Hepatic Adenomatosis in Glycogen Storage Disease Type Ia: Report of a Case With Unusual Histology Open Access

Glycogen storage disease type Ia (GSD-Ia), first described by von Gierke in 1929, is due to the absence of glucose-6-phosphatase, an enzyme necessary for gluconeogenesis and glycogenolysis.1 The disease is rare, with patients usually presenting during the first year of life with hypoglycemia and marked hepatomegaly. The inability to metabolize glycogen properly and maintain appropriate blood glucose levels leads to short stature, chronic lactic acidosis, and other metabolic derangements such as hyperlipidemia. The most important complications of GSD-Ia are renal disease, specifically focal segmental glomerulosclerosis and hepatic adenomas. The association between GSD-Ia and hepatic adenomatosis has been well described in the literature, but only a few reports have noted unusual histology in the adenomas.2,3 In particular, Mallory hyaline appears to be less frequent in patients with GSD-Ia,4,5 and, to our knowledge, steatohepatitis has not been previously reported. We report a case of GSD-Ia–associated hepatic adenomatosis with diffuse, extensive Mallory hyaline, steatohepatitis, and granulomatous inflammation.

A 28-year-old white woman with a history of glycogen storage disease presented for evaluation of multiple liver masses. She was diagnosed with GSD-Ia by enzyme studies at 14 months of age and had developed well with tight control of blood glucose levels. At the age of 19 years, she was briefly admitted to our institution for chronic diarrhea. A workup at that time showed multiple small liver masses, presumed to be adenomas. Over the next several years, serial sonograms showed no significant increase in the size of the liver masses. She continued to experience occasional episodes of fatigue and diarrhea but showed no evidence of jaundice, ascites, or encephalopathy. Her colonoscopic examination had normal results, and repeated workups for an infectious etiology were negative. Her therapeutic regimen included cornstarch (4–8 tablespoons approximately every 2–4 hours), allopurinol for hyperuricemia, and Colestid for diarrhea. Her only other significant drug exposure was to oral contraceptives for approximately 15 years. She had no history of infectious hepatitis, no known alcohol use, and no other risk factors for liver disease.

The patient presented for a follow-up of her hepatic nodules. On examination, she was of short stature (height, 1.544 m) but well nourished (weight, 63.7 kg) and in no acute distress.

Results of her physical examination were normal, except for a liver edge that was palpable 5 to 6 cm below the right costal margin. A laboratory workup showed elevated alkaline phosphatase concentrations (210 U/L; reference range, 31–135 U/L). Bilirubin, aspartate aminotransferase, alanine aminotransferase, albumin, and prothrombin time were all within normal limits. Total carbon dioxide values were slightly decreased (20 mEq/L; reference range, 21–30 mEq/L), uric acid values were elevated (9.5 mg/dL [0.57 mmol/L]; reference range, 2.5–8.0 mg/dL [0.15–0.48 mmol/L]), and lactic acid values were increased (54 mg/dL [6.0 mmol/L]; reference range, 4.5–19.8 mg/dL [0.5–2.2 mmol/L]). Blood urea nitrogen and creatinine levels were within normal limits. The patient had hypercholesterolemia (279 mg/dL [7.21 mmol/L]) and markedly elevated triglyceride levels (970 mg/dL [10.95 mmol/L]). α-Fetoprotein was undetectable. Urine chemistry showed moderately elevated levels of urine organic acids, microalbuminuria (2581.0 mg/L; reference range, <23 mg/L), and 4+ protein.

A computed tomography scan of the abdomen showed 11 enhancing hypervascular lesions throughout the liver (8 in the left lobe and 3 in the right). The masses varied in size from 0.8 to 7.5 cm in diameter and involved the left lobe more than the right. The 2 largest lesions were in the left lobe and had increased significantly when compared to imaging studies from 18 months earlier. The surrounding liver parenchyma showed mild diffuse steatosis. There were several hyperdense foci within the left kidney, likely representing calculi. There was no evidence of hydronephrosis, and the spleen, pancreas, and gallbladder appeared normal. No lymphadenopathy was noted, and additional studies showed no masses in the pelvis or thorax. Because of the recent increase in size and irregular appearance of the liver lesions, the patient was admitted for exploratory laparotomy, left hepatic trisegmentectomy (segments 2, 3, 4A, 5, and 8), and cholecystectomy.

