MAPL loss dysregulates bile and liver metabolism in mice.

Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin-sensitive, and protected from diet-induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis.

Comparison of Radiologists and Deep Learning for US Grading of Hepatic Steatosis.

Background Screening for nonalcoholic fatty liver disease (NAFLD) is suboptimal due to the subjective interpretation of US images. Purpose To evaluate the agreement and diagnostic performance of radiologists and a deep learning model in grading hepatic steatosis in NAFLD at US, with biopsy as the reference standard. Materials and Methods This retrospective study included patients with NAFLD and control patients without hepatic steatosis who underwent abdominal US and contemporaneous liver biopsy from September 2010 to October 2019. Six readers visually graded steatosis on US images twice, 2 weeks apart. Reader agreement was assessed with use of κ statistics. Three deep learning techniques applied to B-mode US images were used to classify dichotomized steatosis grades. Classification performance of human radiologists and the deep learning model for dichotomized steatosis grades (S0, S1, S2, and S3) was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. Results The study included 199 patients (mean age, 53 years ± 13 [SD]; 101 men). On the test set (n = 52), radiologists had fair interreader agreement (0.34 [95% CI: 0.31, 0.37]) for classifying steatosis grades S0 versus S1 or higher, while AUCs were between 0.49 and 0.84 for radiologists and 0.85 (95% CI: 0.83, 0.87) for the deep learning model. For S0 or S1 versus S2 or S3, radiologists had fair interreader agreement (0.30 [95% CI: 0.27, 0.33]), while AUCs were between 0.57 and 0.76 for radiologists and 0.73 (95% CI: 0.71, 0.75) for the deep learning model. For S2 or lower versus S3, radiologists had fair interreader agreement (0.37 [95% CI: 0.33, 0.40]), while AUCs were between 0.52 and 0.81 for radiologists and 0.67 (95% CI: 0.64, 0.69) for the deep learning model. Conclusion Deep learning approaches applied to B-mode US images provided comparable performance with human readers for detection and grading of hepatic steatosis. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Tuthill in this issue.

IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease.

Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes. ARTICLE HIGHLIGHTS: IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.

Ultrasound Shear Wave Attenuation Imaging for Grading Liver Steatosis in Volunteers and Patients With Non-alcoholic Fatty Liver Disease: A Pilot Study.

OBJECTIVE: The aims of the work described here were to assess shear wave attenuation (SWA) in volunteers and patients with non-alcoholic fatty liver disease (NAFLD) and compare its diagnostic performance with that of shear wave dispersion (SWD), magnetic resonance imaging (MRI) proton density fat fraction (PDFF) and biopsy. METHODS: Forty-nine participants (13 volunteers and 36 NAFLD patients) were enrolled. Ultrasound and MRI examinations were performed in all participants. Biopsy was also performed in patients. SWA was used to assess histopathology grades as potential confounders. The areas under curves (AUCs) of SWA, SWD and MRI-PDFF were assessed in different steatosis grades by biopsy. Youden's thresholds of SWA were obtained for steatosis grading while using biopsy or MRI-PDFF as the reference standard. RESULTS: Spearman's correlations of SWA with histopathology (steatosis, inflammation, ballooning and fibrosis) were 0.89, 0.73, 0.62 and 0.31, respectively. Multiple linear regressions of SWA confirmed the correlation with steatosis grades (adjusted R2 = 0.77, p < 0.001). The AUCs of MRI-PDFF, SWA and SWD were respectively 0.97, 0.99 and 0.94 for S0 versus ≥S1 (p > 0.05); 0.94, 0.98 and 0.78 for ≤S1 versus ≥S2 (both MRI-PDFF and SWA were higher than SWD, p < 0.05); and 0.90, 0.93 and 0.68 for ≤S2 versus S3 (both SWA and MRI-PDFF were higher than SWD, p < 0.05). SWA's Youden thresholds (Np/m/Hz) (sensitivity, specificity) for S0 versus ≥S1, ≤S1 versus ≥S2 and ≤S2 versus S3 were 1.05 (1.00, 0.92), 1.37 (0.96, 0.96) and 1.51 (0.83, 0.87), respectively. These values were 1.16 (1.00, 0.81), 1.49 (0.91, 0.82) and 1.67 (0.87, 0.92) when considering MRI-PDFF as the reference standard. CONCLUSION: In this pilot study, SWA increased with increasing steatosis grades, and its diagnostic performance was higher than that of SWD but equivalent to that of MRI-PDFF.

Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs.

Following acute genotoxic stress, both normal and tumorous stem cells can undergo cell-cycle arrest to avoid apoptosis and later re-enter the cell cycle to regenerate daughter cells. However, the mechanism of protective, reversible proliferative arrest, "quiescence," remains unresolved. Here, we show that mitophagy is a prerequisite for reversible quiescence in both irradiated Drosophila germline stem cells (GSCs) and human induced pluripotent stem cells (hiPSCs). In GSCs, mitofission (Drp1) or mitophagy (Pink1/Parkin) genes are essential to enter quiescence, whereas mitochondrial biogenesis (PGC1α) or fusion (Mfn2) genes are crucial for exiting quiescence. Furthermore, mitophagy-dependent quiescence lies downstream of mTOR- and PRC2-mediated repression and relies on the mitochondrial pool of cyclin E. Mitophagy-dependent reduction of cyclin E in GSCs and in hiPSCs during mTOR inhibition prevents the usual G1/S transition, pushing the cells toward reversible quiescence (G0). This alternative method of G1/S control may present new opportunities for therapeutic purposes.

Quantitative ultrasound, elastography, and machine learning for assessment of steatosis, inflammation, and fibrosis in chronic liver disease.

OBJECTIVE: To develop a quantitative ultrasound (QUS)- and elastography-based model to improve classification of steatosis grade, inflammation grade, and fibrosis stage in patients with chronic liver disease in comparison with shear wave elastography alone, using histopathology as the reference standard. METHODS: This ancillary study to a prospective institutional review-board approved study included 82 patients with non-alcoholic fatty liver disease, chronic hepatitis B or C virus, or autoimmune hepatitis. Elastography measurements, homodyned K-distribution parametric maps, and total attenuation coefficient slope were recorded. Random forests classification and bootstrapping were used to identify combinations of parameters that provided the highest diagnostic accuracy. Receiver operating characteristic (ROC) curves were computed. RESULTS: For classification of steatosis grade S0 vs. S1-3, S0-1 vs. S2-3, S0-2 vs. S3, area under the receiver operating characteristic curve (AUC) were respectively 0.60, 0.63, and 0.62 with elasticity alone, and 0.90, 0.81, and 0.78 with the best tested model combining QUS and elastography features. For classification of inflammation grade A0 vs. A1-3, A0-1 vs. A2-3, A0-2 vs. A3, AUCs were respectively 0.56, 0.62, and 0.64 with elasticity alone, and 0.75, 0.68, and 0.69 with the best model. For classification of liver fibrosis stage F0 vs. F1-4, F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4, AUCs were respectively 0.66, 0.77, 0.72, and 0.74 with elasticity alone, and 0.72, 0.77, 0.77, and 0.75 with the best model. CONCLUSION: Random forest models incorporating QUS and shear wave elastography increased the classification accuracy of liver steatosis, inflammation, and fibrosis when compared to shear wave elastography alone.

Age, operation time and surgical approach can be used to detect incidental gallbladder carcinoma in cholecystectomy specimens from low-incidence settings.

