—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 4 - Budd-Chiari Syndrome
Associated with Portal Changes Mimicking Chronic Biliary Disease

Sanjay Kakar
VA and University of California San Francisco Medical Center
San Francisco, CA


Click on each slide thumbnail image for an enlarged view
Clinical History
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

Discussion:
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 considerations:
  1. 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 disease?
  2. What is the specificity of histologic features (sinusoidal dilatation, hepatic plate atrophy and RBC extravasation) for the diagnosis of venous outflow impairment?
(1) Portal changes in venous outflow obstruction: Pathologic changes of venous outflow obstruction in the centrizonal region are well described [1, 2, 3, 4] , 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 [5]. The liver biopsies in these cases showed:

(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 cases.

(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 [5], 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 hypertension [6].

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 [7], which presumably result from localized increase in arterial blood flow [8]. 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) [9].The regenerative nodules can show copper accumulation indicating some sort of biliary perturbation [10].

(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 [11, 12] . 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 [4, 12, 13] . Nodular regenerative hyperplasia can lead to sinusoidal dilatation by a combination of compression of hepatic microvasculature and areas of hepatocyte atrophy [12, 14] . 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 [14, 15] .

(b) Systemic inflammatory conditions like Crohn disease, rheumatoid arthritis, Still disease and polymyalgia rheumatica [12, 14] as well as granulomatous conditions like sarcoidosis without direct liver involvement [11, 14] . There are several reports in literature that describe marked sinusoidal dilatation in liver biopsies in patients with Castleman disease [12, 16] .

(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 involvement [14, 17] . RCC accompanied by liver dysfunction has been termed Stauffer syndrome [17, 18] . Sinusoidal dilatation can be seen in around 10% of patients with renal cell carcinoma in the absence of metastatic disease [17]. Other tumors that have been associated with sinusoidal dilatation include carcinoma of the stomach, uterus and colon [14].

(d) Other. Sinusoidal dilatation can be observed in wedge biopsies obtained during abdominal surgeries [12]. 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 [12]. However, the presence of fibrosis favors venous outflow impairment [12]. Among the cases without venous outflow impairment, fibrosis has been observed in nodular regenerative hyperplasia and portal vein thrombosis, but not in others.

Conclusions
(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.

References

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