a small, 14- to 20-lb (6- to 9-kg) spitz-type canine breed originating

from northern Norway, Iceland, the FaroeIslands, the Orkney Islands, and the Hebrides1

(Figure 1). One of the breed characteristics ispolydactyly (Figure 2); in fact, the breed stan-dard of the Norwegian Kennel Club requiresthat Norwegian Lundehunds have at least six

toes on each foot.a In addi-tion, their joints are unusuallyflexible, making it possible forthese dogs to stretch out theirfront legs laterally and bend

their necks far backwards (Figure 3). Lunde-hunds can also retract the cartilage of their earsto voluntarily close their ear canals.2 The Nor-wegian Lundehund is an old breed, datingback to the 17th century.3 The breed wasthought to be extinct until a surviving popula-tion was discovered in 1925 on the island ofVæroy, Norway.3 After almost all of the popu-lation was lost as a result of distemper andother circumstances, a breeding program wasstarted in 1961 with only five remaining dogs,consisting of two females and three males.4 In1964, one of the original males developedascites, edema of the hind legs, and gastroin-testinal (GI) disturbances at 3 years of age.1

Since then, several authors have reported a

COMPENDIUM 456 August 2007

Gastroenteropathy in Norwegian LundehundsNora Berghoff, MedVet, DrMedVet

Texas A&M University

Craig G. Ruaux, BVSc, PhD, MACVSc

Oregon State University

Jörg M. Steiner, MedVet, DrMedVet, PhD, DACVIM, DECVIM-CA

Texas A&M University

David A. Williams, MA, VetMB, PhD, DACVIM, DECVIM-CA

University of Illinois at Urbana-Champaign

T

ABSTRACT: Norwegian Lundehunds are often affected by gastrointestinal disease, the most common

clinical signs of which are intermittent diarrhea, vomiting, weight loss, lethargy, ascites, and subcutaneous

edema of the hind legs. The most frequent laboratory changes include hypoalbuminemia (with or without

hypoglobulinemia), hypocalcemia, a decrease in the serum cobalamin concentration, and an increase or

decrease in the serum folate concentration, reflecting microbial synthesis or malabsorption, respectively.

Histopathologic abnormalities can include chronic atrophic gastritis, intestinal lymphangiectasia, and

lymphoplasmacytic enteritis. Because the underlying cause of gastroenteropathy in Norwegian

Lundehunds has not been identified, treatment is symptomatic.

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Gastroenteropathy in Norwegian Lundehunds 457CE

similar c linical presentation, called Lundehundsyndrome, in Norwegian Lundehunds in Europe andNorth America.1,5–7 It is assumed that the prevalence ofthis gastroenteropathy in Norwegian Lundehunds inthe United States is high, although accurate estimatesof the prevalence in the United States or elsewherehave not been established.5

CLINICAL, GROSS PATHOLOGIC,ANDHISTOPATHOLOGIC FINDINGS

Norwegian Lundehunds affected by gastroenteropa-thy may exhibit a variety of clinical signs, includingintermittent diarrhea, vomiting, weight loss, lethargy,ascites, and subcutaneous edema, mostly of the hindlegs.1,4,5 However, there is evidence that subclinical dis-ease is also very common.

In the past, this disease has been referred to merelyas protein-losing enteropathy (PLE), although it is nowwell established that gastric abnormalities are presentas well.1,4,5,8 Lundehund syndrome, as described in thisarticle, may include components of gastritis, PLE,intestinal lymphangiectasia, inflammatory bowel dis-ease (IBD), and malabsorption and has been describedin the Lundehund populations of Europe and NorthAmerica.1,4–7

Most studies evaluated only a small number of dogs;therefore, care should be taken in extrapolating find-ings to the whole breed. However, many findings seemto be consistent throughout the different reports, indi-cating that they are probably widespread abnormalitieswithin the existing population of Norwegian Lunde-hunds worldwide.

Figure 1. A typical Norwegian Lundehund.Figure 2. Polydactyl foot of a Norwegian Lundehund.Note the desired double dewclaws.

Figure 3. Norwegian Lundehunds have extremely flexible shoulder joints and necks.

COMPENDIUM August 2007

Gastroenteropathy in Norwegian Lundehunds458 CE

PATHOLOGY AND HISTOPATHOLOGYSome Norwegian Lundehunds never exhibit signs of

GI disease. However, investigations have shown thateven Lundehunds that appear healthy often haveabnormal histopathologic findings within the GI tract.These abnormalities can be seen throughout the stom-ach and small intestine, with the severity of the changesgenerally decreasing from the proximal to the distal

intestinal tract.1,6 To obtain reliable results, intestinalbiopsy specimens should be obtained from live dogs orwithin 5 minutes of euthanasia to avoid subtle post-mortem changes that can be confused with changescharacteristic of Norwegian Lundehund enteropathy.6

At necropsy, various degrees of emaciation have beenobserved in Norwegian Lundehunds.1 In severe cases,ascites is common and often accompanied by hydrotho-rax, hydropericardium, and subcutaneous edema. Analy-sis of the ascites fluid has revealed no or little proteinand a specific gravity below 1.018, which is a classic fea-ture of pure transudate.1

StomachKolbjørnsen et al4 reported gastric abnormalities dur-

ing necropsy of 14 Lundehunds diagnosed with intes-

Figure 4. Histopathologic image of the gastric mucosa in a dog with Lundehund gastroenteropathy.Note themononuclear cell infiltrate. (Hematoxylin–eosin; original magnification×100).

tinal lymphangiectasia. Macroscopic findings in thestomachs of Lundehunds included submucosal edema,mucosal erosion, and thickening of the stomach walldue to formation of firm, fibrous, grayish-white tissue.4

