Portal Hypertension Pathophysiology Diagnosis and Treatment.pdf

Review
Portal Hypertension: Pathophysiology, Diagnosis, and Treatment
S. Buob, A.N. Johnston, and C.R.L. Webster
Portal hypertension (PH) is the result of increased vascular resistance in the portal circulation, increased portal venous blood
flow, or both. In veterinary medicine, where portal pressure is seldom measured directly, the diagnosis of PH often is inferred
from identification of associated complications including multiple acquired portosystemic shunts, ascites, and hepatic encepha-
lopathy. Likewise, treatment of PH primarily is aimed at controlling these complications. The goal of this review is to provide
an update on the pathophysiology, diagnosis, and treatment of PH. The review draws from information in the veterinary
hepatology literature, reviews, and consensus statements in human hepatology and the literature on experimental models of PH.
Key words: Ascites; Cirrhosis; Hepatic disease; Portosystemic shunts.
Portal hypertension (PH) is caused by increased
resistance, increased blood flow, or both in the por-
tal circulation. The clinical consequences of PH, which
include the development of multiple acquired portosys-
temic shunts (MAPSS), ascites, hepatic encephalopathy
(HE), or some combination of these, cause significant
morbidity and mortality.1–3
Reviews of PH appeared in
the veterinary literature in the 1980s, which the interested
reader is encouraged to consult.4–6
Anatomy and Physiology of Hepatic Blood Flow
The liver receives approximately 25% of the cardiac
output through a dual vascular supply. The portal ve-
nous circulation provides 75–80% of the blood supply
through a low pressure system.6–8
The hepatic artery de-
livers the rest of the blood supply.9
Blood from the portal
vein and hepatic artery enter the hepatic lobule at the
portal triad and mix together in the hepatic sinusoids
(Fig 1). Because sinusoidal endothelial cells (SEC) have
large fenestrae and lack a basement membrane, the sinu-
soids are considered a ‘‘leaky’’ capillary bed. After
passing through the hepatic cords, sinusoidal blood
drains into the hepatic central vein and then out of the
liver through the hepatic veins, eventually reaching the
caudal vena cava for return to the right atrium (Fig 1).
In accordance with Ohm’s law: P (pressure) 5 Q
(blood flow) R (resistance), portal vein pressure (PVP)
is equal to the product of portal blood flow (PBF) and
the resistance to that flow (intrahepatic venous resistance
[IHVR]): PVP 5 PBF IHVR.4,10–13
The PVP can be
measured directly or indirectly. Direct measurement is
obtained by catheterization of the portal vein or one of
its tributaries and insertion of a manometer (cmH2O) or
pressure transducer (mmHg). A considerable body of
data exists on the direct measurement of PVP in dogs and
cats in both the experimental literature and in reports on
surgical attenuation of congenital portosystemic shunts
(CPSS).4,5,14–42
In experimental studies in healthy, anes-
thetized dogs, PVP averages 8.24 0.72 mmHg (multiply
by 1.36 to convert to cmH2O), with a mean of 5.98
1.99 mmHg in clinical reports. In experimental studies in
anesthetized cats, PVP is 8.9 0.35 mmHg with a mean
of 7.38 2.7 mmHg in the literature on portosystemic
shunts. The variability in normal PVP reflects the effects
of different anesthetic protocols as well as lack of stan-
dardization of the baseline zero value, which can be set at
the right atrium, liver hilus, or vena cava.
In humans, indirect measurement of PVP is obtained
by angiographic balloon catherization.43
A balloon-
tipped catheter is inserted into the jugular or femoral
vein and advanced with fluoroscopic guidance into the
hepatic vein where measurement of the free hepatic vein
pressure (FHVP) is taken (Fig 1). This measurement ap-
proximates pressure in the caudal vena cava. The balloon
is inflated to occlude the hepatic vein, and the wedged
hepatic vein pressure (WHVP) is measured. The WHVP
is equivalent to sinusoidal pressure, which approximates
PVP. A slight pressure gradient exists between the sinu-
soids (WHVP) and the caudal vena cava and hepatic vein
From the Department of Clinical Sciences, Tufts Cummings
School of Veterinary Medicine, North Grafton, MA. The literature
review was undertaken at Tufts Cummings School of Veterinary Med-
icine. No primary research was conducted. The summarized data have
not appeared at any meeting.
Corresponding author: Cynthia R.L. Webster, DVM, DACVIM,
Tufts Cummings School of Veterinary Medicine, Department of Clin-
ical Sciences, 200 Westboro Road, North Grafton, MA 01536; e-mail:
cynthia.leveille_webster@tufts.edu.
Submitted August 2, 2010; Revised October 27, 2010; Accepted
January 6, 2011.
Copyright r 2011 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2011.00691.x
Abbreviations:
ADH antidiuretic hormone
CPSS congenital portosystemic shunts
CT contrast-enhanced helical computed tomography
FHVP free hepatic venous pressure
HE hepatic encephalopathy
HVPG hepatic venous portal pressure gradient
IHVR intrahepatic venous resistance
MAPSS multiple acquired portosystemic shunts
NCPH noncirrhotic portal hypertension
NO nitric oxide
NOS nitric oxide synthase
PBF portal blood flow
PH portal hypertension
PHPV primary hypoplasia of the portal vein
PVP portal vein pressure
SEC sinusoidal endothelial cell
WHVP wedged hepatic venous pressure
J Vet Intern Med 2011;25:169–186

(FHVP). This difference (WHVPFHVP), the so-called
hepatic venous pressure gradient (HVPG), provides the
driving force for hepatopedal blood flow.10–13,43
Normal values for HVPG in humans are between 1
and 5 mmHg. Limited data in the dog and cat suggest
that normal HVPG values are similar to those reported
in humans.16,43,44
The normal FHVP and WHVP re-
ported in a series of 11 normal dogs was 1.9 1.0 and 5.6
1.2 mmHg, respectively, resulting in a HVPG of 3.7
1.4 mmHg.16
In a limited number of cats, FHVP and
WHVP were reported as 1.5 0.7 and 6.9 1.7 mmHg,
respectively, with a calculated HVPG of 5.4 mmHg.16
In
humans, increases (412 mmHg) in HVPG directly cor-
relate with the clinical consequences of PH in cirrhotic
patients.10–13,43
In addition, the success of treatment for
PH is defined either by a 420% decrease in HVPG or
reduction to o12 mmHg.10–13,43
Indirect measurement of PVP also can be obtained by
catheterization of the splenic pulp. Normal splenic pulp
values in veterinary patients appear to be 0.5–1.5 mmHg
greater than those obtained by direct measurement.16
As direct or indirect measurement of PVP seldom is
performed in veterinary medicine, the presence of PH
most often is inferred by detection of late-stage clinical
Fig 1. Schematic representation of the anatomic classification of portal hypertension (PH). Portal hypertension can be because of prehepatic,
intrahepatic (presinusoidal, sinusoidal or postsinusoidal) and posthepatic causes. Indirect evaluation of portal venous pressure (PVP) can be
obtained by catheterization of the caudal vena cava and advancement of the catheter into the hepatic veins. This permits measurement of the
free hepatic vein pressure (FHVP), which reflects caudal vena cava pressure. Measurement of the wedged hepatic vein pressure (WHVP) is
accomplished by occluding the hepatic vein by inflation of the catheter balloon. WHVP is a measure of sinusoidal pressure which in the
normal state is slightly lower (about 1 mmHg) than PVP. The hepatic venous pressure gradient (HVPG) is calculated as the difference between
the WHVP and FHVP. This gradient is increased with intrahepatic sinusoidal and postsinusoidal PH, but not with prehepatic and presinu-
soidal intrahepatic PH (where both WHVP and FHVP are usually normal) or with posthepatic PH (where WHVP, FHVP and central venous
pressure, CVP, are elevated).
170 Buob, Johnston, and Webster

