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Hepatopulmonary Syndrome With Progressive Hypoxemia as an Indication for Liver Transplantation: Case Reports and Literature Review

1997; Elsevier BV; Volume: 72; Issue: 1 Linguagem: Inglês

10.4065/72.1.44

1942-5546

Michael J. Krowka, Michael K. Porayko, David J. Plevak, S. Chris Pappas, Jeffrey L. Steers, Ruud A. F. Krom, Russell H. Wiesner,

Transplantation: Methods and Outcomes

In the hepatopulmonary syndrome (HPS), a pulmonary vascular complication of liver disease, severe hypoxemia due to pulmonary vascular dilatation can be extremely debilitating. Determining whether patients with advanced liver disease and HPS should be considered for liver transplantation is difficult. We describe three patients with progressive and severe hypoxemia who underwent successful liver transplantation and had resolution of their arterial hypoxemia. In these patients, the progressive pulmonary deterioration accelerated the need and was considered an indication for liver transplantation rather than being considered an absolute or relative contraindication. In addition, we review the literature on 81 pediatrie and adult patients with HPS who underwent liver transplantation and specifically highlight mortality, morbidity, syndrome resolution, and prognostic factors. Posttransplantation mortality (16%) was associated with the severity of hypoxemia (mean arterial oxygen tension [Pao2] in 68 survivors was 54.2 ± 13.2 mm Hg and in 13 nonsurvivors was 44.7 ± 7.7 mm Hg; P<0.03). Patients with a pretransplantation Pao2 of 50 mm Hg or lower had significantly more frequent mortality (30%) in comparison with those with a Pao2 greater than 50 mm Hg (4%; P<0.02). Pulmonary recommendations that address the severity of hypoxemia and candidacy for liver transplantation are discussed. In the hepatopulmonary syndrome (HPS), a pulmonary vascular complication of liver disease, severe hypoxemia due to pulmonary vascular dilatation can be extremely debilitating. Determining whether patients with advanced liver disease and HPS should be considered for liver transplantation is difficult. We describe three patients with progressive and severe hypoxemia who underwent successful liver transplantation and had resolution of their arterial hypoxemia. In these patients, the progressive pulmonary deterioration accelerated the need and was considered an indication for liver transplantation rather than being considered an absolute or relative contraindication. In addition, we review the literature on 81 pediatrie and adult patients with HPS who underwent liver transplantation and specifically highlight mortality, morbidity, syndrome resolution, and prognostic factors. Posttransplantation mortality (16%) was associated with the severity of hypoxemia (mean arterial oxygen tension [Pao2] in 68 survivors was 54.2 ± 13.2 mm Hg and in 13 nonsurvivors was 44.7 ± 7.7 mm Hg; P<0.03). Patients with a pretransplantation Pao2 of 50 mm Hg or lower had significantly more frequent mortality (30%) in comparison with those with a Pao2 greater than 50 mm Hg (4%; P<0.02). Pulmonary recommendations that address the severity of hypoxemia and candidacy for liver transplantation are discussed. The hepatopulmonary syndrome (HPS) is characterized as a triad: liver disease, intrapulmonary vascular dilatation, and arterial hypoxemia.1Krowka MJ Cortese DA Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation.Hepatology. 1990; 11: 138-142Crossref PubMed Scopus (210) Google Scholar, 2Lange PA Stoller JK The hepatopulmonary syndrome.Ann Intern Med. 1995; 122: 521-529Crossref PubMed Scopus (339) Google Scholar Although HPS is an infrequent cause of hypoxemia in adults or children with hepatic dysfunction (5 to 29% of patients studied), the syndrome can result in debilitating, severe hypoxemia (arterial oxygen tension [Pao2], 50 mm Hg or lower with the patient breathing room air) that necessitates 24-hour continuous oxygen supplementation.2Lange PA Stoller JK The hepatopulmonary syndrome.Ann Intern Med. 1995; 122: 521-529Crossref PubMed Scopus (339) Google Scholar, 3Castro M Krowka MJ Hepatopulmonary syndrome: a pulmonary vascular complication of liver disease.Clin Chest Med. 1996 Mar; 17: 35-48Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar