Severe acute liver disease in adults: Contemporary role of histopathology.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).

Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation.

Seventeen out of 764 liver biopsies from transplanted (Tx) livers in children showed glycogen-ground glass (GGG) hepatocytic inclusions. The inclusions were not present in pre-Tx or in the explanted or donor's liver. Under the electron microscope (EM), the stored material within the cytosol appeared as non-membrane-bound aggregates of electron-lucent globoid or fibrillar granules, previously described as abnormally structured glycogen and identified as Polyglucosan bodies (PB). The appearance of GGG in our children was analogous to that of PB-GGG occurring in a number of congenital diseases due to gene mutations such as Lafora's d., Andersen's d., Adult Polyglucosan Body Disease and glycogenin deficiency. The same type of GGG was previously reported in the liver of patients undergoing transplants, immunosuppressive or antiblastic treatment. To explore the potential mechanism of GGG formation, we examined whether the drugs after whose treatment this phenomenon was observed could have a role. By carrying out molecular docking, we found that such drugs somehow present a high binding affinity for the active region of glycogenin, implicating that they can inactivate the protein, thus preventing its interaction with glycogen synthase (GS), as well as the maturation of the nascent glycogen towards gamma, beta or alfa glycogen granules. We could also demonstrate that PG inclusions consist of a complex of PAS positive material (glycogen) and glycogen-associated proteins, i.e., glicogenin-1 and -2 and ubiquitin. These features appear to be analogous to congenital GGG, suggesting that, in both cases, they result from the simultaneous dysregulation of glycogen synthesis and degradation. Drug-induced GGG appear to be toxic to the cell, despite their reversibility.

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain.

The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.

Hepatic and Extrahepatic Sources and Manifestations in Endoplasmic Reticulum Storage Diseases.

Alpha-1-antitrypsin (AAT) and fibrinogen are secretory acute phase reactant proteins. Circulating AAT and fibrinogen are synthesized exclusively in the liver. Mutations in the encoding genes result in conformational abnormalities of the two molecules that aggregate within the rough endoplasmic reticulum (RER) instead of being regularly exported. That results in AAT-deficiency (AATD) and in hereditary hypofibrinogenemia with hepatic storage (HHHS). The association of plasma deficiency and liver storage identifies a new group of pathologies: endoplasmic reticulum storage disease (ERSD).

The Recruitment-Secretory Block ("R-SB") Phenomenon and Endoplasmic Reticulum Storage Diseases.

In this article, we review the biological and clinical implication of the Recruitment-Secretory Block ("R-SB") phenomenon. The phenomenon refers to the reaction of the liver with regard to protein secretion in conditions of clinical stimulation. Our basic knowledge of the process is due to the experimental work in animal models. Under basal conditions, the protein synthesis is mainly carried out by periportal (zone 1) hepatocytes that are considered the "professional" synthesizing protein cells. Under stimulation, midlobular and centrolobular (zones 2 and 3) hepatocytes, are progressively recruited according to lobular gradients and contribute to the increase of synthesis and secretion. The block of secretion, operated by exogenous agents, causes intracellular retention of all secretory proteins. The Pi MZ phenotype of Alpha-1-antitrypsin deficiency (AATD) has turned out to be the key for in vivo studies of the reaction of the liver, as synthesis and block of secretion are concomitant. Indeed, the M fraction of AAT is stimulated for synthesis and regularly exported while the Z fraction is mostly retained within the cell. For that reason, the phenomenon has been designated "Recruitment-Secretory Block" ("R-SB"). The "R-SB" phenomenon explains why: (a) the MZ individuals can correct the serum deficiency; (b) the resulting immonohistochemical and electron microscopic (EM) patterns are very peculiar and specific for the diagnosis of the Z mutation in tissue sections in the absence of genotyping; (c) the term carrier is no longer applicable for the heterozygous condition as all Pi MZ individuals undergo storage and the storage predisposes to liver damage. The storage represents the true elementary lesion and consequently reflects the phenotype-genotype correlation; (d) the site and function of the extrahepatic AAT and the relationship between intra and extracellular AAT; (e) last but not least, the concept of Endoplasmic Reticulum Storage Disease (ERSD) and of a new disease, hereditary hypofibrinogenemia with hepatic storage (HHHS). In the light of the emerging phenomenon, described in vitro, namely that M and Z AAT can form heteropolymers within hepatocytes as well as in circulation, we have reviewed the whole clinical and experimental material collected during forty years, in order to evaluate to what extent the polymerization phenomenon occurs in vivo. The paper summarizes similarities and differences between AAT and Fibrinogen as well as between the related diseases, AATD and HHHS. Indeed, fibrinogen gamma chain mutations undergo an aggregation process within the RER of hepatocytes similar to AATD. In addition, this work has clarified the intriguing phenomenon underlying a new syndrome, hereditary hypofibrinogenemia and hypo-APO-B-lipoproteinemia with hepatic storage of fibrinogen and APO-B lipoproteins. It is hoped that these studies could contribute to future research and select strategies aimed to simultaneously correct the hepatocytic storage, thus preventing the liver damage and the plasma deficiency of the two proteins.

