Essential Fatty Acid Deficiency in Total Parenteral Nutrition Detection by Changes in Intraocular Pressure HERBERT FREUND, M.D.,* NAVA FLOMAN, M.D., BERNARD SCHWARTZ, M.D., PH.D., JOSEF E. FISCHER, M.D. Essential fatty acid deficiency (EFAD) has been commonly and readily diagnosed during fat-free total parenteral nutrition (TPN), with only vague awareness of possible functional and clinical derangements secondary to essential fatty acid deficiency. Arachidonic acid is known to be a precursor for prostaglandin (PG) synthesis. Prostaglandins are known to be intermediaries between stimulus and cellular response in a variety of physiologic and pathologic processes; one would suspect therefore that EFAD would result in PG deficiency with resultant multiple derangements in functions regulated by PG. We tested this hypothesis by serially measuring intraocular pressure (IOP) in patients before and during fat-free TPN and after supplementing these patients with fat. In the eye as well as in various other organs PG are believed to act as mediators of adrenergic neurotransmission by a negative feedback mechanism. As catecholamines are potent ocular hypotensive agents, decreased levels of PG due to EFAD will cause increase in catecholamine turnover with a reduction in IOP. Two groups of patients matched as to their age, sex, nutritional status and diseases were studied. One group (control) was receiving a normal diet or fat-containing TPN while the other group was receiving fat-free TPN. IOP in the fat-free TPN group dropped from 13.7 ± 0.4 mmHg pre-TPN to 9.3 ± 0.5 mmHg during the first week of fat-free TPN. Within two weeks after supplementation of fat or return to normal oral diet IOP returned to 13.9 ± 0.3 mmHg. Prostaglandin levels, which were 0.025 ± 0.004 ng/ml pre-TPN or in control patients decreased to 0.012 ± 0.002 ng/ml (p < 0.001) during fat-free TPN, to return to normal after fat was added to TPN regime or patients returned to normal oral diet. During fat-free TPN linoleic acid levels decreased to 40% of its initial value with a mild increase upon the addition of fat, while eicosatrienoic acid and the triene:tetraene ratio increased to 6.5 times their initial values. Arachidonic acid levels did not change during fat-free TPN or after repletion with fat. Intraocular pressure determination seem to be a simple, harmless, inexpensive, reliable and sensitive indicator of EFAD. Moreover, IOP determination represent a functional derangement which in a clinical setting lends functional credence to the biochemical changes of EFAD whose entire significance has not yet * Present address: Department of Surgery, Hebrew UniversityMadassah Medical Center, Jerusalem, Israel. Reprint requests to: Josef E. Fischer, M.D., Professor & Chairman, Department of Surgery, University of Cincinnati Medical Center, 231 Bethesda Avenue, Cincinnati, Ohio 45267. Submitted for publication: December 6, 1978.
From the Department of Surgery, Massachusetts General Hospital and Harvard Medical School and the Department of Ophthalmology, New England Medical Center Hospital and Tufts University School of Medicine, Boston, Massachusetts
been determined. Similarly, serial IOP determinations are sensitive in detecting adequate functional repletion of EFAD. As PG are known to act as intermediaries in a variety of physiological processes it seems reasonable to assume that the change in IOP is only one of many different changes and derangements to occur as a result of PG and EFA defiiency.
