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PORTAL HYPERTENSION 447
Liver dysfunction:
- Impaired ability
to clear ammonia
- Decreased bile
acid secretion
Chronic liver disease:
Brain
Pathophysiology of hepatic
https://t.me/med1917
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.
PORTAL HYPERTENSION 449
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Gastrointestinal bleeding is another common precipitant of HE.
In addition to overt evidence of bleeding, high blood urea nitrogen-to-creatinine ratio or history of known varices or portal hypertensive gastropathy may be clues. Gastrointestinal bleeding decreases
perfusion to key organs in ammonia clearance including the liver and
kidneys. In addition, blood also acts as a large protein substrate in the
gut, leading to increased production of ammonia.
Patients with cirrhosis are at risk for volume depletion and electrolyte imbalance, each of which can precipitate HE. Overdiuresis or
misuse of laxatives can both cause and exacerbate volume depletion.
TREATMENT FOR HE IN CHRONIC
LIVER DISEASE
Nonabsorbable Disaccharides
Lactulose is recommended by the American Association for the
Study of Liver Diseases (AASLD) and European Association for the
Study of the Liver (EASL) guidelines as first-line treatment for overt
HE (grade II B) (Table 4). It is a nonabsorbable disaccharide that is
thought to acidify the gut environment, making it less favorable to
ammonia-producing bacteria. It also increases bowel movement,
increasing excretion of nitrogen-containing compounds.
Lactulose is titrated to effect and required dose varies among
patients. Initially it should be started at 20 to 30 g every hour until defecation occurs. It can then be spaced to 20 to 30 g every 4 to 6 hours
depending on clinical improvement. In patients unable to take oral
lactulose, enteral access may be obtained via nasogastric tube for
lactulose administration. In some patients, placement of a nasogastric
tube may be contraindicated (i.e., esophageal varices or recent banding), and lactulose can also be administered rectally by enema.
After an initial episode of HE, lactulose is recommended to prevent recurrent episodes of HE and is generally titrated to 2 or 3 bowel
movements per day. Recent studies, however, suggest that fewer
bowel movements may be as effective. Common side effects include
nausea, bloating, and diarrhea. Lactinol is another nonabsorbable
disaccharide with comparable effectiveness; however, it is not available in the United States.
Oral Nonabsorbable Antibiotics
Rifaximin is the primary nonabsorbable antibiotic used for the treatment of HE. It suppresses intestinal flora and thus decreases their
production of ammonia and associated toxins in the gut and has been
studied for treatment in HE in several clinical trials. Rifaximin has
mainly been studied as an addition to lactulose therapy. There is some
evidence that rifaximin monotherapy may be appropriate in those who
have HE refractory to lactulose or with lactulose intolerability, though
further research is needed. Unfortunately, rifaximin is often not covered by insurance and is expensive as an outpatient therapy. Currently,
rifaximin is recommended for use in combination with lactulose for
prevention of recurrent HE (grade IA recommendation).
TABLE 4 Medical Treatments for Hepatic Encephalopathy
Drug Dosing Comments
GUIDELINE RECOMMENDED FIRST-LINE THERAPIES
Lactulose Oral: Initial: 20 to 30 g every hour until
defecation. Reduce to 20 g every 4–6 hours
until clinical improvement. Maintenance:
20 g every 8–12 hours, titrated to goal
2–3 stools/day
Rectal: Enema. 200 g lactulose in tap water
Repeat every 4–6 hours
Rifaximin Oral: 550 mg twice a day Guideline recommended
ALTERNATIVE THERAPIES
Polyethylene glycol (PEG) Oral: PEG-based electrolyte solution: 4 L admin-
istered over 4 hours or 2 L every 12 hours
PEG powder: 17 g twice daily to three times
daily, titrated to 2-3 bowel movements daily
BCAA No standard dosing Add-on or alternative therapy
LOLA IV: 30 g daily Add-on or alternative to first-line therapy
Probiotics Varies Many different types available commer-
Zinc Varies depending on zinc level Patients should be screened for zinc deficiency;
First-line guideline recommended therapy
SE: bloating, nausea, diarrhea
Recent studies suggesting increased number of
BMs may not be needed for lactulose to be
effective
Add on to lactulose or as alternative if lactu-
lose not tolerated
Can be expensive and may not be covered by
insurance
Second-line therapy
May be more effective than lactulose, further
studies needed
IV BCAA not effective
Oral LOLA not effective
Not available in the United States
cially, most effective for HE appear to be
Lactobacilli and Bifidobacteria species
empiric supplementation has less evidence
BCAA, Branched-chain amino acids; BM, bowel movement; LOLA, L-ornithine and L-aspartate; SE, side effects.
