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DIABETIC LIPÆMIA COMPLICATING ACUTE PANCREATITIS
1041
888, and phospholipid 1194 mg. per 100 ml. The haematocrit was 42%; the white blood-cell count 12,500 per c.mm.; plasma-glucose 284, calcium 10-3, and phosphorus 3-3 mg. per 100 ml.; bicarbonate 12, sodium 111, and potassium
DIABETIC LIPÆMIA COMPLICATING ACUTE PANCREATITIS
JOHN D. BAGDADE Department of Medicine, University of Washington School of Medicine, and Veterans Administration Hospital, Seattle,
Washington Sum ary in
Profound hyperlipæmia
was
observed
a patient
with acute pancreatitis. Tests done during the acute illness and during convalescence indicated that pancreatitic inflammation was sufficiently severe to cause a transient but reversible state
of insulin deficiency, symptomatic diabetes
mellitus, and an acquired form of fat-induced lipæmia
(type I) due to impaired assimilation (chylomicrons).
of
dietary
fat
4-0 mg. per litre, (electrolytes not corrected for lipeemia). Serum-amylase was 176 units per ml. (normal less than 150) but urinary amylase was 710 units per hour (normal less than 300 units per hour). The serum-lipase was 1.2 units
(normal 0-2-1-5) serum-glutamic-oxaloacetic-transaminase 12 units, alkaline phosphatase 1.6 units (normal less than 27); total bilirubin 0-9 mg. per 100 ml.; protein 7-6 and albumin 5-2 g. per 100 ml. The stool guaiac was negative. Urinalysis gave a 4+ test for glucose and acetone. X-ray films of the abdomen showed diffuse haziness, gastric retention of fluid and gas, and enlargement of both liver and spleen, but no evidence of free air or calcifications in the The chest film and electrocardiogram area of the pancreas. were
normal.
Course After fluid replacement and insulin therapy, the patient improved clinically, but leucocytosis and low-grade fever persisted. X-ray studies done on the seventh hospital day revealed a left upper quadrant retroperitoneal mass which increased progressively in size over the next week and was easily palpated on abdominal examination. A laparotomy was done on day 14 and a large pancreatic cyst was drained. At the time of hospital discharge 10 weeks after admission, his diabetic state was well-controlled on diet alone. Fasting blood-glucose was 85, 2-hour postprandial blood-glucose 152, and plasma-triglyceride 164 mg. per 100 ml.
Hospital
Introduction THE clinical course of acute pancreatitis may be associated with a variety of unusual complications. I describe here a previously unreported but completely reversible sequel-diabetic lipeemia-in a non-diabetic patient with severe pancreatitis.
Case-report A 38-year-old merchant seaman, in previous good health, was admitted to hospital because of abdominal pain, vomiting, and " skin bumps ". During a 2-week beer drinking binge before admission he had had progressive constant upper abdominal pain radiating to the back, increasing thirst, and frequent urination, followed by the appearance of papular skin lesions over trunk and extremities. His pain was relieved by sitting up and assuming the knee chest position, but not by antacids or milk. He had vomited small amounts of bile-stained material on three occasions and for 2 days before admission was able to tolerate only milk. He denied nausea, dark urine, light stools, or past knowledge of liver disease, peptic ulcer, jaundice, or family history of diabetes mellitus or plasma-lipid abnormality. On admission, the vital signs were normal. The conjunctivx and skin were not icteric. Papules with firm whitish-yellow centres and slightly erythematous margins were present over the knees and buttocks and were proved to be eruptive xanthomas on biopsy. Pale retinal vessels typical of lipaemia retinalis were noted, but no microaneurysms were seen. The heart and lungs were normal. The abdomen was obese and diffusely tender, particularly in the upper quandrants where voluntary guarding was present. No rebound tenderness was elicited. The bowel tones were significantly diminished. A firm, non-tender liver edge was felt two fingerbreadths below the costal
Methods Plasma fat
particles, blood-glucose, electrolytes, triglyceride, cholesterol, and phospholipids were measured by methods described elsewhere.1 Post-heparin lipolytic activity was estimated by the method of Fredrickson2 after intravenous administration of heparin (380 units per sq. m. of body-surface area). Results
Plasma-lipid Analyses After flocculation with polyvinylpyrrolidone (P.v.p.), nearly all (95%) of the patient’s plasma-triglyceride PLASMA-LIPID LEVELS AND LIPID COMPOSITION OF NORMAL DIETARY FAT PARTICLES
margin. Laboratory Findings Admission laboratory tests revealed grossly creamy plasma with a triglyceride concentration of 7790, cholesterol *Obtained values. 6. 7. 8.
