Early syphilitic hepatitis in an immunocompetent patient: really so uncommon?

Abstract

The incidence of syphilis has increased substantially over the past years, particularly in men who have sex with men. The clinical manifestations of syphilis are variable and liver involvement is uncommon, but may occur at any stage of the disease. We report a case of early syphilitic hepatitis (ESH) in an immunocompetent patient referring multiple bisexual exposures, who presented at admission with jaundice, tiredness, an ulcerated genital lesion and an increase of liver aminotransferases. During his hospital stay, he developed a skin rash, and serology for syphilis was found positive. Our case report strengthens the need to take into consideration the diagnosis of ESH in all patients with unexplained liver enzyme increase and epidemiological data of unsafe sexual exposures. Indeed, an early recognition of the clinical manifestations of syphilis can lead to a prompt treatment, and allows the prevention of the transmission of this disease to other individuals.

Keywords

acute hepatitis syphilis immunocompetent patient

Introduction

Syphilis is a systemic disease caused by Treponema pallidum, and its incidence has increased substantially over the past years in populations engaged in high-risk behaviour, particularly men who have sex with men.¹ The clinical manifestations of syphilis are variable,² and liver involvement is uncommon, but may occur at any stage of the disease. Early syphilitic hepatitis (ESH), often manifesting with a mild liver dysfunction,^{3

5} is relatively rare and often undiagnosed.

We report a case of ESH in a young immunocompetent man.

Case Report

A 27-year-old man presented to the National Institute for Infectious Diseases ‘Spallanzani’ on 21 February 2005 with a five-day history of tiredness and jaundice. He referred a hospital stay for acute virus A hepatitis (HAV) two years before. A history of multiple bisexual partners in the last six months was ascertained, even though he denied unprotected sexual exposures. No alcohol or drug use was referred.

Physical examination evidenced sclerocutaneous icterus, cervical and axillary lymphadenopathy, and hepatosplenomegaly. An indurated, ulcerated lesion, 1 cm in diameter, was found on his penis.

Aspartate aminotransferase (AST) was 989 U/L (normal value Ϗ 40 U/L); alanine aminotransferase (ALT), 1879 U/L (normal value < 40); total bilirubin, 13.3 mg/dL (normal value Ϗ 1.3 mg/dL); and alkaline phosphatase (ALP), 234 U/L (normal value >129). Assays for hepatitis B, C, E, transfusion transmitted virus and antinuclear antibodies were negative. Antibodies to Epstein–Barr virus, cytomegalovirus and HAV were positive as past infection.

On the fourth day of his stay, the patient developed a maculopapular rash all over his body. Antibody and antigen for HIV, antibodies to parvovirus B19, and syphilis were performed. Both HIV assays and parvovirus B19 resulted negative. Rapid plasma reagin (RPR) test was positive at a titre of 1:64 and was confirmed by a fluorescent treponemal antibody test.

Treatment was started with benzathine penicillin (2.4 million units) once a week for three weeks, with disappearance of the skin rash within one week. On the 24th day of his stay, AST was 737 U/L and RPR 1:16. Liver biopsy showed portal and sinusoidal infiltration of polymorphonuclear cells, lymphocytes, plasma cells and few macrophages. Scattered foci of hep-atocyte necrosis were present in liver parenchyma (Figure 1). Warthin–Starry stain did not reveal any treponema in the liver tissue.

Figure 1

Hepatic sinusoids are infiltrated by inflammatory cells (lymphocytes and plasma cells) and hepatocytes display lytic necrosis and apoptosis (haematoxylineosin, × 40)

The patient was discharged in good clinical condition after one month of stay, and was followed up for six months. Liver assays resulted in the normal range within one month, and RPR proved negative at the fourth month of follow-up.

Discussion

In our case report, the patient presented with signs and symptoms of acute viral hepatitis. The observation of penile lesion and skin rash, in the absence of any viral-positive marker, and the past unsafe sexual exposures induced us to focus on a syphilitic aetiology, which was confirmed by syphilis serology and by the fast improvement of his clinical signs and symptoms following antibiotic treatment.

Liver involvement in syphilis has been recognized for 400 years,⁶ but is uncommon and tends to be overlooked. After the first systematic autopsy description of liver damage in the course of syphilis, made by Hahn⁷ in 1943, sporadic case reports or small series were published in the literature,^{8

25} but in recent years the incidence of primary and secondary syphilis has increased, especially among people engaged in unsafe sexual practices.²⁶

The clinical manifestations of ESH are likely to be subsequent to dissemination of treponemes from the site of the primary lesion to the liver.^27,28 A generalized rash and hepatomegaly are often present. Laboratory findings show a modest increase in transaminases and bilirubin, and a marked increase in ALP.^3,4,12,16,17 The presence of spirochaetes in the liver tissue is diagnostic but difficult to demonstrate, as in our case, and it is likely due to technical factors in the storage and staining or to Kupffer cell phagocytosis.^{8,12,15,19,21,29}

Liver damage has also been described in HIV-positive patients with syphilis.^30,31 In a series of seven HIV-infected patients with ESH³¹ and with mean CD4 T-cell count >300/ mm³, there was a relationship between RPR title and CD4 T-cell count, suggesting a major inflammatory response in patients with a relatively normal immune response.

Antibiotic therapy almost always determines a complete resolution of hepatitis,³² even though Lo et al.³³ recently described a case of fulminant hepatitis resulting in liver transplantation.

