DOI: 10.1148/radiol.2251010374
(Radiology 2002;225:67-70.)
© RSNA, 2002
Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin
Ross L. Titton, MD and
Fergus V. Coakley, MD
1 From the Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY. Received January 29, 2001; revision requested March 6; revision received March 21; accepted April 3. Address correspondence to F.V.C., University of California, San Francisco, Box 0628, Rm M-372, 505 Parnassus Avenue, San Francisco, CA 94143-0628 (e-mail: Fergus.Coakley@radiology.ucsf.edu).
Index terms: Budd-Chiari Syndrome, 761.659 • Diagnosis Please • Hepatic veins, thrombosis, 959.751
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HISTORY
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A 32-year-old woman presented to the emergency department with a 3-day history of epigastric pain, vomiting, increasing pallor, and dark urine. Her medical history disclosed no abnormal findings. Physical examination revealed mild jaundice, abdominal distention, and bilateral lower extremity edema. Laboratory studies disclosed anemia, with a hemoglobin level of 70 g/L (7.0 g/dL), where the normal range is 115–160 g/L (11.5–16.0 g/dL). Hyperbilirubinemia was also disclosed, with a total serum bilirubin level of 75.2 µmol/L (4.4 mg/dL), where the normal range is 0–17.1 µmol/L (0–1.0 mg/dL). Liver enzyme levels were elevated, with an alanine aminotransferase, or ALT, level of 51 U/L (normal range, 5–37 U/L) and an aspartate aminotransferase, or AST, level of 170 U/L (normal range, 10–37 U/L). Serum creatinine level was normal. Findings at abdominal radiography showed a small amount of bowel gas but disclosed no other abnormalities. Abdominal ultrasonography (US) (Fig 1), contrast material–enhanced computed tomography (CT) (Fig 2), and contrast-enhanced magnetic resonance (MR) imaging (Fig 3) were performed, in that order.
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Figure 1. Transverse US image of the intrahepatic inferior vena cava. Echogenic thrombus (arrow) is visible in the inferior vena cava, the caudate lobe (*) is prominent, and the liver parenchyma is mildly heterogeneous.
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Figure 2a. Transverse contrast-enhanced CT images of the upper part of the abdomen. (a) Image shows filling defect in the inferior vena cava that extends into the central left hepatic vein (black arrow). The caudate lobe and central area of the liver (*) are preferentially enhanced when compared with the peripheral area of the liver. A small amount of ascites is visible around the spleen (white arrow). (b) Image shows filling defects in the inferior vena cava (straight arrow) and portal vein (curved arrow).
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Figure 2b. Transverse contrast-enhanced CT images of the upper part of the abdomen. (a) Image shows filling defect in the inferior vena cava that extends into the central left hepatic vein (black arrow). The caudate lobe and central area of the liver (*) are preferentially enhanced when compared with the peripheral area of the liver. A small amount of ascites is visible around the spleen (white arrow). (b) Image shows filling defects in the inferior vena cava (straight arrow) and portal vein (curved arrow).
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Figure 3. Transverse contrast-enhanced spoiled gradient-echo T1-weighted MR image (repetition time msec/echo time msec, 215/4.2; flip angle, 70°) of the upper part of the abdomen. Filling defects are seen in the inferior vena cava (straight white arrow) and portal vein (curved arrow). Both kidneys demonstrate a diffuse reduction in renal cortical signal intensity (black arrows).
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IMAGING FINDINGS
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US (Fig 1) depicted an echogenic thrombus in the intrahepatic inferior vena cava, a prominent caudate lobe, and mild diffuse heterogeneity of the liver parenchyma. Contrast-enhanced CT (Fig 2) depicted a filling defect in the inferior vena cava that extended into the left hepatic vein, preferential enhancement of the central liver and an enlarged caudate lobe, mild ascites, and a filling defect in the portal vein. Findings at contrast-enhanced MR imaging (Fig 3) confirmed the filling defects in the inferior vena cava and portal vein and also showed a diffuse reduction in renal cortical signal intensity.
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DISCUSSION
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US and CT findings included inferior vena caval, hepatic venous, and portal venous thrombosis, with an associated Budd-Chiari syndrome. In strict usage, the Budd-Chiari syndrome includes the clinical combination of abdominal pain, jaundice, hepatomegaly, and ascites, but in radiologic usage, the term is used to refer to the characteristic imaging findings seen with hepatic venous occlusion. The MR imaging finding of diffusely reduced signal intensity in the renal cortex, without an obvious renal cortical calcification at CT, suggests hemosiderin deposition. Paroxysmal nocturnal hemoglobinuria is the most likely diagnosis for this constellation of findings.
The Budd-Chiari syndrome includes a group of conditions characterized by hepatic venous obstruction (1). The syndrome may be primary or secondary. The primary type is caused by a membrane in the inferior vena cava. Secondary causes include neoplasms, oral contraceptive use, pregnancy, hypercoagulable states, myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria. In practice, no identifiable cause is found in up to 70% of patients (1). The patient described here was not using oral contraceptives, and test results for pregnancy, protein C deficiency, protein S deficiency, factor V deficiency, and antithrombin III deficiency were all negative.
