Diabetic Ketoacidosis in Arthur B.
Atlas, MD; David N. Finegold, MD; Dorothy Becker, MB, BCh; Massimo Trucco, MD; Geoffrey Kurland,
the insulin-dependent gluintolerance associated with cystic fibrosis from type I diabetes mellitus in patients with cystic fibrosis. \s=b\
Objective.\p=m-\Todifferentiate
cose
Design.\p=m-\Patientreport. Setting.\p=m-\Tertiarycare referral center. Participant.\p=m-\An11-year-old boy with cystic fibrosis who developed diabetic ketoacidosis. Measurement/Main Result.\p=m-\Biochemical,immunologic, and molecular techniques were used to support the sporadic association of type I diabetes mellitus in a patient with cystic fibrosis. Cystic fibrosis was confirmed by sweat test and further supported by the demonstration of a heterozygous deletion of the F508 locus. Evidence for the diagnosis of type I diabetes mellitus was developed from the clinical presentation of diabetic ketoacidosis with hyperglycemia, ketonemia, and ketonuria. Immunologic evidence included the
demonstration of anti-insulin antibodies. The demonstration of homozygous absence of aspartic acid at position 57 of the HLA DQ-\g=b\chain placed this child at high risk of type I diabetes mellitus. Conclusion.\p=m-\Theclinical presentation and the presence of immunologic and genetic markers characteristic of type I diabetes mellitus supports the concordance of cystic fibrosis and type I diabetes mellitus in this patient.
(AJDC. 1992;146:1457-1458)
is a common genetic disease in whites. is a relatively common reported to be as high as 75% ,1 finding in and As improved care continues to increase life expectancy for patients with CF, glucose intolerance is expected to become more prevalent.2 The cause of the glucose intolerance in CF is believed to be due to loss of pancreatic function and a decreased ratio of ß cells to other pancreatic islet cells.3 As there is usually insulin secretion sufficient to prevent ke¬ tosis, diabetic ketoacidosis (DKA) is not seen in the glucose intolerance associated with CF. In contrast, DKA is a common presentation in patients with type I diabetes mellitus. The finding of DKA in a pa¬ tient with CF raises the possibility that both type I diabe¬ tes mellitus and CF exist in that patient. However, this as¬ sociation is extremely rare. We describe a boy with CF who
(CF) Cystic fibrosis Glucose intolerance has been CF,
Accepted for publication August 27,
From the Pa.
1992.
Department of Pediatrics, Children's Hospital of Pittsburgh,
to Division of Pediatric Pulmonology, Morristown Hospital, 100 Madison Ave, Morristown, NJ 07960 (Dr Atlas).
Reprint requests
Memorial
Cystic Fibrosis MD
acutely developed DKA. We believe that in this patient, the
of DKA represents the concordance of CF and diabetes mellitus. This hypothesis is supported by I type demonstrating genetic markers for both CF and type I di¬ abetes mellitus in our patient. We believe that in other rare instances of associated DKA and CF, the concordance of these two diseases is likely. occurrence
PATIENT REPORT A 6-month-old white boy presented with failure to thrive and metabolic alkalosis. He was diagnosed by sweat tests to have CF, and improved with an elemental formula and supplemental pan¬ creatic enzymes. A sibling had died of CF at age 2l/i years. The patient did well clinically, with no further hospitalizations. At age 11 years, he presented with a 1-week history of polydipsia, polyuria, and a 7-kg weight loss over the preceding month. He was afebrile, tachycardiac, and anxious, but alert. His respiratory rate was 42 breaths per minute with a Kussmaul pattern. He had clin¬ ical evidence of severe dehydration. There were bibasilar inspira¬ tory crackles and decreased breath sounds on the right. He had decreased capillary blood flow to his nailbeds, and his nails were mildly clubbed. A complete