Glycogenic hepatopathy (GH) is a rare or possibly under-diagnosed complication seen in children and young adults with poorly controlled type 1 diabetes mellitus and few patients with type 2 diabetes mellitus.[1][2] It is characterized by a reversible accumulation of excess glycogen in hepatocytes, causing hepatomegaly and transient elevation of liver enzymes, especially transaminases. The diagnosis is confirmed by liver biopsy and staining of glycogen using hematoxylin and eosin (HE) stain.

Glycogenic hepatopathy was first described by Pierre Mauriac in 1930 in a pediatric patient with poorly controlled type 1 diabetes (brittle diabetes) who presented with hepatomegaly, cushingoid features, and poor growth, developing a condition known as Mauriac syndrome.[3][4] Since then, many cases have been reported without all the clinical features of Mauriac syndrome. Various terminology was used before glycogenic hepatopathy like hepatic glycogenosis, glycogen storage hepatomegaly, and hepatic glycogen storage disease.[5][6][7][8][9][10] In 2006 Torbenson and colleagues coined the term “glycogenic hepatopathy,” which has been universally adopted.[10]

Other Causes of Glycogenic Hepatopathy

Glycogenic hepatopathy has been observed not only in patients with diabetes mellitus but also in patients with dumping syndrome after gastrectomy, anorexia nervosa, high dose corticosteroids, azathioprine use, and high doses of insulin usage.[9][11][12][13].

Glycogenic Hepatopathy in Dumping Syndrome

Dumping syndrome is a complication seen in gastric surgeries like Gastric bypass surgery where “chyme” rapidly dumps into the small intestine from the stomach without complete absorption. There is a fluctuation between hyperglycemia from feed load and hyperinsulinemia, similar to diabetes mellitus.[12]

Anorexia Nervosa

Kransdorf and colleagues reported a case of anorexia nervosa with elevated liver function tests and glycogen deposition.[11] It is thought that hepatic glycogenosis is the adaptive protective mechanism from potential hypoglycemia in malnutrition.

 Short Term Use of High Dose Steroid Therapy

High dose steroids elevate glucose levels, gluconeogenesis, and glycogen deposition. Lancu and colleagues studied 141 patients who had received steroid therapy, 13% had hepatomegaly, and 3 patients had glycogenic hepatopathy.[14] After discontinuation of steroid therapy, hepatomegaly resolved in all patients. Steroids induce hyperglycemia, causing an increased glycogen production and deposition in the liver, by activation of phosphorylase and subsequent activation of glycogen synthase.

Insulin Overdose

Tsujimoto et al. reported a case in which a patient with type 2 diabetes mellitus (DM) self-injected a large dose of insulin in an apparent suicide attempt.[9] He was hypoglycemic and was administered large amounts of intravenous glucose to counteract the persistent hypoglycemia. After the administration of insulin and glucose, he acutely developed acute glycogen storage hepatomegaly. His baseline liver enzymes before suicide attempt were normal and later increased to 30 fold of the upper normal limits.

True incidence and prevalence of glycogenic hepatopathy are unknown, Much of the knowledge is through reported case studies, case series, retrospective cohort study, and more recently case-control study.[4][15] The prevalence of liver disease among diabetics is estimated to be between 17% to 100%, with NAFLD and hepatic glycogenosis being the most predominant. [16] Approximately 98% of GH cases were reported in type 1 DM and the remaining 2% in type 2 DM. 62% of the reported cases are female patients, and 38% of reported cases are male patients, indicating a slight female predominance, with most cases occurring in adolescence.[17] 

The pathophysiology of glycogenic hepatopathy is incompletely understood. It is believed to be the consequence of recurrent fluctuations in glucose level with hyperglycemia, hypoglycemia, and hyper insulinization. Glycogenic hepatopathy occurs when prolonged or marked hyperglycemia is treated with supraphysiological amounts of insulin.[10] It has been reported first with hyperglycemia and hypoglycemia with ketoacidosis in type 1 DM. It has also been reported without ketosis or acidosis in patients with type 2 DM and with variable insulin requirements.[10][18] Glycogen is the polymer of glucose. After feeding, the liver takes up glucose and utilizes it for fuel with the excess to be converted into glycogen. Glycogen is the reservoir for glucose. Glycogenosis and glycogenolysis keep the balance of glycogen levels in the liver. High glucose levels move into the hepatocytes via facilitated diffusion through GLUT 2 transporter, independent of insulin.[19] The glucose is trapped in the cell after irreversible phosphorylation to glucose-6 phosphate by the enzyme glucokinase. Further, hyperglycemia treated with high doses of insulin polymerizes the glucose 6-phosphate to glycogen by the enzyme glycogen synthase.[19]

The enzyme glycogen synthase exists in two forms, the active form (dephosphorylated) and the inactive form (phosphorylated). The enzyme phosphatase converts the inactive phosphorylated glycogen synthase to the active dephosphorylated form. The phosphatase enzyme is stimulated by high levels of glucose and insulin. Glycogen synthesis continues for some time even after insulin levels have declined while inhibiting glycogenolysis.[20] With continued glycogen storage, hepatomegaly can develop within a few days to a week and can improve rapidly once the hyperglycemia is controlled.[21]

Liver biopsy is the gold standard for diagnosis of glycogenic hepatopathy, typical features are swollen hepatocytes, due to the accumulation of glycogen in the cytoplasm. The hematoxylin and eosin (HE) stain shows pale and enlarged hepatocytes with numerous glycogenated nuclei. Diastase enzyme, when added to the PAS stained specimen, causes enzymatic degradation of glycogen, causing empty hepatocytes (“ghost cells”).[22]