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52-Year-Old Man With Acute Midabdominal Pain

      A 52-year-old man with a history of previously treated hepatitis C was admitted to the hospital after presenting to the emergency department with acute abdominal pain of 12 hours’ duration. The continuous, throbbing pain was diffuse but most prominent in the midabdomen. It had progressed throughout the day, and by the time of presentation, the pain was rated 10 on a scale of 1 to 10. The patient described it as “excruciating” and was at times writhing in an effort to find relief. He had not had fever or chills, nausea, vomiting, hematemesis, melena, hematochezia, or diarrhea. He reported ongoing use of chewing tobacco but did not use alcohol or illicit drugs. His family history was remarkable for an unprovoked pulmonary embolism in his sister.
      Vital signs were stable, and the patient was afebrile. Physical examination confirmed diffuse abdominal pain, most prominent in the epigastric and periumbilical regions. However, there was no rebound, guarding, or peritoneal signs, and the patient allowed several physicians to examine his abdomen thoroughly. Neither abdominal bruits nor Murphy sign was appreciated. The Rovsing sign (palpation of the left lower quadrant resulting in pain in the right lower quadrant) was absent. His physical examination findings were otherwise unremarkable.
      Laboratory studies revealed the following (reference ranges shown parenthetically): hemoglobin, 14.5 g/dL (13.5-17.5 g/dL); leukocytes, 9.6 × 109/L (3.5-10.5 × 109/L); platelet count, 105 × 109/L (150-450 × 109/L); creatinine, 0.7 mg/dL (0.8-1.3 mg/dL); lactate, 0.6 mmol/L (0.6-2.3 mmol/L); alkaline phosphatase, 175 U/L (45-115 U/L); aspartate aminotransferase, 42 U/L (8-48 U/L); alanine aminotransferase, 30 U/L (7-55 U/L); total bilirubin, 0.5 mg/dL (0.1-1.0 mg/dL); direct bilirubin, 0.1 mg/dL (0.0-0.3 mg/dL); amylase, 36 U/L (26-102 U/L); lipase, 25 U/L (10-73 U/L); and international normalized ratio, 1.2 (0.8-1.2).
      • 1.
        Which one of the following is the most likely cause of this patient’s abdominal pain?
        • a.
          Peptic ulcer disease
        • b.
          Ruptured appendix
        • c.
          Acute cholecystitis
        • d.
          Acute mesenteric venous thrombosis (MVT)
        • e.
          Abdominal aortic aneurysm
      Peptic ulcer disease is an important cause of epigastric pain and can lead to severe diffuse abdominal pain if perforation occurs. However, one would expect peritoneal signs in the acute phase due to chemical peritoneal irritation, followed by evidence of infection as a secondary bacterial peritonitis develops. Appendicitis is an important cause of midabdominal pain that can often start in the periumbilical area before localizing to the right lower quadrant. However, in the case of a ruptured appendix, one would also expect peritoneal signs. Acute cholecystitis is a common cause of abdominal pain. However, it typically occurs in the right upper quadrant with radiation toward the right shoulder. It is often associated with recent fatty food intake and nausea. Because our patient had the classic finding of pain out of proportion to the abdominal examination findings that is seen in various intestinal ischemic syndromes,
      • Harnik I.G.
      • Brandt L.J.
      Mesenteric venous thrombosis.
      acute MVT is the most likely cause of his symptoms. Abdominal aortic aneurysm is also an important cause of midabdominal pain, but the pain associated with abdominal aortic aneurysm often radiates to the back. Furthermore, this patient lacks vascular risk factors or a smoking history, making this diagnosis less likely.
      We initiated intravenous fentanyl for pain control and fluid hydration. The suspicion for acute MVT was very high. His family history of unprovoked pulmonary embolism also provided a clue that he may have an underlying disorder that predisposes him to venous thrombosis.
      • 2.
        To further evaluate the patient’s abdominal pain, which one of the following would be the most appropriate next step?
