Saudi Journal of Gastroenterology
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Year : 2000  |  Volume : 6  |  Issue : 1  |  Page : 41-46
Hepatic granulomas in an arab population: A retrospective study from a teaching hospital in Riyadh

1 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Date of Submission20-Dec-1998
Date of Acceptance23-Oct-1999


This is a retrospective analysis of the medical records of 116 patients who presented to the gastroenterology division, department of medicine at King Khalid University Hospital (KKUH) in Riyadh, Kingdom of Saudi Arabia and subsequently had a histopathologic diagnosis of hepatic granulomas. Infections contributed to 56% and were represented mainly by schistosomiasis and to a lesser extent by tuberculosis, brucellosis and hydatid disease. Lymphomas (8%) were the major representative of noninfectious causes. The etiology of 25% of granulomas remained undetermined. Weight loss, fever, anorexia and abdominal pain were the most frequent presenting symptoms in 53, 45, 43 and 42% of patients, respectively. Ten percent of the patients were asymptomatic. Hepatomegaly and splenomegaly were the predominant physical findings in 55% and 43% of patients respectively. Hepatic granulomas in this study are mainly caused by infections. Schistosomiasis, tuberculosis and brucellosis represented the most common etiologic factors.

Keywords: Hepatic granuloma - liver biopsy.

How to cite this article:
Al Mofleh IA, Al Rashed RS, Ayoola E A, Al Faleh FZ, Al Amri SM, Al Rikabi A C, Al Sohaibani MO, Reyes AH. Hepatic granulomas in an arab population: A retrospective study from a teaching hospital in Riyadh. Saudi J Gastroenterol 2000;6:41-6

How to cite this URL:
Al Mofleh IA, Al Rashed RS, Ayoola E A, Al Faleh FZ, Al Amri SM, Al Rikabi A C, Al Sohaibani MO, Reyes AH. Hepatic granulomas in an arab population: A retrospective study from a teaching hospital in Riyadh. Saudi J Gastroenterol [serial online] 2000 [cited 2022 Nov 26];6:41-6. Available from:

Hepatic granulomas (HG) represent a non-specific reaction to specific antigens and consist mainly of microscopic aggregates of epithelioid histiocytes, giant cells and variable numbers of lymphocytes and eosinophils. They form as a result of immunological or non-immunological host response to invasion by an inciting agent[1],[2]. Several investigators have emphasized the important role of lymphokines and cytokines in the formation and maintenance of HG in schistosomiasis. Various cytokines including macrophage colony-stimulating factor (M-CSF) are produced by Kupffer cells. Intrahepatic production and consumption of M-CSF may play a crucial role in the granulomatous inflammatory process[3]. Furthermore, intracellular adhesion molecule has accounted to the important factors that influence the formation of schistosomal granulomas[4]. Hepatic granulomas are found in 10% of liver tissue specimens[5] and are mostly localized to the portal tracts but can be seen within hepatic lobules. Hepatic granulomas are found in association with a wide variety of infectious and noninfectious diseases[6],[7],[8] but the relative incidence and etiologic factors vary between different geographic locations.

Most of the published studies on the etiologic factors of HG have originated from the Westren world and there is paucity of reports from Arab populations in which granulomatous diseases such as schistosomiasis, tuberculosis and  Brucellosis More Details are common[9],[10]. In this retrospective study, we analyze the clinical features and etiologic factors of HG in an Arab population and compare our results with similiar published works from other populations. It is essential for all gastroenterologists and pathologists to be familiar with the pattern of HG in their community in order to approach such problems in a rational sequence with regard to further investigations and treatment.

   Patients and methods Top

All liver biopsy specimens obtained at King Khalid University Hospital in Riyadh over a 14 years period, 1403-1416 (1983-1996) were reviewed. The records of patients on whom a histologic diagnosis of HG was made were carefully analyzed with particular reference to clinical and pathologic features, final diagnosis and prognosis. The liver biopsies were obtained by a Menghini or a Jamshidi needle, specimens were fixed in 10% formalin and stained with the haematoxyline-eosin stain. Special stains such as PAS, reticulin, Ziehl­Neelsen, copper and iron stains were also routinely applied. Culture of biopsies for tuberculosis was not performed but serologic values for brucellosis were obtained from all suspected cases. Patients were treated according to the final histopathologic diagnoses and followed in the outpatient clinics at regular intervals.