Czerniak, P., Borochowski, S., Tracool, L. Harefuah, 1965, 69, 161. Miller, H., Weetch, R. S. Lancet, 1955, ii, 1013. Weaver, J. C., Kamm, H. L., Dobson, R. L. J. Am. med. Ass. 1960, 173, 872. 9. Seltzer, R. A., Kereiakes, J. G., Saenger, E. L., Myers, D. H. Radiology, 1964, 82, 486. 10. Kereiakes, J. G., Wellman, H. N., Tieman, J., Saenger, E. L. ibid. 1968, 90, 925. 11. Gross, J., Ben-Porath, M., Rosin, A., Bloch, M. in Thyroid Neoplasia (edited by S. Young and D. R. Inman); p. 291. London, 1968.
12. 13.
Dolphin,
G. W. Hlth Phys. 1968, 15, 219. L. H., Pifer, J. W., Burke, G. W., Terry, R., J. Nat. Cancer Institute, 1967, 38, 317.
Hempelmann, W. R.
Ames,
by subtraction
of post-treatment values from admission
fraction floated to the top of a P.v.P. column, which is characteristic of dietary-fat particles (chylomicrons). The composition of these particles has been shown to be similar to that of fat particles obtained from plasma of healthy people after a fat meal.33 The increment above normal of each plasma-lipid fraction reflected the lipid composition of these dietary particles (see table) and indicated that the hyperlipaemia was due predominantly to chylomicron accumulation.
1042
Postheparin Lipolytic Activity
consistent with the rarity with which plasma-lipid levels are raised in alcoholic pancreatitis.6 Although alcohol undoubtedly stimulated endogenous (hepatic) triglyceride production in the patient described, as has been shown previously,’ his disproportionate and strikingly abnormal accumulation of chylomicrons indicated that endogenously syntyesized lipoprotein represented only a small part of his total circulating triglyceride concentration, and suggested that assimilation of dietary fat was signi-
these results
Subnormal postheparin lipolytic activity (P.H.L.A.) demonstrated at the time of admission and during diabetic acidosis (see figure). This activity indirectly reflects tissue levels of lipoprotein lipase, an enzyme system presumably associated with the removal of dietary fat from plasma and one which requires insulin for normal function.1 A circulating antagonist did not seem to contribute to the subnormal P.H.L.A.
was
are
ficantly impaired. Owing to the lack of a precise method for evaluating triglyceride assimilation in vivo, this important physiological process is quantitated indirectly by the measurement of lipolytic activity released into plasma after the intravenous administration of heparin (P.H.L.A.). This activity correlates well with tissue lipoprotein lipase levels. Not only have this tissue enzyme system9 and P .H.L.A.1o both been shown to be insulin-dependent, but also small changes in insulin availability result in a decline in P.H.L.A. and increased plasma-triglyceride levels, presumably indices of impaired triglyceride assimilation. Since the insulin reserve may be limited in patients with chronic pancreatitis," it is not surprising that in some cases of severe acute pancreatitis, pancreatic endocrine function may be compromised sufficiently to limit insulin availability and cause symptomatic diabetes mellitus. In these patients, reduced enzyme activity and some impairment in triglyceride removal might be anticipated. Thus, by decreasing lipoprotein lipase and the normal capacity to assimilate dietary fat, insulin deficiency in either inherited or acquired forms of diabetes mellitus may result in Post-heparin lipolytic activity (P.H.L.A.) and plasma-triglyceride and blood-glucose levels during the course of acute pancreatitis complicated by diabetic lipsemia and acidosis. The range of normal activity (10-minute values 2) is shown in the shaded area.