blood cell count revealed leukocytosis with a left shift. Measurement of arterial blood gases showed the following values: pH, 7.11; PCO2, 9.8 mm Hg; bicarbonate, 3.2 mm Hg; and Po2,130 mm Hg, while the patient was receiving 2 L/min of sup¬ plemental oxygen by mask. Serum electrolyte levels were normal, but the serum glucose was elevated at 54.3 mmol/L (978 mg/dL). The serum osmolality was 368 mmol / kg, and serum ketones were positive at 1:64 dilution. The urinalysis was positive for glucose and ketones. The stable glycosylated hemoglobin was 13.8% (up¬ per limits of normal, 7.3%). Anti-insulin antibodies were present in serum samples before the administration of insulin, and cytoplasmic islet cell antibodies were absent. The patient was treated with isotonic fluid hydration and con¬ tinuous intravenous low-dose insulin, and improved over the ensuing 24 hours. He has remained insulin-dependent and cur¬ rently receives 1.4 U/kg per day of insulin divided into two in¬ jections. His stable glycosylated hemoglobin levels remain ele¬ vated between 9.4% and 11% (normal, up to 7.3%). Genetic analysis of the alíeles associated with cystic fibrosis revealed a hétérozygote deletion of the F508 mutation. His HLA analysis showed DR5 and DR7 antigens. The analysis of the DQ-ß alíele showed homozygous absence of aspartic acid in position 57.
COMMENT Glucose intolerance may be severe enough to require insulin in as many as 8% of patients with CF (insulinrequiring diabetes mellitus of CF).4 Insulin-requiring dia¬ betes mellitus of CF is thought to have a pathogenesis dis¬ tinct from type I diabetes mellitus. The former is believed
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/19/2015
result from progressive fibrosis of the pancreas, while the latter is thought to result from autoimmune destruction of ß cells. Although DKA is a frequent complication of type I di¬ abetes mellitus, it has rarely been documented in patients with CF, even those requiring insulin. Rodman et al,5 in a review of 24 cases of diabetes mellitus in patients with CF, noted only one patient who had episodes of DKA. The single patient had been diagnosed with diabetes mellitus 12 years before the diagnosis of CF was established. Other reports of patients with CF and diabetes mellitus do not mention DKA.67 Moreover, prior descriptions of severe glucose intolerance in CF have confused type I diabetes mellitus and insulin-requiring diabetes mellitus of CF.8 We hypothesize that, in our patient, DKA indicated the concordance of CF and type I diabetes mellitus. Our patient was noted to have serum anti-insulin antibodies on admission to the hospital before insulin treatment. The presence of such antibodies has been described in children with type I diabetes mellitus9 and is extremely rare in nor¬ mal individuals.10 Cytoplasmic islet cell antibodies were absent; however, such antibodies are noted in only 70% of newly diagnosed patients.10 Moreover, HLA analysis of the DQ-ß chain showed this patient to be homozygous for the absence of aspartic acid at position 57. This observation has been noted to carry more than a hundredfold risk of type I diabetes mellitus.11 The prevalence of type I diabetes mellitus is reported as high as 1 in 60012 and the prevalence of CF is 1 in 2500.13 Therefore, the expected rate of concor¬ dance of the two diseases should be approximately 1 in 1 to 2 million. Despite the predicted rarity of CF and type I diabetes mellitus, the evidence in this patient is consistent to
with the concordance of the two diseases. We believe that DKA in other patients with CF should also imply the con¬ cordance of these two separate illnesses. References 1. Shehan JP, Ulchaker MM, Doershuk CF, Stern
tic fibrosis and diabetes:
1990;336:501.
making
friends with the
RC, Amini SB. Diet, cys-
perfect
enemy. Lancet.