AIMS: Gallbladders resected for non-neoplastic diseases are systemically examined microscopically to rule out incidental dysplasia and carcinoma. The main aim of this study was to test whether a pre-grossing algorithm can detect incidental gallbladder carcinoma. The secondary aim was to test whether the algorithm can detect high-grade dysplasia. METHODS AND RESULTS: A retrospective study of clinical, pathological and radiological findings in cholecystectomy recipients was performed on a test set to develop a classification and regression tree algorithm. Cholecystectomy cases were included; exclusion criteria were age <18 years, missing pathology reports, preoperative suspicion of neoplastic disease, and cholecystectomy for non-gallbladder oncological disease. Five thousand nine hundred and eighty-two cholecystectomies from 2006 to 2018 were included in the study, with 18 cases of incidental gallbladder carcinoma and 11 cases of high-grade dysplasia. Three hundred and ninety controls were randomly selected for the testing set. Patient age, surgical approach, operation duration, dilatation of the biliary tract and gallbladder gross anomalies were statistically significant distinguishing factors in multivariate analysis (P < 0.00-0.026). Unsupervised testing with a conditional inference tree suggested that age, procedure type and operation duration can be used to identify incidental gallbladder carcinoma from controls, whereas high-grade dysplasia also requires grossing parameters to identify half of the cases (5/11). CONCLUSION: Readily available clinical parameters and postoperative data can be used to detect incidental gallbladder carcinoma. High-grade dysplasia mostly requires grossing and microscopic examination.

Multiparametric in vivo ultrasound shear wave viscoelastography on farm-raised fatty duck livers: human radiology imaging applied to food sciences.

Nine mulard ducks that were being raised for foie gras (steatosis) production went through in vivo shear wave (SW) elastography imaging of their liver during the force-feeding period to investigate changes in liver tissue characteristics. A total of 4 imaging sessions at an interval of 3 to 4 d were conducted at the farm on each animal. Three ducks were sacrificed at the second, third, and fourth imaging sessions for histopathology analysis of all animals at these time points. Six SW elastography parameters were evaluated: SW speed, SW attenuation, SW dispersion, Young's modulus, viscosity, and shear modulus. Shear waves of different frequencies propagate with different phase velocities. Thus, SW speed and other dependent parameters such as Young's modulus, viscosity, and shear modulus were computed at 2 frequencies: 75 and 202 Hz. Each parameter depicted a statistically significant trend along the force-feeding process (P-values between 0.001 and 0.0001). The fat fraction of the liver increased over the 12-day period of feeding. All parameters increased monotonically over time at 75 Hz, whereas modal relations were seen at 202 Hz. Shear wave dispersion measured between 75 and 202 Hz depicted a plateau from day 5. Based on this validation, proposed imaging methods are aimed to be used in the future on naturally fed ducks and geese.

Intravoxel incoherent motion diffusion-weighted MRI for the characterization of inflammation in chronic liver disease.

OBJECTIVE: To evaluate the diagnostic performance of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for grading hepatic inflammation. METHODS: In this retrospective cross-sectional dual-center study, 91 patients with chronic liver disease were recruited between September 2014 and September 2018. Patients underwent 3.0-T MRI examinations within 6 weeks from a liver biopsy. IVIM parameters, perfusion fraction (f), diffusion coefficient (D), and pseudo-diffusion coefficient (D*), were estimated using a voxel-wise nonlinear regression on DWI series (10 b-values from 0 to 800 s/mm2). The reference standard was histopathological analysis of hepatic inflammation grade, steatosis grade, and fibrosis stage. Intraclass correlation coefficients (ICC), univariate and multivariate correlation analyses, and areas under receiver operating characteristic curves (AUC) were assessed. RESULTS: Parameters f, D, and D* had ICCs of 0.860, 0.839, and 0.916, respectively. Correlations of f, D, and D* with inflammation grade were ρ = - 0.70, p < 0.0001; ρ = 0.10, p = 0.35; and ρ = - 0.27, p = 0.010, respectively. When adjusting for fibrosis and steatosis, the correlation between f and inflammation (p < 0.0001) remained, and that between f and fibrosis was also significant to a lesser extent (p = 0.002). AUCs of f, D, and D* for distinguishing inflammation grades 0 vs. ≥ 1 were 0.84, 0.53, and 0.70; ≤ 1 vs. ≥ 2 were 0.88, 0.57, and 0.60; and ≤ 2 vs. 3 were 0.86, 0.54, and 0.65, respectively. CONCLUSION: Perfusion fraction f strongly correlated, D very weakly correlated, and D* weakly correlated with inflammation. Among all IVIM parameters, f accurately graded inflammation and showed promise as a biomarker of hepatic inflammation. KEY POINTS: • IVIM parameters derived from DWI series with 10 b-values are reproducible for liver tissue characterization. • This retrospective two-center study showed that perfusion fraction provided good diagnostic performance for distinguishing dichotomized grades of inflammation. • Fibrosis is a significant confounder on the association between inflammation and perfusion fraction.

