Introduction:
Hepatic granuloma is a liver condition with a localized collection of inflammatory cells because of a hypersensitivity reaction to antigenic stimulation. They are usually associated with an underlying systemic disease, or it can be an incidental finding upon liver biopsy. The morphology and localization of granuloma can help in definitive diagnosis and treatment.
What Are the Causes of Hepatic Granuloma?
According to a clinical study, 66 % of hepatic granulomas occurred due to a reaction to secondary systemic disease, 28 % due to primary liver disease, and 6 % were idiopathic. Most cases resulted from sarcoidosis, mycobacterial infection, primary biliary cirrhosis, and drug-induced liver injury.
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Autoimmune disorders like sarcoidosis (collection of tiny granulomas or clumps of inflammatory cells in any part of the body), primary biliary cholangitis (a type of liver disease that damages the bile duct), and polymyalgia rheumatica (a disease that causes pain, inflammation, and stiffness in the muscles).
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Malignancies include Hodgkin's lymphoma, non-Hodgkin's lymphoma, renal cell carcinoma, and hepatic metastases.
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Inherited disorders like chronic granulomatous disease.
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Chronic gastrointestinal diseases like Chron’s disease.
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Metal toxicity of copper, silica, and beryllium.
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Vasculitides (inflammation of walls of blood vessels that can restrict blood flow to the organs) like granulomatosis with polyangiitis, polyarteritis nodosa, and Churg-Strauss syndrome.
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Infections such as bacterial (tuberculosis, listeriosis, brucellosis, and secondary syphilis melioidosis), fungal (histoplasmosis, cryptococcus, candidiasis, and nocardiosis), viral (cytomegalovirus, Epstein-Barr virus, hepatitis A, B, and C), and parasitic (schistosomiasis, toxoplasmosis, visceral larva migrans, and visceral leishmaniasis).
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Drug-induced such as Nitrofurantoin, Allopurinol, Phenytoin, sulfa drugs, Quinidine, and Carbamazepine.
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Ingestion of foreign materials like mineral oil, talc, and starch.
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Intravesical administration of toxins such as bacillus Calmette-Guerin.
What Is the Histopathology Of Hepatic Granuloma?
Granulomas are localized lesions that form because of an inflammatory reaction or after chronic exposure to antigens. When there is no accompanying inflammation, it is called bland granulomas. Histopathology contains macrophages in the center surrounded by lymphocytes, plasma cells, and fibroblasts, and they form multinucleated giant cells. Though there are a lot of variants, it does not specify the cause but helps in differential diagnosis such as:
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Non-caseating Granuloma (Non-necrotizing) - Seen in sarcoidosis brucella.
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Caseating Granuloma (Central Necrotizing) - Seen in tuberculosis, vasculitis, and mycobacterium tuberculosis.
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Fibrin Ring Granuloma - In this, epithelioid cells surround the vacuole within a circled fibrin ring, seen in Q fever, fatty liver disease, hepatitis A, etc.
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Foreign Body Granuloma - It consists of particulate material within cytoplasmic vacuoles like mineral oil, starch, talc, and silicone.
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Lipogranuloma- Has central lipid vacuole, is associated with hepatic stenosis and does not cause bile duct injury, and is seen in granulomas that occur due to ingestion of starch, mineral oil, or talc.
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Epithelioid Granuloma - This type produces many cytokines and gives a homogenous appearance to the cytoplasm, the cells fuse to form giant cells (Langhans cells), and a fibrin ring is formed in the periphery seen in Q fever.
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Lymphohistiocytic Granuloma - In this type, epithelioid cells are not found.
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Calcified Granulomas - These can also be formed because of infections (lesions are less than 0.7 inches) such as TB, echinococcal cysts, cytomegalovirus, benign liver neoplasms (lesions are less than 1.5 inches) such as hemangioma or malignant tumors like hepatocellular carcinoma. Usually identified using a CT (computed tomography) scan, MRI (magnetic resonance imaging), or ultrasound. Lesions can be solitary, multifocal, or diffuse.
