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Clinical Manifestations of Portal Hypertension


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The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension.
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Hindawi Publishing Corporation
International Journal of Hepatology
Volume 2012, Article ID 203794, 10 pages
Review Article
Clinical Manifestations of Portal Hypertension
Said A. Al-Busafi,1, 2 Julia McNabb-Baltar,2Amanda Farag,3and Nir Hilzenrat4
1Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, 123 Muscat, Oman
2Department of Gastroenterology, Royal Victoria Hospital, McGill University Health Center, Montreal, QC, Canada H3A 1A1
3Department of Medicine, Royal Victoria Hospital, McGill University Health Center, Montreal, QC, Canada H3A 1A1
4Department of Gastroenterology, Jewish General Hospital, McGill University, Montreal, QC, Canada
Correspondence should be addressed to Said A. Al-Busafi,
Received 27 February 2012; Revised 20 July 2012; Accepted 25 July 2012
Academic Editor: Averell Sherker
Copyright © 2012 Said A. Al-Busafi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct
consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal
hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal
hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous
bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary
1. Introduction
Portal hypertension (PH) is a common clinical syndrome
defined as the elevation of hepatic venous pressure gradient
(HVPG) above 5 mm Hg. PH is caused by a combination
of two simultaneous occurring hemodynamic processes: (1)
increased intrahepatic resistance to passage of blood flow
through the liver due to cirrhosis and (2) increased splanch-
nic blood flow secondary to vasodilatation within the
splanchnic vascular bed. PH can be due to many dierent
causes at prehepatic, intrahepatic, and posthepatic sites
(Tabl e 1). Cirrhosis of the liver accounts for approximately
90% of cases of PH in Western countries.
The importance of PH is defined by the frequency and
severity of its complications including variceal bleeding,
spontaneous bacterial peritonitis, and hepatorenal syn-
drome, which represent the leading causes of death and of
liver transplantation in patients with cirrhosis. PH is con-
sidered to be clinically significant when HVPG exceeds 10
to 12 mm Hg, since this is the threshold for the clinical com-
plications of PH to appear [1]. Proper diagnosis and manage-
ment of these complications are vital to improving quality of
life and patients’ survival. This paper will review the multi-
systemic manifestations of PH in cirrhosis.
2. Gastrointestinal Manifestations
2.1. Gastroesophageal (GE) Varices. Approximately 5–15% of
cirrhotics per year develop varices, and it is estimated that the
majority of patients with cirrhosis will develop GE varices
over their lifetime. The presence of GE varices correlates
with the severity of liver disease; while only 40% of child
A patients have varices, they are present in 85% of child C
patients (Tabl e 2)[2].
Collaterals usually exist between the portal venous sys-
tem and the systemic veins. The resistance in the portal ves-
sels is normally lower than in the collateral circulation, and
so blood flows from the systemic bed into the portal bed.
However, when PH develops, the portal pressure is higher
than systemic venous pressure, and this leads to reversal of
flow in these collaterals. In addition, the collateral circulatory
bed also develops through angiogenesis and the development
of new blood vessels in an attempt to decompress the portal
2International Journal of Hepatology
Tab le 1: Causes of portal hypertension (PH).
Prehepatic PH (normal wedged hepatic venous pressure (WHVP)
and free hepatic venous pressure (FHVP) with normal hepatic
venous pressure gradient (HVPG))
Portal vein thrombosis
Splenic vein thrombosis
Congestive splenomegaly (Banti’s syndrome)
Arteriovenous fistula
Hepatic PH (increased WHVP, normal FHVP, and increased
Congenital hepatic fibrosis
Cirrhosis—many causes
Alcoholic hepatitis
Nodular regenerative hyperplasia
Polycystic liver disease
Sinusoidal obstructive syndrome
Budd-Chiari syndrome
Posthepatic PH (increased WHVP and FHVP and normal HVPG)
Inferior vena cava webs, thrombosis
Cardiac causes (restrictive cardiomyopathy, constrictive
pericarditis, and congestive heart failure)
Pulmonary hypertension
circulation [3]. The areas where major collaterals occur
between the portal and systemic venous system are shown in
Tabl e 3. Unfortunately these collaterals are insucient to
decompress the PH, leading to complications including vari-
ceal bleeding.
GE area is the main site of formation of varices [4].
Esophageal varices (EV) form when the HVPG exceeds
10 mm Hg [5]. In the lower 2 to 3 cm of the esophagus, the
varices in the submucosa are very superficial and thus have
thinner wall. In addition, these varices do not communicate
with the periesophageal veins and therefore cannot easily be
decompressed. These are the reasons why EV bleeds only at
this site.
Over the last decade, most practice guidelines recom-
mend to screen known cirrhotics with endoscopy to look for
GE varices. Varices should be suspected in all patients with
stigmata of chronic liver disease such as spider nevi, jaundice,
palmar erythema, splenomegaly, ascites, encephalopathy,
and caput medusae. EV are graded as small (<5 mm) and
large (>5 mm), where 5 mm is roughly the size of an open
biopsy forceps [6].
The rate of progression of small EV to large is 8% per
year [2]. Decompensated cirrhosis (child B or C), presence
of red wale marks (defined as longitudinal dilated venules
resembling whip marks on the variceal surface), and alco-
holic cirrhosis at the time of baseline endoscopy are the main
factors associated with the progression from small to large EV
Tab le 2: Child-Pugh-Turcotte (CPT) Classification of the Severity
of Cirrhosis.
