Case report
A 49-year-old male with a history of hypertension presented to the hospital complaining of right upper quadrant abdominal pain with associated chills, jaundice, and darkening urine. He denied taking any new medications or supplements, recent illnesses, travel, illicit drug use, body piercing, or family history of liver disease. Vital signs were normal on admission. Blood work revealed total bilirubin (Tbili) of 19.9 mg/dL, direct bilirubin of 15.5 mg/dL, alkaline phosphatase (ALP) of 147 U/L, aspartate aminotransferase (AST) of 1,280 U/L, alanine aminotransferase (ALT) of 1,652 U/L, and international normalized ratio (commonly referred to as INR) of 1.6. Abdominal imaging was unremarkable. Extensive work-up for common infectious, drug-related, and inherited causes of hepatitis was unrevealing. Serology was positive for antinuclear antibodies (ANA) with titer of 1:160. Anti-smooth muscle antibodies (commonly known as ASMA), antibodies against liver-kidney microsome type 1 (i.e. anti-LKM-1), antibodies against soluble liver antigen/liver-pancreas protein (i.e. anti-SLA/LP) were not detected. Immunoglobulin G (IgG) was normal at 1,301 mg/dL (reference range: 700–1,600 mg/dL). A liver core needle biopsy revealed acute hepatitis with inflammatory infiltrate, severe lobular inflammation, ballooning and degeneration of hepatocytes (Fig. 1). Given the severity of the patient’s liver injury and lack of clinical improvement, he was evaluated for liver transplant. Incidentally, rapid plasma reagin (RPR) was reactive, with a 1:2 titer and confirmed with positive fluorescent treponemal antibody absorption test (FTA-ABS). Subsequently, immunostaining of the liver biopsy revealed spirochetes (Fig. 1), confirming the diagnosis of SH. The patient was treated for late latent syphilis and SH with intramuscular penicillin G benzathine (benzylpenicillin). He experienced substantial clinical and biochemical improvement (AST of 350 U/L, ALT of 675 U/L, Tbili of 4.6 mg/dL) within days of the first dose, was discharged, and completed the antibiotic course as an outpatient.
The patient’s follow-up blood work showed continued improvement; however, on an office visit at 10 weeks following discharge, he presented with worsening jaundice and generalized pruritus. Liver markers were significantly elevated, with Tbili of 10.3 mg/dL, direct bilirubin of 7.02 mg/dL, AST of 1,007 U/L, ALT of 1,000 U/L, ALP of 223 U/L and INR of 1.6. He was admitted to the hospital for further evaluation of worsening liver disease. Serology revealed elevated IgG of 2,275 mg/dL and atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) with titer of 1:320, along with ANA titer of 1:160 (consistent with prior serology). ASMA, anti-SLA/LP, anti-LKM-1, cytoplasmic-ANCA (c-ANCA) and p-ANCA were undetected. Acute viral hepatitis panel was negative. RPR was still positive, with a titer of 1:2, along with positive FTA-ABS. Liver biopsy revealed severe acute hepatitis with bridging fibrosis and interface activity; this time, immunostaining for spirochetes was negative (Fig. 2). The presence of autoantibodies, hypergammaglobulinemia, absence of viral markers, and interface activity on biopsy translated to high scores on the revised and simplified AIH scoring system, indicating a diagnosis of AIH. The patient was treated with systemic glucocorticoids, producing marked improvement in liver function abnormalities and further supporting the diagnosis of AIH. He was discharged on oral prednisone, and outpatient follow-up lab work revealed AST of 90 U/L, ALT of 139 U/L, Tbili of 2.5 mg/dL and INR of 1.1. The prednisone dose was tapered and the patient continued to have sustained improvement.
Discussion
We report a unique case of biopsy-proven SH, which improved with antibiotic therapy but subsequently triggered an immunogenic response suggestive of AIH, with recovery after glucocorticoid therapy.
