Hypoxemia is frequent in individuals with end-stage liver disease, with a frequency of up to 45 % of properly assessed patients. When patients awaiting liver transplantation are evaluated, 15% to 30% develop hepatopulmonary syndrome. It is a dangerous disorder that can occur in any patient suffering from chronic or acute liver disease. To avoid the severe morbidity and mortality associated with this disorder, it must be recognized and treated as soon as possible.
What is Hepatopulmonary syndrome (HPS)?
Based on autopsy and clinical observations, hepatopulmonary syndrome was initially postulated in 1977. Autopsies revealed dilated pulmonary vasculature in individuals with liver cirrhosis, which was assumed to be the origin of some of the pulmonary symptoms found in chronic liver disease patients.
Hepatopulmonary syndrome (HPS) is defined as decreased arterial oxygen saturation caused by dilated pulmonary vasculature in the presence of severe liver disease or portal hypertension.
Diagnostic criteria for HPS
- While breathing room air, the partial pressure of oxygen (PaO2) should be 80 mm Hg, or the alveolar-arterial oxygen gradient (A-aO2) should be 15 mm. A-aO2 >20 mm Hg is considered diagnostic in adults above the age of 64. The patient should be sitting up and relaxed.
- Positive contrast-enhanced echocardiography or radioactive lung-perfusion scanning reveals pulmonary vascular dilatation (brain shunt percentage >6%).
- Portal hypertension (with or without cirrhosis).
The severity of HPS is based on PaO2 levels:
- Mild - PaO2 ≥ 80 mm Hg with A-aO2 ≥ 15 mm Hg while breathing room air
- Moderate - PaO2 ≥ 60 mm Hg to <80 mm Hg with A-aO2 ≥ 15 mm Hg while breathing room air.
- Severe - PaO2 ≥ 50 mm Hg to <60 mm Hg with A-aO2 ≥ 15 mm Hg while breathing room air.
- Very severe - PaO2 <50 mm Hg with A-aO2 ≥ 15 mm Hg while breathing room air Or PaO2 <300 mm Hg while breathing 100% oxygen.
Around 70% of cirrhotic patients awaiting orthotopic liver transplantation (replace the recipient liver with the donor liver) experience dyspnea, 34-47 percent have intrapulmonary vascular dilatations (IPVDs), and 5-32 percent have HPS.
HPS affects both children and adults, both men and women, and people of all ethnic origins. Though HPS has been reported in people with non-cirrhotic portal hypertension and normal synthetic liver function (e.g., nodular regenerative hyperplasia), cirrhosis remains the most common cause, though neither the etiology nor severity of cirrhosis has been found to be associated with the incidence or severity of HPS.
Hepatopulmonary syndrome Causes
The etiology of HPS is unknown, as is why some people with liver illness develop Intrapulmonary vascular dilatations (IPVDs) whereas others do not. Hypoxemia in HPS is caused largely by limits in the passage of oxygen from the lungs into the circulation (diffusion limitation) and mismatching between air and blood moving through the lungs (ventilation-perfusion mismatch), both of which are induced by the presence of IPVDs.
As a result, efforts to determine the etiology of HPS have concentrated on the IPVDs that underpin the hypoxemia of HPS. Autopsies of HPS patients revealed that the lungs' capillaries are substantially swollen (dilated). These enlargements may be caused by excessive production or poor liver clearance of chemicals that relax blood vessels (vasodilators), or by reduced production or lack of sensitivity to a chemical typically produced by a healthy liver that induces blood vessels to contract (vasoconstrictor).
Though the origin of this underlying "liver factor" is unknown, it is apparent that nitric oxide (NO) has emerged as a key cause of blood vessel dilatation at the level of the pulmonary blood vessels (vasodilation). Inflammation-induced by bacteria and bacterial debris escaping from the gut into the blood circulation in cirrhotic patients (gut bacterial translocation), which induces recruitment of cells called macrophages to the pulmonary blood arteries, where they create and release NO. Furthermore, rats with HPS have an increase in the synthesis of a molecule called endothelin-1 in the liver, which induces local NO generation and releases in the lungs.
