Karen L. Swanson

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia

Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

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.)

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.)

Pulmonary Arteriovenous Fistulas: Mayo Clinic Experience, 1982-1997

OBJECTIVE To describe the results of analysis of clinical, physiologic, diagnostic, and therapeutic aspects and complications in patients with pulmonary arteriovenous fistulas (PAVFs). PATIENTS AND METHODS Retrospective review of medical records of all patients with the diagnosis of PAVF evaluated at Mayo Clinic Rochester from 1982 through 1997. Demographic characteristics, presence or absence of hereditary hemorrhagic telangiectasia, clinical features, and results of imaging studies and blood gas analyses, treatments, and complications related to PAVFs were reviewed. RESULTS Among the 93 patients, 44 were male and 49 female. The mean age at the time of evaluation was 40 years (range, 5-83 years). Fifteen patients (16%) were asymptomatic. History of hereditary hemorrhagic telangiectasia was present in 52 patients (56%). Notable clinical findings included epistaxis in 46 (49%), hemoptysis in 14 (15%), cyanosis in 27 (29%), clubbing in 18 (19%), dyspnea in 53 (57%), and pulmonary bruits/murmurs in 32 (34%). Chest x-ray films with or without tomograms showed abnormal findings in 87 (94%), of which 68 (73%) suggested PAVF. Polycythemia was detected in 12 (13%). Pretherapy arterial PO2 measured on room air averaged 56 mm Hg (range, 32-95 mm Hg), and the posttherapy PO2 averaged 77 mm Hg (range, 46-110 mm Hg). Echocardiography with indocyanine green dye was diagnostic of extracardiac right-to-left shunt in 26 (90%) of 29 patients tested. Diagnostic studies revealed single lesions in 32 patients (34%) and multiple lesions in 61 (66%). The most prominent complications of the disease were neurologic events in 34 patients (37%). These complications included transient ischemic attacks, hemiplegia, brain abscesses, and seizures. Surgical resection alone was carried out in 18 patients (19%), embolization therapy alone in 41 (44%), and both therapies in 7 (8%). The 48 patients treated with embolization required 78 embolization sessions with more than 200 lesions occluded. Complications of treatment included postembolization hemothorax in 1 patient and right-sided hemiparesis in another patient. Follow-up disclosed that 1 patient died from PAVF-related complications. CONCLUSIONS Among our patients with PAVFs, hereditary hemorrhagic telangiectasia was observed in more than half and neurologic complications in more than one third. Because of the considerable risk of neurologic and other complications, definitive treatment should be considered in patients with PAVFs. Embolization is currently the preferred treatment in most patients. Frequent follow-up of treated patients is necessary because PAVFs tend to increase both in number and in size over time.

Safety and Efficacy of Ambrisentan for the Treatment of Portopulmonary Hypertension

BACKGROUND Ambrisentan is a selective endothelin-receptor antagonist that is approved by the US Food and Drug Administration for the treatment of pulmonary arterial hypertension. We describe hemodynamic responses and clinical outcomes of patients with portopulmonary hypertension (POPH) treated with ambrisentan. METHODS In this observational study, we prospectively identified and followed consecutive adult patients with POPH who received monotherapy with ambrisentan ≤ 10 mg daily from January 2007 until December 2009. Liver enzymes were assessed monthly. Pulmonary hemodynamic responses were assessed using echocardiograms and right-sided heart catheterizations. RESULTS We identified 13 patients (seven men) with POPH and began monotherapy with ambrisentan. The median age was 57 (interquartile range [IQR], 52-60). Patients were followed for a median of 613 days (IQR, 385-1,011). The median model for end-stage liver disease score was 10 (IQR, 8.5-15); eight patients had Child-Turcotte-Pugh A classification. Median time on ambrisentan therapy was 390 days (IQR, 363-611). Two patients died, one of advanced hepatocellular carcinoma and one of septic shock following pneumonia. The mean pulmonary artery pressure decreased from a baseline median of 58 mm Hg (IQR, 37-63) to 41 mm Hg (IQR, 27-48) (P = .004). The pulmonary vascular resistance median was reduced from 445 dynes/s/cm(5) (IQR, 329-834) to 174 dynes/s/cm(5) (IQR, 121-361) (P = .008). There was no difference in the longitudinal analysis of liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) after 12 months of therapy. One patient underwent successful liver transplantation and normalized pulmonary hemodynamic responses after transplantation. CONCLUSIONS In this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, we have shown that ambrisentan monotherapy can significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function.

