Anaemia in Waldmann’s disease: A rare presentation of a rare disease

Abstract

A 32-year-old female presented with 5-year history of iron deficiency anemia, marked pallor and edema of both lower limbs. Laboratory investigations including complete blood count, blood film, iron studies, lipid profile, ascitic fluid analysis, test of stool for occult blood and alpha 1 anti-trypsin. Upper, lower gastrointestinal (GIT) endoscopies, and enteroscopy were performed. Imaging techniques as abdominal ultrasonography and computed tomography were done. Echocardiography, lymph node biopsy and bone marrow examination were normal. The case was diagnosed as Waldmann’s disease with protein losing enteropathy and recurrent GIT bleeding. Management started with low fat diet with medium chain triglyceride, octreotide 200 μg twice a day, tranexamic acid and blood transfusion. Then, exploratory laparotomy with pathological examination of resected segment was done when recurrent GIT bleeding occurred and to excluded malignant transformation.

Key Words: Waldmann’s disease; Lymphangiectasia; Gastrointestinal bleeding; Iron deficiency anemia

Core tip: To our knowledge, this is the first “Egyptian” case of primary intestinal lymphangiectasia. In addition, its presentation is rare with blood loss anemia in contrast to the more common presentation with hypoproteinemia and edema. So, we are reporting a case with a rare clinical presentation of a rare disease. Double balloon enteroscopy was so beneficial in the diagnosis of the case superior to capsule endoscopy because the advantage of biopsy and histopathologic examination. There is controversy about medical treatment options, surgical treatment may be preferred in localized lesions otherwise, has no role. Prognosis may be favorable.

INTRODUCTION

Waldmann’s disease; also called primary intestinal lymphangiectasia (PIL) is a rare form of protein losing enteropathy caused by leakage of lymph inside the small intestinal lumen from dilated lacteals. The manifestations begin before the age of 30 years in 90% of cases, often in childhood. Whether bleeding into gastrointestinal tract a feature of PIL or not is still controversial. Here, we present a case of a young women with chronic blood loss anemia (iron deficiency and positive fecal occult blood test) caused by Waldmann’s disease.

CASE REPORT

A 32-year-old female with 5 year history of iron deficiency anemia was referred to our Gastroenterology Unit for further evaluation. History was irrelevant apart from easily fatigability and repeated blood transfusions as well as iron therapy. Examination revealed marked pallor and edema of both lower limbs.

Laboratory findings of a 32 years old female with Waldmann's disease are shown in Table 1.

Table 1 Laboratory results for the patient.

Test	Result	Normal reference
Complete blood count
Hemoglobin	5.2 g/dL	12-18 g/dL
HCT	18.30%	37%-51%
MCV	70.2 pg	80-97 flpg
MCHC	28.4 g/dL	31-36 g/dL
Platelets	284	140-440 cell/cm3
WBCs	3.8	4.1-10.9 cell/cm3
Lymphocytes	500	600-1400
Blood film
Hypercellular bone marrow with no blast cells
Blood chemistry
s. Albumin	2.1 g/dL	3.5-5 g/ dL
AST	30 IU/L	Up to 40 U/L
ALT	25 IU/L	Up to 45 U/L
s. cholesterol	107 mg/dL	Up to 200 mg/dL
s. triglyceride	54 mg/dL	Up to 160 mg/dL
s. iron	23 ng/dL	28-170 ng/dL
s. ferritin	12 ng/mL	40-430 ng/mL
TIBC	750 ng/dL	261-478 ng/dL
s. TSH	1.2 mIU/L	0.3-3.04 mIU/L
Stool tests
Occult blood	Positive
α-1 AT clearance	2 folds above normal range

HCT: Hematocrit; MCV: Mean corpusclar volume; MCHC: Mean corpuscular hemoglobin concentration; WBCs: White blood cells; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TIBC: Total iron binding capacity; TSH: Thyroid stimulating hormone; α-1 AT: Alpha 1 antitrypsin.

Upper and lower GI endoscopies were done twice within two-month period and did not reveal any gross pathology. So, Fujinon’s Double Balloon Endoscopy System (with 2.8 mm forceps channel) was used to examine the small bowel through oral route down to 310 cm from the ligament of Trietz. Multiple lymphangectasias (Figure 1) were seen starting at about 100 cm, extending all through the assessed parts; some of them were actively bleeding. The most affected area (at about 100 cm) was tattooed with India Ink. Histopathological examination of the lesions revealed multiple dilated vascular and lymphatic spaces and few lymphocytes with no evidence of malignancy, picture consistent with capillary telangiectasia.

Figure 1 Multiple jejunal lymphangiectasia.

Abdominal ultrasonography, abdominal computed tomography (CT), echocardiography, inguinal lymph node biopsy, and bone marrow examination were performed to exclude secondary causes of lymphangiectasia. All tests were normal except for mild splenomegaly (due to multiple hemangiomas).

