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Paediatric fatty liver disease (PeFLD): All is not NAFLD – Pathophysiological insights and approach to management

Published:February 19, 2018DOI:https://doi.org/10.1016/j.jhep.2018.02.006

      Summary

      The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.

      Graphical abstract

      Keywords

      Introduction

      The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD)
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      – the most common chronic liver disease in adults today. The global epidemic of obesity has been attributed as a major factor in the pathogenesis of this condition. The paediatric community also joined the bandwagon of adult hepatology and embraced the term despite alcohol consumption, or certainly its contribution to liver disease state, being minimal pre-adolescence.
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      Alcoholic and non-alcoholic fatty liver in adolescents: a worrisome convergence.
      The cause and effect relationship of obesity to fatty liver appears to hold true in adults, but extrapolation of this relationship to the paediatric age group, particularly to young children, should be done with caution, as inherited metabolic disorders (IMD) can mimic or co-exist with a diagnosis of NAFLD. This review is aimed at discussing the ever more complex subject of fatty liver disease in children and young adults by describing its aetiopathogenesis according to the clinical phenotype. Furthermore, the nomenclature of NAFLD as a diagnostic entity needs to be revisited in children: the term paediatric fatty liver disease (PeFLD) may be more appropriate as alcohol consumption is usually not a factor, therefore, NAFLD is incongruous.
      The aetiologies of fatty liver in children are different to adults: alcohol consumption is largely not a factor and inherited metabolic disorders (IMD) can mimic or co-exist with NAFLD.
      Steatosis is defined by the presence of fat in hepatocytes when examined under light microscopy and can be classed as microvesicular or macrovesicular. In macrovesicular steatosis there is accumulation of large fat droplets from excess delivery of free fatty acids and the nucleus is displaced to the periphery of the cell. The large fat droplets occupy much of the cell, but small droplet macrovesicular steatosis can also be seen, in which one or more well defined small fat droplets are present and may not cause nuclear displacement. In microvesicular steatosis hepatocytes have a “bubbly” cytoplasmic appearance and contain small vesicles of fat (usually <1 µm in diameter) without displacement of the nucleus.
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      Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease.
      In practice, both macrovesicular and microvesicular steatosis can co-exist (for example, in Wilson’s disease or in NAFLD). Whilst a liver histopathologist is easily able to recognise the different types of steatosis present in a biopsy sample, interpretation of the aetiological or prognostic significance of the different types of steatosis present can be more challenging. The clinical associations of microvesicular steatosis are different in adults and children; the significance in clinical practice is also disparate, with a link to an IMD typically considered in children. However, whether microvesicular steatosis is the histological bystander in an adult with viral hepatitis or the diagnostic feature in an infant with an IMD, a common mechanistic concept can be considered at the cellular level: increased delivery of lipids, impaired efflux of lipids or increased intrinsic esterification of fatty acids because of organelle dysfunction.
      Bearing these points in mind liver biopsies are still indispensable. Specifically, in the context of steatosis and NAFLD, the European Society of Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) expert committee recommend liver biopsies, “to exclude other treatable disease, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment”.
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      Biopsies enable investigation of tissue specific gene and protein expression patterns underlying the progression of PeFLD and they facilitate study of the natural history of PeFLD progressing into adulthood. Furthermore, a large-scale study of PeFLD biopsy material in conjunction with a comprehensive clinical database would support development of scoring systems specific for PeFLD. Taking the above into account, we advise liver biopsies to be interpreted by a pathologist with expertise in paediatric hepatology to maximise diagnostic yield.
      In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. A comprehensive diagnostic work-up of metabolic and non-metabolic aetiologies is required; we describe our investigational approach (Fig. 1) alongside the typical age group of presentation (Table 1), as well as offering pathophysiological insights that can be applied for all patients (Fig. 2). In doing so we highlight the importance of identifying steatosis as an independent entity with its own merits that require careful consideration (Fig. 3).
      Figure thumbnail gr1
      Fig. 1Paediatric fatty liver disease: disorders to consider and investigational approach according to patient phenotype.
      Table 1Typical presenting age groups of conditions associated with paediatric fatty liver disease.
      ConditionInfantsChildrenAdults
      Mitochondrial hepatopathies++++++
      Disorders of fatty acid metabolism++++++
      Urea cycle disorders++++++
      Disorders of carbohydrate metabolism+++++
      Disorders of endoplasmic reticulum++++++
      Tyrosinemia type 1+++++
      Niemann-Pick C++++++
      Cystic fibrosis++++
      Alpha 1-antitrypsin deficiency++++
      Glycogen storage disorders++++++
      Mauriac syndrome++++
      Disorders of protein metabolism++++++
      Myopathic disorders+++++
      Hypothyroidism+++++
      Celiac disease/inflammatory bowel disease+++++
      Lysosomal acid lipase deficiency+++++++
      Abetalipoproteinemia+++++
      Lipodystrophies+++++
      Congenital disorder of glycosylation++++++
      Non-alcoholic fatty liver disease+++++
      Wilson disease++++
      Drugs+++++
      Viral hepatitis++++
      Figure thumbnail gr2
      Fig. 2Schematic representation of the mitochondria and other organelle dysfunction leading to the accumulation of fat droplets. A1AT-D, alpha 1-antitrypsin deficiency; ACAD9, acyl-CoA dehydrogenase 9; AT, ataxia telangiectasia; CACT, carnitine-acylcarnitine translocase; CPS1, carbamoylphosphate synthetase I; CDG, congenital disorder of glycosylation; CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyltransferase 2; DLD, dihydrolipoamide dehydrogenase deficiency; GSD, glycogen storage disease; HFI, hereditary fructose intolerance; LCHAD, long-chain acyl-CoA dehydrogenase; LPI, lysinuric protein intolerance; LAL-D, lysosomal acid lipase deficiency; MCAD, medium chain acyl-CoA dehydrogenase; MD, muscular dystrophy; NAFLD, non-alcoholic fatty liver disease; NBAS, neuroblastoma amplification sequence; NPC, Niemann-Pick C; OA, organic acidemia; OTC, ornithine transcarbamylase deficiency; VLCHAD, very long-chain acyl-CoA dehydrogenase; WRS, Wolcott Rallison syndrome.
      Figure thumbnail gr3
      Fig. 3Balancing the contributions of fat: risk factors to consider when trying to understand the aetiologies of steatosis. ALF, acute liver failure; BMI, body mass index; DM, diabetes mellitus; IR, insulin resistance; NAFLD, non-alcoholic fatty liver disease.

      Steatosis in the context of acute liver failure

      The number of children with acute liver failure of unknown origin has declined because of more-ready recognition of IMDs.
      The number of children with acute liver failure of unknown origin has declined from about half of cases
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      to one-third over the last decade.
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      This is largely to do with the more-ready recognition of underlying IMD that were hitherto undiagnosed. Fat as a finding on biopsy or explant is strongly suggestive of an IMD as the aetiology of acute liver failure (ALF). This is thought to be predominantly due to mitochondrial-related pathology, although non-mitochondrial-related accumulation of fat, mainly in the form of microvesicular steatosis, is also recognised.

