Case 3 -
Hepatocellular Carcinoma Arising in Glycogen Storage Disease Type Ia
Indiana University School of Medicine
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A 21 year old Hispanic female underwent liver transplantation for massive hepatomegaly, intractable
abdominal pain and multiple enhancing liver lesions consistent with hepatic adenomas. The patient has
had a long-standing medical history since childhood that includes multiple episodes of hypoglycemia,
epistaxis, bleeding gums, hepatomegaly and chronic abdominal pain. An abdominal CT scan in November 1999
showed diffuse increased echogenicity of the liver without any focal lesions. In March, 2004 she was
admitted for increasing abdominal pain – mainly over the right hypochondrium and epigastrium, nausea,
vomiting and episodes of hypogylcemia. Her mother had also noticed an increase in the abdominal girth
since January 2004. A CT scan of her abdomen showed multiple enhancing lesions consistent with hepatic
adenomas. Her liver function tests were as follows: bilirubin 1.0, alkaline phosphatase 77, AST 72 and
ALT 63, ammonia 28 and INR 1.03. She continued to have abdominal pain and nausea despite medication and
during a repeat admission, her lipase was over 1000 and triglycerides were 1105, suggestive of chemical
pancreatitis. A CT scan of the abdomen did not show any changes in the liver lesions; alpha-feto protein
was 1.6. The pancreatitis responded to discontinuation of oral intake, TPN and Lopid to lower her
triglycerides. She was worked up for liver transplantation during which time a lytic lesion was found in
her left shoulder and a mass was present in her mediastinum. She underwent surgical resection of the 2
In September 2004, she underwent orthotopic liver transplantation. The liver weighed 3080 grams, and
was soft and pale in appearance. Eight nodules measuring between 0.3 to 3.5 cm in diameter were present,
6 in the right and 2 in the left lobe. A representative section is submitted.
Case 3 - Figure 1 - The liver showed extensive macro and microvesicular steatosis.
Case 3 - Figure 2 - High power view illustrating macrovesicular steatosis.
Case 3 - Figure 3 - High power view illustrating microvesicular steatosis in which numerous small fat droplets have accumulated around a central nucleus.
Case 3 - Figure 4 - An adenoma consisting of crowded small basophilic hepatocytes arranged in one to 2 cell thick plates. Focal sinusoidal dilatation is present.
Case 3 - Figure 5 - Hepatocellular carcinoma consisting of sheets of cells with abundant eosinophilic cytoplasm and centrally placed nuclei with prominent eosinophilic nucleolus.
Glycogen storage disease I
Glycogen Storage disease III
Diagnosis: Hepatocellular carcinoma arising in glycogen storage disease Type Ia
Type I glycogen storage disease (GSD 1) is an autosomal recessive disorder resulting from deficient
activity of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis that catalyses the
terminal step in both glycogenolysis and gluconeogenesis
G6Pase is a multicomponent enzyme complex located in the membrane of the endoplasmic
reticulum of hepatocytes as well as kidney and intestinal epithelium. The enzyme consists of 9
transmembrane domains include that a catalytic subunit located on the luminal surface of the endoplasmic
reticulum membrane, and multiple transporters or translocases that transport the substrate and hydrolytic
products across the microsomal membrane. The glucose 6 phosphate (G6P) translocase (T1) transports G6P
into the endoplasmic reticulum from the cytosol, the phosphate/ pyrophosphate translocase (T2) and the
glucose translocase (T3 or GLUT 7) transport the hydrolytic products out of the endoplasmic reticulum.
Type I glycogen storage disease may result from deficient activity of any of these components; deficiency
in the catalytic subunit characterizes GSD 1a. So far, 56 different mutations in the gene have been
described . The gene, cloned and characterized in 1993 by Lei et al is localized on chromosome 17q21.
The gene for the G6P translocase (T1) has been mapped to chromosome 11 q23. Mutations in this gene lead
to GSD type 1b. Additionally, defects have been reported by kinetic studies in transporters for
inorganic phosphate (GSD 1c) and glucose (GSD 1d). It is not clear if the latter are due to independent
mutations in the transporters, or due to mutations in the G6P transporter itself, with subsequent kinetic
effects on enzyme activity. Therefore, at this point, GSD 1 is probably best classified into types 1a
and non- 1a.
