Pancreatitis in patients with organic acidemias

Pancreatitis in patients with organic acidemias Stephen G. Kahler, MD, W. G e o f f r e y Sherwood, MD, David Woolf, MRCP, Stephen T. Lawless, MD, Arno Zaritsky, MD, James Bonham, PhD, C. J. Taylor, MD, Joe T. R. Clarke, MD, PhD, Peter Durie, MD, a n d J a m e s V. Leonard, PhD, FRCP From the Department of Pediatrics, Duke UniversityMedical Center, Durham, North Carolina, the Hospital for Sick Children, Toronto, Ontario, Canada, the Institute for Child Health, University of London, United Kingdom, the Department of Pediatrics, Universityof North Carolina, Chapel Hill,and Children's Hospital, Universityof Sheffield, United Kingdom

Study objective: The discovery of pancreatitis in two children with methylm a l o n i c a c i d e m i a led us to review the e x p e r i e n c e with pancreatitis in a large number of patients with organic a c i d e m i a s to determine whether pancreatitis is an important c o m p l i c a t i o n of these disorders. Design: Case series. Setting: Pediatric metabolism services at five tertiary care centers. Patients: Records of all patients with organic a c i d e m i a s followed at the five institutions during the past 10 years were reviewed. Pancreatitis was recognized by symptoms and laboratory findings and confirmed by imaging studies, surgery, or autopsy. At three institutions all cases of pancreatitis in children younger than 10 years were reviewed. Measurements and results: Nine children with pancreatitis (seven with acute and two with chronic cases) were identified among 108 children with branched-chain organic acidemias. They ranged in a g e from 13 months to 9 years. Five had methy l m a l o n i c a c i d e m i a , three had isovaleric a c i d e m i a , and one had m a p l e syrup urine disease. There were three deaths; acute hemorrhagic pancreatitis occurred in two children, and chronic pancreatitis was found at autopsy in a third. All three patients with isovaleric a c i d e m i a and pancreatitis were identified after the occurrence of pancreatitis. The survey of pancreatitis at three institutions found 57 other patients (none with an inborn error) in addition to three patients with inborn errors included in this study. Conclusions: Acute or chronic pancreatitis may c o m p l i c a t e branched-chain organic a c i d e m i a s and must be considered in the assessment of patients with these disorders who have acute clinical deterioration and vomiting, a b d o m i n a l pain, e n c e p h a l o p a t h y or shock, or milder symptoms. Conversely, an inborn error of organic a c i d metabolism should be considered in children with pancreatitis of unknown origin. (J PEDIATR1994;124:239-43) Supported in part by grant M01-RR-30, National Centers for Research Resources, General Clinical Research Centers, National Institutes of Health. Submitted for publication April 14, 1993; accepted Aug. 31, 1993. Reprint requests: Stephen G. Kahler, MD, Divisionof Genetics and Metabolism, Department of Pediatrics, Box 3028, Duke University Medical Center, Durham, NC 27710. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94 $3.00 + 0 9/20/51216

Patients with severe forms of the inherited disorders of organic acid metabolism usually are recognized in the neonatal period because of overwhelming acidosis, frequently accompanied by hyperammonemia, pancytopenia, and encephalopathy. Later episodes of decompensation may be precipitated by intercurrent infections, but the cause is often not identified. Milder or intermittent forms may be seen later in childhood. Management is based on restriction of

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Table. Background data and details of pancreatitis in nine patients with organic acidemias Patient No. I

2

Sex Diagnosis Age at first symptoms Age diagnosis made Diet

F MSUD 10 days 10 days Restricted in BCAA

F IVA 4 wk 4 yr No restrictions

Control Age when pancreatitis diagnosed Number of episodes Outcome Interval between onset and amylase measurement Amylase (IU/L) (range)* SI units (~kat/L) (range) Imaging

Poor 7 yr

Good 4 yr

Other problems

3

F IVA 3 yr 4 yr Self-selected low-protein Good 3 yr

4

M IVA 6 yr 6 yr Self-selected low-protein Good 6 yr

1

1

3

1

Died 2 days

Survived 2 days

Survived 6 hr?

Survived 7d

2648-9114 (<300)t 44-142 (<5) Enlargement of pancreas; diffuse attenuation and calcification of head (us) Thalassemia major; transfusions; developmental delay; ataxia; bypotonia

4280 (<300)t 71 (<5) Swelling of tail of pancreas (US)

228; 400; 21" (<117)t 3.8 (<2.0) Swelling of pancreas (CT, US)

103 (40-180)t 1.7 (0.7-3.0) Fluid around head of pancreas, dilated duodenal loop (US)

Pyloric stenosis Intussusception

Recurrent pancreatitis (3 episodes before IVA was diagnosed)