      Impaired mitochondrial respiratory chain function

      The normal function of the mitochondria includes beta-oxidation of fatty acids, production of energy through the electron transport chain and the Krebs cycle. The first step in this process is the mobilisation of triglycerides from fat stores under fasting conditions. Long-chain fatty acids (12–20 carbons) released by lipases from triglycerides are activated to acyl-CoA esters in the cell cytoplasm. Whilst shorter chain fatty acids (10 carbons) can independently enter the mitochondria, long-chain fatty acids need to be transported by the carnitine shuttle. The carnitine shuttle is composed of carnitine palmitoyltransferase I (CPT1), carnitine translocase and carnitine palmitoyltransferase II (CPT2). Several length specific enzymes such as long-chain acyl-CoA dehydrogenase (LCHAD; 12–18 carbons) and medium chain acyl-CoA dehydrogenase (MCAD; 6–12 carbons) then act to shorten acyl-CoA in subsequent beta-oxidation cycles. The protons generated by dehydrogenases enter the electron transport chain whilst acetyl-CoA enters the Krebs cycle or undergoes ketogenesis. Primary or acquired events that impair any of these functions lead to fatty acids being poorly oxidised by the mitochondria and instead being esterified into triglycerides.
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      This is the case with mitochondrial hepatopathies in which patchy or diffuse microvesicular steatosis is a consistent finding with light microscopy (Fig. 4A). Impaired mitochondrial function can result from tissue mitochondrial DNA depletion or a translational disorder secondary to mutations in nuclear or mitochondrial DNA that encode for mitochondrial enzymes and proteins.
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      Mutations in polymerase gamma catalytic subunit (POLG), deoxyguanosine kinase (DGUOK), MPV17, succinate-CoA ligase (SUCLG1), twinkle protein (TWINKLE) and TRMU are amongst the more common genotypes that cause ALF; all demonstrated to cause microvesicular steatosis.
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      Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy.
      Mutations in the leucyl-tRNA synthetase (LARS) gene, the enzyme responsible for making leucine, should also be considered as they were recently reported as a cause of infantile, recurrent ALF in a group of Irish travellers.
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      Figure thumbnail gr4
      Fig. 4Patterns of steatosis in mitochondrial hepatopathy, tyrosinemia type 1, glycogen storage disorder type 1a and lysosomal acid lipase deficiency. (A) Mitochondrial disorders can demonstrate varying degrees of steatosis (microvesicular steatosis indicated by the short arrows, macrovesicular steatosis demonstrated by the long arrows, H&E ×200 magnification). (B) Tyrosinemia type I in a 6-month child with mixed macro- and microvesicular steatosis (microvesicular steatosis indicated by the short arrows, H&E ×200 magnification). (C) Liver biopsy from an 18-month old child with glycogen storage disease type 1a showing severe predominantly microvesicular steatosis admixed with glycogen (H&E ×400 magnification. Inset shows microvesicular steatosis, short arrows, within hepatocytes at ultrastructural level). (D) A liver biopsy from a nine-year old child with lysosomal acid lipase deficiency, demonstrating severe microvesicular steatosis (H&E ×400 magnification). The inset shows cholesteryl ester storage material within Kupffer cells (Inset D, short arrows, Diastase Periodic Acid-Schiff ×400 magnification).

      Impaired mitochondrial carnitine transport and fatty acid oxidation

      Beta-oxidation of fatty acids is one of the primary functions of the mitochondria. As in mitochondrial respiratory chain disorders it is, therefore, unsurprising to find that microvesicular steatosis is a consistent finding in fatty acid oxidation disorders. Amongst them deficiencies in MCAD, LCHAD, very long-chain acyl-CoA dehydrogenase (VLCHAD) and acyl-CoA dehydrogenase 9 (ACAD 9) can present as ALF with microvesicular steatosis.
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      Similarly, liver failure and steatosis can result when the transport of fatty acids is impaired because of defects in the carnitine transporter: severe neonatal forms of carnitine palmitoyltransferase and carnitine-acylcarnitine translocase (CACT) deficiencies can give rise to this phenotype.
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      Impaired pyruvate metabolism

      The end product of glycolysis is pyruvate, which enters the mitochondria to be metabolised by pyruvate dehydrogenase complex or pyruvate carboxylase, forming acetyl-CoA or oxaloacetate, respectively. Dihydrolipoamide dehydrogenase forms part of the pyruvate dehydrogenase complex and its dysfunction results in recurrent episodes of ALF. In between episodes of ALF, microvesicular steatosis is observed but is not a permanent feature.
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      Steatosis is also a feature in pyruvate carboxylase deficiency.
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      Urea cycle disorders

      Microvesicular steatosis is a consistent finding on liver histological examination of patients with urea cycle disorders. Ornithine transcarbamylase (OTC) deficiency and carbamoylphosphate synthetase I (CPSI) deficiency are such examples that can present acutely in the neonatal period with rapid development of hyperammonemia. Mitochondrial dysfunction is implicated in disorders of the urea cycle, which operates mainly in the liver between the mitochondria and cytoplasm. At the molecular level the accumulation of ammonia has been attributed to increased mitochondrial permeability leading to defective oxidative phosphorylation and the production of reactive oxygen species, eventually leading to cell death.
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      However, it is not known what relation the histological findings of the liver have with respect to the variable clinical expression.
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      Significant hepatic involvement in patients with ornithine transcarbamylase deficiency.
      Microvesicular steatosis is also seen in lysinuric protein intolerance, a rare autosomal recessive disorder that can cause post prandial hyperammonemia because of functional deficiencies of urea cycle intermediates.
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      Impaired carbohydrate metabolism

      Disorders of carbohydrate metabolism such as hereditary fructose intolerance, caused by deficiency in aldolase b or galactosemia due to deficiency in galactose-1-phosphate uridyl transferase, can result in ALF. In galactosemia there is early, often diffuse, macrovesicular fatty infiltration of the liver, alongside cholestasis with minimal inflammation. In recent studies, the pathogenesis of galactosemia links galactose exposure to oxidative stress.
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      Reactive oxygen species, in turn, cause direct damage to cellular components including the mitochondria. Hereditary fructose intolerance also manifests as diffuse micro- and macro- vesicular steatosis.
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      Disorders of endoplasmic reticulum function

      Wolcott Rallison syndrome is a disorder thought to be related to endoplasmic reticulum dysfunction in response to cellular stress. It can cause recurrent ALF triggered by febrile illnesses and microvesicular steatosis is a documented feature.
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      Wolcott-Rallison syndrome.
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      Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.
      In Walcott Rallison syndrome, the defect lies in the PKR-like endoplasmic reticulum transmembrane protein (PERK) which senses cellular stress by detecting misfolded proteins: part of the cell unfolded protein response (UPR). PERK activates stress related proteins such as activation transcription factor-4 (ATF4) that regulate a variety of cellular processes including oxidative stress.
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      Wolcott-Rallison syndrome.
      Maintenance of endoplasmic reticulum integrity by the UPR is integral to the metabolism of lipid and glucose metabolism in the liver: in mice where cytoplasmic polyadenylation element-binding (Cpeb) protein 4, a regulator of UPR upregulation, is knocked out, fat accumulates in the liver because of a defect in mitochondrial fatty acid oxidation and respiration.
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      Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress.
      In neuroblastoma amplification sequence (NBAS) deficiency, recently discovered to be a cause of recurrent ALF, docking and fusion of transport vesicles between the endoplasmic reticulum and Golgi is thought to be impaired.
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      Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.
      NBAS deficiency causes recurrent ALF from infancy triggered by febrile illnesses.
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      Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy.
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      It was demonstrated by in vitro studies that, indeed, a temperature shift from 37 °C to 40 °C results in reduced NBAS protein levels.
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      Steatosis has been described in children with this disorder.

