An Uncommon Cause of Hematemesis

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Abbreviations

GOV

gastroesophageal varices

HVPG

hepatic venous pressure gradient

IGV

isolated gastric varices

PSVD

portal‐sinusoidal vascular disease

RAP

right atrial pressure

TIPS

transjugular intrahepatic portosystemic shunt

WHVP

wedged hepatic venous pressure

Case Presentation

A 55‐year‐old woman with a medical history of colon adenocarcinoma status post sigmoid resection presented to the hospital with hematemesis. The patient woke up feeling unwell and had sudden‐onset large‐volume hematemesis. She denied any abdominal pain, fevers, or chills. She denied any recent travel abroad. She denied any history of heartburn or peptic ulcer disease. She denied any use of nonsteroidal anti‐inflammatory medications or anticoagulation. Her medical history was significant for stage 3a colon adenocarcinoma status post 12 cycles of FOLFOX (5‐fluorouracil, leucovorin, oxaliplatin), which was completed 5 years ago. Her surgical history was notable for a sigmoid resection in 2014, cholecystectomy in 2013, and a partial hysterectomy in 2011. She had no smoking or illicit drug use history. She endorsed drinking two to three glasses of wine, two to three times a week. Her father had alcohol‐related cirrhosis. She had no other family history of gastrointestinal or liver disease. She denied any travel outside of the United States. She did not take medications. She denied any supplements or over‐the‐counter medications.

On arrival to the emergency department the patient was afebrile with a heart rate of 101 beats/min and a blood pressure of 98/52 mm Hg. Her oxygen saturation was 95% on room air. The patient was sitting comfortably in bed and able to speak in complete sentences. Her physical examination was otherwise notable for blood in the oropharynx. She had no signs of scleral icterus, jaundice, palmar erythema, spider angioma, organomegaly, abdominal ascites, or asterixis. Her admission laboratory tests revealed a hemoglobin level of 11.3 g/dL and a platelet count of 177 cells/L. Her white blood cell count and basic metabolic panel were within normal limits. Her liver chemistries were notable for an aspartate aminotransferase concentration of 22 IU/L, an alanine aminotransferase of 28 IU/L, an alkaline phosphatase of 86 IU/L, and a total bilirubin of 1.0 mg/dL. Her coagulation studies were unremarkable.

The patient was started on intravenous pantoprazole drip and underwent an emergent upper endoscopy that revealed small esophageal varices and gastroesophageal varices (GOV) extending along the greater curvature of the stomach with high‐risk stigmata of recent bleeding (Fig. 1).

FIG 1.

Esophagogastroduodenoscopy: (A) nonbleeding esophageal varices, (B) GOV2 extending along the greater curvature of the stomach, and (C) visible vessel overlying a gastric varix.

Question 1: Based on the patient’s history, physical examination, and endoscopic imaging, what is the next best step in management?

1. Endoscopic variceal ligation alone.

2. Endoscopic variceal ligation plus sclerotherapy.

3. Injection of epinephrine and hemostatic clip placement.

4. Referral for transjugular intrahepatic portosystemic shunt (TIPS).

Hemostatic spray was deployed in anticipation of the need for TIPS, and the patient was started on an octreotide drip. A liver ultrasound with Doppler imaging was obtained and revealed mild surface nodularity of the liver concerning for hepatic cirrhosis and patent hepatic vasculature with normal directional flow of the portal veins. A follow‐up computed tomography of the abdomen and pelvis (Fig. 2) showed that the liver was normal in size without cirrhotic morphology. The portal vein branches were patent. A few GOV were present, and a small recannulized paraumbilical vein was noted.

FIG 2.

Computed tomography of the abdomen and pelvis revealing a normal‐size liver with mild decreased attenuation and heterogenous appearance of the liver. A few GOV and a small recanalized paraumbilical vein are noted.

A transhepatic liver biopsy with portal pressures was obtained (Fig. 3). The right atrial pressure (RAP) was 5 mm Hg. The wedged hepatic venous pressure (WHVP) was 10 mm Hg. The RAP was 5 mm Hg. The liver biopsy showed mild macrovesicular fat without fibrosis. The portal tracts were unremarkable.

