Clinical Case Conundrum: Hyperlactataemia in a Case of Type 1 Diabetes with Chronic Hyperglycaemia

Introduction

A 13-year-old girl with a 9-year history of type 1 diabetes with chronic hyperglycaemia [haemoglobin A1c 69 mmol/mol (8.5%) – 90 mmol/mol (10.4%)] presented in diabetic ketoacidosis (DKA). After receiving DKA treatment and ketoacidosis resolved, she had persistent metabolic acidosis with an elevated lactate. On arrival, her plasma lactate was 13.8 mmol/L and decreased to a minimum of 2.7 mmol/L by discharge. Her transaminases were also elevated (peak alanine aminotransferase 516 U/L, peak aspartate aminotransferase 1482 U/L). Lactate and transaminase elevation persisted for the subsequent 2 years, even between DKA episodes (Table 1). An ultrasound, MRI and liver biopsy were performed.

Table 1.

Pertinent Laboratory Results

Laboratory Name	Peak Value around time of Initial Presentation	On Discharge from Initial Hospitalisation	6 Months Later (not associated with DKA)	2 Years Later (during DKA)	Most Recent (2-2.5 Years Later)
Plasma lactate (mmol/L) (normal 0.5-2.2) **	13.8	3.6	8.2	8.4	*
Aspartate aminotransferase (AST) (U/L) (normal 12-32)	1482	248	32	218	17
Alanine aminotransferase (ALT) (U/L) (normal 5-32)	516	224	45	102	16
Lactate-to-pyruvate ratio (normal 10-20)	22	*	*	22	*
Haemoglobin A1c (mmol/mol (%)) (normal < 41 (5.9))	90 (10.4)	*	102 (11.5)	125 (13.6)	73 (8.8)

^*Not tested at this time

^**Lactate Whole Blood Venous collected from Super Gas w/ Lactate Venous tested during initial hospitalisation (normal range 0.5-2.2mmol/L), Lactate Plasma tested 6 months and 2 years later (normal range 0.6-2.0 mmol/L)

Questions

1. What diagnosis is determined through the imaging and histopathologic images shown?

2. What are the risk factors for this condition and what is the aetiology of the associated hyperlactataemia?

3. What are the recommended monitoring and treatment options for this condition?

Answers

1. Glycogenic Hepatopathy. The imaging demonstrates hepatomegaly, hepatic steatosis, and an incidental hepatic abnormality consistent with an adenoma (unrelated to disease process) (Figure 1). Histopathologic examination of background liver parenchyma reveals pale hepatocytes and glycogenated nuclei by H&E stain (Figure 2A, arrowheads) with extensive PAS positive (diastase-sensitive) cytoplasmic and nuclear glycogen (Figure 2B). This case also has macrovesicular steatosis and evidence of hepatocellular damage, including acidophil bodies (Figure 2A inset), ballooning degeneration, and mitotic figures (Figure 2C, arrowhead). In conjunction with the clinical findings, the histopathologic features are most compatible with glycogenic hepatopathy. Glycogenic hepatopathy is characterised by hepatic glycogen deposits, elevated liver transaminases, and gastrointestinal symptoms.^1,2 Glycogenic hepatopathy can be a presenting feature of Mauriac syndrome, a complication of Type 1 Diabetes (T1D) with chronic hyperglycaemia.^1–3

2. Hepatic glycogen deposition in T1D occurs when excess glucose enters hepatocytes and is converted into glycogen, a process enhanced by the presence of high doses of insulin.^2,4–6 Individuals with T1D are at highest risk for the development of glycogenic hepatopathy in the setting of persistent hyperglycaemia and high insulin doses (mean of 1.33 units/kg/day) or repeated episodes of DKA (40% of presentations occur during a DKA episode).⁵ Glycogenic hepatopathy occurs most frequently in adolescence-early adulthood (mean age 23.4 years), women (~70%), and with average diabetes duration of ten years.² High plasma lactate concentrations in glycogenic hepatopathy have been described in only a few case series and are likely secondary to a defect in the mitochondrial electron transport chain, as evidenced by an elevated lactate-to-pyruvate ratio, which was noted in this case.^1,7

3. Glycogenic hepatopathy has been shown to improve with limitation of hyperglycaemia and is not known to progress to fibrosis.^2,4,7 There are no established guidelines for imaging or liver biopsy if glycogenic hepatopathy is suspected, although the diagnosis can be confirmed through histopathological evaluation. Clinical status, insulin regimen, and transaminase and lactate levels should be monitored closely. Normalisation of labs should be considered a reassuring clinical finding that hepatic injury has been reversed.^4,8 This diagnosis should also prompt further evaluation for other aspects of Mauriac syndrome in children and adolescents including pubertal delay or pauses and growth failure.^1,2,9,10

Figure 1.

Radiology images demonstrating hepatic enlargement, steatosis and focal hepatic lesion. (A) Ultrasound image shows hepatic steatosis and a rounded hypoechoic lesion in the posterior right hepatic lobe (arrows) with mild peripheral vascularity (arrowhead) detected on colour Doppler, but no significant internal flow. (B) Hepatomegaly is seen on Axial T2 MRI; the lesion (arrows) is noted to be heterogeneously T2 hyperintense. There was subtle signal loss on out of phase imaging (not shown). (C) Post contrast T1 VIBE imaging shows persistent central enhancement (arrows) of the lesion and (D) restricted diffusion (arrows) on DWI.

Figure 2.

Pathology images. A) Haematoxylin and eosin stain (H&E) at 200x power shows liver with periportal hepatocytes with glycogenated nuclei (arrowheads) and zone 2-3 macrosteatosis. Apoptotic hepatocytes (acidophil bodies) were identified (inset). B) PAS stain at 200x power highlights extensive glycogen within the hepatocytes while fat droplets do not stain. C) Higher power (400x) H&E stain images of hepatocytes with reactive changes including multinucleation, mitotic figures (arrowhead), and ballooning degeneration.

Learning Points

1. Hyperlactataemia and liver transaminase elevation in T1D, especially in the context of diabetes with chronic hyperglycaemia and recurrent DKA episodes, should prompt consideration for glycogenic hepatopathy.

2. Glycogenic hepatopathy is confirmed through liver biopsy and histopathological evaluation.

Novelty Statement:

This case demonstrates that hyperlactataemia and liver transaminase elevation in Type 1 Diabetes, especially in the context of diabetes with chronic hyperglycaemia and recurrent diabetic ketoacidosis episodes, should prompt consideration for glycogenic hepatopathy. Glycogenic hepatopathy is most often confirmed through liver biopsy and histopathological evaluation.