Atypical case of syphilitic hepatitis

Abstract

A 31-year-old immunocompetent, heterosexual man with no relevant medical history presented with 1 week of jaundice, abdominal pain, cough and headache. Examination revealed scleral icterus, right upper quadrant tenderness and hepatomegaly. Initial investigations revealed hyperbilirubinaemia and elevated transaminases. Serum studies were positive for antinuclear antibodies, antimitochondrial antibodies, and herpes simplex virus IgM. Despite being started on intravenous acyclovir, his bilirubin and transaminase levels continued to rise. He was subsequently tested for syphilis given his maculopapular rash on the soles of his feet and it returned positive. He improved clinically with the initiation of penicillin. In this case, we will discuss the presentation, diagnosis and treatment of syphilitic hepatitis.

Background

This report describes an unusual presentation of hepatitis associated with underlying syphilis infection, its diagnosis and subsequent treatment. We hope that the contribution to the knowledge of both typical and atypical patterns of syphilitic hepatitis will assist clinicians in diagnosis when the cause of hepatitis is unclear or confounded by multiple positive tests.

Case presentation

A 31-year-old immunocompetent, heterosexual man with no known medical history presented to the emergency department prior to the COVID-19 pandemic with a 1-week history of worsening jaundice, cough, headaches and abdominal pain. On examination, he was noted to have whole-body jaundice, right upper quadrant tenderness and hepatomegaly. The neurological examination was normal with no signs of meningitis or encephalopathy. He had multiple tattoos, which he received in a friend’s basement several years ago. Further inquiry revealed no alcohol use within the last 10 years, no history of intravenous drug use, no family history of autoimmune or liver disease, no recent travel. He had one female sexual partner during the last 2 years, last intercourse 6 months prior to presentation, and denied any sex with male partners. He had no history of syphilis or known syphilis contacts. His urine drug screen was negative, and his acetaminophen level was undetectable. He had a 13-year smoking history but quit cigarettes 1 year ago and started vaping.

A chest X-ray was obtained, which was unremarkable. Ultrasound showed patency of the portal and hepatic vasculature as well as the bile ducts. Initial laboratory evaluation revealed a total bilirubin level of 15.6 mg/dL (normal <1.1; direct bilirubin 12.8 mg/dL, normal <0.3), alkaline phosphatase (ALP) of 181 U/L (normal <98), alanine aminotransferase (ALT) of 518 U/L (normal <45), and aspartate aminotransferase (AST) of 829 U/L (normal <43). Lipase was 8 U/L (normal 13–60) and gamma-glutamyl transferase (GGT) was 60 U/L (normal 8–61). INR was 1.2.

The patient was admitted to the hospital, where his transaminases and bilirubin levels continued to rise. He started having problem of worsening cough and developed chills and night sweats. Herpes simplex (HSV) IgM was positive with negative IgG for HSV1 and HSV2. Given his positive HSV IgM, he was started on 900 mg intravenous acyclovir every 8 hours as an empiric treatment for suspected HSV hepatitis. Despite the high dosing of acyclovir, his bilirubin and transaminases continued to rise (figure 1).

Figure 1.

Trends in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP).

On the sixth day of his admission, he developed a confluent maculopapular rash that covered his back and trunk, arms and legs, including his palms and soles (figure 2). Testing for syphilis revealed a positive rapid plasma reagin (RPR) titre of 1:128 and a reactive fluorescent treponemal antibody absorption test. A transjugular liver biopsy obtained 1 day after he received penicillin, showed inflammation consistent with syphilitic hepatitis. In the days following penicillin administration, the patient’s transaminases began trending down for the first time since his admission, and he reported a profound improvement in his symptoms. Because the patient’s headaches resolved, and his neurological examination was normal, a lumbar puncture was not performed.

Figure 2.

Patient’s body appearance and skin findings. (A) Erythematous macular rash confluent over the neck and back. (B) Rash present on the chest and antecubital areas. (C) Presence of targetoid macules on the soles of the feet. (D) Maculopapular rash noted on the palms.

Investigations

Additional microbiology and serology tests

Serological testing confirmed immunity to hepatitis A and hepatitis B. Testing for hepatitis C by both antibody and PCR were negative, and HIV, Epstein-Barr virus (EBV), cytomegalovirus, adenovirus and varicella-zoster were negative. HSV1 and HSV2 were not detected by PCR in the patient’s serum. Additional rheumatological testing was positive for antinuclear antibodies (ANA) in a speckled pattern at 1:640 dilution as well as antimitochondrial antibody (anti-F actin). The patient’s total IgG was elevated at 1944 (normal 700–1600). Testing for antismooth muscle and antineutrophil cytoplasmic antibodies was negative. Ceruloplasmin was within normal limits and alpha-1 antitrypsin was elevated at 221 (normal <200).

Liver biopsy

A transjugular liver biopsy was obtained to exclude other possible aetiologies of hepatitis given his unclear clinical presentation. The biopsy demonstrated portal and lobular hepatitis, intact bile ducts with reactive changes, mild cholestasis and hepatocyte necrosis with diffuse mononuclear inflammation. HSV-1 and HSV-2 immunohistochemical stains were both non-reactive, and spirochetes were not visible with a Steiner stain.

