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  • Case report
  • Open Access
  • Open Peer Review

A suspected case of Clostridium perfringens sepsis with intravascular hemolysis after transhepatic arterial chemoembolization: a case report

  • 1, 2Email author,
  • 2,
  • 2,
  • 2,
  • 2,
  • 2,
  • 2,
  • 2,
  • 2 and
  • 2
Journal of Medical Case Reports201913:125

https://doi.org/10.1186/s13256-019-2023-x

  • Received: 3 July 2018
  • Accepted: 20 February 2019
  • Published:
Open Peer Review reports

Abstract

Introduction

Sepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization.

Case presentation

An 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected.

Conclusion

Intravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection.

Keywords

  • Intravascular hemolysis
  • Clostridium perfringens
  • Transhepatic arterial chemoembolization

Introduction

Sepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies [1, 2]. Although C. perfringens sepsis is rare, massive intravascular hemolysis due to C. perfringens sepsis can have a particularly rapid fatal clinical course [3]. A literature review showed that chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for C. perfringens sepsis [4]. In particular, C. perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma (HCC). This case report focuses on findings characteristic of an intravascular hemolysis secondary to C. perfringens sepsis after transhepatic arterial chemoembolization (TACE).

Case presentation

An 83-year-old Japanese man presented to our hospital because of a third recurrence of HCC. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation for a partial HCC of S4/S8 in his liver 3 years ago. Because abdominal computed tomography (CT) revealed multiple HCC of S4/S8 and S2 in his liver 1 year ago, he underwent TACE therapy with an emulsified mixture of Lipiodol (ethiodized oil) and Farmorubicin (epirubicin) together with gelatin sponge particles for multiple tumors. After the second TACE, abdominal CT revealed sufficient Lipiodol (ethiodized oil) retention and the inefficacy of this treatment. However, follow-up CT showed a HCC recurrence in the left lobe 2 months ago. His medical history included reflux esophagitis, hypertension, and pancreatic carcinoma and he underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. His medications included amlodipine 5 mg, candesartan 4 mg, and esomeprazole 20 mg, all once daily. He was nondiabetic, did not smoke tobacco or drink alcohol, and had no history of any drug or food allergies. His family and social history were unremarkable. He appeared well on presentation. His body mass index was 26.2 kg/m2, with no noticeable body weight changes. He had an axillary temperature of 36.0 °C, a heart rate of 70 beats/minute, and blood pressure of 118/52 mmHg, with an oxygen saturation of 98% on room air at admission. No conjunctival pallor, icterus, cyanosis, or spider nevi were detectable on physical examination. Cardiovascular and respiratory examinations indicated normal jugular venous pressure and heart sounds, with no detectable murmurs, and normal breath sounds, with no crackle or wheeze. There were no particular abnormal physical findings. Laboratory studies indicated elevated creatinine and α-fetoprotein levels (Table 1). Abdominal ultrasonography showed several hypoechoic masses in his liver; an abdominal plane CT showed multiple lesions with the greatest extent more than 40 mm in the left lobe of his liver (Fig. 1).
Table 1

Summary of the laboratory data

 

Normal range

Before procedure

The sixth day after the procedure

Complete blood count

 White blood cells

× 102/ μL

30–97

40

291

 Neutrophils

%

36.6–79.9

70.1

92

 Hemoglobin

g/dL

13.1–17.6

9.3

5.1

 Platelet counts

× 104/ μL

12.4–30.5

11.6

11.4

Biochemistry

 Total bilirubin

mg/dL

0.1–1.2

0.7

14

 Aspartate aminotransferase

IU/L

12–35

33

1300

 Alanine aminotransferase

IU/L

6–40

76

362

 Lactate dehydrogenase

IU/L

119–229

235

4523

 γ-glutamyl transpeptidase

IU/L

0–48

82

108

 Alkaline phosphatase

IU/L

115–359

427

751

 Blood-urea-nitrogen

mg/dL

7.4–19.5

32.8

45.9

 Creatinine

mg/dL

0.5–1.2

1.35

1.50

 Total protein

g/dL

6.4–8.3

6.7

6.0

 Albumin

g/dL

3.8–5.2

3.2

2.4

 Sodium

mEq/L

135–147

140

132

 Potassium

mEq/L

3.4–4.8

4.1

4.7

 Ammonia

μg/dL

12–66

102

145

 HbA1c

%

4.6–6.2

5.5

 