        • a.
          Abdominal radiography
        • b.
          Computed tomographic (CT) angiography of the abdomen and pelvis
        • c.
          Esophagogastroduodenoscopy (EGD)
        • d.
          Mesenteric angiography
        • e.
          Abdominal Doppler ultrasonography
      Abdominal radiography with an upright view that includes the diaphragm would be an ideal test to quickly identify a perforated viscus by revealing free intraperitoneal air. However, in this patient who lacks peritoneal signs, this test would not be helpful in identifying the cause of his pain. Furthermore, although acute MVT leading to intestinal ischemia may exhibit a characteristic thumbprint of mucosal edema or pneumatosis intestinalis, these findings are nonspecific, and further evaluation would be needed.
      • Gore R.M.
      • Thakrar K.H.
      • Mehta U.K.
      • Berlin J.
      • Yaghmai V.
      • Newmark G.M.
      Imaging in intestinal ischemic disorders.
      Computed tomographic angiography of the abdomen and pelvis with intravenous contrast is the ideal test for diagnosis of MVT because it can quickly visualize the bowel, surrounding structures, and vasculature. It is highly sensitive and specific up to 93% and 96%, respectively, in diagnosing mesenteric ischemia and can provide direct visualization of the thrombus.
      • Menke J.
      Diagnostic accuracy of multidetector CT in acute mesenteric ischemia: systematic review and meta-analysis.
      Esophagogastroduodenoscopy would be useful in the evaluation of a patient with suspected pathology of the upper gastrointestinal mucosa if direct visualization is required but would not be appropriate in our patient at this time. Before the advent of advanced cross-sectional imaging, angiography was considered the criterion standard for diagnosis of intestinal ischemia, and it also provides a direct means for treatment.
      • Gore R.M.
      • Thakrar K.H.
      • Mehta U.K.
      • Berlin J.
      • Yaghmai V.
      • Newmark G.M.
      Imaging in intestinal ischemic disorders.
      However, it is an invasive test, and other noninvasive modalities should be used to confirm the diagnosis first. Angiography may be indicated in arterial ischemia or embolism, especially if intra-arterial therapy is considered.
      • Brandt L.J.
      • Boley S.J.
      AGA technical review on intestinal ischemia.
      Doppler ultrasonography may be able to diagnose MVT, and it provides information on the flow within the vessels. However, it is operator dependent, affected by air within loops of bowel, and requires patient cooperation that is often difficult during an episode of acute pain.
      • Gore R.M.
      • Thakrar K.H.
      • Mehta U.K.
      • Berlin J.
      • Yaghmai V.
      • Newmark G.M.
      Imaging in intestinal ischemic disorders.
      Furthermore, it may be difficult to visualize all of the necessary veins on ultrasonography, especially the superior mesenteric vein, if there is interference from overlying bowel gas.
      Computed tomographic angiography of the abdomen revealed an area of central lucency in the superior mesenteric vein and extension into the portal vein and a surrounding area of edema, characteristic of acute MVT. There was also evidence of underlying chronic MVT with the formation of collateral vessels. However, CT angiographic findings of local inflammation and edema suggested a superimposed acuity. Therefore, acute MVT was diagnosed, and the patient was admitted to the hospital for further management.
      • 3.
        Which one of the following is the best immediate treatment strategy for this patient’s condition?
        • a.
          Supportive management alone
        • b.
          Emergent laparotomy
        • c.
          Heparin anticoagulation
        • d.
          Thrombolysis with tissue plasminogen activator (tPA)
        • e.
          Anticoagulation with warfarin
      Supportive management including fluid hydration and symptom control are important but do not address the underlying cause. Therefore, supportive management alone is not indicated in symptomatic MVT. The initial decision point in the treatment algorithm for MVT is to determine if there is evidence of intestinal infarction, which would prompt emergent laparoscopy or laparotomy.
      • Harnik I.G.
