Primary Intestinal Lymphangiectasia
Synonyms and keywords: PIL, Waldmann disease, Waldmann's disease

# Overview
Primary intestinal lymphangiectasia (Waldmann's disease) was first discovered by Waldmann T.A. in 1961, when he reported 18 cases of patients having edema with low serum albumin, gammaglobulin, and protein levels and he called it ''idiopathic hypercatabolic hypoproteinemia". PIL develops as a result of enlargement or dilatation of intestinal lymphatic vessels (lacteals) with leakage of their contents into the bowel lumen leading to hypoalbuminemia, hypogammaglobulinemia, and lymphopenia. The cause of PIL has not yet been identified. The prevalence of PIL is unknown. It can be asymptomatic. It primarily affects children (generally diagnosed before the age of 3) and young adults but may be diagnosed later in adults. Symptoms include pitting edema, diarrhea, fatigue, abdominal discomfort, and malabsorption syndrome. PIL is diagnosed by biopsy revealing dilated intestinal lymphatics. Video-capsule endoscopy may be helpful when endoscopic findings are not conclusive. Common complications of PIL include infections, malignant transformation (lymphoma), and skin warts. There is no definitive treatment for PIL; the mainstay of therapy is a low-fat, high protein diet with medium-chain triglyceride oral supplementation and supplemental calcium and vitamins. PIL is associated with significant morbidity and requires adherence to dietary modification and oral supplements; otherwise. it would be associated with poor outcomes and low quality of life. It can be fatal in some cases if anasarca or malignancy develops.

# Historical Perspective
- In 1961, primary intestinal lymphangiectasia (Waldmann's disease) was first discovered by Waldmann T.A., who reported 18 cases of patients having edema with low serum albumin, gammaglobulin, and protein levels and he called it ''idiopathic hypercatabolic hypoproteinemia". Assessment using radio-labeled 131I-albumin resulted in low levels in those patients. In addition, small intestinal biopsies were examined under a microscope revealing different degrees of lymphatic vessel dilatation.
- In 1964, Samman and White first described the yellow nail syndrome, a very rare condition that may be associated with PIL. This syndrome is associated with the following symptoms:
Dystrophic yellow nails
Nail ridging
Loss of lunula
Lymphedema
Pleural effusions
- Dystrophic yellow nails
- Nail ridging
- Loss of lunula
- Lymphedema
- Pleural effusions

# Pathophysiology

## Pathology
- PIL develops as a result of enlargement or dilatation of intestinal lymphatic vessels (lacteals) with leakage of their contents into the bowel lumen leading to hypoalbuminemia, hypogammaglobulinemia, and lymphopenia.
- Hypoproteinemia leads to edema.
- It is a form of protein-losing enteropathy.

## Genetics
- Abnormal expression of the following genes is associated with the pathogenesis of PIL:
VEGFR3
LYVE-1
PROX1 and FOXC2
- VEGFR3
- LYVE-1
- PROX1 and FOXC2

## Associated conditions
- Following five syndromes have been reported to be associated with PIL:
Turner syndrome
Noonan syndrome
von Recklinghausen disease
Klippel-Trenaunay syndrome
Hennekam syndrome
- Turner syndrome
- Noonan syndrome
- von Recklinghausen disease
- Klippel-Trenaunay syndrome
- Hennekam syndrome

## Gross pathology
- On gross pathology, the jejunal villi appear creamy yellowish or whitish due to the dilated lymphatics in the intestinal mucosa.

## Microscopic Pathology
- The most important histopathological characteristics of PIL include:
Dilated intestinal lymphatic vessels
Lacteal juice in the biopsies from duodenum, jejunum, and ileum
- Dilated intestinal lymphatic vessels
- Lacteal juice in the biopsies from duodenum, jejunum, and ileum

# Causes
- The exact underlying cause of PIL has not yet been identified.
- Abnormal expression of the following several genes involved in the development of the lymphatic system is associated with PIL:
VEGFR3 (vascular endothelial growth factor receptor 3)
Forkhead transcriptional factor FOXC2 and SOX18
Prospero-related homeobox-transcriptional factor PROX1
- VEGFR3 (vascular endothelial growth factor receptor 3)
- Forkhead transcriptional factor FOXC2 and SOX18
- Prospero-related homeobox-transcriptional factor PROX1

