Acute hepatitis with synchronous acalculous cholecystitis and pancreatitis in a patient with Epstein–Barr viral infection: a case report

Abstract

Background

Epstein–Barr virus infection is common. However, to our knowledge, it has never been reported to cause synchronous acute acalculous cholecystitis and acute pancreatitis alongside hepatitis. This case highly suggests the potential for novel multiorgan involvement.

Case presentation

A 32-year-old Asian male patient presented with high-grade fever, abdominal pain, and jaundice. Comprehensive diagnostic evaluation confirmed acute hepatitis, acute acalculous cholecystitis, and acute pancreatitis. Histopathological examination of lymph node and liver biopsy specimens identified Epstein–Barr virus infection as the underlying cause of all three conditions. The patient was treated with dexamethasone at a dose of 5 mg per day combined with acyclovir. Significant clinical improvement was observed, and the patient was subsequently discharged.

Conclusion

This is the first reported case of concurrent Epstein–Barr-virus-induced hepatitis, acute acalculous cholecystitis, and acute pancreatitis. The patient’s full recovery through nonsurgical management, including antiviral and antiinflammatory therapies, may provide valuable insights for future clinical practice.

Background

Epstein–Barr virus (EBV) infection is one of the most common infectious diseases, with approximately 95% of people experiencing EBV infection at some point in their lives [1]. The virus can be transmitted through body fluids, handshakes, sharing toothbrushes, and other close contacts. EBV can be detected in the saliva of infected individuals for extended periods, potentially lifelong. Typically, the highest viral loads are shed during the first year following infection [2].

EBV infection is mostly asymptomatic; however, some patients may develop infectious mononucleosis (IM), a self-limiting syndrome characterized by fever, sore throat, lymphadenopathy, splenomegaly, an increased lymphocyte count in routine blood tests, and the presence of atypical lymphocytes. Additionally, EBV infection can cause other rare clinical complications, such as splenic rupture [3], neurological symptoms [4], cholestasis and hepatitis [5], acute renal failure [6], hemolysis [7], cholecystitis, and pancreatitis [8–11].

A previous article reviewed all cases of pancreatitis and cholecystitis associated with primary acute symptomatic Epstein–Barr virus infection from 1966 to 2016; however, none involved concurrent acalculous cholecystitis (AAC) and acute pancreatitis (AP) [11]. Therefore, we present a case of a patient who developed acute hepatitis accompanied by both AAC and AP, aiming to contribute to the literature on these rare pathological manifestations.

Case presentation

A 32-year-old Asian male worker was admitted with a high-grade fever of 39.8 ℃ accompanied by chills, sweating, fatigue, dizziness, headache, dry cough, mild chest tightness, wheezing, and a marked aversion to greasy food. These symptoms had persisted for 6–7 days prior to admission, and 2 days before hospitalization, he also developed a sore throat, upper abdominal pain with nausea, two episodes of retching, diarrhea, and frequent urination. Blood tests revealed total white blood cell (WBC) count of 6.10 × 10⁹/L, lymphocyte percentage (LY%) of 58.9%, and C-reactive protein (CRP) level of 24.40 mg/L. Computed tomography (CT) of the abdomen and pelvis showed cholecystitis with gallbladder subserosal edema, pelvic fluid collection, multiple small lymph nodes in both the abdominal cavity and retroperitoneal space, and splenomegaly.

The patient denied any past medical illnesses or concerns and consistently adhered to an annual schedule of routine wellness check-ups. He reported occasional alcohol consumption and denied any history of significant familial diseases.

Physical examination upon admission revealed the following: height 175 cm, body weight 62 kg, temperature 38 ℃ (100.4 ℉), blood pressure 106/67 mmHg, yellowish skin and sclera, reddened and swollen pharynx, purulent left tonsil, enlarged but painless left cervical lymph nodes, tenderness in the mid and right upper abdomen, percussion pain over the liver area with a questionable Murphy’s sign, and absent bowel sounds. One week after hospitalization, the patient developed a generalized diffuse rash without significant pruritus (Fig. 1).

Fig. 1.

