Hepatic Failure in Infants on Total P a r e n t e r a l Nutrition (TPN): Clinical and H i s t o p a t h o l o g i c Observations By Jonathan E. Hodes, Jay L. Grosfeld, Thomas R. Weber, Richard L. Schreiner, Joseph F. Fitzgerald, and L. David Mirkin Indianapolis, Indiana 9 Total parenteral nutrition (TPN) is an i m p o r t a n t adjunct in the care of neonates w i t h surgical disorders. Although cholestasis complicates TPN in 30% of cases, it is usually transient in nature. This report, h o w e v e r , describes 9 instances (8 fatal) of progressive liver failure in surgical neonates w h o w e r e maintained on prolonged TPN (6 w k - 1 5 me) and d e m o n s t r a t e d distinct hepatic pathologic changes. Diagnosis included complicated gastroschisis, (2) bowel atresia w i t h peritonitis (1), NEC (4), prune belly and antenatal peritonitis (1), and t o t a l colonic and ileal aganglionosis (1). Mean gestational age was 35 w k w i t h sexes equally affected. The 8 fatal cases had persistant cholestasis t h a t failed t o respond to changes in parenteral protein or glucose concentrations. Enteral feedings w e r e not tolerated. Clinical d e t e r i o r a t i o n was manifested by increasing serum bilirubin ( 2 2 - 3 5 mg%), clotting dysfunction, enzyme elevations (SGOT}, and hepatomegaly. Histologic e x a m i n a t i o n of the liver showed significant distort i o n of hepatic a r c h i t e c t u r e w i t h h e p a t o c y t e s arranged in pseudoacini rather than cords and trapped by fibrous tissue. Bile duct proliferation was noted, but ducts contained no bile. Bile plugs w e r e seen in canaliculi only. Hepatocytes s h o w e d diffuse vacuolization ( + for fat) and contained b r o w n pigm e n t (-I- for iron). Portal triads w e r e free of inflammation. Ultrastructural examination showed hepatocytes in an acinar array surrounded by collagen. Cystic changes in the endoplasmic reticulum, osmophilic cytoplasmic pigment, lipid droplets, and severe glycogen depletion consistent w i t h a c y t o t o x i c insult w e r e seen. Prematurity, i m m a t u r e liver function, and amino acid imbalance w i t h f o r m a t i o n of a t o x i c bile salt are implicated in these findings. Peritonitis, sepsis and inability t o t o l e r a t e enteral feedings may also play a role. These observations indicate a need t o modify TPN application in selected prematures requiring long-term nutritional support.
ment, catheter related sepsis, physiologic responses to a rapid increase or decrease in the administered carbohydrate load, vitamin, trace element and fatty acid deficiencies, electrolyte disturbances, and hyperosmolar coma. More recently, cholestatic jaundice and liver disease associated with total parenteral nutrition (TPN) have also been described) -29 Cholestasis has been reported as a complication of TPN in 30%-42% of cases. 7"22It is usually benign and transient in nature. Transient cholestasis has been observed with short periods (less than 14 days) of either total parenteral nutrition (TPN) or partial parenteral nutrition (PPN). 2~ In neonates receiving parenteral nutritional support for greater than 14 days, severe chemical hepatic dysfunction has also been described and correlated with histologic changes in the liver. 22'2s In the majority of infants with cholestasis, enzymatic and histologic abnormalities usually return to normal following the discontinuation of parenteral nutrition and the initiation of oral alimentation. In some infants however, oral intake cannot be tolerated and continued parenteral nutrition is required. These babies, especially the premature infant, are at risk of developing cholestasis related hepatocellular dysfunction and, in some cases, death secondary to progressive hepatic failure. MATERIALS A N D METHODS This report concerns nine infants treated on the Pediatric Surgical Service at the James Whitcomb Riley Hospital for Children, Indiana University Medical Center, from J u l y
INDEX WORDS: Total parenteral nutrition; cholestasis.
