The Liver and Glycogen: In Sickness and in Health

Abstract

The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

Keywords: Mauriac syndrome; clear cell hepatocellular carcinoma; glycogenic hepatopathy; hepatic glycogenosis; pathology; pseudoground glass.

Figure 1

H&E and PAS staining characteristics in the normal liver (original magnification 400×): (A) H&E stain; (B) PAS stain.

Figure 2

Pathogenesis of hepatocellular glycogen accumulation in the liver, highlighting the role of both elevated glucose levels and insulin treatment in glycogenic hepatopathy (modified from Munns et al. [26]). Glucose enters hepatocytes via facilitated diffusion through glucose transporter 2 (GLUT2) independent of insulin, where it is then phosphorylated to glucose-6-phosphate by glucokinase and subsequently converted to glycogen by glycogen synthase. Insulin activates glucokinase, and also acts together with elevated glucose levels to stimulate the phosphatase enzyme to produce the active dephosphorylated form of glycogen synthase [1].

Figure 3

A liver biopsy from a patient with glycogenic hepatopathy demonstrating swollen hepatocytes with abundant clear cytoplasm due to glycogen accumulation (H&E stain; original magnification 600×). Occasional glycogenated nuclei can be seen.

Figure 4

Patchy glycogenosis in NAFLD (original magnification 400×). The empty rounded spaces are large lipid droplets displacing the cell nuclei, while the glycogenated hepatocytes show cytoplasmic pallor but retain the central position of the nuclei and angular cell contours.

Figure 5

Glycogen storage disease (original magnification 400×): (A) type IX, with a similar histological appearance to glycogenic hepatopathy; (B) type IV, demonstrating hepatocellular ground-glass type cytoplasmic inclusions. These PAS-positive inclusions may be diastase-resistant as they comprise amylopectin-like material rather than typical glycogen. Chronic hepatitis B infection and drug-induced glycogen pseudoground-glass type changes can have a similar appearance and should be excluded.

Figure 6

Drug-induced changes in the liver (original magnification 600×): (A) glycogen pseudoground glass changes in polypharmacy; (B) “two-tone” hepatocyte cytoplasmic appearance highlighted by PAS stain, possibly due to abnormal endoplasmic reticulum proliferation.

Figure 7

Clear cell hepatocellular carcinoma with abundant cytoplasmic glycogen (original magnification 400×): (A) H&E; (B) PAS stain.