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      Steatosis in the context of neonatal or infantile conjugated jaundice

      Tyrosinemia type 1

      Tyrosinemia classically presents in infancy with jaundice, progressive liver disease and coagulopathy if it is not picked up by routine screening. The main findings on histology depend on the timing in which the biopsy is carried out, with progressive fibrosis and ultimately cirrhosis featuring later in the disease course. Patchy macro- and micro- vesicular steatosis is commonly identified (Fig. 4B).
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      Mice models designed to elucidate the pathophysiology of tyrosinemia suggest that homogentisate, an intermediate metabolite of the tyrosine catabolic pathway, induces apoptosis by releasing cytochrome c of the respiratory chain into the cytosol of hepatocytes.
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      Niemann-Pick disease type C

      Lysosomal storage disorders can present in the neonatal period with jaundice and hepatosplenomegaly. In NPC, mild to moderate micro- and macro- vesicular steatosis can be observed, although the prevailing finding on light microscopy is that of abnormal accumulation of glycolipids and cholesterol within Kupffer cell lysosomes. Increased glycogen content can resemble steatosis.
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      Cystic fibrosis

      In the infantile period, cholestasis is the predominant finding on liver biopsy and we have also encountered periportal macrovesicular steatosis. Steatosis observed in older age groups is thought to be multifactorial in aetiology, influenced by nutrition, infection, drugs, pancreatic insufficiency as well as genetic modifiers.

      Alpha 1-antitrypsin deficiency

      Liver biopsies from patients with alpha 1-antitrypsin deficiency typically demonstrate giant cell hepatitis with variable degrees of cell necrosis, inflammation, bile duct damage with PAS-positive, and diastase resistant periportal globules.
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      Predominantly, macrovesicular steatosis is seen, classically in a periportal distribution in the neonatal period. The mechanism of hepatocyte injury in ZZ alpha 1-antitrypsin deficiency is understood to intricately involve the endoplasmic reticulum – mitochondria axis: mutant Z proteins are retained in the endoplasmic reticulum leading to autophagic response with caspase activation, redox injury and mitochondrial changes.
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      Inborn error of bile acid synthesis

      This is a group of rare disorders that typically present in infancy with cholestasis or spasticity in adult life. Both micro- and macro-vesicular steatosis is evident on liver biopsy, along with giant cell hepatitis and extramedullary haematopoiesis.
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      Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy.
      The hepatic steatosis is likely to be caused by disordered cholesterol homeostasis: tendon xanthoma and atherosclerosis is observed as bile acid intermediates build up and are deposited around the body.
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      Disorders of bile acid synthesis.

      Citrin deficiency

      Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is recognised to be accompanied by a diffusely fatty liver which is histologically similar to NAFLD.
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      A case of adult-onset type II citrullinemia having a liver histology of nonalcoholic steatohepatitis (NASH).
      NICCD may resolve by the age of one with the appropriate treatment. Older children may present with failure to thrive and dyslipidaemia caused by citrin deficiency, which is also characterised by fatty liver.

      Intestinal failure associated liver disease

      Conjugated jaundice in the context of an infant born prematurely or with intestinal failure is a common scenario in paediatric practice. The hepatic manifestations of intestinal failure are multiple and include periportal inflammation and cholestasis, bile duct proliferation, steatosis and perivenular fibrosis.
      • Naini B.V.
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      Total parenteral nutrition therapy and liver injury: a histopathologic study with clinical correlation.
      Steatosis may commence in acinar zone 1 and progress to a pan-lobular distribution. The steatosis can be attributed to delivery of lipid emulsion from parenteral nutrition itself,

      Adolph M, Heller AR, Koch T, Koletzko B, Kreymann KG, Krohn K, et al. Lipid emulsions – Guidelines on Parenteral Nutrition, Chapter 6. GMS Ger Med Sci [Internet]. 2009 Nov 18 [cited 2017 Oct 25];7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795378/.

      excess energy,
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      • Jewell L.D.
      • Coutts R.T.
      Effects of intravenous lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine elimination: a study using isolated rat liver perfusion.
      as well as the effects of insulin on increasing mitochondrial fatty acid biosynthesis.
      • Li S.
      • Nussbaum M.S.
      • Teague D.
      • Gapen C.L.
      • Dayal R.
      • Fischer J.E.
      Increasing dextrose concentrations in total parenteral nutrition (TPN) causes alterations in hepatic morphology and plasma levels of insulin and glucagon in rats.
      Exogenous fat in the form of parenteral nutrition, as opposed to enterally delivered fat, lacks apolipoproteins and interferes with physiological processing of triglycerides; characteristically fat vacuolations are found in Kupffer cells and hepatocyte lysosomes.
      • Roth B.
      • Fkelund M.
      • Fan B.G.
      • Hägerstrand I.
      • Nilsson-Ehle P.
      Lipid deposition in Kupffer cells after parenteral fat nutrition in rats: a biochemical and ultrastructural study.
      • Lacaille F.
      • Gupte G.
      • Colomb V.
      • D’Antiga L.
      • Hartman C.
      • Hojsak I.
      • et al.
      Intestinal failure-associated liver disease: a position paper of the ESPGHAN Working Group of Intestinal Failure and Intestinal Transplantation.

      Steatosis in the context of organomegaly

      Glycogen storage disorders

      Disorders that cause abnormal breakdown and synthesis of glycogen resulting in its excess end organ accumulation are classed as glycogen storage disorders (GSD). Those that present in their hepatic forms include types III, IV, VI, IX and XI. Dyslipidaemia is well described and leads to mixed macro- and micro- vesicular steatosis in a patchy or diffuse distribution
      • Kishnani P.S.
      • Austin S.L.
      • Arn P.
      • Bali D.S.
      • Boney A.
      • Case L.E.
      • et al.
      Glycogen storage disease type III diagnosis and management guidelines.
      and the mechanism is twofold. The first is exemplified by GSD III (glycogen debranching enzyme deficiency), a ketotic form of GSD, whereby increased fatty acids and glycerol are released from adipose tissue to provide an alternative energy source.
      • Teckman J.H.
      • Mangalat N.
      Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions.
      Children with this condition have higher serum triglyceride levels leading to fatty infiltration of the liver. The second mechanism is due to the inherent physiological link of glycolysis to mitochondrial function and beta-oxidation of fatty acids. In GSD I (glucose-6-phosphatase deficiency), a hypoketotic GSD, intracellular accumulation of glucose-6-phosphate leads to increased glycolysis and its downstream products, acetyl-CoA and malonyl CoA.
      • Derks T.G.J.
      • van Rijn M.
      Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.
      This is important as malonyl CoA is the primary regulator which determines the switch between the reciprocal relationship of fatty acid synthesis and oxidation: when levels are elevated, as in GSD I, malonyl CoA inhibits fatty acid beta-oxidation and promotes its synthesis.
      • Foster D.W.
      Malonyl-CoA: the regulator of fatty acid synthesis and oxidation.
      This leaves more substrate to be esterified into triglycerides in the mitochondria (Fig. 4C).

