my presentation on molecular mechanism of portal htn..

1. • PORTAL HYPERTENSION :
Pathophysiology {molecular mechanism}
and Classification
Dr. Gnanendra DM
Postgraduate trainee,
Dept of Gastroenterology.

2. • As early as the 17th century, it was realized that
structural changes in the portal circulation could
cause gastrointestinal bleeding.
• In 1902, Gilbert and Carnot introduced the term
"portal hypertension" to describe this condition.
Introduction of Portal Hypertension
Then, What's Portal Hypertension?

3. Definition
• Portal hypertension is defined by a
pathologic increase in portal pressure, in
which the pressure gradient between the
portal vein and inferior vena cava (the
portal pressure gradient (PPG)) is increased
above the upper normal limit of 5 mmHg.
• PPG values between 6 and 10mmHg
represent subclinical portal hypertension

4. • Portal hypertension becomes clinically
significant when the PPG increases above the
threshold value of
• >10mmHg ( formation of varices)
• >12mmHg ( variceal bleeding, ascites)
• This increased pressure results from a
functional obstruction to blood flow from any
point in the portal system's origin (in the
splanchnic bed) through the hepatic veins (exit
into the systemic circulation) or from an
increase in blood flow in the system.

7. Anatomy of Portal System
The portal vein
supplies 70% of the
blood flow to the
liver, but only 40% of
the liver oxygen
supply. The remainder
of the blood comes
from the hepatic
artery, and blood from
both of these vessels
mixes in the
sinusoids.

8. Venous anatomy of gastroesophageal junction

9. The intrinsic veins of the gastroesophageal junction
are divided into four well-defined zones.
• 1 Gastric zone: 2–3 cm zone with its upper border at the
gastroesophageal junction and is composed of a radial
band of veins in the submucosa and lamina propria.
• 2 Palisade zone: commences at the gastroesophageal
junction and extends cranially for 2–3 cm and is a direct
extension of the veins of the gastric zone, which run in
“palisades” or packs of longitudinally arrayed veins in the
lamina propria. These veins are the primary site of
communication between the portal bed and azygous bed.
• 3 Perforating zone: the intrinsic veins drain into the
extrinsic veins primarily in this region via valved per-
forating veins.

10. • 4 Truncal zone: an 8–10 cm zone extending upward from
the perforating zone.
• Flow direction in these veins is from a cranial to caudal
direction and drains via the perforating veins into the
extrinsic veins.
• In cases of portal hypertension, an adaptive increase in
flow through the portasystemic communications occurs to
return blood to the heart.
• The vessels involved, especially the intrinsic veins around
the gastroesophageal(GE) junction dilate and become
tortuous forming varicose veins.

11. • The pathophysiologic process of portal
hypertension consists of three components:
intrahepatic circulation, systemic (splanchnic)
circulation, and collateral circulation.
• Additionally, continuous abnormalities in
systemic circulation induce hyperdynamic
circulation.
Guturu P, Shah V. New insights into the pathophysiology of portal hypertension. Hepatol
Res 2009;39:1016-1019

12. Pathogenesis
The portal vein carries approximately 1500 mL/min of
blood from the small and large bowel, the spleen, and
the stomach to the liver.
Obstruction of portal venous flow, whatever the
etiology, results in a rise in portal venous pressure.
The response to increased venous pressure is the
development of collateral circulation that diverts the
obstructed blood flow to the systemic veins.
These portosystemic collaterals form by the opening and
dilatation of preexisting vascular channels connecting
the portal venous system and the superior and inferior
vena cava.

13. • Development of portal hypertension can be influenced by
changes in resistance and flow in the hepatic vasculature.
• Increased resistance of portal blood flow in cirrhotic liver
induces portal venous dilatation and congestion of portal
venous flow, leading to elevated portal pressure.
Subsequently, portosystemic collaterals develop to
counterbalance the increased resistance in portal blood
flow, and induce an increase in venous return to heart
which results in increased portal venous inflow. This
hyperdynamic splanchnic circulation contributes to the
maintaince and aggravation of portal hypertension
Ohm law is P = F R, (pressure= flow×resistance).

