PET/MRI: pictorial review of hepatobiliary and pancreatic applications.

PET and MRI both play valuable roles in the management of hepatobiliary and pancreatic (HBP) malignancies. Simultaneous PET/MRI combines the excellent soft-tissue resolution and anatomic details from MRI with functional information from PET in a single comprehensive examination. MRI is the main imaging modality in evaluating HCC, playing important roles in screening, characterization, local extent, and evaluating tumor response, whereas 18F-fluorodeoxyglucose (FDG) PET can help evaluate for lymph node involvement and metastatic disease. In cholangiocarcinoma and pancreatic malignancies, both PET and MRI have excellent utility in initial staging as well as assessing treatment response. In all HBP malignancies, FDG-PET/MRI is a unique problem-solving tool in complex cases and diagnostic challenges, especially after locoregional therapy and when differentiating residual or recurrent viable disease from inflammatory and other benign processes. In this manuscript, we review the role of PET/MRI in the diagnosis, staging, assessing treatment response, and characterizing post-treatment processes. With the introduction of multiple new tracers, the value of PET/MRI has not yet been fully realized, and more studies are needed to demonstrate the utility and efficacy of PET/MRI in improving patient care in hepatobiliary and pancreatic oncology.

Whole-Body Multiparametric PET in Clinical Oncology: Current Status, Challenges, and Opportunities.

The interpretation of clinical oncologic PET studies has historically used static reconstructions based on SUVs. SUVs and SUV-based images have important limitations, including dependence on uptake times and reduced conspicuity of tracer-avid lesions in organs with high background uptake. The acquisition of dynamic PET images enables additional PET reconstructions via Patlak modeling, which assumes that a tracer is irreversibly trapped by tissues of interest. The resulting multiparametric PET images capture a tracer's net trapping rate (Ki) and apparent volume of distribution (VD), separating the contributions of bound and free tracer fractions to the PET signal captured in the SUV. Potential benefits of multiparametric PET include higher quantitative stability, superior lesion conspicuity, and greater accuracy for differentiating malignant and benign lesions. However, the imaging protocols necessary for multiparametric PET are inherently more complex and time-intensive, despite the recent introduction of automated or semiautomated scanner-based reconstruction packages. In this Review, we examine the current state of multiparametric PET in whole-body oncologic imaging. We summarize the Patlak methodology and relevant tracer kinetics, discuss clinical workflows and protocol considerations, and highlight clinical challenges and opportunities. We aim to help oncologic imagers make informed decisions about whether to implement multiparametric PET in their clinical practices.

18F-DOPA PET/MRI With Carbidopa for the Diagnosis of Hyperinsulinemic Hypoglycemia in an Adolescent Patient.

Hyperinsulinism due to focal or diffuse pancreatic lesions causing recurrent episodes of hypoglycemia is rare in mid-childhood. There is no consensus on the gold-standard imaging method to diagnose focal insulin-producing lesions beyond infancy. A 14-year-old boy with a complex medical history and refractory epilepsy, presented with blood glucose (BG) of 52 mg/dL (2.9 mmol/L) (normal reference range: 70-100 mg/dL [3.9-5.6 mmol/L]) and increased seizure frequency. He failed a fast within 4 hours, with BG of 48 mg/dL (2.7 mmol/L) and insulin level of 4.6 µIU/mL (24.6 pmol/L) (diagnostic at the time of hypoglycemia >1.25 µU/mL [8.7 pmol/L]). Conventional imaging studies showed no pancreatic lesion. Fluorine-18-L-dihydroxyphenylalanine positron emission tomography/magnetic resonance imaging (18F-DOPA-PET/MRI) scan premedicated with carbidopa demonstrated intense focal 18F-DOPA uptake in the distal pancreatic tail. He underwent distal pancreatectomy. Histopathology showed focal pancreatic islet cell hyperplasia, with more than 90% of the neuroendocrine islet cells being positive for chromogranin and synaptophysin, with no loss of p57 staining. Genetic studies were negative for mutations in ABCC8, KCNJ11, GCK, or GLUD1 genes, multiple endocrine neoplasia (MEN) type 1, and Beckwith-Wiedemann syndrome. BG normalized after surgery. Seizure frequency improved. This case highlights the utility of 18F-DOPA PET/MRI imaging in diagnosing focal hyperinsulinism beyond infancy.

