Portacaval shunt in siblings for type I glycogenosis

Portacaval Shunt in Siblings for Type I Glycogenosis By David Liebschutz and R. T. Soper

EN YEARS AGO Starzl and his associates performed the first portal diversion for glycogenosis, based on theoretical speculation as to its benefit by Field and after extensive animal experiments of their o w n . 1'2 To date, 13 children with this metabolic disorder have undergone portal diversion) Surgical treatment has revolutionized the prognosis of these enzyme-deficient children. This procedure increases systemic glucose levels, making more glucose available for direct use by muscle and other peripheral tissues to improve the acidosis, hypoglycemia, and growth retardation of the disease. Starzl first performed portacaval transposition in a patient with type III glycogenosis and subsequently patients with type I disease, the most common type) '5 Hermann and Mercer in 1968 first reported using an end-to-side portacaval shunt in a 1-yr-old infant with severe glycogen storage disease, instead of the previously used portacaval transposition. 6 Since then, all portal diversions have been achieved by the relatively easier portacaval shunt which eliminates virtually all of the portal venous inflow into the liver. A further advance in therapy of this disorder was reported in 1972 by Folkmann, who demonstrated that glycogenosis patients who were given a month of preoperative parenteral hyperalimentation had fewer operative and postoperative complications.7 Among the benefits of preshunt parenteral hyperalimentation are: predetermination of the benefits of the shunt, reduction of liver size, restoration of blood coagulation to normal, correction of acidosis and hypoglycemia, improved nutrition, and startling improvement in demeanor and personality of the children. This paper summarizes two siblings with type I glycogenosis who were recently treated at the University of Iowa Hospitals utilizing these improved principles of care. One sibling had, in addition, evidence of hypophosphatemic rickets (S. C.), a combination which has been described by Lampert et al, s and Fanconi and Bickel.9 This paper concerns itself with the effect of hyperalimentation and portacaval shunt on the glycogenosis; the combination of hypophosphatemic rickets and glycogenosis will be discussed elsewhere.

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CASE HISTORIES

Case 1 (R. C.) A 789 male was referred for treatment ofgtycogenosis was the first born child of healthy parents, after a normal pregnancy, labor, a n d delivery. The family history revealed that the mother has a sibling who is mentally retarded and another who is a deaf mute. The patient was of normal weight and height at delivery, but by 5 m o of age had developed an enlarging a b d o m e n . Type I glycogenosis was diagnosed by liver biopsy, a n d he was begun on nonspecific dietary treatment.

From the Department of Surgery, University of lowa College of Medicine, Iowa City, Iowa. Address for reprint requests: R. T. Soper, M.D., Department of Surgery, University Hospitals, Iowa City, Iowa 52242. 9 1976 by Grune & Stratton, Inc. Journal of Pediatric Surgery, VoL 11, No. 4 (August), 1976

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He continued to do poorly, demonstrating periods of lethargy, hypoglycemia, and irritability with severe growth retardation, hepatomegaly, splenomegaly, and a doll-like face. He was first seen at the University of Iowa Hospitals in 1974. Initial laboratory studies revealed: serum cholesterol 286 mg/dl, serum triglyceride 2332 mg/dl, SGOT 325 mU/ml, alkaline phosphatase 510 mU/ml, and fasting blood sugar 3 mg/dl which rose to 97 mg/dl 2 hr postprandially. The PTT control was 38 sec and the patient's was 51 sec. Needle liver biopsy revealed enlarged hepatocytes filled with fat which stained strongly for glycogen. Intravenous pyelography showed bilateral renal enlargement. Serum electrolytes were normal as were the calcium and phosphorus (10.2 mg/dl and 3.6 mg/dl, respectively). X-ray of the long bones showed mild osteoporosis but no evidence of rickets. The arterial pH was 7.38 and HCO3 7 mEq/liter. After these baseline studies, central venous nutrition was administered through a silastie catheter into the superior vena cava for 4 wk. The patient quickly lost his lethargy and irritability, and was much more cooperative, and obviously felt better. After 4 wk of central venous nutrition, laboratory studies revealed: cholesterol 140 mg/dl, triglyceride 233 mg/dl, SGOT 60 mU/ml, LDH 250 mU/ml, and alkaline phosphatase 241 mU/ml. The pH and HCO3 quickly returned to normal. The liver, which before central venous nutrition descended to the right iliac crest and filled two-thirds of the rotund abdomen, rapidly shrank to within 4 cm of the right costal margin. In spite of considerably better nutritional status, the patient lost 0.2 kg of body weight. After 4 wk of parenteral alimentation, an end-to-side portacaval shunt was performed. The operation was technically uneventful and the postoperative course of the patient was unremarkable. Two weeks after the operation the SGOT was 85 mU/ml. The patient was discharged from the hospital 3 wk after the operation at which time he was able to fast 6 hr and still maintain a blood sugar of 22 mg/dl. After 4 hr of fasting, the true blood sugar was 70 mg/dl. The blood pH, cholesterol, and triglycerides remain normal. At 7 weeks after opera~ion the child was clinically well and alert, the wound had healed per primam, and the liver edge was now 8 cm below the costal margin. Six months postoperatively the child was described by the parents as markedly improved. He was more alert, playing normally with other children, and maintaining his position with his peers in school. His hematocrit was 32 vol~, cholesterol 230 mg/dl, alkaline phosphatase 196 mU/ml, LDH 160 mU/ml, HCO3 12 mEq/liter, and SGOT 310 mU/ml. The 4-hr fasting blood sugar was 75 mg/dl. The patient's liver edge extended 14 cm below the costal margin.