consequences (eg, ascites, MAPSS, HE) on physical ex-
amination or imaging studies or by assessment of portal
vein hemodynamics with Doppler ultrasound.45
In the normal liver, PVP is remarkably stable despite
changes in PBF.10–13
A large sinusoidal reserve and
adaptive responses in the intrahepatic vasculature con-
tribute to a compliant vascular bed that can increase its
volume considerably to accommodate additional PBF
without changes in pressure. Increased PBF stimulates
SEC’s to release nitric oxide (NO), which dilates intrahe-
patic vessels to accommodate a larger blood volume.10–13
Several factors cause minor fluctuations in the PVP.
Lower PVP occurs during anesthesia, inspiration,
fasting, and exercise. Transient increases develop
postprandially, during expiration, by increases in intra-
abdominal pressure (such as during barking or defeca-
tion), after blood volume expansion and after the
injection of angiographic agents.4,15,46
Classification of PH
PH is classified based on anatomical location as pre-
hepatic, intrahepatic, or posthepatic (Table 1).4,10–13
Prehepatic PH is because of increased resistance in the
extrahepatic portal vein and is associated with mural
or intraluminal obstruction (eg, congenital atresia or
fibrosis, thrombosis, neoplasia) or extraluminal com-
pression.4,5,8,47–52
Hepatic arteriovenous fistulas cause
prehepatic PH as arterial blood floods the portal venous
system.8,53–55
These fistulas usually are congenital, but
may develop secondary to surgery, trauma, or neoplastic
vascular erosion. Prehepatic PH also may occur as a
complication of CPSS attenuation.7
Intrahepatic PH is because of increased resistance in
the microscopic portal vein tributaries, sinusoids, or
small hepatic veins. Intrahepatic PH is further classified
by histological criteria into presinusoidal, sinusoidal, and
postsinusoidal PH (Table 1, Fig 1). Presinusoidal PH
occurs because of increased resistance in the terminal
intrahepatic portal vein tributaries.48,51,56–63
In humans,
the most common cause is noncirrhotic portal hyperten-
sion (NCPH) (also called hepatoportal sclerosis and
idiopathic portal hypertension).56
Similar clinical syn-
dromes called NCPH, primary hypoplasia of the portal
vein (PHPV), idiopathic hepatic fibrosis, and hepatopor-
tal fibrosis have been reported in dogs.57–64
Fibropolycystic liver disorders, such as congenital he-
patic fibrosis and Caroli’s disease, also can cause
presinusoidal PH in dogs and cats.64–68
These develop-
mental disorders because of the persistence of embryonic
duct structures are referred to as ductal plate malforma-
tions. They lead to varying degrees of bile duct pathology
and portal fibrosis. When the latter is severe, PH can oc-
cur. A rare cause of prehepatic PH occurs in dogs with
trematode infestations (Schistosoma japonicum and
Heterobilharzia americana).8,69
Increased resistance to
flow is because of granulomatous inflammation in the
portal veins triggered by trematode eggs.
Sinusoidal intrahepatic PH most often is the result of
fibrotic hepatopathies.70,71
In these disorders, SEC’s lose
their fenestrae and acquire a collagenous basement mem-
brane (capillarization of the sinusoids) increasing IHVR.
In addition, lobular fibrosis and the presence of regener-
ative nodules contribute to the obliteration and
distortion of the sinusoids further increasing IHVR.
Although not typical, canine nodular hyperplasia, a com-
mon idiopathic lesion in old dogs, also may distort the
sinusoids leading to PH.58,72,73
Postsinudoidal intrahepatic PH is associated with
veno-occlusive disease (also called sinusoidal obstruc-
tion syndrome). Veno-occlusive disease is caused by
damage to the sinusoidal endothelium and hepatocytes
in the centrilobular region, resulting in obliteration of
the small terminal hepatic veins and central veins by fi-
brosis. It has been associated with toxins, graft-versus-
host disease and chemotherapy agents in humans, and
been reported as an idiopathic condition in veterinary
patients.74–78
Table 1. Classification of portal hypertension.
Prehepatic (Portal Vein) Intrahepatic (Liver) Posthepatic (Heart, CVC, Hepatic Veins)
Congenital portal vein
atresia
Intraluminal obstruction
Thrombus
Neoplasia
Stenosis
Extraluminal obstruction
Neoplasia
Lymph node
Granuloma
Abscess
Presinusoidal
Primary hypoplasia portal vein (noncirrhotic portal
hypertension)
Chronic cholangitis
Hepatic arteriovenous fistula
Schistosomiasis
Nodular hyperplasia
Ductal plate abnormalities (Caroli’s disease)
Sinusoidal
Cirrhosis/chronic hepatitis
Chronic cholangiohepatitis
Ductal plate abnormalities (Congenital hepatic
fibrosis)
Lobular dissecting hepatitis
Postsinusoidal
Veno-occlusive disease (Sinusoidal obstruction
syndrome)
Right heart failure
Congestive
Pericardial tamponade
Constrictive pericarditis
Intracardiac neoplasia
Congenital cor triatriatum CVC/hepatic vein
obstruction (Budd-Chiari syndrome)
Intraluminal
Thrombosis
Vena cava syndrome
Neoplasia
Extraluminal
Neoplasia
Kinking of CVC
CVC, caudal vena cava.
171
Portal Hypertension

