Ultrasound findings in early congenital syphilis: Two case reports and literature review.

Syphilis is caused by treponema pallidum. If untreated, or inadequately treated, during pregnancy, it can result in congenital syphilis (CS), which is classified as early and late. Early CS displays before 2 years of age. We herein describe 2 cases of early CS, whose clinical onset included liver failure, edema, organomegaly, and respiratory distress. We focus on liver, intestinal, and brain ultrasound (US) and other peculiar radiological findings. To date, there are no scientific data on intestinal and brain US findings in patients with early CS whereas data on abdominal US are scarce. Increasing knowledge about US findings in early CS could be useful to improve the diagnostic and therapeutic approach to these patients.

Continuous Erector Spinae Plane Block for Pain Management in a Pediatric Kidney Transplant Recipient: A Case Report and Review of the Current Literature.

Pain management in patients undergoing kidney transplantation requires careful consideration due to their altered physiology, and potential risks associated with certain analgesic options. In recent years, personalized and multimodal approaches have proven to be pivotal in perioperative pain management, as well as in children. Implementing regional analgesia methods offers a valuable solution in many pediatric surgical settings and the erector spinae plane block (ESPB) could represent a possible analgesic strategy in pediatric patients undergoing renal transplantation. Here, we report the case of a 13-year-old child who underwent living-donor kidney transplantation (LDKx) and received continuous erector spinae plane block (ESPB) for perioperative pain management. This multimodal approach with continuous ESPB resulted in optimal pain control without the need for opioids, allowing for early mobilization and for an optimal postoperative course.

Telemedicine in Patients Affected by Chronic Liver Disease: A Scoping Review of Clinical Outcomes and the Devices Evaluated.

For patients with chronic liver disease (CLD), telemedicine is emerging as a useful tool to prevent liver decompensation or hospitalization, allowing access to and the decentralization of care, even for patients with limited resources. However, research and attendant evidence are still lacking; thus, this review aims to systematically explore the topic of telemonitoring for CLD to describe the currently used tools and clinical outcomes. The review was conducted by using key terms on PubMed/EMBASE and searching for observational studies or clinical trials (according to PRISMA recommendations) that were published between 6 April 2013 and 6 April 2023 to keep the technological framework limited to the last 10 years. The studies were described and grouped according to the aim of telemonitoring, the underlying disease, and the tools adopted to achieve remote monitoring. A total of 32 articles met the inclusion criteria. Of these, 11 articles report the successful use of a telehealth program to support and improve access to care in the management of HCV-related cirrhosis, eight articles examine the efficacy of telemedicine for remote monitoring interventions to prevent or decrease the risk of decompensation in high-risk patients, and five articles examine improvements in the physical performance and quality of life of cirrhotic patients through telehealth rehabilitation programs. Four studies were completed during the recent COVID-19 pandemic. Telehealth has the potential to provide and expand treatment access and reduce barriers to care for the most disadvantaged patients and might be able to reduce the need for hospital readmission for CLD, though most practice to test feasibility is still in the pilot stage.

Thrombotic Features as the Primary Cause of SARS-CoV-2 Related Acute Abdomen in Children.

OBJECTIVES: We performed a retrospective case control study to evaluate the histological characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive pediatric patients undergoing laparoscopic exploration for acute abdomen symptoms. To our knowledge this is the first study that analyzes histopathological characteristics of abdominal tissues in SARS-CoV-2 children. STUDY DESIGN: We enrolled 8 multisystem inflammatory syndrome in children (MIS-C) patients and 4 SARS-CoV-2 positive patients who underwent intestinal resection versus 36 control appendectomies from 2 pediatric tertiary referral centers between March 2020 and July 2021. Surgical resection samples were evaluated on several histological sections focusing on general inflammatory pattern and degree of inflammation. Peculiar histological features (endotheliitis and vascular thrombosis) were semi-quantitatively scored respectively in capillary, veins, and arteries. RESULTS: All SARS-CoV-2 related surgical samples showed thrombotic patterns. Those patterns were significantly less frequent in SARS-CoV-2 negative appendectomies ( P = 0.004). The semi-quantitative score of thrombosis was significantly higher ( P = 0.002) in patients with SARS-CoV-2 related procedures. CONCLUSIONS: Our results showed that SARS-CoV-2 can cause thrombotic damage in abdominal tissues both in the acute phase of the infection (SARS-CoV-2 related appendectomies) and secondary to cytokine storm (MIS-C).