As our understanding of what causes HPS grows, it becomes clear that these NO-mediated changes in pulmonary blood vessel size likely culminate in a more chronic alteration in the structure of the blood vessels themselves, known as vascular remodeling. This may be due to an imbalance of liver-released substances that stimulate and inhibit pulmonary blood vessel cell (endothelial cell) formation, which has yet to be discovered.
The fundamental cause of HPS is assumed to be pulmonary vascular dilatation caused by an imbalance between vasodilators and vasoconstrictors. The particular process of vasodilation is unknown, and several investigations are being conducted to understand the mechanism. Because of increased hepatic synthesis of endothelin 1 (ET1) and pulmonary endothelin B (ETB) in response to stress, pulmonary endothelial nitric oxide synthetase (eNOS) activation occurs in the lungs. Nitric oxide (NO), a powerful vasodilator, is produced in response to eNOS activation.
In individuals with liver illness, intestinal bacteria translocation and endotoxemia cause a significant buildup of macrophages and monocytes in the lungs. In pulmonary arteries, these macrophages produce tumor necrosis factor-alpha (TNF-alpha), which activates inducible nitric oxide synthase (iNOS). Increased nitric oxide (NO) generation is also caused by iNOS activation.
Bacterial growth and increasing NO produce a rise in heme oxygenase levels. Heme oxygenase degrades heme, resulting in increased carbon monoxide (CO) generation. Because NO and CO are powerful vasodilators, their increased synthesis is critical in pulmonary vasodilation. Furthermore, macrophages and monocytes, as well as TNF alpha, activate vascular endothelial growth factor (VEGF), resulting in enhanced angiogenesis in the pulmonary vasculature.
Vasodilation and angiogenesis result in the creation of arteriovenous (AV) shunts within the pulmonary vasculature, resulting in a ventilation-perfusion mismatch. In HPS, the pulmonary capillaries enlarge to 15-500mm, compared to a typical diameter of 8-15mm.
The pulmonary vasculature dilates, resulting in a shorter transit time for blood cells and a huge volume of blood moving through without gas exchange. Because some blood may flow via AV shunts without reaching alveoli, the gas exchange does not occur in these blood cells. Increased pulmonary capillary wall thickness has also been noted, resulting in decreased gas diffusion.
Because of the pulmonary vasodilation, AV shunts, and decreased diffusion, there is a mismatch between ventilation and perfusion, resulting in an elevated alveolar-arterial gradient and hypoxemia. Pulmonary vasodilation is particularly noticeable in the lung bases, explaining symptoms such as platypnoea and orthodeoxia associated with HPS.
Two types of HPS have been based on the location of dilated pulmonary vessels.
- Type I HPS – dilatation of arteries at the precapillary level near the lungs' gas exchange units. In this kind of HPS, supplemental O2 raises PaO2.
- Type II HPS – Larger artery dilatation causes arteriovenous shunts away from the lungs' gas exchange units. Supplemental oxygen is ineffective.
Hepatopulmonary Syndrome symptoms
The great majority of HPS patients (82%) arrive with symptoms of their liver illness first, while a minority (18%) report with lung (pulmonary) issues first. The most prevalent symptom is an insidiously growing shortness of breath (dyspnea) at rest or during exertion, which is observed in 95 percent of patients and often develops after years of liver illness.
However, because of the great incidence and frequently complex character of dyspnea in cirrhotic patients, this complaint is readily ignored, and HPS patients suffer respiratory symptoms for an average of 4.8 years before diagnosis. Dyspnea and hypoxemia worsen with time in the vast majority of individuals. Furthermore, despite steady liver function, this gradual decrease happens often.
