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PORTAL HYPERTENSION 439
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Parallel Transjugular Intrahepatic Portosystemic
Shunt
Rarely, despite a previous TIPS, the patient’s symptoms may not
be alleviated completely. If revision has already been attempted, a
second TIPS may be placed using the other hepatic and portal veins
(Fig. 4).
Transumbilical, Transplenic, or Direct Portal Access
When access into the portal vein is challenging due to anatomy or
thrombosis of the portal vein, the operator has several other options.
First, access into the umbilical vein, which is usually dilated, provides
a conduit to the left portal vein. A catheter there allows opacification
of the portal venous system, which provides a better target for TIPS.
FIG. 3 Direct intrahepatic portosystemic shunt (DIPS) in a patient with Budd-Chiari. Frontal subtracted hepatic (A) and post-TIPS portal (B) venograms in
a patient with Budd-Chiari. Hepatic venogram (A) shows the “spider-like” appearance (arrow) of multiple small collateral draining veins. The TIPS stent (arrowheads) allows the venous drainage to bypass the thrombosed hepatic veins (B). Because the hepatic vein is thrombosed, the stent extends directly from the
inferior vena cava (IVC) directly to the right portal vein.
FIG. 4 Parallel TIPS. Frontal subtracted portal venogram (A) via a catheter placed through the middle hepatic vein shows the previously placed right hepat-
ic to right portal vein TIPS (white arrow) to be occluded. Because of this, the patient had recurrent bleeding from gastric varices (white arrowheads). Repeat
portal venogram (B) after placement of a parallel TIPS (white arrow) shows antegrade flow into the right atrium and lack of filling of the gastric varices.
Previously placed TIPS stent (black arrow) is unchanged and does not contribute to flow.
440 TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
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Second, access through a naturally occurring portosystemic shunt,
such a splenorenal shunt, sometimes can be used to gain access to the
portal circulation. Finally, direct access through the spleen into the
splenic vein is an option (Fig. 5). When these options are not feasible,
direct percutaneous access into the right or left portal vein can allow
for contrast opacification and targeting.
Reversal or Revision of Transjugular Intrahepatic
Portosystemic Shunt
Occasionally, a TIPS reversal or revision is necessary. This is most
commonly in the setting of recurrent bleeding or ascites, in which
case a duplex ultrasound of the stent can determine flow and detect
stenosis. This can be addressed by placing a second stent and/or balloon angioplasty. Limited liver reserve or overzealous shunting may
result in liver failure or intractable encephalopathy. In such cases, the
interventional radiologist has the option to decrease the shunting or
shut down the TIPS altogether. Several maneuvers exist to reduce
shunting, including placing a stent within the TIPS, two stents sideby-side, or even a waisted (hourglass-like) stent (Fig. 6). If these
interventions are not possible or inadequate, the entire TIPS can
be shut down. TIPS shutdown is a rarely performed and advanced
procedure.
FIG. 5 Transsplenic TIPS in patient with complete portal vein occlusion and worsening ascites. The thrombosed portal vein makes splenic vein access
necessary. (A) Splenic venogram via direct percutaneous splenic puncture (black arrowhead). Angiography demonstrates prominent varices and collateral
vessels (black arrows). Angioplasty of the splenic vein (B) near the confluence (black arrowhead) through the transsplenic catheter (white arrow). A catheter
has been placed in the right internal jugular vein and hepatic vein. A long needle used for creation of the parenchymal tract (black arrowhead) extends partially into the hepatic parenchyma. The balloon was used as the target for the TIPS needle. Incidental note is made of a plastic internal common bile duct
drain (white arrowhead). After wire access (black arrow) to the portal vein (white arrow) via the right hepatic vein (C) through the portal vein the transgressed
hepatic parenchyma is dilated (black arrowheads). After TIPS shunt deployment (D), final portal venogram through the transsplenic catheter (black arrowhead)
demonstrates patent flow through the stent placed in the proximal splenic and portal veins (white arrow) and TIPS stent connecting the right portal vein and
right hepatic vein (black arrowhead).
PORTAL HYPERTENSION 441
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TIPS in the Setting of Portal Vein Thrombus
Originally, portal vein thrombosis was considered a contraindication
to TIPS. However, a large recent meta-analysis has shown that portal
venous recanalization performed with TIPS is a safe and highly successful option (recanalization rates >85%) in patients with portal vein
thrombus. Because portal vein thrombosis is a relative contraindication to transplant, the treatment of portal vein thrombus with TIPS
is now routinely practiced at several large transplant centers in the
United States and even in patients with complete portal vein thrombus
(see Fig. 5). Either transsplenic or transhepatic access is required to
assist with recanalization. Recanalization techniques can be complex,
particularly in the setting of tortuous collateral formation. The primary complication of portal vein recanalization is perisplenic bleeding; thus, dropping hemoglobin after the procedure should warrant
a search for a perisplenic hematoma and potentially embolization.
Additionally, portal vein rupture, which is a very rare complication,
should be prepared for in the setting of angioplasty and appropriately
sized stent grafts should be on hand to treat rupture if necessary.
CLINICAL OUTCOMES
Clinical Response to TIPS
Regardless of whether TIPS is performed as an elective or emergent
procedure, admission overnight to the critical care unit is routine. If
the postoperative course is uneventful, a patient who underwent an
elective TIPS can be discharged the next day. Follow-up of liver function tests (LFTs) and evaluation for encephalopathy are performed
during the inpatient stay directly following TIPS placement; a small
increase in LFTs is expected postprocedurally.
TIPS is the most effective option for treating gastroesophageal
FIG. 6 TIPS stent revision in the setting of persistent encephalopathy. To
reduce flow through the TIPS stent, a second longer stent can be partially
opened (white arrow) through the original stent (black arrow). Pressures are
sequentially measured as the second stent is gradually deployed to desired
effect.