The pulmonary pathophysiologic feature (that is, hypoxemia as a consequence of pulmonary vascular dilatation and possible proliferation) involves ventilation-perfusion mismatching, oxygen diffusing limitation, and intrapulmonary shunting in varying degrees.4Wolfe JD Tashkin DP Holly FE Brachman MB Genovesi MG Hypoxemia of cirrhosis: detection of abnormal small pulmonary vascular channels by a quantitative radionuclide method.Am J Med. 1977; 63: 746-754Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 5Edell ES Cortese DA Krowka MJ Rehder K Severe hypoxemia and liver disease.Am Rev Respir Dis. 1989; 140: 1631-1635Crossref PubMed Scopus (114) Google Scholar, 6Hedenstierna G Soderman C Eriksson LS Wahren J Ventilationperfusion inequality in patients with non-alcoholic liver cirrhosis.Eur Respir J. 1991; 4: 711-717PubMed Google Scholar, 7Rodriguez-Roisin R Agusti AG Roca J The hepatopulmonary syndrome: new name, old complexities [editorial].Thorax. 1992; 47: 897-902Crossref PubMed Scopus (227) Google Scholar The oxygen abnormality may worsen as the patient moves from the supine to the standing position (orthodeoxia), and the response to 100% inspired oxygen varies considerably.3Castro M Krowka MJ Hepatopulmonary syndrome: a pulmonary vascular complication of liver disease.Clin Chest Med. 1996 Mar; 17: 35-48Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Pulmonary angiography has demonstrated diffuse (type I) and discrete (type II) vascular lesions associated with hypoxemia in HPS.3Castro M Krowka MJ Hepatopulmonary syndrome: a pulmonary vascular complication of liver disease.Clin Chest Med. 1996 Mar; 17: 35-48Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar The natural history of HPS is poorly understood to date, but progressive hypoxemia has been well described in the setting of clinically stable hepatic dysfunction. Significant mortality, despite medical therapeutic approaches to correct the hypoxemia, has been reported.2Lange PA Stoller JK The hepatopulmonary syndrome.Ann Intern Med. 1995; 122: 521-529Crossref PubMed Scopus (339) Google Scholar, 3Castro M Krowka MJ Hepatopulmonary syndrome: a pulmonary vascular complication of liver disease.Clin Chest Med. 1996 Mar; 17: 35-48Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Of recent interest is the diagnosis of HPS in patients with end-stage liver disease in whom liver transplantation is the only viable therapeutic option for the hepatic dysfunction. Initially, severe hypoxemia (Pao2, 50 mm Hg or lower) due to HPS was considered an absolute contraindication to transplantation due to the perioperative deaths associated with hypoxemia.8Van Thiel DH Schade RR Gavaler JS Shaw Jr, BW Iwatsuki S Starzl TE Medical aspects of liver transplantation.Hepatology. 1984; 4: 79S-83SCrossref PubMed Scopus (142) Google Scholar Over time, liver transplantations were successful for various end-stage liver disorders in patients who also had varying degrees of HPS. Subsequently, severe hypoxemia due to HPS became a relative contraindication to transplantation.9Maddrey WC Van Thiel DH Liver transplantation: an overview.Hepatology. 1988; 8: 948-959Crossref PubMed Scopus (137) Google Scholar A recent survey of 52 medical centers that performed 2,656 transplantations in 1992 indicated that 33% excluded patients with HPS from consideration for liver transplantation.10Lake JR (Liver and Intestinal Subcommittee of the American Society of Transplant Physicians). A lack of consensus regarding contraindications to liver transplantation (OLT) in the U.S. [abstract].Hepatology. 1994; 20: 120AGoogle Scholar Herein we describe three adult patients with advanced liver disease, HPS, and progressively severe hypoxemia who underwent liver transplantation in an attempt to correct the hepatic and associated pulmonary dysfunction. In all three patients, successful transplantation resulted in the resolution of arterial hypoxemia. In addition, we review the literature on patients with HPS who underwent liver transplantation, with particular reference to mortality, morbidity, syndrome resolution, and possible prognostic factors. —A 28-year-old woman was referred to the Mayo Clinic Rochester liver transplant service in April 1993 for consideration for transplantation. In 