The major histologic finding was the presence of gastri-tis in all 14 Lundehunds studied. The changes weremainly localized to the gastric fundus and body andwere identified as chronic atrophic gastritis in mostLundehunds, based on observation of degeneratedfundic glands and mononuclear cell infiltration (Figure4). In some Lundehunds, dilated gastric lymphaticswere observed. Histopathology revealed the presence ofprimary gastric carcinoma in four dogs. Gastric granulo-mas, consisting of epitheloid-like cells with a center offibrous material, were found in six Lundehunds, mainlyin the submucosa of the pyloric antrum.4 However,intestinal metaplasia, a premalignant conditiondescribed in humans resulting from atrophic gastritisand characterized by the presence of enterocyte-likecells with a brush border and goblet cells, was not foundin the Lundehunds.4,8–10

These results suggest a possible link between theoccurrence of intestinal lymphangiectasia and chronicatrophic gastritis or even gastric carcinoma in Lunde-hunds and that Lundehunds with chronic atrophic gas-tritis may have an increased risk of developing gastric

carcinoma. It has been shown that chronic atrophic gas-tritis is a predisposing condition for the development ofgastric carcinoma in humans, often following or concur-rent with Helicobacter pylori infection.9,10 Spiral bacteria(i.e., Helicobacter spp) were not detected in any of theLundehunds examined.4

Small IntestineMorphologic changes of the intestines of Norwegian

Lundehunds have been described in several reports. Fre-quent macroscopic findings during necropsy includedwhitish, dilated mesenteric and subserosal intestinallymphatic vessels. The mucosa of the small intestineappeared thickened and rough or granular.1,5,6 The villiappeared whitish and enlarged, with a patchy or diffusepattern of distribution.1,6

All Norwegian Lundehunds should be monitored frequently for hypoproteinemia and fecal proteinloss to facilitate early symptomatic treatment and exclude severely affected dogs from breeding.



Figure 5. Images from a scanning electron microscope.

Normal ileal mucosal surface. Villus atrophy in the ileum of a Norwegian Lundehund.

bypass the lymphatic obstruction.6 This disorder wouldsubsequently lead to increasing pressure within the lymphvessels, causing them to dilate and possibly rupture. In con-trast, secondary lymphangiectasia is caused by obstructionof lymph vessels due to neoplasia, inflammation, or ele-vated venous pressure.6,17 No evidence of secondary lym-phangiectasia has been reported in Lundehunds; thus, it isassumed that lymphangiectasia in this breed is primary,although it should be remembered that intestinal inflam-mation, as described in Lundehunds, could also contributeto lymphangiectasia, especially if there is a genetic predis-position to the development of primary lymphangiectasia.

PancreasAbnormalities in the pancreas of Norwegian Lunde-

hunds were reported in one study.1 During macroscopicexamination, the pancreas was often edematous, andsmall areas of peripancreatic fat necrosis were found insome cases. Acute pancreatitis was diagnosed in onedog, although it is unknown how this diagnosis wasmade, and histopathologic alterations in this patientwere not detailed. During histopathologic examination,dilated interstitial lymph vessels were found in the pan-creas.1 None of the other studies describes any pancre-atic abnormalities in the dogs examined, so thesignificance of this single study is unclear.

Implications for Prevalence of DiseaseIt is remarkable that all of the Lundehunds that were

examined by histopathology were affected by at least

Histologic examination revealed thickening of themucosa in the duodenum and jejunum, villus atrophy(Figure 5), and villus fusion.1,6 Crypt hyperplasia andfilling of the crypts of Lieberkühn with mucin and cel-lular debris were also observed.6 The epitheliumappeared attenuated with a thinned brush border, wasfrequently desquamated from the lamina propria due tosubepithelial fluid accumulation, and was often associ-ated with edema in the lamina propria.1,6 Lymphoplas-macytic infiltration was also found, indicating thepresence of an inflammatory process1,5 (Figure 6).

Intestinal lymphangiectasia was frequently described.1,4–6

Lymphangiectasia was characterized by balloon-like dis-tentions of villi and occasional villus rupture but was alsopresent in deeper sections of the intestinal wall, withlacteals protruding toward the serosal and mesenteric sur-face in some cases1,6 (Figure 7). Granulomas associatedwith lymphatic vessels have been observed.5 Granuloma-tous changes are often found in the small intestinal mesen-tery of dogs with intestinal lymphangiectasia and arethought to be a result of leakage of lymph into the sur-rounding tissue.11–15 Lymphangiectasia in Norwegian Lun-dehunds has similarities to primary lymphangiectasia inhumans.6 Primary intestinal lymphangiectasia is a congeni-tal defect within the lymphatic system characterized byhypoplasia of lymphatic vessels, which creates a functionalobstruction to lymphatic flow and subsequently leads todilation of lymph vessels throughout the body.16 It has beenspeculated that the underlying defect may be an inability ofthe lymphatic system to form effective anastomoses to



Figure 6. Lymphocytic–plasmacytic enteritis in aLundehund. (Hematoxylin–eosin; original magnification ×100)

Figure 7. Intestinal lymphangiectasia in the jejunalmesenteric surface of a Norwegian Lundehund. The arrowsshow granulomatous changes associated with lymphangiectasia.

some of the abnormalities mentioned above and none wasfree of GI abnormalities. This suggests that the actualprevalence of gastroenteropathy within this breed is veryhigh and that many Lundehunds that seem healthy may,in fact, be affected by gastroenteropathy.