TIPS in Transplanted Livers
TIPS is often used to bridge to liver transplantation in patients with
end-stage liver disease. Before transplantation, TIPS is used to manage complications of portal hypertension and ensure patients can
remain as transplant candidates. The same etiologies that resulted
in native liver failure in the first place can occur in the transplanted
liver, leading to the recurrent portal hypertension. For this reason,
indications for TIPS in transplanted livers are the same as those
for patients pretransplantation. Studies have shown that TIPS can
be effective in addressing early complications such as portal vein
thrombosis and delayed graft functions. Understanding of the
venous anastomosis of the inferior vena cava is critical to performing
a TIPS in a transplanted liver; the piggyback technique to TIPS can
be used to address this challenge. In this technique, TIPS placement
is performed in the left internal jugular vein rather than in the right.
Fewer shunt stenoses and procedural complications have been
recorded in posttransplant patients compared with pretransplant
patients. Approximately 10% to 20% of stents in patients with
transplants require revision compared with 70% in patients without
transplants. However, patients with transplants who undergo TIPS
have higher risks of infection, renal failure, and neurologic complications than patients without transplants. Clinical success rate of TIPS
in patients without transplants is much higher than in patients with
transplants (93% vs. 77%).
variceal bleeding. The rebleeding rate after TIPS placement is 4% per
year, the lowest amongst all treatment options, including endoscopic
management. TIPS is reserved for use after failure of endoscopic
management, only because of the greater risks associated with it,
particularly encephalopathy. Cessation of bleeding is evident almost
immediately after TIPS creation.
TIPS also has been shown to be effective in treating ascites, as
well as reducing the risk of ascites by 50% to 80% over the patient’s
life. In addition, TIPS has been shown to improve survival and
transplant-free survival compared with other treatment options.
Resolution of ascites may take up to 4 weeks after TIPS placement.
In patients with HRS, TIPS can improve renal function in 62%
of patients. However, it can occasionally be difficult to distinguish
noncirrhotic-related chronic renal insufficiency from HRS.
Complications and Management
The complications related to TIPS are shown in Table 3. The most
feared complication is liver failure, which usually results from excessive portohepatic venous shunting in a liver with limited baseline
reserve. If patients with limited liver reserve are excluded appropriately, the risk of liver failure is 2% to 4%.
Encephalopathy can be seen in up to 12% of patients with compensated liver disease and up to 50% of patients with decompensated
liver disease. Flagyl and lactulose provide significant relief for such
patients, but a small percentage (∼4%) will not respond and may
require TIPS reversal.
Death from sepsis is rare (<1%). Bacteremia results in TIPS stent
seeding; the stent graft infection can be very challenging or impossible to treat. Broad-spectrum antibiotics may clear the bacteremia,
but in some cases, it recurs after cessation of treatment, as the seeded
stent elutes more bacteria. Active infection is an absolute contraindication to TIPS, and any infection must be cleared before intervention.
The overall post-TIPS 30-day mortality ranges from less than
2% to 30% and is mostly dependent on whether the procedure is
performed emergently or electively. Higher mortality rates are seen
442 MANAGEMENT OF REFRACTORY ASCITES
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TABLE 3 Complications of TIPS
Complication Predisposing Factor(s) Mitigating Factors
Liver failure Limited reserve
High bilirubin
Overshunting
Encephalopathy History of
encephalopathy
High ammonia levels
Limited reserve
Bleeding Difficult anatomy
Abnormal coagulation
profile
Sepsis Active infection Treat infection
Renal failure Elevated creatinine
Dehydration
High contrast load
in patients with poorly compensated liver disease who are having
TIPS placed on an emergent basis, usually for life-threatening variceal bleeding. For patients with compensated liver disease who are
having an elective TIPS created, mortality is less than 5%. It is therefore important to carefully select patients and refer for TIPS before
an emergency. Administration of vasoactive drug therapy, such as
somatostatin and octreotide, in patients presenting with acute variceal hemorrhage has been shown to reduce the risk of mortality at
7 days, in addition to improving hemostasis and shortening length
of stay.
The MELD score, routinely used to predict survival with endstage liver disease and allocate transplants, was initially developed
to predict poor survival in patients after creation of a TIPS. The
cut-off score for high-risk short-term mortality (expected survival of
less than 3 months after TIPS creation) was 18. Subsequent research
using the Na-MELD score that also incorporates serum sodium (Na)
has been shown to be a more accurate predictor of risk post-TIPS
(≥15). Most versions of the MELD score are more accurate predictors
of risk after TIPS than the Child-Pugh score.
Reduce or close the
TIPS
Reduce or close the
TIPS
Flagyl or lactulose
Correct coagula-
tion profile
before TIPS
Hydrate
Bicarbonate
Utilize CO
2
Follow-Up
Long-term TIPS follow-up is based mostly on clinical signs and
symptoms. Ultrasound surveillance is useful if signs or symptoms of
recurrent portal hypertension occur; importantly, TIPS ultrasound
should generally be avoided for the first 2 weeks after TIPS creation.
This is because the newly placed TIPS has air trapped within it,
which limits ultrasound penetration and can simulate the sonographic appearance of an occluded TIPS. Recurrent variceal bleeding
or ascites is a very specific indicator of TIPS restenosis or occlusion
and should prompt a diagnostic venogram or intervention.
