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Hepatopulmonary Syndrome in Patients With Cystic Fibrosis and Liver Disease OPEN ACCESS

Oded Breuer, MD; Eyal Shteyer, MD; Michael Wilschanski, MD; Zeev Perles, MD; Malena Cohen-Cymberknoh, MD; Eitan Kerem, MD; David Shoseyov, MD
Author and Funding Information

CORRESPONDENCE TO: David Shoseyov, MD, Pediatric Pulmonology Unit and CF Center, Hadassah-Hebrew University Medical Center, Kiryat Hadassah, POB 12000, Jerusalem 91120, Israel


Copyright 2016, The Authors. All Rights Reserved.


Chest. 2016;149(2):e35-e38. doi:10.1016/j.chest.2015.10.040
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Hepatopulmonary syndrome (HPS) is a liver-induced lung disorder defined as a triad of liver disease, pulmonary vascular dilatation, and a defect in oxygenation. It can complicate chronic liver disease of any etiology, but is most commonly associated with portal hypertension. Severe liver disease with portal hypertension is present in 2% to 8% of patients with cystic fibrosis (CF), but to date, to our knowledge, only one patient with CF has been reported to suffer from HPS. Here, we describe two patients with CF diagnosed with HPS, one subsequent to unresolved hypoxemia and the other following screening for HPS performed in our center. We speculate that HPS is underdiagnosed in patients with CF because of their coexisting respiratory morbidity, and we advocate routine screening for every patient with CF who has liver disease and portal hypertension.

Cystic fibrosis-associated liver disease (CFLD) is considered a major cause of morbidity and is the third-leading cause of mortality after pulmonary disease and transplantation complications in patients with cystic fibrosis (CF).,, The prevalence of CFLD is not well established and ranges from 2% to 68%., Clinical presentation may include mildly elevated liver enzyme levels in an asymptomatic patient, hepatic steatosis, focal biliary cirrhosis, and multilobular biliary cirrhosis with accompanying portal hypertension,,, which occurs in 2% to 8% of the patients.,,

Hepatopulmonary syndrome (HPS) is a triad comprising liver disease, impaired oxygenation, and intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations.,, The estimated prevalence of HPS among patients with non-CF chronic liver disease, based on data from liver transplant centers, ranges between 5% and 32%. To our knowledge, only one case report of HPS in a patient with CF is available in the literature. Since HPS is characterized by hypoxemia, and patients with CF often suffer hypoxia because of their lung disease, it is likely that in these patients, HPS might be underdiagnosed. Still, the unique hemodynamic-gas exchange pattern of HPS enables it to be distinguished from cardiopulmonary disorders. Here, we report two cases of HPS that were diagnosed in our CF center and present the screening tests required for evaluation of HPS in patients with CF and current treatment.

Case 1

A 16-year-old male patient received a diagnosis of CF at the age of 4 months (genotype ΔF508/G542X). His CFLD was first detected at the age of 3 years because of elevated liver transaminase levels and subsequent progressive portal hypertension. He developed esophageal varices, which were first ligated at the age of 7 years. At age 14 years, he developed hypoxemia that gradually progressed within 6 months, with a decrease in arterial oxygen saturation (Sao2) at room air of 95% to 83%. At that time, his lung disease was stable, with a FEV1 of around 70% predicted and with no episodes of severe pulmonary exacerbations requiring hospitalization. His sputum showed growth of chronic methicillin-resistant Staphylococcus aureus and, intermittently, Pseudomonas aeruginosa, as well as different Aspergillus species. On physical examination, the patient was cyanotic without apparent dyspnea, his lungs were clear, and heart sounds were normal; the spleen was significantly enlarged (20 cm) but stable over the last 3 years. Supplemental oxygen, 1.5 L/min by nasal cannula, was associated with an increase in Sao2 to 92%. Chest CT scan showed mild progression of his pulmonary disease with right upper lobe and right middle lobe bronchiectasis. His serum IgE levels were normal, whereas specific IgE levels for Aspergillus were slightly elevated. Thrombocytopenia secondary to hypersplenism was stable, liver synthetic function was mildly impaired but stable (international normalized ratio = 1.75 s; albumin serum levels within normal limits). Treatment with oral and inhaled antibiotics did not improve his FEV1 or Sao2. Additional clinical characteristics are presented in Table 1.

