Hipertension Portal

Disease-a-Month 62 (2016) 411426
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Disease-a-Month
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Portal hypertension: Etiology, evaluation, and

management
Eula Plana Tetangco, MD, Rogelio G. Silva, MD,
Edgar V. Lerma, MD, FACP, FASN
Introduction
Structural changes in the portal venous system have been associated with gastrointestinal
bleeding as far back as the 17th century.1 The term portal hypertension was rst used in late
1920s by McIndoe, who found that portal pressures are increased in patients with cirrhosis. An
abnormal increase in pressure within the portal venous system, portal hypertention (PHTN) is
dened as a hepatic venous pressure gradient (HVPG) greater than 5 mmHg,2 and is clinically
signicant at 10 mmHg.3,4 It is associated with the most severe complications of chronic liver
disease such as ascites, bleeding from esophageal varices, and hepatic encephalopathy.5
Pathogenesis
The liver receives dual blood supply, with 75% coming from the portal vein (carrying partially
deoxygenated blood) that drains the mesenteric and splenic veins, and 25% from the hepatic
artery (carrying oxygenated blood). This inux is carried through the sinusoids and collects in a
central vein that drains into the hepatic vein, which in turn drains into the inferior vena cava
(Fig. 1).2
Portal hypertension is a product of increased outow resistance. With time, the liver
withstands increased portal blood ow, contributing to increased portal pressure. Resistance to
outow is due to both mechanical obstruction from brosis,2 and to decreased synthesis of nitric
oxide that results in active reversible contraction of the portohepatic bed.6 Increased portal
inow is the outcome of dilation of arteriolar splanchnic vessels and hyperdynamic circulation, a
state of low vascular resistance and mean arterial pressure with high cardiac output.2,6
Etiology
Cirrhosis is by the far the most common cause of portal hypertension, accounting for 90% of
cases in the West and 80% of cases in Asia and Africa.3 A minority of cases is due to non-cirrhotic
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E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426
HEPATIC ARTERY
25% of blood supply
LIVER
oxygenated blood
Splenic vein
PORTAL VEIN
75% of blood supply
partially deoxygenated blood
Inferior mesenteric vein

Superior mesenteric vein
Fig. 1. Dual blood supply of the liver.
causes. Most of these are vascular in nature, with pathology in endothelial cells, intimal
thickening, thrombotic obliterations, and scarring of intrahepatic or portal vein circulation
(Table 1). Non-cirrhotic causes tend to present at a younger age, are more common in the
developing countries and lower socioeconomic classes, and have a better prognosis.3
Clinical manifestations
Portal hypertension is generally asymptomatic until complications develop; namely
esophageal and gastric varices, variceal bleeding, ascites, spontaneous bacterial peritonitis,
splenomegaly, and hepatic encephalopathy.
Esophagogastric varices and variceal bleeding
As the body attempts to decompress the portal vein, it diverts up to 80% of portal ow
through portosystemic collaterals back to the heart. This increased ow remodels and enlarges
these vessels in the esophagus and stomach, driven by vascular endothelial growth factor (VEGF)
and platelet-derived growth factor (PDGF).2 Esophageal varices are far more common in PHTN of
all etiologies, and gastric varices are more common in non-cirrhotic PHTN.3 This article will
focus on the former type.
Varices are unlikely to form until the HVPG is greater than 10 mmHg.4 Bleeding is often seen
when the pressure gradient reaches 12 mmHg, and continuous bleeding when it reaches more
than 20 mmHg. Variceal bleeding can be life threatening and requires immediate assessment
and intervention.2
Ascites and spontaneous bacterial peritonitis
Ascites in PHTN is a function of systemic arteriolar vasodilation, sodium and water retention,
and increased sinusoidal pressure.2 Arteriolar vasodilation results in low effective circulating
volume, which in turn activates the reninangiotensinaldosterone system and the sympathetic
nervous system, and promotes release of antidiuretic hormone. All this causes sodium and water
retention. Dilutional hyponatremia is a marker of advanced disease, an independent predictor of
outcome,7 and predicts development of hepatorenal syndrome.2
Increased sinusoidal pressure decreases permeability of the sinusoidal endothelium,
explaining why PHTN ascitic uid has a low protein and albumin content and thus a serum
ascites albumin gradient (SAAG) greater than 1.1. This decreased permeability also increases risk
of spontaneous bacterial peritonitis (SBP) because of low opsonin content in the ascitic uid.2
SBP should be suspected in any patient with chronic liver disease and new or worsening ascites.
The diagnosis is made by peritoneal uid analysis showing polymorphonuclear count above
413
Table 1
Causes of non-cirrhotic portal hypertension.
Prehepatic
Extrahepatic portal vein thrombosis
Portal vein stenosis
External compression of portal vein
Splenic vein thrombosis
Splanchnic arteriovenous stula
Splenomegaly
Intrahepatic
Granulomatous disease (schistosomiasis, tuberculosis, sarcoidosis, amyloidosis, and mineral oil granuloma)
Alcoholic liver disease
Arsenic, copper sulfate, and vinyl chloride toxicity
Polycystic disease
Gauchers disease
RenduOslerWeber syndrome
Angiosarcoma
Presinusoidal
Idiopathic portal hypertension (IPH)/noncirrhotic portal brosis (NCPF)
Congenital hepatic brosis
Primary biliary cholangitis
Primary sclerosing cholangitis
Hepatic arteriopetal stula
Adult polycystic liver disease
Arteriovenous stulas
Autoimmune cholangiopathy
Occlusion of the intrahepatic portal vein
Sinusoidal
Drugs (e.g., amiodarone and methotrexate)
Non-alcoholic fatty liver disease
Zellweger syndrome
Viral hepatitis
Chronic Q fever
Amyloid or light-chain deposition in the space of Disse
Acute hepatic injury
Mastocytosis
Agnogenic myeloid metaplasia
Acute fatty liver of pregnancy
Postsinusoidal
Sinusoidal obstruction syndrome (veno-occlusive disease)
BuddChiari syndrome
Chronic radiation injury
Hypervitaminosis A
Epithelioid hemangioendothelioma
Mycobacterium avium or M. intracellulare infection
Posthepatic
IVC obstruction or thrombosis
Hepatic vein thrombosis (BuddChiari syndrome)
Constrictive pericarditis
Restrictive cardiomyopathy
Tricuspid valve disease
250 cells/mm3.8 When ascitic uid travels across fenestrae in the diaphragm, it can manifest as
hepatic hydrothorax,2 a transudative pleural effusion.
Hepatic encephalopathy
Hepatic encephalopathy (HE) manifests as potentially reversible neurologic abnormalities
such as decreased level of consciousness, impaired intellect, personality and behavioral changes,
414
and neuromuscular abnormalities such as incoordination and asterixis.8 Hyperammonemia,