SUMMARY
The most important determinant of clinical outcomes after TIPS
placement is proper patient selection and preparation. Cirrhotic
patients with portal hypertension should be under surveillance and
referred for TIPS after conservative management fails but before complications of portal hypertension manifest into an emergency. This,
along with optimal patient preparation, can help reduce the once
high morbidity and mortality related to TIPS. The benefits of TIPS
include reduced drop-off rate from the liver transplant list, improved
lifestyle quality (i.e., resolution of ascites), and reduction of many
portal-hypertension-related complications. Most importantly, TIPS
is often a lifesaving procedure for those with variceal hemorrhage.
S U G G E S T E D R E A D I N G S
Carrion AF, Martin P. Keeping Patients with End-Stage Liver Disease Alive
While Awaiting Transplant: Management of Complications of Portal
Hypertension. Clin Liver Dis. 2021;25(1):103–120.
Ferral H, Behrens G, Lopera J. Budd-Chiari syndrome. AJR Am J Roentgenol.
2012;199(4):737–745.
Ferral H, Gamboa P, Postoak DW, et al. Survival after elective transjugular
intrahepatic portosystemic shunt creation: prediction with model for endstage liver disease score. Radiology. 2004;231:231–236.
García-Pagán JC, Caca K, Bureau C, et al. Early TIPS (Transjugular
Intrahepatic Portosystemic Shunt) Cooperative Study Group. Early use
of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med.
2010;362(25):2370–2379.
Kim DJ, Darcy MD, Mani NB, etal. Modified Balloon-Occluded Retrograde
Transvenous Obliteration (BRTO) Techniques for the Treatment of Gastric
Varices: Vascular Plug-Assisted Retrograde Transvenous Obliteration
(PARTO)/Coil-Assisted Retrograde Transvenous Obliteration (CARTO)/
Balloon-Occluded Antegrade Transvenous Obliteration (BATO).
Cardiovasc Intervent Radiol. 2018;41(6):835–847.
Valentin N, Korrapati P, Constantino J, Young A, Weisberg I. The role of tran-
sjugular intrahepatic portosystemic shunt in the management of portal
vein thrombosis: a systematic review and meta-analysis. European Journal
of Gastroenterology & Hepatology. 2018;30(10):1187–1193.
Management of
Refractory Ascites
Justin Brilliant, MD, and James P. Hamilton, MD
INTRODUCTION
Ascites, the abnormal accumulation of fluid in the peritoneal cavity,
is one of the major complications of portal hypertension in cirrhosis
and portends a poor prognosis. Ascites is the most common complication of cirrhosis with approximately 50% of patients developing
ascites within 10 years. The initial workup for a cirrhotic patient
with ascites should include evaluation of the ascitic fluid and kidney
function because of common complications such as spontaneous
bacterial peritonitis (SBP) and hepatorenal syndrome. All patients
should restrict their daily sodium intake to 2 grams to minimize fluid
retention, consume at least 1 g/kg of their body weight of protein
each day to avoid malnourishment, and start diuretics for a goal of
0.5 kg of fluid loss each day. In the meantime, prompt referral for
liver transplant should be undertaken as one-half of all cirrhotic
patients with ascites die within 5 years.
However, as cirrhosis progresses with worsening ascitic fluid
retention, patients have greater difficulty maintaining their effective
arterial blood volume leading to impaired renal solute-free water
excretion and renal vasoconstriction. This complication is known
PORTAL HYPERTENSION 443
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as refractory ascites and is defined as fluid that cannot be mobilized
despite a 2-gram sodium-restricted diet and high-dose diuretic
treatment (160 mg of furosemide and 400 mg of spironolactone)
or that reaccumulates rapidly after therapeutic paracentesis. Signs
of diuretic failure include lack of weight loss, inadequate sodium
excretion in the urine (<78 mEq/day), and development of complications such as progressive azotemia, hepatic encephalopathy, or
progressive electrolyte imbalances. Refractory ascites only occurs in
10% of patients with both cirrhosis and ascites. Importantly, detailed
assessment of dietary and medicine compliance, abstinence from
alcohol and medications that reduce effective arterial blood volume
(e.g., nonsteroidal antiinflammatory drugs, angiotensin-converting
enzyme inhibitors, angiotensin II receptor antagonists, etc.), and
exclusion of infection should be done before the diagnosis and
subsequent management of refractory ascites.
Urinary Electrolyte Measurement in Refractory
Ascites
Patients who gain weight on maximum diuretics but excrete less than
78 mEq of sodium per day from the urine are refractory to diuretics.
To measure urinary sodium excretion, a 24-hour urinary collection
is necessary as an inadequate collection can underestimate the true
value; however, it can be difficult to obtain an accurate 24-hour
urinary collection in a real-life setting. A random urinary sodium/
potassium ratio can quickly estimate urinary sodium excretion.
Approximately 90% of patients with a urine sodium/potassium
ratio greater than 1 excreted more than 78 mEq/day of sodium in a
24-hour collection. In patients with excretion of more than 78 mEq
of sodium per day from the urine, they are identified as being diuretic-sensitive, thus ruling out refractory ascites; these patients should
theoretically lose weight if adherent to a sodium-restricted diet and
diuretics.
SPONTANEOUS BACTERIAL
PERITONITIS
Diagnosis
Spontaneous bacterial peritonitis (SBP) is an infection of the ascitic
fluid in the absence of an intraabdominal, surgically treatable source.
SBP represents the most frequent bacterial infection in patients with
cirrhosis with the clinical presentation ranging from no symptoms to
mild abdominal pain to sepsis. One-half of the episodes of SBP are
present at the time of hospital admission, and therefore, prompt recognition of SBP, ideally within 6 hours, via a diagnostic paracentesis
is essential in patients hospitalized with both cirrhosis and ascites.
The diagnosis is made in the presence of an elevated polymorphonuclear leukocyte (PMN) count of 250 cells/mm
ascitic fluid, with or without a positive culture in the ascitic fluid, in
the absence of other causes of peritonitis.