HE PARENTERAL INFUSION of proT tein hydrolysates, dextrose, essential amino acids, and emulsions of fat to support neonates who are unable to appropriately utilize their alimentary tracts has been a major advance in pediatric care. The majority of patients that are supported in this manner demonstrate few ill effects. Complications that have been reported include those associated with catheter placeJournal of Pediatric Surgery, Vol, 17, No. 5 (October), 1982
From the Sections of Pediatric Surgery, Neonatology, Gastroenterology, and Pathology, Indiana University School of Medicine and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Presented before the 30th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, New Orleans, La., October 31-November l, 1981. Address reprint requests to Jay L. Grosfeld, M.D., Surgeon-in-Chief J.W. Riley Hospital for Children, 1100 W. Michigan Street, Indianapolis, Ind. 46223. 9 1982 by Grune & Stratton, Inc. 0022-3468/82/1705~9003501.00/0
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1978 through June 1981, who developed cholestasis while receiving total parenteral nutrition and subsequently had progressive severe hepatic dysfunction. Diagnoses included necrotizing enterocolitis (NEC) in 4, bowel atresia and peritonitis in 1, gastroschisis in 2, prune belly and antenatal peritonitis in 1, and total colonic and partial ileal aganglionosis in I. In addition, 8 of:the 9 patients were premature (28-36 wk gestation), 7 required ventilatory support because of respiratory distress, 2 had renal failure, all had evidence of peritonitis, and all had documented sepsis at least once during hospitalization. Operative procedures included gastro-
schisis repair (2), resection of small bowel stricture (1), right colectomy (2), appendectomy (2), enterostomy (4), subtotal colectomy and distal ileectomy (2), lysis of adhesions (2), Nissen fundoplication (1), gastrostomy (4), abdominal abscess drainage (1), inguinal herniorrhaphy (2), transhepatic cholangiography (1), and peritoneal dialysis (1). Indications for parenteral nutrition included inability "to use the alimentary tract following operation, sepsis, prematurity, and failure to thrive. All patients were maintained on parenteral nutrition for prolonged periods of time (6 wk-15 mo). All but 1 patient
Table 1. Gestationa| Age, Weight, Diagnoses and Procedures Performed in Infants Receiving Parenteral Nutrition Patient
Gestational Age (wk)
Total colonic and partial ileal agan glionosis
Prune belly antenatal peritonitis
Gastroschisis with jejunal atresia
Jejunal atresia with malrotation
Birth Weight (kg)
Procedures 2-stage gastroschisis repair Liver biopsy Central line • 3 50% small bowel resection, right colectomy, double barrel colostomy Central line • 3 Resection and primary anastomosis of small bowel stricture, appendectomy Liver biopsy Double barre) anastomosis Central line • 2 Total colectomy, 63-cm ileectomy, ileostomy Lysis of adhesions Nissen fundoplication with anterior vagotomy, gastrostomy and pyloroplasty Liver biopsy Central line x 5 Distal jejunal and proximal ileal resection, double barrel enterostomy Takedown enterostomy and gastrostomy Central line x 3 Massive enterolysis Left inguinal herniorrhaphy Drainage intra-abdominal abscesses with enterostomy Liver biopsy Central line X 2 Total colectomy, terminal ileectomy, ileostomy, gastrostomy Peritoneal dialysis Intra-abdominal abscess drainage revision ileostomy and gastrostomy Central line x 2 2-stage gastroschisis repair Jejunal segment resection with primary anastomosis Liver biopsy Lysis of adhesions Central line • 3 Tapering jejunoplasty, small bowel Resection, jejuno-ileostomy, Gastrostomy, appendectomy, Central line x 6
HEPATIC FAILURE ON TPN
eventually died secondary to hepatic failure. Serial serum glutamic oxaloacetic transaminase (SGOT) and total and direct serum bilirubin concentrations were reviewed in all 9 patients. Liver biopsies were examined from 3 infants while alive and in 8 autopsied patients. In the 3 patients who underwent early liver biopsy, hepatic tissue was obtained for both routine histology and electron microscopic examination. Biopsy specimens were fixed in 10% formalin or 3% glutaraldeyde solutions and processed for routine and ultrastructural pathological examination. Five micron sections were stained with oil red-O, Prussian blue, hematoxylin and eosin, trichrome and reticulin. In all the infants studied, alpha1-antitrypsin deficiency, hepatitis B and A infection, and other congenital infections (Toxoplamosis, Rubella, Cytomegalovirus, Herpes simplex and Syphilis) were excluded. Extrahepatic obstruction was excluded either during life by PIPIDA scan or at autopsy. Total or peripheral parenteral nutrition was started within the first 2 wk of life in each instance. Infants received a minimum of 100 Kcal/kg/day with an average of 1.5-3.0 g/kg/day protein, 12-20 g/kg/day glucose, and 1.5-3.0 g/kg fat (10% Intralipid--Abbott Laboratories) every other day. Infants received water soluble vitamins including folic acid daily and fat soluble vitamins and trace mineral solution three times per week. Protein was provided as a solution of amino acids (Aminosyn--Abbott Laboratories or Freamine--McGraw Laboratories). R E S U L T S
The gestational age, birth weight, and diagnoses of affected patients are presented in Table 1. The mean gestational age of the patients was 35 _+ 6 wk with a range of 29-40 wk. The mean birthweight was 1.5 kg _+ 2.75 kg, with a range of 0 . 9 4 . 2 3 kg. All 9 patients had 1 or more episodes of documented bacterial sepsis. In each instance the primary disease process precluded discontinuation of total parenteral nutrition although in some infants, attempts at oral supplemental feedings were initiated several times. One such infant could not be weaned from parenteral nutrition because of the inability to tolerate any form of enteral nutrition secondary to severe intractable diarrhea. All patients showed a consistant and progressive increase in total and direct bilirubin concentrations (Fig. 1). The increase in the serum total bilirubin concentrations (maximum level 22-35 mg%) coincided with elevation of liver enzymes and abnormalities of other liver function tests. All patients received vitamin K parenterally without improvement in their prothrombin times. Hypoalbuminemia was also observed. The only survivor (no. 7) was successfully weaned from T P N and eventually tolerated an enteral diet. This patient's serum total biliru-
D~,,cqh i .
