a systematic literature review of syphilitic hepatitis in adults

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Syphilitic Hepatitis: A Rare Cause of Elevated Liver Function Tests

Shaharyar salim, rabeea farhan, asif surani.

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Shaharyar Salim [email protected]

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Accepted 2023 Jan 27; Collection date 2023 Jan.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Syphilitic hepatitis is a rare manifestation of syphilis with an incidence of 0.2-38%. We describe a case of a healthy, immunocompetent male patient with elevated liver function tests (LFTs) who was found to have syphilitic hepatitis.

A 28-year-old male with no past medical history presented with abdominal pain for two to three weeks. He also reported diminished appetite, intermittent chills, weight loss, and fatigue. His history was positive for high-risk sexual behavior including multiple partners and absence of using protection. His physical examination was remarkable for right-sided abdominal tenderness and a painless chancre on his penile shaft. His workup revealed elevated aspartate aminotransferase (AST: 169 U/L), alanine transaminase (ALT: 271 U/L), and alkaline phosphatase (ALP: 377 U/L). His abdominal CT scan was unremarkable except for the abdominal and pelvic lymphadenopathy. A thorough serology panel revealed negative hepatitis A, B, C, human immunodeficiency virus (HIV) (including HIV RNA), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). His immunological workup was negative as well. His rapid plasma reagin (RPR) was reactive with positive IgG/IgM treponemal antibodies. He was managed as secondary syphilis and received 2.4 million units of benzathine penicillin. Upon follow-up after one week, he reported a complete resolution of his symptoms, and his LFTs were normalized on a repeat checkup.

Given the significant morbidity associated with a missed diagnosis, syphilitic hepatitis should be considered an essential part of the workup for evaluating elevated LFTs in an appropriate clinical setting. This case also highlights the importance of obtaining a comprehensive sexual history and performing a thorough genital examination.

Keywords: treponema pallidum, hepatic enzymes, hepatic manifestations, sexually transmitted infection (sti), infectious hepatitis, liver function test (lft), sexual transmitted diseases, deranged liver function test, syphilis

Introduction

Syphilis, commonly known as "the great imitator," can virtually affect any organ of the body. Syphilitic hepatitis, also called "luetic jaundice," is a rare manifestation of syphilis signifying spirochete dissemination to the liver. It was first recognized in 1585 [ 1 ] and was initially reported in the literature by Harn in 1943 [ 2 ]. The actual incidence of syphilitic hepatitis is uncertain; however, it occurs in 0.2-38% of patients with a history of syphilis diagnosis [ 3 , 4 ].

Syphilitic hepatitis is usually defined as a cholestatic pattern of liver enzyme elevation with serological treponemal evidence in the absence of other causes of hepatic dysfunction, and improvement after appropriate antimicrobial therapy [ 5 ]. Liver involvement can occur at any disease stage, although most cases have been reported to occur during the early stages of syphilis [ 6 ].

Due to the recent increase in the incidence of primary and secondary syphilis, it is imperative that clinicians should consider syphilis in the differential diagnosis of patients with liver dysfunction and elevated liver function tests (LFTs) of unclear etiology [ 5 ]. In this article, we describe a case of a healthy, immunocompetent 28-year-old male with elevated LFTs who was diagnosed with syphilitic hepatitis.

Case presentation

A 28-year-old male with no significant past medical history presented to the emergency department with complaints of abdominal pain for two to three weeks. His abdominal pain was located in the right upper quadrant, was constant, radiated to the back, and throbbing in nature. His pain was aggravated by movements and deep breaths, with no significant relieving factors. He reported diminished appetite, chills, 10 pounds of weight loss, and fatigue which preceded his current symptoms by several months. Of note, the patient had a history of gonorrhea one year prior to this presentation and was treated appropriately. He reported being sexually active with his current female partner for more than three years. On enquiring about safe sexual practices, he admitted to have had unprotected sexual intercourse with other female partners. His recent rapid plasma reagin (RPR) screen was negative six months prior to the presentation. Interestingly, he had an urgent care visit one month prior to the presentation for a non-healing penile lesion; Treponema pallidum total antibody was negative at that time. He denied any history of drug abuse except for the minimal alcohol intake of one to two drinks of wine per week.

