Glycogenic hepatopathy, an underdiagnosed cause of relapsing hepatitis in uncontrolled type 1 diabetes mellitus

Discussion

Hepatomegaly with or without raised transaminase levels is common in patients with DM. Glycogen-induced hepatomegaly in type 1 DM was described first by Mauriac in 1930, as a component of a syndrome characterized by hepatomegaly, growth retardation, cushingoid appearance, and delayed puberty. Mauriac syndrome has become rare with the advent of better insulin regimens and improved multidisciplinary care.2 However, there have recently been increasing numbers of case reports describing this condition in both children and adults with type 1 diabetes, but without other components of Mauriac syndrome.1,3 There have also been some cases reported in patients with type 2 DM1.4 The term glycogenic hepatopathy has been proposed by Torbenson et al1 to represent a pattern of glycogen accumulation within hepatocytes, which is characterized by elevated serum transaminases and/or hepatomegaly, in patients with uncontrolled DM. The exact incidence and prevalence of the condition are not well known, as the condition is underrecognized. The clinical symptoms and signs of GH are nonspecific, and include abdominal pain, hepatomegaly, and marked transaminases elevation resembling acute and relapsing hepatitis. Liver synthetic functions are typically preserved.

The hepatic glycogen level is maintained by the balance between glycogenesis and glycogenolysis in the liver. In diabetic patients with poor glycemic control, blood glucose and insulin levels often demonstrate significant fluctuations, with hypo- and hyperglycemic attacks.

In the presence of hyperglycemia, glucose passively diffuses into hepatocytes (insulin-independent mechanism), and is subsequently converted to glucose-6-phosphate, which is then converted to glycogen under the influence of insulin; these changes are exaggerated in the presence of hyperglycemia and over-insulinization, which are believed to represent the primary mechanism in the development of GH.5,6 In addition to GH, there are several differential diagnoses that need to be considered in any patient with DM and hepatomegaly; these include NAFLD, glycogen storage disease (GSD), and autoimmune disorders, such as celiac disease and autoimmune hepatitis, both of which may be associated with DM. While NAFLD is the most likely diagnosis in obese patients with type 2 DM, GH is more common in patients with poorly controlled type 1 DM. It is difficult to distinguish GH from NAFLD neither on the basis of clinical presentation nor by liver ultrasound. So far, liver biopsy is the only diagnostic tool that can differentiate between the 2 conditions.

The clinical presentation of markedly elevated liver enzymes in the background of poorly controlled type 1 DM is highly suggestive of GH. Genetic testing, as performed in our case, can help to rule out GSD. Liver biopsy is the gold standard test for GH diagnosis. The main histological features of GH are marked glycogen accumulation, leading to pale, swollen hepatocytes, with typically minimal inflammation, steatosis, and fibrosis.1 A recent report by Fitzpatrick et al.7 described the histopathology findings in 31 young patients (median age of 15 years) with GH; they reported a high percentage of inflammation (42%) and fibrosis (73%), but these were generally mild. There is still a need for larger-scale and long-term studies to explore the consequences of fibrosis over time. Some case reports described the utility of radiological imaging studies such as computed tomography (CT scan) and magnetic resonance imaging (MRI) in establishing the diagnosis of GH depending primarily on the interval changes in the liver density and its correlation with the clinical picture; however, further larger-scale studies are needed to confirm the findings from these reports, and to establish their sensitivity and specificity for this condition.8,9

Glycogenic hepatopathy is a benign condition that is potentially reversible within 2 to 14 weeks, both clinically and biochemically, with good glycemic control.10,3 The degree of glycemic control required to achieve this result has not been well described, but aggressive insulin therapy is not necessarily required.10,6 Parmar et al,6 reported a case in which an improvement of just 0.6% in HbA1c led to symptomatic relief of abdominal pain and a decline in liver enzymes.

In conclusion, Although it is a well-known complication of poorly controlled type 1 DM, GH is still an underdiagnosed cause of elevated transaminase levels and hepatomegaly in these patients. Physicians should be aware of this condition and should consider it in the differential diagnosis of hepatomegaly with elevated liver enzymes during the workup of type 1 DM patients. Early diagnosis and subsequent implementation of good glycemic control will ultimately lead to an excellent prognosis. Larger-scale and long-term studies are still needed to clarify the incidence and prevalence of the condition, and to tests the utility of noninvasive diagnostic modalities such as MRI in the diagnosis of this condition.