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• W2158694551 abstract "See “Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease,” by Roberts KE, Kuwat SM, Krowka MJ, et al, on page 130. See “Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease,” by Roberts KE, Kuwat SM, Krowka MJ, et al, on page 130. The hepatopulmonary syndrome (HPS) is typically defined by a triad reflecting underlying liver disease, intrapulmonary dilatation or shunting, and a consequence thereof. Portal hypertension in the absence of liver disease has also been associated with the development of HPS and it has been argued that portal hypertension, rather than cirrhosis itself, is the principal association with HPS.1Kaymakoglu S. Kahraman T. Kudat H. et al.Hepatopulmonary syndrome in non-cirrhotic portal hypertensive patients.Dig Dis Sci. 2003; 48: 556-560Google Scholar The intrapulmonary shunting results in an increase in alveolar–arterial oxygen gradient, and consequently, either PA–aO2 ≥ 15 mm Hg or oxygen desaturation has been incorporated into the definition of HPS. Oxygen desaturation is accentuated typically in the erect position (orthodeoxia). This characteristic has been used clinically as a screen for the presence of the HPS in patients with portal hypertension with a fall of ≥4 mm Hg from supine to erect being considered significant.2Gomez F.P. Martinez-Palli G. Barbera J.A. et al.Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome.Hepatology. 2004; 40: 660-666Google Scholar The absolute requirement for the diagnosis of HPS is evidence of intrapulmonary shunting that was previously obtained with macroaggregated albumin radionucleotide scans, but more recently with transthoracic contrast echocardiography. The appearance of microbubbles of agitated saline in the left atrium within 3–6 cardiac cycles of opacification of the right atrium is highly suggestive of HPS.3Rodriguez-Roisin R. Krowka M.J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder.N Eng J Med. 2008; 358: 2378-2387Google Scholar The pathophysiologic basis for the shunting is a combination of vasodilatation and vascular remodelling in the lung resulting in vascular diversion away from the alveolus at levels that range from the microscopic to shunts demonstrable by radiologic investigation (Figure 1). The extent of vasodilatation can result in demonstrably increased intrathoracic blood volumes.4Joshi D. Sizer E. Wendon J. et al.High volumes of intrathoracic blood volume in hepatopulmonary syndrome.Crit Care Resuscit. 2009; 11: 129-131Google Scholar There is also evidence of an increase in lung capillary density and an accumulation of monocytes in the microvasculature.5Zhang J. Luo B. Tang L. et al.Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome.Gastroenterology. 2009; 136: 1070-1080Abstract Full Text Full Text PDF Scopus (129) Google Scholar Alveolar nitric oxide production is increased and this correlated with HPS but not with arterial oxygen impairment,6Degano B. Mittaine M. Herve P. et al.Nitric oxide production by the alveolar compartment of the lungs in cirrhotic patients.Eur Respir J. 2009; 34: 138-144Google Scholar implying a specific role in the pathogenesis of the condition rather than a secondary phenomenon. Other implicated mediators include heme oxygenase, tumor necrosis factor-α and vascular endothelial growth factor-A.5Zhang J. Luo B. Tang L. et al.Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome.Gastroenterology. 2009; 136: 1070-1080Abstract Full Text Full Text PDF Scopus (129) Google Scholar, 7Yeshua H. Blendis L.M. Oren R. Pulmonary manifestations of liver disease.Semin Cardiothorac Vasc Anesth. 2009; 13: 60-69Google Scholar Although there is some correlation between HPS and parameters of liver function, probably the more relevant observation is that it can occur across the full spectrum of liver functionality. No correlation was found between HPS and the severity of liver disease as classified by Child–Turcotte–Pugh or Model for End-Stage Liver Disease scores,3Rodriguez-Roisin R. Krowka M.J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder.N Eng J Med. 2008; 358: 2378-2387Google Scholar but a correlation was identified when liver function was assessed using the more sensitive and direct techniques of indocyanine green or galactose clearance rates.8Moller S. Krag A. Madsen T.L. et al.Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension.Liver Intl. 2009; 29: 1528-1537Google Scholar Similarly, HPS did not correlate with the clinical complications of portal hypertension, although a correlation was identified when portal pressures were measured.8Moller S. Krag A. Madsen T.L. et al.Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension.Liver Intl. 2009; 29: 1528-1537Google Scholar This disparity between HPS and severity of the clinical manifestations of the underlying condition is reflected in the fact that HPS may sometimes be the only clinical indication to prompt liver transplantation. The typical symptom of HPS is shortness of breath, both at rest and on exertion. HPS has also been demonstrated to cause a broader deterioration in quality of life, as well as an increased cause of death when compared with patients with cirrhosis with similar disease severity profiles but without HPS.9Fallon M.B. Krowka M.J. Brown R.S. et al.Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates.Gastroenterology. 2008; 135: 1168-1175Abstract Full Text Full Text PDF Scopus (183) Google Scholar The quoted incidence of HPS in cirrhosis ranges from 5% to 32%, although there is clustering in the 10%–20% range. There are a number of potential explanations for the relatively wide range, including small numbers of patients studied, selection bias, and different thresholds for diagnosing HPS.10Schenk P. Fuhrmann V. Madl C. et al.Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences.Gut. 2002; 51: 853-859Google Scholar There is also a lack of longitudinal studies to determine if more subtle indications of abnormal respiratory function might progress to HPS with time. Physiologic evaluations indicate that 50%–60% of patients with cirrhosis have increased alveolar-arterial oxygen gradients but only 10%–22% of these were formally diagnosed with HPS.8Moller S. Krag A. Madsen T.L. et al.Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension.Liver Intl. 2009; 29: 1528-1537Google Scholar, 11Degano B. Mittaine M. Guenard H. et al.Nitric oxide and carbon monoxide lung transfer in patients with advanced cirrhosis.J Applied Physiol. 2009; 107: 139-143Google Scholar Despite these caveats, the currently available data suggest that only a minority of patients with cirrhosis develop HPS and a possible explanation for this is that there is an additional unrecognized susceptibility requirement, which in turn could be genetically determined. In this issue of Gastroenterology, Roberts et al12Roberts K.E. Kuwat S.M. Krowka M.J. et al.Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease.Gastroenterology. 2010; 139: 130-139Google Scholar present data suggesting that genes involved in the regulation of angiogenesis are associated with an increased risk of developing HPS. The study involved 59 patients with HPS and 126 control patients who were being evaluated for liver transplantation. The diagnosis was based on the late appearance of microbubbles after injection of agitated saline together with an in alveolar-arterial oxygen gradient ≥15 mm Hg in patients aged 18–64 years or ≥25 mm Hg in those aged ≥65 years. One thousand eighty-six single nucleotide polymorphisms (SNPs) were genotyped for 94 candidate genes together with a control set of 61 SNPs used to screen for potential population stratification. Of the 42 SNPs identified, 32 were clustered in 8 genes and 2 of these (caveolin 3 and runt-related transcription factor 1) were also identified when relationships between genotype and disease phenotype were explored. Of note, no genetic associations were identified for 3 signaling pathways implicated in pulmonary vasodilatation, namely, carbon monoxide, nitric oxide, and endothelin. These findings were interpreted as the genetic associations being related to regulation of angiogenesis. The authors considered the possibility that the sample size could result in a type 1 error and failure to detect potentially significant associations, particularly those dependent on gene–gene or gene–environment interactions. However, they point out that this is the largest such study in HPS conducted to date and aspects of the study design were intended to reduce the risk of false-positive results. From a clinician's perspective, a more powerful argument giving credence to these findings is the plausibility generated by the tangible relationship with the defining lesion, as well as the clear distinction between regulation of angiogenesis and mediating pathways. A similar analysis by this group in portopulmonary hypertension identified a range of potential genetic associations that were, from a clinical perspective, more speculative than those observed in this HPS study.13Roberts K.E. Fallon M.B. Krowka M.J. et al.Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease.Gastroenterology. 2009; 179: 835-842Google Scholar Furthermore, these findings are consistent with the clinical observation in HPS that only a minority of patients with cirrhosis or portal hypertension develop the condition. Treatment options in HPS are extremely limited and pharmacologic intervention is largely ineffective.3Rodriguez-Roisin R. Krowka M.J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder.N Eng J Med. 2008; 358: 2378-2387Google Scholar There are some data suggesting that decompression of the portal system can result in an improvement in HPS, but this has been inconsistent.14De B.K. Sen S. Biswas P.K. et al.Occurrence of hepatopulmonary syndrome in Budd-Chiari syndrome and the role of venous decompression.Gastroenterology. 2002; 122: 897-903Abstract Full Text Full Text PDF Scopus (61) Google Scholar Liver transplantation is the only effective treatment and it has been suggested it should be targeted to patients with PaO2 between 50 and 60 mm Hg. Patients with PaO2 < 50 mm Hg were considered to be too high risk, and those with PaO2 > 60 mm Hg were thought not to require transplantation, although monitoring at 3-month intervals was recommended.15Pastor C.M. Schiffer E. Therapy insight: hepatopulmonary syndrome and orthotopic liver transplantation.Nature Clin Pract Gastroenterol Hepatol. 2007; 4: 614-621Google Scholar The outcomes after liver transplantation were comparable with other patient populations, except in those patients with the most severe disease (defined by PaO2 < 50 mm Hg) and, as a result, the latter were being considered less favorably for transplantation.15Pastor C.M. Schiffer E. Therapy insight: hepatopulmonary syndrome and orthotopic liver transplantation.Nature Clin Pract Gastroenterol Hepatol. 2007; 4: 614-621Google Scholar, 16Swanson K.L. Wiesner R.H. Krowka M.J. et al.Natural history of hepatopulmonary syndrome: impact of liver transplantation.Hepatology. 2005; 41: 1122-1129Google Scholar However, a recent study has extended the excellent results of liver transplantation to the high-risk group by incorporating intensive pulmonary rehabilitation into pre- and postoperative care.17Gupta S. Castel H. Rao R.V. et al.Improved survival after liver transplantation in patients with hepatopulmonary syndrome.Am J Transpl. 2010; 10: 354-363Google Scholar The last decade has witnessed considerable prognosis in HPS, particularly with respect to clinical characterization, pathophysiology, and improved outcomes through liver transplantation. The latest information on genetic associations fills in another piece of the clinical jigsaw puzzle and opens the way for confirmatory and advancing science in this intriguing condition. It would also be very exciting if these observations led to identification of potential targets for badly needed novel therapies. Or am I being naïve?" @default.
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• W2158694551 title "Hepatopulmonary Syndrome: Is It Naïve or Enlightening When Genetic Associations Match Clinical Perspective?" @default.
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