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.