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Oxaliplatin-Induced Hepatoportal Sclerosis, Portal Hypertension, and Variceal Bleeding Successfully Treated With Transjugular Intrahepatic Portosystemic Shunt

Clinical Colorectal Cancer, Vol. 11, No. 3, 224-7

Clinical Practice Points
  • Oxaliplatin is commonly used for metastatic colon or rectal cancer. Side effects of oxaliplatin are well known and are predictable in terms of their onset and duration. Furthermore, oxaliplatin side effects are almost always reversible and will go away after treatment cessation.
  • Although studies have shown oxaliplatin to be associated with hepatic vascular injury, herein the authors describe a case of symptomatic portal hypertension, hepatoportal sclerosis, and variceal bleeding secondary to the use of oxaliplatin. The liver biopsy specimen revealed no signs of cirrhosis but did demonstrate evidence of hepatoportal sclerosis and vascular injury. The patient was successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS) and remained in good health with no recurrence of symptoms at 3.5-years of follow-up.
  • Clinicians should be aware that rapid, acute, and symptomatic portal hypertension is a rare manifestation of the oxaliplatin chemotherapeutic regimen; furthermore, successful long-term treatment with TIPS is possible to manage the sequelae.

Introduction

We report a case of rapid progression of acute oxaliplatin-induced portal hypertension and liver disease successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). Our patient was receiving oxaliplatin-based chemotherapy for colorectal cancer and presented with massive variceal gastrointestinal (GI) bleeding caused by hepatoportal sclerosis, obliterated portal venules, and portal hypertension. Oxaliplatin-induced portal hypertension is uncommon, and the use of TIPS to successfully treat the sequelae of oxaliplatin-induced hepatic injury with a favorable long-term prognosis has not yet been reported to our knowledge.

Case Report

A 45-year-old woman presented acutely with uncontrolled hematemesis, anemia, and upper GI bleeding and underwent emergency esophagogastroduodenoscopy (EGD). Her history was significant for stage III (Dukes C) colorectal cancer for which she underwent sigmoidectomy and an 8-month FOLFOX (5-fluorouracil, leucovorin, oxaliplatin)/bevacizumab regimen that ended 1 month before presentation. The patient had tolerated chemotherapy well until the development of a sudden onset of hematemesis before admission. A serologic viral workup was performed, and there was no history of alcohol abuse, hepatitis, or any underlying chronic liver disease. Emergency EGD revealed 4 columns of grade 2 esophageal varices extending to the distal third of the esophagus, and an actively bleeding varix was seen just proximal to the gastroesophageal junction. In addition, fresh blood clots were seen in the fundus along with 3 gastric varices, which showed no stigma of recent hemorrhage. There was evidence of marked portal hypertensive gastropathy of unknown cause; the pylorus and duodenum appeared normal. Interventional radiology was consulted for emergent TIPS after resuscitation with transfusion of packed red blood cells and octreotide drip administration; later the patient was placed on 40 mg esomeprazole magnesium twice daily, 1 mg folic acid orally (p.o.) daily, and 150 mg iron polysaccharide p.o. daily.

Results from 2 18-gauge core liver biopsy specimens obtained at the time of the TIPS procedure revealed no evidence of cirrhosis, portal triaditis, fibrosis, cholestasis, venoocclusive disease, or colorectal metastasis. The hepatic parenchyma displayed mild lobular and predominantly lymphocytic inflammation with scattered hepatocyte dropout (Figure 1).

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Figure 1

The Initial Liver Biopsy Specimen Showing Focal Hepatocytic Necrosis/Dropout (Arrow) With Adjacent Reactive Hepatocytes Having an Uneven Nuclear Size (anisonucleosis) (hematoxylin and eosin stain, original magnification ×400)

 

On the pre-TIPS portogram, multiple collaterals including a paraesophageal varix were noted (Figure 2), and the preprocedural portosystemic shunt pressure was measured to be 23 mm Hg (20 and 43 mm Hg in the right atrium and portal vein, respectively). A 12 mm × 10 cm (8 cm covered and 2 cm uncovered) and a 12 mm × 6 cm (4 cm covered and 2 cm uncovered) Viatorr TIPS endoprosthesis (W. L. Gore and Associates Inc, Flagstaff, AZ) were deployed, and the TIPS tract was first dilated to 10 mm, resulting in pressures of 31 and 24 mm Hg in the portal vein and the right atrium, respectively. However, given that the patient was actively bleeding and there was persistent flow in the left portal vein, the TIPS tract was subsequently dilated with a 12 mm × 4 cm balloon. After dilation, there was good flow through the widely patent shunt, no filling of collaterals, and decreased flow into the left portal vein (Figure 3). The successful creation of the TIPS shunt from the right hepatic vein to the right portal vein resulted in an overall reduction in the portosystemic gradient from 23 mm Hg to 3 mm Hg (24 and 27 mm Hg in the portal vein and right atrium, respectively). The patient was transferred back to intensive care after the procedure, and 5-day follow-up Doppler ultrasonography at discharge showed a patent TIPS shunt. The patient remained in stable condition without any immediate postprocedural complications or episodes of encephalopathy; a routine 3-month follow-up ultrasonography was performed.