Patients present with hypoglycemia, growth retardation, hepatomegaly, lactic academia, hyperuricemia
and hyperlipidemia. Patients with GSD 1b additionally suffer from quantitative and qualitative defects
in leucocyte function. They are also more prone to inflammatory bowel disease, probably related to their
leucocyte abnormality. Long term complications of the disease include adenoma, hepatocellular carcinoma,
progressive renal disease related to their hyperlipidemia, osteopenia, growth retardation, gout and
delayed puberty . Acute pancreatitis is another consequence of hyperlipidemia. Renal disease is
manifested as focal segmental glomerulosclerosis of which hyperfiltration and proteinuria are early signs
Besides the abnormalities in carbohydrate metabolism, GSD 1 is associated with distinct
hyperlipidemia; the hyperlipidemia is more severe in GSD 1a than in GSD 1b. Both serum triglyceride and
cholesterol concentrations are increased in patients with GSD1. Cholesterol and triglyceride fractions
are increased both in VLDL and LDL particles, which increase both in number and size.. The
hyperlipidemia is due to both increased lipogenesis and decreased lipolysis. Deficicency of G6Pase
increases glycolysis and production of acetyl-CoA. This leads to stimulation of lipogenesis and
cholesterologenesis and inhibition of fatty acid oxidation via malonyl CoA. Increased amounts of free
fatty acids are released from adipose tissue, taken up by the liver and channeled into triglyceride
Platelet function is impaired secondary to the metabolic abnormalities; reduced platelet adhesiveness,
abnormal platelet aggregation and impaired release of ADP in response to collagen and epinephrine have
been observed. Patients may therefore present with a bleeding tendency manifested as recurrent epistaxis
or oozing following dental surgery.
The prevalence of adenomas is 25-75% depending on the series; series with older patients show
increased prevalence since incidence of adenomas increases with age
. These tumors develop
mostly during or after puberty, and are usually multiple. Some series report a slight male
preponderance; while others do not. The suggested etiopathogenesis follows 3 lines of thought:
Increased levels of glucagon which is associated with hepatocarcinogenesis in experimental models;
however, glucagons levels are infrequently elevated in GSD I. The second suggests that glycogen storage
leads to a shift to the pentose phosphate pathway favoring synthesis of DNA from pyrimidines and RNA from
purines. The third theory implicates extra-mitochondrial or peroxisomal oxidation of excess fatty acids
that leads to formation of H2O2 leading to oxidative stress and DNA mutagenesis.
Hepatocellular carcinomas arise in patients with GSD I, most seem to arise in preexisting adenomas;
whether some occur de novo is not known with certainty. Alpha-feto protein is not reliable in monitoring
for malignant transformation due to both false negative and false positive results. No imaging technique
is sensitive enough to predict malignant transformation. Serum inflammatory markers like CRP,
pre-albumin and fibronectin are higher in patients with tumors than in those without .
Histologically, Mallory hyaline, which is not usually present in adenomas, has been described in adenomas
in patients with GSD I.
Treatment of GSD I aims at control of fasting hypoglycemia and consists of nocturnal nasogastric
infusion of glucose or orally administered uncooked cornstarch. This cures the glucose metabolism;
triglyceride levels decrease but not to normal levels. Treatment with fibrates and fish oil may lower
hyperlipidemia, but the response is known to diminish over time. Adenomas may regress after intragastric
feeding but this is not true for all cases. When treatment is initiated early in life, renal impairment
and development of adenomas may be prevented
Liver transplantation in patients with GSD I is usually undertaken for poor metabolic control or for
presence of tumors and the associated risk of malignant transformation
hyperlipidemia, hyperuricemia and lactic academia are corrected in these patients. Catch-up growth is
however not observed regularly. It is unclear whether liver transplantation results is prevention or
reversal of kidney disease; renal toxicity of immunosuppressive drugs like cyclosporine complicates the
issue. Neutrophil function and number are not helped by liver transplantation in patients with GSD Ib.
