Glycogenic hepatopathy as a cause of severe deranged liver enzymes in a young patient with type 1 diabetes mellitus

Abstract

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.

Background

Glycogenic hepatopathy (GH) is a rare condition first described in the context of Mauriac syndrome in 1930, in a set of clinical features including hepatomegaly, growth retardation and cushingoid characteristics in children with poorly controlled type 1 diabetes mellitus (T1DM).¹ Later, with the evolution of treatment and the improvement of life expectancy in T1DM patients, GH has also been reported as a rare complication of brittle diabetes in young adults.

The clinical presentation of GH includes typically hepatomegaly combined with non-specific symptoms such as abdominal pain, nausea, vomiting and anorexia.^{2 3} Laboratory work-up is characterised by poorly controlled diabetes mellitus and a marked rise of aminotransferases ranging from threefold to levels of acute hepatitis, although the synthetic capacity of the liver is preserved. At the histological level, the hepatocytes are swollen with considerable intracellular glycogen accumulation on periodic acid–Schiff stain (PAS) that characteristically disappears after PAS diastase digestion (PASD).^2–4 In this context, the elevation of aminotransferases is probably due to alterations of the hepatocyte membrane and not hepatocellular death per se.

In terms of pathophysiology, the mechanisms leading to glycogen overload are obscure. Normally in the postprandial phase, hepatic glucose uptake through the glucose transporter 2 is driven freely by the gradient between the high plasma concentration and low intracellular concentration. In addition, insulin promotes glycogen production by activating glycogen synthase enzyme that is responsible for the conversion of glucose-1-phosphate to glycogen (direct pathway). It is also known, through 13C nuclear magnetic resonance spectroscopy, that glycogen production is enhanced by an indirect pathway driven by glucose concentrations in patients with poorly controlled insulin-dependent diabetes mellitus during a full fasted-feeding circle.^{5 6} This is thought to be a result of alterations in portal vein concentrations of insulin and glucagon and more precisely changes in insulin-to-glucagon ratios.⁷

So far, the effects of profound hyperglycemia followed by intense insulin therapy along with the distortion in net hepatic glycogen synthesis provide an explanation for glycogen overload in poorly controlled T1DM. Yet, it is ambiguous why this results in hepatopathy in a group of T1DM patients. Gene defects and post-translational errors in the enzymes that regulate glycogen production are areas of interest in the quest for the culpable pathogenetic mechanism.

Herein, we describe a case of acute anicteric hepatitis in a female patient with poorly controlled T1DM proved to be due to GH and highlight the crucial steps in establishing the diagnosis in conjunction with the approach to treatment.

Case presentation

A 19-year-old woman was admitted to the department of medicine because of abrupt onset intermittent abdominal pain in the right upper quadrant unrelated to food consumption over the past 2 weeks accompanied by laboratory evidence of acute anicteric hepatitis. The patient reported also anorexia and early satiety. Her medical history included Hashimoto thyroiditis under levothyroxine and T1DM diagnosed 7 years ago. The patient denied any travel history last year or the use of alcohol, any supplement or herbals and intravenous or nasal illicit drugs. Three months ago, the treatment for diabetes was switched from insulin pump (glulisine) to subcutaneous insulin (glargine), due to difficulties in glycemic control. However, the patient failed to maintain the levels of glycated haemoglobin <10%. Physical examination revealed significant hepatomegaly and cushingoid appearance, although her body mass index was 24.

Investigations

Laboratory work-up on admission showed deranged liver enzymes with a marked increase in aspartate and alanine aminotransferases (AST: 1061 IU/L and ALT: 568 IU/L; upper limit of normal [ULN]: 40 IU/L). The cholestatic enzymes γ-glutamyl-transpeptidase (γ-GT) and alkaline phosphatase (ALP) were moderately increased (γ-GT: 277 IU/L [ULN: 55 IU/L] and ALP: 225 IU/L [ULN: 120 IU/L]) while bilirubin and markers of synthetic capacity of the liver such as albumin and international normalised ratio were within normal limits. Blood glucose was also increased (196 mg/dL) along with haemoglobin A1c (11.2%), cholesterol (302 mg/dL), triglycerides (394 mg/dL) and low-density lipoprotein levels (146 mg/dL). Urine analysis did not reveal the presence of ketones. Complete blood count, thyroid hormones, serum IgG and serum inflammatory markers such as C reactive protein and erythrocyte sedimentation rate were also normal. An ultrasound of the upper abdomen showed only hepatomegaly. Chest X-ray and electrocardiography were also unrevealing. The remaining haematological, microbiological, virological and biochemical parameters including blood, stools and urine cultures and investigation for hepatitis A, B, C and E as well as for other viruses, serum ceruloplasmin, 24-hour urinary copper concentration, alpha1-antitrypsin and ferritin levels were within normal limits.

