The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

C. Corey Hardin, M.D., Ph.D., Editor

Primary Budd–Chiari Syndrome

Juan Carlos Garcia‑Pagán, M.D., Ph.D., and Dominique‑Charles Valla, M.D.​​

P
rimary Budd–Chiari syndrome (BCS) is a spontaneously fatal dis- From the Barcelona Hepatic Hemody-
ease characterized by an obstruction of the hepatic venous outflow tract due namic Laboratory, Liver Unit, Hospital
Clínic (a provider of the European Refer-
to thrombosis or a primary disease of the venous wall.1 The primary form of ence Network on Rare Liver Disorders
BCS is extremely rare, with the prevalence estimate (1 case per 1 million persons [ERN-Liver]), Institut de Investigacions
per year) falling well below the threshold of 2 cases per 10,000 for rare diseases.2 Biomèdiques August Pi i Sunyer, Univer-
sity of Barcelona, Barcelona, and Centro
The median age at diagnosis is 35 to 40 years. The two sexes appear to be equal- de Investigación Biomédica en Red
ly affected. Recent advances have changed our understanding of this disease, as ­Enfermedades Hepáticas y Digestivas,
well as the outcomes. In this review, we confine our discussion to primary BCS. Madrid — both in Spain (J.C.G.-P.); and
Université Paris Cité, Unite Mixte de Re-
cherche 1149, INSERM, Paris, and Centre
de Référence des Maladies Vasculaires
C ause s du Foie, Service d’Hépatologie, Assis-
tance Publique–Hôpitaux de Paris, Hôpi-
An underlying disorder, such as a hereditary or an acquired hypercoagulable state tal Beaujon (a provider of the ERN-Liver),
(Table 1), can be found in approximately 75% of patients, and in at least one third Clichy — both in France (D.-C.V.). Dr.
of patients, more than one prothrombotic condition is identified.6 BCS may de- Garcia-Pagán can be contacted at
­jcgarcia@​­clinic​.­cat or at Hospital Clínic,
velop during pregnancy or in the postpartum period. Even in these situations, BCS Villaroel 170, Barcelona 08036.
is often associated with an underlying prothrombotic disorder. Therefore, a com-
N Engl J Med 2023;388:1307-16.
prehensive and systematic evaluation for underlying prothrombotic disorders is DOI: 10.1056/NEJMra2207738
always important. However, in approximately 20% of patients with suspected BCS, Copyright © 2023 Massachusetts Medical Society.

the evaluation is negative and the disease is classified as idiopathic BCS. The pro-
CME
portion of such cases has decreased in studies using new diagnostic tools such as at NEJM.org
next-generation sequencing for the diagnosis of myeloproliferative neoplasms.7

Pathoph ysiol o gic a l Fe at ur e s

Liver congestion due to chronic hepatic venous obstruction leads to the develop-
ment of hepatic fibrosis. The fibrotic response is triggered by hepatocyte ischemia
and necrosis together with sinusoidal thrombosis.8,9 Increased sinusoidal pressure
causes ascites formation and portal hypertension. A regional decrease in portal
venous perfusion contributes to regional parenchymal atrophy. Acute ischemic
liver injury resulting from an abrupt occlusion can induce severe liver dysfunction.
Compensatory mechanisms that tend to limit parenchymal congestion and ische­
mia include the development of intrahepatic collaterals and increased arterial
blood flow. Because hepatic venous involvement develops unevenly in time and
location, hepatic-vein collaterals — gross as well as microscopic — develop from
obstructed areas to venous segments that have remained patent. Venous collaterals
may eventually become obstructed. A focal imbalance between portal and arterial
perfusion is responsible for the development of regenerative or neoplastic nodules
of hepatocytes in hyperarterialized areas.10 It is thought that hepatocellular carci-
noma arising in the context of BCS, but also in the context of other vascular liver
diseases, is due to elevated hepatic arterial blood flow rather than to progressive
fibrosis from chronic inflammation, which occurs with other chronic liver condi-
tions.10

