Evaluating the Risks of High Altitude Travel in Chronic Liver Disease Patients

Abstract

Luks, Andrew M., and Erik R. Swenson. Clinician's Corner: Evaluating the risks of high altitude travel in chronic liver disease patients. High Alt Med Biol 16:80–88, 2015.—With improvements in the quality of health care, people with chronic medical conditions are experiencing better quality of life and increasingly participating in a wider array of activities, including travel to high altitude. Whenever people with chronic diseases travel to this environment, it is important to consider whether the physiologic responses to hypobaric hypoxia will interact with the underlying medical condition such that the risk of acute altitude illness is increased or the medical condition itself may worsen. This review considers these questions as they pertain to patients with chronic liver disease. While the limited available evidence suggests there is no evidence of liver injury or dysfunction in normal individuals traveling as high as 5000 m, there is reason to suspect that two groups of cirrhosis patients are at increased risk for problems, hepatopulmonary syndrome patients, who are at risk for severe hypoxemia following ascent, and portopulmonary hypertension patients who may be at risk for high altitude pulmonary edema and acute right ventricular dysfunction. While liver transplant patients may tolerate high altitude exposure without difficulty, no information is available regarding the risks of long-term residence at altitude with chronic liver disease. All travelers with cirrhosis require careful pre-travel evaluation to identify conditions that might predispose to problems at altitude and develop risk mitigation strategies for these issues. Patients also require detailed counseling about recognition, prevention, and treatment of acute altitude illness and may require different medication regimens to prevent or treat altitude illness than used in healthy individuals.

Introduction

With improvements in medical care, people with chronic medical conditions are experiencing opportunities to engage in a wider variety of activities than previously possible, including high altitude travel. The benefits of such activities are potentially great, and include opportunities to visit beautiful places, participate in active pursuits such as hiking or skiing, or less vigorous activities such as attending an arts festival, relaxing at a resort, or visiting family. However, travel to altitudes above 2340 m (8000 ft) also poses risks. Regardless of underlying health status, all individuals traveling to these altitudes are at risk for developing one of several acute altitude illnesses, including acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). In patients with chronic diseases, there is the added consideration of whether physiologic responses to hypobaric hypoxia will interact with the underlying medical condition such that the risk of developing acute altitude illness is increased or the underlying condition itself will worsen in this environment.

In this review, we consider these issues as they pertain to patients with hepatic insufficiency and cirrhosis. After reviewing hepatic responses to hypoxia, we consider two groups of cirrhosis patients who are potentially at increased risk for problems, hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) patients. We then briefly consider the risks for liver transplant patients, as well as issues associated with long-term residence in this environment. We conclude by addressing the proper selection and dosing of medications for the management of acute altitude illness and providing recommendations about pre-travel evaluation and planning for these patients.

The fact that the evidence regarding these issues is limited will not stop patients from seeking to travel to this environment nor remove the need for clinicians to evaluate and mitigate the risks of these activities. The information provided below should be viewed as tentative recommendations in light of the available evidence to guide assessment until further data are available.

Hepatic Responses at Acute Hypoxia

While much is known about the human cardiac, respiratory, and renal responses to hypobaric hypoxia, less is known about the responses of the human liver. The available data in humans suggest that exposure to altitudes between 3400 and 5000 m leads to increases in hepatic blood flow (Kalson et al., 2010; Ramsoe et al., 1970), but does not lead to changes in markers of liver injury such as SGOT, SGPT, and alkaline phosphatase (Berendsohn, 1962; Hu et al., 2013; Ramsoe et al., 1970) or significant changes in cytochrome P450 function (Jurgens et al., 2002; Streit et al., 2005) or other markers of hepatic function such as bromsulfothalein transport or galactose elimination (Ramsoe et al., 1970). Evidence regarding tissue oxygenation in hypoxia derives largely from animal models and suggests that while tissue Po₂ and hemoglobin oxygen content are decreased in normobaric hypoxia models in which the inspired oxygen concentrations were decreased to various levels below 0.21, cytochrome oxidase levels are maintained with inspired oxygen concentrations as low as 0.1, likely as a result of increased oxygen extraction (Larsen et al., 1976; Seifalian et al., 2001; Yang et al., 2003). Mitochondrial respiratory capacity and oxidative phosphorylation also appear to be preserved (Ou et al., 2013) while lactate uptake is preserved with moderate degrees of hypoxia but decreases with extreme hypoxemia above an equivalent of 4600 m (Pastor, 2000; Tashkin et al., 1972).

