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.

Alpha1-antitrypsin deficiency allele carriers among lung cancer patients.

Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD with LC, few studies examined the association of alpha1AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with >70 variants reported. There are at least 10 alleles associated with deficiency in alpha1-antitrypsin. Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). alpha1AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, P < or = 0.01, respectively). Our preliminary findings suggest that individuals who carry an alpha1AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.

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.

Pulmonary hypertension: diagnostics and therapeutics.

Pulmonary hypertension (PH) may develop because of a spectrum of insults to the lungs; in some patients, there seems to be no cause. Noninvasive tests, such as standard chest radiography, electrocardiography, and transthoracic Doppler echocardiography, provide effective screening if PH is suspected. This synopsis focuses on these screening studies and the more common clinical problems, including primary cardiac abnormalities, obstructive sleep apnea, chronic pulmonary embolism, pulmonary parenchymal problems, connective tissue disorders, cirrhosis with portal hypertension, and use of appetite suppressants, that should be considered when PH exists. Treatment options for PH, including intravenous prostacyclin (epoprostenol), and investigational agents such as subcutaneous or oral prostacyclin analogues and oral endothelin receptor antagonists are described.

Severe hypoxemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate.

Severe hypoxemia associated with chronic liver disease is an uncommon disorder most likely due to an intrapulmonary vascular abnormality that has characteristics of both ventilation-perfusion mismatching and diffusion limitation. Anatomically, the intrapulmonary vascular abnormalities can occasionally be detected by angiography. Physiologically, the gas exchange abnormalities can be substantiated by contrast-enhanced two-dimensional echocardiography. Although orthodeoxia and platypnea have frequently been found in these patients, echocardiographic data suggest that vascular abnormalities can exist in the absence of orthodeoxia. We describe 11 patients who had severe hypoxemia and chronic liver disease and review their pulmonary angiographic, contrast echocardiographic, and arterial blood gas findings. Among five of these patients who were given almitrine bismesylate, an experimental medication thought to alter ventilation-perfusion relationships in patients with chronic obstructive pulmonary disease, one had improved oxygenation. We recommend that patients with hypoxemia associated with chronic liver disease have detailed studies to rule out reversible forms of hypoxemia and that those with severe hypoxemia undergo testing to determine the existence of intrapulmonary vascular abnormalities, especially if liver transplantation is considered.

Pulmonary aspects of chronic liver disease and liver transplantation.

A vast spectrum of pulmonary pathologic conditions occurs in association with chronic liver diseases, and clinically important manifestations, such as arterial hypoxemia, can result. Both pulmonary vascular and parenchymal abnormalities can contribute to the dysfunction, as evidenced by results of pulmonary function tests and gas exchange studies. The clinical implications of identifying such pulmonary problems range from alleviation of symptoms, especially dyspnea, to comprehensive assessment of patients before and after liver transplantation. Physicians should be aware of these potential pulmonary disorders that can complicate liver disease and liver transplantation so that management of affected patients can be improved.

A prospective study of airway reactivity before bone marrow transplantation.

The purposes of this study were to assess baseline airway function and to determine the frequency of airway reactivity in patients before bone marrow transplantation (BMT). The ratio of the forced expiratory volume at 1 second to the forced vital capacity (FEV1/FVC) was the measure of baseline airflow. Using methacholine challenge, we tested 53 patients before conditioning chemotherapy, total-body irradiation, and BMT. All patients had a baseline FEV1/FVC of 70% or more. The mean baseline FEV1/FVC was 84(+)/- 6%. The response to methacholine challenge was defined by the change in FEV1 from baseline (delta FEV1). A positive response (delta FEV1 of 20% or more) occurred in 11 of 53 patients (21%), a borderline response of (delta FV1 of less than 20% but greater than or equal to 10%) was was found in 10 (19%), and no response (Delta FEV1 of less than 10%) was elicited in 32 (60%). In our group of patients with a positive or borderline response to methacholine, we found no significant relationship to baseline FEV1/FVC, smoking history, hematologic diagnosis or study, or major post-BMT pulmonary complications including bronchiolitis obliterans. We concluded that pretransplantation airway reactivity, as measured by methacholine challenge and in the setting of normal baseline FEV1/FVC, was common before BMT. The presence of a borderline or positive response to methacholine challenge before transplantation was not associated with the development of either clinical or pathologically proven posttransplantation bronchiolitis obliterans.

