—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 2 - Q Fever Presenting with Granulomatous Hepatitis with Fibrin-Ring Granulomas

Dhanpath Jain
Yale University
New Haven, CT





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Clinical History
Patient is a 55 year old male who presented with fever and Jaundice.

Pertinent Laboratory Data:

Transaminases (AST and ALT) were elevated in about ~250 U range. Antinuclear antibodies were weakly positive (ANA 1:40), Anti smooth muscle antibodies (SMA), antimitochondrial antibodies (AMA), liver kidney and microsomal (LKM) antibodies, serology for hepatitis (A, B and C) were all negative. Liver biopsy was performed.


Case 2 - Figure 1
Low magnification of the liver biopsy showing multiple granulomas scattered through-out the parenchyma.
Case 2 - Figure 2
Higher magnification of the liver biopsy showing the morphology of the granulomas
Case 2 - Figure 3
Higher magnification of the granuloma showing epithelioid histiocytes surrounded by a rim of dense eosinophilic fibrinous material and many neutrophils.

Case 2 - Figure 4
Low magnification of the liver biopsy (trichrome stain) showing areas of hepatocyte loss and early fibrosis.
Case 2 - Figure 5
Higher magnification of the granuloma (trichrome stain) showing the fibrin-ring much better.

Introduction:
Detailed clinical history: Patient is a 55-year-old male who presented at an outpatient clinic with fever for 4 days. His other symptoms at that time included generalized malaise, body aches, chills and sweats. He had subsequently also developed sore throat, cough and loose stools. His was screened for influenza and streptococcus pharyngitis, which were negative. He was prescribed Tequin (Gatifloxacin) following which his fever disappeared and symtoms improved however, his urine turned dark. He decided to stop the Tequin and his urine became normal. His fever and symptoms recurred and he started Tequin again following which his urine again turned dark. Discontinuation of Tequin this time did not normalize the urine color, and he sought medical attention at a hospital. He works as a welder and keeps goats and sheep at home. One week prior to developing this illness he had travelled to Houston to attend a livestock show. There is no significant past medical history. Investigations revealed mild leukocytosis (11,900/mm3) with neutrophilia, mild anemia (Hb= 12.3g/dl), elevated transaminases (AST 53U, ALT 60U), elevated alkaline phosphatase (232U), bilurubin (3.5 mg/dl), and low albumin (1.3g/dl) . Transaminases Antinuclear antibodies were weakly positive (ANA 1:40), Anti smooth muscle antibodies (SMA), antimitochondrial antibodies (AMA), liver kidney and microsomal (LKM) antibodies, serology for hepatitis (A, B and C) were all negative. His transaminases, bilirubin and blood ammonia levels continued to rise, and he was suspected to be developing liver failure. A liver biopsy was performed.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The most notable finding in the liver biopsy is the presence of many scattered granulomas through-out the liver biopsy that have an unique appearance. Most of the granulomas seem to have a central fat vacuole surrounded by epithelioid histiocytes and occasionally multinucleated giant cells. In addition there is a deposition of deeply eosinophilic material in circular ring-like pattern in the granuloma. Fair number of neutrophils are seen associated with the granulomas and appear to the most common inflammatory cells besides histiocytes. This morphology is typical of so-called "fibrin-ring" granulomas. The fibrin ring is highlighted by the trichrome or a fibrin stain. The fibrin-ring granulomas are numerous and distributed very randomly throughout the liver biopsy. The hepatocytes show moderate macrovesicular steatosis. The bile ducts appear preserved and without any evidence of inflammation or injury. There is a mild accompanying chromic inflammatory infiltrate that contains plasma cells and lymphocytes with focal mild interface activity. Grocott, PAS and Zeihl-Neelsen stains failed to reveal any microorganisms. The loss of hepatocytes, fibrosis and collapse was limited to the areas of inflammation. Regenerative changes were minimal and nodularity was not seen.

Differential Diagnoses:
Considering the presence of granulomas a variety of differential diagnosis can be considered, however, due to the presence of fibrin-ring type granulomas the differential diagnosis can be narrowed to a fewer conditions that include infections, (Q fever, rickettsial infection, cytomegalovirus infection Epstein- Barr virus infection, leishmaniasis, hepatitis A, staphylococcal infection, etc.), drug reactions, lymphoma, systemic lupus erythromatosus (SLE) and giant cell arteritis. In the presence of ANA a possibility of autoimmune hepatitis can also be considered in the differential diagnosis.