Vitamin D Levels in the Pre- and Post-COVID-19 Pandemic Periods and Related Confinement at Pediatric Age.

Coronavirus disease 2019 (COVID-19) restrictions have been correlated with vitamin D deficiency in children, but some uncertainties remain. We retrospectively studied vitamin 25-(OH) D blood levels in 2182 Italian children/adolescents hospitalized for various chronic diseases in the year before (n = 1052) and after (n = 1130) the nationwide lockdown. The type of underlying disease, gender, and mean age (91 ± 55 and 91 ± 61 months, respectively) of patients included in the two periods were comparable. Although mean levels were the same (p = 0.24), deficiency status affected a significantly higher number of subjects during the lockdown period than in the pre-COVID period (p = 0.03), particularly in summer (p = 0.02), and there was also a smoothing of seasonal variations in vitamin D levels. Particularly at risk were males (OR = 1.22; p = 0.03), the 1-5 year age group (OR = 1.57; p < 0.01) and the 6-12 year age group (OR = 1.30; p = 0.04). Infants appeared not to be affected (p = 1.00). In the post-COVID period, the risk of vitamin D deficiency was unchanged in disease-specific groups. However, the proportion of deficiency or severe deficiency differed significantly in the subgroup with endocrinopathy (higher; Chi-square p = 0.04), and with respiratory problems and obesity (lower; Chi-square p = 0.01 and p < 0.01, respectively). Conflicting/opposite literature results advocate for further studies to clearly indicate the need for supplementation during possible future periods of confinement.

Case Report: Add-on treatment with odevixibat in a new subtype of progressive familial intrahepatic cholestasis broadens the therapeutic horizon of genetic cholestasis.

Odevixibat, an ileal bile acid transporter (IBAT) inhibitor, is effective for the treatment of pruritus in children diagnosed with progressive familial intrahepatic cholestasis (PFIC) type 1 and 2. There are no studies showing the efficacy of Odevixibat in children with different subtypes of PFIC. We describe the case of a 6-year-old girl with chronic cholestatic jaundice. In the last 12 months laboratory data showed high serum levels of bilirubin (total bilirubin x 2.5 ULN; direct bilirubin x 1.7 ULN) and bile acids (sBA x 70 ULN), elevated transaminases (x 3-4 ULN), and preserved synthetic liver function. Genetic testing showed homozygous mutation in ZFYVE19 gene, which is not included among the classic causative genes of PFIC and determined a new non-syndromic phenotype recently classified as PFIC9 (OMIM # 619849). Due to the persistent intensity of itching [score of 5 (very severe) at the Caregiver Global Impression of Severity (CaGIS)] and sleep disturbances not responsive to rifampicin and ursodeoxycholic acid (UDCA), Odevixibat treatment was started. After treatment with odevixibat we observed: (i) reduction in sBA from 458 to 71 µmol/L (absolute change from baseline: -387 µmol/L), (ii) reduction in CaGIS from 5 to 1, and (iii) resolution of sleep disturbances. The BMI z-score progressively increased from -0.98 to +0.56 after 3 months of treatment. No adverse drug events were recorded. Treatment with IBAT inhibitor was effective and safe in our patient suggesting that Odevixibat may be potentially considered for the treatment of cholestatic pruritus also in children with rare subtypes of PFIC. Further studies on a larger scale could lead to the increasing of patients eligible for this treatment.

Congenital syphilis in the twenty-first century: an area-based study.

