Diagnostic and Management of Emphysematous Hepatitis with Emphasis on Biopathology

Emphysematous hepatitis is a rare infectious disease, which corresponds to the presence of gas in the liver, without collection and after exclusion of vascular origin. This entity belongs to the group of emphysematous infections, whose physiopathology seems to be linked to the presence of unbalanced diabetes and to bacterial fermentation, leading to the production of gas within the liver parenchyma. Very few cases of emphysematous hepatitis have been described in the literature, and most of them had a rapidly fatal course. In this manuscript, we report the case of a 59-year-old man with emphysematous hepatitis due to wild-type Klebsiella pneumoniae that was successfully managed by surgery, and we perform a review of the literature to describe the clinical and biopathological aspects of this rare hepatic disease. Our manuscript underlines the need to perform biological and histopathological sampling to better understand the pathophysiology of this rare entity. The causes and mechanisms of emphysematous hepatitis, which seem to be multiple, lead us to believe that it is a syndrome rather than a simple infectious disease.


Introduction
Emphysematous hepatitis is a rare and recent entity, first described in 2002 [1].It corresponds to the presence of gas in the liver, without collection and after exclusion of vascular origin.This entity belongs to the group of emphysematous infections whose physiopathology seems to be linked to the presence of unbalanced diabetes and to bacterial fermentation, leading to the production of gas [2].
Emphysematous hepatitis must be distinguished from other etiologies associated with the presence of air in the liver.The air is initially present in the liver parenchyma and not in the vascular, biliary or lymphatic ducts, but may secondarily disseminate to these structures.Emphysematous hepatitis differs from gas-secreting pyogenic abscesses by the absence of wall, pus and collection inside the lesion [3].Few cases of emphysematous hepatitis have been described in the literature, and most of them had a rapidly fatal course.
We describe here a case of emphysematous hepatitis that was successfully managed by surgery and antimicrobial drugs; then, we perform a literature review to describe the clinical and histopathological aspects of this rare hepatic disease.

Case Report
We report the case of a 59-year-old man who presented to the Emergency Unit of Cayenne Hospital (Cayenne, French Guiana) for fever and worsened general condition.He had a medical history of uncontrolled type 2 diabetes and hypertension.On arrival at the Emergency Unit, the patient was febrile (39.8 • C) and confused, but had no hemodynamic or respiratory failure.His abdomen was soft and painless.
We conducted abdominal ultrasounds and then a computed tomography (CT) scan with contrast.It found a poorly limited area in the liver containing multiple gas bubbles without enhancement wall nor collection, located in the right anterior segment dome (segment VIII) measuring 58 × 50 mm associated with moderate left aerobilia (Figure 1).An ultrasound-guided fine needle aspiration (FNA) was performed and sent to the laboratory for microbiological analysis.
absence of wall, pus and collection inside the lesion [3].Few cases of emphysematous hepatitis have been described in the literature, and most of them had a rapidly fatal course.
We describe here a case of emphysematous hepatitis that was successfully managed by surgery and antimicrobial drugs; then, we perform a literature review to describe the clinical and histopathological aspects of this rare hepatic disease.

