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Unsuspected Syphilitic Hepatitis in a Patient With Low-Grade Proteinuria and Abnormal Liver Function
Case Report Unsuspected Syphilitic Hepatitis in a Patient With Low-Grade Proteinuria and Abnormal Liver Function
ELLEN K. BLAIR, M.D., Naval Medical Clinic, Quantico, Virginia; RICHARD E. SEDLACK, M.D., Division of Gastroenterology and Internal Medicine; J O S E P H P. SNYDER, M.D., J. MARK LAWSON, M.D., United States Naval Hospital, Portsmouth, Virginia
A 25-year-old p a t i e n t w a s found t o h a v e c h o l e s t a t i c liver e n z y m e abnormalities d u r i n g a s s e s s m e n t for a s y m p t o m a t i c low-grade p r o t e i n u r i a at t h e U S Naval Hospital i n P o r t s m o u t h , Virginia. T h e s e a b n o r m a l i t i e s p e r s i s t e d for a 6-month period, a n d a n e x t e n s i v e w o r k u p , i n c l u d i n g viral serologic s t u d i e s , rapid p l a s m a reagin test, iron s t u d i e s , c e r u l o p l a s m i n , a n t i m i t o c h o n d r i a l , a n t i n u c l e a r , a n d anti-human i m m u n o d e ficiency v i r u s a n t i b o d i e s , e n d o s c o p i c retrograde c h o l a n g i o p a n c r e a t o g r a p h y , a n d liver biopsy, w a s u n r e v e a l i n g until serologic t e s t s for s y p h i l i s w e r e r e p e a t e d t o e v a l u a t e a n e w o n s e t of urethral d i s c h a r g e . T h e p a t i e n t h a d n o n e of t h e m o r e c h a r a c t e r i s t i c s i g n s of s e c o n d a r y syphilis. T h e liver e n z y m e abnormalities rapidly r e s o l v e d after t r e a t m e n t w i t h p e n i c i l l i n . Syphilis r e m a i n s t h e great impostor a n d still m u s t b e c o n s i d e r e d i n t h e differential d i a g n o s i s of u n e x p l a i n e d liver e n z y m e abnor m a l i t i e s , e v e n i n a p a t i e n t w i t h n o s y m p t o m s o r s i g n s of early syphilis.
Although thought to be rare, liver involvement in patients with syphilis is not uncommon. In more t h a n 50% of cases of secondary syphilis, increased liver e n z y m e v a l u e s can be detected and m a y become c h r o n i c ' Clinical hepatitis i s rare, a s is concomitant renal involvement.'"' If other clinical s y m p t o m s and signs of syphilis are absent, t h e diagnosis m u s t be based on high diagnostic acuity a n d serologic testing, a s t h e following case illustrates.
REPORT OF CASE In February 1988, an asymptomatic 25-year-old m a n w a s referred for a s s e s s m e n t of abnormal cholestatic liver enzyme values, discovered during an evaluation for low-grade proteinuria, During t h e initial physical examination, 3-tproteinuria w a s found on routine urinalysis. A 24-hour urine collection showed excretion of 850 m g of protein per 2 4 hours (normal, 0 to 150 mg/ 2 4 h). A multichemistry profile included t h e following: alkaline phosphatase, 7 6 8 U/liter (normal, 3 0 to 115 U/liter); γ-glutamyltransfer-
The views expressed herein are those ofthe authors and do not reflect the official views ofthe US Navy, the Department
9»^, 6 5 6 U/liter (normal, 0 to 6 5 U/liter); lactate dehydrogenase, 194 U/liter (normal, 6 0 to 225 U /
of Defense, or the US government.
liter); aspartate aminotransferase, 188 U/liter
Address reprint requests to Dr. R. E. Sedlack, Division of Gastroenterology, Mayo Clinic, Rochester, MN 55905.