2. National Institute of Arthritis, Metabolism, and Digestive Diseases. Cystic fibrosis: a disease in search of ideas. Clin Sci. 1979;2:33-34. 3. Soejima K, Landing BH. Pancreatic islets in older patients with cystic
fibrosis with and without diabetes mellitus. Pediatr Pathol. 1986;6:25-46. 4. Finkelstein SM, Wielinski CL, Elliot GR, et al. Diabetes mellitus associated with cystic fibrosis. J Pediatr. 1988;112:373-377. 5. Rodman HM, Doershuk CP, Roland JM. The interaction of 2 diseases: diabetes mellitus and cystic fibrosis. Medicine. 1986;65:389-397. 6. Lanng S, Thorsteinsson B, Eridhsen G, Nerup J, Koch C. Glucose tolerance in cystic fibrosis. Arch Dis Child. 1991;66:612-616. 7. Reisman J, Corey M, Canny G, Levison H. Diabetes mellitus in patients with cystic fibrosis: effect on survival. Pediatrics. 1990;86:374-377. 8. Poncher JR, Rowley WF, Traisman HS. Cystic fibrosis and juvenile diabetes mellitus: a case report. J Ind State Med Assoc. 1967;60:907\x=req-\ 909. 9. Palmer JT,
Esplim CM, Clemons P, et al. Insulin antibodies in diabetes before insulin treatment. Science. 1983;222:1337-1339. 10. Drell DW, Notkins AL. Multiple immunological abnormalities in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia. 1987;
30:132-143. 11. Dorman J, LaPorte R, Stone R, Trucco M. Worldwide differences in the incidence of type I diabetes are associated with amino acid variation of position 57 of the HLA-DQ beta chain. Proc Natl Acad Sci U S A. 1990;87: 7370-7374. 12. LaPorte RE, Tajima N. Prevalence of insulin-dependent diabetes. In: National Diabetes Data Group, eds. Diabetes in America: Diabetes Data Compiled 1984. Bethesda, Md: National Institutes of Diabetes and Digestive and Kidney Diseases; 1985. US Dept of Health and Human Services publication NIH 85-1468. 13. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill International Book Co; 1989:2649-2660.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/19/2015
Atlas, MD; David N. Finegold, MD; Dorothy Becker, MB, BCh; Massimo Trucco, MD; Geoffrey Kurland,
the insulin-dependent gluintolerance associated with cystic fibrosis from type I diabetes mellitus in patients with cystic fibrosis. \s=b\
Objective.\p=m-\Todifferentiate
cose
Design.\p=m-\Patientreport. Setting.\p=m-\Tertiarycare referral center. Participant.\p=m-\An11-year-old boy with cystic fibrosis who developed diabetic ketoacidosis. Measurement/Main Result.\p=m-\Biochemical,immunologic, and molecular techniques were used to support the sporadic association of type I diabetes mellitus in a patient with cystic fibrosis. Cystic fibrosis was confirmed by sweat test and further supported by the demonstration of a heterozygous deletion of the F508 locus. Evidence for the diagnosis of type I diabetes mellitus was developed from the clinical presentation of diabetic ketoacidosis with hyperglycemia, ketonemia, and ketonuria. Immunologic evidence included the
demonstration of anti-insulin antibodies. The demonstration of homozygous absence of aspartic acid at position 57 of the HLA DQ-\g=b\chain placed this child at high risk of type I diabetes mellitus. Conclusion.\p=m-\Theclinical presentation and the presence of immunologic and genetic markers characteristic of type I diabetes mellitus supports the concordance of cystic fibrosis and type I diabetes mellitus in this patient.
(AJDC. 1992;146:1457-1458)
is a common genetic disease in whites. is a relatively common reported to be as high as 75% ,1 finding in and As improved care continues to increase life expectancy for patients with CF, glucose intolerance is expected to become more prevalent.2 The cause of the glucose intolerance in CF is believed to be due to loss of pancreatic function and a decreased ratio of ß cells to other pancreatic islet cells.3 As there is usually insulin secretion sufficient to prevent ke¬ tosis, diabetic ketoacidosis (DKA) is not seen in the glucose intolerance associated with CF. In contrast, DKA is a common presentation in patients with type I diabetes mellitus. The finding of DKA in a pa¬ tient with CF raises the possibility that both type I diabe¬ tes mellitus and CF exist in that patient. However, this as¬ sociation is extremely rare. We describe a boy with CF who
(CF) Cystic fibrosis Glucose intolerance has been CF,
Accepted for publication August 27,
From the Pa.