Posthepatic PH is associated with obstruction of the
larger hepatic veins, the posthepatic caudal vena cava, or
right atrium. Obstruction at the right atrium because of
right heart failure, pericardial disease, or pulmonary
hypertension is a common reason for posthepatic PH in
small animals.79–81
When obstruction occurs in the hepatic
venous outflow in the caudal vena cava or larger extrahe-
patic hepatic veins, it is known as Budd-Chiari syn-
drome.74
Budd-Chiari syndrome most often is because of
intraluminal (tumor, thrombosis, congenital fibrous webs)
or extraluminal (tumor) compression.44,82–89
Classification of the site of PH has clinical relevance
because the level of obstruction often dictates the clinical
presentation (ie, whether MAPSS, ascites, or HE devel-
ops), diagnostic evaluation (increases in liver enzyme
activities, protein content of ascitic fluid, type of diag-
nostic imaging), and treatment (Table 2). The impact of
PH classification on these variables is discussed next.
Pathophysiology of PH
PH secondary to prehepatic or posthepatic obstructive,
stenotic, or constrictive vascular lesions develops primarily
because of increased resistance to flow in the vessels in
accordance with Ohm’s law. The pathophysiologic mech-
anisms controlling the development of intrahepatic
sinusoidal PH are less intuitive and, despite extensive in-
vestigation, not fully understood. An important factor is
mechanical obstruction secondary to architectural changes
in the liver. These changes include fibrosis, capillarization
of the sinusoids, presence of microthrombi in the intrahe-
patic vasculature, and regenerative nodule formation.10–13
In addition to mechanical obstruction, dynamic changes in
sinusoidal tone contribute to increased IHVR (Fig 2).10–12
The SECs normally produce vasoactive substances that
regulate sinusoidal resistance. These include vasodilatory
substances such as NO, carbon monoxide, and prostag-
landin E2, and vasoconstrictors such as endothelin-1,
angiotensin II, leukotrienes, and norepinephrine. In the
diseased liver, overproduction of inflammatory mediators
and the resultant oxidative stress cause SEC dysfunction,
which leads to overproduction and enhanced sensitivity to
vasoconstrictors and underproduction of vasodilators. The
net result is impaired sinusoidal relaxation.
Vascular NO, the most important vasodilator in the
liver, is synthesized in reactions catalyzed by 1 of 2 iso-
forms of nitric oxide synthase (NOS): endothelial NOS,
which stimulates endothelial cell production of NO in re-
sponse to physical stimuli such as shear stress, and
inducible NOS, which is induced by proinflammatory
cytokines.10,11,90
The intrahepatic NO deficiency seen
with PH is due primarily to decreased activation of
endothelial NOS.10–13,90,91
Activation of hepatic stellate cells, which in the un-
stimulated state are quiescent lipid-storing cells
surrounding the sinusoids, also contributes to increased
IHVR. During injury, stellate cells differentiate into con-
tractile, fibrogenic myofibroblasts, which produce large
amounts of extracellular matrix and secrete inflamma-
tory cytokines and vasoconstrictive substances such as
endothelin-1. These vasoconstrictors act in an autocrine
fashion to stimulate stellate cell contraction, which re-
duces the diameter of the sinusoidal space and increases
IHVR.11,12,90
Unlike the vasoconstriction seen in the intrahepatic
vasculature during PH, the splanchnic vasculature un-
dergoes progressive vasodilatation because of an excess
of vasodilatory substances, particularly NO.11,90,91
The
mechanisms responsible for the overproduction of NO
include increased vascular shear stress and intestinal ab-
sorption of lipopolysaccharide. Increased sheer stress
activates endothelial NOS. Increased intestinal absorp-
tion of lipopolysaccharide secondary to the changes in
intestinal permeability that accompany PH stimulates
the release of inflammatory cytokines such as tumor ne-
crosis factor-a from the macrophages, which enhances
the activity of inducible NOS.90–92
Other substances that
contribute to peripheral vasodilatation include hydrogen
sulfide, carbon monoxide, prostaglandins, and endo-
cannabinoids.11,90
The combined action of the all these
vasodilatory compounds mediates progressive and sus-
tained vasodilatation of the splanchnic circulation
leading to higher PBF, which maintains and aggravates
the development of PH (Fig 2).
Recent studies suggest that angiogenesis also contrib-
utes to the establishment and maintenance of PH.11,92
The development of fibrotic septa and capillarization of
the hepatic sinusoids results in relative hepatic hypoxia
stimulating the release of angiogenic factors from hepatic
stellate cells and SEC. These factors, particularly vascu-
lar endothelial growth factor and platelet-derived growth
factor, stimulate angiogenesis fueling higher PBF and
worsening PH.
Consequences of PH
Ascites
Ascites occurs as a consequence of imbalances in Star-
ling’s law so that the forces keeping fluid in the vascular
space are less than the forces moving fluid out of the vas-
cular space.12,13,93,94
In PH, increased PVP drives fluid
into the interstitial space. When the capacity of the re-
gional lymphatics is overwhelmed, ascites develops. The
development of ascites is perpetuated by the splanchnic
vasodilatation that accompanies PH. This vasodilatation
results in pooling of blood in the abdomen, which leads
to a decrease in effective systemic blood volume (Fig 2).
Initially, increased cardiac output is compensatory, es-
tablishing the hyperdynamic circulation of hepatic
disease marked by high cardiac output and low systemic
vascular resistance.90–94
As liver disease progresses,
vasodilators that escape hepatic degradation accumulate
in the systemic circulation and systemic arteriolar vaso-
dilatation worsens (Fig 2). Eventually, inotropic and
chronotropic compensation fails, and systemic hypoten-
sion ensues. This results in activation of the endogenous
vasopressor system, including the renin-angiotensin-
aldosterone system, sympathetic neurons, and the non-
osmotic release of antidiuretic hormone (ADH).
Resultant volume expansion further increases hydrostatic
pressure in the portal vasculature causing increased lymph

Table
2.
Clinical
assessment
of
common
syndromes
associated
with
portal
hypertension.
Classification
Physical
Exam
Laboratory
Values
MAPSS
Liver
Biopsy:
Histopathology
Prehepatic
(PVP-,
FHVP-N,
WHVP-N,
HVPG-N)
PV
atresia
Young
with
ascites,
HE
LE:
N
to
mild

Ascites:
pure
transudate
11
Chronic
hypoperfusion
PV
obstruction
Acute
onset,
abdominal
pain,
ascites

Normal
or
abnormal
with
concurrent
hepatic
disorder
Intrahepatic
Presinusoidal
(PVP-,
FHVP-N,
WHVP-N,
HVPG-N)
Hepatic
arteriovenous
fistula
Young
with
ascites,
HE,
bruit
LE:
N
to
mild

Ascites:
low-protein
transu-
date

Chronic
hypoperfusion
Primary
hypoplasia
of
the
portal
vein/
noncirrhotic
portal
hypertension
Young
adult
with
ascites,
GI
signs,
HE,

icterus
LE:
moderate

Coagulopathy

bilirubin
Ascites:
low-protein
transu-
date

Chronic
hypoperfusion

periportal
fibrosis;
no
inflammation
or
nodular
hyperplasia
Ductal
plate
abnormalities
(Caroli’s
syndrome)
Young
with
ascites,
GI
signs,
PU/PD
LE:
moderate

Ascites:
low-protein
transu-
date

Numerous
irregular
bile
ducts
localized
along
the
edge
of
limiting
plate,
portal
fibrosis,
no
inflammation,
or
regenerative
nodules

renal
cysts
Sinusoidal
(PVP-,
FHVP-N,
WHVP-,
HVPG-)
Inflammatory/fibrotic
Ascites,
HE,
GI
signs,
PU/PD

icterus,
Breed
predilections
LE:
mild
to
marked

serum
bilirubin
Coagulopathy
Ascites:
pure
or
modified
transudate
a
11
Inflammation/necrosis/apoptosis,
fibrosis,

regenerative
nodules
Lobular
dissecting
hepatitis
Young
to
middle
age
dog,
ascites
HE,
GI
signs

icteric
11
Parenchymal
inflammation,
infiltration
of
lobular
reticulin
and
collagen
fibers
Ductal
plate
abnormalities
(congenital
hepatic
fibrosis)
Young
with
ascites,
HE,
GI
signs
1
As
in
Caroli’s
above,
but
extensive
panlobular
fibrosis,
mild
degree
of
portal
vasculature
hypoplasia
and
arteriolar
proliferation

renal
cysts/fibrosis
Postsinusoidal
(PVP-,
FHVP-,
WHVP-,

HVPG-)
Veno-occlusive
disease
(sinusoidal
obstruction
syndrome)
Ascites,
HE,
GI
signs,
LE:
N
toa
mild

Ascites:
high
protein
modified
transudate
11

Centrilobular
fibrosis,
intra/extraluminal
HV
compression,

thrombosis,

dilated
centrilobular
lymphatics/vasculature
Posthepatic
(PVP-,
FHVP-,
WHVP-)
Cardiac
(CVP

,
HVPG-N)
Ascites,
edema,
jugular
distension,
murmur,
arrhythmia
LE:
N
to
mild

Ascites:
high
protein
modified
transudate

Hepatic
congestion,
dilated
centrilobular
lymphatics/vasculature
Budd-Chiari
(CVC
or
HV)
(
HVPG-)
Ascites
11
CrVC,
cranial
vena
cava;
CVC,
caudal
vena
cava;
CVP,
central
venous
pressure;
FHVP,
free
hepatic
venous
pressure;
GI,
gastrointestinal;
HE,
hepatic
encephalopathy;
HV,
hepatic
veins;
HVPG,
hepatic
venous
pressure
gradient;
LE,
liver
enzymes;
N,
normal;
PVP,
portal
venous
pressure;
PU/PD,
polyuria/polydipsia;
WHVP,
wedged
hepatic
venous
pressure;
‘‘11’’,
always
present;
‘‘1’’,
typically
present;
‘‘’’,
variably
present;
‘‘’’,
not
present.
a
Protein
content
of
ascites
because
of
intrahepatic
sinusoidal
PH
is
dependent
on
the
presence
or
absence
of
sinusoidal
capillarization.
173
Portal Hypertension

