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\begin{document}

\title{Diagnostic Dilemma In Diagnosing Rare Cause Of Protein Losing
Enteropathy:Waldmann's Disease}



\author[1]{Sarita Prajapati}%
\author[2]{Sujan Bohara}%
\author[3]{Gaurab Mainali}%
\author[3]{Samikshya Karki}%
\author[4]{Sharan Thapa}%
\author[1]{Nirjala Aryal}%
\affil[1]{Birendra Military Hospital}%
\affil[2]{Nepal Mediciti}%
\affil[3]{Nepalese Army Institute of Health Sciences College of Medicine}%
\affil[4]{Lekhnath City Hospital Pvt. Ltd.}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Waldmann's disease / Primary intestinal lymphangiectasia, is an unusual
cause of protein losing enteropathy primarily characterized by
lymphopenia, hypoalbuminemia and hypogammaglobulinemia. However,
variable clinical presentation results in diagnostic dilemma and
effective management. We present a toddler diagnosed with Waldmann's
disease managed with high protein diet and medium chain triglycerides
supplementation.%
\end{abstract}%



\sloppy


\textbf{Diagnostic Dilemma In Diagnosing Rare Cause Of Protein Losing
Enteropathy:Waldmann's Disease}

Sarita Prajapati\textsuperscript{1}, Sujan Bohara\textsuperscript{2},
Gaurab Mainali\textsuperscript{3}, Samikshya Karki\textsuperscript{3},
Sharan Thapa\textsuperscript{4}, Nirjala Aryal\textsuperscript{1}

\textsuperscript{1} Department of Pediatrics, Birendra Military
Hospital, Chhauni, Kathmandu, Nepal.

\textsuperscript{2} Department of General and Gastrointestinal Surgery,
Nepal Mediciti Hospital, Lalitpur, Nepal

\textsuperscript{3} Nepalese Army Institute of Health Sciences,
Kathmandu, Nepal

\textsuperscript{4} Lekhnath City Hospital Private Limited, Pokhara,
Nepal

\textbf{Corresponding Author:} Dr. Sujan Bohara, Nepal Mediciti
Hospital, Lalitpur, Nepal

\textbf{Email} \textbf{address} : mjsujan777@gmail.com \textbf{Phone} :
+977-9860103009

Disclosures can be found in Additional Information at the end of the
article\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Abstract} Waldmann's disease / Primary intestinal
lymphangiectasia, is an unusual cause of protein losing enteropathy
primarily characterized by lymphopenia, hypoalbuminemia and
hypogammaglobulinemia. However, variable clinical presentation results
in diagnostic dilemma and effective management. We present a toddler
diagnosed with Waldmann's disease managed with high protein diet and
medium chain triglycerides supplementation.\tabularnewline
\bottomrule
\end{longtable}

\textbf{Keywords: Waldmann's disease, protein losing enteropathy,
intestinal lymphangiectasia, medium chain triglycerides}

\textbf{Introduction}

Intestinal lymphangiectasis is rare cause of protein losing enteropathy
characterized by diffuse or local dilatation of the enteric lymphatics
mostly presenting with feature of hypoproteinemia leading to bilateral
lower limb edema, ascites or rarely anasarca. Waldmann and Schwabb in
1961 reported this rare disease with intestinal protein loss leading to
hypoproteinemia and anasarca.(1) Intestinal lymphangiectasia can be
either primary (idiopathic) or secondary. Primary intestinal
lymphangiectasia usually occurs in children and adolescents, due to the
congenital deformity of the small bowel lymphatic system, whereas
secondary intestinal lymphangiectasia is more often seen in adults and
occurs secondary to an elevated lymphatic pressure such as in lymphoma,
systemic lupus erythematosus, inflammatory bowel disease, malignancies,
constrictive pericarditis, and cardiac surgery.(2)

Primary intestinal lymphangiectasia (PIL) is a congenital disorder of
the lymphatic system characterized by marked ectasia of the lymphatic
vessels resulting in obstruction and leakage of lymph fluid.(3) The time
of presentation may be vary from early childhood to adult with different
presentation. Diagnosis of primary intestinal lymphangiectasia done with
histo-pathological examination of biopsy taken from the involved part of
the intestine via demonstrating dilated lymphatics in mucosa, sub mucosa
and serosa in the absence of coexistent inflammation.(2,4,5) Treatment
vary from symptomatic management like nutritional supplement to advanced
surgical treatment. (2,3)

We herein reported a 3 years old toddler with primary intestinal
lymphangiectasia presented with periorbital edema, abdominal distension
with bilateral pitting edema i.e generalized anasarca managed with
medium chain triglycerides, high protein diet and multivitamin with fat
soluble vitamin supplementation.

