Michael J. Krowka

Hepatopulmonary Syndrome — A Liver-Induced Lung Vascular Disorder

The hepatopulmonary syndrome is characterized by defects in oxygenation due to pulmonary abnormalities associated with chronic liver disease. Dyspnea and hypoxemia can be severe and often worsen in the upright position. Gross dilatation of the precapillary and capillary vessels occurs with ventilation–perfusion mismatch. The syndrome usually improves after liver transplantation.

Portopulmonary hypertension and hepatopulmonary syndrome

The clinically and pathophysiologically distinct entities of portopulmonary hypertension and hepatopulmonary syndrome occur in a substantial proportion of patients who have advanced liver disease of different causes. These disorders are notoriously underdiagnosed, but they have a substantial impact on survival and require focused treatment. Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure. Insights into the pathogeneses of these syndromes have led to novel therapeutic approaches. However, in severely affected patients, effective treatment remains a difficult task. In selected patients, liver transplantation represents the only treatment option, but the decision to do isolated liver transplantation is particularly challenging in patients who have severe pulmonary disease involvement. Data from several centres have contributed to provide criteria that allow improved prediction of which patients may, or may not, benefit from liver transplantation alone.

Natural history of hepatopulmonary syndrome: Impact of liver transplantation.

Few data exist concerning survival after the diagnosis of hepatopulmonary syndrome (HPS). Although orthotopic liver transplantation (OLT) frequently results in complete resolution of HPS, the relationship between transplantation and survival has not been described. The study rationale was to describe long‐term survival in patients with HPS. Data were derived from patients diagnosed with HPS at Mayo Clinic (n = 61) between 1985 and 2002, including those undergoing OLT (n = 24) and those who did not (n = 37). A case‐control, Kaplan‐Meier survival analysis between HPS patients and 77 patients without HPS matched for liver disease cause, model for end‐stage liver disease (MELD), severity of liver disease by the Child classification, and age was described for OLT and non‐OLT groups. Patients with HPS had a mean partial pressure of arterial oxygen (PaO2) decline of 5.2 + 2.3 mm Hg per year awaiting OLT. For HPS patients, despite similar baseline PaO2, brain uptake of technetium macroaggregated albumin (99mTcMAA), or measures of hepatic dysfunction, 5‐year survival associated with OLT was 76% versus 23% who did not undergo transplantation (P < .0001). Comparing those who did not undergo transplantation, HPS patients had worse 5‐year survival than matched controls (P = .0003). However, reasons to deny OLT (comorbidity) in the setting of HPS may well have contributed to observed survival differences. Baseline PaO2 ≤50 mm Hg was associated with worse survival irrespective of the decision to perform OLT. In conclusion, hypoxemia of HPS is frequently progressive. As OLT outcome relates to pretransplantation PaO2, additional MELD points should advance the priority for OLT in HPS. (HEPATOLOGY 2005.)

Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PortoPH) are pulmonary vascular consequences of advanced liver disease associated with significant mortality after orthotopic liver transplantation (OLT). Data from 10 liver transplant centers were collected from 1996 to 2001 that characterized the outcome of patients with either HPS (n = 40) or PortoPH (n = 66) referred for OLT. Key variables (PaO2 for HPS, mean pulmonary artery pressure [MPAP], pulmonary vascular resistance [PVR], and cardiac output [CO] for PortoPH) were analyzed with respect to 3 definitive outcomes (those denied OLT, transplant hospitalization survivors, and transplant hospitalization nonsurvivors). OLT was denied in 8 of 40 patients (20%) with HPS and 30 of 66 patients (45%) with PortoPH. Patients with HPS who were denied OLT had significantly worse PaO2 compared with patients who underwent transplantation (47 vs. 52 mm Hg, P < .005). Transplant hospitalization survival was associated with higher pre‐OLT PaO2 (55 vs. 37 mm Hg; P < .005). MPAP was significantly higher (53 vs. 45 mm Hg; P < .015) and PVR was significantly worse (614 vs. 335 dynes · s · cm−5; P < .05) in patients with PortoPH who were denied OLT compared with patients who underwent transplantation. Transplant hospitalization mortality was 16% (5/32) in patients with HPS and 36% (13/36) in patients with PortoPH. All of the deaths in patients with PortoPH occurred within 18 days of OLT; 5 of the 13 deaths in patients with PortoPH occurred intraoperatively. We concluded that patients with HPS (based on a combination of low PaO2 and nonpulmonary factors) and patients with PortoPH (based on pulmonary hemodynamics) were frequently denied OLT because of pre‐OLT test results and comorbidities. For patients who subsequently underwent OLT, transplant hospitalization mortality remained significant for both those with HPS (16%) and PortoPH (36%). (Liver Transpl 2004;182:10.)

