Anna Mae Diehl

Overview:

Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD).

Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.

Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.

Positions:

Florence McAlister Distinguished Professor of Medicine

Medicine, Gastroenterology
School of Medicine

Professor of Medicine

Medicine, Gastroenterology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1978

Georgetown University

Medical Resident, Medicine

Johns Hopkins University

Fellow in Gastroenterology, Medicine

Johns Hopkins University

Grants:

NASH Clinical Research Network

Administered By
Medicine, Gastroenterology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

TAIWANJ JKB 121-001

Administered By
Medicine, Gastroenterology
Awarded By
TaiwanJ Pharmaceuticals Co. Ltd
Role
Principal Investigator
Start Date
End Date

Impact of Fructose on Metabolism, Energy Homeostasis and MR biomarkers in NAFLD

Administered By
Radiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Drug Abuse: Discovering Ligands for Pertinent GPCRs

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Rac1 Promotes Hepatic Stellate Accumulation/Activation in Liver Injury

Administered By
Medicine, Gastroenterology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Publications:

Prospective study of outcomes in adults with nonalcoholic fatty liver disease

BACKGROUND The prognoses with respect to mortality and hepatic and nonhepatic outcomes across the histologic spectrum of nonalcoholic fatty liver disease (NAFLD) are not well defined. METHODS We prospectively followed a multicenter patient population that included the full histologic spectrum of NAFLD. The incidences of death and other outcomes were compared across baseline histologic characteristics. RESULTS A total of 1773 adults with NAFLD were followed for a median of 4 years. All-cause mortality increased with increasing fibrosis stages (0.32 deaths per 100 person-years for stage F0 to F2 [no, mild, or moderate fibrosis], 0.89 deaths per 100 persons-years for stage F3 [bridging fibrosis], and 1.76 deaths per 100 person-years for stage F4 [cirrhosis]). The incidence of liver-related complications per 100 person-years increased with fibrosis stage (F0 to F2 vs. F3 vs. F4) as follows: variceal hemorrhage (0.00 vs. 0.06 vs. 0.70), ascites (0.04 vs. 0.52 vs. 1.20), encephalopathy (0.02 vs. 0.75 vs. 2.39), and hepatocellular cancer (0.04 vs. 0.34 vs. 0.14). As compared with patients with stage F0 to F2 fibrosis, patients with stage F4 fibrosis also had a higher incidence of type 2 diabetes (7.53 vs. 4.45 events per 100 person-years) and a decrease of more than 40% in the estimated glomerular filtration rate (2.98 vs. 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across fibrosis stages. After adjustment for age, sex, race, diabetes status, and baseline histologic severity, the incidence of any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy) was associated with increased all-cause mortality (adjusted hazard ratio, 6.8; 95% confidence interval, 2.2 to 21.3). CONCLUSIONS In this prospective study involving patients with NAFLD, fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and death. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; NAFLD DB2 ClinicalTrials.gov number, NCT01030484.)
Authors
Sanyal, AJ; van Natta, ML; Clark, J; Neuschwander-Tetri, BA; Diehl, AM; Dasarathy, S; Loomba, R; Chalasani, N; Kowdley, K; Hameed, B; Wilson, LA; Yates, KP; Belt, P; Lazo, M; Kleiner, DE; Behling, C; Tonascia, J
MLA Citation
Sanyal, A. J., et al. “Prospective study of outcomes in adults with nonalcoholic fatty liver disease.” New England Journal of Medicine, vol. 385, no. 17, Oct. 2021, pp. 1559–69. Scopus, doi:10.1056/NEJMoa2029349.
URI
https://scholars.duke.edu/individual/pub1500524
Source
scopus
Published In
The New England Journal of Medicine
Volume
385
Published Date
Start Page
1559
End Page
1569
DOI
10.1056/NEJMoa2029349

Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Whether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histological severity of NASH. APPROACH AND RESULTS: Using the Duke NAFLD Clinical Database, we examined patients with biopsy-proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group-based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01). CONCLUSIONS: Glycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH-related fibrosis progression.
Authors
Alexopoulos, A-S; Crowley, MJ; Wang, Y; Moylan, CA; Guy, CD; Henao, R; Piercy, DL; Seymour, KA; Sudan, R; Portenier, DD; Diehl, AM; Coviello, AD; Abdelmalek, MF
MLA Citation
Alexopoulos, Anastasia-Stefania, et al. “Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease.Hepatology, vol. 74, no. 3, Sept. 2021, pp. 1220–33. Pubmed, doi:10.1002/hep.31806.
URI
https://scholars.duke.edu/individual/pub1476460
PMID
33724511
Source
pubmed
Published In
Hepatology
Volume
74
Published Date
Start Page
1220
End Page
1233
DOI
10.1002/hep.31806

Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury.