both before and after insulin treatment, since no inhibition of lipolytic activity was observed when fasting plasma samples obtained from the patient on days 1 and 5 were incubated with postheparin plasma from a healthy control. These samples correspond to periods of active pancreatitis and both uncontrolled and treated diabetes. P.H.L.A. levels in the lownormal range were observed postoperatively when the patient’s diabetic state was well controlled, and continued to rise as his dietary intake improved. Discussion
Hypertriglyceridamlia always results from one or two basic physiological processes: increased hepatic synthesis of triglyceride-rich lipoprotein or decreased triglyceride removal by peripheral tissues, a process believed to be mediated by the lipoprotein lipase enzyme system. It was formerly believed that lipoprotein-lipase activity was inhibited in pancreatitis4 in the absence of clinical diabetes, and that, as a result impaired assimilation of circulating triglyceride-rich lipoprotein might contribute to hyperlipaemia. Subsequent work in these patients, however, has not revealed any correlation between plasma-triglyceride and lipoprotein-lipase levels,5and both of
chvlomicron accumulation in olasma. Consequently, because of transient insulin deficiency, the occasional patient with acute pancreatitis may have clinical and laboratory features of diabetic lipxmia-symptomatic diabetes mellitus, and an" acquired but reversible form of dietary " fat-induced lipxmia associated with subnormal P.H.L.A. abdominal pain, lipaemia retinalis, and eruptive xanthoma. This clinical picture is indistinguishable from that observed in hereditary fat-induced lipxmia (type i) in which there is a congenital lipoprotein-lipase deficiency.12 The severe pancreatitis-like pain characteristically observed in patients with type-I hyperlipoproteinasmia leads me to suggest that excessive concentrations of chylomicrons in plasma may directly incite pancreatitic inflammation. Such a mechanism may have compounded the toxic effects of alcohol on the pancreas in this patient and contributed to diabetic ketoacidosis and his unusually severe clinical course. In the typical case of diabetic lipoemia, the plasmatriglyceride level, the P.H.L.A., and presumably tissue lipoprotein-lipase concentration promptly return to normal after insulin treatment. The catabolic state observed postoperatively in this patient associated with his continued active pancreatic inflammation and lack of dietary intake, factors which tend to depress L.P.L. synthesis,13 probably delayed the return of the P.H.L.A. to normal despite insulin therapy. The increase in P.H.L.A. levels observed after the pancreatic inflammation had subsided and pancreatic endocrine function and a normal diet were restored supports such a possibility.
1043
Results of this study emphasise the necessity of obtaining urinary amylase measurements to establish the diagnosis of pancreatitis in patients with hyperlipaemia, since plasma lactescence 6 may interfere with the serum-amylase determination.
Supported
in part
by U.S. Public Health Service
grant
AM-06670.
Requests for reprints should Administration Hospital, 4435 Washington 98108, U.S.A.
be addressed to J. B., Veterans Beacon Avenue South, Seattle,
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8.
Bagdade, J. D., Porte, D., Jr., Bierman, E. L. New Engl. J. Med. 1967, 276, 427. Fredrickson, D. S., Ono, K., Davis, L. L. J. Lipid Res. 1963 4, 24. O’Hara, D. D., Porte, D., Williams, R. H. ibid. 1966, 7, 264. Kessler, J. I., Kniffen, J. C., Janowitz, H. D. New Engl. J. Med. 1963, 269, 943. Verdy, M., Gattereau, A. Am. J. clin. Nutr. 1967, 20, 997. Greenberger, N. J., Hatch, F. T., Drummey, G. D., Isselbacher, K. J. Medicine, Baltimore, 1966, 45, 616. Lieber, C. S. Ann. Rev. Med. 1967, 18, 35. Payza, A. N., Eiber, H. B., Walters, S. Proc. Soc. exp. Biol. Med.
1967, 125 188. Schnatz, J. D., Williams, R. H. Diabetes, 1963, 12, 174. Bagdade, J. D., Porte, D., Jr., Bierman, E. L. ibid. 1968, 17, 127. Joffee, B. I., Bank, S., Jackson, W. P. U., Keller, P., O’Reilly, I. G., Vinik, A. I. Lancet, 1968, ii, 890. 12. Fredrickson, D. S., Levy, D. I., Lees, R. S. New Engl. J. Med. 1967, 276, 94. 13. Hollenberg, C. H. J. clin. Invest. 1960, 39, 1282.