Risks of High Altitude Exposure in Cirrhosis Patients

The risks for cirrhosis patients include those that apply to all high altitude travelers, regardless of health status, and those that may apply more specifically to these patients.

Risks faced by all high altitude travelers

All individuals traveling to altitudes above 2340 m, including those with chronic liver disease, are at risk for three forms of acute altitude illness, including acute mountain sickness (AMS), high altitude cerebral edema (HACE), or high altitude pulmonary edema (HAPE). The clinical features of these illnesses have been reviewed elsewhere (Bartsch and Swenson, 2013; Hackett and Roach, 2001; 2004; Maggiorini, 2006) while consensus guidelines describe best practices for their prevention and treatment. (Luks et al., 2014)

Risks faced by travelers with cirrhosis

No studies have examined the risks of high altitude exposure in cirrhosis patients. Because they have increased minute ventilation, preserved hypoxic ventilatory responses (HVR) (Stanley et al., 1976) and, in up to 30% of patients, absent or diminished hypoxic pulmonary vasoconstriction (HPV) (Daoud et al., 1972; Rodriguez-Roisin et al., 1987), it is reasonable to speculate that they might be at less risk for altitude illness compared to healthy travelers, as blunted HVR (Hackett et al., 1988a; Moore et al., 1986) and exaggerated HPV (Bartsch et al., 2005; Swenson et al., 2002) have been implicated as precipitating factors for AMS and HAPE. Unfortunately, there are no data evaluating these concepts, and all cirrhosis patients should adhere to standard recommendations for altitude illness prevention (Luks et al., 2014). Beyond these general considerations, two groups of cirrhosis patients may be at increased risk for problems at high altitude.

Portopulmonary hypertension

PoPH is defined by the presence of pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg at rest) and increased pulmonary vascular resistance (>240 dyne/s/cm⁵) in the setting of portal hypertension and absence of left ventricular dysfunction (Fritz et al., 2013; Rodriguez-Roisin et al., 2004). The disease, which has been reviewed extensively elsewhere (Fritz et al., 2013; Rodriguez-Roisin et al., 2004), is present in up to 5% of patients with Child-Turcotte-Pugh score ≥7 evaluated for liver transplantation (Krowka et al., 2006).

There is reason to suspect that PoPH patients may be at increased risk for complications at high altitude, including HAPE and/or worsening right ventricular dysfunction. HAPE occurs as a result of exaggerated HPV whereby overly large rises in pulmonary vascular resistance and pulmonary artery pressure lead to increased pulmonary hydrostatic pressure and leakage of fluid into the interstitium and alveolar spaces (Bartsch et al., 2005). The disorder commonly affects individuals with no underlying medical problems, but reports document its occurrence in patients with pulmonary hypertension due to factors such as absent pulmonary artery (Hackett et al., 1980; Rios et al., 1985), Down's syndrome (Durmowicz, 2001), granulomatous mediastinitis (Torrington, 1989), and anorexigen use (Naeije et al., 1996). When viewed together, these reports are suggestive of an increased risk of HAPE in pulmonary hypertension patients (Luks, 2009a). The phenomenon has not been reported in patients with PoPH due to cirrhosis, but Bogaard et al. (2007) reported a case in a patient with portal hypertension due to an Abernethy malformation.