neurosteroids, infection, and manganese deposition in the basal ganglia have been implicated in
its pathogenesis.9
Intrahepatic portosystemic shunting and decreased urea and glutamine synthesis decrease
the hepatic uptake of ammonia. Gastrointestinal bleeding and hypovolemia further increase the
release of renal ammonia. The decreased muscle mass often seen in patients with cirrhosis also
decreases the muscle capacity to clear ammonia. This leads to net positive balance of ammonia.2
With hepatic portosystemic shunts, ammonia circumvents the liver and is able to reach cerebral
astrocytes, where it is metabolized into glutamine. This provides an osmotic pull, causing
cerebral edema. Ammonia is also directly toxic to the brain, producing nitrosative and oxidative
stress.8
Neuroinhibitory steroids and benzodiazepine activate the gamma-aminobutyric acid (GABA)
receptors, leading to depressed mental status. Infection and the subsequent systemic
inammatory response enhance cerebral permeability and increase diffusion of ammonia into
astrocytes.8 Manganese deposits in the globus pallidus also induce oxidative stress and may
account for the Parkinsonian symptoms seen in HE.2
Differential diagnosis
It is important to consider differential diagnoses for patients with clinical manifestations of
PHTN, as these will guide management (Table 2).10
Patient evaluation and diagnosis

While hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing PHTN, the
presence of clinical manifestations in the setting of a known risk factor, such as cirrhosis, is
sufcient to make the diagnosis. Measurement of the HVPG is useful in the absence of risk
factors and when the diagnosis is uncertain (Fig. 2).11 It also correlates with the degree of brosis
on histology and yields prognostic information on mortality and risk of decompensation (Fig. 3
and Table 3).12 Following diagnosis, it is imperative to determine the underlying cause of PHTN
as a target for therapy.
Table 2
Differential diagnoses for signs and symptoms of portal hypertension.
Upper gastrointestinal bleeding
Esophagitis
MalloryWeiss tear
Gastritis
Ulcer disease
Dieulafoy lesion
Ascites and pleural effusion
Heart failure
Nephrotic syndrome
Malignancy
Tuberculosis
Secondary bacterial peritonitis (from visceral perforation)
Drugs and toxins

Electrolyte disturbances
Endocrine abnormalities
Hypoxemia or hypercapnia
Central nervous system infection
Intracranial mass effect (tumor and hemorrhage)
Uremia
415
Clinical signs of portal hypertension