("ormal, 0 to 4 0 U/liter); a l a n i n e aminotransferase, 2 8 8 U/liter (normal, 10 to 6 0 U/liter); and
Mayo Clin Proc
65:1365-1367,1990
1365
1366 UNSUSPECTED SYPHILITIC HEPATITIS
total bilirubin, 0.7 mg/dl (normal, 0.2 to 1.2 mg/ dl). A rapid p l a s m a reagin t e s t w a s negative. The fluorescent treponemal antibody absorption t e s t w a s not done. The patient denied h a v i n g a history of expo sure to hepatitis, intravenous drug abuse, homo sexuality, tattoos, or blood transfusions or any constitutional symptoms. Specifically, he said that he had h a d 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 w i t h hepa titis B, hepatitis A, Epstein-Barr virus, cytomega lovirus, or h u m a n immunodeficiency virus. Other laboratory data were as follows: serum ceruloplasmin, 60 mg/dl (normal, 2 1 to 53 mg/dl); ferritin, 325 μg/liter (normal, 18 to 2 5 0 μg/liter); antinuclear antibody, positive at 1:10; and antimitochondrial antibody, positive at 1:40. The patient w a s observed clinically for 6 months. During this period, no significant change occurred in his liver function tests, and he re mained asymptomatic. Endoscopic retrograde cholangiopancreatography yielded normal re sults. A liver biopsy specimen showed mild portal inflammation and mild hepatocellular unrest. N o evidence of cholestasis or organisms w a s noted. Shortly after t h e s e procedures, a clear ure thral discharge and pyuria developed. A ure thral culture w a s negative for Neisseria gonor rhoeae; however, a rapid p l a s m a reagin t e s t w a s positive at a titer of 1:128, and the fluorescent treponemal antibody absorption t e s t also w a s positive. The patient w a s treated with benzathine penicillin, 2.4 million units intramuscularly. N o Jarisch-Herxheimer reaction w a s noted. One week later, his liver e n z y m e values had become normal. The proteinuria (800 mg/24 h) persisted for 6 m o n t h s after penicillin treatment, but the rapid p l a s m a 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 intramem-
Mayo Clin Proc, October 1990, Vol 65
Fig. 1. Electron micrograph, showing irregular thickening of basement membrane due to presence of electron-lucent immunologic deposits (arrows), consistent with resolving membranous glomerulonephritis. (x22,800.)
branous electron-lucent immunologic deposits, a finding consistent with resolving membra nous nephropathy. DISCUSSION Hepatic involvement in early syphilis h a s been known since 1585, w h e n it w a s first reported by Paracelsus.'' A review of 10,000 cases of early syphilis by Hahn"^ in the preantibiotic era dem onstrated that clinical hepatitis w a s 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.' The potential for prolonged abnormalities on liver enzyme tests in secondary syphilis h a s 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 chole stasis with a substantially increased alkaline phosphatase value and minor increases in the aminotransferases.'* ** Jaundice is uncommon.*
Mayo Clin Proc, October 1990, Vol 65
This Hver enzyme picture is thought to be re lated to t h e pericholangiolar inflammation t h a t frequently is evident on liver biopsy. '·"' In early syphilis, histologic changes in the liver can be variable and nonspecific, including portal in flammatory infiltrates, hepatocellular necrosis, granuloma, and, rarely, cholestasis.'*" Spiro chetes are detected infrequently on histologic examination.' The response to penicillin usually is rapid, and liver e n z y m e v a l u e s become normal in days to w e e k s , although delayed reso lution h a s b e e n r e p o r t e d . ' * " " A JarischHerxheimer reaction can occur." Concomitant renal and hepatic involvement, which can occur rarely, usually consists of chole static liver e n z y m e values and mild protein u r i a . ' ' ' A more severe clinical picture with nephrotic range proteinuria h a s been reported in association with liver d i s e a s e . ' Both renal and hepatic involvement is typically noted at the time the rash of secondary syphilis appears.' The renal lesion in secondary syphilis s e e m s to be related to the deposition of i m m u n e com plexes in the glomerulus.''^ These antitreponemal antibodies consist of IgG and C3 in a sub epithelial location.'^ Electron microscopy can disclose fusion of the epithelial foot p r o c e s s e s . " Unlike the situation in the case presented herein, the proteinuria usually responds favorably to antibiotic t r e a t m e n t within w e e k s and m a y even resolve spontaneously."'