Keywords
primary myelofibrosis - portal system - thrombosis - portal-biliary cavernoma - diagnostic
imaging - ultrasonography
Introduction
The portal cavernoma and more uncommon biliary cavernomatosis are pathologies characterized
by formation of hepatopetal collateral venous circles in the context of the wall of
these two anatomical structures, and in most cases, they are due to a progressive
obstruction of an extensive portion of the portal vein.[1]
[2]
[3]
Biliary involvement in cavernomatous transformation, also called biliary cavernomatosis
or portal biliopathy, is a pathological condition which has witnessed a growing interest.
The first cases were reported in 1961 by Saint[4] and in 1965 by Hunt.[5] Saint first described the surgical and histopathological aspect of a venous plexus
in close contact with the wall of the main bile duct (MBD) and suggested the possibility
that this anomaly could be related to the presence of some specific liver pathologies.
For a long time, the cavernous transformation of the biliary tract has been considered
a very rare and unusual condition[3]
[6]
[7]; Novellas et al[6] accidently found this pathological entity with relative greater frequency during
the execution of some diagnostic imaging techniques, more frequently in the course
of endoscopic retrograde cholangiopancreatography (ERCP) and MR-cholangiography.
This condition is still poorly known and easily confused with other causes of parietal
thickening of the MBD. Thus, this diagnosis is fundamental for an appropriate therapeutic
treatment, which is reserved exclusively for symptomatic cases[8]
[9] and is important to avoid the onset of potentially life-threatening complications,
such as massive bleeding, during the execution of some procedures such as ECRP and
choledocholithotomy.[6]
[10]
Previous studies have shown the wall of the biliary tract affected by cavernomatosis
have a thickness ranging from 5 to 6 mm.[7]
Portal and biliary cavernomatosis is caused by portal hypertension, seen in 40% of
cases with extrahepatic obstruction of the portal vein (EHOPV).[11] The most common causes of obstruction of the portal vein in adults include thrombosis,
malignant tumors, trauma, and inflammatory abdominal diseases.[12]
In 40 to 70% of patients without liver cirrhosis or hepatocellular carcinoma, portal
thrombosis is related to the presence of hereditary or acquired thrombophilic factors
and blood hypercoagulability that increases probability of thrombi formation in splanchnic
veins[13]
[14]
[15] ([Table 1]). Acquired states of hypercoagulability include oral contraceptives, pregnancy,
inflammatory states and myelolymphoproliferative diseases.[16]
Table 1
Acquired or hereditary conditions that determine hypercoagulable conditions
|
Acquired conditions
|
Hereditary or congenital conditions
|
|
Anticardiolipin antibody syndrome
|
Antithrombin deficiency
|
|
Antiphospholipid antibodies
|
Prothrombin defect G20210A
|
|
Disseminated intravascular coagulation
|
Dysfibrinogenemia
|
|
Cancer and chemotherapy
|
Thrombomodulin defect
|
|
Heparin thrombocytopenia
|
Heparinic cofactor II deficiency
|
|
Factor VIII, VII, I (fibrinogen) and von Willebrand factor increase
|
Plasminogen tissue activator deficiency
|
|
Lupus anticoagulant activity
|
Protein S deficiency
|
|
Hormone replacement therapy
|
Protein C deficiency
|
|
Pregnancy and postpartum
|
Plasminogen deficiency
|
|
Inflammatory conditions
|
Excess of inhibitor 1 of plasminogen activator
|
|
Paroxysmal nocturnal hemoglobinuria
|
Activated protein C resistance
|
|
Hyperhomocysteinemia
|
Hyperhomocysteinemia
|
Myelofibrosis is a rare chronic myelolymphoproliferative disease characterized by
megakaryocyte and myeloid proliferation, reactive medullary fibrosis, ineffective
erythropoiesis and extramedullary hematopoiesis.[17]
[18]
The aim of this work was to retrospectively evaluate patients with initial diagnosis
of primary myelofibrosis who had undergone abdominal ultrasound with color Doppler
and subsequent multidetector CT, abdominal MRI with the administration of contrast
media (MDC) and MR-cholangiography to identify portal thrombosis and the presence
of portobiliary cavernomatosis.