Parameter Points assigned
Ascites None Mild/Moderate Tense
Hepatic encephalopathy None Grade 1-2 Grade 3-4
Bilirubin micromol/L
(mg/dL) <34.2 (<2) 34.2–51.3 (2-3) >51.3 (>3)
Albumin g/L (g/dL) >35 (>3.5) 28–35 (2.8–3.5) <28 (<2.8)
PT (Sec over control) or
<1.7 1.7–2.3 >2.3
CPT classification
Child A: 5-6 points
Child B: 7-9 points
Child C: 10–15 points
[2]. EV bleeding occurs at a yearly rate of 5%–15% [7]. The
predictors of first bleeding include the size of varices, severity
of cirrhosis (Child B or C), variceal pressure (>12 mm Hg),
and the endoscopic presence of red wale marks [7,8].
Although EV bleeding stops spontaneously in up to 40% of
patients, and despite improvements in therapy over the last
decade, the 6 weeks mortality rate is still 20% [9].
Gastroesophageal varices (GOV) are an extension of EV
and are categorized based on Sarin’s classification into 2
types (Figure 1). The most common are Type 1 (GOV1)
varices, which extend along the lesser curvature. Type 2 GOV
(GOV2) are those that extend along the fundus. They are
longer and more tortuous than GOV1. Isolated gastric
varices (IGV) occur in the absence of EV and are also clas-
sified into 2 types. Type 1 (IGV1) are located in the fundus
located in the body, antrum, or around the pylorus. When
IGV1 is present, one must exclude splenic vein thrombosis.
GV are less common than EV and are present in 5%–30%
of patients with PH with a reported incidence of bleeding of
about 25% in 2 years, with a higher bleeding incidence for
fundal varices [10]. Predictors of GV bleeding include the
size of fundal varices (large (>10 mm) >medium (5–10 mm)
>small (<5 mm)), severity of cirrhosis (child class C>B>A),
and endoscopic presence of variceal red spots (defined as
localized reddish mucosal area or spots on the mucosal
surface of a varix) [11].
2.2. Ectopic Varices (EcV). EcV are best defined as large por-
tosystemic venous collaterals occurring anywhere in the
abdomen except for the GE region [12]. They are an unusual
cause of GI bleeding, but account for up to 5% of all vari-
ceal bleeding [13]. Compared to GE varices, EcV are dicult
to locate, occur at distal sites, and when identified, the
choice of therapy is unclear, therefore representing a clinical
challenge [12]. Furthermore, bleeding EcV may be associated
with poor prognosis, with one study quoting mortality
reaching 40% [14]. Dierent areas of EcV are the duodenum,
International Journal of Hepatology 3
Tab le 3: Location and blood vessels of collaterals between the portal and systemic venous circulations.
Location Postal circulation Systemic circulation
Gastroesophageal junction Short gastric and left gastric (coronary) veins Azygos vein
Rectum Superior hemorrhoidal veins Middle and inferior hemorrhoidal veins
Umbilical (caput medusa) Left portal via a recannulated umbilical vein Epigastric venous plexus of the abdominal wall
Retroperitoneum Mesentric veins Intercostal, phrenic, lumbar, and renal veins
Gastroesophageal varices (GOV)
Isolated gastric varices (IGV)
Figure 1: Sarin classification of gastric varices.
jejunum, ileum, colon, rectum, peristomal, biliary tree, gall-
bladder, peritoneum, umbilicus, bare area of the liver, ovary,
vagina, and testis [15,16].
The prevalence of EcV varies in the literature and seems
to be related to the etiology of the PH and the diagnostic
modalities used [17]. In patients with PH due to cirrhosis,
duodenal varices are seen in 40% of patients undergoing
angiography [18]. Results of a survey for EcV conducted over
5 years in Japan identified 57 cases of duodenal varices; they
were located in the duodenal bulb in 3.5%, the descending
part in 82.5%, and the transverse part in 14.0% [15].
In contrast to duodenal varices, it appears that most cases
of varices in other portions of the small bowel and colonic
varices are seen in patients with cirrhosis who have previ-
ously undergone abdominal surgery [12]. Using advanced
endoscopic technologies, particularly capsule endoscopy
and enteroscopy, the prevalence of small bowel varices is
estimated to be approximately 69% in patients with PH [19].
The prevalence of colonic varices and rectal varices has been
found to be 34% to 46% [20,21] and 10% to 40% [22],
respectively, in patients with cirrhosis undergoing colono-
scopy. It is important to dierentiate rectal varices from
hemorrhoids; rectal varices extend more than 4 cm above the
anal verge, are dark blue in color, collapse with digital pres-
sure, and do not prolapse into the proctoscope on examina-
tion, whereas hemorrhoids do not extend proximal to the
dentate line, are purple in color, do not collapse with digital
pressure, and often prolapse into the proctoscope [22,23].
Stomal varices are a particularly common cause of EcV and
can occur in patients with cirrhosis secondary to primary
sclerosing cholangitis (PSC) [12].
In the west, because the prevalence of noncirrhotic PH
is low, most bleeding EcV is usually associated with cirrhotic
PH (6,8). Although EcV can occur at several sites, bleeding
EcV are most commonly found in the duodenum and at sites
of previous bowel surgery including stomas.
In a review of 169 cases of bleeding EcV, 17% occurred
in the duodenum, 17% in the jejunum or ileum, 14% in the
colon, 8% in the rectum, and 9% in the peritoneum. In the
review, 26% bled from stomal varices and a few from infreq-
uent sites such as the ovary and vagina [24].
Portal biliopathy, which includes abnormalities (stricture
and dilatation) of both extra and intrahepatic bile ducts and
varices of the gallbladder, is associated with PH, particularly
extrahepatic portal vein obstruction [25,26]. They are also
seen associated with cirrhosis, non-cirrhotic portal fibrosis,
and congenital hepatic fibrosis [27]. While a majority of these
patients are asymptomatic, some present with a raised alka-
line phosphatase level, abdominal pain, fever, and cholan-
gitis. Choledocholithiasis may develop as a complication
and manifest as obstructive jaundice with or without cholan-
gitis [26]. On cholangiography, bile-duct varices may be
visualized as multiple, smooth, mural-filling defects with
narrowing and irregularity resulting from compression of the
portal vein and collateral vessels. They may mimic PSC or
cholangiocarcinoma (pseudocholangiocarcinoma sign) [28].
