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Acute Liver Injury as a Manifestation of Secondary Syphilis

Acute Liver Injury as a Manifestation of Secondary Syphilis ACG CASE REPORTS JOURNAL CASE REPORT | LIVER Acute Liver Injury as a Manifestation of Secondary Syphilis 1 2 2 2 Jamil Shah, MD , Vivek Lingiah, MD , Mumtaz Niazi, MD , Raquel Olivo-Salcedo, MD , 2 3 4 Nikolaos Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP , Mark Galan, MD, MS , and Abul Shahidullah, MD Division of Gastroenterology and Hepatology, Department of Internal Medicine, the Brooklyn Hospital Center, Academic Affiliate of Icahn School of Medicine at Mount Sinai, Clinical Affiliate of the Mount Sinai Hospital, Brooklyn, NY Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ Department of Pathology, Immunology, and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ Department of Medicine, Henry J. Carter Specialty Hospital and Nursing Facility, New York, NY ABSTRACT In the United States, the incidence of new cases of syphilis has been rising. The number of cases of primary and secondary syphilis has continued to increase almost every year over the past 2 decades. Secondary syphilis has a variety of clinical manifestations. A frequently overlooked presentation is that of syphilitic hepatitis, which should be part of the differential diagnosis for patients with elevated liver enzymes, a maculopapular rash, and/or risk factors for contracting syphilis. In this study, we report a rare and unusual case of a man with a remote history of syphilis infection who developed acute liver injury. INTRODUCTION Syphilis is a chronic, systemic bacterial infection caused by Treponema pallidum. Even in the 21st century, the disease continues to be a public health challenge. The World Health Organization periodically generates a report of estimates of the global prevalence and incidence of the most common curable sexually transmitted infections. Based on prevalence data from 2009 to 2016, the estimated pooled global prevalence of syphilis in both men and women, aged 15–49 years, was 0.5% (95% confidence interval: 0.4–0.6) with regional values ranging from 0.1% to 1.6%. Among the 55 nations that participated, the median incidence rate of syphilis was 25.1 cases per 100,000 population. In the United States, in 2018, 35,063 cases of primary and secondary syphilis were reported, with an incidence rate of 10.8 cases per 100,000 population. Syphilis is a common disease, but syphilitic hepatitis is not as well known. 3–5 Among patients with syphilis, the reported incidence ranges from 0.2% to 9.7%. Furthermore, liver involvement can occur during any stage of the disease. In a 2018 systematic review that included 144 cases of syphilitic hepatitis, 128 (88.9%) had early syphilis (including primary and secondary syphilis), 7 (4.9%) had latent syphilis, and 9 (6.3%) had tertiary syphilis. Rarely, patients present with acute liver injury with markedly elevated liver enzymes and coagulopathy. In this study, we report a rare and unusual case of acute liver injury resulting from syphilis infection. CASE REPORT A 49-year-old Hispanic man with a history of essential hypertension, genital herpes, and a remote history of syphilis infection 10–12 years ago visited his local emergency department with severe right upper quadrant abdominal pain for 1 week. The pain was dull, aching, 6-7/10 in intensity, persistent, and nonradiating. He also experienced yellowish discoloration of the eyes, dark urine, fatigue, nausea, and poor appetite. He reported no skin lesions or rashes. The patient took losartan and denied taking any other medications, complementary and alternative therapies, or herbal supplements. He stated that he had completed antibiotic therapy for syphilis many years ago, but he could not provide details regarding his treatment course. He denied any drug allergies. He denied any history of alcohol use, intravenous drug use, smoking, acquiring ACG Case Rep J 2021;8:e00668. doi:10.14309/crj.0000000000000668. Published online: October 13, 2021 Correspondence: Jamil Shah, MD (jshahid00@gmail.com). ACG Case Reports Journal / Volume 8 acgcasereports.com 1 Shah et al Acute Liver Injury tattoos or piercings, receiving transfusions of blood or blood products, occupational exposure to toxins, or previous liver diseases. He denied any family history of liver disease. The patient was afebrile and hemodynamically stable. The physical examination was remarkable for icteric sclera and generalized jaundice. There were no rashes. He was fully alert and oriented. Initial liver chemistries showed aspartate aminotransferase 1,280 U/L, alanine aminotransferase 1,652 U/L, alkaline phos- phatase 147 U/L, total bilirubin 19.9 mg/dL, and direct bilirubin Figure 1. (A) 1003 and (B) 2003 magnification histopathology of 15.5 mg/dL. The international normalized ratio was 1.6. The the acute liver injury showing severe acute hepatitis with a portal, complete blood count showed white blood cells 6.2 3 103/uL, periportal, and lobular mixed inflammatory infiltrate comprising hemoglobin 15.1 g/dL, and platelet count 100 3 109/L. The lymphocytes, eosinophils, plasma cells, and extensive neutrophils. serum electrolytes and renal function were normal. No previous Zone 3 collapse and confluent necrosis are seen, abundant single- cell apoptosis and degenerative hepatocyte changes. Cholestasis is laboratory results were available. An abdominal ultrasound present. Trichrome and reticulin stains highlight the areas of con- revealed no hepatomegaly, no hepatic steatosis, no bile duct fluent necrosis, and the trichrome stain also shows increased peri- dilatation, and mild splenomegaly. portal fibrosis and sinusoidal fibrosis. The patient was transferred to a tertiary care liver transplant causes, drug-induced liver injury, autoimmune disorders, and center. He was started on intravenous N-acetylcysteine for sup- ischemic hepatitis. portive care. An magnetic resonance imaging/magnetic resonance cholangiopancreatography revealed normal liver size, no bile duct To the best of our knowledge, this is among the very few dilatation, mild splenomegaly, and no masses. A viral hepatitis reported cases of syphilitic hepatitis presenting as the sole panel showed immunity to the hepatitis B virus (HBV) as a result clinical manifestation of secondary syphilis. Furthermore, of previous natural HBV infection. The HBV DNA was un- when manifesting as acute hepatitis, syphilis is generally ac- detectable. Herpes simplex virus 2 IgG was positive, while tests for companied by an elevated alkaline phosphatase level, frequently herpes simplex virus 1/2 IgM, cytomegalovirus IgM, Epstein-Barr with normal or only mildly elevated aminotransferase levels. virus IgM, and human immunodeficiency virus were negative. An Rarely, as in this case, patients develop acute liver injury and autoimmune panel was positive for antinuclear antibodies (1:80) present with a mixed, rather than a purely cholestatic, picture. but was otherwise negative. A ceruloplasmin level and iron studies were normal. Serologic tests for rapid plasma reagin, followed by Liver biopsy typically shows focal hepatocyte necrosis, non- fluorescent treponemal antibody-absorption test, were reactive. caseating granulomas, and portal tracts with mixed inflammatory infiltrate. Importantly, immunohistochemical staining only de- Over the next several days, the liver chemistries showed no tects spirochetes in up to 50% of patients and, therefore, has poor meaningful improvement, the international normalized ratio 5,9,10 sensitivity for diagnosing syphilitic hepatitis. The presence of increased to 2.5, and the patient underwent a liver biopsy, which spirochetes is uncommon, but it is confirmatory. Penicillin is the showed severe acute hepatitis with a mixed inflammatory in- treatment of choice for all stages of syphilis. filtrate in the portal, periportal, and lobular areas (Figure 1). There were substantial areas of liver cell death along with cholestasis. The specimens were further immunostained for spirochetes and were positive (Figure 2). Because of uncertainty regarding his previous treatment course for syphilis, he was administered benzathine penicillin G. Afterward, his clinical status and