The Journal of Emergency Medicine, Vol 11, pp 265-269, 1993 Printed in the USA . Copyright 0 1993 Pergamon Press Ltd.

ACUTE MANAGEMENT OF GLYCOGEN STORAGE DISEASE TYPE la

John M. Wightman, MD, MA,* and Stacy Gordon, MDt

*University of Illinois Emergency Medicine Residency, and tuniversity of Chicago Pritzker School of Medicine, Department of Pediatrics, Wyler Children’s Hospital, Chicago, Illinois

Reprint Address: USAF Medical Center I SGHE I ES, AlTN: Capt. John M. Wightman, 4881 Sugar Maple Drive, Wright-Patterson AFB, OH 454336529

0 Abstract-Rapid metabolic deterioration may occur in patients with some glycogen storage diseases (GSDs) re- gardless of presenting complaint. Hepatic, renal, and he- mostatic abnormalities may also complicate diagnosis and treatment of trauma victims. We report the case of a man presenting with an epidural hematoma and a history of GSD type Ia.

0 Keywords - glucosephosphatase deficiency; glycogeno- sis 1; head injuries; hematoma, epidural; hematoma, epi- dural, delayed

INTRODUCTION

Glycogen storage diseases (GSDs) are a heterogenous group of inherited disorders of glycogen metabolism (1). In Glycogen Storage Disease Type Ia (GSD-Ia), also known as Glycogenosis Ia or von Gierke’s Dis- ease, a deficiency of glucose-6-phosphatase activity in the liver prevents formation of glucose from glu- cased-phospate during glycogenolysis and gluconeo- genesis. Patients are thus impaired in their ability to provide endogenous energy sources during stress or fasting with subsequent rapid onset of hypoglycemia and metabolic acidosis.

Survival into adulthood is now common for this autosomal-recessive inherited disorder (1). We wish to make emergency physicians aware of this entity because of the potential to be able to rapidly reverse the morbid or lethal consequences of the disease when patients cannot relate their past medical his- tory. The following case describes the delayed pre- sentation of an epidural hematoma in a young man with GSD-Ia.

PATIENT PRESENTATION

A 27-year-old male was the victim of a battery five days before presentation to our emergency depart- ment (ED). He stated that, according to his watch, he was found after approximately two hours of un- consciousness but was quickly aroused by paramed- ics. He related that his primary complaints at that time were severe right-sided headache, right shoulder pain, and bilateral lower-rib pain. He had transient blurred and double vision but remained awake and alert. His past medical history was significant for an allergy to intravenous radiographic-contrast material and GSD-Ia.

The patient brought copies of the ED evaluation made the day of the injury. They revealed hemoglo- bin of 11.5 g/dL (115 g/L), 5-7 RBCs/hpf in his urine, fluid in the right maxillary sinus on an x-ray interpretation, and an overriding fracture of the dis- tal right clavicle. He was discharged to make an ap- pointment with the pediatrician who followed him for his GSD-Ia.

Five days after the initial trauma, he presented to us with persistent right-sided headaches and intermit- tent vertigo. Examination noted the patient to be a moderately obese adult male with stunted growth and a “doll face” typical of GSD-Ia (1). Vital signs were regular pulse of 80 beats/min; nonlabored respira- tions of 24 breaths/min; blood pressure of 136/67 mmHg; and oral temperature of 36.4 “C on a cold day. Skin examination demonstrated multiple contu- sions and abrasions over his face, trunk, and extremi- ties. Battle’s sign was present on the right. There was no hemotympanum. The right mastoid process and

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266 John M. Wightman and Stacy Gordon

maxillary sinus were extremely tender. Extraocular muscle movements were intact. The fundi were unre- markable.

Pulmonary and cardiac examinations were nor- mal. Right costovertebral-angle tenderness was noted. A gastric feeding tube was present for noctur- nal nutrition (see Discussion). The right lobe of the liver extended into the pelvis and the left lobe into the left hypogastric area. No spleen was palpable. There was mild left upper quadrant tenderness with- out involuntary guarding or rebound tenderness. Stool tested guaiac negative.

Neurologically, the patient was awake, alert, and fully oriented. Cranial nerves were intact except for decreased light-touch and pinprick sensation in all three distributions of the right trigeminal nerve. Hearing in the right ear was also decreased. The pa- tient became vertiginous when changing positions from sitting to lying and vice versa. There was no nystagmus, gait was normal, and Romberg’s sign was not present. He was not orthostatic.

The hemoglobin was 10.3 g/dL (103 g/L) and there were 387,000 platelets/p1 (3.9 x lO”/L). Uri- nalysis was negative, except for moderate ketonuria. The serum glucose was 64 mg/dL (3.5 mmol/L). Fol- lowing application of a proximal tourniquet for phle- botomy, a scab on the patient’s elbow began to bleed. The PT and PTT were normal, but his bleeding time was in excess of 15 minutes (900 s). A computed tomographic (CT scan) of the head demonstrated an approximately 30-mL (0.03-L) epidural hematoma in the anterior portion of the right middle cranial fossa. No temporal skull fracture was evident.