450 MANAGEMENT OF HEPATIC ENCEPHALOPATHY
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Alternative Therapies for HE
Polyethylene glycol (PEG) has been used both as a PEG-based electrolyte solution (Golytely, Nulytely) and in powder form (MiraLAX). It
has been shown to improve measures of HE as well as outcomes such
as hospitalization and survival in patients with HE. Recent studies show
that it may be more effective than standard therapy with lactulose. It is
not yet recommended in guidelines as a first-line treatment; however, it
is a good alternative, especially in patients unable to tolerate lactulose.
Other laxatives have been studied, but more research is required to
examine their efficacy and safety in HE.
Branched-chain amino acids (BCAA) including valine, leucine,
and isoleucine enhance ammonia detoxification to glutamine, particularly in skeletal muscle. BCAA supplementation may also reduce
malnutrition and decrease loss of muscle mass common in severe
liver disease. Studies in patients with HE showed improvement in
outcomes in patients with or without symptoms of muscle wasting.
However, BCAAs also carry side effects such as disruption of certain
metabolic pathways and altered neurotransmission, and thus further
research is needed to evaluate their use in patients with HE.
L-Ornithine and L-aspartate (LOLA) are involved in the urea
cycle and help glutaminase convert ammonia and accelerate its
elimination from the body. Although LOLA is not widely used, it is a
good option, particularly for patients with HE due to portosystemic
shunting. LOLA is recommended as an adjuvant treatment, not as a
monotherapy, but it is not currently available in the United States.
OTHER THERAPIES REQUIRING
FURTHER RESEARCH
Probiotics are cultures of live microorganisms that help balance the
normal flora of the gut. Most commercially available probiotic products are derived from food sources, especially milk products. There
are many microorganisms that have been studied, with the most
efficacious species for HE being Lactobacilli or Bifidobacteria. Some
studies have suggested benefit in prevention of recurrent HE. However,
more data are needed for a strong recommendation for the treatment
or prevention of HE.
Zinc is a cofactor in the urea cycle and may facilitate ammonia
clearance. Zinc deficiency should be screened for and repleted in all
patients with HE. Clinical trial data regarding empiric zinc supplementation is lacking; however, it has few side effects.
Metabolic ammonia scavengers act as urea surrogates and
have been used in treatment for inborn errors of the urea cycle.
Ornithine phenylacetate and glyceryl phenylbutyrate have been
studied for HE; however, further clinical trials are needed for clinical
recommendation.
Flumazenil is an antagonist of benzodiazepine receptors. It has
been shown in small randomized controlled trials to transiently
improve mental status, however, is not commonly used for this indication and is not recommended for routine treatment of HE.
Phenylbutyrate reduces glutamine availability, suppressing
ammonia production. It also promotes ammonia detoxification
via glutamine synthetase reaction. Studies have shown that use of
glycerol phenylbutyrate and sodium phenylbutyrate in patients with
recurrent HE resulted in fewer episodes of HE. However, phenylbutyrate also causes a decrease in BCAA in the blood.
Other antibiotics: Neomycin was previously used in treatment of HE. It is a nonabsorbable antibiotic, a known glutaminase
inhibitor and functions similarly to rifaximin. However, it has
been shown to have some systemic absorption with ototoxic and
nephritic side effects and thus is not recommended for long-term
first-line use. Metronidazole has similarly been studied as a shortterm therapy, but is also associated with ototoxicity, nephrotoxicity,
and neurotoxicity.
Other laxatives: Other laxatives, without the prebiotic properties of disaccharides, may also be beneficial by increasing bowel
movement. However, further research is needed before these can be
recommended in routine use.
OTHER CONSIDERATIONS
Nutrition
Nutrition plays a crucial role in patients with cirrhosis and especially HE,
as they are prone to malnutrition and sarcopenia. Muscle tissue in particular plays a compensatory role in HE through metabolism of ammonia
via glutamine synthetase. Protein restriction, previously recommended
in this patient population, is no longer routinely advised. Recent studies
recommend daily intake of energy of 35 to 40 kcal/kg and 1.2 to 1.5 g protein/kg (grade IA recommendation). Regular caloric ingestion with frequent meals or snacks is also recommended (grade IA recommendation),
as conversion of amino acids for glucose production in gluconeogenesis
depletes tissue protein stores and produces ammonia. Consultation with
a nutritionist is often helpful in tailoring an optimal diet.