Splenomegaly, hypersplenism
Gastroesophageal varices
Ascites
Portovenous collaterals
Exclude chronic liver disease causing cirrhosis or non-cirrhotic PHTN

Chronic hepatitis B or C
Alcoholic or non-alcoholic steatohepatitis
Autoimmune hepatitis
Hereditary hemochromatosis
Wilson disease
Primary biliary cirrhosis
Confirmation of patent portal and hepatic veins
Exclude cirrhosis and non-cirrhotic PHTN by liver biopsy + HVPG
Exclude extrahepatic causes of non-cirrhotic PHTN
Idiopathic non-cirrhotic PHTN

Fig. 2. Approach to evaluation of portal hypertension. (Adapted with permission from Koh and Heller.14)
Measuring the hepatic venous pressure gradient

The HVPG is obtained by hepatic vein catheterization. It is calculated as follows2:
HVPG wedged hepatic vein pressure (WHVP) free hepatic vein pressure (FHVP)
Obtaining the WHVP involves inserting a balloon catheter into the hepatic vein and
occluding it, thus allowing a static column of blood to form, the pressure of which equals to the
pressure in hepatic sinusoids. The FHVP is the pressure in the non-occluded hepatic vein.12 The
formula corrects for intra-abdominal pressure, giving an accurate measurement of portal vein
pressure.2 Conrmation of proper occlusion is done by slowly injecting 5 ml of contrast dye
into the vein while the balloon is inated. Absence of washout through communications with
other hepatic veins is consistent with cirrhosis, while veno-venous communications are
commonly seen in idiopathic portal hypertension and other non-cirrhotic portal hypertensive
diseases.13 Of note, the HVPG is normal in extrahepatic portal venous obstruction (such as
BuddChiari syndrome), and normal or only slightly elevated in non-cirrhotic portal brosis
(NCPF), as these disease entities do not have signicant parenchymal dysfunction.13 HVPG
should be interpreted with caution in these cases and always correlated with clinical
manifestations.
416
Fig. 3. Risks associated with increasing hepatic venous pressure gradients. (Reproduced with permission from Koh and
Heller.14)
Non-invasive diagnostic modalities

Serum surrogate markers for cirrhosis, studied largely in the hepatitis C population, include
aspartate aminotransferase-to-platelet ratio index (APRI),15 the Forns index,16 and FibroTest17
(Table 4). However, these have limitations in evaluating dynamic changes in brosis and PHTN.
Ultrasound (US) allows qualitative assessment of hepatic parenchyma and surrounding
structures (Table 5). The most sensitive sign of portal hypertension is splenomegaly.13 It is also
the marker for clinically signicant portal hypertension in patients with compensated cirrhosis,
as well as an independent predictor of esophageal varices. The most accurate sign of cirrhosis is
liver surface nodularity.13
When used with Doppler, ultrasonography aids in detecting hemodynamic changes. The
hepatic vein ow pattern and waveform in particular, are associated with advanced brosis and
predict severe PHTN, respectively.12 Accuracy in detecting portal vein and hepatic vein
thrombosis, two causes of non-cirrhotic PHTN, is also high.13
Doppler and US are limited by operator dependence, in addition to patient-related factors
such as respiration and timing of meals in the case of Doppler sonography.12 US ndings do not
correlate well with HVPG, and so cannot be used as a surrogate as such.13
More recently, tissue elastography has emerged as a reliable non-invasive tool in assessing
liver brosis.
Table 3
Prognostic signicance of hepatic venous pressure gradient measurements.
HVPG threshold (mmHg)
Increased risk of
5
10
12
20
Portal hypertension
Formation of gastroesophageal varices
Variceal bleeding
Continuous bleeding from varices
417
Table 4
Serum surrogate markers for cirrhosis.
Test
Components
Clinical utility
AST to platelet
ratio index
(APRI)14
Forns index15
AST and platelet count
Patients with chronic HCV
Patients with chronic hepatitis C

(HCV)
Patients with chronic HCV
FIB-4 index21
Age, gamma-glutamyl transferase (GGT), cholesterol, and

platelet count
Serum hyaluronic acid, tissue inhibitor of metalloproteinase1 (TIMP-1), and alpha-2-macroglobulin
Age, sex, alpha-2-macroglobulin, alpha-2-globulin
(haptoglobin), gamma globulin, apolipoprotein A1, GGT,
and total bilirubin
Platelet count, prothrombin index, AST, alpha-2macroglobulin, hyaluronic acid, and blood urea nitrogen
Age, sex, bilirubin, GGT, hyaluronic acid, and
alpha-2-macroglobulin
Age, sex, platelet count, ALT, and AST
NAFLD brosis
score22
Age, body mass index (BMI), blood glucose levels,

aminotransferase levels, platelet count, and albumin
FibroSpect II
18
Fibrotest16
Fibrometer19
Hepascore20
Patients with chronic hepatitis B