Pulmonary complications of orthotopic liver transplantation.

We retrospectively reviewed the pulmonary complications and associated morbidity and mortality of 44 consecutive patients who underwent 52 orthotopic liver transplantations (OLTs) at the Mayo Clinic during 1987. All survivors participated in follow-up for 1 year after OLT. Of the five deaths in the study group, three were associated with pulmonary infections. On postoperative chest roentgenograms, 24 cases of pulmonary infiltrates were noted; 12 were caused by infections. Ten opportunistic pulmonary infections developed in nine patients: four cytomegalovirus, three Pneumocystis carinii pneumonia, and one each of Cryptococcus, Aspergillus, and Candida. All except one of the opportunistic infections were diagnosed after the sixth postoperative week. Fiberoptic bronchoscopy was helpful for diagnosing opportunistic pulmonary infections in six patients. One Aspergillus pulmonary infection was diagnosed by transthoracic needle aspiration. Bacterial pneumonia occurred in five patients. Preoperative pulmonary function tests, performed in 40 patients, revealed a restrictive ventilatory defect in 28% and impaired gas transfer in 52%. Pleural effusion was present in 18% of patients preoperatively and in 77% during the first week after OLT. Preoperative severity of liver disease and results of arterial blood gas determinations, pulmonary function tests, and chest roentgenography were not associated with postoperative mortality and pulmonary infections. Infectious and noninfectious pulmonary complications are common in liver transplant recipients. Attempts to decrease the frequency and severity of pulmonary complications by early diagnosis and effective treatment may diminish the morbidity and mortality associated with OLT.

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.

Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients.

OBJECTIVE: To characterize the pulmonary hemodynamics and identify predictors of pulmonary hypertension in a group of patients before liver transplantation and to determine whether pulmonary hypertension in these patients is related to survival. MATERIAL AND METHODS: In 362 patients before their first liver transplantation (between 1985 and 1993), the clinical history, laboratory data, and results of pulmonary function tests were recorded. Pulmonary artery (PA) catheterization was performed after induction of anesthesia at the time of transplantation. Monthly follow-up was maintained. RESULTS: A hyperdynamic circulation was often present -- an increased mean cardiac output (7.6 L/min), increased mean PA pressure (20.9 mm Hg), correlation of mean PA pressure with cardiac output (r = 0.25; P<0.001), and decreased mean pulmonary vascular resistance (60 dynes times s/cm5). Mean PA pressures were more than 25 mm Hg in 72 patients (20%). Pulmonary hypertension (defined as mean PA pressure of more than 25 mm Hg and pulmonary vascular resistance in excess of 120 dynes times s/cm5) occurred in 15 patients (4%). Pulmonary function tests revealed obstruction in 7%, restriction in 18%, and low diffusing capacity in 46%. By univariate analysis, lower forced expiratory volume in 1 second, forced vital capacity, and total lung capacity were the only preoperative factors associated with pulmonary hypertension (P<0.05). Survival was significantly lower in patients with acute fulminant hepatitis (P<0.001), the group with the highest mean PA pressure, than in those with other diagnoses. Increased PA pressures or mild to moderate pulmonary hypertension was not found to be associated with a worse survival by univariate or multivariate analysis. CONCLUSION: Increased PA pressure is common in liver transplant patients (20%). "True" pulmonary hypertension occurred in only 4% of our patients and was not associated with an adverse outcome.

Hepatopulmonary syndrome. Clinical observations and lack of therapeutic response to somatostatin analogue.