IN RECENT YEARS essential fatty acid deficiency (EFAD) has been reported in patients treated with fat-free parenteral nutrition.4,5,11,12'14,16 The symptomatology of EFAD falls into three categories: 1) Clinical manifestations of growth retardation, dermatitis, hair loss and susceptibility to bacterial infections. 2) Histologic changes in kidneys, skin, ovaries and testes. 3) Biochemical abnormalities involving increased levels of 5,8,1 1-eicosatrienoic acid and decreased levels of linoleic and arachidonic acid.2'6'8"2'16'17 The biochemical abnormalities are usually the earliest signs of EFAD.8 Under normal circumstances the body converts linoleic acid (C 18:2 w6) to arachidonic acid (C 20:4 w6). In case of linoleic acid deficiency the same enzyme system elongates and desaturates oleic acid (C 18:1 w9) to produce 5,8,1 1-eicosatrienoic acid (C 20:3 w9) rather than arachidonic acid. Arachidonic acid is the precursor of prostaglandin E2 (PGE2) and prostaglandin F2a(PGF2a) which are synthetized in a variety of tissues and participate in multiple physiologic processes as intermediaries between stimulus and cellular response. Because of their widespread distribution and multiplicity of effects they have been implicated in a great variety of physiologic and pathologic processes, among them the regulation of intraocular pressure (IOP). It is therefore to be expected that EFAD states will result in a decrease in prostaglandin synthesis. Indirect evi-
0003-4932/79/0800/0139 $00.75 X J. B. Lippincott Company
139
140
FREUND AND OTHERS TABLE 1. Diagnosis of Patients Studied
Cancer, lymphoma Inflammatory bowel disease Gastrointestinal fistulas Abdominal aortic aneurism Diverticulitis Cirrhosis of liver Infection, sepsis, abscess Sprue Anorexia nervosa Multiple trauma
Fat-free TPN Group
Control
8 8 2 2 1
7 5 1
2
Group
2 2 2 I
1 I
dence for this assumption has been offered in EFA deficient rats reported to have a reduced inflammatory response, a function known to be prostaglandin mediated.1 3
The prostaglandins are believed to act as important mediators in the adrenergic transmission system by a negative feedback mechanism.7 It has been shown in rats that inhibition of prostaglandin synthesis results in increased norepinephrine turnover. Likewise, animals exhibiting low prostaglandin levels as a result of EFAD can be expected to have an increased catecholamine turnover. The catecholamines are important regulators of ocular neuromuscular transmission,10 and potent ocular hypotensive agents, (widely used in the treatment of glaucoma) believed to exert their hypotensive effect by decreasing aqueous flow into the anterior chamber of the eye.20 An increase in catecholamine turnover in the eye, expected to occur in EFA and PG deficient patients, should eventually result in reduction of IOP. We examined the changes in IOP, fatty acid levels and plasma prostaglandin E2 metabolite levels before and during fat-free total parenteral nutrition (TPN). Chemical EFAD occurred early in the course of fat-free TPN, resulting in a significant decrease in IOP and PGE2 levels. The administration of fat in EFA deficient patients restored IOP and PGE2 levels to normal. These results suggest that serial determinations of intraocular pressure may be a simple, noninvasive means of detecting and following essential fatty acid deficiency during parenteral nutrition. Materials and Methods Two groups of patients were studied: Group I Fat-free TPN group included 25 patients hospitalized at the Massachusetts General Hospital who received total parenteral nutrition without fat for various periods of time (Table 1). Parenteral nutrition in this group included a mixture of crystalline amino acids, hypertonic glucose, electrolytes and vitamins but no fat. These patients had their intraocular pressure measured repeatedly during the course of parenteral nutrition. Some of the patients had their IOP measured also be-
Ann. Surg. * August 1979
fore starting TPN and/or during supplementation of TPN with a fat solution (Intralipid 10%) or when put back on normal oral fat containing diet. Group II Control group included 20 patients matched as to their sex, age (Table 2), nutritional status and diagnosis (Table 1) to Group I patients. However, the patients in this group were receiving either normal oral diet or TPN supplemented with fat during the course of their disease. Parenteral nutrition in this group consisted of a mixture of crystalline amino acids, hypertonic glucose, electrolytes, vitamins and 500 ml of Intralipid 10% 2-3 times/week. Intraocular Pressure Determination
Intraocular pressure was measured as a bedside procedure by the Schoitz tonometer® with both 5.5 mg and 10.0 mg weights using ophthalmic Proparacaine hydrochloride 0.5% for local anesthesia. Determinations were always performed by the same ophthalmologist at the same time of the day (10-12 AM). Prostaglandin Determinations Prostaglandin levels were determined by a radioimmunoassay measuring a PGE2 metabolite (13,14dihydro-15-keto prostaglandin E2), using a specific antiserum.9 13,14-dihydro-15-keto PGE2 levels were determined in the plasma of eight pre-TPN and control patients, in seven patients during fat-free TPN and in ten patients who were returned to normal oral diet or in whom fat was added to their TPN regime. Fatty Acid Determinations
