Fibrin-ring Granulomas Research Articles

A case of coexistent acute severe alcoholic and Q fever hepatitis: The useful contribution of repeated liver biopsies

Acute Q fever is a worldwide zoonotic infection due to C. burnetii that may be associated with hepatitis. Nonspecific clinical and biological manifestations may accompany liver involvement, including hepatomegaly and elevated liver biological tests. However, the presence of jaundice is rare. Therefore, making a diagnosis of Q fever hepatitis may be difficult in an afebrile patient with jaundice of recent onset, altered liver function tests, excessive alcohol intake and no reported contact with animals. We report here the diagnostic work-up and complex clinical management of a patient presenting with acute hepatitis resulting from both C. burnetii infection and severe alcoholic steatohepatitis. Positive serology together with a detailed examination of the liver biopsy was able to reveal the coexistence of both Q fever hepatitis with typical fibrin-ring granulomas as well as florid lesions of alcoholic steatohepatitis. A combination of antibiotics, hydroxychloroquine and steroids, guided by the helpful description of changes in histological alterations on repeated liver biopsies during the course of the disease contributed to the slow but favorable outcome.

Fevers, Acute Hepatitis, and Hypercoagulability in an Immunocompetent Host

Question: A 46-year-old man who worked as a garbage hauler was admitted to the hospital with an 8-day history of daily fevers and progressively worsening right upper quadrant pain. He had no prior health conditions and did not take any medications on a regular basis. He denied tobacco, alcohol, or recreational drug use. At presentation, his vital signs were as follows: temperature 39.0°C, heart rate 119 beats per minute, blood pressure 142/84 mm Hg, respiratory rate 20 breaths per minute, and oxygen saturation of 97% on room air. Physical examination revealed jaundice and right upper quadrant abdominal tenderness without rebound or guarding. Laboratory studies (reference range in parenthesis) showed hemoglobin 16.3 g/L (reference range, 13.2–16.6 g/L) , leukocytes 10,000/L (3400–10,000/L), neutrophils 8390/L (1560–6450/L), alanine aminotransferase 404 U/L (7–55 U/L), aspartate aminotransferase 307 U/L (8–48 U/L), alkaline phosphatase 251 U/L (40–129 U/L), total bilirubin 5.8 mg/dL (≤1.2 mg/dL), erythrocyte sedimentation rate 41 mm/h (1–22 mm/h), C-reactive protein 306.4 mg/L (0–8 mg/L), iron 23 μg/dL (50–150 μg/dL), and ferritin 10,173 μg/L (31–409 μg/L). Right upper quadrant ultrasound with liver Dopplers demonstrated a normal-appearing liver without biliary obstruction or vascular abnormalities. Computed tomography abdomen with intravenous contrast illustrated diffuse hepatic steatosis without intra- or extrahepatic biliary dilation and multiple wedge-shaped hypoenhancing areas in the spleen suggestive of infarcts (Figure A). Hepatitis A, B, and C serologies, antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody were unremarkable. A fine-needle biopsy of the liver was performed with representative pathology images highlighted in Figure B. What is the most likely diagnosis? Look on page 55 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and images in GI. Liver biopsy revealed non-necrotizing granulomatous inflammation including fibrin ring granulomas and mild microvascular steatosis. Additional laboratory evaluation (reference range in parenthesis) revealed a positive Coxiella burnetii polymerase chain reaction on the liver biopsy with a serum Q fever phase II immunoglobulin (Ig)M level 1:2048 (<1:16), serum Q fever phase II IgG level 1:64 (<1:16), and negative phase I IgG and IgG, consistent with acute Q fever. On further questioning, he revealed that he hauled garbage from a sheep farm, a likely source of exposure to Coxiella burnetii. Given the splenic infarcts, a thrombophilia workup was pursued that showed serum antiphospholipid (aPL) antibody IgM level 108.9 MPL (<15 MPL) and serum aPL antibody IgG level 60.9 GPL (<15 GPL). He underwent a screening transesophageal echocardiogram that did not reveal any valvular abnormalities or vegetations. Doxycycline 100 mg twice daily and hydroxychloroquine 200 mg 3 times daily was initiated. At the time of last follow-up, he continued to experience fatigue, but fever resolved and right upper quadrant pain improved. Coxiella burnetii, the bacterium responsible for causing Q fever, is a ubiquitous zoonosis that infects humans who are exposed to contaminated aerosols from mammalian amniotic fluid or placenta.1Fournier P.E. Marrie T.J. Raoult D. Diagnosis of Q fever.J Clin Microbiol. 1998; 36: 1823-1834Crossref PubMed Google Scholar Patients with acute Q fever commonly present with acute hepatitis, seen in 46.3% of 1668 cases in one study.2Melenotte C. Protopopescu C. Million M. et al.clinical features and complications of Coxiella burnetii infections from the French National Reference Center for Q Fever.JAMA Netw Open. 2018; 1e181580Crossref Scopus (61) Google Scholar The characteristic pathology features from tissue infected with Coxiella burnetii is commonly described as “doughnut granulomas” which consist of dense fibrin rings surrounding a central lipid vacuole.1Fournier P.E. Marrie T.J. Raoult D. Diagnosis of Q fever.J Clin Microbiol. 1998; 36: 1823-1834Crossref PubMed Google Scholar Positive aPL antibodies are associated with a high risk of clinical complications in acute Q fever, including hepatitis, as seen in our patient, and pneumonia and acute endocarditis, which were not seen in our patient.2Melenotte C. Protopopescu C. Million M. et al.clinical features and complications of Coxiella burnetii infections from the French National Reference Center for Q Fever.JAMA Netw Open. 2018; 1e181580Crossref Scopus (61) Google Scholar The treatment for patients with acute Q fever with positive aPL antibodies and without evidence of acute Q fever endocarditis includes doxycycline plus hydroxychloroquine until aPL antibody levels normalize.3Anderson A. Bijlmer H. Fournier P.E. et al.Diagnosis and management of Q fever--United States, 2013: recommendations from CDC and the Q Fever Working Group.MMWR Recomm Rep. 2013; 62: 1-30PubMed Google Scholar