The resurgence of syphilis and subsequent risk for newborns has been described worldwide; however, European data on this congenital infection is lacking. We report the activity of a multidisciplinary specialized unit assisting a large area in the Southern Italy. A retrospective cohort study has been conducted at the Perinatal and Pediatric Infectious Diseases Units of the Federico II University of Naples, enrolling all newborns and children referred from January 2010 to June 2022 exposed to Treponema pallidum in utero and/or congenitally infected. A total of 323 patients were included in the analysis. Twenty (6.2%) received a diagnosis of confirmed congenital syphilis (CS) and one died. Fifteen CS cases had typical clinical features. Since 2017, the number of referred neonates tripled while the rate of late maternal diagnoses did not significantly differ. When compared with mothers of exposed infants, mothers of CS cases were younger (25 ± 7.2 vs 29.9 ± 6 years, p = 0.041), had less previous pregnancies (0.64 vs 1.11, p = 0.044), and received a diagnosis of syphilis at a later stage of pregnancy (86% vs 20%, from third trimester or later on; p < 0.001). Appropriate maternal therapy was protective against vertical transmission (- 1.2; - 1.4, - 1 95% CI; p < 0.001). Paternal syphilis status was known in 36% of cases. CONCLUSION: CS has still a significant impact. Prevention should be implemented towards specific maternal risk profiles. A specialized unit is the preferable model to improve surveillance and healthcare for this neglected population. WHAT IS KNOWN: • The resurgence of syphilis and subsequent risk for newborns has been described worldwide. • European data on this congenital infection is lacking. WHAT IS NEW: • Congenital syphilis has a significant impact still in Europe and prevention should be implemented towards specific maternal risk profiles.  • A specialized unit is the preferable model to improve surveillance and healthcare for this neglected population.

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

Liver and Pancreatic Involvement in Children with Multisystem Inflammatory Syndrome Related to SARS-CoV-2: A Monocentric Study.

Liver and pancreatic involvement in children with Multisystem Inflammatory Syndrome related to SARS-CoV-2 (MIS-C) has been poorly investigated so far. We reviewed a cohort of MIS-C patients to analyze the prevalence of acute liver injury (ALI) and pancreatic injury and their correlation with clinical outcomes. Demographic, clinical, laboratory and imaging features of children with MIS-C at admission and during hospital stay were prospectively collected. Fifty-five patients (mean age 6.5 ± 3.7 years) were included. At admission, 16 patients showed ALI and 5 had increased total serum lipase. During observation, 10 more patients developed ALI and 19 more subjects presented raised pancreatic enzymes. In comparison to those with normal ALT, subjects with ALI were significantly older (p = 0.0004), whereas pancreatic involvement was associated to a longer duration of hospital stay compared with patients with normal pancreatic enzymes (p = 0.004). Time between hospital admission and onset of ALI was shorter compared to the onset of raised pancreatic enzymes (3.2 ± 3.9 versus 5.3 ± 2.7 days, respectively; p = 0.035). Abdominal ultrasound showed liver steatosis in 3/26 (12%) and hepatomegaly in 6/26 (16%) patients with ALI; 2 patients presented enlarged pancreas. Although liver and pancreatic involvement is commonly observed in MIS-C patients, it is mild in most cases with a complete recovery.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature.