Protein Misfolding and Aggregation: The Relatedness between Parkinson's Disease and Hepatic Endoplasmic Reticulum Storage Disorders.

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism.

Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human.

BACKGROUND & AIMS: Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules. METHODS: Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase. RESULTS: Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules. CONCLUSION: Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression.

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child.

BACKGROUND AND AIMS: Fibrinogen gene mutations can rarely result in hepatic fibrinogen storage disease (HFSD). Herein, we report on the first Turkish family carrying the mutation p.Arg375Trp (fibrinogen Aguadilla) in the γ-chain of the fibrinogen (FGG) gene. METHODS: Clinical, laboratory and histopathological findings of the patient were documented. Molecular study of fibrinogen gene was performed in the patient and her family members. RESULTS: The proband was 5 years old girl presenting with advanced liver fibrosis of unknown origin. The child had very low plasma levels of fibrinogen and hypobetalipoproteinemia. Immunomorphologic and electron microscopic studies showed selective and exclusive accumulation of fibrinogen within the endoplasmic reticulum in liver biopsy of the patient. Patient, mother, two sisters and one brother carried p.Arg375Trp mutation (fibrinogen Aguadilla) in FGG gene. The patient was treated with ursodeoxycholic acid and carbamazepine. After 3 months, carbamazepine was suspended upon family decision and unresponsiveness of carbamazepine. CONCLUSIONS: HFSD is characterized by hypofibrinogenemia and accumulation of abnormal fibrinogen within hepatocytes. In addition, hypofibrinogenemia is associated with hypobetalipoproteinemia in Aguadilla mutation.

Pathology of the liver sinusoids.

The hepatic sinusoids comprise a complex of vascular conduits to transport blood from the porta hepatis to the inferior vena cava through the liver. Under normal conditions, portal venous and hepatic artery pressures are equalized within the sinusoids, oxygen and nutrients from the systemic circulation are delivered to the parenchymal cells and differentially distributed throughout the liver acini, and proteins of liver derivation are carried into the cardiac/systemic circulation. Liver sinusoid structures are lined by endothelial cells unique to their location, and Kupffer cells. Multifunctional hepatic stellate cells and various immune active cells are localized within the space of Disse between the sinusoid and the adjacent hepatocytes. Flow within the sinusoids can be compromised by physical or pressure blockage in their lumina as well as obstructive processes within the space of Disse. The intimate relationship of the liver sinusoids to neighbouring hepatocytes is a significant factor affecting the health of hepatocytes, or transmission of the effects of injury within the sinusoidal space. Pathologists should recognize several patterns of injury involving the sinusoids and surrounding hepatocytes. In this review, injury, alterations and accumulations within the liver sinusoids are illustrated and discussed.

Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy.