Hepatic Encephalopathy after Transjugular
Intrahepatic Portosystemic Shunt
Transjugular intrahepatic portostytemic shunt (TIPS) is often
performed in patients with chronic liver disease for management
of bleeding esophageal varcies or refractory ascites. HE is a major
complication after TIPS, and patients must be carefully selected
before undergoing TIPS. Lactulose and rifaximin are not recommended prophylactically after TIPS; however, they can be used
if HE develops. Post-TIPS HE may be refractory to conventional
management, and in these cases shunt diameter reduction, or
higher goal portal pressure, can be helpful.
Portosystemic Shunts
Recurrent HE with relatively preserved hepatic function should lead
to investigation for spontaneous portosystemic shunts. Depending
on the type of shunt, it may be possible to embolize the shunt, with
resolution of HE in many patients.
Liver Transplantation
HE alone is not considered an indication for liver transplantation
(LT). However, in some patients with relatively good liver status, HE
may be severe and significantly worsen quality of life, and LT may
be considered. Although HE should improve after LT, those with
large PSSs may have persistent symptoms. Additionally, patients may
develop confusion during the postoperative period due to the toxic
effect of immunosuppressant drugs.
Acute Liver Failure
ALF is defined as severe liver injury in the absence of prior liver
disease with development of coagulopathy (INR >1.5) and HE. In
the developing world, acetaminophen toxicity is the most common
etiology, while viral hepatitis is the most common in the developing
world. Given the potential for rapid deterioration, early transfer
to the Intensive Care Unit for monitoring and management is recommended. Patients with grade 3 HE or higher will likely require
intubation for airway protection and should have regular neurologic
checks to evaluate for signs of elevated intracranial pressure (ICP).
Patients with ALF should be transferred to a liver transplant center
early in their course for evaluation for LT.
In contrast to chronic liver disease, arterial ammonia levels have
been shown to correlate with severity of HE in ALF. Ammonia levels
>200 have been associated with increased risk of cerebral edema and
intracranial hypertension. Conventional treatments for HE, lactulose
and rifaximin, have not been shown to be beneficial in ALF. Continuous renal replacement therapy (CRRT) is an effective method of
rapid and clinically meaningful ammonia clearance.
CT scans should be carefully considered in these patients, as moving
patients with severe HE can lead to surges of ICP. Furthermore, CT scans
may be insensitive to small changes in ICP, though they are helpful in
PORTAL HYPERTENSION 451
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the diagnosis of intracranial hemorrhage and cerebral herniation. Other
neuroprotective interventions include elevation of the head to 30 degrees,
avoiding fever, and maintaining euglycemia. It is also recommended to
maintain serum sodium between 140 and 145 mmol/L with use of hypertonic saline when needed. Development of clinical signs of increased
ICP should be treated with hypertonic saline (200 mL, 2.7% or 20 mL,
30%) or intravenous mannitol (150 mL, 20%) given over 20 minutes.
Hyperventilation to reduce arterial PaCO
be beneficial in the acute setting to promote cerebral vasoconstriction.
The use of invasive ICP monitoring devices is controversial, especially given high risk of bleeding in patients with ALF. In patients
with monitored ICP, the goal pressure is below 20 to 25 mm Hg, and
the cerebral perfusion pressure should be above 50 mm Hg. Noninvasive techniques such as transcranial Doppler ultrasound and jugular
venous oximetry may be helpful as another tool for risk stratification.
to 25 to 30 mm Hg may also
2
Extracorporeal Liver Support Devices
Extracorporeal liver support (ELS) is an invasive option in patients
with ALF, with limited data showing benefit in HE but no clear mortality benefit. The Molecular Adsorbent Recirculating System (MARS)
dialyzes blood across an albumin-impermeable membrane, with
protein-bound and water-soluble toxins removed through a secondary circuit. Randomized trials have not shown overall benefit effect
of MARS on morality in patients with ALF or acute on chronic liver
failure, though some nonrandomized trials have suggested benefit in
HE symptoms or in need of transplantation. The fractionated plasma
separation, adsorption, and dialysis technology of the Prometheus system separates patients’ albumin and plasma from blood and then uses
two columns of absorbents and a high-flux dialyzer to clear toxins.