formation.93,94
Concurrent hypoalbuminemia secondary
to hepatic synthetic failure lowers vascular colloid osmotic
pressure that furthers aggravates ascites formation.94
The
presence of ascites is a negative prognostic factor in dogs
with chronic hepatitis.1
Acquired Portosystemic Shunts
As the HVPG increases above 12 mmHg, MAPSS de-
velop from the opening of embryonic vessels between the
portal vasculature and the cranial and caudal vena cava.
Initially, blood flow through MAPSS may lower PVP,
but parallel increases in PBF because of splanchnic vaso-
dilatation eventually restore PH. In experimental canine
models of PH, MAPPS form over a period of 5–14
weeks.95,96
Although MAPSS form primarily because of
pressure gradients, there also is evidence that angiogenic
factors contribute to their formation and maintenance.92
All forms of PH can be accompanied by MAPSS with the
exception being posthepatic PH in which no pressure
Fig 2. Pathophysiology of intrahepatic sinusoidal portal hypertension and ascites formation in cirrhosis. Increases in the intrahepatic vas-
cular resistance (IHVR) occur because of mechanical (fibrosis in the sinusoids, microthrombi in hepatic veins, and regenerative nodule
formation) and dynamic (failure of sinusoidal relaxation) obstructive processes within the liver. At the same time, the splanchnic circulation
undergoes progressive vasodilatation, leading to increases in portal blood flow (PBF) that further increase portal vein pressure. Systemic
compensation for the splanchnic arterial vasodilation creates a hyperdynamic circulation marked by increased cardiac output (CO) and de-
creased peripheral vascular resistance (PVR). Progressive splanchnic vasodilatation, however, leads to eventual failure of this circulatory
response and development of systemic vasodilatation and hypotension. This decrease in effective circulatory blood volume leads to activation
of the renin-angiotensin-aldosterone-sympathetic system (RAAS) and the nonosmotic release of antidiuretic hormone (ADH). This leads to
avid renal sodium and water retention creating a volume overload and the development of ascites. ATII, angiotensin II; CO, carbon mon-
oxide; ET, endothelin; NE, norepinephrine; NO, nitric oxide.

gradient exists between the portal and systemic circula-
tion (ie, HVPG is normal, Table 2).
Acquired shunts are classified based on anatomic lo-
cation. Portal precaval shunts connect the portal vein
with the caudal vena cava either directly or by way of the
azygous vein, whereas portal postcaval shunts connect
the portal vasculature to the cranial vena cava. In hu-
mans, a common site for precaval MAPSS is between the
portal vein and submucosal esophageal vessels.97
These
shunts, called esophageal varices, are prone to rupture
and bleeding and are an important cause of morbidity in
humans with PH. Esophageal varices form in the dog
and cat, but are rarely of clinical relevance.98–100
Most
MAPSS in small animals are portal postcaval shunts. In
dogs, large velar-omental shunts arise from the splenic
vein, anastomose with embryonic connections to the left
gonadal veins and empty into the left renal vein and ul-
timately the caudal vena cava.4,5,8,100
In dogs, smaller
portal collateral vessels develop and are classified by their
location and drainage patterns as left gastric, gastro-
phrenic, omental, gallbladder, abdominal wall duodenal,
and colic varices.4,5,100
Cats tend to develop shunts be-
tween the left gastric veins and phrenicoabdominal veins
and from the left colic vein to the left gonadal vein.4,5,8
HE
HE is a syndrome of neurocognitive impairment that
clinically is manifested as a range of signs from subtle
behavioral deficits to stupor and coma.101–103
The patho-
genesis is multifactorial, and associated with toxins
derived from the gastrointestinal tract that bypass he-
patic metabolism. Ammonia derived primarily from the
action of colonic bacterial on the breakdown products of
ingested protein is one of the most important toxins.
Ammonia, which normally is transported to the liver via
the portal circulation where it is metabolized in the urea
cycle, directly enters the systemic circulation through
MAPSS. The excess blood ammonia penetrates the
blood brain barrier and causes neuronal dysfunction by
incompletely understood mechanisms. Current evidence
supports a central role of ammonia-induced astrocyte
dysfunction.101–103
Astrocytes, which are the only cells in
the brain that express glutamine synthetase, detoxify
brain ammonia with this enzyme to catalyze the conver-
sion of glutamate to glutamine. The intracytoplasmic
accumulation of osmotically active glutamine results in
low-grade astrocyte swelling and subsequent induction
of signaling pathways that lead to the formation of reac-
tive oxygen species. This results in astrocyte dysfunction
and altered neurotransmission.103
Hyponatremia
The same forces that promote ascites formation can
lead to development of dilutional (hypervolemic) hypo-
natremia.93,104
Nonosmotic release of ADH, in response
to decreased effective blood volume secondary to periph-
eral vasodilatation, acts on water channels in the renal
tubules to promote water retention. This action eventu-
ally leads to a deficit in free water excretion and results in
hyponatremia. In human patients with cirrhosis, the de-
velopment of hyponatremia is a marker of late stage
disease and a negative prognostic indicator.93,104
Hepatorenal Syndrome
Another consequence of the hyperdynamic circulatory
derangements associated with PH is hepatorenal syn-
drome. This syndrome, a form of reversible renal failure,
occurs as a consequence of profound renal vasocon-
striction secondary to the release of angiotensin, norepi-
nephrine, and ADH in response to splanchnic
vasodilatation.105,106
Although hepatorenal syndrome
can be induced in experimental canine models,107,108
it has not been reported clinically in veterinary patients.
In humans, the syndrome is always accompanied
by a state of refractory ascites and end-stage liver
failure.11–13,105,106
Hepatopulmonary Syndrome, Portopulmonary
Syndrome, and Hepatic Hydrothorax
Hepatopulmonary syndrome, portopulmonary hyper-
tension, and hepatic hydrothorax are pulmonary
complications of PH in humans that have not been re-
ported in veterinary medicine.109–112
Hepatopulmonary
syndrome occurs because of microvascular pulmonary
arterial dilatation (most likely because of NO overpro-
duction in the lung) leading to ventilation-perfusion
mismatch.109–111
Portopulmonary hypertension is likely
mediated by humoral substances that enter the systemic
circulation through MAPSS.110,112
Initially, these
substances cause vasoconstriction, but subsequent
thrombosis leads to vessel obliteration. Hepatic hydro-
thorax is the presence of pleural effusion in patients with
hepatobiliary disease. It likely arises because of direct
passage of ascites from the abdomen to the thorax
through undetectable diaphragmatic rents.111
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis is infection of ascitic
fluid without a detectable nidus.113,114
It occurs in 8–30%
of hospitalized cirrhotic human patients with ascites,
with an associated mortality of 20–40% if untreated.113
Many patients are asymptomatic, but clinical signs can
include abdominal pain, fever, and diarrhea. A neutro-
phil count 4250 cells/mm3
in the ascitic fluid is
diagnostic, regardless of whether or not organisms are
visible cytologically. The pathophysiology of spontane-
ous bacterial peritonitis is incompletely understood but 4
key components are involved: (1) the presence of small
intestinal bacterial overgrowth, (2) increased intestinal
permeability, (3) intestinal bacterial translocation, and
(4) immunosuppression. Spontaneous bacterial peritoni-
tis occurs in dogs and cats,115,116
but has not been
reported in the setting of PH.
Hypersplenism
Splenomegaly is a rare finding in PH in dogs and
cats,117
but is common in humans with PH and can lead
175
Portal Hypertension

