Glycogenic Hepatopathy

Etiology

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 the suicide attempt were normal and later increased to 30 fold of the upper normal limits.

Epidemiology

True incidence and prevalence of glycogenic hepatopathy (GH) 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 non-alcoholic fatty liver disease (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]

Pathophysiology

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]

Histopathology

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 periodic acid-Schiff (PAS) stained specimen, causes enzymatic degradation of glycogen, causing empty hepatocytes (“ghost cells”).[22]

History and Physical

Patients with glycogenic hepatopathy can present with asymptomatic elevated liver enzymes or with symptoms of hyperglycemia like polyuria, polydipsia, weight loss, and lethargy. They can also present with diabetic ketoacidosis symptoms like abdominal pain, nausea, and vomiting. Pediatric patients can present with growth failure, delayed puberty, and hepatomegaly. The rapid stretching of the liver capsule due to hepatomegaly can cause abdominal pain. Physical examination reveals hepatomegaly, no other remarkable physical finding is present in patients with glycogenic hepatopathy.

Evaluation

Liver biopsy is crucial for the diagnosis of glycogenic hepatopathy as there is no single serological test to diagnose glycogenic hepatopathy. Based on clinical features, other common causes of chronic hepatitis should be ruled out. Autoimmune serology testing may be done. Glycogen storage diseases result from the congenital absence of various enzymes and usually present in neonates and infants with hepatomegaly and hypoglycemia.[13]

Biochemical Features

In more than 90% of the cases, hepatomegaly has been reported, with the varying elevation of transaminases and almost no alkaline phosphatase elevation. The synthetic functions of the liver are preserved. The elevated enzymes are thought to be due to cell membrane injury rather than necrosis.

Imaging

Ultrasound imaging shows hepatomegaly with uniform echogenicity, which can also occur in non-alcoholic fatty liver disease (NAFLD). It cannot differentiate NAFLD from glycogenic hepatopathy.

The computed tomography can help in differentiating fatty liver from glycogenic hepatopathy. The fatty liver is hypodense on the CT scan, whereas the glycogen loading of the liver appears hyperdense on the CT scan. The bright liver on computed tomography can be used as a clue to the diagnosis of glycogenic hepatopathy while taking into consideration other causes of increased hepatic attenuation like hemochromatosis.[23] Magnetic resonance imaging (MRI) can also help in establishing the diagnosis of glycogenic hepatopathy.

Treatment / Management

Glycogenic hepatopathy (GH) is a benign and potentially reversible condition within 2-14 weeks. Improved glycemic control is the key to successful management; with good glycemic control, both clinical and biochemical features of glycogenic hepatopathy can resolve within days to weeks.[24] The exact glycemic control to treat glycogenic hepatopathy is not yet established but aggressive insulin treatment is not necessary. Parmar et al published a case report in which just 0.6% improvement in HbA1c led to the relief of abdominal pain and a decrease in liver enzymes.[25](B3)

Differential Diagnosis

Other diseases that can cause elevated transaminases with hepatomegaly in patients with diabetes mellitus include:

• Non-alcoholic fatty liver disease (NAFLD)
• Autoimmune hepatitis
• Celiac disease
• Viral hepatitis
• Hemochromatosis
• Wilson disease

Prognosis

Glycogenic hepatopathy (GH) is a benign and potentially reversible condition within few days to weeks with good glycemic control. GH has a very good prognosis and it must be carefully differentiated from non-alcoholic fatty liver disease (NAFLD) because NAFLD can progress to fibrosis while GH does not.

Complications

Glycogenic hepatopathy itself is a hepatic complication of uncontrolled diabetes mellitus and it is benign and self-limiting with good glycemic control. It does not have any grave complications.