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

SummaryImmune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.

Something old, something new: liver injury associated with total parenteral nutrition therapy and immune checkpoint inhibitors

Drug-induced liver injury (DILI) is a challenging and constantly changing field. The pathologist plays a key role in interpreting liver biopsies by classifying the pattern of injury, grading the severity of injury, and evaluating for other possible causes. Reports of iatrogenic liver injury are reviewed here with a focus on total parenteral nutrition (ie, intestinal failure-associated liver disease [IFALD]) and immune checkpoint inhibitors (ICIs). The hallmark features of IFALD are cholestasis and steatosis. Cholestasis is more common in infants, whereas steatosis and steatohepatitis are more commonly seen in older children and adults. Infants tend to have a faster progression to fibrosis and cirrhosis. Perivenular fibrosis and ductopenia may also be seen in IFALD. Although fish oil-based lipid emulsions can reverse cholestasis, recent studies have shown persistent or progressive fibrosis. ICI-induced liver injury usually presents as an acute hepatitis with features similar to those seen in idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. However, it lacks a prominent plasma cell infiltrate and serological markers of autoimmune hepatitis. Other features such as fibrin ring granulomas and cholangitis have also been reported in association with ICIs. Treatment for ICI-induced liver injury includes corticosteroids and other immunosuppressants.

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors

Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.

Prolonged Pyrexia and Hepatitis: Q fever

PRESENTATION Despite an ever-expanding spectrum of available tests, fever of unknown origin remains a diagnostic dilemma. A 40-year-old Nepalese man living in Rhode Island presented with a 1-week history of nausea, vomiting, fevers, and frontal headache. He denied neck stiffness, abdominal pain, diarrhea, rash, or urinary symptoms. In the emergency department, he had a temperature of 100.4 F (38.0 C) and was tachycardic to 108 beats per minute. His physical examination was otherwise normal. Lumbar puncture demonstrated no pleocytosis. Polymerase chain reaction testing of cerebrospinal fluid was negative for herpes simplex virus and enterovirus; a western blot was negative for Lyme IgM and IgG. Whole-body computed tomography was unrevealing. The patient was discharged but returned 4 days later with persistent headaches and fever, so he was admitted for further workup. His past medical history was notable for hypertension, for which he took chlorthalidone, and anxiety, for which he was prescribed paroxetine. Three years earlier, he had completed a 9-month course of isoniazid for latent tuberculosis infection. He lived with his wife and denied new sexual contacts, as well as use of any alcohol, tobacco, or illicit drugs. The patient had not travelled outside of New England following his emigration from Nepal 3 years before. He lived in an urban area and worked as a maintenance worker at a suburban warehouse where he had rodent contact and cut the grass but he denied tick bites. He had visited a farm

A Case of Acute Q Fever Hepatitis Diagnosed by F-18 FDG PET/CT

A 53-year-old man with fever of unknown origin underwent F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) as a workup for a fever of unknown origin. On presentation, he complained of fever, chills, and myalgia. The F-18 FDG PET/CT scan showed diffusely increased uptake of the liver with mild hepatomegaly. A liver biopsy then revealed fibrin-ring granulomas typically seen in Q fever. The patient was later serologically diagnosed as having acute Q fever as the titers for C. burnetii IgM and IgG were 64:1 and 16:1, respectively. He recovered completely following administration of doxycycline. This indicates that F-18 FDG PET/CT may be helpful for identifying hepatic involvement in Q fever as a cause of fever of unknown origin.