•4 22 20 18
Fig. 1. Serial total and direct bilirubin concentration in patient no. 5.
bin concentration gradually returned to normal from a high value of 29 mg %. In the 8 patients that died, severe jaundice persisted despite attempts to modify both the glucose and protein concentrations of the T P N solutions. The terminal course was associated with multiple organ failure. S G O T values did not correlate well with the degree of hepatic failure; however, all the terminal patients had S G O T values in excess of 10 times the normal value when they expired. Liver histology was remarkably consistent from patient to patient. By light microscopy significant distortion of hepatic cytologic architecture was evident. Hepatocytes were arranged in pseudoacini and pseudotubules rather than cords and groups of hepatocytes were trapped by fibrous tissue (Fig. 2). There were areas of extensive fibrosis that disrupted the pseudoacinar pattern. The pseudoacini were centered by bile filled canaliculi. All biopsy specimens showed bile duct proliferation (Fig. 3) with bile plugs seen only in canaliculi. Bile ducts appeared clear of bile. Hepatocytes showed diffuse cytoplasmic vacuolization without significant nuclear displacement. Vacuoles stained positively for fat. Golden brown pigment that stained positive for iron was seen in many hepatocytes. Normal appearing portal triads were seen without evidence of triaditis or chronic inflammation. Ultrastructural examination showed groups of hepatocytes in an acinar-like array surrounded by collagen (Fig. 4). Nearly all canaliculi appeared normal. Ballooning cystic changes in the endoplasmic reticulum, osmophilic cytoplasmic pigment, lipid droplets, and severe glycogen depletion were seen. These findings are consistent with a primary cytotoxic insult. The finding
HODES ET AL.
Fig. 2. Diffuse fibrosis surrounding hepatocytes (dark cytoplasm). Many hepatocytes contain large clear vacuoles. Few bile plugs are present (arrow).
of normal canaliculi is evidence against a primary obstructive mechanism as the cause of cholestasis. DISCUSSION
Cholestasis has been associated with sepsis, prematurity, dehydration, gastrointestinal obstruction, drug toxicity, prolonged fasting and erythroblastosis fetalis. In the infants described in this article, the cholestasis was not transient or benign but rather progressive and resulted in the death of 8 of the 9 patients from chronic hepatic insufficiency. The cause of severe hepatic dysfunction in these patients is probably multifactorial; however, parenteral nutrition is certainly implicated. Rodgers et al. described 11 similar infants with progressive cholestasis, 9 of whom died. 9 Their liver histology and clinical courses were quite similar to our series of patients. Postuma et al. described two additional deaths in infancy related9 to TPN cholestasis and progressive liver failure, z2
Fig. 3. Biliary duct proliferation enmeshed in loose fibrous tissue.