liver enzymes gradually improved, and he was discharged home. DISCUSSION Syphilis is in the differential diagnosis of genital ulcers (primary syphilis, chancre) and a diffuse, symmetric maculopapular rash (secondary syphilis), particularly in patients at high risk of contracting syphilis. It is known as a “great imitator” because its symptomatology and physical examination findings in the different stages mimic a variety of other illnesses. In this case, other causes of hepatitis and chronic liver disease were ex- cluded. Notably, given the degree of liver enzyme elevations, in Figure 2. Histopathologic image of the patient’s acute liver injury this case, the differential diagnosis included other infectious from liver biopsy showing positive immunostaining for spirochetes. ACG Case Reports Journal / Volume 8 acgcasereports.com 2 Shah et al Acute Liver Injury Rarely, syphilitic hepatitis can lead to fulminant liver failure, as REFERENCES demonstrated in the case of a patient who ultimately needed 1. Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: Global prevalence and incidence estimates. liver transplantation. Given the morbidity and mortality re- Bull World Health Organ. 2019;97(8):548–62. lated to a missed diagnosis, keen suspicion, timely recognition, 2. Centers for Disease Control and Prevention (CDC). Sexually Transmitted Dis- and therapy are essential. This uncommon presentation high- ease Surveillance 2018. U.S. Department of Health and Human Services: Atlanta, GA, 2019. https://www.cdc.gov/std/stats18/default.htm. Accessed June 14, 2020. lights the importance of high clinical suspicion in identifying 3. Hahn RD. Syphilis of the liver. Am J Syph Gonorrhea Vener Dis. 1943;27: syphilis as a cause of unexplained acute liver injury. This case 529–62. should alert physicians to consider syphilis in the differential 4. Lee RV, Thornton GF, Conn HO. Liver disease associated with secondary syphilis. N Engl J Med. 1971;284(25):1423–5. diagnosis—even in patients who lack the common clinical 5. Feher ´ J, Somogyi T, Timmer M, Jozsa ´ L. Early syphilitic hepatitis. Lancet. manifestations of the disease. 1975;2(7941):896–9. 6. Huang J, Lin S, Wan B, Zhu Y. A systematic literature review of syphilitic hepatitis in adults. J Clin Transl Hepatol. 2018;6(3):306–9. 7. Hussain N, Igbinedion SO, Diaz R, Alexander JS, Boktor M, Knowles K. DISCLOSURES Liver cholestasis secondary to syphilis in an immunocompetent patient. Case Rep Hepatol. 2018;2018:8645068. Author contributions: J. Shah wrote the manuscript and is the 8. German MN, Matkowskyj KA, Hoffman RJ, Agarwal PD. A case of syph- guarantor of the article. V. Lingiah, M. Niazi, R. Olivo-Salcedo, ilitic hepatitis in an HIV-infected patient. Hum Pathol. 2018;79:184–7. N. Pyrsopoulos, and A. Shahidullah revised the manuscript for 9. Young MF, Sanowski RA, Manne RA. Syphilitic hepatitis. J Clin Gastro- enterol. 1992;15(2):174–6. intellectual content. M. Galan provided the images. 10. Pratt DS. Liver chemistry and function tests. In: Feldman M, Friedman LS, Brandt LJ (eds). Sleisenger and Fordtran’s Gastrointestinal and Liver Dis- Financial disclosure: None to report. ease. Elsevier: Philadelphia, PA, 2016, pp 1243–52. 11. Lo JO, Harrison RA, Hunter AJ. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation. J Infect. 2007;54(3):e115-7. Previous presentation: This case was presented at the American College of Gastroenterology Annual Scientific Meeting, Octo- ber 23–28, 2020; Virtual. Copyright:ª 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology. This is an open access article distributed Informed consent was obtained for this case report. under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used com- Received June 18, 2020; Accepted May 7, 2021 mercially without permission from the journal. ACG Case Reports Journal / Volume 8 acgcasereports.com 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png ACG Case Reports Journal Wolters Kluwer Health

Acute Liver Injury as a Manifestation of Secondary Syphilis

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© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.
