When the Sailor’s Handshake Fails: A Case of Syphilitic Hepatitis in an HIV Patient With Nonspecific Liver Biopsy and Atypical Cutaneous Presentation

Secondary syphilis has variable systemic manifestations, impersonating the presentation of more common pathologies, deceiving clinicians, and creating a difficult-to-diagnose patient. The case discussed combines hepatic syphilis with an uncommon syphilitic dermatologic presentation in a patient with HIV and a history of hepatitis A and B. Due to the challenge of diagnosis, the relative ease of confirming the diagnosis with serological assays, and reversibility of hepatic injury, the inclusion of syphilitic hepatitis on a differential diagnosis of hepatitis is warranted.


Introduction
Syphilitic hepatitis is an uncommon, potentially underreported manifestation of early and secondary syphilis. Spirochete dissemination has variable systemic manifestations, including hepatic, gastrocolic, renal, and dermatologic injury [1]. Inflammatory response to spirochetes may be responsible for pathology, as evidenced by lesion histopathology displaying various inflammatory infiltrates [2]. The degree of injury and clinical presentation may be influenced by individual immune-responsiveness, specifically augmented responses in HIV patients [3]. Hepatic pathology is more easily observed in congenital syphilis than acquired syphilis [4]. Acquired syphilis typically displays the characteristic non-pruritic maculopapular rash accompanied by signs of hepatic injury on liver function tests, most notable elevations of alkaline phosphatase (ref: 35-145 U/L). This case study combines an uncommon presentation of intensely pruritic and atypical dermatologic symptoms, comorbid HIV infection, and a liver biopsy negative for spirochetes.

Case Presentation
The patient is a 48-year-old male with a past medical history of HIV on elvitegravir, cobicistat, emtricitabine, and tenofovir combination pill (GENVOYA) (inconsistently adherent), polysubstance use disorder (crystal methamphetamine, marijuana, tobacco), ureteral stent placement for recurrent kidney stones and glaucoma who presented to the emergency department (ED) with a one-month history of recurrent skin abscesses and pruritis most significant on the right shin. He also complained of generalized weakness and decreased oral intake. One month prior to presentation, the patient's CD4 count was 398 with an undetectable HIV viral load.
Dermatologic exam of the distal left second and fourth digit found painful ulcerations without purulent discharge and separation of the nail bed on the second digit ( Figures 1A, 1B). Multiple healing lesions and raised, violaceous nodules with sporadic lichenification were present on bilateral lower extremities ( Figure  1C). Similar lesions were discovered on the scalp, trunk, and upper extremities. Notably, the palms and soles were free from cutaneous pathology. The perianal region displayed few pedunculated papules. Right anterior tibial cellulitis with a small abscess (+methicillin-resistant Staphylococcus aureus) was drained at the bedside and treated with trimethoprim/sulfamethoxazole. No Osler nodes, splinter hemorrhages, or jaundice were visualized. Liver function tests (LFT) continued to rise during admission without an obvious etiology. Zenith values for liver enzymes were ALP 1,143 U/L, total bilirubin 4.1 mg/dL, AST 158 U/L, and ALT 228 U/L. The patient did not have any abdominal complaints. Imaging of the abdomen by CT scan failed to delineate an etiology, prompting a liver biopsy (Figures 2, 3   There is no record of the patient receiving the third dose, and they were lost to follow up.

Discussion
While hepatitis remains an uncommon manifestation of syphilis, hepatic involvement has been a known sequela since 1585, as described by Paracelsus [3]. Kellock and Laird noted in 1956 that the diagnosis was predominantly clinical and supported by positive serological evidence, response to treatment, and lack of evidence for alternate etiologies [5].  (4) clinical improvement of LFTs following initiation of pharmacologic therapy. Liver function tests often present a cholestatic pattern more often than hepatocellular, notably with significant elevation in ALP [2,3,6]. However, patients can present with variable liver function tests and physical presentations, further challenging diagnosis and requiring a high index of suspicion (  Most case reports reviewed described rashes typical of syphilis and laboratory findings suggestive of syphilitic hepatitis, specifically marked elevation in ALP. Liver biopsy findings were variable when performed. Pruritic rashes were described by Baveja et al. [7] and Cordoso et al. [10].
Hepatic dysfunction in the context of HIV may be related to increased rates of coinfection with hepatotropic pathogens, the pathophysiology of which may be related to immune deficiency permissive of pathogenic dissemination [3]. While the patient discussed was reactive for both hepatitis A and B during admission, his presentation suggested an alternate etiology for serologic findings based on medical history. Hepatitis reactivity was discovered on prior outpatient workups without concomitant elevations in LFTs. Further, liver enzymes were not elevated while adherent to GENVOYA, an antiretroviral with known hepatotoxicity. As previously reported [1], due to the cross-reactivity of specific antibodies with the T. pallidum membrane, some diagnostic workup, including anti-smooth muscle antibodies, may be falsely elevated and will return to normal upon syphilis-targeted therapy. Our patient met previously outlined criteria by combining serological evidence of hepatic injury, infection with syphilis, exclusion of alternate etiologies, and response to treatment. A biopsy is not required to confirm the diagnosis of syphilitic hepatitis, especially with a positive response to treatment, because cellular changes are variable, and spirochetes may not be visible [2,3,6]. Liver biopsy for our patient was suggestive of mixed inflammation with patchy necrosis and negative for granulomas and spirochetes ( Figure 2). Other cases reported granulomas and inflammatory cells in portal tracts and hepatic lobules [3][4][5][6][7][8]. Our case presented a patient with primarily dermatologic complaints whose evaluation led to the diagnosis of syphilitic hepatitis. Rashes and dermatologic lesions are more often reported as painless and non-pruritic [1-4, 8, 9]. Sparse cases reported pruritic rashes but not subjective pain [4,10]. Interestingly, immunohistochemical staining of skin biopsies highlighted numerous spirochetes, further supporting the diagnosis of secondary syphilis ( Figure 5).
Despite the challenge of diagnosis, the relative ease of confirming the diagnosis with serological assays and reversibility of hepatic injury warrant inclusion on a differential diagnosis of hepatitis. With rates of syphilis on the rise, suspicion should be increased in patients with a history of risk factors for syphilis and in communities with high rates of transmission.

Conclusions
Clinicians should highly suspect syphilitic hepatitis in patients with risk factors (HIV, men having sex with men, multiple anonymous sexual partners) and elevated LFTs (predominantly the elevated ALP) when alternative etiology is unlikely. The initial syphilitic hepatitis presentation may be symptomatic or asymptomatic and with or without concurrent skin lesions. The clinician should always carefully examine the patient's skin and assess the need for a biopsy. Having syphilitic hepatitis as part of differential and obtaining syphilis serology as part of the initial workup may expedite the diagnosis and treatment plan for the patient in this clinical context. Normalizing LFTs after syphilis-targeted treatment may reasonably spare liver biopsy and its complications.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.