# Differentiating PIL from other Diseases
- PIL must be differentiated from the secondary causes that lead to intestinal lymphangiectasia such as:
Intestinal tuberculosis
Inflammatory bowel disease
Intestinal lymphoma
Constrictive pericarditis
Sarcoidosis
Systemic sclerosis
Whipple disease
Radiation and/or chemotherapy with retroperitoneal fibrosis
HIV-related enteropathy
- Intestinal tuberculosis
- Inflammatory bowel disease
- Intestinal lymphoma
- Constrictive pericarditis
- Sarcoidosis
- Systemic sclerosis
- Whipple disease
- Radiation and/or chemotherapy with retroperitoneal fibrosis
- HIV-related enteropathy
- PIL must be differentiated from other diseases causing enteric loss of plasma proteins but do not involve intestinal lymphangiectasia such as:
Menetrier's disease
Inflammatory states of systemic lupus erythematosus
- Menetrier's disease
- Inflammatory states of systemic lupus erythematosus

# Epidemiology and Demographics
- The prevalence of PIL is unknown as it can be asymptomatic.
- It primarily affects children (generally diagnosed before the age of 3) and young adults but may be diagnosed later in adults.
- There are rare familial forms that have been reported.

## Age
- PIL is more commonly observed among children (less than 3 years old) and young adults.

## Race
- There is no racial predilection for PIL.

# Risk Factors
- In 1964, Samman and White first described the yellow nail syndrome, a very rare condition that may be associated with PIL. This syndrome is associated with the following symptoms:
Dystrophic yellow nails
Nail ridging
Loss of lunula
Lymphedema
Pleural effusions
- Dystrophic yellow nails
- Nail ridging
- Loss of lunula
- Lymphedema
- Pleural effusions
- Other five syndromes considered as risk factors and associated with primary intestinal lymphangiectasia include:
von Recklinghausen disease or Neurofibromatosis 1 (NF1)
Turner syndrome (X0)
Noonan syndrome
Klippel-Trenaunay syndrome
Hennekam syndrome
- von Recklinghausen disease or Neurofibromatosis 1 (NF1)
- Turner syndrome (X0)
- Noonan syndrome
- Klippel-Trenaunay syndrome
- Hennekam syndrome

# Natural History, Complications and Prognosis
- The majority of patients with PIL remain asymptomatic for years.
- Early clinical features include edema of the lower limbs, diarrhea, and steatorrhea.
- If left untreated, patients with PIL may progress to develop edema of the external genitalia, edema of serous membranes, and life-threatening anasarca.
- Common complications of PIL include:
Infections such as:
Group G streptococcal empyema
Cryptococcal meningitis
Malignant transformation (lymphoma)
Skin warts
- Infections such as:
Group G streptococcal empyema
Cryptococcal meningitis
- Group G streptococcal empyema
- Cryptococcal meningitis
- Malignant transformation (lymphoma)
- Skin warts
- A very rare complication is the gelatinous transformation of bone marrow in which hematopoietic cells and adipocytes are replaced by amorphous extracellular material composed of acid mucopolysaccharides.
- PIL is associated with significant morbidity and requires adherence to dietary modification and oral supplements; otherwise. it would be associated with poor outcomes and low quality of life.
- It can be fatal in some cases if anasarca or malignancy develops.

