IN CHRONIC LIVER DISEASE CASES

1. HEPATOPULMONARY
SYNDROME
DR.GANESH
MURKUT
DNB MEDICINE

2. HPS-: DEFINITION
 Hepatopulmonary syndrome (HPS) is considered
present when the following triad exists.
 Liver disease / PHTN
 Abnormal arterial oxygenation (Hypoxia)
 Intrapulmonary vascular abnormalities, ..as
intrapulmonary vascular dilatations (IPVDs)
 +/- Congenital portosystemic shunts.

3. PREVALENCE
Among patient of CLD -4 to 47%  HPS –
data taken from liver transplant centers
(retrospective). While one prospective study in
cirrhotic pt. shows 26 % pt. develope HPS.

4. HPS-: PREVALENCE
 Among patients with chronic liver disease
 Range from 4 to 47 percent, depending upon the
diagnostic criteria and methods used.
 These estimates derive primarily from liver
transplantation centers.
 Prospective, multicenter prevalence studies
have not been performed.

5. HPS-: CAUSES
 Complication of liver disease
 Most commonly associated with portal
hypertension (with or without cirrhosis),
 CLD of virtually any etiology can be associated
with HPS .
 Some acute liver diseases (rarely) have been
associated with HPS - eg: Ischemic hepatitis
 Other pulmonary disease like COPD may
agrivate hpoxia.

6. H

8. PATHOLOGICAL FEATURE
 Gross dilatation of the pulmonary pre-
capillary and capillary vessels.
 Absolute increase in the number of dilated
vessels.
 A few pleural and pulmonary arteriovenous
shunts and portopulmonary anastomoses
may also be seen.

9. PATHOPHYSIOLOGY
I) Vasodilatation:
 Persistent pulmonary and systemic vasodilatation is mostly
explained by the imbalance of vasodilator and
vasoconstrictor agents favoring vasodilators.
This could be due to:
A- Overproduction of the vasodilators from injured
hepatobiliary system.
B- Decrease in their clearance by the liver.
C- Production of a vasoconstrictor inhibitor.
D- Normal sensitivity of the pulmonary vessels to
vasoconstrictors in response to hypoxemia is blunted in HPS.
 Numerous vasodilators are suspected but nitric oxide ( NO)
is the most appreciated one.
 Other mediators include vaso-active intestinal peptide (VIP),
calcitonin related peptide, glucagon, substance P and
platelet activating factor.

10. POSSIBLE MEDIATORS OF VASCULAR
DILATATION IN HPS

11. PATHOPHYSIOLOGY
II) Hypoxemia:
 widespread pulmonary precapillary and capillary
vasodilatation.
 Pulmonary capillary diameter is normally
about 8-15 micrometer (m) and this could rise
up 15 to 500 m in HPS.
 Distinct arterio-venous (AV) malformations and
direct AV communications.
 Pleural spider angiomas may also form.

12. PATHOPHYSIOLOGY
These changes lead to the following:
A- Ventilation perfusion ( V/Q) mismatch:
 Results from widespread pulmonary
vasodilatation and decreased V/Q ratio
in alveolar-capillary units leading to low pressure
of oxygen in arterial blood ( PaO2) and low
oxygen (O2) content of the blood leaving these
units.
 This hypoxemia is correctable by breathing 100%
oxygen.

13. THE OXYGEN DIFFUSION ALTERATIONS DUE TO
ABNORMAL VESSELS IN HPS

14. PATHOPHYSIOLOGY
B- Right to left shunting of the blood:
 This results from direct arterio-venous
communications that have no contact with breathed
air.
 If numerous, they can give rise to severe
hypoxemia unresponsive to breathing 100%
oxygen.

16. PATHOPHYSIOLOGY
C– Diffusion impairment:
 Excessive vasodilatation causes O2 molecules
not to reach the center of dilated capillaries
readily.
 Increased cardiac out put and decreased
transition time of blood through pulmonary
vascular bed on the other hand impairs diffusion,
this is called diffusion-perfusion defect or
alveolar capillary oxygen disequilibrium.

17. PATHOPHYSIOLOGY
D- Response to breathing 100% O2 :
 In response to breathing 100% oxygen if PaO2
rise to levels 600mmHg, shunting of blood is
unlikely.
 If it failed to exceed 500 mmHg, shunt can't be
ruled out.
 If it didn't rise to levels above 150-200mmHg,
shunt is most probably the main mechanism of
hypoxemia.