\textbf{Case Presentation}

We presented a three-years-old female toddler, product of full term
normal vaginal delivery born out of non-consanguineous marriage,
presented in our pediatric department with complaint of abdominal
distension since 1 month and periorbital as well as bilateral limb
swelling since 3 days.There was no history of passing of red color
urine, urgency, frequency, painful micturition, cough, altered
sensorium, abnormal body movement, headache, photophobia, rash, joint
pain. Her feeding and activities were normal. There was no history of
recurrent infections, chronic or significant genetic diseases in her
family.

Her anthropometric and nutritional assessment affirmed as follows;
Height- 91 cm, Weight-14.5 kg, HC- 47 cm, MUAC-13 cm, Weight for age- 0
to -1 SD, Height for age- 0 to +1 SD, Weight for height- +1 to +2 SD

Physical examination revealed bilateral lower limb pitting edema with
periorbital edema and distended abdomen (with abdominal girth of 56 cm
at umbilicus level) with flank fullness, slit-like centrally placed
umbilicus along with presence of fluid thrill and shifting dullness but
hepatosplenomegaly was not noted. Other systemic finding and vital
parameters were within normal limit.

Patient had been admitted with provisional diagnosis of nephrotic
syndrome and further work-up was done.Initial laboratory reports
revealed anemia (Hb 11.2 gm/dl), lymhopenia (15\%), thrombocytosis
(668000/mm\textsuperscript{3}), hypocalcemia (8 mg/dl), normal
C-reactive protein, liver function test, renal function test and
electrolytes, lipid profile and thyroid function test. Peripheral blood
smears showed microcytic hypochromic anemia with thrombocytosis. Iron
profile and fat soluble vitamin assessment showed decreased in total
iron level (54 mcg/dl) and decreased vitamin D (13.6 ng/dl)
respectively. Ultrasonography of whole abdomen showed moderate ascities,
multiple enlarged mesenteric lymph nodes with mildly diffused mucosal
thickening of bowel loop but normal shape, outline and echo-texture of
hepatic, renal and splenic structure.Urinalysis, culture and sensitivity
and a 24- hour urinary protein (2.7 gm/dl) were normal which ruled out
the renal cause. Transthoracic echocardiography appeared normal thus
ruling out cardiac cause through clinical examination and
echocardiography. Ascitic fluid analysis revealed triglycerides rich
chylous ascites (exudative type). Upper gastrointestinal endoscopy (Fig.
1) showed normal mucosa over the esophago-gastric region along with
white patches or streaks over the 1\textsuperscript{st} and
2\textsuperscript{nd} part of duodenum. H and E staining of Duodenal
biopsy (Fig. 2) showed tissue lined by columnar epithelium forming
crypts and villi with apical goblet cells and multiple dilated lymphatic
channels in lamina propria with inflammatory infiltrates comprising of
lymphocytes, plasma cells and eosinophils suggestive of intestinal
lymphangiectasia. Colonoscopy showed no any distint mucosal
abnormalities. Other biological workup like parasitological stool
examination, Serological test (HIV, CMV), and tuberculosis assessment
appears normal. ANA, anti-double stranded DNA and IgA, anti-tissue
transglutaminase were negative. Serum electrophoresis revealed decrease
in IgG serum protein with normal other types of proteins.

Considering all the clinical history examination and investigations, a
diagnosis of primary intestinal lymphangiectasia (Waldmann's Disease)
was considered. Thereafter, child was treated with human albumin
infusion as a protein supplements (@ 1 gm/kg, 75ml over 3 hours once a
day for 3 days) with furosemide, multivitamins including fat-soluble
vitamin, oral iron (syrup ferrofolic @ 4mg/kg/day), calcium
supplementation (syrup calvit @40 mg/kg/day) and MCT (Medium Chain
Triglyceride) based oils.She responded to the treatment dramatically
along with gradual stabilization and improvement in her clinical
conditions and discharged on the 3\textsuperscript{rd} week after her
admission along with advice on intake of protein rich diet, low fat diet
and MCT oil based food supplementation on her diet as a lifelong dietary
therapy.

Regular follow up was done once a month for first 3 months and then
every three monthly from the diagnosis made till 18 months of diagnosis.
Follow up visit showed satisfactory result, as child physical growth was
not hampered, no any symptoms developed during follow up period and
investigation were within normal limit.