      Mauriac syndrome

      Mauriac syndrome which is characterised by growth failure, cushingoid appearance and hepatomegaly in patients with type 1 diabetes mellitus can be considered under the umbrella of disordered glycogen storage. Another term is glycogenic hepatopathy in patients with poor glycaemic control without the other associated clinical features. Glycogen is difficult to discern from steatosis by ultrasonography,
      • Torres M.
      • López D.
      Liver glycogen storage associated with uncontrolled type 1 diabetes mellitus.
      leading to the condition being recognised in association with NAFLD. However, liver biopsies in glycogenic hepatopathy demonstrate swollen hepatocytes, with glycogen and no or mild fatty change,
      • Torbenson M.
      • Chen Y.-Y.
      • Brunt E.
      • Cummings O.W.
      • Gottfried M.
      • Jakate S.
      • et al.
      Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus.
      as well as megamitochondria indicating mitochondrial stress.
      • Fitzpatrick E.
      • Cotoi C.
      • Quaglia A.
      • Sakellariou S.
      • Ford-Adams M.E.
      • Hadzic N.
      Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre.

      Steatosis in the context of developmental delay/psychomotor retardation

      Disorders of protein metabolism

      Disorders of amino acid metabolism and organic acid metabolism can present acutely in the neonatal period with encephalopathy or later on in childhood with psychomotor retardation. These patients have a variable degree of liver involvement from mild abnormalities in their aminotransferases to frank hepatitis with hyperammonaemia. Microvesicular steatosis is a consistent finding in organic acidaemias and amino acidopathies. Propionic and methylmalonic acidaemias are such examples and reduced levels of complex III and IV secondary to accumulation of toxic metabolites have been implicated in their pathogenesis. In glutaric aciduria type II, an inherited disorder of amino acid and fatty acid metabolism, there is defective electron transfer flavoprotein. The biochemical consequence of which is deficient transfer of electrons to the mitochondrial respiratory chain. Micro- and macro- vesicular steatosis is observed.
      • Wolfe L.A.
      • He M.
      • Vockley J.
      • Payne N.
      • Rhead W.
      • Hoppel C.
      • et al.
      Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle.
      Homocysteinuria, similarly, should form part of the differential diagnosis.
      • Mack C.L.
      • Emerick K.M.
      • Kovarik P.
      • Charrow J.
      Early speech delay and hepatitis as presenting signs of homocystinuria.

      Myopathic disorders

      Disorders that primarily affect the muscle, wherein the replacement of muscle by fat and connective tissue leads to pseudohypertrophy, are another class of disorders that must be considered. Obesity and NAFLD are known to be associated with muscular dystrophy. The altered composition of lipid in cells observed in muscular dystrophy is likely due to decreased physical activity, as well as decreased intracellular carnitine and mitochondrial metabolism.
      • Le Borgne F.
      • Guyot S.
      • Logerot M.
      • Beney L.
      • Gervais P.
      • Demarquoy J.
      Exploration of lipid metabolism in relation with plasma membrane properties of Duchenne muscular dystrophy cells: influence of L-carnitine.
      One must keep an open mind as elevated aminotransferases, often due to muscle rather than hepatocyte release, with elevated creatinine phosphokinase, rapid weight gain or microvesicular steatosis on liver biopsy may be the presenting problem.
      • Paolella G.
      • Pisano P.
      • Albano R.
      • Cannaviello L.
      • Mauro C.
      • Esposito G.
      • et al.
      Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance.
      • Veropalumbo C.
      • Del Giudice E.
      • Capuano G.
      • Gentile C.
      • Di Cosmo N.
      • Vajro P.
      Duchenne and Becker muscular dystrophy presenting as nonalcoholic fatty liver disease.
      Similar findings may be observed in limb-girdle muscular dystrophy.
      • Liang W.-C.
      • Zhu W.
      • Mitsuhashi S.
      • Noguchi S.
      • Sacher M.
      • Ogawa M.
      • et al.
      Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype.
      In patients with spinal muscular atrophy, deficiencies in the survival of motor neurone (SMN) protein lead to defective motor neurones. Secondary metabolic defects have been proposed to mimic those of acyl-CoA dehydrogenase deficiency – perhaps part of the explanation for liver biopsy findings in these patients.
      • Harpey J.P.
      • Charpentier C.
      • Paturneau-Jouas M.
      • Renault F.
      • Romero N.
      • Fardeau M.
      Secondary metabolic defects in spinal muscular atrophy type II.
      • Zolkipli Z.
      • Sherlock M.
      • Biggar W.D.
      • Taylor G.
      • Hutchison J.S.
      • Peliowski A.
      • et al.
      Abnormal fatty acid metabolism in spinal muscular atrophy may predispose to perioperative risks.
      Mitochondrial cytopathies can also present under the heading of a patient with microvesicular steatosis with developmental delay or neurological impairment. GFM1 mutation, Leigh disease and mitochondrial neurogastrointestinal encephalopathy syndrome, so called MNGIE syndrome, are such examples.
      • Balasubramaniam S.
      • Choy Y.S.
      • Talib A.
      • Norsiah M.D.
      • van den Heuvel L.P.
      • Rodenburg R.J.
      Infantile progressive hepatoencephalomyopathy with combined OXPHOS deficiency due to mutations in the mitochondrial translation elongation factor gene GFM1.
      • Sofou K.
      • De Coo I.F.M.
      • Isohanni P.
      • Ostergaard E.
      • Naess K.
      • De Meirleir L.
      • et al.
      A multicenter study on Leigh syndrome: disease course and predictors of survival.
      • Finkenstedt A.
      • Schranz M.
      • Bösch S.
      • Karall D.
      • Bürgi S.S.
      • Ensinger C.
      • et al.
      MNGIE syndrome: liver cirrhosis should be ruled out prior to bone marrow transplantation.

      Hypothyroidism

      The inverse correlation between free T4 levels and the presence of NAFLD has previously been demonstrated.
      • Liangpunsakul S.
      • Chalasani N.
      Is hypothyroidism a risk factor for non-alcoholic steatohepatitis?.
      • Xu L.
      • Ma H.
      • Miao M.
      • Li Y.
      Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: a prospective case-control study.
      Hepatic fat deposition may be secondary to the hormone’s role in lipid metabolism
      • Zhu X.
      • Cheng S.
      New insights into regulation of lipid metabolism by thyroid hormone.
      • Jung K.Y.
      • Ahn H.Y.
      • Han S.K.
      • Park Y.J.
      • Cho B.Y.
      • Moon M.K.
      Association between thyroid function and lipid profiles, apolipoproteins, and high-density lipoprotein function.
      as well as its association to metabolic syndrome.
      • Erdogan M.
      • Canataroglu A.
      • Ganidagli S.
      • Kulaksızoglu M.
      Metabolic syndrome prevalence in subclinic and overt hypothyroid patients and the relation among metabolic syndrome parameters.
      However, even after the removal of these confounding factors the association between hypothyroidism and NAFLD is significant, suggesting that there may be a direct correlation.
      • Chung G.E.
      • Kim D.
      • Kim W.
      • Yim J.Y.
      • Park M.J.
      • Kim Y.J.
      • et al.
      Non-alcoholic fatty liver disease across the spectrum of hypothyroidism.
      It is not clear if patients with NAFLD and hypothyroidism demonstrate a different steatotic pattern histologically to those without hypothyroidism. Certainly, in hypothyroid rats mild microvesicular steatosis with random distribution was demonstrated.

      Demir Ş, Ünübol M, Aypak SÜ, İpek E, Aktaş S, Ekren GS, et al. Histopathologic Evaluation of Nonalcoholic Fatty Liver Disease in Hypothyroidism-Induced Rats [Internet]. International Journal of Endocrinology. 2016 [cited 2018 Jan 13]. Available from: https://www.hindawi.com/journals/ije/2016/5083746/.

