Implication of gastroparesis in diabetes mellitus Research Paper
Clinical Autonomic Research 2, 221-224 (1992)
THE prognosis and survival in 13 patients with Type II diabetes mellitus who had delayed gastric emptying as shown by radionuclide tests performed between August 1985 and August 1987 was determined in July 1990. The two patients that were over 80 years of age died within 18 months of the diagnosis of diabetic gastroparesis, but ten of the remaining eleven patients survived. The clinical data on these patients suggest that despite the usual presence of significant co-existent pathology, gastroparesis diabeticorum carries a less ominous prognosis than currently believed.
Prognostic implication of gastroparesis in patients with diabetes mellitus Tapan K. Chaudhuri, M D cA and Sidney Fink, MD Nuclear Medicine and Ambulatory Care Services, VA Medical Center, Hampton, VA 23667, USA.
Key words: Diabetic autonomic neuropathy, Gastric emptying, Gastroparesis
CACorresponding Author
Introduction
time in minutes when 50% of the radioactive test meal has left the stomach. Although the test meal we used is in a liquid state prior to ingestion, it becomes semisolid curd-like in consistency immediately after ingestion due to the presence of acid gastric juice. We therefore describe it as a semisolid test meal, rather than a liquid test meal such as water or normal saline, or a solid test meal such as chicken liver or eggs. Ninety-eight per cent of the radioactivity remained in the semisolid component of our meal. The normal gastric emptying half time (GET1/2) with the semi-solid meal used in our laboratory is 25-69 rain (42 + 13 min, mean _ SD). The records of the nuclear medicine service listed 13 diabetic patients who had delayed gastric emptying as measured by radionuclide testing during the period under study. Eleven had been referred based upon clinical suspicion of gastroparesis including post-prandial fullness and vomiting. Two (Nos 8 and 10) had aroused clinical suspicion without exhibiting vomiting or significant nausea after meals. Chart review noted the age when delayed gastric emptying was documented, the number of months from the testing date to the date of chart review or death, and whether the patient was treated with metoclopramide during the interval. We used recently designated criteria 1 to document the presence of hypertension, macrovascular disease, retinopathy, and nephropathy. By these criteria, subjects were considered to be hypertensive if they were taking blood pressure medication and/or had a blood pressure of more than 140/90 mmHg. Macrovascular disease was defined as the presence of peripheral vascular disease, coronary artery disease, and/or cerebrovascular disease. Peripheral vascular disease was considered present if there were signs and/or symptoms of ischaemia which may have needed surgery. Coronary artery
It is considered that diabetic autonomic neuropathy carries a poor prognosis, 1 particularly when gastroparesis is present. 2'3 Related to this, proposed criteria for pancreatic transplantation in patients without end-stage diabetic nephropathy have included an abnormal radionuclide gastricemptying study and symptoms consistent with gastroparesis. 4,s Although the limited data available suggest that transplantation can reverse gastroparesis, 6 the need for more data about the current prognostic significance of diabetic autonomic neuropathy, including gastroparesis, in developing appropriate transplantation criteria has been emphasized] We therefore reviewed the clinical course of all diabetics who had delayed gastric emptying as demonstrated by radionuclide testing during the period 1985-87 to determine whether there was a high death rate.
Materials and Methods During July of 1990 we determined the status of diabetic patients who had delayed gastric emptying as shown by radionuclide tests during the period August 1985 to August 1987. The gastric emptying time was determined using a test meal consisting of a mixture of a 35 gm packet of Carnation Instant Breakfast and a half-pint (236 ml) carton of whole milk made up to 600 ml with water.* Each subject received 4 ml/kg of body weight of this meal thoroughly mixed with 100-300 uCi of Tc-99m-sulphur colloid. Sequential images of the stomach were then recorded every 15 min for 90-120min using a gamma camera interfaced with a computer. At the end of the study, a region of interest was drawn on the stomach area and a time activity curve was generated. Gastric emptying half time (GET1/2) was defined as the © Rapid Communications of Oxford Ltd.