1975, esophageal variceal bleeding had developed, which was managed by splenectomy and a splenorenal vascular shunt. A liver biopsy was also done in 1975, and findings were compatible with a diagnosis of autoimmune chronic active hepatitis. She was treated periodically with corticosteroids between 1975 and 1986. The patient was first examined at the Mayo Clinic in 1989, and baseline arterial blood gas studies were done. She experienced progressive shortness of breath, and HPS was diagnosed in 1990 (pulmonary vascular dilatation suggested by delayed, abnormal contrast echocardiographic findings with arterial hypoxemia1Krowka MJ Cortese DA Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation.Hepatology. 1990; 11: 138-142Crossref PubMed Scopus (210) Google Scholar). During follow-up examinations, sequential arterial blood gas studies were conducted and are summarized in Figure 1. Her liver function was clinically stable and remained unchanged until November 1992, when she sought medical assessment because of substantially increased jaundice, pruritus, edema, and ascites. At that time, the total and direct bilirubin levels were 11.0 and 5.1 mg/dL, respectively; platelet count was 294 × 109/L; prothrombin time was 15 seconds (normal, 8.4 to 12); and albumin level was 1.3 g/dL. Hepatitis B and C serologies were negative. The smooth muscle antibody was positive at a titer of 1:80. During the ensuing 4 months, her condition continued to deteriorate despite medical management. In April 1993, her prothrombin time was 15.8 seconds; total and direct bilirubin levels were 14.3 and 7.9 mg/dL, respectively, and albumin level was 1.1 g/dL. In addition, her oxygenation status had further deteriorated (Fig. 1), which was accompanied by progressive dyspnea and fatigue. On physical examination, the patient appeared ill; jaundice and diffuse spider angiomas over the thorax were evident. Clubbing and cyanosis were noted. Pulmonary function testing showed a single-breath diffusing capacity of 38% of the predicted value, with normal expiratory airflow and lung volumes. Chest roentgenographic findings were normal. Pulmonary angiography was not done because of the patient's excellent response to 100% inspired oxygen. At that time, she was advised to undergo liver transplantation to address the hepatic dysfunction and reverse the oxygenation deterioration in a definitive manner. The patient received a liver transplant at the Mayo Clinic in June 1993, and no difficulty was encountered. Four hours postoperatively, however, she experienced a worsening of her Pao2, from 303 mm Hg to 65 mm Hg, while intubated and receiving mechanical ventilation (100% oxygen). Chest roentgenography suggested no etiologic factor. Despite trials of positional changes, ventilator alterations, and intravenous somatostatin infusion, the patient had hypoxemia for 72 hours, with a documented Pao2 nadir of 44 mm Hg. She then experienced a gradual resolution of the severe hypoxemia and was extubated 96 hours after transplantation; the resultant Pao2 was 114 mm Hg while she received 100% oxygen through a close-fitting mask. One year postoperatively, follow-up arterial blood gas studies performed with the patient sitting and breathing room air indicated a Pao2 of 87.5 mm Hg. The patient had no pulmonary symptoms. A repeated contrast echocardiogram obtained in May 1995 showed no evidence of pulmonary vascular dilatation. —A 47-year-old woman with a 20-year history of cryptogenic liver disease sought medical assessment. At age 27, she had pancytopenia, portal hypertension, and splenomegaly of unknown origin. Multiple episodes of esophageal bleeding had occurred. Splenectomy with a splenorenal shunt was done in 1986. In 1988, exertional dyspnea, arterial hypoxemia, and clubbing developed. Chest roentgeno-graphic findings were unremarkable. Single-breath diffusing capacity was 52% of the predicted value, with a normal ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) and a shunt fraction of 13% calculated by the 100% inspired oxygen method. Findings on a pulmonary angiogram showed no pulmonary emboli or pulmonary hypertension. Supplemental oxygen was ordered. In mid-1990, she was assessed for consideration for orthotopic liver transplantation due to the hepatic