The resected left hepatic lobe measured 34 × 21 × 7 cm and weighed 2400 g. The surface was smooth and pale, with a mottled appearance. Sectioning showed 8 nodules that ranged in diameter from 0.4 to 8.5 cm and corresponded to those seen in the left hepatic lobe on imaging studies. The 2 largest nodules (8.5 and 8.0 cm) had a variegated appearance, with yellow-orange areas alternating with foci of apparent hemorrhage (Figures 1 and 2). The remaining nodules were a more uniform yellow-orange color, and one had a distinct central scar, grossly similar to focal nodular hyperplasia. Each of the nodules bulged slightly from the cut surface and had a smooth contour. No gross necrosis or significant hemorrhage was seen. The surrounding parenchyma had a light yellow appearance postfixation. The liver was extensively sampled; one section was submitted per centimeter of the 2 large nodules, and representative sections were submitted from the smaller ones, for a total of 20 blocks of tumor.

Histologically, the nodules were well demarcated from the surrounding liver, and most showed at least a partial fibrous capsule, although few were entirely encapsulated. Varying degrees of fibrosis were seen within the nodules, some forming thin lamellar structures and others forming thick fibrous trabeculae. No bile ducts were seen in the nodules. The hepatocytes were large and swollen, with pale cytoplasm, and many had hyperglycogenated nuclei. Impressive amounts of Mallory hyaline were seen throughout the adenomatous nodules, some in rather large aggregates. Macrovesicular and microvesicular fat accumulation was noted, and pericellular fibrosis with neutrophilic infiltrate was seen. Reticulin stains showed good retention of the reticulin framework with hepatocyte plates generally 2 cells thick. Focal necrosis was seen within one large scarred area, but no atypia or mitoses were noted in any of the nodules. Immunohistochemistry showed an MIB-1 index of less than 1% in both the nodules and surrounding parenchyma. Chronic inflammation and granulomatous inflammation were also seen in the nodules. Immunohistochemistry for cytokeratins 8 and 18 (1:25; Zymed, San Francisco, Calif) highlighted the extensive Mallory hyaline within the adenomas.

The nonneoplastic parenchyma contained glycogen-engorged hepatocytes, which were confirmed by strong staining for periodic acid–Schiff and depleted by diastase treatment. Morphologically normal portal areas contained minimal chronic inflammation; scattered neutrophils were also seen but were likely procedure related. Numerous foci of granulomatous inflammation were also present. Histochemical stains for acid-fast bacteria (Kinyoun) and fungal organisms (silver methenamine) were negative. No foreign bodies were evident.

The patient was recently reevaluated 4 months postoperatively. On imaging studies, the 3 remaining nodules in the right lobe showed no change in size. There was no lymphadenopathy and no evidence of tumor in the abdomen, thorax, or brain. Serum α-fetoprotein and carcinoembryonic antigen were undetectable. There was no immediate plan to treat the remaining nodules, although percutaneous alcohol injection was under consideration.

GSD-Ia is a rare metabolic disorder in which patients present during the first year of life with hypoglycemia and marked hepatomegaly. Features of GSD-Ia include short stature, lactic acidosis, liver adenomas, iron deficiency, proteinuria, renal calcification, osteopenia, hyperlipidemia, and hyperuricemia.1 Treatment is aimed at maintaining adequate blood glucose levels, which may be accomplished by continuous glucose drips or feedings with uncooked cornstarch. Liver transplants have been successful in curing GSD-Ia.2,3,6 

Grossly, the liver in GSD-Ia is enlarged and pale, and tumor nodules of various sizes may be visible. Histologically, the hepatocytes are enlarged with prominent cell membranes due to the peripheral displacement of organelles by accumulated glycogen, which is readily demonstrated by periodic acid–Schiff staining. Ultrastructural studies show double-contoured vesicles in the endoplasmic reticulum, increased volumes of glycogen per unit volume of hepatocyte cytoplasm, and increased collagen depositions in the space of Disse.1 Other findings may include glycogenated nuclei, neutral lipids, and perivenular Mallory bodies, which have been seen in rare cases of GSD-Ia.4,5 

