Introduction
Syphilis, caused by Treponema pallidum (TP), is a sexually transmitted infection with a significantly rising global incidence in recent years, particularly among HIV-infected individuals.1,2 Due to impaired immune function, HIV-infected patients are more susceptible to disease progression following TP infection, which can involve multiple organs, including neurosyphilis, ocular syphilis, cardiovascular syphilis, and visceral (including hepatic) involvement.3 In this context, when liver dysfunction occurs in HIV-infected patients, in addition to common causes such as viral hepatitis, drug-induced liver injury, and opportunistic infections, syphilis-induced liver injury (eg, syphilitic hepatitis) should also be considered. In patients with advanced HIV infection, acquired immunodeficiency syndrome (AIDS)-associated cholangiopathy, which may present with papillary stenosis or sclerosing changes of the bile ducts, is another potential cause of cholestasis.4 Biliary obstruction and hepatobiliary involvement by malignancies such as lymphoma should also be considered.5
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of the small intrahepatic bile ducts, and its pathogenesis is closely associated with immune dysregulation. Recent studies have suggested that HIV infection may participate in the development of autoimmune diseases by disrupting immune homeostasis (eg, T cell subset dysregulation and abnormal cytokine secretion). However, the direct association between HIV and PBC remains incompletely understood, and reports of their co-occurrence are rare.
In addition to HIV-associated immune dysregulation, immune reconstitution following initiation of antiretroviral therapy (ART) may be accompanied by the emergence or clinical unmasking of autoimmune disease, potentially involving immune responses to self-antigens.6 Autoimmune hepatitis during immune reconstitution and PBC–autoimmune hepatitis overlap after ART initiation have been reported, suggesting a possible relationship between immune recovery and the clinical expression of autoimmune liver disease.6,7 These observations provide a rationale for considering immune reconstitution when PBC is recognized after ART initiation, but do not establish that immune recovery causes PBC.
Therefore, in HIV-infected patients, although syphilis and PBC belong to infectious and autoimmune disease spectra respectively, both can affect the liver and cause liver dysfunction. Their symptoms, laboratory indicators, and some pathological findings may overlap, leading to missed diagnosis or misdiagnosis. In patients with active syphilis and evidence of bile duct injury, the abnormalities should not be solely attributed to infectious liver injury, and the possibility of co-existing autoimmune liver disease such as PBC should be considered.
This article reports a case of a 34-year-old male with HIV infection and active syphilis, in whom PBC was subsequently confirmed during follow-up and on repeat liver biopsy, aiming to improve the differential diagnosis of complex liver injury and to discuss the possible role of ART-associated immune reconstitution in the clinical recognition of PBC.
Case Presentation
A 34-year-old male patient was admitted to our hospital for the first time in November 2024, with a chief complaint of self-detected HIV antibody positivity for one month. He had a five-year history of syphilis without regular anti-syphilitic treatment or follow-up. Physical examination on admission revealed stable vital signs, no significant abnormalities in the heart, lungs, or abdomen, and no jaundice or liver tenderness.
Laboratory tests showed: hemoglobin 77 g/L, alanine aminotransferase (ALT) 183 U/L, aspartate aminotransferase (AST) 144 U/L, gamma-glutamyl transferase (GGT) 189 U/L, alkaline phosphatase (ALP) 137 U/L, total bilirubin (TBIL) 4.4 μmol/L, direct bilirubin (DBIL) 2.0 μmol/L, and albumin 28.4 g/L. HIV-1 antibody was positive, HIV p24 antigen was positive, CD4+ T lymphocyte count was 99 cells/μL (CD4 percentage, 4.31%), CD4+/CD8+ ratio was 0.05, and HIV viral load was 666,642 copies/mL. Additional investigations for cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection, as well as viral hepatitis, yielded negative results.
Baseline antinuclear antibody (ANA) and antimitochondrial antibody (AMA) tests were both negative.
Serological tests for syphilis revealed a positive toluidine red unheated serum test (TRUST) with titer >1:256 and a positive Treponema pallidum particle agglutination test (TPPA), indicating active syphilis. Lumbar puncture was subsequently performed, showing an opening pressure of 110 mmH2O. Cerebrospinal fluid (CSF) analysis revealed: white blood cell count 0.011 × 109/L (mononuclear cells 0.011 × 109/L, polymorphonuclear cells 0.000 × 109/L), Pandy’s test positive, chloride 130.2 mmol/L, protein 18.6 mg/L, glucose 2.72 mmol/L.