A 32-year-old male with infectious mononucleosis: a left tonsil covered with pus; b rashes present over the body

Laboratory data revealed WBC count of 6.50 × 10⁹/L, LY% at 62.4% (with 14% atypical lymphocytes), absolute eosinophil count of 0.10 × 10⁹/L, CRP of 14.96 mg/L, alanine aminotransferase (ALT) of 526 U/L, aspartate aminotransferase (AST) of 297 U/L, total bilirubin (TBIL) of 144.18 µmol/L, direct bilirubin (DBIL) of 98.54 µmol/L, indirect bilirubin (IBIL) of 45.64 µmol/L, amylase (AMY) of 305 U/L, and lipase (LIP) of 413.1 U/L. Procalcitonin (PCT) was 0.97 ng/mL. Additional serological results are presented in Table 1.

Table 1.

Summary of serological studies

Tests	Results
EBV-DNA (plasma)	2046 copies/mL (positive)
EBV-IgM	> 160 U/mL
EA-IgG	35.20 U/mL (positive)
EB-IgG	39.70 U/mL (Positive)
Acute hepatitis A, B, C & E serology	Nonreactive
HIV-1 & 2 antibody	Negative
Cytomegalovirus-IgM	Negative
Cytomegalovirus-DNA	Negative
Toxoplasma-IgM	Negative
Rubella virus-IgM	Negative
Herpes simplex virusI + II-IgM	Negative
Respiratory organism panel (a)	All negative
Epidemic hemorrhagic fever IgM + IgG	Negative
Adenovirus-IgM	Negative
Coxsackie virus-IgM	Negative
Direct antiglobin test (Coombantiglo)	Negative
Urine for hemosiderin (Rous) test	Positive
Alpha-fetoprotein (AFP)	0.99 ng/ml (negative)
Ceruloplasmin (CER)	0.34 g/L (negative)
AMA-M2 (b)	3.35 U/mL (negative)
Sp100 antibody (b)	3.52 U/mL (negative)
gp210 antibody (b)	2.57 U/mL (negative)
LKM-1 (c)	0.92 U/mL (negative)
SLA (c)	1.51 U/mL (negative)
ANA scan	Negative
ANCA scan(IF-ANCA, MPO-IgG, PR3-IgG)	Negative
IgG1-4	Negative
Brucella tiger red plate agglutination test	Negative
G-test	Negative

(a) Respiratory organism panel: Legionella pneumophila; Mycoplasma pneumoniae; Rickettsia of Q fever; Chlamydia pneumoniae; Respiratory syncytial virus; Influenza A & B; Parainfluenza virus 1, 2 & 3; (b) all serological studies for primary biliary cholangitis (PBC); (c) all serological studies for autoimmune liver disease (ALD)

Further magnetic resonance cholangiopancreatography (MRCP) revealed no obstruction of the pancreatic or biliary ducts (Fig. 2) but showed hepatomegaly, splenomegaly, and multiple enlarged lymph nodes in the portal area and retroperitoneum. To exclude other possible malignant diseases, the patient underwent positron emission tomography-computed tomography (PET-CT). The ¹⁸F-FDG (¹⁸F-fluorodeoxyglucose, a glucose analog radiotracer) PET-CT scan demonstrated increased uptake in the bilateral parotid glands and bilateral tonsils; with a maximum standardized uptake value (SUVmax) of 14.9 in the left tonsil, bilateral cervical lymphadenopathy with an SUVmax of 6.9, and splenomegaly measuring approximately 11 rib units with an SUVmax of 3.3 (Fig. 3). However, no typical signs of malignancy were identified. Echocardiography revealed no abnormalities, showing an ejection fraction (EF) of 0.66 and no significant valvular vegetations. Subsequently, biopsies of a lymph node (Fig. 4) and liver were performed, followed by pathological examination using in situ hybridization for Epstein–Barr virus (EBV)-encoded small RNA (Fig. 5). The findings indicated hepatitis, cholecystitis, and pancreatitis, which may be related to EBV infection.

Fig. 2.

Magnetic resonance cholangiopancreatography showing no evidence of gallstones or masses in the biliary tract and pancreatic duct (arrows indicate the common bile duct and pancreatic duct)

Fig. 3.

Positron emission tomography-computed tomography clearly demonstrating the absence of biliary or pancreatic duct obstruction, effectively ruling out gallstones and masses

Fig. 4.

Histopathological and immunohistochemical analysis of the cervical lymph node biopsy. Hematoxylin and eosin (H&E) staining reveals changes indicative of reactive hyperplasia (amplification: ×200). (CD30, CD20, CD3, TIA-1) Immunohistochemical staining demonstrates a mixed population of B cells (CD20 +) and T cells (CD3 +), with a high proliferation index (Ki-67, 50%) (amplification: CD30 × 200; CD20 × 40; CD3 × 100; TIA-1 ×200). In situ hybridization for Epstein–Barr virus-encoded RNA (EBER) is positive in numerous nuclei, confirming Epstein–Barr virus (EBV) infection (amplification: ×400)

Fig. 5.

