ATP depletion, a possible role in the pathogenesis of hyperuricemia in glycogen storage disease type I.

Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and P(i) and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis. Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 +/- 0.09 to 0.73 +/- 0.06 mumol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 mumol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 +/- 21 to 311 +/- 17 mumol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 +/- 0.51 to 6.68 +/- 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 mumol/g liver), fructose-6-phosphate (from 0.17 to 0.45 mumol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 mumol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min. Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid. We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.

Campylobacter jejuni-associated hemolytic-uremic syndrome in a mother and daughter.

A mother and daughter with Campylobacter jejuni-associated hemolytic-uremic syndrome (HUS) are discussed. The mother was hospitalized with bloody diarrhea and HUS; C jejuni was isolated from her stool. The 2-year-old daughter had been admitted five days prior to her mother with HUS following a three-day prodrome of vomiting and diarrhea. Multiple stool cultures were negative for enteric pathogens; however, cultures were not obtained until the eighth hospital day and after antibiotic therapy. Extensive investigation failed to identify another cause for the diarrheal illness or HUS in our patients. Indirect immunofluorescent antibody titers for C jejuni were 1:32 and 1:16 for the mother and daughter, respectively. An asymptomatic 9-month-old son had C jejuni isolated from his stool and had an immunofluorescent antibody titer of 1:64. Three other family members were asymptomatic, stool-culture negative, and had immunofluorescent antibody titers less than or equal to 1:4. The susceptibility to develop HUS following an enteric antigenic stimulus is illustrated by the patients presented. The need for systematic investigation of all HUS cases for potential susceptibility markers, as well as an exhaustive etiologic search, is emphasized.

Methodology of serial ECG classification using an adaptation of the NOVACODE for Q wave myocardial infarction in the Bypass Angioplasty Revascularization Investigation (BARI).

Serial electrocardiographic (ECG) changes are a critical component of the diagnostic algorithm for classification of myocardial ischemic events in large-scale clinical trials. This study describes a computerized serial ECG classification program developed at the St. Louis University Core ECG Laboratory for use in the Bypass Angioplasty Revascularization Investigation (BARI) trial, in which patients with multivessel coronary artery disease were randomized to receive either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. The St. Louis University program detects and codes serial changes in Q, ST, and T wave items according to Minnesota code (MC) criteria using a modified NOVACODE hierarchical classification system. Measurements using a seven-power calibrated coding loupe are used to generate the MC from a customized software program. Significant minor or major changes are detected by the serial comparison program and referred to a physician coder for verification. Serial comparison coding rules are used to adjust for weaknesses in the standard MC classification system resulting from instability at decision boundaries. Of 4,244 BARI randomized and registry study participants with follow-up ECGs received at the Core ECG Laboratory as of March 1995, a grade 2 MC Q wave progression was noted in 568 participants (13.4%) using MC criteria alone, as compared with 367 (8.6%) after the St. Louis University coding rules were applied. The incidence of grade 1 MC Q wave progressions was 16.4% (697/4,244) versus 6.1% (259/4,244) when the St. Louis University program was applied. Intraobserver variability for grade 2 Q wave progression codes determined from a sample of 812 serial.

Persistent succinylacetone excretion after liver transplantation in a patient with hereditary tyrosinaemia type I.

A liver transplant was performed on a 4-year-old female in liver failure caused by hereditary tyrosinaemia, with hepatocellular carcinoma following a negative evaluation for metastases. However, serum alpha-fetoprotein levels never returned to normal after the surgery. Urinary succinylacetone (SA) was detected in her urine prior to transplantation despite strict adherence to a low-tyrosine diet. Other patients with severe liver disease awaiting liver transplantation do not excrete SA in the urine. She continued to excrete SA during the postoperative period despite normal liver functions. Oral tyrosine loading resulted in significant elevation of SA excretion. Possible explanations for this observation and clinical and therapeutic relevance are discussed.