Hepatocellular Carcinoma Occurring in Crohn’s Disease Patients
Table 1: Clinicopathologic Features of Hepatocellular Carcinoma Occurring in Crohn's Disease Patients Case
Number 1 2 3 4 5 6 7 8 9 10
Sex Age at Onset Medication of CD/
for CD
Discovery of HCC (Year)
F F 29/43 9/22 M 13/33 F F 63/63 14/28 M 17/33 M 19/37 M 16/52 M 13/25 M 29/37 AZA, PSL 5-ASA, AZA 5-ASA, AZA 5-ASA AZA, IFx AZA
5-ASA, AZA, PSL
5-ASA
Serum AFP/ Histology PIVKA II (ng/ml,
of HCC
mAU/ml) NA/NA
55,000/NA NA/NA NA/1,100 26.9/NA Normal
range/NA 15/NA
13.9/16,300 AZA, IFx, PSL 78/NA
5-ASA, AZA, PSL
7.7/757 NA Trabecular NA NA
Trabecular, pleomorphic NA
Trabecular to sinusoidal,
pleomorphic Trabecular
Pleomorphic Histology of
Non-neoplastic Liver
No cirrhosis
No cirrhosis FHG(+)
No cirrhosis PSC
No cirrhosis FHG(+)
No cirrhosis PSC
No cirrhosis (only CT imaging)
Chronic liver damage
No cirrhosis FHG(+)
Pseudoglandular No cirrhosis FHG(+)
No recurrence was found on
CT imaging, but PIVKA II was 1,980 No metastasis or recurrence one year after surgery No recurrence two years after surgery
9 10 11
AFP = alpha-fetoprotein; 5-ASA = 5-aminosalicylic acid; AZA = azathioprine; CD = Crohn's disease; CT = computed tomography; DOD = died of disease; F = female; FHG = focal hepatocyte glycogenosis; HCC = hepatocellular carcinoma; Ifx = infiximab; M = male; NA = not available; PIVKA II = protein induced by vitamin K absence-II; PSC = primary sclerosing cholangitis; PSL = prednisolone.
HCC. Azathioprine, an inhibitor of purine synthesis, is prescribed widely in patients with inflammatory bowel disease or organ transplantation. It was reported recently that patients who underwent long-term azathioprine-based immunosuppression treatment showed an increased risk for non-Hodgkin lymphoma and cutaneous squamous cell carcinoma.12,13
The occurrence of HCC in patients who received azathioprine therapy in the absence of liver cirrhosis and viral hepatitis remains exceptional. Only one case of HCC has been reported in a patient who showed no apparent risk factor developing HCC other than prolonged azathioprine therapy due to a renal transplant (no hepatitis C studies were available at that time).14
Figure 1: Histopathologic Findings of Hepatocellular Carcinoma Occurring in a Crohn’s Disease Patient
AB
DOD with intra-abdominal and intrathoracic metastases Recurrence at six months,
liver transplantation performed Lung metastases
No evidence of recurrence NA
Mediastinal and abdominal metastases; died one year after DOD three months after surgery 8 2 3 4 5 6 7 Outcome
Reference
A: hepatocellular carcinoma of the pseudoglandular type; B: focal hepatocyte glycogenosis in the non-neoplastic liver.
Another case of HCC after azathioprine therapy was also reported in a patient with ulcerative colitis but without hepatitis B and C.15
It was hypothesized previously that the degree of immunosuppression by prolonged azathioprine therapy was associated with the incidence of neoplasia.14
These results suggest that azathioprine therapy is associated with the development of HCC in CD patients, although the precise mechanism behind this association has not been resolved.
Focal Hepatocyte Glycogenosis
Focal hepatocyte glycogenosis (FHG) is patchy foci of glycogen-enriched clear hepatocytes in response to changes in hepatocyte glycogen
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
In addition, azathioprine has also been reported to increase hepatocytes turnover in one experimental study.16
metabolism (see Figure 1). Although the cause and significance of FHG are not well-established, FHG can be observed in the liver of the patients with Reye’s syndrome, viral hepatitis, or cirrhosis, and also in those who use long-term oral contraception. FHG can be considered a pre-neoplastic lesion because FHG and lesions observed during drug-induced hepatocarcinogenesis have histologic and biochemical similarities, and the presence of FHG within non-malignant hepatocellular nodules of cirrhotic liver can predict their malignant transformation.17
Cattan et al. reported a case of HCC occurring in a CD patient who had a medication history of azathioprine and disseminated FHG in the non-neoplastic liver tissue.3
FHG was observed in the non-neoplastic
liver in four of 10 cases of HCC in CD patients. All four of these patients had a medication history of azathioprine (see Table 1), supporting the suspected pathogenic link between long-term azathioprine therapy and FHG, prior to the development of HCC.
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