      • Brandt L.J.
      Mesenteric venous thrombosis.
      However, this patient had evidence that made infarction unlikely, including an absence of peritoneal findings, normal vital signs, normal leukocyte count and lactate level, and lack of radiologic findings. Although laparotomy is not indicated immediately, it should be reconsidered if decompensation occurs. The goals of immediate treatment are to improve survival, prevent intestinal infarction in the acute setting, and provide recanalization of the occluded mesenteric vein to prevent chronic complications. Standard therapy is to immediately initiate heparinization, which has been shown to achieve these goals when compared with supportive management alone.
      • Brandt L.J.
      • Boley S.J.
      AGA technical review on intestinal ischemia.
      Concerns that heparinization could induce bleeding of necrotic bowel should not delay treatment.
      • Bergqvist D.
      • Svensson P.J.
      Treatment of mesenteric vein thrombosis.
      Several smaller case series have reported the efficacy of thrombolysis or thrombectomy in the venous system, but these methods should be considered an adjunct to anticoagulation until the results of larger studies are reported.
      • Harnik I.G.
      • Brandt L.J.
      Mesenteric venous thrombosis.
      Furthermore, the safe use of tPA is dependent on expertise and experience. Therefore, tPA is not the best choice at this time. Once patients are stable while receiving heparin and additional evaluation is completed, treatment can be converted to a vitamin K antagonist such as warfarin for long-term treatment of MVT.
      • Brandt L.J.
      • Boley S.J.
      AGA technical review on intestinal ischemia.
      Our patient should be monitored for clinical improvement while receiving heparin before warfarin therapy is initiated.
      Heparin was administered immediately, and the patient was monitored closely for signs of decompensation and bleeding. We provided supportive management with analgesics, fluid hydration, and antiemetics. He was given nothing by mouth until he was able to tolerate a diet. He improved clinically while receiving heparin and had no evidence of bowel infarction. He was ultimately transitioned to warfarin therapy and discharged from the hospital with no further need for analgesics.
      • 4.
        Which one of the following tests would be best to identify the underlying cause of this patient’s condition?
        • a.
          Fibrin D-dimer measurement
        • b.
          Repeated measurement of amylase and lipase levels and CT of the abdomen
        • c.
          Hepatitis C virus RNA and antibody testing
        • d.
          α-Fetoprotein (AFP) testing for detection of hepatocellular carcinoma
        • e.
          Serologic testing for prothrombotic conditions
      Elevation of fibrin degradation products in the serum, specifically D-dimer, indicates intravascular coagulation. However, it is elevated in several conditions and would not be helpful in identifying the underlying cause of MVT in this patient. Furthermore, once the diagnosis of thrombosis is established, this test provides no additional diagnostic value. Acute interstitial pancreatitis can result in MVT due to local inflammatory effects.
      • Acosta S.
      Epidemiology of mesenteric vascular disease: clinical implications.
      However, the diagnosis of pancreatitis was excluded by the absence of classic clinical symptoms and pancreatic enzyme elevation and suggestive CT findings. Repeating these tests would not provide additional diagnostic yield. A link between hepatitis C and MVT has not been established, other than in a single case report of a patient undergoing interferon treatment, which in itself is procoagulant.
      • Monterrubio Villar J.
      • Córdoba López A.
      Mesenteric vein thrombosis and protein C and S deficiency in a patient with chronic hepatitis C on treatment with interferon and ribavirin.
      Although our patient has a history of previously treated hepatitis C, testing for hepatitis C virus RNA and antibodies would not assist in the management of his MVT. In patients with hepatitis C leading to cirrhosis, screening ultrasonography for hepatocellular carcinoma is indicated, with some debate about using AFP measurements in conjunction. Although malignancy can cause local inflammation leading to acute thrombosis, CT would have effectively ruled out hepatocellular carcinoma. Therefore, AFP measurements would not be helpful in this patient. Prothrombotic conditions, including both inherited and acquired thrombophilia, account for a large percentage of the underlying disorders associated with development of MVT.