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Poorly Formed Granulomatous Reaction - Without necrosis is seen in AIDS. The location of granuloma can also help in the differential diagnosis. For example, in the case of primary biliary sarcoidosis, the granulomas are near the portal region, and in drug-induced granuloma, they are found within hepatic lobules.
What Is the Pathogenesis of Hepatic Granuloma?
A granuloma is formed when a cellular immune response cannot eliminate foreign bodies, causing delayed hypersensitivity. It is a chronic inflammatory reaction.
Two reactions can cause granuloma. They are -
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Reaction to an immunologically inert foreign body which can be intracellular or extracellular. In intracellular, the TH1 targets intracellular pathogens leading to the formation of cytokines and interferon-gamma, IL-2, and IL-12 (interleukins), whereas in extracellular, TH2 forms IL- 4, 5, 6, and 10.
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Reaction to immunologically active antigenic particles that cause phagocytosis by macrophages, which activates T lymphocytes to produce cytokines, which causes the conversion of histocytes and macrophages into epithelioid histocytes, which form giant cells and causes necrosis leading to necrotizing granulomas.
What Are the Clinical manifestations of Hepatic Granuloma?
Granulomas can be asymptomatic or symptomatic. The symptoms depend on underlying diseases and their severity. They can cause the following symptoms:
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Fever, night sweats, weight loss, anorexia in case of tuberculosis, sarcoidosis, and infections.
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Hepatosplenomegaly in the case of schistosomiasis (a parasitic infection).
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Hepatic fibrosis with portal hypertension in sarcoidosis, primary biliary cirrhosis, and schistosomiasis.
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Adenopathy (swelling of lymph nodes).
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Jaundice is rare unless there is an injury to the bile duct.
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There can be severe pain in the right upper quadrant of the liver.
What Are the Diagnosis and Investigation of Hepatic Granuloma?
Health care should obtain thorough medical history, physical examination, extensive medication, and travel history. In addition, specific tests should be done since there are a lot of causes for this disease.
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Chest radiograph for sarcoidosis and tuberculosis.
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Tuberculin skin test.
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Blood cultures in case of bacterial, fungal, or viral infections.
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Serum antimitochondrial antibodies and immunoglobulin-M test for primary biliary cholangitis.
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Fungal stains on liver biopsy for any fungal infections.
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Viral serology for viral infections.
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Assess for schistosome eggs which is a parasitic infection.
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Syphilis and Coxiella serology.
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Imaging studies using magnetic resonance imaging (MRI), computed tomography (CT) scan, or ultrasound for large-sized livers in which granulomas of 0.19 inch are seen, showing a homogenous, coarse, or calcified appearance.
What Is the Treatment of Hepatic Granuloma?
Treatment depends on the underlying disease.
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If asymptomatic, idiopathic, or incidental findings, no medications are required. Instead, just monitoring of liver function is required.
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If symptomatic or idiopathic, immunosuppressants with corticosteroids should be given after excluding tuberculosis. Relapse can occur if treatment is discontinued. In this case, the course should be repeated. Methotrexate is effective in patients who relapse and are intolerant to steroids.
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In the case of tuberculosis, standard anti-tuberculous therapy should be initiated. For sarcoidosis, corticosteroids are useful. Amphotericin, with or without Flucytosine or Fluconazole, is useful for fungal infections.
What Is the Prognosis of Hepatic Granuloma?
Granulomas caused by a drug regress with appropriate treatment. In the case of sarcoid granuloma, if not treated, it can cause progressive fibrosis, portal hypertension, and cirrhosis. In the case of schistosomiasis, portal scarry (pipestem fibrosis), splenomegaly, and variceal bleeding can occur.
Conclusion:
Hepatic granulomas, as such, do not cause any symptoms unless a systemic disease is involved. Although the causes are numerous, healthcare professionals should make thorough clinical history and laboratory investigations. Treatment depends on the underlying systemic disorder and should include preventing complications such as portal hypertension and liver failure.