Coagulation

 PT-INR

 

0.89–1.12

1.04

1.58

 APTT

seconds

23.6–31.3

22.9

44.1

Tumor marker

 Alpha-fetoprotein

ng/mL

0–10

36,690

 

 PIVKA-II

mAU/mL

0–39

3743

 

Serology

 Hepatitis B surface antigen

  

negative

 

 Hepatitis C virus antibody

  

negative

 

APTT activated partial thromboplastin time, HbA1c glycated hemoglobin, PIVKA-II protein induced by vitamin K absence-II, PT-INR prothrombin time-international normalized ratio

Fig. 1
Fig. 1

Computed tomography images in the axial plane. A low-density nodule (white arrow) in the left lobe is shown. Dynamic computed tomography was difficult to perform in this patient because of decreased renal function

Owing to our patient’s high risk of liver abscess after TACE because of his medical history of pancreaticoduodenectomy, the treatment course was carefully decided after consultation with our patient and his family. He underwent TACE with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil) (Fig. 2). A few days after undergoing the procedure, he was generally well except for mild symptoms attributed to postembolization syndrome. Despite antibiotic therapy (cefmetazole 3 grams daily) to prevent infection, he complained of fever, nausea, and hematuria on the sixth day after the procedure. He appeared unwell, severely jaundiced, and extremely restless. When his condition deteriorated, he had an axillary temperature of 39.0 °C, a heart rate of 110 beats/minute, and blood pressure of 90/40 mmHg. He presented with deterioration in hemoglobin levels and renal function, anemia, and a coagulation dysfunction. Furthermore, total bilirubin and direct bilirubin levels increased. Because elevated bilirubin and lactate dehydrogenase due to destruction of red blood cells showed hemolytic anemia, we performed a Coombs test for autoimmune hemolytic anemia to detect the presence of antibodies against red blood cells. However, the results for both the direct and indirect Coombs tests were negative. Based on our patient’s severe clinical course and laboratory data suggestive of hemolysis, intravascular hemolysis secondary to C. perfringens sepsis was suspected.
Fig. 2
Fig. 2

Hepatic angiogram showing a large 40-mm hepatic tumor corresponding to the lesion on plane computed tomography. The hypervascular tumor in the left lobe is depicted as a round mass of contrast opacification (straight white arrow) and as being supplied by the left hepatic artery

Because the embolic and necrotic lesion after TACE was suspected to be the focus of infection, we initiated antibiotic therapy (piperacillin/tazobactam 4.5 grams and clindamycin 600 mg) combined with surgical debridement. However, he died within 6 hours following unsuccessful cardiopulmonary resuscitation. An autopsy showed a 4-cm local, necrotic, hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion (Fig. 3). In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed (Fig. 4). The culture obtained by fluid aspiration from the hepatic abscess revealed C. perfringens.
Fig. 3
Fig. 3

Gross appearance of the liver at autopsy. The cut surface revealed a tumor with an internal spongiform appearance, that of a pseudocystic and partially necrotic lesion measuring 50 mm in the maximum dimension (white arrowhead)

Fig. 4
Fig. 4

a Pathogenesis of multiple small abscesses. These abscesses contained a thin rim of epithelioid histiocytes and other inflammatory cells (Gram stain × 10). b Colonies of Gram-positive rods observed on Gram staining (arrows) in the heart (Gram stain × 550)

Discussion

We reported a suspected case of massive intravascular hemolysis due to C. perfringens after TACE. In the present case, the role of C. perfringens was never established during the life of the patient. However, based on the severe clinical course and the culture obtained by fluid aspiration from the hepatic abscess at postmortem, intravascular hemolysis secondary to C. perfringens sepsis was suspected.

C. perfringens is an anaerobic Gram-positive rod that is naturally found in the intestines of humans and wild animals [4]. Although C. perfringens sepsis is rare, its association with massive hemolysis is well known, with death occurring within hours of presentation in patients similar to the present case [57]. The alpha toxin produced by C. perfringens is primarily responsible for the disease pathogenesis. This toxin, which possesses phospholipase C and sphingomyelinase activities, can damage the structural integrity of the red blood cell membrane, leading to spherocytosis and subsequent hemolysis [8, 9].