19. CLINICAL FEATURES
 More than 80% present with symptoms and signs of
liver disease.
 In less than 20%, the presenting symptoms and signs
are related to lung disease. These include dyspnea,
cyanosis, clubbing, platypnea and orthodeoxia.
 Liver and portal hypertension manifestations (82% of
patients).
 Several clinical signs and symptoms characterize this
syndrome; most persons will present with the signs
and symptoms of liver disease, including
gastrointestinal bleeding, esophageal varices,
ascites, palmar erythema, and splenomegaly

20. SIGNS OF LIVER FAILURE

22. CLINICAL FEATURES
 Dyspnea (18%); may be accompanied by
platypnea and orthodeoxia.
 Platypnea It is an increase in dyspnea that is
induced by moving into an upright position and
relieved by recumbency.
 Orthodeoxia refers to a decrease in the arterial
oxygen tension (by more than 4 mmHg [0.5 kPa])
or arterial oxyhemoglobin desaturation (by more
than 5 percent) when the patient moves from a
supine to an upright position, which is improved by
returning to the recumbent position.


23.  Platypnea and orthodeoxia occur because the pulmonary AVMs
occur predominantly in the bases of the lungs
 Therefore, when sitting up or standing, blood pools at the
bases of the lung with resultant increased AV shunting
 Portal hypertension + spider nevi + clubbing + hypoxemia 
highly suggestive of HPS.
 The presence of orthodeoxia in a patient with liver disease is
strongly suggestive of HPS.
 It can be seen in other situations (eg, post-pneumonectomy,
recurrent pulmonary emboli, atrial septal defects, and chronic
lung disease)
 Orthodeoxia affects up to 88 percent of patients with HPS,
compared to 5 percent or fewer of patients with cirrhosis alone
 Hyperdynamic circulation characterized by systemic
vasodilatation and elevated cardiac output.
 Cardiac output often exceeds 7 L/min, systemic and pulmonary
vascular resistances decrease, and the difference between the
arterial and the mixed-venous oxygen content narrows

24. DIAGNOSIS
 The diagnosis of (HPS) can be made when all of
the following abnormalities have been
confirmed :
A) Portal hypertension (with or without concomitant
liver parenchymal disease)
B) Impaired oxygenation
C) Intrapulmonary vascular abnormalities, referred
to as IPVDs

25. DIAGNOSIS- IMPAIRED OXYGENATION
Arterial blood gas analysis :
Performed in the supine and sitting positions.
Variability in oxygenation over time.
 Requires two consecutive abnormal oxygenation
results on different days - improve the accuracy
of diagnosis..
 Most sensitive measure of impaired
oxygenation is an elevated alveolar-arterial (A-a)
oxygen gradient, defined as ≥15 mmHg when
breathing room air .
 An arterial oxygen tension (PaO2) of <80
mmHg also indicates impaired oxygenation.

26. DIAGNOSIS- IMPAIRED OXYGENATION
 Right-to-left shunt fraction
 Measure of the degree to which oxygenation is
impaired.
 Estimated by measuring the PaO2 while the patient
wears a nose clip and breathes 100 percent
oxygen through a tightly fitting mouthpiece for 20
minutes and then calculating the shunt fraction.

27. DIAGNOSIS- IMPAIRED OXYGENATION
 Qs/Qt = ([PAO2 - PaO2] x 0.003) ÷ [([PAO2 -
PaO2] x 0.003) + 5]
 Qs and Qt refer to shunt and total blood flow,
 PAO2 and PaO2 refer to the alveolar and arterial
partial pressure of oxygen.
 As a general rule of thumb, the shunt increases 5
percent (above the normal level of 5 percent) for
every 100 mmHg drop in PaO2 below 600 mmHg

28. DIAGNOSIS-: INTRAPULMONARY VASCULAR
DILATATIONS
 Contrast-enhanced echocardiography.
 Performed by injecting a contrast material
intravenously and then performing
echocardiography.
 contrast material is usually agitated saline (forms a
stream of microbubbles 60 to 150 microns in
diameter) or indocyanine green dye.

29. CONTRAST-ENHANCED ECHOCARDIOGRAPHY.
Under normal resting circumstances-: the contrast
opacifies only the right heart chambers because it is
filtered by the pulmonary capillary bed.
 The contrast may opacify the left heart chambers if
a right-to-left intracardiac or intrapulmonary shunt is
present.
 With an intracardiac shunt, contrast generally
appears in the left heart within three heart beats
after injection

30. CONTRAST-ENHANCED ECHOCARDIOGRAPHY.
 In contrast, with an intrapulmonary shunt, contrast
generally appears in the left heart three to six heart
beats after its appearance in the right heart.
 In patients with liver disease, detection of an
intrapulmonary right-to-left shunt is considered
indicative of IPVDs.

31. DIAGNOSIS
Chest X-ray and chest CT:
 Are normal or show non-specific minor
reticulonodular changes in the base of the lungs
and /or dilatation of the peripheral pulmonary
vasculature.
Pulmonary function tests:
 commonly show decreased diffusion ability of the
lungs pointing to intrapulmonary vasodilatation.

32. DIAGNOSIS
Macro aggregated albumin scanning:
 Technetium 99m- labeled macroaggregated
albumin is used.
 The estimated sensitivity of this method for
diagnosing intrapulmonary vasodilatation is about
84% and its specificity is 100%.
 In addition, shunt fraction can be calculated by this
procedure.