Pulmonary Hypertension in Patients With Interstitial Lung Diseases

Pulmonary hypertension (PH) in patients with interstitial lung diseases (ILDs) is not well recognized and can occur in the absence of advanced pulmonary dysfunction or hypoxemia. To address this topic, we identified relevant studies in the English language by searching the MEDLINE database (1966 to November 2006) and by individually reviewing the references of identified articles. Connective tissue disease-related ILD, sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary Langerhans cell histiocytosis are the ILDs most commonly associated with PH. Pulmonary hypertension is an underrecognized complication in patients with ILDs and can adversely affect symptoms, functional capacity, and survival. Pulmonary hypertension can arise in patients with ILDs through various mechanisms, Including pulmonary vasoconstriction and vascular remodeling, vascular destruction associated with progressive parenchymal fibrosis, vascular inflammation, perivascular fibrosis, and thrombotic angiopathy. Diagnosis of PH in these patients requires a high index of suspicion because the clinical presentation tends to be nonspecific, particularly in the presence of an underlying parenchymal lung disease. Doppler echocardiography is an essential tool in the evaluation of suspected PH and allows ready recognition of cardiac causes. Right heart catheterization is needed to confirm the presence of PH, assess its severity, and guide therapy. Management of PH in patients with ILDs is guided by identification of the underlying mechanism and the clinical context. An increasing number of available pharmacologic agents in the treatment of PH allow possible treatment of PH in some patients with ILDs. Whether specific treatment of PH in these patients favorably alters functional capacity or outcome needs to be determined.

Pulmonary Arteriovenous Malformations

Pulmonary arteriovenous malformations (PAVMs) are abnormal vascular structures that most often connect a pulmonary artery to a pulmonary vein, bypassing the normal pulmonary capillary bed and resulting in an intrapulmonary right-to-left shunt. As a consequence, patients with PAVM can have hypoxemia and paradoxical embolization complications, including stroke and brain abscess. PAVMs may be single or multiple, unilateral or bilateral, and simple or complex. Most PAVMs are hereditary and occur in hereditary hemorrhagic telangiectasia, an autosomal dominant vascular disorder, and screening for PAVM is indicated in this subgroup. PAVMs may also be idiopathic, occur as a result of trauma and infection, or be secondary to hepatopulmonary syndrome and bidirectional cavopulmonary shunting. Diagnostic testing involves identifying an intrapulmonary shunt, with the most sensitive test being transthoracic contrast echocardiography. Chest CT scan is useful in characterizing PAVM in patients with positive intrapulmonary shunting. Transcatheter embolotherapy is the treatment of choice for PAVM. Lifelong follow-up is important because recanalization and collateralization may occur after embolization therapy. Surgical resection is rarely necessary and reserved for patients who are not candidates for embolization. Antibiotic prophylaxis for procedures with a risk of bacteremia (eg, dental procedures) is recommended in all patients with PAVM because of the risk of cerebral abscess.

