Hepatopulmonary Syndrome (HPS)

1
Hepatopulmonary Syndrome (HPS)

• Presented by Ri ???
• 2002/11/28

2
Hepatopulmonary Syndrome Diagnostic Criteria

• Chronic liver disease
• Usually complicated by portal hypertension (with
  or without cirrhosis)
• Arterial hypoxemia
• PaO2 lt 70 mm Hg (10 kpa) or AaO2 gradient gt 20 mm
  Hg while breathing room air
• Intrapulmonary vascular dilatation (IPVD)
• Delayed, positive contrast-enhanced
  echocardiography results or extrapulmonary (brain
  uptake of radioisotope after 99m TcMAA lung
  scanning.

AaO2, arterial-alveolar
Liver Transplantation, Vol 6, No 4, Suppl 1
(July), 2000pp S31-35
3
Epidemiological Characteristics and Natural
History

• Uncommon
• In patients with terminal liver disease, the
  prevalence of the syndrome ranges from 4 to 47.
• Mortality rate of 41 ( 9 of 22 adult patients )
  at a mean of 2.5 years ( range, 1 to 5 years )
  after the diagnosis.

PCCU Lesson 1, Volume 14,1999
4
Pathologic Findings (1)

• Intrapulmonary vascular dilatation(IPVD) in
  patients with significant hepatic dysfunction and
  hypoxemia.
• Diffuse precapillary and capillary dilatation (
  up to 500µm normal capillary diameter, 8 to
  10µm).
• Direct arteriovenous communications.

Liver Transplantation, Vol 6, No 4, Suppl 1
(July), 2000pp S31-35
5
Pathophysiology (1)Right-to-left shunt

• Mild hypoxemia 1/3 of patients with chronic
  liver disease, but IPVD cannot be demonstrated in
  all of these patients.
• Usually results from right-to-left intrapulmonary
  shunts through dilatations in intrapulmonary
  vessels
• Mechanisms of shunt formation unclear
• One animal model suggests that endothelin-1
  levels and pulmonary nitric oxide, raised in
  cirrhosis, correlate with degree of shunting.

6
Pathophysiology (2)Perfusion-diffusion defect

• Vascular dilatation is associated with a
  relatively low resistance to flow
• Normal to low pulmonary vascular resistance
  normal to increased cardiac output (depending on
  volume status)
• Gas exchanging vessels may be five or ten times
  of normal size.
• This sepsis-like hyperdynamic state ? further
  decrease in erythrocyte transit time through the
  alveolus ? difficult for the most distant red
  cells to become fully saturated with oxygen.

PCCU Lesson 8, Volume 13, 1998
7
The oxygen diffusion alterations due to abnormal
vessels in HPS.
PAO2FiO2(760-47)-PaO21.25
PCCU Lesson 1, Volume 14,1999
8
Pathophysiology (3)Ventilation-perfusion
mismatching

• IPVD hyperdynamic circulatory states overperfuse
  alveolar units relatively normally ventilated ?
  low ventilation-perfusion mismatches and arterial
  hypoxemia.

PCCU Lesson 8, Volume 13, 1998
9
Possible Mediators of Vascular Dilatation in HPS
Increased Pulmonary Vasodilators
Glucagon Atrial natriuretic factor Calcitonin
gene-related peptide Substance P Platelet-activati
ng factor Prostaglandin I2 or E1 Nitric oxide
Endothelin
Decreased Vasoconstrictors Prostaglandin
F2a Angiotensin I Adapted from Castro and
Krowka. PCCU Lesson 8, Volume 13, 1998
10
Nitric oxide (NO)

• A potent inhibitor of hypoxic pulmonary
  vasoconstriction.
• Normalization of increased exhaled NO in HPS
  after successful OLT (orthotopic liver
  transplantation) has been reported.

Liver Transplantation, Vol 6, No 4, Suppl 1
(July), 2000pp S31-35
11
Disorders Associated With HPS
Hepatic cirrhosis Primary biliary
cirrhosis Chronic active hepatitis Fulminant
hepatic failure Chronic hepatic allograft
rejection Nodular regenerative hyperplasia Congeni
tal hepatic fibrosis
Biliary atresia Budd-Chiari syndrome a1-antitrypsi
n deficiency Tyrosinemia Wilson's
disease Schistosomiasis Adapted from Krowka.
PCCU Lesson 8, Volume13, 1998
12
Clinical Features of the HPS

• Liver and portal hypertension manifestations (82
  of patients).
• Dyspnea (18) may be accompanied by platypnea
  and orthodeoxia.
• Platypnea an increase in dyspnea in the upright
  position which improves in the recumbent
  position.
• Orthodeoxia a decrease of gt 10 mmHg in PaO2 when
  changing from the recumbent to the seated
  position.
• Alterations in skin and nails spider nevi, one
  of the most sensitive and suggestive.
• Portal hypertension spider nevi clubbing
  hypoxemia ? highly suggestive of HPS.

PCCU Lesson 8, Volume13, 1998
13
Diagnostic methods for IPVD

• Contrast-enhanced bubble echocardiography
• Technectium-99 macroaggregated albumin (MAA)
  perfusion scanning
• Pulmonary angiography

PCCU Lesson 1, Volume 14, 1999
14
Contrast-enhanced bubble echocardiography

• Peripheral vein injection of an agitated saline
  solution bubble 60150 microns in diameter.
• Normally, these bubbles are trapped and resorbed
  in precapillary vessels.
• HPS some of the bubbles become visible in the
  left-sided heart chamber (after 36 cardiac
  cycles).
• Delayed opacification specific for
  intrapulmonary shunting.
• Early opacification intracardiac shunts (after
  one or two cardiac cycles).

