Overall Bottom Line
- HPS is defined by decreased arterial oxygenation due to right to left shunting in patients with liver disease in the absence of intrinsic lung disease.
- HPS is a relatively common disease that can present without symptoms and therefore is often under-diagnosed.
- The diagnosis of HPS can be suspected based on arterial blood gas measurement and is usually confirmed by contrast echocardiography.
- Medical treatment of HPS is limited and the disease is slowly progressive but liver transplantation can be curative in selected patients.
Section 1: Background
Definition of disease
- HPS is defined by an increased alveolar–arterial gradient on room air with evidence of IPVDs occurring in patients with liver disease and in the absence of intrinsic lung disease.
Incidence/prevalence
- Prevalence estimates for HPS are varied due to the difficulty in making a definitive diagnosis on clinical grounds and the different criteria used. Some series suggest that up to half of all cirrhotics have evidence of HPS based on arterial hypoxemia on room air.
- In a recent study of cirrhotic patients undergoing liver transplant evaluation, 32% were found to have HPS and in older studies of patients with cirrhosis, 24% had a diagnosis of HPS.
- Most studies would suggest that it is routinely under-diagnosed.
Economic impact
- There is no data on the economic impact of HPS.
- Since it occurs commonly in cirrhotic patients and is a cause of increased pre-transplant mortality, the economic impact should be considerable. In addition, the main treatment for HPS involves supplemental oxygen and frequent clinical monitoring.
Etiology
- The reason why some cirrhotic patients develop HPS and others do not is unclear.
- The presence of cirrhosis is not essential for the development of HPS as it can occur in non-cirrhotic portal hypertension and in ischemic hepatitis (with reversal of intrapulmonary vasodilation with correction of the underlying ischemia).
- There is no correlation between the degree of arterial hypoxemia or amount of shunting and the severity of liver disease (as measured by the Child–Pugh score).
Pathology/pathogenesis
- IPVDs are thought to arise due to poor clearance or excess production of pulmonary vasodilators and inhibition of circulating vasoconstrictors by the cirrhotic liver likely mediated through nitric oxide.
- The resultant dilation of the pulmonary vasculature leads to a large right to left shunt, which is not a true anatomical shunt as it partially responds to increased inspired oxygen concentration.
- The mechanism for this observation is unclear but may be a consequence of the vasodilation. The red cells stay in the center of the capillary lumen relatively distant to the oxygen in the alveolus. By increasing the inspired oxygen concentration more oxygen diffuses to the center of the capillary leading to increased arterial oxygen saturation.
- The important role of nitric oxide is suggested by animal studies demonstrating upregulation of endothelial nitric oxide synthetase in the pulmonary vasculature in rat models of HPS.
- In humans, nitric oxide inhibitors such as methylene blue can improve oxygenation in patients with HPS.
Section 2: Prevention
No interventions have been demonstrated to prevent the development of the disease
Screening
- All cirrhotic patients undergoing liver transplant evaluation should be screened for HPS using arterial oxygen saturation on room air and then arterial blood gas testing if necessary.
- A room air pulse oximetry value of ≤94% detects all patients with a partial pressure of oxygen <60 mmHg with a specificity of 93%.
Section 3: Diagnosis (Algorithm 23.1)
Bottom Line/Clinical Pearls
- The majority of patients with HPS do not present with pulmonary type symptoms but rather with symptoms related to chronic liver disease.
- Dyspnea in patients with cirrhosis should raise the suspicion for HPS. Platypnea (worsening dyspnea in the upright position) can be seen.
- Examination findings in HPS reflect stigmata of chronic liver disease but spider nevi tend to be more common. There should be no abnormal lung findings.
- Routine investigations which suggest HPS include arterial oxygen desaturation to <80 mmHg and an increased alveolar-arterial oxygen gradient (>20 mmHg) on room air.
- IPVDs can be confirmed by contrast echocardiography, macro-aggregated albumin scan or pulmonary angiogram.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Chronic lung disease: COPD | Abnormal lung examination, abnormal lung imaging |
| Recurrent pulmonary emboli | Abnormal lung imaging |
| Portopulmonary hypertension | Abnormal echocardiogram |
Typical presentation
- The typical presentation of HPS is not based on pulmonary complaints but rather symptoms related to ESLD such as fatigue, ascites, HE and variceal bleeding. Dyspnea is noted in a minority of patients and some of these patients will describe worsening dyspnea when standing upright from a recumbent position (platypnea). Physical examination is usually unhelpful in making a diagnosis of HPS although spider nevi tend to be more numerous and there can be signs of a hyperdynamic circulation.
- Since there is a paucity of specific symptoms, there needs to be a high index of suspicion for HPS, particularly in patients being evaluated for liver transplantation.
Clinical diagnosis
History
- The history in patients with HPS is usually unrevealing. Since the diagnosis only occurs in those with underlying liver disease, most of the symptoms reflect this including fatigue, confusion, abdominal distension, ankle swelling and gastrointestinal bleeding.
- It is important to ask about shortness of breath, particularly if it is worsened by standing upright from a recumbent position.
- HPS can occur even if the liver disease does not appear to be so severe.
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