-' Although we cannot prove that this patient's renal lesion w a s due to treated syphilitic nephritis, several factors sug gest such an association. The low titer on a repeat rapid p l a s m a reagin t e s t did not suggest active infection, and the renal biopsy specimen lacked electron-dense immunologic deposits consistent with an ongoing process. The intram e m b r a n o u s location of the deposits and the lack of fluorescent staining for immunoglobulins also suggest that this lesion w a s resolving. Other diseases to be considered in the differ ential diagnosis of hepatitis in association with nephritis include hepatitis B, a u t o i m m u n e dis ease, malaria, leptospirosis, tuberculosis, lym phoma, and Stauffer's syndrome. Stauffer's syndrome, first diagnosed at the Mayo Clinic in 1961, consists of reversible low-grade transami-
UNSUSPECTED SYPHILITIC HEPATITIS 1367
n a s e m i a , increased alkaline phosphatase, and hepatosplenomegaly in association with nonmetastatic 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. CONCLUSION E v e n today, syphilis remains the great impostor and should be considered in cases of obscure or chronic liver disease, especially w h e n associated with proteinuria. High-titer serologic results and a prompt response to penicillin treatment are diagnostic. REFERENCES 1. SchlossbergD: Syphilitic hepatitis: a case report and review ofthe literature. Am J Gastroenterol 82:552553, 1987 2. Morrison 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 25:875-878, 1980 3. McMillan A, Anderson JR, Robertson DHH: Hepati tis in early syphilis: report of three cases. BrJVener Dis 53:295-298, 1977 4. Paracelsus: Cited by Schlossberg D' 5. Hahn RD: Cited by McMillan A, Anderson JR, Robertson D H f f 6. Tiliakos N, Shamma'a JM, Nasrallah SM: Syphilitic hepatitis. Am J Gastroenterol 73:60-61, 1980 7. Keisler DS Jr, Starke W, Looney DJ, Mark WW Jr: Early syphilis with liver involvement. JAMA 247:1999-2000, 1982 8. Petersen LR, Mead RH, Perlroth MG: Unusual manifestations of secondary syphilis occurring after orthotopic liver transplantation. Am J Med 75:166170, 1983 9. Young E, Bahr G, Waye JD: The Jarisch-Herxheimer reaction in syphilitic hepatitis. Am J Gastroenterol 61:476-477, 1974 10. Hjort M, Olsson R, Smith U, Zettergren L: Hepatitis in secondary syphilis. Scand J Infect Dis 9:59-61, 1977 11. Campisi D, Whitcomb C: Liver disease in early syphilis. Arch Intern Med 139:365-366, 1979 12. Bansal RC, Cohn H, Fani K, Lynfield YL: Nephrotic syndrome and granulomatous hepatitis in secondary syphilis. Arch Dermatol 114:1228-1229,1978 13. Gamble CN, Reardan JB: Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits. Ν Engl J Med 292:449-454, 1975
ELLEN K. BLAIR, M.D., Naval Medical Clinic, Quantico, Virginia; RICHARD E. SEDLACK, M.D., Division of Gastroenterology and Internal Medicine; J O S E P H P. SNYDER, M.D., J. MARK LAWSON, M.D., United States Naval Hospital, Portsmouth, Virginia
A 25-year-old p a t i e n t w a s found t o h a v e c h o l e s t a t i c liver e n z y m e abnormalities d u r i n g a s s e s s m e n t for a s y m p t o m a t i c low-grade p r o t e i n u r i a at t h e U S Naval Hospital i n P o r t s m o u t h , Virginia. T h e s e a b n o r m a l i t i e s p e r s i s t e d for a 6-month period, a n d a n e x t e n s i v e w o r k u p , i n c l u d i n g viral serologic s t u d i e s , rapid p l a s m a reagin test, iron s t u d i e s , c e r u l o p l a s m i n , a n t i m i t o c h o n d r i a l , a n t i n u c l e a r , a n d anti-human i m m u n o d e ficiency v i r u s a n t i b o d i e s , e n d o s c o p i c retrograde c h o l a n g i o p a n c r e a t o g r a p h y , a n d liver biopsy, w a s u n r e v e a l i n g until serologic t e s t s for s y p h i l i s w e r e r e p e a t e d t o e v a l u a t e a n e w o n s e t of urethral d i s c h a r g e . T h e p a t i e n t h a d n o n e of t h e m o r e c h a r a c t e r i s t i c s i g n s of s e c o n d a r y syphilis. T h e liver e n z y m e abnormalities rapidly r e s o l v e d after t r e a t m e n t w i t h p e n i c i l l i n . Syphilis r e m a i n s t h e great impostor a n d still m u s t b e c o n s i d e r e d i n t h e differential d i a g n o s i s of u n e x p l a i n e d liver e n z y m e abnor m a l i t i e s , e v e n i n a p a t i e n t w i t h n o s y m p t o m s o r s i g n s of early syphilis.