DIAGNOSISSignalment and Clinical Signs DuringExamination

Of 43 Lundehunds that were examined in differentstudies, information about the sex and age was availablefor 36 dogs. Fifteen of 36 dogs (41.7%) were female,and 21 (58.3%) were male. The mean age for the 36dogs was 5.2 years (range: 0.5 to 10 years).1,4,6,7

The clinical signs observed in the 43 Lundehundsincluded diarrhea (76.7%), vomiting (72.1%), ascites(46.5%), edema (44.2%), weight loss (32.6%), andlethargy (20.9%). Most of the dogs presented with sev-eral of these clinical signs at the same time, and themost common combination was diarrhea with vomitingand ascites and/or edema. One of the 43 dogs wasapparently clinically healthy. The clinical history wasunavailable for one dog.1,4–7

Clinical PathologyHematology

Hematologic examinations, including hematocrit, ery-throcyte sedimentation rate, erythrocyte counts, andleukocyte differential counts, were conducted in threeinvestigations, and no abnormalities were reported inany of these studies.1,4,5 Lymphopenia has been fre-

quently reported in dogs of other breeds with PLE, butthis did not appear to be the case in the Lundehundsexamined. The reason for the absence of lymphopenia isunknown.

Serum Biochemistry ProfileThe following serum parameters have been investi-

gated in different studies: serum total protein, albuminand globulin, calcium, phosphorus, magnesium, choles-terol, urea nitrogen, aspartate transaminase, alaninetransaminase, and alkaline phosphatase. The results formost serum parameters were within the reference range,with the exception of the serum total protein, albumin,and calcium concentrations.1,5

Hypocholesteremia is often found in patients withPLE due to a lack of fat absorption, but this was notreported in the studies investigating Lundehunds.However, the cholesterol level was measured in only asmall number of patients (n = 11) and, therefore, maynot be fully representative of the affected population. Itis also interesting that the serum magnesium concen-tration was normal in all the Lundehunds tested,although this parameter was also determined in only avery small number of dogs (n = 5). Hypomagnesemiacan develop as a result of chronic diarrhea and malab-sorption due to various intestinal mucosal diseases,including intestinal lymphangiectasia.18–20 Possiblemechanisms leading to malabsorption of magnesiumare reduced mucosal surface area, increased intestinalsecretion, vitamin D deficiency, and formation of insol-uble magnesium soaps with unabsorbed fat.18 Dogs



with small intestinal inflammation can have mildlyincreased liver enzyme concentrations due to develop-ment of a “reactive hepatopathy,” but this was notobserved in the Lundehunds investigated.21 Furtherstudies are needed to determine whether these findingsare representative of Lundehund gastroenteropathy orwere falsely negative due to the low number of dogsevaluated so far.

Clinicians should pay close attention to the coagula-tion profile because these patients may develop throm-boembolic disease. The major mechanism seems to beloss of antithrombin III concurrent with intestinal lossof other plasma proteins, inducing a hypercoagulablestate.17,20 Up to 10% of all dogs with PLE are affected bythis complication, but the incidence of a hypercoagula-ble state in Norwegian Lundehunds is unknown.22 Also,intestinal fat malabsorption can reduce the absorption ofthe fat-soluble vitamin K, which may lead to vitamin Kdeficiency and increase the risk of bleeding in affected

patients. While none of the clinical studies has exam-ined coagulation profiles in Lundehunds, Kolbjørnsen etal4 noted thrombosis of gastric submucosal vessels intwo of 14 Lundehunds during necropsy. In addition, athrombus in the pulmonary artery was found in anotherdog.6 These studies suggest that Lundehunds with gas-troenteropathy are at risk of developing thromboem-bolic disease; therefore, a coagulation profile should beroutinely evaluated.

Serum total protein and albumin concentrations—Two different studies investigated serum protein con-centrations in a total of 19 Lundehunds affected bygastroenteropathy.1,7 All the dogs were hospitalized forclinical signs of disease when the samples wereobtained. Fourteen dogs were hypoproteinemic, whereasfour had hypoalbuminemia only. Five dogs were hypo-globulinemic.1,5,7 One dog had a normal serum albuminconcentration and slightly elevated serum total proteinand globulin concentrations.7 A preliminary study byWilliams and Melgarejo5 investigated protein concen-

trations in seven Lundehunds, six of which had a his-tory of diarrhea and weight loss but were not necessarilyexhibiting any clinical signs of disease during testing.One dog had no history of GI problems. Althoughthese dogs did not appear to be sick, hypoalbuminemiawas present in three of the seven dogs, whereas theserum globulin concentration was normal in all dogstested.5

Thus, hypoalbuminemia could be identified in 21 of26 dogs (80.8%), hypoglobulinemia in 13 of 26 dogs(50%), and general hypoproteinemia in 17 of 26 dogs(65.4%). In addition to these study results, Kolbjørnsenet al4 found hypoproteinemia in seven of 13 dogs forwhich clinical data were available, but it was not speci-fied whether this included hypoalbuminemia only,hypoglobulinemia only, or panhypoproteinemia.

Because liver enzyme abnormalities were not identi-fied in any of the studies, it is unlikely that hypoalbu-minemia is caused by a decrease in hepatic albumin

synthesis due to liver disease. Most dogs with PLE havedecreased albumin and globulin concentrations.21 How-ever, in some dogs, hypoalbuminemia is accompanied bynormal globulin concentrations or hyperglobulinemiarather than hypoglobulinemia. This mostly occurs inBasenjis with immunoproliferative small intestinal dis-ease, although it can occur in dogs with certain infec-tious diseases leading to globulin production, such asehrlichiosis, histoplasmosis, heartworm disease, orchronic inflammatory liver disease.21–23 It is not clearwhy some Lundehunds with PLE have normal globulinconcentrations, but it could be hypothesized that thismay simply reflect progression of the severity of the dis-ease, with initial hypoalbuminemia as the only findingin less severely affected dogs and panhypoproteinemiain severely and often chronically affected dogs. We haverecently evaluated serum total protein, albumin, andglobulin concentrations in approximately 100 Norwe-gian Lundehunds. Hypoproteinemia based on serumtotal protein concentrations was found in more than

While the gold standard for the diagnosis of gastroenteropathy in Lundehundsis histologic examination of GI biopsy samples, assessment of the GI health of aLundehund can be facilitated by measurement of fecal α1-proteinase inhibitor

and serum albumin, globulin, cobalamin, and folate concentrations.