33. DIAGNOSIS
Pulmonary angiography:
Two different angiographic patterns in HPS:
Type I: more common. There are minimal changes
with diffuse spider like branches to more advanced
changes with a blotchy, spongy appearance ( the
type that responds to breathing 100% oxygen).
Type II: less common.
 There are vascular lesions as vascular dilatations
representing A-V communications ( the type that
responds poorly to breathing oxygen and liver
transplantation is not as suitable as for type I
vascular lesions).

34. PULMONARY
ARTERIOGRAMS
TYPE 1:-
DENSE SPONGY
APPEARENCE

35. PULMONARY
ARTERIOGRAMS
TYPE 2 VASCULAR
ABNORMALITIES
DISCREATE
ARTERIOVENOUS
FISTULAS

36. HPS SEVERITY-: CLASSIFICATION
 Mild – An alveolar to arterial (A-a) oxygen gradient ≥15
mmHg and an arterial oxygen tension (PaO2) ≥80
mmHg while breathing room air
 Moderate – An A-a gradient ≥15 mmHg and a PaO2 in
between ≥60 mmHg and <80 mmHg while breathing
room air
 Severe – An A-a gradient ≥15 mmHg and a PaO2 in
between ≥50 mmHg and <60 mmHg while breathing
room air
 Very severe – An A-a gradient ≥15 mmHg and a
PaO2 <50 mmHg while breathing room air;
alternatively, a PaO2 <300 mmHg while breathing 100
percent oxygen

37. TREATMENT AND PROGNOSIS OF HPS
Only definative treatment of HPS is liver
transplant but it reserve for severe and very
severe HPS.
Mild to modrate HPS requre only monitoring for
disease progresion and serial oxygen (ABG)
monitoring and O2 support if PaO2 < 55
mmHg, duration is about 6-12 months
But for core pulmnale and some special
situations oxygen therapy indication are
different –LTOT requires

40. TREATMENT
 oxygenation
 Methylene blue
 Indomethacin
 Tamoxifen
 Somatostatin analog
 Sympathomimetic
drugs
 Liver transplantation
 b-blockers
 Allium sativum (garlic)

41. TREATMENT
Excellent PaO2 response to 100% O2 (PaO2 > 550
mmHg)
  ventilation-perfusion mismatch or diffusion-perfusion
defect
  benefit clinically with this treatment.
Poor response (PaO2 < 150 mmHg) strongly
suggests
  direct AV communications or extensive and extremely
vascular channels
  pulmonary angiography  type 2 pattern 
therapeutic embolization

42. TREATMENT
-adrenergic blocking agents and direct pulmonary
vasoconstrictors
 Directly influence pulmonary vascular tone
 No significant improvement in arterial oxygenation
Somatostatin
 Inhibits the secretion of vasodilating neuropeptides.
 Subsequent investigations failed to confirm a positive
response.
Indomethacin
 Inhibiting the production of vasodilating prostaglandins
 Enhance hypoxic pulmonary vasoconstriction and improve
oxygenation.
Methylene blue
 Inhibits the activation of soluble guanylate cyclase by NO.
Allium sativum (garlic)
 Limited oxygenation improvement

44. LIVER TRANSPLANTATION
complete resolution of HPS.
Normalization of the abnormal oxygenation
 Require up to 15 months
 Presumed vascular remodeling.
Refractory hypoxemia :
 Probably contributes to a nonpulmonary event that
subsequently results in death.

45. HPS AND EFFECTS OF
OLT
 Syndrome resolution after LT reported in 62% ~
82%; usually slow improvement, may require
months of supplemental oxygen.
 Post-LT mortality rates: 16% within 90 days of
LT & 38% at 1 year
 30% mortality if pre-LT PaO2 < 50 mmHg
 Post-LT nonresolution of HPS uncommon (2%)
 Post-LT recurrence of HPS extremely rare; 1
case reported (pre-LT diagnosis was
nonalcoholic steatohepatitis that recurred post-
LT)

48. HPS - DIAGNOSTIC ALGORITHM

49. SUMMARY
 HPS is a triad of
 Portal hypertension with/ without liver disease,
 Arterial Gas exchange defect(hypoxia)
 IPVDs.
 The most frequent anatomic substrate
 Precapillary or capillary pulmonary vascular
dilatation.
 Incidence: 4 to 47% of patients with severe chronic
liver disease.

50.  Clinical manifestations:
 Progressive dyspnea, spider nevi, clubbing,
platypnea, and cyanosis.
 Pulmonary function impairment:
 An increase in P(A-a)O2 >15 mm Hg.
 Chest radiograph (on occasion)
 Reticulonodular opacities that represent IPVDs.
 Contrast echocardiography
 The method of choice to demonstrate IPVDs.
 Pulmonary vascular resistance is commonly low,
cardiac output is usually high, and the oxygen
arteriovenous difference decreased.
 HPS can be corrected by liver transplantation

51. THANK YOU