One study showed safety and efficacy in patients with ALF, though it
did not improve survival of patients with acute on chronic liver failure.
Single pass albumin dialysis (SPAD) uses a specialized high-flux albumin impermeable membrane and addition of HSA to a standard dialysis setup. In the few studies thus far, it has not shown to have an impact
on survival or referral to transplantation. High volume therapeutic
plasma exchange (HVP) is based on removal of toxins and harmful
inflammatory mediators, as well as replacement of beneficial plasma
proteins (such as coagulation factors) and in small studies has been
shown to have a survival benefit, though further research is needed.
ELS is used at some centers in patients with ALF as a bridging
option to either transplant or recovery of liver function, though
studies for these indications are still needed. In addition, ELS
has been used in cases of secondary liver failure, for example, in
hypoxic hepatitis or in conjunction with extracorporeal life support
(i.e., extracorporeal membrane oxygenation [ECMO]). Studies have
shown improvement in HE and a trend toward decrease in mortality;
however, there is still no clear data showing a benefit in mortality and
morbidity in specific patient populations, for example, as a bridge to
transplant or in concurrence with ECMO.
S U G G E S T E D R E A D I N G S
Bajaj JS. The role of microbiota in hepatic encephalopathy. Gut Microbes.
2014;5(3):397–403.
Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary
approach and gut microbiota modulation for chronic hepatic encephalop-
athy in cirrhosis. World J Hepatol. 2019;11(6):489–512.
Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs. Polyethylene
Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic
Encephalopathy: The HELP Randomized Clinical Trial. JAMA Intern
Med. 2014;174(11):1727.
Vilstrup H, Amodio P, Bajaj J, etal. Hepatic encephalopathy in chronic liver
disease: 2014 Practice Guideline by the American Association for the
Study of Liver Diseases and the European Association for the Study of the
Liver: Vilstrup etal. Hepatology. 2014;60(2):715–735.
Wendon J, Cordoba J, Dhawan A, et al. EASL Clinical practical guide-
lines on the management of acute (fulminant) liver failure. J Hepatol.
2017;66(5):1047–1081.
Wiesmann T, Hoenl D, Wulf H, Irqsusi M. Extracorporeal liver support:
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Management of
Budd-Chiari Syndrome
Joseph DiNorcia, MD, and Ronald W. Busuttil, MD, PhD
INTRODUCTION
Budd-Chiari syndrome (BCS) is a rare disorder that results from
the obstruction of hepatic venous outflow, leading to progressive
liver damage and portal hypertension. In 1845, George Budd, a
British internist, first described the clinical syndrome as a triad of
abdominal pain, hepatomegaly, and ascites. In 1899, Hans Chiari,
an Austrian pathologist, described the pathologic features of BCS as
occlusion of the hepatic veins. This venous occlusion can be due to
various causes. Primary BCS results from intrinsic thrombosis of the
hepatic veins secondary to prothrombotic, hypercoagulable states or
a congenital venous web. Secondary BCS results from thrombosis due
to extrinsic compression or invasion of the hepatic veins, for example, due to a tumor, granuloma, cyst, or abscess (Box 1).
PATHOGENESIS
Hepatic venous outflow obstruction causes increased pressure in the
hepatic sinusoids, leading to venous congestion and decreased intrahepatic portal venous perfusion within the liver. The congestion induces
hepatic fibrosis that progresses over time to cirrhosis with resultant
portal hypertension, collateral venous flow, and ascites. The decreased
intrahepatic portal venous perfusion further contributes to ischemia,
hepatocyte necrosis, and fibrosis that causes hepatic dysfunction. Gross
pathologic examination of livers with BCS commonly demonstrates
large regenerative nodules. Acute histologic features include marked
sinusoidal dilatation with centrilobular congestion, edema, and hemorrhage, which progresses in the chronic setting to hepatocyte necrosis,
fibrosis, and cirrhosis. Central venous thrombi may be seen as well.
