To the Editor: The discovery of a V617F mutation in the Januskinase 2 (JAK2) gene was a seminal advance in our understandingof the chronic myeloproliferative disorders (MPDs). Ostensibly,the recent Case Record by Chung et al. (May 18 issue)1 was chosento showcase the expression of this mutation in defining thecause of hepatic-vein thrombosis. However, although the expressionof the V617F mutation identifies the presence of an MPD, itdoes not define the limits of the phenotype, and the absenceof the mutation does not rule out an MPD.
The discussants focused on borderline thrombocytosis and WorldHealth Organization criteria for the diagnosis of MPDs —criteria that have recently been discredited2 — to suggestthat essential thrombocytosis was responsible for the hepatic-veinthrombosis. Evidence that essential thrombocytosis causes hepatic-veinthrombosis is anecdotal, whereas polycythemia vera is a well-documentedcause.3 Furthermore, V617F expression occurs in more than 90percent of patients with polycythemia vera but in less than50 percent of patients with essential thrombosis. Until provenotherwise, a hematocrit of 45 percent in a woman with ascites,splenomegaly, and hepatic-vein thrombosis suggests the presenceof erythrocytosis masked by an expanded volume of plasma4,5,6(Table 1). In this clinical setting, analyses of red-cell massand plasma volume have diagnostic and therapeutic implicationsthat 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{at}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. [Free Full Text]
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. [CrossRef][Web of Science][Medline]
Parker RG. Occlusion of the hepatic veins in man. Medicine (Baltimore) 1959;38:369-402. [Medline]
Lamy T, Devillers A, Bernard M, et al. Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 1997;102:14-20. [CrossRef][Web of Science][Medline]
Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood 2002;100:4272-4290. [Free Full Text]
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. [Web of Science][Medline]
To the Editor: Chung et al. classified the condition of theirpatient as "subacute-to-chronic Budd–Chiari syndrome"on the basis of the duration of symptoms; mesocaval shuntingwas subsequently performed. However, in our view, the classificationof conditions as acute, subacute, and chronic lacks scientificfoundation and should not be used as guidance for therapy.1We were surprised by the decision to perform surgical shuntingrather than place a transjugular intrahepatic portosystemicshunt (TIPS). Two studies assessing the effect of surgical shuntson survival (after adjustment for prognostic factors) did notshow either a favorable effect2 or a beneficial outcome in aselected group,3 suggesting that operative mortality and morbidityswamp the benefit. The extremely positive results describedby Orloff et al.4 are probably subject to selection bias, sincethe criteria for the selection of patients and the proportionof those patients who were not suitable for surgery were notmentioned. We would suggest that TIPS, preferably with the useof covered stents, has surpassed surgical shunting in both efficacyand 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{at}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. [CrossRef][Web of Science][Medline]
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. [CrossRef][Web of Science][Medline]
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. [CrossRef][Web of Science][Medline]
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. [CrossRef][Web of Science][Medline]
To the Editor: In the analysis of ascitic fluid in a patientwith the Budd–Chiari syndrome, Chung et al. incorrectlystate that "a high serum–ascites albumin gradient withlow ascitic fluid total protein (<2.5 g per deciliter) isobserved." The total protein in ascitic fluid in patients withpostsinusoidal portal hypertension, including the Budd–Chiarisyndrome, is more than 2.5 g per deciliter owing to the preservedinherent "leakiness" of the hepatic sinusoidal membrane. Onlylate in the course of postsinusoidal obstruction, when significantfibrosis occurs, does the composition of the ascitic fluid beginto reflect the low total protein commonly seen in cirrhosis.Early recognition of an elevated total protein level in asciticfluid is important clinically, since it can direct further diagnostictesting toward cardiac and vascular conditions and potentiallyobviate the need for liver biopsy.
Anish A. Sheth, M.D. Yale University School of Medicine New Haven, CT 06520 anish.sheth{at}yale.edu
The discussants reply: Drs. Murad and Janssen correctly pointout that TIPS can be associated with excellent short-term outcomesin the management of the Budd–Chiari syndrome.1 However,long-term follow-up will be required to assess the durabilityof this benefit. They also suggest a prognostic classificationscheme with the use of simple, objective criteria that appearto correlate well with the outcome when the criteria are appliedretrospectively.1 Although this scheme is attractive, prospectivestudies are still needed to confirm the validity of these criteria.When the criteria are applied to patients with moderately advancedcases of the Budd–Chiari syndrome, such as our patient,improved survival was actually suggested for patients who underwentportosystemic shunt surgery. The team that was involved in thecare of this patient thought that the durability of shunt surgeryand its greater potential for improved survival justified thisoption as the first choice.
Dr. Spivak and colleagues correctly point out that a definitivediagnosis of polycythemia vera or essential thrombocythemiacould not be made in this patient with the Budd–Chiarisyndrome. We were not implying that essential thrombocythemiawas the operative diagnosis but merely pointing out that thrombocytosiswas the only overt hematologic manifestation. In the past, thediagnosis of polycythemia vera required the assessment of red-cellmass. However, many centers now follow the World Health Organizationcriteria, which permit the substitution of an elevated hemoglobinlevel (>18.5 g per deciliter for men and >16.5 g per deciliterfor women) for the elevated red-cell mass.2 In fact, our centerno longer offers an analysis of red-cell mass as a diagnostictest, since it is no longer routinely ordered. With the availabilityof molecular markers of disease such as the V617F mutation inJAK2, the classification of myeloproliferative disorders willdoubtless evolve toward more precisely defined disease entities.
Dr. Sheth is correct. The sentence regarding the analysis ofascitic fluid should have read, "a high serum–ascitesalbumin gradient with a high ascitic fluid albumin (>2.5g 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. [CrossRef][Web of Science][Medline]
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.
Spivak, J. L., Silver, R. T.
(2008). The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood
112: 231-239
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Kiladjian, J.-J., Cervantes, F., Leebeek, F. W. G., Marzac, C., Cassinat, B., Chevret, S., Cazals-Hatem, D., Plessier, A., Garcia-Pagan, J.-C., Murad, S. D., Raffa, S., Janssen, H. L. A., Gardin, C., Cereja, S., Tonetti, C., Giraudier, S., Condat, B., Casadevall, N., Fenaux, P., Valla, D. C.
(2008). The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood
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