   Results Top

Over a 14-year period, 1548 liver biopsies were performed at KKUH for various indications and granulomas were identified in 116 biopsies (7.5%). The sex distribution was 39 women and 77 men with a ratio of 1:2 and the patients ages ranged from 18 to 65 years. Weight loss, fever, anorexia and hepatosplenomegaly were the commonest clinical features [Table - 1]. The etiology of HG along with patients age, gender and main clinical symptoms and signs are summarized in [Table - 2]. Schistosomiasis occuring in 42 (36%) patients was the most frequent cause of HG. In 29 (25%) patients, no specific diagnoses were made after extensive investigations and follow-up. The follow-up period ranged from 6 months to 4 years (median 2.3 years). Of the 29 patients with unexplained etiology, eight were lost to follow up after nine months and the remaining 19 were followed for more than two years. There was no significant morbidity and no mortality has occured in the cases studied.

   Discussion Top

The total number of liver biopsies obtained within the period studied, represented an underestimation of the total number of liver diseases seen in our hospital. The need for liver biopsies became less, with the availability of seroimmunologic tests, in addition to various imaging facilities and interventional techniques. For these reasons, it became difficult to estimate the exact frequency of HG in the population studied. The difficulty was also compounded by the nonavailability of autopsy data with which our findings could have been compared. Despite the limitations of this retrospective analysis, the observations made in this study would be useful for clinical practitioners and pathologists alike and may also serve as a basis for comparison with the pattern of granulomatous infections among populations from other geographic areas.

Granulomas are generally reported in approximately 10 percent of liver biopsies[5]. Our own findings show similar incidence. The significance of HG is not well-defined and may vary according to the causative factor. For instance, schistosoma mansoni-induced hepatic granulomas have altered cytochrome p450 and microsomal proteins in vitro with consequent alteration in the biotransformation of some drugs[11]. In contrast, experimental leishmaniasis-induced granulomas have not interfered with hepatic drug metabolism[12]. Patients with HG may remain asymptomatic and ten percent of our patients were in this category. The commonest presenting clinical symptoms have however, been fever, abdominal pain, weight loss, hepatomegaly, splenomegaly and lymphadenopathy. Our findings are consistent with the clinical patterns reported elsewhere[13],[14],[15]Liver biopsy is mandatory for the diagnosis of HG. Ultrasonography may, however, suggest a prehistologic diagnosis in the presence of hyperchoic or focal hypoechoic pattern[16]. More specific changes in the form of multiple, 3-5 mm, large lesions surrounded by hypoechoic halos have also been reported[17]. Laparoscopy is helpful in the classification of capsular granulomas into macular, exudative, pinpoint granular and cord-like pattern which may suggest particular etiologies. The exudative pattern is the most frequent type and has a high prevalence in brucellosis, while the granular type is more frequently associated with tuberculosis [18]. There are many causes of HG including local irritants, infections, infestations and hypersensitivity to drugs[6]. The causes, which vary in frequency from one study to another [Table - 3], greatly outnumber the morphologic points of distinction, so that it is often impossible to reach an etiologic diagnosis on histological criteria alone.

