Arch Dis Child: first published as 10.1136/adc.60.8.774 on 1 August 1985. Downloaded from

774 Archives of Disease in Childhood, 1985, 60

This study was conducted at the Medical Research Council 3 Grosvenor P. Influences affecting mothers' decisions about Epidemiology Unit, Cardiff. The support of Professor Gray, infant feeding. (Thesis). Edinburgh, 1969. Robert Newcombe, and the lactation nurse is acknowledged. 4 Newson J, Newson E. Infant care in an urban community. London: George Allen and Unwin, 1963. 5 Martin J. Infant feeding 1975: attitudes and practice in England References and Wales. OPCS Social Survey Division. London: HMSO, 1978. 'Sloper K, McKean L, Baum JD. Factors influencing breast- feeding. Arch Dis Child 1975;50:165. Correspondence to Dr D A Jones, Research Team for Care of 2 Department of Health and Social Security. Present day practice Elderly, Welsh National School of Medicine, Cardiff CF4 4XN. in infant feeding. Report on Health and Social Subjects. London: HMSO, 1974. Received 15 March 1985

Pathogenesis of liver damage during parenteral nutrition: is lipofuscin a clue?

H M BERGER, A L DEN OUDEN, AND J J CALAME Departments of Pediatrics and Pathology, University Hospital Leiden, The Netherlands

arteriosus. This did not respond to fluid restriction SUMMARY Lipofuscin develops in cells when per- or treatment with frusemide and indomethacin, oxidation damage occurs. Its development in the and surgical ligation was performed (on day 60).

liver of patients receiving prolonged parenteral The baby received total parenteral nutrition for copyright. nutrition suggests that peroxidation damage by free the first 20 days. Repeated attempts to introduce radicals has occurred. Deficiencies in antioxidants expressed mother's milk or formula feeds failed, and such as vitamin E may be an important contributing a further 40 days of total or partial parenteral factor. feeding was needed. The regimen (150 ml, 372 KJ/Kg/24 hours) included 7% Vamin (Kabivitrum, Stockholm, Sweden) (30 ml/Kg/24 hours) and 10% Peroxidation damage by free radicals can cause Intralipid (Kabivitrum, Stockholm, Sweden) (30 disease of the liver-for example, carbon tetra- ml/Kg/24 hours) with added fat soluble vitamins A, http://adc.bmj.com/ chloride poisoning' and alcoholic cirrhosis.2 The D, and K (Vitalipid; Kabivitrum, Stockholm, pathogenesis of the damage to the liver in patients Sweden). Water soluble vitamins and trace elements receiving parenteral nutrition is unknown. Lipo- were added to the 10% glucose and electrolyte fuscin found often in hepatic cells may be an infusion. Enteral vitamin E (alpha tocopherol ace- important clue. Lipofuscin, a complex of lipids, tate, 10 mg/Kg/24 hours) was given when milk feeds proteins, and malonaldehyde, develops when sub- were tolerated.

cellular membranes are damaged by peroxidation of The initial physiological jaundice (highest level on on September 27, 2021 by guest. Protected free radicals.1 3 day 5; total serum bilirubin concentration 181 limol/l; and conjugated bilirubin concentration 14 Case report ,umol/l) resolved after phototherapy. On day 30 the baby developed cholestatic jaundice with a 2 cm A 930 g girl was born at 27 weeks' gestation after her hepatomegaly. The bilirubin (total concentration mother had developed amnionitis. She was elec- 200 ,umol/l, conjugated bilirubin concentration 164 tively ventilated and treated for pneumonia with ,umol/l), serum aspartate transaminase (122 U/l), intravenous ampicillin and gentamicin for 14 days. and serum alainine transaminase (42 U/l) con- No bacteria were cultured, and on day 10 treatment centrations had increased. Serology showed no with intravenous fluorocytosine and amphotericin evidence of infection-for example with cytomega- were started after Candida albicans had been cul- lovirus. The serum a, antitrypsin concentration and tured in urine obtained by bladder puncture. Con- concentration of chloride in sweat were normal, and tinuous positive airway pressure was required for no reducing substances were present in the urine recurrenAI- apnoeic attacks. when the baby was given milk feeds. Ultrasound Cardiac failure developed due to a patent ductus study of the liver and biliary tree showed normal Arch Dis Child: first published as 10.1136/adc.60.8.774 on 1 August 1985. Downloaded from