      • Bayraktar Y.
      • Harmanci O.
      Etiology and consequences of thrombosis in abdominal vessels.
      Thorough evaluation for thrombophilia should be performed in all patients in whom the underlying cause of MVT is unknown. This patient had a family history of unprovoked pulmonary embolism, which raises the suspicion of an inherited thrombophilia.
      Three months after his acute thrombus had resolved, the patient underwent further serologic evaluation, including testing for factor V Leiden sequence variation, prothrombin G20210A sequence variation, protein C and S deficiency, antithrombin deficiency, JAK2 sequence variation, antiphospholipid syndrome, hyperhomocysteinemia, and paroxysmal nocturnal hemoglobinuria. Decreased activity of antithrombin was detected, suggesting antithrombin deficiency. With the diagnosis of antithrombin deficiency, lifelong anticoagulation is recommended.
      • 5.
        In the long-term follow-up of this patient, which one of the following interventions is most likely to prevent complications and reduce mortality?
        • a.
          Serial CT until complete resolution is documented
        • b.
          Extensive evaluation for occult malignancy
        • c.
          Screening for and treatment of underlying esophageal varices
        • d.
          Transesophageal echocardiography to identify cardioembolic risks
        • e.
          Avoidance of anticoagulation to prevent variceal bleeding
      An additional factor to consider in the management of this patient is the evidence of underlying chronic MVT on CT. Chronic MVT typically occurs over an extended period in asymptomatic individuals but could occur in the setting of nonresolving acute MVT. Chronic MVT is often diagnosed incidentally when cross-sectional imaging reveals the presence of a thrombus with extensive venous collaterals.
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      Demonstrating complete resolution of MVT is unnecessary even in patients who have isolated acute MVT without chronicity. The use of serial CT will also expose patients to excessive radiation. Therefore, serial CT is not indicated. Although the survival in patients with chronic MVT is shortest in those with an underlying occult malignant tumor,
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      guidelines do not recommend an extensive diagnostic work-up to identify such a lesion. Most underlying cancers in patients with MVT are either local, widely metastatic with peritoneal involvement, or hematologic.
      • Acosta S.
      Epidemiology of mesenteric vascular disease: clinical implications.
      Therefore, the initial CT, a complete blood cell count, and a thorough history would rule out malignancy as a cause of a prothrombotic state, and further evaluation would not be indicated without a high index of suspicion. Symptoms of chronic MVT involve complications of portal hypertension such as ascites or variceal bleeding, which can occur in the absence of cirrhosis.
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      In one series, variceal bleeding occurred in 76% of patients with chronic MVT.
      • Orr D.W.
      • Harrison P.M.
      • Devlin J.
      • et al.
      Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
      Therefore, as in patients with cirrhosis, this patient should be screened for esophageal varices and given primary prophylaxis if indicated. Transesophageal echocardiography might be used to look for an embolic source in acute mesenteric ischemia, but it does not have a role in the evaluation of MVT. Lastly, although anticoagulation increases the risk of bleeding, it is often initiated for treatment of MVT, even in the presence of gastrointestinal bleeding,
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      because the risk of intestinal infarction in untreated MVT often outweighs the risk of bleeding, even in the presence of varices.
      • Condat B.
      • Pessione F.
      • Hillaire S.
      • et al.
      Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.
      Therefore, withholding anticoagulation at this time would not be indicated.
      The patient underwent screening EGD, which revealed small esophageal varices but no bleeding or red wale signs. Primary prophylaxis with nonselective β-blocker therapy or endoscopic band variceal ligation was not indicated. Because his esophageal varices had low risk for bleeding, risk-benefit discussions concluded that lifelong anticoagulation would be recommended with close gastroenterology follow-up. He was counseled on signs and symptoms of variceal hemorrhage.