There are undoubtedly multiple contributing factors to the progressive hepatic failure in these infants. It appears that prematurity predisposes the infant to cholestasis, as the vast majority of infants with TPN related cholestasis reported in the literature have been premature. Some evidence suggests that taurine may be an essential amino acid in preterm and small neonates due to hepatic enzyme immaturity or deficiency. ~3 In premature infants, inadequate levels of cysteinesulfonic acid decarboxylase, which is required to convert methionine and cysteine to taurine, result in increased methionine and cysteine and decreased taurine concentrations. Taurolithocholate, the conjugated secondary bile salt, has been shown to cause cholestasis and result in direct damage to the canalicular membrane in experimental animals. Taurocholate, the conjugated bile salt, exerts a protective effect on taurolithocholate induced cholestasis. ~5 Sondheimer et al. reported that serum conjugates of cholic acid increase after 2 wk of intravenous hyperalimentation in neonates weighing less than 2 kg at birth. ~9 Our experience seems to confirm
HEPATIC FAILURE ON TPN
Fig. 4. Electron micrograph of pseudoacinus in cirrhotic liver secondary to TPN. Note collagen surrounding hepatocytes, normal canaliculi (arrows), dilated endoplasmic reticuIum, osmophilic pigment accumulation, and glycogen depletion.
that premature infants are much more susceptible to T P N related cholestasis. Sepsis and peritonitis must also be considered as possible contributing factors. Six of nine infants in the current report and the majority of infants in previously reported studies had necrotizing enterocolitis (NEC) or gastroschisis. In addition, all of our patients' clinical courses were complicated by sepsis at least once. Manginello found no difference in bile acid concentrations in severely ill patients on T P N and those fed enterally except in those infants with documented sepsis who received TPN. These latter patients had increased levels of serum bile acids. 23 Our patients were treated with a variety of systemic antibiotics for varying lengths of time. None of the antibiotics used have been shown to cause intrahepatic cholestasis. The neonates all had more than one surgical operation with exposure to volatile anesthetic agents including halothane. The hepatic histology observed in these infants however, is not at all consistent with the fulminant hepatitis pattern that has been observed occasionally in adults given halothane. Some investigators have suggested that a lack of enteral stimulation may contribute to choles-
tasis. 6 Seven of the nine patients in the present study received a small part of their alimentation orally. Although Intralipid has been implicated as a cause of bile stasis ]~ more recent investigations have not shown lipid to correlate with severe hepatic dysfunction. <2~ Infusion of protein hydrolysates may change the serum amino acid composition. 2 Vileisis et al. observed that patients receiving a high proportion (33%) of daily calories in the form of protein developed higher serum bilirubin concentrations earlier than those receiving less protein (27%). 27 In an experimental model, amino acid infusions resulted in a marked anticholeretic effect. 17 Recent biochemical evidence suggests that amino acid infusion may initially cause canalicular membrane dysfunction in neonates. 29 Cases of progressive cholestasis and hepatic failure due to T P N in infants previously described in the literature as well as our patients had a similar clinical course and pathologic pattern. With obvious multiple contributing factors it is difficult to assess the extent that T P N contributes to this pathologic entity. The affected infants were in a high risk group that would most likely die without parenteral nutrition support. The most compelling observation that implicates T P N as the inducer of hepatic failure is that when the patient can be alimented orally and T P N is discontinued, biochemical evidence of hepatic dysfunction disappears. The only survivor in this group of nine infants was fully supported nutritionally by the enteral route and weaned from TPN. On the other hand, a more recent liver biopsy obtained from this infant at the time of enterostomy closure (for NEC) showed evidence of portal fibrosis and cirrhosis. This observation suggests that even in survivors, the risk of chronic liver disease is present. The clinical picture of hepatic dysfunction related to T P N in older children is both biochemically and histologically different than that seen in infancy. Symptoms usually begin with hepatomegaly and elevated aminotransferase levels. When the latter is greater than 400 IU, jaundice is noted. Biopsy in the older child shows hepatocytes distended with glycogen and fat vacuoles. These findings are transient and reversible in nature. Prematurity, immature liver function, amino acid imbalance with possible formation of a toxic
HODES El" AL.
bile salt m a y all be i m p l i c a t e d in t h e h e p a t i c f a i l u r e in infants. P e r i t o n i t i s , sepsis, a n d t h e i n a b i l i t y to t o l e r a t e e n t e r a l f e e d i n g s m a y also p l a y a significant role in t h e initial d e v e l o p m e n t a n d s u b s e q u e n t p r o g r e s s i o n o f this illness. P r o -
gressive and often fatal cholestasis most comm o n l y o c c u r s in i n f a n t s w i t h N E C . T h e s e observ a t i o n s i n d i c a t e a n e e d to m o d i f y T P N a p p l i c a tion in s e l e c t e d p r e m a t u r e i n f a n t s r e q u i r i n g l o n g term parenteral nutritional support.