(HBV) or HCV
Patients with chronic HBV and HCV
Patients with HCV
Patients with chronic HCV or
non-alcoholic fatty liver disease
(NAFLD)
Patients with NAFLD
Tissue elastography
The gold standard for assessing hepatic brosis is liver biopsy.13 Apart from being an invasive
procedure, concerns about rare but serious complications and susceptibility to sampling
variation limit its use.23
Tissue elastography is a non-invasive method of measuring liver stiffness, predicting liver
brosis.24 Two large categories are shear wave-based elastography and real-time tissue
elastography.25 Transient elastography (TE; Fibroscans, Echosens, Paris, France) is a shear
wave-based method that is gaining popularity. It has the advantage of being painless, brief
(lasting o 5 min), easy to perform at bedside or in clinic,22 and more cost-effective than liver
biopsy.26 Patients are examined while lying supine, with the right arm behind the head. The
probe is placed between the ribs at the level of the right lobe of the liver, and the measurement
is taken. Results are expressed in kPa and have been well validated against histologic assessment
Table 5
Ultrasound ndings in portal hypertension and cirrhosis.
Clinically signicant portal hypertension
Portal ow mean velocity o12 cm/s
Portosystemic collaterals (patent paraumbilical vein, spleno-renal collaterals, dilated left, and short-gastric veins)
Flow inversion in the portal system
Dilatated portal vein (diameter 4 13 mm)
Absent or reduced respiratory variation in splenic and superior mesenteric vein diameter
Reduced portal vein velocity
Increased intraparenchymal hepatic and splenic artery resistance and pulsatility index
Increased intraparenchymal renal artery resistance and pulsatility index
Reduced mesenteric artery resistance and pulsatility index
Cirrhosis
Ascites
Increased intrarenal arteriolar resistance index (correlates with renal vasoconstriction and hepatorenal syndrome
Small liver size
Splenomegaly 4 14.5 cm
Mean portal vein velocity below 10 cm/s
Absent pulsatility of hepatic veins
418
Table 6
The METAVIR scoring system.
Fibrosis (F)
F0
F1
F2
F3
F4
no brosis
portal brosis without septa
portal brosis with rare septa
numerous septa without cirrhosis
cirrhosis
Necroinammatory Activity (A)