      Discussion

      Mesenteric vein thrombosis is an important cause of intestinal ischemia that typically involves the superior mesenteric vein. It is responsible for up to 15% of all mesenteric ischemic events
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      and has an estimated incidence of 2.7 per 100,000 patient-years.
      • Acosta S.
      Epidemiology of mesenteric vascular disease: clinical implications.
      The causes of MVT can frequently be explained by the classic Virchow triad of stasis, endothelial damage, and hypercoagulable state. Intra-abdominal causes include inflammatory bowel disease, pancreatitis, postoperative states, and trauma.
      • Harnik I.G.
      • Brandt L.J.
      Mesenteric venous thrombosis.
      These factors can lead to both stasis and endothelial damage. Acquired hypercoagulable states include oral contraceptive use, pregnancy, antiphospholipid syndrome, hyperhomocysteinemia, paroxysmal nocturnal hemoglobinuria, and polycythemia vera. Heritable thrombophilias include factor V Leiden sequence variation, antithrombin III deficiency, prothrombin 20210 sequence variation, and protein C and S deficiencies.
      • Harnik I.G.
      • Brandt L.J.
      Mesenteric venous thrombosis.
      • Bayraktar Y.
      • Harmanci O.
      Etiology and consequences of thrombosis in abdominal vessels.
      Acute MVT often presents with colicky midabdominal pain. With both venous and arterial forms of mesenteric ischemia, the pain is out of proportion to physical examination findings.
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      Chronic MVT is typically asymptomatic. Patients will have formation of collateral vessels and often development of gastric or esophageal varices with extension of the MVT to the portal or splenic vein.
      • Kumar S.
      • Sarr M.G.
      • Kamath P.S.
      Mesenteric venous thrombosis.
      With improvements in diagnostic techniques, the management of MVT has changed over the past several decades.
      Before the advent of improved cross-sectional imaging techniques, diagnosis was made by laparotomy or at autopsy. The criterion standard diagnostic test had previously been angiography, but CT is now considered the test of choice because of the ability to both rule out other causes of pain and directly visualize the vasculature.
      • Gore R.M.
      • Thakrar K.H.
      • Mehta U.K.
      • Berlin J.
      • Yaghmai V.
      • Newmark G.M.
      Imaging in intestinal ischemic disorders.
      Computed tomography has also allowed for earlier diagnosis than in the past, which permits the use of noninvasive treatment modalities. Acute MVT without evidence of bowel infarction should be treated with immediate heparinization in order to prevent further extension of thrombosis and to promote recanalization of the vasculature.
      • Bergqvist D.
      • Svensson P.J.
      Treatment of mesenteric vein thrombosis.
      However, surgical intervention is needed if there is clinical or radiologic evidence of infarction. Patients with chronic MVT do not require heparinization because collateral vessels have formed, but they do need to be screened and appropriately treated for esophageal and gastric varices. If MVT is diagnosed, screening for underlying causes will determine the need for lifelong anticoagulation.
      This patient with MVT presented with classic midabdominal pain that was out of proportion to the physical examination findings. Computed tomography revealed acute-on-chronic MVT, with extension of the thrombus to the portal vein. Therefore, he was treated with heparin anticoagulation. Screening EGD detected small esophageal varices that did not require additional treatment. Additional testing suggested antithrombin deficiency. Currently, the patient and his primary physician are considering the benefit of continuing lifelong treatment with anticoagulation vs the risk of variceal bleeding.

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        Imaging in intestinal ischemic disorders.
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        Diagnostic accuracy of multidetector CT in acute mesenteric ischemia: systematic review and meta-analysis.
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        AGA technical review on intestinal ischemia.
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        Epidemiology of mesenteric vascular disease: clinical implications.
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        Mesenteric vein thrombosis and protein C and S deficiency in a patient with chronic hepatitis C on treatment with interferon and ribavirin.
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        Etiology and consequences of thrombosis in abdominal vessels.
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        Mesenteric venous thrombosis.
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        Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.
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