      Further data from animals show that hypothyroidism promotes hepatic enzymes of lipid metabolism,
      • Lopez D.
      • Abisambra Socarrás J.F.
      • Bedi M.
      • Ness G.C.
      Activation of the hepatic LDL receptor promoter by thyroid hormone.
      oxidative stress
      • Baquer N.Z.
      • Cascales M.
      • McLean P.
      • Greenbaum A.L.
      Effects of thyroid hormone deficiency on the distribution of hepatic metabolites and control of pathways of carbohydrate metabolism in liver and adipose tissue of the rat.
      and farnesoid receptor
      • Rodríguez-Castelán J.
      • Corona-Pérez A.
      • Nicolás-Toledo L.
      • Martínez-Gómez M.
      • Castelán F.
      • Cuevas-Romero E.
      Hypothyroidism induces a moderate steatohepatitis accompanied by liver regeneration, mast cells infiltration, and changes in the expression of the farnesoid X receptor.
      alluding to potential mechanistic pathways.

      Coeliac disease and inflammatory bowel disease

      Liver steatosis is well recognised in gastrointestinal disease. In coeliac disease the histological findings are frequently non-specific, although steatosis is seen in both micro and macro- vesicular, and focal or diffuse distributions. The mechanism of liver injury may be related to the increase in permeability of the gut or related autoimmunity;
      • Vo H.D.
      • Xu J.
      • Rabinowitz S.S.
      • Fisher S.E.
      • Schwarz S.M.
      The liver in pediatric gastrointestinal disease.
      steatosis related to malabsorption, altered intestinal microbiota and nutritional deficiency states as seen in starvation-associated kwashiorkor.
      • Miele L.
      • Valenza V.
      • La Torre G.
      • Montalto M.
      • Cammarota G.
      • Ricci R.
      • et al.
      Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.
      • Freeman H.J.
      Hepatic manifestations of celiac disease.
      Similarly, hepatic steatosis in inflammatory bowel disease is multifactorial in aetiology and its prevalence has been estimated to be around 23% (range, 1.5%–55%).
      • Bessissow T.
      • Le N.H.
      • Rollet K.
      • Afif W.
      • Bitton A.
      • Sebastiani G.
      Incidence and predictors of nonalcoholic fatty liver disease by serum biomarkers in patients with inflammatory bowel disease.
      The distribution is usually zone 1 and the causes have been attributed to co-existing metabolic syndrome, chronic inflammation, steroid exposure, drugs and alterations in the gut microbiota.
      • Long M.D.
      • Crandall W.V.
      • Leibowitz I.H.
      • Duffy L.
      • del Rosario F.
      • Kim S.C.
      • et al.
      The prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease.
      • McGowan C.E.
      • Jones P.
      • Long M.D.
      • Barritt A.S.
      The changing shape of disease: non-alcoholic fatty liver disease in crohn’s disease a case series and review of the literature.
      • Carr R.M.
      • Patel A.
      • Bownik H.
      • Oranu A.
      • Kerner C.
      • Praestgaard A.
      • et al.
      Intestinal inflammation does not predict nonalcoholic fatty liver disease severity in inflammatory bowel disease patients.
      • Sourianarayanane A.
      • Garg G.
      • Smith T.H.
      • Butt M.I.
      • McCullough A.J.
      • Shen B.
      Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease.

      Lysosomal acid lipase deficiency

      Lysosomal acid lipase deficiency (LAL-D) was originally described in infants with failure to thrive, diarrhoea and hepatosplenomegaly. Recent understanding has evolved to a very heterogeneous condition that can present in older children or adults.
      • Bernstein D.L.
      • Hülkova H.
      • Bialer M.G.
      • Desnick R.J.
      Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease.
      Abnormal accumulation of cholesteryl esters within lysosomes, because of deficient LAL, results in the appearance of microvesicular steatosis on liver biopsy, associated with vacuolated Kupffer cells (Fig. 4D). Whilst immunohistochemistry with lysosomal markers can confirm the lysosomal nature of the lipid deposits,
      • Hůlková H.
      • Elleder M.
      Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens.
      detection of vacuolated Kupffer cells, that would support the diagnosis, is possible using Diastase Periodic Acid-Schiff stain. It has been observed in the context of children with NAFLD who failed to respond to weight loss and were diagnosed following liver biopsy.
      • Himes R.W.
      • Barlow S.E.
      • Bove K.
      • Quintanilla N.M.
      • Sheridan R.
      • Kohli R.
      Lysosomal acid lipase deficiency unmasked in two children with nonalcoholic fatty liver disease.
      Importantly, patients with LAL-D demonstrate substantially higher low-density lipoprotein-cholesterol levels.
      • Burton B.K.
      • Deegan P.B.
      • Enns G.M.
      • Guardamagna O.
      • Horslen S.
      • Hovingh G.K.
      • et al.
      Clinical features of lysosomal acid lipase deficiency.

      Abetalipoproteinemia/hypobetaliproproteinemia

      Defective processing and packaging of apolipoprotein B as a result of mutations in the MTP and APOB genes results in impaired lipid absorption and transport.
      • Lee J.
      • Hegele R.A.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      • Di Filippo M.
      • Moulin P.
      • Roy P.
      • Samson-Bouma M.E.
      • Collardeau-Frachon S.
      • Chebel-Dumont S.
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      It is characterised clinically by fat malabsorption and failure to thrive in the first year of life, followed by cerebellar dysfunction and retinal degeneration that is amenable to high dose oral vitamin E supplementation.
      • Zamel R.
      • Khan R.
      • Pollex R.L.
      • Hegele R.A.
      Abetalipoproteinemia: two case reports and literature review.
      Hypobetalipoproteinemia may be asymptomatic or associated with less severe diarrhoea. The hepatic manifestation includes steatosis,
      • Collins J.C.
      • Scheinberg I.H.
      • Giblin D.R.
      • Sternlieb I.
      Hepatic peroxisomal abnormalities in abetalipoproteinemia.
      but has been reported to lead to chronic liver disease and transplantation.
      • Black D.D.
      • Hay R.V.
      • Rohwer-Nutter P.L.
      • Ellinas H.
      • Stephens J.K.
      • Sherman H.
      • et al.
      Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia.
      It has been postulated that this steatosis results from the defective synthesis and processing of apolipoprotein B, leading to failure to assemble very-low-density lipoprotein which cannot then be expulsed from hepatocytes.
      • Lee J.
      • Hegele R.A.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      • Black D.D.
      • Hay R.V.
      • Rohwer-Nutter P.L.
      • Ellinas H.
      • Stephens J.K.
      • Sherman H.
      • et al.
      Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia.

      Lipodystrophies

      Lipodystrophy is an umbrella term describing patients with selective loss of body fat.
      • Agarwal A.K.
      • Garg A.
      Genetic disorders of adipose tissue development, differentiation, and death.
      Infants with the congenital forms fail to gain weight despite adequate calorie intake. Later on patients exhibit paucity of adipose tissue, insulin resistance, hypertriglyceridemia and macrovesicular hepatic steatosis.
      • Agarwal A.K.
      • Arioglu E.
      • De Almeida S.
      • Akkoc N.
      • Taylor S.I.
      • Bowcock A.M.
      • et al.
      AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.
      • Caux F.
      • Dubosclard E.
      • Lascols O.
      • Buendia B.
      • Chazouillères O.
      • Cohen A.
      • et al.
      A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy.
      The problem lies in the defective lipid formation in the adipocytes.
      • Garg A.
      • Agarwal A.K.
      Lipodystrophies: disorders of adipose tissue biology.
      This results in excess circulating free fatty acids and eventual accumulation of triglycerides in the liver.
      • Agarwal A.K.
      • Garg A.
      Genetic disorders of adipose tissue development, differentiation, and death.
      The effects are that of hepatic steatosis and metabolic syndrome
      • Garg A.
      • Misra A.
      Lipodystrophies: rare disorders causing metabolic syndrome.
      and progressive insulin resistance with loss of the body fat compartment.
      • Garg A.
      • Agarwal A.K.
      Lipodystrophies: disorders of adipose tissue biology.