14. Increase in vascular resistance
 The initial factor in the etiology of portal
hypertension is the increase in vascular resistance to
the portal blood flow.
Poiseuille’s law, which can be applied to portal
vascular resistance, R, states that R = 8hL/pr4, where
h is the viscosity of blood, L is the length of the blood
vessel, and r is the radius of the blood vessel.
The viscosity of the blood is related to the
hematocrit. The lengths of the blood vessels in the
portal vasculature are relatively constant.

15. Thus, changes in portal vascular resistance are
determined primarily by blood vessel radius.
Because portal vascular resistance is indirectly
proportional to the fourth power of the vessel radius,
small decreases in the vessel radius cause large
increases in portal vascular resistance and,
therefore, in portal blood pressure (P = F8hL/pr4,
where P is portal pressure and F is portal blood
flow).
Liver disease that decreases the portal vascular
radius produces a dramatic increase in portal
vascular resistance.
In cirrhosis, the increase occurs at the hepatic

16. Increased hepatic vascular resistance in cirrhosis is
not only a mechanical consequence of the hepatic
architectural disorder; a dynamic component also
exists due to the active contraction of myofibroblasts,
activated stellate cells, and vascular smooth-muscle
cells of the intrahepatic veins.
Endogenous factors and pharmacologic agents that
modify the dynamic component include those that
increase or decrease hepatic vascular resistance.

17. Factors that increase hepatic vascular resistance
include endothelin-1 (ET-1), alpha-adrenergic
stimulus, and angiotensin II.
Factors that decrease hepatic vascular resistance
include nitric oxide (NO), prostacyclin, and
vasodilating drugs (eg, organic nitrates,
adrenolytics, calcium channel blockers).

19. 1 Intra hepatic circulation
• Vasoregulatory imbalances and increased
intrahepatic resistance
• Sinusoidal Remodeling and Angiogenesis

21. Vasoregulatory imbalances and increased intrahepatic resistance
Hepatic stellate cells (HSCs) play a central role in producing
dynamic components of intra hepatic resistance by causing
sinusoidal vasoconstriction through “contractile machinery” and
relaxation in response to the interaction between sinusoidal
endothelial cells (SECs) and HSCs; their paracrine effects are
accomplished through endothelin-1 (ET-1) and nitric oxide (NO).
Normally, ET-1 is secreted from SECs and acts on ETA receptors on
HSCs leading to HSC contraction. Conversely, NO released from
SECs by endothelial NO synthase (eNOS) induces relaxation of
HSCs through the guanylate catalase pathway. Consequently, the
balance between the ET-1 and NO accounts for the control of
sinusoidal flow.
Intra hepatic circulation

22. • in cirrhotic liver, the overproduction of ET-1 and
increased susceptibility to autocrine ET-1 leading
to activated HSCs result in increasing HSC
contraction. In addition, multiple derangements in
eNOS derived NO generation by SECs contribute
to impaired sinusoidal relaxation and increased
intrahepatic resistance (endothelial dysfunction).
SECs show a prominent increase in the inhibitory
protein caveolin binding to eNOS with
concomitant decreased calmodulin binding, which
may contribute to NOS dysfunction.

23. Recent studies have shown impaired
phosphorylation and activation of eNOS
mediated through alterations in G-protein
coupled receptor signaling and defects in
endogenous inhibitors of NOS, which suggest
that multiple molecular defects likely
contribute to a significant deficiency in hepatic
NO production during cirrhosis.

24. Animal experiments have demonstrated that
activation of hepatic eNOS can improve portal
hemodynamics in cirrhotic rat liver.
Langer DA, Shah VH. Nitric oxide and portal hypertension: interface of vasoreactivity
and angiogenesis. J Hepatol 2006;44:209-216.

25. Recent study evaluated the effects of simvastatin
on intrahepatic vascular tone acting as an eNOS
activator in humans.
Patients who received simvastatin showed
increased hepatic venous NO products and
decreased hepatic vascular resistance without
untoward systemic vascular effects.
Fernandez M et al, Gastroenterology 2009;126:749-755.