1992.
Department of Pediatrics, Children's Hospital of Pittsburgh,
to Division of Pediatric Pulmonology, Morristown Hospital, 100 Madison Ave, Morristown, NJ 07960 (Dr Atlas).
Reprint requests
Memorial
Cystic Fibrosis MD
acutely developed DKA. We believe that in this patient, the
of DKA represents the concordance of CF and diabetes mellitus. This hypothesis is supported by I type demonstrating genetic markers for both CF and type I di¬ abetes mellitus in our patient. We believe that in other rare instances of associated DKA and CF, the concordance of these two diseases is likely. occurrence
PATIENT REPORT A 6-month-old white boy presented with failure to thrive and metabolic alkalosis. He was diagnosed by sweat tests to have CF, and improved with an elemental formula and supplemental pan¬ creatic enzymes. A sibling had died of CF at age 2l/i years. The patient did well clinically, with no further hospitalizations. At age 11 years, he presented with a 1-week history of polydipsia, polyuria, and a 7-kg weight loss over the preceding month. He was afebrile, tachycardiac, and anxious, but alert. His respiratory rate was 42 breaths per minute with a Kussmaul pattern. He had clin¬ ical evidence of severe dehydration. There were bibasilar inspira¬ tory crackles and decreased breath sounds on the right. He had decreased capillary blood flow to his nailbeds, and his nails were mildly clubbed. A complete blood cell count revealed leukocytosis with a left shift. Measurement of arterial blood gases showed the following values: pH, 7.11; PCO2, 9.8 mm Hg; bicarbonate, 3.2 mm Hg; and Po2,130 mm Hg, while the patient was receiving 2 L/min of sup¬ plemental oxygen by mask. Serum electrolyte levels were normal, but the serum glucose was elevated at 54.3 mmol/L (978 mg/dL). The serum osmolality was 368 mmol / kg, and serum ketones were positive at 1:64 dilution. The urinalysis was positive for glucose and ketones. The stable glycosylated hemoglobin was 13.8% (up¬ per limits of normal, 7.3%). Anti-insulin antibodies were present in serum samples before the administration of insulin, and cytoplasmic islet cell antibodies were absent. The patient was treated with isotonic fluid hydration and con¬ tinuous intravenous low-dose insulin, and improved over the ensuing 24 hours. He has remained insulin-dependent and cur¬ rently receives 1.4 U/kg per day of insulin divided into two in¬ jections. His stable glycosylated hemoglobin levels remain ele¬ vated between 9.4% and 11% (normal, up to 7.3%). Genetic analysis of the alíeles associated with cystic fibrosis revealed a hétérozygote deletion of the F508 mutation. His HLA analysis showed DR5 and DR7 antigens. The analysis of the DQ-ß alíele showed homozygous absence of aspartic acid in position 57.