AIH is an inflammatory disease caused by autoimmune-mediated destruction of the liver parenchyma, with resultant chronic inflammation and fibrosis.1 It is characterized by elevated aminotransferases, interface hepatitis histologically and hypergammaglobulinemia, in particular IgG, along with the presence of autoantibodies against liver autoantigens, including ANA, ASMA, anti-LKM-1, anti-SLA/LP and seldom atypical p-ANCA.2,3
Clinical presentation of AIH ranges from asymptomatic elevation in aminotransferases to fulminant hepatitis, or as indolent inflammation progressing to cirrhosis, hepatocellular carcinoma and death.3 A numerical scoring system established by the International Autoimmune Hepatitis Group (commonly known as IAIHG) devised diagnostic criteria for AIH based on biochemical (hypergammaglobulinemia with elevated IgG), serologic (serum autoantibodies) and histologic (interface hepatitis) findings, with exclusion of alternate etiology of liver disease.4
Though the pathogenesis of AIH is not completely understood, evidence suggests that it involves an interplay of genetic predisposition, molecular mimicry and regulatory T lymphocytes. Immune reactions against liver antigens not adequately contained by impaired regulatory T cells are believed to be the main contributors to AIH.5
Environmental factors associated with AIH include hepatitis A, B and C viruses, measles virus, varicella zoster virus, cytomegalovirus and Epstein-Barr virus. Viruses with hepatic tropism have the potential to cause AIH secondary to inflammation and subsequent cytotoxic immune response targeting the pathogen, leading to an abnormal T cell response.1 The only known bacterial genus associated with AIH is Rickettsia, as one of its proteins drives an autoimmune response mediated by CD4+ T cells.3
Syphilis is a sexually transmitted infection caused by Treponema pallidum, a spirochete. Its presentation is characterized by stages, including primary, secondary, latent, and tertiary syphilis.6T. pallidum is a non-hepatotropic pathogen that causes hepatitis.7 Interestingly, liver damage in syphilis often occurs early in the disease course and is often misdiagnosed.6
Clinical presentations of SH are nonspecific and variegated. Patients may present with low-grade fever, abdominal pain, sore throat, weight loss, arthralgia, myalgia, jaundice or maculopapular rash on the trunk, palms and soles.7 Histologically, SH manifests as inflammatory bile duct infiltration, hepatocellular periportal necrosis, hepatic granulomas, and visualization of spirochetes by immunogenic or Warthin-Starry staining.7,8 Serologically, SH presents with elevated ALP, gamma-glutamyl transferase and abnormal aminotransferases, with disproportionate elevation of ALP due to pericholangiolar inflammation.6,8 Initial screening is accomplished by RPR and venereal disease research laboratory tests.9 Positive FTA-ABS and visualization of spirochetes on liver biopsy confirms the diagnosis of SH; however, spirochetes are only visible by staining in up to half of patients with SH.10
Our patient initially presented with acute hepatitis of unknown etiology, and blood work incidentally revealed positive RPR and confirmatory FTA-ABS. Visualization of T. pallidum on liver biopsy confirmed the diagnosis of SH, and the patient responded well to a course of benzylpenicillin. On the patient’s subsequent admission weeks later, evidence pointed towards AIH as the cause of acute liver injury, with elevated IgG, positive ANA and atypical p-ANCA titers, and interface hepatitis on liver biopsy, a hallmark finding of AIH. Immunostaining was negative for T. pallidum, which excluded the diagnosis of recurrent or incompletely treated SH.
Drug-induced Liver Injury (DILI) secondary to penicillin G benzathine was investigated as a potential cause of liver injury in the second presentation. Many medications and herbal supplements have been implicated in DILI; however, first-generation penicillins are rarely implicated.11 Clinically significant penicillin-induced DILI is usually secondary to a severe hypersensitivity reaction, or presents as delayed cholestatic hepatitis, which is more commonly associated with broad spectrum penicillins.12 There is one reported case of DILI associated with benzylpenicillin, in which a patient treated with high dose, intravenous benzylpenicillin developed asymptomatic elevation in aminotransferases and peripheral eosinophilia 3 weeks after treatment initiation, which rapidly resolved upon changing the antibiotic to a cephalosporin.13 Our patient presented with acute hepatitis 9 weeks after completion of treatment of SH with intramuscular benzylpenicillin, which is later than would be expected in DILI, and, in contrast to the case presented above, did not exhibit any peripheral eosinophilia. Given the strong supporting evidence for AIH, differences from the reported case of benzylpenicillin-associated DILI, and rarity of DILI associated with first generation penicillins, it is unlikely that our patient’s acute liver injury was secondary to benzylpenicillin-induced DILI.11
After review of the literature, we believe this is the first reported case of AIH presenting after treatment of SH. This case was unique in that it demonstrated a paradigm shift in pathologic etiology of hepatitis from infection to autoimmunity. Exactly how this shift occurred and whether the two processes were interrelated is still in question.
Various autoimmune diseases, including AIH, are known to manifest following the resolution of an infection. Molecular mimicry describes a phenomenon where a pathogen evades immune surveillance due to the structural similarities that its proteins share with the host’s self-antigens. However, once the pathogen is detected and eliminated by the host immune system, the sensitized immune system may go on to attack the host’s self-antigens that shared similarities with the pathogenic epitopes, resulting in autoimmunity.14 This phenomenon is commonly described in relation to viral pathogens with regards to AIH; however, bacteria, specifically Rickettsia species, have been shown to trigger AIH via molecular mimicry. Using molecular homology modeling and docking methods, researchers identified a statistically significant structural similarity between a region of the SLA/LP protein recognized by CD4+ T lymphocytes, and a region of a Rickettsia species protein called ‘surface antigen PS-120’. This constitutes supporting evidence that CD4+ T lymphocytes that recognize the self-antigen SLA/LP can cross-react with foreign Rickettsia species’ antigens, inciting a molecular mimicry event that may result in the onset of AIH.15
Several studies have investigated the immunopathologic mechanisms that link T. pallidum and autoimmunity. It has been established that syphilis triggers a humoral autoimmune response that results in the production of autoantibodies against several targets.16 Syphilis has also been shown to effect cell-mediated immunity. One study demonstrated a depression in total T lymphocytes and subpopulations of T lymphocytes at specific stages of infection, resembling hematologic patterns observed in patients with systemic lupus erythematosus as well as other autoimmune diseases associated with increased autoantibody production.17
In another study, researchers observed ANA titers in patients with syphilis at 12 months after they had been appropriately treated for the infection. They observed ANA titer of 1:160 or above in all patients (10/10) who did not respond appropriately to treatment, compared to only 5.3% (2/38) of patients who were serologically cured. Researchers hypothesized that the destruction of host tissues in genetically susceptible individuals led to the breakdown of immune tolerance and production of autoantibodies.18
A molecular database query investigating structural similarities between moieties on T. pallidum proteins and liver antigens has not yet been reported in the literature. Such a study would elucidate whether a molecular mimicry event could explain the association between SH and AIH as it presented in this case, and help determine if SH and its treatment are risk factors for AIH.