Case Report
We report the case of a 59-year-old man who presented to the Emergency Unit of Cayenne Hospital (Cayenne, French Guiana) for fever and worsened general condition.He had a medical history of uncontrolled type 2 diabetes and hypertension.On arrival at the Emergency Unit, the patient was febrile (39.8 °C) and confused, but had no hemodynamic or respiratory failure.His abdomen was soft and painless.
We conducted abdominal ultrasounds and then a computed tomography (CT) scan with contrast.It found a poorly limited area in the liver containing multiple gas bubbles without enhancement wall nor collection, located in the right anterior segment dome (segment VIII) measuring 58 × 50 mm associated with moderate left aerobilia (Figure 1).An ultrasound-guided fine needle aspiration (FNA) was performed and sent to the laboratory for microbiological analysis.The patient was transferred to the Intensive Care Unit to manage the hydroelectrolytic disorders.He was treated with intravenous antibiotics, including ceftriaxone 2 g/24 h and metronidazole 1500 mg/24 h.Ultrasound-guided drainage of the lesion was also performed the day after.
Two days after the patient's arrival in our hospital and in the absence of clear clinical improvement, surgical management was performed by median laparotomy, drainage, and placement of a Pezzer drain in order to decrease the inoculum (Figure 2a,b).A Pezzer drain is a catheter with a swollen and capped end that holds it in place, widely used to drain natural and pathological cavities.Blood cultures, liver ultrasound-guided FNA and The patient was transferred to the Intensive Care Unit to manage the hydroelectrolytic disorders.He was treated with intravenous antibiotics, including ceftriaxone 2 g/24 h and metronidazole 1500 mg/24 h.Ultrasound-guided drainage of the lesion was also performed the day after.
Two days after the patient's arrival in our hospital and in the absence of clear clinical improvement, surgical management was performed by median laparotomy, drainage, and placement of a Pezzer drain in order to decrease the inoculum (Figure 2a,b).A Pezzer drain is a catheter with a swollen and capped end that holds it in place, widely used to drain natural and pathological cavities.Blood cultures, liver ultrasound-guided FNA and surgical samples, as well as cytobacteriological examination of urine (CBEU), were positive for wild-type Klebsiella pneumoniae.The string test was in favour of a hyper mucosal phenotype, but we were unable to perform molecular tests to confirm the presence of a hypervirulent phenotype.
surgical samples, as well as cytobacteriological examination of urine (CBEU), were positive for wild-type Klebsiella pneumoniae.The string test was in favour of a hyper mucosal phenotype, but we were unable to perform molecular tests to confirm the presence of a hypervirulent phenotype.The histological examination of the surgical specimen showed necrotic hepatic tissue, a diffuse fibrinous coating associated with numerous neutrophils (Figure 3).The microscopical examination also revealed several images of microthrombosis (Figure 4).The histological examination of the surgical specimen showed necrotic hepatic tissue, a diffuse fibrinous coating associated with numerous neutrophils (Figure 3).The microscopical examination also revealed several images of microthrombosis (Figure 4).
surgical samples, as well as cytobacteriological examination of urine (CBEU), were positive for wild-type Klebsiella pneumoniae.The string test was in favour of a hyper mucosal phenotype, but we were unable to perform molecular tests to confirm the presence of a hypervirulent phenotype.The histological examination of the surgical specimen showed necrotic hepatic tissue, a diffuse fibrinous coating associated with numerous neutrophils (Figure 3).The microscopical examination also revealed several images of microthrombosis (Figure 4).The patient's general condition improved progressively with the disappearance of the fever.Antibiotics were continued for a total course of three weeks without adaptation to the microbiological documentation.A follow-up CT scan 20 days after surgery showed a common postoperative collection in the resection site with no evidence of emphysema.The patient was discharged from the hospital 23 days after arrival.

Literature Review
We performed a bibliographic search on the PubMed, Cochrane, and Google Scholar websites of all English-published cases of emphysematous hepatitis from inception until December 2021, using the following keywords: emphysematous hepatitis, emphysematous liver abscess and emphysematous liver.We eliminated manuscripts concerning animals, duplicate cases, emphysematous involvement of an organ other than the liver (including emphysematous cholecystitis), manuscripts with no link to our subject, and reviews with no new case.We then excluded patients with pyogenic abscesses with airborne components, defined by the presence of fluid or the presence of an organised structure (rounded or oval delineation, presence of wall or septa).Key information about the articles was extracted into a predefined datasheet: study characteristics include author, year of publication, patient characteristics (age and comorbidities), laboratory values (PCT levels, WBC levels, CRP levels, AST/ALT, bilirubin), method of diagnosis and imaging results, microbiological documentation (blood culture and/or culture from a liver sample), patient's management and outcome.We identified 14 cases in the literature (Table 1) [1,[3][4][5][6][7][8][9][10][11][12][13][14].The patient's general condition improved progressively with the disappearance of the fever.Antibiotics were continued for a total course of three weeks without adaptation to the microbiological documentation.A follow-up CT scan 20 days after surgery showed a common postoperative collection in the resection site with no evidence of emphysema.The patient was discharged from the hospital 23 days after arrival.

Literature Review
We performed a bibliographic search on the PubMed, Cochrane, and Google Scholar websites of all English-published cases of emphysematous hepatitis from inception until December 2021, using the following keywords: emphysematous hepatitis, emphysematous liver abscess and emphysematous liver.We eliminated manuscripts concerning animals, duplicate cases, emphysematous involvement of an organ other than the liver (including emphysematous cholecystitis), manuscripts with no link to our subject, and reviews with no new case.We then excluded patients with pyogenic abscesses with airborne components, defined by the presence of fluid or the presence of an organised structure (rounded or oval delineation, presence of wall or septa).Key information about the articles was extracted into a predefined datasheet: study characteristics include author, year of publication, patient characteristics (age and comorbidities), laboratory values (PCT levels, WBC levels, CRP levels, AST/ALT, bilirubin), method of diagnosis and imaging results, microbiological documentation (blood culture and/or culture from a liver sample), patient's management and outcome.We identified 14 cases in the literature (Table 1) [1,[3][4][5][6][7][8][9][10][11][12][13][14][15].