We retrospectively studied 22 patients with hepatopulmonary syndrome (HPS) evaluated at the Mayo Medical Center from 1984 to 1991. All patients had hepatic cirrhosis with clinical evidence of portal hypertension; 13 (59 percent) had severe hypoxemia while breathing room air in the supine position (PaO2 < 60 mm Hg), and 14 of 16 (88 percent) had orthodeoxia breathing room air. On the basis of angiographic observations, we defined type 1 and type 2 patterns of pulmonary vascular abnormalities in HPS. Response to 100 percent oxygen and therapeutic regimens may differ in the angiographic patterns. Substantial deterioration in PaO2 associated with clinically stable hepatic dysfunction was documented in five of seven patients studied with sequential arterial blood gas testing; four subsequently died within 48 months. Overall mortality was 41 percent, occurring a mean of 2.5 years after diagnosis. In 7 of the 22 patients, we prospectively studied the effect of somatostatin analogue given subcutaneously for 4 consecutive days. No significant improvement in PaO2 was documented while breathing room air or 100 percent oxygen (p < 0.05). We conclude that in selected patients with clinically stable hepatic dysfunction and deteriorating oxygenation, the prognosis is poor. Our data in combination with recent surgical reports suggest that liver transplantation may be the treatment of choice in patients with HPS and worsening oxygenation.

Azathioprine-associated pulmonary dysfunction.

We present a case of azathioprine-associated alveolitis diagnosed by gallium-67 scanning and transbronchial biopsy. The patient denied respiratory symptoms, exhibited spiking fevers, and had normal chest roentgenograms. Allopurinol inhibition of azathioprine metabolism may have been a contributing factor.

Pulmonary complications of bone marrow transplantation.

Bone marrow transplantation (BMT) for hematologic disorders is potentially curative in selected persons. These patients may be immunocompromised for months after engraftment as a consequence of chemotherapy, irradiation, acute and chronic graft-vs-host disease (GVHD), and maturing recipient marrow. Pulmonary complications commonly occur during the early and late periods after BMT and are associated with significant morbidity and mortality. The leading early-onset complication is interstitial pneumonitis, most commonly associated with cytomegalovirus infection but also related to possible toxicities from chemotherapy and irradiation. Major late-onset problems include bacterial sinopulmonary infections and obstructive airway disease thought to be associated with chronic GVHD. The exact mechanisms of lung injury are probably quite complex, and unfortunately, often cause irreversible pulmonary disease, even in the patient who has had successful transplantation. Antimicrobial prophylaxis, modified chemotherapy and irradiation dosages, and antiviral immunization have been shown to reduce the incidence of early-onset pulmonary problems. Early recognition and treatment of late-onset problems will, it is hoped, minimize respiratory limitations.

Cardiac dysrhythmia following pneumonectomy. Clinical correlates and prognostic significance.

Cardiac tachydysrhythmias occurred in 53 (22 percent) of 236 consecutive patients undergoing pneumonectomy. All patients had preoperative electrocardiograms which showed normal sinus rhythm. Patients did not receive digitalis before surgery. Atrial fibrillation was the most common dysrhythmia (64 percent; 34/53), followed by supraventricular tachycardia (23 percent; 12/53) and atrial flutter (13 percent; 7/53). No episodes of ventricular tachycardia were documented. Elevated concentrations of cardiac enzymes were associated with 12 (28 percent) of 43 tachydysrhythmias. Recurrent or persistent dysrhythmias were documented in 29 (55 percent) of 53 patients despite medical management or electrocardioversion (or both). Thirty-one percent (9/29) of these patients subsequently died during their hospitalization. There was no correlation between standard preoperative pulmonary function tests and the incidence of postoperative dysrhythmia. In addition, there was no correlation of dysrhythmia with postoperative diagnoses, surgical staging for lung cancer, postoperative arterial blood gas levels, or the fact that a completion pneumonectomy or chest wall resection was undertaken. An increased incidence of tachydysrhythmia was noted in patients undergoing intrapericardial dissections and those who developed postoperative interstitial or perihilar pulmonary edema. Twenty-five percent (13) of the patients experiencing tachydysrhythmias died within 30 days following their pneumonectomy. We conclude that tachydysrhythmias after pneumonectomy are associated with significant mortality, have poor correlation to preoperative pulmonary function, and occur more frequently following intrapericardial dissection and in patients who develop postoperative interstitial pulmonary edema or perihilar pulmonary edema.