In vivo Ultrafast Quantitative Ultrasound and Shear Wave Elastography Imaging on Farm-Raised Duck Livers during Force Feeding.

Shear wave elastography (speed and dispersion), local attenuation coefficient slope and homodyned-K parametric imaging were used for liver steatosis grading. These ultrasound biomarkers rely on physical interactions between shear and compression waves with tissues at both macroscopic and microscopic scales. These techniques were applied in a context not yet studied with ultrasound imaging, that is, monitoring steatosis of force-fed duck livers from pre-force-fed to foie gras stages. Each estimated feature presented a statistically significant trend along the feeding process (p values <10-3). However, whereas a monotonic increase in the shear wave speed was observed along the process, most quantitative ultrasound features exhibited an absolute maximum value halfway through the process. As the liver fat fraction in foie gras is much higher than that seen clinically, we hypothesized that a change in the ultrasound scattering regime is encountered for high-fat fractions, and consequently, care has to be taken when applying ultrasound biomarkers to grading of severe states of steatosis.

Nodular Regenerative Hyperplasia: Expression Pattern of Glutamine Synthetase and a Potential Role for Hepatic Progenitor Cells.

Nodular regenerative hyperplasia (NRH) is one of the most frequent causes of noncirrhotic intrahepatic hypertension, but is a difficult histologic diagnosis. The expression of glutamine synthetase (GS) and cytokeratin 7 (CK7) has been reported to be increased in other regenerative/vascular conditions, while CK7 and BerEP4 are also markers of hepatic progenitor cells. The aims of this study were to investigate the use of GS, CK7, and BerEP4 as the potential markers for NRH. This is a retrospective case series of NRH at Centre Hospitalier de l'Universite de Montreal between 1993 and 2013. Normal liver from partial hepatectomies for tumors were used as controls. GS, CK7, CK19, and BerEP4 immunohistochemical stains were performed on all specimens. Immunohistochemical staining patterns were scored from 0 to 3+. NRH was identified in 46 samples obtained from 26 patients. Liver chemistry profile was cholestatic in 45% of the patients. In 93% of the NRH cases, there was abnormal zone 2 expression of GS. Weak panacinar GS staining was seen in all the NRH cases. Aberrant CK7 expression was present in all cases of NRH, but were not associated with cholestasis. BerEP4 was overexpressed in 47% of the NRH cases (P<0.05); all cases with diffuse BerEP4 staining also showed extensive CK7 expression (P<0.01). NRH showed increased immunohistochemical GS staining that may support its morphologic diagnosis. Our findings suggest that there is an activation of hepatic progenitor cells in NRH.

Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes Reveal Differences Between Ulcerative Colitis and Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease [CD] and ulcerative colitis [UC] are distinct forms of inflammatory bowel disease. Heterogeneity of HLA-DR+SIRPα + mononuclear phagocytes [MNPs], including macrophages [MΦ], monocyte-derived [Mono] cells, and dendritic cells [DCs], was reported in gut tissue but not yet investigated in mesenteric lymph nodes [MLNs] of IBD patients. We here compared the phenotype, function, and molecular profile of HLA-DR+SIRPα + MNPs in CD and UC MLNs. METHODS: Cell distribution, morphology, immune function, and transcriptomic [bulk RNAseq] and high-dimensional protein expression profiles [CyTOF] of HLA-DR+SIRPα + MNPs were examined in MLNs of UC [n = 14], CD [n = 35], and non-IBD [n = 12] patients. RESULTS: Elevated frequencies of CD14+CD64+CD163+ [Mono/MΦ-like] MNPs displaying monocyte/MΦ morphology and phagocytic function were a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- [DC-like] cells was augmented relative to Mono/MΦ-like cells; DC-like cells drove naïve T cell proliferation, Th1 polarisation, and Th17 TCM plasticity. Gene expression profile corroborated the nature of DC-like cells, best represented by BTLA, SERPINF, IGJ and, of Mono/MΦ-like cells, defined by CD163, MARCO, MAFB, CD300E, S100A9 expression. CyTOF analysis showed that CD123+ plasmacytoid cells predominated over conventional DCs in DC-like cells. Four CD163+ clusters were revealed in Mono/MΦ-like cells, two of which were enriched in MARCO-CD68dimHLA-DRdim monocyte-like cells and MARCOhiCD68hiHLA-DRhi Mɸ, whose proportion increased in UC relative to CD. CONCLUSIONS: Defining the landscape of MNPs in MLNs provided evidence for expansion of CD163+ Mono/MΦ-like cells in UC only, highlighting a distinction between UC and CD, and thus the potential contribution of monocyte-like cells in driving colitis.

MRI cine-tagging of cardiac-induced motion for noninvasive staging of liver fibrosis.

BACKGROUND: MR elastography is a noninvasive technique that provides high diagnostic accuracy for the staging of liver fibrosis; however, it requires external hardware and mainly assesses the right lobe. PURPOSE: To evaluate the diagnostic performance of MRI cine-tagging for staging fibrosis in the left liver lobe, using biopsy as the reference standard. STUDY TYPE: Institutional Review Board (IRB)-approved two-center prospective study. POPULATION: Seventy-six patients with chronic liver disease who underwent an MRI cine-tagging examination and a liver biopsy within a 6-week interval. FIELD STRENGTH/SEQUENCE: 2D-GRE multislice sequence at 3.0T with spatial modulation of the magnetization preparation sequence and peripheral pulse-wave triggering on two coronal slices chosen underneath the heart apex to capture maximal deformation with consecutive breath-holds adapted to patient cardiac frequency. ASSESSMENT: A region of interest was selected in the liver close to the heart apex. Maximal strain was evaluated with the harmonic phase (HARP) technique. STATISTICAL TESTS: Spearman's correlation, Kruskal-Wallis test, Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were performed. RESULTS: Liver strain measured on tagged images decreased with higher histological fibrosis stage (ρ = -0.68, P < 0.0001). Strain values were significantly different between all fibrosis stages (P < 0.0001), and between groups of fibrosis stages ≤F3 vs. F4 (P < 0.05). Areas under the ROC curves were 0.95 (95% confidence interval: 0.89-1.00) to distinguish fibrosis stages F0 vs. F4, 0.81 (0.70-0.92) for stages F0 vs. ≥F1, 0.84 (0.76-0.93) for stages ≤F1 vs. ≥F2, 0.86 (0.78-0.94) for stages ≤F2 vs. ≥F3, and 0.87 (0.77-0.96) for stages ≤F3 vs. F4. DATA CONCLUSION: MRI cine-tagging is a promising technique for measuring liver strain without additional elastography hardware. It could be used to assess the left liver lobe as a complement to current techniques assessing the right lobe. LEVEL OF EVIDENCE: 1 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;51:1570-1580.

Prospective comparison of transient, point shear wave, and magnetic resonance elastography for staging liver fibrosis.

OBJECTIVES: To perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE). METHODS: This prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6 weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method. RESULTS: TE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85-0.93), 0.90 (95% CI 0.85-0.94), and 0.94 (95% CI 0.91-0.96). CONCLUSION: MRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis. TRIAL REGISTRATION: NCT02044523 KEY POINTS: • The technical failure rate was similar between MRE and US-based elastography techniques. • Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis. • MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.