PoPH patients may also be at risk for increasing right ventricular dysfunction and ischemia. Further rises in pulmonary artery pressure with acute hypoxia, particularly during exertion, could increase right ventricular afterload, leading to worsening systolic function, increasing chamber dilation, and possible subendocardial ischemia. This phenomenon has not been described in pulmonary hypertension patients but has been reported with hypobaric hypoxia during commercial flight in patients with morbid obesity and severe kyphoscoliosis, two disorders often associated with pulmonary hypertension (Noble and Davidson, 1999; Toff, 1993).

The degree of pulmonary hypertension necessary to increase risk is unclear, as the range of pulmonary artery pressures documented in the reports noted above is broad. Risk may also be a function of how much further pulmonary artery pressure rises upon ascent due to both HPV and the increase in cardiac output and pulmonary blood flow. Another unresolved question is the altitude at which the risk is increased. HAPE typically occurs at elevations >2500 m, but several of the reports noted above documented its occurrence at altitudes as low as 1500–1750 m (Durmowicz, 2001; Rios et al., 1985). In the absence of clearly defined thresholds, portopulmonary hypertension patients should likely receive careful evaluation with planned travel to elevations lower (∼1500–2000 m) than that typically associated with risk in the general population (2500 m). Pre-travel evaluation and planning is discussed further below.

Hepatopulmonary syndrome

Marked by the presence of impaired gas exchange, HPS affects between 5% and 32% of patients with portal hypertension evaluated at liver transplant centers (Schenk et al., 2002) and may also affect individuals with acute and chronic hepatitis in the absence of established portal hypertension (Regev et al., 2001; Teuber et al., 2002). The key pathophysiologic defects in HPS, which have been reviewed extensively elsewhere (Fritz et al., 2013; Rodriguez-Roisin and Krowka, 2008; Rodriguez-Roisin et al., 2004), are the presence of intrapulmonary capillary dilation ranging from 15 to 160 microns and/or arteriovenous malformations which contribute to abnormal gas exchange by one of three mechanisms: (1) diffusion limitation resulting from a combination of increased diffusion distance between the alveolar space and red cells in the dilated capillaries and shorter capillary transit time due to increased cardiac output; (2) areas of low ventilation-perfusion ratio due to increased perfusion through the dilated capillaries in the setting of preserved ventilation and, in some cases absent or impaired HPV; and (3) true shunt due to passage of mixed venous blood through arteriovenous malformations. The mechanism responsible for these vascular abnormalities is unclear but may related to increased nitric oxide production (Cremona et al., 1995; Fritz et al., 2013; Rodriguez-Roisin and Krowka, 2008). Of note, HPS appears to be less common at high altitude with a 46% decrease in prevalence per 1000 m gain in elevation of residence (Valley et al., 2014). One plausible explanation for this observation is that HPV at altitude may act to limit blood flow through these shunt-like pathways. Alternately, patients with HPS may move to lower elevations due to an inability to tolerate higher altitude.

With exposure to high altitude, each of the gas exchange abnormalities noted above worsens, leading to hypoxemia out of proportion to that seen in normal individuals at a given elevation. Lower ambient pressure decreases P_Ao₂, which worsens gas exchange in the setting of low ventilation-perfusion ratios. Diffusion limitation also worsens because the pressure gradient for diffusion across the alveolar–capillary interface is decreased. In conjunction with the greater diffusion distances in intrapulmonary vascular dilations, the smaller gradient slows diffusion across the alveolar capillary membrane, increasing the likelihood of incomplete equilibration as red blood cells transit the pulmonary microcirculation, particularly if cardiac output is increased on exertion. Finally, when tissue oxygen extraction increases at high altitude to compensate for the decreased arterial oxygen content, mixed venous oxygen content decreases. This worsens the hypoxemia associated with shunt due to arteriovenous malformations as the oxygen-depleted mixed venous blood bypasses gas exchange surfaces in the lungs.