Differential diagnosis

As most of the causes of acute or chronic liver diseases such as acute hepatitis A, B, C and E, Wilson’s disease, alpha-1 antitrypsin deficiency and haemochromatosis were excluded, the differential diagnosis was guided towards the presence of autoimmune liver diseases, taking into account the female sex, the young age of the patient and her history of two well-established autoimmune diseases (T1DM and Hashimoto thyroiditis).^8–11 In addition, the possibility of GH and non-alcoholic fatty liver disease (NAFLD) were also considered, although the latter clinical entity very rarely can cause acute hepatitis. Liver autoimmune serology showed the presence of smooth muscle antibodies (titre: 1/160; cut-off: 1/40) while antinuclear, antimitochondrial, liver kidney microsomal and soluble liver antigen/liver pancreas autoantibodies and antibodies related to celiac disease tested negative.^{10 11}

As the simplified score for the diagnosis of autoimmune hepatitis was 4 and keeping in mind that normal serum levels of IgG cannot exclude the diagnosis of autoimmune hepatitis, we performed a liver biopsy which is a prerequisite for establishing the diagnosis of autoimmune hepatitis but also the gold standard for GH diagnosis.^12–14 Liver biopsy revealed the presence of swollen hepatocytes with abundant cytoplasmic glycogen deposits without fatty change, inflammation, interface and/or lobular hepatitis or fibrosis (figure 1). Typically, considerable intracellular glycogen accumulation was shown on PAS stain (figure 2A) that characteristically disappeared after PASD stain (figure 2B). These findings are typical of GH and attributed to the patient’s medical history of brittle diabetes mellitus.

Figure 1.

The hepatocytes show clear cytoplasm with distinct cytoplasmic membranes. There is no steatosis. (A) Original magnification H&E 10×; (B) original magnification H&E 40×.

Figure 2.

(A) Intense cytoplasmic staining is seen in PAS stain (original magnification 40×). (B) Loss of cytoplasmic staining in PAS diastase stain, consistent with accumulation of glycogen (original magnification 40×). PAS, periodic acid–Schiff stain.

Treatment

The patient was started intense treatment targeting aggressive glycemic control with insulin (glulisine 10 units subcutaneously thrice daily and glargine 20 units subcutaneously once daily) along with a strict carbohydrate restricted diet. The patient was also monitored closely for adherence to both diet and insulin therapy by her parents and a clinical dietician.

Outcome and follow-up

At week 12 posttreatment, there was full normalisation of the liver biochemistry (AST: 23 IU/L, ALT: 26 IU/L) along with absence of symptoms, normalisation of liver size and amelioration of metabolic parameters (haemoglobin A1c: 8.8%). So far, no evidence of elevated aminotransferases or any symptom has been recorded in a follow-up period of 1 year.

Discussion

GH is a rare and underreported complication of poorly controlled T1DM, although occasionally this condition can also be observed in patients with type 2 diabetes mellitus. Indeed, up to now ~130 cases with GH have been published in the PubMed database.^15–26 In general, GH is considered a benign and reversible disease but recent studies have also reported varying degree of fibrosis including bridging fibrosis in a minority of patients.^{2 18–21} Indeed, a recent retrospective cohort study from UK in 31 GH patients reported that 73% of them had fibrosis which was in general mild but 2 patients had already established bridging fibrosis.¹⁹ In another case–control retrospective study from USA in 36 GH patients, the clinical and biochemical characteristics of the patients compared with T1DM patients without GH were described.²⁰ The most common symptom and clinical sign was abdominal pain and hepatomegaly, respectively. All GH patients had poorly controlled diabetes as attested by the high haemoglobin A1c levels (mean level: 11.2%) but most importantly, GH patients suffered from significantly higher rate of recurrent episodes of diabetic ketoacidosis compared with T1DM patients without GH (61% vs 9%; p=0.009).²⁰

So far, many terms have been used to describe this condition such as glycogen hepatopathy, hepatic glycogenosis, glycogen storage hepatomegaly and hepatic glycogen storage.^27–34 In 2006, Torbenson et al suggested for the first time the term GH for patients with excess deposition of glycogen into hepatocytes but without the extrahepatic manifestations of Mauriac syndrome.² Since then, this definition has been used widely to describe this characteristic pathological finding.