FIG 3.

(A) Hematoxylin and eosin stain showing multiple liver fragments from transjugular liver biopsy, (B) trichrome stain without evidence of fibrosis, and (C and D) mild macrovesicular fat without ballooning degeneration. The portal tracts were unremarkable.

Question 2: Based on the earlier imaging and pathology, what is the best diagnosis?

1. The patient does not have portal hypertension.

2. The patient has posthepatic portal hypertension.

3. The patient has presinusoidal portal hypertension.

4. The patient has sinusoidal portal hypertension.

Question 3: What is the next best step in management?

1. Continue with conservative management.

2. Obtain right heart catheterization.

3. Obtain direct portal pressure measurement and proceed with TIPS if elevated.

4. Proceed directly with TIPS.

Given high clinical suspicion for portal hypertension despite a normal hepatic venous pressure gradient (HVPG), a direct portal vein pressure was obtained and demonstrated a portal vein pressure of 17 mm Hg with a portosystemic gradient of 12 mm Hg. The patient subsequently underwent a TIPS procedure with embolization of the gastrorenal shunt and reduction of the portosystemic gradient from 12 to 1 mm Hg (Fig. 4). The patient was diagnosed with noncirrhotic portal hypertension associated with oxaliplatin administration.

FIG 4.

(A) Interventional radiology‐guided catherization of the middle hepatic vein through the right internal jugular vein. The catheter was advanced into the splenic vein to reveal a gastrorenal shunt and coronary varix. The gastrorenal shunt was embolized using a combination of embolization coils/plugs and gel foam. This was followed by the placement of a TIPS with dilation of the tips shunt to 8 mm and reduction of portosystemic gradient from 12 to 1 mm Hg. (B) Postembolization and TIPS placement.

Discussion

This patient presented with hematemesis secondary to type 2 GOV (GOV2) secondary to noncirrhotic portal hypertension. The Sarin classification of gastric varices categorizes varices based on their location and relationship to esophageal varices, and divides varices into GOV1 and GOV2 and isolated gastric varices (IGV; type 1 and type 2). GOV were characterized by the extension of esophageal varices along the lesser curvature (GOV1) or the greater curvature (GOV2). GOV1 is the most common type, accounts for 75% of all gastric varices, and can be managed the same as isolated esophageal varices (endoscopic variceal ligation). GOV2, however, require treatment with sclerotherapy using cyanoacrylate‐ or interventional radiology‐guided TIPS, as in this case versus balloon‐occluded retrograde transvenous obliteration, depending on the clinical scenario.

Portal hypertension is a clinical syndrome defined as the elevation of the hepatic vein pressure gradient (HVPG) to more than 5 mm Hg that results in the development of ascites, splenomegaly, gastrointestinal varices, and encephalopathy. ¹ , ² Although cirrhosis is a common cause of portal hypertension, portal hypertension can develop in the absence of cirrhosis. Noncirrhotic portal hypertension (NCPH) can occur at different levels of the hepatic circulation and is categorized as prehepatic, intrahepatic, and posthepatic, each with different portal venous pressure measurements (Table 1); for example, see fig. 3 of Koh et al. ¹ The majority of NCPH occurs at the intrahepatic level and is often the result of injury to the prehepatic or presinusoidal structures of the liver. ² Because of this, HVPG values tend to be normal or only mildly elevated, as seen in our patient; for example, see table 1 of Etzion et al. ²

TABLE 1.

Portal Hemodynamic Parameters by Etiology of Portal Hypertension

Etiology	RAP	WHVP	HVPG
Prehepatic	Normal	Normal	Normal
Intrahepatic
Presinusoidal	Normal	Normal or slightly elevated	Normal or slightly elevated
Sinusoidal	Normal	Elevated	Elevated
Postsinusoidal	Elevated	Elevated	Normal
Posthepatic	Elevated	Elevated	Normal

Causes of prehepatic portal hypertension include portal vein thrombosis or splenic vein thrombosis. Common causes of presinusoidal intrahepatic portal hypertension include schistosomiasis, infiltrative disorder (sarcoidosis, lymphoma, etc.), congenital hepatic fibrosis, primary biliary cirrhosis, early‐stage idiopathic portal hypertension, and nodular regenerative hyperplasia. Causes of sinusoidal and/or postsinusoidal intrahepatic portal hypertension include cirrhosis, schistosomiasis, primary biliary cirrhosis, advanced idiopathic portal hypertension, and acute alcoholic hepatitis. Causes of posthepatic portal hypertension include Budd‐Chiari syndrome, right heart failure, constrictive pericarditis, inferior vena caval obstruction, and severe tricuspid regurgitation.

