Case 4 -
Associated with Portal Changes Mimicking Chronic Biliary Disease
VA and University of California San Francisco Medical Center
San Francisco, CA
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40 year old woman presented with fatigue and abdominal pain. Physical exam revealed low grade
ascites, mild jaundice, mildly enlarged liver and splenomegaly. There was a history of bloody diarrhea
for a few months two years back, but it was not clear if the diagnosis of inflammatory bowel disease was
clearly established at that time. There were no gastrointestinal symptoms at this presentation.
Alkaline phosphatase was five times normal and transaminaseswere barely out of the normal range.A liver
biopsy was performed (since the needle biopsy has limited material, an open biopsy obtained at a later
date is being provided. The needle biopsy and open biopsy show the same features).
Case 4 - Figure 1 - Sinusoidal dilatation and congestion predominantly affecting zone 3 of the liver.
Case 4 - Figure 2 - Pericentral fibrosis accompanied by sinusoidal dilatation and congestion.
Case 4 - Figure 3 - Many portal tracts are expanded and show bile ductular proliferation.
Case 4 - Figure 4 - Bile ductular proliferation is accompanied by a mild lymphoplasmacytic infiltrate.
Case 4 - Figure 5 - In addition to pericentral fibrosis, there is portal-based fibrosis with irregular septa.
Diagnosis: Budd-Chiari syndrome associated with portal changes mimicking chronic biliary disease
The liver biopsy shows sinusoidal dilatation and congestion, predominantly in zone 3 of the acinus
(centrizonal). Hepatic plate atrophy, RBC extravasation into the space of Disse and pericentral fibrosis
is present. In addition, the portal tracts show bile ductular reaction (proliferation), mild
lymphoplasmacytic infiltrate and portal-based fibrosis. These features raise the following two
(1) Portal changes in venous outflow obstruction: Pathologic changes of venous outflow
obstruction in the centrizonal region are well described
, but abnormalities seen in portal tracts
have not been widely studied. In our experience, portal tract changes that mimic a biliary disease are
frequently present in cases with typical morphologic findings of venous outflow impairment. In a study
of 34 patients with a confirmed diagnosis of venous outflow impairment, pathologic changes in the portal
tracts were present in more than half of the cases . The liver biopsies in these cases showed:
- Are the portal changes like bile ductular proliferatioin, portal inflammation and
portal-based fibrosis part of venous outflow impairment or reflection of a coexistent chronic biliary
- What is the specificity of histologic features (sinusoidal dilatation, hepatic plate
atrophy and RBC extravasation) for the diagnosis of venous outflow impairment?
(a) Portal expansion with bile ductular proliferation (47%). This was accompanied by a mild
lymphoplasmacytic infiltrate and portal or periportal fibrosis. Lymphocytic cholangitis was seen in 3
(b) Portal and/or periportal fibrosis without ductular proliferation (9%)
(c) Normal portal tracts (44%)
As shown by this study, nearly half of the cases showed bile ductular proliferation in portal tracts
often accompanied by portal-based fibrosis and mild lymphoplasmacytic inflammation. The ductular
reaction is generally mild but can occasionally be florid and accompanied by evidence of bile duct damage
in the form of lymphocytic cholangitis. These morphologic changes can be easily interpreted as
indicating chronic biliary disease.
These patients often have elevated alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT)
with mild elevation of liver aminotransferases. This liver enzyme profile reinforces the suspicion of a
biliary etiology. In the study mentioned above , the possibility of chronic biliary disease was
raised in the original pathology report in several cases; however, radiological evaluation of bile ducts
failed to reveal any abnormality in the biliary tree.
The mechanism of bile ductular proliferation and portal-based fibrosis in venous outflow impairment is
not known. Sinusoidal dilatation and increased venous pressure or compromised arterial flow due to
abnormal shunts may lead to a low level of ischemic damage to the biliary tree. Ischemic injury is
implicated in rare cases of biliary abnormalities (portal biliopathy) that develop in extrahepatic portal
In addition to the changes in portal tracts described above, bile ductular proliferation can also
occur in association with large regenerative nodules in Budd-Chiari syndrome , which presumably result
from localized increase in arterial blood flow . These nodules with bile ductular proliferation and
can resemble focal nodular hyperplasia (FNH). However, as per the recommendedations of The International
Working Party, FNH-like lesions associated with the Budd-Chiari syndrome should not be designated as FNH,
but rather referred to as regenerative nodules ('FNH-like' nodules) .The regenerative nodules can show
copper accumulation indicating some sort of biliary perturbation .
