G&H Why might a granuloma develop in the liver?
EW A granuloma is a large collection of immune cells and connective tissue that can form in response to a chronic inflammatory stimulus. This stimulus can come in different forms: it can be an infection, a cancer, a drug, a metal, or some inorganic matter. Sometimes, a granuloma can be idiopathic. It can occur in a variety of organs, including the lungs, skin, eyes, and intestines, not just the liver. A granuloma can be found in the liver if a stimulus exists there in an at-risk host.
G&H How can granulomas be categorized?
EW Granulomas are classically categorized by their histologic appearance as lipogranulomas or epithelial granulomas. Clinically significant granulomas almost always refer to the latter group, which has 2 major subtypes: caseating (or necrotizing) and noncaseating (or nonnecrotizing). Caseating granulomas tend to be associated with infections, whereas noncaseating granulomas tend to be associated with an autoimmune disease process. In the gastroenterology and hepatology community, such diseases commonly include sarcoid, primary biliary cholangitis, and Crohn’s disease. Caseating granulomas tend to be larger than noncaseating ones, partly because the former have a necrotic center composed of dead cells. The chapter on granulomas of the liver written by Dr James Lewis in Schiff’s Diseases of the Liver catalogs the different types, causes, etiologies, and treatments of granulomas and is a good foundation for understanding this condition.
G&H What is granulomatous hepatitis?
EW A granuloma can be present in the liver without a neighboring inflammatory response; it is the presence of an inflammatory response that makes it a granulomatous hepatitis. Biopsy studies, including one by Ricker and colleagues in 1949 and one by Awai and colleagues in 1964, found that up to 80% of people who die with sarcoidosis can have hepatic granulomas. However, only a very small percentage of patients with systemic sarcoidosis have granulomatous hepatitis. Sarcoid and hepatic sarcoid are examples that show how granulomas can be present in the liver but are not necessarily granulomatous hepatitis. It is not known why some people with granulomas within the liver develop hepatitis and others do not.
G&H How often is sarcoidosis the cause of granulomatous hepatitis?
EW It depends on the location. Tuberculosis is the most common cause of granulomatous hepatitis in areas where that disease is prevalent, such as Sub-Saharan Africa, South Asia, and Southeast Asia. Systemic sarcoidosis is more commonly seen in Northern Europe, the United States, Canada, and Japan. In the United States, infections are still the most common cause of granulomatous hepatitis, with tuberculosis leading the way, although other infections should also be considered, such as Mycobacterium, histoplasmosis, coccidiosis, Aspergillus, and some common viruses. Sarcoidosis moves to the front of the differential diagnosis when an infectious cause has not been found. An unknown cause of granulomatous hepatitis is somewhat common; in my opinion, unknown causes are often drug-related, as it can be difficult to assess causality in such cases. Clinicians often perform an extensive workup and say that a patient does not meet the criteria for sarcoidosis, an infection cannot be found, and that perhaps the patient has an idiosyncratic reaction to a drug that led to this immune response. Thus, it is difficult to answer how often sarcoidosis is the cause.
G&H How does granulomatous hepatitis typically present?
EW The presentation depends on the etiology. Infectious causes of granulomatous hepatitis are often accompanied by fever, weight loss, and sometimes jaundice. Drug-induced granulomatous hepatitis can present similarly as well, which is one of the reasons the condition can be so difficult to diagnose. Clinicians can be so focused on not missing an infection that they do not realize the cause is sometimes not an infection. Making diagnosis more difficult, hepatic sarcoid can also present this way. More often, though, I see patients with hepatic sarcoid present with mild liver enzyme abnormalities without these types of symptoms. Occasionally, patients will report itching or right upper quadrant pain as the liver capsule is being stretched. Other patients can be asymptomatic. Most often, hepatic sarcoid patients may not have associated symptoms.
G&H How is the diagnosis of granulomatous hepatitis typically established?
EW Liver biopsy is the first step in diagnosing granulomatous hepatitis, although infections that are associated with this condition can be diagnosed without requiring a biopsy. The list of infections that can lead to granulomatous hepatitis is very long; the aforementioned chapter by Dr Lewis lists approximately 30 different types of infection. Clinical context is essential. Some infections can be detected through blood cultures, although many infections that cause liver granulomas require organism-specific testing such as the QuantiFERON-TB Gold Plus test for tuberculosis, polymerase chain reaction testing for Q fever and cat scratch fever, and rapid plasma reagin testing for syphilis. All these infections can cause granulomas in the liver. Specific reagents can be applied to the liver biopsy to highlight certain types of organisms. For example, periodic acid-Schiff with diastase is a stain often used to diagnose alpha-1 antitrypsin deficiency but will also pick up cell wall polysaccharides for Aspergillus and histoplasmosis. Acid-fast staining is most commonly associated with the identification of mycobacteria and can be used for either tuberculosis or nontuberculous mycobacteria. Acid-fast staining of liver biopsy tissue can also be used to aid in the diagnosis of schistosomiasis, nocardiosis, and coccidia, all of which can cause granulomas in the liver. A recent article by Hänscheid and colleagues nicely goes over the different stains that can be used, especially acid-fast staining, and what can be uncovered. Acid-fast staining has been used for a long time and can help determine an infectious cause of granulomatous hepatitis.