Quantitative Assessments of Tumor Activity in a General Oncologic PET/CT Population: Which Metric Minimizes Tracer Uptake Time Dependence?

In oncologic PET, the SUV and standardized uptake ratio (SUR) of a viable tumor generally increase during the postinjection period. In contrast, the net influx rate (Ki ), which is derived from dynamic PET data, should remain relatively constant. Uptake-time-corrected SUV (cSUV) and SUR (cSUR) have been proposed as uptake-time-independent, static alternatives to Ki Our primary aim was to quantify the intrascan repeatability of Ki , SUV, cSUV, SUR, and cSUR among malignant lesions on PET/CT. An exploratory aim was to assess the ability of cSUR to estimate Ki Methods: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic PET/CT. SUV and Ki images were reconstructed from dynamic PET data obtained before (∼35-50 min after injection) and after (∼75-90 min after injection) standard-of-care imaging. Tumors were manually segmented. Quantitative metrics were extracted. cSUVs and cSURs were calculated for a 60-min postinjection reference uptake time. The magnitude of the intrascan test-retest percent change (test-retest |%Δ|) was calculated. Coefficients of determination (R 2) and intraclass correlation coefficients (ICC) were also computed. Differences between metrics were assessed via the Wilcoxon signed-rank test (α, 0.05). Results: This study enrolled 78 subjects; 41 subjects (mean age, 63.8 y; 24 men) with 116 lesions were analyzed. For both tracers, SUVmax and maximum SUR (SURmax) had large early-to-late increases (i.e., poor intrascan repeatability). Among [18F]FDG-avid lesions (n = 93), there were no differences in intrascan repeatability (median test-retest |%Δ|; ICC) between the maximum Ki (Ki ,max) (13%; 0.97) and either the maximum cSUV (cSUVmax) (12%, P = 0.90; 0.96) or the maximum cSUR (cSURmax) (13%, P = 0.67; 0.94). For DOTATATE-avid lesions (n = 23), there were no differences in intrascan repeatability between the Ki ,max (11%; 0.98) and either the cSUVmax (13%, P = 0.41; 0.98) or the cSURmax (11%, P = 0.08; 0.94). The SUVmax, cSUVmax, SURmax, and cSURmax were all strongly correlated with the Ki ,max for both [18F]FDG (R 2, 0.81-0.92) and DOTATATE (R 2, 0.88-0.96), but the cSURmax provided the best agreement with the Ki ,max across early-to-late time points for [18F]FDG (ICC, 0.69-0.75) and DOTATATE (ICC, 0.90-0.91). Conclusion: Ki ,max, cSUVmax, and cSURmax had low uptake time dependence compared with SUVmax and SURmax The Ki ,max can be predicted from cSURmax.

FAST (fast analytical simulator of tracer)-PET: an accurate and efficient PET analytical simulation tool.

Objective.Simulation of positron emission tomography (PET) images is an essential tool in the development and validation of quantitative imaging workflows and advanced image processing pipelines. Existing Monte Carlo or analytical PET simulators often compromise on either efficiency or accuracy. We aim to develop and validate fast analytical simulator of tracer (FAST)-PET, a novel analytical framework, to simulate PET images accurately and efficiently.Approach. FAST-PET simulates PET images by performing precise forward projection, scatter, and random estimation that match the scanner geometry and statistics. Although the same process should be applicable to other scanner models, we focus on the Siemens Biograph Vision-600 in this work. Calibration and validation of FAST-PET were performed through comparison with an experimental scan of a National Electrical Manufacturers Association (NEMA) Image Quality (IQ) phantom. Further validation was conducted between FAST-PET and Geant4 Application for Tomographic Emission (GATE) quantitatively in clinical image simulations in terms of intensity-based and texture-based features and task-based tumor segmentation.Main results.According to the NEMA IQ phantom simulation, FAST-PET's simulated images exhibited partial volume effects and noise levels comparable to experimental images, with a relative bias of the recovery coefficient RC within 10% for all spheres and a coefficient of variation for the background region within 6% across various acquisition times. FAST-PET generated clinical PET images exhibit high quantitative accuracy and texture comparable to GATE (correlation coefficients of all features over 0.95) but with ∼100-fold lower computation time. The tumor segmentation masks comparison between both methods exhibited significant overlap and shape similarity with high concordance CCC > 0.97 across measures.Significance.FAST-PET generated PET images with high quantitative accuracy comparable to GATE, making it ideal for applications requiring extensive PET image simulations such as virtual imaging trials, and the development and validation of image processing pipelines.