Hepatocellular adenomas are a common complication of GSD-Ia; Labrune et al7 monitored 43 GSD-Ia patients and reported adenomas in 51.8%. In a review by Bianchi,3 adenomas had been detected in patients from 3 to 40 years old (average age, 19.8 years), with a marked male predominance (2–3:1). Several authors have noted that these adenomas are not necessarily associated with elevated α-fetoprotein levels2,3,8; hence, serial imaging studies are generally relied on for detection. Unlike oral contraceptive–associated adenomas, GSD-Ia adenomas are generally small and multiple and show variable encapsulation. Hemorrhage in GSD-Ia adenomas is rare.8 Transformation to carcinoma has been described in GSD-Ia patients, although this is a rare occurrence in oral contraceptive–associated adenomas. Hepatocellular carcinoma has been described in GSD-Ia patients as young as 14 years,9 with a mean age of 23 years.3 One review indicated a 2- to 7-year period over which adenomas transformed to carcinomas.3 Rates of transformation to hepatocellular carcinoma have varied from 0% to 11%.6,7 Focal nodular hyperplasia has also been reported in GSD-Ia, but it is much less common than adenoma.2,3 

The current case of GSD-Ia–associated adenomatosis showed some unusual histologic characteristics. First, the adenomas were extensively involved by diffuse Mallory hyaline deposition, which was not seen in the nonneoplastic liver. Mallory hyaline is generally associated with alcohol ingestion but may be seen in a variety of liver diseases, including Indian childhood hepatitis, alcoholic hepatitis, Wilson disease, primary biliary cirrhosis, hepatocellular tumors, morbid obesity, and intestinal bypass surgery.10 Mallory hyaline is sporadically seen in focal nodular hyperplasia.10 The current patient had no known history of alcohol consumption. Three prior cases of Mallory hyaline within GSD-Ia adenomas have been reported and supported by immunohistochemical staining for AE1/AE3 in 2 cases2 and for CAM 5.2 in the third.3 Mallory hyaline was confirmed in the present case by positive immunostaining for cytokeratins 8 and 18. Poe and Snover2 described Mallory hyaline as centered on fibrous areas in one case and diffusely distributed in another. Neither case had Mallory hyaline in the nonneoplastic liver. Bianchi3 also reported Mallory hyaline in GSD-Ia adenomas but did not comment on its distribution. Mallory hyaline has been described in the nonadenomatous livers of 2 GSD-Ia patients, usually in a centrilobular distribution.4,5 Intrasinusoidal amyloid has been reported in one case.2 

Another unusual observation in the current case was a varying degree of fibrosis within adenomas. In some instances, the fibrosis formed thin, delicate, radiating septa, whereas in other tumors, the fibrosis was dense and formed a large central scar, reminiscent of focal nodular hyperplasia. Unlike focal nodular hyperplasia, however, the fibrous areas contained no portal structures or blood vessels. Poe and Snover2 reported similar findings in 2 cases of GSD-Ia adenomatosis.

This case also showed marked steatohepatitis, which was completely localized to the adenomas. Although other authors have observed the individual findings of steatosis, pericellular fibrosis, and acute inflammation, frank steatohepatitis has not, to our knowledge, been previously reported in GSD-Ia. Steatohepatitis may be associated with alcohol use, diabetes mellitus, morbid obesity, lipodystrophy, or ingestion of a myriad of pharmacologic agents. Since the patient had no exposure to agents associated with steatohepatitis, the cause and significance of this finding is unclear. Finally, the lesions and surrounding liver also showed numerous foci of granulomatous inflammation, a common finding in large sporadic adenomas.

The case presented in this study illustrates hepatocellular adenomatosis, one of the most important complications of GSD-Ia. The adenomas in this case showed some histologic characteristics that have been only rarely described, including extensive Mallory hyaline and radiating bands of lamellar fibrosis. One adenoma had a large, stellate central scar, imitating the gross appearance of focal nodular hyperplasia. The adenomas also showed marked steatohepatitis, a finding that, to our knowledge, has not been previously described in association with GSD-Ia.