Annals of Diagnostic Paediatric Pathology

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92 Summary Liver steatosis of severe degree involving 100% of liver parenchyma was found in three patients (No 1, 2, and 5) who died during ALTE. Moderate steatosis involving approximately 60% of liver was present in one biopsy ( No 3). Mild steatosis affecting 30% and 15% of liver parenchyma was found in two biopsies coming from cases 4 and 6, respectively. In one autopsy sample liver steatosis involved 10% of parenchyma (No 7). Steatosis was macrovacuolar or mixed. The first type was found in two sequential examinations of the same patient (biopsy – No 4 and autopsy – No 5) and in two autopsies (samples No 2 and 7). Macrovacuolar steatosis was severe in two cases (No 2 and 5) and mild in two others (No 4 and 7). Mixed steatosis was seen in two biopsies (No 3 and 6) and one autopsy (No 1). Its degeree was mild (sample No 6), moderate (sample No 3), and severe (sample No 1). None of the patients had pure microvacuolar fatty liver. In six cases distribution of steatotic hepatocytes was diffuse, in one focal (sample No 4). Inflammation was present in three cases. It was mild (cases No 3 and 5) or severe (case No 4). Fibrosis was disclosed in four examined samples derived from three patients: in two cases its intensity was mild (No 2 and 7) in two severe (samples No 4 and 5). Liver biopsy samples available for assessment from the same patient disclosed progression from precirrhosis to cirrhosis. Data concerning patients and their liver morphology are presenting in Table 1. Discussion It is known that the process of mitochondrial fatty acid oxidation can be divided in two stages. First involves transport through mitochondrial membrane, the second consists of cutting off two-carbon moieties from fatty acid chain by several enzymes for long, medium, and short chain fatty acids, respectively [5, 9, 11]. Fatty liver may develop in both patients with defects of the first stage involving carnitine dependent transport [2, 3, 12], and with defects of the proper beta-oxidation [2, 4, 6-8, 10, 11]. Baldridge in his study of 82 patients with liver steatosis reported only one child in whom the LCHAD deficiency was established [1]. Our group comprises six patients with this diagnosis. Roe and Coates provided general description of liver morphology in LCHAD deficiency [9]. They pointed lipid accumulation and sometimes accompanying fibrosis as characteristic features of this disorder. Our findings are consistent with this observation. However, they have not provided particulars concerning intensity, type, and distribution of steatosis. Gilbert-Barness and Barness have presented more detailed description of liver microscopical pathology in LCHAD deficient patients [5]. They considered diffuse or zonal macrovacuolar severe fatty liver to be characteristic of the majority of LCHAD-deficient patients. In our group this type of morphological pattern was found in three patients always when the liver biopsy was performed at the acute clinical presentation. In a number of described patients with LCHAD deficiency the liver discloses only focal steatosis of mild intensity [5]. We observed focal fatty changes only in one case out of seven (sample No 4). In remaining patients the degree of steatosis was mild to moderate and was almost invariably diffusely distributed. Moore described morphology of the liver in six months old girl with LCHAD deficiency [7]. There were mixed steatosis accompanied by mild cholestasis. Author has not provided data concerning intensity and localization of fatty changes. In our series of seven cases we did not find any case with the features of cholestasis. Tyni described liver morphology including microscopical findings of 16 patients coming from 12 families, who died with diagnosis of LCHAD deficiency [11]. All patients in her study had features of macrovacuolar fatty liver. In our patients steatosis was not only macrovacuolar, but also mixed. Tyni concluded that steatosis was typical for fatty acid beta oxidation defects, and emphasized that accompanying fibrosis was Table 1 Details of morphological changes of the liver in patients with LCHADD Type of examination Sample No Age (mo) Intensity of steatosis (%) Type of steatosis Localization of steatosis Inflammation Fibrosis Cholesta A 3299 4 100 mixed diffuse no no no A 3289 3 100 macro diffuse no mild no B 30573 12 60 mixed diffuse mild no no B 30760 3 30 macro focal severe precirrhosis no A 2701 6 100 macro diffuse mild cirrhosis no B 51605 7 15 mixed diffuse no no no A 3070 6 10 macro diffuse no mild no