to hypersplenism.10–13
Hypersplenism is associated with
pooling of blood in the spleen, destruction of blood
cells by the enlarged spleen, or both. The clinical conse-
quence is pancytopenia. This syndrome has not been
described in dogs or cats with PH, perhaps because of
anatomic differences that prevent splenic congestion in
these species.117
Portal Hypertensive Gastropathy
In humans, gastric mucosal lesions associated with
portal hypertensive gastropathy are present in 51–98%
of patients with PH.118
Histologically, this gastropathy is
defined by mucosal and submucosal vascular ectasia in
the absence of inflammation. Similar lesions can be
found in the small and large bowel. Many factors includ-
ing alterations in splanchnic blood flow, humoral factors,
and local dysregulation of vascular tone have been im-
plicated in the pathophysiology. In humans, portal
hypertensive gastropathy increases the risk for acute
and chronic gastrointestinal bleeding.118
Although the characteristic histologic lesion associ-
ated with portal hypertensive gastropathy has not been
reported in veterinary patients, dogs and cats with he-
patic disease are at increased risk for gastrointestinal
ulceration.59,119,120
In humans with PH, impairment of
gastric mucosal defense occurs and is associated with
thrombosis of mesenteric vessels because of circulatory
stasis, alterations in gastrointestinal motility, bacterial
overgrowth because of lack of intestinal bile acids, and
mucosal edema because of increases in gastrointes-
tinal mucosal permeability. Overproduction of vaso-
contrictors such as endothelin-1, increased generation of
free oxygen radicals, or both also have been implicated in
the pathophysiology.
Diagnostic Evaluation of PH
Clinical Pathology
CBC. Microcytosis is seen in dogs with MAPSS. It is
not associated with iron deficiency, but rather with a cur-
rently unknown defect in mobilization of iron
stores.121,122
Mild thrombocytopenia, anemia, or both
maybe seen in some dogs with PH.59,123,124
Serum Liver Enzyme Activity. The magnitude of in-
creases in serum liver enzyme activities is dependent on
the underlying disorder causing PH. Typically, moderate
to marked liver enzyme activity increases are associated
with intrahepatic PH secondary to inflammatory or
fibrotic hepatobiliary disorders. Disorders associated
with posthepatic PH typically result in mild to moderate
increases in serum enzyme activity, particularly the ami-
notransferases, because of hepatic necrosis or ischemia
from congestion. Serum liver enzyme activities usually
are normal or only mildly increased in prehepatic PH.
Liver Function Tests. Abnormal liver function tests
can be used to infer the presence of PH. Blood ammonia
or total serum bile acid concentrations can be increased
in the presence of MAPSS or functional hepatic fail-
ure.125
Based on evidence in the literature on CPSS,
postprandial total serum bile acid concentrations may
be the most sensitive test for detection of MAPSS.126
Blood ammonia concentration, however, is more specific
for MAPSS, reflecting the fact that total serum bile acid
concentrations are more likely to be increased in chole-
static disorders.125,127
Ammonia is the only HE toxin
that can be measured clinically, and documentation of
hyperammonemia suggests the presence of HE (Table 3).
Other clinicopathological indicators of hepatic dysfunc-
tion such as hyperbilirubinemia and decreases in serum
albumin, urea nitrogen, and cholesterol concentrations
may be seen in dogs or cats with intrahepatic sinusoidal
PH (Table 2).
Coagulation Parameters. Because the liver is responsi-
ble for the synthesis, activation, and clearance of both
anti- and procoagulant factors, patients with hepatobili-
ary disease are in a precariously balanced state of
coagulation.128
Spontaneous bleeding or thrombosis is
rare, but when other predisposing factors such as infec-
tion, renal failure, endotoxemia, anesthesia, or drugs (eg,
corticosteroids or nonsteroidal anti-inflammatory drugs)
are present, they can tip the balance in favor of bleeding
or thrombosis.128
In the literature available on the coag-
ulation status of dogs with PH, the presence of prolonged
bleeding times (prothrombin time and activated partial
thromboplastin time) seems to parallel the extent of func-
tional hepatic failure,48,123,124,129
and 2 studies in dogs
have shown a relationship between prolongation of these
parameters and survival.124,129
Other coagulation abnor-
malities that accompany hepatic disorders in dogs
associated with PH are decreased serum concentrations
of fibrinogen, antithrombin, and protein C.123,126
In cats
Table 3. Clinical features of portal hypertension in dogs and cats.
Parameter Change with Portal Hypertension
Measurement of portal vein pressurea
Dog: 411 mmHg
Cat: 412 mmHg
Ultrasound Detection of MAPSS
Decreased velocity of portal vein blood flow
Hepatofugal flow in portal vein
Portal vein/aortic o0.65 in the absence of single CPSS
Detection of complications Ascites: Nonneoplastic, noninflammatory pure or modified transudate
HE: Neurologic signs compatible with diffuse cerebral disease increased blood ammonia
Gastrointestinal bleeding
CPSS, congenital portosystemic shunt; HE, hepatic encephalopathy; MAPSS, multiple acquired portosystemic shunts.
a
Values in anesthetized dogs and cats.

(with their predilection to cholestatic biliary disorders),
the most common coagulation abnormality reported is
vitamin K-dependent prolongation of prothrombin
time.130
Ascitic Fluid. In PH, the ascitic fluid typically is a pure
or modified transudate (Table 3). The protein content of
the fluid often reflects the anatomic location of PH. Prehe-
patic and presinusoidal PH increases intestinal lymph
formation. Because the intestinal lymphatic system has a
large absorptive capacity and tight capillary beds, the asci-
tic fluid has a low protein concentration (
o2.5g/dL).
Posthepatic, postsinusoidal, and sinusoidal intrahepatic
PH increase hepatic lymph formation, resulting in loss of
a high protein fluid (42.5g/dL) through the leaky sinusoi-
dal endothelium. However, because sinusoidal intrahepatic
PH most often is accompanied by capillarization of the
sinusoids and hepatic synthetic failure, the accumulating
fluid typically has a low protein content.
Diagnostic Imaging
Radiography. The presence of ascites can be inferred
on survey abdominal radiographs by loss of abdominal
detail. Radiographic microhepatica or hepatomegaly
may help confirm the presence of a hepatic disorder.
Changes in thoracic radiographs, including cardiome-
galy, prominent pulmonary vasculature, or compression
or dilatation of the caudal vena cava, may indicate a
posthepatic intrathoracic cause of PH.
Ultrasonography. Ultrasound examination of the
abdomen is essential in the diagnostic appraisal of
PH. Several findings can indicate the presence of PH
(Table 2).131–136
First, ultrasonography can demonstrate
the presence of even small amounts of ascites and aid in
the acquisition of a diagnostic sample to determine if its
composition is compatible with PH. Second, ultrasono-
graphy can identify the presence of MAPSS. Typically,
MAPSS appear as a plexus of small, tortuous splenic to
renal vessels in the left dorsal perirenal area.8,117,131,132
Large left splenogonadal shunts can be identified in some
patients.100,117
MAPSS commonly run caudally from the
site of origin and tend to disappear into the intestine. Mul-
tiple shunts can be differentiated from single congenital
shunts by their greater number (42), and smaller size
(o0.4 cm).131
Postprandial increases in PBF may facilitate
detection of MAPSS. Additional ultrasonographic find-
ings suggestive of PH include an enlarged portal vein,
decreased PBF velocity (
o10cm/s) hepatofugal flow, a di-
lated left gonadal vein, and a portal-vein-to-aorta ratio
(PV/Ao) 0.65 (Table 3).100,117,131–135
In humans, ultra-
sonographic findings of increased PBF, decreased PBF
velocity and increased congestive index (cross-sectional
area of the PV/mean PV velocity) have 95% sensitivity
and specificity for the identification of PH.45,136
Ultrasonographic evaluation of the hepatic paren-
chyma and biliary tract may help to anatomically
localize the cause of PH. The liver may appear large and
hypoechoic with congestion because of posthepatic
PH or small with focal or diffuse parenchymal lesions
in chronic hepatic disease leading to intrahepatic PH.
Vascular anomalies such as intrahepatic hepatic arterio-
venous fistulas and thrombosis in the portal vein can be
identified. Evaluation of the biliary tree may show
changes such as biliary tract dilatations, cysts, or miner-
alization that may be consistent with ductal plate
abnormalities. Ultrasonographic evaluation of the heart
and thorax can identify causes of posthepatic PH such as
right heart failure, pericardial effusion, pulmonary hyper-
tension, or intra- or extraluminal obstruction of the
caudal vena cava.
Scintigraphy. Rectal or transplenic scintigraphy can
confirm the presence of portosystemic hepatic by-
pass.137,138
Neither method, however, reliably defines the
location of portosystemic bypass or differentiates between
a single CPSS and MAPSS. Transplenic scintigraphy may
enable visualization of a distinct plexus of multiple anom-
alous vessels in some, but not all patients.132
Angiography. Angiography is most useful for eval-
uating hepatic arteriovenous fistula and obstructive
vascular causes of PH, which typically are pre- or post-
hepatic.45,86,138,139
Contrast-Enhanced Helical Computed Tomography
(CT). Standard protocols for CT developed to evaluate
the portal vasculature for CPSS in dogs, can be applied to
the investigation of the portal vasculature in PH.100,140–142
The use of CT permits the identification of MAPSS, ob-
structive venous lesions, and hepatic arteriovenous fistula
as well as determination of hemodynamic changes such as
hepatofugal blood flow.142
A recent study provided a de-
tailed description of patterns of MAPSS in veterinary
patients with naturally occurring PH.100
Contrast-Enhanced Magnetic Resonance Angiography
(MRA). MRA permits both accurate depiction of por-
tal vascular anatomy and measurement of portal
hemodynamics.143–146
Anatomical image quality is supe-
rior to CT for vascular assessment, but additional studies
are needed to validate the method for use in disorders
associated with PH.
Liver Histopathology
Histopathology is crucial in the evaluation of intra-
hepatic PH because it can differentiate among congeni-
tal, inflammatory, fibrotic, and vascular disorders. In
inflammatory disorders, the distribution and type of in-
filtrating cells can be determined and the extent of both
fibrosis and inflammation evaluated.8,124,147
Ductal plate
abnormalities can be identified by typical patterns of bile
duct proliferation and fibrosis. Diseases associated with
chronic portal hypoperfusion of the liver such as hepatic
arteriovenous fistula, NCPH, or portal vein obstruction,
atresia or stenosis cause a stereotypical histological pat-
tern in the liver that includes loss or diminution of the
portal vasculature, arteriolar hyperplasia and tortuosity,
hypertrophy of parenchymal hepatic arterioles, and he-
patocellular atrophy.8
Biopsy changes with posthepatic
syndromes such as veno-occlusive disease, Budd-Chiari
syndrome, and cardiac failure can be subtle and difficult
to differentiate. Changes occur predominantly in centri-
lobular or perivenular areas and include congestion
within the space of Disse and centrilobular hepatocyte
degeneration. With chronicity, fibrosis may appear in
177
Portal Hypertension