Common imaging findings in patients with Budd-Chiari syndrome include hepatosplenomegaly, caudate lobe enlargement, ascites, and hepatic parenchymal inhomogeneity (2). Enlargement of the caudate lobe and hepatic parenchymal inhomogeneity are probably caused by emissary veins from the caudate lobe that enter the inferior vena cava separately to the hepatic veins. Intraluminal clot may be seen in the acute phase. Findings in the chronic phase include nonvisualization of occluded veins and formation of venous collaterals within the liver or from the liver to the left renal vein or the pericardiophrenic vein (3–5).
The MR imaging finding of diffusely reduced signal intensity in the renal cortex is the inverse of the normal pattern of corticomedullary signal intensity (6). Diffuse reduction of cortical signal intensity may be caused by hemosiderin deposition or calcification (7,8), but there was no evidence of calcification at CT in our patient (Fig 2). Therefore, the primary consideration was renal cortical hemosiderin deposition. Hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma. Free hemoglobin that exceeds the binding capacity of plasma haptoglobin is filtered by the glomerulus and reabsorbed in the proximal convoluted tubule, where it is stored as hemosiderin (9). When the proximal renal tubular reabsorptive capacity is exceeded, hemoglobin passes directly into the urine, causing hemoglobinuria (10).
Causes of intravascular hemolysis include paroxysmal nocturnal hemoglobinuria and malfunctioning prosthetic heart valves (9,11). Other hemolytic anemias, such as sickle cell anemia, thalassemia, autoimmune hemolytic anemia, and hereditary spherocytosis, are characterized by the extravascular degradation of defective red blood cells in the spleen. Therefore, in these conditions, hemosiderin accumulates primarily in the spleen. However, intravascular hemolysis with renal hemosiderin deposition may occur in acute hemolytic crises or severe disease, particularly in sickle cell anemia (12). Hemosiderin deposition in the renal cortex results in signal intensity loss on both T1- and T2-weighted MR images because of susceptibility artifact from the contained ferric iron (13). Hemosiderin deposition does not appear to substantially impair renal function (14).
Paroxysmal nocturnal hemoglobinuria is an acquired disorder of hematopoietic stem cells caused by a somatic gene mutation that results in an abnormal predisposition to complement-mediated hemolysis (9,15). Clinically, paroxysmal nocturnal hemoglobinuria results in a variable mix of acute and chronic hemolysis. As the name implies, nocturnal hemolysis is well recognized. Acute episodes may also be precipitated by infection, transfusion, exercise, drugs, immunization, surgery, or iodinated intravenous contrast medium (10). Known complications of paroxysmal nocturnal hemoglobinuria include venous thromboses, aplastic anemia, and leukemia (16,17). In a prospective study of 80 patients with paroxysmal nocturnal hemoglobinuria, 39% had at least one episode of venous thrombosis, with the hepatic vein being the most common site (16). Patients in that study also developed pulmonary emboli, sagittal vein thrombosis, and mesenteric vein thrombosis. The median survival time after the diagnosis of paroxysmal nocturnal hemoglobinuria was 10 years.
Imaging findings in paroxysmal nocturnal hemoglobinuria include renal cortical signal intensity loss and venous thrombosis. The liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis (18). Vascular thromboses can complicate other hemolytic disorders, including sickle cell disease, ß thalassemia major, and thalassemia intermedia (19). However, these conditions are congenital and are present in childhood; the described patient’s medical history revealed no such findings.
In summary, the combination of radiologic findings of Budd-Chiari syndrome, multiple venous thromboses, and renal cortical hemosiderin deposition is highly suggestive of paroxysmal nocturnal hemoglobinuria. In the described patient, the diagnosis was confirmed with red blood cell flow cytometry results, which demonstrated a paroxysmal nocturnal hemoglobinuria phenotype in 60% of the cells. It is important to consider the possibility of paroxysmal nocturnal hemoglobinuria in patients with Budd-Chiari syndrome, because the definitive treatment is systemic (bone marrow transplantation) rather than hepatic (surgical decompression or transjugular intrahepatic portosystemic shunt creation) (17).
