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• W3009542223 abstract "Watch an interview with the author Watch a video presentation of this article With the advent of successful liver transplantation came a renewed interest in what we now appreciate as two distinct adverse pulmonary vascular consequences of advanced liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). The interest was not simply academic. Indeed, once these entities were recognized and accurately characterized, it was clear that their natural histories and effects on both attempts at and outcomes of liver transplantation could be quite concerning. Given millennia of experience with cirrhosis, had these pulmonary complications always been around and were they simply not recognized as such because of the absence of characterization of the syndromes, lack of diagnostic criteria, and/or failure to appreciate their clinical importance? Perhaps. And so, as a prelude to a historical review of these entities, and to help clarify the frequent confusion between the two syndromes, a concise, comparative summary of characteristics of each syndrome is provided in Table 1. Why does arterial blood lack oxygen in the setting of liver disease? That simple question was first addressed in 1894 by Dr. M. Fluckiger1 with the support of Professor F. D. von Recklinghausen, who conducted the autopsy on his 37-year-old patient who died of massive hematemesis and cirrhosis of the liver caused by syphilis. Subsequently, complex explanations for arterial hypoxemia over the years have culminated in the description of an entity, coined by Kennedy and Knutson2 in 1977 as the “hepatopulmonary syndrome.” It was not until 1998 that a seminal review article regarding the pulmonary vascular disorders in portal hypertension was published by French investigators.3 This article described potential pathophysiological mechanisms based on clinical experiences; it paved the way for the first animal model for HPS described by Chang4 from Northwestern University and subsequently expanded on and continued in-depth by Fallon and colleagues5 at the University of Alabama. The observation that pulmonary hypertension (PH) could complicate portal hypertension was first made by Mantz and Craig6 at the University of Minnesota in 1951. The link between PH and portal hypertension was initially thought to be caused by pulmonary emboli originating from the portal venous territory and passing through portosystemic shunts to reach the pulmonary circulation. In addition to emboli, subsequent autopsy studies have demonstrated other pathologies.7 Specifically, thrombosis in the pulmonary arteries could be caused by constriction of its peripheral, that is, muscular arterial branches, by endothelial/smooth muscle proliferation, intimal lesions including proliferation and fibrosis, dilatation lesions and platelet aggregates, but not an embolic phenomenon. The constellation of these nonembolic changes was termed “plexogenic arteriopathy,” which derives from the Latin word plexus meaning a “braid.” The network/web morphology metaphor is borrowed from neuroanatomy—remember nerve plexuses. The term “plexiform” has been used to indicate the stage of the lesion, but it is best given a wide berth to avoid confusion.8 The unifying idea was an obstruction to pulmonary arterial flow caused by mediators emanating from or bypassing the portal circulation. The entity was termed “portopulmonary hypertension,” a phrase arguably first used by Yoshida et al.9 in 1993. Despite the clinical and hemodynamic characterizations of PH in the setting of liver disease, no experimental animal model exists to date for POPH. In 1990, a small group of clinicians convened at the Mayo Clinic satellite practice in Jacksonville, Florida, for what was arguably the first international gathering to discuss “liver-lung” problems (Fig. 1). This was the first national or international conference that I could find that included a talk on the topic of HPS; a fitting (and appreciative) lecturer for the inaugural presentation was Dame Sheila Sherlock (1918-2001)10 of the Royal Free Hospital in London (Fig. 2). Interestingly, the topic of pulmonary artery hypertension as a complication of liver disease was given scant attention, but subsequent anecdotes of liver transplant (LT) failures in the setting of that disorder would soon become apparent in the late 1990s. As a final aside, the liver-lung theme also included a lecture on sarcoidosis, provided by the husband of Prof. Sherlock, David Geraint (Gerry) James (1922-2010), M.D., F.R.C.P. During the 2000 European Respiratory Society (ERS) Annual Congress held in Florence, Italy, experts in pulmonology and hepatology held a symposium entitled “Advances in Understanding Pulmonary Complications in Hepatic Diseases.” From this symposium was born the ERS Task Force on Pulmonary-Hepatic Disorders that subsequently published its landmark paper in 200449 (Fig. 3) that had three goals: (1) to increase awareness of HPS and POPH; (2) to improve diagnosis and management; and (3) to suggest and stimulate research. The