Materials and Methods
The proposed work is a retrospective study. The completed study was performed in accordance
with the ethical standards expressed by the 1964 Helsinki Declaration. Patients admitted
in our institution signed a written informed consent, which allows us to use patients’
data for educational and research purposes. Furthermore, the criteria of anonymity
and confidentiality of the sensitive data of the enrolled patients was followed in
the retrospective evaluation. No supplementary tests were added to these patients
during their diagnostic workup and therapeutic procedures.
Patients Selection
Between January 2005 and November 2019, 125 patients with primary idiopathic myelofibrosis
preliminarily underwent US examination completed by evaluation with color Doppler
and pulsed Doppler within 1 month from the diagnosis. All patients came to our observation
with clinical symptoms of nonspecific abdominal pain in the superior quadrants.
Idiopathic myelofibrosis in all patients had always been diagnosed according to World
Health Organization (WHO) criteria through a histological examination of the medullary
puncture performed at the level of the iliac crests, use of molecular biology techniques
and microscopic assessments on peripheral blood.
Among our sample (125 patients), we identified 13 patients with partial or complete
portal vein thrombosis associated with portal and biliary cavernomatosis (5 males
and 8 females, aged between 45 and 85 years).
Diagnostic Imaging Techniques
The US examination of the upper abdomen was performed by one of the authors (MS) with
a supine patient after a fast of at least 6 hours to ensure a good visualization of
the gallbladder and the biliary tree using two devices (Philips HD 5000 - Eindhoven,
Netherlands; Esaote MyLabX6–Genua, Italy) equipped with convex probe. Scans were performed
with the B-Mode technique for a morphological evaluation of the splanchnic organs
by means of subcostal scans performed at the midline and at the right of the midline,
both transversal and longitudinal, to visualize both the liver lobes and the gallbladder,
and by means of intercostal, transverse and longitudinal subcostal scans to the left
of the midline to visualize the spleen. The US examination was integrated with the
use of color Doppler technique to evaluate caliber, course and any anomalies of the
wall portal vein and suprahepatic veins. Doppler flowmetry was then performed for
the dynamic sampling of the portal flow performed in inspiratory apnea.
The criteria used to diagnose biliary cavernomatosis included the detection of a concentric
thickening of the walls of the MBD equal or greater than 5 mm and the presence of
vicariant collateral venous circles within the walls of the main biliary route with
demonstration of hepatopetal reduced flow rate with Doppler flowmetry.
Subsequently, all patients underwent dynamic contrast-enhanced CT scan of the abdomen
with IV administration of nonionic organo-iodine contrast media. CT exams were performed
using 16-detector dual MDCT equipments (Brilliance, Philips Medical System IDT, Netherlands
and Lightspeed, General Electrics, USA) before and after IV administration of 120
ml of nonionic organo-iodine contrast medium (Ultravist 300, Bayer Pharma, Germany)
with an infusion rate of 3 mL/sec. Four scan acquisitions were performed on the supine
patient: a precontrast phase, an early arterial phase, a portal phase, and a late
phase. The contrast medium was injected into the antecubital vein through an 18G needle
using an automatic injector (MK-IV, Medrad, Pittsburgh, Pennsylvania, USA) with 15
second (arterial phase) and 60 second (venous phase) scan delays, considering the
scan time and the moment of reaching 150 HU opacification value of the abdominal aorta
(bolus tracking technique). The late equilibrium scan was acquired 180 seconds after
IV administration of contrast medium.
The CT scans were performed using the following parameters: collimation 16 × 0.75
mm, layer thickness of 1 mm, increment of 1 mm, pitch 1.1, table speed 17.6 mm, rotation
time 0.5 second. and current tube 120/250 KVp/mAs, reconstruction interval and advancement
of 1 mm. Arterial and equilibrium scans were conducted from the diaphragmatic dome
to the lower pole of the kidneys; those in the portal venous phase from the diaphragmatic
dome to the pubic symphysis.
At the end of the CT examination, the data obtained was transferred to a workstation
(Hp Kayak XU Hewlett Packard, Palo Alto, California, USA) equipped with dedicated
software (GE Centricity, USA). The images obtained were analyzed by postprocessing
multiplanar reformation or reconstruction (MPR) algorithms that allowed reconstructions
in the axial, coronal and sagittal planes and along oblique planes.