A review of studies on hemolysis associated with C. perfringens in the literature showed that infection was attributed to immunosuppression related to ageing, chronic disease, and presence of malignancies [10]. As the infected focus was commonly the liver and gastrointestinal tract, suspecting C. perfringens sepsis after TACE for HCC in liver cirrhosis was reasonable. Therefore, C. perfringens sepsis should always be considered in the differential diagnosis of HCC in patients presenting with fever and hemolysis after the procedure.

According to a search of reports in PubMed using the medical subject terms “TACE/transarterial embolization (TAE),” “clostridial sepsis,” and/or “hemolysis,” there were five cases of intravascular hemolysis secondary to C. perfringens sepsis after TACE/TAE [1113] (Table 2). The median age of patients at presentation was 74 years (range, 70–83 years), with all five patients being male. Some patients had important risk factors for infection in the gastrointestinal tract, such as gastrectomy, or invasive endoscopic procedures, resulting in tissue damage. In particular, TACE for HCC after biliary reconstruction including pancreaticoduodenectomy should be avoided as much as possible because severe liver abscess could frequently occur. The median tumor diameter was 99 mm (range, 40–179 mm). In all cases of infection after TACE, epirubicin, doxorubicin, and oxaliplatin were administered, with epirubicin being the most frequently used.
Table 2

Patients with intravascular hemolysis secondary to Clostridium perfringens sepsis after transhepatic arterial chemoembolization/transarterial embolization

Case

Reference

Year

Age

Sex

Tumor

Diameter

Liver cirrhosis

POD

Risk factor

ALT

Drug

Treatment

Outcome

Pre TACE

Post TACE

Hemolysis

1

[11]

1992

83

Male

HCC

115 mm

 

1

 

Normal range

  

Doxorubicin

Antibiotic

Dead

2

[12]

2010

74

Male

HCC

  

5

Gastrectomy

   

Epirubicin

Antibiotic

Drainage

Survival

3

[12]

2011

70

Male

HCC

83 mm

 

2

ERBD

316

  

Epirubicin

Antibiotic

Drainage

Dead

4

[13]

2014

71

Male

HCC

179 mm

+

2

 

145

1652

2312

5-fluorouracil

Oxaliplatin

Antibiotic

Survival

5

Our case

2017

83

Male

HCC

40 mm

+

6

PPPD

76

120

362

Epirubicin

Antibiotic

Dead

ALT alanine aminotransferase, ERBD endoscopic retrograde biliary drainage, HCC hepatocellular carcinoma, POD postoperative day, PPPD pancreaticoduodenectomy, TACE transhepatic arterial chemoembolization

The common symptoms of sepsis associated with hemolysis were hematuria, fever, and hypotension, which began within 1 week (range, 1–6 days) after the procedure. Although some reports did not mention laboratory data, the review showed a decrease in the median hemoglobin level from pre-procedure (11.6 mg/dL) to the occurrence of hemolysis (6.6 mg/dL). An increase in the median total bilirubin level from 1.15 mg/dL to 11.9 mg/dL, an increase in the median aspartate aminotransferase (AST) level from 73 to 1626 IU/L, and an increase in the alanine aminotransferase (ALT) level from 110.5 to 1337 IU/L was observed at hemolysis associated with C. perfringens. Of note, a few cases showed that liver function enzyme levels at post-procedure were elevated compared with those at pre-procedure. Liver damage after chemo-embolic therapy for HCC may be a high risk factor for C. perfringens infection.

Imaging studies, especially ultrasonography and CT, showed multiple hypovascular lesions, but it was difficult to distinguish hepatic abscesses from tumors because there were no diagnostic features of hepatic abscesses after TACE/TAE for HCC. Therefore, diagnosis was bacteriologically confirmed through identification of the presence of C. perfringens in the blood culture or the abscess.

With respect to treatment, all the patients received antibiotic therapy, and two patients underwent surgery. The mortality rate was 60.0%, with a median time to death of 9.7 hours (range, 0–96 hours). In all fatal cases, patients already went into shock or died before a diagnosis and decision to operate could be made. In one patient who survived, surgical drainage in combination with appropriate antibiotic therapy may have improved survival. If there was a perceived infected focus such as a hepatic abscess, the recommended treatment included aggressive surgical drainage together with high-dose antibiotic therapy.

Conclusion

Intravascular hemolysis secondary to C. perfringens should always be considered in patients who present with liver damage after chemo-embolic therapy for HCC. Biliary reconstruction is an especially important risk factor for infection.