Intrapulmonary vascular dilatations (IPVD) in liver transplant candidates. Screening by two-dimensional contrast-enhanced echocardiography.

Intrapulmonary vascular dilatations (IPVD) are extrahepatic complications of acute and chronic liver disorders that can result in severe hypoxemia. Contrast-enhanced (CE) echocardiography provides a noninvasive method to detect right-to-left shunting associated with IPVD. We prospectively studied 40 consecutive liver transplant candidates to determine the relationship between CE echocardiography, arterial blood gases, and standard pulmonary function tests. Two patients had technically unacceptable results of echocardiographic studies. Thirty-eight patients had acceptable results of studies; seven (18.4 percent) of 38 were hypoxemic (PaO2 less than 70 mm Hg). Thirty-one patients (81.6 percent) had PaO2 greater than or equal to 70 mm Hg. Positive CE echocardiograms suggesting IPVD were found in five (13.2 percent) of 38. Three (9.7 percent) of the 31 patients with PaO2 greater than or equal to 70 mm Hg had positive CE echocardiograms. Two (28.6 percent) of the seven hypoxemic patients had positive CE echocardiography. Mean PaO2 and pulmonary function parameters were not significantly different between those with positive CE echocardiogram compared with those with normal CE echocardiograms. We conclude that for our group of liver transplant candidates, (1) IPVD as suggested by CE echocardiography were not uncommon (13.2 percent), and (2) positive CE echocardiography could be documented in patients who were not hypoxemic (9.7 percent).

Unexplained pulmonary hypertension in chronic myeloproliferative disorders.

AIM: To investigate the potential association between the chronic myeloid disorders (CMDs), including the chronic myeloproliferative disorders, and pulmonary hypertension (PH). METHODS: Retrospective chart review of patients who had received diagnoses of both CMD and PH. Patients with a known cause of PH were excluded. The diagnosis of a CMD was based on established criteria. The diagnosis of PH was based on echocardiographic data or right heart catheterization data. RESULTS: Twenty-six patients satisfied the criteria for both a CMD and PH. Twelve patients had myeloid metaplasia with myelofibrosis (MMM), 5 patients had essential thrombocythemia (ET), 6 patients had polycythemia vera, 2 patients had a myelodysplastic syndrome, and 1 patient had chronic myeloid leukemia. Twenty-two patients (92%) received treatment for their CMDs, which included therapy with hydroxyurea (18 patients), anagrelide (7 patients), and busulfan (3 patients). PH was diagnosed a median of 8 years after recognition of the CMD (range, 0 to 26 years). The median right ventricular systolic pressure (RVsys) was 71 mm Hg (range, 32 to 105 mm Hg). RVsys correlated with the platelet count in patients with MMM (r = 0.30) and ET (r = 0.6) and with the hemoglobin levels in patients with PV (r = 0.77). Treatment of CMD did not seem to affect the severity of the pulmonary artery pressures as measured by serial echocardiography. With a median survival time of 18 months after the diagnosis of PH, the cause of death in the majority of the patients was cardiopulmonary. CONCLUSIONS: The current study suggests a higher than expected incidence of PH in patients with MMM, PV, and ET. Prognosis in such a setting is poor and may not be influenced by aggressive treatment of the underlying hematologic disorder.

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.