n engl j med 388;14  nejm.org  April 6, 2023 1307

The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Causal Factors in Patients with Primary Budd–Chiari Syndrome.* reason, there is a risk of misclassifying these
cases as triple-negative myeloproliferative neo-
Factor Prevalence plasms or ruling out the diagnosis of myelopro-
%
liferative neoplasms.
Next-generation sequencing allows for direct
Acquired disorders
and concurrent analysis of these genes with high
Myeloproliferative neoplasms 40–50 sensitivity. In a recent study, next-generation se-
Antiphospholipid syndrome 10–12 quencing detected JAK2 exon 12 mutations that
Paroxysmal nocturnal hemoglobinuria 7–12 had not been previously detected by conven-
Inherited disorders tional techniques.11 Indeed, next-generation se-
Factor V Leiden 8
quencing identified a mutation in the hotspot
exon 12 region of JAK2 in two of three patients
Factor II mutation 3
with BCS who had previously received a diagno-
Protein C deficiency 5 sis of triple-negative myeloproliferative neo-
Protein S deficiency 4 plasm. Other prothrombotic disorders that have
Antithrombin deficiency 1 been associated with BCS include factor V
Hormonal factors Leiden (which is twice as common in patients
Recent pregnancy 1 with BCS as in the general population), paroxys-
mal nocturnal hemoglobinuria, and antiphos-
Oral contraceptive use 22
pholipid syndrome.6,7 Testing for the factor II
Systemic diseases† 6
mutation is usually also performed, although
Local factors the prevalence of this mutation is not clearly
Inflammatory intraabdominal conditions‡ 2 higher among patients with BCS than in the
Intraabdominal surgery 1 general population.
Abdominal trauma 2 Tests for inherited protein C, protein S, and
antithrombin deficiencies must also be per-
* The information is from Van Wettere et al.,3 Garcia-Pagán et al.,4 and Hamulyák formed. These proteins are synthesized by the
et al.5
† Systemic diseases include connective-tissue disease, celiac disease, Behçet’s
liver, so it can be challenging to diagnose an
disease, mastocytosis, inflammatory bowel disease, human immunodeficiency inherited deficiency in patients with liver dys-
virus infection, sarcoidosis, and myeloma. function. A suggestion for overcoming this
‡ Inflammatory intraabdominal conditions include acute pancreatitis and biliary
or intestinal infection or inflammation.
problem is to assess the ratio of these proteins
to other proteins synthesized by the liver. A ratio
of one of these proteins to other hepatic proteins
([factor II + factor X] ÷ 2) that is less than 0.7 sup-
ports the presence of a hereditary deficiency.12 In
E va luat ion in Suspec ted C a se s
of BC S the future, improved access to genetic tools is
likely to reveal the real contribution of inherited
Myeloproliferative neoplasm is the most frequent deficiencies in natural anticoagulant proteins to
underlying condition leading to BCS. Therefore, the development of BCS.
if BCS is suspected, testing should be performed Although local factors such as abdominal
for driver somatic mutations in the gene encod- infection, inflammatory diseases, and local
ing Janus kinase 2 (JAK2), including V617F and trauma have been reported, they are much less
exon 12 mutations, and in the genes encoding frequent in patients with BCS than in patients
calreticulin (CALR) and the thrombopoietin re- with thrombosis of the portomesenteric axis.
ceptor (MPL). These genetic tests are usually per- Use of oral contraceptives, pregnancy, and the
formed sequentially; if the test for JAK2 V617F is immediate postpartum state are well-known
negative, then tests for JAK2 exon 12 mutations prothrombotic factors that may increase the risk
and for CALR and MPL mutations are performed. of BCS. Even in these situations, evaluation of
Conventional genetic tests can have false nega- patients with suspected BCS should include an
tive results when there is a low allele burden or exhaustive search for other underlying causes
noncanonical mutations are present. For this of thrombophilia (Table 1).13

1308 n engl j med 388;14  nejm.org  April 6, 2023

The New England Journal of Medicine

Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Primary Budd – Chiari Syndrome

Cl inic a l M a nife s tat ions larged caudate lobe. Frequently, a complex of

Demographic and clinical characteristics of pa-
tients with BCS are extremely varied and non-
specific (Fig. 1).6,14-17 The absence of clinical
manifestations is not rare. The combination of
abdominal pain, fever, an enlarged liver, and
ascites of recent onset, which is regarded as sug-
gestive of BCS, is far from common. Therefore,
it is important to evaluate for an obstructed he-
patic venous outflow tract in any patient with
any form of acute or persistent liver anomalies.
The presence of large, subcutaneous cavocaval
collaterals on the trunk, seen on physical ex-
amination, is a specific manifestation of an ob-
struction of the inferior vena cava that allows for
a rapid diagnosis.
Patients may present with acute, chronic, or
acute-on-chronic manifestations of BCS. Fulmi-
nant BCS is extremely rare.18,19 The clinical pre-
sentation does not correspond well with the actual
history of venous obstruction. Indeed, an acute
presentation may correspond with a recent ob-
stacle (i.e., a thrombus) superimposed on a pro-
gressive, previously undetected obstruction.20
Associated portal vein thrombosis is usually an
imaging finding without specific clinical features.
L a bor at or y Findings
Laboratory abnormalities are also diverse. Serum
aminotransferase activity tends to be markedly
increased in the acute clinical presentation, with
a possible rapid decrease that is reminiscent of
acute ischemic liver injury.21 Tests for liver dys-
function (serum bilirubin and albumin measure-
ments and the international normalized ratio)
show varying degrees of alteration. Blood-cell
counts may show the usual features of hyper-
splenism related to portal hypertension. In many
patients with underlying myeloproliferative neo-
plasms, obvious features of portal hypertension,
including splenomegaly, contrast with platelet
counts above 200,000 × 109 per liter. A high serum–
ascites albumin gradient increases the suspicion
for BCS.
Im aging Findings
Typical histopathological changes — ischemic
Imaging without vascular enhancement usually liver cell loss, sinusoidal dilatation, and perisi-
shows a dysmorphic liver, typically with an en- nusoidal fibrosis — predominate in centrilobu-
atrophic areas and hypertrophic areas is present.
Features of portal hypertension — portosys-
temic collaterals (including esophageal varices),
splenomegaly, and ascites — are common, al-
though they may be absent.22
The most specific imaging test is computed
tomography (CT) or magnetic resonance imag-
ing (MRI) obtained at the arterial, portal, and
late phases after injection of a vascular contrast
agent or with the use of Doppler ultrasonogra-
phy and vascular contrast enhancement. Patchy
enhancement of the parenchyma (a so-called
mosaic pattern) appearing at the arterial phase,
and disappearing at the portal or late phase, is
indicative of sinusoidal dilatation or congestion.
Late-phase enhancement of variably extensive
and broad reticular areas indicates fibrous tis-
sue. The hepatic veins, inferior vena cava, or
both may appear abnormal. There may be dif-
fuse obliteration of the lumen (veins appearing
as fibrous cord remnants) or dilatation upstream
of a short-length stenosis, which may appear as
a membrane or “web.” Recent clots in the form
of hyperattenuating material within the venous
lumen may be seen, although they are not a
common finding.
Venovenous collaterals, mostly intrahepatic
(Fig. 2A through 2D) but also extrahepatic, are
usually present at varying degrees of develop-
ment. In patients with obstruction of the termi-
nal portion of the inferior vena cava, cavocaval
collaterals can develop, although the bypass
routes are not predictable. At the time of diag-
nosis, hepatic and portal venous obstructions
are seen together in approximately 20% of pa-
tients. Portal venous obstruction is usually
caused by a thrombus and less frequently caused
by a cavernoma. It is common to find parenchy-
mal nodules of various sizes and numbers.
Assessment of liver stiffness, often measured
with the use of ultrasonography or MRI, shows
markedly increased values. Increased liver stiff-
ness appears to be related largely to congestion
of the liver, in addition to fibrosis.23
His t opathol o gic a l Fe at ur e s