CSF TRUST was negative, TPPA was positive, and fluorescent treponemal antibody absorption (FTA-ABS) test was positive for IgG but negative for IgM. CSF cryptococcal antigen testing was negative, and India ink staining of the CSF revealed no cryptococcal organisms.
Contrast-enhanced abdominal CT (Figure 1A and B) revealed a space-occupying lesion in the right hepatic lobe, approximately 75 mm in diameter, suspicious for malignancy with lymphoma not excluded, and further liver biopsy was recommended. The initial liver biopsy (Figure 2A and B) showed: (1) severe hepatic steatosis, extensive infiltration of lymphocytes and plasma cells, and widespread perisinusoidal fibrosis; (2) non-suppurative destructive cholangitis with a reduction in small bile ducts; (3) no neoplastic lesions. The pathological opinion considered that the above findings lacked histological specificity and, in conjunction with the clinical context, were more suggestive of severe infection-related (eg, Treponema pallidum) liver injury.
Follow-up after anti-infective treatment and repeat liver biopsy if necessary were recommended. Although the bile duct injury raised the possibility of PBC, the initial pathology report explicitly stated that characteristic features of PBC were not identified. PBC therefore remained a diagnostic consideration rather than an established diagnosis at that stage.
Figure 1Dynamic changes in contrast-enhanced abdominal CT.Four-panel contrast-enhanced abdominal computed tomography montage with axial and coronal liver views.Note: (A) Initial axial CT in November 2024. (B) Initial coronal CT from the same examination. Initial imaging showed a right hepatic lesion approximately 75 mm in diameter, suspicious for malignancy with lymphoma not excluded.
(C) Follow-up axial CT in July 2025. (D) Follow-up coronal CT from the same examination. Follow-up imaging after ART and anti-syphilitic treatment showed significant regression of the right hepatic lesion, with possible splenomegaly.
Panels are arranged chronologically, with initial imaging in the upper row and follow-up imaging in the lower row.Figure 2Pathological findings of the two liver biopsies.Composite figure: 4 micrographs (A-D), 2 H&E stained with inflammation, 1 IHC showing cytokeratin 7 biliary.Note: (A) Initial liver biopsy in November 2024, hematoxylin and eosin (HE) stain, 10×, showing marked steatosis and inflammatory infiltration. The red box marks a representative inflammatory region. (B) Higher-magnification view of the initial biopsy, HE stain, 20×.
The red arrow indicates an inflammatory infiltrate. The initial biopsy report described non-suppurative destructive cholangitis and reduced small bile ducts, but the findings were not considered diagnostic of primary biliary cholangitis (PBC) at that stage. (C) Repeat liver biopsy in August 2025, HE stain, 400×.
The red arrow marks an inflamed portal region. The repeat biopsy report described chronic cholangitis with irregular small bile ducts and mild ductular reaction. (D) Repeat liver biopsy in August 2025, cytokeratin 7 (CK7) immunohistochemistry.
The red arrows highlight CK7-positive biliary structures. Interpreted together with the clinical findings and follow-up antimitochondrial antibody positivity, the repeat biopsy supported the diagnosis of PBC stage 1–2.
In summary, the diagnoses of HIV infection and active syphilis were confirmed. Considering the liver dysfunction, liver biopsy findings suggestive of TP infection-related liver injury, and subsequent treatment response, syphilis-associated liver injury was considered a presumptive diagnosis. Antiretroviral therapy (ART) was initiated two days after admission in November 2024 with bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy).
Six days later, albuvirtide was added with the patient’s agreement and administered on three consecutive days, followed by once-weekly administration, while Biktarvy was continued. Aqueous penicillin G (5.6 million IU intravenously every 6 hours) was administered for 14 days as anti-syphilitic treatment, followed by consolidation therapy with benzathine penicillin G (2.4 million IU intramuscularly once weekly for three doses). During hospitalization, supportive treatment for liver injury included bifendate (25 mg), silybin meglumine (100 mg), magnesium isoglycyrrhizinate (200 mg), and glutathione (2.4 g).