MR examinations were performed with 1.5 Tesla equipment (Siemens Sonata, Germany)
using a phased array body coil, with the patient in supine position. The following
acquisition sequences with relative scan plans have been used:
-
Axial gradient-echo T1-weighted in phase and in phase opposition (TE: 5.04 milliseconds,
TR: 110 milliseconds, flip angle: 70°, thickness: 5 mm, number of averages: 1).
-
Axial turbo spin echo (TSE) T2-weighted (TE: 102 milliseconds, TR: 2800 milliseconds,
flip angle: 150°, thickness: 5 mm, number of averages: 1).
-
Axial TSE T2-weighted with saturation of the adipose tissue signal (TE: 102 milliseconds,
TR: 2800 milliseconds, flip angle 150°thickness: 5 mm, number of averages: 1).
-
Axial volumetric interpolated breath-hold sequences (VIBE) T1-weighted with saturation
of the adipose tissue signal (TE: 1.48 milliseconds, TR: 4.3 milliseconds, flip angle:
12, thickness 4 mm, number of averages: 1) with acquisitions made at the basal condition
and repeated at 30 seconds (arterial phase), 70 seconds (portal phase) and 180 seconds
(late phase) after the IV administration of 0.1 mmol/Kg of a paramagnetic contrast
medium (GADOVIST, Bayer Pharma, Germany) through an 18G needle positioned in the antecubital
vein with 2 mL/sec flow rate followed by the injection of 20 mL of saline solution.
In four patients, MR-cholangiography study was also performed using the following
acquisition sequences with the related scan plans:
-
Coronal T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE) (TE:
122 second, TR: 699 second, flip angle: 150°thickness: 3 mm, number of averages: 1).
3D coronal TSE T2-weighted (TE: 681 second, TR: 4.69 second, flip angle: 170°, thickness:
1.5 mm, number of averages: 1). These latest 3D acquisitions have been reconstructed
with maximum intensity projection (MIP) technique to obtain cholangiographic-like
images.
The subsequent follow-up controls in all these patients were performed only with US
and MRI of the upper abdomen, avoiding CT, to reduce radiation exposure.
Statistical Analysis
The correlation between primary myelofibrosis and the association of partial thrombosis
with portal-biliary cavernoma was calculated using Chi-squared test (χ2 test). Statistical analysis was performed using SPSS version 21.0 (SPSS Inc. Chicago,
IL).
Results
As many as 13 out of 125 patients with known primary myelofibrosis (10%), studied
for painful abdominal symptoms, showed in the preliminary US study partial or complete
thrombosis of the portal venous system and marked concentric thickening of the wall
of the main biliary duct together with portal cavernomatosis. MBD thickening in these
patients was between 5 mm and 9 mm (average value 7 mm) ([Fig. 1]). The thickening of the walls of the MBD was extended in two patients to both common
hepatic ducts.
Fig. 1 (A, B) B-mode US scan performed with convex probe focused at the level of the hepatic hilum
performed on two different patients with primary myelofibrosis, which demonstrates
the presence of 7 mm concentric thickening of the main bile duct (MBD) wall in the
first one (A) and of 6 mm in the second one (B).
Only the use of the color Doppler technique detected within the thickened wall of
the biliary tract involved the presence of ectasic serpiginous collateral veins ([Fig. 2]), characterized by Doppler sampling and venous flow with hepatopetal direction and
a mean average speed of approximately 15 cm/s ([Fig. 3]).
Fig. 2 (A–C) B-mode US scan performed on a patient with primary myelofibrosis, which demonstrates
the presence of a 7 mm concentric thickening of the main bile duct (MBD) wall (A). Color Doppler showed the absence of flow within the portal lumen due to a complete
thrombosis and the evidence of flow within the MBD wall thickened due to collateral
venous vessels (B, C).
Fig. 3 (A–C) B-mode US scan performed on patient with primary myelofibrosis, which shows 6 mm
concentric thickening of the main bile duct (MBD) wall and a partial portal thrombosis
(A, B). Color Doppler (B) with flow-velocity sampling (C) of the vessels within the MBD wall was performed confirming the definitive diagnosis
of biliary cavernoma.
Portal vein thrombosis was partial in eight patients (62%) and complete in five patients
(38%) and was localized at the level of the common trunk in 12 patients with extension
in 10 patients to the right portal branch and in two patients to the left portal branch.