n engl j med 388;14  nejm.org  April 6, 2023 1309

The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Young adults (any

age possible)

Both sexes

Esophageal varices
Scarce data
Hepatomegaly
Common but not Gastrointestinal
always present bleeding
Approximately 1 in 7
patients
Hepatorenal syndrome
Scarce data Splenomegaly
Common but not
always present
Related to portal
Esophageal
varices hypertension or
Inferior myeloproliferative
vena cava neoplasms

Web
Abdominal pain
Approximately half of
Stenosis patients
Thrombus

LIVER
Ascites
STOMACH
Very common but
not always present
Portal vein

Caudate lobe hypertrophy

Common but not always
present

Dysmorphic liver (atrophy–

hypertrophy complex)
Almost always present

Leg edema
Common

1310 n engl j med 388;14 nejm.org April 6, 2023

The New England Journal of Medicine

Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Primary Budd – Chiari Syndrome

Figure 1 (facing page). Demographic and Clinical Features laterals provides strong support for the diagnosis,
Associated with Budd–Chiari Syndrome. although such features can also be encountered
Various clinical manifestations, all of which are non- in portosinusoidal vascular disease. Doppler ul-
specific, can be observed in patients with Budd–Chiari trasonography is highly sensitive when per-
syndrome. formed by a skilled operator who is aware of the
diagnostic suspicion. Similarly, CT or MRI, per-
formed before and after injection of a vascular
lar areas (Fig. 3). Fibrosis may eventually evolve contrast agent, requires expertise for the most
to cirrhosis, with altered hepatic venules at the useful description of the obstructed vessels. A
periphery and a portal tract at the center of the major pitfall is the misinterpretation of large
nodules.10 Microscopic and macroscopic hepato- venovenous collaterals as patent native hepatic
cellular nodules (nodular regenerative hyperpla- veins. In approximately 1% of patients with BCS,
sia and focal nodular hyperplasia, respectively) liver biopsy performed for an unexplained liver
are common. These changes are unevenly dis- disease shows so-called small-vein BCS, even
tributed within the liver. Hepatocellular adeno-
mas have been described.24 Hepatocellular carci-
noma may develop over time, with a 10-year A B
cumulative incidence of approximately 10%.25
When imaging shows a blocked outflow tract,
liver biopsy is of little help, except for character-
izing nodules, and the procedure might be par-
ticularly hazardous because of congestion and
venous collaterals.
*
Di agnosis
C D
BCS is most easily diagnosed by identifying ob-
struction of the hepatic venous system on imag-
ing. Detection of intrahepatic or cavocaval col-

Figure 2. Imaging Features of Budd–Chiari Syndrome.

Various imaging findings can be observed in patients
with Budd–Chiari syndrome. An ultrasound image of
the liver shows serpiginous anechoic structures corre-
sponding to intrahepatic collaterals (Panel A, arrows).
The caudate lobe and caudate vein are hypertrophic E F
(Panel B; asterisk and arrow, respectively). Acute
thrombosis of the left hepatic vein is evident (Panel C);
a Doppler color study confirms the absence of flow. A
CT scan, obtained in the venous phase at the level of
the terminal portion of the hepatic veins, shows that
the three major hepatic veins have no enhancement
(Panel D, arrows), whereas the inferior vena cava is
well enhanced. There is enhancement of the central
part of the liver, as compared with the periphery,
which suggests preserved venous drainage through
the patent veins of the caudate lobe draining directly G H
into the inferior vena cava. An ultrasound image of the
liver shows a patent proximal hepatic vein with a
short-length stenosis at the outlet to the inferior cava
vein (Panel E, arrow). A CT scan confirms the short-
length stenosis at the right hepatic vein (Panel F, ar-
row). After balloon dilation of the hepatic stenosis was
performed (Panel G, arrowhead), hepatic blood flow
was restored (Panel H, arrowhead).