A0
A1
A2
A3
no histologic necroinammatory activity

minimal activity
moderate activity
severe activity
using the METAVIR scale (Table 6), with small differences in threshold values (Table 7).22 The
METAVIR scale27 is a histological scoring system that is validated for chronic hepatitis C. It grades
both necroinammatory activity (A) and stage of brosis (F). Threshold values were found as
follows: 4 7.9 kPa for marked brosis (F Z 2; sensitivity 72%, specicity 84%), 4 10.3 kPa
for severe brosis (F Z 3; sensitivity 76%, specicity 90%), and 4 11.9 kPa for cirrhosis
(sensitivity 91%, specicity 89%).
A study of 200 patients with chronic liver disease of various etiologies (78% of whom had
hepatitis C) showed TE to be highly reliable and reproducible in predicting moderate to severe
brosis.23 The technique was limited by steatosis, body mass index (BMI) greater than 25 kg/m2,
and mild degree of liver brosis. Results were compared with ultrasound-guided liver biopsy,
with brosis staged on the METAVIR scale. Of note, patients with ascites were excluded. The
authors acknowledge that the METAVIR scale being inappropriate in alcoholic liver disease and
non-alcoholic steatohepatitis also limits the study.
Another study of 228 patients with hepatitis C conrmed TEs reliability and reproducibility.28 Threshold values were 8.3 kPa for Z F2 (sensitivity 85.2%, specicity 90.7%) and
14 kPa for cirrhosis (sensitivity 78.3%, specicity 98.2%). TE performed better than the
surrogate markers serum transaminases, APRI, Forns index, and FibroTest (P o 0.001).
TE has also been useful in identifying risk of portal hypertension and esophageal varices in
patients with cirrhosis (Table 5). Threshold values of 17.6 kPa and 21 kPa had 90% sensitivity for
detecting HVPG above 1012 mmHg.29,30 Liver stiffness of o19 kPa had 84% sensitivity and 93%
negative predictive value for the absence of esophageal varices grade 2 or higher.31
Increased liver stiffness is associated with a higher risk of developing hepatocellular
carcinoma (HCC) with patients with chronic hepatitis B and C.32 Combined with alanine
aminotransferase, alpha-fetoprotein, and interquartile range, liver stiffness of 42 kPa has been
found to accurately predict HCC in patient with hepatitis C-related cirrhosis.33
TE is inuenced by hepatitis exacerbations characterized by an increase ALT.32 In such cases
brosis is overestimated, with stiffness increasing 1- to 1.3-fold during a are in chronic
hepatitis. Stiffness is similarly increased in patients with hepatitis B, toxic hepatitis, and
autoimmune hepatitis.34 This suggests that inammation and edema inuence TE, thus results
should be interpreted with caution in the setting of acute liver damage in chronic liver disease.
Table 7
Threshold values in transient elastography for predicting hepatic brosis, cirrhosis, and complications thereof.
Threshold value (kPa)
Clinical prediction
79
10
1114
19
1721
42
Marked brosis (F Z 2)
Severe brosis (F Z 3)
Cirrhosis
Gastroesophageal varices
Clinically signicant portal hypertension
Hepatocellular cancer (in conjunction with other parameters)
419
Management
Management of PHTN revolves around addressing the underlying cause, reducing intrahepatic resistance, and treating complications.
Reducing intrahepatic resistance and portal pressure
Splanchnic vasoconstrictors reduce splanchnic blood ow and hyperdynamic circulation.35
Vasopressin, somatostatin, and analogs thereof are intravenous splanchnic vasoconstrictors.
Venodilators such as nitrates decrease intrahepatic resistance and portal pressure that is
related to decrease in ow rather than decrease in resistance.34 When utilizing HVPG to guide
therapy, the goal is to reduce the gradient to less than 12 mmHg or 20% of baseline.22
Vasoconstrictors and vasodilators have a synergistic effect in reducing portal pressure-reducing
effect without increasing adverse effects on liver and renal perfusion or liver function.36,37
Combination therapy has shown increased response in portal pressure, but also in adverse
effects, and offer no survival benet.35
Esophageal and gastric varices
Upon diagnosis of cirrhosis, patients should undergo esophagogastroduodenoscopy (EGD) to
screen for esophageal varices. Prophylactic therapy should be provided for those that are at
increased risk of bleeding (Table 8).38 For those without varices or with small varices, follow-up
screening should be done every 23 years or at the time of decompensation.2 Pre-primary
prophylaxis includes preventing progression of cirrhosis. Beta-blockers have not been shown to
provide benet in cirrhosis without esophageal varices and should not be administered.11
Risk of bleeding correlates with size of the varices. Small varices have a 4% risk of bleeding.
NSBBs may be given to these patients with these. Medium to large varices (4 5 mm) have a high
risk of bleeding. Varices of any size in patients with ChildPugh class B or C, those with HVPG 4
12 mmHg, and varices with red wale signs on endoscopy, carry a similar high risk.37 These
patients should be given NSBB or undergo endoscopic variceal ligation (EVL) to prevent rst
occurrence of hemorrhage. NSBBs decrease portal ow and portal pressure, thus reducing risk of
Table 8
Management of esophageal varices.
Intervention
Recommendations
Pre-primary prophylaxis
Screening EGD, then follow-up screening should be done every 23 years or

at time of decompensation
Prevent progression of cirrhosis
Beta-blockers have no benet
Primary prophylaxis
Non-selective -blockers, OR
Endoscopic variceal ligation
Management of active bleeding
Hemodynamic support
Maintain patent airway
Transfuse to maintain hemoglobin 7 g/dL
Pharmacologic therapy (somatostatin and analogs)
Endoscopic therapy (EVL, sclerotherapy)
Antibiotic prophylaxis
Shunt surgery or TIPS as salvage therapy
Secondary prophylaxis
NSBB EVL
Variceal obliteration with EVL
First surveillance EGD at 13 months, then every 612 months thereafter
Evaluate for liver transplant eligibility
420
Table 9
Primary prophylaxis for esophageal varices.
Therapy
Starting dose
Maintenance dose
Propranolol
20 mg orally twice a day
Nadolol
Endoscopic variceal
ligation
40 mg orally once a day

Repeat every 12 weeks
until obliteration
Titrate to decreased heart to 2025% from baseline,