Five siblings died in infancy

BCAA, Branched-chain amino acids; IVA, isovalericacidemia;MMA, methylmalonicacidemia;MSUD, maple syrup urine disease; NA, not available;ND, not done. Imaging: CT, computed tomography; US, ultrasonography. SI conversionfactor for amylase: 60 IU/L = 1/zkat/L. *Data from three separate episodes of pancreatitis. tNormal range for hospital laboratory. protein intake to the amount needed for growth and on supplementation with nontoxic amino acids, vitamin cofactors, and L-carnitine. When we discovered pancreatitis in two patients with methylmalonic acidemia, a review of patients with inborn metabolic errors was undertaken to determine whether a significant association of these disorders could be identified. METHODS

Patients with inborn metabolic errors who were followed at five centers during a 10-year period were reviewed. Amino acids were quantified by liquid column chromatography. Organic acids were analyzed by gas chromatography with identification by retention time or mass spectrometry. Carnitine was measured by radioenzymatic assay, 1 and acylcarnitines were identified by tandem mass spectrometry. 2 The inborn errors were unequivocally identified by metabolite excretion and confirmed by enzyme assay when possible. For comparison, all cases of pancreatitis in children less than 11 years of age, identified during a 10-year

period at two institutions and during a 5-year period at a third, were reviewed. RESULTS Nine children with pancreatitis and impaired amino acid catabolism were found (Table). All had errors of branchedchain amino acid metabolism. One patient had maple syrup urine disease, a deficiency of the branched-chain keto acid dehydrogenase complex. Three had isovaleric acidemia, a deficiency of isovaleryl-coenzyme A dehydrogenase. Five had methylmalonic acidemia, which can be due to defects of methylmalonyl-coenzyme A mutase or its cobalamin cofactor. The nine patients represent 8% of the 108 patients with branched-chain organic acidemias (maple syrup urine disease 26, isovaleric acidemia 8, propionic acidemia 26, methylmalonic acidemia 30, unspecified 18) cared for at the five centers during a 10-year period. The severity of pancreatitis varied. Two patients died of acute hemorrhagic pancreatitis shortly after onset. Five recovered from mild to severe acute pancreatitis. Two were

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Patient N o . - - c o n t ' d 5

6

M MMA Birth Birth Low-protein

F MMA 6 days 6 mo Low-protein

Fair 3yr

Poor 5yr

7

8

M MMA 7 mo 7 mo Low-protein ( 1 - 1 . 5 gm/kg/d) Good 7yr

9

M MMA 2 wk 2 wk Low-protein

F MMA NA Prenatal Low-protein

Good 9yr

Fair 13mo

1

1

10

1

1

Died 10 d

Survived <6 hr

Survived <24 hr?

Survived 3d

Died ND

125 (<405)'~ 2.1 (<6.8) ND

5790 (<405)t 96.3 (<6.8) Edema of pancreas

133-200 (20-140)t 2.2-3.3 (0.3-2.3) Repeatedly normal (US); calcifications late

252-449 (< 122)t 3.2-7.5

ND

Pancreatic enlargement, diminished echogenicity; edema of gallbladder

ND

Developmental delay; anorexia; nasogastric feeding

Chronic renal failure; mild developmental delay

Poor weight gain; recurrent pancreatitis

found to have chronic calcifying pancreatitis, one (patient 9) at autopsy at 13 months of age and one (patient 7) after numerous episodes of abdominal pain and vomiting during a period of more than 4 years and several investigations for suspected pancreatitis. Plasma amylase levels in the nine patients ranged from normal to severely elevated. Lipase level was determined in only two patients and was elevated in one. On admission to the hospital, nearly all patients had an elevated blood glucose level. The severity of the inborn errors also varied greatly. The three patients with isovaleric acidemia had good health and normal growth, and the metabolic error was not recognized until after pancreatitis had occurred (in patient 3, after the third attack). Patient 4 had five siblings who died in infancy or childhood; one of them had recognized pancreatitis. Some of these siblings may have had isovaleric acidemia. Although some patients with isovaleric acidemia have the characteristic odor of free isovaleric acid when sick, none of our patients did. None of the patients with methylmalonic acidemia responded to vitamin BI2. For comparison, we conducted a review of pancreatitis seen in children less than 10 years of age during the past 10 years at two centers and during the past 5 years at a third

center. Sixty patients were found, of whom three were known to have an inborn error; 37 patients with branchedchain organic acidemias have been followed at these centers. At the other two centers, 71 patients with branchedchain organic acidemias have been followed; six of them have had pancreatitis. The data from these nine patients who had both pancreatitis and an inborn error are summarized in the Table. DISCUSSION It is not surprising that pancreatitis may be unrecognized in children with organic acidemia. Vomiting and anorexia are common; the presence of abdominal pain may be difficult to ascertain in infants; encephalopathy is common during metabolic decompensation,3, 4 and amylase and lipase determinations are not part of routine chemistry panels. Two of the patients with pancreatitis in this report were discovered to have an inborn error after we became aware of the association with organic acidemias. The investigation of patient 3 for an inborn error was prompted by new observations during her third episode of pancreatitis. Pancreatitis in patients of any age may be difficult to diagnose. In acute pancreatitis theamylase level is typically

