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Unsuspected Syphilitic Hepatitis in a Patient With Low-Grade Proteinuria and Abnormal Liver Function

1990; Elsevier BV; Volume: 65; Issue: 10 Linguagem: Inglês

10.1016/s0025-6196(12)62147-8

1942-5546

ELLEN K. BLAIR, Richard E. Sedlack, JOSEPH P. SNYDER, J. Mark Lawson,

Eosinophilic Disorders and Syndromes

A 25—year-old patient was found to have cholestatic liver enzyme abnormalities during assessment for asymptomatic low-grade proteinuria at the US Naval Hospital in Portsmouth, Virginia. These abnormalities persisted for a 6-month period, and an extensive workup, including viral serologic studies, rapid plasma reagin test, iron studies, ceruloplasmin, antimitochondrial, antinuclear, and anti-human immunodeficiency virus antibodies, endoscopic retrograde cholangiopancreatography, and liver biopsy, was unrevealing until serologic tests for syphilis were repeated to evaluate a new onset of urethral discharge. The patient had none of the more characteristic signs of secondary syphilis. The liver enzyme abnormalities rapidly resolved after treatment with penicillin. Syphilis remains the great impostor and still must be considered in the differential diagnosis of unexplained liver enzyme abnormalities, even in a patient with no symptoms or signs of early syphilis. A 25—year-old patient was found to have cholestatic liver enzyme abnormalities during assessment for asymptomatic low-grade proteinuria at the US Naval Hospital in Portsmouth, Virginia. These abnormalities persisted for a 6-month period, and an extensive workup, including viral serologic studies, rapid plasma reagin test, iron studies, ceruloplasmin, antimitochondrial, antinuclear, and anti-human immunodeficiency virus antibodies, endoscopic retrograde cholangiopancreatography, and liver biopsy, was unrevealing until serologic tests for syphilis were repeated to evaluate a new onset of urethral discharge. The patient had none of the more characteristic signs of secondary syphilis. The liver enzyme abnormalities rapidly resolved after treatment with penicillin. Syphilis remains the great impostor and still must be considered in the differential diagnosis of unexplained liver enzyme abnormalities, even in a patient with no symptoms or signs of early syphilis. Although thought to be rare, liver involvement in patients with syphilis is not uncommon. In more than 50% of cases of secondary syphilis, increased liver enzyme values can be detected and may become chronic.1Schlossberg D Syphilitic hepatitis: a case report and review of the literature.Am J Gastroenterol. 1987; 82: 552-553PubMed Google Scholar Clinical hepatitis is rare, as is concomitant renal involvement.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar, 3McMillan A Anderson JR Robertson DHH Hepatitis in early syphilis: report of three cases.Br J Vener Dis. 1977; 53: 295-298PubMed Google Scholar If other clinical symptoms and signs of syphilis are absent, the diagnosis must be based on high diagnostic acuity and serologic testing, as the following case illustrates. In February 1988, an asymptomatic 25-year-old man was referred for assessment of abnormal cholestatic liver enzyme values, discovered during an evaluation for low-grade proteinuria. During the initial physical examination, 3+ proteinuria was found on routine urinalysis. A 24-hour urine collection showed excretion of 850 mg of protein per 24 hours (normal, 0 to 150 mg/24 h). A multichemistry profile included the following: alkaline phosphatase, 768 U/liter (normal, 30 to 115 U/liter); γ-glutamyltransferase, 656 U/liter (normal, 0 to 65 U/liter); lactate dehydrogenase, 194 U/liter (normal, 60 to 225 U/liter); aspartate aminotransferase, 188 U/liter (normal, 0 to 40 U/liter); alanine aminotransferase, 288 U/liter (normal, 10 to 60 U/liter); and total bilirubin, 0.7 mg/dl (normal, 0.2 to 1.2 mg/dl). A rapid plasma reagin test was negative. The fluorescent treponemal antibody absorption test was not done. The patient denied having a history of exposure to hepatitis, intravenous drug abuse, homosexuality, tattoos, or blood transfusions or any constitutional symptoms. Specifically, he said that he had had no rash, swollen lymph nodes, penile lesions, or fever in the preceding 6 months. On physical examination, findings were normal. Further blood studies disclosed no serologic evidence of past or present infection with hepatitis B, hepatitis A, Epstein-Barr virus, cytomegalovirus, or human immunodeficiency virus. Other laboratory data were as follows: serum ceruloplasmin, 60 mg/dl (normal, 21 to 53 mg/dl); ferritin, 325 μg/liter (normal, 18 to 250 μg/liter); antinuclear antibody, positive at 1:10; and antimitochondrial antibody, positive