Abbreviations

CT: 

Computed tomography

HCC: 

Hepatocellular carcinoma

TACE: 

Transhepatic arterial chemoembolization

TAE: 

Transarterial embolization

Declarations

Acknowledgements

We thank Robert E. Brandt, founder, CEO, and CME of MedEd Japan, for editing the manuscript.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors’ contributions

MO, HU, HH, NW, YT, TI, KK, TN, AS, and WK contributed equally to this work. HU and MO collected and analyzed the data; MO drafted the manuscript; HH, NW, YT, TI, KK, TN, AS, and WK offered technical or material support. All authors have read and approved the final version of the manuscript to be published.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review from this journal.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Gastroenterology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura Kanagawa, 247-8533, Japan
(2)
Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara Kanagawa, 252-0375, Japan

References

  1. Martí Gelonch L, Jiménez Agüero R, Rodríguez Canas N, Enríquez Navascués JM. Massive haemolysis due to sepsis caused by Clostridium perfringens secondary to liver abscess. Presentation of two cases with a similar history. Gastroenterol Hepatol. 2018;41(9):562–3. https://doi.org/10.1016/j.gastrohep.2017.11.012. PubMedView ArticleGoogle Scholar
  2. García Carretero R, Romero Brugera M, Vazquez-Gomez O, Rebollo-Aparicio N. Massive haemolysis, gas-forming liver abscess and sepsis due to Clostridium perfringens bacteraemia. BMJ Case Rep. 2016; https://doi.org/10.1136/bcr-2016-218014.
  3. Lim AG, Rudd KE, Halliday M, Hess JR. Hepatic abscess-associated Clostridial bacteraemia presenting with intravascular haemolysis and severe hypertension. BMJ Case Rep. 2016; https://doi.org/10.1136/bcr-2015-213253.
  4. Shindo Y, Dobashi Y, Sakai T, Monma C, Miyatani H, Yoshida Y. Epidemiological and pathobiological profiles of Clostridium perfringens infections: review of consecutive series of 33 cases over a 13-year period. Int J Clin Exp Pathol. 2015;8:569–77.PubMedPubMed CentralGoogle Scholar
  5. Dutton D, Gavrilova N. Massive intravascular hemolysis with organ failure due to Clostridium perfringens: evidence of intracytoplasmic C. perfringens. Blood. 2013;122:310.PubMedView ArticleGoogle Scholar
  6. Ingimarsdottir IJ, Asmundsdottir LR, Gottfredsson M. Case of the month: patient with septic shock and massive intravascular haemolysis. Laeknabladid. 2012;98:289–90.PubMedGoogle Scholar
  7. Ng H, Lam SM, Shum HP, Yan WW. Clostridium perfringens liver abscess with massive haemolysis. Hong Kong Med J. 2010;16:310–2.PubMedGoogle Scholar
  8. Ochi S, Oda M, Nagahama M, Sakurai J. Clostridium perfringens alpha-toxin-induced hemolysis of horse erythrocytes is dependent on Ca2+ uptake. Biochim Biophys Acta. 2003;1613:79–86.PubMedView ArticleGoogle Scholar
  9. Sakurai J, Nagahama M, Oda M. Clostridium perfringens alpha-toxin: characterization and mode of action. J Biochem. 2004;136:569–74.PubMedView ArticleGoogle Scholar
  10. van Bunderen CC, Bomers MK, Wesdorp E, Peerbooms P, Veenstra J. Clostridium perfringens septicaemia with massive intravascular haemolysis: a case report and review of the literature. Neth J Med. 2010;68:343–6.PubMedGoogle Scholar
  11. Gerson LB, Pont A, Cummins RT. Clostridial bacteremia and death following chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 1994;5:167–70.PubMedView ArticleGoogle Scholar
  12. Oshima S, Takaishi K, Tani N, Hirano M, Ikeda K, Makari Y, et al. Two cases of liver abscess caused by Clostridium perfringens after transcatheter arterial chemoembolization. Gan To Kagaku Ryoho. 2013;40:1795–7.PubMedGoogle Scholar
  13. Li JH, Yao RR, Shen HJ, Zhang L, Xie XY, Chen RX, et al. Clostridium perfringens infection after transarterial chemoembolization for large hepatocellular carcinoma. World J Gastroenterol. 2015;21:4397–401.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

© The Author(s). 2019

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