Clinical Autonomic Research. vol 2.1992
221
T. K. Chaudhuri and S. Fink
disease included physician-diagnosed angina pectoris or a history of myocardial infarction. Myocardial infarction was confirmed by electrocardiographic changes (i.e. pathological Q waves) or if review of previous hospital records met the criteria for definite myocardial infarction of the Community Cardiovascular Surveillance Project Study. 9 Cerebrovascular disease was based on a history of stroke. Retinopathy was listed if defined by ophthalmological examination within 6 months of the GET1/2 determination or if laser treatment was used. Overt nephropathy was defined as an albumin excretion rate of more than 200 #g/min in at least two or three urine collections (24-h overnight), or if end-stage renal disease was present (renal dialysis or transplant). A serum creatinine of more than 178.8 #mol/1 (2mg%) was also considered to be indicative of nephropathy. We also noted the presence of peripheral neuropathy and cystoparesis. Peripheral neuropathy was considered present if the diagnosis was made clinically by a neurologist, and/or peroneal motor nerve conduction velocity, whenperformed within three months of the GET1/2 determination was less than 42 m/s. Cystoparesis was based upon urological investigation (including cystometry), and/or radionuclide studies. 1°'11 The radionuclide test for detecting cystoparesis involved measuring residual urine volume (RUV) following i.v. injection of 2-4 mCi of Tc-99m-DTPA. A RUV greater than 150 ml with a normal sized prostate on rectal examination was considered clinically significant for diabetic autonomic neuropathy involving the urinary bladder (cystoparesis). Six patients (Nos 5, 6, 8, 9, 10 and 11) had been tested for cholecystoparesis using radionuclide demonstration of the response to exogenous cholecystokinin. 12'13 The radionuclide test for diagnosing diabetic autonomic neuropathy of the gall bladder (chole-
cystoparesis) involves measuring the gall bladder response (ejection fraction) to i.v. injection of 0.02 #g/kg body weight of cholecystokinin (Kinevac; Squibb Princeton, N J) using 5mCi of Tc-99m-DISIDA (diisopropyl iminodiacetic acid) as a bile marker. The normal gall bladder ejection fraction by this method is 60 -t- 6%. The majority of records listed the cigarette smoking history as 'yes' or ' n o ' without providing data as to length of abstinence, and this was listed as ' + ' or ' - ' . Alcohol consumption was considered negative if the record indicated abstinence at the time of GET1/2 testing and during the period under observation. The patients' heart rate responses to the Valsalva manoeuvre, the blood pressure response to sustained handgrip, and the postural effect upon blood pressure were not measured. Although the usual cardiovascular tests of autonomic functions were not performed, the findings of delayed gastric emptying, diminished gallbladder response to exogenous cholecystokinin administration, and large residual urine volume in the absence of obstruction all suggest autonomic neuropathy affecting the stomach, gall bladder, and urinary bladder respectively.
Results Table 1 shows the age distribution, GET1/2 values, therapy, observation periods, and prognosis of 13 patients. The patients were 40-94 years of age. Three patients (Nos 7, 12 and 13) died at 7, 12, and 17 months after radionuclide gastric emptying time examination. This included the two oldest patients, 80 and 94 years of age. One patient (No. 1) was lost to follow-up after 18 months. The survivors remained under out-patient medical care for 44-52 months. Figure 1 shows the graphical representa-
Table 1. Gastric emptying T1/2, length of observation period, and prognosis in 13 patients with diabetes mellitus Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13
Age
G ET1/2
Rxa
40 45 5O 51 58 59 64 66 66 69 72 80 94
85 98 81 120 90 9O 140 111 86 82 82 111 100
+
18--then lost to follow- up
+ + + + + + + -
46 48 52 44 46 7 48 46 52 44 12 17
a Rx = m e t o c l o p r a m i d e . b X = died.
222
Clinical Autonomic Research'vol 2 ' 1 9 9 2
Months observed
Prognosisb
X Pneumonia
X Urinary infection and septicaemia X Aspiration pneumonia
Implication of gastroparesis in diabetes mellitus -~ 100 -
~
b2
:_~ c~
~._~
:::::::::::::::::::::::::::::::
,o{CE 50
0
~::ii{i¢i!ii~{i{{ i -~i:)i)i:):):}~i)ii
20
40
60
80 Time
100
120
140
I T1/2
160
(min)
FIG. 1. Graphical representation of delayed GET1/2 in 13 patients with diabetes mellitus and gastroparesis. The shaded area shows the normal range of GET1/2 for the test meal used in our laboratory.
tion of delayed GET1/2 in 13 patients with diabetic gastroparesis compared to the normal values. Figure 2 shows the scattergram of GET1/2 and patient survival at different observed periods. Our findings for the monitored variables are listed in Table 2. Peripheral neuropathy was diagnosed in eleven patients; no evidence of peripheral neuropathy was found in cases No. 2 and No. 3. Cholecystoparesis was demonstrated ( < 50% gall bladder ejection fraction) in the six patients tested (Nos 5, 6, 8, 9, 10 and 11). The highest value (32% ejection fraction) was in patient No. 10, the other values were 15% or less including three patients (Nos 8, 9 and 11) who had no response (0% ejection fraction). Eight patients (Table 1) had the pro-kinetic agent metoclopramide included in their maintenance therapy. Patient No. 1 (Table 2) had chronic renal failure, and was in a dialysis programme when lost to follow-up. With the exception of peripheral neuropathy, the most common co-incident factor 140
•
120 ZX
A
100
A
E I-
LU 't-o
AA A A ,,,
& 80
z~
TM
60-
40"
20
• - died z~- ellvs
0
i
10
i
20
310
410
510
610
Observed Period (months)
FIG. 2, Scattergram of GET1/2 and patient survival against the number of months observed for the 13 patients with diabetes mellitus. The shaded area represents the normal range of GET1/2 in our laboratory.
