A case study of a liver transplant-treated patient with glycogen storage disease type Ia presenting with multiple inflammatory hepatic adenomas: an analysis of clinicopathologic and genetic data

Abstract

Background: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay.

Case presentation: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient's father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of β-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred.

Conclusion: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

Keywords: Clinicopathologic; G6PC gene; GSD-Ia; Hepatic adenomas; Liver transplant-treated.

Fig. 1

Imaging examination. a The arterial phase of the contrast-enhanced CT image shows multiple nodules and masses in the liver with significant enhancement. b The portal phase of the contrast-enhanced CT image shows that some nodules have mild and persistent enhancement. c B-ultrasonography showed multiple solid nodules in the context of fatty liver

Fig. 2

Mutational analysis of the patient pedigree. a The genotypes of the G6PC gene for family members. Roman numerals indicate generations, and Arabic numerals indicate individuals. Squares = males, circles = females. Affected individuals are denoted by yellow symbols, and unaffected individuals are denoted by grey symbols. The index patient is indicated by an arrow. The two mutations were inherited from the father (c.262delG) and mother (c.648 G > T), respectively. b Validation of the c.262delG mutation in exon 2 by Sanger sequencing. The grey area indicates a frameshift mutation. c Validation for the c. G648T of exon 5 by Sanger sequencing. The grey area represents the mutation point

Fig. 3

Pathological examination. a HE staining of liver biopsy tissue (20 ×). b At high magnification, an isolated arteriole is observed (400 ×). c CK7 showed slight proliferation of fine bile ducts (40 ×). d PAS staining of liver biopsy tissue suggested a large deposition of glycogen in hepatocytes (100 ×). e–f Gross image of the surgically resected liver. g-i HE staining of the adenoma tissue showed that the liver cells were arranged regularly against the background of fatty liver without atypia, the boundary between the normal liver tissue and the adenoma was clear, and the mallory body could be seen at high magnification (20 × -400 ×). j IHC showed positive CD34 staining of adenoma vascular endothelial cells, indicating incomplete vascularization (40 ×). k IHC showed negative GS staining in the adenomas (40 ×). l Ki-67 staining showing a proliferative rate of less than 2% in adenoma tissue (40 ×). m IHC showed no absence of L-FABP in the adenomas (40 ×). n IHC showed that beta-catenin was not activated in the adenomas (100 ×). o IHC shows that CRP is strongly and diffusely positive in adenomas (lower right) but not in normal liver tissue (upper left) (100 ×). p Foot’s staining methods showed that reticulin was not lost (100 ×). q Masson staining showing wide fibrous septa between normal liver tissue and adenoma tissue (40 ×). r HE staining of surrounding liver tissue (100 ×). s PAS staining of the specimen showed a large amount of glycogen deposition in the surrounding liver tissue (100 ×). t PAS-stained hepatocytes that were mostly digested by PAS-D (100 ×)