Evaluating the Change in 18F-Fluorodeoxyglucose Uptake in Perianal Fistulas on PET/CT over Time: A Serial Retrospective Analysis.

RATIONALE AND OBJECTIVES: Perianal fistulas on18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) can be an incidental site of FDG uptake in patients undergoing PET for other indications. There are no longitudinal studies describing FDG uptake patterns in perianal fistulas. Therefore, we aimed to analyze changes in FDG uptake over time in patients with incidental perianal fistulas. PATIENTS AND METHODS: Patients who underwent at least two FDG-PET/CTs between January 2011 and May 2023, with incidental perianal fistula, were retrospectively identified. We analyzed all sequential PET/CTs to determine the presence of a perianal fistula and recorded the fistula's maximum standardized uptake value (SUVmax). Statistical analysis compared fistula FDG-avidity in the initial versus final PET/CT examinations and assessed the correlation between initial fistula SUVmax and percent change over time. RESULTS: The study included 15 fistulas in 14 patients, with an average of 5 PET/CT examinations per patient. The average interval between the first and last PET/CT was 24 months (range: 6-64). The average initial fistula SUVmax (11.28 ± 3.81) was significantly higher than the final fistula SUVmax (7.22 ± 3.99) (p = 0.0067). The fistula SUVmax declined by an average of 32.01 ± 35.33% with no significant correlation between initial fistula SUVmax and percent change over time (r = -0.213, p = 0.443, 95% CI -0.66-0.35). CONCLUSION: FDG uptake in perianal fistulas shows temporal fluctuations but follows a decreasing SUVmax trend, possibly indicating a relationship with inflammatory activity. Further studies with larger cohorts paired with perianal fistula pelvic MR imaging are needed to validate these observations and their utility in guiding further management.

Patlak Slope versus Standardized Uptake Value Image Quality in an Oncologic PET/CT Population: A Prospective Cross-Sectional Study.

Patlak slope (PS) images have the potential to improve lesion conspicuity compared with standardized uptake value (SUV) images but may be more artifact-prone. This study compared PS versus SUV image quality and hepatic tumor-to-background ratios (TBRs) at matched time points. Early and late SUV and PS images were reconstructed from dynamic positron emission tomography (PET) data. Two independent, blinded readers scored image quality metrics (a four-point Likert scale) and counted tracer-avid lesions. Hepatic lesions and parenchyma were segmented and quantitatively analyzed. Differences were assessed via the Wilcoxon signed-rank test (alpha, 0.05). Forty-three subjects were included. For overall quality and lesion detection, early PS images were significantly inferior to other reconstructions. For overall quality, late PS images (reader 1 [R1]: 3.95, reader 2 [R2]: 3.95) were similar (p > 0.05) to early SUV images (R1: 3.88, R2: 3.84) but slightly superior (p ≤ 0.002) to late SUV images (R1: 2.97, R2: 3.44). For lesion detection, late PS images were slightly inferior to late SUV images (R1 only) but slightly superior to early SUV images (both readers). PS-based TBRs were significantly higher than SUV-based TBRs at the early time point, with opposite findings at the late time point. In conclusion, late PS images are similar to early/late SUV images in image quality and lesion detection; the superiority of SUV versus PS hepatic TBRs is time-dependent.

Test-Retest Repeatability of Patlak Slopes versus Standardized Uptake Values for Hypermetabolic Lesions and Normal Organs in an Oncologic PET/CT Population.

