portal hypertention hypertension portal system portal

1. RECENT ADVANCE MANAGEMENT OF
PORTAL HYPERTENSION
 https://tinyurl.com/y7zjeb8z

2. Introduction of portal
hypertension
 As early as the 17th century, it was realized that structural changes in
the portal circulation could cause gastrointestinal bleeding.
 In1902, Gilbert and Carnot introduced the term “ portal hypertension”
to describe the condition.
 https://tinyurl.com/y7zjeb8z

4. Defination of portal hypertension
 Portal hypertension is a clinical syndrome defined by a hepatic venous
pressure gradient (HVPG) exceeding 5 mm Hg.
 HVPG values between 6 and 10 mm of Hg represent subclinical portal
hypertension.
 HVPG = Wedged hepatic vein pressure(WHVP)- Free hepatic vein
pressure(FHVP).
 WHVP is a marker of sinusoidal pressure and FHVP is measured with
radiological assistance.
 Portal hypertension becomes clinically significant when the HVPG increases
above the threshhold value of
>10 mm of Hg (formation of varices)
>12 mm of Hg (variceal bleeding, ascitis).

5. PROGNOSTIC IMPLICATIONS OF
HVPG THRESHOLDS
 In patients with compensated cirrhosis:
•HVPG 10 mmHg: Development of gastroesophageal varices, hepatocellular carcinoma,
decompensation after surgery for hepatocellular carcinoma
•HVPG 12 mmHg: Variceal bleeding
•HVPG 16 mmHg: First clinical decompensation in patients with varices, mortality
 In patients with decompensated cirrhosis:
•HVPG 16 mmHg: Variceal rebleeding, mortality
•HVPG 20 mmHg (in patients with active variceal hemorrhage): Failure to control active
variceal hemorrhage, low one-year survival
•HVPG 22 mmHg: Mortality in patient with alcoholic cirrhosis and acute alcoholic hepatitis
•HVPG 30 mmHg: Spontaneous bacterial peritonitis
Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases.
Expert Rev Gastroenterol Hepatol 2013; 7:141.

6. CLASSIFICATION
OF CAUSES OF
PORTAL
HYPERTENSION
 https://tinyurl.com/y7
zjeb8z

7. Pathophysiology
of portal
hypertension

9. ROLE OF HEPATIC STELLATE CELLS IN
PORTAL HYPERTENSION
HSCs are perisinusoidal and pericyte like cells, and reside in the space between LSECs and
hepatocytes. In response to liver injury, HSCs activated and transformed into myofibroblasts,
which start to express several pro inflammatory and fibrotic genes. HSCs become contractile in
an activated state. Increased recruitment of these activated HSCs around newly formed
sinusoidal vessels increase intrahepatic vascular resistance in cirrhosis. Therefore, activated
HSCs play a crucial role in the development of portal hypertension because of the contractile
phenotype.
Furthermore, activated HSCs display a decreased response to vasodilators, such as NO. In
addition, ET-1, which is increased in cirrhosis, enhances the contraction of HSCs. Increased ET-
1 production and decreased NO production in cirrhotic livers therefore augment intrahepatic
resistance to the portal blood flow through activate HSCs, which facilitates the development
of portal hypertension.
https://tinyurl.com/y7zjeb8z

11. ROLE OF VEGF AND ANGIOGENESIS
IN PORTAL HYPERTENSION
 In portal hypertension, angiogenesis plays a crucial role in intrahepatic
circulation. An increased number of vessels in the fibrotic septa and the
surrounding regenerative nodules has been observed in cirrhotic livers.
Activated HSCs and/or other myofibroblasts, such as portal myofibroblasts,
are thought to promote angiogenesis in liver cirrhosis. Activated HSCs
activate LSECs by releasing angiogenic factors, such as angiopoietin, and
vascular endothelial growth factor (VEGF).
 A change in portal pressure is thought to be detected first by the intestinal
microcircular vascular bed, followed by arteries of the splanchnic circulation.
These vascular beds subsequently generate various angiogenic factors, such
as VEGF and placental growth factor (PlGF), which promote the formation of
portosystemic collaterals.
https://tinyurl.com/y7zjeb8z

12. ROLE OF
VEGF AND
ANGIOGENES
IS IN PORTAL
HYPERTENSIO
N

13. ROLE OF NO IN PORTAL
HYPERTENSION
Nitric oxide (NO) is likely the most potent vasodilator molecule known today. In
cirrhotic livers, NO production/bioavailability is significantly diminished, which
contributes to increased intrahepatic vascular resistance., At least 2 mechanisms
explain the decreased NO production.
1. The NO synthesizing enzyme endothelial NO synthase (eNOS) is inhibited by
negative regulators (such as caveolin-1), which are upregulated during cirrhosis;
as a result, NO production decreases.
2. oxidative stress is increased in cirrhosis. LSECs receive oxidative stress in
response to a wide variety of agents, such as bacterial endotoxins, viruses,
drugs, and ethanol. During cirrhosis, increased superoxide radicals
spontaneously react with NO to form peroxynitrite (ONOO), an endogenous
toxicant, thereby decreasing NO’s bioavailability as a vasodilator.
Pathophysiology of portal hypertension by YASUKO IWAKIRI; 282