the sinusoids and centrilobular area eventually bridging
between central veins.74
In prehepatic PH, histologic
abnormalities may be absent unless the obstruction is
longstanding in which case some degree of centrilobular
hepatocyte degeneration can occur.
Clinical Differentiation of Pre-, Post-, and
Intrahepatic PH (Table 2)
Prehepatic causes of PH involve portal vein obstruction
and hepatic arteriovenous fistula. Because some causes
such as portal vein atresia and hepatic arteriovenous fistula
are congenital lesions, the typical clinical presentation is a
young animal with ascites and signs of HE.48–53
With por-
tal vein obstruction, animals may present with abdominal
pain and acute onset of ascites. Portal vein thrombosis of-
ten occurs in the presence of predisposing conditions such
as chronic hepatitis, cirrhosis, pancreatitis, peritonitis, ab-
dominal neoplasia, or endogenous or exogenous excess of
corticosteroids.47,148–151
With prehepatic PH, serum liver
enzyme activities typically are normal to mildly increased
unless an underlying hepatopathy is present. Low protein
ascites may be present. The diagnosis is made with ultra-
sound examination, CT, or contrast-enhanced MRA.
Posthepatic causes of PH involve the heart, cranial vena
cava, and hepatic veins. Clinically, jugular venous disten-
sion, increased central venous pressure, cardiac murmur,
high protein ascites, and hepatomegaly may be present.79–
81
Hepatic congestion and subsequent ischemia cause mild
to moderate increases in serum transaminase activities.
Thoracic and abdominal ultrasonography or contrast
angiography is needed for diagnosis.
Reports of presinusoidal intrahepatic PH, although
not confirmed by manometry, have been described in
dogs.48,51,57,59–63
In these reports, the syndrome has been
called NCPH, hepatoportal scleral fibrosis, idiopathic
hepatic fibrosis, and PHPV. The latter term is recom-
mended by the World Small Animal Veterinary
Association liver study group.8
It is unclear, however, if
the lesion in all cases is primary hypoplasia of the intra-
hepatic portal vasculature or a consequence of a primary
congenital or acquired disorder in hepatic perfusion. The
pathogenesis of NCPH/PHPV in veterinary patients is
unknown, but in humans NCPH is a vasculopathy in-
volving the small and medium branches of the portal vein
associated with exposure to toxins absorbed from the
gastrointestinal tract (eg, lipopolysaccharide), autoim-
mune disorders, prothrombotic states, drugs or toxins
(eg, methotrexate, arsenic, vinyl chloride), and hypervit-
aminosis A.59,152
Typically, dogs with NCPH/PHPV are young (
o2
years of age), with ascites, HE, and gastrointestinal signs.
Rottweilers, Cocker Spaniels, and Doberman Pinschers
may be predisposed.51,57–59,62,63
Dogs have moderate to
severe increases in liver enzyme activities, mild to mod-
erate hyperbilirubinemia, increased total serum bile acids
and blood ammonia concentrations, hypoalbuminemia,
and a low protein ascitic fluid. Imaging studies show mi-
crohepatica with MAPSS. It may be impossible to
differentiate this disorder from intrahepatic sinusoidal
PH caused by inflammatory or fibrotic disease on the
basis of clinical presentation, biochemical testing, and
imaging findings. Instead, hepatic biopsy is necessary. In
NCPH/PHPV, the liver has lesions associated with
chronic hypoperfusion with varying degrees of peripor-
tal or centrilobular fibrosis. Noteworthy is the absence of
inflammation and regenerative nodules. Supportive
treatment has resulted in extended long-term survival in
some dogs. Dogs with this syndrome appear to be pre-
disposed to gastric ulceration.48,59,63
Postsinusoidal intrahepatic PH is caused by diseases
affecting the small sublobular hepatic veins and central
veins. It can occur as an idiopathic lesion in young,
primarily large breed, dogs. German Shepherds appear
to be overrepresented in these reports.61,63,78,145
Clini-
cally and biochemically, they can be difficult to
differentiate from dogs with NCPH/PHPV. Histo-
pathologically, the liver has moderate to marked nonin-
flammatory perivenular fibrosis, but not the classic signs
of hypoperfusion seen with NCPH/PHPV. There are re-
ports of extended survival in some of these dogs with
symptomatic management. Whether some affected dogs
represent overlap with NCPH/PHPV requires additional
study.
Sinusoidal PH most often is associated with fibrosis in
the sinusoids and accompanies chronic hepatitis or cir-
rhosis. Several breed-specific hepatopathies marked by
copper- and noncopper-associated chronic hepatitis are
known to progress to cirrhosis with development of
PH.8,70,71
These diseases are seen in the Bedlington
Terrier, West Highland White Terrier, Dalmatian, Do-
berman Pinscher, Cocker Spaniel, and Labrador
Retriever.71
Another inflammatory disorder that culmi-
nates in PH in dogs is lobular dissecting hepatitis, a
disorder reported primarily in young large breed
dogs.153–155
Histologically, it is marked by a mixed in-
flammatory infiltrate in the sinusoids and hepatic
parenchyma with rare involvement of portal areas. The
lobular parenchyma is infiltrated by fine reticulin and
collagen fibers. Regenerative nodules may be present but
are not a prominent feature. The cause is unknown and
response to supportive treatment is poor with most dogs
dying within a few weeks of diagnosis.
Fibropolycystic hepatobiliary disease (ductal plate ab-
normalities) can cause either sinusoidal or presinusoidal
PH. When the ductal plate abnormality is associated
with small bile ducts (eg, congenital hepatic fibrosis),
diffuse fibrosis and sinusoidal PH occur.64,68
Ductal ab-
normalities in larger bile ducts (Caroli’s disease) may be
associated primarily with portal fibrosis and result in
presinusoidal PH.65,156
Histologically, the fibropolycys-
tic diseases are characterized by the presence of
numerous irregular bile duct profiles localized along the
edge of the limiting plate with extensive, portal fibrosis.
Inflammation and regenerative nodules are absent. In
congenital hepatic fibrosis, dogs may have some degree
of hypoplastic portal vasculature on biopsy with mild ar-
teriolar proliferation. Thus, it may be difficult to
differentiate congenital hepatic fibrosis from NCPH/
PHPV, but the latter lacks profound changes in the bile
ducts.64
Dogs with Caroli’s disease typically have imag-
ing abnormalities of the larger bile ducts, including

