Journal of Gastroenterology and Hepatology (2002) 17, S482–S487
Pathophysiology of portal hypertension
D KAPOOR AND SK SARIN
Department of Gastroenterology, GB Pant Hospital, New Delhi, India
INTRODUCTION
The term ‘portal venous system’ is applied to a system
that begins and terminates in capillaries. In the ab-
domen, this system springs up as the capillaries of the
intestine, and ends in the hepatic sinusoids. A schematic
representation of the main splanchnic venous channels
is shown in Fig. 1.
Normal physiology of portal circulation
Portal pressure (P) like pressure in any vascular bed is
determined by the product of portal venous inflow (Q)
and the vascular resistance (R) to this flow, that is:
P =Q¥R [1]
The normal hepatic blood flow is about 1.5 L/min of
which approximately four-fifths is contributed by the
portal vein. The portal vein pressure ranges from 5 to
8 mmHg and that of the hepatic veins as well as the infe-
rior vena cava is approximately 1–2 mmHg. The pres-
sure gradient between the portal venous and hepatic
outflow venous system is thus approximately 4 mmHg.
Thomson et al. are credited with the first description of
portal pressure measurements and the modern classifi-
cation of portal hypertension (PHT).1
The hepatic microcirculation is peculiar in that the
ratio of pre-to-post sinusoidal resistance is about 49:1,
in stark contrast to that seen in skeletal muscle, where
the pre- to post-capillary resistance ratio is 4:1.The high
ratio in hepatic bed which translates into a lack of
outflow resistance at the level of sinusoids, is in fact a
protective mechanism considering the fact that the
hepatic endothelium is discontinuous and the wide
pores between endothelial cells would favour the ex-
udation of plasma proteins if the post-capillary sphinc-
ter pressure were to be high.2,3
Another peculiarity of the hepatic macrocirculation is
the interrelationship between hepatic artery and portal
vein blood flow. A decrease in portal venous blood flow
or sinusoidal pressure, reflexly increases the hepatic
arterial flow—thus maintaining adequate perfusion of
Correspondence: Dr. S.K. Sarin, M.D, D.M, Department of Gastroenterology, G.B. Pant Hospital, New Delhi—110002, India.
Email: sksarin@nda.vsnl.net.in
the lobule.This response is possibly mediated by adeno-
sine, which has a vasodilatory action. Conversely an
increase in sinusoidal pressure decreases the hepatic
arterial flow.3 The hepatic arterial flow however, lacks
the potential to cause changes in portal venous flow in
response to physiological or metabolic stimuli.
From a clinical stand point, portal pressure is mea-
sured using hepatic vein catheterisation.4 An end-hole
catheter or a balloon catheter is passed into the hepatic
veins. The catheter is advanced maximally and the vein
occluded so that a sinusoidogram is obtained on injec-
tion of contrast with no reflux of same into the hepatic
vein. The pressure recording at this stage gives the
sinusoidal or the ‘wedged’ hepatic venous pressure
(WHVP). The catheter is then withdrawn into the free
lumen of the hepatic vein and the corresponding pres-
sure reading is called the ‘free’ hepatic venous pressure
(FHVP). The difference between the two values yields
the hepatic venous pressure gradient (HVPG = WHVP
- FHVP).
DEFINITION AND
CLASSIFICATION OF PHT
As already mentioned, the normal portal venous pres-
sure is 5–8 mmHg (or 7–14 cm water). Portal hyper-
tension is defined as a HVPG of greater than 6 mmHg.
Alternatively, a splenic pulp pressure of more than
15 mmHg or a direct portal vein pressure of greater
than 21 mmHg (or 30 cm water) at surgery also consti-
tutes PHT.5 A locial classification of PHT is based on
the site of increased resistance to portal flow (Table 1).
The possible sites are:
• Pre-sinusoidal extrahepatic.
• Presinusoidal intrahepatic.
• Sinusoidal.
• Post-sinusoidal.
A schematic representation of the hepatic vein catheter-
isation findings in these situations is shown in Fig. 2.
As can be seen from Table 1, a particular condition
can contribute to PHT in more than one way and at
Pathophysiology of portal hypertension S483