was cystoparesis (seven patients). Patient No. 6 had the highest RUV (1019 ml), five patients (Nos 1, 9, 10, 11 and 12) had RUV between 200-300 ml, and one patient (No. 13) had an RUV of 180 ml. Three patients (Nos 4, 5 and 8) had clinically insignificant RUV (33 ml, 4 ml and 16 ml respectively). Eleven of the patients had never smoked or had given up smoking, and ten of the patients abstained from alcohol. Eight of the 13 patients were negative for both factors.
Discussion With one exception, those of our patients who were under 80 years of age were alive and ambulatory at the end of the observation period which was approximately 4 years for most of the patients. This was contrary to the pessimistic prognosis predicted by the literature. Diabetic gastropathy is considered to be a sign of advanced diabetic autonomic neuropathy and has been singled out as signifying a poor prognosis by several observers. 3'2 The former study 3 reported that twelve of 35 patients (aged 26-73 years), died within 3 years of a diagnosis of diabetic gastropathy. These twelve individuals had chronic renal disease (four cases), acute myocardial infarction (three cases) and cerebrovascular accident (one case); in the others (4 cases) the cause was unknown. Five expired after less than 1 year. The second study 2 found that over half the patients with diabetic gastroparesis died within 5 years, as compared to 21% of those with normal autonomic function. It has been suggested TM that there is a sequence of autonomic abnormalities in which thermoregulatory function and sweating are impaired first in the feet, followed by impotence and urinary bladder problems, cardiovascular reflex abnormalities, and finally the late severe symptomatic manifestations of upper body sweating disturbance, hypoglycaemic unawareness, postural hypotension and gastroparesis. Supporting this concept, multiple observations have shown signs of peripheral Clinical A u t o n o m i c Research. vol 2 . 1 9 9 2
223
T. K. Chaudhuri and S. Fink Table 2. Clinical data of 13 diabetics w i t h p r o l o n g e d gastric e m p t y i n g T 1 / 2 Patient No. 1 2 3 4 5 6 7
HTN
PVD
CAD
CVA
RET
BUN/Cr
PN
N.B.
Alcohol
Tobacco
GBEF
+ . + + +
+ -
+ + . -
-
+ +
+
-
+ -+ + + +
+ + +
+
-
40/8.2 10/1.3 11/0.9 12/1.0 10/0.9 28/1.3 31/1.6
-
-+ -
N.P. N.P. N.P. N.P. 12% 1 5% N.P.
.
. -. + +
.
. .
.
+ +
8
+
+
-
-
-
21/1.3
+
-
-
+
0%
9 10 11 12 13
-+ .
+ + + -
+ .
-+ -
+ -
14/1.2 16/1.2 22/1.1 23/1.8 19/0.9
+ + + + +
+ + + + +
+ + -
-
0% 32% 0% N.P. N.P.
.
.
.
RUV 2 0 0 ml N.P. N.P. 33 ml 4 ml 101 9 ml N.P.* 16 ml
303 228 205 200 180
ml ml ml ml* ml*
HTN: Hypertension. PVD: Peripheral vascular disease. C A D : Coronary artery disease. C V A : Cerebrovascular accident. RET: Retinopathy. B U N / C r : Blood urea nitrogen/creatinine. PN: Peripheral neuropathy. N.B,: neurogenic bladder. GBEF: Gall Bladder Ejection Fraction. RUV = Residual Urine Volume. N.P: N o t performed. * Died.