history and pulmonary dysfunction. At that time, synthetic liver function showed a mild abnormality; the prothrombin time was 15 seconds (international normalized ratio, 1.5), and the albumin level was 3.3 g/dL. No ascites or edema was evident. No spider nevi were noted. In December 1990, the patient was examined at Mayo Clinic Jacksonville because of progressive dyspnea and for a second opinion about the cause of stable hepatic dysfunction with worsening dyspnea and arterial hypoxemia. Chest roentgenographic findings were normal. Pulmonary function testing showed a single-breath diffusing capacity of 53% of the predicted value with an FEV1/FVC ratio of 80%, FVC of 99% of the predicted value, and total lung capacity of 120% of the predicted value. While the patient was standing, the Pao2 was 44 mm Hg. A transthoracic contrast echo-cardiogram was diagnostic for intrapulmonary vascular dilatation with left atrial opacification noted 5 to 6 cardiac cycles after appearance of microbubbles in the right ventricle. Color flow Doppler echocardiography and contrast studies demonstrated no evidence of intracardiac right-to-left shunt. Right ventricular systolic pressure was estimated to be 30 mm Hg (tricuspid peak velocity was 2.3 m per second). The pulmonary angiogram obtained in 1988 was reviewed and suggested a subtle spongy-diffuse arterial phase with no discrete arteriovenous communication evident. HPS (type I) was diagnosed. Liver function testing at that time indicated total and direct bilirubin levels of 1.6 and 0.4 mg/dL, respectively, and the albumin level was 2.8 mg/dL. A 4-day trial of subcutaneous somatostatin analogue therapy2Lange PA Stoller JK The hepatopulmonary syndrome.Ann Intern Med. 1995; 122: 521-529Crossref PubMed Scopus (339) Google Scholar, 11Krowka MJ Dickson ER Cortese DA Hepatopulmonary syndrome: clinical observations and lack of therapeutic response to somatostatin analogue.Chest. 1993; 104: 515-521Crossref PubMed Scopus (276) Google Scholar resulted in no improvement in the Pao2. Liver transplantation was suggested as a therapeutic option for the HPS; however, the patient wished to use supplemental oxygen and continue a conservative course. In 1992, she returned with worsening dyspnea and now needed 4 to 5 L/min of oxygen (by nasal cannula) 24 hours a day. Her quality of life was deteriorating. The Pao2 deteriorated to 44 mm Hg while she was standing and breathing room air; it increased to 465 mm Hg while she was breathing 100%11Krowka MJ Dickson ER Cortese DA Hepatopulmonary syndrome: clinical observations and lack of therapeutic response to somatostatin analogue.Chest. 1993; 104: 515-521Crossref PubMed Scopus (276) Google Scholar oxygen. At that time, she was advised, again, to undergo liver transplantation primarily for the HPS. Results of liver function testing remained stable; the prothrombin time was 15.5 seconds, the albumin level was 3.1 g/dL, and the total and direct bilirubin levels were 1.5 and 0.3 mg/dL, respectively. The patient declined the transplantation option and chose to continue supplemental oxygen use. Approximately 1 year later, a trial of prednisone was initiated in an attempt to improve the oxygenation, but the Pao2 did not improve. Approximately 1 to 2 months later, substantial pneumonitis developed in conjunction with respiratory failure that necessitated mechanical ventilation. Adult respiratory distress syndrome was diagnosed; an open-lung biopsy was nondiagnostic for infection. The patient was in the intensive-care unit for 20 days. Again, after further consultation, the patient was encouraged to undergo liver transplantation because of the lack of other therapeutic options to correct her severe hypoxemia. In January 1994, uncomplicated liver transplantation was successfully accomplished at another institution (per S.C.P.). Six months after the transplantation, the hemoglobin saturation determined by finger oximetry was 99% while the patient was breathing room air. Approval for a follow-up contrast echocardiogram was denied by the patient's health maintenance organization (HMO). The patient has required no further supplemental oxygen. —A 23-year-old woman with Child's class A micronodular cirrhosis with fatty infiltration was referred to the Mayo liver transplant