26. Sinusoidal Remodeling and Angiogenesis
HSC density and coverage of the sinusoidal lumen are increased in
cirrhosis. The contractile nature and long cytoplasmic processes of
HSCs encircling endothelial cells induce sinusoidal vessel
constriction with increased vascular resistance termed “sinusoidal
vascular remodeling”.
The characteristics of sinusoidal remodeling are distinct from process
of fibrosis, collagen deposition of HSC. In this process, HSC motility
and migration is absolutely required to promote enhanced coverage of
HSCs around a SECs-lined sinusoid.
Straub AC et al . sinusoidal endothelial cell capillarization and vessel remodeling in mouse
liver. Hepatology 2007;45:205-212

27. While Transforming growth factor-β (TGF-β) is largely recognized
for its contribution to HSC-based collagen deposition, there is
significant crosstalk between TGF-β and PDGF involved in HSCs
motility. Indeed, these signals may converge at the level of c-abl
tyrosine kinase. A number of signaling pathways mediate HSC
recruitment to vessels in vascular remodeling and angiogenesis
including PDGF, TGF-β, angiopoietins, and NO. Platelet derived
growth factor (PDGF) is probably the most critical factor in the
recruitment of pericytes to newly formed vessels.SECs also undergo
substantive phenotypic changes in cirrhosis that likely contribute to
changes in sinusoidal structure. Indeed, recent studies have identified
a number of alterations in SEC phenotypes
Ceni E,et al : Gastroenterology 2006;131: 1235-1252

28. • Peptide hormone Relaxin
RXFP1receptor
Activates intra hepatic NO signaling
Decrease the activaion and fibrinogenic
phenotype of HSC.
Relaxin treatment reduces poratl pressure
without systemic hypotension
Fernandez Hepatology, vol 61, no 4 , april 2015

29. Eicosanoids
Thromboxane A2
Cox
Prostaglandin H2
LTc4
Lox LTd4
LTe4
Inhibition of leukotriene receptor(montelukast) reduces portal
perfusion pressure.
Fernandez Hepatology, vol 61, no 4 , 2015
• Vasoconstrictor
• Fibrogenesis
• angiogenesis

30. • Nago –B belongs to family reticulon proteins.
• It promotes liver fibrosis by facilitating TGF-
beta signaling pathway induces antiapoptotic
effects on HSCs
• Selective blockade of Nago-B in HSC
represent therapeutic strategy to mitigate liver
fibrosis.
Tashiro K et al, Am J pathol 2013:182;786-795

31. Micro RNAs
• They act as fine tuning regulators of HSC and
Enothelial cell functions
• Their dysregulation have a role in liver
fibrogenesis and angiogenesis
• Micro RNAs ,Which inhibits proteins involved in
activation of HSC in down regulated liver fibosis
• Inhibits expression of aquaporin-1, that promotes
angiogenesis, fibrosis , PHT in cirrhotic liver.
• Lakner AM et al. inhibitory effect of micro RNA19b in HSC mediated
fibrogenesis. Hepatology 2013;56:300-310

33. Systemic and splanchnic circulation
• Vasoregulatory imbalances in the splanchnic
circulation
• Vascular remodeling of systemic vessels in
portal hypertension

34. Molecular pathways associated to splanchnic vasodilation
Martell M et al . Splanchnic vasodilation in portal hypertensionWorld J Hepatol 2010 June
27; 2(6): 208-220

35. Vasoregulatory imbalances in the splanchnic circulation
In contrast to diminished intrahepatic bioavailability of NO,
splanchnic (and systemic) circulation shows a relative excess in
regional NO generation.This increased production is largely
endothelium-dependent, and is thought to be evidence of eNOS
activation in splanchnic endothelium.
Some studies have shown that eNOS activation by the angiogenic
growth factor, vascular endothelial growth factor (VEGF), may
be a primary factor in initial eNOS activation which demonstrates
interesting links between vasodilating, angiogenesis and vascular
remodeling.
Wiest R, et al, J Clin Invest 1999;104:1223-1233