Management started with low fat diet with medium chain triglyceride, octreotide 200 μg/twice a day, tranexamic acid and blood transfusion till an acceptable level of hemoglobin was achieved (about 9 g/dL). She was discharged on diet regimen and regular follow up.

Nine months later during routine follow up, clinical examination showed marked pallor (Hb 6 g/dL) and abdominal ultrasonography revealed moderate ascites and mild right sided pleural effusion. Ascitic fluid was milky and turbid. Chemical analysis of ascitic fluid sample revealed glucose of 108 mg/dL, total protein of 1170 mg/dL, lactate dehydrogenase of 195 U/L, triglycerides of 1232 mg/dL (diagnostic of chylous ascites), WBCs of 250 cell/cm³ mainly lymphocytes, and RBCs of 0.01 × 10⁶. Cytological examination of ascitic fluid revealed no atypical or malignant cells. ZN stain and adenosine deaminase were negative. Triphasic CT scan was performed by 8 multi-slice G.E. CT scanner. It revealed right pleural effusion, mild ascites; both had uncomplicated fluid density: 0-20HU (Figure 2) and multiple splenic hemangiomas (Figure 3). Regarding small intestine, CT revealed dilated small intestinal loops with diffuse, nodular wall thickening (reaching up to 9 mm), mesenteric hypodense bands representing dilated lymphatic channels and mesenteric edema (Figure 4). Neither lymphadenopathy nor hepatomegaly was detected.

Figure 2 Pre contrast axial computed tomography scan showing (A) mild right-sided pleural effusion and (B) mild ascites.

Figure 3 Triphasic post contrast axial computed tomography showing. Multiple splenic hemangiomas in portal (A) and delayed (B) phases respectively showing filling in (arrows).

Figure 4 Triphasic post contrast axial computed tomography (portal phase) showing. A: Dilated small intestinal wall (arrows); B: Mesenteric hypodense bands indicating obstructed lymphatics (arrows), and dirty fat appearance due to mesenteric oedema (arrow heads).

Surgical opinion was sought and malignant transformation was suspected. So, exploratory laparotomy was done through midline incision. Findings include minimal ascites, multiple cysts related to the small intestinal wall and its mesentry and a discolored segment of the proximal jejunum previously marked with India Ink by enteroscopy (Figure 5) but no masses were found. Resection anastomosis of the discolored segment was done. Histopathological examination revealed large gaping vascular spaces lined by flat endothelial cells and filled by lymph fluid, picture consistent with primary intestinal lymphangectasia (Figure 6).

Figure 5 Exploratory laparotomy, multiple cysts was seen related to the small intestinal wall and its mesentry and a discolored segment of the proximal jejunum.

Figure 6 Histopathological examination of the resected part of small intestine. A: The sub-mucosa shows large gaping vascular filled by RBCs (HE × 40); B: The vascular spaces are lined by flat endothelial cells (HE × 100); C: Black staining is due to labeling material (India Ink) (HE × 100); D: The sub-mucosal vascular are see encroaching upon the mucosal lining (HE × 100); E: Some vascular spaces lined by flat endothelial cells and filled by lymph fluid (HE × 100).

Postoperative outcome was favorable and she was discharged home after 5 d.

On the 20^th postoperative day, patient achieved marked improvement of her general condition, disappearance of edema lower limb, ascites, and pleural effusion. Laboratory investigations were; s. albumin 4.1 g/dL, HB 10.9 g/dL, platelets count 147 cell/cm³, WBCs 4900 cell/cm³ with normal distribution. Six months later, she remained asymptomatic with weight gain of 5 kg and rather stable hemoglobin level.

DISCUSSION

Protein losing enteropathy (PLE) is a rare cause of hypoproteinemia due to gastrointestinal (GI) loss of serum protein. This rare condition has many reported causes (Table 2) including the rare Waldmann’s disease (PIL) in which GI protein loss results from leakage of lymph through the ectatic intestinal lacteals[2].

Table 2 Causes of protein losing enteropathy[1].

Erosive gastrointestinal disease

Inflammatory bowel disease

Gut malignancy

Non steroidal anti-inflammatory drug enteropathy

Erosive gastropathy

Acute graft vs host disease

Pseudomembranous enterocolitis

Ulcerative jejunoenterocolitis

Intestinal lymphoma

Sarcoidosis

Non erosive gastrointestinal disease

Celiac disease

Hypertrophic gastropathies

Eosinophilic gastroenteritis

Connective tissue disorders

Small intestinal bacterial overgrowth

Amyloidosis

Microscopic colitis

Tropical sprue

Whipple's disease

Parasitic diseases

Viral gastroenteritis

Increased interstitial pressure

Intestinal lymphangiectasia

Congestive heart failure

Constrictive pericarditis

Congenital heart diseases

Fontan procedure for single ventricle

Portal hypertensive gastroenteropathy

Hepatic venous outflow obstruction

Enteric lymphatic fistula

Mesenteric venous thrombosis

Sclerosing mesenteritis

Mesenteric tuberculosis or sarcoidosis

Neoplasia involving mesenteric lymph nodes or lymphatics

Chronic pancreatitis with pseudocysts

Congenital malformations of lymphatic

Retoperitoneal fibrosis

PIL predominantly affects young children although it may also be diagnosed in older age. There is slight male preponderance with 3:2 ratio. On the other hand, race is not a predictor of PIL[3,4].

