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Fibrocalculous pancreatic diabetes in infancy — two case reports
ELSEVIER
Diabetes
Fibrocalculous
Research
and Clinical
Practice
25 (1994) 137-140
pancreatic diabetes in infancy -
two case reports
Gopal Premalatha, Viswanathan Mohan* hf. V. Diabetes Specialiries Cenlre (P) Ltd., 44, Royapettah High Road, Royapetrah, Madras Received
16 February
1994 revision
accepted
600 014, India
9 June 1994
Abstract Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes secondary to tropical calcific pancreatitis (TCP). The usual age of onset of FCPD is between 15 and 50 years. This paper reports on two unusual cases of FCPD with age of onset below 5 years. This is the first report of FCPD in infancy and raises intriguing questions about the rapidity with which calcification occurs in this entity. Keywords: Fibrocalculous Chronic pancreatitis
pancreatic diabetes; Childhood
onset; Tropical calcitic pancreatitis;
Pancreatic calculi;
1. Introduction
2. Patient 1
Fibrocalculous pancreatic diabetes (FCPD) is a unique form of diabetes prevalent in tropical countries [I]. FCPD is secondary to tropical calcific pancreatitis (TCP) which is a youth onset form of non-alcoholic chronic pancreatitis seen in tropical countries of the world. The classic features of this disease are: a history of recurrent abdominal pain from childhood, pancreatic calculi which are usually diagnosed in adolescence and diabetes which manifests by early adulthood [ 11.The usual age of onset of diabetes in FCPD is between 15 and SO years. Onset of FCPD below the age of 15 years is extremely uncommon and below 5 years, virtually unknown. We report here on two unusual cases of FCPD with onset in infancy.
Baby P.A., a 3-year-old female child first presented to us in January 1986. There was no history of childhood malnutrition and there was no history of cassava ingestion. On examination, we found that she was lean with a body mass index of 17 kg/m*. The relevant laboratory findings are shown in Table 1. Diabetes had been diagnosed 2 months earlier when she was investigated for polyuria and polydipsia. Random plasma glucose at the time of diagnosis was 584 mg/dl but there was no documented evidence of_diabetic ketoacidosis or indeed, even of ketonuria. The glycosylated haemoglobin (HbAI) was 10.6% (normal value for our laboratory, 5-8%). A provisional diagnosis of insulin-dependent diabetes mellitus (IDDM) was made and we treated her with twice daily insulin after which the blood sugar levels were stabilised. As she lived in an ad-
* Corresponding
author.
0168-8227/94/%07.00 0 1994 Elsevier Science Ireland SSDI 0168-8227(94)00964-V
Ltd. All rights reserved
138
G. Premalatha, V. MohanlDiabetes
jacent state in our country, she subsequently did not come for follow-up for over 4 years. In July 1990, when we saw her again and reviewed her diabetic history, we noticed that during the interim period she had stopped insulin injections often and on some occasions had gone without insulin for several months. However, despite high blood sugar levels, she had never developed diabetic ketoacidosis. She also gave a history of recurrent abdominal pain. This raised the possibility of FCPD and we did a plain X-ray of the abdomen to look for pancreatic calculi. The X-ray showed small discrete calculi in the head and tail region of the pancreas (Fig. 1). Ultrasonogram of the abdomen revealed a dilated pancreatic duct (0.5 ems) with multiple intraductal pancreatic calculi (Fig. 2). There was also increased echogenicity of the pancreas. A faecal chymotrypsin assay was done and it showed a value of 4.1 units/g confirming evidence of exocrine pancreatic insufficiency (normal value for our laboratory is > 13.0 units/g and a value < 5.8 units/g is indicative of exocrine pancreatic insufficiency) [2]. 3. Patient 2 Baby M.B., a 5-year-old female child was referred to our centre in December 1992. She complained of increased frequency of motions (diarrhoea) which were oily in nature (steatorrhoea). She also gave history of recurrent pain abdomen of 2 years
Res. Clin. Pratt. 25 (1994)
137-140
Fig. 2. Ultrasonogram of Patient 1. Arrows calculi within the dilated pancreatic duct.