His physical examination was significant for temporal wasting and right upper quadrant abdominal tenderness without guarding or rigidity. A painless chancre was noted on the ventral aspect of the penile shaft without any obvious discharge. His blood work was remarkable for deranged LFTs - aspartate aminotransferase (AST) 169 U/L (peak: 197 U/L), alanine aminotransferase (ALT) 271 U/L (peak: 371 U/L), alkaline phosphatase (ALP) 377 U/L (peak: 529 U/L), bilirubin 1.0 mg/dL (peak: 2.4 mg/dL) with direct bilirubin of 0.6 mg/dL, and normal albumin and international normalized ratio (INR). The abdominal ultrasound and CT scan were unremarkable except for several large abdominal and pelvic lymph nodes.

During the hospital course, he underwent extensive workup for his elevated LFTs that revealed normal acetaminophen levels, negative hepatitis panel (A, B, and C), human immunodeficiency virus (HIV) screen and HIV-1 RNA, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (IgG and IgM) titers, anti-nuclear antibody (ANA) and anti-smooth muscle antibody (ASMA). His Helicobacter pylori ( H. pylori ) stool antigen was positive. In addition, he had a positive RPR screen with titers of 32 dils along with a positive treponema IgM/IgG antibody.

Due to the presence of a penile chancre, positive RPR screen and titers, and significant abdominopelvic lymphadenopathy, he was managed as secondary syphilis with intramuscular penicillin G benzathine 2.4 million units. He was also started on omeprazole, clarithromycin, and amoxicillin triple therapy for H. pylori eradication. His pain was managed with opiates which were tapered down during the hospital course. Though his LFT trend slightly worsened after penicillin administration, it subsequently improved with repeat testing (Table 1 ). Due to the overall stability and a slight improvement observed in the LFT trend, the liver biopsy was deferred.

Table 1. LFTs trend on presentation and after receiving antibiotics.

LFT: liver function test

On the follow-up visit after two weeks, he reported improvement in his abdominal pain. His penile chancre was resolved and his LFTs improved significantly (Table 1 ). However, he was noted to have persistent inguinal lymphadenopathy.

We report a case of a healthy, immunocompetent 28-year-old male patient who presented with abdominal pain and deranged LFTs along with abdominopelvic lymphadenopathy. He was diagnosed with secondary syphilis and syphilitic hepatitis. Although there are no established criteria for the diagnosis of syphilitic hepatitis, Mullick et al. proposed the following criteria: (1) elevated liver enzymes indicating liver involvement; (2) positive serological evidence for syphilis; (3) exclusion of alternative causes of liver injury; and (4) improvement in liver enzyme after appropriate antimicrobial therapy [ 5 ]. Our patient satisfied all four diagnostic criteria.

Clinical signs and symptoms of syphilitic hepatitis can be non-specific. In a literature review of 97 cases by Huang et al., rashes were the most common clinical manifestation, followed by fatigue or poor appetite, fever, weight loss, and abdominal pain [ 6 ]. Common physical examination findings highlighted in the same review were hepatomegaly, lymphadenopathy, splenomegaly, and uveitis. Our patient had abdominal pain, weight loss, poor appetite, and fatigue along with a physical examination finding of lymphadenopathy which were similar to the aforementioned literature review.

The pattern of liver function testing in syphilitic hepatitis is typically cholestatic. However, hepatocellular or mixed patterns are also observed. Marked increase in ALP and gamma-glutamyl transferase (GGT) is also characteristic [ 6 , 7 ]. Our patient had a similar pattern of ALP and GGT elevation along with mild elevation of transaminases (ALT>AST). Intriguingly, our patient had worsening of ALP, bilirubin, and transaminases 24 hours after penicillin administration. It slightly improved after 72 hours but remained elevated compared to the pre-antibiotic levels. Elevated transaminases and bilirubin levels completely resolved after two weeks; ALP did down-trend but remained above the normal limits at the two-week follow-up visit. The worsening of LFTs after penicillin administration contrasts with the reported finding of Pereira et al. who noted significant improvement in transaminases and ALP at the 72-hour mark [ 8 ].