\textbf{Discussion}

Waldmann et al. first described 18 cases of ''idiopathic hypercatabolic
hypoproteinemia in 1961.(1) Intestinal lymphangiectasia is an uncommon
but important cause of protein loss intolerance and is characterized by
poor lymph drainage in small intestines associated with enlarged
lymphatic channels. The prevalence of clinically PIL is not known.(2,6)
It occurs mainly in children and is equally common among both
sexes.(6,7) Although most cases are sporadic, Le Bougeant et al reported
rare familial forms of Waldmann's disease.(8,9)

Primary and secondary, are the two types of intestinal lymphangiectasia
described in literature according to cause of the disease. In primary
lymphangiectasia, there is no predisposing condition to increased lymph
pressure and is probably caused by congenital anatomical malformation of
the lymphatic system. PIL is associated with Yellow nail syndrome,
Klippel-trenaunay-Weber syndrome, Von Recklinghausen, Noonan, Turner and
Hennekam.(1--4) There is no given associated disease in our case. Hokari
et al. reported inconsistently changed expressions of regulatory
molecules for lymphangiogenesis in the duodenal mucosa of PIL
patients.(10) Secondary intestinal lymphangiectasia is an acquired
disease characterized by an increased leakage of the intestinal lymph,
secondary to an increase in pressure due to obstruction in the
lymphatics. (2)

The diagnosis is based on a set of clinical, biological, radiological,
endoscopic and histopathological. The disease is characterized by
hypoproteinemia, lymphocytopenia, edema and ascites. Clinical
manifestations may be presented as asymptomatic or fatigue, lower
abdominal pain, edema, chylothorax, chronic diarrhea, ascites.(1--6,8)
Iron deficiency anemia and hypocalcemic tetany can be observed.(2,8)
Supporting the fact, our case also had micronutrient deficiency of Iron
and calcium /Vitamin D3. Along with above clinical features , Stool
analysis may show steatorrhea and increased \selectlanguage{greek}α \selectlanguage{english}anti trypsin clearance
(\textgreater{}24 ml/day) .(2,8,11) PIL diagnosis is confirmed by the
presence of intestinal lymphangiectasia based on endoscopic findings
with the corresponding histology of intestinal biopsy specimens.(12) .
Histological examination of duodenum-jejunum and ileum biopsies confirms
the presence of lacteal juice, dilated mucosal (from moderate to severe)
and submucosal lymphatic vessels (and also in the serosa) with
polyclonal normal plasma cells.(2)(11) Martins et. al reported an
enteroscopy showing white spots with a ``snowflake'' appearance, which
are the typical findings of intestinal lymphangiectasia.(8) Sometimes,
endoscopy may be negative when there is segmental or localized lesion.
In that cases, videocapsule endoscopy is a useful tool to detect the
presence of intestinal lymphangiectasia and to specify its localization.
(2) Exclusion of secondary causes of intestinal lymphangiectasia like
erosive and non-erosive intestinal disorders, conditions involving
mesenteric lymphatic obstruction and cardiovascular disorders that
increase central venous pressure, is necessary for definitive diagnosis
of Waldmann's disease. (8)

A wide range of presenting symptoms provide a challenge to appropriate
therapy. The treatment protocol depends on presenting symptoms
localization of disease and associated complications. The treatment is
based on a diet free of long-chain lipids, enriched with protein and
medium-chain triglycerides.(2--8,11) But, Ballinger et al, stated that
it doesn't always give good results.(13) .In literature reported by
Aoyagi et al, In patients not responding to a low fat diet, enteral
nutritional therapy (elemental, semi-elemental and polymeric diets) may
be required.(14) It was reported that somatostatins such as octreotide
can decrease triglyceride absorption.(2,3,8,13) Antiplasmin therapy may
have some role when fibrinolysis is increased.(2,11) Surgical treatment
is helpful in localized intestinal involvement, intestinal
obstruction.(2,8)

\textbf{Conclusions}

Rareity and variable presentation of disease can led into dilemma in
diagnosing the disease and management. Clinician should be aware about
this rare disease and consider as one of the differential whenever
patient clinically presents with anasarca, lymphedema with peri-orbital
puffiness. Though rare, it can be managed early and effectively with
dietary therapy and nutritional supplementation.