93 especially typical for LCHAD deficiency [11]. In our series the fibrosis was found in four out of seven liver samples (obtained from three children). Tyni suggested presence of relationship between the severity of clinical course and the intensity of morphological changes in the liver [11]. Our observations are in agreement with this statement. Our observations strongly underline that liver steatosis of any degree detected at autopsy of a child died without clearly established diagnosis obliges to include fatty acids oxidation disorders into the differential diagnosis [2]. One of our patient, died many years ago with the diagnosis of hypertrophied cardiomyopathy, was detected just recently as LCHAD-deficient during genetic family study, after establishing LCHAD deficiency in her younger brother. Lack of acute life threatening episode in her medical history and only mild degree of liver steatosis in her post mortem examination, preliminarily did not paid our attention and missed from correct diagnosis. In general our results are consistent with observations of other authors and warrant drawing the following conclusions: 1. Fatty liver is characteristic of LCHAD deficiency. 2. Intensity of steatosis is related to severity of clinical symptoms 3. In patients with mitochondrial beta-oxidation defects liver steatosis may be accompanied by fibrosis which is suggestive of LCHAD deficiency. 4. Fatty liver found in a patient who died of undiagnosed disease should suggest the possibility of LCHAD deficiency as a cause of death. 5. Semi-thin plastic embedded tissue section postfixed in osmium tetroxide and stained with toluidine blue is very helpful in reliable assessment of liver steatosis Acknowledgments The study was supported by a statutory grant No S 86 of The Children’s Memorial Health Institute References 1. Baldridge AD, Perez-Atayde AR Graeme-Cook F, Higgins L, Lavine JE (1995) Idiopathic steatohepatitis in childchood A multicenter study. J Pediatr 127:700-704 2. Chace DH, DiPerna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW (2001) Electrospray Tandem Mass Spectrometry or Analysis of Acylcarnitines in Dried Postmortem Blood Spcimens Collcted at Autopsy from Infants with Unexplained Cause of Death. Clin Chemist 47(7):1166-1182 3. Chalmers RA, Stanley CA, English N, Wigglesworth JS (1997) Mitochondrial carnitine-acylcarnitine translocase deficiency presenting as sudden neonatal death. J Pediatr 131:220-225 4. Dawson DB, Waber L, Hale DE, Bennett MJ (1995) Transient organic aciduria and persistent lacticacidemia in a patient with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 126:69-71 5. Gilbert-Barness and Barness (2000) Fatty acids beta-oxidation defects. In: Gilbert-Barness and Barness (eds) Metabolic Diseases Eaton Publishing, Natick, pp113-136 6. Iafolla AK, Thompson RJ, Roe CR (1994) Medium-chain acyl-coenzyme A dehydrogenase deficiency: Clinical course in 120 affected children. J Pediatr 124:409-415 7. Moore R, Glasgow JFT, Bingham MA, Dode JA, Pollitt RJ,Olpin SE, Middleton B, Carpentier K (1993) Long chain 3- hydroxyacyl-coenzyme A dehydrogenase deficiency – diagnosis, plasmacarnitine fractions and management in a further patient. Eur J Pediatr 152:433-6 8. Roe CR Millington DS, Maltby DA Kinnebrew P (1986) Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reye-like syndromes. J Pediatr 108:13-18 9. Roe CR, Coates PM (1995) Mitochondrial fatty acids oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1501-1535 10. Santer R, Schmidt-Sommerfeld E, Leung YK, Fischer JE, Lebental E (1990) Medium-chain acyl-CoA dehydrogenase deficiency: electron microscopic differentiation from Reye syndrome. Eur J Pediatr 150:111-114 11. Tyni T, Rapola J, Paetau A, Palotie A, Pihko H (1997) Patology of long chain 3-hydroxyacyl-CoA dehydrogenase deficiency causes by the G1528C mutation. Ped Path Lab Med 17:427-447 12. Winter SC, Szabo-Aczel S, Curry CJR, Hutchinson HT, Hogue R, Shug A (1987) Plasma carnitine deficiency Clinical Observations in 51 Pediatric Patients. AJDC 141:660-665
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Annals of Diagnostic Paediatric Pathology

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