2.3. Portal Hypertensive Intestinal Vasculopathies. Mucosal
changes in the stomach in patients with PH include portal
hypertensive gastropathy (PHG) and gastric vascular ectasia.
PHG describes the endoscopicappearance of gastric mucosa
with a characteristic mosaic, or snake-skin-like appearance
with or without red spots. It is a common finding in patients
with PH [29]. The prevalence of PHG parallels the severity of
PH and it is considered mild when only a mosaic-like pattern
is present and severe when superimposed discrete red spots
are also seen. Bleeding (acute or chronic) from these lesions
is relatively uncommon, and rarely severe [30]. Patients with
chronic bleeding usually present with chronic iron deficiency
In gastric vascular ectasia, collection of ectatic vessels
can be seen on endoscopy as red spots without a mosaic-
like pattern [31]. When the aggregates are confined to the
antrum of the stomach, the term gastric antral vascular
ectasia (GAVE) is used, and if aggregates in the antrum are
4International Journal of Hepatology
linear, the term watermelon stomach is used to describe the
lesion. The prevalence of GAVE syndrome in cirrhosis is
low [32] and can be endoscopically dicult to dierentiate
from severe PHG. Therefore, gastric biopsy may be required
to dierentiate them as histologically GAVE lesions are
completely distinct from PHG (Tab l e 4)[33].
Small bowel might also show mucosal changes related to
PH, which is called portal hypertensive enteropathy (PHE).
The diagnosis of PHE has been limited in the past due to the
dicult access to the small bowel. With advanced endoscopic
techniques such as capsule endoscopy and enteroscopy, PHE
is now thought to be a frequent finding in patients with cir-
rhosis, perhaps as common as PHG, and may cause occult GI
blood loss [34,35].
Portal hypertensive colopathy (PHC) refers to mucosal
edema, erythema, granularity, friability, and vascular lesions
of the colon in PH. PHC may be confused with colitis [36,
37]. Although they are found in up to 70% of patients with
PH and are more common in patients with EV and PHG,
they rarely cause bleeding [38,39].
2.4. Ascites and Spontaneous Bacterial Peritonitis (SBP).
Ascites is defined as the accumulation of free fluid in the
peritoneal cavity. Cirrhotic PH is the most common cause of
ascites, which accounts for approximately 75% patients with
ascites. About 60% of patients with cirrhosis develop ascites
during 10 years of observation [40]. The development of
ascites is an important event in cirrhosis as the mortality is
approximately 50% at 2 years without a liver transplantation
[41]. The formation of ascites in cirrhosis is due to a com-
bination of abnormalities in both renal function and portal
and splanchnic circulation. The main pathogenic factor is
sodium retention [42].
The main clinical symptom of patients with ascites is an
increase in abdominal girth, often accompanied by lower-
limb edema. In some cases, the accumulation of fluid is
so severe that respiratory function and physical activity is
impaired. In most cases, ascites develop insidiously over the
course of several weeks. Patients must have approximately
1500 mL of fluid for ascites to be detected reliably by
physical examination. Dyspnea in these patients can occur
as a consequence of increasing abdominal distension and/or
accompanying pleural eusions. Increased intra-abdominal
pressure might favour the development of abdominal hernias
(mainly umbilical) in patients with cirrhosis and longstand-
ing ascites [43].
The current classification of ascites, as defined by the
International Ascites Club, divides patients in three groups
(Tabl e 5)[44]. Patients with refractory ascites are those that
do not respond to sodium restriction and high doses of diur-
etics or develop diuretic-induced side eects that preclude
their use.
Ascites may not be clinically detectable when present
in small volumes. In larger volumes, the classic findings of
ascites are adistended abdomen with a fluid thrill or shifting
dullness. Ascites must be dierentiated from abdominal
distension due to other causes such as obesity, pregnancy,
gaseous distension of bowel, bladder distension, cysts, and
Tab le 4: Comparison of portal hypertensive gastropathy (PHG)
and gastric antral vascular ectasia (GAVE).
Relation with PH Causal Coincidental
Distribution in stomach Mainly proximal Mainly distal
Mosaic pattern Present Absent
Red color signs Present Present
Thrombi +++
Spindle cell proliferation +++
Fibrohyalinosis +++
Antrectomy and
Billroth I
Liver transplantation
PH: portal hypertension, TIPS: transjugular intrahepatic portosystemic
Tab le 5: International ascites club grading system for ascites.
Grade of ascites Definition
Grade 1 ascites Mild ascites only detectable by ultrasound
Grade 2 ascites Moderate ascites evident by moderate
symmetrical distension of abdomen
Grade 3 ascites Large or gross ascites with marked abdominal
tumours. Ultrasonography is used to confirm the presence
of minimal ascites and guide diagnostic paracentesis.
Successful treatment depends on an accurate diagnosis of
the cause of ascites. Paracentesis with analysis of ascitic fluid
is the most rapid and cost-eective method of diagnosis.
It should be done in patients with ascites of recent onset,
cirrhotic patients with ascites admitted to hospital, or those
with clinical deterioration. The most important analyses are
cell count, fluid culture, and calculation of the serum: ascites
albumin gradient (SAAG), which reflects dierences in
oncotic pressures and correlates with portal venous pressure.
It SAAG is greater or equal to 1.1g/dL (or 11 g/L), ascites is
ascribed to PH with approximately 97% accuracy [45].