n engl j med 388;14 nejm.org April 6, 2023 1311

The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A
* are similarly hyperenhanced at the arterial
* *
B cific contrast agents may show patterns that can
* though biopsy carries risks, including the need
* to suspend anticoagulant therapy. Also, when
Figure 3. Histopathological Features of Acute Budd–
Chiari Syndrome.
The histopathological changes shown correspond to a
pattern of venous outflow obstruction, which can also
be observed with cardiac failure and sinusoidal obstruc-
tion syndrome or veno-occlusive disease. Panel A (he-
matoxylin and eosin) shows marked centrilobular and
midzonal congestion and dilatation, associated with
hemorrhage and hepatocellular necrosis (asterisks).
Periportal hepatocytes are spared (arrows), and portal
tracts are normal (arrowhead). In Panel B (hematoxylin
and eosin), hepatocytes at the periphery show atrophic
changes, with thinned plates and small cells (arrows).
Focal extravasation of erythrocytes into the space of
Disse is also evident (asterisks).
ity of 95%.26 Still, CT or MRI is needed (or both
are needed) for the characterization of hepatic
nodules. Benign and malignant hepatic nodules
phase. Washout of contrast material at the portal
or late phase has only 67% specificity for hepa-
tocellular carcinoma in patients with BCS.26 An
abnormal perfusion pattern of the background
parenchyma may explain why washout is not as
diagnostically specific in patients with BCS as it
is in patients with liver cirrhosis. MRI per-
formed with the administration of hepatospe-
be helpful in characterizing hepatic nodules. In
one study, benign lesions showed homogeneous
or peripheral hyperintensity on hepatobiliary
imaging, whereas hepatocellular carcinomas
were homogeneously hypointense.3 These recent
findings require confirmation. Therefore, guid-
ed liver biopsy often remains necessary, al-
multiple nodules are present, it is often unclear
which nodules should be biopsied.
Data on which to base routine screening for
hepatocellular carcinoma, with respect to ap-
propriate tools and frequency and the risk–ben-
efit ratio, are limited. It seems reasonable to
recommend screening every 6 months with a
combination of serum alpha-fetoprotein mea-
surement and liver imaging performed by an
experienced ultrasonographer. Current recom-
mendations stress the importance of referring
patients with BCS to highly specialized centers
in order to help address these diagnostic com-
plexities.

though the gross hepatic venous outflow tract is
fully patent.
A precise description of the nature of the
obstruction is a crucial step in considering
therapy. Short-length stenosis (Fig. 2E and 2F),
which may be amenable to percutaneous angio-
plasty, can be identified on hepatic-vein cathe-
terization. During catheterization, the typical
spiderweb pattern (representing intrahepatic
new-vessel formation) can be observed.
Diagnosis of hepatocellular carcinoma is chal-
lenging. Serum alpha-fetoprotein levels exceed-
ing 15 ng per milliliter appear to have a specific-
Pro gnosis
BCS is associated with high mortality (>80% at
3 years).27 However, the risk markedly changes if
the diagnosis is established early and adequate
management is provided. Indeed, when BCS is
managed appropriately, survival at 5 years ex-
ceeds 80%.28 Several prognostic scores have
been developed (Table 2),4,28-31 all of which are
useful in classifying the severity of BCS. In addi-
tion, an alanine aminotransferase level that is
5 or more times the upper limit of the normal
range at presentation and that does not decrease
rapidly in the next few days has been associated

1312 n engl j med 388;14 nejm.org April 6, 2023

The New England Journal of Medicine

Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Primary Budd – Chiari Syndrome

Table 2. Prognostic Scores for Budd–Chiari Syndrome.*

Score and Formula Cutoff Point Predicted Survival Study

Clichy prognostic score
(ascites score × 0.75) + (Pugh score × 0.28) + (age × 0.037) ≤5.4 or >5.4 At 5 yr: Zeitoun et al.29
+ (creatinine level [μmol/liter] × 0.0036)† Score ≤5.4, 95%
Score >5.4, 65%
New Clichy prognostic score
(ascites score × 0.95) + (Pugh score × 0.35) + (age × 0.047) <5.1 or >5.1 At 5 yr: Langlet et al.30
+ (serum creatinine level [μmol/liter] × 0.0045) Score <5.1, 100%
+ (clinicopathological form × 2.2) − 2.6†‡ Score >5.1, 65%
Rotterdam score
(encephalopathy × 1.27) + (ascites × 1.04) + (prothrombin Class I: <1.1 At 5 yr: Darwish Murad
time × 0.72) + (bilirubin level [mg/dl] × 0.004)§ Class II: 1.1–1.5 Class I, 89% et al.31
Class III: >1.5 Class II, 74%
Class III, 42%
BCS-TIPS prognostic score
(age [yr] × 0.08) + (bilirubin level [mg/dl] × 0.16) + (INR × 0.63) ≤7 or >7 At 1 yr, OLT-free: Garcia-Pagán
Score ≤7, 95% et al.4
Score >7, 12%
BCS intervention-free survival prognostic score
(ascites × 1.675) + (ln creatinine level [μmol/liter] × 0.613) Interval 1: <5 At 5 yr, intervention- Seijo et al.28
+ (ln bilirubin level [μmol/liter] × 0.440)§ Interval 2: 5–6 free:
Interval 3: >6 Interval 1, 78.3%
Interval 2, 27.8%
Interval 3, 6.8%
BCS survival score
(age ÷ 10 × 0.370) + (ln creatinine level [μmol/liter] × 0.809) Interval 1: <7 At 5 yr: Seijo et al.28
+ (ln bilirubin level [μmol/liter] × 0.496) Interval 2: 7–8 Interval 1, 87.5%
Interval 3: >8 Interval 2, 63.3%
Interval 3, 42.9%

