Clinical Case Presentation* PROBLEhI A 28-year-old female has received the usual mix of hypertonic glucose and amino acid solution for nutritional support for three weeks as treatment of a post-traumatic duodenal fistula. Although her weight has been maintained and she is now afebrile, her liver function tests are abnormal: alkaline phosphatase, total bilirubin and hepatic enzymes have all gradually increased. List your steps in evaluating this patient. What is the probable cause of this altered liver function? Would you alter nutritional therapy?
DISCUSSION OF CASE George F. Sheldon, MD Associate Professor of Surgery Chief of Trauma and Hyperalimentation Services University of California Service San Francisco General Hospital San Francisco, California 94 I I0 The case describes a common complication of parenteral nutrition (PN), intrahepatic cholestasis, which usually occurs approximately three weeks or longer after the initiation of intravenous feeding. It frequently occurs in patients who are successfully maintained on PN, in positive nitrogen balance and gaining weight. Intrahepatic cholestasis probably represents a n imbalance between the dextrose calories administered and the amino acids provided. It may be comparable to the severe fatty infiltration of the liver, which frequently occurs in patients with kwashiorkor. Patients with kwashiorkor have inadequate amino acid intake for lipoprotein synthesis, in the presence of sufficient carbohydrate intake. In the presence of sufficient carbohydrate intake but inadequate amino acid intake, acetyl, COA, is converted t o fatty acids whichare trapped by hepatocytes. It is unclear if this is the mechanism which results in intrahepatic cholestasis in patients receiving TPN, but such a mechanism is likely. It is conceivable that the somewhat nonspecific histological findings that are found in this syndrome may be secondary to fatty acid deficiency. With Intralipid lo%, currently available, we continue t o administer fat emulsion on a weekly or biweekly basis in patients developing signs of intrahepatic cholestasis. Although intrahepatic cholestasis occurs after extended periods (greater than 3 weeks) of PN, patients receiving home P N consisting of hypertonicdextrose and amino acids rapidly administered during a night time *This secriori of rhe Joirrnal was origirialed aridisediretl bJ Doirglus If'. ItThore. MD, f o r IIie pirrpose of exchurigiri~ ideas relerarlr 10 purerileral arid erireral riirtriiioti.
T H E JOURNAL OF PARENTERAL A N D ENTERAL NUTRITION
infusion will often develop swelling, tenderness and enlargement of the liver. Presumably the mechanism is comparable to the more gradual occurrence of intrahepatic cholestasis, although excess hepatic storage of glycogen probably occurs in hepatomegaly associated with home PN. The Hyperalimentation Service at San Francisco General Hospital has recently reported 33 cases of intrahepatic cholestasis in which liver biopsies were obtained in patients with this syndrome. Frequently the patients had received prolonged PN, but histological findings determined that intrahepatic cholestasis occurred in some patients within 24 hours. The histological appearance of the liver in intrahepatic cholestasis is that of pericanalicular round cell filtration, bile plugs and frothy and foamy hepatocytes. The syndrome is totally reversible; follow-up liver biopsies after iesumption of oral feeding reveal normal liver architecture. Patients with intrahepatic chqlestasis develo p characteristic liver function abnormalities. The initial abnormality is a n increase in the alkaline phosphatase test. Following elevation of the alkaline phosphatase, gradual increase in isoenzymes occurs, followed by elevation in the serum bilirubin. These nonspecific findings, of course, are compatible with the cholestatic phase of viral hepatitis, calculous disease of the biliary tract and metastatic carcinoma, diagnoses which must be entertained. Intrahepatic cholestasis is a reversible syndrome if appropriately treated. Treatment entails decreasing the dextrose component of the intravenous feeding routine. If the patient is receiving standard 25% dextrose, 4.25% amino acid solution, we would lower the dextrose concentration t o 15% while maintaining the same concentration of amino acids. An alternative approach' is to continue dextrose 25%:4.45% amino acids infusion for 12 of the 24 hours of infusion and alternate that solution with dextrose-free amino acids. Our preference, however, is for lowering the caloriemitrogen ratio, instead of cycling the therapy, as intermittent hypoglycemia has occurred in some patients who have been cycled. Liver 569
CIJNICAI. CASE PRESENTATIOS
function abnormalities will return t o normal within two weeks of lowering the ca1orie:nitrogen ratio. SU hl h l A R Y Intrahepatic cholestasis is a reversible complication of parenteral nutrition. Although histological abnormalities of lipid deposition and bile stasis occur relatively early, usually three weeks or longer are necessary for liver function tests to become abnormal. It is important 'to differentiate this syndrome from other causes of cholestasis, such as hepatitis, choledocholithiasis and carcinoma. This reversible syndrome can effectively be managed by lowering the dextrose calories in hyperalimentation solution.