In one patient, the thrombosis was localized only to the left portal branch without
any evidence of involvement of the common trunk; in this patient, the portal cavernoma
was located only to the left side of the portal vein without any involvement peripheral
to MBD.
The portal thrombosis never showed internal vascularity on color Doppler imaging and
was always classified as a bland thrombus ([Fig. 3]).
In 12 patients, the other US finding was the presence of thickening of the walls of
the gallbladder without any intramural varices (one patient had undergone previous
laparoscopic cholecystectomy), while a slight dilatation of the intrahepatic biliary
tree was found in four patients. Even patients with minimal dilation of the intrahepatic
biliary tracts did not have raised bilirubin or abnormal liver functions.
All 13 patients had splenomegaly with a longitudinal diameter greater than 12 cm with
a maximum recorded value of approximately 19 cm; in nine patients, a volumetric increase
of the liver was associated without evidence by ultrasound, CT or MRI of chronic liver
disease.
Both contrast-enhanced CT and MRI confirmed the wall thickening of the biliary tract
comparable to that detected on US examination ([Figs. 4]
[5]
[6]). Both diagnostic techniques allowed visualization of progressive enhancement of
the thickened MBD walls during portal and late equilibrium phase caused by peribiliary
ectasic collateral circles. Both these techniques did not allow an accurate flowmeter
characterization, like the color Doppler examination, and therefore the differential
diagnosis with other pathological conditions of MBD enhancing wall thickening could
be difficult.
Fig. 4 (A, B) Multi-detector computed tomography (MDCT) scans performed at the level of the hepatic
hilum on two different planes (A, B) after the IV administration of contrast media during the portal phase. It is possible
to demonstrate the portal vein thrombosis (short black arrow), a concentric thickening
of the main bile duct (MBD) wall with contrast enhancement due to biliary cavernoma
(long black arrow) and the presence of numerous dilated collateral periportal vessels
due to portal cavernoma (white arrow).
Fig. 5 (A, B) Multi-detector computed tomography (MDCT) scans performed at the level of the hepatic
hilum on axial plane (A) and a multiplanar reformatting on coronal plane (B) after the IV administration of contrast media during the portal phase. It is possible
to demonstrate the normal caliber of the main bile duct (MBD) (white arrow) and the
presence of numerous dilated collateral periportal vessels due to portal-biliary cavernoma
(black arrows), which is better detectable on axial plane.
Fig. 6 (A–D) Axial contrast-enhanced MRI performed in a patient with primary myelofibrosis, portal
thrombosis and biliary cavernoma at the level of the hepatic hilum during the arterial
(A), portal (B) and late phase (C), which detected progressive enhancement of the main bile duct (MBD) thickened wall
(black arrow). MR-cholangiography (D) shows the normal caliber of the MBD.
CT and MRI always confirmed the preliminary US diagnosis of portal thrombosis, allowing
evaluation of its extension with greater accuracy (partial or complete thrombosis)
and demonstrating the involvement of splenic vein in one patient and superior mesenteric
vein in two patients.
Both contrast-enhanced CT and MRI allowed detection of the presence of areas of liver
parenchyma increase density during the arterial dynamic phase (transient hepatic attenuation
differences [THAD]) in nine patients and the presence of multiple perigastric and
perisplenic vicariant venous collateral circles in four patients.
In the four patients studied with MR-cholangiography, 3D coronal acquisitions and
MIP reconstructions, a filiform aspect of the main biliary duct was always detected
associated with minimal ab extrinsic compression but without the detection of a sudden
interruption of the lumen caliber ([Fig. 6)].
In our study the concurrent occurrence of simultaneous portal thrombosis with portal-biliary
cavernomatosis in patients with primary myelofibrosis was observed in 13 cases. This
result implies a “Chi squared” value χ2 = 0 that confirms the coexistence of portal thrombosis together with portal-biliary
cavernoma in our patients.
Discussion
Our experience confirmed the possibility of a close association between portal thrombosis
and cavernomatous transformation of the biliary tract in patients with primary myelofibrosis,[19]
[20]
[21] which was found in 10% of our patients. All thirteen patients with primary myelofibrosis
observed for portal system thrombosis also developed portal and biliary cavernomatosis.
Biliary cavernomatosis is rather unusual and uncommon compared with the more known
and frequent portal cavernomatosis.