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ACG CASE REPORTS JOURNAL CASE REPORT | LIVER Acute Liver Injury as a Manifestation of Secondary Syphilis 1 2 2 2 Jamil Shah, MD , Vivek Lingiah, MD , Mumtaz Niazi, MD , Raquel Olivo-Salcedo, MD , 2 3 4 Nikolaos Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP , Mark Galan, MD, MS , and Abul Shahidullah, MD Division of Gastroenterology and Hepatology, Department of Internal Medicine, the Brooklyn Hospital Center, Academic Affiliate of Icahn School of Medicine at Mount Sinai, Clinical Affiliate of the Mount Sinai Hospital, Brooklyn, NY Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ Department of Pathology, Immunology, and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ Department of Medicine, Henry J. Carter Specialty Hospital and Nursing Facility, New York, NY ABSTRACT In the United States, the incidence of new cases of syphilis has been rising. The number of cases of primary and secondary syphilis has continued to increase almost every year over the past 2 decades. Secondary syphilis has a variety of clinical manifestations. A frequently overlooked presentation is that of syphilitic hepatitis, which should be part of the differential diagnosis for patients with elevated liver enzymes, a maculopapular rash, and/or risk factors for contracting syphilis. In this study, we report a rare and unusual case of a man with a remote history of syphilis infection who developed acute liver injury. INTRODUCTION Syphilis is a chronic, systemic bacterial infection caused by Treponema pallidum. Even in the 21st century, the disease continues to be a public health challenge. The World Health Organization periodically generates a report of estimates of the global prevalence and incidence of the most common curable sexually transmitted infections. Based on prevalence data from 2009 to 2016, the estimated pooled global prevalence of syphilis in both men and women, aged 15–49 years, was 0.5% (95% confidence interval: 0.4–0.6) with regional values ranging from 0.1% to 1.6%. Among the 55 nations that participated, the median incidence rate of syphilis was 25.1 cases per 100,000 population. In the United States, in 2018, 35,063 cases of primary and secondary syphilis were reported, with an incidence rate of 10.8 cases per 100,000 population. Syphilis is a common disease, but syphilitic hepatitis is not as well known. 3–5 Among patients with syphilis, the reported incidence ranges from 0.2% to 9.7%. Furthermore, liver involvement can occur during any stage of the disease. In a 2018 systematic review that included 144 cases of syphilitic hepatitis, 128 (88.9%) had early syphilis (including primary and secondary syphilis), 7 (4.9%) had latent syphilis, and 9 (6.3%) had tertiary syphilis. Rarely, patients present with acute liver injury with markedly elevated liver enzymes and coagulopathy. In this study, we report a rare and unusual case of acute liver injury resulting from syphilis infection. CASE REPORT A 49-year-old Hispanic man with a history of essential hypertension, genital herpes, and a remote history of syphilis infection 10–12 years ago visited his local emergency department with severe right upper quadrant abdominal pain for 1 week. The pain was dull, aching, 6-7/10 in intensity, persistent, and nonradiating. He also experienced yellowish discoloration of the eyes, dark urine, fatigue, nausea, and poor appetite. He reported no skin lesions or rashes. The patient took losartan and denied taking any other medications, complementary and alternative therapies, or herbal supplements. He stated that he had completed antibiotic therapy for syphilis many years ago, but he could not provide details regarding his treatment course. He denied any drug allergies. He denied any history of alcohol use, intravenous drug use, smoking, acquiring ACG Case Rep J 2021;8:e00668. doi:10.14309/crj.0000000000000668. Published online: October 13, 2021 Correspondence: Jamil Shah, MD (jshahid00@gmail.com). ACG Case Reports Journal / Volume 8 acgcasereports.com 