PURPOSE: We aimed to determine the test-retest repeatability of quantitative metrics based on the Patlak slope (PS) versus the standardized uptake value (SUV) among lesions and normal organs on oncologic [18F]FDG-PET/CT. PROCEDURES: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic [18F]FDG-PET/CTs. Early (35-50 min post-injection) and late (75-90 min post-injection) SUV and PS images were reconstructed from dynamic whole-body PET data. Repeat imaging occurred within 7 days. Relevant quantitative metrics were extracted from lesions and normal organs. Repeatability was assessed via mean test-retest percent changes [T-RT %Δ], within-subject coefficients of variation (wCVs), and intra-class correlation coefficients (ICCs). RESULTS: Nine subjects (mean age, 61.7 ± 6.2 years; 6 females) completed the test-retest protocol. Four subjects collectively had 17 [18F]FDG-avid lesions. Lesion wCVs were higher (i.e., worse repeatability) for PS-early-max (16.2%) and PS-early-peak (15.6%) than for SUV-early-max (8.9%) and SUV-early-peak (8.1%), with similar early metric ICCs (0.95-0.98). Lesion wCVs were similar for PS-late-max (8.5%) and PS-late-peak (6.4%) relative to SUV-late-max (9.7%) and SUV-late-peak (7.2%), with similar late metric ICCs (0.93-0.98). There was a significant bias toward higher retest SUV and PS values in the lesion analysis (T-RT %Δ [95% CI]: SUV-late-max, 10.0% [2.6%, 17.0%]; PS-late-max, 20.4% [14.3%, 26.4%]) but not in the normal organ analysis. CONCLUSIONS: Among [18F]FDG-avid lesions, the repeatability of PS-based metrics is similar to equivalent SUV-based metrics at late post-injection time points, indicating that PS-based metrics may be suitable for tracking response to oncologic therapies. However, further validation is required in light of our study's limitations, including small sample size and bias toward higher retest values for some metrics.

Treatment of metastatic rectal squamous cell carcinoma in a pregnant patient.

Rectal squamous cell carcinoma is an exceedingly rare form of rectal cancer, with limited data available regarding its presentation and effective treatment. Rectal cancer occurring during pregnancy is uncommon as well. This is a case of metastatic rectal squamous cell carcinoma presenting in a 22-week pregnant, female patient in her early 30s. The patient was treated with 5-fluorouracil and cisplatin and delivered a healthy male child born via uncomplicated vaginal delivery at 35 weeks. This article demonstrates that despite the rare nature of this cancer, in the already rare context of pregnancy, effective and safe treatment is possible with a multidisciplinary team.

LI-RADS CT and MRI Ancillary Feature Association with Hepatocellular Carcinoma and Malignancy: An Individual Participant Data Meta-Analysis.

Background The independent contribution of each Liver Imaging Reporting and Data System (LI-RADS) CT or MRI ancillary feature (AF) has not been established. Purpose To evaluate the association of LI-RADS AFs with hepatocellular carcinoma (HCC) and malignancy while adjusting for LI-RADS major features through an individual participant data (IPD) meta-analysis. Materials and Methods Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus were searched from January 2014 to January 2022 for studies evaluating the diagnostic accuracy of CT and MRI for HCC using LI-RADS version 2014, 2017, or 2018. Using a one-step approach, IPD across studies were pooled. Adjusted odds ratios (ORs) and 95% CIs were derived from multivariable logistic regression models of each AF combined with major features except threshold growth (excluded because of infrequent reporting). Liver observation clustering was addressed at the study and participant levels through random intercepts. Risk of bias was assessed using a composite reference standard and Quality Assessment of Diagnostic Accuracy Studies 2. Results Twenty studies comprising 3091 observations (2456 adult participants; mean age, 59 years ± 11 [SD]; 1849 [75.3%] men) were included. In total, 89% (eight of nine) of AFs favoring malignancy were associated with malignancy and/or HCC, 80% (four of five) of AFs favoring HCC were associated with HCC, and 57% (four of seven) of AFs favoring benignity were negatively associated with HCC and/or malignancy. Nonenhancing capsule (OR = 3.50 [95% CI: 1.53, 8.01]) had the strongest association with HCC. Diffusion restriction (OR = 14.45 [95% CI: 9.82, 21.27]) and mild-moderate T2 hyperintensity (OR = 10.18 [95% CI: 7.17, 14.44]) had the strongest association with malignancy. The strongest negative associations with HCC were parallels blood pool enhancement (OR = 0.07 [95% CI: 0.01, 0.49]) and marked T2 hyperintensity (OR = 0.18 [95% CI: 0.07, 0.45]). Seventeen studies (85%) had a high risk of bias. Conclusion Most LI-RADS AFs were independently associated with HCC, malignancy, or benignity as intended when adjusting for major features. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Crivellaro in this issue.