Platypnea is a more specific symptom characterized by breathlessness in the upright posture that improves while lying down (supine position)7. This, in turn, coincides with the objective finding of orthodeoxia, defined as a loss of 4mmHg in PaO2 or 5% in saturation after changing from the supine to the standing position, which occurs in up to 88 percent of HPS patients.
Other clinical manifestations of HPS include:
- Spider angiomata (small, dilated blood vessels clustered very close to the surface of the skin.
- Clubbing of fingers or toes
- Cyanosis: abnormal blue coloring of skin or mucous membranes caused by insufficient oxygen saturation in tissues near the skin's surface
It is crucial to highlight that chest x-rays and thoracic CT scans are frequently unremarkable in HPS; the absence of radiographic abnormalities does not rule out HPS.
It should also be highlighted that HPS is not confined to patients with severe liver impairment; in fact, many patients with mild to severe HPS have comparably intact hepatic function.
Hepatopulmonary Syndrome Diagnosis
The first step in screening for HPS is to use a pulse oximeter to determine PaO2. A PaO2 of 70 mm Hg and an O2 saturation of 96 percent indicate a positive screen. If the screen is positive, the patient should have an arterial blood gas (ABG) assay to assess PaO2 and A-aO2.
The gold standard for identifying pulmonary vascular dilatation is contrast-enhanced echocardiography with agitated saline. Normal saline is agitated to produce microbubbles larger than 10 micrometers in diameter. A peripheral vein in the arm is injected with normal saline, and simultaneous transthoracic echocardiography (TTE) is done. Microbubbles are often retained in the pulmonary circulation and absorbed by the alveoli.
However, in the presence of pulmonary dilatation and AV shunts, microbubbles avoid pulmonary capture and reach the left atrial chamber of the heart, where they may be observed by TTE. Microbubbles appearing in the left atria during the 4th and 6th cardiac cycles suggest pulmonary vasodilation. If microbubbles form on the left side of the heart before the third cardiac cycle, this indicates intracardiac shunting.
Transesophageal echocardiograms are more accurate than transthoracic echocardiograms in detecting pulmonary dilatation and intracardiac shunting. However, due to esophageal varices in many cirrhotic and portal hypertensive individuals, this test is more intrusive and risky.
Another diagnostic for pulmonary vascular dilation is radioactive lung perfusion scanning. It is not, however, as sensitive as contrast-enhanced echocardiography. This test cannot tell the difference between intrapulmonary and intracardiac shunting. It might help determine whether HPS is causing hypoxemia in individuals with associated pulmonary illness. The peripheral vein is injected with radiolabeled albumin aggregates of about 20 micrometers in diameter.
Particles of this size are normally confined in the pulmonary microvasculature, and scintigraphy shows practically full absorption in the lungs. When there is significant intrapulmonary shunting, some albumin flows through the pulmonary vasculature and into the systemic circulation. Scintigraphy may be used to detect uptake in organs other than the lung, allowing the shunt fraction to be calculated. A brain shunt fraction more than 6% is considered significant.
Pulmonary angiography can be used to detect and differentiate type I and type II HPS. However, because it is a more costly and intrusive test, it is not the recommended technique of diagnosis. It is also less sensitive than agitated saline contrast-enhanced echocardiography.
A chest X-ray may be normal or reveal increased bibasilar nodular opacities and pulmonary dilatation. It aids in the exclusion of coexisting pulmonary diseases.
CT chest scans may reveal larger dilated vessels; however, they are normally performed to rule out pulmonary pathology. Carbon monoxide diffusion capacity may be reduced in pulmonary function testing (DLCO).
Hepatopulmonary Syndrome Management
- Medical therapies
There is presently no recognized medicinal treatment for HPS. Garlic, pentoxifylline, mycophenolate mofetil, aspirin, methylene blue, inhaled nitric oxide, nitric oxide inhibitors, and somatostatin have all been explored as medicinal therapies. Nonetheless, none of them have shown clear benefit, and none have been authorized by the FDA.
