B. Hepatopulmonary syndrome
Discussion
The perfusion scan demonstrates radiotracer uptake within the brain
suggestive of a right to left shunt. With the history of alcohol use
disorder, untreated hepatitis C, thrombocytopenia and low albumin, the
patient was suspected to have cirrhosis and/or portal hypertension, and a
right upper quadrant ultrasound confirmed this. Liver disease, high A-a
gradient (216 mmHg) on oxygen (FiO2 60%), with orthodeoxia raised
suspicion for hepatopulmonary syndrome. A positive perfusion scan was
followed by an echocardiogram with bubble study, which confirmed delayed
presence of intravenous saline contrast in the left heart
characteristic of an intrapulmonary shunt. A CT angiogram was then
performed, which showed 2 small left lower lobe pulmonary arteriovenous
malformations (AVMs), however, they were not amenable to any
interventions.
Probability of PE was low as there was no evidence of a perfusion
defect. The patient did not have any symptoms and signs suggestive of an
active infection and there was no radiographic evidence of a lobar
pneumonia. PPH can also cause hypoxia in patients with cirrhosis, but in
that case the perfusion scan would not show evidence of a right to left
shunt unless there was a concomitant intracardiac shunt. PPH would be
suggested by signs of pulmonary hypertension on echocardiogram, such as
dilated right ventricle and elevated RVSP, and confirmed with right
heart catheterization. Although initial echocardiogram was technically
limited which could have missed signs of pulmonary hypertension, PPH
would not explain his orthodeoxia.
Hepatopulmonary syndrome (HPS)
Definition and Classification
It is characterized by the presence of the following triad1:
- Arterial oxygenation defect (A-a gradient > 15 mmHg on room air)
- Intrapulmonary vascular dilatations (IPVD) as evidenced by Contrast
enhanced echocardiography (CE-TTE) or abnormal uptake of radiotracer on
lung perfusion imaging
- Liver disease (not necessarily with portal hypertension or cirrhosis as it has been reported in other conditions as well)
HPS occurs in 10-30% of patients with cirrhosis. The severity of HPS
is determined by the degree of hypoxemia, graded from mild (Pa02 > 80 mmHg), moderate (Pa02 > 60 to < 80 mmHg), severe (Pa02 > 50 to < 60 mmHg) and very severe (Pa02 < 50 mmHg) by the ERS Task Force1.
Mechanisms of Hypoxemia and Pathophysiology in HPS
Berthelot described the pathological findings of HPS in 1966 as
widespread dilatations of pulmonary microvessels encompassing the
pulmonary precapillary and alveolar capillary beds2. Impaired gas exchange occurs by 3 physiological mechanisms due to the IPVD:
- Diffusion limitation (most common) - The distance at the gas
exchange interface increases due to the dilated microvessels. This is
exacerbated by the rapid blood flow due to hyperdynamic circulation in
some patients.
- V/Q mismatch – Increased perfusion of the less ventilated dependent
lower zones with a blunted vasoconstriction response to hypoxemia.
- Shunt – Arteriovenous shunts are formed which bypass alveoli, increasing the mixed venous blood entering the pulmonary veins.
These IPVD and shunts occur primarily at lung bases, worsening the
hypoxemia in sitting or standing position, as gravity forces more blood
to flow through them. Orthodeoxia occurs when the patient sits up, as
pulmonary blood flow is unevenly distributed worsening oxygenation.
Supplemental oxygen should theoretically correct hypoxemia from causes a
and b, but not c, which forms the basis of the shunt fraction test at
100% FiO2.
IPVD occur due to endogenous vasoactive molecules, like NO and ET-13,
and pulmonary angiogenesis is thought to be a result of monocyte
stimulation (causing increased TNF) from bacterial translocation which
increases in patients with liver disease.
Key Investigations:
Hypoxemia in liver disease which does not improve with oxygen
supplementation suggests shunt physiology and should be investigated
with a CE-TTE once other causes of an elevated A-a gradient are ruled
out. CT-TTE would pick up an intra-cardiac shunt if the bubbles of
agitated saline are seen within 2-3 cardiac cycles on the left side or
an intrapulmonary shunt if the bubbles are seen on the left side after
5-6 cardiac cycles. In a Tc-99m macroaggregated albumin (MAA) perfusion
scan of the lung, radiotracer should be trapped in the pulmonary
alveolar capillary bed. Thus, detection of radiotracer in the brain or
kidneys suggests IPVD or anatomical shunts. MAA perfusion scan is highly
specific but less sensitive than CE-TTE for detecting intrapulmonary
shunting consistent with HPS. Therefore, MAA perfusion scan is a better
test to perform in patients with coexistent lung disease due to its
specificity3, 5.
Treatment
Liver transplant is currently the only effective treatment for HPS.
Pentoxifylline (due to the role of TNF), methylene blue (inhibition of
NO) and garlic have been studied, however no medical therapeutics have
yet been established3.
Our patient was not a candidate for liver transplant and was discharged home on oxygen.
References
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Berthelot P, Walker JG, Sherlock S, Reid L. Arterial changes in the lungs in cirrhosis of the liver—lung spider nevi. N. Engl. J. Med.1966; 274: 291–298.
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Grace JA, Angus PW. Hepatopulmonary syndrome: update on recent
advances in pathophysiology, investigation, and treatment. J
Gastroenterol Hepatol. 2013;28(2):213-219. doi:10.1111/jgh.12061
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