Patients with cirrhosis and ascites are also at risk of de-
veloping infections, particularly spontaneous bacterial peri-
tonitis (SBP). SBP occurs in approximately 10% of hospital-
ized cirrhotic patients [46], with an associated mortality of
20–40% if untreated [47]. Many patients are asymptomatic,
but clinical signs can include abdominal pain, fever, and diar-
rhea. The diagnosis of SBP is based on neutrophil count
>250 cells/mm3in the ascitic fluid.
3. Renal Manifestations
3.1. Hepatorenal Syndrome. Hepatorenal syndrome (HRS)
is a common complication seen in patients with advanced
cirrhosis and PH [48]. HRS can also be seen in other types
International Journal of Hepatology 5
Tab le 6: Revised diagnostic criteria of Hepatorenal syndrome.
(i) Chronic or acute liver disease with advanced liver failure
and portal hypertension
(ii) Plasma creatinine concentration >1.5 mg/dL
(133 micromol/L)
(iii) The absence of other apparent cause: shock, ongoing
bacterial infection, volume depletion, current or recent use
of nephrotoxic drugs
(iv) Lack of improvement in renal function after volume
expansion with intravenous albumin (1 g/kg of body weight
per day up to 100 g/day) for at least two days and
withdrawal of diuretics
(v) Absence of parenchymal kidney disease as indicated by
proteinuria >500 mg/day, microhematuria (>50 red blood
cells per high power field) or ultrasonographic evidence of
obstructive uropathy or renal parenchymal disease
of severe chronic liver disease, alcoholic hepatitis, or in acute
liver failure. This syndrome generally predicts poor progno-
sis [48]. HRS has been defined in the literature as a reversible
functional renal impairment in the absence of other causes of
renal failure, tubular dysfunction, proteinuria, or morpho-
logical alterations in histological studies. Precise and accurate
diagnostic criteria have been established in order to clearly
define this syndrome (Tabl e 6)[49]. The diagnosis remains
one of exclusion.
The reported incidence of HRS is approximately 10%
among hospitalized patients with cirrhosis and ascites. The
probability of occurrence of HRS in patients with cirrhosis
is around 20% after 1 year and 40% after 5 years [50]. The
pathogenesis of HRS is not completely understood, but is
likely the result of an extreme underfilling of the peripheral
arterial circulation secondary to arterial vasodilatation in the
splanchnic circulation [51]. In addition, recent data indicates
that a reduction in cardiac output also plays a significant role
HRS-associated renal failure is seen in late stages of
cirrhosis and is marked by severe oliguria, increased sodium
and water retention, volume overload, hyperkalemia, and
spontaneous dilutional hyponatremia. There are two main
subtypes of HRS described [49]. Type 1 HRS is a rapidly
progressive renal failure that is defined by doubling of serum
creatinine >2.5 mg/dL (>221 μmoL/L) or a decrease of 50%
in creatinine clearance (<20 mL/min) in less than 2 weeks.
This form of HRS is usually precipitated by gastrointestinal
bleeds, large volume paracenthesis, acute alcoholic hepatitis
and SBP [53]. In addition to renal failure, patients with type
1 HRS present deterioration in the function of other organs,
including the heart, brain, liver, and adrenal glands. The
median survival of these patients without treatment is <2
weeks, and almost all of them die within 10 weeks after onset
of HRS. Type 2 HRS is a moderate and stable renal failure
with a serum creatinine of >1.5 mg/dL (>133 μmoL/L) that
remains stable over a longer period and is characterized by
diuretics resistant ascites [49,54].
4. Neurological Manifestations
4.1. Hepatic Encephalopathy. Hepatic encephalopathy (HE)
is defined as neurologic and psychiatric dysfunction in a
patient with chronic liver disease. The exact mechanism
leading to this dysfunction is still poorly understood, but
multiple factors appear to play a role in its genesis. The liver
normally metabolizes ammonia, produced by enteric bac-
teria [56] and enterocytes [57,58]. In a patient with PH,
ammonia bypasses the liver through portosystemic shunt
and reaches the astrocytes in the brain. Within the astrocyte,
ammonia is metabolized into glutamine, which acts as an
osmole to attract water, thus causing cerebral edema. In addi-
tion, direct ammonia toxicity triggers nitrosative and oxida-
tive stress, which lead to astrocyte mitochondrial dysfunction
[59,60]. Another important factor is the enhancement of
gamma-aminobutyric acid (GABA-A) receptors through
neuroinhibitory steroids (i.e., allopregnanolone) [61]and
benzodiazepine. Benzodiazepine also contributes to astro-
cyte swelling through a specific receptor [62]. Finally, tryp-
tophane byproducts indole and oxindole [63], manganese
[64], inflammation, hyponatremia [65], and reduced acetyl-
choline through acetylcholinesterase activity [66] also con-
tribute to cerebral dysfunction.
The clinical manifestations of HE can be subtle. Minimal
hepatic encephalopathy (grade 0) (Tabl e 7)canpresentwith
impaired driving ability [67], minimally impaired psycho-
metric tests, decreased global functioning, and increased risk
of falls [68]. In overt hepatic encephalopathy, diurnal sleep
pattern changes will often precede neurologic symptoms. To
add to the complexity, HE can be intermittent or persistent.
The severity of presentation is usually classified using the
West Haven criteria (Tab l e 7). Grade 1 hepatic encephalopa-
thy represents lack of awareness, anxiety or euphoria, and
short attention span. Change of personality, lethargy, and
inappropriate behavior can be seen in grade 2 encephalopa-
thy. More advanced features include disorientation, stupor,
confusion (grade 3), and can even reach coma (grade 4).
Focal neurologic symptoms, including hemiplegia, may also
be observed [69]. Physical examination may be normal, but
typical signs include bradykinesia, asterixis, hyperactive deep
tendon reflexes and even decerebrate posturing [55].
