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enhanced glycogen deposits were observed with activity in positive control was also indicated [Figure 1a
[5,6]
increasing frequency in patients with brittle diabetes. and b].
Excessive storage of glycogen [glycogen-storing foci
(GSF)] has been observed in pre-neoplastic foci of Histologic examination showed a well- to moderately-
altered hepatocytes (FAH), and in highly differentiated differentiated HCC [Figure 2a], with the background
subpopulations of benign and malignant hepatocellular liver showing steatohepatitis with alcoholic pericellular
lesions in animal models of hepatocarcinogenesis. fibrosis [Figure 2b]. Both PAS-positive [Figure 2c and
[7-9]
Glycogenotic cells (clear cell) have been observed in liver d] and D-PAS-negative (glycogen-storing) hepatocytes
biopsies and explants from the patients harboring foci [Figure 2e and f] were detected in the background
and nodules of altered hepatocytes. [10,11] Although clear liver and in HCC tissues. However, the PAS-positive
cell HCCs have been described, their glycogen content hepatocytes were more abundant in the background
was usually not determined. [12] liver than in the HCC tissues. No pronounced clear cells
were detected. HK-II expression was weak in HCC [Figure
To our knowledge, there have been no comparative 2g] and faint in background liver [Figure 2h]. Clinical and
studies on changes in hepatocellular glycogen content pathological data are summarized in Table 1.
of HCC and background livers in patients with T2DM.
This study describes two patients with HCC and T2DM, Case 2
who showed marked changes in hepatocellular glycogen A 73-year-old Japanese man with T2DM and non-
content. alcoholic steatohepatitis (NASH) was diagnosed with
HCC by CT examination. At the age of 64, he was
CASE REPORT diagnosed with T2DM and NASH via needle biopsy of the
liver. Laboratory examination showed AST 51 IU/L, ALT
Case 1 22 IU/L, AFP 4.4 ng/mL, PIVKA-II 22 mAU/mL, FBS 140 mg/
A 72-year-old Japanese man with T2DM and alcoholic dL, and HbA1c 6.3%.
liver disease was diagnosed with HCC by computed
tomography (CT) examination. Laboratory data Partially, hepatectomized liver tissue was fixed as
showed aspartate transaminase (AST) 95 IU/L, alanine described in Case 1. Macroscopically, the HCC was
transaminase (ALT) 65 IU/L, alpha-fetoprotein (AFP) revealed as simple nodular type (size, 1.8 cm × 1.5
cm; stage 1, T1N0M0; Child-Pugh grade A). Histological
8.2 ng/mL, protein-induced by vitamin K absence examination showed a well-differentiated HCC [Figure
factor II (PIVKA-II) 26 mAU/mL, fasting blood sugar 3a], with the background liver presenting as type B
(FBS) 228 mg/dL, and hemoglobin A1c (HbA1c) 7.9%. cirrhosis [Figure 3b]. PAS-positive [Figure 3c and d]
CT arterial portography and CT hepatic arteriography and D-PAS-negative [Figure 3e and f] hepatocytes were
revealed 2 minor nodules (3-4 mm) at S5, and a larger detected in both background liver and in HCC tissues,
nodule (2.5 cm × 2.3 cm) at S8. although the PAS-positive hepatocytes were more
abundant in background liver than in the tumors. HK-
A specimen, obtained from needle biopsy of the S8 II was weakly expressed in HCC [Figure 3g] and faintly
tumor, was fixed with Carnoy’s solution, and formalin for expressed in background liver [Figure 3h]. No obvious
a routine histological diagnosis. Samples were stained clear cells were detected.
with periodic acid-Schiff (PAS) and PAS after diastase pre-
treatment (D-PAS). Hexokinase II (HK-II) was detected DISCUSSION
immunohistochemically using anti-HK II (C64G5) rabbit
mAb (Cell Signaling Technology, Inc. Danvers, US). HK-II This study describes the two patients with T2DM, who
developed HCC. Background liver in both patients
showed steatohepatitis, suggesting that HCC may have
been mainly due to steatohepatitis. The alcohol intake
[2]
may have been a risk factor for HCC in Case 1, whereas
occult HBV infection with positivity for hepatitis B surface
anti-body/hepatitis B core anti-body may have been a risk
factor in Case 2. [13]

Figure 1: Control - hexokinase II activity in hepatocellular carcinoma tissues Glycogenotic hepatocytes are a common pre-
(a) and background liver (b) of positive control (65-year-old male, well- neoplastic liver lesion in human at a high risk of HCC
differentiated adenocarcinoma in background of chronic hepatitis C) (a and b:
hexokinase II, ×400) development. [11,14] FAH, including GSF, was detected in

Hepatoma Research | Volume 2 | Issue 1 | January 15, 2016 27