Budd-Chiari syndrome

* Context.-Impairment of venous outflow manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. However, the finding of SDC is not specific for venous outflow impairment.

Objectives.-To determine the specificity of SDC in liver biopsies for venous outflow impairment and to seek an explanation for SDC in patients without clinical or radiologic features of venous outflow impairment.

Design.-Liver biopsies from 51 patients with sinusoidal dilatation were reviewed. Biopsies from transplant recipients, patients with cirrhosis, and patients with hepatic neoplasms (primary or metastatic) were not included. Clinical records were reviewed for laboratory tests and final clinicopathologic diagnosis.

Results.-Thirty-four patients (66.7%) had confirmed venous outflow impairment. Of the 17 cases (33.3%) without clinical and/or radiologic evidence of venous outflow impairment, vascular causes were present in 5 cases (9.8%; nodular regenerative hyperplasia in 2 cases and portal vein thrombosis, congenital absence of the portal vein, and sickle cell anemia in 1 case each). Systemic inflammatory disorders were identified in 6 patients (11.8%). These included 2 cases of Castleman disease and 1 each of sarcoidosis, Crohn disease, rheumatoid arthritis, and Still disease. Three patients (5.9%) had tumors without direct involvement of the liver (1 case each of Hodgkin lymphoma, renal cell carcinoma, and pancreatic serous pseudopapillary tumor). In the remaining 3 patients, SDC was identified in wedge liver biopsies performed at the time of surgery, including gastric bypass surgery, cholecystectomy, and splenectomy. No other disease association was apparent in these cases.

Conclusion.-Sinusoidal dilatation and congestion in liver biopsy is associated with venous outflow impairment in two thirds of the cases. In the absence of clinical and/or radiological evidence of venous outflow, diagnostic considerations include other vascular conditions, such as portal vein insufficiency and nodular regenerative hyperplasia. Sinusoidal dilatation and congestion can also occur in the setting of systemic inflammatory diseases, granulomatous disorders, and neoplasms, as well as in wedge biopsies obtained during abdominal surgery.

(Arch Pathol Lab Med. 2004;128:901-904)

Sinusoidal dilatation and congestion (SDC) in liver biopsy is often the result of venous outflow impairment.1"5 This impairment can occur at the level of the small hepatic veins (veno-occlusive disease), large hepatic veins (Budd-Chiari syndrome), or the heart (right-sided heart failure, tricuspid valve disease, constrictive pericarditis).4-6 These changes are most pronounced in zone 3 and are often accompanied by hepatocyte atrophy. However, these changes are not specific for venous outflow impairment and can occur in other disorders, such as those associated with sinusoidal infiltration, including sickle cell anemia7,8; hematologic malignancies, malaria, and extramedullary hematopoiesis''; and in granulomatous and neoplastic diseases.9,10 Dilatation of zone 1 sinusoids has been reported with oral contraceptive use.11

This retrospective study was designed to test the specificity of SDC for venous outflow impairment and to examine other clinical associations of SDC in patients without clinical or radiologie features of venous outflow impairment.

MATERIALS AND METHODS

All available liver biopsies obtained at the Mayo Clinic Rochester between 1994 and 2001 in which sinusoidal dilatation had been noted in the report or in which a histopathologic diagnosis of venous outflow impairment had been suggested were retrieved. Biopsies from liver transplant recipients, patients with cirrhosis, and hepatic neoplasms (primary or metastatic) were not included in the study. The biopsies were reviewed to confirm the diagnosis and the following features were recorded: (1) adequacy (biopsies with 4 or more portal tracts were considered adequate); (2) degree of fibrosis (sinusoidal, portal, periportal, and septal); (3) degree of sinusoidal dilatation (mild [zone 3], moderate [zones 2 and 3], and marked [zones 1, 2, and 3]); and (4) displacement of red blood cells in the space of Disse.

The clinical records of the patients were reviewed for the following characteristics: (1) clinical history; (2) liver chemistry tests (bilirubin and liver enzymes, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutaryl transferase, serum protein, and albumin); (3) radiological tests (ultrasound, computed tomographic scan, magnetic resonance imaging, angiography of the liver; and (4) final clinicopathologic diagnosis.

The study was approved by the Institutional Review Board of the Mayo Clinic Rochester. A Fisher exact test and [chi]^sup 2^ test were used for statistical analysis.

RESULTS

Of 141 total liver biopsies retrieved, 51 cases met the inclusion criteria. The 90 cases that were excluded were biopsies from liver transplant recipients and cirrhotic patients. The biopsies were adequate in all cases with 4 or more portal tracts.

