Introduction:
Diabetes mellitus (DM) is linked to a variety of structural and functional abnormalities of the liver, such as non-alcoholic fatty liver disease (NAFLD) and hepatic glycogenosis (HG). NAFLD constitutes the most widely accepted liver disease associated with diabetes, particularly in type 2 diabetes and patients with metabolic syndromes. HG is connected with poorly controlled diabetes, particularly type 1 diabetes, and includes pathological glycogen storage in hepatocytes. This condition is assumed to be underdiagnosed because it is barely distinguishable from NAFLD without a liver biopsy. The difference between these two diabetes-related complications is highly crucial: whereas NAFLD can proceed to fibrosis and cirrhosis, HG may be reversible with long-term glycemic control.
What Is the Definition and Epidemiology of Hepatic Glycogenosis?
Hepatomegaly and a temporary rise in liver transaminases are symptoms of HG, described as a pathological elevated glycogen accumulation in hepatocytes. Although the exact prevalence of HG is unknown, it is thought to be the leading cause of hepatomegaly in children and adolescents with type 1 diabetes. Mauriac first described glycogen accumulation in the liver in children as a component of Mauriac's syndrome in 1930. He discovered glycogen accumulation in a child with type 1 diabetes and poor diabetic control, which was linked to hepatomegaly and abnormal liver enzymes, as well as other symptoms like retardation of growth, delayed puberty, cushingoid features, and hypercholesterolemia.
What Is the Underlying Pathology of Hepatic Glycogenosis?
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Blood glucose and insulin levels often fluctuate in diabetic patients with poor metabolic control, thereby promoting hepatic glycogen accumulation. High plasma glucose levels cause an insulin-independent glucose influx into hepatocytes by facilitated diffusion.
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In the cytoplasm of hepatocytes, glucose is irreversibly converted into glucose-6-phosphate by glucokinase, an enzyme regulated by glucose and insulin. Then, glucose-6-phosphate is converted into glycogen by glycogen synthase and converted from the inactive form into the activated form by a phosphatase.
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This phosphatase plays a crucial role in regulating this step in the pathway, and its concentration is maintained by insulin, and its activity depends on the presence of glucose.
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As a result, hepatic glycogen synthesis results from high blood glucose levels (which enhance glucose flow into hepatocytes) and hyperinsulinemia (which promotes glucose conversion to glycogen).
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This is common in patients with unstable diabetes treated with insulin for severe or prolonged hyperglycemia.
What Is the Clinical Presentation of Hepatic Glycogenosis?
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The clinical manifestations are variable and can involve abdominal pain that is sometimes accompanied by nausea, vomiting, and anorexia (loss of appetite for food).
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The main clinical characteristics are hepatomegaly and a mild to moderate rise in transaminases, though transaminase levels can be significantly raised in some cases.
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Although alkaline phosphatase levels can be raised, synthetic liver function is generally expected. Ascites (fluid accumulation in the peritoneal cavity leading to abdominal swelling) are rare.
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Adults and children have similar clinical and pathological features.
What Is the Diagnosis of Hepatic Glycogenosis?
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History, physical examination, and laboratory blood tests cannot differentiate hepatic glycogenosis (HG) from non-alcoholic fatty liver disease (NAFLD). Furthermore, ultrasound cannot distinguish between fatty liver and glycogen accumulation.
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Moreover, in the early stages of non-alcoholic fatty liver disease (NAFLD), a low liver density by CT may not be evidenced, and CT only offers qualitative information. On the other hand, gradient dual-echo magnetic resonance imaging (MRI) has recently been shown to distinguish glycogen from fat in the liver.
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A gradient dual-echo magnetic resonance imaging (MRI) series and magnetic resonance spectroscopy can quantify intrahepatic lipid content and detect even minor amounts of fat accumulation.
What Is the Differential Diagnosis of Hepatic Glycogenosis?
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In addition to NAFLD, the differential diagnosis of HG must take into account many other contributing factors of liver damage, like infection (for example - viral hepatitis), metabolic disorders (for instance - deficiency of alpha one antitrypsin and Wilson's disease), obstruction, autoimmune liver disease, and celiac disease.
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In contrast, there is substantial evidence that focal, but occasionally diffuse, HG is a preneoplastic lesion.
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Studies conducted on various animal models of chemical, viral, and hormonal hepatocarcinogenesis and some human observations demonstrate that focal HG is an essential early event in the pathogenesis of benign and malignant hepatocellular neoplasms.
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Although the actual mechanism is unknown, recent evidence suggests that oncogenic representatives have an early insulin-like effect. In addition, several epidemiology studies have revealed that diabetes is a risk factor for the onset of hepatocellular carcinoma. Moreover, no link has been established between diabetes-related HG and hepatocellular neoplasms, so more research is needed to address this issue.
What Are the Histology Findings of Hepatic Glycogenosis?
A liver biopsy is the only way to diagnose HG. However, many histological features distinguish HG:
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In distinct glycogen accumulation, typically, glycogen is removed from hepatocytes after standard tissue preparation (fixation with a formaldehyde solution and stained with hematoxylin and eosin stain). Thus, the hepatocytes are swollen diffusely with pale cytoplasm and cell membrane accentuation, frequently with nuclei displaced to the cell periphery, with compressed sinusoids, glycogenated nuclei, and giant mitochondria are evident; accumulation of glycogen within hepatocytes is evident by periodic acid-Schiff staining, which disappeared after diastase digestion.
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No or minor alteration in fat content.
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No or minor inflammation.
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No or minor presence of spotty lobular necrosis.
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The architecture of the liver is intact with no or minimal fibrosis.
Conclusion:
HG is much more likely an undiagnosed hepatic complication of diabetes that is challenging to distinguish from NAFLD. As a result, a diagnosis of HG must be considered in diabetic patients, particularly those with type 1 diabetes, who have poor metabolic control and have a temporary rise of liver transaminases and hepatomegaly. Even though HG is diagnosed histologically, a gradient dual-echo magnetic resonance imaging pattern coupled with a liver CT is an effective method for distinguishing HG from NAFLD. The definitive diagnosis of this disease is critical because it has the potential to resolve after improved glycemic control.
