Michael J. Krowka and Michael D. Leise Mayo Clinic, Rochester, MN, USA Two relatively common lung abnormalities – arterial hypoxemia and pulmonary artery hypertension (PAH) – may have a pathophysiologic origin in the diseased liver. Of course, the more common clinical presentation is that a liver disease manifests first and as part of that evaluation, a lung condition is uncovered. But the reverse is not uncommon (lung issue first), especially as seen in pulmonary subspecialty clinics. The clinical liver issues can be relatively asymptomatic or have such minimal expression as to not attract as much attention as the ongoing lung presentation. These two disorders have special clinical importance in that both have significant implications for potential liver transplant candidates, despite the severity of their lung presentation [1]. Arterial hypoxemia that occurs in the setting of occult of or covert liver dysfunction has been called “hepatopulmonary syndrome” (HPS) [2]. It is characterized by the triad of arterial hypoxemia, evidence for intrapulmonary vascular dilation and liver dysfunction. Clues of a possible liver aspect to the finding arterial hypoxemia (by pulse oximetry or arterial blood gas) start with the severity hypoxemia. Moderate to severe arterial hypoxemia (oxygen saturation by oximetry < 90% or partial pressure of oxygen, PaO2 < 70 mmHg by arterial blood gas) and a normal chest radiograph can be challenging. Obtaining a careful liver history (heavy alcohol use, previous hepatitis C infection, longstanding obesity) may be a productive start. Laboratory‐wise, the concomitant findings of thrombocytopenia and anemia may be present. Importantly, it is not unusual to note normal or minimally elevated serum bilirubin, aspartate amino transferase (AST), or alanine amino transferase (ALT) levels in the setting of HPS. The finding of modest elevations of alkaline phosphatase (ALP) can also suggest the possibility of nodular regenerative hyperplasia, which does not cause cirrhosis but can cause portal hypertension and is sometimes associated with HPS. The possibility of liver disease as the culprit is significantly increased with physical examination findings of digital clubbing and spider angiomas over the upper thorax and extremities in the setting of arterial hypoxemia. The finding of ascites would also strongly suggest the possibility of liver disease. From the liver perspective, we would advise a liver ultrasound with Doppler as the first imaging of choice, followed by consultation with a liver specialist. Cirrhosis can be diagnosed with non‐invasive modalities such as magnetic resonance imaging or transient elastography. For non‐cirrhotic portal hypertension entities (of which nodular regenerative hyperplasia would be most common in the context of HPS), a consultation with a hepatologist is imperative. From the lung perspective, it is necessary to document the existence of intrapulmonary vascular dilation (IPVD) as the cause of the hypoxemia. This is easily done non‐invasively using lung–brain perfusion scanning (Figure 10.1) or contrast‐enhanced transthoracic echocardiography. A “positive” contrast echocardiogram demonstrates the passage of agitated saline‐induced microbubbles through dilated pulmonary capillary blood vessels, which, because of the dilation, interferes with the normal of oxygen from the alveoli into the capillary blood stream, thus causing hypoxemia. Figure 10.1 Lung–brain perfusion scan evaluation for severe arterial hypoxemia associated with cirrhosis. Patient had hepatopulmonary syndrome with PaO2 50 mmHg and normal chest x‐ray. Intrapulmonary shunt of 41% (normal < 5%). It is unclear as that the factors that are either not metabolized or not produced by a diseased liver that cause the IPVD. However, a leading theory suggests that BMP9 (a bone morphogenetic protein made in the liver) is deficient in the those with HPS. This protein is needed to support a normal pulmonary vascular bed. Its deficiency leads to pulmonary vascular dilatations which cause the hypoxemia. Importantly, the degree of hypoxemia is not necessarily related to the severity of liver dysfunction, measured either by the Child–Pugh score or the MELD (Model for End‐stage Liver Disease) score or the type of liver disease. Usually, cirrhosis is liver issue that has been present, but HPS may occur only in the setting of portal hypertension without cirrhosis. Severe arterial hypoxemia due to HPS (PaO2 < 60 mmHg) is important to document as it warrants an expedited priority for liver transplantation. Finally, the importance of documenting this etiology for arterial hypoxemia rests on the well‐documented experiences that HPS is expected to totally resolve weeks to months following a successful liver transplant. Pulmonary hypertension can have grave consequences including right‐heart failure and death. Importantly and often not appreciated, is that pulmonary hypertension should be categorized as either PAH or pulmonary venous hypertension (PVH) [3]. The distinction and diagnostic criteria for each type of pulmonary hypertension are established by right‐heart catheterization measurements (pulmonary artery pressures and cardiac output) and subsequent calculations (pulmonary vascular resistance). The therapeutic implications for PAH compared with PVH can be dramatic and harmful if this distinction is not appreciated. The third leading cause or association of PAH noted in French and US registries (roughly 10–15% of all PAH) is portal hypertension. PAH diagnosed in the setting of portal hypertension is known as “portopulmonary hypertension” (POPH; Figure 10.2). The cause of POPH in the setting of portal hypertension is unknown, but failure to metabolize substances emanating from the gut, which leads to pulmonary endothelial/smooth muscle proliferation and subsequent vascular obstruction, is the current conjecture. During the diagnostic evaluation for pulmonary hypertension (which includes screening echocardiography to assess right ventricular size and function for evaluation of exertional dyspnea), the main clue as to the possibility of POPH is the presence of thrombocytopenia due to splenic enlargement/platelet sequestration due to portal hypertension. Serum AST and ALT may be normal or mildly elevated; total bilirubin may be increased. The international normalized ratio may be elevated. Clinical manifestations of portal hypertension (ascites, splenomegaly, history of gastrointestinal bleeding) may be subtle or absent. Consultation with a liver specialist is advised to further explore the reasons for these laboratory abnormalities, possible portal hypertension and its clinical management. A variety of PAH medications are now available that improve pulmonary hemodynamics and right‐heart function in the setting of POPH. POPH associated with autoimmune liver disease, primary biliary cholangitis (PBC), or primary sclerosing cholangitis may be more difficult to treat than other causes of liver disease. Figure 10.2 Chest x‐ray showing pulmonary hypertension, enlarged pulmonary arteries, and portal hypertension. Patient had portopulmonary hypertension due to primary biliary cholangitis, which was treated with intravenous prostacyclin. Confirmation of POPH requires a documentation of portal hypertension (clinically or by portal pressure measurements) and PAH by right‐heart catheterization (mean pulmonary artery pressure mPAP, > 21 mmHg and calculated pulmonary vascular resistance > 3 Wood units). Importantly, severe POPH (mPAP > 45 mmHg) is considered an absolute contraindication to liver transplant consideration. Successful treatment with pulmonary vasomodulators may alter that consideration. Although pulmonary vasomodulating drugs are now available to treat POPH, the risk of intraoperative/immediate postoperative death is increased in transplant attempts with moderate POPH pressures (mPAP > 35 mmHg). Unlike HPS, resolution of lesser degrees of POPH following liver transplant is possible, but unpredictable. Although both HPS and POPH are most commonly seen in centers that evaluate patients for liver transplantation, the surprise finding of these patients in the non‐transplant settings, subspecialty clinics (pulmonary hypertension, chronic obstructive pulmonary disease) can be expected due to their subtle and not infrequent presentations. The accumulation of fluid around the lungs can be quite symptomatic and a diagnostic challenge (Figure 10.3) [4]
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Respiratory Disease
Lung Problems Due to Unexpected Liver Issues
Arterial Hypoxemia
Pulmonary Hypertension
Pleural Effusions
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