Myelofibrosis is a rare chronic myeloproliferative disease recognized in two forms,
the idiopathic or primary form and the secondary form which represents the late evolution
of a pre-existing true polycythemia or essential thrombocythemia. It consists of a
clonal disease of the hematopoietic stem cell characterized by megakaryocyte and myeloid
proliferation, a reactive medullary fibrosis with consequent ineffective erythropoiesis
and extramedullary hematopoiesis.[17]
[18] The diagnosis of primary myelofibrosis, according to WHO, is based on histopathological,
molecular and clinical criteria, and histopathology represents the key in the diagnostic
process with the demonstration of atypia in the proliferation of megakaryocytes.[22]
[23] The most frequent clinical manifestations are anemia, asthenia, hepatosplenomegaly,
extramedullary hematopoiesis and thrombohemorrhagic complications.[16]
[17]
[24] Among myeloproliferative diseases, idiopathic myelofibrosis has the worst prognosis
in terms of both survival and quality of life with an average survival of approximately
69 months from the time of diagnosis reported. The main causes of death are the evolution
of acute myeloid leukemia, occurrence of an accelerated non-leukemic phase, recurrent
infections and thrombosis.[24]
Denys et al[7] found an association between myelofibrosis and cavernomatous transformation of the
portal system and biliary tree, and our study appears to support the correlation between
these two pathologies. The cause of this association with primary myelofibrosis is
probably due to the gradual formation of portal vein thrombosis, which is related
to hypercoagulability status. This would result in a slow development of portal and
biliary cavernomatosis, even in patients with partial portal vein thrombosis. The
portal thrombosis was always due to a bland thrombus (nonmalignant venous thrombus)
which appear avascular on color Doppler. The differential diagnosis is very important
for the therapeutic approach because bland thrombus may resolve after thrombolytic
and anticoagulant therapy, unlike tumor thrombus.
Our experience also shows that cavernomatosis of the main biliary tract is not a rare
and unusual condition as suggested by the available literature, but is probably a
more frequent condition often confused with other causes of parietal thickening of
the biliary tree and gallbladder.[6]
[7]
[25]
The thickness of the MBD wall found was always between 5 mm and 9 mm. These values
confirm the work of Denys et al[7] in which the three patients showed wall thickening between 5 mm and 6 mm. Thickening
of the MBD equal or greater than 5 mm can be considered compatible with the possible
diagnosis of biliary cavernomatosis. In this regard, the thickening of the MBD and
common hepatic ducts found on B-mode US examination in patients with portal vein thrombosis
could be incorrectly attributed to various pathological conditions such as chronic
cholangitis and Klatskin's tumor rather than a cavernous transformation of the portal
and biliary spaces.[6]
[7] In our study, B-mode US proved to be completely ineffective in identifying the nature
of the concentric thickening of the biliary tract walls; only the color Doppler allowed
to detect the presence of serpiginous vessels with hepatopetal venous flow within
the wall of the biliary tract; in our opinion, this is the pathognomonic US sign of
biliary cavernomatosis.
Compared with the US, MDCT and MRI allowed better assessment of the extent of venous
thrombosis and the morphological aspect of the biliary system and usually permitted
exclusion of an obstruction of the main biliary duct. MRI with MR-cholangiography
are particularly accurate in the evaluation of the biliary tract lumen and in the
differential diagnosis with malignant conditions of MBD parietal thickening, allowing
to exclude the presence of tight stenosis suggestive of malignancy.
According to Aguirre et al,[26] and in our experience, in biliary cavernomatosis, MR-cholangiography demonstrates
a thread-like aspect of MBD with signs of ab extrinsic compression and without the
finding of significative caliber reduction.
In conclusion, the constant finding in primary myelofibrosis of the association of
portal thrombosis with portal-biliary cavernoma indicates the existence of a correlation
between these two pathologies. For the detection of the ectasic vessels developing
from the vasa vasorum of the portal vein and biliary tract, characteristic of the
cavernomatous conditions, the most accurate diagnostic technique is represented by
US with color Doppler, which allows one to make a definitive diagnosis, without using
more expensive techniques and contrast media.[3] CT and/or MRI must be used to evaluate the extent of portal thrombosis, to follow-up
thrombolytic therapy and correctly study the manifestations and complications of the
underlying disease such as spleen involvement and extramedullary hematopoiesis.