The patient was admitted to the Neurosurgical In- tensive Care Unit for observation. Conservative management of the epidural hematoma was chosen in light of the age of the injury, absence of symptoms referable to a space-occupying lesion (2), and compli- cating medical-management issues.

The patient remained neurologically and hemody- namically stable throughout his 11-day hospital course. Serial head CT scans documented complete resolution of the hematoma without a drainage proce- dure. His cranial nerve abnormalities were attributed to a basilar skull fracture. A CT scan and serial exami- nations of the abdomen were negative for injury.

Clinic follow-up two weeks after discharge noted persistent, mild, right-sided headaches responsive to acetaminophen but no neurological deficit.

DISCUSSION

Hepatic glucose-6-phosphatase catalyzes the final step in glycogenolysis by breaking down glucose-6-

phosphate into glucose. Inactivity of this enzyme in patients with GSD-Ia (3) results in the principal se- quela of low blood glucose due to a shortage of en- dogenous energy sources (1,4). In order to produce energy during fasting, “overflow” glycolysis (5) in the liver (beginning with conversion of the excess glu- cose-6-phosphate to fructose-6-phosphate using a different enzyme) results in accumulation of pyru- vate and lactate and leads to acute and chronic meta- bolic acidosis (4,5). Because glucose-6-phosphatase also catalyzes the final step in gluconeogenesis, the formation of glucose from noncarbohydrate precur- sors such as lactate is impaired; the metabolic abnor- malities are further exacerbated (4). A type B3 lactic acidosis ensues (6). Lactate formation in euglycemic patients appears not to be “excessive” in the abscence of infection or other severe stress (1,4).

Low blood glucose is the most frequent complica- tion of GSD-Ia and the most common life threat in the ED. Following as little as two to four hours of fasting, blood glucose will almost always be less than 70 mg/dL (3 mmol/L). Six to eight hours without exogenous energy sources commonly results in levels less than 10 mg/dL (0.6 mmol/L) (4). An additional danger can be present because some profoundly hy- poglycemic patients can be asymptomatic for brief periods (1). It is thought that they use the excess lactate as a cerebral energy source (7,8).

The hypoglycemia of GSD-Ia is unresponsive to in- creased endogenous hepatotrophic hormones such as epinephrine and glucagon, which are normally se- creted to break down glycogen in response to low blood glucose concentrations (1). Additionally, sub- cutaneous administration of glucagon is not help- ful (9).

During chronic therapy, hypoglycemia and hy- perlactatemia can be minimized by careful dietary manipulation of glucose and caloric intake to avoid triggering gluconeogenic responses in the liver. Rec- ommended regimens involve daytime feedings of slow-release carbohydrates or uncooked starch ac- companied by a bedtime starch meal or nighttime gastric infusions of glucose or glucose-protein prepa- rations (1,4,10,11).

During stress or when the out-patient feeding regi- men cannot be maintained, as in many ED scenarios, a constant intravenous dextrose infusion, calculated to meet at least normal glucose requirements and maintain euglycemia, is essential and must be accom- panied by frequent blood-glucose monitoring (12).

One recommended infusion for patients in the ED has been glucose at 10 mg/kg/min with additional bicarbonate (1). This will provide anywhere from 150-300% of maintenance glucose requirements, de-

Glycogen Storage Disease 267

pending on age (11). The solution of choice is one liter of DSW with two 25-g ampules of D,W (to make it D,,W) and at least 75 mEq of sodium bicarbonate (Frank Thorp, personal communication). This solu- tion would be infused at 0.1 mL/kg/min to meet the above glucose requirements, although the volume could be excessive if infused for long periods of time. Because gluconeogenesis is impaired, lactated Ring- er’s solution should not be used routinely (1).

During resuscitations from major trauma, adher- ence to this guideline can obviously not be accom- plished. Management must still follow the recom- mendations of the American College of Surgeons Committee on Trauma (13). However, rapid glucose determination should be routinely performed for all trauma patients as the potential for hypoglycemia exists from diverse etiologies. If hypoglycemia is dis- covered, the treatment is immediate dextrose admin- istration. GSD-Ia patients will need to be monitored frequently and bolus dextrose probably repeated.

The liver in GSD-Ia patients cannot metabolize lactate normally produced at other body sites (e.g., skeletal muscle). Furthermore, the liver actually pro- duces lactate during gluconeogenesis and glycogenol- ysis. Stress-initiating stimuli for these metabolic pathways exacerbates the hyperlactatemia (4). Ad- ministration of glucagon in experimental studies has demonstrated a marked increase in circulating lactate without increase in blood glucose (9).

Individuals with GSD-Ia can tolerate severe chronic metabolic acidosis through respiratory com- pensation (14). Nonetheless, some authorities recom- mend prophylactic daily bicarbonate and treatment of even mild degrees of acidemia, thus giving patients a more normal pH in case a pronounced metabolic acidosis is precipitated by stress (1). When moder- ately severe acute acidemia develops, exogenous bi- carbonate may be the only method of bringing the pH into a more physiological range short of intuba- tion and forced hyperventilation.