REFERENCES I . Sheldon GF, Peterson SR, Sanders R: Hepaticdysfunction during hyperalimentation. Arch Surg I13:504-508. 1978. 2. Blackburn GL, Flatt J P , Clo\\er G H K : Peripheral intravenous feeding with isotonic amino acid solutions. Am J Surg 125:447.
DISCUSSION OF CASE E. Steiger, M D Department of General Surgery The Cleveland Clinic Cleveland, Ohio 44106 Patients receiving total parenteral nutrition (TPN) can develop hepatic cellular dysfunction from a variety of non-nutritionally related causes. These include hepatitis (infectious, serum or drug-related) as well as cholangitis or biliary ductal obstruction. In evaluating this patient, 1 would first rule out these causative agents for this patient's liver dysfunctions. In the absence of fever, pain or known exposure to hepatoxins, and with a negative H A A (hepatitis-associated antigen) test, most of these causes for liver dysfunction could be effectively ruled out. A negative' biliary tract history and normal biliary tract findings at a previous laparotomy would also help t o rule out anatomic causes of biliary tract dysfunction. For purposes of this discussion, we will assume that the patient does not have any other sources for her liver dysfunction that are readily discernible except those that might be related to her T P N , and does not have liver failure. (For special applications of T P N in liver failure see Aguirre et al: "Parenteral Nutrition in Hepatic Failure" in Toral Parenreral Nit1rifiotz. J.E. Fischer (ed), Little, Brown and Company, 1976). There are three important causes for liver dysfunction in patients receiving T P N that are directly related t o the infusion of the nutrient solutions. The first i s a benign process in which SGOT, S G P T and alkaline phosphatase values become increased during TPN. With continuing intra570
venous feeding, these values tend to rcturn to\vard normal. This finding was reported in dogs infused with TPN fluids for four to eight weeks. Liver biopsies done prior to and at the end of the infusion period did not show any morphologic changes to account for the liver function abnormalities. These abnormalities may be d u e to induction ofenzyme systems secondary t o the high calorie amino acid feeding, but d o not seem t o be deleterious. The liver enzyme changes occurred whether the dogs received protein hydrolysate or crystalline amino acid solutions, but did not occur in orally fed controls. In a review of 75 consecutive patients who received T P N at o u r institution during the past year with crystalline amino acid solutions, we noted that the S G O T values tended to increase to their highest value (three times the baseline value) at about the 15th day of TPK; after that, they tended to decrease toward normal without any alterations in volume or composition of the infused fluid. The L D H (lactic dehydrogenase) showed n o significant change throughout the period of TI" in these patients, and the alkaline phosphatase values doubled, with the maximum value being noted at the 15th day again. These values tended to decrease toward normal with continuing T P N . The total bilirubin did not seem to change during the entire period of TPN. N o alteration in the intravenous dietary program was made in the 75 patients despite the fact that these elevations in the SGOT a n d alkaline phosphatase were noted. Yet these values did tend to return toward normal, and in this way mirrored the findings noted in the dogs, which had normal liver biopsies. Another potential liver problem that can be induced by T P N is the development of a fatty liver. This occurs when a n excess of dextrose calories is given iri relation t o the patient's caloric requirement, and the dextrose is converted into fatty acids and triglycerides and stored in the liver, causing a fatty liver. This has been reported experimentally in rats.' This manifests itself in the form of hepatomegaly, which can be appreciated by physical examination and liver scanning. For this reason, patients on T P N should have repeated physical examinations of the abdomen to ascertain whether or not hepatomegaly has developed. In its extreme forms, this can be associated with hypoalbuminemia and edema formation. Fatty liver is usually not associated with marked liver enzyme abnormalities or abnormalities in the bilirubin, but it can be in some instance^.^ My approach to treating T P N patients who have developed hepatomegaly along \vith liver function abnormalities is to decrease the intravenous dextrose load in each liter of T P X solution. For instance, I willgive 500 cc of amino acids plus 150 cc of 50% dextrose and 350 cc VOLUhlE 2 : S U h l B E R 4;1978