Table Graphic Jump Location
Table 1 Patient Characteristics at Time of Diagnosis of HPS

A-a Po2 = alveolar-arterial Po2 gradient; ALT = alanine transaminase; AST = aspartate transaminase; CFLD = cystic fibrosis-associated liver disease; CFTR = cystic fibrosis transmembrane conductance regulator; Dlco(Hb) = single-breath carbon monoxide diffusing capacity adjusted for hemoglobin; HPS = hepatopulmonary syndrome; INR = international normalized ratio; Kco(Hb) = Dlco, adjusted for hemoglobin, corrected for alveolar volume; pred = predicted; RV = residual volume; TLC = total lung capacity.

Arterial blood-gas sample results showed Pao2 of 37.6 mm Hg, and the alveolar-arterial oxygen gradient (A-a gradient) was elevated (45 mm Hg). A contrast-enhanced echocardiography (CEE) with agitated saline injected to a peripheral vein demonstrated a nonintracardiac right to left shunt, with no evidence of pulmonary hypertension. This established the diagnosis of HPS. Platypnea and orthodeoxia, which are clinical features of HPS, were not assessed in this patient.

According to the marked diminished oxygenation and the disease severity categorization, HPS was staged as very severe. Subsequently, the patient underwent a successful liver transplantation. Sao2 improved gradually to 95% on room air within 2 months after liver transplantation. Repeated CEE analysis normalized with no evidence of a shunt, a single-breath carbon monoxide diffusing capacity was 1.46 mmol/min/kPa/L (84% predicted), and an annual best FEV1 following the liver transplant was 91% predicted.

Subsequent to diagnosing HPS in this patient, we decided to screen for HPS all patients with CF at our center who had CFLD. Two additional patients were screened by performing measurements of arterial blood gas and CEE. Concomitant HPS was diagnosed in one (case 2).

Case 2

A 17-year-old male patient (genotype W1282X/W1282X) received a diagnosis of CF at the neonatal period subsequent to the diagnosis of an older sibling. He developed CFLD at the age of 7 years and had progressive portal hypertension, splenomegaly, and persistent thrombocytopenia. His pulmonary disease was relatively mild with localized bronchiectasis, as evident in the chest high-resolution CT scan, a FEV1 of approximately 90% predicted, and intermittent growth of methicillin-resistant S. aureus and P. aeruginosa in sputum cultures, with good response to oral antibiotic treatment. In addition, he had received a diagnosis of CF-related diabetes mellitus at the age of 13 years, which was not well controlled. At the time of diagnosis of HPS, his pulmonary condition was stable (Table 1) and he did not suffer from platypnea or orthodeoxia. For 6 years prior to the diagnosis, the patient had not been treated with IV antibiotics and his Sao2 on room air was 94%. Pao2 measurement from an arterial blood-gas sample was 72.3 mm Hg, the calculated A–a gradient was 21 mm Hg (Table 1), and a CEE confirmed the diagnosis of HPS with no evidence of pulmonary hypertension. Due to his relatively mild pulmonary disease and moderate HPS, the patient was not considered a candidate for orthotropic liver transplantation (OLT). Currently, he is closely followed and aggressively treated for his pulmonary disease and CF-related diabetes mellitus.

In patients with CF, pulmonary symptoms related to progressive chronic lung disease are the most frequent cause of morbidity and mortality. Thus, caretakers of patients with CF attribute respiratory symptoms and signs like dyspnea or hypoxemia to the chronic lung disease and not to a putative undiagnosed liver disease. We suspect that in patients with CF who have known CFLD, HPS is much more frequent than currently reported and that underdiagnosis based on confounding symptoms due to the coexisting chronic lung disease is the reason for the rare reported occurrence. At the Hadassah CF Center in 2013, where over 140 patients with CF (children and adults) are treated, three patients were found to have significant liver disease, of whom two had portal hypertension and received a diagnosis of HPS. HPS can be associated with any form of chronic liver disease, but is most commonly associated with portal hypertension. In these patients, hypoxemia with a relatively mild pulmonary disease raised the suspicion of HPS.