9. 10. 11.
the postganglionic sympathic nerve terminals.5 L-dopa is converted to dopamine in the brain, and dopamine is probably pharmacologically active in the amelioration of the symptoms of Parkinson’s disease. 6-hydroxy-dopamine is closely related chemically to dopamine but is not known to be formed in vivo. line
at
However, 6-hydroxy-dopamine produces depletion of noradrenaline from sympathetically innervated tissues in the rat and degeneration of adrenergic nerve-fibres.6 Thus 6-hydroxy-dopamine appears to " act in some species to produce a chemical sympathectomy " ; and in man if L-dopa were metabolised to 6-hydroxy-dopamine a hypotensive effect would be
expected. We considered it important to investigate whether the hypotensive effect of L-dopa was due to an action on the sympathetic nervous system. As part of a clinical trial of L-dopa in patients with Parkinson’s disease we have studied the effects of L-dopa on mydriatic responses of the pupil to phenylephrine and tyramine using the methods of Sneddon and Turner.7 The mydriatic responses of the human iris have proved a reliable index of postganglionic sympathetic blockade or denervation in man. MATERIALS AND METHODS
Preliminary
Communication
MYDRIATIC RESPONSES TO SYMPATHOMIMETIC AMINES IN PATIENTS TREATED WITH L-DOPA
R. B. GODWIN-AUSTEN National Hospital, Queen Square, London W.C.1
N. A. LIND
P. TURNER
Division of Clinical Pharmacology, Medical Professorial Unit, St. Bartholomew’s Hospital, London E.C.1
Pupil size and mydriatic responses to phenylephrine and tyramine have been studied in eighteen patients undergoing treatment with oral L-dopa in order to investigate the possible effects of L-dopa or its metabolites on the sympathetic nervous system. During treatment with L-dopa no change in resting pupil size was demonstrated, nor was the mydriatic response to tyramine affected. There was, however, a significant reduction of phenylephrine mydriasis during treatment. These results suggest that L-dopa or its metabolites may produce a competitive adrenergic &agr;-receptor blockade Sum ary
with
a
rise in the noradrenaline
content
of the
adrenergic nerve-ending. The hypotension sometimes observed during treatment with L-dopa may be explained by this mechanism.
The eighteen patients studied were taking part in a double-blind cross-over trial of L-dopa for the treatment of All were receiving other antiParkinson’s disease.3 before the trial; no changes were made parkinsonian therapy in this, and no additional therapy was prescribed to counteract the side-effects of L-dopa. The dosage of L-dopa was 3-8 g. daily. In all patients the mydriatic responses to sympathomimetic amines were studied on two occasions-namely, when they had received the placebo preparations for three weeks, and when they had been treated with L-dopa for at least two weeks. Two sympathomimetic amines were usedthe indirectly acting tyramine, and the directly acting phenylephrine.8 Eleven patients were treated with tyramine 2%, and twelve with phenylephrine 5%. The method used has been described elsewhere. 9 patients sat in a small room with their faces illuminated by two lamps each containing a 60-watt bulb. These produced an illumination on the eyes of 7 foot lamberts. The eyes were photographed five times at one-second intervals with a Nikon F singlereflex 35 mm. camera with a constant magnification, using Ilford HP3 film. Further photographs were taken under the same conditions at ten, twenty, and thirty minutes after instillation of one drop of the sympathomimetic amines under study into the conjunctival sac of one eye. After development the films were projected using an adapted microfilm viewer giving a final magnification of eight. Pupil diameters were measured, and the mean of each group of five was calculated. The percentage mydriasis was expressed as the increase in diameter of the pupil at thirty minutes over the control diameter before instillation of the amine. RESULTS
INTRODUCTION
L-dihydroxyphenylalanine (L-dopa) has been shown to benefit patients with Parkinson’s disease.1-3 A side-effect of has this treatment frequently reported been hypotension3 or postural hypotension.2,4 The mechanism of this hypotensive effect is obscure, and it is not known whether hypotension is caused by L-dopa itself or by a metabolite. L-dopa might have a similar hypotensive action to oc-methyldopa, which blocks the actions of noradrena-
L-dopa did not size. Thus the
produce any change in resting pupil resting pupil diameter in thirteen was 3-8 before and 3-9 mm. during treatmm. patients ment with L-dopa (standard error of mean=013, Furthermore the mydriatic response to P>0-05). tyramine 2% (see accompanying table) was unchanged during treatment with L-dopa when compared with the reading after placebo treatment. However, the mydriasis produced by phenylephrine 5% was
888, and phospholipid 1194 mg. per 100 ml. The haematocrit was 42%; the white blood-cell count 12,500 per c.mm.; plasma-glucose 284, calcium 10-3, and phosphorus 3-3 mg. per 100 ml.; bicarbonate 12, sodium 111, and potassium
DIABETIC LIPÆMIA COMPLICATING ACUTE PANCREATITIS
JOHN D. BAGDADE Department of Medicine, University of Washington School of Medicine, and Veterans Administration Hospital, Seattle,
Washington Sum ary in
Profound hyperlipæmia
was
observed
a patient
with acute pancreatitis. Tests done during the acute illness and during convalescence indicated that pancreatitic inflammation was sufficiently severe to cause a transient but reversible state
of insulin deficiency, symptomatic diabetes
mellitus, and an acquired form of fat-induced lipæmia
(type I) due to impaired assimilation (chylomicrons).