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Figure 2

Before the Deployment of the 12 mm × 10 cm Viatorr TIPS Endoprosthesis in the TIPS Tract, the Pre-TIPS Carbon Dioxide Portogram Showed Filling of Collaterals and Paraesophageal Varices

 

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Figure 3

The Post-TIPS Portogram Demonstrating Successful Placement of the TIPS and a Widely Patent Shunt. Dilatated Paraesophageal Varices were no Longer Visualized

 

During follow-up liver biopsy to reassess hepatic histologic findings, the liver was noted to be small and a dilatated large bowel loop was observed along the right abdominal wall. The repeat liver biopsy showed hepatoportal sclerosis and moderate mixed macrovesicular/microvesicular steatosis that had a centrizonal distribution estimated at approximately 60%. There was no cirrhosis, steatohepatitis, lobular activity, or fibrosis. Portal tracts were small and inconspicuous, and there was no triaditis. Bile ducts and hepatic arterioles were present, but most of the portal venules appeared to be obliterated (Figure 4). At 3.5 years of follow-up, the patient remains well with no further episodes of GI bleeding or ascites, interventions, or complaints related to portal hypertension. No institutional review board consent was required at this institution for a case report.

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Figure 4

Follow-Up Liver Biopsy Specimen Showing Hepatoportal Sclerosis and Moderate Mixed Macrovesicular/Microvesicular Steatosis. Portal Tracts were Small and Inconspicuous Without Triaditis. Bile ducts (open arrows) and Hepatic Arterioles (black arrows) were Present, but Most of the Portal Venules Appeared to be Absent/Obliterated, as Depicted Here. The Periodic Acid–Schiff Stain With Diastase (PAS/D) Highlights a Macrophage Containing PAS-Positive Material (black arrowhead), Suggestive of Localized Injury (upper left: hematoxylin and eosin; upper right: PAS/D; lower left: trichrome stain; lower right: reticulin; original magnification for all ×400)

 

Discussion

This report demonstrates the potential for the development of the sudden onset of oxaliplatin-induced noncirrhotic presinusoidal portal hypertension manifested by acute hematemesis and variceal hemorrhage in a patient with colorectal cancer that has been successfully managed long-term by TIPS placement. Few studies have shown oxaliplatin to be associated with hepatic vascular injury leading to observed portal hypertension. To our knowledge, this is the first case report of effective management of acute oxaliplatin-induced liver injury and portal hypertension with TIPS.

Oxaliplatin is a third-generation platinum derivative that is commonly used in the treatment of early-stage and metastatic colorectal cancer.1 and 2 Patients treated with oxaliplatin in addition to 5-fluorouracil have a significant improvement with respect to progression-free survival (a median of 9.0 vs. 6.2 months) and response rate (50.7% vs. 22.3%) when compared with counterparts treated with only 5-fluorouracil.3 Commonly reported toxicities associated with oxaliplatin include peripheral neuropathy, splenic enlargement, and thrombocytopenia. Several case series have confirmed the association between hepatic sinusoidal injury and oxaliplatin therapy; the incidence of hepatic sinusoidal injury ranges between 19% and 54%.4 Rubbia-Brandt et al showed that among 274 patients treated with oxaliplatin, sinusoidal dilatation and microscopic hemorrhage developed in 54% because of damage to the hepatic sinusoidal endothelial cell barrier.5 In the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial, patients with stage IV colorectal cancer were randomized to receive either surgery or induction FOLFOX followed by surgery. Pathologic evaluation of the 57 patients enrolled in the trial revealed a significantly higher incidence of sinusoidal lesions in patients receiving preoperative chemotherapy (48% vs. 11%; P = .003).6

Hepatic sinusoidal injury can range from mild sinusoidal dilatation to hepatic sinusoidal obstruction syndrome. Clinical manifestations of hepatic sinusoidal obstruction include hepatomegaly, jaundice, and ascites. The progression of events leading to chemotherapy-induced portal hypertension is as follows. First, oxaliplatin is thought to cause an increase in the reactive oxygen species and depletion of glutathione transferase, leading to a toxic insult to sinusoidal endothelial cells. In turn, this injury compromises the integrity of the vascular wall. Subsequent obstruction presumably occurs by matrix deposition in the sinusoids and endothelial sloughing.7 The result is hepatic congestion leading to elevated portal pressures. This sequence of events triggers an increase in the concentration of angiogenic factors (vascular endothelial factor, plasminogen-activating factor) and activation of the matrix metalloproteinases, which in turn further propagate the vascular injury. Second, centrilobular fibrosis and nodular regenerative hyperplasia (NRH) are both believed to modify intrahepatic blood flow, eventually causing portal hypertension. Interestingly, a significant feature of NRH is that it can become clinically evident long after chemotherapy.1 and 8 Finally, oxaliplatin use can lead to fibrotic reactions resulting in obliteration of small vessels, hepatocyte plate disruption, and parenchymal extinction lesions.9 The occurrence of these 3 histologic findings together can lead to increased resistance to blood flow between the portal and hepatic venous systems and the eventual clinical presentation of portal hypertension. Oxaliplatin was the most likely causative agent for the obliterated portal veins and hepatoportal sclerosis in this case, which would explain portal hypertension in the absence of fibrosis. The patient's portal tracts were small and inconspicuous (Figure 4), and most of the portal venules appeared to be obliterated. As is characteristic of noncirrhotic portal hypertension, there were no signs of cirrhosis or pseudonodule formation in the liver.10 and 11 Also, parenchymal atrophy of the liver secondary to portal malperfusion was an observed pathologic alteration. These changes in hepatic structure laid the foundation for the observed portal hypertension and the emergency episode of acute variceal hemorrhage.