Predictably, renal transplantation alone for renal failure fails to improve glucose metabolism .
Evaluation of liver biopsies for metabolic diseases is discussed in detail in references 14 and 15.
Questions for the Clinician:
- Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Phenotypic, genetic and biochemical characteristics, and therapy. Endocrinology and Metabolism Clinics North America 1999; 28: 801-823.
- Moses SW. Historical highlights and unsolved problems in glycogen storage disease type 1. Eur J Pediatr 2002; 161: S2-S9.
- Arion WJ, Canfield WK. Glucose-6-phosphatase and tpe 1 glycogen storage disease: some critical considerations. Eur J Pediatr 1993; 152 (S1): S7-S13.
- Rake JP, ten Berge AM, Visser G et al. Glycogen storage type 1a: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flowchart. Eur J Pediatr 2000; 159: 322-330.
- Lee PJ, Leonard JV. The hepatic glycogen storage diseases – problems beyond childhood. J Inher Metab Dis. 1995; 18: 462-472.
- Chen Y-T et al. Renal disease in type I glycogen storage disease. N Eng J Med 1988; 318: 7-11.
- Bandsma RHJ, Smit PA, Kuipers F. Disturbed lipid metabolism in glycogen storage disease type 1. Eur J Pediatr 2002; 161: S65-69.
- Lee PJ. Glycogen storage disease type I: pathophysiology of liver adenomas. Eur J Pediatr 2002; 161: S46-S49.
- Bianchi L. Glycogen storage disease I and hepatocellular tumors. Eur J Pediatr 1993; 152 (S1): S63-S70.
- Labrune P. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J Pediatr Gastenterol Nutr 1997; 24: 276-279.
- Wolfsdofr JI. Metabolic control and renal dysfunction in type I glycogen storage disease. J Inherit Metab Dis 1997; 20: 559-568.
- Matern D. Liver transplantation for glycogen storage disease types I, III and IV. Eur J Pediatr 1999; 158 (S2): S43-S48.
- Labrune P. Glycogen storage disease type I: indications for liver and/ or kidney transplantation. Eur J Pediatr 2002; 161: S53-S55.
- Jevon GP, Dimmick JE. Histopathologic approach to metabolic liver disease: Part 2. Pediatr Dev Pathol. 1998; 1: 179-199.
- Jevon GP, Dimmick JE. Histopathologic approach to metabolic liver disease: Part 2. Pediatr Dev Pathol. 1998; 1: 261-269.
1) How was she diagnosed?
2) What was the dietary management? Was she controlled?
3) What was management for hyperlipidemia?
4) Did she have renal disease?
5) Gout, short stature?
6) AFP, imaging?
7) Follow-up after transplantation, especially with relation to metabolism, kidney disease.
The hepatic glycogen storage disease include GSD Ia (G6Pase deficiency), GSD III (debranching enzyme
deficiency), GSD VI (phosphorylase deficiency) and GSD IX (phosphorylase b kinase deficiency).
Hypoglycemia occurs in GSD 1 and III; it is more severe in GSD 1, and is not invariable in GSD III.
Ketosis occurs in GSD III, VI and IX.
Von Gierke described the first patient with the disease in 1929 in a paper titled "hepatonephromegalia
glycogenica". In 1952, the Coris provided evidence that absence of G6Pase causes the disease. In 1993,
Lei et al cloned and characterized the G6Pase gene which was mapped to chromosome 17q21. The enzyme
consists of nine transmembrane helices. In 1996, they generated a G6Pase deficient mouse model.
Differential diagnosis of steatotic pattern (Jevon Dimmick):
Hereditary fructose intolerance
Glycogen storage disorder I
Glycogen storage disorder III Wolman's disease/ cholesterol ester storage disease
Mitochondrial respiratory chanin disorders
Fatty acid oxidative disorders
Pyruvate carboxylase deficiency
Pyruvate dehydrogenase deficiency
Infantile Refsum disease
Urea cycle disorders