Empiric Treatment
When the ascitic fluid PMN count is 250 cells/mm3 or higher, empiric
antibiotic therapy is indicated even before cultures grow bacteria to
mitigate risks of sepsis, end-organ damage, and mortality. Patients
who meet the PMN criterion but have negative ascitic fluid cultures
have been labeled with culture-negative neutrocytic ascites. These
patients have the same symptoms and mortality as those with SBP
and thus require the same treatment as SBP. Patients with fewer than
250 cells/mm
bacterial fluid culture, have been labeled with nonneutrocytic bacteras-
cites. The positive bacterial fluid culture in this setting may represent
a short-lived, reversible colonization that may not warrant antibiotics;
it has been reported that 62% to 86% of cases resolve spontaneously.
However, if a follow-up paracentesis is performed (∼48 hours later)
and the bacterial fluid culture remains positive, empiric treatment is
3
of PMN in their ascitic fluid, but who have positive
3
or higher in the
recommended, especially if patients develop any convincing signs of
infection including sepsis, fever, abdominal pain, and encephalopathy.
Finally, the recognition of secondary bacterial peritonitis is critical
in patients who have localized abdominal symptoms, polymicrobial
growth in ascitic fluid culture, elevated ascitic protein concentration,
or worsening symptoms on broad-spectrum antibiotics because dedicated imaging with surgical management may be necessary.
Choice of Antibiotics
Broad-spectrum antibiotic therapy is warranted for the treatment
of SBP. The treatment of choice is a third-generation cephalosporin
including cefotaxime or ceftriaxone because it provides coverage
against 95% of the three most common bacterial species that cause
SBP. Piperacillin-tazobactam or meropenem may be options in
patients with suspected healthcare-associated or nosocomial SBP
because of higher incidence of bacteria resistant to third-generation
cephalosporins. Furthermore, empiric coverage with carbapenems
such as meropenem may have decreased in-house mortality compared with third-generation cephalosporins among critically ill
patients. However, carbapenem-resistant bacteria have emerged over
the past decade necessitating alternative treatment regimens, such as
combining β-lactams or carbapenems with β-lactamase inhibitors,
that are still currently being investigated. Five days of treatment
has been shown to be efficacious, and treatment may be narrowed
based on sensitivities of cultured organisms. Oral-based regimens
including ofloxacin were as effective as third-generation cephalosporins in asymptomatic SBP but is not routinely recommended
until additional trials are performed. Patients who had received
fluoroquinolones as prophylaxis against SBP should be treated with
nonfluoroquinolone-based regimens secondary to risk of microbial
resistance to the former regimen.
Intravenous Albumin Infusion
The administration of albumin can theoretically improve the
decreased effective arterial blood volume to reduce the risk of renal
failure that afflicts 30% to 40% of patients with SBP. In addition
to the previously discussed antibiotics, IV albumin 25% (1.5 g/kg
within 6 hours on the first day followed by 1 g/kg on day 3) has been
shown to decrease mortality in SBP. The beneficial effect of albumin
was shown particularly in patients with hepatic decompensation or
renal dysfunction (serum bilirubin ≥4 mg/dL, BUN ≥30 mg/dL, and
serum creatinine ≥1 mg/dL).
β-Blockers
Recent studies have called in to question the previous notion that
there was higher mortality in SBP associated with continuation of
nonselective β-blockers for prevention of variceal hemorrhage in
portal hypertension. Previously, β-blockers in SBP increased the
risk for hepatorenal syndrome and acute kidney injury, the time of
hospitalization, and reduced transplant-free survival. However, mortality seems to be more related to the degree of impaired systemic
perfusion. Therefore, nonselective β-blockers may be considered or
reintroduced as long as patients have no evidence of circulatory dysfunction (e.g., mean arterial pressure <65 mm Hg). Future studies are
needed to clarify the optimal duration of nonselective β-blockers and
scenarios when the risk of complications outweighs their benefits.
Follow-Up Paracentesis
A repeat paracentesis to document resolution of SBP is generally not
necessary. Most cirrhotic patients with SBP and typical ascitic fluid
analysis will show clinical response on antibiotic treatment. However,
if symptoms persist or worsen, atypical organisms grow in culture, or
suspicion of secondary peritonitis arises, then a repeat paracentesis
can be performed to evaluate for unresolved infection.
444 MANAGEMENT OF REFRACTORY ASCITES
epigastr
iliac spine
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MEDICAL TREATMENT CONSIDERATIONS
IN REFRACTORY ASCITES
β-Blockers
As stated previously, there may be a role for nonselective β-blockers
in refractory ascites, but they should be used with extreme caution
because patients are predisposed to circulatory collapse. Several
recent studies have shown that increased left ventricular systolic
function via activation of β-1-receptors serves as a compensatory
mechanism due to peripheral vasodilation and decreased effective
arterial blood volume. This physiologic state may underlie the
association from prior studies between nonselective β-blockers that
suppress this cardiac response and poor survival in patients with
refractory ascites. However, only when arterial perfusion pressure
falls below a certain threshold (blood pressure <90/60 mm Hg) does
risk of renal failure, circulatory dysfunction, and mortality increase.
Therefore, a therapeutic window exists for nonselective β-blockers,
and they should be used with caution in patients with hypotension,
hyponatremia, or acute kidney injury. These medications offer a
survival benefit in variceal bleeding prophylaxis and should be
carefully reintroduced if appropriate; doses greater than 160 mg/
day of propranolol or 80 mg/day of nadolol should be avoided.