duration, which was severe and radiated to the back. She was diagnosed elsewhere to have ‘malabsorption syndrome’ and juvenile diabetes was also diagnosed on routine testing. The dietary history revealed that there was no history of ingestion of cassava. On presentation to our centre she was found to have severe diabetes but there was no evidence of ketonuria. She was lean with a BMI of 11.9 kg/m’. The relevant clinical and laboratory findings are summarized in Table 1. In view of her presenting complaints of pain abdomen and steatorrhoea, an X-ray of the abdomen was done which showed evidence of small scattered calculi in the head region of the pancreas (Fig. 3). Ultrasound examination of the abdomen showed that the pancreatic duct was dilated and there were intraductal calculi (Fig. 4). The faecal chymotrypsin level was
Table I Clinical and laboratory
findings
Height (cm) Weight (kg) BMI (kg/m*) Insulin dose (units/kg) Serum cholesterol (mgdl) Serum triglycerides (mg/dl) Fig. 1. Pancreatic calculi in Patient 1.Arrows point to small discrete calculi in the head and tail region of pancreas.
point to pancreatic
Faecal chymotrypsin Islet cell antibodies
(units/g) (ICA)
in the two patients Baby P.A.
Baby M.B.
94 15.0 17.0 2 169 174 4.1 Negative
100 11.9 11.9 1.5 120 132 3.4 Not done
G. Premalatha, V. Mohan/Diabetes
Rex Clin. Pratt. 25’ (1994)
137-140
139
3.4 units/g, confirming evidence of exocrine pancreatic insufficiency. She was started on insulin therapy, to which she responded promptly. 4. Discussion
Fig. 3. Multiple
pancreatic
calculi
in Patient
2.
Fig. 4. Ultrasonogram of Patient 2 showing dilated pancreatic duct and increased echogenicity of the gland. Arrow points to intraductal calculi.
The natural history of FCPD has been succintly summarized by Geevarghese [l] as abdominal pain in childhood, pancreatic calculi in adolescence and diabetes in adulthood. Diabetes and steatorrhoea are late features of tropical calcific pancreatitis (TCP) and usually occur at least a decade after the first episode of abdominal pain. An analysis of the age at onset of the first 222 FCPD patients seen at our centre, showed that in 88.7% of patients it was between 16 and 45 years [3]. Onset below 15 years was seen only in 11 cases (4.9%) and in all of them the onset was above 10 years of age. The two cases presented here are most unusual because the age at onset was below 5 years and both were female. In patient 1, the diabetes was diagnosed at the age of 3 years and pancreatic calculi were spotted at the age of 7 years. Unfortunately, we did not suspect FCPD at her first visit because of the very young age and hence did not do an X-ray of the abdomen for her, assuming that she had IDDM. Indeed it is also possible that even had we looked for the calculi, they may not have been present at that time. Geevarghese [l] has shown that diabetes may precede the occurrence of pancreatic calculi in some cases. In patient 2, diabetes and calculi were diagnosed simultaneously at the age of 5 years. However, the patient had a history of chronic pain abdomen for at least 2 years prior to the diagnosis and she also gave a history of steatorrhoea, indicative of exocrine pancreatic insufficiency. In both the patients described in this report, the diagnosis is most unlikely to be IDDM because despite having insulin requiring diabetes, they were ketosis resistant. In one of patients (P.A.) we could estimate the islet cell antibodies (ICA) and this was found to be negative. Moreover, there was unequivocal clinical, radiological, and ultrasonographic evidence of chronic pancreatitis, as well as evidence from exocrine pancreatic function testing. This report raises some intriguing questions. How long does it take for pancreatic calculi to form? Since the calculi were diagnosed in these two patients at the
140
G. Premalatha,
V. Mohan / Diabetes Res. Clin. Pratt.
age of 7 years and 5 years, respectively, at what age did the process of calcification start?. It is well known that calcification takes several years to develop. Amman et al. [4] have shown that calcification occurs after a mean duration of lo-20 years after the first episode of abdominal pain. In both our patients the period before calcification could not have been more than 5 years and is possibly much less indicating that calcification and the endocrine and exocrine dysfunction have all occurred very rapidly in these patients. It also raises the exciting possibility that the pathogenesis of chronic pancreatitis and/or calculi formation in these patients may have been initiated in utero. To our knowledge there is only one anecdotal report of pancreatic calculi occurring below the age of 5 years. Geevarghese [l] in his monogram mentions a 4-year-old boy who presented with acute abdominal pain, and left sided pleural effusion. A button like sphincter of Oddi could be palpated at surgery and three calculi were removed from the pancreatic duct. However it is likely that Geevarghese’s patient is different from the two cases reported here because the presence of pleural effusion and the abnormality of the sphincter of Oddi suggest that the patient probably had acute pancreatitis which is rather unusual in FCPD. The rare entity known as hereditary pancreatitis which is an autosomal dominant condition characterised by three-generation transmission of the disease, presents in childhood [5]. However, in our cases there was no family history of abdominal pain, pancreatic calculi or diabetes. Moreover, diabetes occurs less frequently in hereditary pancreatitis than in other forms of chronic pancreatitis [5]. It is therefore most unlikely that these two patients had heriditary pancreatitis.
