Microbiological Agents Involved In Fitz-Hugh-Curtis Syndrome

Overview of fitz-hugh-curtis syndrome

Fitz-Hugh-Curtis syndrome (FHCS), sometimes known as perihepatitis, is inflammation around the liver capsule resulting from pelvic inflammatory disease (PID). Around 1 in 4 patients with PID experience FHCS as a complication.¹ PID occurs when bacteria from sexually transmitted infections (STIs) enter the upper reproductive tract. These bacteria can sometimes migrate from the pelvis and produce inflammation in the liver tissue, resulting in sticky strands that adhere the liver capsule to the diaphragm, which is known as FHCS. It is characterised by pain below the right ribs, where the liver is located. This rare condition predominantly affects individuals assigned female at birth (AFAB), particularly those who have not yet undergone menopause. 

Cause and pathophysiology

Since FHCS originates from PID, it is primarily caused by STIs. Microbiological agents that cause STIs include Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium, which can ascend from the lower reproductive tract to the upper reproductive tract. These microorganisms cause inflammation in the uterus, fallopian tubes, and/or ovaries, but they can sometimes spread outside the pelvis, such as to the liver. The precise mechanism by which the bacteria spread from the pelvis isn’t known, but there are three theories:¹

• Direct infection of the liver - Bacteria travel via the fallopian tubes and peritoneum to the liver 
• Hematogenous spread - Bacteria travel via the bloodstream. 
• Lymphatic spread 

Microbiological agents 

Chlamydia trachomatis

Chlamydia trachomatis is the most common causative agent of FHCS.² It has a unique infection cycle where the bacteria exist in two forms: the elementary body (EB) and the reticulate body (RB). EB is taken up by host cells, where it differentiates into RB and uses host energy sources to replicate and form new EB. These new EB can then go on to infect squamocolumnar epithelial cells of the cervical canal, among other sites.³ These infections are often asymptomatic, particularly in people with AFAB, making them difficult to diagnose quickly. As a result, Chlamydia trachomatis infections can develop into urethritis, cervicitis, or endometritis.⁴  Furthermore, Chlamydia infections increase vulnerability to other microbes, such as gram-positive bacteria and anaerobes.⁵

The most sensitive and specific test for detecting Chlamydia trachomatis is the nucleic acid amplification test (NAAT). For individuals with AFAB, a cervical swab is taken, which does not require the use of a speculum. Once lab testing confirms Chlamydia trachomatis, antibiotics such as doxycycline and azithromycin are prescribed. Doxycycline should be taken for a week, while azithromycin is typically taken for three days. In the UK, sexually active individuals under the age of 25, as well as those with new or casual sexual partners, should be tested annually to prevent the development of other conditions, such as PID or FHCS.

Neisseria gonorrhoeae

Neisseria gonorrhoeae is now thought to be the second most common causative agent of FHCS.²  Neisseria gonorrhoeae infections are often associated with higher rates of hospitalisation and complications, such as FHCS, in individuals with PID. This association is believed to be linked to the emergence of gonorrhoea antibiotic resistance.⁶  Additionally, in individuals with AFAB, Neisseria gonorrhoeae affects the cervix, causing cervicitis and highlighting the prevalence of secondary conditions associated with gonorrhoea. On a molecular level, infection begins with adhesion to epithelial cells by pili (hair-like projections from the bacteria). This adhesion induces the rearrangement of surface proteins, allowing the bacteria to enter host cells and initiate infection. 

Approximately 50% of infections are symptomatic in individuals with AFAB and over 90% in people assigned male at birth (AMAB).⁷ When an AFAB person has symptoms, they may experience pelvic pain and discoloured vaginal discharge. AMAB individuals may have unusual discharge from the penis and inflammation of the foreskin. Pain during urination is common. Like Chlamydia trachomatis, Neisseria gonorrhoeae is also diagnosed using NAATs. Treatment usually involves antibiotics, which are usually administered as an injection in the thigh or buttocks. Symptoms should improve within a few days, though pelvic pain may take longer to resolve. 

Ureaplasma urealyticum

Ureaplasma urealyticum is associated with FHCS in only a small percentage of cases. It is a commensal organism, meaning it normally lives in the urogenital tract of humans without causing health problems. However, overgrowth can cause pain and discomfort and may lead to FHCS. It is not usually considered an STI because it is not pathogenic in most people, although it can still be transmitted through unprotected sex, similar to STIs. Ureaplasma urealyticum is often asymptomatic,  leading to it being left untreated and potentially resulting in bacterial vaginosis, cervicitis, and PID. 