Vasoconstrictors and Albumin
Vasoconstrictors have been used in the management of hepatorenal syndrome and the prevention of hemodynamic instability after
large volume paracentesis (LVP), along with albumin. The use of
vasoconstrictors with intravenous albumin in patients with cirrhosis
can improve sodium excretion, circulatory function, and ascites
control as long as kidney function is preserved. When taken for at
least 30 days, midodrine, an α-1 receptor agonist, has been shown
to be as effective as albumin in reducing morbidity and mortality
among patients undergoing an LVP at a significantly lower cost.
Midodrine can treat severe hypotension with systolic blood pressures
in the 70s or 80s characteristic of patients with refractory ascites
and improve sensitivity to diuretics while preserving hemodynamic
stability (along with cessation of a β-blocker, if applicable). The
addition of midodrine to standard medical therapy for refractory
ascites can improve renal perfusion, increase renal sodium excretion,
and reduce ascites. Octreotide, a somatostatin analogue, can cause
splanchnic vasoconstriction and improve renal perfusion. Parenteral
octreotide has been effective with oral midodrine and albumin in
reversing type-1 hepatorenal syndrome. In one study analyzing
patients with hepatorenal syndrome, therapy with midodrine, octreotide, and albumin compared with albumin alone was associated
with resolution of kidney injury and decreased mortality. Terlipressin, a vasopressin derivative, also induces splanchnic vasoconstriction and can be used to control ascites. Although terlipressin is not
available in the United States, it has been widely used in Europe and
other parts of the world for hepatorenal syndrome. Recently, a large
randomized, double-blind, placebo-controlled trial (CONFIRM
trial) comparing the safety and efficacy of terlipressin and albumin
in patients with hepatorenal syndrome to those treated with placebo
and albumin was performed. This trial showed that terlipressin and
albumin is associated with a higher likelihood of reversal of hepatorenal syndrome for at least 30 days and 10-day survival without
renal replacement therapy when compared with placebo. However,
patients who received terlipressin were more likely to have respiratory failure within 90 days after the first dose. Terlipressin is not yet
approved in the United States for the management of type-1 hepatorenal syndrome until safety concerns are resolved.
INTERVENTIONAL METHODS IN THE
TREATMENT OF REFRACTORY ASCITES
Liver Transplantation
Liver transplantation is the definitive therapy for patients with cirrhosis and refractory ascites. The development of refractory ascites
confers a poor prognosis, with approximately half of patients dying
within 1 year without transplantation. Therefore, suitable candidates
should be referred to a liver transplant center.
Large Volume Paracentesis with Albumin
Replacement
LVP with albumin replacement is one of the first-line treatments for
refractory ascites while patients are awaiting liver transplantation.
This procedure ameliorates the characteristic symptoms of large
volume ascites such as early satiety, bloating, abdominal pain, and
shortness of breath. Based on the available studies, an infusion of
albumin is recommended after a paracentesis that removes 5 liters
or more of ascitic fluid; the recommended dose of albumin is 6 to
8 g/L of ascites removed. The use of albumin in patients requiring
the removal of at least 5 liters of ascitic fluid reduced electrolyte
abnormalities, renal dysfunction, and postparacentesis circulatory
dysfunction (PPCD). Although there has traditionally been no set
limit on the amount of volume removed, limiting each LVP session
to less than 8 liters with additional albumin (9.0 ± 2.5 g/L of ascites
removed) in one study may reduce mortality and preserve renal
function over a mean period of 2 years despite the onset of PPCD in
40% in this cohort of patients. Furthermore, albumin infusion can be
considered in patients who have <5 L of ascites removed and either
systolic blood pressure <90 mm Hg, hyponatremia (Na <130 g/dL),
or an acute kidney injury. Patients can be scheduled for serial LVPs
every 2 weeks as an outpatient, but this treatment is not an ideal longterm solution because repeated LVPs cause protein depletion, leading
to worsening malnutrition.
The preferred site for needle entry is 3 cm medial and 3 cm superior to the anterosuperior iliac spine on the left lower quadrant of the
abdomen. The right lower quadrant is less desirable because the cecum
can become distended in patients who take lactulose. A distended
cecum has a higher risk of perforation. The needle should avoid areas
with cutaneous infection, abdominal wall hematoma, scars, or visibly
engorged subcutaneous areas. Bedside ultrasound is useful in locating
a safe site for needle entry away from vascular structures.
The paracentesis needle can be inserted with either the angular
technique or the Z-track technique. In the angular technique, the
needle is inserted obliquely from the cutaneous site into the peritoneum. In the Z-track technique, cutaneous tissues are pulled down
and the needle is inserted straight into the peritoneum. These techniques ensure that cutaneous and peritoneal needle entry sites do
not directly overlap, thereby minimizing postprocedure ascitic fluid
leakage (Fig. 1).
Inferior
ic
artery
FIG. 1 Preferred needle entry site for paracentesis.
(From Drake R, Vogel AW. Gray’s Atlas of Anatomy. Philadelphia: Elsevier; 2007.)
Anterior
superior
PORTAL HYPERTENSION 445
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B
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Transjugular Intrahepatic Portosystemic Shunt
Transjugular intrahepatic portosystemic shunt (TIPS) is an artificial
communication between the portal vein and hepatic vein usually
placed by an interventional radiologist (Fig. 2). The direct result of
TIPS placement is a significant reduction in portal pressure through
the creation of an alternative pathway for portal venous flow. Before
and after TIPS placement, the proceduralist can quantify the degree
of portal hypertension by measuring the portosystemic gradient.
The benefit of TIPS is in reversing portal hypertension, the cause of
many complications of cirrhosis. After successful TIPS procedure,
ascites may completely resolve along with portosystemic shunts (e.g.,
esophageal varices) over the span of months.