36. Bacterial translocation during cirrhosis increases tumor necrosis
factor-α (TNF-α) production which can also induce the increase of
systemic NO production.Therefore, increased NO production in
systemic and splanchnic circulation contributes to decreased systemic
vascular resistance and resultant hyperdynamic circulation. This in
turn results in sodium retension and ascites mediated by a reduction
of effective circulating volume, stimulation of sympathetic system,
an activation of the renin-angiotensin-aldosteron system, and an
increase of antidiuretic hormone release
Rudic RD,et al : Direct evidence for the importance of endothelium-derived nitric oxide
vascular remodeling. J Clin Invest 1998;101:731-736

37. Vascular remodeling of systemic vessels in portal
hypertension
Vascular remodeling is a long-term adaptive response to chronic
changes in blood flow. Chronic increases in flow with dilation of the
vascular channel are implicated in endothelial-based signals that
mediate restructuring of the vessel, thereby allowing for chronic
increases in vessel diameter and capacity for high volume flow. This
change has been demonstrated in peripheral vessels including
experimental models of portal hypertension which may be related to
activation of eNOS.

38. 3.Collateral circulation
• Vasoregulatory imbalances in collateral
circulation
• Angiogenesis and vascular remodeling in
collateral circulation

39. Four ramus communicans between
portal and systemic circulations
esophageal and gastric veins
inferior rectal-anal veins
anterior abdominal wall veins
retroperitoneal venous plexus

40. Vasoregulatory imbalances in collateral circulation
The development of portosystemic shunts and collateral
circulation such as esophageal and hemorrhoidal collateral
vessels is a compensatory response to decompress the portal
circulation and hypertension, but unfortunately contributes to
significant morbidity and mortality. Vasodilation of pre-
existing collateral vessels results in increased collateral blood
flow and volume. The control of collateral circulation could be
a key in managing complications of portal hypertension,
therefore, experimental studies are performed.
The Korean Journal of Hepatology Vol. 16. No. 4, December 2010

41. Angiogenesis and vascular remodeling in collateral
circulation
In addition to vasodilatation, the collateral circulatory bed
develops through angiogenesis.
Angiogenesis occurs through the proliferation of endothelial and
smooth muscle cells in addition to vasculogenesis.
Vasculogenesis refers to the recruitment of endothelial progenitor
cells for the de novo synthesis of vessels.
Angiogenesis and vasculogenesis are also influenced by NO and
highly dependent on VEGF as the growth factor exerting
pleiotropic effects to promote new vessel formation.

42. 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 HSCs.
Fernandez M. et al, Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral
circulations in portal hypertensive and cirrhotic rats. Hepatology 2009;49:1245-1256.

43. • 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

44. • Vasohibin -1 : recently identified
endogenous inhibitor of angiogenesis by
VEGF- vasohibin negative – feed back loop
• Vasohibin-1 might be a novel and
promising therapeutic strategy for halting
Chronic liver disease progression.
Fernandez Hepatology, vol 61, no 4 , april 2015.

45. Formation of varices
An elevated pressure difference between systemic and
portal circulation (ie, HVPG) directly contributes to the
development of varices.
HVPG is a surrogate marker of portal pressure gradient and
is derived from WHVP corrected (subtracted) with free
hepatic venous pressure (FHVP).
The hypertensive portal vein is decompressed by diverting
up to 90% of the portal flow through portasystemic
collaterals back to the heart, resulting in enlargement of
these vessels.
These vessels are commonly located at the
gastroesophageal junction, where they lie subjacent to the
mucosa and present as gastric and esophageal varices.

46. Varices form when the HVPG exceeds 10 mm
Hg; they usually do not bleed unless the HVPG
exceeds 12 mm Hg (normal HVPG: 1-5 mm
Hg). Gastroesophageal varices have 2 main
inflows. The first is the left gastric or coronary
vein, and the second is the splenic hilum,
through the short gastric veins.
The gastroesophageal varices are important
because of their propensity to bleed.