Nutritional support was also provided, and liver enzymes and intrahepatic lesions were dynamically monitored. During hospitalization, liver enzymes gradually decreased and normalized. The patient was discharged in December 2024, after clinical improvement.
Follow-up continued after discharge. Seven months later, repeat testing showed: GGT 60 U/L, ALP 70 U/L, CD4+ T lymphocyte count 221 cells/μL, HIV viral load below the lower limit of detection (target not detected, TND), and persistently positive TRUST (titer >1:256), with liver enzymes remaining within normal range. This was the latest available TRUST result; both the pretreatment and follow-up results were reported as >1:256 rather than exact endpoint titers.
Autoantibody testing revealed positive ANA at a titer of 1:320 and positive AMA at a titer of 1:320. Contrast-enhanced abdominal CT (Figure 1C and D) showed that the right hepatic lesion had significantly regressed compared to previous imaging, with possible splenomegaly. Follow-up AMA positivity, together with the initial findings of non-suppurative destructive cholangitis and reduced small bile ducts, strengthened the suspicion of PBC.
Given that the initial histological assessment had not established PBC, a repeat liver biopsy was performed in August 2025 to further clarify the biliary pathology. Pathological examination (Figure 2C and D) revealed: on hematoxylin and eosin (HE) staining (400×), expanded portal tracts with moderate mixed inflammatory cell infiltration predominantly composed of mononuclear cells, frequent plasma cells and eosinophils, presence of small bile ducts with irregular morphology, and mild ductular reaction, suggesting chronic cholangitis. Cytokeratin 7 (CK7) immunohistochemical staining showed degeneration of small bile ducts and a mild ductular reaction around the portal tracts.
The repeat biopsy showed chronic cholangitis and was interpreted, in conjunction with the clinical findings, as consistent with PBC stage 1–2. These findings, together with follow-up AMA positivity, supported the final diagnosis of PBC. Ursodeoxycholic acid therapy was subsequently initiated for PBC.
Discussion
HIV and syphilis co-infection has become increasingly common worldwide in recent years, particularly among men who have sex with men.8 Due to impaired immune function in HIV-infected individuals, the clinical manifestations of syphilis can be atypical or even subclinical, with some patients lacking classic features such as rash or lymphadenopathy and instead presenting with visceral involvement or laboratory abnormalities as the initial manifestation.9,10 The patient in this case did not exhibit typical secondary syphilitic rash or obvious peripheral lymphadenopathy; instead, liver dysfunction and a space-occupying lesion in the right hepatic lobe were the main clues, increasing the difficulty of early identification and etiological diagnosis. This suggests that in the context of HIV infection, for unexplained liver injury, particularly in patients with high-titer positive syphilis serology, syphilis-related liver injury should be included in the routine differential diagnosis.
Syphilitic hepatitis is relatively rare in clinical practice and is more commonly seen in secondary or latent syphilis. Its histological changes are usually non-specific and may include portal tract or hepatic lobular inflammatory cell infiltration, plasma cell infiltration, bile duct injury, cholestasis, and varying degrees of fibrosis.8,11 A previous systematic review showed that the most common clinical manifestations of syphilitic hepatitis in adults are rash, followed by fatigue, anorexia, and jaundice; laboratory findings predominantly show a cholestatic or mixed pattern of liver injury, with elevated ALP and GGT being more prominent, while detection of spirochetes in liver tissue may be challenging.11 Although Treponema pallidum was not detected in liver tissue, the positive syphilis serology, non-specific inflammatory biopsy findings, and improvement after treatment were compatible with a syphilis-associated component of the liver injury. However, ART and supportive care were administered concurrently, and PBC provided another potential explanation for the bile duct injury.
Therefore, syphilis-associated liver injury remained presumptive, and the treatment response alone did not establish a syphilitic etiology.
Alternative infectious and drug-related causes also warrant consideration. The reported investigations for CMV and EBV infection and viral hepatitis were negative, but these results should not be interpreted as excluding all opportunistic causes of hepatic injury. Liver biochemical abnormalities were documented before initiation of bictegravir/emtricitabine/tenofovir alafenamide, with albuvirtide added subsequently; this chronology argues against ART-related hepatotoxicity as the cause of the initial liver abnormalities.
However, it does not exclude a possible contribution of later antiretroviral or concomitant medication exposure to the subsequent biochemical course.