Blood for fatty acid determination was drawn into heparinized tubes, centrifuged and the plasma frozen until analysis, performed by extraction and gas liquid chromatography of total plasma lipids. Fatty acids were determined in seven control patients, in four patients during fat-free TPN and in six patients in whom fat was added to their TPN regime or who were put back on normal diet after a period of fat-free TPN. All results are given as mean + SEM and statistical significance was determined by Student's t-test. These studies were approved by the Human Studies Committee of the Massachusetts General Hospital and informed consent was obtained. TABLE 2. Distribution of Patients
Number of patients males females Average age of patients Age range
Fat-free TPN Group
Control Group
25 11 14 55.5 years 22-75 years
20 10 10 54.0 years 28-80 years
Vol. 190 . No. 2
EFAD IN PARENTERAL NUTRITION
Results
i
141
15
Intraocular Pressure Changes (IOP) Mean IOP was 13.7 0.4 mmHg in the fat-free TPN and 14.4 + 0.3 mmHg in the control group before the initiation of TPN (normal IOP 14 + 0.5). In the fat-free TPN group IOP pressure dropped within the first week to 9.3 + 0.5 mmHg (p < 0.001). Similarly low pressures ranging from 8.2-10.2 mmHg were maintained during fat-free TPN periods of up to 16 weeks (Fig. 1). After the initial drop in IOP occurring within the first week of fat-free TPN, no further significant drop in IOP occurred and the pressures during the following weeks are very similar (Fig. 1). IOP in the fat-free TPN group returned to pre-TPN levels (13.9 0.3 mmHg) when patients were returned to normal oral diet or fat was added to their TPN regime, the pressures being significantly higher than during fat-free TPN (p < 0.001). IOP returned to normal after supplementation of fat within 2.2 ± 0.2 weeks. However as IOP determinations were performed only every seven to ten days this figure is misleading as IOP may have returned to normal after a shorter period of fat supplementation.
IJ
group
10
QS p
From the Department of Surgery, Massachusetts General Hospital and Harvard Medical School and the Department of Ophthalmology, New England Medical Center Hospital and Tufts University School of Medicine, Boston, Massachusetts
been determined. Similarly, serial IOP determinations are sensitive in detecting adequate functional repletion of EFAD. As PG are known to act as intermediaries in a variety of physiological processes it seems reasonable to assume that the change in IOP is only one of many different changes and derangements to occur as a result of PG and EFA defiiency.
IN RECENT YEARS essential fatty acid deficiency (EFAD) has been reported in patients treated with fat-free parenteral nutrition.4,5,11,12'14,16 The symptomatology of EFAD falls into three categories: 1) Clinical manifestations of growth retardation, dermatitis, hair loss and susceptibility to bacterial infections. 2) Histologic changes in kidneys, skin, ovaries and testes. 3) Biochemical abnormalities involving increased levels of 5,8,1 1-eicosatrienoic acid and decreased levels of linoleic and arachidonic acid.2'6'8"2'16'17 The biochemical abnormalities are usually the earliest signs of EFAD.8 Under normal circumstances the body converts linoleic acid (C 18:2 w6) to arachidonic acid (C 20:4 w6). In case of linoleic acid deficiency the same enzyme system elongates and desaturates oleic acid (C 18:1 w9) to produce 5,8,1 1-eicosatrienoic acid (C 20:3 w9) rather than arachidonic acid. Arachidonic acid is the precursor of prostaglandin E2 (PGE2) and prostaglandin F2a(PGF2a) which are synthetized in a variety of tissues and participate in multiple physiologic processes as intermediaries between stimulus and cellular response. Because of their widespread distribution and multiplicity of effects they have been implicated in a great variety of physiologic and pathologic processes, among them the regulation of intraocular pressure (IOP). It is therefore to be expected that EFAD states will result in a decrease in prostaglandin synthesis. Indirect evi-
0003-4932/79/0800/0139 $00.75 X J. B. Lippincott Company
139
140
FREUND AND OTHERS TABLE 1. Diagnosis of Patients Studied
Cancer, lymphoma Inflammatory bowel disease Gastrointestinal fistulas Abdominal aortic aneurism Diverticulitis Cirrhosis of liver Infection, sepsis, abscess Sprue Anorexia nervosa Multiple trauma
Fat-free TPN Group
Control
8 8 2 2 1
7 5 1
2
Group
2 2 2 I
1 I
dence for this assumption has been offered in EFA deficient rats reported to have a reduced inflammatory response, a function known to be prostaglandin mediated.1 3