In the present study, schistosomiasis was the single most common cause, which is in concordance with other findings reported from the Eastern Province of Saudi Arabia[19]. This is in contrast to the pattern in Western population in which sarcoidosis is the commonest cause (35%) while schistosomiasis is uncommon[20]. Worldwide, approximately 200 million individuals are infected by schistosoma species distributed over 71 countries. Saudi Arabia and its neighboring countries are considered endemic[9]. Tuberculosis was the next common cause of HG, occurring in 10% of our patients. This is in corcordance with rates reported in the literature ranging between 2 and 32%[14],[15]18],[19],[20],[21] Eight per cent of HG were due to Hodgkin's lymphomas which were more frequent in comparison to other reports[13],[14],[17],[19].Despite the high prevalence of brucellosis in Saudi Arabia[10], it was surprising to observe brucellosis as the cause of HG in only 5% of cases. This is probably related to the infrequent need for liver biopsy in the diagnosis of brucellosis. This low figure, is however, relatively higher than the rates reported from Western population except from Spain, where brucellosis has been the predominant cause of HG[18]. Several commonly used drugs have been reported to induce HG[22],[23],[24],[25],[26],[27] Strong points of clinical and histologic distinction in favor of drug etiology were not evident in the current report. In a previous study on the etiology of pyrexia of unknown origin (PUO), we have found that tuberculosis was the leading cause of HG in patients who underwent liver biopsy[28]. None of those patients has had HIV infection. In a study from Italy, tuberculosis was, however, the most frequent cause of granulomas with PUO and HIV infection. In contrast, Q fever was the most frequent cause in patients with PUO without HIV[29]. Various studies demonstrated that the etiology of granulomas remained unknown in 11 to 50% of cases[13],[14],[17]. In this study, the etiology of HG could not be determined in 25% of the cases.

It is not always an easy task to differentiate histopathologically between the various etiologic factors of HG. Certain morphologic findings may, however, help to achieve a final diagnosis. For instance, tissue eosinophilia occurs in association with schistosomiasis, lymphoma and hypersensitivity to drugs. [Table - 4] summarises the points of etiologic distinction between hepatic granulomas according to their favoured sites within the liver and some of the histopathologic features. The pathologists are, however, cautioned that these histologic diagnostic criteria are not absolute and should be adopted after correlation with other laboratory data and clinical findings. Recently, polymerase chain reaction (PCR) has been valuable in detecting mycobacterial DNA in tissue with 58% sensitivity and 96% specificity for tuberculosis-associated HG. Despite the relatively low sensitivity, this method is superior to culture in the diagnosis of tuberculosis[30]. In addition, this method may help in differentiating HG due to tuberculosis from other etiologies. Microbiologic and serologic methods are required to confirm the diagnosis of brucellosis and in few instances, the clinical response to empiric treatment of tuberculosis or sarcoidosis is the only method to confirm the diagnosis.

   Conclusion Top

Infections, especially schistosomiasis and tuberculosis represented the major etiologies of HG's in this study. Due to the availability of serologic and microbiologic diagnosis of brucellosis, liver biopsy is not usually performed in such cases and this may explain the unexpectedly low rate of brucellosis in this study. Among noninfectious causes, Hodgkin's lymphoma was the leading etiologic factor. Fever, weight loss, hepatomegaly and splenomegaly may indicate the presence of a granulomatous disorder and hence necessitate a liver biopsy. Granulomatous disorders of the liver are associated with low morbidity and mortality and apprarently have good prognosis. Both clinician and pathologist should be aware of the limitations of the liver biopsy in determining the cause of a granuloma. Clinical circumstances and the results of other investigations, do, however, help in difficult cases.

   Acknowledgement Top

The authors would like to express their gratitude to Mr. Hasim S. Mammah and Miss Vivian C. Darusin for their excellent secretarial help during the typing of this manuscript.