Hiding in plain sight: A case of fever, rash, and jaundice.

A 25-year-old man presented to the emergency department with a 3-day history of fever, anorexia, jaundice, and a generalized skin eruption. His liver function tests showed marked cholestatic and cytolytic abnormalities without liver insufficiency. A liver biopsy was performed, and morphology with routine stains was considered non-specific. Because of the dermatological findings, the non-specific biopsy morphology, and the absence of an identified infectious etiology, a diagnosis of Kawasaki disease was presumed. However, additional colorations on liver biopsy with Warthin-Starry stain revealed multiple thin and coiled microorganisms compatible with spirochetes. His serology for leptospirosis was found to be positive for IgM, supporting the diagnosis of acute leptospirosis with liver involvement. Our case illustrates the diagnostic challenge of leptospirosis and highlights the utility of conventional laboratory tests to confirm the diagnosis. Exceptionally, Warthin-Starry stain allowed the identification of leptospires in liver biopsy and confirmed liver involvement of systemic leptospirosis.

Un homme de 25 ans a consulté à l'urgence parce qu'il faisait de la fièvre depuis trois jours, de l'anorexie, un ictère et une éruption cutanée généralisée. Les tests de fonction hépatique ont révélé des anomalies cholestatiques et cytolytiques marquées, sans insuffisance hépatique. La coloration standard de la biopsie hépatique a révélé une morphologie cellulaire considérée comme non spécifique. Compte tenu des observations dermatologiques, de la morphologie non spécifique de la biopsie et de l'absence d'étiologie infectieuse établie, un diagnostic de maladie de Kawasaki a été présumé. Cependant, l'ajout d'une coloration de Warthin-Starry a révélé de multiples microorganismes minces et torsadés compatibles avec des spirochètes. La sérologie pour la leptospirose s'est avérée positive pour les anticorps IgM, appuyant un diagnostic de leptospirose aiguë avec atteinte hépatique. Ce cas illustre les difficultés diagnostiques de la leptospirose et fait ressortir l'utilité des tests de laboratoire traditionnels pour confirmer le diagnostic. Exceptionnellement, la coloration de Warthin­Starry a permis d'observer des leptospires à la biopsie hépatique et confirmé la leptospirose systémique avec atteinte hépatique.

Quantitative ultrasound and machine learning for assessment of steatohepatitis in a rat model.

OBJECTIVES: To develop a machine learning model based on quantitative ultrasound (QUS) parameters to improve classification of steatohepatitis with shear wave elastography in rats by using histopathology scoring as the reference standard. METHODS: This study received approval from the institutional animal care committee. Sixty male Sprague-Dawley rats were either fed a standard chow or a methionine- and choline-deficient diet. Ultrasound-based radiofrequency images were recorded in vivo to generate QUS and elastography maps. Random forests classification models and a bootstrap method were used to identify the QUS parameters that improved the classification accuracy of elastography. Receiver-operating characteristic analyses were performed. RESULTS: For classification of not steatohepatitis vs borderline or steatohepatitis, the area under the receiver-operating characteristic curve (AUC) increased from 0.63 for elastography alone to 0.72 for a model that combined elastography and QUS techniques (p < 0.001). For detection of liver steatosis grades 0 vs ≥ 1, ≤ 1 vs ≥ 2, ≤ 2 vs 3, respectively, the AUCs increased from 0.70, 0.65, and 0.69 to 0.78, 0.78, and 0.75 (p < 0.001). For detection of liver inflammation grades 0 vs ≥ 1, ≤ 1 vs ≥ 2, ≤ 2 vs 3, respectively, the AUCs increased from 0.58, 0.77, and 0.78 to 0.66, 0.84, and 0.87 (p < 0.001). For staging of liver fibrosis grades 0 vs ≥ 1, ≤ 1 vs ≥ 2, and ≤ 2 vs ≥ 3, respectively, the AUCs increased from 0.79, 0.92, and 0.91 to 0.85, 0.98, and 0.97 (p < 0.001). CONCLUSION: QUS parameters improved the classification accuracy of steatohepatitis, liver steatosis, inflammation, and fibrosis compared to shear wave elastography alone. KEY POINTS: • Quantitative ultrasound and shear wave elastography improved classification accuracy of liver steatohepatitis and its histological features (liver steatosis, inflammation, and fibrosis) compared to elastography alone. • A machine learning approach based on random forest models and incorporating local attenuation and homodyned-K tissue modeling shows promise for classification of nonalcoholic steatohepatitis. • Further research should be performed to demonstrate the applicability of this multi-parametric QUS approach in a human cohort and to validate the combinations of parameters providing the highest classification accuracy.

