Fever and cholestasis in a male

A 53-year-old man, without any past medical condition, was referred to our liver unit because of jaundice. The patient reported 3 weeks of general malaise, fever, chills and sweats. During the last week, jaundice and choluria appeared. Blood tests revealed a cholestatic hepatitis with alkaline phosphatase 649 U/L (normal range [N] <116 U/L), gamma-glutamyltransferase 804 U/L (N <40 U/L), aspartate aminotransferase 65 U/L (N <40 U/L), alanine aminotransferase 143 U/L (N <40 U/L), total bilirubin 3.6 mg/dl (N <1.0 mg/dl), and C-reactive protein 9.78 mg/dl (N <1.0 mg/dl). An enlarged spleen was observed on abdominal ultrasound, but no alterations were observed in the liver parenchyma or biliary tract. Blood and urine cultures were negative. Serologies for hepatitis A, B, C and E were negative, the same for cytomegalovirus and other herpes viruses. Autoantibodies were also negative (except anti-M2), and no evidence of inherited metabolic disorders was found. Because of these results, new blood tests were performed and a liver biopsy was obtained (Fig. 1). -Tuberculosis-Q fever-Sarcoidosis-Primary Biliary Cholangitis New blood tests included Coxiella burnetti serologies that were positive (IgM 1/80 and IgG 1/320). Quantiferon, and serological tests for Brucella species, Treponema pallidum and other less common infectious diseases were negative. In our case, tuberculosis and other infections were ruled out, primary biliary cholangitis was unlikely due to the presence of fever for 2 weeks (anti-M2 was negative after performing a new measurement of antibodies), and the patient was not receiving any treatments. Taken together, the presence of an enlarged spleen, fever, hepatic granulomas and positive serological tests for Coxiella burnetti, confirmed the diagnosis of Q fever. Treatment with doxycycline was started and the patient was discharged. Fever disappeared rapidly and liver enzyme tests normalized within a few weeks. Q fever is a disease caused by Coxiella burnetti. This bacterium resides in some animals such as cattle, goats, or sheep, and other domestic animals, like cats and dogs. Human infection occurs mainly via the inhalation of spores, or the ingestion of contaminated animal products.[1]Eldin C. Mélenotte C. Mediannikov O. Ghigo E. Million M. Edouard S. et al.From Q fever to Coxiella burnetii infection: a paradigm change.Clin Microbiol Rev. 2017; 30: 115-190Crossref PubMed Scopus (492) Google Scholar Based on data from the European Centre for Disease Prevention and Control (ECDPC), in 2019, Q fever occurred at an incidence of 0.2 cases per 100,000 habitants, with Spain, Romania and Bulgaria being the three countries where most cases were reported.[2]European Centre for Disease Prevention and ControlIntroduction to the annual epidemiological report stockholm: ECDC.2020https://ecdc.europa.eu/en/annual-epidemiological-reports/methodsGoogle Scholar Symptoms are non-specific and arise 2-3 weeks after exposure. Fever, general malaise, chills and sweats are commonly seen. Some patients may also develop infection of the liver or lungs. Few patients will develop chronic Q fever that takes place months after initial infection and can present as endocarditis, vascular or osteoarticular infections, and chronic hepatitis or pneumonia.[1]Eldin C. Mélenotte C. Mediannikov O. Ghigo E. Million M. Edouard S. et al.From Q fever to Coxiella burnetii infection: a paradigm change.Clin Microbiol Rev. 2017; 30: 115-190Crossref PubMed Scopus (492) Google Scholar Patients with liver involvement in the acute infection of Coxiella burnetti may report upper right quadrant abdominal pain and other non-specific gastrointestinal symptoms, like anorexia, nausea or vomiting.[1]Eldin C. Mélenotte C. Mediannikov O. Ghigo E. Million M. Edouard S. et al.From Q fever to Coxiella burnetii infection: a paradigm change.Clin Microbiol Rev. 2017; 30: 115-190Crossref PubMed Scopus (492) Google Scholar,[3]James S. Dooley and Christopher McNamara. "Chapter 32. The Liver in Systemic Diseases"Sherlock’s Diseases of the Liver and Biliary System, Thirteenth Edition. Edited by James S. Dooley, Anna S. F. Lok, Guadalupe Garcia-Tsao and Massimo Pinzani. John Wiley & Sons Ltd 2018, pp 622 – 651.Google Scholar Hepatic enzyme levels are commonly increased (2 to 10x normal levels). It should be mentioned that some autoantibodies, such as smooth muscle, can be positive. The diagnosis can be established based on serological findings: in the acute phase, patients display positive IgG anti-phase II antibodies, while in the chronic Q fever forms, diagnosis is based on IgG anti-phase I antibodies >1:800 with an identifiable site of infection (i.e. endocarditis). PCR of blood samples may provide a positive result at the beginning of the acute phase, but a negative result does not rule out infection. PCR from the infected site may be helpful to diagnose chronic forms. When liver biopsy is performed, pathological analysis reveals granulomatous hepatitis.[1]Eldin C. Mélenotte C. Mediannikov O. Ghigo E. Million M. Edouard S. et al.From Q fever to Coxiella burnetii infection: a paradigm change.Clin Microbiol Rev. 2017; 30: 115-190Crossref PubMed Scopus (492) Google Scholar Adult patients diagnosed with acute Q fever should be treated with doxycycline 100 mg every 12 hours for 14 days. Histological changes in Q fever can vary from one case to another and include non-specific inflammation, granulomas with or without necrosis and the typical fibrin-ring granulomas. The latter were classically described in association with Coxiella burnetti. However, we now know that they are not specific, as they have also been observed in other infections (Epstein-Barr virus, cytomegalovirus, leishmaniasis, etc.), Hodgkin disease, as well as allopurinol and immune-checkpoint inhibitor toxicity. There is no liver enzyme pattern associated with hepatic granulomas. The most common finding in blood tests is an increase in serum alkaline phosphatase, followed by gamma-glutamyl transferase and alanine aminotransferase. Severe liver function test abnormalities are rare, with mild increases in serum bilirubin tests.[3]James S. Dooley and Christopher McNamara. "Chapter 32. The Liver in Systemic Diseases"Sherlock’s Diseases of the Liver and Biliary System, Thirteenth Edition. Edited by James S. Dooley, Anna S. F. Lok, Guadalupe Garcia-Tsao and Massimo Pinzani. John Wiley & Sons Ltd 2018, pp 622 – 651.Google Scholar From the pathologist’s point of view, the differential diagnosis of a non-necrotizing granulomatous hepatitis is wide, and even more so in the case of microgranulomas; it must include infections, drug-induced liver injury, systemic disorders or neoplasia. It should be mentioned that a significant number of hepatic granulomas may not have an identifiable cause.[3]James S. Dooley and Christopher McNamara. "Chapter 32. The Liver in Systemic Diseases"Sherlock’s Diseases of the Liver and Biliary System, Thirteenth Edition. Edited by James S. Dooley, Anna S. F. Lok, Guadalupe Garcia-Tsao and Massimo Pinzani. John Wiley & Sons Ltd 2018, pp 622 – 651.Google Scholar The authors received no financial support to produce this manuscript. The authors declare that they have no competing interest. Please refer to the accompanying ICMJE disclosure forms for further details. All authors drafted, reviewed and take final responsibility for the decision to submit the manuscript for publication. The following are the supplementary data to this article: Download .pdf (.91 MB) Help with pdf files Multimedia component 1