or 55 beats per minute
Same as propranolol
EGD 13 months after obliteration, then every 612
months to monitor for recurrence
bleeding. Non-selective -blockers (NSBB) given orally or intravenously allow unopposed 1adrenergic activity, thus promoting splanchnic vasoconstriction and the reduction of portal
inow. They have the added effects of reducing cardiac output and improving hyperdynamic
circulation as well as reducing azygos blood ow and variceal pressure. Introduced in the late
1980s, propranolol is the rst and most well-studied NSBB used in the treatment of portal
hypertension. It is started upon detection of varices at a dose of 20 mg/day and is titrated to
maximally tolerated doses and a heart rate goal (Table 9).37 Nadolol has also been reported to be
safe and as effective as propranolol in decreasing portal pressure.39,40
Carvedilol is a non-selective beta-blocker with additional alpha-1 blocking properties,
conferring vasodilator action that further decreases portal hepatic resistance and portal
pressure.41 It has been found to be at least as powerful as propranolol in reducing the HVPG,42
even in non-responders, with subsequent decrease in risk of variceal bleeding and clinical
decompensation.43 This added vasodilation, however, has the potential to promote arterial
hypotension and sodium retention, of particular concern in patients with decompensated
cirrhosis.40 Further studies on the safety of carvedilol are needed before it can be recommended
in the management of portal hypertension outside of clinical trials.44
Although the addition of isosorbide-5-mononitrate provides a greater reduction in portal
pressure than propranolol alone, the combination does not lower risk or increase survival, and
only increases the frequency of adverse effects.45 EVL is comparable to NSBB in terms of risk of
rst bleed and survival.46,47 It may be considered in patients with contraindications or
intolerance to -blockers, and non-responders. The combination of EVL and propranolol does not
decrease risk of rst bleed or mortality, but a reduction in recurrence of varices is seen.48
Patients need follow-up endoscopy 13 months after ligation.45
Acute gastrointestinal hemorrhage from variceal bleeding is an emergency. Patients require
intravascular volume support37 and blood transfusions to maintain hemoglobin of 7 g/dL.49
Airway must be kept patent and the patient intubated if necessary. The somatostatin analog
octreotide should be initiated at presentation with a 50 g intravenous bolus, followed by an
infusion of 50 g/h that is continued for 35 days after diagnosis is conrmed.50 Vapreotide,51
another somatostatin analog, and terlipressin,52 a vasopressin analog, are two alternatives that
have not yet been approved by the United States Food and Drug Administration in the treatment
of bleeding esophageal varices.
Urgent EGD should be performed within 12 h,37 allowing for both diagnosis and therapy with
EVL or sclerotherapy. Both interventions are equally effective in controlling acute bleed, but
endoscopic variceal ligation has a signicantly lower rate of development of portal gastropathy
and rebleeding, with fewer side effects, making it the preferred choice.53 Balloon tamponade is a
temporizing measure for those waiting to undergo denitive endoscopic therapy and has fallen
out of favor due to side effects and low efcacy. The tamponade is limited to a maximum of
24 h.37 Additionally, a 7-day course of antibiotic prophylaxis should be given to cirrhotic patients
with gastrointestinal hemorrhage for the following reasons: possible reduction in overall
infectious complications, possible reduced mortality, and possible reduced risk of recurrent
bleeding.54 The choice of optimum antibiotic is unclear. Oral noroxacin at a dose of 400 mg BID,
or intravenous ciprooxacin for patients unable to tolerate oral intake, is the recommended
421
antibiotic. In centers with high quinolone resistance, consider intravenous ceftriaxone at a dose
of 1 g/day.37
A single episode of clinically signicant rebleeding after day 5 constitutes failure to prevent
rebleeding. Clinically signicant rebleeding is dened as recurrent melena or hematemesis with
subsequent hospital admission, blood transfusion, 3-g drop in hemoglobin, or death within
6 weeks.37 Approximately 60% of variceal hemorrhages rebleed.4 In early rebleeding, EVL may be
reattempted once. Decreasing portal pressure remains the mainstay. Shunt therapy, either
through surgery or through transjugular intrahepatic portosystemic shunting (TIPS), is effective
as salvage therapy for those who fail to respond to endoscopic or pharmacological measures.55
Secondary prophylaxis involves a combination of NSBB and EVL.52 Obliteration of varices
should be achieved with EVL every 12 weeks, after which surveillance EGD should be done 13
months after obliteration, and then every 612 months to check for recurrence.37
Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt (TIPS) is an interventional radiologic
procedure designed to decompress the portal vein. It is used as salvage therapy and secondary
prophylaxis in variceal bleeding, treatment for refractory ascites, and as a bridge to liver
transplant. It has not been shown to reduce mortality. Absolute contraindications to the
procedure are primary prevention of variceal bleeding, congestive heart failure, multiple hepatic
cysts, uncontrolled systemic infection or sepsis, unrelieved biliary obstruction, and severe
pulmonary hypertension. Relative contraindications are hepatoma, obstruction of all hepatic
veins, portal vein thrombosis, severe coagulopathy with INR 4 5, thrombocytopenia of 20,000/
cm3, and moderate pulmonary hypertension.56 The model for end-stage liver disease (MELD)
score was initially developed to predict mortality for patients after undergoing TIPS.57 Similarly,
elevated bilirubin above 3 mg/dL is an independent predictor of 30-day mortality after TIPS.58
Patients with high MELD scores 4 15, or serum bilirubin 4 4.0 mg/dL, should be informed of
their prognosis, and TIPS performed only if no other options are feasible. Benets may outweigh
the risks of these relative contraindications for recurrent variceal hemorrhage and refractory
ascites requiring serial paracenteses; particularly in the setting of palliative TIPS, occluded portal
veins, or progressive liver failure in BuddChiari syndrome with no patent hepatic veins.55
Complications of TIPS placement include intra-abdominal hemorrhage, shunt stenosis,55 and
hepatic encephalopathy.59 Recently, polytetrauoroethylene (PTFE)-covered stentgrafts have
shown improved patency rates by minimizing the inltration of bile and mucin and reducing
tissue ingrowth into the graft. These stents showed higher survival rates within 2 years after
TIPS implantation (76% in ePTFE vs. 62% in conventional TIPS)60 and were found to have a
decreased risk of encephalopathy (67% encephalopathy-free in PTFE vs. 51% in uncovered
group).61
Ascites and spontaneous bacterial peritonitis
All patients with new or worsening ascites should undergo diagnostic paracentesis, and the
uid analyzed for cell count and differential, uid total protein, cultures, and serumascites
albumin gradient (SAAG). A high gradient 4 1.1 g/dL points to portal hypertension as the
etiology.62
Management of ascites aims to minimize ascitic uid and lower extremity edema without
depleting intravascular volume. The mainstays are sodium restriction to 2 g/day and a dual
diuretic regimen beginning with oral spironolactone at 100 mg and furosemide at 40 mg. If no
response is seen in 35 days, doses may be doubled until a maximum of 400 mg spironolactone
and 160 mg furosemide is reached. Fluid restriction for patients with hyponatremia with plasma
sodium less than 120 mEq/L or neurologic symptoms may help decrease ascites.63 Therapeutic
paracentesis will provide relief. Patients who undergo large-volume paracenteses 4 5 L are at
risk of circulatory dysfunction characterized by worsened vasodilation, hyponatremia, and
422
hyperreninemia.2 These patients should receive an albumin infusion of 68 g/L of uid removed
as this appears to improve survival.58 Preventing progression of cirrhosis is also important in
preventing uid reaccumulation.
An elevated PMN count of Z250 cells/mm3 in ascitic uid along with positive cultures
conrms the diagnosis of spontaneous bacterial peritonitis (SBP).58 In the setting of PHTN,
decreased intestinal motility and local immunodeciency result in intestinal bacterial
overgrowth. Translocation into the peritoneum causes SBP. Majority of cases are caused by
gram-negative enteric pathogens, most commonly Escherichia coli and Klebsiella pneumoniae.64
An intravenous third-generation cephalosporin is the antibiotic of choice, preferably cefotaxime
2 g every 8 h. Patients with serum creatinine 4 1 mg/dL, blood urea nitrogen 430 mg/dL, or
total bilirubin 44 mg/dL should receive volume support with albumin at 1.5 g/kg body weight
on day 1 and 1 g/kg on day 3.58
The diagnosis of hepatic encephalopathy (HE) is one of exclusion of other organic causes of
altered mental status and cognition. A normal ammonia level does not exclude the diagnosis.
Severity is graded by the West Haven Criteria (WHC) and Glasgow Coma Scale (GCS).
Precipitating factors include infection, gastrointestinal bleeding, diuretic overdose, electrolyte
disturbances, and constipation.65 These should be sought and addressed. The non-absorbable
disaccharide lactulose is given for overt HE, starting at a dose of 20 g thrice daily and titrated to
produce 23 loose stools a day.66 The use of rifaximin has shown improvement in cognition,
inammation, and quality of life. It is unclear if this difference is clinically signicant.67 As an
add-on therapy to lactulose, rifaximin is effective in preventing overt HE recurrence when
compared to lactulose alone. Neomycin and metronidazole are alternative agents for the
treatment of overt HE (Table 10).66,68
Many patients with end-stage liver disease and HE are malnourished, and indeed
malnutrition is a prognostic factor for quality of life, outcome, and survival.69 This gives oral
branched-chain amino acids (BCAAs) a role as alternative or additional agents for those not
responding to medical therapy, as we will discuss later.64
Assessment of nutritional status must be done for all patients with HE. This includes taking a
good dietary history, measuring muscle strength, and obtaining anthropometric data. Daily
energy intake is optimal at 3540 kcal/kg ideal body weight, while daily protein intake should
be 1.21.5 g/kg ideal body weight.70
A meta-analysis of randomized controlled trials found that oral BCAA supplements and
enteral hepatic formulations enriched with BCAAs (e.g., Nutra-Hep) are safe and improve
symptoms of HE when compared with control supplements, but have no effect on survival.71,72
For those with chronic manifestations of overt HE unresponsive to conventional therapy,
intravenous l-ornithine l-aspartate (LOLA) has been shown to be a safe alternative or additional
agent.64
Multivitamins are generally recommended, although their benets are not clear. If measured
deciencies in specic micronutrients are conrmed, replacement is given.69 Oral zinc
Table 10
Medical management of hepatic encephalopathy.
Medication
Lactulose
Indications
First line of therapy for overt HE,