Mycoplasma genitalium and mycoplasma hominins 

Mycoplasma genitalium and Mycoplasma hominis both belong to the same genus of bacteria. They can infect the urogenital tract as well as the respiratory tract, due to their ability to adhere to mucous epithelial cells where they are then internalised. Similar to Ureaplasma urealyctium, Mycoplasma hominis is a commensal, whereas Mycoplasma genitalium is not. Mycoplasma hominis is linked with FHCS in only a small number of patients. The precise role of Mycoplasma genitalium in FHCS is less well defined, but it is known to contribute to FHCS through its close association with PID.⁸ 

Other bacteria

Microorganisms that have weak associations with FHCS include:⁹

• Mycobacterium tuberculosis 
• Anaerobic bacteria
• Other gram-negative bacteria 

In a significant number of cases, multiple microorganisms may be responsible for FHCS. It is also not unusual to fail to identify the specific causative microbe.⁹ In such cases, treating the condition with a variety of antibiotics is often the best approach.

Diagnosis

Diagnosing FHCS is challenging because its symptoms mimic those of other conditions, often requiring a process of elimination. It is most commonly mistaken for cholecystitis (inflammation of the gallbladder), especially when the pain below the ribs is more pronounced than pelvic pain.¹ 

Other conditions that need to be considered and ruled out include:

• Hepatitis 
• Cholelithiasis (gallstones)
• Pneumonia 
• Ectopic pregnancy
• Renal colic (kidney stone pain)
• Pyelonephritis (kidney infection)
• Appendicitis
• Pulmonary embolism

Diagnosis begins with a physical examination, where patients usually exhibit moderate to severe tenderness in the right upper quadrant (the right side beneath the ribs). A pelvic examination may detect vaginal discharge, cervical motion tenderness, or adnexal tenderness that the patient may not have noticed or felt.^1,5 Taking cervical swabs and testing for the presence of Neisseria gonorrhoeae and Chlamydia trachomatis is important for differential diagnosis, as it helps indicate FHCS or PID over other conditions. Additionally, taking a blood sample to detect liver enzyme levels can help rule out hepatitis.¹

Furthermore, radiographic studies are useful for ruling out alternative causes of pain. Chest and abdominal radiographs can eliminate pneumonia or free air under the diaphragm as potential causes. Ultrasounds evaluate the liver and gallbladder, thereby ruling out cholecystitis and cholelithiasis from the diagnosis. If the patient has FHCS, there will be peritoneal abnormalities on an ultrasound, as well as liver capsule enhancement.¹⁰ It may also reveal abscesses, such as tubo-ovarian abscesses, that would indicate chronic PID. A CT scan can demonstrate contrast enhancement of the liver capsule, which can be used to support the diagnosis.¹

Treatment and prevention

Initially, a combination of antibiotics will be administered to eliminate microbiological agents, and analgesics can be provided for pain management. In severe cases and/or the presence of complications, hospitalisation might be necessary to administer intravenous antibiotics or to perform surgical correction.¹¹ If antibiotics fail, either laparoscopy or traditional surgery may be used to remove adhesions and sticky strands connecting the diaphragm to the liver. 

However, the best way to avoid developing FHCS is to prevent contracting the microbes. To prevent FHCS:

• Practise safe sex by using condoms or another physical barrier method 
• Get regularly tested for STIs if sexually active, and ensure partners are also tested
• Avoid douching 

Summary

Fitz-Hugh-Curtis syndrome (FHCS) is a complication of PID that primarily affects people assigned to females at birth (AFAB). It is characterised by inflammation around the liver capsule, causing pain below the right ribs. The primary microbiological agents responsible for FHCS include Chlamydia trachomatis, Neisseria gonorrhoeae, as well as, in rare instances, Ureaplasma urealyticum, Mycoplasma genitalium, and Mycoplasma hominin. All of these microbes have the ability to ascend from the lower to the upper reproductive tract. Diagnosing FHCS involves ruling out other potential conditions and testing for the presence of bacteria, which is primarily done using NAATs. Treatment includes a range of antibiotics, with surgery required in severe cases, while prevention focuses on safe sex practices and regular STI testing.