Thirty-four cases (66.7%) had confirmed venous outflow impairment. These included 2 patients with veno-occlusive disease, 13 with Budd-Chiari syndrome, and 19 with cardiac disease (Figure, a). The remaining 17 cases (33.3%) did not reveal clinical and/or radiologie evidence of venous outflow impairment (Figure, b). The degree of sinusoidal dilatation and presence of fibrosis was significantly greater in the cases with venous outflow impairment; there was no difference between the 2 groups with regard to red blood cell extravasation into the space of Disse (Table 1).

The clinical and pathologic features of the 17 cases with no venous outflow impairment are summarized in Table 2. Presinusoidal vascular causes accounted for the liver pathology in 5 (9.8%) of these 17 cases. There was 1 case each of portal vein thrombosis and congenital absence of the portal vein. The portal vein thrombosis was thought to be secondary to a prior episode of acute pancreatitis. Two cases had nodular regenerative hyperplasia; one of these patients had polycythemia vera and the second was a kidney transplant recipient. One patient had sickle cell anemia and showed sickled red blood cells in the dilated sinusoids.

Systemic inflammatory disorders were identified in 6 patients (11.7%). Two of these patients had Castleman disease and presented with long and complex histories. Their symptoms included fatigue, weakness, anemia, arthralgia, and increased erythrocyte sedimentation rates. The diagnoses were elusive despite extensive workup, and liver biopsies were performed due to elevated alkaline phosphatase (4 and 8 times greater than normal, respectively) in both cases. Computed tomography-guided biopsies of intra-abdominal "lymph nodes" in both cases led to the diagnosis of hyaline vascular Castleman disease. The symptoms resolved after resection of the mass lesion. The other inflammatory disorders were 1 case each of common variable immunodeficiency with granulomas, Crohn disease, rheumatoid arthritis, and Still disease. The patient with common variable immunodeficiency presented with fatigue, hepatosplenomegaly, cytopenia, and abnormal liver biochemical tests. Small epithelioid granulomas, presumably noninfectious, were identified in the liver and spleen. Special stains and cultures for microorganisms were negative. The patient with Crohn disease was clinically thought to have primary sclerosing cholangitis, but the liver biopsy and endoscopie retrograde cholangiopancreatography did not support this diagnosis. One patient had rheumatoid arthritis with granulomatous meningitis, which was thought to be noninfectious. One patient had an equivocal diagnosis of Still disease with several years' history of diffuse fatigue, some night sweats, a marked normochromic anemia, and markedly elevated sedimentation rate.

Three patients (5.9%) had tumors without direct involvement of the liver. These included 1 case each of nodular sclerosis Hodgkin lymphoma, sarcomatoid renal cell carcinoma (RCC), and serous pseudopapillary tumor of the pancreas. In the remaining 3 patients, SDC was identified in wedge liver biopsies performed at the time of surgery (gastric bypass surgery for obesity, cholecystectomy for cholelithiasis, and splenectomy for autoimmune hemolytic anemia). No other disease associations were identified in these patients.

COMMENT

Impairment of venous outflow from the liver at the level of the hepatic veins, inferior vena cava, or due to cardiac disease leads to passive venous congestion manifested as sinusoidal dilatation, congestion, and hepatocyte atrophy.1-6 However, these histologie changes are not specific and can be observed in other disease processes in the absence of venous outflow impairment.

In this study, SDC in liver biopsy was attributable to venous outflow impairment in 66.7% of cases. This figure is in agreement with the results of Poulsen et al,10 who found evidence of venous outflow impairment in 61.9% of cases in their series of 21 liver biopsies. We identified other vascular causes responsible for SDC in 5 cases, including portal vein thrombosis, congenital absence of the portal vein, 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.12,13 Nodular regenerative hyperplasia can lead to SDC by a combination of compression of hepatic microvasculature and areas of hepatocyte atrophy.9,13 Disorders with sinusoidal infiltration and destruction of the reticulin framework are known to cause SDC. These disorders include sickle cell anemia,7,8 leukemia, malaria, and extramedullary hematopoiesis.9

Interestingly, more than 35% of cases with SDC without venous outflow impairment had systemic inflammatory conditions. Sinusoidal dilatation and congestion in the setting of inflammatory disorders has not been widely studied, and its significance and pathogenesis are not well understood. Two patients in our study had Castleman disease and presented with long, perplexing histories of nonspecific symptoms. The liver biopsy in both cases showed marked SDC as the only significant finding. In both instances, the symptoms resolved after removal of the offending mass lesion. The association between Castleman disease with SDC and peliosis hepatis has been noted in case reports.14-16 In the former, systemic symptoms resolved after surgery, similar to the outcome in both our cases. It has been suggested that a humoral factor produced by the mass lesion may be responsible for the systemic symptoms as well as SDC in the liver.14