BACKGROUND: Because of the spectrum of intrapulmonary vascular dilation that characterizes hepatopulmonary syndrome (HPS), PaO(2) while breathing 100% oxygen varies. Abnormal extrapulmonary uptake of (99m)Tc macroaggregated albumin (MAA) after lung perfusion is common. GOAL: To describe relationships between (1) severity of liver disease measured by the Child-Pugh (CP) classification; (2) PaO(2) while breathing room air (RA) and 100% oxygen on 100% oxygen; and (3) extrapulmonary (brain) uptake of (99m)Tc MAA after lung scanning. METHODS AND PATIENTS: We prospectively measured PaO(2) on RA, PaO(2) on 100% oxygen, and brain uptake after lung perfusion of (99m)Tc MAA in 25 consecutive HPS patients. RESULTS: Mean PaO(2) on RA, PaO(2) on 100% oxygen, PaCO(2) on RA, and (99m)Tc MAA brain uptake were similar when categorized by CP classification. Brain uptake was abnormal (> or = 6%) in 24 patients (96%). Brain uptake was 29 +/- 20% (mean +/- SD) and correlated inversely with PaO(2) on RA (r = -0.57; p<0.05) and PaO(2) on 100% oxygen (r = -0.41; p<0.05). Seven patients (28%) had additional nonvascular pulmonary abnormalities and lower PaO(2) on 100% oxygen (215+/-133 mm Hg vs 391+/-137 mm Hg; p<0.007). Eight patients (32%) died. Mortality in patients without coexistent pulmonary abnormalities was associated with greater brain uptake of (99m)Tc MAA (48+/-18% vs 25+/-20%; p<0.04) and lower PaO(2) on RA (40+/-7 mm Hg vs 57+/-11 mm Hg; p<0.001). CONCLUSION: The degree of hypoxemia associated with HPS was not related to the CP severity of liver disease. HPS patients with additional nonvascular pulmonary abnormalities exhibited lower PaO(2) on 100% oxygen. Mortality was associated with lower PaO(2) on RA, and with greater brain uptake of (99m)Tc MAA.

A prospective study of pulmonary function and gas exchange following liver transplantation.

Pulmonary function and gas exchange were prospectively studied in 95 patients before and 9 to 15 months following liver transplantation. Pretransplant, the most common PF abnormality was impaired efficiency of gas exchange as measured by Dss. As a group, the mean Dss was 78.0 +/- 16.6 percent predicted and was found to be less than 80 percent predicted in 50 patients. As a group, patients with the most severe liver diseases clinically (Child's C classification) had the lowest mean Dss pretransplant. Posttransplant, three findings were of clinical importance: PaCO2 significantly improved posttransplantation, suggesting a resolution of pretransplant respiratory alkalosis. Expiratory airflow obstruction, measured by a change in the FEV1/FVC, was extremely uncommon posttransplant. Mean Dss improved significantly in patients with Child's C severity of liver disease. The most frequent deteriorations in Dss statistically were associated with posttransplant thoracotomy, ARDS, nonspecific pneumonitis, significant pleural effusions and hepatic retransplantation.

Recent pulmonary observations in alpha 1-antitrypsin deficiency, primary biliary cirrhosis, chronic hepatitis C, and other hepatic problems.

Patients with metabolic, immunologic, viral, and other types of hepatic disorders can have a spectrum of complicating pulmonary abnormalities. The natural history of these associations is poorly understood. Significant reversibility in hepatic and pulmonary dysfunction, however, has been well documented in the era of organ transplantation. The continued relationship among pulmonologists, hepatologists, and transplant surgeons hopefully will provide enlightening data on these interesting clinical associations, their natural histories, and their response to evolving therapeutic approaches.

Hepatopulmonary syndrome. A pulmonary vascular complication of liver disease.

Hepatopulmonary syndrome is part of the spectrum of pulmonary vascular disorders seen in advanced liver disease. The pathophysiology of these entities likely is dependent on the degree of pulmonary vasoconstriction or vasodilation that occurs. Our understanding of hepatopulmonary syndrome has helped further our knowledge of the interaction of the liver and the lung. Advances in the management of this disorder, especially liver transplantation, finally have allowed us to offer some hope to patients with this disease.