Hepatopulmonary syndrome: Favorable outcomes in the MELD exception era

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disorder occurring as a consequence of advanced liver disease, characterized by hypoxemia due to intrapulmonary vascular dilatations. HPS independently increases mortality, regardless of the cause or severity of liver disease. Liver transplantation (LT) improves survival in HPS. We present the largest consecutive series of HPS patients specifically addressing long‐term survival relative to the degree of hypoxemia and the era in which LT was conducted. We evaluated 106 HPS patients at the Mayo Clinic from 1986 through 2010. Survival was assessed using Kaplan‐Meier methodology. LT was accomplished in 49 HPS patients. Post‐LT survival (1, 3, 5, and 10 years) did not differ between groups based on baseline partial pressure of arterial oxygen (PaO2) obtained at the time of HPS diagnosis. Improvements in overall survival at 1, 3, and 5 years post‐LT in those HPS patients transplanted after January 1 2002 (n = 28) (92%, 88%, and 88%, respectively) as compared with those transplanted prior to that time (n = 21) (71%, 67%, and 67%, respectively) did not reach statistical significance (5‐year P = 0.09). Model for Endstage Liver Disease (MELD) exception to facilitate LT was granted to 21 patients since January 1 2002 with post‐LT survival of 19/21 patients and one wait‐list death. Conclusion: Long‐term outcome after LT in HPS is favorable, with a trend towards improved survival in the MELD exception era since 2002 as compared to earlier HPS transplants. Survival after LT was not associated with PaO2 levels at the time of HPS diagnosis. (HEPATOLOGY 2012)

Mediastinoscopy in Patients With Lung Cancer and Negative Endobronchial Ultrasound Guided Needle Aspiration

BACKGROUND Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has been proposed as a safe, less-invasive alternative to mediastinoscopy to stage mediastinal lymph nodes in patients with lung cancer. We evaluated the negative predictive value of EBUS-TBNA in lung cancer patients suspected of having N2 nodal metastases. METHODS This study is a single-institution retrospective review of cases with suspected or confirmed lung cancer undergoing mediastinoscopy after a negative EBUS-TBNA between June 2006 and February 2008. RESULTS A total of 494 patients underwent EBUS-TBNA during the study period. Twenty-nine patients with suspected or confirmed lung cancer had a negative EBUS-TBNA and underwent subsequent mediastinoscopy. Mediastinoscopy was performed for findings suspicious of N2 disease based on noninvasive imaging. Mediastinoscopy found metastatic nodes in eight of 29 patients (28%) for a patient-specific negative predictive value of EBUS-TBNA of 72% (95% CI, 56% to 89%). Mediastinal lymph node dissection found four further patients with positive N2 nodes (19%). The EBUS-TBNA and mediastinoscopy sampled the same lymph node station on 36 occasions in the 29 patients. The average lymph node size was 10 mm. Mediastinoscopy was positive in 5 of 36 stations, for a nodal-specific negative predictive value of EBUS-TBNA of 86% (95% CI, 75% to 97%). CONCLUSIONS Endobronchial ultrasound with transbronchial needle aspiration can effectively sample mediastinal lymph node stations in patients with lung cancer. However, in this early experience, 28% of patients with high clinical suspicion of nodal disease had N2 mediastinal nodal metastases confirmed by mediastinoscopy despite negative EBUS-TBNA.

Abdominal Findings in Hereditary Hemorrhagic Telangiectasia: Pictorial Essay on 2D and 3D Findings with Isotropic Multiphase CT

The rapid evolution in multidetector computed tomographic (CT) technology has produced improvements in temporal and spatial resolution, leading to greater recognition of the spectrum of abdominal findings in hereditary hemorrhagic telangiectasia (HHT). In this multisystem vascular disorder, the abdominal findings are predominantly within the liver. Hepatic vascular lesions in HHT range from tiny telangiectases to transient perfusion abnormalities and large confluent vascular masses. Focal hepatic lesions are often associated with arteriovenous, arterioportal, or portovenous shunts. Pancreatic, splenic, and other vascular abnormalities are also observed because they are included in the field of view. By taking advantage of the increased z-axis spatial resolution and faster scanning times, and by using a bolus tracking technique, multiphase CT can be used to identify hepatic and extrahepatic lesions in HHT and to characterize the associated vascular shunts. Coronal maximum intensity projection images are particularly helpful in depiction of small hepatic vascular lesions.