nerve impairment preceeding those of gastroparesis, 3J5 and in our series eleven of the 13 patients had a peripheral neuropathy. The application of radionuclide techniques has facilitated the diagnosis of diabetic gastroparesis) 6 This is fortunate since accurate study of diabetic gastroparesis requires objective studies despite the fact that it is often suggested by early satiety, postprandial nausea, and vomiting of undigested food) 7 A study of 114 diabetic subjects with these symptoms found that they were often associated with psychiatric illness rather than diabetic autonomic neuropathy. 18 Objective testing may also detect asymptomatic gastroparesis. This term has been used to describe delayed gastric emptying accompanied by minimal symptoms which do not include significant vomiting, and two of our patients fit this description. Asymptomatic gastroparesis has been demonstrated with a barium meal 19 and radionuclide studies 2° and has been advanced as an explanation for otherwise unexplained fluctuations in glucose control in patients who have positive radionuclide gastric emptying studies) 7 The life-style of our patients, a majority of whom were not smoking cigarettes or drinking alcohol, undoubtedly contributed to their survival rate. A majority of our patients were taking metoclopramide, 21 and it is possible that this played a role in the improved prognosis. None of the patients had repeat GET1/2 evaluations during treatment, so that no firm conclusion can be made. The data suggest that studies of the prognosis of diabetic patients should take note of pro-kinetic agent used as well as the presence of gastroparesis. There is a need to accurately select patients for surgical treatment and to evaluate the long-term contribution of both surgical and medical treatment in the care of patients with varying forms of diabetic autonomic neuropathy. 224
Clinical A u t o n o m i c Research-vol 2 . 1 9 9 2
References 1. Maser RE, Pfeifer MA, Dorman JS, Kuller LH, Becker DJ, Orchard TJ. Diabetic autonomic neuropathy and cardiovascular risk. Arch Intern Med 1990; 150:1218-1222. 2. Ewing D J, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-~108. 3. Zitomer BR, Gramm HF, Kozak GP. Gastric neuropathy in diabetes mellitus: clinical and radiologic observations. Metabolism 1968; 17: 199-211. 4. The University of Michigan Pancreas Transplant Evaluation Committee. Pancreatic transplantation as treatment for IDDM: proposed candidate criteria before end-stage diabetic nephropathy. Diabetes Care 1988; 11: 669-675. 5. Dafoe DC, Vinik AI. Is pancreas transplantation for insulin-dependent diabetes mellitus worthwhile? (Letter to Ed.) NEJM 1990; 3 2 2 : 1608-1069. 6. Murat A, Pouliquen B, Bizais Y, Vecchierini M F, Lucas B, Cantarovich D, Paineau J, Galmiche JP, Reversibility of diabetic gastroparesis after renal and pancreatic transplantation. Gastroenterology 1990; 9 8 : A 9 3 (abstract). 7. Tattersall R. Is pancreas transplantation for insulin-dependent diabetes mellitus worthwhile? (Reply to letter to Ed.) NEJM 1990; 3 2 2 : 1608-1609. 8. Goetsch RA, Fink S, Chaudhuri TK. Effect of nifedipine on gastric emptying. Military Medicine 1986; 161 : 4 3 8 4 3 9 . 9. Orchard TJ on behalf of the Community Cardiovascular Surveillance Project investigators. Validation of corononary heart disease mortality data: the Community Cardiovascular Surveillance Project Pilot Experience. CVD Epid Newslett 1985; 157: 46. 10. Chaudhuri TK, Palmer JDK, Burger RH, Fink S. Urinary retention in diabetic patients. Ann Intern Med 1988; 108: 642. 11. Chaudhuri TK, Fink S, Burger RH, Netto ICV, Palmer JDK. Physiological considerations in radionuclide urodynamic studies. Am J Physiol Imaging 1989; 4: 70-74. 12. Chaudhuri TK, Fink S. Physiologic considerations in radionuclide imaging of the extrahepatic biliary tract. Am J Physiol Imaging 1988; 3: 114-120, 13. Chaudhuri TK, Fink S. Clues to gallbladder dysfunction in patients with diabetic neuropathy. Am J Gastroent 1988; 83: 587-588. 14. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab 1986; 15: 855-888. 15. Chaudhuri TK, Palmer JDK, Fink S. Asymptomatic gastric retention and diabetic neuropathy. Dig Dis Sci 1988; 33: 1048. 16. Chaudhuri TK, Fink S. Clinical review: gastric emptying in human disease states. Am J Gastroenterol 1991 ; 86: 533-538. 17. Bays HE, Pfeifer MA, Peripheral diabetic neuropathy. Med Clin No Am 1988; 6: 1439-1464. 18. Clouse RE, Lustman PJ. Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol 1989; 84: 868-872. 19, Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum), Ann Intern Med 1958; 48:797-812. 20, Palmer JDK, Chaudhuri TK, Fink S. Gastric emptying in diabetics without gastrointestinal symptoms. Am J Gastr 1986; 81 : 858. 21. Chaudhuri TK, Fink S. Update: pharmaceuticals and gastric emptying. Am J Gastroentero11990; 85:223-230.