1 Shah et al Acute Liver Injury tattoos or piercings, receiving transfusions of blood or blood products, occupational exposure to toxins, or previous liver diseases. He denied any family history of liver disease. The patient was afebrile and hemodynamically stable. The physical examination was remarkable for icteric sclera and generalized jaundice. There were no rashes. He was fully alert and oriented. Initial liver chemistries showed aspartate aminotransferase 1,280 U/L, alanine aminotransferase 1,652 U/L, alkaline phos- phatase 147 U/L, total bilirubin 19.9 mg/dL, and direct bilirubin Figure 1. (A) 1003 and (B) 2003 magnification histopathology of 15.5 mg/dL. The international normalized ratio was 1.6. The the acute liver injury showing severe acute hepatitis with a portal, complete blood count showed white blood cells 6.2 3 103/uL, periportal, and lobular mixed inflammatory infiltrate comprising hemoglobin 15.1 g/dL, and platelet count 100 3 109/L. The lymphocytes, eosinophils, plasma cells, and extensive neutrophils. serum electrolytes and renal function were normal. No previous Zone 3 collapse and confluent necrosis are seen, abundant single- cell apoptosis and degenerative hepatocyte changes. Cholestasis is laboratory results were available. An abdominal ultrasound present. Trichrome and reticulin stains highlight the areas of con- revealed no hepatomegaly, no hepatic steatosis, no bile duct fluent necrosis, and the trichrome stain also shows increased peri- dilatation, and mild splenomegaly. portal fibrosis and sinusoidal fibrosis. The patient was transferred to a tertiary care liver transplant causes, drug-induced liver injury, autoimmune disorders, and center. He was started on intravenous N-acetylcysteine for sup- ischemic hepatitis. portive care. An magnetic resonance imaging/magnetic resonance cholangiopancreatography revealed normal liver size, no bile duct To the best of our knowledge, this is among the very few dilatation, mild splenomegaly, and no masses. A viral hepatitis reported cases of syphilitic hepatitis presenting as the sole panel showed immunity to the hepatitis B virus (HBV) as a result clinical manifestation of secondary syphilis. Furthermore, of previous natural HBV infection. The HBV DNA was un- when manifesting as acute hepatitis, syphilis is generally ac- detectable. Herpes simplex virus 2 IgG was positive, while tests for companied by an elevated alkaline phosphatase level, frequently herpes simplex virus 1/2 IgM, cytomegalovirus IgM, Epstein-Barr with normal or only mildly elevated aminotransferase levels. virus IgM, and human immunodeficiency virus were negative. An Rarely, as in this case, patients develop acute liver injury and autoimmune panel was positive for antinuclear antibodies (1:80) present with a mixed, rather than a purely cholestatic, picture. but was otherwise negative. A ceruloplasmin level and iron studies were normal. Serologic tests for rapid plasma reagin, followed by Liver biopsy typically shows focal hepatocyte necrosis, non- fluorescent treponemal antibody-absorption test, were reactive. caseating granulomas, and portal tracts with mixed inflammatory infiltrate. Importantly, immunohistochemical staining only de- Over the next several days, the liver chemistries showed no tects spirochetes in up to 50% of patients and, therefore, has poor meaningful improvement, the international normalized ratio 5,9,10 sensitivity for diagnosing syphilitic hepatitis. The presence of increased to 2.5, and the patient underwent a liver biopsy, which spirochetes is uncommon, but it is confirmatory. Penicillin is the showed severe acute hepatitis with a mixed inflammatory in- treatment of choice for all stages of syphilis. filtrate in the portal, periportal, and lobular areas (Figure 1). There were substantial areas of liver cell death along with cholestasis. The specimens were further immunostained for spirochetes and were positive (Figure 2). Because of uncertainty regarding his previous treatment course for syphilis, he was administered benzathine