Under fluoroscopic guidance, the interventional radiologist
accesses the liver through the internal jugular vein in the neck. Once
venous access is confirmed, the radiologist inserts a guidewire and
introducer sheath that enables access to the hepatic veins by passing
the superior vena cava and inferior vena cava. Once the catheter
enters the hepatic vein, the radiologist injects contrast to locate the
portal vein and advances a needle through the liver parenchyma
to connect the two veins. An inflated angioplasty balloon creates a
Inferior vena cava
Catheter
(enters body
in neck)
channel for the shunt along the needle tract. Last, the shunt forms by
placing a polytetrafluoroethylene-covered stent to maintain the tract.
The covered stent has been a standard for many years. It has a higher
patency interval compared with the older uncovered stent.
Absolute contraindications for TIPS include heart failure, severe
tricuspid regurgitation, and severe pulmonary hypertension. TIPS
in the setting of these conditions can lead to severe cardiac volume
overload because blood flow is diverted past the liver and into the
right heart. Sepsis, biliary obstruction, and severe hepatic encephalopathy are other absolute contraindications to TIPS placement.
Patient selection and the timing of a TIPS procedure are very important predictors of patient outcome. The Model for End-Stage Liver
Disease (MELD) score, now used to prioritize organ allocation in
liver transplantation, was initially developed to predict the 3-month
mortality after TIPS. Patients with a MELD score of ≥18 have poorer
outcomes after TIPS. The use of smaller diameter (8–10 mm) stents
has been associated with a lower incidence of hepatic encephalopathy following TIPS with no reduction in ascites clearance. One
study showed that earlier TIPS placement after patients developed
ascites improved 1-year transplant survival compared with patients
receiving serial LVPs, albumin infusions, and diuretics (93% vs.
Balloon
inflated to
dilate tract
Catheter
Guidewire
Portal vein
Right hepatic vein
Balloon
inflated
to expand
wall stent
Stent
x-ray
Varices
Balloon
FIG. 2 Transjugular intrahepatic portosystemic shunt
placement. (Courtesy Johns Hopkins Medical Institutions.)
446 MANAGEMENT OF REFRACTORY ASCITES
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53%, respectively). With additional studies, the optimal timing of
TIPS with appropriate selection criteria can be investigated for safe
and expedited stent placement to improve mortality before liver
transplant.
Peritoneovenous Shunts
Peritoneovenous shunts drain ascitic fluid from the peritoneal cavity into systemic veins, such as the superior vena cava. The Denver
shunt, popular in the 1970s, is the only peritoneovenous shunt still
manufactured today. Although historically requiring an invasive
approach, today it is placed percutaneously in a minimally invasive
procedure through an internal jugular or subclavian route. The
shunt is made of soft tubing connected to a pump chamber that lies
subcutaneously over the lower ribs. Ascitic fluid flows spontaneously
from the peritoneum to the superior vena cava, but manual pumping
helps avoid buildup of proteinaceous material in the shunt. Nonetheless, because of poor long-term patency and complications such
as obstructions, coagulopathy, superior vena cava thrombosis, and
sepsis, peritoneovenous shunts are infrequently used today.
Peritoneal Catheters
A peritoneal catheter (PleurX) inserted into the peritoneum can be
an option for ascites removal in patients with the goal of palliation.
Given the risk of introducing infection into the peritoneum, this
option is typically reserved for patients who are near the end of life.
The catheter can be placed with minimal discomfort using a small
incision. It is then sutured in place to the skin and connected to a
catheter bag. Patients may open the catheter to the bag at their convenience, allowing patients who may be less mobile to avoid traveling
to medical facilities for repeated paracenteses.
EXPERIMENTAL OPTIONS
Clonidine and Midodrine
Clonidine is an α-2-adrenergic receptor agonist that suppresses
the renin-aldosterone system, which is activated in patients with
refractory ascites. Clonidine has shown promise when used in combination with furosemide and spironolactone in refractory ascites
with one study showing a 60% diuretic-response rate after 3 months.
The combination of clonidine with midodrine, an oral α-1-receptor
agonist, and standard medical therapy (sodium restriction, use of
diuretics, and serial LVPs as needed) was investigated in one trial.
The effect of combination therapy on systemic hemodynamics, renal
function, and control of ascites was not greater than clonidine or
midodrine by themselves when used with standard medical therapy.
Sodium-Glucose Cotransporter 2 Inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are medications
that are now used in type 2 diabetes mellitus for treating hyperglycemia. These medications block a major transport protein, SGLT2,
in the proximal tubules of the kidney to block nearly 90% of the
kidney’s glucose reabsorption. SGLT2 inhibitors have been shown
to exhibit protective effects on the liver, heart, and kidney through
natriuresis, deactivation of the renin-angiotensin-aldosterone system, and antiinflammatory effects. In three patients who had cirrhosis due to nonalcoholic steatohepatitis and diabetes along with fluid
retention, SGLT2 inhibitors were associated with reduction in ascites
and peripheral edema. Serum sodium levels improved as well. Clinical trials are needed to investigate the safety and efficacy of SGLT2
inhibitors in refractory ascites.
Low-Flow Ascites Pump (ALFApump)
European surgeons and radiologists have collaborated to develop
a pump (ALFApump) that moves ascitic fluid from the peritoneal
cavity into the urinary bladder. Previous studies showed a decrease in
the need for large-volume paracentesis in those with refractory ascites, with most patients not requiring paracentesis after implantation
of the pump system. In a multicenter randomized controlled trial
including 60 patients with refractory ascites, the median time to first
LVP was not reached after 6 months in patients with an ALFApump
compared with 15 days for the standard-of-care group. Improved
quality of life was also seen in the ALFApump group. However, the
frequency of severe adverse events, including acute kidney injury
and reintervention for pump-related issues, was significant in the
ALFApump group but did not impact survival. Commonly observed
complications in low-flow ascites pumps include blockage of the
peritoneal catheter, infections, and bleeding. Careful discussion on
the risks and benefits of these devices need to be undertaken with
close longitudinal follow-up. Currently, the ALFApump is not available in North America but is currently under clinical investigation in
the United States and Canada.