25 (1994) 137-140
Another rare entity encountered in childhood is idiopathic relapsing chronic pancreatitis [6]. However, in this entity, although pain abdomen may start in childhood, the calcification occurs much later and again this is associated with congenital anomalies of the pancreatic duct. This report of early onset FCPD emphasizes the need for doing routine abdominal X-rays and the elicitation of a history of abdominal pain in all childhood onset diabetics, particularly in tropical countries where FCPD is common. FCPD must be included in the differential diagnosis of all childhood onset diabetics in these countries. Acknowledgement We thank Dr S. Suresh of Mediscan Systems, Madras for the ultrasonography. References 111 Geevarghese, P.J. (1986) Calciflc pancreatitis. Varghese Publishing House. Bombay p. 2.
121 Mohan, V., Snehalatha, C., Ahmed, MR. et al. (1989) Exocrine pancreatic function in tropical tibrocalculous pancreatic diabetes. Diabetes Care 12, 145-147. (31 Mohan, V., Ramachandran, A. and Viswanathan, M. (1990) Childhood onset tlbrocalculous pancreatic diabetes. Int. J. Diabetes Dev. Countries 10, 24-26. [41 Ammann, R.N., Akovbianiz, A. and Iargiarder, F. (1984) Course and outcome of chronic pancreatitis-Longitudinal study of a mixed medical surgical series of 245 patients. Gastroenterology 86, 820-828. 151 Bell, D.A., Alba-Greco, M., Mitrick, J.S. et al. (1981) Chronic relapsing pancreatitis in childhood. J. Pediatr. Surg. 16, 741-742. Rattwinkel, J.W., Allen, L., Paul, A. et al. (1973) HerediEl tary pancreatitis: three new kindreds and a critical review of the literature. Paediatrics 51, 55-67.
Diabetes
Fibrocalculous
Research
and Clinical
Practice
25 (1994) 137-140
pancreatic diabetes in infancy -
two case reports
Gopal Premalatha, Viswanathan Mohan* hf. V. Diabetes Specialiries Cenlre (P) Ltd., 44, Royapettah High Road, Royapetrah, Madras Received
16 February
1994 revision
accepted
600 014, India
9 June 1994
Abstract Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes secondary to tropical calcific pancreatitis (TCP). The usual age of onset of FCPD is between 15 and 50 years. This paper reports on two unusual cases of FCPD with age of onset below 5 years. This is the first report of FCPD in infancy and raises intriguing questions about the rapidity with which calcification occurs in this entity. Keywords: Fibrocalculous Chronic pancreatitis
pancreatic diabetes; Childhood
onset; Tropical calcitic pancreatitis;
Pancreatic calculi;
1. Introduction
2. Patient 1
Fibrocalculous pancreatic diabetes (FCPD) is a unique form of diabetes prevalent in tropical countries [I]. FCPD is secondary to tropical calcific pancreatitis (TCP) which is a youth onset form of non-alcoholic chronic pancreatitis seen in tropical countries of the world. The classic features of this disease are: a history of recurrent abdominal pain from childhood, pancreatic calculi which are usually diagnosed in adolescence and diabetes which manifests by early adulthood [ 11.The usual age of onset of diabetes in FCPD is between 15 and SO years. Onset of FCPD below the age of 15 years is extremely uncommon and below 5 years, virtually unknown. We report here on two unusual cases of FCPD with onset in infancy.
Baby P.A., a 3-year-old female child first presented to us in January 1986. There was no history of childhood malnutrition and there was no history of cassava ingestion. On examination, we found that she was lean with a body mass index of 17 kg/m*. The relevant laboratory findings are shown in Table 1. Diabetes had been diagnosed 2 months earlier when she was investigated for polyuria and polydipsia. Random plasma glucose at the time of diagnosis was 584 mg/dl but there was no documented evidence of_diabetic ketoacidosis or indeed, even of ketonuria. The glycosylated haemoglobin (HbAI) was 10.6% (normal value for our laboratory, 5-8%). A provisional diagnosis of insulin-dependent diabetes mellitus (IDDM) was made and we treated her with twice daily insulin after which the blood sugar levels were stabilised. As she lived in an ad-
* Corresponding
author.