In acidotic GSD-Ia patients, especially following major trauma, one must consider the potential contri- bution of inadequate perfusion, type A lactic acidosis (6). Management must necessarily be first directed to- ward shock, but type B lactic acidoses should be con- sidered in refractory acid-base disturbances.

Of interest to emergency physicians is a unique response to ethanol seen in GSD-Ia patients. In con- trast to the expected decrease in blood glucose levels after an ethanol infusion in normal individuals, glu- cose levels increase in well controlled GSD-Ia pa- tients (15). It seems to have no effect on chronically hypoglycemic patients.

Lactate is paradoxically decreased while ethanol is

in the circulation (15,16). However, in patients whose glucose levels are well controlled, ethanol elimination and the change in lactate are qualitatively similar to individuals without GSD-Ia.

Hepatomegaly and renomegaly are ubiquitous findings (14). Whether the larger sizes of the liver and kidneys increase their susceptibility to blunt in- jury has not been determined. The greater surface area presented would increase the likelihood of dam- age due to penetrating trauma. The liver is the most commonly injured organ in penetrating abdominal trauma and second only to the spleen following blunt abdominal injury (17). The spleen, though, is not typically enlarged in patients with GSD-Ia (11). Nev- ertheless, a solid-organ injury should be sought in trauma patients with GSD-Ia.

Hepatomegaly begins before birth and is secon- dary to glycogen deposition (11). Multiple adeno- mata can also be found in adult life (18). These have been known to hemorrhage and undergo malignant transformation (19).

Additional renal abnormalities include impaired proximal (20), and possibly distal (21), renal tubular function; hypertension (22); and proteinuria (23). Hematuria may also be seen (22). Evaluation of the urine in these cases should always include dipstick and microscopic examinations.

A significant management issue, especially in the trauma setting, is the potential for clinically signifi- cant hemorrhage secondary to a bleeding diathesis characteristic of GSD-Ia. Manifestations include easy bruisability, epistaxis, and bleeding after inva- sive procedures (24).

As demonstrated by our patient, platelet count and coagulation studies are typically normal (4,25). Bleeding time is prolonged, however, due to develop- mental platelet defects of adhesiveness and aggrega- tion acquired during periods of hypoglycemia (26, 27). It takes several days of euglycemia to correct these problems believed to result from impaired re- lease of nucleotides necessary for platelet hemostatic functions (4,27).

It is unknown whether donor platelets would be useful for life-threatening hemorrhage in vivo. Nor- mal platelets in plasma from GSD-Ia patients will behave normally in vitro (27). Their use is warranted when the bleeding time is prolonged and hemorrhage has not been controlled by local hemostatic measures (24). One study demonstrated a correction in bleed- ing times in individuals with GSD-Ia following infu- sion of 1-deamino-8-D-arginine vasopressin (25). The same study suggested the possibility that patients with GSD-Ia may also have an acquired form of von Willebrand’s syndrome.

268 John M. Wightman and Stacy Gordon

Regardless of the underlying metabolic abnormal- ity, internal hemorrhage will have to be definitively addressed early in a patient’s course. The risks of operating on a patient with a bleeding diathesis will have to be weighed against the patient’s hemody- namic and perfusion status.

Older patients may be more prone to gout (4,20) and renal calculi (20,21). However, development of these complications are not universal (14,30) and not of equal severity (1,4).

Because of the hemostatic abnormalities and he- patomegaly, if diagnostic peritoneal lavage is consid- ered, it should be performed by a surgeon using the open technique. To our knowledge, this invasive procedure has not been performed on a patient with GSD-Ia, and therefore, the risks are unknown. When available within the time frame that lavage is planned, donor platelets should be given if the pa- tient demonstrates any evidence of prolonged bleed- ing time, such as from wounds or following veni- puncture.

SUMMARY

Glycogen storage disease type Ia affects 1 of every 200,000 live births (4). Regardless of the presenting problem, patients with GSD-Ia are at risk for hypo- glycemia if not given metabolic exogenous energy sources early when subjected to stress or fasting in the ED. If the medical or surgical condition prohibits enteral feedings, intravenous dextrose must be ad- ministered.

Examination of all potential occult sites of hemor- rhage (i.e., head, chest, abdomen, closed fractures) must proceed aggressively for any patient with a bleeding diathesis and a history of trauma. This prin- ciple would also apply to complaints possibly related to hemorrhage from medical causes (e.g., bleeding ulcer).

In trauma patients, the most important features of GSD-Ia are the tendencies toward hypoglycemia and hyperlactatemia; the hepatomegaly and reno- megaly, possibly making the liver and kidneys more prone to injury; and the frequency of abnormal he- mostasis.

Other complications of GSD-Ia include a predis- Acknowledgment-We would like to thank Drs. Richard position to osteoporosis (1 l), hypercholesterolemia Feldman, Gary Strange, and Frank Thorp for their criti- and hyperlipidemia (4,28), and hyperuricemia (29). cisms and comments.

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