There are no studies in HPS patients demonstrating how far the P_ao₂ falls in hypobaric hypoxia. A single study in patients with anatomic shunts due to cyanotic congenital heart disease demonstrated a fall in oxygen saturation from 86±5% to 78±5% with exposure to the equivalent of 2440 m for 7 hours compared to a drop from 98±1% to 91±2% in healthy controls (Harinck et al., 1996). Because the pathophysiology in these patients is different than HPS, the magnitude of changes in oxygenation may also differ. In the end, the expected degree of hypoxemia will be a function of the number and size of the intrapulmonary vascular dilations and arteriovenous malformations and the ultimate altitude attained and, subsequently, will vary between patients.

As a result of the worsening oxygenation at high altitude, these patients will likely experience impaired exercise tolerance and, in cases of severe hypoxemia, dyspnea with minimal activity or at rest. There is some suggestion in the literature that more severe hypoxemia may also predispose to acute altitude illness following ascent, as several studies report a relationship between low oxygen saturation upon arrival at high altitude and development of AMS (Burtscher et al., 2004; Karinen et al., 2010; Roach et al., 1998). There are methodological concerns with many of the studies on this question, however, and other studies have found no relationship (O'Connor et al., 2004; Roach et al., 1995), limiting one's ability to draw firm conclusions in this regard.

Despite these concerns, the lower P_ao₂ at high altitude may not necessarily pose a major risk to all patients. Rather than the P_ao₂, the key issue is whether a patient can ensure adequate oxygen delivery to the tissues, which is affected to a greater extent by cardiac output and hemoglobin concentration than the P_ao₂. Berman et al. (1987), for example, examined oxygen delivery in cyanotic congenital disease patients and found that systemic oxygen transport was not correlated with arterial oxygen content but instead varied directly with cardiac index, suggesting that as long as HPS patients have adequate cardiac output and hemoglobin concentration, they may maintain adequate oxygen delivery and tolerate the hypoxemia at high altitude.

Other issues in cirrhosis patients

While hypoxia alters human and rat GI tract bacterial flora toward more a more anaerobic spectrum including the Enterobacteriaceae (Adak et al., 2013; 2014) and studies in rats show greater bacterial translocation occurring at 7000 m (Zhou et al., 2011), there is no evidence from human studies to suggest that hypobaric hypoxia increases the risk of other complications of chronic liver disease such as hepatic encephalopathy, spontaneous bacterial peritonitis, or gastrointestinal bleeding. Several case reports have described esophageal variceal bleeding during air transport (Vajro et al., 1995; Waisman et al., 1991), perhaps due to hypoxemia-induced increases in hepatic blood flow; but this phenomenon has not been described at terrestrial high altitude. Anemia can be seen in a large percentage of patients with chronic liver disease (Gonzalez-Casas et al., 2009) and may impair tissue oxygen delivery and limit exercise capacity.

Liver Transplant Patients

In addition to two case reports of successful liver transplantation and long-term outcome in native residents in Tibet at greater than 4000 m (Dou et al., 2010; Jin et al., 2009), a single study has examined whether travel to high altitude can be done following liver transplantation and found no differences between 6 transplant patients using tacrolimus-based immunosuppression and 15 control subjects regarding physical performance, AMS incidence, summit success, perceived exertion, and oxygen saturation during an ascent to 5895 m (Pirenne et al., 2004). While these results suggest that high altitude travel is safe in these patients, it should be noted that all of the patients in this study used multi-drug pharmacologic prophylaxis versus AMS and HAPE (dexamethasone and salmeterol, but not acetazolamide due to concerns of interaction with tacrolimus metabolism), had normal cardiopulmonary function, were ≤50 years of age, and were more than 2 years past transplantation. How patients who do not fit these criteria will fare remains unknown. Patients with unresolved portopulmonary hypertension or hepatopulmonary syndrome following transplant may still be at risk for significant problems.