PRESENTATION
The clinical presentation of BCS depends on the onset, severity, and
duration of the disease and can be categorized as acute liver failure
(life-threatening symptoms of acute liver injury), acute (rapid symptom
onset without acute liver failure), subacute (insidious symptom onset
before cirrhosis), and chronic (late symptom onset after the development
of cirrhosis). Acute liver failure secondary to BCS is rare and results from
massive liver necrosis causing coma, severe coagulopathy, and hypoglycemia. The chronic form of BCS is more common, presenting with stigmata of end-stage liver disease such as fatigue, hepatic encephalopathy,
jaundice, gastrointestinal bleeding, abdominal distension due to ascites,
renal dysfunction, sarcopenia, and lower extremity edema. Right upper
quadrant abdominal pain, hepatosplenomegaly, and an enlarged caudate
lobe, which can be felt as a mass in the epigastrium, are additional signs
and symptoms. About 10% of patients may be asymptomatic.
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BOX 1 Etiologies of Budd-Chiari Syndrome
Myeloproliferative disorders
Essential thrombocythemia
Polycythemia vera
JAK2 mutation
Idiopathic myelofibrosis
Hypercoagulable disorders
Hyperhomocysteinemia
Factor V Leiden mutation
Prothrombin gene mutation G20210A
MTHFR C677T mutation
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Antiphospholipid syndrome
Paroxysmal nocturnal hemoglobinuria
Thalassemia
Malignancy
Cholangiocarcinoma
Hepatocellular carcinoma
Benign hepatic lesions
Adenoma
Cyst
Cystadenoma
Polycystic liver disease
Infection
Hepatic abscess
Invasive aspergillosis
Mucormycosis
Mycotic aortic aneurysm
Syphilitic gumma
Oral contraceptives
Pregnancy
Alpha-1 antitrypsin deficiency
Behçet syndrome
Systemic lupus erythematosus
Hypereosinophilic syndrome
Idiopathic granulomatous venulitis
Inflammatory bowel disease
Protein-losing enteropathy
Minimal change nephrotic syndrome
Mixed connective tissue disease
Neurofibromatosis
Sarcoidosis
Sjögren’s syndrome
Trauma
Torsion of the liver
Membranous web
Venoocclusive disease
Idiopathic
FIG. 1 CT scan of a patient with chronic Budd-Chiari syndrome shows
a heterogeneous appearance of the liver with regenerative nodules
(arrowhead) and caudate lobe hypertrophy (white arrows). Black arrow
points to an occluded transjugular intrahepatic portosystemic shunt (TIPS).
FIG. 2 Direct hepatic venography demonstrates the classic “spiderweb”
morphology of intrahepatic venous collaterals. Percutaneous access via the
right internal jugular vein allowed the catheter to traverse the occluded
hepatic veins (arrow).
DIAGNOSIS
The diagnosis of BCS should be considered in any patient with acute
or chronic liver disease. Routine laboratory tests reflect hepatocyte
injury and dysfunction. Elevated transaminases, alkaline phosphatase, bilirubin, and prothrombin time are common, and the albumin
level may be low depending on the degree of liver dysfunction and
protein loss in ascites. When present, the ascites is characterized by a
high serum–ascites albumin gradient (>1.1 g/dL).
The initial diagnostic imaging to assess the hepatic venous
outflow is Doppler ultrasound. Secondary studies include contrast-enhanced cross-sectional imaging, either CT or MRI, to image
the inferior vena cava (IVC), hepatic veins, and consequent venous
collaterals from the obstruction. Historically, invasive hepatic venography played a major role in the diagnosis of BCS, but advances in
noninvasive imaging have made it less important in the diagnosis.
Now, direct hepatic venography is performed at the time of endovascular intervention. Classic imaging findings include an enlarged
caudate lobe and “spiderweb” appearance of intrahepatic venous
collaterals (Figs. 1 and 2). Additional diagnostic studies for patients
with BCS include upper endoscopy to assess varices and workup for
hypercoagulable disorders.
MEDICAL MANAGEMENT
The management of patients with BCS involves prevention of
thrombus propagation, restoration of hepatic venous outflow to
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decompress the liver, and prevention and treatment of complications
of portal hypertension. Initial management involves prompt identification and treatment of the underlying cause of the venous outflow
obstruction. Early initiation of anticoagulation is essential to treat
any hypercoagulable state and prevent propagation of thrombus.
When patients have signs and symptoms of portal hypertension,
prophylaxis against variceal bleeding with beta-blockade, endoscopy
for surveillance and banding of varices, and control of ascites with
sodium restriction, diuretics, or paracentesis become very important
management tools.