clinic because of severe hypoxemia and for transplantation assessment. A diagnosis compatible with nonalcoholic steatohepatitis was made based on the history and a liver biopsy done in December 1990, when she was scheduled to undergo tonsillectomy and was found to have abnormal results of coagulation studies, hepato-splenomegaly, and mild ascites. Assessment for hepatitis A, B, and C; α1-antitrypsin deficiency; hemochromatosis; and Wilson's disease revealed normal findings. Panhypopitu-itarism was also diagnosed and thought to be due to an intra-cranial hemorrhage of unknown cause during childhood. Right coronary catheterization, conducted in August 1993, showed a cardiac output of 12.5 L/min and a pulmonary artery systolic/diastolic pressure of 28/14 mm Hg with a pulmonary artery occlusion pressure of 12 mm Hg. A 99mTc macroaggregated albumin (99mTcMAA) lung scan showed substantial right-to-left shunt with pronounced activity over the brain and kidneys. Contrast echocardiography demonstrated no evidence of an intracardiac shunt; delayed opacification was noted in the left side of the heart. During the ensuing 12 months, the patient's condition deteriorated, and she experienced progressive fatigue, especially with exertion. Oxygen (by nasal cannula), 6 L/min, failed to maintain hemoglobin saturations higher than 90% during exertion. On physical examination of the patient, cyanosis of the nailbeds and clubbing were evident. Her skin had multiple telangiectases that blanched with compression; a prominent telangiectasia was present on the lower lip. Findings on the ear, nose, and throat examination were unremarkable, as were those on the chest examination. Hepatic evaluation yielded the following results: hemoglobin, 14.5 g/dL; platelet count, 79×109/L; serum albumin, 4.1 g/dL; total bilirubin, 1.2 mg/dL; aspartate amino-transferase, 41 U/L; alanine aminotransferase, 26 U/L; γ-glutamyltransferase, 39 U/L; and prothrombin time, 14.4 seconds. Ultrasonography of the liver showed diffuse increase in homogeneity in echotexture, consistent with cirrhosis. Findings on roentgenography and computed tomography of the chest were normal. Doppler studies of the portal venous system, hepatic veins, splenic vein, and inferior vena cava showed patency with normal direction of flow. Splenomegaly was noted. Pulmonary studies included a review of the pulmonary angiogram obtained elsewhere, which showed no evidence of either diffuse or discrete arteriovenous communications. Transit through the pulmonary vascular bed seemed to be rapid with rapid venous filling. A 99mTcMAA study showed a shunt estimate of 22.5% (normal, less than 5%), as measured over the brain and adjusted for a blood flow of 13% to the brain. The Pao2 deteriorated from 57 to 53 mm Hg while the patient was standing and breathing room air and further deteriorated to 42 mm Hg while she was exercising; the Pao2 was 481 mm Hg while she was breathing 100% oxygen. Because of the patient's stable hepatic status but severe and debilitating pulmonary situation, liver transplantation was done at Mayo Clinic Rochester on Jul. 15, 1995. The explanted liver confirmed the diagnosis of steatohepatitis with cirrhosis. The patient had an unremarkable postoperative course and was dismissed from the hospital on Aug. 5, 1995. At that time, arterial blood gas studies (while the patient was sitting and breathing room air) indicated a Pao2 of 70 mm Hg and an alveolar-arterial oxygen difference gradient of 31 mm Hg. She required no supplemental oxygen. Four months posttransplantation, Pao2 determinations with the patient breathing room air at rest were normal: 76 mm Hg (while supine) and 81 mm Hg (while standing). While the patient was standing and breathing 100% oxygen, the Pao2 was 560 mm Hg. A repeated 99mTcMAA scan showed a shunt estimate of less than 3%. Contrast echocardiography still showed evidence of mild pulmonary vascular dilatation. —In our three patients with liver disease, the severity of HPS was considered an indication for liver transplantation. Hypoxemia due to HPS was a major factor in the recommendation for liver transplantation because of concerns about the patients' ability to survive the procedure and postoperative course in light of the deterioration in pulmonary