(2) Sinusoidal dilatation and congestion: differential diagnosis: Impairment of venous
outflow from the liver at the level of small hepatic veins (veno-occlusive disease), large hepatic veins
or inferior vena cava (Budd-Chiari syndrome) or due to cardiac disease (right heart failure, constrictive
pericarditis) leads to passive venous congestion manifested as sinusoidal dilatation, congestion and
hepatocyte atrophy.However, these histologic changes are not specific and can be observed in other
disease processes in the absence of venous outflow impairment. Sinusoidal dilatation in liver biopsy is
attributable to venous outflow impairment in around 65% of cases
. Other causes that can be
considered in the absence of venous outflow impairment include:
(a) Other vascular causes like portal vein thrombosis, nodular regenerative hyperplasia and
sickle cell anemia. Obstruction of portal vein blood flow to the liver can lead to hepatocyte atrophy
and an appearance of dilated sinusoids because of excess sinusoidal volume
regenerative hyperplasia can lead to sinusoidal dilatation by a combination of compression of hepatic
microvasculature and areas of hepatocyte atrophy
. Disorders with sinusoidal infiltration and
destruction of the reticulin framework are known to cause sinusoidal dilatation. These include sickle
cell anemia,leukemia, malaria and extramedullary hematopoeisis
(b) Systemic inflammatory conditions like Crohn disease, rheumatoid arthritis, Still disease
and polymyalgia rheumatica
as well as granulomatous conditions like sarcoidosis without direct
. There are several reports in literature that describe marked sinusoidal
dilatation in liver biopsies in patients with Castleman disease
(c) Extrahepatic neoplasms without liver involvement. Sinusoidal dilatation has been most
commonly associated with renal cell carcinoma (RCC) and Hodgkin lymphoma in the absence of liver
. RCC accompanied by liver dysfunction has been termed Stauffer syndrome
Sinusoidal dilatation can be seen in around 10% of patients with renal cell carcinoma in the absence of
metastatic disease . Other tumors that have been associated with sinusoidal dilatation include
carcinoma of the stomach, uterus and colon .
(d) Other. Sinusoidal dilatation can be observed in wedge biopsies obtained during abdominal
surgeries . The mechanism of SDC in these situations is unclear, but may represent an artifact of
wedge biopsy of the subcapsular liver parenchyma. Alternatively, alterations in portal blood flow may
occur during abdominal surgery and lead to transient SDC.
It would be useful to identify features on liver biopsy that can help distinguish cases with venous
outflow impairment from other causes of sinusoidal dilatation. Features like degree of sinusoidal
dilatation and presence of RBC in the space of Disse are not reliable for this distinction .
However, the presence of fibrosis favors venous outflow impairment . Among the cases without venous
outflow impairment, fibrosis has been observed in nodular regenerative hyperplasia and portal vein
thrombosis, but not in others.
(1) Portal tract changes in the form of bile ductular proliferation, lymphoplasmacytic
inflammation and portal/periportal fibrosis are commonly encountered in liver biopsies with venous
outflow impairment. These changes closely resemble the features of chronic biliary disease, a suspicion
that is heightened by the frequent elevation of alkaline phosphatase and gamma-glutamyl transferase.
Awareness of these morphologic changes can prevent overemphasizing the risk of biliary disease in this
setting and prevent unnecessary diagnostic evaluation.
(2) Sinusoidal dilatation and congestion in liver biopsy is associated with venous outflow
impairment in 2/3 of cases. Other diagnostic considerations should include vascular conditions such as
portal vein insufficiency, nodular regenerative hyperplasia, and sinusoidal infiltration by diseases like
sickle cell anemia. Other important associations are inflammatory conditions like Castleman disease and
rheumatoid arthritis, and granulomatous disorders like sarcoidosis and Crohn disease. Sinusoidal
dilatation can also be observed in neoplasms such as renal cell carcinoma and Hodgkin lymphoma without
direct liver involvement.
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