Received 28 February 1992; accepted with revision 14 May 1992.
Clinical Autonomic Research 2, 221-224 (1992)
THE prognosis and survival in 13 patients with Type II diabetes mellitus who had delayed gastric emptying as shown by radionuclide tests performed between August 1985 and August 1987 was determined in July 1990. The two patients that were over 80 years of age died within 18 months of the diagnosis of diabetic gastroparesis, but ten of the remaining eleven patients survived. The clinical data on these patients suggest that despite the usual presence of significant co-existent pathology, gastroparesis diabeticorum carries a less ominous prognosis than currently believed.
Prognostic implication of gastroparesis in patients with diabetes mellitus Tapan K. Chaudhuri, M D cA and Sidney Fink, MD Nuclear Medicine and Ambulatory Care Services, VA Medical Center, Hampton, VA 23667, USA.
Key words: Diabetic autonomic neuropathy, Gastric emptying, Gastroparesis
CACorresponding Author
Introduction
time in minutes when 50% of the radioactive test meal has left the stomach. Although the test meal we used is in a liquid state prior to ingestion, it becomes semisolid curd-like in consistency immediately after ingestion due to the presence of acid gastric juice. We therefore describe it as a semisolid test meal, rather than a liquid test meal such as water or normal saline, or a solid test meal such as chicken liver or eggs. Ninety-eight per cent of the radioactivity remained in the semisolid component of our meal. The normal gastric emptying half time (GET1/2) with the semi-solid meal used in our laboratory is 25-69 rain (42 + 13 min, mean _ SD). The records of the nuclear medicine service listed 13 diabetic patients who had delayed gastric emptying as measured by radionuclide testing during the period under study. Eleven had been referred based upon clinical suspicion of gastroparesis including post-prandial fullness and vomiting. Two (Nos 8 and 10) had aroused clinical suspicion without exhibiting vomiting or significant nausea after meals. Chart review noted the age when delayed gastric emptying was documented, the number of months from the testing date to the date of chart review or death, and whether the patient was treated with metoclopramide during the interval. We used recently designated criteria 1 to document the presence of hypertension, macrovascular disease, retinopathy, and nephropathy. By these criteria, subjects were considered to be hypertensive if they were taking blood pressure medication and/or had a blood pressure of more than 140/90 mmHg. Macrovascular disease was defined as the presence of peripheral vascular disease, coronary artery disease, and/or cerebrovascular disease. Peripheral vascular disease was considered present if there were signs and/or symptoms of ischaemia which may have needed surgery. Coronary artery
It is considered that diabetic autonomic neuropathy carries a poor prognosis, 1 particularly when gastroparesis is present. 2'3 Related to this, proposed criteria for pancreatic transplantation in patients without end-stage diabetic nephropathy have included an abnormal radionuclide gastricemptying study and symptoms consistent with gastroparesis. 4,s Although the limited data available suggest that transplantation can reverse gastroparesis, 6 the need for more data about the current prognostic significance of diabetic autonomic neuropathy, including gastroparesis, in developing appropriate transplantation criteria has been emphasized] We therefore reviewed the clinical course of all diabetics who had delayed gastric emptying as demonstrated by radionuclide testing during the period 1985-87 to determine whether there was a high death rate.
Materials and Methods During July of 1990 we determined the status of diabetic patients who had delayed gastric emptying as shown by radionuclide tests during the period August 1985 to August 1987. The gastric emptying time was determined using a test meal consisting of a mixture of a 35 gm packet of Carnation Instant Breakfast and a half-pint (236 ml) carton of whole milk made up to 600 ml with water.* Each subject received 4 ml/kg of body weight of this meal thoroughly mixed with 100-300 uCi of Tc-99m-sulphur colloid. Sequential images of the stomach were then recorded every 15 min for 90-120min using a gamma camera interfaced with a computer. At the end of the study, a region of interest was drawn on the stomach area and a time activity curve was generated. Gastric emptying half time (GET1/2) was defined as the © Rapid Communications of Oxford Ltd.