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APPENDIX
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Congratulations to the 86 individuals who submitted the most likely diagnosis (Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome) for Diagnosis Please, Case 51. Credit was given only if paroxysmal nocturnal hemoglobinuria was mentioned in the diagnosis. The names and locations of the individuals, as submitted, are as follows:
- Hisashi Abe, Osaka, Japan
- Dr. Jorge Ahualli, Tucumán, Argentina
- Okan Akinci, MD, Istanbul, Turkey
- Albert J. Alter, Madison, Wis
- Arangasamy Anbarasu, MD, Coventry, United Kingdom
- Hernando Arana Lenis, Bogota, Colombia
- Lionel Arrivé, Paris, France
- Edward L. Baker, MD, San Francisco, Calif
- Debra M. Berger, MD, New York, NY
- Michel Blery, Paris, France
- Paul Burn, Toronto, Canada
- Dr. Mariano R. Carballo, Las Heras, Mendoza, Argentina
- Oscar Luis Casado Verdugo, Vizcaya, Spain
- Bharath Chinta, Pontiac, Mich
- James W. Cole, MD, Cincinnati, Ohio
- Y-S Cordoliani, MD, Paris, France
- Flavio Corti, MD, Mar del Plata, Argentina
- Federico Dalla Torre, MD, Rio Negro, Argentina
- M.G. de Baets, MD, Lugano, Switzerland
- Alejandro de la Vega, MD, Buenos Aires, Argentina
- Manoel de Souza Rocha, MD, Sao Paulo, Brazil
- Kemal Demir, MD, Istanbul, Turkey
- Tom Dunphy, Oak Park, Ill
- Juliet Fallah, St. Louis, Mo
- Gabriel C. Fernández Pérez, Vigo, Spain
- Roberto García Figueiras, MD, Santiago De Compostela, Spain
- Mark Flyer, MD, Brooklyn, NY
- Milton R. Fuentealba, MD, San Rafael, Mendoza, Argentina
- Akira Fujikawa, Tokyo, Japan
- Douglas Gardner, MD, Windsor, Ontario, Canada
- Bhaskar Golla, Kingston, Pa
- Neil B. Green, MD, Fredericksburg, Va
- Alberto Iaia, MD, Wilmington, Del
- Christophe Ide, Namur, Belgium
- Hirotsugu Kado, Echizen, Japan
- Masako Kataoka, MD, Kyoto, Japan
- Douglas Katz, MD, Mineola, NY
- Steven A. Klein, MD, Shrewsbury, Mass
- Mario A. Laguna, West Allis, Wis
- Roger Lao, Brookline, Mass
- Charles C. Liu, MD, Palo Alto, Calif
- Julio L. Loureiro, Buenos Aires, Argentina
- Antonio Carlos Maia, Jr, São Paulo, Brazil
- Françoise Mallemouche, Paris, France
- N. B. S. Mani, MD, Nassau, Bahamas
- Frank McKowne, MD, Vancouver, Wash
- Carolina Mendiondo, MD, Mar del Plata, Argentina
- Edward Menges, Aptos, Calif
- Bernard Mengiardi, MD, Zurich, Switzerland
- Manabu Minami, MD, Tokyo, Japan
- Sankar Ranjan Mondal, Nassau, Bahamas
- Eduardo Mondello, MD, Buenos Aires, Argentina
- Paula Moraes, São Paulo, Brazil
- Tammam Nehme, Milwaukee, Wis
- Raquel Oliva, Recife, PE, Brazil
- Sanford M. Ornstein, MD, Phoenix, Ariz
- R. B. Parsons, MD, Philadelphia, Pa
- Narendrakumar P. Patel, MD, Newburgh, NY
- Carlo L. E. Petralli, MD, Bruderholz, Switzerland
- Shawn P. Quillin, MD, Charlotte, NC
- Denis Regent, Vandoeuvre les Nancy, France
- Enrique Remartinez-Escobar, MD, Melilla, Spain
- Erick Paul Remer, III, Cleveland, Ohio
- Mathieu H. Rodallec, Paris, France
- Marilyn A. Roubidoux, MD, Ann Arbor, Mich
- N. Saravanan, Chandigarh, India
- Matt Shapiro, MD, Lowell, Mass
- Taro Shimono, MD, Osaka, Japan
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- Efthymios Stamoulis, Alexandroupolis, Greece
- Wing H. Tam, MD, Windsor, Ontario, Canada
- Douglas L. Teich, MD, Brookline, Mass
- Alejandro Tempra, MD, Mar del Plata, Argentina
- John S. To, MD, Iron Mountain, Mich
- Gustavo A. Triana, Santa Fe De Bogota, Colombia
- Ricardo H. Trueba, MD, Buenos Aires, Argentina
- Ender Uysal, MD, Sisli, Istanbul, Turkey
- Carlos Valls, MD, PhD, Barcelona, Spain
- Angelo Vanzulli, Milan, Italy
- Kai Vilanova Busquets, MD, Girona, Spain
- Christopher Vittore, MD, Rockford, Ill
- Zhen Jane Wang, MD, San Francisco, Calif
- Benjamin M. Yeh, MD, San Francisco, Calif
- Satoru Yoshida, MD, Muroran, Japan
- Joe Yut, Olathe, Kan
- Yu Zhang, Nagoya, Japan
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FOOTNOTES
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Part 1 of this case appeared 4 months previously and may contain larger images.
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REFERENCES
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- Bemba M, Guardiola P, Garderet L. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Br J Haematol 1999; 105:366-368.[CrossRef][Medline]
- Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333:1253-1257.[Abstract/Free Full Text]
- Graham M, Rosse W, Halprein E, et al. Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1996; 92:707-709.[CrossRef][Medline]
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- Barker JE, Wandersee NJ. Thrombosis in heritable hemolytic disorders. Curr Opin Hematol 1999; 6:71-75.[CrossRef][Medline]
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HISTORY
IMAGING FINDINGS