47. Normal venous flow through the
portal and systemic circulation. IMC
= inferior mesenteric vein; IVC =
inferior vena cava; SVC = superior
vena cav
Redirection of flow through the left gastric
vein secondary to portal hypertension or
portal venous occlusion. Uphill varices
develop in the distal one third of the
esophagus. IMC = inferior mesenteric vein;
IVC = inferior vena cava; SVC = superior
vena cava.

48. Grading of esophageal varices
• Esophageal varices are often graded by size
• F1: small, straight varices.
• F2: enlarged, tortuous varices, occupying less
than one third of the lumen.
• F3: large, coil-shaped varices, occupying more
than one third of the lumen.

49. Grading of Gastric varices
• Gastric varices are classified by location
• type 1 : along the lesser curve.
• type 2: along the greater curve extending
towards the fundus of the stomach.
Isolated gastric varices:
• type 1: isolated cluster of varices in the
fundus of the stomach.
• type 2 : isolated gastric varices in other
parts of the stomach.

51. Mechanisms of variceal
hemorrhage
Increased portal pressure contributes to
increased varix size and decreased varix wall
thickness, thus leading to increased variceal
wall tension. Rupture occurs when the wall
tension exceeds the elastic limits of the
variceal wall. Varices are most superficial at
the gastroesophageal junction and have the
thinnest wall in that region; thus, variceal
hemorrhage invariably occurs in that area

52. The following are risk factors for variceal hemorrhage :
Variceal size - The larger the varix, the higher the risk of rupture
and bleeding; however, patients may bleed from small varices too
The presence of endoscopic red color signs (eg, red wale
markings, cherry red spots)
Child B or C classification, especially the presence of ascites,
increases the risk of hemorrhage
Active alcohol intake in patients with chronic, alcohol-related liver
diseases
Local changes in the distal esophagus (eg, gastroesophageal
reflux) – These have been postulated to increase the risk of
variceal hemorrhage.
Bacterial infection - A well-documented association exists
between variceal hemorrhage and bacterial infections, and this
may represent a causal relationship

53. Note that bacterial infection could also trigger
variceal bleeding through a number of
mechanisms, including the following:
• The release of endotoxin into the systemic
circulation
• Worsening of hemostasis
• Vasoconstriction induced by the contraction of
stellate cells
Goulis J, et al. Bacterial infection is independently associated with failure to control bleeding in
cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1998;27:1207-1212

55. 4.Hyperdynamic circulation
The hyperdynamic circulation is characterized by increased
cardiac output and heart rate, and decreased systemic vascular
resistance with low arterial blood pressure in cirrhotic patients.
These hemodynamic alterations are initiated by systemic and
splanchnic vasodilatation, and eventually lead to abnormalities
of the cardiovascular system and several regional
vascular beds including ones involved in hepatic, splanchnic,
renal, pulmonary, skeletal muscle and cerebral circulation.

56. Pathogenesis of hyperdynamic circulation in cirrhosis and portal hypertension.

57. Multi-organ involvement
gut and liver receive a third of the entire cardiac output,
hyperdynamic circulation directly or indirectly contributes to
two of the most troublesome complications of cirrhosis: ascites
and variceal bleeding

58. Heart
Cirrhotic cardiomyopathy was first described in the late 1960s
These individuals show blunted systolic and diastolic
contractile responses , ventricular hypertrophy or chamber
dilatation, and electrophysiological abnormalities including
prolonged QT intervals.
The pathogenesis of ths includes
diminished β-adrenergic receptor signal transduction,
cardiomyocyte cellular plasma membrane dysfunction,
increased activity or levels of cardio- depressant substances
such as cytokines, endogenous cannabinoids, and nitric oxide.

59. cirrhotic cardiomyopathy may contribute to the
pathogenesis of hepatorenal syndrome precipitated by
spontaneous bacterial peritonitis, acute heart failure after
insertion of transjugular intrahepatic portosystemic
shunts, and increased cardiovascular associated
morbidity and mortality after liver transplantation.
Kim MY, Baik SK. Cirrhotic cardiomyopathy. Korean J Hepatol 2007; 13:20-26.