dilatation and associated calcification, and have many
concurrent renal cysts on ultrasound examination.65,156
PH and ascites formation occurs in cats with posthe-
patic PH (eg, right heart failure, Budd-Chiari syndrome),
intrahepatic disease (eg, HAV, chronic hepatitis, congen-
ital hepatic fibrosis), or prehepatic PH (eg, portal vein
thrombus, postattenuation of CPSS).42,55,68,84,150,157–159
PH, however, is not as common in cats with inflamma-
tory biliary disease.160,161
This may be related to the fact
that feline cholangitis initally is marked by periductual
fibrosis, but only in later stages does fibrosis progress to
the hepatic architectural distortion or perisinusoidal fi-
brosis typically associated with development of PH in
other species.161
Alternatively, cats may succumb to
complications of hepatic failure before an advanced stage
marked by ascites develops.159,162–165
Treatment of PH
Correct Etiologic Factors
Treatment of PH ideally is based on correction of the
underlying disease. This often is possible for PH associ-
ated with right-sided heart failure (after- and preload
reduction), pre- or posthepatic thrombotic or obstructive
vascular lesions (placement of stents,86
surgical embolec-
tomy, use of thrombolytics, and anticoagulants), or HAV
(liver lobectomy, ligation of the nutrient artery, flu-
oroscopically guided glue embolization of the fistula).7,53
Although specific therapies to directly lower PH accom-
panying intrahepatic PH are used in humans, their use has
not been explored in veterinary patients. Thus, treatment
is centered on management of complications and control
of factors that potentiate PH. Potentiating factors that
may exacerbate PH are fluid overload, excessive sodium
intake and increased intra-abdominal pressure. Thus, ju-
dicious use of low sodium fluids, rest, fasting, dietary
sodium restriction, and sedation is indicated.
Manage Complications
Ascites. Mobilization of ascites requires establishment
of natriuresis. Sodium restriction is the initial therapeutic
step. A diet that delivers o0.05 g/100 kcal of sodium is
initiated. Diuretics are added if there is no response to
sodium restriction. The diuretic of choice is the aldoste-
rone antagonist, spironolactone, which acts in the renal
collecting ducts to increase sodium excretion and con-
serve potassium. Spironolactone works slowly to
mobilize fluid, and in humans, a response may take up
to 14 days.94,102,166
The initial dosage is 1–2 mg/kg/d,
which may be increased gradually over 3–5 day cycles.
Low dose furosemide (0.5–1 mg/kg/d) facilitates estab-
lishment of natriuresis. Daily weight and abdominal
girth assessments should be performed and hematocrit
as well as serum creatinine and electrolyte concentrations
monitored. A safe rate of diuresis extrapolated from
human medicine is 0.5% of body weight daily.166
Di-
uretic dosage is tapered to the lowest effective dosage
with maintenance on spironolactone alone. Diuretics
should be discontinued or re-evaluated when hypo-
natremia, hypokalemia, azotemia, or worsening signs of
HE occur.8,166
Abdominal paracentesis may be necessary initially or
intermittently if tense ascites is present. Benefits include
improvements in renal blood flow, splanchnic venous re-
turn, and respirations. Typically, 20–50% of the ascitic
volume may be removed without incident, but circula-
tory collapse or decreased renal function can occur when
removing large fluid volumes.94,166
In humans, treatment
pre- or postparacentesis with human albumin or colloids
IV is used when total volume paracentesis is performed
to prevent alterations in renal function.94,166
Refractory ascites may necessitate greater dietary so-
dium restriction, total volume paracentesis, or the use of
experimental therapies. Intravenous infusion of human or
canine albumin to enhance intravascular colloid concen-
tration may be attempted in acutely decompensating
patients.166
In humans, transjugular intrahepatic porto-
systemic shunts are created.166
This technically
challenging procedure lowers PVP by creating a direct in-
trahepatic pathway between the hepatic and portal veins.
This procedure has not been used in veterinary patients,
but surgical vena cava banding to attenuate MAPSS in
dogs with experimentally induced hepatic failure has been
reported.26
In this study, long-term survival and quality of
life were similar in banded dogs and those treated medi-
cally, and thus the procedure was not recommended.
Hyponatremia. Aquaretics (tolvaptan and lixivaptan)
bind to V2 receptors in the renal collecting ducts and an-
tagonize the action of ADH, effectively blocking
reabsorption of water.104
They are used in humans for the
acute management of hyponatremia in a hospital setting.
They have not been evaluated in veterinary patients.
HE. Modulation of intestinal production and absorp-
tion of toxins is the mainstay of HE treatment.102,167
Enteral administration of nonabsorbable disaccharides
(eg, lactulose and lactitol) acidifies the colonic lumen,
leading to conversion of NH3 to NH4
1
, which is mem-
brane impermeable. Lactulose also provides a cathartic
effect and limits intestinal bacterial ammonia produc-
tion. Adverse effects of treatment include diarrhea,
flatulence, and abdominal cramps. The initial dosage is
0.25–0.5 mL/kg PO q12h–q8h, but the dosage should be
adjusted to achieve 2–3 soft stools per day. Lactulose en-
emas after a warm cleansing enema may be used as an
emergency treatment for patients with severe HE. Lacti-
tol (0.5–0.75 g/kg PO q12h) or lactulose powdera
may
be better tolerated or more easily administered in some
patients.
Antibiotics frequently are used in combination with
lactulose for a synergistic effect in treating HE.168
Anti-
biotics work in the gut to limit urease-producing
bacteria. The antibiotics most commonly used are met-
ronidazole and neomycin.102
Neomycin’s adverse effects
include nephrotoxicity and ototoxicity, whereas metron-
idazole may cause neurotoxicity. In human medicine,
there is a shift toward the use of rifaximin, an oral ri-
famycin-based antibiotic, because of its superior safety
profile.168
The use of rifaximin has not been described in
veterinary medicine, but safety profiles have been com-
pleted in dogs.169
179
Portal Hypertension