prevention of recurrence
Rifaximin
Treatment for overt HE, prevention
of recurrence
Neomycin
Alternative treatment for overt HE
Metronidazole Alternative treatment for overt HE
Regimen
20 g orally thrice a day and titrated to produce 23 loose stools
daily, may be given every 1 h in overt HE
550 mg orally twice a day
412 g daily divided every 46 h and taken orally for 56 days
250 mg orally twice a day, not recommended for long-term use
423
supplementation has been found to decrease the grade of HE and improve quality of life,73 but
has not been linked to reduction in HE recurrence or improved mortality.74
Lastly, sodium benzoate is used off-label to treat patients with HE who have elevated
ammonia levels. It is thought to promote a non-urea cycle pathway for ammonia removal. While
its efcacy has not been established, it may be considered for selected patients with refractory
HE, as an inexpensive adjunct to lactulose and rifaximin. Because effects are dose-dependent on
sodium content, sodium benzoate should be used with caution in patients with signicant uid
retention or kidney disease.75
Recurrent intractable overt HE, together with liver failure, is an indication for liver
transplantation.64
Future therapies
Future therapies under investigation include inhibiting angiogenesis and attenuating
pathways that contribute to hyperdynamic circulation. For example, blocking vascular
endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) in rats reversed
portal hypertension and reduced splanchnic neovascularization in these animals.76 Rats with
prehepatic PHTN treated with sorafenib had reductions in portal pressure and portosysymitc
collateral circulation, without affecting systemic hemodynamic parameters.77 A pilot human
study showed a signicant HVPG decrease of 20% or more in 4 of 13 patients with ChildPugh
class A or B cirrhosis, and hepatocellular carcinoma but larger trials are needed.78
Conclusion
Portal hypertension is responsible for the most severe complications of chronic liver disease.
Majority of cases are caused by cirrhosis of any etiology, while non-cirrhotic causes are in the
minority and are more commonly seen in younger ages and in developing countries. PHTN is
generally asymptomatic until complications develop, namely esophageal and gastric varices,
variceal bleeding, ascites, spontaneous bacterial peritonitis, splenomegaly, and hepatic
encephalopathy. The diagnosis is made when one of these clinical manifestations is present in
the setting of a known risk factor. Measurement of the HVPG, the gold standard for diagnosing
PHTN, is useful in the absence of risk factors and when the diagnosis is uncertain. Management
of PHTN revolves around addressing the underlying cause, reducing intrahepatic resistance, and
treating complications. Future therapies will likely involve inhibition of angiogenesis and
neovascularization.
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Disease-a-Month 62 (2016) 411426