50% of dogs, hypoalbuminemia in approximately 40% ofdogs, and hypoglobulinemia in approximately 15% ofdogs. None of the dogs in our study presented withhyperglobulinemia.

The specific mechanism of enteric protein loss inLundehunds is unknown. Rupture of lymphatic vesselsdue to intestinal lymphangiectasia, leading to loss ofchylous protein, is likely a major cause. However, inves-tigations have shown that increased mucosal tissue pres-sure, as occurs in edematous tissue, can cause passivesecretion of tissue fluids and their components, includ-ing protein.24 Intestinal inflammation could also con-tribute to protein loss. Therefore, a combination ofseveral pathologic mechanisms leading to enteric pro-tein loss in Lundehunds is likely.

Calcium concentrations—In two studies, serum totalcalcium concentrations were measured in five and threeLundehunds, respectively, and both found mild to moder-ate hypocalcemia in all dogs evaluated.1,7 Low serum cal-cium concentrations were attributed to hypoalbuminemiadue to loss of protein-bound calcium. Because approxi-mately 40% of serum calcium is bound to albumin, enteralloss of albumin in patients with PLE can cause a decreasein the serum total calcium concentration while increasingfecal calcium output.11,25–27 It has recently been shown thatsome dogs with GI diseases have low total and ionizedserum calcium concentrations and remain hypocalcemiceven after correction for the serum albumin concen-tration.17,19,20,27 Thus, it is apparently more accurate tomeasure the ionized fraction of serum calcium than thetotal serum calcium concentration. Unfortunately, thesedata are not available for Norwegian Lundehunds becauseonly total calcium concentrations have been reported todate. The exact cause of this generalized hypocalcemia isunclear, but a variety of mechanisms other than hypoalbu-minemia may contribute to hypocalcemia in dogs with GIdisease. For example, malabsorption of dietary fats canreduce calcium absorption because unabsorbed fatty acidsbind calcium and prevent calcium absorption.26 Calciumabsorption is also tightly regulated by the serum concentra-tion of 1,25-dihydroxycholecalciferol, the active metaboliteof vitamin D. Malabsorption of vitamin D, as may occurduring small intestinal disease, could subsequently lead tovitamin D deficiency and, therefore, contribute to thedevelopment of hypocalcemia.27

Intestinal Function TestingSerum cobalamin and folate concentrations—

Cobalamin is a water-soluble vitamin that undergoes a

complex series of biochemical reactions before beingabsorbed in the distal small intestine. Therefore, theserum cobalamin concentration is often decreased inpatients with diseases involving the distal small intes-tine. Folate is also a water-soluble vitamin but isabsorbed in the proximal small intestine; thus, adecrease in the serum folate concentration indicatesinvolvement of that part of the small intestine. Anincrease in the serum folate concentration may indicatethe presence of small intestinal bacterial overgrowth(SIBO) or some other shift in the upper small intestinalmicroflora. Both vitamins can be measured in serumusing a commercial chemiluminescence immunoassay.

Cobalamin and folate concentrations were measuredin a preliminary study in seven Lundehunds.5 Theserum cobalamin concentration was subnormal (<225ng/L) in three dogs, and the serum folate concentrationwas above normal (>17.4 µg/L) in two dogs.5 Morerecently, we measured cobalamin and folate concentra-tions in a large number of Lundehunds and found adecreased cobalamin concentration in approximately10% of the dogs and a decreased serum folate concen-tration in approximately 13% of the dogs. An increasedfolate concentration was detected in approximately 40%of the dogs. The serum cobalamin assay appears to behelpful in assessing intestinal absorptive dysfunction inNorwegian Lundehunds, although not all dogs that arediagnosed with GI disease have a decreased cobalaminconcentration. This is possibly due to the fact that alarge number of Lundehund owners participate in avariety of research projects and are thus aware of the riskfor cobalamin deficiency in their dogs and are regularlysupplementing them. Therefore, the data accumulatedmay not reflect the actual prevalence of cobalamin defi-ciency in untreated dogs and should be evaluated withcaution.

Several factors could lead to malabsorption of cobal-amin in Lundehund gastroenteropathy. Chronic smallintestinal inflammation can damage the specific receptorsneeded for absorption of cobalamin in the distal smallintestine.28,29 Also, the stomach fulfills an important func-tion in cobalamin absorption. While, in humans, a largeportion of intrinsic factor is synthesized in the stomach,in dogs, this portion is likely less than 10%; thus, lack ofintrinsic factor due to atrophic gastritis is unlikely a sig-nificant factor. However, another important componentinvolved in cobalamin absorption is R protein, which issecreted by the gastric mucosa and, therefore, may beaffected by atrophic gastritis. A lack of R protein could



disturb the complex mechanism of cobalamin absorption,thereby promoting cobalamin malabsorption.30