Persistent nontreponemal seroreactivity can occur after treatment, particularly in individuals treated later in the course of infection.12 The patient’s five-year history of syphilis provides a possible context for this finding, but does not establish its cause. Both pretreatment and follow-up TRUST values were reported as >1:256, preventing assessment of the magnitude of any titer change or whether a fourfold decline had occurred. Therefore, these results alone do not establish a serofast state or treatment failure, and the reason for the persistently high reported result remains uncertain.
It is important to emphasize that not all liver enzyme abnormalities in this case could be explained solely by active syphilis. The initial liver biopsy already revealed non-suppurative destructive cholangitis and reduced small bile ducts, indicating definitive bile duct injury. Repeat autoantibody testing seven months later showed positive AMA (titer 1:320), providing further serological support.
The repeat liver biopsy in August 2025 ultimately confirmed the diagnosis of primary biliary cholangitis stage 1–2, forming a relatively complete diagnostic closure for PBC. The patchy distribution of PBC-related lesions can limit their representation in a needle biopsy.13 Sampling variability may therefore have contributed to the initial assessment being non-diagnostic for PBC, although the available reports do not establish that characteristic lesions were missed in this patient. The early core change in PBC is immune-mediated injury and destruction of the small intrahepatic bile ducts, and serological antibodies, particularly AMA, may appear at different time points and are not necessarily synchronized with histological changes.14 Therefore, this case suggests that in the context of infection, when pathology already reveals evidence of bile duct injury, PBC or other autoimmune cholangiopathies should not be easily excluded simply because autoantibodies are negative at a single time point.
For patients with suspected PBC, dynamic monitoring of autoantibodies and repeat liver biopsy when necessary can improve diagnostic accuracy.
Immune reconstitution after ART may involve responses against self-antigens and has been proposed as a setting for the emergence or clinical unmasking of autoimmune liver disease.6 O’Leary et al reported autoimmune hepatitis during immune reconstitution, while Caplan et al described biopsy-confirmed PBC–autoimmune hepatitis overlap following ART initiation.6,7 A subsequent series documented autoimmune hepatitis in 13 patients with HIV in the setting of virological suppression and restored immune status.15 These reports provide relevant clinical precedents, but concern autoimmune hepatitis or overlap disease rather than demonstrating that immune reconstitution causes isolated PBC.
This case documents the coexistence of active syphilis and PBC, but does not establish a causal relationship between them. Following ART initiation, the CD4+ T lymphocyte count increased from 99 to 221 cells/μL and HIV viremia declined, providing a context of immune recovery in which PBC was subsequently recognized. Immune recovery may have contributed to the clinical manifestation of autoimmune liver disease, but this remains a hypothesis.
Bile duct injury was already present on the initial biopsy, and previously unrecognized PBC identified through continued evaluation remains an alternative explanation. The sequence of diagnoses should therefore not be equated with disease onset or interpreted as evidence that syphilis or immune reconstitution caused PBC.
This case illustrates the diagnostic challenge of recognizing PBC in a young man with HIV when concurrent syphilis offers an apparent explanation for liver abnormalities. Its clinical relevance lies in showing that an infectious diagnosis should not preclude evaluation for coexisting autoimmune cholangiopathy when bile duct injury is present.
This case has several limitations. First, syphilis-associated liver injury remained presumptive. The clinical and histological findings and improvement after treatment suggested a possible association but did not provide direct etiological confirmation of hepatic involvement by Treponema pallidum.
Second, there was a lack of continuous histological follow-up between the initial liver biopsy and the subsequent repeat biopsy, making it difficult to more precisely determine the dynamic evolution of the biliary lesions and the relative contributions of infectious and autoimmune factors at different time points.
This case illustrates the coexistence of active syphilis and PBC in a man with HIV infection, while syphilis-associated liver injury remained presumptive. Neither coexistence nor the sequence of diagnoses establishes that syphilis caused or exacerbated PBC. The recognition of PBC during immune recovery after ART raises the possibility that immune recovery contributed to its clinical recognition, but a causal role cannot be established from this single case.
Clinically, this case suggests the importance of considering coexisting autoimmune liver disease when liver abnormalities or bile duct injury cannot be adequately explained by infection alone, including during immune recovery. Follow-up integrating liver biochemistry, autoantibody testing, imaging, and repeat liver biopsy when clinically indicated may help clarify the diagnosis and guide individualized management.