The prostaglandins are believed to act as important mediators in the adrenergic transmission system by a negative feedback mechanism.7 It has been shown in rats that inhibition of prostaglandin synthesis results in increased norepinephrine turnover. Likewise, animals exhibiting low prostaglandin levels as a result of EFAD can be expected to have an increased catecholamine turnover. The catecholamines are important regulators of ocular neuromuscular transmission,10 and potent ocular hypotensive agents, (widely used in the treatment of glaucoma) believed to exert their hypotensive effect by decreasing aqueous flow into the anterior chamber of the eye.20 An increase in catecholamine turnover in the eye, expected to occur in EFA and PG deficient patients, should eventually result in reduction of IOP. We examined the changes in IOP, fatty acid levels and plasma prostaglandin E2 metabolite levels before and during fat-free total parenteral nutrition (TPN). Chemical EFAD occurred early in the course of fat-free TPN, resulting in a significant decrease in IOP and PGE2 levels. The administration of fat in EFA deficient patients restored IOP and PGE2 levels to normal. These results suggest that serial determinations of intraocular pressure may be a simple, noninvasive means of detecting and following essential fatty acid deficiency during parenteral nutrition. Materials and Methods Two groups of patients were studied: Group I Fat-free TPN group included 25 patients hospitalized at the Massachusetts General Hospital who received total parenteral nutrition without fat for various periods of time (Table 1). Parenteral nutrition in this group included a mixture of crystalline amino acids, hypertonic glucose, electrolytes and vitamins but no fat. These patients had their intraocular pressure measured repeatedly during the course of parenteral nutrition. Some of the patients had their IOP measured also be-
Ann. Surg. * August 1979
fore starting TPN and/or during supplementation of TPN with a fat solution (Intralipid 10%) or when put back on normal oral fat containing diet. Group II Control group included 20 patients matched as to their sex, age (Table 2), nutritional status and diagnosis (Table 1) to Group I patients. However, the patients in this group were receiving either normal oral diet or TPN supplemented with fat during the course of their disease. Parenteral nutrition in this group consisted of a mixture of crystalline amino acids, hypertonic glucose, electrolytes, vitamins and 500 ml of Intralipid 10% 2-3 times/week. Intraocular Pressure Determination
Intraocular pressure was measured as a bedside procedure by the Schoitz tonometer® with both 5.5 mg and 10.0 mg weights using ophthalmic Proparacaine hydrochloride 0.5% for local anesthesia. Determinations were always performed by the same ophthalmologist at the same time of the day (10-12 AM). Prostaglandin Determinations Prostaglandin levels were determined by a radioimmunoassay measuring a PGE2 metabolite (13,14dihydro-15-keto prostaglandin E2), using a specific antiserum.9 13,14-dihydro-15-keto PGE2 levels were determined in the plasma of eight pre-TPN and control patients, in seven patients during fat-free TPN and in ten patients who were returned to normal oral diet or in whom fat was added to their TPN regime. Fatty Acid Determinations
Blood for fatty acid determination was drawn into heparinized tubes, centrifuged and the plasma frozen until analysis, performed by extraction and gas liquid chromatography of total plasma lipids. Fatty acids were determined in seven control patients, in four patients during fat-free TPN and in six patients in whom fat was added to their TPN regime or who were put back on normal diet after a period of fat-free TPN. All results are given as mean + SEM and statistical significance was determined by Student's t-test. These studies were approved by the Human Studies Committee of the Massachusetts General Hospital and informed consent was obtained. TABLE 2. Distribution of Patients
Number of patients males females Average age of patients Age range
Fat-free TPN Group
Control Group
25 11 14 55.5 years 22-75 years
20 10 10 54.0 years 28-80 years
Vol. 190 . No. 2
EFAD IN PARENTERAL NUTRITION
Results
i
141
15
Intraocular Pressure Changes (IOP) Mean IOP was 13.7 0.4 mmHg in the fat-free TPN and 14.4 + 0.3 mmHg in the control group before the initiation of TPN (normal IOP 14 + 0.5). In the fat-free TPN group IOP pressure dropped within the first week to 9.3 + 0.5 mmHg (p < 0.001). Similarly low pressures ranging from 8.2-10.2 mmHg were maintained during fat-free TPN periods of up to 16 weeks (Fig. 1). After the initial drop in IOP occurring within the first week of fat-free TPN, no further significant drop in IOP occurred and the pressures during the following weeks are very similar (Fig. 1). IOP in the fat-free TPN group returned to pre-TPN levels (13.9 0.3 mmHg) when patients were returned to normal oral diet or fat was added to their TPN regime, the pressures being significantly higher than during fat-free TPN (p < 0.001). IOP returned to normal after supplementation of fat within 2.2 ± 0.2 weeks. However as IOP determinations were performed only every seven to ten days this figure is misleading as IOP may have returned to normal after a shorter period of fat supplementation.
IJ
group
10
QS p