HPS is characterized by progressive hypoxemia with no identifiable respiratory cause. The underlying reason for HPS is not entirely understood, but it has been suggested that increased circulating pulmonary vasodilators secondary to the liver disease create intrapulmonary vascular dilatations. These cause hypoxemia by the combination of intrapulmonary shunting, an alveolar-capillary diffusion limitation, and a ventilation/perfusion mismatch., The estimated 5-year survival of patients diagnosed with HPS is 23%, with worse estimated survival in patients with a Pao2 < 50 mm Hg. To date, no drug therapy has been shown to be useful in treatment of HPS, and supplemental oxygen administration, though commonly advised, lacks data regarding its efficacy in long-term management. OLT has been shown to induce complete resolution of HPS in > 80% of patients, with an improved posttransplant 5-year survival rate of 76%. Therefore, diagnosis of HPS in a hypoxemic patient (Pao2 < 60 mm Hg) is currently considered an indication for OLT with a higher priority than for patients with other liver disorders., In patients with CF, a combined lung and liver transplant may be considered. However, in view of the mild pulmonary disease in our patient, with an FEV1 of 70% predicted, this was not indicated. Furthermore, pulmonary disease in patients with HPS usually improves after OLT.,

Due to the high mortality rate of HPS, the European Respiratory Society task force on pulmonary-hepatic vascular disorders suggests screening for HPS by performing measurements of A-a gradient in all patients with chronic liver disease who report dyspnea or who are candidates for liver transplantation. In patients in whom an A-a gradient ≥ 15 mm Hg is found, it is recommended to perform a CEE or an IV 99mTc-labeled albumin scan for the diagnosis of HPS. CEE is considered the gold standard for the diagnosis of HPS, but a 99mTc-labeled albumin scan may determine the degree of the shunt, and has been shown to serve as a prognostic predictor in patients with HPS.

However, in patients with CF, the characteristic lung disease may mask the presence of HPS. Furthermore, an increased A-a gradient is not uncommon in patients with moderate to severe CF lung disease. Therefore, respiratory symptoms or A-a gradient measurements are not useful to detect HPS in patients with CFLD. Clinical observation of platypnea and orthodeoxia may raise suspicion in an alert physician and should be routinely assessed in patients with CFLD, but absence of these findings does not rule out HPS. Therefore, we recommend that in patients with CFLD and portal hypertension or with CFLD with hypoxemia, a CEE should be regularly performed for the evaluation of HPS.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Chryssostalis A. .Hubert D. .Coste J. .et al Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. J Hepatol. 2011;55:1377-1382 [PubMed]journal. [CrossRef] [PubMed]
 
Staufer K. .Halilbasic E. .Trauner M. .Kazemi-Shirazi L. . Cystic fibrosis related liver disease—another black box in hepatology. Int J Mol Sci. 2014;15:13529-13549 [PubMed]journal. [CrossRef] [PubMed]
 
Herrmann U. .Dockter G. .Lammert F. . Cystic fibrosis-associated liver disease. Best Pract Res Clin Gastroenterol. 2010;24:585-592 [PubMed]journal. [CrossRef] [PubMed]
 
Colombo C. .Battezzati P.M. . Liver involvement in cystic fibrosis: primary organ damage or innocent bystander? J Hepatol. 2004;41:1041-1044 [PubMed]journal. [CrossRef] [PubMed]
 
Kobelska-Dubiel N. .Klincewicz B. .Cichy W. . Liver disease in cystic fibrosis. Prz Gastroenterol. 2014;9:136-141 [PubMed]journal. [PubMed]
 
Colombo C. .Battezzati P.M. . Hepatobiliary manifestations of cystic fibrosis. Eur J Gastroenterol Hepatol. 1996;8:748-754 [PubMed]journal. [PubMed]
 
Lamireau T. .Monnereau S. .Martin S. .Marcotte J.E. .Winnock M. .Alvarez F. . Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol. 2004;41:920-925 [PubMed]journal. [CrossRef] [PubMed]
 
Hoeper M.M. .Krowka M.J. .Strassburg C.P. . Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363:1461-1468 [PubMed]journal. [CrossRef] [PubMed]
 
Rodríguez-Roisin R. .Krowka M.J. . Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N Engl J Med. 2008;358:2378-2387 [PubMed]journal. [CrossRef] [PubMed]
 
Rodríguez-Roisin R. .Krowka M.J. .Hervé P. .Fallon M.B. . ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee Pulmonary-hepatic vascular disorders (PHD). Eur Respir J. 2004;24:861-880 [PubMed]journal. [CrossRef] [PubMed]
 
Schenk 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;51:853-859 [PubMed]journal. [CrossRef] [PubMed]
 