# Diagnosis

## Diagnostic Criteria

### Biopsy
- PIL is diagnosed by biopsy revealing dilated intestinal lymphatics.

### Video-capsule endoscopy
- Video-capsule endoscopy may be helpful when endoscopic findings are not conclusive.

## History and Symptoms
- The hallmark of PIL is pitting edema which usually affects lower limbs in moderate cases whereas face and external genitalia in severe cases. In some cases, it can extend to serous membranes causing pericardial effusion, pleural effusion, and chylous ascites. Rarely, it can cause anasarca.
- Other symptoms include:
Diarrhea
Steatorrhea
Malabsorption syndrome
Fatigue
Abdominal pain
Abdominal mass
Immunodeficiency
Vitamin D deficiency leading to osteomalacia and convulsions
Iron deficiency anemia
Mechanical ileus
Chylous reflux into skin
Necrolytic migratory erythema
Recurrent GI bleeding
Recurrent hemolytic uremic syndrome
Children have growth retardation, abdominal pain, nausea, and vomiting
Lymphedema may be associated with PIL:
It is less pitting and usually localized to the lower limbs; however, it may involve the upper limbs, breasts, and external genitalia.
Stemmer sign differentiates lymphedema from the pitting edema; in lymphedema, it is impossible to lift and wrinkle the dorsal skin on the second toe due to fibrosis and skin thickening.
- Diarrhea
- Steatorrhea
- Malabsorption syndrome
- Fatigue
- Abdominal pain
- Abdominal mass
- Immunodeficiency
- Vitamin D deficiency leading to osteomalacia and convulsions
- Iron deficiency anemia
- Mechanical ileus
- Chylous reflux into skin
- Necrolytic migratory erythema
- Recurrent GI bleeding
- Recurrent hemolytic uremic syndrome
- Children have growth retardation, abdominal pain, nausea, and vomiting
- Lymphedema may be associated with PIL:
It is less pitting and usually localized to the lower limbs; however, it may involve the upper limbs, breasts, and external genitalia.
Stemmer sign differentiates lymphedema from the pitting edema; in lymphedema, it is impossible to lift and wrinkle the dorsal skin on the second toe due to fibrosis and skin thickening.
- It is less pitting and usually localized to the lower limbs; however, it may involve the upper limbs, breasts, and external genitalia.
- Stemmer sign differentiates lymphedema from the pitting edema; in lymphedema, it is impossible to lift and wrinkle the dorsal skin on the second toe due to fibrosis and skin thickening.

## Laboratory Findings
- Low albumin levels
- Low immunoglobulin IgM, IgA, and IgG levels
- CBC shows lymphopenia
- Elevated 24-hour 1-antitrypsin clearance in stool, which is an indication of the degree of protein loss and disease severity.

## Ultrasound
- Ultrasound may be helpful in the diagnosis of PIL.
- Findings on ultrasound suggestive of PIL include:
Dilation of the intestinal loops
Diffuse regular thickening of the intestinal wall
Mesenteric edema
Ascites (sometimes)
- Dilation of the intestinal loops
- Diffuse regular thickening of the intestinal wall
- Mesenteric edema
- Ascites (sometimes)

## CT scan
- Abdominal CT scan with oral and intravenous contrast medium enhancement may be helpful in the diagnosis of PIL.
- Findings on CT scan suggestive of PIL include:
Diffuse thickening of the small intestinal wall and edema
"Halo sign" (in some cases)
- Diffuse thickening of the small intestinal wall and edema
- "Halo sign" (in some cases)
- CT scan can also detect the localized lesions.

## Albumin scintigraphy
- 99mTechnetium-labeled human serum albumin (99mTc-HSA) scintigraphy may reveal enhancement in the bowel, which indicates protein and lymph leakage into this part.

## Lymphangiography
- CT lymphangiography (CTL) may be helpful in the diagnosis of PIL.
- Findings on lymphangiography suggestive of PIL include the abnormal dilation of the intestinal lymphatics.

# Treatment

## Medical Therapy
- There is no definitive treatment for PIL.
- The mainstay of therapy is a low-fat, high protein diet with medium-chain triglyceride oral supplementation and supplemental calcium and vitamins.
- Other reported therapeutic options include:
Tranexamic acid (used to increase immunoglobulins and lymphocyte count)
Steroids
Octreotide
Albumin infusion
It is a symptomatic treatment to improve hypoalbuminemia and edema but its effect is transient due to continuous lymph leakage into the bowel lumen.
- Tranexamic acid (used to increase immunoglobulins and lymphocyte count)
- Steroids
- Octreotide
- Albumin infusion
It is a symptomatic treatment to improve hypoalbuminemia and edema but its effect is transient due to continuous lymph leakage into the bowel lumen.
- It is a symptomatic treatment to improve hypoalbuminemia and edema but its effect is transient due to continuous lymph leakage into the bowel lumen.

## Surgery
- Segmental small bowel resection is only performed for localized lesions.

## Prevention
- There are no primary preventive measures available for PIL.