      Congenital disorders of glycosylation

      Congenital disorders of glycosylation (CDG) are a group of disorders that result in defective synthesis of glycoproteins or glycolipids.
      • Jaeken J.
      • Matthijs G.
      Congenital disorders of glycosylation: a rapidly expanding disease family.
      Since the first description of CDG in 1980, the term has has grown to encompass a heterogeneous condition of nearly 100 subtypes including: mono- or multi-organ diseases; presentation in children as well as young adults; mild to severe phenotypes.
      • Jaeken J.
      • Matthijs G.
      Congenital disorders of glycosylation: a rapidly expanding disease family.
      • Marques-da-Silva D.
      • Dos Reis Ferreira V.
      • Monticelli M.
      • Janeiro P.
      • Videira P.A.
      • Witters P.
      • et al.
      Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature.
      Liver involvement is seen in about 22% of patients and can manifest as steatosis, cirrhosis and failure.
      • Marques-da-Silva D.
      • Dos Reis Ferreira V.
      • Monticelli M.
      • Janeiro P.
      • Videira P.A.
      • Witters P.
      • et al.
      Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature.
      • Tegtmeyer L.C.
      • Rust S.
      • van Scherpenzeel M.
      • Ng B.G.
      • Losfeld M.-E.
      • Timal S.
      • et al.
      Multiple phenotypes in phosphoglucomutase 1 deficiency.
      • Schiff M.
      • Roda C.
      • Monin M.-L.
      • Arion A.
      • Barth M.
      • Bednarek N.
      • et al.
      Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.
      The aetiology of the steatosis remains unknown but CDG that give rise to liver disease tend to be grouped at the early steps in the glycosylation pathway involving the endoplasmic reticulum.
      • Marques-da-Silva D.
      • Dos Reis Ferreira V.
      • Monticelli M.
      • Janeiro P.
      • Videira P.A.
      • Witters P.
      • et al.
      Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature.
      The authors recommend CDG testing in patients with Wilson’s disease and hepatocerebral manifestations when typical features are not met.
      • Marques-da-Silva D.
      • Dos Reis Ferreira V.
      • Monticelli M.
      • Janeiro P.
      • Videira P.A.
      • Witters P.
      • et al.
      Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature.

      Ataxia telangiectasia

      Ataxia telangiectasia (AT) is a disorder that presents in childhood with ocular telangiectasia, progressive cerebellar dysfunction, variable immunodeficiency, sensitivity to radiation and increased cancer susceptibility.
      • Rothblum-Oviatt C.
      • Wright J.
      • Lefton-Greif M.A.
      • McGrath-Morrow S.A.
      • Crawford T.O.
      • Lederman H.M.
      Ataxia telangiectasia: a review.
      It falls under the umbrella of chromosome breakage syndromes characterised by chromosome instability due to defective DNA repair mechanisms. Fatty liver resembling NAFLD is common with AT and may progress to advanced liver disease in young patients.
      • Daugherity E.K.
      • Balmus G.
      • Al Saei A.
      • Moore E.S.
      • Abi Abdallah D.
      • Rogers A.B.
      • et al.
      The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease.
      Patients with AT are vulnerable to DNA damage from oxidative stress which leads to mitochondrial dysfunction;

      Caballero T, Caba-Molina M, Salmerón J, Gómez-Morales M. Nonalcoholic Steatohepatitis in a Patient with Ataxia-Telangiectasia [Internet]. Case Reports in Hepatology. 2014 [cited 2017 Oct 30]. Available from: https://www.hindawi.com/journals/crihep/2014/761250/.

      together with impaired insulin secretion and development of diabetes this can lead to liver steatosis.
      • Miles P.D.
      • Treuner K.
      • Latronica M.
      • Olefsky J.M.
      • Barlow C.
      Impaired insulin secretion in a mouse model of ataxia telangiectasia.
      • Bhatwadekar A.D.
      • Duan Y.
      • Chakravarthy H.
      • Korah M.
      • Caballero S.
      • Busik J.V.
      • et al.
      Ataxia telangiectasia mutated dysregulation results in diabetic retinopathy.

      Steatosis in the context of an asymptomatic child with elevated aminotransferases

      Steatosis as the hepatic manifestation of the metabolic syndrome (NAFLD)