Quantifying 18F-Fluorodeoxyglucose Uptake in Perianal Fistulas on PET/CT: A Retrospective Analysis.

RATIONALE AND OBJECTIVES: The use of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in assessing inflammatory diseases has shown significant promise. Uptake patterns in perianal fistulas, which may be an incidental finding on PET/CT, have not been purposefully studied. Our aim was to compare FDG uptake of perianal fistulas to that of the liver and anal canal in patients who underwent PET/CT for hematologic/oncologic diagnosis or staging. MATERIALS AND METHODS: We retrospectively identified patients who underwent FDG-PET/CT imaging between January 2011 and May 2023, where the report described a perianal fistula or abscess. PET/CTs of patients included in the study were retrospectively analyzed to record the maximum standardized uptake value (SUVmax) of the fistula, abscess, anal canal, rectum, and liver. Fistula-to-liver and Fistula-to-anus SUVmax ratios were calculated. We statistically compared FDG activity among the fistula, liver, and anal canal. We also assessed FDG activity in patients with vs. without anorectal cancer, as well as across different St. James fistula grades. RESULTS: The study included 24 patients with identifiable fistulas. Fistula SUVmax (mean=10.8 ± 5.28) was significantly higher than both the liver (mean=3.09 ± 0.584, p < 0.0001) and the anal canal (mean=5.98 ± 2.63, p = 0.0005). Abscess fistula SUVmax was 15.8 ± 4.91. St. James grade 1 fistulas had significantly lower SUVmax compared to grades 2 and 4 (p = 0.0224 and p = 0.0295, respectively). No significant differences existed in SUVmax ratios between anorectal and non-anorectal cancer groups. CONCLUSION: Perianal fistulas have increased FDG avidity with fistula SUVmax values that are significantly higher than the anal canal.

Comparative Performance of 2018 LI-RADS versus Modified LIRADS (mLI-RADS): An Individual Participant Data Meta-Analysis.

BACKGROUND: LI-RADS version 2018 (v2018) is used for non-invasive diagnosis of hepatocellular carcinoma (HCC). A recently proposed modification (known as mLI-RADS) demonstrated improved sensitivity while maintaining specificity and positive predictive value (PPV) of LI-RADS category 5 (definite HCC) for HCC. However, mLI-RADS requires multicenter validation. PURPOSE: To evaluate the performance of v2018 and mLI-RADS for liver lesions in a large, heterogeneous, multi-national cohort of patients at risk for HCC. STUDY TYPE: Systematic review and meta-analysis using individual participant data (IPD) [Study Protocol: https://osf.io/duys4]. POPULATION: 2223 observations from 1817 patients (includes all LI-RADS categories; females = 448, males = 1361, not reported = 8) at elevated risk for developing HCC (based on LI-RADS population criteria) from 12 retrospective studies. FIELD STRENGTH/SEQUENCE: 1.5T and 3T; complete liver MRI with gadoxetate disodium, including axial T2w images and dynamic axial fat-suppressed T1w images precontrast and in the arterial, portal venous, transitional, and hepatobiliary phases. Diffusion-weighted imaging was used when available. ASSESSMENT: Liver observations were categorized using v2018 and mLI-RADS. The diagnostic performance of each system's category 5 (LR-5 and mLR-5) for HCC were compared. STATISTICAL TESTS: The Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2 was applied to determine risk of bias and applicability. Diagnostic performances were assessed using the likelihood ratio test for sensitivity and specificity and the Wald test for PPV. The significance level was P < 0.05. RESULTS: 17% (2/12) of the studies were considered low risk of bias (244 liver observations; 164 patients). When compared to v2018, mLR-5 demonstrated higher sensitivity (61.3% vs. 46.5%, P < 0.001), similar PPV (85.3% vs. 86.3%, P = 0.89), and similar specificity (85.8% vs. 90.8%, P = 0.16) for HCC. DATA CONCLUSION: This study confirms mLR-5 has higher sensitivity than LR-5 for HCC identification, while maintaining similar PPV and specificity, validating the mLI-RADS proposal in a heterogeneous, international cohort. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Individual Participant Data Meta-Analysis of LR-5 in LI-RADS Version 2018 versus Revised LI-RADS for Hepatocellular Carcinoma Diagnosis.