The fecal αα1-proteinase inhibitor (Fαα1-PI) immuno-assay—This assay is used to detect the presence of intes-tinal protein loss in patients with GI disease andsuspected PLE. Historically, PLE has been assessedusing 51chromium chloride (51CrCl3), a radioactive iso-tope. 51CrCl3 can be used to radiolabel albumin ex vivo,with subsequent intravenous administration of thelabeled protein, or can be given intravenously, leading toin vivo radiolabeling of albumin. If the patient has PLE,the radioactivity from enterically lost 51CrCl3 can bemeasured in the feces.31,32 Although this method is stillconsidered the gold standard for PLE testing, it isimpractical for clinical practice because the use ofradioactive material is limited to certified institutionsand the administration of 51CrCl3 requires confinementof the dog in certified premises for several days afterconducting the test. The fecal test to quantify Fα1-PIconcentration is not invasive and avoids the need forhandling and storage of radioactive waste. This testrequires the owner of the dog to collect three separatefecal samples into special tubes (Figure 8), preferablyfrom consecutive bowel movements, which need to befrozen immediately and, after the collection cycle hasbeen completed, shipped frozen to the GI Laboratory atTexas A&M University (www.cvm.tamu.edu/gilab),which is currently the only laboratory offering this test.The reference range for Fα1-PI is 0 to 5.7 µg/g. Becauseof normal variation, healthy dogs can occasionally have asingle elevated Fα1-PI concentration. If a single fecalsample has a concentration greater than 15 µg/g or if themean concentration of all three samples exceeds 9.4µg/g, PLE is diagnosed. This method of interpretationreduces the probability of obtaining false-positive results.

Measurement of Fα1-PI in a small study with sevenLundehunds showed elevated concentrations (>6 µg/gof feces) in five dogs, three of which also had hypoalbu-minemia. The fecal excretion of intravenously adminis-tered 51CrCl3 was increased in three of four dogs, whichalso had increased Fα1-PI concentrations, indicating ahigh prevalence of PLE in this breed.5

We have also obtained Fα1-PI results from approxi-mately 100 Lundehunds in North America, more than40% of which had mean Fα1-PI concentrations of 9.4µg/g or more, suggesting that PLE is common in Nor-wegian Lundehunds. It should be noted that the mea-surement of Fα 1-PI is not indicated in everyLundehund. If a patient presents with chronic clinical

signs of GI disease, has panhypoproteinemia, and hasno hepatic or renal abnormalities, PLE can be diag-nosed without the measurement of Fα1-PI. However,not all patients with PLE have signs of GI disease, andthis test may be useful to screen these patients.

The xylose absorption test—This test has been con-ducted in Lundehunds with nonspecific GI signs.7 Axylose solution is administered by gastric gavage using agastric tube. The concentration of xylose in plasma isthen determined at half-hour intervals for 3 hours afterthe test solution has been given.7 Of the three dogstested, only one had a marginally decreased xylose con-centration (43.5 mg/dl after 1 hour).7

Pancreatic Function TestingThe serum canine trypsin-like immunoreactivity

(cTLI) test—Measurement of trypsin and trypsinogenin serum can be used to diagnose exocrine pancreaticinsufficiency (EPI), with a low cTLI concentrationbeing strongly suggestive of EPI.28,33,34 When serumcTLI is normal, abnormal serum vitamin concentrationsindicate the presence of small intestinal disease. In onestudy, serum cTLI concentrations were normal in allseven Lundehunds.5 In addition, we have recently evalu-ated cTLI concentrations in approximately 100 Lunde-hunds. Only one dog had a serum cTLI concentrationdiagnostic for EPI; three additional dogs had slightlysubnormal serum cTLI concentrations. These findingssuggest that EPI is uncommon in Norwegian Lunde-hunds and that decreased serum cobalamin and folateconcentrations almost always reflect malabsorption dueto small intestinal disease.

Figure 8. Collection of a fecal sample to measure theαα1-proteinase inhibitor concentration. Approximately 1 g offeces has to be collected into special tubes.

www.cvm.tamu.edu/gilab



Hepatic Function TestingThe bromosulphophthalein (BSP) retention test—

This test was used to evaluate hepatic function in 11 Nor-wegian Lundehunds.1 BSP is a cholephilic dye that isadministered intravenously, undergoes hepatic uptake, andis excreted in bile. An increased retention of BSP 30 min-utes after administration may indicate impaired hepaticfunction.35,36 Flesjå and Yri1 found a 30-minute BSPretention of 30% in one Lundehund and less than 10% inthe other 10 dogs, indicating normal liver function in allbut one of the dogs. It was concluded that the high reten-tion rate for the one dog may have been due to the factthat the dog had ascites, although the authors did notspeculate as to the mechanism of this association.1 Possiblecauses may be hepatic congestion, delayed cholephil circu-lation to the liver, diffusion of BSP into ascitic fluid, oreven an overdose of BSP due to falsely increased bodyweight resulting from abdominal fluid accumulation.35,36

Although the test used has subsequently been shown tohave poor sensitivity and specificity compared with serumbile acid and ammonia testing, these data suggest thatLundehunds generally have normal hepatic function.35

SummaryOne of the most dramatic changes apparent in Lunde-

hund gastroenteropathy is protein loss, which can be severein individual patients. Therefore, serum total protein, albu-min, and globulin concentrations should be evaluated inLundehunds presenting with clinical signs of small intes-tinal disease. If PLE is suspected, but serum protein con-centrations are not grossly abnormal, the Fα1-PI test maybe helpful in the diagnosis because the Fα1-PI concentra-tion may be increased before the serum protein concentra-tion becomes abnormal.28 Another important parameter inassessing small intestinal disease in Lundehunds is theserum cobalamin concentration, which should ideally beevaluated in combination with the serum folate and cTLIconcentrations. Potential deficiencies of other nutrients,including vitamins A, D, E, and K, should be considered.

UrinalysisUrine parameters examined included color, odor, sedi-

ment, pH, specific weight, and the presence of blood aswell as concentrations of protein, sugar, bilirubin, ketonebodies, and bacteria. Samples were examined in twostudies, but no abnormalities were reported.1,5 This fur-ther confirms that hypoalbuminemia and hypoproteine-mia in Norwegian Lundehunds are results of entericrather than renal protein loss.