      It is not currently possible to predict which children with fatty liver may develop progressive fibrotic disease.
      NAFLD is present in 9% of children and young people between the ages of two and 19,
      • Schwimmer J.B.
      • Deutsch R.
      • Kahen T.
      • Lavine J.E.
      • Stanley C.
      • Behling C.
      Prevalence of fatty liver in children and adolescents.
      3% of whom have steatohepatitic/fibrotic disease. Fatty liver may be present in 55–80% of obese children.
      • Schwimmer J.B.
      • Newton K.P.
      • Awai H.I.
      • Choi L.J.
      • Garcia M.A.
      • Ellis L.L.
      • et al.
      Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease.
      • Giorgio V.
      • Prono F.
      • Graziano F.
      • Nobili V.
      Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets.
      Clearly this is a very heterogeneous group. Similar to adult NAFLD, the disease may or may not be progressive and predicting those who have a propensity to develop progressive fibrotic disease vs. those who remain with simple steatosis is not yet possible. Undoubtedly, there are several modifiers involved, whether genetic or epigenetic.
      • Wattacheril J.
      • Lavine J.E.
      • Chalasani N.P.
      • Guo X.
      • Kwon S.
      • Schwimmer J.
      • et al.
      Genome-wide associations related to hepatic histology in nonalcoholic fatty liver disease in hispanic boys.
      In terms of nutrient intake, body mass index and other clinical features, no risk factors for progressive disease have been identified which reliably distinguish those children with simple non-progressive steatosis from those who develop fibrotic change. In children, certainly, a higher body mass index in the morbidly obese range is not a useful correlate of more advanced disease.
      • Gibson P.S.
      • Lang S.
      • Gilbert M.
      • Kamat D.
      • Bansal S.
      • Ford-Adams M.E.
      • et al.
      Assessment of diet and physical activity in paediatric non-alcoholic fatty liver disease patients: a united kingdom case control study.
      Histologically, both paediatric and adult NAFLD is characterised by predominantly macrovesicular steatosis affecting at least 5% of the parenchyma.
      • Yeh M.M.
      • Brunt E.M.
      Pathological features of fatty liver disease.
      In adults, NAFLD typically features acinar zone 3 fat accumulation. If fibrosis is seen, it usually commences in acinar zone 3. The progressive form of non-alcoholic steatohepatitis (NASH) in adults features steatotic hepatocytes in a diffuse acinar zone 3 distribution, lobular inflammation and cell injury in the form of hepatocyte ballooning and inflammation, whereby ballooning denotes a pattern of liver cell injury of cytoplasmic swelling and rounding.
      • Brunt E.M.
      Nonalcoholic steatohepatitis.
      In paediatric NAFLD, inflammation is often portal based, steatosis may be periportal in distribution, located in acinar zone 3 or panacinar and ballooning is uncommon.
      • Nobili V.
      • Alisi A.
      • Newton K.P.
      • Schwimmer J.B.
      Comparison of the phenotype and approach to pediatric vs. adult patients with nonalcoholic fatty liver disease.
      The morphological features of paediatric NASH fall into three types. The centrilobular pattern of steatosis and inflammation, hepatocellular ballooning and perisinusoidal pattern of fibrosis characteristic of adult NASH is termed type 1 NASH. This pattern is the least common form of paediatric NASH. Type 2 NASH is the predominant form in the paediatric population characterised by the presence of zone 1 or panacinar steatosis, portal inflammation, infrequent ballooning and portal-based fibrosis. An overlap between types 1 and 2 NASH can be seen in up to 75% of cases.
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      Histopathology of pediatric nonalcoholic fatty liver disease.
      It is associated with more advanced disease
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      although puberty seems to exert protective factors.
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      Association between puberty and features of nonalcoholic fatty liver disease.
      Furthermore, the presence of microvesicular steatosis in both 10% of adults and 19% of children
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      • et al.
      Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease.
      more strongly correlates with severity of disease, both in terms of fibrosis and presence of inflammation, as well as ballooning and the presence of megamitochondria. Again, the coexistence of micro- and macro- vesicular steatosis is not fully understood. Certainly, accumulation of excess free fatty acids in a milieu of elevated plasma glucose and insulin levels where packaging and transport of triglycerides is overwhelmed or impaired leads to macrovesicular steatosis. In turn mitochondrial dysfunction may be precipitated by tumour necrosis factor-alpha, reactive oxygen species, peroxynitrite and lipid peroxidation products which disrupt respiratory chain polypeptides and mitochondrial DNA.
      • Pessayre D.
      Role of mitochondria in non-alcoholic fatty liver disease.
      The downstream consequence of a blocked electron transport chain is a further increase in mitochondrial reactive oxygen species. This may be a contributory mechanism for microvesicular steatosis in this context. The heterogeneity of the disease needs much further explanation, particularly focussed on whether the term NAFLD is a mixed bag of different susceptibilities and in essence different diseases which manifest in the context of a precipitant.
      Inherited conditions associated with NAFLD that should be considered include Prader-Willi,
      • Bedogni G.
      • Grugni G.
      • Nobili V.
      • Agosti F.
      • Saezza A.
      • Sartorio A.
      Is non-alcoholic fatty liver disease less frequent among women with Prader-Willi syndrome?.
      Alstrom
      • Gathercole L.L.
      • Hazlehurst J.M.
      • Armstrong M.J.
      • Crowley R.
      • Boocock S.
      • O’Reilly M.W.
      • et al.
      Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.
      and Bardet Biedel syndromes.
      • Branfield Day L.
      • Quammie C.
      • Héon E.
      • Bhan A.
      • Batmanabane V.
      • Dai T.
      • et al.
      Liver anomalies as a phenotype parameter of Bardet-Biedl syndrome.
      Prader-Willi syndrome patients exhibit unique body composition in comparison to obese controls
      • Fintini D.
      • Inzaghi E.
      • Colajacomo M.
      • Bocchini S.
      • Grugni G.
      • Brufani C.
      • et al.
      Non-alcoholic fatty liver disease (NAFLD) in children and adolescents with Prader-Willi Syndrome (PWS).
      • Bedogni G.
      • Grugni G.
      • Nobili V.
      • Agosti F.
      • Saezza A.
      • Sartorio A.
      Is non-alcoholic fatty liver disease less frequent among women with Prader-Willi syndrome?.
      with higher insulin sensitivity alluding to alternative pathogenic pathways.
      • Mele C.
      • Grugni G.
      • Mai S.
      • Vietti R.
      • Aimaretti G.
      • Scacchi M.
      • et al.
      Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome.
      • Goldstone A.P.
      • Thomas E.L.
      • Brynes A.E.
      • Castroman G.
      • Edwards R.
      • Ghatei M.A.
      • et al.
      Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance.

      Wilson’s disease

      A wide spectrum of histological findings can be found in Wilson’s disease, ranging from a chronic porto-lobular hepatitis with no steatosis to a steatohepatitis-like picture, similar to that seen in alcoholic liver disease. Special stains for copper may help point towards the diagnosis, but the distribution of copper may be patchy and not always be present. Abundant hepatocyte ballooning and formation of Mallory-Denk body may also favour Wilson’s disease over steatohepatitis in a child. Both microvesicular and macrovesicular steatosis can be encountered and work has been carried out to verify the link between intracellular copper accumulation and, in its early stages, the findings of micro- and macro- vesicular steatosis.
      • Ludwig J.
      • Moyer T.P.
      • Rakela J.
      The liver biopsy diagnosis of Wilson’s disease. Methods in pathology.
      In vivo studies demonstrated that excess copper catalyses peroxisomal lipid peroxidation and mitochondrial copper accumulation leads to its structural and functional disruption.
      • Myers B.M.
      • Prendergast F.G.
      • Holman R.
      • Kuntz S.M.
      • Larusso N.F.
      Alterations in hepatocyte lysosomes in experimental hepatic copper overload in rats.
      • Sternlieb I.
      • Quintana N.
      • Volenberg I.
      • Schilsky M.L.
      An array of mitochondrial alterations in the hepatocytes of Long-Evans Cinnamon rats.
      • Zischka H.
      • Lichtmannegger J.
      • Schmitt S.
      • Jägemann N.
      • Schulz S.
      • Wartini D.
      • et al.
      Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease.
      Furthermore, in clinical practice, the degree of steatosis correlated with hepatic parenchymal copper concentration.
      • Liggi M.
      • Murgia D.
      • Civolani A.
      • Demelia E.
      • Sorbello O.
      • Demelia L.
      The relationship between copper and steatosis in Wilson’s disease.
      However, it is likely that steatosis in Wilson’s disease is multifactorial in aetiology, as demonstrated by a recent study which identified PNPLA G allele and paediatric age as independent variables for steatosis in Wilson’s disease.
      • Stättermayer A.F.
      • Traussnigg S.
      • Dienes H.-P.
      • Aigner E.
      • Stauber R.
      • Lackner K.
      • et al.
      Hepatic steatosis in Wilson disease–Role of copper and PNPLA3 mutations.

      Following recovery from sepsis

      Steatosis is also seen in the setting of biopsies carried out following sepsis when abnormalities in patients’ liver function tests persist. In these patients, the aetiology of liver damage may be multifactorial including hypoxia, bacterial toxin-mediated causes as well as parenteral nutrition. At the molecular level, there is a recognised association between sepsis and mitochondrial dysfunction. Systemic inflammation causes: i) impaired organ perfusion and tissue hypoxia, compromising oxidative phosphorylation and energy production; ii) reactive oxygen species, products of inflammation, directly damaging cell constituents including the mitochondria; iii) downregulation of genes transcribing mitochondrial proteins.