5. Pulmonary Manifestations
5.1. Hepatopulmonary Syndrome. Hepatopulmonary syn-
drome (HPS) is a triad of liver disease, pulmonary vascular
ectasia and impaired oxygenation. HPS is defined in the
literature as a widened alveolar-arterial oxygen dierence
(A-a gradient) in room air (>15 mm Hg or >20 mm Hg in
patients >64 years of age) with or without hypoxemia due to
intrapulmonary vasodilatation in the presence of hepatic
dysfunction [70,71]. This syndrome occurs mostly in those
with PH (with or without cirrhosis) and indicates poor
prognosis and higher mortality. Estimates of the prevalence
of HPS among patients with chronic liver disease range
from 4 to 47%, depending upon the diagnostic criteria and
methods used [7173].
6International Journal of Hepatology
Tab le 7: West Haven Criteria of Severity of Hepatic Encephalopathy
(Adapted with permission [55]).
Grade 1
Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impaired performance of addition
Grade 2
Lethargy or apathy
Minimal disorientation for time and place
Subtle personality change
Inappropriate behavior
Impaired performance of subtraction
Grade 3
Somnolence to semistupor, but responsive to
verbal stimuli
Gross disorientation
Grade 4 Coma (unresponsive to verbal or noxious stimuli)
HPS results in hypoxemia through pulmonary microvas-
cular vasodilatation and intrapulmonary arteriovenous
shunting resulting in ventilation-perfusion mismatch [74],
and can occur even with mild liver disease [75]. Clinically,
patients with HPS complain of progressive dyspnea on exer-
tion, at rest, or both. Severe hypoxemia (PaO2<60 mm Hg)
is often seen and strongly suggests HPS [70,71]. A classical
finding in HPS is orthodeoxia defined as a decreased arterial
oxygen tension by more than 4mm Hg or arterial oxyhe-
moglobin desaturation by more than 5% with changing
position from supine to standing. It is associated with
platypnea defined as dyspnea worsened by upright position
[70,71]. Platypnea-orthodeoxia is caused by the worsening
of diusion-perfusion matching and increased shunting at
the lung bases in the upright position. There are no hall-
mark signs on physical exam; however, cyanosis, clubbing,
and cutaneous telangiectasia (spider nevi) are commonly
noted. Furthermore, systemic arterioembolisation may cause
stroke, cerebral hemorrhage, or brain abscess, and can
present with neurological deficits.
5.2. Portopulmonary Hypertension. Portopulmonary hy per-
tension (PPH), a well-recognized complication of chronic
liver disease, refers to pulmonary arterial hypertension
(PAH) associated with PH when no alternative causes
exist. It is defined by the presence of elevated pulmonary
arterial pressure (mean pressure >25 mm Hg at rest and
30 mm Hg on exertion) elevated pulmonary vascular resis-
tance (>240 dyne s1cm5)inthepresenceofapulmonary
capillary wedge pressure <15 mm Hg [76].
The prevalence of PPH depends on the patient popula-
tion studies and severity of the liver disease, 0.7–2% and 3.5–
16.1% in cirrhotics and patients undergoing liver transplan-
tation, respectively. The development of PPH is independent
of the cause of PH, and it is often seen in cirrhosis. It is
however, also described in those with PH due to nonhepatic
pathologies such as portal venous thrombosis [71,77]. PH
seems to be the driving force of PAH. The pathogenesis of
PPH is not completely understood; however, several theories
have been oered. The most widely accepted theory is that
a humoral vasoactive substances (e.g., serotonin, endothelin-
1, interleukin-1, thromboxane B2, and secretin), normally
metabolized by the liver, is able to reach the pulmonary
circulation via portosystemic shunts, resulting in PPH [71,
Clinically, most patients with PPH present with evidence
of both PAH and PH. Typically manifestations of PH precede
those of PAH. The most common presenting symptom is
progressive dyspnea on exertion [80] and less frequently
fatigue, palpitations, syncope, hemoptysis, orthopnea, and
chest pain. On physical exam, classical features include
edema, an accentuated P2 and a systolic murmur, indicating
tricuspid regurgitation [71,77,80]. In severe cases, signs and
symptoms of right-heart failure can be noted.
5.3. Hepatic Hydrothorax. Hepatic hydrothorax is an uncom-
mon complication of end-stage liver disease. It is defined
as a pleural eusion greater than 500 mL in patients with
cirrhosis in absence of primary cardiac, pulmonary, or
pleural disease [81]. The underlying pathogenesis of hepatic
hydrothorax is incompletely understood. Patients with cir-
rhosis and PH have abnormal extracellular fluid volume
regulation resulting in passage of ascites from the peritoneal
space to the pleural cavity via diaphragmatic defects generally
in the tendinous portion of the diaphragm [82]. Negative
intrathoracic pressure during inspiration pulls the fluid
from the intra-abdominal cavity into the pleural cavity.
Hydrothorax develops when the pleural absorptive capacity
is surpassed, leading to accumulation of fluid in the pleural
space. Multiple studies have shown the passage of fluid from
the intra-abdominal space to the pleural space via 99mTc-
human albumin or 99mTc-sulphur colloid [81].
Clinical manifestations of hepatic hydrothorax include
shortness of breath, cough, hypoxemia, and chest discomfort
[81]. Ascites may not always be present. Hepatic hydrothorax
should always be suspected in patients with cirrhosis or PH
and undiagnosed pleural eusion, regardless of the presence
of ascites. Serious complications include acute tension
hydrothorax with dyspnoea and hypotension [83] and spon-
taneous bacterial empyema [84].