Final Diagnosis:
Q Fever presenting with granulomatous hepatitis with fibrin-ring granulomas

Case Discussion:
Granulomas are not uncommon in liver biopsies, and have been reported in <3% of all liver biopsies. The etiology of granulomatous hepatitis is generally known in majority of cases (75%) at the time of evaluation of the liver biopsy and becomes clear in a remaining 15% of patients on further follow-up. The list of disorders associated or causing granulomas in the liver is fairly long however, broadly speaking majority represent either infections, sarcoidosis, primary biliary cirrhosis, drug reactions, foreign body reaction or association with certain tumors. In only about 5-10% of patients with granulomatous hepatitis the etiology remains unknown, and the disorder is considered "Idiopatic granulomatous hepatitis". While in majority of patients the liver involvement is the part of a systemic granulomatous disease, in some the liver involvement could be isolated. Work-up of cases of granulomatous hepatitis where the etiology is unclear at the time of presentation can be challenging, and besides good clinical work- up it may require testing of the biopsy for various infections with immunohistochemical stains or PCR-based methods, and a good clinical follow-up. Careful review of the review of the clinical history revealed that the patient had contact with goat and sheep, and had visited a livestock show a week prior to developing the illness. In this case the diagnosis was established with positive serology for Q fever. Fibrin ring granulomas are unique in appearance and although initially reported to be pathognomonic of Q Fever, subsequently they have been shown to be associated with a variety of disorders that include infections (Boutonneuse fever, cytomegalovirus infection Epstein-Barr virus infection, leishmaniasis, hepatitis A, staphylococcal infection), drug reactions (allopurinol), non-Hodgkin or Hodgkin lymphoma, systemic lupus erythromatosus (SLE) and giant cell arteritis. They have rarely been described with autoimmune hepatitis that in this case in view of ANA positivity was one of the considerations however, neither the plasma cells were prominent in the inflammatory infiltrate nor-other featues (rosettes) of autoimmune hepatitis were seen. The underlying pathogenesis of this unique morphology is not understood however; with appropriate work-up as in this case the etiology becomes obvious in most cases.

Review of the Literature/Treatment Options (if applicable):
Q Fever is a Zoonotic disease caused by Coxiella burnetti, a gram negative bacterium that is found in cattle, sheep and goats, who are the primary reservoirs. The organism are excreted in milk, urine, and feces of infected animals, and are also shed in high number within amniotic fluid and placenta. The organisms are resistant to heat drying and many common disinfectants. Human infection occurs by inhalation of the organisms in the dust, although rarely it can be spread by ticks or direct contact. Ingestion of unpasteurized contaminated milk may also transmit the infection. The disease in the United States is seen mainly with occupational exposure in veterinarians, livestock farmers, and people working with meat processing or those working with sheep or cattle. Only about 50% people infected with the organisms develop clinical disease. Most patients develop sudden onset of fever with headache, myalgia, confusion, sore throat, non-productive cough, nausea, vomiting, diarrhea, abdominal pain and chest pain. The fever lasts for 1-2 weeks, and most patients recover spontaneously within several months without any treatment. Although majority of patients have abnormal liver enzymes, only a few develop clinical features of hepatitis. The mortality from severe infection is uncommon and occurs in 1-2% of all patients. While most patients have acute self-limited illness, some may have persistent disease that lasts more than 6 months leading to chronic Q Fever, which is a serious disease. Immunocompromised patients or those with chronic renal disease are at a higher risk of developing chronic Q fever. A serious complication of chronic disease is endocarditis. As many as 65% of patients with chronic disease may succumb to it. The diagnosis is confirmed by serology showing antibodies to Coxiella burnetti antigens. The organisms may also be detected by using IHC or PCR- based assay that are available in limited centers. Doxycycline is the treatment of choice for acute Q Fever, and is most effective when started within the first 3 days of illness. Chronic disease, especially endocarditis is much more difficult to treat and requires multiple antibiotics in combination. A vaccine is available and has been used in Australia in the high-risk population.

Conclusion(s):
Granulmatous hepatitis is not uncommon and careful evaluation of the histology of the granuloma may be very helpful in establishing the correct diagnosis. However, despite careful evaluation of the histology, extensive clinical work-up and follow-up of the patients, the etiology of the granulomas may still remain unclear in a small subset of patients.

References:
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  2. Sanai FM, Ashraf S, Abdo AA, et al. Hepatic granuloma: decreasing trend in a high-incidence area. Liver Int 2008 Dec; 28(10): 1402-7.

  3. Tjwa M, De Hertogh G, Neuville B, et al. Hepatic fibrin-ring granulomas in granulomatous hepatitis: report of four cases and review of the literature. Acta Clin Belg 2001 Nov-Dec; 56(6): 341-8.

  4. Pedro-Botet J, Lopez MJ, Barranco C, Coll J, Bruguera M. Granulomatous hepatitis and giant cell arteritis. Am J Gastroenterol 1994 Oct; 89(10): 1898- 9.

  5. Brouqui P, Raoult D. Coxiella burnetii serology in granulomatous hepatitis. J Infect 1994 Mar; 28(2): 229-30.

  6. Biest S, Schubert TT. Chronic Epstein-Barr virus infection: a cause of granulomatous hepatitis? J Clin Gastroenterol 1989 Jun; 11(3): 343-6.

  7. Thung SN, Gerber MA, Lebovics E, Reichman S. Granulomatous hepatitis in Q fever. Mt Sinai J Med 1986 Apr; 53(4): 283-5.

  8. Weir WR, Bannister B, Chambers S, De Cock K, Mistry H. Chronic Q fever associated with granulomatous hepatitis. J Infect 1984 Jan; 8(1): 56-60