60. Kidney
Renal vasoconstriction is characteristic in kidney with
splanchnic vasodilation and hyperdynamic circulation,
and may be responsible for the development of
hepatorenal syndrome.
Renal vasoconstriction develops as a consequence of
effective hypovolemia and ensuing neurohumoral
activation.This provides the rationale for treating
hepatorenal syndrome with albumin infusion and
vasoconstrictors (terlipressin, norepinephrine, or
midodrine)
Arroyo V et al. Ascites and hepatorenal syndrome in cirrhosis: J Hepatol 2003;38(Suppl 1):S69-S8

61. Lung
Vasodilatation in the lung leads to ventilation perfusion mismatch
and even arterio-venous shunts in the pulmonary circulation; these
result in hepatopulmonary syndrome, characterized by marked
hypoxemia.
In some cases, this may evolve into the opposite situation with
markedly increased pulmonary vascular resistance seen in
portopulmonary hypertension.This is thought to develop through
endothelial dysfunction and vascular remodeling of the pulmonary
circulation
Rodriguez-Roisin R, Pulmonary-Hepatic vascular Disorders (PHD).
Eur Respir J 2004;24:861-880.

62. Brain
cerebral blood flow and vascular reactivity associated with portal
hypertension are considered to contribute and facilitate some of
the brain abnormalities of hepatic encephalopathy.

63. Classification of portal htn

64. Prehepatic resistance
Prehepatic causes of increased
resistance to flow include the
following:
•Portal vein thrombosis
•Splenic vein thrombosis
•Congenital atresia or stenosis of portal
vein
•Extrinsic compression (tumors)
•Splanchnic arteriovenous fistula

65. Intrahepatic resistance
•A reduction of sinusoidal caliber due to hepatocyte
enlargement
•An alteration in the elastic properties of the sinusoidal
wall due to collagen deposition in the space of Disse
•Compression of hepatic venules by regeneration
nodules
• Central vein lesions caused by perivenous fibrosis
• Veno-occlusive changes ,Perisinusoidal block by
portal inflammation, portal fibrosis, and piecemeal
necrosis

66. More specifically, intrahepatic, predominantly
presinusoidal causes of resistance to flow
include the following:
 Schistosomiasis (early stage)
 Primary biliary cirrhosis (early stage)
 Idiopathic portal hypertension (early stage)
 Nodular regenerative hyperplasia
Myeloproliferative diseases
 Polycystic disease
 Hepatic metastasis
 Granulomatous diseases (sarcoidosis,
tuberculosis)

67. Intrahepatic, predominantly sinusoidal causes of
resistance include the following:
• Hepatic cirrhosis
• Acute alcoholic hepatitis
• Schistosomiasis (advanced stage)
• Primary biliary cirrhosis (advanced stage)
• Idiopathic portal hypertension (advanced stage)
• Acute and fulminant hepatitis
• Congenital hepatic fibrosis
• Peliosis hepatitis

68. • Vitamin A toxicity
• Sclerosing cholangitis
• Hepatitis B virus–related and hepatitis C virus–
related cirrhosis
• Wilson disease
• Hemochromatosis
• Alpha-1 antitrypsin deficiency
• Chronic active hepatitis

69. Postsinusoidal obstruction syndrome
 veno-occlusive disease of the liver
Postsinusoidal causes of resistance

70. Posthepatic resistance
Thrombosis of the inferior vena cava (IVC)
 Right-sided heart failure
 Constrictive pericarditis
 Severe tricuspid regurgitation
 Budd-Chiari syndrome
 Arterial-portal venous fistula
 Increased portal blood flow
 Increased splenic flow

74. Extra Hepatic Portal Vein Obsrtuction
• Portal hypertension caused by EHPVO
occurs when the site of block is in the portal
vein before the blood reaches the liver.
• EHPVO is a vascular disorder of the liver.

