Case 15-2006: The Budd–Chiari Syndrome and V617F Mutation in JAK2
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《新英格兰医药杂志》
To the Editor: The discovery of a V617F mutation in the Janus kinase 2 (JAK2) gene was a seminal advance in our understanding of the chronic myeloproliferative disorders (MPDs). Ostensibly, the recent Case Record by Chung et al. (May 18 issue)1 was chosen to showcase the expression of this mutation in defining the cause of hepatic-vein thrombosis. However, although the expression of the V617F mutation identifies the presence of an MPD, it does not define the limits of the phenotype, and the absence of the mutation does not rule out an MPD.
The discussants focused on borderline thrombocytosis and World Health Organization criteria for the diagnosis of MPDs — criteria that have recently been discredited2 — to suggest that essential thrombocytosis was responsible for the hepatic-vein thrombosis. Evidence that essential thrombocytosis causes hepatic-vein thrombosis is anecdotal, whereas polycythemia vera is a well-documented cause.3 Furthermore, V617F expression occurs in more than 90 percent of patients with polycythemia vera but in less than 50 percent of patients with essential thrombosis. Until proven otherwise, a hematocrit of 45 percent in a woman with ascites, splenomegaly, and hepatic-vein thrombosis suggests the presence of erythrocytosis masked by an expanded volume of plasma4,5,6 (Table 1). In this clinical setting, analyses of red-cell mass and plasma volume have diagnostic and therapeutic implications that an assay of a V617F mutation in JAK2 cannot offer.
Table 1. Hepatic-Vein Thrombosis and Masked Erythrocytosis in a 30-Year-Old Woman with a Hematocrit of 44.8 Percent and Polycythemia Vera.
Jerry L. Spivak, M.D.
Alison R. Moliterno, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
jlspivak@jhmi.edu
Richard T. Silver, M.D.
Cornell University Medical College
New York, NY 10021
References
Case Records of the Massachusetts General Hospital (Case 15-2006). N Engl J Med 2006;354:2166-2175.
Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 2005;129:701-705.
Parker RG. Occlusion of the hepatic veins in man. Medicine (Baltimore) 1959;38:369-402.
Lamy T, Devillers A, Bernard M, et al. Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 1997;102:14-20.
Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood 2002;100:4272-4290.
Pearson TC, Guthrie DL, Simpson J, et al. Interpretation of measured red cell mass and plasma volume in adults. Br J Haematol 1995;89:748-756.
To the Editor: Chung et al. classified the condition of their patient as "subacute-to-chronic Budd–Chiari syndrome" on the basis of the duration of symptoms; mesocaval shunting was subsequently performed. However, in our view, the classification of conditions as acute, subacute, and chronic lacks scientific foundation and should not be used as guidance for therapy.1 We were surprised by the decision to perform surgical shunting rather than place a transjugular intrahepatic portosystemic shunt (TIPS). Two studies assessing the effect of surgical shunts on survival (after adjustment for prognostic factors) did not show either a favorable effect2 or a beneficial outcome in a selected group,3 suggesting that operative mortality and morbidity swamp the benefit. The extremely positive results described by Orloff et al.4 are probably subject to selection bias, since the criteria for the selection of patients and the proportion of those patients who were not suitable for surgery were not mentioned. We would suggest that TIPS, preferably with the use of covered stents, has surpassed surgical shunting in both efficacy and safety and should be considered as a first-line intervention.
Sarwa Darwish Murad, M.D.
Harry L.A. Janssen, M.D., Ph.D.
Erasmus Medical Center
3015 GD Rotterdam, the Netherlands
h.janssen@erasmusmc.nl
References
Janssen HL, Garcia-Pagan JC, Elias E, Mentha G, Hadengue A, Valla DC. Budd-Chiari syndrome: a review by an expert panel. J Hepatol 2003;38:364-371.
Zeitoun G, Escolano S, Hadengue A, et al. Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatology 1999;30:84-89.
Murad SD, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004;39:500-508.
Orloff MJ, Daily PO, Orloff SL, Girard B, Orloff MS. A 27-year experience with surgical treatment of Budd-Chiari syndrome. Ann Surg 2000;232:340-352.
