Lymphatic dysfunction in advanced cirrhosis: Contextual perspective and clinical implications

Table 1 Assessment of risk factors, clinical markers and investigations for lymphatic dysfunction in cirrhosis

Parameters	Findings that support or indicate lymphatic dysfunction
Risk factors	(1) Old age; (2) metabolic syndrome (obesity, diabetes, dyslipidemia); and (3) concomitant inflammatory disorders
Clinical examination	(1) Diuretic-resistant ascites; (2) severe generalised edema, scrotal/penile swelling; (3) lymphedema: Peau-d’orange appearance and a positive stemmer sign; (4) frequent cellulitis/lymphangitis of affected limbs; and (5) hyperkeratotic skin lesions, yellow nail
Blood investigations	(1) Hypoproteinaemia and hypoalbuminemia; (2) lymphocytopenia; and (3) hypogammaglobulinemia
Ascitic fluid analysis	Chylous ascites: Milky appearance, fluid triglyceride level ≥ 110mg/dL
Upper endoscopy	Intestinal lymphangiectasia: Whitish congested villi in duodenum
Radiological imaging: (lymphography, lymphoscintigraphy)	Abnormal lymphatic structure and/or lymph flow dynamics: Dilated lymphatic vessels, lymph stasis, lymph leakage
Histopathological examination (liver/intestine)	(1) Increase in number and size of lymphatic structures; and (2) specific lymphatic endothelial markers for accurate identification: Prox-1, podoplanin, LYVE-1

LYVE-1: Lymphatic vessel endothelial hyaluronan receptor.

Table 2 Possible therapeutic strategies for treatment of lymphatic dysfunction in cirrhosis

To decrease formation of lymph
Decrease water retention	Low salt diet, diuretic therapy
Control of portal hypertension	Beta-blocker, octreotide, transjugular intrahepatic portosystemic shunt
Increase interstitial pressure	Compression therapy
To promote lymphatic drainage
Facilitate fluid movement into the lymphatic vessels	Compression therapy, limb elevation, diuretic therapy (limited role)
Increase contractility of the lymphatic vessels	Nor-adrenaline, phenylephrine, nitric oxide-inhibitors (experimental)
Facilitate lysis of interstitial protein	Benzopyrones (coumarin and flavoids)
Promote lymphangiogenesis	Prostaglandins E2 (experimental), vascular endothelial growth factor-C (experimental)
To control aggravating factors for lymphatic dysfunction
Care of lymphedema	Control of infection (aggressive use of antibiotics), avoidance of trauma, hot bath and other heat-producing treatment
Control risk factors	Control of diabetes, dyslipidemia and obesity
To decrease leakage of lymph
Decrease stimulants of intestinal lymph flow	Low fat diet, octreotide
Decrease leakage of lymph by intervention	Compression therapy, antiplasmin (tranexamic acid); radiological intervention to obliterate the site of leak
To correct underlying condition
Definitive therapy of cirrhosis	Liver transplantation