* INR denotes international normalized ratio, ln natural logarithm, and OLT orthotopic liver transplantation.
† For the ascites score, 3 denotes intractable, 2 easy to treat, and 1 absent.
‡ For the clinicopathological form, 1 denotes the presence of at least one acute and one chronic feature, and 0 denotes the absence of chronic
or acute features. Acute features include acute right-upper-quadrant abdominal pain, a serum alanine aminotransferase level that is at least
5 times the upper limit of the normal range, and liver cell loss in a liver-biopsy specimen, when available. Chronic features include previous
hospitalization for unexplained symptoms that regressed spontaneously and that were subsequently related to Budd–Chiari syndrome (e.g.,
acute right-upper-quadrant abdominal pain, ascites, jaundice, and abnormal liver function), splenomegaly, a combination of atrophy and
hypertrophy of liver lobes, and centrilobular fibrosis or cirrhosis in a liver-biopsy specimen, when available.
§ For the ascites and encephalopathy values, 1 denotes present and 0 absent.

with a poor outcome.21,32 However, none of the T r e atmen t

prognostic scores can predict the outcome for an
individual patient, and although they can help
guide treatment decisions, they cannot be di-
rectly used to select the treatment for a given
patient.32 The BCS-TIPS (transjugular intrahe-
patic portosystemic shunt) prognostic score was
developed to predict the outcome in patients
with BCS who are considered to be candidates
for placement of a TIPS.4 Again, the score can be
used as a guide but not as the basis for definitive
clinical decisions.
Treatment of BCS includes treatment of the un-
derlying prothrombotic disorder and restoration
of hepatic venous outflow. Until the latter is
achieved, management of portal hypertension
— with diuretics as treatment for ascites and
nonselective beta-blockers as prophylaxis for
variceal bleeding, as recommended for patients
with cirrhosis33 — is strongly recommended for
patients with BCS. A prompt diagnosis of the
underlying prothrombotic disorder and specific

n engl j med 388;14  nejm.org  April 6, 2023 1313

The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
treatment for that disorder prevent thrombotic
progression and markedly influence the out-
come. This is especially true in the cases of
myeloproliferative neoplasms5 and paroxysmal
nocturnal hemoglobinuria,34 for which treat-
ments directed toward the causes of the disease
have better outcomes than anticoagulant therapy
alone.
The best approach for improving hepatic ve-
nous outflow is a progressive therapeutic strat-
egy,28,33,35 starting with less invasive treatments
and progressing to more invasive treatments
according to the clinical response. However,
there are no good measures for establishing the
right time to alter therapy in a given patient.
Therefore, this decision is mainly based on close
monitoring of the course of clinical, biochemi-
cal, and imaging features. Patients should be
referred to tertiary centers with dedicated multi-
disciplinary teams of hepatologists, radiologists,
transplantation surgeons, hematologists, and
specialists in systemic disorders.
All patients with BCS should receive long-
term anticoagulant therapy, even in the absence
of a recognized prothrombotic disorder. The
main aim of anticoagulation is to prevent the
progression of thrombosis. The probability of
achieving recanalization of the obstructed he-
patic veins is very low. Administration of low-
molecular-weight heparin followed by a vitamin
K antagonist, once the patient is in a stable
condition, is the most common approach. Un-
fractionated heparin is best avoided because of a
particularly high risk of heparin-induced throm-
bocytopenia.35 Direct oral anticoagulants also
appear to be effective and safe for long-term
anticoagulation. However, the number of pa-
tients receiving these agents in studies reported
so far is low enough that the findings require
confirmation.36 In very selective cases of recent
thrombosis, local mechanical and chemical
thrombolysis after catheterization of the throm-
bosed hepatic vein may help to restore venous
outflow.37 However, the risk–benefit ratio for
this approach is not well understood. Bleeding
complications can occur and may even be fatal.
Thus, if considered, thrombolysis should be per-
formed only in tertiary centers.
In cases of segmental vein stenosis affecting
the inferior vena cava or a hepatic vein, percuta-
neous transluminal angioplasty with or without
stenting may restore physiologic hepatic venous
1314 n engl j med 388;14  nejm.org  April 6, 2023
The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
outflow and relieve symptoms (Fig. 2G and 2H).
In Asian cohorts, inferior vena cava obstruction
predominates, and this strategy is effective in
more than 70% of patients38; in European popu-
lations, such obstruction is more unusual, and
this therapeutic approach, used alone, appears
to be successful in only 10% of patients.10 One
randomized, controlled trial suggested that rou-
tine stenting with angioplasty is superior to an-
gioplasty alone.39 However, this trial did not
show significant differences in survival, and
stenting may jeopardize the potential option for
subsequent treatment with a TIPS, if required.
Therefore, we initially recommend angioplasty,
reserving stenting for cases in which angioplasty
is unsuccessful.40
For patients in whom the disease progresses,
the next step is to decompress the liver by con-
verting the portal system to an outflow tract. At
present, placement of a TIPS is the preferred
method. However, because of the technical dif-
ficulty of the procedure, TIPS placement should
be performed only in centers with expertise in
this treatment. Indeed, because it is impossible
to enter a remnant hepatic vein, TIPS insertion
requires a direct transcaval approach in more
than 40% of patients with BCS.4 In a European
prospective cohort of 157 consecutive patients
enrolled over a period of 2 years, 62 of the pa-
tients (39.5%) received a TIPS.28 This treatment
has a high success rate, with 5-year liver trans-
plantation–free survival of 78%.4 Surgical proce-
dures for liver decompression are associated
with high early morbidity and mortality41 and
have mostly been abandoned.
Liver transplantation is generally the last op-
tion for patients in whom other treatments have
failed or patients who are ineligible for alterna-
tive treatments, although transplantation may
be performed early in patients with liver failure.
Some patients may undergo TIPS placement as a
bridge to transplantation in order to improve
liver function. In a cohort of 248 patients with
decompensated BCS who underwent liver trans-
plantation — with transplantation being the first
treatment option in most patients and with TIPS
placement preceding transplantation in less than
10% of patients — overall survival was 76%,
71%, and 68% at 1, 5, and 10 years, respective-
ly.42 When a stepwise treatment approach was
used, and liver transplantation was performed in
only 7% of patients, survival was similar, which
 Primary Budd – Chiari Syndrome