Although thought to be rare, liver involvement in patients with syphilis is not uncommon. In more t h a n 50% of cases of secondary syphilis, increased liver e n z y m e v a l u e s can be detected and m a y become c h r o n i c ' Clinical hepatitis i s rare, a s is concomitant renal involvement.'"' If other clinical s y m p t o m s and signs of syphilis are absent, t h e diagnosis m u s t be based on high diagnostic acuity a n d serologic testing, a s t h e following case illustrates.
REPORT OF CASE In February 1988, an asymptomatic 25-year-old m a n w a s referred for a s s e s s m e n t of abnormal cholestatic liver enzyme values, discovered during an evaluation for low-grade proteinuria, During t h e initial physical examination, 3-tproteinuria w a s found on routine urinalysis. A 24-hour urine collection showed excretion of 850 m g of protein per 2 4 hours (normal, 0 to 150 mg/ 2 4 h). A multichemistry profile included t h e following: alkaline phosphatase, 7 6 8 U/liter (normal, 3 0 to 115 U/liter); γ-glutamyltransfer-
The views expressed herein are those ofthe authors and do not reflect the official views ofthe US Navy, the Department
9»^, 6 5 6 U/liter (normal, 0 to 6 5 U/liter); lactate dehydrogenase, 194 U/liter (normal, 6 0 to 225 U /
of Defense, or the US government.
liter); aspartate aminotransferase, 188 U/liter
Address reprint requests to Dr. R. E. Sedlack, Division of Gastroenterology, Mayo Clinic, Rochester, MN 55905.
("ormal, 0 to 4 0 U/liter); a l a n i n e aminotransferase, 2 8 8 U/liter (normal, 10 to 6 0 U/liter); and
Mayo Clin Proc
65:1365-1367,1990
1365
1366 UNSUSPECTED SYPHILITIC HEPATITIS
total bilirubin, 0.7 mg/dl (normal, 0.2 to 1.2 mg/ dl). A rapid p l a s m a reagin t e s t w a s negative. The fluorescent treponemal antibody absorption t e s t w a s not done. The patient denied h a v i n g a history of expo sure to hepatitis, intravenous drug abuse, homo sexuality, tattoos, or blood transfusions or any constitutional symptoms. Specifically, he said that he had h a d 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 w i t h hepa titis B, hepatitis A, Epstein-Barr virus, cytomega lovirus, or h u m a n immunodeficiency virus. Other laboratory data were as follows: serum ceruloplasmin, 60 mg/dl (normal, 2 1 to 53 mg/dl); ferritin, 325 μg/liter (normal, 18 to 2 5 0 μg/liter); antinuclear antibody, positive at 1:10; and antimitochondrial antibody, positive at 1:40. The patient w a s observed clinically for 6 months. During this period, no significant change occurred in his liver function tests, and he re mained asymptomatic. Endoscopic retrograde cholangiopancreatography yielded normal re sults. A liver biopsy specimen showed mild portal inflammation and mild hepatocellular unrest. N o evidence of cholestasis or organisms w a s noted. Shortly after t h e s e procedures, a clear ure thral discharge and pyuria developed. A ure thral culture w a s negative for Neisseria gonor rhoeae; however, a rapid p l a s m a reagin t e s t w a s positive at a titer of 1:128, and the fluorescent treponemal antibody absorption t e s t also w a s positive. The patient w a s treated with benzathine penicillin, 2.4 million units intramuscularly. N o Jarisch-Herxheimer reaction w a s noted. One week later, his liver e n z y m e values had become normal. The proteinuria (800 mg/24 h) persisted for 6 m o n t h s after penicillin treatment, but the rapid p l a s m a 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 intramem-
Mayo Clin Proc, October 1990, Vol 65
Fig. 1. Electron micrograph, showing irregular thickening of basement membrane due to presence of electron-lucent immunologic deposits (arrows), consistent with resolving membranous glomerulonephritis. (x22,800.)
