HPHS Journal Watch: July/August 2021
American Journal of Clinical Pathology
The Utility of Liver Biopsy in the Evaluation of Liver Disease and Abnormal Liver Function Tests
Khalifa A, Lewin DN, Sasso R, et al. Am J Clin Pathol. 2021 August;156(2):259-267.
Elevated liver function tests (LFTs) are common and when history, clinical findings, and/or serologic/immunologic tests are unable to account for the elevations, liver biopsy is performed, despite being an invasive procedure. This study of 383 liver biopsy specimens performed at a single institution from 2014 to 2018 found that by correlating histologic and clinical findings, specific diagnoses could be made in 85% of patients undergoing liver biopsy for unexplained LFT abnormalities. Despite abnormal LFTs, 15% of patients (56 patients) had normal histology; of these, 3 patients were ultimately thought to have drug-induced liver injury (DILI), 2 were thought to have transplant rejection, 1 did not have further follow-up, and an underlying etiology could not be determined in 50 patients. 5% of patients with no history of liver disease or clinical features of portal hypertension were found to have cirrhosis on histology. The LFT values/patterns were not predictive of the diagnosis and correlated poorly with the stage of the liver disease. Overall, liver biopsy remains a valuable tool in the evaluation of abnormal LFTs with high diagnostic yield.
American Journal of Gastroenterology
A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis
Goet JC, Murillo Perez CF, Harms MH, et al. Am J Gastroenterol. 2021 Jul 1;116(7):1514-1522.
The authors studied a large cohort of 1100 Ursodeoxycholic acid–treated patients with primary biliary cholangitis (PBC) from 7 centers participating in the GLOBAL PBC Study Group and aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. The prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 times the upper limit of normal and advanced fibrosis estimate of Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was 10.4% and 12.5% for the MRS (1989) and GLOBE score, respectively. All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.
Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications
Faruqui S, Okoli FC, Olsen SK, et al. Am J Gastroenterol. 2021 Jul 1;116(7):1414-1425.
The authors studied a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging, frequently with strictures similar to secondary sclerosing cholangitis (SSC) as previously described in critically ill patients. The author conducted a retrospective study of COVID-19 patients, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangio-pancreatography. Twelve patients were identified with a marked male predominance (11 men and 1 woman, with a mean age of 58 years). The mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. The peak median serum alanine aminotransferase was 661 U/L with peak median serum ALP was 1855 U/L. Magnetic resonance cholangiopancreatography revealed beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in four patients showed acute and/or chronic large duct obstruction without clear bile duct loss. A progressive biliary tract damage was demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. The author postulates that the hepatobiliary injury may be a result of ischemic injury related to microvascular coagulopathy and/or hypotension during severe illness or sepsis. Direct virus-mediated damage to the biliary epithelium may be involved in the pathogenesis of the cholangiopathy as biliary epithelial cells richly express ACE2. Another possible explanation may be drug-induced liver injury for the cholestatic liver injury seen in the patients. During the pandemic, a large assortment of medications were subjected to trials. Remdesivir and IL-6 receptor agonists, which are often used in the treatment of covid-19 patients, have been implicated as a cause of ALT elevations, but not the pattern of cholestatic injury seen in these patients. The similarities between SSC in critically ill patients and COVID cholangiopathy suggest a possible link between hypoxic liver injury or ischemic hepatopathy and cholestatic liver injury.
Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B
Nam H, Lee SW, Kwon JH, et al. Am J Gastroenterol. 2021 Mar 10.
The aim of this study is to assess the accuracy of non-invasive fibrosis marker (NFM) in a large cohort of 5147 patients of chronic hepatitis B (CHB) who were receiving potent anti-viral therapy (AVT) for more than 12 months to predict the development of HCC. In addition, these authors tried to develop a breakthrough NFM response-based prediction model for HCC. This was a multicentric study, including 5,147 patients with chronic hepatitis B on entecavir/tenofovir for more than 12 months in the eleven-year study period from February 2007 to January 2018. This included 4,028 patients for derivation cohort and 1,119 for validation cohort. Non-invasive fibrosis markers (NFMs), such as the fibrosis index based on 4 factors (FIB-4) and the aspartate aminotransferase-to-platelet ratio index (APRI), showed only moderate sensitivity and accuracy for determining liver fibrosis. This study tried to investigate whether NFM responses during potent AVT could accurately predict the development of HCC. In addition, using the role of NFM as a surrogate indicator, these authors developed a breakthrough NFM response-based prediction model for HCC. The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. NFM response, sex, age, and cirrhosis (FSAC) were independently predictive of HCC. The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050) (PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005)). Early on-therapy change in NFM is a strong predictor of HCC in patients with CHB receiving entecavir/ tenofovir. The study has several limitations. The first is that this is a retrospective, which may impart selection bias. Another limitation was the lack of elastography study, which is the most accurate non-invasive method for determining fibrosis, and histologic confirmation.