penicillin G. Afterward, his clinical status and liver enzymes gradually improved, and he was discharged home. DISCUSSION Syphilis is in the differential diagnosis of genital ulcers (primary syphilis, chancre) and a diffuse, symmetric maculopapular rash (secondary syphilis), particularly in patients at high risk of contracting syphilis. It is known as a “great imitator” because its symptomatology and physical examination findings in the different stages mimic a variety of other illnesses. In this case, other causes of hepatitis and chronic liver disease were ex- cluded. Notably, given the degree of liver enzyme elevations, in Figure 2. Histopathologic image of the patient’s acute liver injury this case, the differential diagnosis included other infectious from liver biopsy showing positive immunostaining for spirochetes. ACG Case Reports Journal / Volume 8 acgcasereports.com 2 Shah et al Acute Liver Injury Rarely, syphilitic hepatitis can lead to fulminant liver failure, as REFERENCES demonstrated in the case of a patient who ultimately needed 1. Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: Global prevalence and incidence estimates. liver transplantation. Given the morbidity and mortality re- Bull World Health Organ. 2019;97(8):548–62. lated to a missed diagnosis, keen suspicion, timely recognition, 2. Centers for Disease Control and Prevention (CDC). Sexually Transmitted Dis- and therapy are essential. This uncommon presentation high- ease Surveillance 2018. U.S. Department of Health and Human Services: Atlanta, GA, 2019. https://www.cdc.gov/std/stats18/default.htm. Accessed June 14, 2020. lights the importance of high clinical suspicion in identifying 3. Hahn RD. Syphilis of the liver. Am J Syph Gonorrhea Vener Dis. 1943;27: syphilis as a cause of unexplained acute liver injury. This case 529–62. should alert physicians to consider syphilis in the differential 4. Lee RV, Thornton GF, Conn HO. Liver disease associated with secondary syphilis. N Engl J Med. 1971;284(25):1423–5. diagnosis—even in patients who lack the common clinical 5. Feher ´ J, Somogyi T, Timmer M, Jozsa ´ L. Early syphilitic hepatitis. Lancet. manifestations of the disease. 1975;2(7941):896–9. 6. Huang J, Lin S, Wan B, Zhu Y. A systematic literature review of syphilitic hepatitis in adults. J Clin Transl Hepatol. 2018;6(3):306–9. 7. Hussain N, Igbinedion SO, Diaz R, Alexander JS, Boktor M, Knowles K. DISCLOSURES Liver cholestasis secondary to syphilis in an immunocompetent patient. Case Rep Hepatol. 2018;2018:8645068. Author contributions: J. Shah wrote the manuscript and is the 8. German MN, Matkowskyj KA, Hoffman RJ, Agarwal PD. A case of syph- guarantor of the article. V. Lingiah, M. Niazi, R. Olivo-Salcedo, ilitic hepatitis in an HIV-infected patient. Hum Pathol. 2018;79:184–7. N. Pyrsopoulos, and A. Shahidullah revised the manuscript for 9. Young MF, Sanowski RA, Manne RA. Syphilitic hepatitis. J Clin Gastro- enterol. 1992;15(2):174–6. intellectual content. M. Galan provided the images. 10. Pratt DS. Liver chemistry and function tests. In: Feldman M, Friedman LS, Brandt LJ (eds). Sleisenger and Fordtran’s Gastrointestinal and Liver Dis- Financial disclosure: None to report. ease. Elsevier: Philadelphia, PA, 2016, pp 1243–52. 11. Lo JO, Harrison RA, Hunter AJ. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation. J Infect. 2007;54(3):e115-7. Previous presentation: This case was presented at the American College of Gastroenterology Annual Scientific Meeting, Octo- ber 23–28, 2020; Virtual. Copyright:ª 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology. This is an open access article distributed Informed consent was obtained for this case report. under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used com- Received June 18, 2020; Accepted May 7, 2021 mercially without permission from the journal. ACG Case Reports Journal / Volume 8 acgcasereports.com 3

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Published: Oct 13, 2021

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