at 1:40. The patient was observed clinically for 6 months. During this period, no significant change occurred in his liver function tests, and he remained asymptomatic. Endoscopic retrograde cholangiopancreatography yielded normal results. A liver biopsy specimen showed mild portal inflammation and mild hepatocellular unrest. No evidence of cholestasis or organisms was noted. Shortly after these procedures, a clear urethral discharge and pyuria developed. A urethral culture was negative for Neisseria gonorrhoeae; however, a rapid plasma reagin test was positive at a titer of 1:128, and the fluorescent treponemal antibody absorption test also was positive. The patient was treated with benzathine penicillin, 2.4 million units intramuscularly. No Jarisch-Herxheimer reaction was noted. One week later, his liver enzyme values had become normal. The proteinuria (800 mg/24 h) persisted for 6 months after penicillin treatment, but the rapid plasma reagin titer had decreased to 1:4. A renal biopsy specimen demonstrated thickening of the glomerular capillary loops in association with normal cellularity. Immunofluorescent staining showed no immunoglobulins. Electron microscopy (Fig. 1) demonstrated intramembranous electron-lucent immunologic deposits, a finding consistent with resolving membranous nephropathy. Hepatic involvement in early syphilis has been known since 1585, when it was first reported by Paracelsus.4Tiliakos N Shamma'a JM Nasrallah SM Syphilitic hepatitis.Am J Gastroenterol. 1980; 73 (Paracelsus: Cited by Schlossberg D1 Hahn RD: Cited by McMillan A, Anderson JR, Robertson DHH3): 60-61PubMed Google Scholar A review of 10,000 cases of early syphilis by Hahn5Hahn RD: Cited by McMillan A, Anderson JR, Robertson DHH3Google Scholar in the preantibiotic era demonstrated that clinical hepatitis was extremely rare. In 50% of cases of secondary syphilis, increased liver enzyme values are noted but usually in conjunction with the more common manifestations of the disease such as rash, adenopathy, or penile lesions.1Schlossberg D Syphilitic hepatitis: a case report and review of the literature.Am J Gastroenterol. 1987; 82: 552-553PubMed Google Scholar The potential for prolonged abnormalities on liver enzyme tests in secondary syphilis has not been well recognized in the literature and frequently is not included in the differential diagnosis of chronic liver disease. The typical hepatitic enzyme picture is cholestasis with a substantially increased alkaline phosphatase value and minor increases in the aminotransferases.1Schlossberg D Syphilitic hepatitis: a case report and review of the literature.Am J Gastroenterol. 1987; 82: 552-553PubMed Google Scholar, 3McMillan A Anderson JR Robertson DHH Hepatitis in early syphilis: report of three cases.Br J Vener Dis. 1977; 53: 295-298PubMed Google Scholar, 6Tiliakos N, Shamma'a JM, Nasrallah SM: Syphilitic hepatitis. Am J Gastroenterol 73:60–61, 1980Google Scholar Jaundice is uncommon.3McMillan A Anderson JR Robertson DHH Hepatitis in early syphilis: report of three cases.Br J Vener Dis. 1977; 53: 295-298PubMed Google Scholar This liver enzyme picture is thought to be related to the pericholangiolar inflammation that frequently is evident on liver biopsy.1Schlossberg D Syphilitic hepatitis: a case report and review of the literature.Am J Gastroenterol. 1987; 82: 552-553PubMed Google Scholar, 6Tiliakos N, Shamma'a JM, Nasrallah SM: Syphilitic hepatitis. Am J Gastroenterol 73:60–61, 1980Google Scholar, 7Keisler Jr, DS Starke W Looney DJ Mark Jr, WW Early syphilis with liver involvement.JAMA. 1982; 247: 1999-2000Crossref PubMed Scopus (20) Google Scholar In early syphilis, histologic changes in the liver can be variable and nonspecific, including portal inflammatory infiltrates, hepatocellular necrosis, granuloma, and, rarely, cholestasis.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar, 8Petersen LR Mead RH Perlroth MG Unusual manifestations of secondary syphilis occurring after orthotopic liver transplantation.Am J Med. 1983; 75: 166-170Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 9Young E Bahr G Waye JD The Jarisch-Herxheimer reaction in syphilitic hepatitis.Am J Gastroenterol. 1974; 61: 476-477PubMed Google Scholar Spirochetes are detected infrequently on histologic examination.1Schlossberg D Syphilitic hepatitis: a case report and review of the literature.Am J Gastroenterol. 