As stated above, our patient had a recent urgent care visit for a non-healing penile lesion. His Treponema pallidum total antibodies were negative at that time. This false negative could be due to prozone phenomena that result from overwhelming antibody titers which hamper the formation of antigen-antibody lattice required for the visualization of a positive flocculation test. The prozone effect has been previously reported in secondary syphilis leading to delayed diagnosis [ 9 ].

Interestingly, our patient had a positive concomitant H. pylori infection. Human studies have highlighted an association between H. pylori infection and disease progression in established chronic viral hepatitis (hepatitis B and C) [ 10 ]. Salehi et al. in the same article have also suggested a role of H. pylori infection in some cases of mild unexplained hypertransaminasemia with improvement after receiving eradication therapy [ 10 ]. Though our patient had positive H. pylori testing, he had a negative viral hepatitis panel including hepatitis B and C. In addition, the presence of penile chancre, positive serology of syphilis, and lymphadenopathy suggest syphilis be the likely etiology of LFT derangement in our patient.

Conclusions

Syphilitic hepatitis is an important and under-recognized cause of LFTs elevation. Due to an increased incidence of syphilis, clinicians should consider this diagnosis in a patient with elevated LFTs of unknown etiology and high-risk sexual behavior. This report highlights the paramount importance of obtaining a comprehensive sexual history and performing a detailed genital examination. Timely diagnosis and prompt treatment with penicillin can lead to clinical recovery and prevention of complications.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study

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Syphilitic hepatitis: Case report of an overlooked condition

Pedro marcos, liliana eliseu, martinha henrique, helena vasconcelos.

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Correspondence , Pedro Miguel Ribeiro Marcos, Serviço de Gastrenterologia, Centro Hospitalar de Leiria, Rua das Olhalvas, 2410‐197 Leiria, Portugal. Email: [email protected]

Corresponding author.

Received 2019 Jun 24; Revised 2019 Oct 24; Accepted 2019 Oct 30; Collection date 2020 Jan.

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Syphilis is an overlooked cause of hepatitis. Syphilitic hepatitis should be a differential diagnosis in all patients with abnormal liver biochemical marker levels. Syphilitic hepatitis has been defined as the combination of increased liver enzymes, positive serology for syphilis, the absence of alternative causes for hepatobiliary injury, and liver enzyme improvement with proper antibiotic therapy.

Keywords: Syphilis, Syphilitic hepatitis, Treponema pallidum

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1. INTRODUCTION

Syphilis is a sexually and vertically transmitted infection that is caused by the bacterium, Treponema pallidum ( T pallidum ), an obligate human pathogen well‐known for its invasiveness and immune‐evasive properties. 1 Syphilis was first described at the end of the fifteenth century, and it remains a major public health problem worldwide. 2 According to the most recent global estimation of the World Health Organization, approximately 19.9 million individuals had syphilis in 2016, and an estimated 6.3 million new cases occur every year. 3

During its natural course, syphilis progresses from early (including primary, secondary, and early latent syphilis) to late stages (including late latent and tertiary syphilis) if left untreated. Primary syphilis classically presents with a single ulcer (chancre) or multiple lesions at the site of inoculation; these are typically painless, they resolve spontaneously, and they may go unnoticed by patients. Secondary syphilis, also known as the dissemination phase, is commonly characterized by a non‐itchy skin rash that can mimic other infectious and non‐infectious conditions, but the rash can spontaneously disappear even without treatment. When left untreated, the infection enters a latent stage, which is asymptomatic and can last for years (early latent stage, infection with a duration of ≤1 year; late latent stage, infection with a duration of >1 year). Tertiary syphilis is characterized by the development of major complications during the latent phase, such as gumma, cardiosyphilis, or late neurosyphilis. 1 , 4

Syphilis can involve multiple organs and produce diverse and often subtle clinical manifestations that can mimic other infectious and non‐infectious conditions. 1 Liver involvement associated with syphilis is not observed in daily clinical practice. Here, we presented the uncommon case of a man with syphilitic hepatitis, which is an overlooked entity that warrants attention.