Because most people with liver transplants are taking a calcineurin inhibitor, the risk exists that hypertension may develop at high altitude, as it does in many healthy subjects (Luks, 2009c). In this case, nifedipine might be a useful drug, as it also has a role in the prevention of HAPE (Bartsch et al., 1991). Little is known about whether the hypoxia affects serum levels of calcineurin inhibitors, but given that their side effect profile resembles symptoms of AMS (headache, dizziness) (Bechstein 2000), it may be difficult to distinguish drug toxicity from acute altitude illness.

Patients with Neurologic Changes at High Altitude

In healthy individuals, neurologic changes within 1–5 days of ascent typically prompt concern for HACE and warrant immediate descent and treatment with dexamethasone (Luks et al., 2014). Because cirrhosis patients are at risk for hepatic encephalopathy and infection is a common trigger, a broader differential must be applied to cirrhosis patients with neurologic changes in this environment. Cirrhotic patients with altered mental status at high altitude should not be treated with dexamethasone alone, as one would do in HACE, because this could worsen untreated infection. Instead, they should also be treated empirically for infection, while starting oxygen and/or descending to lower elevation and moving the individual to a health facility where appropriate evaluation can be completed.

Long-Term Residence at High Altitude

While epidemiologic studies suggest high altitude residence may affect mortality in other chronic diseases such as COPD (Cote et al., 1993; Moore et al., 1982) or chronic kidney disease (Winkelmayer et al., 2009), data are lacking regarding cirrhosis patients. Animal studies suggest a possible link between chronic hypoxia and progression of liver disease. Hepatic injury is associated with the development of cellular hypoxia in animal models of liver fibrosis (Rosmorduc and Housset, 2010) and one would expect such hypoxia to worsen in a hypobaric environment. More importantly, hypoxemia leads to upregulation of hypoxia-inducible factor-alpha, a transcription factor with many important downstream effects in the liver, including elaboration of pro-fibrotic and vasoactive mediators and upregulation of genes that play a role in angiogenesis, collagen synthesis, and fibrogenesis (Copple et al., 2009; 2010a; 2010b; Novo et al., 2014). Similar hypoxia-inducible factor-alpha-mediated effects have been shown in animal models of chronic kidney disease (Nangaku, 2006; Shoji et al., 2014). Whether the effects seen in such models translate into faster progression of liver injury in cirrhosis patients chronically exposed to hypobaric hypoxia remains an open question.

Pharmacologic Considerations at High Altitude

Because many liver disease patients have impaired synthetic function as well as chronic kidney disease, consideration must be given to the choice and dose of medications used in the prevention and treatment of altitude illness. This topic has been reviewed in detail elsewhere (Luks et al., 2008; Luks and Swenson, 2008) and the key points are summarized below and in Table 1. Most individuals with severe medical problems will travel to altitudes <3000 m where altitude illness is less common than at higher elevations. With adequately slow ascent, most individuals should not require pharmacologic prophylaxis and many of these issues can be avoided. Because plane and car travel allow some individuals to exceed recommended ascent rates, however, these issues may arise.

Table 1.

Dosing of Altitude Illness Medications in Cirrhosis Patients With and Without Chronic Kidney Disease