Histopathological analysis of the liver biopsy. A Hematoxylin and eosin (H&E) staining reveals a lobular inflammatory infiltrate consistent with acute hepatitis (magnification: ×400). B In situ hybridization for Epstein–Barr virus-encoded RNA (EBER) shows scattered positive nuclei (magnification: ×400), supporting the diagnosis of Epstein–Barr-virus (EBV)-associated hepatitis

After admission, the patient received appropriate fluid management, pain relief, nutritional support, compound glycyrrhizin, ademetionine 1,4-butanedisulfonate, and acyclovir at standard doses and schedules. Due to the lack of significant clinical improvement with supportive care and antiviral therapy during the first week, and given mounting evidence of a robust systemic inflammatory response—indicated by persistent fever, marked lymphocytosis with atypical cells, and multiorgan involvement—we hypothesized that the ongoing injury was primarily immunopathological rather than caused by direct viral cytopathy. Therefore, a short course of dexamethasone (5 mg/day for 3 days) was initiated to mitigate this potential and suppress excessive immune activation. This treatment not only reduced the patient’s body temperature, but also progressively normalized ALT, AST, and bilirubin levels. Enteral nutrition was resumed following the resolution of abdominal symptoms. During treatment, the patient developed cutaneous rashes over his body, which gradually faded after several days without specific intervention, and 2 weeks after admission, plasma EBV-DNA levels were below the detection limit, and all clinical symptoms were well controlled; consequently, he was discharged from the hospital. At the last available follow-up, 2 weeks post-discharge, the patient was asymptomatic and had achieved full clinical and biochemical recovery with no signs of relapse. Throughout the diagnostic and therapeutic course, the patient was highly cooperative with all recommended procedures, including invasive biopsies and imaging studies. The chronological sequence of clinical events, diagnostic findings, and management is summarized in Table 2.

Table 2.

Timeline of clinical events, diagnostic findings, and management

Time point (hospital day)	Clinical events and symptoms	Key diagnostic findings and management
Day −7 to −1 (before admission)	High fever, chills, fatigue, dizziness, aversion to greasy food, dry cough, chest tightness	Did not seek medical attention
Day −2 (2 days before admission)	Onset of sore throat, upper abdominal pain, nausea, vomiting (twice), diarrhea, frequent urination	–
Day 1 (day of admission)	Temperature 38 ℃, jaundice, reddish/swollen pharynx, purulent left tonsil, enlarged/painless left cervical lymph nodes, right upper abdominal tenderness, questionable Murphy’s sign	Lab tests: elevated ALT (526 U/L), AST (297 U/L), TBIL (144.18 mmol/L), lipase (413.1 U/L—diagnostic for AP), atypical lymphocytes (14%) Imaging (CT): cholecystitis with gallbladder edema, splenomegaly, lymphadenopathy Initial management: fluid therapy, analgesia, nutritional support, compound glycyrrhizin, ademetionine, acyclovir
Day 7 (during hospitalization)	Development of a generalized diffuse rash	No significant improvement in symptoms with initial therapy
Day 8 (during hospitalization)	–	Initiated therapy: dexamethasone (5 mg/day) added
Day 9 onward (post-treatment)	Body temperature normalized, abdominal symptoms gradually resolved, rash faded	Follow-up Labs: liver enzymes and bilirubin levels progressively normalized
Day 14 (hospital day 14)	All clinical symptoms were well controlled	EBV-DNA (plasma): below detection limit Patient discharged
Day 28 (2 weeks post-discharge)	Asymptomatic	Outpatient reexamination: full recovery confirmed

Discussion

In this case, our patient exhibited nonspecific symptoms, including fever, sore throat, purulent pharynx, cervical lymphadenopathy, hepatosplenomegaly, and a viral rash. Laboratory tests revealed an increased lymphocyte count with 14% atypical lymphocytes, which narrowed the differential diagnosis to EBV infection, with a sensitivity of 75% and specificity of 92% [12]. Concurrently, the diagnosis of IM was confirmed by a combination of positive EBV-immunoglobulin (Ig)M antibodies, plasma EBV-DNA levels exceeding 2 × 10³ copies/mL, and positive lymph node pathology.