Results and Discussion
As described in the flow chart (Figure 5), of the 424 manuscripts selected from these research criteria, only 14 cases were retained as emphysematous hepatitis, half of them published between 2019 and 2021 [10][11][12][13][14].Our case being the 15th, we compared the available data of the 14 patients (Table 1).
The evolution of the disease was almost always fulminant.The average duration of symptoms before the consultation was 2.6 days.Ten patients (77%) developed hemodynamic failure within the 24 h following hospital admission, and 11 (73%) died within a mean time of 2 days (from 1 to 8 days).
Clinical symptoms were non-specific, with dysthermia, abdominal pain, and tenderness on palpation.Biological analyses showed neutrophil hyperleukocytosis, increased CRP, cytolysis predominantly with AST and increased total bilirubin (Table 2).Only one patient had a PCT measurement, which was 83.86 ng/mL.It would be interesting to assess whether PCT is more sensitive in emphysematous hepatitis, as observed in hepatobiliary infections [16].The diagnosis was based on a CT scan, sometimes associated with an ultrasound exam.One patient presented with anaemia associated with C. perfingens bacteraemia (8), possibly toxaemic.
Most patients received antibiotic therapy, but the details concerning the molecule were often not available.Management consisted of antibiotics alone for eight patients, and radiological drainage and antibiotics for three patients.Four patients received antibiotic therapy combined with surgical management within 48 h of hospital admission.This appears to be the main difference between survived and dead patients (Table 2).There are insufficient data to determine whether surgery should be performed systematically from  The mean age was 67 years (ranging from 38 to 82), with a female predominance (10 women/5 men).Eight patients had diabetes (53%), and four (27%) had a history of abdominal cancer (three cholangiocarcinoma and one pancreatic cancer) [5,8,9,11].Two patients had no medical history [14,15].
The evolution of the disease was almost always fulminant.The average duration of symptoms before the consultation was 2.6 days.Ten patients (77%) developed hemodynamic failure within the 24 h following hospital admission, and 11 (73%) died within a mean time of 2 days (from 1 to 8 days).
Clinical symptoms were non-specific, with dysthermia, abdominal pain, and tenderness on palpation.Biological analyses showed neutrophil hyperleukocytosis, increased CRP, cytolysis predominantly with AST and increased total bilirubin (Table 2).Only one patient had a PCT measurement, which was 83.86 ng/mL.It would be interesting to assess whether PCT is more sensitive in emphysematous hepatitis, as observed in hepatobiliary infections [16].The diagnosis was based on a CT scan, sometimes associated with an ultrasound exam.One patient presented with anaemia associated with C. perfingens bacteraemia (8), possibly toxaemic.
Most patients received antibiotic therapy, but the details concerning the molecule were often not available.Management consisted of antibiotics alone for eight patients, and radiological drainage and antibiotics for three patients.Four patients received antibiotic therapy combined with surgical management within 48 h of hospital admission.This appears to be the main difference between survived and dead patients (Table 2).There are insufficient data to determine whether surgery should be performed systematically from the outset of management, or whether in low-risk patients, as in the case of biliary infections, percutaneous drainage followed by reassessment at 24-48 h is possible [17].
Patients with diabetes were more likely to have Klebsiella-related infection, with no other significant difference with non-diabetic patients.We did not observe any difference according to the causal microorganism Clostridium versus Klebsiella, given the small number of cases.Patients were mostly bacteremic.The two most frequently identified microorganisms were Clostridium perfingens and Klebsiella spp.(five pneumoniae and one oxytoca) (Table 3).The other identified microorganisms were Escherichia coli, Enterobacter cloacae, Streptococcus mutans, Enterococcus faecalis and Enterococcus faecium [3,7,9,12,14].
The pathophysiology of emphysematous hepatitis is poorly understood.Given the number of patients with unbalanced diabetes, one of the hypotheses put forward is a mechanism similar to emphysematous cystitis and pyelonephritis [2,18,19].Thus, we can also hypothesise that emphysematous hepatitis is related to gas production by the use of an anaerobic pathway and bacterial fermentation, promoted by microcirculatory abnormalities associated with a reduction in the immunity of the host and a high tissue glycaemic index [18].The most frequently isolated bacteria in this context are Escherichia coli and Klebsiella pneumoniae [19].

