Chemotherapy-induced pneumatosis intestinalis followed by hepatic portal venous gas. A case report

Abstract

Pneumatosis intestinalis (PI) is a rare disease, and there are many theories about its pathogenesis. Hepatic portal venous gas (HPVG), is thought to occur secondary to intramural intestinal gas emboli migrating through the portal venous system via the mesenteric veins. PI accompanied by HPVG is usually a sign of bowel ischaemia and is associated with a high mortality rate. We report here, a patient with liver metastases from colorectal cancer who developed PI followed by HPVG after treatment with 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6). Timely attention and management of gastrointestinal symptoms following chemotherapy are essential in the treatment of this type of patient.

Background

Pneumatosis intestinalis (PI) is a rare condition and is defined as the presence of gas filled cysts within the walls of the small or large intestine that may be detected in radiographs or computed tomography (CT) scans.^1,2 Primary PI occurs in 15% cases and is idiopathic, whereas 85% cases are known as secondary PI, and are of varied aetiology. ³ Hepatic portal venous gas (HPVG), is thought to occur secondary to intramural intestinal gas emboli migrating through the portal venous system via the mesenteric veins. ⁴ PI in association with HPVG is often a radiological sign of bowel ischemia and is associated with a high mortality rate of up to 75%. ²

Several chemotherapeutic agents have been directly linked to the development of secondary PI and HPVG. ⁴ During chemotherapy, it is thought that killing tumour cells also causes damage to intestinal wall mucosal cells, and impairment of the intestinal mucosal barrier mechanism. This permits gas-producing bacteria to enter the hepatic portal venous system and in turn, allows facilitated entry of gas within the bowel wall.

We report here, a case of a patient with rectal cancer who developed PI followed by HPVG following treatment with 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6).

Case report

A man in his 50’s was diagnosed with liver-spreading colorectal cancer. For the first cycle of chemotherapy, the patient received, a modified mFOLFOX6 regimen (i.e., oxaliplatin 150 mg d1, calcium levofolinate 300 mg d1 and 5-fluorouracil 0.6 g intravenous bolus and then 4 g over 46 hours continuous infusion (i.e., mFOLFOX6)). He received this treatment every two weeks thereafter.

The patient received six cycles of chemotherapy and on the day after treatment stopped, he developed abdominal pain, particularly in the left lower quadrant. He had no rebound pain, the left lower abdominal soreness was considerable, and the body assessment was soft. An urgent abdominal CT scan showed multiple tiny emphysemas in the colon and intestinal wall, multiple tumour metastases in the liver, and liver cysts. However, there were no obvious signs of gas accumulation in the liver (Figure 1). The patient was given laxatives and bifidobacterium triple live bacteria to improve his gut flora.

Figure 1.

On the first day after chemotherapy had discontinued, a non-contrast abdominal computed tomography (CT) scan showed that the colon and intestinal wall were scattered with emphysema, and there were no obvious signs of gas accumulation in the liver. The three scans, from left to right, show emphysema in the small intestinal wall, emphysema of the colon wall, and no pneumata in the hepatic portal vein. Orange arrows indicate the emphysema.

On the second day following the conclusion of chemotherapy, his abdominal pain had decreased but he experienced diarrhoea more than ten times per day and had pale red faeces. Physical examination showed rebound discomfort, no visible soreness, and a blood pressure (BP) of 105/84 mmHg. A further abdominal CT scan showed a small quantity of fluid in the abdominal cavity, a liver cyst, multiple gas accumulation in the liver, a minute intestinal obstruction, and gas in the small intestinal wall; these signs indicated that the liver had not changed significantly from its initial state (Figure 2). The patient was prescribed broad-spectrum antimicrobials (i.e., intravenous imipenem/cilastatin [0.5 g every 6 hours] and intravenous vancomycin [15 mg/kg every 12 hours]).

Figure 2.

On the second day after chemotherapy had finished, a plain abdominal computed tomography (CT) scan showed small bowel emphysema and hepatic gas. The first two scans show increased emphysema in the small bowel wall and the third scan shows gas beginning to appear in the hepatic portal vein. Orange arrows indicate the emphysema.

On the third day after chemotherapy had stopped, an abdominal contrast-enhanced CT scan showed an accumulation of gas in the small intestine intestinal wall, mesenteric venous gas, and hepatic gas (Figure 3). Analysis of a blood sample showed the following: prothrombin time, 16 seconds; fibrinogen 4.58 g/l; antithrombin 60%; D-dimer 4420 ng/l; haemoglobin, 182 g/l; red blood cell (RBC) count 6 × 10¹²/l. We suggest that the disorder in coagulation function had been caused by ischemia in the liver, which lead to an increase in RBCs and an increase in D-dimer. On this day, the patient’s family requested that his treatment be discontinued and he be discharged from hospital; the patient was subsequently lost-to follow-up.

Figure 3.

On the third day after the end of chemotherapy, contrast-enhanced computed tomography (CT) of the abdomen showed the patient's small intestinal emphysema and a significant air plug in the hepatic portal vein. The top two images show a large amount of gas in the intestinal wall of the small intestine. The bottom two images show a large number of air plugs in the hepatic portal vein. Orange arrows indicate the emphysema.

The reporting of this study conforms to CARE guidelines. ⁵ Written informed consent was obtained from the patient for publication of his anonymised data. This report was approved by the clinical ethics committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (NO.2022-0694).

Discussion

For patients with unresectable colorectal cancer and widespread hepatic metastatic disease, chemotherapy has a major impact on quality of life, survival duration, and tumour-related symptom reduction. ⁶ However, chemotherapeutic agents may coincidentally cause damage to gastrointestinal cells while acting on tumour cells, inducing a destructive tissue response in the gastrointestinal epithelium. ⁷ This damage may lead to the entry of gas-producing bacteria into the bloodstream. A systematic review of 88 different episodes of PI concluded that oncological patients with respiratory system cancers and those treated with targeted therapies appeared be at high risk of PI. ⁸ Signs of HPVG have also been reported in patients following chemotherapy for oesophageal cancer tumors. ⁹ In addition, avascular necrosis of the small intestine, PI, and HPVG, have been linked to necrotizing colitis treated with high-dose prednisone and mercaptopurine. ¹⁰

The coexistence of intestinal wall emphysema and HPVG may be explained by three hypotheses namely, mechanical, bacterial or pulmonary. ¹¹ The mechanical theory hypothesises that an increase in intraluminal pressure, from bowel ischaemia or obstruction, leads to mucosal damage. Air is absorbed into the mesenteric capillary veins or mechanically interrupted through damage to the gastrointestinal mucosal barrier; The bacterial theory suggests that gas-producing bacteria such as Escherichia coli and Clostridia species can invade the intraluminal compartments. The pulmonary theory hypothesises that gas can propagate caudally into the retroperitoneum and mesentery from the mediastinum.

PI accompanied by HPVG is usually a sign of bowel ischaemia which is associated with a high mortality rate. ² However, its clinical presentation may vary from asymptomatic to critical illness. ³ Symptomatic patients may present with abdominal pain, weight loss, constipation or diarrhoea but more alarming clinical features such as bowel obstruction, bowel ischemia, pneumoperitoneum or peritonitis, with or without hemodynamic instability can also occur. ³ Diagnosis is typically radiological, and a CT scan is the gold standard for establishing the presence of PI. Promptly identifying patients that requiring emergency treatment is critical. More importantly, timely attention and management of gastrointestinal symptoms following chemotherapy are essential in the treatment of this type of patient.