Dietary protein restriction decreases colonic ammonia
production, but in order to avoid protein calorie malnu-
trition, it should not be first-line treatment to control HE.
Protein tolerance should first be increased with lactulose
and antibiotic therapy, and protein restriction initiated if
these interventions do not control HE. The protein source
used is crucial. Dairy and soy protein along with higher
amounts of vegetable fiber are best tolerated.170,171
Correction of factors that might precipitate HE such
as metabolic alkalosis, infection, increased protein load
(eg, gastrointestinal bleeding, diet), azotemia, constipa-
tion, and concurrent administration of sedatives or
analgesics should be addressed.
Gastropathy. Gastrointestinal ulceration accompany-
ing hepatobiliary disease can be treated by gastric acid
reduction with H2 receptor antagonists or proton pump
inhibitors and use of gastric mucosal cytoprotective
agents such as sucralfate. Hepatotoxicity because of H2
receptor antagonists occurs as a rare idiosyncratic drug
reaction in humans, but has not been reported in veter-
inary patients.172
Target Vasoactive Regulatory Pathways (Table 4)
Induce Splanchnic Vasoconstriction (Reverse
Splanchnic Vasodilatation)
b Blockers. Oral treatment with nonselective b block-
ers such as propanolol and nadolol is used in humans to
lower PVP on a chronic basis.97
They reduce PVP by way
of both b1 and b2 blockade, which decreases cardiac
output and mediates splanchnic vasoconstriction, respec-
tively. However, 3 experimental studies and 1 clinical
study in dogs have failed to document any reduction in
PVP with propranolol even at doses high enough to elicit
systemic hypotension.173–175
Carvedilol, another nonse-
lective b blocker, also lowers PVP in humans. It is 2–3
times more potent than propranolol as a b-receptor an-
tagonist.176
It also has mild a-1 adrenergic activity, which
decreases IHVR resulting in a further reduction in PVP,
but also may be associated with systemic vasodilatation
and hypotension. Carvedilol has antioxidant activity,
which may benefit patients with inflammatory or fibrotic
disease.176
Its use has not been reported in veterinary pa-
tients with PH.
Somatostatin and Analogues. Somatostatin can de-
crease PVP in humans without leading to systemic
hypotension.97
Somatostatin inhibits the release of
splanchnic vasodilators such as glucagon and has a direct
splanchnic vasoconstrictor effect. Somatostatin analogues
such as octerotide are used parenterally to acutely lower
PVP during active variceal bleeding in humans. Octreotide
has been used in dogs to treat glucagonomas and insulin-
omas, but its use for PH has not been reported.177–178
Vasopressin and Analogues. Vasopressin acting at V1
receptors is a potent splanchnic vasoconstrictor.97
Terli-
pressin, a synthetic ADH analog, often is used alone or in
combination with a somatostatin analogue to acutely
lower PVP in humans with variceal bleeding.97
Adverse
effects include systemic hypertension, arrhythmias, and
myocardial and intestinal ischemia. In 1 experimental
study, vasopressin was able to decrease gastric mucosal
ischemia in dogs with PH.174
Potential applications of
combinations of ADH and somatostatin analogue ther-
apy in veterinary medicine include PH associated with
acute increases in PVP such as might occur after PVT or
as a complication of CPSS ligation.
Induce Sinusoidal Vasodilatation (Decrease IHVR)
Drugs that Increase the Availability of NO. Nitrovaso-
dilators (which increase intrahepatic NO) decrease
Table 4. Potential therapeutic agents to modulate portal hypertension.
Therapeutic Goal Agent Mechanism of Action Clinical Use (Humans) Limitations/Advantages
Splanchnic vasocontriction Propranolol
Nadolol
Carvedilol
Nonselective b-
adrenergic antagonists
Chronic maintenance to
# PVP
Propranolol not effective
in dogs
Carvedilol also an a1
agonist
Octreotide Somatostatin analogue Acute # PVP Parenteral only
Terlipressin Vasopressin analogue Acute # PVP Parenteral only
Sinusoidal vasodilation
(#IHVR)
Isosorbid 5- mononitrate
Isosorbid –dinitrate
Deliver NO to intrahe-
patic vasculature
Use in combination with
b blockers for chronic
maintenance to # PVP
Worsens splanchnic
vasodilation
Symptomatic systemic
hypotension
Lovastatin
Atrovastatin
endothelial NOS Preclinical to # PH
additive effect with
b blockers
Cholesterol lowering
Corrects endothelial cell
dysfunction
Losartan Angiotensin II receptor
antagonist
Preclinical to # PH and
portopulmonary
hypertension
Antifibrotic
Bosentan Nonselective endothelin
receptor antagonist
Portopulmonary hyper-
tension
Antifibrotic
#Splanchnic neovascular-
ization
Sorafenib Tyrosine kinase
inhibitor
Preclinical to # PH and
portopulmonary
hypertension
IHVR, intrahepatic venous resistance; NO, nitric oxide; NOS, nitric oxide synthase; PVP, portal vein pressure; PH, portal hypertension.

IHVR, but often at the expense of potentiating splanchnic
vasodilatation and systemic hypotension.97
Thus, these
compounds are not used as sole treatment for PH. Chronic
oral treatment with isosorbide 5-mononitrate, however, is
frequently used in combination with nonselective b block-
ade as first-line treatment to treat PH in humans.97,179,180
Although pharmacokinetic data are available for the oral
administration of isosorbide 5-mononitrate in dogs, its use
in PH has not been described.171
The statins, best known for their cholesterol lowering
effects, also decrease IHVR without any adverse effects
on systemic hemodynamics.181–183
They work in part by
selectively increasing NO production in the liver through
enhancement of endothelial NOS activity. The use of sta-
tins to control PH has not been investigated in veterinary
patients, although these drugs have been used to lower
cholesterol and treat inflammatory skin disease.184,185
An
important concern with the use of statins is the potential
for inducing idiosyncratic hepatotoxicity. A number of
studies in humans, however, have shown that the safety
profile of statins in patients with liver disease is no differ-
ent than that observed in the general population.186
Renin-Angiotensin System Blockade. Activation of the
renin-angiotensin-aldosterone system system occurs with
PH and contributes to excessive vascular tone in the liver.
ACE inhibitors decrease HVPG in humans, but often
cause systemic hypotension.187
Losartan, an angiotensin
II receptor antagonist, decreases PVP without causing
systemic hypotension.187
Losartan also corrects splanch-
nic and pulmonary vascular endothelial dysfunction by
preventing upregulation of endothelial NOS and
decreasing reactive oxidative stress. Chronic administra-
tion can decrease PVP in some, but not all, studies.187
Losartan also inhibits hepatic stellate cell activation
and can attenuate hepatic fibrosis in experimental rodent
models making it particularly attractive for the
treatment of PH associated with chronic fibrotic hepato-
pathies. Losartan has been used experimentally in dogs,
but not to treat PH.188,189
Blockade of Endothelin-1. Bosentan, an oral endoth-
elin-1 receptor antagonist, decreased PVP in preclinical
studies of PH and is considered a first-line treatment in
managing portopulmonary hypertension.109–111
In addi-
tion, nonselective endothelin-1 antagonists have
antifibrotic effects.190
Inhibition of Angiogenesis. The tyrosine kinase inhibi-
tors such as sorafenib and imatinib block growth factor
pathways crucial to angiogenesis. In experimental mod-
els of PH in rodents, sorafenib decreases splanchnic
neovascularization, markedly attenuates the hyper-
dynamic splanchnic and systemic circulation, and de-
creases in the formation of MAPSS.191,192
The successful
use of imatinib to treat portopulmonary hypertension in
cirrhotic patients also has been reported.193
Although ty-
rosine kinase inhibitors are used in veterinary oncology,
their use in PH has not been described.194
Conclusion
Definitive diagnosis and treatment of PH in dogs and
cats is challenging. Diagnosis often is delayed because it
must be inferred by late-stage clinical signs such as ac-
companying ascites or HE, or by the identification of
MAPSS by imaging techniques. The treatment of veter-
inary patients with PH is primarily directed at controlling
complications such ascites, HE, and gastric ulceration. In
cases, in which these clinical syndromes are refractory to
treatment, pharmacologic intervention to lower PVP
may be indicated. Challenges in veterinary medicine are
to further define the use of imaging techniques to enable
early detection of PH and to conduct clinical trials of
pharmacologic interventions that lower PVP in dogs and
cats in order to assess their effect on survival and quality
of life in patients with PH.
Footnote
a
Kristalose (lactulose), Cumberland Pharmaceuticals Inc, Nash-
ville, TN
Acknowledgment
No grant support or other funding was received for
this project.
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