Consumptive hypothyroidism (CH) is a rare and potentially overlooked complication of hepatic hemangiomas (HH) overexpressing the enzyme deiodinase, which converts thyroxine (T4) to reverse triiodothyronine (rT3). Materials and methods: Here, we report a case series of 3 patients and a systematic review of the literature. Results: Hypothyroidism (mean serum TSH 52.03 mIU/L) was detected at a mean age of 4.6 months (range 3-6) in 3 infants with infantile hepatic hemangiomas, treated with thyroxine (mean dose 12 µg/kg/day). All received treatment with propranolol (1-3 mg/kg/day) from the mean age of 4 months. Hormonal treatment was stopped at a mean age of 20 months (range 12-30). Hypothyroidism reoccurred in a patient concurrently with the increase of liver lesions, requiring liver transplantation (LT) at age 39 months.Literature review retrieved 42 studies (48 patients): HH (n = 43) were isolated in 24 infants and associated with cutaneous hemangiomas in 19. Hemangiomas were only cutaneous in 5.In the first 43 patients, hypothyroidism was detected at a mean age of 1 month; 21 of 43 patients were prescribed propranolol alone (n = 8) or associated with other medicaments (n = 13); 2 of 43 patients underwent LT. Hormonal treatment consisted of T4 in 35 of 43 patients and T3 in 10.CH associated with only cutaneous and extrahepatic visceral hemangiomas (n = 5), detected at a mean age of 7 months (TSH mean levels at diagnosis of 150.3 mIU/L). Three of 5 patients received treatment with propranolol ± other medicaments. All 5 patients were treated with T4. Conclusions: Periodical thyroid function assessment is necessary in patients with hepatic hemangiomas, particularly when lesions' size and number increase rapidly.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Acute disseminated encephalomyelitis in a patient with Noonan syndrome: A rare autoinflammatory complication or coincidence?

We describe a 13-years-old girl, previously diagnosed with PTPN11-associated Noonan Syndrome (NS), who presented to the pediatric emergency department for fever and drowsiness, which gradually worsened within 48 h. On admission, brain magnetic resonance imaging (MRI) scan showed diffuse, symmetric, multiple, poorly demarcated, confluent hyperintense lesions on MRI T2w-images, located in the Central Nervous System (CNS). In the absence of a better explanation and according to the current diagnostic criteria, a diagnosis of Acute Disseminated Encephalomyelitis (ADEM) was performed. The patient was first treated with intravenous methylprednisolone, then with intravenous immunoglobulin (IVIG). Owing to the poor clinical response, three sessions of therapeutic plasma exchange (TPE) were finally performed, with a progressive improvement. Follow-up MRI performed after three months from the onset revealed a considerable reduction in brain lesions, while cervical and dorsal ones were substantially unmodified. Neurological examination showed a full recovery of cognitive function and improved strength and tone of the upper limbs, while tetrahyporeflexia and proximal weakness of lower limbs were still appreciable. To date, this is the first described case of ADEM occurring in a patient with NS.

Multisystem inflammatory syndrome in children. An emerging clinical challenge for pediatric surgeons in the COVID 19 era.

BACKGROUND/PURPOSE: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening condition occurring 2-6 weeks after Coronavirus disease 2019 (COVID-19) in previously healthy children and adolescents, characterized by clinical and laboratory evidence of multiorgan inflammation. We reported the case of a 6-year-old child presented with acute abdomen and then diagnosed with MIS-C. In addition, to better portray this new entity, we performed a systematic review of MIS-C gastrointestinal features and particularly on those mimicking surgical emergencies. METHODS: We described the clinical presentation, the diagnostic approach and the therapeutic outcomes of our MIS-C patient. Parallel to this, we conducted a systematic literature search using Google Scholar, PubMed, EMBASE, Scopus, focusing on gastrointestinal MIS-C. RESULTS: Our patient was initially assessed by the surgical team due to his query acute abdomen. Following the diagnosis of MIS-C with myocarditis, intravenous methylprednisolone (2 mg/Kg/day) and intravenous immunoglobulins (2 gr/Kg single infusion) were promptly started, leading to clinical improvement. According to our literature search, patients with MIS-C have a high rate of severe abdominal symptoms resembling surgical emergencies (appendicitis, obstruction, etc.) and a not negligible number of those patients have been surgically explored with variable findings. CONCLUSIONS: We encourage pediatric surgeons in the upcoming months of COVID-19 pandemic to evaluate myocardial function prior to surgical abdominal exploration. In children with query acute abdomen, MIS-C should be promptly ruled out in order to avoid unnecessary surgeries that could worsen the already frail outcome of this new syndrome. Nevertheless, it should be considered that MIS-C might well encompass complications (e.g. appendicitis, segmental intestinal ischemia) which need swift surgical treatment.