Pathogenesis of liver damage during parenteral nutrition 775 findings. A low plasma vitamin E concentration developing normally and had no evidence of liver (10-4 Rmol/l) was found on day 28. disease. A percutaneous needle biopsy of the liver was performed (day 60). The architecture of the liver Discussion was normal on light microscopy. Stains with haema- toxylin and eosin showed a yellow brown lipofuscin Histochemical and ultrastructural studies have sug- like pigment in some of the Kupffer cells but not in gested that the granules of pigment seen in the liver the hepatocytes. Kupffer cells and hepatocytes after parenteral nutrition are lipofuscin.4 5 The contained periodic acid Schiff positive granules electron microscopic features we found are further resistant to digestion by diastase, suggestive of the evidence3 to support those finding. lipofuscin pigment found after parenteral feeding.4 Previously, the accumulation of this pigment in Bile pigment was present in the hepatocytes and subjects was considered to be a complication of dilated canaliculi. receiving fat emulsions ('intravenous fat pigment').6 Electron microscopy showed phagolysosomal As the damage to the liver also occurs when no fat structures within the cytoplasm of the Kupffer cells emulsion has been used the presence of lipofuscin and hepatocytes (Figure (a) and (b)). These struc- has not been linked to the pathogenesis of the tures, enveloped by a single limiting membrane, disease. When we reviewed previous reports, contained partly electron dense, and partly electron however, we found that lipofuscin had been found in lucent granular material. Electron lucent vacuoles, the liver even when only amino acid and glucose well developed in the Kupffer cells, were also electrolyte mixtures had been infused.4 5 Cohen present. These I3ysosomal structures are compatible and Olsen detected lipofuscin in 90% of their with lipofuscin. babies, though only 35% had received fat emulsion.4 The cholestatic jaundice was as a result of its There is a powerful antioxidant defence system in typical course and exclusion of other causes con- man-for example, enzymes such as glutathione sidered to be related to the parenteral nutrition. The peroxidase and free radical scavengers such as

liver dysfunction rapidly resolved when complete vitamin E.' Nutritional deficiencies-for example, copyright. nasoduodenal feeding was tolerated after day 100. in selenium and vitamin E-that develop with At 2 years of age the child was growing and parenteral feeding could weaken the antioxidant http://adc.bmj.com/ A:: - on September 27, 2021 by guest. Protected

Figure (a) The Kupffer cell between two hepatocytes (A) contains intracytoplasmic structures (arrows), which resemble lipofuscin granules. x 9200 (original magnification). (b) Lipofuscin granule in a hepatocyte. Borders (B) ofthe cell and an adjacent hepatocyte are shown. x26 000 (original magnification). Arch Dis Child: first published as 10.1136/adc.60.8.774 on 1 August 1985. Downloaded from

776 Archives of Disease in Childhood, 1985, 60 defences and allow damage by free radicals. The References vitamin mixtures that we added to the intravenous Dormandy TL. An approach to free radicals. Lancet solutions did not contain vitamin E, and Intralipid 1983;ii:101 1-4. contains only inactive gamma tocopherol. Our 2 Lewis KO, Paton A. Could superoxide cause cirrhosis? Lancet patient did have a low plasma vitamin E concentra- 1982;ii:188-9. 3 Brizzee KR, Ordy JM. Cellular features, regional accumula- tion when damage to the liver became evident. tion, and prospects of modification of age pigments in mammals. The aetiology of cholestatic jaundice after In: Sohal RS, ed. Age pigments. Amsterdam: Elsevier Bio- parenteral feeding is not known. The presence of medical Press, 1981:101-54. lipofuscin in the hepatic cells suggests that 4 Cohen C, Olsen MM. Pediatric total parenteral nutrition, liver peroxida- histopathology. Arch Pathol Lab Med 1981;105:152-6. tion damage by free radicals plays a part in the 5 Bernstein J, Chang CH, Brough AJ, Heidelberger KP. Conju- pathogenesis of this disease. Investigation into the gated hyperbilirubinemia in infancy associated with parenteral role of damage by free radicals is indicated as it may alimentation. J Pediatr 1977;90:361-7. be possible to prevent this disease by antioxidant 6 Koga Y, Swanson VL, Hays DM. Hepatic 'intravenous fat pigment' in infants and children receiving lipid emulsion. treatment. J Pediatr Surg 1975;10:641-8. We thank Professor Kenneth R Brizzee, Delta Regional Primate Correspondence to Dr H M Berger, Department of Paediatrics, Research Center, Louisiana, United States of America, for his University Hospital Leiden, 2333 AA Leiden, The Netherlands. suggestions on the interpretation of the electron microscopic findings. Received 22 April 1985 copyright.

Shredding of manuscripts http://adc.bmj.com/ From 1 January 1986 articles submitted for publication will not be returned if the paper is rejected unless this is requested at the time of submission. Authors whose papers are rejected will be advised of the decision; the manuscripts will be kept under security for three months to deal with any enquiries and then destroyed by shredding. on September 27, 2021 by guest. Protected