Primary Intestinal Lymphangiectasia

Primary Intestinal Lymphangiectasia Microchapters
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating PIL from other Diseases
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
Treatment

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Mohamed Riad, M.D.[3]

Synonyms and keywords: PIL

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.
• 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 on the hands
  • 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

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

• 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

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

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
• 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

Disease	Clinical manifestations	Diagnostic studies
Intestinal Tuberculosis	Fever Night sweats Abdominal pain Weight loss Anemia Patients can present with obstructive symptoms Pain in right iliac fossa (RIF) Palpable mass in the right iliac fossa	Biopsy showing caseating granulomas
Inflammatory bowel disease	Abdominal pain Bloody diarrhea Weight loss Fatigue Fever Arthritis Uveitis Erythema nodosum	Endoscopy for Crohn's disease Colonoscopy for ulcerative colitis
Intestinal lymphoma	Abdominal pain Weight loss Features of malabsorption Rectal bleeding Features of bowel obstruction	Biopsy
Constrictive pericarditis	Chest pain Fatigue Dyspnea Abdominal swelling Lower limb swelling Palpitations	Chest X-ray Echocardiogram CT scan MRI
Sarcoidosis	Cough Dyspnea Fatigue Swollen painful joints Tender reddish bumps on the skin Enlarged and tender lymph nodes Renal stones Arrhythmia Neuropsychiatric manifestations	Chest X-ray Bronchoscopy with biopsy Lab investigations showing elevated serum angiotensin-converting enzyme (ACE) and hypercalcemia
Systemic sclerosis	Skin hardening and thickening Reflux esophagitis Esophageal stricture Arthritis Raynaud's phenomenon Calcinosis Dyspnea Renal failure	Presence of autoantibodies (specifically anti-centromere and anti-scl70/anti-topoisomerase antibodies) Biopsy (occasionally)
Whipple disease	Abdominal pain Features of malabsorption Weight loss Lymph node enlargement Migratory arthropathy Neurological manifestations such as: Confusion Memory loss Dementia Seizures	Duodenal endoscopy with biopsy, which reveals PAS-positive macrophages in the lamina propria containing non-acid-fast, Gram-positive bacilli
Radiation and/or chemotherapy with retroperitoneal fibrosis	Flank pain Abdominal pain Unilateral or bilateral lower extremity swelling Unexplained systemic symptoms such as: Fatigue Weight loss	Biopsy  showing fibro-inflammatory tissue without malignancy
HIV-related enteropathy	Persistent diarrhea Malnutrition Weight loss	Biopsy; however the diagnosis is challenging
Menetrier's disease	Epigastric pain Nausea Vomiting Loss of appetite Edema	X-ray after barium meal Endoscopy with deep mucosal biopsy and cytology
Inflammatory states of systemic lupus erythematosus	Malar rash Arthritis Hair loss Pancytopenia Pericarditis Pleurisy Fatigue Photosensitivity Lupus nephritis	Presence of antinuclear antibody (ANA) or anti-dsDNA antibodies which are highly specific

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 on the hands
  • Lymphedema
  • Pleural effusions
• Other five syndromes considered as risk factors and associated with intestinal lymphangiectasia include:
  • 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
• 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 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 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, 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.

A 23-year-old woman with PIL since infancy. Note the bilateral lower limb lymphedema, with accentuation of the dorsal flexion folds of the toes. [1]

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
  • 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)
• 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

• Lymphangiography 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.

Surgery

• Segmental small bowel resection is only performed for localized lesions.

Prevention

• There are no primary preventive measures available for PIL.