1. Peden VH, Witzleben CL, Skelton MA: Total parenteral nutrition. J Pediatr 78:180-181, 1971 2. Stegink LD, Baker GL: Infusion of protein hydolysates in the newborn infant: Plasma amino acid concentrations. J Pediatr 78:595-602, 1971 3. Johnson JD, Albritton WL, Sunshine P: Hyperamonemia accompanying parenteral nutrition in newborn infants. J Pediatr 81:154-161, 1972 4. Chang S, Silvis SE: Fatty liver produced by hyperalimentation of rats. Am J Gastroenterol 62:410-418, 1974 5. Koga Y, lkeda K, Inokuchi K: Effect of complete parenteral nutrition using fat emulsion on liver. Ann Surg 18l:186-190, 1975 6. Rager R, Finegold M J: Cholestasis in immature newborn infants: Is parenteral alimentation responsible? J Pediair 86:264-269, 1975 7. Touloukain R J, Seashore JH: Hepatic secretary obstruction with total parenteral nutrition in the infant. J Pediatr Surg 10:353-360, 1975 8. Koga Y, Swanson VL, Hays DM: Hepatic "intravenous fat pigment" in infants and children receiving lipid emulsion. J Pediatr Surg 10:641-648, 1975 9. Rodgers MB, Hollenbeck Jl, Donnelly WH, et al: lntrahepatic cholestasis with parenteral alimentation. Am J Surg 131:149-155, 1976 10. Passwell JH, David R, Katznelson D, et al: Pigment deposition in reticuloendothelial system after fat emulsion infusion. Arch Dis Child 51:366-368, 1976 11. Zarif MA, Pildes RS, Szanto PB, et al: Cholestasis associated with administration of L-amino acids and dextrose solutions. Biol Neonate 29:66-76, 1976 12. Neselof R, Lesec G, Ricour C, et al: Cristaux organiques intrahepatiques au cours des nutritions artificilles chez l'enfant. La Nouv Press Med 6:3943-3947, 1977 13. Rigo J, Senterre J: Is taurine essential for the neonates? Biol Neonate 32:73-76, 1977 14. Grant JP, Cox CE, Kleinman LM, et al: Serum hepatic enzyme and bilirubin elevations during parenteral nutrition. Surg Gynecol Obstet 145:573-580, 1977 15. Layden TJ, Boyer JL: Taurolithocholate-induced eholestasis: Taurocholate, but not dehydrocholate, reverses cholestasis and bile canalicular membrane injury. Gastroenterol 73:120-128, 1977
16. Bernstein J, Chang C-H, Brough AJ, et al: Conjugated hyperbilirubinemia in infancy associated with parenteral alimentation. J Pediatr 90:361-367, 1977 17. Preisig R, Rennert O: Biliary transport and cholestatic effects of amino acids. Gastroenterol 73:1240, 1977 (abstr) 18. Brown MR, Putnam TC: Cholestasis associated with central intravenous nutrition in infants. NY State J Med 78:27-30, 1978 19. Sondheimer JM, Bryan H, Andrews W, et al: Cholesratio tendencies in premature infants on and off parenteral nutrition. Pediatrics 62:984-989, 1978 20. Sheldon GF, Petersen SR, Sanders R: Hepatic dysfunction during hyperalimentation. Arch Surg 113:504-508, 1978 21. Allardyce DB, Salvian A J, Quenville NF: Cholestatic jaundice during total parenteral nutrition. Can J Surg 21:332-339, 1978 22. Postuma R, Trevenen CL: Liver disease in infants receiving total parenteral nutrition. Pediatrics 63:110-I 15, 1979 23. Manginello FP, Javitt NB: Parenteral nutrition and neonatal cholestasis. J Pediatr 94:296-298, 1979 24. Lindor KD, Fleming CR, Abrams AA, et al: Liver function values in adults receiving total parenteral nutrition. JAMA 241:2398-2400, 1979 25. Beale EF, Nelson RM, BucciareUi RL, et al: Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 64:342-347, 1979 26. Dahms BB, Halpin TC: Serial liver biopsies in parenteral nutrition associated cholestasis of early infancy. Lab Invest 42:170--171, 1980 (abstr) 27. Vileisis RA, Inwood R J, Hunt CE: Prospective controlled study of parenteral nutrition associated cholestatic jaundice: Effect of protein intake. J Pediatr 96:893-897, 1980 28. Cohen CC, Olsen MM: Pediatric total parenteral nutrition; liver histopathology. Arch Pathol Lab Med 105:152-156, 1981 29. Black DD, Suttle AE, Whitington PF, et al: The effect of short-term total parenteral nutrition on hepatic function in the human neonate: A prospective randomized study of demonstrating alteration of hepatic canalicular function. J Pediatr 99:445-449, 1981