reinforces the benefit of the stepwise approach
and allows a large number of liver grafts to be
saved for other indications.4 If liver transplanta-
tion is indicated, previous use of a TIPS does not
worsen the outcome after transplantation.4
The underlying prothrombotic disease lead-
ing to BCS may be cured with transplantation,
such as in the case of protein C or S deficiency.
However, in patients with other underlying con-
ditions (e.g., myeloproliferative neoplasms and
antiphospholipid syndrome), specific therapies
should be continued, and the patients should be
closely monitored to prevent or detect recurrent
thrombotic complications.43
Pr egna nc y in Pat ien t s w i th BC S
Many patients with BCS are women of reproduc-
tive age, and maternal and fetal outcomes are a
common concern. Retrospective observational
studies have shown a good maternal outcome in
treated patients with BCS during pregnancy.13
The risk of miscarriage or premature birth is
increased. However, if the pregnancy reaches 20
weeks of gestation, birth of a live baby is the
rule. Hence, pregnancy is not contraindicated
for women with BCS.13 Anticoagulant therapy
should be maintained during pregnancy and in
the postpartum period. Low-molecular-weight
heparins are indicated because vitamin K an-
tagonists carry a risk of teratogenicity. For pa-
tients who have not previously received antico-
agulant therapy, the decision to administer an
anticoagulant should be based on the individual
patient’s underlying prothrombotic state and
obstetrical history.
Vaginal delivery, with the use of forceps or a
vacuum device if needed, remains the recom-
mended strategy.13 Patients should be screened
for portopulmonary hypertension, which can
worsen during pregnancy. Screening for esopha-
geal varices is recommended during the second
trimester, if the patient is not already taking a
beta-blocker, in order to provide appropriate
prophylaxis, although varices have been rare
among reported cases. Pregnancy should be
managed by a multidisciplinary team that in-
cludes an obstetrician who is experienced in
managing high-risk pregnancies.
C onclusions
BCS is a rare disease primarily affecting young
adults. Because of its high lethality and good
response to therapy, BCS should be considered
in any patient with liver disease. The diagnosis
is established or ruled out with the use of mini-
mally invasive imaging of the hepatic venous
system. Patients with BCS usually have an under-
lying associated prothrombotic condition, which
in most cases is a blood disorder that should
be treated without delay. When hepatic out-
f low is restored with the use of pharmaco-
therapy or another intervention, good outcomes
are the rule.
There remain substantial gaps in our knowl-
edge of this disease. The underlying pathophysi-
ology is unclear in many patients, and it is dif-
ficult to apply prognostic tools to individual
patients. Thus, it can be difficult to know when
to switch from one therapeutic approach to an-
other. Newer approaches to recanalization of
obstructed circulation could preserve more phys-
iologic circulation, with even better outcomes.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Angeles Garcia-Criado for providing ultrasono-
graphic and CT images and Dr. Alba Diaz for providing histo-
pathological images.