W I I. hf OR E
of distilled water for injection, t o constitute the full liter of T P N solution, and give 3 liters of this solution per day. In this way, the total amount of amino acids, electrolytes, vitamins and minerals are kept the s a m e a s before, but the amount of dextrose calories are markedly reduced. Reduction in liver size, along with improvement in liver function study results, should be noted after 7 t o 14 days of this regimen. A third liver function abnormality associated with T P N is the development of fatty infiltration of the liver secondary to the development of an essential fatty acid deficiency state. Richardson and Sgoutas‘ reported patients o n T P N who developed a fatty liver along with abnormalities in SGOT, S G P T , L D H and C P K (creatinine phosphokinase) which reverted back to normal when a source of essential fatty acids t o the intravenous dietary regimen was added. Bilirubin, total protein and alkaline phosphatase values did not change. Without the clinical manifestations of fatty acid deficiencies, such as scaly skin, rash and alopecia, the only other way t o diagnose this condition in the laboratory is by determination of linoleic, arachidonic a n d 5-8-1 I eicosatrienoic acid levels, and the demonstration that the triene to tetraene ratio, which is usually 0.4 or less, is increased. These biochemical determinations are not available in most hospital laboratories, so that the adequate biochemical diagnosis of essential fatty acid deficiency is often not readily available. For this reason, we have been using one 500-cc bottle of 10% Intralipid three t o four times a week t o provide sufficient amounts of linoleic acid to prevent essential fatty acid deficiency states from developing. This is started in all patients who are on T P N for two
THE JOURXAL OF PAREXTERAL A S D ESTERAL SUTRITIOS
weeks or longer. This would help to avoid the liver dysfunction associated with essential fatty acid deficiency that Richardson and Sgoutas have reportcd. In summary then, liver function abnormalities can occur in T P N secondary to: ( I ) presumed induced enzymatic changes that are not pathologic and d o not require any adjustment of the T P N formula; (2) development of fatty liver that can be remedied by reduction in the total amount of infused carbohydrate calories; and (3) development of fatty acid deficiency that can be prevented or treated by the infusion of a fat emulsion. Our policy is t o continue T P N despite elevation of liver enzymes that can occur in the first two to four weeks of TPN. After two weeks we routinelyadd one 500ml bottle of a 10% fat emulsion to the feeding regimen every other day. If hepatomegaly develops, the dextrose concentration in each liter of T P N solution is significantly reduced. T P N can be continued in each of these instances. If liver .function abnormalities continue to deteriorate, other etiologies must be ruled out and, rarely, one may have to resort to a trial stoppage of T P N therapy.
REFERENCES 1. Steiger E, Dudrick SJ, Daly Jht, et al: Growth and development of puppies nourished intravenously with crystalline amino acids as the sole source of dietary nitrogen. Fed Proc 29:363, 1970. 2. Chang S , Silvis SE: Fatty liver produced by hyperalimentation of rats. Am J Gastroenterol 62:410, 1974. 3. Spiro H hl: Clinical Gastroenterology. h’ew York, hlacmillan Co, 1970, Chapt 4. 4. Richardson TJ, Sgoutas D: Essential fatty acid deficiency in four adult patients during total parenteral nutrition. Am J Clin h’utr 28~258-63,1975.