Figure 1 .
Figure 1.Axial CT scan image after contrast injection showing a poorly limited area containing a little liquid and mainly many gas bubbles, without enhancement wall nor collection (a).Coronal CT scan image after contrast injection showing surgical resection area and the Pezzer drain (b).Hounsfield scale (HU): 60 HU for liver paranchyma and −1000 HU for air..

Figure 1 .
Figure 1.Axial CT scan image after contrast injection showing a poorly limited area containing a little liquid and mainly many gas bubbles, without enhancement wall nor collection (a).Coronal CT scan image after contrast injection showing surgical resection area and the Pezzer drain (b).Hounsfield scale (HU): 60 HU for liver paranchyma and −1000 HU for air.

Figure 2 .
Figure 2. Surgical aspect of the liver specimen (a,b).Macroscopical image of the internal surface of the surgical specimen fixed in formol (c).

Figure 3 .
Figure 3. Histopathological features of emphysematous hepatitis from our case report.(a) This image shows the emphysematous lesion characterised by an empty space with a roof of completely necrotic liver tissue replaced by a fibrinous and haemorrhagic coating (Haematoxylin and Eosin stain, ×200).(b) In the periphery and in contact with liver tissue, there is an abundant fibrinous coating rich in neutrophils.The adjacent liver tissue shows moderate steatosis (Haematoxylin and Eosin stain, ×200).

Figure 2 .
Figure 2. Surgical aspect of the liver specimen (a,b).Macroscopical image of the internal surface of the surgical specimen fixed in formol (c).

Figure 2 .
Figure 2. Surgical aspect of the liver specimen (a,b).Macroscopical image of the internal surface of the surgical specimen fixed in formol (c).

Figure 3 .
Figure 3. Histopathological features of emphysematous hepatitis from our case report.(a) This image shows the emphysematous lesion characterised by an empty space with a roof of completely necrotic liver tissue replaced by a fibrinous and haemorrhagic coating (Haematoxylin and Eosin stain, ×200).(b) In the periphery and in contact with liver tissue, there is an abundant fibrinous coating rich in neutrophils.The adjacent liver tissue shows moderate steatosis (Haematoxylin and Eosin stain, ×200).

Figure 3 .
Figure 3. Histopathological features of emphysematous hepatitis from our case report.(a) This image shows the emphysematous lesion characterised by an empty space with a roof of completely necrotic liver tissue replaced by a fibrinous and haemorrhagic coating (Haematoxylin and Eosin stain, ×200).(b) In the periphery and in contact with liver tissue, there is an abundant fibrinous coating rich in neutrophils.The adjacent liver tissue shows moderate steatosis (Haematoxylin and Eosin stain, ×200).

Figure 4 .
Figure 4.The vascular lesion in emphysematous hepatitis of our case report.(a) This image shows microthrombosis of small blood vessels within necrotic liver tissue g (Haematoxylin and Eosin stain, ×200).(b) This image shows the endothelial cells boarding the vascular lumen, small blood vessels and capillaries stained by the vascular marker CD34 (CD34, Immunohistochemistry ×200).

Figure 4 .
Figure 4.The vascular lesion in emphysematous hepatitis of our case report.(a) This image shows microthrombosis of small blood vessels within necrotic liver tissue g (Haematoxylin and Eosin stain, ×200).(b) This image shows the endothelial cells boarding the vascular lumen, small blood vessels and capillaries stained by the vascular marker CD34 (CD34, Immunohistochemistry ×200).

Figure 5 .
Figure 5. Flow chart of bibliographic search on PubMed, Cochrane and Google Scholar websites.

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No link to our subject = 71 -Not in English = 5 Excluded: 30 case reports (Presence of fluid collection)

Figure 5 .
Figure 5. Flow chart of bibliographic search on PubMed, Cochrane and Google Scholar websites.

Table 1 .
Comparative table describing demographic characteristics (age, sex and country of patient), symptoms and clinical presentation, microbiological findings, associated management (other than antibiotic treatment), and outcome of the 14 cases with emphysematous hepatitis (excluding our case).M = Male, F = Female.

Table 2 .
Demographic characteristics, clinical and paraclinical presentations, microbiological findings, management, and evolution of the 15 patients with emphysematous hepatitis (including our case).