6. Other Organs Manifestations
6.1. Cirrhotic Cardiomyopathy. Cirrhotic cardiomyopathy is
defined as a chronic cardiac dysfunction in patients with
cirrhosis. It occurs in up to 50% of patients with advanced
cirrhosis. It is characterized by impaired contractile response
and/or altered diastolic relaxation in the absence of other
cardiac diseases. The pathophysiology of this condition is
complex, and seemingly related to PH and cirrhosis. In
advanced liver disease, splanchnic vasodilatation leads to a
resting hyperdynamic state [85]. Plasma volume expands,
leading to a relative central volume decrease [86]. In
cirrhosis, the arterial vessel wall thickness and tone decreases,
leading to reduced arterial compliance [87,88]. Autonomic
dysfunction may also contribute to blunted cardiac response
[89]. Ultimately, these factors lead to systolic and diastolic
International Journal of Hepatology 7
Symptoms associated with cirrhotic cardiomyopathy
include dyspnea with exertion, impaired exercise capacity,
paroxysmal nocturnal dyspnea, peripheral edema, and
orthopnea. Less-frequent presentations include long QT on
electrocardiography, arrhythmia, and sudden death [90].
6.2. Hepatic Osteodystrophy. Hepatic osteodystrophy is
defined as bone disease (osteomalacia, osteoporosis, and
osteopenia) associated with liver disease. Osteomalacia and
osteoporosis are frequently seen in cirrhotic patients and can
predispose to pathologic fractures. The pathophysiology of
osteoporosis in liver disease is relatively complex. The leading
hypothesis suggests that it is related to the uncoupling
of osteoblastic and osteoclastic activity. Osteoclastogenic
proinflammatory cytokines (interleukin 1(Il-1) and tumor
necrosis factor α(TNFα)) are increased in hepatic fibrosis.
Moreover, TNFαis increased in a rat model of PH [91].
Decreased osteoblastic activity has also been linked with
insulin-like growth factor 1 in a rat model (IGF-1). Increas-
ing IGF-1 levels are associated with liver disease severity [92].
Finally, vitamin K mediates the carboxylation of glutamyl
residues on osteocalcin, stimulating osteoclastic activity [93].
Patients with osteoporosis are usually asymptomatic.
They may present with pain following a nontraumatic
fracture of the axial skeleton or bone deformity, including
pronounced cervical kyphosis. Osteomalacia presentation is
similar and includes proximal muscle weakness [94].
6.3. Hypersplenism. Hypersplenism is a common complica-
tion of massive congestive splenomegaly in patients with cir-
rhosis and PH. In this condition, splenomegaly is associated
with thrombocytopenia, leucopenia, or anemia or a com-
bination of any the three [95,96]. Severe hypersplenism is
present in about 1/3 of patients with cirrhosis being assessed
for liver transplantation. Most patients have no symptoms
related to hypersplenism, however severe thrombocytopenia
may increase the risk of bleeding, especially after invasive
7. Conclusion
Portal hypertension secondary to cirrhosis has multisystem
eects and complications. Once a patient develops such
complications, they are considered to have decompensated
disease with the high morbidity and mortality. The quality of
life and survival of patients with cirrhosis can be improved
by the prevention and treatment of these complications.
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... Cirrhosis accounts for approximately 90% of portal hypertension cases in the Western world [1,2]. The estimated prevalence of cirrhosis in the USA is 0.27% (greater than 600,000) adults, and there is a preponderance of cirrhosis among patients living below the poverty level and those who have not finished the 12th grade [3]. ...
... Liver cirrhosis, by far the prevailing cause of portal hypertension in the Western world, manifests with fibrosis that obstructs portal venous outflow through the hepatic sinusoids. This and other less common causes of portal hypertension are depicted in Fig. 1 [1,[7][8][9][10][11][12]. Increased inflow into the portal venous system is a distinct pathologic mechanism which occurs as a secondary effect in cirrhotic patients with preexisting portal hypertension. ...
... The altered fluid dynamics in portal hypertension are the direct cause of clinical syndromes such as portal hypertensive gastropathy and ascites and are a contributing cause to others including cardiomyopathy, hepatopulmonary syndrome, and hepatic encephalopathy [1]. Among the direct manifestations of portal hypertension, acute variceal bleeding and type 1 hepatorenal syndrome are two disease processes which manifest acutely and are associated with high short-term mortality. ...
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Portal hypertension represents a dysfunctional hemodynamic alteration within the portal venous system, usually due to cirrhosis. These altered hemodynamics play a direct role in the development of acute, life-threatening variceal hemorrhage and mark an important pathophysiologic step in the development of other sudden and life-threatening complications such as type 1 hepatorenal syndrome and spontaneous bacterial peritonitis. Many life-saving interventions in these patients are aimed at reducing portal venous pressure. The contribution of portal hypertension to the development of variceal hemorrhage, type 1 hepatorenal syndrome (known also by the name HRS-AKI), and spontaneous bacterial peritonitis in cirrhotic patients is discussed. This article reviews the pathophysiology and incidence of life-threatening complications of cirrhotic portal hypertension, with a discussion of management options and treatment costs.
... The presence of atrial brillation was determined from review of the EMR. Evidence of portal hypertension was assessed by the presence of splenomegaly, ascites, variceal bleeding, or encephalopathy (20). ...
... Initial treatment of high-output heart failure secondary to liver AVMs is supportive and includes diuretics, salt and uid restriction, beta-blockers and maintaining adequate hemoglobin levels (1,20). Bevacizumab, an anti-angiogenic agent, has been successfully used to reduce shunting and mitigate symptoms of high-output heart failure, but may expose patients to adverse events including hypertension and arterial thromboembolism (30). ...
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Background Hepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms. Results 176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared. In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372-4.754) and 0.489 (95% CI 0.299-0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816–0.996), sensitivity 80.0% (95% CI 55.7-93.4%), and specificity 75.0% (95% CI 52.9-89.4%). Conclusions CTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.