UNLABELLED: Generalized arterial calcification of infancy (GACI, OMIM 208000) and pseudoxanthoma elasticum (PXE, OMIM 264800) are rare autosomal-recessive disorders which represent the opposite ends of the same spectrum of pathologies characterized by progressive ectopic calcification and degeneration of elastic fibers at skin, eyes, and cardiovascular level. Patients with GACI suffer from hypertension, severe myocardial ischemia, and congestive heart failure and often die within 6 months of life. On the other end, PXE is associated with considerable morbidity, rarely with mortality. GACI and PXE are associated with biallelic mutations in ENPP1 and in ABCC6. We report the case of a 4-year-old Italian child submitted to heart transplant, at 18 months old, for end-stage heart failure due to extensive myocardial infarction of the left ventricle and diffuse coronary calcifications. The histology showed generalized arterial calcification and the molecular analysis identified mutations in ABCC6. Two years after transplantation, the child shows good clinical conditions and growth with no recurrence of calcium deposits in the heart. CONCLUSION: Bisphosphonate therapy at present is the treatment of choice for systemic arterial involvement in GACI, and heart transplant has proven to be the definitive treatment in case with extensive myocardial infarction, as in our. Molecular analysis is mandatory for a complete diagnosis and familial counseling.

Steatohepatitic hepatocellular Carcinoma:A new approach to classifying morphological subtypes of hepatocellular carcinoma.

Histological subtyping of hepatocellular carcinoma (HCC) is challenging in the presence of histological heterogeneity, where distinctly different morphological patterns are present within the same tumor. Current approaches rely on percent cut-offs. We hypothesized that morphologic intratumor heterogeneity is a non-random biological feature and that incorporating recurrent patterns would improve histological subtyping of HCC. Resected HCC were studied and the overall frequency of morphologic intratumor heterogeneity was 45% in 242 specimens. Steatohepatitic HCC (SH-HCC) had the highest frequency of morphologic intratumor heterogeneity (91%); this was confirmed in additional cohorts of SH-HCC from different medical centers (overall frequency of 78% in SH-HCC). Morphologic intratumor heterogeneity in SH-HCC showed distinct and recurrent patterns that could be classified as early, intermediate, and advanced. Incorporating these patterns into the definition of SH-HCC allowed successful resolution of several persistent challenges: the problem of the best cut-off for subtyping SH-HCC, the problem of the relationship between SH-HCC and scirrhous HCC, and the classification for HCC with abundant microvesicular steatosis. This approach also clarified the relationship between SH-HCC and CTNNB1 mutations, showing that CTNNB1 mutations occur late in a subset of SH-HCC. In summary, there is a high frequency of morphologic intratumor heterogeneity in HCC. Incorporating this finding into histological subtyping resolved several persistent problems with the SH-HCC subtype.

Bile salt export pump deficiency: A de novo mutation in a child compound heterozygous for ABCB11. Laboratory investigation to study pathogenic role and transmission of two novel ABCB11 mutations.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal disorders. PFIC type 2 is due to mutation in ABCB11, the gene encoding the bile salt export pump (BSEP) protein. The aim of the study was to describe a child with a de novo mutation in a compound heterozygous for ABCB11 gene. We report a 1.7-year-old girl who presented with pruritus, jaundice and liver dysfunction of PFIC type 2. Immunohistochemistry and molecular analysis are described. Liver biopsy showed micronodular cirrhosis and immunohistochemical staining for BSEP, the protein encoded by ABCB11, displayed a patchy and faint reactivity. Molecular analysis revealed two novel mutations of ABCB11. We give details that one mutation is transmitted by the mother while the second one appears a de novo mutation as mutations or a potential mosaicism were ruled out in the natural father. We further speculate that the ABCB11 mutations do not prevent BSEP glycoprotein to be expressed at the canalicular pole of hepatocytes, but interfere with its ability to export bile salts. As in most instances, mutational analysis is performed following the histochemical demonstration of an undetectable BSEP on liver biopsy specimen. This case stresses that clinical PFIC with an attenuated rather than absent BSEP immunostaining can still be due to ABCB11 mutations presumably encoding a functionally deficient protein.