0168-8227/94/%07.00 0 1994 Elsevier Science Ireland SSDI 0168-8227(94)00964-V
Ltd. All rights reserved
138
G. Premalatha, V. MohanlDiabetes
jacent state in our country, she subsequently did not come for follow-up for over 4 years. In July 1990, when we saw her again and reviewed her diabetic history, we noticed that during the interim period she had stopped insulin injections often and on some occasions had gone without insulin for several months. However, despite high blood sugar levels, she had never developed diabetic ketoacidosis. She also gave a history of recurrent abdominal pain. This raised the possibility of FCPD and we did a plain X-ray of the abdomen to look for pancreatic calculi. The X-ray showed small discrete calculi in the head and tail region of the pancreas (Fig. 1). Ultrasonogram of the abdomen revealed a dilated pancreatic duct (0.5 ems) with multiple intraductal pancreatic calculi (Fig. 2). There was also increased echogenicity of the pancreas. A faecal chymotrypsin assay was done and it showed a value of 4.1 units/g confirming evidence of exocrine pancreatic insufficiency (normal value for our laboratory is > 13.0 units/g and a value < 5.8 units/g is indicative of exocrine pancreatic insufficiency) [2]. 3. Patient 2 Baby M.B., a 5-year-old female child was referred to our centre in December 1992. She complained of increased frequency of motions (diarrhoea) which were oily in nature (steatorrhoea). She also gave history of recurrent pain abdomen of 2 years
Res. Clin. Pratt. 25 (1994)
137-140
Fig. 2. Ultrasonogram of Patient 1. Arrows calculi within the dilated pancreatic duct.
duration, which was severe and radiated to the back. She was diagnosed elsewhere to have ‘malabsorption syndrome’ and juvenile diabetes was also diagnosed on routine testing. The dietary history revealed that there was no history of ingestion of cassava. On presentation to our centre she was found to have severe diabetes but there was no evidence of ketonuria. She was lean with a BMI of 11.9 kg/m’. The relevant clinical and laboratory findings are summarized in Table 1. In view of her presenting complaints of pain abdomen and steatorrhoea, an X-ray of the abdomen was done which showed evidence of small scattered calculi in the head region of the pancreas (Fig. 3). Ultrasound examination of the abdomen showed that the pancreatic duct was dilated and there were intraductal calculi (Fig. 4). The faecal chymotrypsin level was
Table I Clinical and laboratory
findings
Height (cm) Weight (kg) BMI (kg/m*) Insulin dose (units/kg) Serum cholesterol (mgdl) Serum triglycerides (mg/dl) Fig. 1. Pancreatic calculi in Patient 1.Arrows point to small discrete calculi in the head and tail region of pancreas.
point to pancreatic
Faecal chymotrypsin Islet cell antibodies
(units/g) (ICA)
in the two patients Baby P.A.
Baby M.B.
94 15.0 17.0 2 169 174 4.1 Negative
100 11.9 11.9 1.5 120 132 3.4 Not done
G. Premalatha, V. Mohan/Diabetes
Rex Clin. Pratt. 25’ (1994)
137-140
139
3.4 units/g, confirming evidence of exocrine pancreatic insufficiency. She was started on insulin therapy, to which she responded promptly. 4. Discussion
Fig. 3. Multiple
pancreatic
calculi
in Patient
2.
Fig. 4. Ultrasonogram of Patient 2 showing dilated pancreatic duct and increased echogenicity of the gland. Arrow points to intraductal calculi.