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DISCUSSION OF CASE George F. Sheldon, MD Associate Professor of Surgery Chief of Trauma and Hyperalimentation Services University of California Service San Francisco General Hospital San Francisco, California 94 I I0 The case describes a common complication of parenteral nutrition (PN), intrahepatic cholestasis, which usually occurs approximately three weeks or longer after the initiation of intravenous feeding. It frequently occurs in patients who are successfully maintained on PN, in positive nitrogen balance and gaining weight. Intrahepatic cholestasis probably represents a n imbalance between the dextrose calories administered and the amino acids provided. It may be comparable to the severe fatty infiltration of the liver, which frequently occurs in patients with kwashiorkor. Patients with kwashiorkor have inadequate amino acid intake for lipoprotein synthesis, in the presence of sufficient carbohydrate intake. In the presence of sufficient carbohydrate intake but inadequate amino acid intake, acetyl, COA, is converted t o fatty acids whichare trapped by hepatocytes. It is unclear if this is the mechanism which results in intrahepatic cholestasis in patients receiving TPN, but such a mechanism is likely. It is conceivable that the somewhat nonspecific histological findings that are found in this syndrome may be secondary to fatty acid deficiency. With Intralipid lo%, currently available, we continue t o administer fat emulsion on a weekly or biweekly basis in patients developing signs of intrahepatic cholestasis. Although intrahepatic cholestasis occurs after extended periods (greater than 3 weeks) of PN, patients receiving home P N consisting of hypertonicdextrose and amino acids rapidly administered during a night time *This secriori of rhe Joirrnal was origirialed aridisediretl bJ Doirglus If'. ItThore. MD, f o r IIie pirrpose of exchurigiri~ ideas relerarlr 10 purerileral arid erireral riirtriiioti.
T H E JOURNAL OF PARENTERAL A N D ENTERAL NUTRITION
infusion will often develop swelling, tenderness and enlargement of the liver. Presumably the mechanism is comparable to the more gradual occurrence of intrahepatic cholestasis, although excess hepatic storage of glycogen probably occurs in hepatomegaly associated with home PN. The Hyperalimentation Service at San Francisco General Hospital has recently reported 33 cases of intrahepatic cholestasis in which liver biopsies were obtained in patients with this syndrome. Frequently the patients had received prolonged PN, but histological findings determined that intrahepatic cholestasis occurred in some patients within 24 hours. The histological appearance of the liver in intrahepatic cholestasis is that of pericanalicular round cell filtration, bile plugs and frothy and foamy hepatocytes. The syndrome is totally reversible; follow-up liver biopsies after iesumption of oral feeding reveal normal liver architecture. Patients with intrahepatic chqlestasis develo p characteristic liver function abnormalities. The initial abnormality is a n increase in the alkaline phosphatase test. Following elevation of the alkaline phosphatase, gradual increase in isoenzymes occurs, followed by elevation in the serum bilirubin. These nonspecific findings, of course, are compatible with the cholestatic phase of viral hepatitis, calculous disease of the biliary tract and metastatic carcinoma, diagnoses which must be entertained. Intrahepatic cholestasis is a reversible syndrome if appropriately treated. Treatment entails decreasing the dextrose component of the intravenous feeding routine. If the patient is receiving standard 25% dextrose, 4.25% amino acid solution, we would lower the dextrose concentration t o 15% while maintaining the same concentration of amino acids. An alternative approach' is to continue dextrose 25%:4.45% amino acids infusion for 12 of the 24 hours of infusion and alternate that solution with dextrose-free amino acids. Our preference, however, is for lowering the caloriemitrogen ratio, instead of cycling the therapy, as intermittent hypoglycemia has occurred in some patients who have been cycled. Liver 569
CIJNICAI. CASE PRESENTATIOS
function abnormalities will return t o normal within two weeks of lowering the ca1orie:nitrogen ratio. SU hl h l A R Y Intrahepatic cholestasis is a reversible complication of parenteral nutrition. Although histological abnormalities of lipid deposition and bile stasis occur relatively early, usually three weeks or longer are necessary for liver function tests to become abnormal. It is important 'to differentiate this syndrome from other causes of cholestasis, such as hepatitis, choledocholithiasis and carcinoma. This reversible syndrome can effectively be managed by lowering the dextrose calories in hyperalimentation solution.
