Diagnosis and treatment of the hepatopulmonary syndrome
Arterial hypoxemia, liver disease and pulmonary vascular dilatation
The term “hepatopulmonary syndrome” (HPS), first coined in 1977, was preceded by compelling autopsy and clinical descriptions. Indeed, in 1966, post-mortem findings in patients with liver cirrhosis pointed to marked pulmonary vascular dilatation to play a critical role in this unique condition between the liver and the lungs (1). Any acute or chronic form of liver disease can coexist with HPS due to pulmonary vascular dilatation. No relationships have been shown between the existence or degree of HPS and the severity of liver disease as assessed by the Child’s classification or the Model for End-stage Liver Disease (MELD) score.
The diagnosis of HPS refers to a clinical triad including arterial hypoxemia, a liver disease, most commonly cirrhosis, and pulmonary vascular dilatation (2, 3). Although arterial hypoxaemia (PaO2 < 80 mmHg) can be common in the context of hepatic disease due to ascites, hydrothorax or coexisting chronic respiratory disorders such as chronic obstructive pulmonary disease, in the specific case of HPS, this hypoxaemia is unique.
The definition of arterial hypoxaemia associated with HPS includes the standardization of the position in which oxygenation is measured, namely sitting or standing, and the use of the more sensitive alveolar-arterial oxygen gradient (AaPO2) because it can increase abnormally before PaO2 itself becomes abnormally low as it takes into account the reduced levels of arterial carbon dioxide. A recent task force recommended AaPO2 ≥ 15 mm Hg with or without a PaO2 < 80 mmHg (≥ 20 mm Hg and < 70 mm Hg, respectively, for those > age 64 years) (2, 4), as criteria to follow for the clinical diagnosis.
Contrast-enhanced transthoracic echocardiography using hand-agitated saline (creating micro-bubbles > 10 µm in diameter) is the key tool to make the diagnosis of pulmonary vascular dilatation. Following administration of agitated saline into a peripheral arm vein, micro-bubble opacification of the left atrium within 3-6 cardiac cycles following right atrial opacification indicates micro-bubble passage through an abnormally dilated vascular bed (normal capillary < 8 µm in diameter). This qualitative approach is more sensitive than the peripheral vein injection of 99mtechnetium-labeled macro-aggregated albumin (99mTcMAA) lung scanning technique with quantitative brain uptake.
Mild-to-severe dyspnoea becomes the most relevant clinical complaint of HPS in the setting of advanced liver disease, an unspecific but common finding if hypoxaemia is present; no other signs and/or symptoms, including a normal chest radiograph, are characteristic for HPS. Orthodeoxia (defined as PaO2 ≥ 5% or ≥ 4 mm Hg from supine to upright is present), with or without worsening dyspnoea (i.e., platypnoea), can be present in approximately 20-25% of patients with HPS (5).
The differential diagnosis of HPS should include portopulmonary hypertension, often associated with mild hypoxaemia can be frequently confused with, along with Rendu-Osler-Weber syndrome (hereditary hemorrhagic telangiectasia) and post-cavopulmonary shunt congenital heart surgery.
Treatment (Fig. 1)
Several small uncontrolled trials using various classes of medication, such as somatostatin, beta-blockers, cyclooxygenase inhibitors, glucocorticosteroids and immunosuppressors, pulmonary vasoconstrictors, nitric oxide (NO) inhibitors, inhaled NO, antibiotics and garlic preparation, for the treatment of HPS have been all unsuccessfully tested. HPS patients with severe hypoxaemia (PaO2 < 60 mmHg) should receive continuous long-term oxygen therapy. Trans-jugular intra-hepatic porto-systemic shunt (TIPS) with variable short-term effects on pulmonary gas exchange disturbances, have not afforded sufficient data to recommend it as compassionate therapy in HPS. Cavoplasty, an effective de-compressive treatment in patients with supra-hepatic inferior vena cava obstruction causing Budd-Chiari syndrome has been to be promising to reverse coexistent HPS. Complete resolution of HPS following liver transplantation (LT) has been observed in more than two third of reported cases such that currently HPS is viewed as an undisputable indication for LT.
Morbidity may be higher after LT in severe HPS, based on pre-OLT severity of hypoxaemia (PaO2 < 50 mm Hg) with or without abnormal extra-pulmonary 99mTcMAA uptake ( ≥ 20% of brain uptake) (6).
1. Berthelot P, Walker JG, Sherlock S, Reid L (1966) Arterial changes in the lungs in cirrhosis of the liver - lung spider nevi. N Engl J Med 274: 291-298
3. Rodriguez-Roisin R, Krowka MJ (2008) Hepatopulmonary syndrome - a liver-induced lung vascular disorder. N Engl J Med 358: 2378-2387
4. Schenk P, Fuhrmann V, Madl C, Funk G, Lehr S, Kandel O et al (2002) Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences. Gut 51: 853-859
5. Gomez FP, Martinez-Palli G, Barbera JA, Roca J, Navasa M, Rodriguez-Roisin R (2004) Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology. 40: 660-666
6. Arguedas MR, Abrams GA, Krowka MJ, Fallon MB (2003) Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 37: 192-197
Prof. Robert Rodríguez-Roisin, M.D.
Servei de Pneumologia (Institut del Tòrax)
Prof. Rodríguez-Roisin is supported by the CibeRes (CB06/06) and the Generalitat de Catalunya (2005SGR-00822).
Robert Rodríguez-Roisin, Servei de Pneumologia (Institut del Tòrax), Hospital Clínic, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Ciber Enfermedades Respiratorias, Universitat de Barcelona, Barcelona, Spain, Wiener Medizinische Wochenschrift Skriptum 8/2009