Although pathologic changes in hepatic vasculature are commonly seen in patients receiving oxaliplatin, clinical manifestations of hepatic sinusoidal obstruction syndrome from oxaliplatin-induced injury have not been well reported in the literature. Slade et al described 6 patients in whom oxaliplatin-induced portal hypertension developed, as demonstrated by ascites, splenomegaly, persistent thrombocytopenia, and bleeding of esophageal varices. The complications of portal hypertension in these patients were either treated with endoscopic banding or they self-resolved over time.1

The early use of TIPS has been shown to significantly reduce treatment failure and mortality in patients hospitalized for acute variceal bleeding.12 Massive hematemesis from acute variceal bleeding is usually seen in patients with cirrhosis; it occurs in up to 30% of such individuals during the course of illness and is associated with substantial morbidity and mortality. Up to 20% of initial bleeding episodes are fatal, and as many as 70% of survivors have recurrent bleeding within 1 year after the index hemorrhage.13 There is 1 reported case by Tisman et al in which a patient with stage III colorectal cancer was diagnosed with sinusoidal obstruction, hepatic insufficiency, and portal hypertension.14 A portocaval shunt was placed; however the disease progressed to encephalopathy and hepatorenal syndrome and the patient subsequently died after a 7-week hospitalization. This report serves both as a cautionary note to practicing interventional radiologists that portal hypertension and liver disease can occur remarkably quickly in patients receiving FOLFOX and also demonstrates that the use of TIPS can effectively manage and treat acute variceal bleeding from oxaliplatin-induced injury. In this case, the patient has remained in good general health in respect to liver function for 3.5 years of follow-up without any complaints of recurrent bleeding or complications of portal hypertension.

References

  • 1 J.H. Slade, M.L. Alattar, D.R. Fogelman, et al. Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury. Clin Colorectal Cancer. 2009;8:225-230 Crossref
  • 2 T. André, C. Boni, L. Mounedji-Boudiaf, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351
  • 3 A. de Gramont, A. Figer, M. Seymour, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938-2947
  • 4 J.N. Vauthey, T.M. Pawlik, D. Ribero, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065-2072 Crossref
  • 5 L. Rubbia-Brandt, G.Y. Lauwers, H. Wang, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56:430-439 Crossref
  • 6 Julie C, Lutz M, Aust D, et al. Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC intergroup phase III study 40983. Paper presented at: the ASCO Gastrointestinal Cancers Symposium; January 19-21, 2007; Orlando, FL.
  • 7 M.L. Yeong, S.J. Wakefield, H.C. Ford. Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats. Int J Exp Pathol. 1993;74:211-217
  • 8 L. Rubbia-Brandt, V. Audard, P. Sartoretti, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460-466 Crossref
  • 9 P. Ryan, S. Nanji, A. Pollett, et al. Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol. 2010;34:784-791 Crossref
  • 10 S.K. Sarin, D. Kapoor. Non-cirrhotic portal fibrosis: current concepts and management. J Gastroenterol Hepatol. 2002;17:526-534 Crossref
  • 11 S.K. Sarin, A. Kumar. Noncirrhotic portal hypertension. Clin Liver Dis. 2006;10:627-651 Crossref
  • 12 J.C. García-Pagán, K. Caca, C. Bureau, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370-2379
  • 13 D.Y. Graham, J.L. Smith. The course of patients after variceal hemorrhage. Gastroenterology. 1981;80:800-809
  • 14 G. Tisman, D. MacDonald, N. Shindell, et al. Oxaliplatin toxicity masquerading as recurrent colon cancer. J Clin Oncol. 2004;22:3202-3204 Crossref

Footnotes

1 Division of Interventional Radiology and Image-guided Medicine, Emory University School of Medicine, Atlanta, GA

2 Department of Pathology, Emory University School of Medicine, Atlanta, GA

3 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA

4 Division of Hepatology, Emory University School of Medicine, Atlanta, GA

Address for correspondence: Hyun S. Kim, MD, Division of Interventional Radiology and Image Guided Medicine, Emory University School of Medicine, 1364 Clifton Road NE, Suite AG-05, Atlanta, GA 30322 Fax: 404-712-7970


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