\textbf{Abbreviations:}

1. HC- Head circumference

2. MUAC- Mid Upper Arm Circumference

3. SD- Standard Deviation

4. mg/dl: milligram per deciliter

5. gm/dl: gram per deciliter

6. mm\textsuperscript{3}: cubic millimeter

7. mcg/dl: microgram per deciliter

8. ng/dl: nanogram per deciliter

9. H \& E: Hematoxylin and Eosin

10. ANA: Anti-Nuclear Antibody

11. IgA: Immunoglobulin A

12. IgG: Immuonglobulin G

\textbf{Additional Information}

\textbf{Disclosures}

\textbf{1. Conflicts of interest:} None

\textbf{2. Ethical approval:} Study did not include experiments on
humans or animals

\textbf{3. Consent:} For publication of this case report, informed
written consent was taken from patient parents

\textbf{4. Source of funding:} Authors did not receive any grants for
this study

\textbf{Authors Contributions:}

SP contributed on collection of the case information; SP, SB, GM, SK and
ST contributed on reviewing the literature, designing and writing the
manuscript. SB, SK and GM also contributed on revising, re-editing and
reshaping the manuscript. NA established the diagnosis and revised the
manuscript critically for important intellectual content. All authors
read and approved the final version of the manuscript.

\textbf{References}

1. Waldmann Ta, Steinfeld Jl, Dutcher Tf, Davidson Jd, Gordon Rsj. The
role of the gastrointestinal system in ``idiopathic hypoproteinemia''.
Gastroenterology. 1961 Sep;41:197--207.

2. Vignes S, Bellanger J. Primary intestinal lymphangiectasia
(Waldmann's disease). Orphanet J Rare Dis {[}Internet{]}. 2008 Feb
22;3:5. Available from: https://pubmed.ncbi.nlm.nih.gov/18294365

3. Faul JL, Berry GJ, Colby T V, Ruoss SJ, Walter MB, Rosen GD, et al.
Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and
lymphatic dysplasia syndrome. Am J Respir Crit Care Med. 2000 Mar;161(3
Pt 1):1037--46.

4. Roberts SH, Douglas AP. Intestinal lymphangiectasia: the variability
of presentation. A study of five cases. Q J Med. 1976
Jan;45(177):39--48.

5. Hilliard RI, McKendry JB, Phillips MJ. Congenital abnormalities of
the lymphatic system: a new clinical classification. Pediatrics. 1990
Dec;86(6):988--94.

6. El Haddar Z, Sbia Y, Rkain M, Benajiba N, Babakhouya A. Complicated
primary intestinal lymphangiectasia (Waldmann's disease) in a child
successfully treated with octreotide: A case report from a low-resource
setting. Ann Med Surg {[}Internet{]}. 2021 Jul 29;68:102588. Available
from: https://pubmed.ncbi.nlm.nih.gov/34401115

7. Tift WL, Lloyd JK. Intestinal lymphangiectasia. Long-term results
with MCT diet. Arch Dis Child {[}Internet{]}. 1975 Apr;50(4):269--76.
Available from: https://pubmed.ncbi.nlm.nih.gov/50050

8. Martins CR, Gagnaire A, Rostain F, Lepage C. Waldmann's disease: a
rare cause of protein losing enteropathy in an adult patient. Rev Esp
enfermedades Dig organo Of la Soc Esp Patol Dig. 2017 May;109(5):385--8.

9. Le Bougeant P, Delbrel X, Grenouillet M, Leou S, Djossou F, Beylot J,
et al. {[}Familial Waldmann's disease{]}. Ann Med Interne (Paris). 2000
Oct;151(6):511--2.

10. Hokari R, Kitagawa N, Watanabe C, Komoto S, Kurihara C, Okada Y, et
al. Changes in regulatory molecules for lymphangiogenesis in intestinal
lymphangiectasia with enteric protein loss. J Gastroenterol Hepatol.
2008 Jul;23(7 Pt 2):e88-95.

11. Levitt DG, Levitt MD. Protein losing enteropathy: comprehensive
review of the mechanistic association with clinical and subclinical
disease states. Clin Exp Gastroenterol {[}Internet{]}. 2017 Jul
17;10:147--68. Available from: https://pubmed.ncbi.nlm.nih.gov/28761367

12. Lai Y, Yu T, Qiao X-Y, Zhao L-N, Chen Q-K. Primary intestinal
lymphangiectasia diagnosed by double-balloon enteroscopy and treated by
medium-chain triglycerides: a case report. J Med Case Rep. 2013
Jan;7:19.

13. Ballinger AB, Farthing MJ. Octreotide in the treatment of intestinal
lymphangiectasia. Eur J Gastroenterol Hepatol. 1998 Aug;10(8):699--702.

14. Aoyagi K, Iida M, Matsumoto T, Sakisaka S. Enteral nutrition as a
primary therapy for intestinal lymphangiectasia: value of elemental diet
and polymeric diet compared with total parenteral nutrition. Dig Dis
Sci. 2005 Aug;50(8):1467--70.

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