PCCU Lesson 8, Volume 13, 1998
15
Technectium-99 macroaggregated albumin (MAA)
perfusion scanning

• Sizes of MAA particles 20 to 60 mm in diameter
  normally lodge in precapillary vessels within the
  lung.
• HPS
• a portion of these particles traverse the
  pulmonary capillary bed and deposit instead in
  systemic microvascular beds.
• Whole body scans will detect the radiolabelled
  MAA in the brain and other organs.

PCCU Lesson 8, Volume 13, 1998
16
Pulmonary angiography (1)

• Two patterns of IPVD
• Type?or diffuse pattern
• Minimal type? normal vessels or diffuse and
  tenuous spider web vascular abnormalities.
• Advanced type? a spongy or blotchy appearance.
• Type? or focal pattern arteriovenous
  malformations.
• Advanced type?and type ? respond poorly to the
  100 oxygen test.
• Type?patients embolization, since these lesions
  fail to regress with liver transplant, and may be
  accompanied by embolic or brain involvement.

Intrapulmonary vascular dilatation (IPVD)
PCCU Lesson 1, Volume 14,1999
17
Pulmonary arteriograms
PCCU Lesson 8, Volume 13, 1998 From Krowka and
colleagues
Fig. Advanced type ?, dense spongy appearance
18
Pulmonary arteriograms
Fig. Type ? vascular abnormalities PCCU
Lesson 8, Volume 13, 1998 Discrete arteriovenous
fistulas From Krowka and colleagues
19
Pulmonary angiography (2)

• More invasive and less sensitive than either
  contrast echocardiography or radionuclide
  perfusion scanning.
• Arterial oxygenation may improve substantially
  following coil embolization.

PCCU Lesson 8, Volume 13, 1998
20
Treatment (1) Pharmocology
Almitrine bismesylate Methylene
blue Indomethacin Plasma exchange Tamoxifen Chroni
c ambulatory oxygen therapy
Somatostatin analog Pulmonary embolization Sympath
omimetic drugs Liver transplantation b-blockers
Allium sativum (garlic)
PCCU Lesson 1, Volume 14, 1999
21
Treatments (2)

• Excellent PaO2 response to 100 O2 (PaO2 gt 550
  mmHg)
• ? ventilation-perfusion mismatch or
  diffusion-perfusion defect
• ? benefit clinically with this treatment.
• Poor response (PaO2 lt 150 mmHg) strongly
  suggests
• ? direct AV communications or extensive and
  extremely vascular channels
• ? pulmonary angiography ? type 2 pattern ?
  therapeutic embolization.

Liver Transplantation, Vol 6, No 4, Suppl 1
(July), 2000pp S31-35
PCCU Lesson 1, Volume
14, 1999
22
Treatment (3)

• ?-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.

PCCU Lesson 8, Volume 13,1998
23
Treatment (4)

• 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.

PCCU Lesson 8, Volume 13,1998
24
Treatments (3)Orthotopic Liver Transplantation
(OLT)

• OLT 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.
• Liver transplant priority consideration
• In patients with HPS exists in the pediatric
  population,
• Has not been applied to adult listing criteria.

Liver Transplantation, Vol 6, No 4, Suppl 1
(July), 2000pp S31-35
25
Treatments (4) HPS and Effects of OLT (1)

• Syndrome resolution after OLT reported in 62
  82 usually slow improvement, may require months
  of supplemental oxygen.
• Post-OLT mortality rates 16 within 90 days of
  OLT (n81), 38 at 1 year (n14)
• 30 mortality if pre-OLT PaO2 lt 50 mmHg
• Greater pre-OLT extrapulmonary (brain) uptake of
  99m TcMAA associated with decreasing post-OLT
  survival

26
Treatments (5) HPS and Effects of OLT (2)

• Post-OLT nonresolution of HPS uncommon (2)
• Post-OLT recurrence of HPS extremely rare 1 case
  reported (pre-OLT diagnosis was nonalcoholic
  steatohepatitis that recurred post-OLT)
• Many centers (especially pediatric, UNOS Policy
  3.6) consider HPS an indication for OLT

UNOS, United Network for Organ
Sharing Liver Transplantation, Vol 6, No 4,
Suppl 1 (July), 2000pp S31-35
27
HPS diagnostic algorithm
IPVDS Intrapulmonary vasodilatation syndrome
In the absence of bronchopulmonary disease
PCCU, Lesson 1, Volume 14, 1999
28
Summary (1)

• HPS is a triad of
• Portal hypertension with/ without liver disease,
• Gas exchange disorders,
• IPVDs.
• The most frequent anatomic substrate
• Precapillary or capillary pulmonary vascular
  dilatation.
• Incidence 4 to 47 of patients with severe
  chronic liver disease.

29
Summary (2)

• Clinical manifestations
• Progressive dyspnea, spider nevi, clubbing,
  platypnea, and cyanosis.
• Pulmonary function impairment
• An increase in P(A-a)O2 gt15 mm Hg.
• Chest radiograph (on occasion)
• Reticulonodular opacities that represent IPVDs.
• Contrast echocardiography
• The method of choice to demonstrate IPVDs.

30
Summary (3)

• Pulmonary vascular resistance is commonly low,
  cardiac output is usually high, and the oxygen
  arteriovenous difference decreased.
• HPS can be corrected by liver transplantation.

31
Conclusion

• Severe and progressive hypoxemia even in the
  absence of deteriorating hepatic function ?
  indication for proceeding with liver
  transplantation.
• Although drug therapy has been disappointing,
  recent progress in our understanding of the
  pathobiology, and the known reversibility of HPS
  after transplantation, suggests that effective
  medical treatments may soon be forthcoming.