of
dietary
fat
4-0 mg. per litre, (electrolytes not corrected for lipeemia). Serum-amylase was 176 units per ml. (normal less than 150) but urinary amylase was 710 units per hour (normal less than 300 units per hour). The serum-lipase was 1.2 units
(normal 0-2-1-5) serum-glutamic-oxaloacetic-transaminase 12 units, alkaline phosphatase 1.6 units (normal less than 27); total bilirubin 0-9 mg. per 100 ml.; protein 7-6 and albumin 5-2 g. per 100 ml. The stool guaiac was negative. Urinalysis gave a 4+ test for glucose and acetone. X-ray films of the abdomen showed diffuse haziness, gastric retention of fluid and gas, and enlargement of both liver and spleen, but no evidence of free air or calcifications in the The chest film and electrocardiogram area of the pancreas. were
normal.
Course After fluid replacement and insulin therapy, the patient improved clinically, but leucocytosis and low-grade fever persisted. X-ray studies done on the seventh hospital day revealed a left upper quadrant retroperitoneal mass which increased progressively in size over the next week and was easily palpated on abdominal examination. A laparotomy was done on day 14 and a large pancreatic cyst was drained. At the time of hospital discharge 10 weeks after admission, his diabetic state was well-controlled on diet alone. Fasting blood-glucose was 85, 2-hour postprandial blood-glucose 152, and plasma-triglyceride 164 mg. per 100 ml.
Hospital
Introduction THE clinical course of acute pancreatitis may be associated with a variety of unusual complications. I describe here a previously unreported but completely reversible sequel-diabetic lipeemia-in a non-diabetic patient with severe pancreatitis.
Case-report A 38-year-old merchant seaman, in previous good health, was admitted to hospital because of abdominal pain, vomiting, and " skin bumps ". During a 2-week beer drinking binge before admission he had had progressive constant upper abdominal pain radiating to the back, increasing thirst, and frequent urination, followed by the appearance of papular skin lesions over trunk and extremities. His pain was relieved by sitting up and assuming the knee chest position, but not by antacids or milk. He had vomited small amounts of bile-stained material on three occasions and for 2 days before admission was able to tolerate only milk. He denied nausea, dark urine, light stools, or past knowledge of liver disease, peptic ulcer, jaundice, or family history of diabetes mellitus or plasma-lipid abnormality. On admission, the vital signs were normal. The conjunctivx and skin were not icteric. Papules with firm whitish-yellow centres and slightly erythematous margins were present over the knees and buttocks and were proved to be eruptive xanthomas on biopsy. Pale retinal vessels typical of lipaemia retinalis were noted, but no microaneurysms were seen. The heart and lungs were normal. The abdomen was obese and diffusely tender, particularly in the upper quandrants where voluntary guarding was present. No rebound tenderness was elicited. The bowel tones were significantly diminished. A firm, non-tender liver edge was felt two fingerbreadths below the costal
Methods Plasma fat
particles, blood-glucose, electrolytes, triglyceride, cholesterol, and phospholipids were measured by methods described elsewhere.1 Post-heparin lipolytic activity was estimated by the method of Fredrickson2 after intravenous administration of heparin (380 units per sq. m. of body-surface area). Results
Plasma-lipid Analyses After flocculation with polyvinylpyrrolidone (P.v.p.), nearly all (95%) of the patient’s plasma-triglyceride PLASMA-LIPID LEVELS AND LIPID COMPOSITION OF NORMAL DIETARY FAT PARTICLES
margin. Laboratory Findings Admission laboratory tests revealed grossly creamy plasma with a triglyceride concentration of 7790, cholesterol *Obtained values. 6. 7. 8.