Fecal Sample AnalysisSeveral studies have investigated potential irregulari-

ties in Lundehund feces, which are often grossly mucoidor excessively liquid and have a sour or fetid smell inaffected dogs.1,7 Bacteriologic and parasitologic exami-nations have not revealed any abnormalities.1

Diagnostic ImagingFindings from diagnostic imaging using radiography

or ultrasonography are often nonspecific in dogs withGI disease, and it can be especially difficult to differen-tiate intestinal lymphangiectasia from other types ofsmall intestinal disease.17 Nevertheless, ultrasonographicexamination in patients with suspected intestinal diseasecan confirm the suspicion and facilitate initiation of fur-ther diagnostics, such as endoscopy and histopathologyof biopsy specimens. Abdominal ultrasonography canshow various degrees of intestinal wall thickening,hyperechogenicity of the small intestinal mucosa, loss ofintestinal wall layering, and regional lymphadenopa-thy.17,37 In one study that evaluated ultrasonographiccharacteristics in 17 dogs (none of which was a Lunde-hund) with intestinal lymphangiectasia, ultrasono-graphic abnormalities did not seem to correlate with theseverity of intestinal lymphangiectasia, and the smallintestinal wall thickness observed during ultrasonogra-phy did not always correlate with the thickening of thesmall intestine seen during surgery in the dogs investi-gated.17 Another investigation found intestinal wallthickness and loss of wall layering to be significantlygreater in dogs with intestinal neoplasia compared withdogs with intestinal inflammation.37 Regional lym-phadenopathy also seems to be more common and moresevere in patients with intestinal neoplasia.37,38 None ofthe studies investigating intestinal disease in NorwegianLundehunds has described diagnostic imaging. There-fore, it is unclear how Lundehund gastroenteropathywould manifest during abdominal radiography or ultra-sonography. However, it is reasonable to assume thatfindings during these imaging studies would mirrorthose in dogs with similar GI disorders.

In summary, diagnostic imaging is useful in determin-ing the presence of intestinal disease, and although find-ings can be very heterogeneous and do not always yieldenough information to differentiate types of small intes-tinal disease, diagnostic imaging can be an indicator ofwhether neoplasia may be present.37,38 To obtain a defini-tive diagnosis, histopathologic examination is still neededin most cases of dogs with small intestinal disease.17,39



Endoscopic Imaging and GastrointestinalBiopsy

Endoscopy is often performed on patients with GIdisease for which a definitive diagnosis is unclear, and itcan yield valuable information regarding the site andseverity of the lesions. In the only study on endoscopyin a Lundehund, the authors reported gastropathy andenteropathy characterized by abnormal retention offood in the stomach and hyperemia of the gastricmucosa and a granular appearance of the duodenalmucosa, respectively.5 The authors did not specifywhere in the stomach the lesions were observed. Theseresults should be viewed only as preliminary because alarger number of Lundehunds must be investigated toevaluate the significance and prevalence of these find-ings in this breed.

GI biopsies can be obtained through endoscopy orlaparotomy, each of which has advantages and disadvan-tages.40 Obtaining biopsies during endoscopy is lessinvasive, usually requires a shorter anesthesia time, andis associated with less risk compared with surgery.22,40 Italso allows sampling of many biopsies and enables theclinician to evaluate the sampling sites before biopsy sothat mucosal lesions that are not visible from the serosalsurface can be specifically targeted if the gastroen-teropathy appears to have a patchy distribution, thusminimizing the risk of missing affected areas.22,40 Thedisadvantages are that certain areas of the intestine, such

as the jejunum, cannot be reached with an endoscope,and it can be difficult to obtain samples of sufficientquality to allow a histopathologic diagnosis of intestinallymphangiectasia, which is mainly present in the sub-mucosa or muscular layers of the intestinal wall ratherthan in the mucosa.

Surgical procedures allow biopsy of any area of the GItract as well as full-thickness biopsies that are often ofbetter diagnostic quality than endoscopically obtainedones.40 In general, if the clinician suspects that lym-phangiectasia is present, a surgical biopsy may be neces-sary to confirm the diagnosis, but the increased risksassociated with surgery should be considered.

TREATMENTIn all cases of Lundehund gastroenteropathy, the

treatment is symptomatic because an underlying, treat-able cause has not been identified. No single therapeuticplan is ideal in all cases, and individual dogs seem torespond differently to various approaches (Table 1). Nocontrolled studies using different treatment strategieshave been conducted in Lundehunds; therefore, scien-tific statistical data regarding response or remission ratesare not available.

DietIn general, affected Lundehunds should be fed a

highly digestible, low-fat, high-quality protein diet to

Table 1. Medications Used in Treating Lundehund Gastroenteropathy

Drug Dose Use

Medium-chain 1–2 ml/kg/day PO To increase caloric content of food whentriglyceride oil long-chain fatty acids are restricted

Cobalamin See Table 2 To treat cobalamin deficiency

Folic acid 10 µg/kg PO q24h To treat folate deficiency

Tylosin 25 mg/kg PO q12h To treat IBD and SIBO

Metronidazole 10–20 mg/kg PO q12h for 2–4 wk To treat IBD and SIBO

Oxytetracycline 20 mg/kg q8h or q12h To treat IBD and SIBO

Prednisone 2 mg/kg PO q12h for 1 wk, then 1 mg/kg PO q12h for To treat IBD; as an immunosuppressant 6 wk, then taper to lowest possible maintenance dose or antiinflammatory

Azathioprine 2 mg/kg PO q24h for 2 wk, then every other day for To treat IBD; as an immunosuppressant 2 weeks, then taper to 1 mg/kg every other day or antiinflammatory

Dolasetron 0.3–0.6 mg/kg IV or SC q12–24h As an antiemetic

Metoclopramide 0.2–0.5 mg/kg PO, SC, or IV q8–24h As an antiemetic


468 CE

relieve the absorptive load on theintestinal lymphatic system. Medium-chain triglycerides have historicallybeen fed because some may beabsorbed by a nonlymphatic route,decreasing the burden on the lym-phatic system.41,42 However, this hasnot been verified in NorwegianLundehunds with gastroenteropathy.