The natural history of FCPD has been succintly summarized by Geevarghese [l] as abdominal pain in childhood, pancreatic calculi in adolescence and diabetes in adulthood. Diabetes and steatorrhoea are late features of tropical calcific pancreatitis (TCP) and usually occur at least a decade after the first episode of abdominal pain. An analysis of the age at onset of the first 222 FCPD patients seen at our centre, showed that in 88.7% of patients it was between 16 and 45 years [3]. Onset below 15 years was seen only in 11 cases (4.9%) and in all of them the onset was above 10 years of age. The two cases presented here are most unusual because the age at onset was below 5 years and both were female. In patient 1, the diabetes was diagnosed at the age of 3 years and pancreatic calculi were spotted at the age of 7 years. Unfortunately, we did not suspect FCPD at her first visit because of the very young age and hence did not do an X-ray of the abdomen for her, assuming that she had IDDM. Indeed it is also possible that even had we looked for the calculi, they may not have been present at that time. Geevarghese [l] has shown that diabetes may precede the occurrence of pancreatic calculi in some cases. In patient 2, diabetes and calculi were diagnosed simultaneously at the age of 5 years. However, the patient had a history of chronic pain abdomen for at least 2 years prior to the diagnosis and she also gave a history of steatorrhoea, indicative of exocrine pancreatic insufficiency. In both the patients described in this report, the diagnosis is most unlikely to be IDDM because despite having insulin requiring diabetes, they were ketosis resistant. In one of patients (P.A.) we could estimate the islet cell antibodies (ICA) and this was found to be negative. Moreover, there was unequivocal clinical, radiological, and ultrasonographic evidence of chronic pancreatitis, as well as evidence from exocrine pancreatic function testing. This report raises some intriguing questions. How long does it take for pancreatic calculi to form? Since the calculi were diagnosed in these two patients at the
140
G. Premalatha,
V. Mohan / Diabetes Res. Clin. Pratt.
age of 7 years and 5 years, respectively, at what age did the process of calcification start?. It is well known that calcification takes several years to develop. Amman et al. [4] have shown that calcification occurs after a mean duration of lo-20 years after the first episode of abdominal pain. In both our patients the period before calcification could not have been more than 5 years and is possibly much less indicating that calcification and the endocrine and exocrine dysfunction have all occurred very rapidly in these patients. It also raises the exciting possibility that the pathogenesis of chronic pancreatitis and/or calculi formation in these patients may have been initiated in utero. To our knowledge there is only one anecdotal report of pancreatic calculi occurring below the age of 5 years. Geevarghese [l] in his monogram mentions a 4-year-old boy who presented with acute abdominal pain, and left sided pleural effusion. A button like sphincter of Oddi could be palpated at surgery and three calculi were removed from the pancreatic duct. However it is likely that Geevarghese’s patient is different from the two cases reported here because the presence of pleural effusion and the abnormality of the sphincter of Oddi suggest that the patient probably had acute pancreatitis which is rather unusual in FCPD. The rare entity known as hereditary pancreatitis which is an autosomal dominant condition characterised by three-generation transmission of the disease, presents in childhood [5]. However, in our cases there was no family history of abdominal pain, pancreatic calculi or diabetes. Moreover, diabetes occurs less frequently in hereditary pancreatitis than in other forms of chronic pancreatitis [5]. It is therefore most unlikely that these two patients had heriditary pancreatitis.
25 (1994) 137-140
Another rare entity encountered in childhood is idiopathic relapsing chronic pancreatitis [6]. However, in this entity, although pain abdomen may start in childhood, the calcification occurs much later and again this is associated with congenital anomalies of the pancreatic duct. This report of early onset FCPD emphasizes the need for doing routine abdominal X-rays and the elicitation of a history of abdominal pain in all childhood onset diabetics, particularly in tropical countries where FCPD is common. FCPD must be included in the differential diagnosis of all childhood onset diabetics in these countries. Acknowledgement We thank Dr S. Suresh of Mediscan Systems, Madras for the ultrasonography. References 111 Geevarghese, P.J. (1986) Calciflc pancreatitis. Varghese Publishing House. Bombay p. 2.
121 Mohan, V., Snehalatha, C., Ahmed, MR. et al. (1989) Exocrine pancreatic function in tropical tibrocalculous pancreatic diabetes. Diabetes Care 12, 145-147. (31 Mohan, V., Ramachandran, A. and Viswanathan, M. (1990) Childhood onset tlbrocalculous pancreatic diabetes. Int. J. Diabetes Dev. Countries 10, 24-26. [41 Ammann, R.N., Akovbianiz, A. and Iargiarder, F. (1984) Course and outcome of chronic pancreatitis-Longitudinal study of a mixed medical surgical series of 245 patients. Gastroenterology 86, 820-828. 151 Bell, D.A., Alba-Greco, M., Mitrick, J.S. et al. (1981) Chronic relapsing pancreatitis in childhood. J. Pediatr. Surg. 16, 741-742. Rattwinkel, J.W., Allen, L., Paul, A. et al. (1973) HerediEl tary pancreatitis: three new kindreds and a critical review of the literature. Paediatrics 51, 55-67.