Discussion

Currently, we reported a case of DJS diagnosed after a course of brucella hepatitis, confirmed by liver biopsy. The fact that comorbidity can aggravate DJ syndrome is known; however, this is the first study reporting DJ syndrome unmasked with Brucella hepatitis. Previously, there have been cases of acute hepatitis caused by brucella. Denk et al. reported a 19-year-old man with fever, arthralgia, icterus, and impaired liver transaminases with mild conjugated hyperbilirubinemia (6). In contrast, another study demonstrated two patients of brucella hepatitis with normal bilirubin levels, but elevated liver transaminase and LDH 7 times higher than normal (7). Concurrent to fluctuating fever and new-onset jaundice for a month, our patient showed impaired AST, and ALT concentrations with mild rise of LDH to 529 U/L, indicating cell destruction of intracellular brucella. A 79-year-old woman has also shown liver failure due to brucellosis infection with impaired bilirubin more than 20 times normal (8). In this case while he had no other signs of liver failure, he presented with direct hyperbilirubinemia of 8mg/dL and total bilirubin of 10mg/dL. In a study on liver involvements of patients suffering brucellosis, mean total and direct bilirubin in diffuse and granulomatous hepatitis were 2.18±2.33 and 3.78±2.05, respectively (9). Thus, high levels of bilirubin in brucella hepatitis could be a sign of liver failure, however, if liver function remains normal, concomitant underlying liver disease should be evaluated. Moreover, regarding previous reports, after standardized treatment of brucellosis, all the patients showed significant decrease in liver enzyme levels and bilirubin, however, although reduced, jaundice and direct hyperbilirubinemia remained. This also highlights the importance of further assessments. In DJS, liver function tests remain in normal range, and the total serum bilirubin levels increase, generally ranging from 2 to 5 mg/dL. However, in 5% of cases, this increase exceeded 10 mg/dL (10). Other liver function tests yield normal results. Although rare, there are previous reports of persistent conjugated hyperbilirubinemia resulted in the diagnosis of the disease (11, 12). DJS is the impairment of transporting direct bilirubin into the bile duct system, leading to its accumulation in hepatocytes and rise in blood levels (5). Grossly black liver, normal architecture, in the presence of accumulation of coarse granular dark pigments located in the centrilobular hepatocytes are particular pathological characteristics of DJS (13, 14). Similarly, Liver biopsy of our patient showed vivid dark brown pigments in the hepatocyte cytoplasm via PAS-D method. A liver biopsy provides essential information about the extent and severity of liver damage in patients with DJS. This information is critical in determining the appropriate course of treatment and monitoring the progression of the disease. If there is evidence of significant liver damage, the patient may need to undergo a liver transplant. In the presence of minimal damage, the patient may only need to be monitored regularly to ensure that the disease does not progress. A liver biopsy is useful for distinguishing DJS from other liver disorders that have similar symptoms and biochemical abnormalities, such as primary biliary cirrhosis, and primary sclerosing cholangitis can also cause conjugated hyperbilirubinemia (15, 16). In ultrasonographic and CT scan assessments, our patient had massive splenomegaly and hepatomegaly. Liver enlargement has been previously seen among both DJS and patients suffering from brucellosis, however, splenomegaly has been reported upon 30-60% of brucellosis and DJS could not cause splenomegaly (17-19). In a study of 251 patients with brucellosis, Pourbagher et al. identified 21 (8.4%) patients with splenomegaly, 15 (6%) patients with hepatomegaly, 4 (1.6%) patients with splenic abscess, 2 (0.8%) patients with splenic cyst, 2 (0.8%) patients with acute appendicitis, 1 patient (0.4%) with acute acalculous cholecystitis (20). There are also further reports of brucella hepatitis presented with huge splenomegaly, even spleen infarction, and its rupture (21-23). Importantly, massive splenomegaly has limited etiologies such as major beta-thalassemia, acute leukemias, lymphomas, cirrhosis with portal hypertension, and myeloproliferative neoplasms (24). Regarding that massive splenomegaly found in our patient revealed after full-treatment of brucellosis, further analysis of the ethnologies deems necessary to elucidate whether this novel report could be due to DJS and brucellosis concomitancy. It is important to mention certain limitations that were encountered. Firstly, the rarity of both Brucella hepatitis and DJS presents challenges in diagnosing and managing such cases, especially when they occur concomitantly. Limited clinical experience and awareness of these conditions among healthcare professionals may contribute to delays in diagnosis or misinterpretation of symptoms. Additionally, the lack of specific diagnostic markers for DJS can make its identification challenging, often necessitating a comprehensive evaluation and ruling out of other liver pathologies. Based on his past medical history, laboratory tests, and clinical evaluation, a diagnosis of Dubin-Johnson syndrome was suspected. Of course, urine high coproporphyrin I fraction could lead to a straight diagnosis of DJS, nevertheless, unfortunately we do not have the kit in our hospital. We referred the patient to the central hospital of gastroenterology, but he hesitated and in other sessions of follow-up we found out he did not follow the instructions and hesitated to travel to another city for further evaluations. We had to perform liver biopsy to not only approve our diagnosis of DJS, but also make sure there were no sign of viral hepatitis with negative viral markers, further masked infections, alhpah1-anti trypsin deficiency or hepatic granulomatosis. H&E staining only showed vivid dark brown pigments in the hepatocyte cytoplasm, and PAS-D was negative for alpha-1-antitrypsin globules, confirming the diagnosis of DJS.

Conclusion

Currently, we reported the first DJS diagnosed by persistent direct hyperbilirubinemia after brucella hepatitis in a young man. Clinicians should be aware of unusual rise in liver function tests and carefully monitor the response to therapy, to avoid neglecting benign conditions such as DJS and long-term consequences. To date, concomitant DJS with other liver diseases has not been adequately addressed. Further studies should evaluate possible novel and exaggerated clinical findings, as well as the unexpected long-term consequences.