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Original Research |
1 Division of Abdominal Imaging and Intervention, Department of Radiology,
Brigham and Women's Hospital, Harvard Medical School, Radiology Ste., c/o One
Brigham Circle, 1620 Tremont St., Boston, MA 02120.
2 Division of Angiography and Interventional Radiology, Department of Radiology,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School,
Boston, MA.
Received March 26, 2005;
accepted after revision June 7, 2005.
Address correspondence to S. M. Erturk
(mehmeterturk{at}superonline.com).
Abstract
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SUBJECTS AND METHODS. We retrospectively evaluated 18 patients (eight women, 10 men; mean age, 42.4 years) after hematopoietic stem cell transplantation with biopsy-proven hepatic venoocclusive disease (n = 5), hepatic graft-versus-host disease (n = 6), or both (n = 7). Two radiologists reviewed abdominal and pelvic CT scans for hepatomegaly (> 18 cm), splenomegaly (> 13 cm), size of main portal and right hepatic veins, presence of periportal edema, gallbladder wall edema, hydropic gallbladder, ascites, and small-bowel wall thickening. CT and histopathology findings were correlated using analysis of variance and Fisher-Free-man-Holton tests.
RESULTS. Ascites and periportal edema were present in all five patients with venoocclusive disease, but of six patients with graft-versus-host disease, ascites was seen in two (p < 0.05) and periportal edema in only one (p < 0.05). Small-bowel wall thickening was encountered in five patients with graft-versus-host disease and in none with venoocclusive disease (p < 0.05). The right hepatic vein diameter in patients with venoocclusive disease (mean, 0.27 cm) was significantly smaller than the right hepatic vein diameter in patients with graft-versus-host disease (mean, 0.87 cm; p < 0.05).
CONCLUSION. In patients treated with hematopoietic stem cell transplantation, CT findings of periportal edema, ascites, and a narrow right hepatic vein suggest venoocclusive disease rather than graft-versus-host disease. Small-bowel wall thickening suggests graft-versus-host disease.
Keywords: graft-versus-host disease • CT • liver disease • stem cell transplantation • venoocclusive disease
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Venoocclusive disease of the liver, acute hepatic graft-versus-host disease, cholestatic disorders, and infections are the most frequent causes of hepatic dysfunction in the early posttransplantation period [4]. Although cholestatic disorders and infections may be diagnosed by clinical, biochemical, and imaging findings, venoocclusive disease and graft-versus-host disease are more difficult to diagnose because their signs and symptoms are nonspecific [5].
In general, hepatic venoocclusive disease is characterized by painful hepatomegaly, fluid retention, weight gain, and jaundice [6, 7]. Its onset is typically 4 to 5 weeks after hematopoietic stem cell transplantation, although later manifestations have been reported [5]. Acute graft-versus-host disease develops within 2 to 10 weeks of hematopoietic stem cell transplantation [1]; hepatic involvement is usually manifested by cholestatic jaundice, nausea, vomiting, and abdominal pain [2]. Because both conditions present with nonspecific clinical and biochemical findings, a liver biopsy is needed in most cases to differentiate them. An accurate diagnosis is essential because the treatment of venoocclusive disease includes antithrombotic and thrombolytic agents, whereas graft-versus-host disease is treated with corticosteroids [2].
Because patients with both conditions are typically coagulopathic, liver biopsy may be complicated by hemorrhage. Therefore, a noninvasive imaging method that allows accurate differentiation between venoocclusive disease and graft-versus-host disease would be valuable. We sought to evaluate whether CT scans could be used to differentiate hepatic venoocclusive disease from acute hepatic graft-versus-host disease in patients after hematopoietic stem cell transplantation.
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CT Technique
All patients underwent CT of the abdomen and pelvis; 15 were scanned 60-70
sec after an IV injection of 100 mL of 300 mg I/mL of iopromide, at a rate of
3.0 mL/sec; three had unenhanced scans. Unless contraindicated, all patients
received 900 mL of oral contrast material. Abdominopelvic CT scans were
performed using MDCT scanners (Volume Zoom or Sensation 16, Siemens Medical
Solutions) with a reconstruction section thickness of 5 mm and an interval of
5 mm.
Radiologic Assessment and Statistical Analysis
Two radiologists, blinded to clinical, biochemical, and histopathologic
findings, reviewed, in consensus, CT scans for the presence of hepatomegaly
(> 18 cm; craniocaudally), splenomegaly (> 13 cm; craniocaudally),
periportal edema, gallbladder wall edema (> 3 mm), ascites, and small-bowel
wall thickening (> 3 mm). The widest diameter of the main portal vein and
the widest diameter of the right hepatic vein were measured. Because it is
known that the middle and left hepatic veins frequently form a common trunk
[8], only the right hepatic
vein diameter was measured.