... We also used a threshold hemoglobin level of 7 g/dl to exclude patients because anemia related heart failure has been proposed to occur below this level [21].The presence of atrial fibrillation was determined from review of the EMR. Evidence of portal hypertension was assessed by the presence of splenomegaly, ascites, variceal bleeding, or encephalopathy [22]. ...
... Initial treatment of high-output heart failure secondary to liver AVMs is supportive and includes diuretics, salt and fluid restriction, beta-blockers and maintaining adequate hemoglobin levels [1,22]. Bevacizumab, an antiangiogenic agent, has been successfully used to reduce shunting and mitigate symptoms of high-output heart failure, but may expose patients to adverse events including hypertension and arterial thromboembolism [33]. ...
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Background Hepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms. Results 176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared. In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372–4.754) and 0.489 (95% CI 0.299–0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816–0.996), sensitivity 80.0% (95% CI 55.7–93.4%), and specificity 75.0% (95% CI 52.9–89.4%). Conclusions CTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.
... As the portal pressure overrides a certain threshold, it leads to the development of varices [2]. Hepatic venous pressure gradient (HVPG) is the gold standard method accepted for estimating the severity of portal hypertension [3]. In spite of the advantages of HVPG as safety, and feasibility of the technique, it is invasive and also minor complications (<1% of patients) have been identified including local pain, transient cardiac arrhythmias, and vagal reaction [4]. ...
... Patients with NASH are at increased risk of progressive fibrosis with end-stage liver disease characterized by reduced hepatic synthetic function, portal hypertension, encephalopathy, and malignancy such as hepatocellular carcinoma. Portal hypertension can lead to variceal bleeding, splenomegaly, ascites, and renal injury [5]. Prevalence of NASH in the United States has been increasing in recent years in parallel with rising levels of obesity and metabolic syndrome [6]. ...
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Non-alcoholic steatohepatitis (NASH) is a fatty liver disease characterized by accumulation of fat in hepatocytes with concurrent inflammation and is associated with morbidity, cirrhosis and liver failure. After extraction of a liver core biopsy, tissue sections are stained with hematoxylin and eosin (H&E) to grade NASH activity, and stained with trichrome to stage fibrosis. Methods to computationally transform one stain into another on digital whole slide images (WSI) can lessen the need for additional physical staining besides H&E, reducing personnel, equipment, and time costs. Generative adversarial networks (GAN) have shown promise for virtual staining of tissue. We conducted a large-scale validation study of the viability of GANs for H&E to trichrome conversion on WSI ( n = 574). Pathologists were largely unable to distinguish real images from virtual/synthetic images given a set of twelve Turing Tests. We report high correlation between staging of real and virtual stains ( $${\rho} = 0.86$$ ρ = 0.86 ; 95% CI: 0.84–0.88). Stages assigned to both virtual and real stains correlated similarly with a number of clinical biomarkers and progression to End Stage Liver Disease (Hazard Ratio HR = 2.06, 95% CI: 1.36–3.12, p < 0.001 for real stains; HR = 2.02, 95% CI: 1.40–2.92, p < 0.001 for virtual stains). Our results demonstrate that virtual trichrome technologies may offer a software solution that can be employed in the clinical setting as a diagnostic decision aid.
Background and study aims: Portal hypertensive gastropathy (PHG) is an important complication of portal hypertension (PHT) in cirrhotic patients. We aimed in the current study to investigate the validity of serum serotonin as a probable non-invasive marker for PHG in cirrhotic patients with PHT. We conducted this study on 100 HCV-related cirrhotic patients divided into three groups according to their endoscopic findings; group I: patients with no endoscopic signs of PHG; group II: patients with mild PHG; and group III: patients with severe PHG. All subjects had routine laboratory investigations, serum serotonin level using ELISA kits, calculation of Child's score, abdominal ultrasound, and upper GIT endoscopy. Results: Serum serotonin was significantly higher in those with PHG than those without (t= 5.128, p <0.001). Moreover, it was significantly higher in patients with severe degree of PHG than those with mild PHG (t=7.357, p<0.001). Furthermore, a significant positive correlation was observed between serum serotonin and Child Pugh score (t=7.357, p<0.001). Roc curve analysis revealed that serum serotonin at a level ? 26.5 ng/ml had a 78.82% sensitivity, 73.33% specificity, and accuracy of 78% to discriminate between those with signs of PHG and those without. Conclusion: Serum serotonin is a valuable non-invasive marker of PHG in HCV-cirrhotic patients. Furthermore, its serial measurements could be used to monitor disease progression.
We report the case of an 11‐year‐old, female neutered, miniature schnauzer who presented for assessment of recurrent urinary tract and vaginal infections. During investigations, a hepatic mass was incidentally identified on abdominal ultrasound. Cytology following a fine‐needle aspirate biopsy led to a presumptive diagnosis of hepatocellular carcinoma affecting the right lateral liver lobe. Following resolution of the urinary pathology, elective resection of the neoplastic mass was performed. During liver lobectomy, acute portal hypertension developed, evident through venous congestion and marked peristalsis of the gastrointestinal tract, and pancreatic oedema. Consequently, severe haemodynamic disturbances occurred in the form of systemic hypotension and severe tachycardia. Acute portal hypertension is a potentially life‐threatening complication of hepatic surgery and should be immediately resolved through the reversal of portal vein occlusion.
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Portal hypertension is a complication of chronic liver disease. Various radiological interventions are being done to aid in the diagnosis of portal hypertension; further, an interventional radiologist can offer various treatments for the complications of portal hypertension. Diagnosis of portal hypertension in its early stage may require hepatic venous pressure gradient measurement. Measurement of gradient also guides in diagnosing the type of portal hypertension, measuring response to treatment and prognostication. This article attempts to provide evidence-based guidelines on the management of portal hypertension and treatment of its complications.
