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Syphilis Can Attack the Liver in HIV-Positive Men

April 23, 2009

Because syphilis is sexually transmitted, it is common for HIV and syphilis co-infection to occur, particular among men who have sex (MSM). This co-infection poses many problems, including these:

  • Treponemes, the germs that cause syphilis, are notorious for attacking many organ-systems throughout the body, including the brain, skin, lungs and heart.
  • In cases of HIV co-infection, syphilis seems to grow worse quickly and treponemes spread throughout the body faster than usual. In HIV co-infection, doctors have been reporting more cases of the dreaded neurosyphilis in early-stage syphilis.
  • Treponemes can damage the immune system and lower CD4+ cell counts.

A research team in San Diego, working with the United States military, has found that treponemes can apparently infect the liver and damage that organ, resulting in a condition called syphilitic hepatitis. The research team recently presented findings from two cases of this condition, which then stimulated them to search for more cases. Their findings suggest that syphilitic hepatitis may be more common among sexually active HIV positive men than previously suspected.


Case 1

Background: This was a 39-year-old HIV positive man who had been using highly active antiretroviral therapy (HAART) since 2001. His CD4+ count was about 400 cells and his viral load below 50 copies. In January 2008 he sought care because of these symptoms:

  • rash
  • joint pain
  • flu-like symptoms
  • headache

The rash began on the palms of his hands and soles of his feet but later spread to his torso. A physical exam revealed that he had swollen lymph nodes in his neck. Laboratory analysis of his blood samples showed that levels of liver enzymes in the blood were many, many times above the normal range seen at the lab, as follows:

  • AP (alkaline phosphatase) -- 1,838 international units (IU); normal range 38 to 126 IU
  • ALT (alanine aminotransferase) -- 264 IU; normal range 17 to 63 IU
  • AST (aspartate aminotransferase) -- 145 IU; normal range 15 to 41 IU

Tests did not detect any signs of current infection with hepatitis-causing viruses. So doctors suspected syphilis and results of the blood test for this were positive.

Because he had complained of headache, doctors performed a spinal tap but did not find any abnormalities. So they gave him a single intramuscular injection of 2.4 million units of benzathine penicillin. A week later blood tests found that his liver enzyme levels were still high but had started to decrease. Three months later liver enzyme levels were within the normal range and his symptoms had cleared.


Case 2

Background: This was a 25-year-old man whose CD4+ count was 446 cells and viral load nearly 12,000 copies. He was not taking HAART and sought medical care at the Emergency Department of the military medical centre because of these symptoms:

  • abdominal pain
  • loose stools
  • a feeling of constantly needing to empty his bowels

Lab tests of his blood did not reveal any elevated liver enzymes and doctors thought that he had some sort of infection attacking his rectum, so they prescribed medications -- ciprofloxacin (Cipro) and metronidazole (Flagyl) -- to treat a broad spectrum of sexually transmitted bacterial and parasitic infections.

Three weeks after his initial visit, he sought help from his family doctor, complaining of eye pain and reduced vision. A physical exam at that time revealed the following:

  • swollen lymph nodes in the neck
  • a genital ulcer
  • faint rash

An eye exam revealed inflammation in that organ.

Blood tests done at this second visit revealed higher-than-normal levels of liver enzymes in his blood, suggesting that his liver was inflamed. He had been vaccinated against hepatitis A and B viruses, and there was no evidence of hepatitis C virus infection. He said that he had not used alcohol and a spinal tap did not find any abnormalities. However, blood tests revealed that he likely had syphilis.

Because he had complained about his eye, it is possible that treponemes had affected it. Syphilis involving the eye usually means that treponemes have invaded the central nervous system and can gain access to the brain and spinal cord. So doctors gave him intravenous penicillin 24 million units daily for 14 days as well as anti-inflammatory eye drops. A month later his liver enzymes had returned to normal and his symptoms had cleared, including his eye problem.


The Study

Stimulated by these findings of syphilitic hepatitis, the research team decided to conduct a study in February 2008, assessing all HIV positive patients who sought care that month for syphilis and, in particular, syphilitic hepatitis.


Results

Among 600 HIV positive men who attended the naval clinic that month, 33 (6%) had syphilis. Moreover, 12 men (38%) with syphilis had syphilitic hepatitis. None of the 12 men had any obvious reason for elevated liver enzymes, such as alcohol use, hepatitis virus infections or use of liver-toxic medications (as evaluated by the researchers).

The average profile of the 12 men was as follows:

  • age -- 37 years
  • length of HIV infection -- 10 years
  • CD4+ count -- 340 cells
  • 75% of the men were taking HAART
  • 42% had a viral load below the 50-copy mark

Symptoms of syphilis that they had included these:

  • rash
  • swollen lymph nodes
  • sore throat

The proportion of the men with higher-than-normal levels of liver enzymes was as follows:

  • 100% had elevated levels of AP
  • 75% had elevated AST
  • 75% had elevated ALT

The doctors concluded that 11 of the men had hepatitis due to disseminated treponemes (secondary syphilis) and the remaining man had early-stage syphilis. All liver enzymes returned to normal after penicillin therapy, which varied from as little as a single injection of penicillin to 14 days of intravenous penicillin.