Necrosis of the tongue as first symptom of Polyarteritis Nodosa (PAN): unusual presentation of a rare disease in children.

Polyarteritis or panarteritis nodosa (PAN) is a necrotizing, focal segmental vasculitis that affects predominantly medium-sized arteries in many different organ systems. It is extremely rare in childhood. Involvement of the oral mucosa at diagnosis is uncommon in PAN. Here, we report a case of a pediatric patient with tongue necrosis.

Impressive pseudotumoral proliferative nodules in a giant congenital nevus of a newborn.

The potential for malignant transformation of a giant congenital melanocytic nevus (GCMN), although rare, should be considered, especially in proliferative lesions that have nodules on their surface, as they can clinically and histologically mimic melanoma and generally have a poor prognosis. We present the case of a newborn boy with a giant nevus of uneven blackish color on the back with variable degrees of intensity of pigmentation, almost entirely covered by nodules of large and variable sizes, soft texture, and a tendency to ulcerate and bleed. The unusual clinical and histologic appearance made the case particularly interesting and featured a not well-defined biologic behavior, thus deserving a radical surgical approach to fulfill diagnostic and therapeutic aims.

Congenital myxoid and pigmented dermatofibrosarcoma protuberans: a case report.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade, mesenchymal, spindle cell tumor. In addition to the classical form characterized by a storiform pattern of tumor cells, pigmented (Bednar's tumor) and myxoid variants can be observed. Classical DFSP and Bednar's tumor are easily diagnosed. The myxoid variant represents a diagnostic challenge. Pigmented and myxoid variants are rare and thus far have never been reported in association in congenital DFSP. We came across a unique DFSP that was, at the same time, congenital, pigmented, and myxoid. The tumor was surgically excised with broad free margins and no recurrence. The differential diagnosis with other entities such as giant cell fibroblastoma, CD34-positive plaque-like dermal fibroma, superficial plaque-like CD34 DFSP, and neurocristic hamartoma is discussed. The recognition of this hybrid variant of congenital DFSP is important to avoid under- or overtreatment.

The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Haploinsufficiency in SON may affect multiple genes, including those involved in the development and metabolism of multiple organs. Considering the broad spectrum of SON functions, it is to be expected that pathogenic variants in this gene can cause a wide spectrum of clinical symptoms. We present an additional ZTTK syndrome case due to a de novo heterozygous variant in the SON gene (c.5751_5754delAGTT). The clinical manifestations of our patient were similar to those present in previously reported cases; however, the diagnosis of ZTTK syndrome was delayed for a long time and was carried out during the diagnostic work-up of significant chronic liver disease (CLD). CLD has not yet been reported in any series; therefore, our report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement. Correspondingly, we recommend screening patients with SON variants specifically for liver involvement from the first years of life. Once the CLD has been diagnosed, an appropriate follow-up is mandatory, especially considering the role of SON as an emerging player in cancer development. Further studies are needed to investigate the role of SON haploinsufficiency as a downregulator of essential genes, thus potentially impairing the normal development and/or functions of multiple organs.

The role of liver transplantation in the care of primary hepatic vascular tumours in children.

Liver transplantation (LT) is the standard of care for many liver conditions, such as end-stage liver diseases, inherited metabolic disorders, and primary liver malignancies. In the latter group, indications of LT for hepatoblastoma and hepatocellular carcinoma evolved and are currently available for many non-resectable cases. However, selection criteria apply, as the absence of active metastases. Evidence of good long-term outcomes has validated the LT approach for managing these malignancies in the context of specialist and multidisciplinary approach. Nevertheless, LT's role in treating primary vascular tumours of the liver in children, both benign and malignant, remains somewhat controversial. The rarity of the different diseases and the heterogeneity of pathological definitions contribute to the controversy and make evaluating the benefit/risk ratio and outcomes quite difficult. In this narrative review, we give an overview of primary vascular tumours of the liver in children, the possible indications and the outcomes of LT.

Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy.

Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.