Next, considering the patient’s obvious aversion to greasy food, nausea, tenderness in the right upper abdomen with a possible positive Murphy’s sign, biphasic elevation of bilirubin, and subserosal edema of the gallbladder along with cholecystitis observed on abdominal CT imaging, the diagnosis of AAC could be firmly established according to current international guidelines and consensus [13, 14]. It has been reported that AAC can be caused by rare etiologies [15] and pathogens, such as Brucella [16] and fungi [17]; however, related indirect tests in this patient did not support these pathogeneses (Table 1). Therefore, the development of AAC was correlated with EBV infection. Importantly, broad-spectrum antimicrobials are recommended in the management of AAC to prevent possible secondary infections with enteric pathogens [18]. However, many patients with AAC recover smoothly without antimicrobial therapy [11], thus we did not administer antibiotics to our patient. Clinically, the high mortality rate of AAC often necessitates invasive procedures or surgical intervention, but when AAC is secondary to EBV infection, it is usually mild, has a relatively good prognosis, and does not require surgical intervention. Therefore, early identification of the underlying cause can help avoid unnecessary surgical treatment.

The diagnosis of AP requires at least two of the following criteria: (1) characteristic abdominal pain; (2) biochemical evidence of amylase or lipase levels elevated to at least three times the upper limit of normal; and/or (3) radiographic evidence of pancreatitis on cross-sectional imaging [19, 20]. Upon admission, our patient was diagnosed with AP on the basis of typical upper abdominal pain, nausea, retching, and blood lipase levels nearly seven times the normal upper limit. To further investigate the causes of pancreatitis, MRCP was performed but did not reveal any definitive pancreaticobiliary stones. PET-CT was also conducted to rule out ampullary cancer. Additionally, the patient had no history of alcohol intoxication, a normal body mass index (BMI), and nearly normal cholesterol profiles, providing no basis to suspect a lipogenic cause of pancreatitis. On the basis of serological analysis (Table 1) and the patient’s lifestyle, autoimmune and parasitic pancreatitis were also completely excluded.

Sukhchain et al. reported that patients with EBV infection rarely exhibit severe hemolytic anemia [7]. Since our patient presented with elevated bilirubin, we also investigated this possibility. However, our patient showed only a slight decrease in hemoglobin and negative Coombs test, and other examination indicators did not support the presence of hemolysis. Therefore, hemolysis was not considered in this case.

Kottanattu et al. reviewed all cases of EBV-related cholecystitis and pancreatitis reported from 1966 to 2016, identifying only 14 cases of EBV-related pancreatitis in the literature [11]. Most patients were children and adolescents, with an average age of 16 years, and the male-to-female ratio was 6:8. In their review, Kottanattu specifically emphasized that none of the patients concurrently suffered from acalculous cholecystitis and pancreatitis. To confirm that this presentation is indeed unprecedented, we conducted a focused literature search on PubMed. We queried articles published between 2016 and June 2024 using the following key terms in various combinations: “Epstein-Barr virus”, “acute pancreatitis”, and “acalculous cholecystitis”. Our search specifically aimed to identify case reports describing the synchronous occurrence of both conditions. No such cases were identified, reinforcing our conclusion that this is the first reported instance. Therefore, this report represents the very first documented case of EBV-related ACC and AP.

The precise immunopathological mechanisms underlying EBV-related multiorgan involvement, as observed in our patient, remain to be fully elucidated but can be theorized on the basis of the known biology of EBV infection. EBV primarily infects B lymphocytes, leading to a vigorous and widespread activation of the cellular immune system, particularly cytotoxic T cells and natural killer (NK) cells, which are responsible for controlling the proliferation of infected B cells [21]. This massive immune response is believed to be a double-edged sword. First, the direct cytotoxic activity of these activated immune cells against virus-infected cells can cause tissue inflammation and injury in organs where infected cells reside or where viral antigens are presented, such as the liver, lymph nodes, and spleen. Second, the extensive activation of T cells and other immune effectors results in a “cytokine storm,” characterized by a significant release of proinflammatory cytokines such as interleukin (IL)-6, IL-1, and tumor necrosis factor-alpha (TNF-α) [21]. This systemic inflammatory state can cause nonspecific damage to the vascular endothelium and organ parenchyma, potentially explaining the simultaneous injury to the gallbladder (AAC) and pancreas (AP), which may not be directly infected by the virus. In this context, AAC is often considered a consequence of systemic inflammation, sepsis, or hypoperfusion, while AP could be triggered by inflammatory mediators affecting the pancreatic microcirculation or acinar cells. The rapid clinical and biochemical improvement observed in our patient following the initiation of dexamethasone, a potent antiinflammatory and immunosuppressive agent, strongly supports the central role of this dysregulated immune response—rather than direct viral cytopathy—in driving the multiorgan pathology.