Clinical Autonomic Research. vol 2.1992
221
T. K. Chaudhuri and S. Fink
disease included physician-diagnosed angina pectoris or a history of myocardial infarction. Myocardial infarction was confirmed by electrocardiographic changes (i.e. pathological Q waves) or if review of previous hospital records met the criteria for definite myocardial infarction of the Community Cardiovascular Surveillance Project Study. 9 Cerebrovascular disease was based on a history of stroke. Retinopathy was listed if defined by ophthalmological examination within 6 months of the GET1/2 determination or if laser treatment was used. Overt nephropathy was defined as an albumin excretion rate of more than 200 #g/min in at least two or three urine collections (24-h overnight), or if end-stage renal disease was present (renal dialysis or transplant). A serum creatinine of more than 178.8 #mol/1 (2mg%) was also considered to be indicative of nephropathy. We also noted the presence of peripheral neuropathy and cystoparesis. Peripheral neuropathy was considered present if the diagnosis was made clinically by a neurologist, and/or peroneal motor nerve conduction velocity, whenperformed within three months of the GET1/2 determination was less than 42 m/s. Cystoparesis was based upon urological investigation (including cystometry), and/or radionuclide studies. 1°'11 The radionuclide test for detecting cystoparesis involved measuring residual urine volume (RUV) following i.v. injection of 2-4 mCi of Tc-99m-DTPA. A RUV greater than 150 ml with a normal sized prostate on rectal examination was considered clinically significant for diabetic autonomic neuropathy involving the urinary bladder (cystoparesis). Six patients (Nos 5, 6, 8, 9, 10 and 11) had been tested for cholecystoparesis using radionuclide demonstration of the response to exogenous cholecystokinin. 12'13 The radionuclide test for diagnosing diabetic autonomic neuropathy of the gall bladder (chole-
cystoparesis) involves measuring the gall bladder response (ejection fraction) to i.v. injection of 0.02 #g/kg body weight of cholecystokinin (Kinevac; Squibb Princeton, N J) using 5mCi of Tc-99m-DISIDA (diisopropyl iminodiacetic acid) as a bile marker. The normal gall bladder ejection fraction by this method is 60 -t- 6%. The majority of records listed the cigarette smoking history as 'yes' or ' n o ' without providing data as to length of abstinence, and this was listed as ' + ' or ' - ' . Alcohol consumption was considered negative if the record indicated abstinence at the time of GET1/2 testing and during the period under observation. The patients' heart rate responses to the Valsalva manoeuvre, the blood pressure response to sustained handgrip, and the postural effect upon blood pressure were not measured. Although the usual cardiovascular tests of autonomic functions were not performed, the findings of delayed gastric emptying, diminished gallbladder response to exogenous cholecystokinin administration, and large residual urine volume in the absence of obstruction all suggest autonomic neuropathy affecting the stomach, gall bladder, and urinary bladder respectively.
Results Table 1 shows the age distribution, GET1/2 values, therapy, observation periods, and prognosis of 13 patients. The patients were 40-94 years of age. Three patients (Nos 7, 12 and 13) died at 7, 12, and 17 months after radionuclide gastric emptying time examination. This included the two oldest patients, 80 and 94 years of age. One patient (No. 1) was lost to follow-up after 18 months. The survivors remained under out-patient medical care for 44-52 months. Figure 1 shows the graphical representa-
Table 1. Gastric emptying T1/2, length of observation period, and prognosis in 13 patients with diabetes mellitus Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13
Age
G ET1/2
Rxa
40 45 5O 51 58 59 64 66 66 69 72 80 94
85 98 81 120 90 9O 140 111 86 82 82 111 100
+
18--then lost to follow- up
+ + + + + + + -
46 48 52 44 46 7 48 46 52 44 12 17
a Rx = m e t o c l o p r a m i d e . b X = died.
222
Clinical Autonomic Research'vol 2 ' 1 9 9 2
Months observed
Prognosisb
X Pneumonia
X Urinary infection and septicaemia X Aspiration pneumonia
Implication of gastroparesis in diabetes mellitus -~ 100 -
~
b2
:_~ c~
~._~
:::::::::::::::::::::::::::::::
,o{CE 50
0
~::ii{i¢i!ii~{i{{ i -~i:)i)i:):):}~i)ii
20
40
60
80 Time
100
120
140
I T1/2
160
(min)
FIG. 1. Graphical representation of delayed GET1/2 in 13 patients with diabetes mellitus and gastroparesis. The shaded area shows the normal range of GET1/2 for the test meal used in our laboratory.