75. • It is defined by obstruction of the extra-
hepatic portal vein with or without
involvement of the intra-hepatic portal
veins or splenic or superior mesenteric
veins.
• Isolated occlusion of the splenic vein or
superior mesenteric vein does not constitute
EHPVO.
• Portal vein obstruction associated with
chronic liver disease or neoplasia is a
separate entity and does not constitute
EHPVO.
Sarin et al , Liver International 2006: 26: 512–519

76. Prevalence
EHPVO is a common cause of portal hypertension in the
developing countries (up to 30% of all variceal bleeders)
and is second to cirrhosis in the West (up to 5–10%) .
EHPVO is also the most common cause of upper
gastrointestinal bleeding in children. It accounts for almost
70% of pediatric patients with portal hypertension
Khandur A et al , Gastrointestinal bleeding in children. J Gastroenterol Hepatol
1996; 11: 903–7.

77. • EHPVO is a heterogenous disease with regard to
etiology and pathogenesis,especially with respect
to age and geographical location.
Children
• Evidence of umbilical sepsis, umbilical
catheterization and intra-abdominal sepsis
• Congenital anomalies
• hypercoagulable disorder in children

78. Adults
Underlying hypercoagulable and prothrombotic states are
common
Intra-abdominal inflammatory pathology and trauma.
EHPVO could also be secondary to liver cirrhosis and
neoplasia, but it is considered with respect to the primary
disease itself

79. Childhood EHPVO
The typical presenting symptoms are repeated episodes of variceal
bleeding and a feeling of a lump in the abdomen.
 Variceal bleeding: The usual presentation for children with
EHPVO is sudden, unexpected and, often, massive hemetemesis,
recurrent, well-tolerated bleeds without significant hepatocellular
failure are common.
Growth retardation: EHPVO occurring in the pre-pubertal period
could result in growth retardation in around 50% of the children.
Ascitis
Sherlock S. The etiology, presentation and natural history of extra-hepatic portal venous obstruction. Q J
Med 1979; 192: 627–39.

80. Adult EHPVO
The presentation could be either acute (recent) or chronic
EHPVO.
Acute or recent EHPVO: These patients often present with acute
abdominal pain. pain could sometimes accompanied by fever and,
rarely, ascites.
Chronic: Variceal bleeding and hypersplenism are the common
manifestations.
Ectopic varices in EHPVO: These are reported in 27–40% of
patients with EHPVO, and are commonly seen in the duodenum,
anorectal region and gallbladder bed
Hepatic encephalopathy
Intestinal ischemia
Jaundice
Sarin et al , Liver International 2006: 26: 512–519

81. EHPVO and pregnancy
• This is a peculiar situation where there is an apparent
threat to the mother and baby.
• The risk of variceal bleeding in pregnant EHPVO patients
is higher than in pregnant cirrhotic women. While the
maternal outcome following a variceal bleed in pregnant
EHPVO patients is good, the fetal outcome is poor.
• The incidences of abortion, pre-maturity, small for
gestational age babies and perinatal death are high in
pregnant patients with EHPVO

82. Hemodynamics in EHPVO
• Hepatic vein pressure gradient is normal in
EHPVO .
• Intravariceal and intrasplenic pressures
closely reflect portal pressure. These are
elevated in EHPVO patients and suggest
portal hypertension
• Currently, portal pressure measurement has
a limited role in the clinical management of
patients with EHPVO
Sarin et al , Liver International 2006: 26: 512–519

83. NCPF - definition
• Disease of uncertain etiology
• Portal fibrosis & invlv. small and
med.portal veins
• Portal hypertension,splenomegaly,variceal
bleed.
• Liver functions & stucture- normal

84. terminology
• Non –cirrhotic portal fibrosis by ICMR in
1969
• Idiopathic portal hypertension in Japan
• Hepato portal sclerosis in West

85. • In India, NCPF constituted 7.9 to 46.7% of
patients with portal hypertension, with a peak
age of third and fourth decades of life.
• A majority of patients belongs to lower
socioeconomic strata.
• no sex predilection
• although the study from Chandigarh shows a
female predominance.
• Dhiman RK, et al. Noncirrhotic portal fibrosis experience with 151 patients and a
review of the literature. J Gastroenterol Hepatol 2002;17:6–16

86. • IPH in Japan, in contrast has been reported
to have a female preponderance, with a
peak age one to two decades older than
patients with NCPF.