The researchers compared the men with syphilitic hepatitis to other HIV positive men with syphilis who did not have hepatitis and the only significant difference that they could find was that men with syphilitic hepatitis had been living with HIV for about 10 years vs. four years for the men without syphilitic hepatitis.

There was no apparent link between viral load, CD4+ cell count, the use of HAART and the development of syphilitic hepatitis.

In the ideal study, researchers would have monitored people over time and conducted liver biopsies and other in-depth techniques to isolate treponemes and assess liver damage by analysis of tissue samples. However, such studies are expensive and time consuming. Alerted by the San Diego research teams, it is possible that other research centres might be motivated to conduct a more detailed study.


A Long Time Ago

Results of autopsies of thousands of people with syphilis in the U.S., the UK and Spain in the first half of the 20th century suggested that hepatitis related to syphilis was uncommon, occurring in 0.2% to 5% of people depending on which country or region the autopsy was performed in. In those early years, when hepatitis occurred in people with syphilis, it seems to have been blamed on alcoholism. These findings likely influenced doctors' reluctance to conclude that syphilis did indeed affect the liver. But by 1970, some doctors in the UK and Hungary felt that the evidence was strong enough to make a diagnosis of syphilitic hepatitis, at least in some cases. And in the late 20th century, isolated reports of syphilitic hepatitis from around the world were published.

The recent results from San Diego suggest an unusually high degree of syphilitic hepatitis among HIV positive men. Hopefully, other research centres will also investigate this problem in their HIV positive patients.


Key Points

  • Syphilis can cause serious complications in HIV positive people.
  • Hepatitis related to syphilis seems to have been uncommon in the time before AIDS. However, one recent study has reported relatively high rates of this problem in people co-infected with HIV and syphilis.
  • In HIV positive people who have higher-than-normal levels of liver enzymes in the absence of other causes (alcohol abuse, hepatitis-causing viruses, liver-toxic medications, etc.), syphilis could be a cause of this problem.
  • Treatment of syphilis can reduce symptoms and decrease liver inflammation.
  • Safer-sexual practices can help reduce syphilis transmission.


References

  1. Lukehart SA, Hook EW 3rd, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Annals of Internal Medicine. 1988 Dec 1;109(11):855-62.
  2. Expert working group. Canadian guidelines on sexually transmitted infections. January 2008. Available at: http://www.phac-aspc.gc.ca/std-mts/sti_2006/sti_intro2006-eng.php. [Accessed April 1, 2009]
  3. Tramont EC. Treponema pallidum (syphilis). In: Mandell GL, Bennett JE and Dolin R, editors. Principles and Practice of Infectious Diseases. Sixth ed. Philadelphia: Elsevier; 2005. P. 2362-2379.
  4. Lukehart SA. Syphilis. In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison's Principles of Internal Medicine. 17th ed. McGraw-Hill Companies, Inc.; 2008. P. 956-962.
  5. Marra CM. Update on neurosyphilis. Current Infectious Disease Reports. 2009 Mar;11(2):127-34.
  6. Leber A, MacPherson P, Lee BC. Canadian Journal of Public Health. 2008 Sep-Oct;99(5):401-5
  7. Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008 Jun 19;22(10):1145-51.
  8. Kellock IA, Laird SM. Syphilis and hepatic cirrhosis. Editorial. Lancet. 1970 Feb 14;1(7642):369.
  9. Fehér J, Somogyi T, Timmer M, et al. Early syphilitic hepatitis. Lancet. 1975 Nov 8;2(7941):896-9.
  10. Sanofi-Adventis. Flagyl (metronidazole). Product monograph. September 27, 2007.
  11. Crum-Cianflone N, Weekes J, Bavaro M. Syphilitic hepatitis among HIV-infected patients. International Journal of STD and AIDS. 2009 Apr;20(4):278-84.
  12. Salazar JC, Cruz AR, Pope CD, et al. Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: a flow-cytometric analysis. Journal of Infectious Diseases. 2007 Mar 15;195(6):879-87.
  13. Knudsen A, Benfield T, Kofoed K. Cytokine expression during syphilis infection in HIV-1-infected individuals. Sexually Transmitted Diseases. 2009; in press.
  14. Kofoed K, Gerstoft J, Mathiesen LR, et al. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sexually Transmitted Diseases. 2006 Mar;33(3):143-8.


  
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This article was provided by Canadian AIDS Treatment Information Exchange. Visit CATIE's Web site to find out more about their activities, publications and services.
 
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