S U G G E S T E D R E A D I N G S
Adebayo D, Neong SF, Wong F. Refractory ascites in liver cirrhosis. American
Journal of Gastroenterology. 2019;114(1):40–47.
Angermayr B, Cejna M, Karnel F, etal. Child-Pugh versus MELD score in
predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt. Gut. 2003;52(6):879–885.
Biggins SW, Angeli P, Garcia-Tsao G, etal. Diagnosis, evaluation, and manage-
ment of ascites and hepatorenal syndrome. Hepatology. 2021;74(2):1014–
1048.
El-Bokl MA, Senousy BE, El-Karmouty KZ, etal. Spot urinary sodium for
assessing dietary sodium restriction in cirrhotic ascites. World Journal of
Gastroenterology. 2009;15(29):3631.
European Association for The Study of the Liver. EASL Clinical Practice
Guidelines for the management of patients with decompensated cirrhosis.
Journal of Hepatology. 2018;69(2):406–460.
Marciano S, Diaz JM, Dirchwolf M, Gadano A. Spontaneous bacterial peri-
tonitis in patients with cirrhosis: incidence, outcomes, and treatment
strategies. Hepatic Medicine: Evidence and Research. 2019;11:13.
Montalvo-Gordon I, Chi-Cervera LA, García-Tsao G. Sodium-glucose
cotransporter 2 inhibitors (SGLT2-I) ameliorate ascites and peripheral
edema in patients with cirrhosis and diabetes. Hepatology (Baltimore,
Md.). 2020;72(5):1880–1882.
Téllez L, Ibáñez-Samaniego L, Del Villar CP, etal. Non-selective beta-block-
ers impair global circulatory homeostasis and renal function in cirrhotic
patients with refractory ascites. Journal of Hepatology. 2020;73(6):1404–
1414.
Wong F, Pappas SC, Curry MP, etal. Terlipressin plus albumin for the treat-
ment of type 1 hepatorenal syndrome. New England Journal of Medicine.
2021;384(9):818–828.
PORTAL HYPERTENSION 447
Liver dysfunction:
- Impaired ability
to clear ammonia
- Decreased bile
acid secretion
Chronic liver disease:
Brain
Pathophysiology of hepatic
https://t.me/medicina_free
Management of Hepatic
Encephalopathy
Amanda Su, MD, Venkata S. Akshintala, MD, and
Vikesh K. Singh, MD, MSc
epatic encephalopathy (HE) is characterized by a spectrum of
neurocognitive changes, ranging from subclinical symptoms to
H
life-threatening coma, and results from chronic liver disease, acute
liver failure (ALF), or portosystemic shunting (PSS).
PATHOPHYSIOLOGY
The pathogenesis of HE is multifactorial and not completely understood, though prevailing hypotheses frequently implicate the effects
of ammonia on brain function (Fig. 1). Ammonia is produced in
the gut by colonic bacteria and mucosal enzymes that break down
protein. It then enters portosystemic circulation and, under normal
conditions, is excreted from the body mainly via urea production
in the liver. When hepatocyte function is impaired, or if the liver is
bypassed as in portosystemic shunting, hyperammonemia results.
Ammonia can also be processed via glutamine synthetase in skeletal muscle. However, with sarcopenia, or low muscle mass, being
common in patients with cirrhosis, this pathway of excretion is often
limited.
The gastrointestinal tract and microbiome play an important
role in the regulation of ammonia. In hepatic dysfunction, there is
decreased bile acid secretion to the gut, leading to changes in gut
microbiota. Patients with liver dysfunction and HE are more likely
to have an increased proportion of potentially pathogenic microbiota, which are linked to systemic inflammation, endotoxemia and
cognitive impairment, though these underlying pathways remain a
topic of research.
At the cellular level, ammonia crosses the blood-brain barrier,
and excess ammonia in the brain results in neuronal dysfunction.
Astrocytes convert ammonia and glutamate to glutamine, and in
hyperammonemia, accumulation of glutamine leads to cerebral
edema. Additionally, ammonia acts on benzodiazepine receptors,
leading to decreased excitatory neurotransmission. There is additional evidence for increased inflammation in the brain as well as
changes in cerebral blood flow. Other toxins that have been implicated in HE include manganese, mercaptans, lactate, and dopamine
metabolites.
DIAGNOSIS AND GRADING
HE is diagnosed clinically, after other etiologies of altered mental
status and neurocognitive dysfunction are excluded. There are three
major types of HE based on etiology: type A HE results from ALF,
type B HE results from portosystemic bypass/shunting, and type C
HE results from cirrhosis. The severity of HE can range from subclinical symptoms to coma and is graded based on the West Haven
Criteria (Table 1). Overt HE (grade >2) is considered a clinical
manifestation of decompensated liver disease and should be treated
promptly.