Medication	Dose in normal individuals	Liver disease	Chronic kidney disease
Acetazolamide	AMS Prevention: 125 mg twice daily. AMS and HACE treatment: 250 mg twice daily	Use is contraindicated due to risk of provoking hepatic encephalopathy	With GFR 10–50 mL/min, limit dosing to every 12 hours Use is contraindicated in patients with GFR <10 mL/min (Bennett et al., 1987) Also avoid with preexisting metabolic acidosis, hypokalemia, hypercalcemia and hyperphosphatemia, or nephrolithiasis
Dexamethasone	AMS Prevention: 2 mg every 6 hours or 4 mg every 12 h AMS treatment: 4 mg every 6 h HACE Treatment: 8 mg once then 4 mg every 6 h	No contraindications or dose adjustments necessary	No contraindications and no dose adjustments necessary Given issues with acetazolamide, should be considered the safest option for preventing or treating AMS and HACE in patients with cirrhosis and with nondiabetic chronic kidney disease
Nifedipine	HAPE Prevention: 30 mg sustained release version every 12 h HAPE Treatment: 30 mg sustained release version every 12 h	Administer at reduced dose of 10 mg sustained release version twice daily	No contraindication and no dose adjustments necessary Given issues with sildenafil and tadalafil, should be considered the safest option for HAPE treatment and prophylaxis in chronic kidney disease patients
Tadalafil	HAPE Prevention: 10 mg twice a day HAPE Treatment: 10 mg twice a day^*	Child's Class A and B: maximum 10 mg/day Child's Class C: Do not use the medication	With GFR 30–50 mL/min, use 5 mg dose once a day, maximum 10 mg in 48 h With GFR <30 mL/min, no more than 5 mg one time
Sildenafil	HAPE Prevention: 50 mg three times a day^* HAPE Treatment: 50 mg three times a day^*	Recommended starting dose 25 mg three times daily; avoid use in patients with known esophageal or gastric varices	With GFR <30 ml/min, use 25 mg three times a day

Efficacy not established in clinical studies.

Prevention and treatment of acute mountain sickness

While the carbonic anhydrase inhibitor acetazolamide is the most widely used medication for AMS prevention, it is contraindicated in patients with cirrhosis (Friedland and Maren, 1984). By raising urine pH, the medication has the potential to divert ammonium ion from the urine to the blood stream. In the setting of significant synthetic dysfunction, excess ammonium ion cannot be converted to urea and may provoke hepatic encephalopathy. This problem is further exacerbated by the fact that carbonic anhydrase inhibition slows urea synthesis (Dawson et al., 1957; Parkkila, 2000). For this reason, dexamethasone should be used to prevent and treat AMS or HACE in liver disease patients. Transplant patients using cyclosporine or immunosuppression should also rely on dexamethasone for AMS prophylaxis or treatment as acetazolamide can increase serum cyclosporine levels (Tabbara et al., 1998). Ibuprofen has recently been examined as an option for preventing acute mountain sickness (Gertsch et al., 2010; Lipman et al., 2012) but has not become part of standard protocols. Because of the link between nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding and the predilection of cirrhosis patients for this problem, cirrhosis patients should avoid these medications for AMS prophylaxis.

High altitude headache

Headache is a common symptom at high altitude, even among those who do not develop AMS, and acetaminophen and nonsteroidal anti-inflammatory drugs are both effective treatment (Hackett and Roach, 2001; Harris et al., 2003). Given the gastrointestinal bleeding issues noted above, acetaminophen at doses appropriate for their underlying liver disease is the preferred option for this purpose. When this is not effective, dexamethasone can be used to treat headache and other symptoms of AMS (Hackett et al., 1988b; Levine et al., 1989).

High altitude pulmonary edema prevention and treatment

Dose adjustments are necessary when cirrhosis patients have indications for pharmacologic measures to prevent or treat HAPE (Bartsch et al., 2003; Luks et al., 2010). Due to an increase in the elimination half-life and risk of drug accumulation, the dose of nifedipine should be decreased in half to 10 mg of the sustained release version twice daily (Ene and Roberts, 1987; Kleinbloesem et al., 1986). Because there are insufficient data for subjects with severe hepatic dysfunction, tadalafil should not be used in Child's Class C cirrhosis. In patients with Class A and B disease, the dose should be limited to 10 mg/day, as data reveal a comparable area under the curve to normal individuals at this dose (Forgue et al., 2007), but no data are available regarding higher doses [2011 Lilly ICOS LLC. Tadalafil (Cialis^®) US Prescribing Information]. Because 85% of sildenafil metabolism occurs in the liver and peak concentrations are elevated by 47% compared to normal individuals (Muirhead et al., 2002), the dose should be limited to 25 mg three times a day [(2000 Pfizer Inc. Product Information: Viagra(R), sildenafil citrate]. Sildenafil should be used with caution in patients with known varices, given its ability to increase splanchnic blood flow (Wang et al., 2006), and a prior report documenting a fatal variceal hemorrhage in a portopulmonary hypertension patient treated with sildenafil (Finley et al., 2005).