14. Role of beta blocker in portal
hypertension
 NSBB have a dual mode of action decrease portal pressure, i.e., reduction
of cardiac output and splanchnic blood flow by β-1 receptor blockade,
and β-2 receptor blockade, resulting in splanchnic vasoconstriction
caused by unopposed effect of alpha 1 receptors

15. CARVEDILOL
Carvedilol has been investigated as a promising NSBB with the additional
property of vasodilatation due to its intrinsic anti-α1 adrenergic activity and its
capacity to enhance the release of nitric oxide. Thus, carvedilol reduces portal
pressure not only by decreasing portal-collateral blood flow (as all other NSBB)
but also by diminishing the functional component of hepatic vascular resistance
which is increased in cirrhosis. Due to these effects, this drug may cause a higher
risk of arterial hypotension leading to discontinuation of treatment. Indeed, a
reduction in mean arterial pressure has been documented in patients on
carvedilol, proportionally to the dosage. Other promising effects of carvedilol
are those of scavenging and suppressing reactive oxygen species , leading to a
possible cytoprotective and anti-oxidant effect . Amelioration of oxidative stress
with carvedilol might even lead to antifibrotic effects.
WORLD JOURNAL OF GASTROINTESTINAL ENDOSCOPY 2015
MAY2016;7(5)532-539

16. Current
evidence about
carvedilol and
propranolol as
prophylactic
therapy.

18. SIMASTATIN
 Recent study evaluated the effects of simvastatin on intrahepatic vascular
tone acting as an enos activator in humans. Hepatic eNOS activity is
decreased because of impaired Akt-mediated eNOS phosphorylation
which is partially reversible by statins. Patients who received simvastatin
showed increased hepatic venous NO products and decreased hepatic
vascular resistance without untoward systemic vascular effects.

19. NEWER TARGET
 https://tinyurl.com/y7zjeb8z

20. NCX-10002-(Acetyloxy) benzoic acid 3-
(nitrooxymethyl) phenyl ester
(NCX-1000) is a chemical entity
obtained by adding an NO-
releasing moiety to
ursodeoxycholic acid (UDCA), a
compound that is selectively
metabolized by hepatocytes.

21. NCX-999

22. Liver specific NODD:V-PYRROINO
 Is metabolized by hepatocytes in vitro
 Protects the hepatocytes from apoptotic cell death induced by TNF a
 Increased liver cGMP levels in vivo
 Reduces hepatic resistance of the liver both before and after ischemia
/reperfusion in pigs
(Saavedra et al. J Med Chem. 1997 Jun 20;40(13):1947-54.)
https://tinyurl.com/y7zjeb8z

23. VEGF AND OTHERS
 VEGF promotes vasodilation, vascular remodeling, and angiogenesis in part through
NO-dependent or independent mechanisms.
 Multikinase inhibitors such as sorafenib by blocking VEGF receptor result in
decreases of portosystemic shunts and improvement of portal hypertension but also
inactivation of HSC
 Placental Growth Factor(PLGF,) it is another member of VEGF family
 Antagonization of PLGF receptor is a good target for therapy with less sever side
effects than the blockade of VEGF
 Vasohibin -l : recently identified endogenous inhibitor of angiogenesis by VEGF-
vasohibin negative — feed back ioop.
 Vasohibin-l might be a novel and promising therapeutic strategy for halting Chronic
liver disease progression.

25. ROLE OF ANGIOTENSIN-II IN PORTAL
HYPERTENSION
 Drug therapy to reduce portal pressure involves targeting two vascular beds. The first
approach is to reduce intra hepatic vascular tone induced by
 the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the
sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and
pervascular smooth muscle cells.
 The second approach is to reduce mesenteric and portal blood flow
 It is clear that the renin angiotensin system (RAS) contributes to organ dysfunction and
chronic tissue injury in a range of conditions including diabetes, cardiovascular and
renal disease and both hepatic fibrosis and portal hypertension, primarily through the
vasoactive and profibrotic effects of its key effector peptide, angiotensin II. This is
supported by studies which have shown that RAS blockers are able to reduce fibrosis
in experimental models of chronic liver injury and that they can lower portal pressure
in both animal models and in man, primarily by inhibiting angiotensin II mediated
intrahepatic vasoconstriction.

26. ENDOTHELIN RECEPTOR
ANTAGONIST
 Increased ET‐1 production may contribute to portal hypertension.
Endothelin receptor expression is upregulated in liver disease and hepatic
stellate cells express the highest levels of endothelin receptors.
Furthermore, endothelin induced contraction is enhanced in stellate cells
from cirrhotic rat livers and in the intact liver endothelin causes sustained
vasoconstriction. Thus it has been proposed that increased production of
endothelin contributes to portal hypertension by mediating intrahepatic
stellate cell contraction and an increase in hepatic sinusoidal tone.
 REF-Yokomori H, Oda M, Ogi M. et al Enhanced expression of endothelin
receptor subtypes in cirrhotic rat liver. Liver 200121114–122.122 [PubMed]

27. RELAXIN