GH is an underestimated entity, as most of the physicians including gastroenterologists are not aware of this condition and they mistake it for the NAFLD, a much more frequent liver abnormality associated with uncontrolled diabetes mellitus.^{34 35} Therefore, primary care physicians but also clinicians should be aware of this entity in order to prevent diagnostic delay and misdiagnosis as differentiation of GH from NAFLD is of clinical importance, taking into account its association with other comorbidities such as cardiovascular disease, the possibility of progressive liver fibrosis and development of cirrhosis and/or hepatocellular carcinoma in case of non-alcoholic steatohepatitis.³⁶ However, the clinical or radiological discrimination between GH and NAFLD is not always easy, although recently imaging studies—particularly, the gradient dual-echo magnetic resonance imaging—have been proposed as effective tools for the distinction of glycogen deposition from the deposition of fat in the liver.^37–40 Apart from diabetes mellitus, many other disorders have been infrequently associated with GH such as dumping syndrome after gastrectomy, anorexia nervosa, administration of high-dose corticosteroids, azathioprine and insulin overdose.^41–43 However, these conditions were excluded easily according to the history of our patient.

Nevertheless, GH can be diagnosed definitely only by liver biopsy which is still considered the gold standard for the diagnosis of GH.^{15 35} Indeed, in patients with diabetes mellitus, hepatomegaly and increased levels of aminotransferase, the differential diagnosis is wide. Apart from GH, the differential diagnosis in young patients with T1DM should include celiac disease and autoimmune hepatitis while investigation for serological markers of viral hepatitis A, B, C and E seems also mandatory.^{15 41} Finally, haemochromatosis and Wilson’s disease should also be considered depending on the extent and pattern of liver dysfunction at presentation. Accordingly, in our case, there was a step-by-step differential diagnosis excluding all the above mentioned serious diseases in a young female patient with an autoimmune background. Especially, the exclusion of autoimmune hepatitis in this case with two concurrent autoimmune diseases was of paramount importance as this disease is catastrophic with poor prognosis if remains undiagnosed and left untreated.8 9 13 14 In other words, autoimmune hepatitis should be considered in all patients with unexplained acute or chronic liver disease regardless of sex, age and ethnicity and even in the absence of hypergammaglobulinemia and antinuclear antibodies as in some patients with the acute form of the disease these antibodies may be negative at first screening.8 9 13 14 Taking into account that liver biopsy is a prerequisite for the diagnosis of autoimmune hepatitis, we performed a liver biopsy which proved to be very effective in defining a firm diagnosis.

After GH diagnosis, the treatment should aim the intense glycemic control as this is considered the backbone of its management.^{15 34 44} However, resolution of GH has also been described after minimal glucose control.^{34 45} The disease has a benign course with excellent prognosis as after adherence to strict glycemic control and carbohydrate-restricted diet the liver enzymes normalise and symptoms disappear within a few weeks as also observed in our patient. Resolution of GH has also been published after pancreatic transplantation in diabetic patients, further supporting the notion that GH is completely reversible after the effective management of diabetes.²⁹ However, recurrences are not uncommon if metabolic targets are not achieved.15 21 46 47 For this reason, close follow-up for recurrence of symptoms may be needed in patients with a past history of GH and poorly controlled diabetes.

In conclusion, our case highlights that clinicians should be aware of this rare complication of diabetes mellitus in T1DM patients with poor glycemic control. After excluding other common causes of hepatitis including viral and autoimmune hepatitis or celiac disease, an in-depth investigation for GH should be performed. Liver histology remains the cornerstone for the establishment of a firm diagnosis and to exclude other liver pathologies. GH should not be overlooked as this condition bears in general a benign course and good prognosis if an intense glycemic control is achieved.

Learning points.

• Glycogenic hepatopathy (GH) is a rare complication of diabetes mellitus particularly in type 1 diabetes mellitus (T1DM) patients with poor glycemic control.

• The clinical manifestations include typically hepatomegaly in combination with non-specific symptoms of abdominal pain, nausea, vomiting, anorexia accompanied sometimes by cushingoid characteristics.

• Liver tests show marked rise of aminotransferases ranging from threefold to levels of acute hepatitis, although the synthetic capacity of the liver is preserved.

• Liver histology remains the gold standard for a firm diagnosis of GH showing considerable intracellular glycogen accumulation on periodic acid–Schiff (PAS) stain that characteristically disappears after PAS diastase digestion.

• Clinicians should keep in mind and recognise GH in T1DM patients with poor glycemic control, as this condition is reversible and bears a benign course and good prognosis if an intense glycemic control is achieved.