diagnostic criteria and suggestions put forth by that Task Force remain the guideposts followed today. There has been a remarkable evolution of experience and expectations when confronted with these pulmonary vascular syndromes in LT candidates. No proven medical therapies for HPS have evolved via controlled trials, the most recent being a National Institutes of Health (NIH)–sponsored, multicenter, prospective, randomized, placebo-controlled trial using sorafenib to attenuate angiogeneis11 (although supplemental oxygen can improve hypoxemia). POPH can be improved, but not be cured, with pulmonary artery vasomodulators alone. Hence with poor outcomes of the “natural histories” of both syndromes, attempts and experiences to resolve them with liver transplantation have evolved. Notably, only one randomized, placebo-controlled trial has been accomplished in patients with POPH, PORTICO.12 This trial recently reported a significant reduction in pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP; compared with controls) using the endothelin receptor antagonist (ERA) macitentan over a 12-week period. Implications of these findings for liver transplantation will be of interest. In a 1968 report, Starzl et al.,13 while at the University of Colorado, described the extended survival after orthotopic homotransplantation of three children who “had evidence of the venous-to-arterial intrapulmonary shunts.” Interestingly, the oxygen saturations were 85% to 88% breathing room air and did not improve breathing pure oxygen. The shunts were calculated to be approximately 50% of the cardiac output and did improve significantly over a 10-day period posttransplant. However, in 1984, Van Thiel et al.14 from the University of Pittsburgh proposed, but without providing specific data, that a partial pressure of arterial oxygen (PaO2) <50 mm Hg due to pulmonary shunts should be an “absolute contraindication” to liver transplantation. These authors had noted “empirically that shunts that do not close postoperatively for periods of up to several weeks and that the resultant hypoxemia experience post-operatively, is yet another adverse factor that frequently turns a hopeful situation into a hopeless effort.” By the early 1990s, a series of case reports demonstrated that varying degrees of HPS could resolve after LT in adults and children. Over time, with mounting successes combined with a dismal outlook if transplant was not done (5-year survival rate of 23%), HPS became an ”indication” for LT.15 Importantly, because of the poor correlation between the severity of HPS and the severity of liver disease, current American Association for the Study of Liver Diseases (AASLD) guidelines from the AASLD and the International Liver Transplant Society (ILTS) suggest holding an “expedited review” for transplant consideration. To that end, in the setting of HPS, a “Model for End-Stage Liver Disease (MELD) score exception” policy currently exists for moderate to severe HPS (PaO2 < 60 mm Hg).16 It remains prudent to advise that the transplant be done in experienced centers, especially when the arterial hypoxemia is severe (PaO2 < 50 mm Hg), because of the challenges in the immediate posttransplant critical care time period.17 Despite the severity of HPS, expecting complete resolution of the syndrome posttransplant in the era of MELD exceptions has become the norm.18 Outcomes after LT attempts in the setting of POPH and the reporting of those outcomes, have followed a rather tumultuous course since the first descriptions in the early 1990s. Yoshida et al.,9 from the University of Western Ontario, described two interesting cases of POPH: one (extrahepatic portal hypertension) treated with a single lung transplant and one (chronic active hepatitis) treated with a LT. Pulmonary artery hypertension recurred in the transplanted lung 5 months posttransplant but was cured in the other patient with a successful LT. This was the first suggestion that the liver was the culprit inducing pulmonary artery hypertension. Over the years, private discussions at national meetings alluded to the unexpected occurrences of intraoperative death when transplant was attempted in the setting of POPH, as first reported in the literature by Ramsay et al.,19 at Baylor Medical Center, Dallas, Texas. Subsequent descriptions of transplant attempts and outcomes in the setting of POPH were summarized in a literature review and substantiated in a multicenter database experience.20, 21 In analyzing POPH transplant outcomes in 75 patients, a pretransplant mPAP >35 mm Hg appeared to be associated with poor survival during the transplant hospitalization (35% mortality rate). Variable use of intravenous (IV) prostacyclin to treat POPH was a very limited, yet a hopeful and an anecdotal approach to improve POPH posttransplant survival. POPH 5-year survival rates without medical treatment and with uncontrolled medical treatments, but not LT, have ranged from 14% to 40%, respectively.22, 23 There has never been a controlled trial to assess pulmonary vasodilator therapy impact in liver transplantation. Intuitively, it