Portopulmonary hypertension: Results from a 10‐year screening algorithm

Portopulmonary hypertension (POPH) is the elevation of pulmonary artery pressure due to increased resistance to pulmonary blood flow in the setting of portal hypertension. Increased mortality has occurred with attempted liver transplantation in such patients and thus, screening for POPH is advised. We examined the relationship between screening echocardiography and right heart catheterization determinations of pressure, flow, volume, and resistance. A prospective, echocardiography–catheterization algorithm was followed from 1996 to 2005. Consecutive transplantation candidates underwent Doppler echocardiography to determine right ventricular systolic pressure (RVSP). Of 1,235 patients, 101 with RVSP >50 mm Hg underwent catheterization to measure mean pulmonary artery pressure (MPAP), flow via cardiac output (CO), central volume via pulmonary artery occlusion pressure (PAOP), and resistance via calculated pulmonary vascular resistance (PVR). Bland‐Altman analysis suggested marked discordance between echocardiography‐derived RVSP and catheterization results. All‐cause pulmonary hypertension (MPAP >25 mm Hg) was documented in 90/101 (90%) patients. Using current pressure and resistance diagnostic guidelines (MPAP >25 mm Hg, PVR ≥240 dynes/s/cm−5), POPH was documented in 66/101 (65%) patients. Elevated MPAP was due to increased CO and/or PAOP in 35/101 (35%) patients with normal resistance (PVR <240 dynes/s/cm−5). The transpulmonary gradient (MPAP–PAOP) further characterized POPH in the presence of increased volume. Model for end stage liver disease (MELD) scores correlated poorly with MPAP and PVR. In conclusion, right heart catheterization is necessary to confirm POPH and frequently identifies other reasons for pulmonary hypertension (e.g., high flow and increased central volume) in liver transplantation candidates. Severity of POPH correlates poorly with MELD scores. (HEPATOLOGY 2006;44:1502–1510.)

Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups.

To determine the natural history of portopulmonary hypertension (POPH), a retrospective screening‐right heart catheterization‐survival analysis of patients was performed. We categorized patients by three treatment subgroups: (1) no therapy for pulmonary hypertension (PH) or liver transplantation (LT), (2) therapy for PH alone and (3) therapy for PH followed by LT. Seventy‐four patients were identified between 1994 and 2007. Nineteen patients received no therapy for PH and no LT representing the natural history of POPH. Five‐year survival was 14%, and 54% had died within 1 year of diagnosis. Five‐year survival in 43 patients receiving therapy for PH but no LT was 45%, and 12% had died within 1 year of diagnosis. Twelve patients underwent LT and 5‐year survival for the nine receiving therapy for PH was 67% versus 25% in the three who were not pretreated with prostacyclin therapy. The survival of untreated patients with POPH was poor. Subgroups of patients selected to medical treatment with or without LT had better long‐term survival. Mortality did not correlate with baseline hemodynamic variables, type of liver disease or severity of hepatic dysfunction. Medical therapy for POPH should be considered in all patients with POPH, but the treatment effects and impact on those considered for LT still requires well‐designed, prospective study before practice guidelines can be suggested.

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

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 pediatric 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.

Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: A new approach

BACKGROUND & AIMS We have reported that contrast echocardiography is a sensitive screening test for the hepatopulmonary syndrome (HPS). However, contrast echocardiography lacks specificity because many cirrhotic patients have positive study results with normal arterial blood gases and therefore do not fulfill criteria for HPS. The aim of this study was to assess the role of macroaggregated albumin lung perfusion scans (MAA scans) in the diagnosis of HPS. METHODS MAA scans were performed in 25 patients with HPS, 25 cirrhotic patients without HPS, and 15 hypoxemic subjects with intrinsic lung disease alone. An MAA shunt fraction was calculated from brain and lung counts. RESULTS MAA scan results were positive in 21 of 25 patients with HPS and negative in all controls. All 21 patients with positive MAA scans had PO2 values of <60 mm Hg. There was a strong inverse correlation between the degree of the MAA shunt fraction and arterial hypoxemia (r = -0.726). CONCLUSIONS A positive MAA scan result in cirrhosis is specific for the presence of moderate to severe HPS. We speculate that MAA scans may be particularly useful in evaluating the contribution of HPS to the hypoxemia in cirrhotic patients with intrinsic lung disease.

Hepatic hydrothorax: pathogenesis, diagnosis, and management.

Hepatic hydrothorax is defined as a pleural effusion in a patient with cirrhosis of the liver and no cardiopulmonary disease. The estimated prevalence of this often debilitating complication in patients with liver cirrhosis is 4% to 10%. Its pathophysiology involves movement of ascitic fluid from the peritoneal cavity into the pleural space through diaphragmatic defects. As a result patients are at increased risk of respiratory infection. Initial management consists of sodium restriction, diuretics, and thoracentesis. A transjugular intrahepatic portosystemic shunt may be required. Because most patients with hepatic hydrothorax have end-stage liver disease, a liver transplant should be considered if these options fail.

Clinical risk factors for portopulmonary hypertension.

Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case‐control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes · second · cm−5, and pulmonary capillary wedge pressure ≤ 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right‐sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio = 2.90, 95% confidence interval 1.20‐7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14‐14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio = 0.24, 95% confidence interval 0.09‐0.65, P = 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. Conclusion: Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension. (HEPATOLOGY 2008.)