Anticoagulation can mitigate the disease, but once the hepatic
venous outflow is significantly compromised, interventions will be
needed to try to restore venous drainage of the liver. Percutaneous
transluminal angioplasty (PTA) with or without thrombolysis or
stent can be effective, particularly in patients with short-length
occlusion of the hepatic vein. The interventional radiologists can use
transjugular, transfemoral, or, rarely, transhepatic routes for percutaneous access to the hepatic venous system. They can use transsplenic,
transparaumbilical vein, or transhepatic routes to access the portal
venous system for direct portography.
A graded approach is used, beginning with direct hepatic
venography and pressure measurements as a diagnostic step.
Venography can help define the anatomy and degree of occlusion
while pressure measurements can assess for portal hypertension,
defined as an hepatic venous pressure gradient (HVPG) of >10 mm
Hg. Thrombolysis may be needed initially to enable the traverse
of the area of obstruction. Balloon venoplasty then can be used to
open the outflow. Additional thrombolysis may be added to remove
thrombus, using both tissue plasminogen activator (tPA) infusion
and mechanical thrombectomy with suction. Finally, a stent may
need to be placed to treat the area of obstruction if it is recalcitrant
to thrombolysis and balloon venoplasty alone. Postintervention
venography and HVPG measurements can assess the response to
treatment.
If recanalization of the hepatic veins is not possible or if portal
hypertension persists despite attempts at treatment, transjugular
intrahepatic portosystemic shunt (TIPS) may be effective in reducing
pressure in the portal venous system and decompressing the congested liver (Fig. 3). TIPS thus can treat the complications of portal
hypertension, often relieving variceal hemorrhage and ascites. In
FIG. 3 A transjugular intrahepatic portosystemic shunt (TIPS) extends
from the right portal vein into the right atrium, traversing the diseased
hepatic venous outflow tract of a patient with Budd-Chiari syndrome.
cases where the hepatic veins are completely obliterated, interventional radiologists can create a shunt directly between the IVC and
the portal vein, a direct intrahepatic portosystemic shunt (DIPS)
or direct extrahepatic portosystemic shunt (DEPS), depending on
which portion of the portal vein is shunted. These technical modifications of TIPS also have been effective in relieving portal hypertension in patients with BCS.
SURGICAL MANAGEMENT
Surgery may be needed when minimally invasive, endovascular
interventions fail to restore hepatic venous outflow. Options include
surgical shunts and liver transplantation. With advances in interventional radiology techniques, surgical shunts are rarely performed,
reserved for highly select patients with preserved hepatic function
and favorable anatomy. Surgical shunts can have excellent long-term
outcomes when performed early before the development of irreversible liver damage. However, once the liver damage has progressed to
fibrosis and cirrhosis, liver transplantation is the only option to treat
BCS definitively. It is important to note that any intervention for BCS
should be performed at an experienced center in collaboration with
the liver transplantation team because of the real risks of hepatic
decompensation and procedural complications.
Surgical Shunts
The goal of a surgical shunt is to drain the portomesenteric venous
system into the systemic venous system. Portocaval, mesocaval, and
splenorenal shunts can be considered if the IVC is patent and without
a significant pressure gradient between the infrahepatic and suprahepatic sections of the IVC. If the IVC is obstructed, mesoatrial or
cavoatrial shunts are options to bypass the compromised portion of
the IVC, the latter performed in conjunction with a porto- or mesocaval shunt to decompress the port-mesenteric system.
Careful study of cross-sectional imaging is essential for operative
planning to decide which is the optimal shunt for the individual
patient. The surgeon can evaluate the anatomy and patency of the
portomesenteric veins and IVC as well as the extent of caudate lobe
hypertrophy. Attention to the caudate lobe is important because its
hypertrophy, particularly the paracaval portion, may render a portocaval shunt impossible. Doppler ultrasonography to demonstrate
size and patency of saphenous or internal jugular veins is a useful
preoperative adjunct when considering an autologous vein graft for
creation of the shunt. It also is important for the surgeon to review
the available biologic and synthetic graft lengths and diameters in
case the autologous vein is insufficient in size or quality. Finally,
the surgeon can make a biologic graft by paneling or tubularizing
patches of decellularized bovine pericardium or acellular collagen
scaffolding, when available.