Differential diagnosis

Initially, HSV hepatitis was suspected due to the presence of HSV IgM. The presence of autoantibodies suggested autoimmune hepatitis, but due to the lack of personal or family history, as well as the high fatality of HSV hepatitis, treatment with intravenous acyclovir was initiated empirically. Since the patient had no improvement on acyclovir and HSV PCR was pending, we continued to search for other aetiologies. The subsequent development of maculopapular rash involving the palms and soles prompted RPR testing for syphilis and FTA antibody testing, which were both positive. Other aetiologies of his hepatitis were excluded by the liver biopsy. The patient was staged with secondary syphilis given the characteristic rash. Because the patient presented with headache, neurosyphilis was a necessary consideration. In this case, no lumbar puncture was obtained because the headaches had resolved after the diagnosis of syphilis was confirmed, and the patient had a normal neurological examination.

Treatment

The patient was started on 2.4 million units of intramuscular penicillin G benzathine given weekly, and an immediate, rapid improvement in the patient’s liver injury was noted. Although one dose is sufficient to treat secondary syphilis, three weekly doses were prescribed due to the unusual pattern of hepatitis, particularly the uncertain presence of gummatous disease in the liver.

Outcome and follow-up

The patient was discharged with clinical improvement in his rash, abdominal pain and transaminase levels. He was urged to contact his partner to notify her of the diagnosis of syphilis so that she could receive treatment. Based on the patient’s lack of high-risk sexual behaviour, he did not receive HIV PrEP, although this could be offered to patients diagnosed with early syphilis. He was discharged with hepatology follow-up in 4 weeks and infectious disease follow-up in 3 months, with a plan for weekly liver function tests and two more injections of intramuscular penicillin weekly. After discharge, the patient was lost to follow-up as he did not show up to his scheduled gastroenterology outpatient appointments during the following 3-month period.

Discussion

Syphilis is often considered in the context of painless genital ulcers, lymphadenopathy, cutaneous manifestations and in high-risk populations. Most reviews note skin involvement in approximately 90% of cases and abnormal liver enzymes in approximately 10%.¹ Hepatitis is an uncommon manifestation of syphilis and often presents with a rash, appetite changes, hepatomegaly and icterus.² Laboratory findings often follow a cholestatic pattern with marked elevations in ALP and GGT and milder elevations in aminotransferases.^2–4 This case is remarkable because ALP elevations were mild while elevations in AST and ALT predominated. Furthermore, with multiple positive findings across this patient’s serology testing, several possible diagnoses competed before testing for syphilis was even considered. It may appear difficult to exclude other potential causes of his hepatitis, but the diagnosis of syphilitic hepatitis was ultimately made based on the dramatic clinical and laboratory improvement seen after the administration of penicillin. Furthermore, the biopsy findings in this patient were consistent with a recent systematic review of 55 liver biopsies taken from patients with syphilitic hepatitis.²

HSV hepatitis was initially suspected due to the patient’s reactive HSV IgM, and he was started on empiric acyclovir without improvement. Although HSV is typically associated with hepatitis in immunocompromised or pregnant patients, cases have been reported in immunocompetent people.^5–8 Our patient’s pattern of transaminitis with only mild ALP elevations at first seemed consistent with HSV hepatitis.⁵ However, isolated HSV IgM does not help diagnose HSV, and practice guidelines do not endorse its use to guide clinical decision-making.⁹ Several features of our patient’s later hospital course suggest against HSV as the aetiology of his liver disease. The existing literature on HSV hepatitis often notes the resolution of transaminitis within days of initiating acyclovir therapy.^{10 11} In this case despite several days of acyclovir treatment, the transaminitis continued to worsen until the penicillin was administered, and the patient’s HSV PCR returned negative a few days after the sample was obtained (figure 1). Furthermore, our patient lacked other characteristic features of HSV hepatitis such as leucopenia, thrombopenia, encephalopathy or coagulopathy.^{5 12}

Our patient had multiple positive autoantibodies. There is evidence that both ANA and AMA can be falsely positive in patients with bacterial infections, including syphilis.^{13 14} False-positive serologies for autoimmune antibodies have also been reported in viral infections such as EBV.¹⁵ It seems more likely that these results were falsely positive due to the active infection with syphilis.

In 2017, the CDC reported a rate of syphilis infection in 9.5 per 100 000 people, representing a 10.5% increase when compared with the previous year.¹⁶ Factors associated with syphilis include multiple or anonymous sex partners, illicit drug use or incarceration.¹⁷ In this case, the transmission was likely from the patient’s sexual activity despite the patient lacking high-risk sexual behaviours. Given the increased incidence and availability of a simple and effective treatment, syphilis must be suspected as a possible cause in patients with abnormal liver enzymes and non-specific symptoms.

Learning points.

• Consider syphilis in the differential diagnosis of immunocompetent, heterosexual patients who present with acute hepatitis.

• Syphilitic hepatitis may present with a hepatocellular pattern with predominant elevation of aminotransferases, rather than the characteristic cholestatic pattern.

• Recognise that HSV IgM alone is not sufficient to diagnose active HSV infection and should not guide clinical management. Autoantibodies such as ANA and AMA may be falsely elevated due to underlying infections.