   References Top

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2.Dusek J, Kubasta M, Kodousek R, Kubastova B. Needle biopsy of the liver in schistosomiasis mansoni: the value of histological examination. J Trop Med Hyg 1965:68:189-95.  Back to cited text no. 2    
3.Moriyama H, Yamamato T, Takatasuka H, et al. Expression of macrophage colony-stimulating factor and its receptor in hepatic granulomas of Kupffer cell depleted mice. Am J Pathol 1997;150:2047-60.  Back to cited text no. 3    
4.Jacobs W, Bogeys J, Decider A, Van Mark E. Expression of intracellular adhesion molecule-I and lymphocyte function­associated antigen-1 in experimental schistosoma mansoni infection and in synchronos periportal hepatic granulomas in mice: Immunohistochemistry, confocal laser scanning microscopy and immunoelectron microscopy. Parasitol Res 1997;83:405-12.  Back to cited text no. 4    
5.Klatskin G. Hepatic granulomata; Problems in interpretation. Am NY Acad Sci 1976;278:427-31.  Back to cited text no. 5    
6.Ishak KG. Granulomas of the liver. In Loachim HL (Ed) Pathology of granulomas. Raven Press, New York 1983.  Back to cited text no. 6    
7.Cunningham D, Mills PR, Quigley EMM et al. Hepatic granulomas: Experience over a 10-years period in the West of Scotland. Q J Med 1982:51:162-70,  Back to cited text no. 7    
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11.Kyegombe D, Al-Mofleh I. Al Khwaiter S, Mahmoud A, Al Tuwaijri A. Effects of murine schistosomiasis on hepatic cytochrome P450 and microsomal protein. Liver 1986:6:167-72.  Back to cited text no. 11    
12.Al Mofleh IA, Al Khwaiter SA, Mahmoud AA. Kyegombe DB, Al Tuwaijri AS. Hepatic microsomal protein and cytochrome P-450 in BALB/C mice infected with leishmaniasis. J Gastroenterol Hepatol 1989:4:513-9.  Back to cited text no. 12    
13.Mills PR, Russel RI. Diagnosis of hepatic granulomas: A review. J R Soc Med 1983:76:393-7.  Back to cited text no. 13    
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15.Sartin JS and Walker RC. Granulomatous hepatitis: A retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991:66:914-8.  Back to cited text no. 15    
16.Grumbach K, Coleman BG, Gal AA, Arger PH. Mintz MC, Arenson RL, Aquino L. Hepatic and biliary tract abnormalities in patients with AIDS: Sonographic-pathologic correlation. Ultrasound Med 1989;8:247-54.  Back to cited text no. 16    
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18.Moreto M, Testillano M, Zaballa M, Suarez M. Diagnostic yield and endoscopic pattern of laparoscopy in the diagnosis of granulomatous hepatitis. Endoscopy 1988;20:294-7.  Back to cited text no. 18    
19.Satti M, Al-Freihi H, Ibrahim E, Abu-Melha A, Al-Ghassab G, Al-Idrissi H, Al-Sohaibani M. Hepatic granuloma in Saudi Arabia: A clinicopathological study of 59 cases. Am J Gastroenterol 1990;85:669-74.  Back to cited text no. 19    
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26.Veerabagu MP, Finkelstein SD, Rabinowitz M. Granulomatous hepatitis in a patient with chronic hepatitis C treated with interferon alpha. Dig Dis Scie 1997;42:1445-8.  Back to cited text no. 26    
27.Knobel G, Buyanowsky G, Dan M, Zaidel L. Pyrazinamide­induced granulornatous hepatitis. J Clin Gastroenterol 1997;24:264-6.  Back to cited text no. 27    
28.AI-Mofleh IA, Al-Aska Al, Al-Nozha MM. Fever of unknown origin: Experience in Riyadh, Saudi Arabia. Ann Saudi Med 1989;10:620-5.  Back to cited text no. 28    
29.Vilades C, Ferre R, Martin L. Granulomatous hepatitis and fever at unknown origin. Ann Med Interna 1994; 11:334-7.  Back to cited text no. 29    
30.Diaz ML, Herrera T, Lopez-Vidal Y, Calva JJ, Hernandez R, Palacios GR, Sada E. Polymerase chain reaction for the detection of mycobacterium tuberculosis DNA in tissue and assessment of its utility in the diagnosis of hepatic granulomas. J Lab Med 1996;127:359-63.  Back to cited text no. 30    

Correspondence Address:
Ibrahim A Al Mofleh
Department of Medicine (38), College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 19864728

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  [Table - 1], [Table - 2], [Table - 3], [Table - 4]


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