Case2 (S. C.) The 4-yr-old female sibling of R. C. was diagnosed clinically as having type I glycogenosis shortly after birth when she failed to gain weight properly. She had repeated episodes of pneumonia, severe metabolic acidosis, congestive heart failure, and renal failure for which dialysis was required. Epileptiform seizures (probably hypoglycemic), an abnormal EEG, and renal rickets were also documented. She was first seen at the University of Iowa Hospitals with her older male sibling. Physical examination showed a very short, obese, and irritable child with a doll-like face. The abdomen was protuberant and the liver occupied most of the abdominal cavity, particularly on the right side. Radiographs showed delayed bone maturation and rickets. Initial laboratory studies revealed: calcium 9.5 mg/dl, inorganic phosphates 1.4 mg/dl, albumin 3.2 g/dl, alkaline phosphatase 550 mU/ml, LDH 284 mU/ml, SGOT 325 mU/ml, cholesterol 209 mg/dl, triglyceride 708 mg/dl, arterial pH 7.29, HCO 3 5 mEq/liter, and fasting blood sugar 15 mg/dl. Needle biopsy of the liver showed enlarged hepatocytes filled with fat and material which stained strongly for glycogen. A silastic catheter was placed into the superior vena cava through which central venous nutrition was administered. After 1 mo of central venous nutrition, blood calcium was normal (9.8 mg/dl), triglyceride 278 mg/dl, HCO3 20 mEq/liter, serum inorganic phosphates 3.9 mg/dl, SGOT 26 mU/ml, and blood pH normal. The child was remarkably less lethargic and irritable, and the liver had dramatically diminished to 4 cm below the right costal margin. Liver biopsy and an end-to-side portacaval shunt were performed and were well tolerated. Central venous nutrition was given until the patient tolerated an oral diet. The patient was discharged 3 wk after the operation with normal calcium, phosphorus, and SGOT. The triglycerides were 278 mg/dl, cholesterol 179 mg/dl, alkaline phosphatase 445 mU/ml, and HCO3 20 mEq/liter.

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PORTACAVAL SHUNT FOR GLYCOGENOSIS Table 1 Type

Enzyme Defect

Storage Organ

Glucose-6-Phosphatase

Liver, kidney

II Pompe III Cori

Amino 1,4 glucosidase Debrancher amylo 1, 6 glucosidase

Generalized

IV

Branching enzymes

Liver, reticuloendothelial

Von Gierke

Andersen

Liver, muscle

system

V McArdle

Muscle phosphorylase

Muscle

VI Hers

Liver phosphorylase

Liver leukocytes

At 7 wk postoperative follow-up, the child demonstrated a good appetite with increasing activity. The patient began to walk for the first time. The child's calcium was 10.7 mg/dl, inorganic phosphates 2.3 mg/dl, cholesterol 135 mg/dl, 4-hr fasting glucose levels 85 mg/dl, alkaline phosphatase 605 mU/ml, LDH 196 mU/ml, and SGOT 212 mU/ml. Six months postoperatively the child was running and playing but still demonstrated her preexisting renal rickets. The patient is being followed closely for fluctuations in her serum calcium and inorganic phosphorus. The child was noted to be more alert than her preoperative status, less irritable, and had no seizure activity. Calcium was 10.0 mg/dl, inorganic phosphates 3.8 mg/dl, cholesterol 198 mg/dl, alkaline phosphatase 570 mU/ml, LDH 214 mU/ml, and SGOT 310 mU/ml. DISCUSSION