Czerniak, P., Borochowski, S., Tracool, L. Harefuah, 1965, 69, 161. Miller, H., Weetch, R. S. Lancet, 1955, ii, 1013. Weaver, J. C., Kamm, H. L., Dobson, R. L. J. Am. med. Ass. 1960, 173, 872. 9. Seltzer, R. A., Kereiakes, J. G., Saenger, E. L., Myers, D. H. Radiology, 1964, 82, 486. 10. Kereiakes, J. G., Wellman, H. N., Tieman, J., Saenger, E. L. ibid. 1968, 90, 925. 11. Gross, J., Ben-Porath, M., Rosin, A., Bloch, M. in Thyroid Neoplasia (edited by S. Young and D. R. Inman); p. 291. London, 1968.
12. 13.
Dolphin,
G. W. Hlth Phys. 1968, 15, 219. L. H., Pifer, J. W., Burke, G. W., Terry, R., J. Nat. Cancer Institute, 1967, 38, 317.
Hempelmann, W. R.
Ames,
by subtraction
of post-treatment values from admission
fraction floated to the top of a P.v.P. column, which is characteristic of dietary-fat particles (chylomicrons). The composition of these particles has been shown to be similar to that of fat particles obtained from plasma of healthy people after a fat meal.33 The increment above normal of each plasma-lipid fraction reflected the lipid composition of these dietary particles (see table) and indicated that the hyperlipaemia was due predominantly to chylomicron accumulation.
1042
Postheparin Lipolytic Activity
consistent with the rarity with which plasma-lipid levels are raised in alcoholic pancreatitis.6 Although alcohol undoubtedly stimulated endogenous (hepatic) triglyceride production in the patient described, as has been shown previously,’ his disproportionate and strikingly abnormal accumulation of chylomicrons indicated that endogenously syntyesized lipoprotein represented only a small part of his total circulating triglyceride concentration, and suggested that assimilation of dietary fat was signi-
these results
Subnormal postheparin lipolytic activity (P.H.L.A.) demonstrated at the time of admission and during diabetic acidosis (see figure). This activity indirectly reflects tissue levels of lipoprotein lipase, an enzyme system presumably associated with the removal of dietary fat from plasma and one which requires insulin for normal function.1 A circulating antagonist did not seem to contribute to the subnormal P.H.L.A.
was
are
ficantly impaired. Owing to the lack of a precise method for evaluating triglyceride assimilation in vivo, this important physiological process is quantitated indirectly by the measurement of lipolytic activity released into plasma after the intravenous administration of heparin (P.H.L.A.). This activity correlates well with tissue lipoprotein lipase levels. Not only have this tissue enzyme system9 and P .H.L.A.1o both been shown to be insulin-dependent, but also small changes in insulin availability result in a decline in P.H.L.A. and increased plasma-triglyceride levels, presumably indices of impaired triglyceride assimilation. Since the insulin reserve may be limited in patients with chronic pancreatitis," it is not surprising that in some cases of severe acute pancreatitis, pancreatic endocrine function may be compromised sufficiently to limit insulin availability and cause symptomatic diabetes mellitus. In these patients, reduced enzyme activity and some impairment in triglyceride removal might be anticipated. Thus, by decreasing lipoprotein lipase and the normal capacity to assimilate dietary fat, insulin deficiency in either inherited or acquired forms of diabetes mellitus may result in Post-heparin lipolytic activity (P.H.L.A.) and plasma-triglyceride and blood-glucose levels during the course of acute pancreatitis complicated by diabetic lipsemia and acidosis. The range of normal activity (10-minute values 2) is shown in the shaded area.
