What’s The “Take Home”? Severe, Persistent Abdominal Pain in a Young Woman

A 24-year-old woman presents with severe, persistent, left-sided abdominal pain that began about 12 hours earlier. Over-the-counter medications have provided no relief. The pain is not associated with dietary intake, nausea, vomiting, diarrhea, or dysuria. The patient denies fevers, chills, and recent trauma to her abdomen.

HISTORY
The pain is similar to pain she experienced 3 months earlier, when multiple splenic infarcts were diagnosed and significant hepatosplenomegaly was noted. Although all hypercoagulability studies were negative at the time, warfarin was started. She takes no other medications. She has no other significant medical history, and she denies any family history of blood clots or liver disease. She smokes and drinks alcohol occasionally, but she denies current or past illicit drug use.

PHYSICAL EXAMINATION
The patient is awake and alert but in mild distress because of her abdominal pain. Vital signs are normal. Lymph nodes are not enlarged. Lungs are clear bilaterally; her heart rate is 88 beats per minute and regular, with no murmurs. Normal bowel sounds are audible. She exhibits voluntary guarding with percussion and palpation of the left upper abdomen. The spleen is palpable 7 cm below the left costal margin. No edema or cyanosis of her extremities is noted.

LABORATORY AND IMAGING STUDIES
White blood cell count is 13,900/μL, with a normal differential; hemoglobin level, 14.6 g/dL; and platelet count, 422,000/μL. International normalized ratio (INR) is subtherapeutic at 1.5. Results of a basic metabolic panel are normal. Transaminase, alkaline phosphatase, and bilirubin levels are also normal.

CT and ultrasonographic imaging studies reveal marked splenomegaly, with multiple areas of hypoattenuation that suggest infarct; mild ascites; splenic vein thrombosis with a clot propagating along the vein posterior to the body and tail of the pancreas; and possible narrowing of the intrahepatic inferior vena cava. An inferior venacavagram confirms the ultrasonographic and CT findings.

The results of which study are most likely to be positive in this patient?A. Polymerase chain reaction (PCR) testing for the bcr-abl fusion oncogene.
B. PCR testing for the JAK2V617F mutation.
C. PCR testing for the HFE C282Y mutation.
D. Flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH).



CORRECT ANSWER: BThis patient has Budd-Chiari syndrome, an occlusive disorder that results in interruption of blood flow from the liver. Presenting signs and symptoms can range from mild ascites with normal liver function (as in this patient) to fulminant hepatic failure.

In about 80% of patients, a primary disorder causes Budd-Chiari syndrome. The syndrome may be the result of a hypercoagulable state, such as antiphospholipid syndrome, protein S deficiency, or PNH; or it may be associated with malignancy. It also can be a thrombotic complication of a chronic myeloproliferative disorder. In fact, an underlying myeloproliferative disorder is present in at least 50% of patients with Budd-Chiari syndrome.^1,2 Role of JAK2 mutation in Budd-Chiari syndrome. This woman has a JAK2-positive myeloproliferative disorder: testing is positive for a heterozygous-or possibly homozygous-JAK2 V617F mutation (choice B). JAK2 (Janus kinase 2) is a cytoplasmic tyrosine kinase gene found on the short arm of chromosome 9. In mouse models, a mutation in the JAK2 gene leads to constitutive tyrosine phosphorylation activity, which promotes hypersensitivity to cytokines that induce erythrocytosis in the absence of hematopoietic growth factors.^3-5 The discovery of this gene and its association with polycythemia vera in 95% of cases has revolutionized the understanding of myeloproliferative disorders and provides a target for drug treatment of JAK2-associated myeloproliferative disorders. 3 In fact, many of the 20% of cases of Budd-Chiari syndrome labeled “idiopathic” may actually be secondary to an occult underlying myeloproliferative disorder.⁶ Ruling out other causes of Budd-Chiari syndrome. Chronic myelogenous leukemia (CML) can also be associated with Budd-Chiari syndrome. Genetic testing for the presence of the bcr-abl fusion oncogene (choice A) is the test for CML. However, this patient’s blood findings are not typical of this disease. Moreover, although CML can be associated with Budd-Chiari syndrome, the association is far less common than that with JAK2-positive myeloproliferative disorders. Results of PCR testing for the bcr-abl oncogene in this woman are negative. PNH is another cause of abdominal venous thromboses, including Budd-Chiari syndrome. Flow cytometry for PNH marker cells CD55 and CD59 (choice D) is indicated in any patient with abdominal venous thrombosis. However, PNH is an extremely rare disease and is not the most likely diagnosis here. Results of flow cytometry for PNH are negative.

Hereditary hemochromatosis with an associated HFE mutation (choice C) is a well-known cause of unexpected portal hypertension; however, Budd-Chiari is rarely seen in patients with hemochromatosis. Such a diagnosis in this patient would also be atypical from an epidemiological perspective: she is a woman of reproductive age, and hemochromatosis most commonly presents in middle-aged men.

Outcome and long-term management. At 4 months, the patient had no stigmata of liver disease and results of liver function tests were normal. Anticoagulation with warfarin achieved a therapeutic INR. In light of her presenting thrombotic event and the risk of future thrombosis secondary to her myeloproliferative disorder, lifelong anticoagulation will be necessary. Because of her JAK2 mutation and young age, she will be closely monitored for signs of complications and for leukemic transformation of her myeloproliferative disorder.

References:

REFERENCES:

1.

Patel RK, Lea NC, Heneghan MA, et al. Prevalence of the activating

JAK2

tyrosine kinase mutation

V617F

in the Budd-Chiari syndrome. Gastroenterology. 2006;130:2031-2038.

2.

Primignani M, Barosi G, Bergamaschi G, et al. Role of the

JAK2

mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis. Hepatology. 2006;44:1528-1534.

3.

Baxter EJ, Scott LM, Campbell PI, et al. Acquired mutation of the tyrosine kinase

JAK2

in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.

4.

Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355:2452-2466.

5.

Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of

JAK2

in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.

6.

Chung RT, Iafrate AJ, Amrein PC, et al. Case records of the Massachusetts General Hospital. Case 15-2006. A 46-year-old woman with sudden onset of abdominaldistention. N Engl J Med. 2006;354:2166-2175.