Hepatic Steatosis and Steatohepatitis in a Large North American Cohort of Adults With Chronic Hepatitis B
Khalili M, Kleiner DE, King WC, et al. Am J Gastroenterol. 2021 Apr 8.
The study was carried out in a prospective adult cohort with chronic HBV in North American populations who had undergone a liver biopsy to find coexisting Fatty liver disease (FLD). The authors tried to determine the association between FLD with concurrent histological fibrosis and disease progression by using prospectively measured aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and Fibrosis-4 (FIB-4) as surrogate measures and HBV clinical and virologic outcomes on follow-up. Coexisting steatosis was present ≥5% in nearly a third of the adults (31%) and 42% had steatohepatitis. The presence of steatohepatitis was associated with advanced fibrosis, which was independent of HBV DNA levels. A higher AST and ALT value and possibly higher FIB-4 levels was also associated with steatohepatitis. The main limitation of this study was that because liver biopsies were not uniformly performed in all Hepatitis B Research Network (HBRN) participants. Hence, the true prevalence of FLD among patients with HBV, in general, could not be determined. However, it is noteworthy that the prevalence of FLD was similar among those who had a liver biopsy for clinical care versus as entry criteria into a treatment trial. In this study, the authors did not exclude at-risk alcohol use to fully capture the spectrum of FLD.
Unreliable Estimation of Fibrosis Regression During Treatment by Liver Stiffness Measurement in Patients With Chronic Hepatitis B
Ji D, Chen Y, Shang Q, et al. Am J Gastroenterol. 2021 Apr 8;116(8):1676–85.
In this prospective, multicenter study, the author studied 727 treatment-naive patients receiving entecavir-based therapy with paired liver biopsies at treatment baseline and week 72 and Liver stiffness measurement (LSM) changes. The changes in LSM were categorized as ≥30% decrease, minor change, or <30% increase. Multivariate logistic regression was used to estimate odds ratios (ORs) of changes in LSM on clinical outcomes accounting for regression to the mean. A new on-treatment LSM threshold was established by receiver operating curve. In terms of assessing hepatic fibrosis, the study did not show regression of fibrosis during treatment with a decrease in LSM. Some investigations suggested that LSM could be applied for longitudinal monitoring of fibrosis status, which is the opposite of our findings. The association between changes in LSM and improvement of inflammation was nonlinear. LSM decrease of ≥30% was associated with regression of fibrosis, significant histological response, and alanine aminotransferase normalization. After adjusting for regression to the mean, an LSM increase of ≥30% became negatively associated with the above 3 outcomes. A new on-treatment LSM cut off value of 5.4 kPa was established for indicating a significant histological response.
American Journal of Surgical Pathology
Liver Pathology, Including MOC31 Immunohistochemistry, in Congenital Tufting Enteropathy
Chen S, Goldsmith JD, Fawaz R, et al. Am J Surg Pathol. 2021 August; 45(8):1091-1097.
Congenital tufting enteropathy (CTE), which causes severe, intractable diarrhea in infancy, is caused by mutations in epithelial cell adhesion molecule (EpCAM) that result in intestinal malabsorption. The purpose of this study was to evaluate the histologic and immunohistologic features of CTE in pediatric liver biopsies. Three patients with confirmed CTE who had undergone liver biopsy were identified. All patients had required parenteral nutrition, and one also had Hepatitis C, genotype 3a. All liver biopsy specimens showed mild portal and lobular inflammation. The specimens from the patient with Hepatitis C had some portal fibrosis and mild steatosis, while no fibrosis was present in the other two specimens. Bile duct proliferation was noticeably absent in the liver cores from the CTE patients, despite having “reactive” epithelial changes in native bile ducts. Of interest, MOC-31 (anti-EpCAM antibody) immunohistochemistry was negative in the biliary epithelium and hepatocytes of the patients with CTE, but present with strong membranous staining of the biliary epithelium in normal control liver specimens. The authors suggest that loss of EpCAM function may contribute to the lack of ductular reaction in these cases.
Morphologic and Molecular Findings in Myxoid Hepatic Adenomas
Rowan D, Yasir S, Chen ZE, et al. Am J Surg Pathol. 2021 August; 45(8):1098-1107.