References
1. Northup PG, Garcia-Pagan JC, Garcia-
Tsao G, et al. Vascular liver disorders,
portal vein thrombosis, and procedural
bleeding in patients with liver disease:
2020 practice guidance by the American
Association for the study of liver diseases.
Hepatology 2021;​73:​366-413.
2. Ollivier-Hourmand I, Allaire M,
Goutte N, et al. The epidemiology of
Budd-Chiari syndrome in France. Dig
Liver Dis 2018;​50:​931-7.
3. Van Wettere M, Paulatto L, Raynaud
L, et al. Hepatobiliary MR contrast agents
are useful to diagnose hepatocellular car-
cinoma in patients with Budd-Chiari syn-
drome. JHEP Rep 2020;​2:​100097.
4. Garcia-Pagán JC, Heydtmann M, Raffa
S, et al. TIPS for Budd-Chiari syndrome:
long-term results and prognostics factors
in 124 patients. Gastroenterology 2008;​
135:​808-15.
5. Hamulyák EN, Daams JG, Leebeek
FWG, et al. A systematic review of anti-
thrombotic treatment of venous thrombo-
embolism in patients with myeloprolif-
erative neoplasms. Blood Adv 2021;​ 5:​
113-21.
6. Darwish Murad S, Plessier A, Hernan-
dez-Guerra M, et al. Etiology, management,
and outcome of the Budd-Chiari syn-
drome. Ann Intern Med 2009;​151:​167-75.
7. Qi X, Wu F, Ren W, et al. Thrombotic
risk factors in Chinese Budd-Chiari syn-
drome patients: an observational study
with a systematic review of the literature.
Thromb Haemost 2013;​109:​878-84.
8. Wanless IR, Liu JJ, Butany J. Role of
thrombosis in the pathogenesis of con-
gestive hepatic fibrosis (cardiac cirrho-
sis). Hepatology 1995;​21:​1232-7.
9. Simonetto DA, Yang H-Y, Yin M, et al.
Chronic passive venous congestion drives