G&H How should this condition be treated?
EW Like diagnosis of granulomatous hepatitis, treatment of this condition is a challenge. I tend to treat drug-induced granulomatous hepatitis and sarcoidosis similarly with corticosteroids, and organisms are treated with anti-infective therapies. The conundrum is that corticosteroids should not be given to a patient who has an infection. It is important to perform an extensive infectious workup prior to diagnosing a noninfectious cause of granulomatous hepatitis and then treating with corticosteroids. Other medications can also be used for this condition, but corticosteroids tend to be the first option used after diagnosis to decrease inflammation if the cause is noninfectious. If a patient has a primary liver disease such as hepatitis C or primary biliary cholangitis in addition to having a granulomatous hepatitis workup showing a noninfectious cause, the granulomas are immaterial. The workup of granulomas hepatitis requires regular communication with a large multidisciplinary team that includes gastroenterology and hepatology, infectious disease, rheumatology, internal medicine, and pathology. In my patients who have had granulomatous hepatitis, the condition has been difficult to diagnose.
G&H What is the typical prognosis?
EW The prognosis is generally good when the diagnosis is made early by obtaining liver tissue and performing serologic testing early. If a clinician is considering treatment with corticosteroids for a noninfectious cause of granulomatous hepatitis, it is better to wait a few days until all the infectious causes have been ruled out to a satisfactory degree than to treat early.
G&H What misconceptions have you encountered in this area?
EW As mentioned, in general, necrotizing granulomas involve an infection, but not all necrotizing granulomas involve tuberculosis. I saw a patient years ago with rapidly progressing hepatic sarcoid who presented with necrotizing granulomas. I anchored my approach on that histologic finding, and it led to a long delay in the patient’s diagnosis. Eventually, with the help of an expert colleague, we diagnosed hepatic sarcoid and began treatment. At that time, I used a combination of ursodeoxycholic acid and corticosteroids, and the patient is doing well 10 years later. This shows the importance of looking at findings in the context of the entire patient.
G&H What research is needed?
EW Unfortunately, sarcoidosis is generally underfunded, which means that one cause of granulomatous hepatitis is not understood very well. In fact, sarcoidosis as a whole is underfunded, and hepatic sarcoid receives very little attention within sarcoid research. This is partly owing to the lack of preclinical models for sarcoidosis, a human disease that does not have adequate animal correlates. Within hepatic sarcoid, it is not understood why some patients have granulomas with inflammation and others have granulomas without inflammation. Treatment of hepatic sarcoid is mainly based on evidence from
treatment of pulmonary or dermatologic sarcoid, but trials are needed evaluating treatment specifically for hepatic sarcoid. As far as other causes of granulomatous hepatitis, treatment is a little more difficult. Treatment of the infection with appropriate anti-infective therapy is key. Designing studies in this area is challenging. Causes that are noninfectious and are not sarcoid are seen sporadically and are difficult to research. In those cases, epidemiologic research is probably more important.
G&H Is there anything you would like to emphasize about granulomatous hepatitis?
EW It is important that gastroenterologists and hepatologists do not try to diagnose and treat this disease by themselves. I have found that it takes a multidisciplinary team to treat a patient who has granulomatous hepatitis. I often work closely with rheumatology, infectious disease, internal medicine, and pathology colleagues. We often have long email or electronic medical record chats regarding what is being missed, what can be done, and issues like whether it is safe to start corticosteroids and whether the patient should be treated for an infection. I find that multidisciplinary collaboration leads to the best results for my patients with granulomatous hepatitis.
Disclosures
Dr Weinberg has no relevant conflicts of interest to disclose.
Suggested Reading
Coash M, Forouhar F, Wu CH, Wu GY. Granulomatous liver diseases: a review. J Formos Med Assoc. 2012;111(1):3-13.
Hänscheid T, Mahomed S, Oliveira L, Pereira DS, Grobusch MP. Fluorescent acid-fast stains for diagnosing mycobacteria and beyond: back to the future? Lancet Microbe. 2025;6(12):101233.
Kanel GC. Granulomatous hepatitis. In: Kanel GC, ed. Pathology of Liver Diseases. John Wiley & Sons; 2017. https://doi.org/10.1002/9781118894903.ch6.
Lewis JH. Granulomas of the liver. In: Schiff ER, Maddrey WC, Reddy KR, eds. Schiff’s Diseases of the Liver. John Wiley & Sons; 2017. https://doi.org/10.1002/9781119251316.ch40.
Mironova M, Gopalakrishna H, Rodriguez Franco G, et al. Granulomatous liver diseases. Hepatol Commun. 2024;8(4):e0392.
Weinberg EM, Aghayeva S, Reddy RK. Hepatic sarcoid—a review [published online October 8, 2025]. Hepatology. doi:10.1097/HEP.0000000000001568.