To the Editor: In the analysis of ascitic fluid in a patient with the Budd–Chiari syndrome, Chung et al. incorrectly state that "a high serum–ascites albumin gradient with low ascitic fluid total protein (<2.5 g per deciliter) is observed." The total protein in ascitic fluid in patients with postsinusoidal portal hypertension, including the Budd–Chiari syndrome, is more than 2.5 g per deciliter owing to the preserved inherent "leakiness" of the hepatic sinusoidal membrane. Only late in the course of postsinusoidal obstruction, when significant fibrosis occurs, does the composition of the ascitic fluid begin to reflect the low total protein commonly seen in cirrhosis. Early recognition of an elevated total protein level in ascitic fluid is important clinically, since it can direct further diagnostic testing toward cardiac and vascular conditions and potentially obviate the need for liver biopsy.
Anish A. Sheth, M.D.
Yale University School of Medicine
New Haven, CT 06520
anish.sheth@yale.edu
The discussants reply: Drs. Murad and Janssen correctly point out that TIPS can be associated with excellent short-term outcomes in the management of the Budd–Chiari syndrome.1 However, long-term follow-up will be required to assess the durability of this benefit. They also suggest a prognostic classification scheme with the use of simple, objective criteria that appear to correlate well with the outcome when the criteria are applied retrospectively.1 Although this scheme is attractive, prospective studies are still needed to confirm the validity of these criteria. When the criteria are applied to patients with moderately advanced cases of the Budd–Chiari syndrome, such as our patient, improved survival was actually suggested for patients who underwent portosystemic shunt surgery. The team that was involved in the care of this patient thought that the durability of shunt surgery and its greater potential for improved survival justified this option as the first choice.
Dr. Spivak and colleagues correctly point out that a definitive diagnosis of polycythemia vera or essential thrombocythemia could not be made in this patient with the Budd–Chiari syndrome. We were not implying that essential thrombocythemia was the operative diagnosis but merely pointing out that thrombocytosis was the only overt hematologic manifestation. In the past, the diagnosis of polycythemia vera required the assessment of red-cell mass. However, many centers now follow the World Health Organization criteria, which permit the substitution of an elevated hemoglobin level (>18.5 g per deciliter for men and >16.5 g per deciliter for women) for the elevated red-cell mass.2 In fact, our center no longer offers an analysis of red-cell mass as a diagnostic test, since it is no longer routinely ordered. With the availability of molecular markers of disease such as the V617F mutation in JAK2, the classification of myeloproliferative disorders will doubtless evolve toward more precisely defined disease entities.
Dr. Sheth is correct. The sentence regarding the analysis of ascitic fluid should have read, "a high serum–ascites albumin gradient with a high ascitic fluid albumin (>2.5 g per deciliter) is observed."
Raymond T. Chung, M.D.
Philip Amrein, M.D.
Martin Hertl, M.D.
Massachusetts General Hospital
Boston, MA 02114
References
Murad SD, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004;39:500-508.
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
The discussants focused on borderline thrombocytosis and World Health Organization criteria for the diagnosis of MPDs — criteria that have recently been discredited2 — to suggest that essential thrombocytosis was responsible for the hepatic-vein thrombosis. Evidence that essential thrombocytosis causes hepatic-vein thrombosis is anecdotal, whereas polycythemia vera is a well-documented cause.3 Furthermore, V617F expression occurs in more than 90 percent of patients with polycythemia vera but in less than 50 percent of patients with essential thrombosis. Until proven otherwise, a hematocrit of 45 percent in a woman with ascites, splenomegaly, and hepatic-vein thrombosis suggests the presence of erythrocytosis masked by an expanded volume of plasma4,5,6 (Table 1). In this clinical setting, analyses of red-cell mass and plasma volume have diagnostic and therapeutic implications that an assay of a V617F mutation in JAK2 cannot offer.
Table 1. Hepatic-Vein Thrombosis and Masked Erythrocytosis in a 30-Year-Old Woman with a Hematocrit of 44.8 Percent and Polycythemia Vera.
Jerry L. Spivak, M.D.
Alison R. Moliterno, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21205
jlspivak@jhmi.edu
Richard T. Silver, M.D.
Cornell University Medical College
New York, NY 10021
References
Case Records of the Massachusetts General Hospital (Case 15-2006). N Engl J Med 2006;354:2166-2175.
Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 2005;129:701-705.
Parker RG. Occlusion of the hepatic veins in man. Medicine (Baltimore) 1959;38:369-402.
Lamy T, Devillers A, Bernard M, et al. Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 1997;102:14-20.
Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood 2002;100:4272-4290.
Pearson TC, Guthrie DL, Simpson J, et al. Interpretation of measured red cell mass and plasma volume in adults. Br J Haematol 1995;89:748-756.