status. Preliminary experience suggests that liver transplantation can result in improved oxygenation in some patients with HPS. Our first patient (case 1) had a period of clinically stable hepatic dysfunction followed by a fairly rapid decline in synthetic function and quality of life during a minimum of 4 months before liver transplantation. The transplantation was advised for the concomitant indications of hepatic dysfunction and deteriorating arterial oxygenation due to HPS. In our second patient (case 2), liver transplantation was recommended throughout a 3-year period primarily because of debilitating, severe hypoxemia that necessitated increasing amounts of supplemental oxygen 24 hours per day in the setting of a stable hepatic abnormality. Despite the occurrence of the adult respiratory distress syndrome complicating HPS, the patient recovered and subsequently underwent a successful liver transplantation. Both patients experienced complete resolution of their arterial hypoxemia, and our first patient had normal findings on contrast echocardiography after liver transplantation. In our third patient (case 3), the predominant decision for transplantation was the severity of hypoxemia due to HPS; the degree of hepatic dysfunction seemed to be clinically minimal. Oxygénation was normal 4 months posttransplantation. —A critical literature review of 73 patients with HPS who underwent liver transplantation in combination with 8 patients assessed at the Mayo Clinic (including the 3 current patients) is summarized in Table 111Krowka MJ Dickson ER Cortese DA Hepatopulmonary syndrome: clinical observations and lack of therapeutic response to somatostatin analogue.Chest. 1993; 104: 515-521Crossref PubMed Scopus (276) Google Scholar, 12Shaw Jr, BW Wood RP Kaufman SS Williams L Antonson DL Vanderhoof J Liver transplantation for children. Part 1.J Pediatr Gastroenterol Nutr. 1988; 7: 157-166Crossref PubMed Scopus (39) Google Scholar, 13Starzl TE Groth CG Brettschneider L Moon JB Fulginiti VA Cotton EK et al.Extended survival in 3 cases of orthotopic homotransplantation of the human liver.Surgery. 1968; 63: 549-563PubMed Google Scholar, 14Sang Oh K Bender TM Bowen A Ledesma-Medina J Plain radiographic, nuclear medicine and angiographie observations of hepatogenic pulmonary angiodysplasia.Pediatr Radiol. 1983; 13: 111-115Crossref PubMed Scopus (30) Google Scholar, 15Stoller JK Moodie D Schiavone WA Vogt D Broughan T Winkelman E et al.Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation.Hepatology. 1990; 11: 54-58Crossref PubMed Scopus (129) Google Scholar, 16Eriksson LS Soderman C Ericzon BG Eleborg L Wahren J Hedenstierna G Normalization of ventilation/perfusion relationships after liver transplantation in patients with decompensated cirrhosis: evidence for a hepatopulmonary syndrome.Hepatology. 1990; 12: 1350-1357Crossref PubMed Scopus (111) Google Scholar, 17Mews CF Dorney SF Sheil AG Forbes DA Hill RE Failure of liver transplantation in Wilson's disease with pulmonary arterio-venous shunting.J Pediatr Gastroenterol Nutr. 1990; 10: 230-233Crossref PubMed Scopus (28) Google Scholar, 18McCloskey JJ Schleien C Schwarz K Klein A Colombani P Severe hypoxemia and intrapulmonary shunting resulting from cirrhosis reversed by liver transplantation in a pediatrie patient.J Pediatr. 1991; 118: 902-904Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 19Dimand RJ Heyman MB Lavine JE Bass NM Lake JR Roberts JP et al.Hepatopulmonary syndrome: response to hepatic transplantation [abstract].Hepatology. 1991; 14: 55AGoogle Scholar, 20Laberge JM Brandt ML Lebecque P Moulin D Veykemans F Paradis K et al.Reversal of cirrhosis-related pulmonary shunting in two children by orthotopic liver transplantation.Transplantation. 1992; 53: 1135-1138Crossref PubMed Scopus (77) Google Scholar, 21Itasaka H Hershon JJ Cox KL Tokunaga Y Concepcion W Nakazato P et al.Transient deterioration of intrapulmonary shunting after pédiatrie liver transplantation.Transplantation. 1993; 55: 212-214Crossref PubMed Scopus (23) Google Scholar, 22Schwarzenberg SJ Freese DK Regelmann WE Gores PF Boudreau RJ Payne WD Resolution of severe intrapulmonary shunting after liver transplantation.Chest. 