While EBV appears to be the causative agent in our patient, it is important to consider whether other viruses within the Herpesviridae family could produce a similar syndrome. Among human herpesviruses, cytomegalovirus (CMV) is most frequently associated with hepatitis, acalculous cholecystitis, and pancreatitis, particularly in immunocompromised individuals [22–24]. Varicella zoster virus (VZV) has also been implicated in cases of pancreatitis and hepatitis [25]. However, the simultaneous involvement of the liver, gallbladder, and pancreas in a previously healthy, immunocompetent adult—as observed in our case—is exceptionally rare and has not been formally reported as a triad for CMV or VZV. This distinctive multiorgan presentation, combined with our positive EBV serology, polymerase chain reaction (PCR), and biopsy results, underscores the unique role of EBV in this instance and distinguishes it from infections caused by other herpesviruses.

However, our report has limitations. Because it was relatively difficult to obtain biopsies of the gallbladder and pancreas, whether EBV exerted a direct cytopathic effect on these organs or acted through an indirect immunopathological mechanism remains unclear. Therefore, we cannot definitively rule out other potential etiological factors contributing to the development of AAC and AP in this patient.

On the basis of our case and a review of the related literature, we conclude that when AAC and AP occur in a previously healthy young patient, after excluding common causes, the possibility of EBV infection should be considered—especially in cases presenting with severe abdominal pain. Diagnostic evaluation may include testing liver and pancreatic enzyme levels, quantifying EBV-DNA copies, and performing CT imaging as appropriate. Patients with EBV infection, even those with EBV-related ACC and AP, can often be safely managed with simple antiviral and antiinflammatory regimens. The rapid clinical and biochemical improvement observed following corticosteroid administration strongly supports the central role of a dysregulated immune response in the pathogenesis of this multiorgan involvement. This rationale for immunomodulation aligns with the management of other severe viral infections in which the host immune response significantly contributes to tissue damage.

Conclusion

This report documents the first known case of simultaneous acute hepatitis, AAC, and AP in an immunocompetent adult with confirmed EBV infection. The diagnosis was established through a comprehensive evaluation involving serological testing, detection of EBV-DNA in plasma, and distinctive histopathological features. The patient exhibited rapid clinical and biochemical recovery following a brief course of dexamethasone combined with antiviral treatment, indicating that the multiorgan involvement was predominantly mediated by a vigorous immunopathological response rather than direct viral cytopathic effects. In the assessment of young, previously healthy individuals presenting with concurrent AAC and AP, clinicians should consider EBV infection in the differential diagnosis after excluding more common etiologies. Prompt identification of this uncommon presentation can facilitate appropriate therapeutic strategies, potentially avert unnecessary surgical procedures, and support the application of immunomodulatory therapy in severe cases.

Abbreviations

IM

Infectious mononucleosis

EBV

Epstein–Barr virus

AP

Acute pancreatitis

AAC

Acute acalculous cholecystitis

WBC

White blood cell

LY

Lymphocyte

CT

Computed tomography

CHOL

Total cholesterol

PET-CT

Positron emission tomography computed tomography

MRCP

Magnetic resonance cholangiopancreatography

EBER-ISH

EBV-encoded small RNA in situ hybridization

HIV

Human immunodeficiency virus

SUVmax

Maximum standard uptake value

Author contributions

HW was the attending physician for this patient and played a major role in the entire treatment process, as well as in writing the manuscript. LH and CW were also involved throughout the patient’s treatment and were therefore designated as corresponding authors. JY analyzed and interpreted the imaging data from PET-CT scans. YZ analyzed and interpreted the pathological data obtained from the biopsy. XZ contributed to the diagnosis and treatment of hepatitis. WQ participated in the final review of the article. All authors have read and approved the final manuscript.

Funding

No funding sources.

Data availability

All data supporting the findings of this study are available from the corresponding authors (LH and HW) upon request.

Declarations

Ethics approval and consent to participate

Not required.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report and the associated images. A copy of the written consent is available for review by the editor of this journal.

Competing interests

All authors declare no conflict of interests.