Giniès J.L. .Couetil J.P. .Houssin D. .Guillemain R. .Champion G. .Bernard O. . Hepatopulmonary syndrome in a child with cystic fibrosis. J Pediatr Gastroenterol Nutr. 1996;23:497-500 [PubMed]journal. [CrossRef] [PubMed]
 
Martinez G. .Barberà J.A. .Navasa M. .Roca J. .Visa J. .Rodriguez-Roisin R. . Hepatopulmonary syndrome associated with cardiorespiratory disease. J Hepatol. 1999;30:882-889 [PubMed]journal. [CrossRef] [PubMed]
 
Krowka M.J. .Wiseman G.A. .Burnett O.L. .et al Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning. Chest. 2000;118:615-624 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 Patient Characteristics at Time of Diagnosis of HPS

A-a Po2 = alveolar-arterial Po2 gradient; ALT = alanine transaminase; AST = aspartate transaminase; CFLD = cystic fibrosis-associated liver disease; CFTR = cystic fibrosis transmembrane conductance regulator; Dlco(Hb) = single-breath carbon monoxide diffusing capacity adjusted for hemoglobin; HPS = hepatopulmonary syndrome; INR = international normalized ratio; Kco(Hb) = Dlco, adjusted for hemoglobin, corrected for alveolar volume; pred = predicted; RV = residual volume; TLC = total lung capacity.

References

Chryssostalis A. .Hubert D. .Coste J. .et al Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. J Hepatol. 2011;55:1377-1382 [PubMed]journal. [CrossRef] [PubMed]
 
Staufer K. .Halilbasic E. .Trauner M. .Kazemi-Shirazi L. . Cystic fibrosis related liver disease—another black box in hepatology. Int J Mol Sci. 2014;15:13529-13549 [PubMed]journal. [CrossRef] [PubMed]
 
Herrmann U. .Dockter G. .Lammert F. . Cystic fibrosis-associated liver disease. Best Pract Res Clin Gastroenterol. 2010;24:585-592 [PubMed]journal. [CrossRef] [PubMed]
 
Colombo C. .Battezzati P.M. . Liver involvement in cystic fibrosis: primary organ damage or innocent bystander? J Hepatol. 2004;41:1041-1044 [PubMed]journal. [CrossRef] [PubMed]
 
Kobelska-Dubiel N. .Klincewicz B. .Cichy W. . Liver disease in cystic fibrosis. Prz Gastroenterol. 2014;9:136-141 [PubMed]journal. [PubMed]
 
Colombo C. .Battezzati P.M. . Hepatobiliary manifestations of cystic fibrosis. Eur J Gastroenterol Hepatol. 1996;8:748-754 [PubMed]journal. [PubMed]
 
Lamireau T. .Monnereau S. .Martin S. .Marcotte J.E. .Winnock M. .Alvarez F. . Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol. 2004;41:920-925 [PubMed]journal. [CrossRef] [PubMed]
 
Hoeper M.M. .Krowka M.J. .Strassburg C.P. . Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363:1461-1468 [PubMed]journal. [CrossRef] [PubMed]
 
Rodríguez-Roisin R. .Krowka M.J. . Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N Engl J Med. 2008;358:2378-2387 [PubMed]journal. [CrossRef] [PubMed]
 
Rodríguez-Roisin R. .Krowka M.J. .Hervé P. .Fallon M.B. . ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee Pulmonary-hepatic vascular disorders (PHD). Eur Respir J. 2004;24:861-880 [PubMed]journal. [CrossRef] [PubMed]
 
Schenk 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;51:853-859 [PubMed]journal. [CrossRef] [PubMed]
 
Giniès J.L. .Couetil J.P. .Houssin D. .Guillemain R. .Champion G. .Bernard O. . Hepatopulmonary syndrome in a child with cystic fibrosis. J Pediatr Gastroenterol Nutr. 1996;23:497-500 [PubMed]journal. [CrossRef] [PubMed]
 
Martinez G. .Barberà J.A. .Navasa M. .Roca J. .Visa J. .Rodriguez-Roisin R. . Hepatopulmonary syndrome associated with cardiorespiratory disease. J Hepatol. 1999;30:882-889 [PubMed]journal. [CrossRef] [PubMed]
 
Krowka M.J. .Wiseman G.A. .Burnett O.L. .et al Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning. Chest. 2000;118:615-624 [PubMed]journal. [CrossRef] [PubMed]
 
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