2. CASE REPORT

A 48‐year‐old Caucasian man with a 2‐week history of epigastric tenderness and asthenia was referred to our hospital owing to abnormal hepatic and biochemical test results (alanine aminotransferase [ALT] at 324 IU/L [normal, 3–45]; aspartate aminotransferase [AST] at 154 IU/L [normal, 15–50]; gamma‐glutamyl transferase [GGT] at 1384 IU/L [normal < 55]; and alkaline phosphatase at 390 IU/L [normal, 30–120]). The patient did not have a past medical history of liver disease or abnormal liver tests. Essential arterial hypertension under prolonged treatment with olmesartan was the only known medical condition and medication, respectively. He denied significant alcohol intake, as well as the use of acetaminophen, herbals, over‐the‐counter products, recreational drugs, or other potentially toxic substances. He also had no family history of gastrointestinal or hepatic diseases. He was single and frequently traveled for work. The patient mentioned a casual unprotected heterosexual intercourse 2 months prior to his present condition. He showed no signs and symptoms, and he had no history of sexually transmitted infections.

The admission physical examination was unremarkable. He was fully alert and oriented, with good reflexes and no flapping; his sclerae were anicteric; he had no skin lesions; his vital signs, heart, and lung sounds were normal; his abdomen was soft, without tenderness or appreciable hepatosplenomegaly.

The admission blood tests revealed normal complete blood counts and coagulation tests; a high C‐reactive protein at 30.6 mg/L (<5.0 mg/L); levels of creatinine, albumin, amylase, lipase, and bilirubin within the normal ranges; and increased ALT (342 IU/L [3–45]), AST (93 IU/L [15–50]), GGT (1503 IU/L [<55]), and alkaline phosphatase (591 IU/L [30–120]). An abdominal ultrasound revealed normal liver parenchyma, biliary tract, gallbladder, pancreas, and spleen and the absence of lithiasis.

We admitted the patient for further investigation and surveillance. The consecutive blood tests showed a progressive increase in the liver enzymes (ALT, 844 IU/L; AST, 387 IU/L; GGT, 1763 IU/L; alkaline phosphatase, 763 IU/L) with normal liver function parameters. Two days after being hospitalized, the patient developed non‐itchy, erythematous, maculopapular rashes on the palms of both hands (Figure 1 ). He showed no signs of liver failure. Serological test results were negative for hepatitis A, B, C, and E viruses, cytomegalovirus, Epstein‐Barr virus, herpes simplex virus, and human immunodeficiency virus (HIV). The usual liver autoantibodies were also negative. The levels of serum immunoglobulins were normal. Given the dermal findings, we tested him for syphilis and found a reactive venereal disease research laboratory (VDRL) titer of 1:64, a T pallidum hemagglutination assay of 1:640, and a positive IgM fluorescent T pallidum antibody absorbance (FTA‐Abs IgM).

Erythematous maculopapular rashes on the palms of both hands

Taking the clinical and laboratory findings together, the patient was diagnosed with syphilitic hepatitis and initiated his intake of benzathine penicillin G 2.4 million units intramuscularly once weekly, for 3 weeks. Two days after the first dose, he was discharged. A month later, he was completely asymptomatic, the skin lesions had disappeared, the liver biochemical marker levels had completely normalized, and the VDRL was already nonreactive (seroconversion), which confirmed the clinical cure (Table 1 ).

Blood test changes before and after treatment

Abbreviations: INR, international normalized ratio; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma‐glutamyl transferase; VDRL, venereal disease research laboratory.