I (a) min H
V
C HV 1–2

RHV LHV
MHV

S 3

RPV LPV

LGV
MPV
SV PV 5–8

NORMAL

IMV (b)

SMV HV 1–2

Figure 1 Schematic representation of the portal and hepatic

venous system. SMV, superior mesenteric vein; IMV, inferior
mesenteric vein; SV, splenic vein; MPV, RPV, LPV, main, right
and left portal vein; LGV, left gastric vein; IVC, inferior vena
cava; RHV, MHV, LHC, right, middle and left hepatic vein. S 20

more than one site. Apart from the conditions enumer-

ated in Table 1, PHT may rarely result from a commu-
nication between a splanchnic artery to the portal
venous system, for example traumatic arterio venous PV 20
fistula arising from spleric artery or that between
hepatic artery and portal vein.
ALCOHOLIC CIRRHOSIS

(c)
HEMODYNAMICS IN PORTAL
HYPERTENSION HV 1–2

As is evident from Equation 1, portal pressure may

increase in respense to increased resistance to portal
blood flow or an increased flow in this bed (Table 2).

S 20
Increased vascular resistance
As already mentioned, the major site of resistance
within the portal circulation is at the level of sinusoids.

PV 25


Figure 2 Schematic representation of hepatic vein catheter-
isation findings in controls and patients with alcoholic/ NONALCOHOLIC CIRRHOSIS
nonalcoholic cirrhosis. Note the disruption of intersinusoidal
collaterals in B and C. Also in non-alcoholic cirrhosis, there is
a significant intrahepatic presinusoidal component. In this
situation, hepatic venous pressure gradient may underestimate
the actual portal pressure. HV, hepatic vein; PV, portal vein;
S, sinusoid.
S484 D Kapoor and SK Sarin

Table 1 Classification of portal hypertension

SINUSOID
Presinusoidal ET eNOS
Extrahepatic
ETB
Portal vein thrombosis –
Intrahepatic ET IFN-g, LPS, TNF-a
Schistosomiasis cGMP +
Idiopathic PHT LNOS
Congenital hepatic fibrosis
ETA ETB
Sarcoidosis IP3
2+
Felty’s syndrome Ca
DAG
Arsenic poisoning
PKC
Primary biliary cirrhosis
Sinusoidal VSM
Alcoholic cirrhosis Figure 3 Regulation of vascular tone by endothelins and
Non-alcoholic cirrhosis nitric oxide. Endothelin (ET) acts on vascular smooth muscle
Vitamin A intoxication (VSM) ETA receptors to induce smooth muscle contraction
Nodular regenerative hyperplasia (left) and on endothelial cells (ETB) to stimulate endothelial
Postsinusoidal nitric oxide synthase (eNOS) which in turn leads to VSM
Extrahepatic relaxation (right) through its second-messenger -cGMP.
Budd Chiari syndrome Inducible NOS is stimulated by interferon gamma, lipopoly-
Congenital web saccharide and TNF alfa- the stimuli which inhibit eNOS.
Intrahepatic Modified from reference 14 (with permission).
Veno-occlusive disease
Central hyaline sclerosis (alcoholic hepatitis)

PHT, portal hypertension.