Background A simplification of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 (v2018), revised LI-RADS (rLI-RADS), has been proposed for imaging-based diagnosis of hepatocellular carcinoma (HCC). Single-site data suggest that rLI-RADS category 5 (rLR-5) improves sensitivity while maintaining positive predictive value (PPV) of the LI-RADS v2018 category 5 (LR-5), which indicates definite HCC. Purpose To compare the diagnostic performance of LI-RADS v2018 and rLI-RADS in a multicenter data set of patients at risk for HCC by performing an individual patient data meta-analysis. Materials and Methods Multiple databases were searched for studies published from January 2014 to January 2022 that evaluated the diagnostic performance of any version of LI-RADS at CT or MRI for diagnosing HCC. An individual patient data meta-analysis method was applied to observations from the identified studies. Quality Assessment of Diagnostic Accuracy Studies version 2 was applied to determine study risk of bias. Observations were categorized according to major features and either LI-RADS v2018 or rLI-RADS assignments. Diagnostic accuracies of category 5 for each system were calculated using generalized linear mixed models and compared using the likelihood ratio test for sensitivity and the Wald test for PPV. Results Twenty-four studies, including 3840 patients and 4727 observations, were analyzed. The median observation size was 19 mm (IQR, 11-30 mm). rLR-5 showed higher sensitivity compared with LR-5 (70.6% [95% CI: 60.7, 78.9] vs 61.3% [95% CI: 45.9, 74.7]; P < .001), with similar PPV (90.7% vs 92.3%; P = .55). In studies with low risk of bias (n = 4; 1031 observations), rLR-5 also achieved a higher sensitivity than LR-5 (72.3% [95% CI: 63.9, 80.1] vs 66.9% [95% CI: 58.2, 74.5]; P = .02), with similar PPV (83.1% vs 88.7%; P = .47). Conclusion rLR-5 achieved a higher sensitivity for identifying HCC than LR-5 while maintaining a comparable PPV at 90% or more, matching the results presented in the original rLI-RADS study. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Sirlin and Chernyak in this issue.

Low-Field-Strength Body MRI: Challenges and Opportunities at 0.55 T.

Advances in MRI technology have led to the development of low-field-strength (hereafter, "low-field") (0.55 T) MRI systems with lower weight, fewer shielding requirements, and lower cost than those of traditional (1.5-3 T) systems. The trade-offs of lower signal-to-noise ratio (SNR) at 0.55 T are partially offset by patient safety and potential comfort advantages (eg, lower specific absorption rate and a more cost-effective larger bore diameter) and physical advantages (eg, decreased T2* decay, shorter T1 relaxation times). Image reconstruction advances leveraging developing technologies (such as deep learning-based denoising) can be paired with traditional techniques (such as increasing the number of signal averages) to improve SNR. The overall image quality produced by low-field MRI systems, although perhaps somewhat inferior to 1.5-3 T MRI systems in terms of SNR, is nevertheless diagnostic for a broad variety of body imaging applications. Effective low-field body MRI requires (a) an understanding of the trade-offs resulting from lower field strengths, (b) an approach to modifying routine sequences to overcome SNR challenges, and (c) a workflow for carefully selecting appropriate patients. The authors describe the rationale, opportunities, and challenges of low-field body MRI; discuss important considerations for low-field imaging with common body MRI sequences; and delineate a variety of use cases for low-field body MRI. The authors also include lessons learned from their preliminary experience with a new low-field MRI system at a tertiary care center. Finally, they explore the future of low-field MRI, summarizing current limitations and potential future developments that may enhance the clinical adoption of this technology. ©RSNA, 2023 Supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center. See the invited commentary by Venkatesh in this issue.

ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.