BACKGROUND & AIMS: The outcome of liver injury is dictated by factors that control the accumulation of myofibroblastic (activated) hepatic stellate cells (MF-HSCs) but therapies that specifically block this process have not been discovered. We evaluated the hypothesis that MF-HSCs and liver fibrosis could be safely reduced by inhibiting the cysteine/glutamate antiporter xCT. METHODS: xCT activity was disrupted in both HSC lines and primary mouse HSCs to determine its effect on HSC biology. For comparison, xCT expression and function were also determined in primary mouse hepatocytes. Finally, the roles of xCT were assessed in mouse models of liver fibrosis. RESULTS: We found that xCT mRNA levels were almost a log-fold higher in primary mouse HSCs than in primary mouse hepatocytes. Further, primary mouse HSCs dramatically induced xCT as they became MF, and inhibiting xCT blocked GSH synthesis, reduced growth and fibrogenic gene expression and triggered HSC ferroptosis. Doses of xCT inhibitors that induced massive ferroptosis in HSCs had no effect on hepatocyte viability in vitro, and xCT inhibitors reduced liver fibrosis without worsening liver injury in mice with acute liver injury. However, TGFβ treatment up-regulated xCT and triggered ferroptosis in cultured primary mouse hepatocytes. During chronic liver injury, xCT inhibitors exacerbated injury, impaired regeneration and failed to improve fibrosis, confirming that HSCs and hepatocytes deploy similar mechanisms to survive chronic oxidative stress. CONCLUSIONS: Inhibiting xCT can suppress myofibroblastic activity and induce ferroptosis of MF-HSCs. However, targeting xCT inhibition to MF-HSCs will be necessary to exploit ferroptosis as an anti-fibrotic strategy.
Authors
Du, K; Oh, SH; Dutta, RK; Sun, T; Yang, W-H; Chi, J-T; Diehl, AM
MLA Citation
Du, Kuo, et al. “Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury.Liver Int, vol. 41, no. 9, Sept. 2021, pp. 2214–27. Pubmed, doi:10.1111/liv.14945.
URI
https://scholars.duke.edu/individual/pub1482835
PMID
33991158
Source
pubmed
Published In
Liver Int
Volume
41
Published Date
Start Page
2214
End Page
2227
DOI
10.1111/liv.14945

A Beautiful Day in the Neighborhood: Application of Single-Cell Transcriptomics to Unravel Liver Cell Heterogeneity in Diseased Human Livers.

Authors
Chen, T; Diehl, AM
MLA Citation
Chen, Tianyi, and Anna Mae Diehl. “A Beautiful Day in the Neighborhood: Application of Single-Cell Transcriptomics to Unravel Liver Cell Heterogeneity in Diseased Human Livers.Hepatology, vol. 74, no. 2, Aug. 2021, pp. 547–49. Pubmed, doi:10.1002/hep.31827.
URI
https://scholars.duke.edu/individual/pub1476574
PMID
33756021
Source
pubmed
Published In
Hepatology
Volume
74
Published Date
Start Page
547
End Page
549
DOI
10.1002/hep.31827

Tissues &amp; organs

Authors
Ochoa, B; Diehl, AM; Stainbrook, SC
MLA Citation
Ochoa, B., et al. “Tissues & organs.” Encyclopedia of Biological Chemistry: Third Edition, vol. 5, 2021, pp. 437–43. Scopus, doi:10.1016/B978-0-12-819460-7.00268-1.
URI
https://scholars.duke.edu/individual/pub1501350
Source
scopus
Volume
5
Published Date
Start Page
437
End Page
443
DOI
10.1016/B978-0-12-819460-7.00268-1