1993; 103: 1271-1273Crossref PubMed Scopus (37) Google Scholar, 23Scott V Miro A Kang Y DeWolf A Bellary S Martin M et al.Reversibility of the hepatopulmonary syndrome by orthotopic liver transplantation.Transplant Proc. 1993; 25: 1787-1788PubMed Google Scholar, 24Van Obbergh L Carlier M de Clety SC Sokal E Rennotte MT Veyckemans F et al.Liver transplantation and pulmonary gas exchanges in hypoxemic children.Am Rev Respir Dis. 1993; 148: 1408-1410Crossref PubMed Scopus (35) Google Scholar, 25Caldwell SH Brantley K Dent J Keeley RC Pruett T Angle JF et al.The hepatopulmonary syndrome masquerading as pulmonary Langerhans-cell histiocytosis.Ann Intern Med. 1994; 121: 34-36Crossref PubMed Scopus (9) Google Scholar, 26Hobeika J Houssin D Bernard O Devictor D Grimon G Chapuis Y Orthotopic liver transplantation in children with chronic liver disease and severe hypoxemia.Transplantation. 1994; 57: 224-228Crossref PubMed Scopus (62) Google Scholar, 27Fewtrell MS Noble-Jamieson G Revell S Valente J Friend P Johnston P et al.Intrapulmonary shunting in the biliary atresia/polysplenia syndrome: reversal after liver transplantation.Arch Dis Child. 1994; 70: 501-504Crossref PubMed Scopus (52) Google Scholar, 28Stoller JK Lange PA Westveer MK Carey WD Vogt D Henderson JM Prevalence and reversibility of the hepatopulmonary syndrome after liver transplantation: the Cleveland Clinic experience.West J Med. 1995; 163: 133-138PubMed Google Scholar, 29Cremona G Higenbottam TW Mayoral V Alexander G Demoncheaux E Borland C et al.Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome.Eur Respir J. 1995; 8: 1883-1885Crossref PubMed Scopus (173) Google Scholar, 30Riegler JL Lang KA Johnson SP Westerman JH Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome.Gastroenterology. 1995; 109: 978-983Abstract Full Text PDF PubMed Scopus (102) Google Scholar, 31Rodriguez-Roisin R Krowka MJ Is severe arterial hypoxaemia due to hepatic disease an indication for liver transplantation? A new therapeutic approach [editorial].Eur Respir J. 1994; 7: 839-842PubMed Google Scholar, 32Scott VL Nelson F DeWolf AM Paradis I Ziady G Kang Y et al.Hepatopulmonary syndrome: a reversible disease by orthotopic liver transplantation [abstract].Gastroenterology. 1995; 108: A1165Abstract Full Text PDF Google Scholar, 33Bynon JS Langnas AN Sorrell MS Vanderhoof JA Fox IJ Heffron TG et al.Hepatopulmonary syndrome and liver transplantation [abstract].Hepatology. 1994; 19: 461Crossref Google Scholar, 34Petruff CA Gordon FD Chopra S Dushay KM Lewis WD Jenkins RL Hepatopulmonary syndrome reversed by orthotopic liver transplantation [abstract].Gastroenterology. 1996; 110: A1295Google Scholar, 35Poterucha JJ Krowka MJ Dickson ER Cortese DA Stanson AW Krom RAF Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy.Hepatology. 1995; 21: 96-100Crossref PubMed Google Scholar HPS was diagnosed by demonstration of pulmonary vascular dilatation by means of (1) contrast echocardiography, 99mTcMAA lung scanning, or pulmonary angiography (in 73 patients); (2) intrapulmonary shunt demonstrated with use of inert gas elimination techniques (in 4 patients) or oxygen technique in children (3 patients); or (3) evidence of pulmonary shunt-associated orthodeoxia (in 1 patient).1Krowka MJ Cortese DA Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation.Hepatology. 1990; 11: 138-142Crossref PubMed Scopus (210) Google Scholar Subclinical HPS (Pao2 greater than 70 mm Hg but abnormal findings on contrast echocardiography or 99mTcMAA lung scan) was noted in four patients. The other patients had hypoxemia, as defined by a Pao2 of 70 mm Hg or lower or a hemoglobin saturation of less than 88% by means of oximetry.Table 1Summary of Reported Cases of Hepatopulmonary Syndrome and Results of Liver Transplantation*In addition to these cases, Shaw et al12 described two patients with refractory hypoxemia who died after transplantation. No other details were provided.†AIH = autoimmune hepatitis; α,-AT = α1-antitrypsin deficiency; BA = biliary atresia; CAH = chronic active hepatitis; CRC = cryptogenic cirrhosis; ETOH = alcoholic cirrhosis; HEM = hemochromatosis; HPS = hepatopulmonary syndrome; MV = mechanical ventilation; NHP = nodular hyperplasia; Pao2 = arterial oxygen tension; PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; PVT = portal vein thrombosis;