Contents lists available at ScienceDirect

Portal hypertension: Etiology, evaluation, and

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

Inferior mesenteric vein

Fig. 1. Dual blood supply of the liver.

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

and neuromuscular abnormalities such as incoordination and asterixis.8 Hyperammonemia,

Patient evaluation and diagnosis

Ascites and pleural effusion

Drugs and toxins

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

Clinical signs of portal hypertension

Exclude chronic liver disease causing cirrhosis or non-cirrhotic PHTN

Exclude cirrhosis and non-cirrhotic PHTN by liver biopsy + HVPG

Exclude extrahepatic causes of non-cirrhotic PHTN

Idiopathic non-cirrhotic PHTN

Measuring the hepatic venous pressure gradient

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

Non-invasive diagnostic modalities

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

AST and platelet count

Patients with chronic HCV

Patients with chronic hepatitis C

Age, gamma-glutamyl transferase (GGT), cholesterol, and

Age, body mass index (BMI), blood glucose levels,

Patients with chronic hepatitis B

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

Necroinammatory Activity (A)

no histologic necroinammatory activity

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

Screening EGD, then follow-up screening should be done every 23 years or

Management of active bleeding

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

20 mg orally twice a day

40 mg orally once a day

Titrate to decreased heart to 2025% from baseline,

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

First line of therapy for overt HE,

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

E.P. Tetangco et al. / Disease-a-Month 62 (2016) 411426

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