both before and after insulin treatment, since no inhibition of lipolytic activity was observed when fasting plasma samples obtained from the patient on days 1 and 5 were incubated with postheparin plasma from a healthy control. These samples correspond to periods of active pancreatitis and both uncontrolled and treated diabetes. P.H.L.A. levels in the lownormal range were observed postoperatively when the patient’s diabetic state was well controlled, and continued to rise as his dietary intake improved. Discussion
Hypertriglyceridamlia always results from one or two basic physiological processes: increased hepatic synthesis of triglyceride-rich lipoprotein or decreased triglyceride removal by peripheral tissues, a process believed to be mediated by the lipoprotein lipase enzyme system. It was formerly believed that lipoprotein-lipase activity was inhibited in pancreatitis4 in the absence of clinical diabetes, and that, as a result impaired assimilation of circulating triglyceride-rich lipoprotein might contribute to hyperlipaemia. Subsequent work in these patients, however, has not revealed any correlation between plasma-triglyceride and lipoprotein-lipase levels,5and both of
chvlomicron accumulation in olasma. Consequently, because of transient insulin deficiency, the occasional patient with acute pancreatitis may have clinical and laboratory features of diabetic lipxmia-symptomatic diabetes mellitus, and an" acquired but reversible form of dietary " fat-induced lipxmia associated with subnormal P.H.L.A. abdominal pain, lipaemia retinalis, and eruptive xanthoma. This clinical picture is indistinguishable from that observed in hereditary fat-induced lipxmia (type i) in which there is a congenital lipoprotein-lipase deficiency.12 The severe pancreatitis-like pain characteristically observed in patients with type-I hyperlipoproteinasmia leads me to suggest that excessive concentrations of chylomicrons in plasma may directly incite pancreatitic inflammation. Such a mechanism may have compounded the toxic effects of alcohol on the pancreas in this patient and contributed to diabetic ketoacidosis and his unusually severe clinical course. In the typical case of diabetic lipoemia, the plasmatriglyceride level, the P.H.L.A., and presumably tissue lipoprotein-lipase concentration promptly return to normal after insulin treatment. The catabolic state observed postoperatively in this patient associated with his continued active pancreatic inflammation and lack of dietary intake, factors which tend to depress L.P.L. synthesis,13 probably delayed the return of the P.H.L.A. to normal despite insulin therapy. The increase in P.H.L.A. levels observed after the pancreatic inflammation had subsided and pancreatic endocrine function and a normal diet were restored supports such a possibility.
1043
Results of this study emphasise the necessity of obtaining urinary amylase measurements to establish the diagnosis of pancreatitis in patients with hyperlipaemia, since plasma lactescence 6 may interfere with the serum-amylase determination.
Supported
in part
by U.S. Public Health Service
grant
AM-06670.
Requests for reprints should Administration Hospital, 4435 Washington 98108, U.S.A.
be addressed to J. B., Veterans Beacon Avenue South, Seattle,
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8.
Bagdade, J. D., Porte, D., Jr., Bierman, E. L. New Engl. J. Med. 1967, 276, 427. Fredrickson, D. S., Ono, K., Davis, L. L. J. Lipid Res. 1963 4, 24. O’Hara, D. D., Porte, D., Williams, R. H. ibid. 1966, 7, 264. Kessler, J. I., Kniffen, J. C., Janowitz, H. D. New Engl. J. Med. 1963, 269, 943. Verdy, M., Gattereau, A. Am. J. clin. Nutr. 1967, 20, 997. Greenberger, N. J., Hatch, F. T., Drummey, G. D., Isselbacher, K. J. Medicine, Baltimore, 1966, 45, 616. Lieber, C. S. Ann. Rev. Med. 1967, 18, 35. Payza, A. N., Eiber, H. B., Walters, S. Proc. Soc. exp. Biol. Med.
1967, 125 188. Schnatz, J. D., Williams, R. H. Diabetes, 1963, 12, 174. Bagdade, J. D., Porte, D., Jr., Bierman, E. L. ibid. 1968, 17, 127. Joffee, B. I., Bank, S., Jackson, W. P. U., Keller, P., O’Reilly, I. G., Vinik, A. I. Lancet, 1968, ii, 890. 12. Fredrickson, D. S., Levy, D. I., Lees, R. S. New Engl. J. Med. 1967, 276, 94. 13. Hollenberg, C. H. J. clin. Invest. 1960, 39, 1282.