Continuous variables (main portal vein diameter and right hepatic vein diameter) were compared in the patients with venoocclusive disease, the patients with graft-versus-host disease, and the patients with both venoocclusive disease and graft-versus-host disease using analysis of variance. When a difference was found to be significant, multiple comparisons were performed using the Tukey-Kramer test. Dichotomous variables (hepatomegaly, splenomegaly, periportal edema, gallbladder wall thickening, ascites, and small-bowel wall thickening) were compared using the Fisher-Free-man-Holton exact test. Differences were considered statistically significant if p < 0.05.
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Venoocclusive disease may occur after ingestion of "bush tea" containing pyrrolizidine alkaloids [10], inhalation of insecticides [11], and as a complication of a variety of chemotherapy regimens [12] and radiation therapy [2]. In addition, agents used to prevent graft-versus-host disease, including cyclosporine and methotrexate, are also associated with an increased risk of venoocclusive disease [13]. Finally, high-dose radiation therapy (exceeding 13-15.75 Gy) is associated with the development of venoocclusive disease; the risk is particularly high when the radiation is administered in a single high dose rather than in multiple fractionated doses [14].
Clinically, venoocclusive disease is characterized by weight gain not attributable to fluid overload, painful hepatomegaly, jaundice, and ascites [7]. Patients may also develop hepatorenal syndrome with intense sodium avidity, portal hypertension, and multiorgan system failure. Venoocclusive disease develops in 10-60% of patients after hematopoietic stem cell transplantation and ranges in severity from a mild reversible disease to an advanced syndrome with a mortality approaching 100% [15].
Most transplantation centers apply criteria developed by the Seattle and Baltimore groups to diagnose hepatic venoocclusive disease clinically [7]. These criteria include two or three basic manifestations (jaundice, painful hepatomegaly, and fluid retention) to be present within 4-5 weeks after hematopoietic stem cell transplantation. Using these criteria, specificities and sensitivities are approximately 90% and 55%, respectively [16]. However, in the setting of hematopoietic stem cell transplantation, jaundice may be related to other causes, including acute graft-versus-host disease of the liver, hyperbilirubinemia associated with sepsis, and intrahepatic cholestasis secondary to drug toxicity. Whereas sepsis and drug-induced cholestasis usually can be excluded by means of clinical, microbiologic, and biochemical findings, liver biopsy is required in most cases to differentiate venoocclusive disease from graft-versus-host disease. Because patients often are coagulopathic, a transvenous, rather than a percutaneous approach, is preferred to reduce the risk of bleeding. However, transvenous liver biopsy still carries a risk of hemorrhage and is seen in up to 12% of patients [17-19]. Therefore, a noninvasive means of differentiating venoocclusive disease from graft-versus-host disease would be valuable.
To our knowledge, no published studies have compared the imaging findings of venoocclusive disease with those of graft-versus-host disease in patients treated with hematopoietic stem cell transplantation. Previously reported sonographic and CT features of venoocclusive disease include ascites, hepatomegaly, gallbladder wall thickening, and narrowed hepatic veins [6, 20-23]. Using Doppler sonography, McCarville et al. [24] reported that the hepatic artery resistance index and the direction and velocity of portal venous flow were not as useful as the Seattle criteria. MRI features of venoocclusive disease consist of hepatomegaly, hepatic vein narrowing, periportal cuffing, gallbladder wall thickening, marked hyperintensity of the gallbladder wall on T2-weighted images, and ascites [21, 22]. After hematopoietic stem cell transplantation in patients with graft-versus-host disease, reported extraintestinal CT findings include ascites, splenomegaly, periportal edema, pericholecystic fluid, biliary sludge, and gallbladder wall enhancement and thickening [4, 25]. Small-bowel wall thickening was found in all patients with acute graft-versus-host disease in one study [25]; concomitant hepatic and intestinal involvement was common [2].
In our study, we found CT findings to be useful in differentiating venoocclusive disease from graft-versus-host disease. Whereas periportal edema and ascites were found in most patients with venoocclusive disease, small-bowel wall thickening was predominantly seen in graft-versus-host disease. Therefore, we favor a diagnosis of venoocclusive disease in the presence of ascites or periportal edema (or both). Conversely, when small-bowel wall thickening is found, a diagnosis of graft-versus-host disease is much more likely. We found a significantly smaller right hepatic vein diameter in patients with venoocclusive disease compared with patients with graft-versus-host disease. In our study, the right hepatic vein diameters of the patients with venoocclusive disease and the patients with both venoocclusive disease and graft-versus-host disease were smaller than those of the patients with graft-versus-host disease alone, and a narrowed hepatic vein measuring less than 0.45 cm in diameter was highly suggestive of venoocclusive disease, in the proper clinical context.
In summary, abdominal CT should be performed in posttransplantation patients with abnormal liver function tests. CT findings of periportal edema, ascites, and a narrow right hepatic vein suggest venoocclusive disease, rather than graft-versus-host disease; small-bowel wall thickening suggests graft-versus-host disease.
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  C. L. Hollingsworth, D. P. Frush, J. Kurtzburg, and V. K. Prasad Pediatric Hematopoietic Stem Cell Transplantation and the Role of Imaging Radiology, August 1, 2008; 248(2): 348 - 365. [Abstract] [Full Text] [PDF]
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