Primary Intestinal Lymphangiectasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamed Riad, M.D.[2]

Synonyms and keywords:

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 and gammaglobulin and proteins levels 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 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 and gammaglobulin and proteins levels ''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.
• First described in 1964 by Samman and White, yellow nail syndrome is a very rare condition that may be associated with PIL. Dystrophic yellow nails with ridging and loss of lunula on the hands are associated with lymphedema and 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

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

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 are dilated intestinal lymphatic vessels and lacteal juice in the biopsies from duodenum, jejunum and ileum.

Causes

The cause of PIL has not been identified.

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 enteropathyThere are rare familial forms that have been reported.

Epidemiology and Demographics

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

• First described in 1964 by Samman and White, yellow nail syndrome is a very rare condition that may be associated with PIL. Dystrophic yellow nails with ridging and loss of lunula on the hands are associated with lymphedema and pleural effusions.

• Five syndromes are associated with intestinal lymphangiectasia:
  • von Recklinghausen
  • Turner (X0) or Noonan
  • Klippel-Trenaunay and Hennekam
• In general, these syndromes are easily distinguishable by the presence of facial abnormalities (Turner, Noonan, Hennekam), mental retardation (Hennekam, Noonan), seizures (Hennekam), severe limb and/or face lymphedema (Hennekam), neurofibromas and other tumors (von Recklinghausen), and hemihypertrophy of the limbs associated with vascular malformations (Klippel-Trenaunay).

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
• 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

PIL is diagnosed by biopsy revealing dilated intestinal lymphatics. Videocapsule 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 and 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 convulsion
• 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, breast, 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 level
• Low immunoglobulin IgM, IgA, and IgG levels
• CBC shows lymphopenia
• Elevated 24-hour α1-antitrypsin clearance in stool, which is an indication of the degree of protein loss and disease severity Contrast lymphangiography

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, and sometimes ascites.

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. In some cases, it may show a "halo sign". It 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

Lymphangiography may be helpful in the diagnosis of PIL. Findings on lymphangiography suggestive of PIL include 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 is 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.

Surgery

• Segmental small bowel resection is only performed for localized lesions

Prevention

• There are no primary preventive measures available for PIL.