Patients with severe hypoxemia should get oxygen therapy. It is generally provided until a more permanent therapy, such as a liver transplant, can be undertaken. Improved exercise tolerance and quality of life result from increased oxygenation and decreased hypoxemia.
Transjugular intrahepatic portosystemic shunt (TIPS) - TIPS usage has insufficient evidence, and clinical effects can vary. TIPS may exacerbate the hyperkinetic circulatory condition by enhancing intrapulmonary vasodilation, shunting, and hypoxemia. TIPS also carries the risk of hepatic decompensation and encephalopathy.
Pulmonary arterial coil embolization - Its application is limited since it can only be employed in specific circumstances with substantial AV communications.
Liver transplantation is the only proven therapy that has been found to improve long-term survival in HPS patients. In 6 to 12 months, it improves hypoxia. According to research, PaO2 and A-aO2 levels return quickly following transplant, usually within six months. Intrapulmonary shunts reverse as well, but it may take longer than six months. In certain cases, DLCO has also been proven to improve.
Patients with chronic liver disease who have a model for end-stage liver disease (MELD) score of 15 or above are recommended for a liver transplant examination. Patients with HPS have exception points added to their MELD score, allowing them to advance up the waiting list for a liver transplant. It is suggested that individuals have a liver transplant before developing serious illness.
The 5-year survival rate after liver transplantation in HPS patients was found to be around 76 percent, which is comparable to non-HPS patients. After liver transplantation, 80 percent of all HPS patients had full remission, with a mortality rate of 16 % in the overall group and 30 percent in the severe HPS group after 3 months. Some investigations found that patients with PaO2 50 mmHg alone or with an MAA shunt percentage of 20% had a worse chance of survival.
Other studies, however, found no significant differences in survival between HPS and non-HPS individuals. no correlation between PaO2 levels at diagnosis and post-transplant survival rates. Pretransplantation PaO2 of 50 mmHg and a lung scan with brain uptake of 20% or greater are post-transplantation early death indicators.
Patients with advanced HPS (PaO2 60 mmHg) are eligible for MELD exception points, which improve transplant priority. A recent study evaluated US MELD-era data and discovered that the current method of distributing HPS MELD exception points gives a survival benefit to wait listed patients with HPS compared to those without HPS exception.
Those with HPS have a twofold increase in mortality when compared to patients with cirrhosis who do not have HPS. It is linked to a lower quality of life and a lower functional status. The average life span of a patient with HPS (10.5 months) is much less than that of individuals with chronic liver disease who do not have HPS (40.8 months). The chance of death increases with illness severity, with individuals with the very severe diseases having a poor prognosis. In patients with severe HPS, post-transplant survival is also somewhat decreased.
HPS is a deadly disease that dramatically shortens the life of a patient suffering from liver disease. The majority of individuals will experience increasing vasodilation and worsening hypoxemia. Because no other medical therapy is now available, death without a liver transplant is unavoidable.
After a liver transplant, 80 to 85 percent of patients will have better oxygenation and fewer AV shunts. Certain patients, however, may have complications.
- Refractory hepatopulmonary syndrome - Following liver transplantation, some individuals fail to improve their oxygenation or suffer recurrent HPS.
- Severe post-transplant hypoxemia is a failure to maintain oxygen saturation above 85%, even on 100% oxygen.
- Post-transplant portopulmonary hypertension is a rare complication.
Hepatopulmonary syndrome is caused by the production of small intrapulmonary arteriovenous dilations in individuals with chronic liver disease, most commonly when portal hypertension is present. The mechanism is uncertain but it is believed to be caused by increased hepatic production or impaired hepatic clearance of vasodilators. Because patients have higher cardiac output due to systemic vasodilation, the vascular dilations promote overperfusion relative to ventilation, resulting in hypoxemia.