To the Editor: Chung et al. classified the condition of their patient as "subacute-to-chronic Budd–Chiari syndrome" on the basis of the duration of symptoms; mesocaval shunting was subsequently performed. However, in our view, the classification of conditions as acute, subacute, and chronic lacks scientific foundation and should not be used as guidance for therapy.1 We were surprised by the decision to perform surgical shunting rather than place a transjugular intrahepatic portosystemic shunt (TIPS). Two studies assessing the effect of surgical shunts on survival (after adjustment for prognostic factors) did not show either a favorable effect2 or a beneficial outcome in a selected group,3 suggesting that operative mortality and morbidity swamp the benefit. The extremely positive results described by Orloff et al.4 are probably subject to selection bias, since the criteria for the selection of patients and the proportion of those patients who were not suitable for surgery were not mentioned. We would suggest that TIPS, preferably with the use of covered stents, has surpassed surgical shunting in both efficacy and safety and should be considered as a first-line intervention.
Sarwa Darwish Murad, M.D.
Harry L.A. Janssen, M.D., Ph.D.
Erasmus Medical Center
3015 GD Rotterdam, the Netherlands
h.janssen@erasmusmc.nl
References
Janssen HL, Garcia-Pagan JC, Elias E, Mentha G, Hadengue A, Valla DC. Budd-Chiari syndrome: a review by an expert panel. J Hepatol 2003;38:364-371.
Zeitoun G, Escolano S, Hadengue A, et al. Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatology 1999;30:84-89.
Murad SD, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004;39:500-508.
Orloff MJ, Daily PO, Orloff SL, Girard B, Orloff MS. A 27-year experience with surgical treatment of Budd-Chiari syndrome. Ann Surg 2000;232:340-352.
To the Editor: In the analysis of ascitic fluid in a patient with the Budd–Chiari syndrome, Chung et al. incorrectly state that "a high serum–ascites albumin gradient with low ascitic fluid total protein (<2.5 g per deciliter) is observed." The total protein in ascitic fluid in patients with postsinusoidal portal hypertension, including the Budd–Chiari syndrome, is more than 2.5 g per deciliter owing to the preserved inherent "leakiness" of the hepatic sinusoidal membrane. Only late in the course of postsinusoidal obstruction, when significant fibrosis occurs, does the composition of the ascitic fluid begin to reflect the low total protein commonly seen in cirrhosis. Early recognition of an elevated total protein level in ascitic fluid is important clinically, since it can direct further diagnostic testing toward cardiac and vascular conditions and potentially obviate the need for liver biopsy.
Anish A. Sheth, M.D.
Yale University School of Medicine
New Haven, CT 06520
anish.sheth@yale.edu
The discussants reply: Drs. Murad and Janssen correctly point out that TIPS can be associated with excellent short-term outcomes in the management of the Budd–Chiari syndrome.1 However, long-term follow-up will be required to assess the durability of this benefit. They also suggest a prognostic classification scheme with the use of simple, objective criteria that appear to correlate well with the outcome when the criteria are applied retrospectively.1 Although this scheme is attractive, prospective studies are still needed to confirm the validity of these criteria. When the criteria are applied to patients with moderately advanced cases of the Budd–Chiari syndrome, such as our patient, improved survival was actually suggested for patients who underwent portosystemic shunt surgery. The team that was involved in the care of this patient thought that the durability of shunt surgery and its greater potential for improved survival justified this option as the first choice.
Dr. Spivak and colleagues correctly point out that a definitive diagnosis of polycythemia vera or essential thrombocythemia could not be made in this patient with the Budd–Chiari syndrome. We were not implying that essential thrombocythemia was the operative diagnosis but merely pointing out that thrombocytosis was the only overt hematologic manifestation. In the past, the diagnosis of polycythemia vera required the assessment of red-cell mass. However, many centers now follow the World Health Organization criteria, which permit the substitution of an elevated hemoglobin level (>18.5 g per deciliter for men and >16.5 g per deciliter for women) for the elevated red-cell mass.2 In fact, our center no longer offers an analysis of red-cell mass as a diagnostic test, since it is no longer routinely ordered. With the availability of molecular markers of disease such as the V617F mutation in JAK2, the classification of myeloproliferative disorders will doubtless evolve toward more precisely defined disease entities.
Dr. Sheth is correct. The sentence regarding the analysis of ascitic fluid should have read, "a high serum–ascites albumin gradient with a high ascitic fluid albumin (>2.5 g per deciliter) is observed."
Raymond T. Chung, M.D.
Philip Amrein, M.D.
Martin Hertl, M.D.
Massachusetts General Hospital
Boston, MA 02114
References
Murad SD, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004;39:500-508.
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.