REFERENCES I . Sheldon GF, Peterson SR, Sanders R: Hepaticdysfunction during hyperalimentation. Arch Surg I13:504-508. 1978. 2. Blackburn GL, Flatt J P , Clo\\er G H K : Peripheral intravenous feeding with isotonic amino acid solutions. Am J Surg 125:447.
DISCUSSION OF CASE E. Steiger, M D Department of General Surgery The Cleveland Clinic Cleveland, Ohio 44106 Patients receiving total parenteral nutrition (TPN) can develop hepatic cellular dysfunction from a variety of non-nutritionally related causes. These include hepatitis (infectious, serum or drug-related) as well as cholangitis or biliary ductal obstruction. In evaluating this patient, 1 would first rule out these causative agents for this patient's liver dysfunctions. In the absence of fever, pain or known exposure to hepatoxins, and with a negative H A A (hepatitis-associated antigen) test, most of these causes for liver dysfunction could be effectively ruled out. A negative' biliary tract history and normal biliary tract findings at a previous laparotomy would also help t o rule out anatomic causes of biliary tract dysfunction. For purposes of this discussion, we will assume that the patient does not have any other sources for her liver dysfunction that are readily discernible except those that might be related to her T P N , and does not have liver failure. (For special applications of T P N in liver failure see Aguirre et al: "Parenteral Nutrition in Hepatic Failure" in Toral Parenreral Nit1rifiotz. J.E. Fischer (ed), Little, Brown and Company, 1976). There are three important causes for liver dysfunction in patients receiving T P N that are directly related t o the infusion of the nutrient solutions. The first i s a benign process in which SGOT, S G P T and alkaline phosphatase values become increased during TPN. With continuing intra570
venous feeding, these values tend to rcturn to\vard normal. This finding was reported in dogs infused with TPN fluids for four to eight weeks. Liver biopsies done prior to and at the end of the infusion period did not show any morphologic changes to account for the liver function abnormalities. These abnormalities may be d u e to induction ofenzyme systems secondary t o the high calorie amino acid feeding, but d o not seem t o be deleterious. The liver enzyme changes occurred whether the dogs received protein hydrolysate or crystalline amino acid solutions, but did not occur in orally fed controls. In a review of 75 consecutive patients who received T P N at o u r institution during the past year with crystalline amino acid solutions, we noted that the S G O T values tended to increase to their highest value (three times the baseline value) at about the 15th day of TPK; after that, they tended to decrease toward normal without any alterations in volume or composition of the infused fluid. The L D H (lactic dehydrogenase) showed n o significant change throughout the period of TI" in these patients, and the alkaline phosphatase values doubled, with the maximum value being noted at the 15th day again. These values tended to decrease toward normal with continuing T P N . The total bilirubin did not seem to change during the entire period of TPN. N o alteration in the intravenous dietary program was made in the 75 patients despite the fact that these elevations in the SGOT a n d alkaline phosphatase were noted. Yet these values did tend to return toward normal, and in this way mirrored the findings noted in the dogs, which had normal liver biopsies. Another potential liver problem that can be induced by T P N is the development of a fatty liver. This occurs when a n excess of dextrose calories is given iri relation t o the patient's caloric requirement, and the dextrose is converted into fatty acids and triglycerides and stored in the liver, causing a fatty liver. This has been reported experimentally in rats.' This manifests itself in the form of hepatomegaly, which can be appreciated by physical examination and liver scanning. For this reason, patients on T P N should have repeated physical examinations of the abdomen to ascertain whether or not hepatomegaly has developed. In its extreme forms, this can be associated with hypoalbuminemia and edema formation. Fatty liver is usually not associated with marked liver enzyme abnormalities or abnormalities in the bilirubin, but it can be in some instance^.^ My approach to treating T P N patients who have developed hepatomegaly along \vith liver function abnormalities is to decrease the intravenous dextrose load in each liter of T P X solution. For instance, I willgive 500 cc of amino acids plus 150 cc of 50% dextrose and 350 cc VOLUhlE 2 : S U h l B E R 4;1978