VitaminsVitamin supplementation can be

of value, especially if the serumcobalamin concentration is low.Supplementation often dramaticallyimproves the health of dogs withchronic small intestinal disease.Given the chronic nature of Lunde-hund gastroenteropathy, lifelongvitamin supplementation is likely tobe necessary.

CobalaminCobalamin must be administered

parenterally because enteral absorp-tion is compromised and insufficientto treat cobalamin deficiency. Therecommended initial weekly dose is250 µg SC for dogs weighing up to11 lb (5 kg) and 500 µg SC forheavier dogs. Once the serum cobal-amin concentration has normalized,it may be maintained within thenormal range by monthly injections(Table 2).

Folate and Folic AcidFolate deficiency can almost

always be rectified by folic acid sup-plementation (10 µg/kg/day PO).

Other VitaminsIn dogs with chronic GI disease,

serum concentrations of other vita-mins, such as vitamins A, D, E, andK, may be decreased as well. How-ever, this has not been studied inLundehunds with gastroenteropa-thy.



AntibioticsAntibiotic therapy may be helpful in some affected

Lundehunds, probably because of their increased predis-position to SIBO.21 Tylosin, metronidazole, or oxytetra-cycline at standard doses may be useful adjuncts intreating Lundehund gastroenteropathy.

Immunosuppressants andAntiinflammatories

Immunosuppressants and/or antiinflammatories, suchas prednisone, prednisolone, or azathioprine, are fre-quently used and may have to be given for extended peri-ods to control clinical signs in Lundehunds. The exactmechanism of action of these drugs is unclear, althoughtheir effect is most likely due to a combination of antiin-flammatory action, which controls conditions such asIBD, and immunosuppression, which prevents the intes-tinal immune system from overreacting. In the case ofprednisolone, a certain stimulatory effect on enterocytescould also be beneficial.43 Prednisolone has been shown toinduce an increase in jejunal and ileal absorptive capacityand to lead to an increased synthesis of brush-border andmembrane proteins in rats, thus assisting repair of dam-aged mucosa.43 No controlled studies have investigatedthe use of azathioprine in dogs with GI disease.

Octreotide and Antiplasmin TherapySome of the new therapies for intestinal lymphang-

iectasia and PLE in humans include administration ofoctreotide (a somatostatin analogue) and antiplasmin. Itis not fully understood how octreotide acts as a treat-ment in intestinal lymphangiectasia, but it is thought toreduce intestinal blood and lymph flow and inhibittriglyceride absorption, thereby relieving clinical signs.44

Antiplasmin treatment with tranexamic acid has beensuccessfully used in humans with increased tissue fibri-nolytic activity, which can cause PLE by increasing vascu-lar permeability.45,46 No studies regarding the use ofoctreotide or tranexamic acid in dogs with PLE havebeen conducted; therefore, the therapeutic value of theseproducts is unclear. Patients with hypoproteinemia due toPLE may also be antithrombin III deficient and, there-fore, in a hypercoagulable state, which may theoreticallyincrease the risk for thromboembolic disease whenantifibrinolytic agents are administered. These patientsmay benefit from low-dose aspirin (0.5 mg/kg PO q24h).

Other Palliative TreatmentsFurther symptomatic treatment may include tempo-

rary administration of diuretics when ascites or subcuta-

neous edema is present. Antiemetic medications, such asdolasetron or metoclopramide, can be used if the dogexhibits frequent vomiting or nausea.

PROGNOSISThe prognosis for patients with Lundehund gastroen-

teropathy is variable and greatly depends on the patient’sresponse to treatment. The disease is often progressive andcan eventually lead to death due to severe panhypopro-teinemia and generalized debility. Treatment should beattempted using antiinflammatories and/or immunosup-pressants as well as supportive care to improve the clinicalsigns, but complete remission often cannot be achieved inaffected patients. Some Lundehunds require lifelongintermittent treatment to control clinical signs whilemaintaining a good quality of life, whereas others cannotrecover from the initial onset of the disease. Unfortunately,survival data are unavailable due to the lack of scientificlong-term studies and the rarity of this breed, but we arecurrently monitoring a large number of Lundehunds inNorth America to acquire long-term data.

OUTLOOKFurther studies are needed and under way to under-

stand the cause and pathogenesis of Lundehund gas-troenteropathy. The cause of PLE must be investigatedto identify efficacious treatment strategies. Until thenature of the underlying defect is identified, diagnosticand therapeutic possibilities are limited.

REFERENCES1. Flesjå K, Yri T: Protein-losing enteropathy in the Lundehund. J Small Anim

Pract 18:11–23, 1977.

Table 2. Cobalamin Supplementation inNorwegian Lundehunds: RecommendedDoses and Time Regimens

Body Weight Dose (µg SC)/Follow-up

<5 kg (<11 lb) 2505–15 kg (11–33 lb) 500

Time Regimen (wk)

1–6 Once/wk

7–12 Once every 2 wk

16 One additional injection

20 Recheck serum cobalaminconcentration



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3. Frimann-Clausen C, Laane M: Cyto-genetical and anatomical studies in theLundehound, a deviating member of the Canis familiaris palustris group. NyttMag Zool 16:72–78, 1968.