Myxoid hepatic adenomas are a recently defined subtype of hepatocellular neoplasm defined by the presence of abundant extracellular myxoid material and loss of LFABP by immunohistochemistry. The authors of this multicenter retrospective study identified nine cases of myxoid adenoma for further study and characterization. All tumors were well circumscribed and well differentiated with prominent myxoid material. Five patients were described as having hepatocellular carcinoma arising from a single myxoid. The other four patients were found to have multiple benign hepatic adenomas, including one patient with >20 lesions. Sequencing in this patient showed GNAS mutations present in both myxoid and non-myxoid adenomas. All myxoid adenomas had loss of LFABP, and four were found to have alterations in HNF1A. Additional mutations were identified in CDKN1B and RNF123. The authors suggest that myxoid hepatic adenomas are high risk for malignant transformation and should be distinguished from non-myxoid adenomas with HNF1A inactivation.
Clinical Gastroenterology and Hepatology
Electronic Image of the month: A Rare Case of an Aggressive Liver Tumor
Odenwald MA, Aronsohn A, Peeraphatidit TB. Clin Gastroenterol Hepatol. 2021 Jul;19(7):e72.
This case includes a brief case summary and some nice images of sarcomatoid cholangiocarcinoma.
Letter to the editor: Liver Injury in Liver Transplant Patients With COVID-19: A Histopathologic Analysis
Ng A. Clin Gastroenterol Hepatol. 2021 Jul;19(7):1508-1509.
Original articles: https://pubmed.ncbi.nlm.nih.gov/33516952/
This paper has images of liver histopathology in COVID-19 infection including staining for viral antigen, hepatocyte stem cells, and liver regeneration.
Original article research correspondence: Hepatic Vasculopathy and Regenerative Responses of the Liver in Fatal Cases of COVID-19
Kaltschmidt B, Fitzek ADE, Schaedler J, et al. Clin Gastroenterol Hepatol. 2021 Aug;19(8):1726-1729.e3.
There are very few reports that have studied the pathophysiology or histopathology in the liver that is associated with COVID infection. The authors of this study showed that vascular injury is accompanied by activation of the intrahepatic stem cell compartment which causes abnormal regenerative changes. They concluded that the systemic illness caused by the viral infection results in substantial microvascular thrombotic disease, liver injury, and features of hepatocyte regeneration.
Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort
Simon TG, Roelstraete B, Khalili H, et al. Gut. 2021 Jul;70(7):1375-1382.
This study is a population-based data in Sweden from 1966 to 2017 of 10568 patients assessing the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD). The overall mortality rate was found to be increased compared with age, sex, county and calender year matched participants of non-NAFLD patients. All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, but the contributions of cardiovascular disease and HCC were modest. The limitations of this study are that it is a retrospective study and the definition of NAFLD was taken histologically as compared to ultrasound-confirmed fatty liver. The pathology data may be subject to sampling error and interobserver variability.
Commentary: NAFLD-related mortality: simple hepatic steatosis is not as ‘benign’ as thought
Tilg H, Targher G. Gut. 2021 Jul;70(7):1212-1213.
Original article: https://pubmed.ncbi.nlm.nih.gov/33037056/
This commentary is focuses on the fact that patients with simple steatosis exhibited an increased risk of all-cause mortality in a cohort where a long follow-up was available. As the NAFLD liver phenotype progresses over time, even simple steatosis in a certain percentage develop NASH, non- cirrhotic fibrosis, and cirrhosis over a decade long follow-up. This progression of disease might suggest that simple steatosis is not so benign. The absolute excess risk of all-cause mortality in patients with simple steatosis was 10.7%, NASH without fibrosis was 18.5%, non-cirrhotic fibrosis was 25.6%, and cirrhosis was 49.4% compared with control subjects. These results were similar in men and women and in those with and without pre-existing cardiovascular disease, diabetes, hypertension, dyslipidemia, or metabolic syndrome. A liver biopsy represents only a single point in time and disease can fluctuate over time. This can be a major limitation as it is in many other studies investigating NAFLD-related mortality. Another limitation is that, due to its retrospective design, this study lacks detailed information on smoking history, alcohol consumption, body mass index, and laboratory values. This study may have major public health implications as nearly 30% of the world’s population can have any form of NAFLD. The clinical implications of this important nationwide cohort study may have some public health implications. Simple steatosis can no longer be ignored as benign. This patient group should be monitored for the identification of disease progression along with extrahepatic cancer screening and screening for cardiovascular and chronic kidney diseases. Therefore, available screening strategies for cancers such as colorectal, uterine, or breast cancer should be intensified in patients with all stages of NAFLD. There should be an awareness program for increased cancer risks and other hepatic and extrahepatic complications among this group of patients.
A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH
Taylor-Weiner A, Pokkalla H, Han L, et al. Hepatology. 2021 July;74(1):133-147.