W I I. hf OR E
of distilled water for injection, t o constitute the full liter of T P N solution, and give 3 liters of this solution per day. In this way, the total amount of amino acids, electrolytes, vitamins and minerals are kept the s a m e a s before, but the amount of dextrose calories are markedly reduced. Reduction in liver size, along with improvement in liver function study results, should be noted after 7 t o 14 days of this regimen. A third liver function abnormality associated with T P N is the development of fatty infiltration of the liver secondary to the development of an essential fatty acid deficiency state. Richardson and Sgoutas‘ reported patients o n T P N who developed a fatty liver along with abnormalities in SGOT, S G P T , L D H and C P K (creatinine phosphokinase) which reverted back to normal when a source of essential fatty acids t o the intravenous dietary regimen was added. Bilirubin, total protein and alkaline phosphatase values did not change. Without the clinical manifestations of fatty acid deficiencies, such as scaly skin, rash and alopecia, the only other way t o diagnose this condition in the laboratory is by determination of linoleic, arachidonic a n d 5-8-1 I eicosatrienoic acid levels, and the demonstration that the triene to tetraene ratio, which is usually 0.4 or less, is increased. These biochemical determinations are not available in most hospital laboratories, so that the adequate biochemical diagnosis of essential fatty acid deficiency is often not readily available. For this reason, we have been using one 500-cc bottle of 10% Intralipid three t o four times a week t o provide sufficient amounts of linoleic acid to prevent essential fatty acid deficiency states from developing. This is started in all patients who are on T P N for two
THE JOURXAL OF PAREXTERAL A S D ESTERAL SUTRITIOS
weeks or longer. This would help to avoid the liver dysfunction associated with essential fatty acid deficiency that Richardson and Sgoutas have reportcd. In summary then, liver function abnormalities can occur in T P N secondary to: ( I ) presumed induced enzymatic changes that are not pathologic and d o not require any adjustment of the T P N formula; (2) development of fatty liver that can be remedied by reduction in the total amount of infused carbohydrate calories; and (3) development of fatty acid deficiency that can be prevented or treated by the infusion of a fat emulsion. Our policy is t o continue T P N despite elevation of liver enzymes that can occur in the first two to four weeks of TPN. After two weeks we routinelyadd one 500ml bottle of a 10% fat emulsion to the feeding regimen every other day. If hepatomegaly develops, the dextrose concentration in each liter of T P N solution is significantly reduced. T P N can be continued in each of these instances. If liver .function abnormalities continue to deteriorate, other etiologies must be ruled out and, rarely, one may have to resort to a trial stoppage of T P N therapy.
REFERENCES 1. Steiger E, Dudrick SJ, Daly Jht, et al: Growth and development of puppies nourished intravenously with crystalline amino acids as the sole source of dietary nitrogen. Fed Proc 29:363, 1970. 2. Chang S , Silvis SE: Fatty liver produced by hyperalimentation of rats. Am J Gastroenterol 62:410, 1974. 3. Spiro H hl: Clinical Gastroenterology. h’ew York, hlacmillan Co, 1970, Chapt 4. 4. Richardson TJ, Sgoutas D: Essential fatty acid deficiency in four adult patients during total parenteral nutrition. Am J Clin h’utr 28~258-63,1975.
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