Portal hypertension is a complex syndrome with multiple clinical manifestations that develop in a variety of conditions and diseases. The spectrum of portal hypertension manifestations is wide and dependent on the physiologic site of increased portal resistance (pre-, post-, and sinusoidal or intrahepatic), as well as the presence of hepatocellular dysfunction.
We conducted a prospective study of 321 patients with cirrhosis of the liver and esophageal varices with no history of bleeding to see whether a comprehensive analysis of their clinical features and of the endoscopic appearances of their varices could help to identify those at highest risk for bleeding. Varices were classified endoscopically as suggested by the Japanese Research Society for Portal Hypertension. Patients were followed for 1 to 38 months (median, 23), during which 85 patients (26.5 percent) bled. Multiple regression analaysis (Cox's model) revealed that the risk of bleeding was significantly related to the patient's modified Child class (an index of liver dysfunction based on serum albumin concentration, bilirubin level, prothrombin time, and the presence of ascites and encephalopathy), the size of the varices, and the presence of red wale markings (longitudinal dilated venules resembling whip marks) on the varices. A prognostic index based on these variables was devised that enabled us to identify a subset of patients with a one-year incidence of bleeding exceeding 65 percent, The index was prospectively validated on a independent sample of 75 patients with varices and no history of bleeding. We conclude that our prognostic index, which identifies groups of patients with one-year probabilities of bleeding ranging from 6 to 76 percent, can be used to identify candidates for prophylactic treatment.
Background & Aims: The clinical importance of portal hypertensive gastropathy (PHG) as a source of gastrointestinal bleeding in patients with cirrhosis is poorly defined. We investigated the natural history of this condition in a large series of patients. Methods: All patients with cirrhosis seen at 7 hospitals during June and July 1992 were followed up with clinical and endoscopic examinations every 6 months for up to 3 years. Gastropathy was classified according to the classification of the New Italian Endoscopic Club. Results: The prevalence of gastropathy was 80% and was correlated with the duration of disease, presence and size of esophagogastric varices, and a previous history of endoscopic variceal sclerotherapy. During 18 ± 8 months of follow-up, gastropathy was stable in 29% of patients, deteriorated in 23%, improved in 23%, and fluctuated with time in 25%. The evolution of gastropathy with time was identical in patients with and without previous or current sclerotherapy. Acute bleeding from gastropathy occurred in 8 of 315 patients (2.5%). The bleeding-related mortality rate was 12.5%. Chronic bleeding occurred in 34 patients (10.8%). Conclusions: PHG is common in patients with cirrhosis, and its prevalence parallels the severity of portal hypertension. Gastropathy can progress from mild to severe and vice versa or even disappear completely. Bleeding from this lesion is relatively uncommon and rarely severe. Sclerotherapy of esophageal varices does not seem to influence the natural history of this condition.
Spontaneous bacterial empyema (SBEM) is an infection of a preexisting hydrothorax in cirrhotic patients and has seldom been reported. To determine its incidence and primary characteristics, all cirrhotic patients with pleural effusion underwent thoracentesis at our hospital either on admission or when an infection was suspected. Pleural fluid (PF) study included biochemical analysis, polymorphonuclear (PMN) leukocyte count, and culture by two methods: conventional and modified (inoculation of 10 mL of PF into a blood culture bottle at the bedside). SBEM was defined according to previously reported criteria: PF culture positive or PMN count greater than 500 cells/micro L, and exclusion of parapneumonic effusions. Sixteen of the 120 (13 percent) cirrhotic patients admitted with hydrothorax had 24 episodes of SBEM. In 10 of the 24 episodes (43 percent), SBEM was not associated with spontaneous bacterial peritonitis (SBP). PF culture was positive by the conventional method in 8 episodes (33 percent) and by the modified method (blood culture inoculation) in 18 (75 percent) (P = .004, McNemar). The microorganisms identified in PF were Escherichia coli in 8 episodes, Streptococcus species in 4, Enterococcus species in 3, Klebsiella pneumoniae in 2, and Pseudomonas stutzeri in 1. All episodes were treated with antibiotics without inserting a chest tube in any case. Mortality during treatment was 20 percent. We conclude that SBEM is a common complication of cirrhotic patients with hydrothorax. Almost half of the episodes were not associated with SBP; thus, thoracentesis should be performed in patients with cirrhosis, pleural effusion, and suspected infection. Culture of PF should be performed by inoculating 10 mL into a blood culture bottle at the bedside. (Hepatology 1996 Apr;23(4):719-23)
▪ Objective: To compare the serum-ascites albumin gradient to the exudate-transudate concept in the classification of ascites. ▪ Design: Prospective collection of ascitic fluid data from patients with well-characterized causes of ascites. ▪ Setting: Hepatology inpatient and outpatient ward and consult service of a large, urban hospital. ▪ Patients: A total of 901 paired serum and ascitic fluid samples were collected from consecutive patients with all forms of ascites. ▪ Interventions: None. ▪ Main Outcome Measures: The utility of the serumascites albumin gradient and the old exudatetransudate concept (as defined by ascitic fluid total protein concentration [AFTP]) were compared for their ability in discriminating the cause for ascites formation. ▪ Results: The albumin gradient correctly differentiated causes of ascites due to portal hypertension from those that were not due to portal hypertension 96.7% of the time. The AFTP, when used as defined in the old exudate-transudate concept, classified the causes of ascites correctly only 55.6% of the time. This resulted in part because the AFTP of most spontaneously infected samples (traditionally expected to be exudates) was low, and the AFTP of most cardiac ascites samples (traditionally expected to be transudates) was high. ▪ Conclusions: The exudate-transudate concept should be discarded in the classification of ascites. The serum-ascites albumin gradient is far more useful than the AFTP as a marker for portal hypertension, but the latter remains a useful adjunct in the differential diagnosis of ascites.