1987; 82: 552-553PubMed Google Scholar, 6Tiliakos N, Shamma'a JM, Nasrallah SM: Syphilitic hepatitis. Am J Gastroenterol 73:60–61, 1980Google Scholar, 7Keisler Jr, DS Starke W Looney DJ Mark Jr, WW Early syphilis with liver involvement.JAMA. 1982; 247: 1999-2000Crossref PubMed Scopus (20) Google Scholar, 10Hjort M Olsson R Smith U Zettergren L Hepatitis in secondary syphilis.Scand J Infect Dis. 1977; 9: 59-61PubMed Google Scholar The response to penicillin usually is rapid, and liver enzyme values become normal in days to weeks, although delayed resolution has been reported.7Keisler Jr, DS Starke W Looney DJ Mark Jr, WW Early syphilis with liver involvement.JAMA. 1982; 247: 1999-2000Crossref PubMed Scopus (20) Google Scholar, 8Petersen LR Mead RH Perlroth MG Unusual manifestations of secondary syphilis occurring after orthotopic liver transplantation.Am J Med. 1983; 75: 166-170Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 11Campisi D Whitcomb C Liver disease in early syphilis.Arch Intern Med. 1979; 139: 365-366Crossref PubMed Scopus (54) Google Scholar, 12Bansal RC Cohn H Fani K Lynfield YL Nephrotic syndrome and granulomatous hepatitis in secondary syphilis.Arch Dermatol. 1978; 114: 1228-1229Crossref PubMed Scopus (19) Google Scholar A Jarisch-Herxheimer reaction can occur.9Young E Bahr G Waye JD The Jarisch-Herxheimer reaction in syphilitic hepatitis.Am J Gastroenterol. 1974; 61: 476-477PubMed Google Scholar Concomitant renal and hepatic involvement, which can occur rarely, usually consists of cholestatic liver enzyme values and mild proteinuria.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar, 13Gamble CN Reardan JB Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits.N Engl J Med. 1975; 292: 449-454Crossref PubMed Scopus (81) Google Scholar A more severe clinical picture with nephrotic range proteinuria has been reported in association with liver disease.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar Both renal and hepatic involvement is typically noted at the time the rash of secondary syphilis appears.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar The renal lesion in secondary syphilis seems to be related to the deposition of immune complexes in the glomerulus.2Morrison EB Norman DA Wingo CS Henrich WL Simultaneous hepatic and renal involvement in acute syphilis: case report and review of the literature.Dig Dis Sci. 1980; 25: 875-878Crossref PubMed Scopus (21) Google Scholar, 13Gamble CN Reardan JB Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits.N Engl J Med. 1975; 292: 449-454Crossref PubMed Scopus (81) Google Scholar These antitreponemal antibodies consist of IgG and C3 in a subepithelial location.13Gamble CN Reardan JB Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits.N Engl J Med. 1975; 292: 449-454Crossref PubMed Scopus (81) Google Scholar Electron microscopy can disclose fusion of the epithelial foot processes.12Bansal RC Cohn H Fani K Lynfield YL Nephrotic syndrome and granulomatous hepatitis in secondary syphilis.Arch Dermatol. 1978; 114: 1228-1229Crossref PubMed Scopus (19) Google Scholar Unlike the situation in the case presented herein, the proteinuria usually responds favorably to antibiotic treatment within weeks and may even resolve spontaneously.12Bansal RC Cohn H Fani K Lynfield YL Nephrotic syndrome and granulomatous hepatitis in secondary syphilis.Arch Dermatol. 1978; 114: 1228-1229Crossref PubMed Scopus (19) Google Scholar, 13Gamble CN Reardan JB Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits.N Engl J Med. 1975; 292: 449-454Crossref PubMed Scopus (81) Google Scholar Although we cannot prove that this patient's renal lesion was due to treated syphilitic nephritis, several factors suggest such an association. The low titer on a repeat rapid plasma reagin test did not suggest active infection, and the renal biopsy specimen lacked electron-dense immunologic deposits consistent with an ongoing process. The intramembranous location of the deposits and the lack of fluorescent staining for immunoglobulins also suggest that this lesion was resolving. Other diseases to be considered in the differential diagnosis of hepatitis in association with nephritis include hepatitis B, autoimmune disease, malaria, leptospirosis, tuberculosis, lymphoma, and Stauffer's syndrome. Stauffer's syndrome, first diagnosed at the Mayo Clinic in 1961, consists of reversible low-grade transaminasemia, increased alkaline phosphatase, and hepatosplenomegaly in association with non-metastatic hypernephroma. This history and physical findings, supplemented by serologic tests, usually allow the diagnosis to be made. As in this case, early syphilis cannot be excluded from the differential diagnosis of cholestatic liver disease or proteinuria solely on the basis of clinical findings or initial serologic results. Even today, syphilis remains the great impostor and should be considered in cases of obscure or chronic liver disease, especially when associated with proteinuria. High-titer serologic results and a prompt response to penicillin treatment are diagnostic.