lagen in the Space of Disse contribute to increased sinu-
soidal resistance.8,9 More significant however, are the
variable factors which modulate the intrahepatic vascu-
Table 2 Hemodynamic factors in portal hypertension lar resistance.10 Portal flow may be obstructed by com-
pression of simusoids by swollen hepatocytes in
1 Increased resistance to portal blood flow (‘initiator’) alcoholics—even before frank cirrhosis appears.11
Fixed component One of the important reversible factors mediating
Extrahepatic venous obstruction vascular resistance may be endothelin-1 (ET-1).12,13 Two
Intrahepatic fibrosis and ‘capillarization’ of sinusoids types of endothelin receptors have been identified—
Vascular distortion by cirrhotic nodules, ETA and ETB. The primary response mediated by ETA
granulomas etc. is vasoconstriction.14 Binding of endothelins to ETB
Variable component receptors on endothelial cells results in nitric oxide
Hepatocyte swelling
(NO) release and smooth muscle relaxation, while
action on ETB receptors on vascular smooth muscle
Stellate cell response (to endothelins, nitric oxide,
cells causes vasoconstriction. The production and
endotoxins, etc)
actions of endothelins in liver are diagrammatically
Stellate cell activation (alpha-actin levels and
represented in Fig. 3.
contractile state) The liver’s response to chronic injury of any kind is
2 Increased portal blood flow (‘sustainer’) one of scarring and fibrosis and the principal cell type
Nitric oxide synthase system responsible for fibrogenesis is the stellate cell.15 The
Glucagon stellate cells, when activated show high expression of
Prostaglandins alfa actin and assume the shape of myofibroblasts. In
Tumor necrosis factor–alpha response to endothelins, these cells can contract and
Carbon monoxide thus mediate increased resistance to blood flow.16
3 Collateral circulation