Glycogen is a branched polysaccharide of high molecular weight ranging from 3 to 10 million. It is composed entirely of glucose units linked together by alpha 1,4 and 1,6 bonds. A large number of enzyme systems are involved in synthesis and degradation of glucose. Defects in these enzyme systems produce different types of glycogenosis, summarized in Table 1. Types I, IV, and VI theoretically result from liver enzyme defects and thus might benefit from portal diversion. Type I glycogenosis is the most common type, and therefore is the type most commonly treated in the cases reported to date. Diversion from the liver of glycogen and pancreatic hormones (i.e., insulin) have benefited patients with severe acidosis, hypoglycemia, and growth retardation. 2'3 Our two sibling patients demonstrated all the defects of type I glycogenosis; doll facies, acidosis, hypoglycemia, growth retardation and, in the younger one, renal failure with renal rickets and seizures. The month of preoperative hyperalimentation with central venous nutrition produced marked changes in these siblings: they become more tractable in behavior, their acidosis was quickly corrected, mean glucose levels stabilized, and the liver diminished markedly in size (Figs. 1A and B). The change in operation from portacaval transposition to end-to-side portacaval shunt has reduced operative morbidity and mortality. This was first reported by Drs. Hermann and Mercer 6 and has rapidly been embraced as the operation of choice since then. This operation avoids the hepatic swelling and

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Fig. 1. (A) Patients before CVN therapy; enlarged livers marked on abdominal wall. (B) Patients shortly after portacaval shunt.

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u n c o n t r o l l e d a c i d o s i s seen in t h e s e c o n d p a t i e n t on w h o m Starzl ~ p e r f o r m e d portacaval transposition. T h e m e t a b o l i c benefits o f p o r t a l d i v e r s i o n were well r e v i e w e d b y Starzl in 1973. 3 T h e s e benefits were r e a l i z e d in o u r two p a t i e n t s , b u t f o l l o w - u p is t o o s h o r t to p r e d i c t l o n g - t e r m benefits. H o w e v e r , the cases r e v i e w e d by S t a r z l d e m o n s t r a t e a beneficial t r e n d . H o w p o r t a l d i v e r s i o n c h a n g e s the n a t u r a l h i s t o r y o f this d i s o r d e r also has y e t to be defined. P r e s e n t l y , surgical t h e r a p y is i n d i c a t e d o n l y in t h e severely i n v o l v e d p a t i e n t with g l y c o g e n o s i s . C o m p a r i s o n o f o p e r a t e d p a t i e n t s with t h o s e w h o receive no surgical t h e r a p y will be interesting. A t present, p o r t a c a v a l s h u n t a n d central v e n o u s n u t r i t i o n p r o v i d e new t h e r a p e u t i c h o p e for t h o s e p a t i e n t s with severe a c i d o s i s , h y p o g l y c e m i a , a n d g r o w t h r e t a r d a t i o n s e c o n d a r y to g l y c o g e n o s i s o f liver origin. SUMMARY

This p a p e r r e p o r t s t w o siblings with t y p e I g l y c o g e n o s i s , p r e s e n t i n g supp o r t i v e l a b o r a t o r y d a t a b e f o r e a n d after 1 m o o f c e n t r a l v e n o u s n u t r i t i o n a n d l a t e r after surgical p o r t a l d i v e r s i o n . B o t h c h i l d r e n d r a m a t i c a l l y i m p r o v e d with c e n t r a l v e n o u s n u t r i t i o n , a l l o w i n g safe a n d t e c h n i c a l l y easy p o r t a c a v a l s h u n t s to be c o n s t r u c t e d . T h e i r s m o o t h p o s t o p e r a t i v e c o u r s e s are d o c u m e n t e d . C u r r e n t l y , b o t h p a t i e n t s are at h o m e p u r s u i n g relatively n o r m a l lives. REFERENCES

1. Starzl TE, Marchioro TL, Sexton AW, et al; The effect of portacaval transposition on carbohydrate metabolism; experimental and clinical observation. Surgery 57:687, 1965 2. Sexton AW, Marchioro TL, Waddell WR, et al: Liver deglycogenation after portacaval transposition. Surg Forum 15:120, 1964 3. Starzl TE, Putnam CW, Porter KA, et al: Portal diversion for the treatment of glycogen storage disease in humans. Ann Surg 178:525, 1973 4. Starzl TE, Brown BI, Blanchard H, et al: Portal diversion of glycogen storage disease. Pediatr Surg 65:504, 1969 5. Riddell AG, Davies RP, Clark AD: Portacaval transposition in the treatment of glycogen storage disease. Lancet 2:1146, 1966

6. Hermann RE, Mercer RD: Portacaval shunt in the treatment of glycogen storage disease: Report of a case. Surgery 65:499, 1969 7. Folkman J, Philippart A, Wah-Jun Tze, et al: Portacaval shunt for glycogen storage disease: Value of prolonged intravenous hyperalimentation before surgery. Surgery 72:306, 1972 8. Lampert F, Mayer H, Tocci P, et al: Falcon syndrome in glycogen storage disease, in Nyhan WL (ed): Amino Acid Metabolism and Genetic Variation. New York, McGraw-Hill, 1967 9. Fanconi G, Bickel H: Die chronische amino acidurie (aminosaurediabetes oder nephrotisch-glukosurische zwergueschs) beider glykogenase und der cystin kuarkeit. Helu Paediat Acta 4:359, 1949