3. DISCUSSION

Syphilitic hepatitis is a rare clinical presentation of syphilis, with an incidence ranging from 0.25% to 38%. 5 , 6 It occurs relatively more frequently among men who engaged in sexual intercourse with men or with patients with HIV infection, but the disease can emerge in any individual who gets infected. 7 Even though a local inflammatory response elicited by spirochetes is believed to be the cause of all clinical manifestations of syphilis, the precise mechanisms by which T pallidum causes liver damage and the reason behind certain patients with infection developing hepatitis while others do not remain unclear. 1 , 6

Hepatic involvement in syphilis can be observed during any phase of the disease. A systematic review that includes 144 patients found that 89% of cases develop during early syphilis and 6% during late stages. 7 According to the same review, the most frequently occurring signs and symptoms in patients with syphilitic hepatitis are rashes involving the palms of both hands, soles, or any other body part (78%), followed by fatigue/poor appetite (57%), hepatomegaly (54%), jaundice (35%), lymphadenopathy (31%), fever (26%), weight loss (23%), abdominal pain (22%), and splenomegaly (14%). 7

On the basis of other studies, syphilitic hepatitis can be diagnosed when all the following criteria are present: abnormal liver biochemical marker levels, serological evidence of syphilitic infection, exclusion of other etiologies of liver disease, and successful response to the antibiotic treatment with normalization of the liver enzymes. 5 , 8 , 9 The patient in the present case met all these criteria.

The pattern of abnormal liver test results in syphilitic hepatitis is typically cholestatic, but it can also be hepatocellular or mixed. Disproportionally high serum alkaline phosphatase and GGT levels with slight raised or normal serum transaminases and bilirubin are common. 7 , 8 , 9 , 10 , 11 , 12

Serologic testing for the diagnosis of syphilis should include the use of both nontreponemal and treponemal tests. Either test can be used as the initial screening test. In our patient, we were still using the traditional approach (initial screening with nontreponemal test). This algorithm has shown a high positive predictive value when both tests are reactive, although very early primary and previously treated syphilis can be overlooked due to the lower sensitivity of nontreponemal tests. Nowadays, in numerous institutions including ours, the reverse algorithm is used (initial screening with treponemal tests). This approach is associated with higher costs, but it permits the detection and treatment of 99% of cases compared with the traditional algorithm in a low‐prevalence setting. 1

Liver biopsies performed in patients with syphilitic hepatitis often show portal and lobular inflammatory cell infiltrates, hepatocellular necrosis, cholestasis, and/or noncaseating granulomas. Since these findings are non‐specific and spirochete recognition in liver specimens is difficult, even after immunohistochemical or Warthin‐Starry staining, liver biopsy is not considered essential for the diagnosis of syphilitic hepatitis when there is a positive response to therapy. 7 , 8 , 9

Penicillin remains the treatment of choice for patients in all stages of syphilis, with different regimens suggested based on the disease stage. In our case, as we could not be sure of the timing of the infection because the patient did not notice a chancre or any other primary lesion, we preferred to prescribe a 3‐week course of intramuscular administration of benzathine penicillin G at 2.4 million units once weekly (as recommended for latent syphilis) rather than a single dose (used to treat early syphilis). 2

Antibiotic treatment shows rapid improvement in the majority of cases of syphilitic hepatitis. 6 , 7 , 8 , 13 Very rarely, syphilitic hepatitis can result in fulminant liver failure, as shown in the case of a patient who required a liver transplantation. 14

In summary, this case report highlights syphilis as an overlooked etiology of hepatitis that should always be excluded during the evaluation of patients with abnormal liver biochemical marker levels of unknown etiology. Its diagnosis is usually straightforward, and a liver biopsy is not generally necessary for a positive response to antibiotic therapy. Timely diagnoses and prompt treatments are important for limiting clinical effects and preventing progression to tertiary syphilis.

CONFLICT OF INTEREST

None declared.

AUTHOR CONTRIBUTION

Pedro Marcos: revised the literature and drafted the manuscript. Liliana Eliseu: revised the manuscript. Martinha Henrique and Helena Vasconcelos: revised the manuscript and approved the final version.

Marcos P, Eliseu L, Henrique M, Vasconcelos H. Syphilitic hepatitis: Case report of an overlooked condition. Clin Case Rep. 2020;8:123–126. 10.1002/ccr3.2588

Statements: The authors obtained signed informed consent from the patient for the publication of his case.

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