tion of delayed GET1/2 in 13 patients with diabetic gastroparesis compared to the normal values. Figure 2 shows the scattergram of GET1/2 and patient survival at different observed periods. Our findings for the monitored variables are listed in Table 2. Peripheral neuropathy was diagnosed in eleven patients; no evidence of peripheral neuropathy was found in cases No. 2 and No. 3. Cholecystoparesis was demonstrated ( < 50% gall bladder ejection fraction) in the six patients tested (Nos 5, 6, 8, 9, 10 and 11). The highest value (32% ejection fraction) was in patient No. 10, the other values were 15% or less including three patients (Nos 8, 9 and 11) who had no response (0% ejection fraction). Eight patients (Table 1) had the pro-kinetic agent metoclopramide included in their maintenance therapy. Patient No. 1 (Table 2) had chronic renal failure, and was in a dialysis programme when lost to follow-up. With the exception of peripheral neuropathy, the most common co-incident factor 140
•
120 ZX
A
100
A
E I-
LU 't-o
AA A A ,,,
& 80
z~
TM
60-
40"
20
• - died z~- ellvs
0
i
10
i
20
310
410
510
610
Observed Period (months)
FIG. 2, Scattergram of GET1/2 and patient survival against the number of months observed for the 13 patients with diabetes mellitus. The shaded area represents the normal range of GET1/2 in our laboratory.
was cystoparesis (seven patients). Patient No. 6 had the highest RUV (1019 ml), five patients (Nos 1, 9, 10, 11 and 12) had RUV between 200-300 ml, and one patient (No. 13) had an RUV of 180 ml. Three patients (Nos 4, 5 and 8) had clinically insignificant RUV (33 ml, 4 ml and 16 ml respectively). Eleven of the patients had never smoked or had given up smoking, and ten of the patients abstained from alcohol. Eight of the 13 patients were negative for both factors.
Discussion With one exception, those of our patients who were under 80 years of age were alive and ambulatory at the end of the observation period which was approximately 4 years for most of the patients. This was contrary to the pessimistic prognosis predicted by the literature. Diabetic gastropathy is considered to be a sign of advanced diabetic autonomic neuropathy and has been singled out as signifying a poor prognosis by several observers. 3'2 The former study 3 reported that twelve of 35 patients (aged 26-73 years), died within 3 years of a diagnosis of diabetic gastropathy. These twelve individuals had chronic renal disease (four cases), acute myocardial infarction (three cases) and cerebrovascular accident (one case); in the others (4 cases) the cause was unknown. Five expired after less than 1 year. The second study 2 found that over half the patients with diabetic gastroparesis died within 5 years, as compared to 21% of those with normal autonomic function. It has been suggested TM that there is a sequence of autonomic abnormalities in which thermoregulatory function and sweating are impaired first in the feet, followed by impotence and urinary bladder problems, cardiovascular reflex abnormalities, and finally the late severe symptomatic manifestations of upper body sweating disturbance, hypoglycaemic unawareness, postural hypotension and gastroparesis. Supporting this concept, multiple observations have shown signs of peripheral Clinical A u t o n o m i c Research. vol 2 . 1 9 9 2
223
T. K. Chaudhuri and S. Fink Table 2. Clinical data of 13 diabetics w i t h p r o l o n g e d gastric e m p t y i n g T 1 / 2 Patient No. 1 2 3 4 5 6 7
HTN
PVD
CAD
CVA
RET
BUN/Cr
PN
N.B.
Alcohol
Tobacco
GBEF
+ . + + +
+ -
+ + . -
-
+ +
+
-
+ -+ + + +
+ + +
+
-
40/8.2 10/1.3 11/0.9 12/1.0 10/0.9 28/1.3 31/1.6
-
-+ -
N.P. N.P. N.P. N.P. 12% 1 5% N.P.
.
. -. + +
.
. .
.
+ +
8
+
+
-
-
-
21/1.3
+
-
-
+
0%
9 10 11 12 13
-+ .
+ + + -
+ .
-+ -
+ -
14/1.2 16/1.2 22/1.1 23/1.8 19/0.9
+ + + + +
+ + + + +
+ + -
-
0% 32% 0% N.P. N.P.
.
.
.
RUV 2 0 0 ml N.P. N.P. 33 ml 4 ml 101 9 ml N.P.* 16 ml
303 228 205 200 180
ml ml ml ml* ml*
HTN: Hypertension. PVD: Peripheral vascular disease. C A D : Coronary artery disease. C V A : Cerebrovascular accident. RET: Retinopathy. B U N / C r : Blood urea nitrogen/creatinine. PN: Peripheral neuropathy. N.B,: neurogenic bladder. GBEF: Gall Bladder Ejection Fraction. RUV = Residual Urine Volume. N.P: N o t performed. * Died.