n engl j med 388;14  nejm.org  April 6, 2023 1315

The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Primary Budd – Chiari Syndrome
hepatic fibrogenesis via sinusoidal throm-
bosis and mechanical forces. Hepatology
2015;​61:​648-59.
10. Cazals-Hatem D, Vilgrain V, Genin P,
et al. Arterial and portal circulation and
parenchymal changes in Budd-Chiari syn-
drome: a study in 17 explanted livers.
Hepatology 2003;​37:​510-9.
11. Magaz M, Alvarez-Larrán A, Colomer
D, et al. Next-generation sequencing in
the diagnosis of non-cirrhotic splanchnic
vein thrombosis. J Hepatol 2021;​74:​89-95.
12. Janssen HL, Meinardi JR, Vleggaar FP,
et al. Factor V Leiden mutation, pro-
thrombin gene mutation, and deficiencies
in coagulation inhibitors associated with
Budd-Chiari syndrome and portal vein
thrombosis: results of a case-control
study. Blood 2000;​96:​2364-8.
13. Bissonnette J, Durand F, de Raucourt
E, et al. Pregnancy and vascular liver dis-
ease. J Clin Exp Hepatol 2015;​5:​41-50.
14. Sakr M, Barakat E, Abdelhakam S,
et al. Epidemiological aspects of Budd-
Chiari in Egyptian patients: a single-cen-
ter study. World J Gastroenterol 2011;​17:​
4704-10.
15. Afredj N, Guessab N, Nani A, et al.
Aetiological factors of Budd-Chiari syn-
drome in Algeria. World J Hepatol 2015;​7:​
903-9.
16. Cheng D, Xu H, Lu ZJ, et al. Clinical
features and etiology of Budd-Chiari syn-
drome in Chinese patients: a single-center
study. J Gastroenterol Hepatol 2013;​ 28:​
1061-7.
17. Amarapurkar DN, Punamiya SJ, Patel
ND. Changing spectrum of Budd-Chiari
syndrome in India with special reference
to non-surgical treatment. World J Gas-
troenterol 2008;​14:​278-85.
18. Parekh J, Matei VM, Canas-Coto A,
Friedman D, Lee WM. Budd-chiari syn-
drome causing acute liver failure: a multi-
center case series. Liver Transpl 2017;​23:​
135-42.
19. Thuluvath PJ, Alukal JJ, Zhang T.
Acute liver failure in Budd-Chiari syn-
drome and a model to predict mortality.
Hepatol Int 2021;​15:​146-54.
20. Dilawari JB, Bambery P, Chawla Y,
et al. Hepatic outflow obstruction (Budd-
Chiari syndrome). Experience with 177
patients and a review of the literature.
Medicine (Baltimore) 1994;​73:​21-36.
21. Rautou P-E, Moucari R, Cazals-Hatem
D, et al. Levels and initial course of serum
alanine aminotransferase can predict out-
1316 n engl j med 388;14  nejm.org  April 6, 2023
The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
come of patients with Budd-Chiari syn-
drome. Clin Gastroenterol Hepatol 2009;​
7:​1230-5.
22. Brancatelli G, Vilgrain V, Federle MP,
et al. Budd-Chiari syndrome: spectrum of
imaging findings. AJR Am J Roentgenol
2007;​188(2):​W168-W176.
23. Dajti E, Ravaioli F, Colecchia A, Mar-
asco G, Vestito A, Festi D. Liver and
spleen stiffness measurements for assess-
ment of portal hypertension severity in
patients with Budd Chiari Syndrome. Can
J Gastroenterol Hepatol 2019;​2019:​1673197.
24. Sempoux C, Paradis V, Komuta M,
et al. Hepatocellular nodules expressing
markers of hepatocellular adenomas in
Budd-Chiari syndrome and other rare he-
patic vascular disorders. J Hepatol 2015;​
63:​1173-80.
25. Ren W, Qi X, Yang Z, Han G, Fan D.
Prevalence and risk factors of hepatocel-
lular carcinoma in Budd-Chiari syn-
drome: a systematic review. Eur J Gastro-
enterol Hepatol 2013;​25:​830-41.
26. Van Wettere M, Purcell Y, Bruno O,
et al. Low specificity of washout to diag-
nose hepatocellular carcinoma in nodules
showing arterial hyperenhancement in
patients with Budd-Chiari syndrome.
J Hepatol 2019;​70:​1123-32.
27. Tavill AS, Wood EJ, Kreel L, Jones EA,
Gregory M, Sherlock S. The Budd-Chiari
syndrome: correlation between hepatic
scintigraphy and the clinical, radiologi-
cal, and pathological findings in nineteen
cases of hepatic venous outflow obstruc-
tion. Gastroenterology 1975;​68:​509-18.
28. Seijo S, Plessier A, Hoekstra J, et al.
Good long-term outcome of Budd-Chiari
syndrome with a step-wise management.
Hepatology 2013;​57:​1962-8.
29. Zeitoun G, Escolano S, Hadengue A,
et al. Outcome of Budd-Chiari syndrome:
a multivariate analysis of factors related
to survival including surgical portosys-
temic shunting. Hepatology 1999;​30:​84-9.
30. Langlet P, Escolano S, Valla D, et al.
Clinicopathological forms and prognostic
index in Budd-Chiari syndrome. J Hepatol
2003;​39:​496-501.
31. Darwish Murad S, Valla D-C, de Groen
PC, et al. Determinants of survival and
the effect of portosystemic shunting in
patients with Budd-Chiari syndrome.
Hepatology 2004;​39:​500-8.
32. Rautou P-E, Moucari R, Escolano S,
et al. Prognostic indices for Budd-Chiari
syndrome: valid for clinical studies but
insufficient for individual management.
Am J Gastroenterol 2009;​104:​1140-6.
33. de Franchis R, Bosch J, Garcia-Tsao G,
Reiberger T, Ripoll C. Baveno VII — re-
newing consensus in portal hypertension.
J Hepatol 2022;​76:​959-74.
34. Plessier A, Esposito-Farèse M, Baiges
A, et al. Paroxysmal nocturnal hemoglo-
binuria and vascular liver disease: eculi-
zumab therapy decreases mortality and
thrombotic complications. Am J Hematol
2022;​97:​431-9.
35. Plessier A, Sibert A, Consigny Y, et al.
Aiming at minimal invasiveness as a ther-
apeutic strategy for Budd-Chiari syn-
drome. Hepatology 2006;​44:​1308-16.
36. Semmler G, Lindorfer A, Schäfer B,
et al. Outcome of Budd-Chiari syndrome
patients treated with direct oral antico-
agulants: an Austrian multicenter study.
Clin Gastroenterol Hepatol 2022 May 06
(Epub ahead of print).
37. Sharma S, Texeira A, Texeira P, Elias
E, Wilde J, Olliff SP. Pharmacological
thrombolysis in Budd Chiari syndrome:
a single centre experience and review of
the literature. J Hepatol 2004;​40:​172-80.
38. Han G, Qi X, Zhang W, et al. Percuta-
neous recanalization for Budd-Chiari syn-
drome: an 11-year retrospective study on
patency and survival in 177 Chinese pa-
tients from a single center. Radiology
2013;​266:​657-67.
39. Wang Q, Li K, He C, et al. Angioplasty
with versus without routine stent place-
ment for Budd-Chiari syndrome: a ran-
domised controlled trial. Lancet Gastro-
enterol Hepatol 2019;​4:​686-97.
40. Ferrusquía-Acosta J, Hernández-Gea
V, Turón F, García-Pagán JC. Budd-Chiari
syndrome with short-length stenosis: still
room for the angioplasty and wait-and-
see strategy. Lancet Gastroenterol Hepa-
tol 2019;​4:​823.
41. Bachet JB, Condat B, Hagège H, et al.
Long-term portosystemic shunt patency
as a determinant of outcome in Budd-
Chiari syndrome. J Hepatol 2007;​46:​60-8.
42. Mentha G, Giostra E, Majno PE, et al.
Liver transplantation for Budd-Chiari syn-
drome: a European study on 248 patients
from 51 centres. J Hepatol 2006;​44:​520-8.
43. Chinnakotla S, Klintmalm GB, Kim P,
et al. Long-term follow-up of liver trans-
plantation for Budd-Chiari syndrome with
antithrombotic therapy based on the eti-
ology. Transplantation 2011;​92:​341-5.
Copyright © 2023 Massachusetts Medical Society.