Patients usually present with bilateral lower limb edema[2-7]. Other manifestations like pain, loose motion, and malnutrition are less common[8]. Rare manifestations include abdominal mass, Mechanical ileus[9-11], chylous reflux[12,13], iron deficiency with anemia[14], necrolytic migratory erythema[15], recurrent hemolytic uremic syndrome[16], and osteomalacia[17]. Recurrent gastrointestinal bleeding was even more rare being reported in only 2 cases[18,19].

Work up of diagnosis consist of laboratory, imaging studies and GIT endoscopy with confirmatory histopathological examination[20].

The most common laboratory finding is hypoproteinemia. Hypo-albuminemia is most prominent and lymphopenia. Cholesterol levels are not usually elevated. PLE can be confirmed by presence of excess fecal α1-antitrypsin[21,22].

Abdominal CT scan may show dilated thickened small intestinal loops, ascites, halo sign and edematous mesentery. It also helps rule out secondary causes[23,24].

Diagnosis can only be confirmed by finding dilated lacteals both on endoscopic and histopathologic examination[25,26]. Video capsule endoscopy imaging provides the same information and allow exploration of the whole small bowel but does not allow biopsies[27].

PIL has to be differentiated from secondary causes of intestinal lymphangiectasia such as Crohn’s disease, intestinal tuberculosis, and Whipple’s disease as well as from causes of PLE without lymphangiectasia such as Mentrier’s disease and systemic lupus erythematosus (SLE)[20].

Medical management relies on diet modification with low fat replaced by medium-chain triglycerides thus preventing fat overloading of intestinal lacteal[28,29].

Response to other medications, such as[30-31] octreotide[32-36] and steroids[37] is variable.

Small intestinal resection is indicated in localized forms of the disease[38,39].

Natural history of PIL is greatly variable; depending on involvement of intestine either generalized or localized with blockage of mesenteric lymphatic drainage. Prognosis may be favorable unless it is complicated by intestinal B-lymphoma or effusion in serous sacs[20,40].

COMMENTS

Case characteristics

A 32-year-old female presented with 5-year history of iron deficiency anemia, marked pallor and edema of both lower limbs.

Clinical diagnosis

Examination revealed marked pallor and edema of both lower limbs.

Differential diagnosis

Primary intestinal lymphangiectasia has to be differentiated from secondary causes of intestinal lymphangiectasia such as Crohn’s disease, intestinal tuberculosis, and Whipple’s disease as well as from causes of protein losing enteropathy without lymphangiectasia such as Mentrier’s disease and systemic lupus erythematosus.

Laboratory diagnosis

Patient hemoglobin level and serum albumin were 5.2 g/dL, 2.1 g/dL respectively. α-1 AT clearance was 2 folds above normal range and stool test for occult blood yield positive result.

Imaging diagnosis

Computed tomography of the abdomen revealed dilated small intestinal loops with diffuse, nodular wall thickening, mesenteric hypodense bands representing dilated lymphatic channels and mesenteric edema.

Endoscopy diagnosis

Double balloon enteroscopy was performed, and revealed presence of multiple lymphangectasias, some of them were actively bleeding.

Pathological diagnosis

Histopathological examination of the lesions revealed multiple dilated vascular and lymphatic spaces and few lymphocytes with no evidence of malignancy, picture consistent with capillary telangiectasia.

Treatment

Management started with low fat diet with medium chain triglyceride, octreotide 200 μg/twice a day, tranexamic acid and blood transfusion till an acceptable level of hemoglobin was achieved (about 9 g/dL). But the results was unsatisfactory.

Related reports

Only two cases with primary intestinal lymphangiectasia were presented in literatures by gastrointestinal bleeding.

Term explanation

Chronic blood loss anemia (iron deficiency and positive fecal occult blood test) could be a one of manifestation of primary intestinal lymphangiectasia.

Experiences and lessons

This case report represents a case of primary intestinal lymphangiectasia with rare presentation, recurrent gastrointestinal bleeding and iron deficiency anemia. Also, it yields our experience with different treatment modalities that could be used.

Peer-review

The article highlights the clinical characteristics, diagnostic modalities and treatment options available for primary intestinal lymphangiectasia.