      Viral hepatitis

      Evidence of hepatotropic as well as non-hepatotropic viral hepatitis should be sought. Hepatitis B, delta and C are associated with hepatic micro- and macro- vesicular steatosis.
      • Machado M.V.
      • Oliveira A.G.
      • Cortez-Pinto H.
      Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients.
      • Verme G.
      • Amoroso P.
      • Lettieri G.
      • Pierri P.
      • David E.
      • Sessa F.
      • et al.
      A histological study of hepatitis delta virus liver disease.
      • Pokorska-Śpiewak M.
      • Kowalik-Mikołajewska B.
      • Aniszewska M.
      • Pluta M.
      • Walewska-Zielecka B.
      • Marczyńska M.
      Liver steatosis in children with chronic hepatitis B and C: Prevalence, predictors, and impact on disease progression.
      In a meta-analysis of hepatic steatosis in 4,100 chronic hepatitis B virus infected patients the overall prevalence of steatosis was 29.6%
      • Machado M.V.
      • Oliveira A.G.
      • Cortez-Pinto H.
      Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients.
      similar to that of the general population. However, the prevalence of steatosis in chronic hepatitis C virus (HCV) infected adults is double,
      • Czaja A.J.
      • Carpenter H.A.
      • Santrach P.J.
      • Moore S.B.
      Host- and disease-specific factors affecting steatosis in chronic hepatitis C.
      although this figure is lower in children.
      • Giannattasio A.
      • Spagnuolo M.I.
      • Sepe A.
      • Valerio G.
      • Vecchione R.
      • Vegnente A.
      • et al.
      Is HCV infection associated with liver steatosis also in children?.
      • Pokorska-Śpiewak M.
      • Kowalik-Mikołajewska B.
      • Aniszewska M.
      • Pluta M.
      • Walewska-Zielecka B.
      • Marczyńska M.
      Liver steatosis in children with chronic hepatitis B and C: Prevalence, predictors, and impact on disease progression.
      The mechanism is secondary to the increased risk of metabolic syndrome
      • Asselah T.
      • Rubbia-Brandt L.
      • Marcellin P.
      • Negro F.
      Steatosis in chronic hepatitis C: why does it really matter?.
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.
      and HCV specific factors. The virus has been shown to increase de novo lipogenesis,
      • Lambert J.E.
      • Bain V.G.
      • Ryan E.A.
      • Thomson A.B.R.
      • Clandinin M.T.
      Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans.
      interfere with mitochondrial fatty acid oxidation
      • Okuda M.
      • Li K.
      • Beard M.R.
      • Showalter L.A.
      • Scholle F.
      • Lemon S.M.
      • et al.
      Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.
      • Sebastiani G.
      • Vario A.
      • Ferrari A.
      • Pistis R.
      • Noventa F.
      • Alberti A.
      Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C.
      and decrease hepatocellular export of fatty substrates.
      • Domitrovich A.M.
      • Felmlee D.J.
      • Siddiqui A.
      Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion.
      In particular, the prevalence and severity of steatosis in HCV genotype 3 is greatest and the virus core protein has been shown to directly associate with lipids acting as intracellular storage sites;
      • Abid K.
      • Pazienza V.
      • de Gottardi A.
      • Rubbia-Brandt L.
      • Conne B.
      • Pugnale P.
      • et al.
      An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation.
      • Hourioux C.
      • Patient R.
      • Morin A.
      • Blanchard E.
      • Moreau A.
      • Trassard S.
      • et al.
      The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model.
      • Jhaveri R.
      • Qiang G.
      • Diehl A.M.
      Domain 3 of hepatitis C core protein is sufficient for intracellular lipid accumulation.
      the effects of which are increased risk of fibrosis
      • Adinolfi L.E.
      • Gambardella M.
      • Andreana A.
      • Tripodi M.F.
      • Utili R.
      • Ruggiero G.
      Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.
      • Cross T.J.S.
      • Quaglia A.
      • Hughes S.
      • Joshi D.
      • Harrison P.M.
      The impact of hepatic steatosis on the natural history of chronic hepatitis C infection.
      and carcinogenesis.
      • Ohata K.
      • Hamasaki K.
      • Toriyama K.
      • Matsumoto K.
      • Saeki A.
      • Yanagi K.
      • et al.
      Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection.
      Readers are referred to a review dedicated to the subject for further details.
      • Bugianesi E.
      • Salamone F.
      • Negro F.
      The interaction of metabolic factors with HCV infection: does it matter?.

      Drugs

      Microvesicular steatosis in the context of pharmacotherapy has been well documented. Corticosteroids are probably the drug most commonly associated with macrovesicular steatosis. This is because glucocorticoids bind to glucocorticoid receptor, a nuclear receptor and transcription regulator. This stimulates transcription of lipogenic enzymes. Glucocorticoid administration also inhibits fatty acid beta oxidation enzymes, medium and short chain acyl-CoA dehydrogenase.
      • Begriche K.
      • Massart J.
      • Robin M.-A.
      • Borgne-Sanchez A.
      • Fromenty B.
      Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.
      Conventionally, sodium valproate, aspirin, tetracycline, amiodarone and antiretrovirals are drugs implicated in hepatic steatosis. In sodium valproate therapy idiosyncratic hepatotoxicity is well known. Valproate competitively inhibits beta-oxidation of fatty acids in the mitochondria, impairing lipid metabolism and resulting in microvesicular steatosis.
      • Stewart J.D.
      • Horvath R.
      • Baruffini E.
      • Ferrero I.
      • Bulst S.
      • Watkins P.B.
      • et al.
      Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity.
      Similarly, interference with beta-oxidation and oxidative phosphorylation have been proposed as the mechanism behind microvesicular steatosis induced by tetracycline, amiodarone and nucleoside analogues.
      • Fréneaux E.
      • Labbe G.
      • Letteron P.
      • Dinh T.L.
      • Degott C.
      • Genève J.
      • et al.
      Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: Possible role in microvesicular steatosis induced by this antibiotic.

      Congenital porto-systemic shunts

      A congenital porto-systemic shunt results from failed involution of foetal vessels either inside or outside of the liver; the ductus venosus being the most important.
      • Bernard O.
      • Franchi-Abella S.
      • Branchereau S.
      • Pariente D.
      • Gauthier F.
      • Jacquemin E.
      Congenital portosystemic shunts in children: recognition, evaluation, and management.
      If left untreated, it can lead to the development of chronic liver disease, liver tumours and encephalopathy. Under these circumstances hepatocytes are deprived of nutrients and oxygen perfusion leading to cell dysfunction.
      • Uchino T.
      • Endo F.
      • Ikeda S.
      • Shiraki K.
      • Sera Y.
      • Matsuda I.
      Three brothers with progressive hepatic dysfunction and severe hepatic steatosis due to a patent ductus venosus.
      Microvesicular steatosis with mitochondrial enlargement at the ultrastructural level has been observed in this setting.

      Hepatic steatosis due to congenital absence of the portal VE... : J Pediatr Gastroenterol Nutr [Internet]. LWW. [cited 2016 Nov 14]. Available from: http://journals.lww.com/jpgn/Fulltext/1997/10000/HEPATIC_STEATOSIS_DUE_TO_CONGENITAL_ABSENCE_OF_THE.147.aspx.

      Conclusion

      The term paediatric fatty liver disease (PeFLD) may be more appropriate to describe these children.
      Steatosis is an important histological finding with diagnostic and prognostic implications. Traditionally, in paediatrics, steatosis has been considered a finding that is linked to an underlying IMD. Today with the global epidemic of obesity the subject of fatty liver is becoming ever more complex. This review was aimed at describing the aetiopathogenesis of fatty liver in children and young adults according to different clinical presentations. We offer this model as a means to develop a diagnostic approach in relation to clinical presentation. We also request that clinicians shy away from the diagnostic entity of NAFLD, particularly in young children and suggest that in this population the term PeFLD may be a more appropriate umbrella term.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contribution

      AD came up with the idea of the manuscript. RH wrote the first draft of the manuscript. RH, MD, EF and AD contributed to the revised version.

      Supplementary data

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