9. 10. 11.
the postganglionic sympathic nerve terminals.5 L-dopa is converted to dopamine in the brain, and dopamine is probably pharmacologically active in the amelioration of the symptoms of Parkinson’s disease. 6-hydroxy-dopamine is closely related chemically to dopamine but is not known to be formed in vivo. line
at
However, 6-hydroxy-dopamine produces depletion of noradrenaline from sympathetically innervated tissues in the rat and degeneration of adrenergic nerve-fibres.6 Thus 6-hydroxy-dopamine appears to " act in some species to produce a chemical sympathectomy " ; and in man if L-dopa were metabolised to 6-hydroxy-dopamine a hypotensive effect would be
expected. We considered it important to investigate whether the hypotensive effect of L-dopa was due to an action on the sympathetic nervous system. As part of a clinical trial of L-dopa in patients with Parkinson’s disease we have studied the effects of L-dopa on mydriatic responses of the pupil to phenylephrine and tyramine using the methods of Sneddon and Turner.7 The mydriatic responses of the human iris have proved a reliable index of postganglionic sympathetic blockade or denervation in man. MATERIALS AND METHODS
Preliminary
Communication
MYDRIATIC RESPONSES TO SYMPATHOMIMETIC AMINES IN PATIENTS TREATED WITH L-DOPA
R. B. GODWIN-AUSTEN National Hospital, Queen Square, London W.C.1
N. A. LIND
P. TURNER
Division of Clinical Pharmacology, Medical Professorial Unit, St. Bartholomew’s Hospital, London E.C.1
Pupil size and mydriatic responses to phenylephrine and tyramine have been studied in eighteen patients undergoing treatment with oral L-dopa in order to investigate the possible effects of L-dopa or its metabolites on the sympathetic nervous system. During treatment with L-dopa no change in resting pupil size was demonstrated, nor was the mydriatic response to tyramine affected. There was, however, a significant reduction of phenylephrine mydriasis during treatment. These results suggest that L-dopa or its metabolites may produce a competitive adrenergic &agr;-receptor blockade Sum ary
with
a
rise in the noradrenaline
content
of the
adrenergic nerve-ending. The hypotension sometimes observed during treatment with L-dopa may be explained by this mechanism.
The eighteen patients studied were taking part in a double-blind cross-over trial of L-dopa for the treatment of All were receiving other antiParkinson’s disease.3 before the trial; no changes were made parkinsonian therapy in this, and no additional therapy was prescribed to counteract the side-effects of L-dopa. The dosage of L-dopa was 3-8 g. daily. In all patients the mydriatic responses to sympathomimetic amines were studied on two occasions-namely, when they had received the placebo preparations for three weeks, and when they had been treated with L-dopa for at least two weeks. Two sympathomimetic amines were usedthe indirectly acting tyramine, and the directly acting phenylephrine.8 Eleven patients were treated with tyramine 2%, and twelve with phenylephrine 5%. The method used has been described elsewhere. 9 patients sat in a small room with their faces illuminated by two lamps each containing a 60-watt bulb. These produced an illumination on the eyes of 7 foot lamberts. The eyes were photographed five times at one-second intervals with a Nikon F singlereflex 35 mm. camera with a constant magnification, using Ilford HP3 film. Further photographs were taken under the same conditions at ten, twenty, and thirty minutes after instillation of one drop of the sympathomimetic amines under study into the conjunctival sac of one eye. After development the films were projected using an adapted microfilm viewer giving a final magnification of eight. Pupil diameters were measured, and the mean of each group of five was calculated. The percentage mydriasis was expressed as the increase in diameter of the pupil at thirty minutes over the control diameter before instillation of the amine. RESULTS
INTRODUCTION
L-dihydroxyphenylalanine (L-dopa) has been shown to benefit patients with Parkinson’s disease.1-3 A side-effect of has this treatment frequently reported been hypotension3 or postural hypotension.2,4 The mechanism of this hypotensive effect is obscure, and it is not known whether hypotension is caused by L-dopa itself or by a metabolite. L-dopa might have a similar hypotensive action to oc-methyldopa, which blocks the actions of noradrena-
L-dopa did not size. Thus the
produce any change in resting pupil resting pupil diameter in thirteen was 3-8 before and 3-9 mm. during treatmm. patients ment with L-dopa (standard error of mean=013, Furthermore the mydriatic response to P>0-05). tyramine 2% (see accompanying table) was unchanged during treatment with L-dopa when compared with the reading after placebo treatment. However, the mydriasis produced by phenylephrine 5% was