4. Kolbjørnsen Ø, Press CM, Landsverk T: Gastropathies in the Lundehund, I:Gastritis and gastric neoplasia associated with intestinal lymphangiectasia.Acta Path Microbiol Immunol Scand 102(9):647–661, 1994.

5. Williams DA, Melgarejo T: Gastroenteropathy in Norwegian Lundehunds inthe USA [abstract]. J Vet Intern Med 11:114, 1997.

6. Landsverk T, Gamlem H: Intestinal lymphangiectasia in the Lundehund.Acta Path Microbiol Immunol Scand 92:353–362, 1984.

7. Ropstad E: Lundehundsyndromet: Det kliniske bildet. Norsk Veterinær-tidsskrift 95(5):305–310, 1983.

8. Kolbjørnsen Ø, Press CM, Landsverk T: Gastropathies in the Lundehund,II: A study of mucin profiles. Acta Path Microbiol Immunol Scand102(11):801–809, 1994.

9. Kapadia CR: Gastric atrophy, metaplasia, and dysplasia. A clinical perspec-tive. J Clin Gastroenterol 36(suppl 1):S29–S36, 2003.

10. Morson BC, Sobin LH, Grundmann E, et al: Precancerous conditions andepithelial dysplasia in the stomach. J Clin Pathol 33:711–721, 1980.

11. Finco DR, Duncan JR, Schall WD, et al: Chronic enteric disease andhypoproteinemia in 9 dogs. JAVMA 163(3):262–271, 1973.

12. Meschter CL, Rakich PM, Tyler DE: Intestinal lymphangiectasia withlipogranulomatous lymphangitis in a dog. JAVMA 190(4):427–430, 1987.

13. Van Kruiningen HJ, Lees GE, Hayden DW, et al: Lipogranulomatous lym-phangitis in canine intestinal lymphangiectasia. Vet Pathol 21:377–383, 1984.

14. Burns MG: Intestinal lymphangiectasia in the dog: A case report and review.JAAHA 18:97–105, 1982.

15. Kalima TV: The structure and function of intestinal lymphatics and theinfluence of impaired lymph flow on the ileum of rats. Scand J Gastroenterol10(suppl):1–87, 1971.

16. Mazzie JP, Maslin PI, Moy L, et al: Congenital intestinal lymphangiectasia:CT demonstration in a young child. J Clin Imaging 27(5):330–332, 2003.

17. Kull PA, Hess RS, Craig LE, et al: Clinical, clinicopathologic, radiographic,and ultrasonographic characteristics of intestinal lymphangiectasia in dogs:17 cases (1996–1998). JAVMA 219(2):197–202, 2001.

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19. Bush WW, Kimmel SE, Wosar MA, et al: Secondary hypoparathyroidismattributed to hypomagnesemia in a dog with protein-losing enteropathy.JAVMA 219(12):1732–1734, 2001.

20. Kimmel SE, Waddell LS, Michel KE: Hypomagnesemia and hypocalcemiaassociated with protein-losing enteropathy in Yorkshire terriers: Five cases(1992–1998). JAVMA 217(5):703–706, 2000.

21. Hall E, German A: Diseases of the small intestine, in Ettinger S, Feldman E(eds): Textbook of Veterinary Internal Medicine. St. Louis, Elsevier Saunders,2005, pp 1333–1378.

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1. Norwegian Lundehunds frequently developa. PLE. c. pancreatitis.b. EPI. d. hepatitis.

ARTICLE #1 CE TESTThis article qualifies for 2 contact hours of continuingeducation credit from the Auburn University College of Veterinary Medicine. Subscribers may purchaseindividual CE tests or sign up for our annual CE program. Those who wish to apply this credit to fulfill state relicensure requirements should consult theirrespective state authorities regarding the applicability of this program. CE subscribers can take CE tests onlineand get real-time scores at CompendiumVet.com.

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2. __________ are the most common clinical signs ofLundehund gastroenteropathy.a. Weight loss and increased appetiteb. Vomiting and weight lossc. Vomiting, diarrhea, weight loss, and ascitesd. Flatulence and diarrhea

3. Which parameters are useful in assessing patientswith suspected Lundehund gastroenteropathy?a. Fα1-PI concentrationb. serum albumin, globulin, and total protein concentra-

tionsc. serum cobalamin and folate concentrationsd. all of the above

4. Which serum protein concentration usuallydeclines first in Lundehunds with GI disease?a. globulin b. albuminc. total proteind. the albumin and globulin concentrations decrease

simultaneously

5. Which serum or blood parameter abnormalityoften occurs in Norwegian Lundehunds with gas-troenteropathy?a. leukocytosisb. a decrease in the serum cTLI concentrationc. hypocalcemiad. an elevated liver enzyme concentration

6. ________ appears to be the major cause of the lowserum total calcium concentration in Lundehunds.a. Malabsorption

b. Malnutritionc. Vitamin D deficiencyd. Loss of protein-bound calcium

7. Serum cobalamin and folate concentrations canbe abnormal as a result of small intestinal malab-sorption or other conditions, especially EPI.Therefore, which serum parameter(s) shouldalso be determined when evaluating serumcobalamin and folate concentrations?a. serum pancreatic lipase immunoreactivity b. serum cTLI concentrationc. serum calcium concentrationd. liver enzyme activities

8. Which section(s) of the GI tract is most com-monly affected in Lundehund gastroenteropathy?a. the stomach and small intestineb. the small and large intestinesc. the small intestined. the entire GI tract

9. Which histopathologic change(s) can be detectedfrom GI biopsies in Lundehunds?a. chronic atrophic gastritisb. intestinal lymphangiectasiac. lymphoplasmacytic enteritis and villus atrophyd. all of the above

10. Which is not indicated in treating Lundehundgastroenteropathy?a. cobalamin supplementationb. diureticsc. pancreatic enzymesd. glucocorticoids



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