First and foremost, the creation of any surgical shunt requires
proximal and distal control of the involved vasculature. Dissection
of the vasculature in the presence of portal hypertension can be
challenging because of venous collaterals and requires planning,
patience, and purposeful attention to tissue planes. The surgical
shunts can be created directly between veins or via grafts in a
side-to-side or end-to-side fashion depending on the anatomy and
degree of shunting needed. Grafts that can be used include autologous vein grafts (e.g., internal jugular vein or saphenous vein), biologic grafts (e.g., cryopreserved saphenous vein or various acellular
matrices), or synthetic grafts (e.g., Gore-Tex or polytetrafluoroethylene [PTFE]).
A portocaval shunt connects the portal vein and the IVC, meso-
caval the superior mesenteric vein and the IVC, and splenorenal the
splenic vein and the left renal vein. A mesoatrial shunt connects the
superior mesenteric vein to the right atrium, and a cavoatrial shunt
connects the IVC with the right atrium, both via a conduit. If no large
portosystemic collateral veins have formed during the progression of
BCS, a cavoatrial shunt to bypass the obstructed section of the IVC
454 MANAGEMENT OF BUDD-CHIARI SYNDROME
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will be performed in conjunction with a portocaval or mesocaval
shunt to ensure adequate drainage of the portomesenteric venous
system. A meso-cavo-atrial shunt also is an option, where the superior mesenteric vein is shunted directly into the cavoatrial graft. Systemic heparin administration (50 units per kg) should be discussed
with anesthesiology before applying the vascular clamps to the target
veins. The anastomoses are created using fine polypropylene sutures
with appropriate venting maneuvers to de-air any grafts and to evacuate any thrombus that may build up behind the clamps. Doppler
ultrasound (US) can be used to document patency of the shunts
postoperatively, and patients should be anticoagulated indefinitely.
Liver Transplantation
For the patients with BCS who fail anticoagulation, PTA, or endovascular or surgical shunt creation, liver transplantation is the only
treatment with excellent patient survival in large series. Liver transplantation for BCS can be the most technically challenging of liver
operations and should be approached with the utmost caution and
care.
Liver transplantation for BCS involves multidisciplinary evaluation to assess the primary cause of the hepatic venous occlusion, the
degree of liver dysfunction, and the medical, surgical, and psychosocial fitness of the patient to undergo liver transplantation. If deemed
an appropriate candidate, the patient will be waitlisted and ranked
by Model for End-Stage Liver Disease (MELD) score (ages ≥12) or
Pediatric End-Stage Liver Disease (PELD) score (ages <12), which
estimate the 3-month mortality risk without liver transplantation.
Decompensated liver disease should be reflected in the score, but if
the score does not adequately capture the severity of disease in a particular patient, the transplant center can appeal to the National Liver
Review Board for additional exception points for BCS. The appeal
should document failure of standard medical management, etiology
of hypercoagulable state (when present), specific contraindications
to TIPS or reasons for TIPS failure, manifestations of decompensated
portal hypertension (e.g., hepatic hydrothorax requiring thoracentesis for more than 1 L per week), and the absence of extrahepatic
malignancy.
Preoperative planning is essential, particularly for patients with
prior endovascular or surgical portosystemic shunts. For example,
the proximal and distal extent of TIPS should be determined by
cross-sectional imaging to plan the dissection needed for proximal
(i.e., portal vein) and distal (i.e., suprahepatic IVC) clamping. Similarly, the trajectory of DIPS or DEPS should be studied to ensure
complete removal of the portions of portal vein and IVC that the
stent penetrates. Any portal vein thrombosis should be noted, and
thromboendovenectomy or mesenteric venous conduit should be
planned.
The hepatectomy in BCS can be very challenging. The congested
liver and enlarged caudate lobe can make mobilization of the liver
difficult. Large venous collaterals often develop in the perihepatic
ligaments, which need to be ligated and divided securely. Thrombosis of the hepatic veins often leads to dense, inflammatory adhesions
between the liver, diaphragm, and IVC, therefore extra care must be
taken when dissecting and clamping the suprahepatic IVC. Depending on the extent of thrombosis, the suprahepatic IVC may need to
be dissected completely from the diaphragm up to the right atrium
to ensure complete removal of the entire diseased hepatic venous
outflow. Occasionally, dividing the diaphragm from the abdominal
incision or median sternotomy may be needed for adequate control
of the suprahepatic IVC within the pericardium. The cardiac surgery
team should be notified and cardiopulmonary bypass should be
available in cases where the most distal control of hepatic venous
outflow will involve clamping of the right atrium, such as extensive
thrombosis or prior atrial shunts. Equal attention also should be
paid to the infrahepatic IVC, which also may have thrombus. Simple thrombus can be thrombectomized, though chronic, extensive
thrombosis that extends below the renal veins often can be left alone
as venous collaterals provide adequate drainage. In such rare cases,
only a suprahepatic IVC anastomosis will be needed for reconstruction of the hepatic venous outflow.