Clinicopathologic Features of Q Fever Patients with Acute Hepatitis

BackgroundQ fever caused by Coxiella burnetii presents with diverse clinical and pathological features including subclinical or cholestatic hepatitis. However, the pathological features of liver biopsies from patients with Q fever have not been well described.MethodsClinical features and pathological findings of liver biopsies were reviewed in seven cases of Q fever that were confirmed by serological, microbiological, or molecular tests.ResultsAll cases presented with fever. Liver enzymes were mildly elevated except one case with marked hyperbilirubinemia. Characteristic fibrin ring granulomas were present in three cases, epithelioid granulomas with eosinophilic infiltration in two cases, extensive extravasated fibrins without ring configuration mimicking necrotizing granuloma in one case, and acute cholangitis without granuloma in one case. All cases were treated with antibiotics for 20 days. Six cases were completely cured, but one suffered from multiorgan failure.ConclusionsC. burnetii infection is uncommon, but should always be considered in patients with acute hepatitis and fever. Because variable-sized circumferential or radiating fibrin deposition was a consistent feature of the present cases, Q fever can be strongly suggested by pathological features and confirmed by serological and/or molecular tests.

Bone marrow fibrin ring granulomas in Epstein-Barr virus infection

Bone marrow fibrin ring granulomas in Epstein-Barr virus infection

Fibrin ring granulomas in Rickettsia typhi infection

We describe a 71-year-old man hospitalized for fever and productive cough. Laboratory investigation showed anemia, thrombocytopenia, elevated transaminases, hyponatremia, and hypoalbuminemia. Computerized tomography of the abdomen, thorax, and sinuses, echocardiography, and a gallium scan did not reveal the source of the fever. The patient remained febrile despite courses of piperacillin–tazobactam/azithromycin and ceftriaxone/vancomycin. A bone marrow biopsy showed fibrin ring granulomas, and 2 rickettsial serologic panels were positive for Rickettsia typhi infection and negative for Q fever. The patient was given doxycycline, and the fever resolved within 48 h. We propose that fibrin ring granulomas also occur in murine typhus.

65-Year-Old Man With Persistent Fever

65-Year-Old Man With Persistent Fever

A Case of Acute Q Fever with Severe Acute Cholestatic Hepatitis

Minimal hepatic dysfunction can be common in acute Q fever, but severe acute cholestatic hepatitis is rarely reported. We report on a 55-year-old male with acute Q fever and severe acute cholestatic hepatitis. He complained of fever, jaundice, ascites, and restlessness on admission. A liver biopsy revealed the presence of compact fibrin-ring granulomas. Serologic titers for C. burnetii IgM and IgG were 2048:1 and 1024:1, respectively. C. burnetii DNA was detected by a nested polymerase chain reaction on the liver tissue.

Hepatitis with Fibrin-Ring Granulomas

We describe a 66-year-old woman hospitalized with fever, fatigue and hepatopathy. In her medical history arterial hypertension (treated with propranolol and lisinopril), diabetes mellitus type 2 (no treatment before admission) and a gout arthropathy were noted wherefore a therapy with allopurinol 300 mg per day has been started 4 months before. Liver biopsy revealed fibrin-ring granulomas, compatible with allopurinol-induced hepatitis. Because of persistence of high fever after stopping allopurinol, steroids (1 mg/kg) were started. Under this treatment, she developed pancytopenia and fever. The bone marrow aspiration revealed Leishmania infantum. A second liver biopsy showed amastigotes and a disappearance of the granulomas. The history revealed a travel to Malta 2 years earlier. Despite adequate treatment with liposomal amphotericin B the patient deteriorated and finally died in septic shock.

Fibrin Ring Granuloma in Chronic Hepatitis C: Virus-Related Vasculitis and/or Immune Complex Disease?

Fibrin ring granulomas are rare lesions whose pathophysiology has remained somewhat elusive. It has been suggested that these peculiar lesions are related to focal vasculitis with endothelial injury and deposition of immune complexes. Fibrin ring granulomas have been described in Q fever; in viral infections such as cytomegalovirus, Epstein-Barr virus, and hepatitis A virus; and in other conditions. We submit the first reported case of fibrin ring granuloma in a patient with chronic hepatitis C infection, in whom other potential etiologies have been excluded, and offer a brief review of available literature on the pathogenesis of both conditions.

