BACKGROUND: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay.
METHODS: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient\'s father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of β-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred.
CONCLUSIONS: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

BACKGROUND: The most common haemostatic abnormality in dogs with cancer is hypercoagulability. A transient hypercoagulability has been documented in people with hepatocellular carcinoma (HCC) that resolves within weeks following hepatic tumour resection.
OBJECTIVE: The objective was to compare the haemostatic status of dogs with liver tumours and healthy control dogs, by comparing coagulation and thromboelastography (TEG) measurements at three time points.
METHODS: Liver tumour and healthy control dogs receiving surgery for liver lobectomy and ovariohysterectomy, respectively, were prospectively enrolled. All dogs had blood collected at three time points: pre-operative, 24 h post-operative and ~2 weeks post-operative. Haematological and haemostatic values were compared across time points in each group using repeated measures ANOVA tests.
RESULTS: Ten and eight dogs were enrolled for the liver and control groups, respectively. Platelet count was significantly higher in the liver group than the control group at all time points, but within the normal range (pre-operative: 438.7 vs. 300.9 × 109 /L, p = .0078; 24 h post-operative: 416.2 vs. 283.9 × 109 /L, p = .0123; 10-14 days post-operative: 524.6 vs. 317.3 × 109 /L, p = .0072). The measure of the overall coagulant state (G-value) was significantly increased for the liver group compared to the control group at all time points (pre-operative: 15.6 vs. 8.6 d/sc, p = .0003; 24 h post-operative: 18.3 vs. 11.2 d/sc, p = .039; 10-14 days post-operative: 15.1 vs. 9.6 d/sc, p = .015).
CONCLUSIONS: The liver group was hypercoagulable based on elevated G-values at all time points compared to the control group. This hypercoagulability was attributed to the effect of hepatic tumours alone, and not secondary to surgery and anaesthesia.

To evaluate hepatocellular adenoma (HCA) subtyping using qualitative magnetic resonance imaging (MRI) features and feasibility of differentiating HCA subtypes using machine learning (ML) of qualitative and quantitative MRI features with histopathology as the reference standard.
This retrospective study included 39 histopathologically subtyped HCAs (13 hepatocyte nuclear factor (HNF)-1-alpha mutated [HHCA], 11 inflammatory [IHCA], one beta-catenin-mutated [BHCA], and 14 unclassified [UHCA]) in 36 patients. HCA subtyping by two blinded radiologists using the proposed schema of qualitative MRI features and using the random forest algorithm was compared against histopathology. For quantitative features, 1,409 radiomic features were extracted after segmentation and reduced to 10 principle components. Support vector machine and logistic regression was applied to assess HCA subtyping.
Qualitative MRI features with proposed flow chart yielded diagnostic accuracies of 87%, 82%, and 74% for HHCA, IHCA, and UHCA respectively. The ML algorithm based on qualitative MRI features showed AUCs (area under the receiver operating characteristic curve [ROC] curve) of 0.846, 0.642, and 0.766 for diagnosing HHCA, IHCA, and UHCA, respectively. Quantitative radiomic features from portal venous and hepatic venous phase MRI demonstrated AUCs of 0.83 and 0.82, with a sensitivity of 72% and a specificity of 85% in predicting HHCA subtype.
The proposed schema of integrated qualitative MRI features with ML algorithm provided high accuracy for HCA subtyping while quantitative radiomic features provide value for diagnosis of HHCA. The key qualitative MRI features for differentiating HCA subtypes were concordant between the radiologists and the ML algorithm. These approaches appear promising to better inform clinical management for patients with HCA.

We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto\'s test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher\'s exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto\'s test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.

The methylated SEPT9 DNA ( mSEPT9 ) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P <0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P <0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63 y, P =0.01). The extent of SEPT9 staining correlated with age ( rs =0.31, P =0.01), tumor grade ( rs =0.30, P =0.01), and extent of SATB2 staining ( rs =0.28, P =0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.

Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe.
We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy.
The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations.
Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.

Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease.
A nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2 years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course.
The study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal.
NL8231-10 December 2019; Netherlands Trial Register.

Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients.
In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures.
A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only).
During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception.
In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

BACKGROUND. The classification of hepatocellular adenomas (HCAs) was updated in 2017 on the basis of genetic and molecular analysis. OBJECTIVE. The purpose of this article was to evaluate features on gadoxetate disodium-enhanced MRI of HCA subtypes on the basis of the 2017 classification and to propose a diagnostic algorithm for determining subtype using these features. METHODS. This retrospective study included 56 patients (49 women, seven men; mean age, 37 ± 13 [SD] years) with histologically confirmed HCA evaluated by gadoxetate disodium-enhanced MRI from January 2010 to January 2021. Subtypes were reclassified using 2017 criteria: hepatocyte nuclear factor-1α mutated HCA (HHCA), inflammatory HCA (IHCA), β-catenin exon 3 activated HCA (β-HCA), mixed inflammatory and β-HCA (β-IHCA), sonic hedgehog HCA (shHCA), and unclassified HCA (UHCA). Qualitative MRI features were assessed. Liver-to-lesion contrast enhancement ratios (LLCERs) were measured. Subtypes were compared, and a diagnostic algorithm was proposed. RESULTS. The analysis included 65 HCAs: 16 HHCAs, 31 IHCAs, six β-HCA, four β-IHCA, five shHCA, and three UHCAs. HHCAs showed homogeneous diffuse intralesional steatosis in 94%, whereas all other HCAs showed this finding in 0% (p < .001). IHCAs showed the \"atoll\" sign in 58%, whereas all other HCAs showed this finding in 12% (p < .001). IHCAs showed moderate T2 hyperintensity in 52%, whereas all other HCAs showed this finding in 12% (p < .001). The β-HCAs and β-IHCAs occurred in men in 63%, whereas all other HCAs occurred in men in 4% (p < .001). The β-HCAs and β-IHCAs had a mean size of 10.1 ± 6.8 cm, whereas all other HCAs had a mean size of 5.1 ± 2.9 cm (p = .03). The β-HCAs and β-IHCAs showed fluid components in 60%, whereas all other HCAs showed this finding in 5% (p < .001). Hepatobiliary phase iso- or hyperintensity was observed in 80% of β-HCAs and β-IHCAs versus 5% of all other HCAs (p < .001). Hepatobiliary phase LLCER was positive in nine HCAs (eight β-HCAs and β-IHCAs; one IHCA). The shHCA and UHCA did not show distinguishing features. The proposed diagnostic algorithm had accuracy of 98% for HHCAs, 83% for IHCAs, and 95% for β-HCAs or β-IHCAs. CONCLUSION. Findings on gadoxetate disodium-enhanced MRI, including hepatobiliary phase characteristics, were associated with HCA subtypes using the 2017 classification. CLINICAL IMPACT. The algorithm identified common HCA subtypes with high accuracy, including those with β-catenin exon 3 mutations.

Beyond oral contraceptives (OCs), metabolic factors have been suggested to increase the risk of hepatocellular adenoma (HCA). The impact of risks remains poorly defined, particularly among men and those with adenomatosis. Thus, we aimed to examine HCA clinical and outcome characteristics through a large multicenter cohort.
HCA diagnosis was made based on a combination of clinical, radiologic, and histologic criteria. Patient and clinical data including follow-up imaging, complications, and interventions were collected between 2004 and 2018 from 3 large academic centers.
Among 187 patients (163 female and 24 male) with HCA, 75 had solitary HCA, 58 had multiple HCAs, and 54 had adenomatosis. Over a median follow-up of 3.3 years (quartile 1: 1.2, quartile 3: 8.8), 34 patients (18%) had radiologic interventions, 41 (21%) had surgical resections, 10 (5%) developed tumoral hemorrhage, and 1 had malignant transformation. OC and corticosteroid use were present in 70% and 16%, respectively. Obesity (51%), type 2 diabetes (24%), hypertension (42%), and hypertriglyceridemia (21%) were also common. Metabolic comorbidities were more common in patients with large HCAs and adenomatosis. Compared with women, men had less hepatic steatosis (4% vs 27%), smaller HCAs (2.3 cm vs 4.4 cm), and more corticosteroid use (38% vs 11%) ( P < 0.05 for all). With OC cessation, 69% had a decrease in size of HCA, but 25% eventually required advanced interventions.
In this large HCA cohort, obesity and metabolic comorbidities were important risk factors associated with large HCAs and adenomatosis. Long-term adverse outcomes were infrequent, 5% had tumor hemorrhage, and 1 patient exhibited malignant transformation.