Langerhans cell histiocytosis presenting as Crohn's disease: a case report.

PURPOSE: We describe an exceptional case of Langerhans cell histiocytosis (LCH) that presented as Crohn's disease and primary sclerosing cholangitis. METHODS: The patient's clinical, endoscopic, and histologic data from the Centre Hospitalier de l'Universite de Montreal were reviewed, as well as the literature on LCH involving the digestive tract and the liver, with a focus on the similarities with Crohn's disease and primary sclerosing cholangitis. RESULTS: A 39 years-old man first presented with anal fissures and deep punctiform colonic ulcers. Histologic assessment of colon biopsies showed chronic active colitis, consistent with Crohn's disease. Mild cholestasis and endoscopic retrograde cholangiopancreatography (ERCP) showing multiple intra and extrahepatic biliary tract strictures also led to a diagnosis of sclerosing cholangitis. Perianal disease progressed despite conventional treatment with antibiotics and infliximab. Subsequent discovery of non-Langerhans cutaneous xanthogranulomas and panhypopituitarism raised the suspicion of LCH, and a second review of colon biopsies ultimately led to the diagnosis, with the identification of Langerhans cells depicting elongated, irregular nuclei with nuclear grooves as well as immunohistochemical reactivity for S100, CD1a and vimentin. BRAF V600E mutation was detected afterwards by DNA sequencing of a bile duct sample. CONCLUSION: LCH may mimic inflammatory bowel disease (IBD) and must be suspected in the presence of other suggestive clinical signs, or when there is failure of conventional IBD treatment.

Liver Fibrosis Quantification by Magnetic Resonance Imaging.

Liver fibrosis is a hallmark of chronic liver disease characterized by the excessive accumulation of extracellular matrix proteins. Although liver biopsy is the reference standard for diagnosis and staging of liver fibrosis, it has some limitations, including potential pain, sampling variability, and low patient acceptance. Hence, there has been an effort to develop noninvasive imaging techniques for diagnosis, staging, and monitoring of liver fibrosis. Many quantitative techniques have been implemented on magnetic resonance imaging (MRI) for this indication. The most widely validated technique is magnetic resonance elastography, which aims to measure viscoelastic properties of the liver and relate them to fibrosis stage. Several additional MRI methods have been developed or adapted to liver fibrosis quantification. Diffusion-weighted imaging measures the Brownian motion of water molecules which is restricted by collagen fibers. Texture analysis assesses the changes in the texture of liver parenchyma associated with fibrosis. Perfusion imaging relies on signal intensity and pharmacokinetic models to extract quantitative perfusion parameters. Hepatocellular function, which decreases with increasing fibrosis stage, can be estimated by the uptake of hepatobiliary contrast agents. Strain imaging measures liver deformation in response to physiological motion such as cardiac contraction. T1ρ quantification is an investigational technique, which measures the spin-lattice relaxation time in the rotating frame. This article will review the MRI techniques used in liver fibrosis staging, their advantages and limitations, and diagnostic performance. We will briefly discuss future directions, such as longitudinal monitoring of disease, prediction of portal hypertension, and risk stratification of hepatocellular carcinoma.