Oxaliplatin is a third‐generation platinum derivative that has become the cornerstone of chemotherapy regimens for the treatment of colorectal cancer, both as adjuvant therapy and for metastatic disease. Its use has been associated with significant improvement in clinical outcomes when compared with 5‐fluorouracil alone. ³ However, oxaliplatin has been associated with significant toxicity. Common toxicities include peripheral neuropathy, splenic enlargement, thrombocytosis, hepatic steatosis, and portal‐sinusoidal vascular disease (PSVD) with resultant portal hypertension, in the absence of cirrhosis.

Oxaliplatin‐associated noncirrhotic portal hypertension is a well‐recognized complication of oxaliplatin use that is thought to be the result of PSVD. Sinusoidal damage related to oxaliplatin use was first described by Rubbia‐Brandt et al. ⁴ in 2004 and has been confirmed in subsequent case studies. ⁵ Its incidence rate is estimated to range from 19% to 52%. ⁶ Portosinusoidal injury can range in severity from mild sinusoidal dilation to hepatic sinusoidal obstructive syndrome. The proposed mechanism of sinusoidal injury is thought to be the result of increased permeability of the sinusoidal endothelium, resulting in the release of free radicals and depletion of glutathione transferase. This allows for the passage of erythrocytes into the space of Disse and the subsequent formation of perisinusoidal fibrosis. The resultant hypoxia leads to the release of angiogenic factors such as vascular endothelial factor and the activation of metalloproteinases, which results in further vascular damage. It is then believed that the resultant endothelial cell damage obstructs the sinusoids, resulting in hepatic congestion and elevated portal pressures. ⁷ In addition, nodular regenerative hyperplasia is thought to be the result of chronic, long‐term hypoxia in the centrilobular areas. A study in 2010 revealed the relationship between the cumulative dose of oxaliplatin with an increase in the size of the spleen and associated thrombocytopenia during treatment and the development of sinusoidal obstructive syndrome. ⁸ In addition, further studies have suggested that the concomitant use of bevacizumab, an inhibitor of vascular endothelial growth factor A, may have protective effects on the development of portal hypertension. ⁹

Oxaliplatin‐associated portal hypertension should be suspected in any individual treated with oxaliplatin who has clinical signs of portal hypertension in the absence of underlying chronic liver disease and after the exclusion of both portal or hepatic vein thrombosis and other conditions associated with noncirrhotic portal hypertension (congenital liver fibrosis, sarcoidosis, schistosomiasis). There are three typical histological findings suggestive of PSVD. These findings can be observed in isolation or in combination and include: (1) phlebosclerosis and hepatoportal sclerosis affecting medium and small branches, (2) nodular regenerative hyperplasia, (3) and incomplete septal fibrosis. ¹⁰

Our patient was diagnosed with oxaliplatin‐associated noncirrhotic portal hypertension 5 years after the completion of her chemotherapy. She is now status post TIPS and has been doing well for more than a year without any complications.

Teaching Points

1. GOV1 should be treated as esophageal varices. GOV2 and IGV require cyanoacrylate injection and/or TIPS or balloon‐occluded retrograde transvenous obliteration.

2. Noncirrhotic portal hypertension includes a broad group of disorders characterized by elevated portal pressures in the absence of cirrhosis. It can be classified as prehepatic, hepatic (predominantly presinusoidal), or posthepatic. It is often underrecognized and requires high clinical suspicion.

3. Oxaliplatin‐associated portal hypertension is an increasingly recognized toxicity associated with oxaliplatin use and is the result of both sinusoidal and vascular injury.