Pre-Travel Evaluation and Planning

Cirrhosis patients planning high altitude travel warrant pre-travel evaluation to ensure a safe trip. Because data on this topic are limited, firm evidence-based guidelines are lacking and the information provided below should be viewed as tentative recommendations until further data are available.

All patients should be counseled about how to recognize the main forms of altitude illness, the importance of slow ascent, and the role of descent in treatment. Patients should avoid travel into remote areas away from medical care, identify medical resources at their planned destination, and develop plans for accessing those facilities or descending in the event of problems.

Patients with advanced liver disease not previously recognized as having PoPH or HPS should undergo screening for these disorders. This could include an arterial blood gas to document the P_ao₂ and alveolar–arterial oxygen difference and further testing as necessary to confirm the diagnosis of HPS, as well as echocardiography in individuals at risk for PoPH.

Patients with HPS may need supplemental oxygen at high altitude. Because arranging this for airline travel can be difficult, individuals can travel with a plan to monitor symptoms and oxygen saturation upon arrival using a handheld oximeter (Luks and Swenson, 2011) or planned clinic visits, and a prescription for supplemental oxygen that they can fill in the event of symptomatic hypoxemia (Luks, 2009b). Commercially available portable battery powered oxygen concentrators provide an alternative to bottled oxygen that may ease some of the logistical issues. (Luks, 2009b).

Patients with PoPH and mean pulmonary artery pressures >35 mm Hg or systolic pressures >50 mm Hg should likely avoid travel without supplemental oxygen to altitudes >2000 m (Luks, 2009a). If travel cannot be avoided, patients should travel with supplemental oxygen or plans to arrange such therapy upon arrival. Consideration should be given to adding pulmonary vasodilator therapy (e.g., nifedipine or tadalafil) in those individuals not already on such medications. Given its tendency to cause peripheral edema and liver function abnormalities, bosentan should not be used for this purpose. Individuals with lower pulmonary artery pressures are likely safe to travel to elevations <3000 m but should monitor symptoms and pulse oximetry upon arrival and have a pre-arranged plan for obtaining supplemental oxygen, accessing medical care or descending in the event of problems (Luks, 2009a).

To obtain further information about how a patient may fare upon arrival at altitude, patients can undergo a hypoxia altitude simulation test if resources are available (Dine and Kreider, 2008). Symptoms, pulse oximetry, and even pulmonary artery pressure can be monitored to provide some indication of how the patient will fare at altitude, although the duration of the standard test (20 min) is short compared to the duration of the patient's likely sojourn and, as a result, there is a risk of missing problems that might arise with longer exposures (Luks, 2009b).

Future Directions

Data regarding cirrhosis patients at high altitude are limited. Further research into the clinical responses of PoPH and HPS patients to real or simulated hypoxia and documentation of actual clinical experiences at high altitude could clarify these issues and lead to better, evidence-based recommendations regarding the safety of high altitude travel. Larger epidemiologic studies comparing outcomes in cirrhosis patients living at high and low altitude would help assess the risk of disease progression with high altitude residence and may serve as a basis for further work on the role of hypoxia in the pathogenesis of liver fibrosis.

Footnotes

Author Disclosure Statement

Neither of the authors have any conflicts of interest or financial interests to report regarding the material presented in this article. There was no funding from outside sources or foundations for this work.

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