Increased portal blood flow and the

Increased resistance to portal venous blood flow con-
stitutes, the ‘backward’ component of PHT. This may
result from a fixed component that is, distortion of vas-
cular anatomy by fibrotic septae separating cirrhotic
nodules6 or by pericellular, perivenular fibrosis.7
Architectural derangements like ‘capillarization’ of
sinusoids (i.e., loss of fenestrae) and appearance of col-
hyperdynamic systemic circulation
Almost a decade ago, it was proposed that peripheral
arterial vasodilation was an important event contri-
buting to the ‘maintenance’ of PHT. The increased
splanchnic flow resulting from this peripheral vasodi-
latation constitutes the ‘forward’ component of PHT.13
This phenomenon is seen in animal models of PHT
Pathophysiology of portal hypertension
too, whether prehepatic PHT induced by portal vein
ligation or chronic hepatocellular injury caused by
carbon tetrachloride. In these animals, there is de-
creased responsiveness of systemic and splanchnic cir-
culation to such vasoconstrictors as norepihephrine and
endothelin.17
The consequences of these changes on the systemic
circulation are: increased total blood volume and
cardiac output and decreased total systemic vascular
resistance with normal to low arterial pressure.18,19 One
of the first vasodilatory mediators studied in PHT was
glucagon. It however, became clear that it accounts for
only about 30% of the splanchnic vasodilation.20
The production of prostacyclin is increased in
experimental PHT and in patients with chronic liver
disease.21 Administration of the cyclo-oxygenase inhi-
bitor indomethacin improves the hyperdynamic circu-
lation of cirrhosis, as well as improving the vascular
hyporesponsiveness of these subjects to vasoconstrictors
like nonrepinephrine. Treatment with indomethacin
leads to a significant decrease in superior mesenteric
artery blood flow in cirrhotics.22
Recently, NO a vasodilatory agent has received great
attention as a peripheral vasodilatory agent in cirrhosis.
The main factors favouring the role of NO are: (i)
reduced vasopressor response to vasoconstrictors in cir-
rhotics is reversed by inhibition of nitric oxide synthase
(NOS) or endothelial denudation23; (ii) high concen-
tration of cyclic guanosine monophosphate (c-GMP),
an intracellular mesenger of NO in aortic tissue from
cirrhotic rats, which is reduced by NOS inhibitors24;
and (iii) normalization of arterial pressure, cardiac
index and total systemic vascular resistance that is, the
LIVER
LPV
RPV
PUV
SG
S be necessary for the development of esophagogastric
CV P varices.32
L These collaterals are infact, a system of resistance
E
E channels in parallel with the portal venous system. The
LRA N collaterals however, are not passive conduits and re-
SMV
IMV
Figure 4 Schematic representation of portosystemic col-
laterals. Arrows reflect the direction of blood flow which is
reversed in the coronary vein (CV) and the inferior mesen-
teric vein (IMV) leading to esophagogastric and anorectal
varices.There is resumption of flow in the obliterated paraum-
bilical vein (PUV) which forms the abdominal ‘caput’. SMV,
superior mesenteric vein, SG, short gastric collaterals; LRA,
lieno-renal adrenal collaterals.
S485
hyperdynamicity of portal hypertension on administra-
tion of NOS inhibitors.25
Two types of NOS exist—the eNOS (endothelial or
constitutive) and the iNOS (inducible). The former is
calcium—dependent and membrane—associated and is
rapidly activated by changes in local blood flow and
circulating hormones. Histochemical staining of liver
shows increased eNOS levels in PHT, but it is not
known with certainity whether the increase is actually
the result of increased splanchnic blood flow and shear
stress seen in PHT.26 The levels of eNOS are decreased
by sepsis, while those of iNOS are increased by lipo-
polyaccharide (LPS), interleukin-1 and tumor necrosis
factor alpha (TNF-a). Indeed, the iNOS levels are high
even at the stage of prescitic cirrhosis and probably
these cytokines are responsible for this.27,28
Increased NO levels in PHT are in part responsible
for the hyporesponsiveness of mesenteric vasculature to
vasoconstrictive stimuli like alpha adrenergic agonists
as methoxamine. This is party mediated by c-GMP as
administration of NOS inhibitors only partially restores
this responsiveness. However, if K+ channel blockers
like tetraethylammonium are co-administered with
NOS inhibitors, this vasoconstrictor responsiveness is
completely restored.29 It has also been recently shown
that agents which increase the entry of extracellular
calcium into arterial smooth muscle cells may de-
crease cirrhosis induced vasodilation and also reduce
the hyperdynamicity of PHT.30 Seumatsu et al. have
recently focused on carbon monoxide (CO) as a regu-
lator of stellate cell contractility and simusoidal blood
flow.31 Carbon monoxide, which is derived from degra-
dation of heme by heme oxygenase, is not as potent
as NO in stimulating c-GMP synthesis and causing
smooth muscle relaxation. Also, CO may inhibit NO
mediated c-GMP production, thus countering the
relaxing effect of NO.
Collateral circulation
Beyond a critical value of portal pressure, an attempt is
made by the body to dissipate further increase in the
same, by formation of portosystemic collaterals. In alco-
holic cirrhosis, and HVPG of ≥ 12 mmHg appears to
spond reflexively and independently to various hemo-
dynamic and pharmacologic stimuli. The resistance to
flow of blood in these channels is governed by the
Poiseuille’ Law:
R = 8 hl pr 4 , [2]
Where R = resistance, h = viscosity of fluid, 1 = length of
the vessel and r = radius of the vessel. As is evident,
slight changes in the diameter of the collateral can
exquisitely alter the resistance to flow in the same and
this fundamental is made use of in managing PHT
pharmacologically.
S486
The collaterals represent the opening of embryonic
channels or redistribution of flow in the existing veins.
The extent to which the collateral formation occurs
in a given patient can not be predicted, but does de-
pend on the severity of portal hypertension and liver
disease.33 The main territories where these channels
develop are schematically represented in Fig. 4.
CONCLUSIONS
In summary, the understanding of pathophysiology of
PHT has evolved over the years from simple concepts
of obstruction to portal venous flow by architectural
changes in liver and vasodilated splanchnic and sys-
temic circulation to a hemodynamic state which can be
fine tuned by neural, cellular and humoral components
which act in an endocrine, paracrine and autocrine
manner. Future therapies would target these cytokine
mediators and vasoactive substances and may pave way
for selective targeting of effector cells/organs because of
the varied hemodynamic response these agents have on
portal, collateral and systemic circulation.
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