In conclusion, our case report strengthens the need to take into consideration the diagnosis of ESH in patients with unexplained liver enzyme alteration and epidemiological data of unsafe sexual exposures. Early recognition of the clinical manifestations of syphilis can lead to a prompt treatment, and allows the prevention of the transmission of this disease to other individuals.

References

Centers for Diseases Control and Prevention.

Primary and secondary syphilis - United States, 2000.

MMWR 2006; 53: 269–73.

Baughn

, Musher

. Secondary syphilitic lesions. Clin Microbiol Rev 2005; 18: 205–16.

Sobel

, Wolf

. Liver involvement in early syphilis. Arch Pathol 1972; 93: 565–8.

Campisi

, Whitcomb

. Liver disease in early syphilis. Arch Intern Med 1979; 139: 365–6.

Keisler

Jr , Starke

, Looney

, Mark

Jr . Early syphilis with liver involvement. JAMA 1982; 247: 1999–2000.

Wile

, Karshher

. Icterus gravis syphiliticus. JAMA 1917; 68: 1311–14.

Hahn

. Syphilis of the liver. Am J Syph Neurol 1943; 27: 529–62.

Rajam

, Rangiah

. Early syphilitic hepatitis. Indian J Vener Dis 1954; 29: 83–94.

Zellmann

, Norcross

. Early syphilitic hepatitis. Lahey Clin Found Bull 1967; 16: 255–9.

10.

Karmin

, Thirkettle

, Read

. The association of syphilis with hepatic cirrhosis: a case report of 6 cases and review of literature. Postgrad Med J 1969; 45: 675–9.

11.

Baker

, Kaplan

, Wolfe

, McGowan

. Liver disease associated with early syphilis. N Engl J Med 1971; 284: 1422–3.

12.

Lee

, Thornton

, Conn

. Liver disease associated with secondary syphilis. N Engl J Med 1971; 284: 1423–5.

13.

Young

, Bahr

, Waye

. The Jarisch-Herxheimer reaction in syphilitic hepatitis. Am J Gastroenterol 1974; 61: 476–7.

14.

Bhowmick

, Simpson

, Way

. Secondary syphilis presenting jaundice. Postgrad Med J 1975; 571: 412–16.

15.

Feher

, Somogyi

, Timmer

, Jozsa

. Early syphilitic hepatitis. Lancet 1975; 2: 896–9.

16.

Pareek

. Liver involvement in secondary syphilis. Dig Dis Sci 1979; 24: 41–3.

17.

Friedman

, Wright

. Observations on syphilis in Addis Ababa. Br J Vener Dis 1977; 53: 276–80.

18.

Brooks

, Hanchard

, Yerry

, Audretsch

. Hepatitic ultrastructure in secondary syphilis. Arch Pathol Lab Med 1979; 103: 451–5.

19.

Romeu

, Bybak

, Dave

, Coven

. Spirochetal vasculitis and bile ductular damage in early hepatitic syphilis. Am J Gastroenterol 1980; 74: 352–4.

20.

Tiliakos

, Shamma'a

, Nasrallah

. Syphilitic hepatitic. Am J Gastroenterol 1980; 73: 60–1.

21.

Keisler

Jr , Starke

, Looney

, Mark

Jr . Early syphilis with liver involvement. JAMA 1982; 247: 1999–2000.

22.

Agrawal

, Sassaris

, Brooks

, Akdamar

, Hunter

. The liver in secondary syphilis. South Med J 1982; 75: 1136–8.

23.

Schlossemberg

. Syphilitic hepatitis: a case report and review of the literature. Am J Gastroenterol 1987; 82: 552–3.

24.

Blair

, Sedlak

, Snyder

, Lawson

. Unsuspected syphilitic hepatitis in a patient with low grade proteinuria and abnormal liver function. Mayo Clin Proc 1990; 65: 1365–7.

25.

Taniguchi

, Nakae

, Ikoma

. Subclinical syphilitic hepatitis which was markedly worsened by a Jarisch-Herxeimer reaction. Am J Gastroenterol 1999; 94: 1694–6.

26.

Kahn

, Heffelfinger

, Berman

. Syphilis outbreaks among men who have sex with men: a public health trend of concern. Sex Transm Dis 2002; 29: 285–7.

27.

Sherlock

. The liver in secondary (early) syphilis. N Engl J Med 1971; 284: 1437–8.

28.

Fitzgerald

. Pathogenesis and immunology of Treponema pallidum. Annu Rev Microbiol 1981; 35: 29–54.

29.

Petersen

, Mead

, Perloth

. Unusual manifestations of secondary syphilis occurring after orthotopic liver transplantation. Am J Med 1983; 75: 166–70.

30.

Sabbatani

, Manfredi

, Attard

, Salfi

, Chiodo

. Secondary syphilis presenting with acute severe hepatic involvement in a patient with undiagnosed HIV disease. AIDS Patient Care STDS 2005; 19: 545–9.

31.

Mullick

, Liappis

, Benator

, Roberts

, Parenti

, Simon

. Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature. Clin Infect Dis 2004; 39: 100–5.

32.

Mandache

, Coca

, Caro-Sampara

. A forgotten aetiology of acute hepatitis in immunocompetent patient: syphilitic infection. J Intern Med 2006; 259: 214–15.

33.

, Harrison

, Hunter

. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation. J Infect 2006; 54: e115–7. Doi:10.1016/j.jinf.2006.07.005.