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many times the upper limit of normal, but this is not always the case. Patient 4 had a normal plasma amylase concentration but had typical symptoms, elevated amylase concentration in the peritoneal fluid, and pancreatic edema and hemorrhage on direct visualization. Patient 7 was investigated for pancreatitis on many occasions; ultrasonographic findings were normal and convincing evidence of chronic pancreatitis was found only after diffuse stippling was seen on radiographs. Pancreatitis is rare in children. During a 10-year period at three centers, pancreatitis was diagnosed in only 60 children less than 10 years of age. Among the causes that are readily recognized are systemic disorders (e.g., infections, sepsis, peritonitis, inflammatory disorders, Reye syndrome, trauma, hypertriglyceridemia, hypercalcemia, cystic fibrosis, diabetes mellitus), gallstones (particularly in association with hemoglobinopathies), and drugs (e.g., valproic acid, steroid hormones, and L-asparaginase). In some instances no precipitating factor can be identified.5H Unrecognized errors of branched-chain organic acid metabolism may account for some cases of"idiopathic pancreatitis" (as in patient 3). The aforementioned disorders account for most cases of pancreatitis in the children seen at our centers. The pathogenesis of pancreatitis in the organic acidemias is not known; mechanisms of most forms of acute and chronic pancreatitis are poorly understood. Two major mechanisms are proposed--activation of pancreatic enzymes in an inappropriate location (within the pancreatic ducts or the acinar cells) and inability of the pancreas to withstand the metabolic stresses normally encountered. Excess free radical formation and deficiencies of carnitine, methionine, and antioxidants (including vitamins E and C, glutathione, and selenium) may contribute to the onset of pancreatitis. 12-14 Some aspects of these proposed mechanisms might apply to pancreatitis in patients with organic acidemias 1° exacerbated by acidosis and shock. The common factor shared by the nine patients is impaired metabolism of branched-chain compounds. They did not share the same diet or therapy, there was no evidence of gallstones or other obstruction, and the severity of the underlying disorder was apparently not related to the risk of pancreatitis. Carnitine deficiency is not a problem in maple syrup urine disease and would not be expected in the two children receiving carnitine. The three children with isovaleric acidemia had normal growth and were on no direct dietary restriction or special formula, so it is unlikely that they had a significant deficiency of an essential amino acid, especially methionine. Data regarding antioxidant levels are not available for most of the cases reported here. The antieonvulsantagent sodium valproate is a branchedchain organic compound (2-propylpentanoate) that is asso-

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ciated with pancreatitis. 1519 Like the branched-chain organic acidemias, valproate may impair mitochondrial function (as does Reye syndrome) and can be associated with carnitine depletion.2° Its hepatotoxicity may be due to reactive epoxide intermediates and depletion of antioxidant stores.21, 22 These features may be clues to mechanisms of pancreatitis that could be investigated in the organic acidemias. Decompensation of the inborn metabolic error may have preceded or accompanied the onset of pancreatitis in most instances, judging from the acidosis, neutropenia, and thrombocytopenia present at admission in most patients. In most cases, however, pancreatitis was not suspected or investigated early in the illness. Longitudinal data are available for patient 3. At the time of her third admission she had a normal amylase level, which rose during the next 2 days. This suggests that the occurrence of pancreatitis may be due to decompensation of the inborn error, but there could be local causes in the pancreas as well. There are a few reports of pancreatitis in other inborn errors of metabolism. They include hydroxymethylglutaryl-coenzyme A lyase deficiency,23 a disorder of leucine and ketone body metabolism; homocystinuria, a disorder that may bring about occlusion of medium-sized vessels24; and cytochrome c oxidase deficiency, a disorder of the electron transport chain. 25 In one family the association of pancreatitis with cystinuria, a relatively common disorder noted for renal stones, 26 may be fortuitous. We have not yet encountered pancreatitis in a patient with propionic acidemia. This may be a reflection of an important metabolic clue or a matter of chance; at least one patient with this disorder has had pancreatitis (W. L. Nyhan: personal communication, 1990). The metabolic block in propionic acidemia occurs just before that in methylmalonic acidemia. Pancreatitis has not been recognized in our patients with disorders of fatty acid oxidation or of the urea cycle, although patients with these disorders also have episodic metabolic decompensation. If this difference persists, it may point the way to a specific reason, not a nonspecific consequence of shock or acidosis, for pancreatitis in patients with branched-chain organic acidemias. We recommend that pancreatitis be added to the list of late problems being recognized in patients with organic acidemias, including basal ganglion dysfunction27 and progressive renal insufficiency28 in methylmalonic acidemia and brain dysfunction and cardiomyopathy in propionic acidemia.29, 3o Our experience suggests that patients with disorders of branched-chain organic acid metabolism are at particular risk of pancreatitis. Further study should elucidate more details about risk factors and pathogenesis, improve early recognition, and contribute to general understanding of pancreatitis.

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We thank Dr. R. J. Pollitt (patient 4) and Dr. David Rosenblatt (patient 7) for enzyme assays. 15. REFERENCES

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