In cases of liver transplant for acute BCS, complete clamping
of the IVC can cause hemodynamic instability, and portosystemic
venovenous bypass may be needed to preserve venous return and
provide drainage of the splanchnic vasculature (Fig. 4). In cases of
chronic, advanced BCS, complete clamping of the IVC usually is well
tolerated because portosystemic venous collaterals have formed and
provide venous return to the heart. With the widespread use of TIPS,
fewer patients with BCS have had a prior surgical portosystemic
shunt, but when present, shunts must be dissected and ligated to
ensure adequate portal inflow to the new liver. It is best to ligate these
shunts after reperfusion of the new liver, if possible, to avoid acutely
worsening portal hypertension during the hepatectomy (Fig. 5).
Because the obliterated hepatic veins and diseased IVC need to
be removed completely with the explanted liver, the IVC will need
to be replaced. A deceased donor liver, whether a whole or trisection
split allograft, will include the donor IVC, and reconstruction of the
venous outflow involves suprahepatic and infrahepatic IVC anastomoses with polypropylene sutures. A living donor liver allograft
will not have the IVC but rather hepatic veins for outflow, the exact
hepatic vein depending on the type of graft procured (e.g., right
lobe with or without middle hepatic vein or left lobe with middle
and left hepatic veins). The use of a living donor liver allograft in a
patient with BCS will require reconstruction of the IVC with either
a biologic or synthetic interposition graft. The hepatic vein or veins
of the living donor allograft then can be sewn into the side of the
interposition graft with polypropylene sutures, taking care to ensure
an adequate orifice for excellent hepatic venous outflow.
Subclavian vein
Portal
vein
Biopump
External
iliac vein
Saphenous vein
FIG. 4 Venovenous bypass. Immediately before completion of the hepatec-
tomy, the axillary, saphenous, and portal veins are cannulated. A centrifugal
pump returns systemic and portal venous blood to the heart via the axillary vein while the patient is anhepatic.
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not bleeding. Anticoagulation will need to be continued indefinitely.
Recurrent posttransplant BCS can be treated with interventional
techniques as discussed earlier. Retransplantation is reserved for
highly select patients with favorable anatomy who fail less invasive
management.
CONCLUSION
BCS is a rare disease with varied clinical presentation depending
on the acuity of onset and degree of liver dysfunction. Treatment
Caudate lobe hypertrophy
Porto-caval shunt
Portal vein
IVC
A
Caudate
lobe
requires multidisciplinary care; input from hematology, hepatology,
interventional radiology, and transplant surgery are particularly
important. Management first involves anticoagulation to treat the
underlying prothrombotic disorder followed by the prevention and
treatment of sequelae of portal hypertension. In patients with preserved liver function, percutaneous endovascular interventions aim
to restore hepatic venous outflow. Minimally invasive shunts have
essentially replaced surgical portosystemic shunts. When these interventions fail or in cases of irreversible liver damage, liver transplantation becomes the only treatment. The operation is very challenging,
and the surgeon should be prepared to control the intrapericardial
IVC when needed to remove the entire diseased hepatic venous outflow tract. Both whole and partial liver allografts can be used, though
the latter will require reconstruction of the IVC with an interposition
graft. Thoughtful preoperative planning and meticulous execution
are essential to ensure excellent outcomes after liver transplantation
for patients with BCS.
Side-to-side
portocaval
anastomosis
B
FIG. 5 (A) At the time of liver transplant for Budd-Chiari syndrome, a
prior surgical portocaval shunt. Note the caudate lobe hypertrophy. (B)
A side-to-side portocaval shunt. IVC; Inferior vena cava. (Courtesy Corinne
Sandone, Johns Hopkins University.)
Recurrent hepatic venous outflow obstruction is a concern posttransplant for BCS. Anticoagulation needs to be initiated postoperatively as soon as the liver function has recovered and the patient is
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