87. etiology
• Infections – bacterial inf. From gut.
- umblical sepsis,diarrhoea in
infancy & early childhood.
• TOXINS AND DRUGS :chronic exposure to copper
sulfate : chronic arsenicosis , vinyl chloride nmonomers
• Auto- immune disorders.
• Pro-thrombotic state (west).
• protracted treatment with methotrexate, 6-mercaptopurine,
azathioprine, prednisolone irradiation and chemotherapy
• hypervitaminosis A
• Exact etiology is still unknown

88. Clinical Features
• Three-fourths of NCPF patients in India present
with well-tolerated upper gastrointestinal
bleeding. Awareness of a mass in the left
hypochondrium (hypersplenism) The spleen is
massively enlarged, almost reaching the
umbilicus.
• Ascites is uncommon, and may occur after an
episode of gastrointestinal bleeding (9.9%).
Sarin SK. Noncirrhotic portal fibrosis a clinical profile of 366 patients. Am J Gasteroenterol
2006; 101:S19

89. • IPH patients mainly present with splenomegaly
in 88% of patients,
• Gastrointestinal bleeding in 35%.
• Ascites in 12%.
• Thrombosis of portal vein may be seen in
several cases.
Okuda K, et al. Idiopathic Portal Hypertension: a natural study. In:Hepatology a
festschrift for Hans Popper. NewYork: Raven Press;1985:95–108

90. NCPF vs IPH
NCPF IPH
Age (years) 25-35 43-56
M: F 1:1 1:3
Hemetemesis/ malena 94 % 40%
Spenomegaly Dispropationate &
massive
moderate
Autoimmune features rare common
Wedge hepatic venous
pressure
normal Mildly raised
Geography Indian subcontinent Japan

91. parameter EHPVO NCPF Cirrhosis
Median age 10 yr 28 yr 40 yr
Ascites Absent/transientafte
r bleed
Absent/transient
after bleed
+ to +++
Encephalopathy nil nil ++
Jaundice/signs of
liver failure
nil nil ++
Liver function test normal normal deranged
Liver –Gross normal normal Shrunken,nodular
microscopic normal Normal/portal
fibrosis
Necrosis,regeneratio
n
Usg Portal/splenic vein
block & cavernoma
dilated &
patent&thickened
Spleno-portal axis
Dilated & patent
Spleno-portal axis

94. Budd-Chiari Syndrome
• Caused by hepatic venous obstruction
• At the level of the inferior vena cava, the
hepatic veins, or the central veins within the
liver itself
• result of congenital webs (in Africa and
Asia), acute or chronic thrombosis (in the
West), and malignancy

95. Budd-Chiari Syndrome
• Acute symptoms include hepatomegaly, RUQ
abdominal pain, nausea, vomiting, ascites
• Chronic form present with the sequelae of
cirrhosis and portal hypertension, including
variceal bleeding, ascites, spontaneous bacterial
peritonitis, fatigue, and encephalopathy

96. epidemology
• m:f 1:2
• 3rd
and 4th
decade
• Median age – 35
• Location
Hepatic vein 62%
IVC 7%
Both IVC & hepatic veins 31%
Associated portal vein thrombus 14%

97. Pathogenesis
HEPATIC VEIN THROMBOSIS
Sinusoidal pressure
Sinusoidal flow
Sinusoidal dilatation+Interstitial fluid filtration
Fluid passes through hepatic capsule(Ascitis)

98. portal vein pressure & perfusion of liver via
portal vein
Hypoxia of hepatocyte
inflammatory centrilobular cell necrosis
Release of free oxygen radicals
Atrophy

99. chronic
weeks of obstruction
fibrosis of centrilobar area
nodular regeneration in periportal area
cirrhosis portovenous
.
collateral
cirrhosis

100. Etiology:
• majority of patients have an underlying
hematologic abnormality.
• Tumor
– Hepatocellular carcinoma
– Carcinoma of pancreas
– Carcinoma of kidneys
– Metastatic disease