Other inflammatory disorders noted in our series were 1 case each of Crohn disease, sarcoidosis, rheumatoid arthritis with granulomatous meningitis, and probable Still disease. The finding of SDC in granulomatous inflammatory disorders has been described. In a series of 26 liver biopsies with unexplained SDC, Bruguera et al19 identified 3 cases of pulmonary tuberculosis and 1 case of Crohn disease that showed SDC without involvement of the liver. Similarly, in 8 cases with SDC in the liver in which a vascular cause was not identified, Poulsen et al10 described 2 cases of chronic pyelonephritis and 1 case each of polymyalgia rheumatica and an undefined multisystem disorder with high erythrocyte sedimentation rate. The mechanism of SDC in these conditions is not known. It is theoretically possible that in conditions like sarcoidosis, SDC is caused by liver involvement by granulomas that were missed by the biopsy. This possibility does not explain SDC in nongranulomatous inflammatory disorders, and a humoral factor may mediate this morphologic change.

In 3 patients, SDC in liver biopsies was observed in association with extrahepatic neoplasms without liver involvement. These included 1 case each of sarcomatoid RCC, nodular sclerosis Hodgkin lymphoma, and serous pseudopapillary tumor (SPT) of the pancreas. Sinusoidal dilatation and congestion has been well described in association with RCC without liver metastasis; RCC accompanied by liver dysfunction has been termed Stauffer syndrome.17,18 In a study of 45 cases of RCC, SDC was observed in 4 patients in liver biopsies in the absence of metastatic disease.17 The SDC is unrelated to the polycythemia that can be induced by RCC. Similarly, SDC has also been described in Hodgkin lymphoma without direct liver involvement.9,18 Other tumors that have been associated with SDC include carcinoma of the stomach, uterus, and colon.9 The mechanism of SDC in neoplasms is not clear. It is possible that unidentified liver metastasis may alter the microcirculation and lead to SDC in some cases. A hitherto unidentified substance released by the tumor may cause SDC. Sinusoidal dilatation and congestion has not been described in SPT of the pancreas. In addition to the possibilities described above, SPT may lead to compression of the portal vein and compromise of portal blood flow to the liver due to its location, and it can lead to the appearance of SDC due to hepatocyte atrophy.

In 3 cases, SDC was observed in wedge biopsies obtained during surgical procedures, including cholecystectomy, splenectomy for autoimmune hemolytic anemia, and gastric bypass for obesity. Although the mechanism of SDC in these situations is unclear, they 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 SDC. The presence of fibrosis and moderate to marked sinusoidal congestion favors venous outflow impairment as the cause of SDC in the biopsy. In this study, the degree of sinusoidal dilatation was significantly greater in cases with venous outflow impairment. Similarly, portal-based and/or sinusoidal fibrosis was seen in a vast majority of cases with venous outflow impairment. Among the cases without venous outflow impairment, only 1 case with portal vein thrombosis showed portal-based fibrosis, while sinusoidal fibrosis was not seen in any case. Red blood cell extravasation in the space of Disse is thought to occur in venous outflow impairment due to increased pressure in the hepatic sinusoids. Although this feature was seen in nearly all the cases with venous outflow impairment, it also was frequently observed among cases without any impairment of venous outflow and is therefore not useful in their distinction. It is possible that SDC due to any cause can raise the intrasinusoidal pressure and displace red blood cells in the space of Disse.

In conclusion, SDC in liver biopsy is not entirely specific for venous outflow impairment. In the absence of clinical or radiological evidence of venous outflow impairment, 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, such as Castleman disease and rheumatoid arthritis, and granulomatous disorders, such as sarcoidosis and Crohn disease. Sinusoidal dilatation and congestion also can be observed in neoplasms such as RCC and Hodgkin lymphoma, and in wedge biopsies obtained during abdominal surgery.

References

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Sanjay Kakar, MD; Patrick S. Kamath, MD; Lawrence J. Burgart, MD

Accepted for publication April 12, 2004.

From the Department of Pathology, Veteran Affairs and University of California Medical Center, San Francisco, Calif (Dr Kakar); and the Departments of Gastroenterology (Dr Kamath) and Pathology (Dr Burgart), Mayo Clinic, Rochester, Minn.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Lawrence J. Burgart, MD, Department of Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: Iburgart@ mayo.edu).

Copyright College of American Pathologists Aug 2004
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