COMMENT Glucose intolerance may be severe enough to require insulin in as many as 8% of patients with CF (insulinrequiring diabetes mellitus of CF).4 Insulin-requiring dia¬ betes mellitus of CF is thought to have a pathogenesis dis¬ tinct from type I diabetes mellitus. The former is believed
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/19/2015
result from progressive fibrosis of the pancreas, while the latter is thought to result from autoimmune destruction of ß cells. Although DKA is a frequent complication of type I di¬ abetes mellitus, it has rarely been documented in patients with CF, even those requiring insulin. Rodman et al,5 in a review of 24 cases of diabetes mellitus in patients with CF, noted only one patient who had episodes of DKA. The single patient had been diagnosed with diabetes mellitus 12 years before the diagnosis of CF was established. Other reports of patients with CF and diabetes mellitus do not mention DKA.67 Moreover, prior descriptions of severe glucose intolerance in CF have confused type I diabetes mellitus and insulin-requiring diabetes mellitus of CF.8 We hypothesize that, in our patient, DKA indicated the concordance of CF and type I diabetes mellitus. Our patient was noted to have serum anti-insulin antibodies on admission to the hospital before insulin treatment. The presence of such antibodies has been described in children with type I diabetes mellitus9 and is extremely rare in nor¬ mal individuals.10 Cytoplasmic islet cell antibodies were absent; however, such antibodies are noted in only 70% of newly diagnosed patients.10 Moreover, HLA analysis of the DQ-ß chain showed this patient to be homozygous for the absence of aspartic acid at position 57. This observation has been noted to carry more than a hundredfold risk of type I diabetes mellitus.11 The prevalence of type I diabetes mellitus is reported as high as 1 in 60012 and the prevalence of CF is 1 in 2500.13 Therefore, the expected rate of concor¬ dance of the two diseases should be approximately 1 in 1 to 2 million. Despite the predicted rarity of CF and type I diabetes mellitus, the evidence in this patient is consistent to
with the concordance of the two diseases. We believe that DKA in other patients with CF should also imply the con¬ cordance of these two separate illnesses. References 1. Shehan JP, Ulchaker MM, Doershuk CF, Stern
tic fibrosis and diabetes:
1990;336:501.
making
friends with the
RC, Amini SB. Diet, cys-
perfect
enemy. Lancet.
2. National Institute of Arthritis, Metabolism, and Digestive Diseases. Cystic fibrosis: a disease in search of ideas. Clin Sci. 1979;2:33-34. 3. Soejima K, Landing BH. Pancreatic islets in older patients with cystic
fibrosis with and without diabetes mellitus. Pediatr Pathol. 1986;6:25-46. 4. Finkelstein SM, Wielinski CL, Elliot GR, et al. Diabetes mellitus associated with cystic fibrosis. J Pediatr. 1988;112:373-377. 5. Rodman HM, Doershuk CP, Roland JM. The interaction of 2 diseases: diabetes mellitus and cystic fibrosis. Medicine. 1986;65:389-397. 6. Lanng S, Thorsteinsson B, Eridhsen G, Nerup J, Koch C. Glucose tolerance in cystic fibrosis. Arch Dis Child. 1991;66:612-616. 7. Reisman J, Corey M, Canny G, Levison H. Diabetes mellitus in patients with cystic fibrosis: effect on survival. Pediatrics. 1990;86:374-377. 8. Poncher JR, Rowley WF, Traisman HS. Cystic fibrosis and juvenile diabetes mellitus: a case report. J Ind State Med Assoc. 1967;60:907\x=req-\ 909. 9. Palmer JT,
Esplim CM, Clemons P, et al. Insulin antibodies in diabetes before insulin treatment. Science. 1983;222:1337-1339. 10. Drell DW, Notkins AL. Multiple immunological abnormalities in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia. 1987;
30:132-143. 11. Dorman J, LaPorte R, Stone R, Trucco M. Worldwide differences in the incidence of type I diabetes are associated with amino acid variation of position 57 of the HLA-DQ beta chain. Proc Natl Acad Sci U S A. 1990;87: 7370-7374. 12. LaPorte RE, Tajima N. Prevalence of insulin-dependent diabetes. In: National Diabetes Data Group, eds. Diabetes in America: Diabetes Data Compiled 1984. Bethesda, Md: National Institutes of Diabetes and Digestive and Kidney Diseases; 1985. US Dept of Health and Human Services publication NIH 85-1468. 13. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill International Book Co; 1989:2649-2660.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/19/2015