seemed reasonable to treat transplant patients with POPH before they experienced development of moderate-to-severe POPH and to attempt transplant if treatments could improve the hemodynamic and right ventricular function. To that end, and because of the poor correlation between the severity of POPH and the severity of liver diseases, a MELD exception for POPH was proposed and initiated in 2006.24 This approach has been justified because approximately 50% of patients with POPH, treated successfully prior to transplant (i.e., mPAP deceased to <35 mm Hg), could discontinue the pulmonary vascular modulators and be considered hemodynamically cured of POPH.25 However, it is currently cautioned that POPH, by itself, is not an indication for LT, especially in those with low native MELD score (<15), due to the unpredictable risks and outcomes after transplantation.26 For those with MELD score >15 and baseline PVR >450 dyne/s/cm5, wait-list mortality is increased, but transplant risk appears to lessen if mPAP can be decreased to <35 mm Hg with acceptable right ventricle function.27 The latter parameter is perhaps the most important and in need of further study. We have not identified specific circulating mediators directly linked to either HPS or POPH. Current thinking points toward the lack of a “good substance” emanating from the hepatic veins as the cause for intrapulmonary vascular dilatation (IPVD) in HPS, and the lack of clearance of a “bad substance” that invokes pulmonary vasoconstriction and endothelial/smooth muscle proliferation causing obstruction to flow in POPH. Time and more study will determine whether these ideas are sound. Interestingly, we have also seen that HPS can spontaneously resolve (seen in alcoholic patients with cirrhosis who stop drinking; personal observations). Such resolution has never been reported in POPH, but a fascinating and more concerning “resolution” of HPS has been reported by Aucejo et al.28 from the Cleveland Clinic. These authors described HPS resolution posttransplant, which transitioned into posttransplant pulmonary artery hypertension. The thought has been that the pulmonary vascular pathophysiology of HPS and POPH, respectively, could coexist, and that HPS could essentially “offload” the right ventricle pretransplant at the expense of worsening oxygenation. With posttransplant resolution of vascular dilatations caused by HPS, any obstruction to pulmonary blood flow is now unopposed and manifests itself as evolving pulmonary artery hypertension. This clinical picture, albeit uncommon, has been well documented and necessitated the initiation of pulmonary vasomodulator therapy. As Koch et al.29 have pointed out, indeed pulmonary artery hypertension (should we still call it POPH?) may evolve de novo after LT for reasons that remain unclear. The historical lessons of HPS and POPH are fascinating and evolving. The possible links (and causative circulating mediators) between these two syndromes remain enigmatic. For those interested in a more detailed chronological perspective of HPS and POPH, Tables 2 and 3 summarize selected key studies and contributions that have led to the current understanding of syndrome pathophysiology and the specific implications for LT. One final and simple observation should be stressed. Despite the risks in treating and transplanting patients with either HPS or POPH, it remains remarkable that replacement of the liver can result in total reversal of the severe dysfunction of a distal organ (e.g., the lungs) that otherwise would have dismal outcomes. In his fastidious review of the progress that has been made in recognizing and characterizing both HPS and POPH, Michael Krowka has given us a step-by-step account of the history of these two syndromes, since the term HPS was first coined in 1977. Although the mediators of these circulatory abnormalities in the lungs of patients with cirrhosis have yet to be identified, it is tempting to speculate that these syndromes either result from the effects of pulmonary “vasculotoxins” released from the diseased liver into the hepatic veins and hence into the pulmonary arteries, or from the cirrhosis-related deficiency of a pulmonary “vasculoprotective“ agent. Fortunately, this Gordian knot can be cut, so to speak, by a LT surgeon, because liver replacement can cure both syndromes. Very occasionally POPH can supervene posttransplant, sometimes when HPS was present preoperatively. The detailed histories of HPS and POPH that Michael Krowka has labored to provide here will serve us well by giving context to future developments in this field." @default.
• W3009542223 created "2020-03-13" @default.
• W3009542223 creator A5016679095 @default.
• W3009542223 date "2020-02-01" @default.
• W3009542223 modified "2023-10-17" @default.
• W3009542223 title "Hepatopulmonary Syndrome and Portopulmonary Hypertension: The Pulmonary Vascular Enigmas of Liver Disease" @default.
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• W3009542223 doi "https://doi.org/10.1002/cld.846" @default.
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