branous electron-lucent immunologic deposits, a finding consistent with resolving membra nous nephropathy. DISCUSSION Hepatic involvement in early syphilis h a s been known since 1585, w h e n it w a s first reported by Paracelsus.'' A review of 10,000 cases of early syphilis by Hahn"^ in the preantibiotic era dem onstrated that clinical hepatitis w a s 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.' The potential for prolonged abnormalities on liver enzyme tests in secondary syphilis h a s 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 chole stasis with a substantially increased alkaline phosphatase value and minor increases in the aminotransferases.'* ** Jaundice is uncommon.*
Mayo Clin Proc, October 1990, Vol 65
This Hver enzyme picture is thought to be re lated to t h e pericholangiolar inflammation t h a t frequently is evident on liver biopsy. '·"' In early syphilis, histologic changes in the liver can be variable and nonspecific, including portal in flammatory infiltrates, hepatocellular necrosis, granuloma, and, rarely, cholestasis.'*" Spiro chetes are detected infrequently on histologic examination.' The response to penicillin usually is rapid, and liver e n z y m e v a l u e s become normal in days to w e e k s , although delayed reso lution h a s b e e n r e p o r t e d . ' * " " A JarischHerxheimer reaction can occur." Concomitant renal and hepatic involvement, which can occur rarely, usually consists of chole static liver e n z y m e values and mild protein u r i a . ' ' ' A more severe clinical picture with nephrotic range proteinuria h a s been reported in association with liver d i s e a s e . ' Both renal and hepatic involvement is typically noted at the time the rash of secondary syphilis appears.' The renal lesion in secondary syphilis s e e m s to be related to the deposition of i m m u n e com plexes in the glomerulus.''^ These antitreponemal antibodies consist of IgG and C3 in a sub epithelial location.'^ Electron microscopy can disclose fusion of the epithelial foot p r o c e s s e s . " Unlike the situation in the case presented herein, the proteinuria usually responds favorably to antibiotic t r e a t m e n t within w e e k s and m a y even resolve spontaneously."'-' Although we cannot prove that this patient's renal lesion w a s due to treated syphilitic nephritis, several factors sug gest such an association. The low titer on a repeat rapid p l a s m a reagin t e s t did not suggest active infection, and the renal biopsy specimen lacked electron-dense immunologic deposits consistent with an ongoing process. The intram e m b r a n o u s location of the deposits and the lack of fluorescent staining for immunoglobulins also suggest that this lesion w a s resolving. Other diseases to be considered in the differ ential diagnosis of hepatitis in association with nephritis include hepatitis B, a u t o i m m u n e dis ease, malaria, leptospirosis, tuberculosis, lym phoma, and Stauffer's syndrome. Stauffer's syndrome, first diagnosed at the Mayo Clinic in 1961, consists of reversible low-grade transami-
UNSUSPECTED SYPHILITIC HEPATITIS 1367
n a s e m i a , increased alkaline phosphatase, and hepatosplenomegaly in association with nonmetastatic 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. CONCLUSION E v e n today, syphilis remains the great impostor and should be considered in cases of obscure or chronic liver disease, especially w h e n associated with proteinuria. High-titer serologic results and a prompt response to penicillin treatment are diagnostic. REFERENCES 1. SchlossbergD: Syphilitic hepatitis: a case report and review ofthe literature. Am J Gastroenterol 82:552553, 1987 2. Morrison 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 25:875-878, 1980 3. McMillan A, Anderson JR, Robertson DHH: Hepati tis in early syphilis: report of three cases. BrJVener Dis 53:295-298, 1977 4. Paracelsus: Cited by Schlossberg D' 5. Hahn RD: Cited by McMillan A, Anderson JR, Robertson D H f f 6. Tiliakos N, Shamma'a JM, Nasrallah SM: Syphilitic hepatitis. Am J Gastroenterol 73:60-61, 1980 7. Keisler DS Jr, Starke W, Looney DJ, Mark WW Jr: Early syphilis with liver involvement. JAMA 247:1999-2000, 1982 8. Petersen LR, Mead RH, Perlroth MG: Unusual manifestations of secondary syphilis occurring after orthotopic liver transplantation. Am J Med 75:166170, 1983 9. Young E, Bahr G, Waye JD: The Jarisch-Herxheimer reaction in syphilitic hepatitis. Am J Gastroenterol 61:476-477, 1974 10. Hjort M, Olsson R, Smith U, Zettergren L: Hepatitis in secondary syphilis. Scand J Infect Dis 9:59-61, 1977 11. Campisi D, Whitcomb C: Liver disease in early syphilis. Arch Intern Med 139:365-366, 1979 12. Bansal RC, Cohn H, Fani K, Lynfield YL: Nephrotic syndrome and granulomatous hepatitis in secondary syphilis. Arch Dermatol 114:1228-1229,1978 13. Gamble CN, Reardan JB: Immunopathogenesis of syphilitic glomerulonephritis: elution of antitreponemal antibody from glomerular immune-complex deposits. Ν Engl J Med 292:449-454, 1975