Author Correction: Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chronic liver involvement in urea cycle disorders.

The increased survival of urea cycle disorders (UCDs) patients has led the attention to clinical manifestations that characterize the long-term disease course. Acute and chronic liver disease have been anecdotally reported since the very first description of UCDs. However, a detailed analysis of long-term liver involvement in large patient cohorts is still needed. Chronic liver damage in UCDs has probably a multifactorial origin, but the specific underlying mechanisms of liver disease have not yet been well elucidated. In this study, we report on chronic liver involvement and on associated metabolic abnormalities in a large cohort of 102 UCD patients, followed by two reference centers in Italy. Chronic liver involvement was observed in over 60% of UCDs patients, and comparison between individual diseases showed a significant higher frequency in argininosuccinate lyase deficiency (ASLD) and in hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome with elevation of transaminases and of gamma-GT in ASLD, and of alpha-fetoprotein in HHH syndrome. Also, consistent with a chronic hepatic dysfunction, ultrasound examination revealed more pronounced abnormalities in ASLD and in HHH syndrome, when compared to other UCDs. Our study highlights in a large UCDs patients' cohort that chronic liver disease is a common finding in UCDs, often with a distinct phenotype between different diseases. Furthers studies are needed to elucidate the specific involvement of different metabolic pathways in the pathogenesis of liver dysfunction in UCDs.

Nutritional Deficiencies in Children with Celiac Disease Resulting from a Gluten-Free Diet: A Systematic Review.

BACKGROUND: A strictly gluten-free diet (GFD) is the basis for managing celiac disease (CD). Numerous studies have reported nutritional deficiencies/imbalances ascribable to a GFD. The aim of this review is to describe nutritional deficiencies observed in children with celiac disease on a GFD, to discuss the clinical consequences related to these nutritional imbalances, and to identify strategies that may be adopted to treat them. METHODS: We reviewed the MEDLINE and EMBASE databases between January 1998 and January 2019. RESULTS: Children are, regardless of whether they are on a gluten-free diet or not, at risk of consuming too much fat and insufficient fiber, iron, vitamin D, and calcium. These imbalances may be exacerbated when children are on a gluten-free diet. In particular, the intake of folate, magnesium, zinc, and foods with a high glycemic index in children with CD who are on a GFD is significantly altered. CONCLUSIONS: Therapeutic protocols should include nutritional education to help teach subjects affected by disorders such as CD the importance of labels, the choice of foods, and the combination of macro- and micronutrients. Children with CD on a GFD should be encouraged to rotate pseudo-cereals, consume gluten-free commercial products that have been fortified or enriched, and use foods that are local and naturally gluten-free.

Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.

The first patients affected by argininosuccinic aciduria (ASA) were reported 60 years ago. The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. Over the last decade, novel discoveries enabled by the generation of new transgenic argininosuccinate lyase (ASL)-deficient mouse models have been achieved, such as, a better understanding of ASL and its close interaction with nitric oxide metabolism, ASL physiological role outside the liver, and the pathophysiological role of oxidative/nitrosative stress or excessive arginine treatment. Here, we present a collaborative review, which highlights these recent discoveries and novel emerging concepts about ASL role in human physiology, ASA clinical phenotype and geographic prevalence, limits of current standard of care and newborn screening, pathophysiology of the disease, and emerging novel therapies. We propose recommendations for monitoring of ASA patients. Ongoing research aims to better understand the underlying pathogenic mechanisms of the systemic disease to design novel therapies.

Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis.

BACKGROUND & AIMS: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting ß gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD. METHODS: We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b-/- and Atp7b+/- (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with WD in Italy and liver tissues from patients without WD (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, apoptosis assays, and electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy. RESULTS: After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b-/- mice and rats (but not controls) had multiple autophagosomes. In ATP7B-knockout cells, mammalian target of rapamycin (mTOR) had decreased activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB to the nucleus and activation of autophagy-related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated the death of ATP7B-knockout HepG2 cells compared with wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death. CONCLUSION: ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.