Differentiation of granulomatous lesions in the bone marrow

Granulomas are an infrequent finding in bone marrow biopsies and may be associated with a broad spectrum of infectious and non-infectious disorders. In this context sarcoidosis generally reveals the highest incidence of such bone marrow lesions. Other granulomas may be encountered in drug-induced secondary changes (toxic myelopathy) and in particular also in HIV myelopathy. In these cases the granulomas are small, ill-defined and difficult to recognize. Special staining methods are required to detect microorganisms. Fibrin ring granulomas (doughnut granulomas) are typical for Q-fever, but may also be seen in reactive conditions, after drug therapy and in the course of other infectious disorders, such as Lyme disease. Therefore a broad serological testing should be performed. In conclusion, in most cases the morphological findings in the bone marrow are not specific so that a synoptical approach regarding histological, clinical and serological data is warranted to reach the correct diagnosis.

HEPATIC FIBRIN-RING GRANULOMAS IN GRANULOMATOUS HEPATITIS : REPORT OF FOUR CASES AND REVIEW OF THE LITERATURE

The differential diagnosis of hepatic fibrin-ring granulomas includes infective agents (Coxiella burneti, CMV, EBV,....), hypersensitivity to medication (allopurinol) and malignancy. During a period of 6 months, four patients presented at our university hospital with a similar clinical picture of fever and abnormal liver tests, and fibrin-ring granulomas on liver biopsy. Clinical course, laboratory and imaging findings, and histopathological features were compared. Clinical manifestations, and laboratory and imaging findings were similar. Histopathological assessment of the hepatic fibrin-ring granulomas appeared not to be helpful in identifying the causative agent. Other histopathological features (e.g. sinusoidal rows of lymphocytes, eosinophilic polymorphonuclear infiltrate) were suggestive for the causative agent, yet conclusive identification was obtained by either serology (Q fever, CMV, EBV), or by exclusion with concomitant stop of medication (allopurinol). In the differential diagnosis of hepatic fibrin-ring granulomas, serologic titers remain the determining factor, since an infective agent is the most common cause. When hepatic fibrin-ring granulomas are present, other histopathological features may be helpful in making the differential diagnosis.

Transient hepatic fibrin‐ring granulomas in a patient with acute hepatitis A

A case of acute hepatitis A associated with fibrin-ring granulomas in the liver is presented. Because a relationship between acute hepatitis A infection and granuloma formation had not previously been established, liver specimens were examined from both the hepatitic and recovery phases. Numerous fibrin-ring granulomas were observed in the parenchyma during the hepatitic phase. The cellular components of the granulomas were largely macrophages and CD4-positive T-cells. Granulomas had disappeared completely by the recovery phase. These results suggest that fibrin-ring granulomas were caused by hepatitis A virus infection. This virus may activate macrophages and CD4-positive T-cells through an as-yet undetermined mechanism.

Hepatic fibrin-ring granulomas in giant cell arteritis

Hepatic fibrin-ring granulomas were found in a 70-year-old man with prolonged fever and inflammatory syndrome. Diagnosis of giant cell arteritis was confirmed by temporal artery biopsy. Other diseases usually associated with fibrin-ring granulomas in liver, such as Q fever, cytomegalovirus hepatitis, infectious mononucleosis, Hodgkin's disease, non-Hodgkin's lymphoma, allopurinol treatment, and visceral leishmaniasis, were ruled out. This report suggests that giant cell arteritis should be considered as an additional cause of hepatic fibrin-ring granulomas.

Hepatic fibrin-ring granulomas: A clinicopathologic study of 23 patients

Twenty-three patients with characteristic hepatic fibrin-ring granulomas were studied. Q fever accounted for 10 cases (43%), visceral leishmaniasis for five cases (22%), boutonneuse fever for two cases (9%), and toxoplasmosis, Hodgkin's disease, and allopurinol hypersensitivity for one case each (4%). The etiology remained undetermined in three cases (13%). This report broadens the range of etiologies of hepatic fibrin-ring granulomas to include boutonneuse fever and toxoplasmosis in the differential diagnosis of ring granulomas, and it could serve as a guideline to the clinican and pathologist for the most frequent categories of disease associated with this morphologic pattern.

Hepatic fibrin-ring granulomas in a patient with hepatitis A

Hepatic fibrin-ring granulomas were found in a 30-year-old patient with serologically confirmed hepatitis A. Other causes associated with the presence of fibrin-ring granulomas in the liver, such as Hodgkin's and non-Hodgkin's lymphoma, cytomegalovirus infection, visceral leishmaniasis, and consumption of allopurinol, were ruled out. It is suggested that hepatitis A must be included in the differential diagnosis of a patient with hepatic fibrin-ring granulomas.