nerve impairment preceeding those of gastroparesis, 3J5 and in our series eleven of the 13 patients had a peripheral neuropathy. The application of radionuclide techniques has facilitated the diagnosis of diabetic gastroparesis) 6 This is fortunate since accurate study of diabetic gastroparesis requires objective studies despite the fact that it is often suggested by early satiety, postprandial nausea, and vomiting of undigested food) 7 A study of 114 diabetic subjects with these symptoms found that they were often associated with psychiatric illness rather than diabetic autonomic neuropathy. 18 Objective testing may also detect asymptomatic gastroparesis. This term has been used to describe delayed gastric emptying accompanied by minimal symptoms which do not include significant vomiting, and two of our patients fit this description. Asymptomatic gastroparesis has been demonstrated with a barium meal 19 and radionuclide studies 2° and has been advanced as an explanation for otherwise unexplained fluctuations in glucose control in patients who have positive radionuclide gastric emptying studies) 7 The life-style of our patients, a majority of whom were not smoking cigarettes or drinking alcohol, undoubtedly contributed to their survival rate. A majority of our patients were taking metoclopramide, 21 and it is possible that this played a role in the improved prognosis. None of the patients had repeat GET1/2 evaluations during treatment, so that no firm conclusion can be made. The data suggest that studies of the prognosis of diabetic patients should take note of pro-kinetic agent used as well as the presence of gastroparesis. There is a need to accurately select patients for surgical treatment and to evaluate the long-term contribution of both surgical and medical treatment in the care of patients with varying forms of diabetic autonomic neuropathy. 224
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References 1. Maser RE, Pfeifer MA, Dorman JS, Kuller LH, Becker DJ, Orchard TJ. Diabetic autonomic neuropathy and cardiovascular risk. Arch Intern Med 1990; 150:1218-1222. 2. Ewing D J, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-~108. 3. Zitomer BR, Gramm HF, Kozak GP. Gastric neuropathy in diabetes mellitus: clinical and radiologic observations. Metabolism 1968; 17: 199-211. 4. The University of Michigan Pancreas Transplant Evaluation Committee. Pancreatic transplantation as treatment for IDDM: proposed candidate criteria before end-stage diabetic nephropathy. Diabetes Care 1988; 11: 669-675. 5. Dafoe DC, Vinik AI. Is pancreas transplantation for insulin-dependent diabetes mellitus worthwhile? (Letter to Ed.) NEJM 1990; 3 2 2 : 1608-1069. 6. Murat A, Pouliquen B, Bizais Y, Vecchierini M F, Lucas B, Cantarovich D, Paineau J, Galmiche JP, Reversibility of diabetic gastroparesis after renal and pancreatic transplantation. Gastroenterology 1990; 9 8 : A 9 3 (abstract). 7. Tattersall R. Is pancreas transplantation for insulin-dependent diabetes mellitus worthwhile? (Reply to letter to Ed.) NEJM 1990; 3 2 2 : 1608-1609. 8. Goetsch RA, Fink S, Chaudhuri TK. Effect of nifedipine on gastric emptying. Military Medicine 1986; 161 : 4 3 8 4 3 9 . 9. Orchard TJ on behalf of the Community Cardiovascular Surveillance Project investigators. Validation of corononary heart disease mortality data: the Community Cardiovascular Surveillance Project Pilot Experience. CVD Epid Newslett 1985; 157: 46. 10. Chaudhuri TK, Palmer JDK, Burger RH, Fink S. Urinary retention in diabetic patients. Ann Intern Med 1988; 108: 642. 11. Chaudhuri TK, Fink S, Burger RH, Netto ICV, Palmer JDK. Physiological considerations in radionuclide urodynamic studies. Am J Physiol Imaging 1989; 4: 70-74. 12. Chaudhuri TK, Fink S. Physiologic considerations in radionuclide imaging of the extrahepatic biliary tract. Am J Physiol Imaging 1988; 3: 114-120, 13. Chaudhuri TK, Fink S. Clues to gallbladder dysfunction in patients with diabetic neuropathy. Am J Gastroent 1988; 83: 587-588. 14. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab 1986; 15: 855-888. 15. Chaudhuri TK, Palmer JDK, Fink S. Asymptomatic gastric retention and diabetic neuropathy. Dig Dis Sci 1988; 33: 1048. 16. Chaudhuri TK, Fink S. Clinical review: gastric emptying in human disease states. Am J Gastroenterol 1991 ; 86: 533-538. 17. Bays HE, Pfeifer MA, Peripheral diabetic neuropathy. Med Clin No Am 1988; 6: 1439-1464. 18. Clouse RE, Lustman PJ. Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol 1989; 84: 868-872. 19, Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum), Ann Intern Med 1958; 48:797-812. 20, Palmer JDK, Chaudhuri TK, Fink S. Gastric emptying in diabetics without gastrointestinal symptoms. Am J Gastr 1986; 81 : 858. 21. Chaudhuri TK, Fink S. Update: pharmaceuticals and gastric emptying. Am J Gastroentero11990; 85:223-230.
Received 28 February 1992; accepted with revision 14 May 1992.