HE can lead to various cognitive, behavioral, and motor changes,
though these do not necessarily occur in parallel, and presentations
can vary. Cognitive and behavioral changes can be more formally
evaluated using neuropsychometric and neurophysiologic testing,
though there are no tests specifically studied for HE. Early stages of
HE are often characterized by reduced awareness of surroundings,
decreased attention, and impaired balance. In later stages of HE,
patients often exhibit impairment of consciousness with fluctuating
attention and slow responses, and progression to stupor. On physical examination, asterixis is a characteristic sign of overt HE that
encephalopathy due to liver
dysfunction
Urea
Glutamine
Glutamine
Ammonia
Neuron
dysfunction
LIVER
Urea Cycle
Ammonia
Glutamine
synthetase
FIG. 1 Pathophysiology of hepatic encephalopathy due to liver dysfunction.
synthetase
Gut
Urease-producing
bacteria
Digested
protein
Glutaminase
Glutamine
Cerebral
edema
Portosystemic
shunt
Liver dysfunction:
- Impaired blood-brain barrier
- Hyperammonemia leads to
neuron dysfunction
- Increased glutamine production
leads to astrocyte swelling
and cerebral edema
Ammonia
Ammonia,
endotoxins,
inflammatory
cytokines
Skeletal Muscle
Glutamine
synthetase
Glutamine
Liver dysfunction:
- Dysbiosis–overgrowth of certain
bacteria
- Increased intestinal permeability
Increased release of ammonia,
endotoxin, and inflammatory cytokines
- Sarcopenia in
liver disease
leads to
decreased ability
to clear ammonia
448 MANAGEMENT OF HEPATIC ENCEPHALOPATHY
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TABLE 1 Grading of Hepatic Encephalopathy
Grade/Severity Description
Minimal Covert Alterations of psychometric or neu-
rophysiologic tests without clinical evidence of mental change
Grade 1
Grade 2 Overt • Lethargyorapathy
Grade 3 Overt • Somnolence
Grade 4 Overt • Coma
represents loss of postural tone and can be elicited by hyperextension
of the wrists. This can occur in other disease states as well, however,
so it should not be considered pathognomonic for HE. Other motor
disturbances seen in HE include hypertonia, hyperreflexia, and a
positive Babinski sign.
HE is associated with changes in electroencephalographic (EEG)
pattern, including dyssynchronization of fast activity, dysrhythmicity, and slower delta activity and disorganization. Triphasic-wave
patterns appear in grade 2 or 3 HE and disappear in the comatose
state. Brainstem-evoked potentials may be helpful for detection of
subclinical HE. It should be noted that EEG findings are not necessary for diagnosis of HE, and in assessment of patients with potential
HE, EEG may be most useful in ruling out nonconvulsive status
epilepticus.
Measurement of serum ammonia levels has limited utility in the
diagnosis and management of HE in chronic liver disease. There is
wide variability and lability of serum ammonia levels related to sample collection, fasting state, and protein load which may confound
interpretation. Studies have shown that ammonia testing does not
improve outcomes in HE. The American Association for Study of
Liver Disease/European Association for the Study of Liver guidelines
recommends against using ammonia levels alone for managing HE
(grade IIA recommendation).
Covert
• Triviallackofawareness
• Euphoriaoranxiety
• Shortenedattentionspan
• Alteredsleeprhythm
• Disorientationtotime
• Inappropriatebehavior
• Asterixis
• Confusion
• Grossdisorientation
Differential Diagnosis
HE remains a diagnosis of exclusion, so it is critical to evaluate for
other causes of altered mental status before initiating treatment.
Some common etiologies that may produce a similar clinical picture
are listed in Table 2. Alcohol intoxication or withdrawal can result
in delirium and slurred speech. Wernicke-Korsakoff ’s syndrome,
in particular, can produce an altered state including inattention and
amnesia, though it is additionally associated with ophthalmoplegia,
gaze-evoked nystagmus, and ataxia. Metabolic derangements including hyponatremia, hypoglycemia, and metabolic alkalosis should be
screened for and can be corrected as clinically appropriate. Nonconvulsive status epilepticus must also be considered and requires
careful interpretation of EEG findings. Chronic or acute subdural
hematoma may mimic some signs of HE, and liver dysfunction
increases risk of intracerebral hemorrhage; thus, CT scans are often
part of the initial assessment in patients with suspected HE.
TABLE 2 Differential Diagnosis for Hepatic
Encephalopathy
Disorders Comments
Alcohol Alcohol intoxication or withdrawal
Consider Wernicke-Korsakoff’s
syndrome
Drugs/toxins Benzodiazepines, opiates,
neuroleptics
Electrolyte disorder Common electrolyte abnormalities
include hyponatremia, hypoglycemia, metabolic alkalosis
Nonconvulsive epilepsy Consider EEG to evaluate seizure
activity
Psychiatric disorder Consider psychiatric evaluation
Intracranial bleeding or
stroke
CT scan is often part of initial
workup
TABLE 3 Precipitating Factors of Hepatic
Encephalopathy
Precipitating
Factors
Infection Diagnostic paracentesis is indicated in
GI bleeding Consider history of varices, portal hyper-
Diuretic overdose Due to low albumin, patients with cirrho-
Electrolyte disorder Prone to electrolyte derangements due to
Constipation Noncompliance with laxatives, particularly
Sedating agents Benzodiazepines, opiates, hypnotic agents,
Notes
initial workup to rule out spontaneous
bacterial peritonitis (SBP), in addition
to blood, urine and imaging studies.
tensive gastropathy
sis may have edema but be intravascularly dry
liver dysfunction as well as commonly
prescribed diuretics and laxatives
Some patients may have chronic
hyponatremia
lactulose is common
alcohol
PRECIPITATING FACTORS
Patients with overt HE often present with precipitating factors
(Table 3), and identification and management of these factors are an
important initial step in treatment of HE.
Infection is a common precipitant of HE, and patients with
chronic liver disease may be prone to infection due to a proinflammatory state. Sources of infection to consider in initial evaluation
include spontaneous bacterial peritonitis (SBP), in addition to urinary tract, pulmonary, and skin and soft tissue infections. Empiric
antibiotic therapy should be initiated if there is high clinical suspicion for infection. Empiric coverage for SBP may have slightly different dosing compared with other infections.
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