There has been much discussion in recent years on the methodologies behind liver biopsy evaluation in NASH clinical trials, particularly in light of some of the disappointing results of some large trials evaluating pharmaceutical intervention. In this article, funded by Gilead Sciences, the authors describe a machine learning (ML)-based approach to liver histology assessment. Using slides from three clinical trials, they evaluated their ML-based predictions. There are of course many issues surrounding this model of evaluating NASH, its progression, and its response to therapeutic interventions. The reader is referred to a recent excellent editorial by Dr. Brunt, one of our leading NASH hepatopathology experts and voices of our field, in which she addresses many of these issues: https://pubmed.ncbi.nlm.nih.gov/32890594/
Characteristics and Prognosis of De Novo Hepatocellular Carcinoma After Sustained Virologic Response
Toyoda H, Hiraoka A, Uojima H, et al. Hepatol Commun. 2021 May 5;5(7):1290-1299.
The authors present a study where they compared survival in patients that were diagnosed with HCV and either had SVR or still had persistent HCV infection. They showed that patients with SVR had significantly prolonged survival, even though recurrence of HCC was similar between the two groups. A higher prevalence of curative treatment for recurrent HCC and improved liver function in the patients with SVR attributed to these results.
Heterozygosity of the Alpha 1-Antitrypsin Pi*Z Allele and Risk of Liver Disease
Hakim A, Moll M, Qiao D, et al. Hepatol Commun. 2021 Apr 3;5(8):1348-1361.
This group studied the importance of serpin family A member 1 (SERPINA1) Z allele heterozygosity in the risk of developing chronic liver disease. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1-antitrypsin deficiency and is a proven risk factor for cirrhosis; however, less is known about heterozygotes. They evaluated patients in both the United Kingdom (UK) and at Massachusetts General Brigham. They determined that SERPINA1 Z allele heterozygosity is an important risk factor for liver disease and that this risk is amplified by increasing BMI.
Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria
Deniz K, Umetsu SE, Ferrell L, et al. Histopathology. 2021 Jul;79(1):23-33.
The authors describe the clinicopathological features of Hepatocellular adenoma (HCA) subtypes in Turkey. They reviewed 59 resection cases of HCA collected from 15 institutions to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, β-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. Of them, 24 (50%) were hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) β-catenin-activated HCAs, three (6%) β-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumor diameter of 60 mm. In the β-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the β-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The authors conclude that the major HCA subtype was HNF1α-inactivated HCA. They found a low incidence of inflammatory-type HCA. Their data also showed that β-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings contrast with those of most other studies of HCA subtypes.
Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma
Montasser A, Beaufrère A, Cauchy F, et al. Histopathology. 2021 Jul;79(1):36-46.
The authors evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression profiles in a cohort of surgically treated HCCs. They reviewed 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD-1 and of PD-L1 were analyzed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analyzed. Follow-up data were retrieved from patients’ charts. PD-1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD-L1 expression (≥1%) in ICs and PD-L1 expression in tumor cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD-1 expression (<1%) was associated with strong and diffuse glutamine synthetase overexpression (8% versus 27%, P = 0.024). HCCs from patients with TACE pretreatment showed significantly higher PD-L1 expression in TCs than those from patients without TACE pretreatment (2% versus 0.4%, P = 0.027). PD-1 expression in ICs and PD-L1 expression in both ICs and TCs were higher in TACE-resected tumors than in corresponding pre-TACE biopsies (respectively: 1.8% versus 8.1%, P = 0.034; 0.8% versus 7.1%, P = 0.032; and 0% versus 2.4%, P = 0.043). The authors conclude that increases in PD-1 expression and PD-L1 expression in HCCs following TACE, support the use of TACE in combination with immunotherapy in selected cases to optimize tumor response.
Erythropoietic protoporphyria- associated hepatopathy: expanding the spectra of brown pigments encountered in hepatic specimens
Wang Y, Karamchandani DM. Histopathology. 2021 Jul;79(1):122-124.
The authors describe a case report of erythropoietic protoporphyria associated hepatopathy in 56-year-old male.
Can primary hepatocellular carcinoma histomorphology predict extrahepatic metastasis?
Kumar D, Hafez O, Jain D, et al. Hum Pathol. 2021 Jul;113:39-46.
This study compared the pathologic features of primary hepatocellular carcinoma (HCC) to its corresponding metastasis in a total of 39 cases. The most common sites of metastasis were lung (28.21%), abdominal cavity (25.64%), lymph nodes (20.51%), bone (17.95%), soft tissue (15.38%), and adrenal gland (10.26%). The pathologic features (histologic pattern, subtype, and grade) of the primary tumor and metastases differed in about 50% cases (48.72%, 48.72%, and 51.28%, respectively). The solid and macrotrabecular histologic patterns and the macrotrabecular-massive subtype were the most common features seen in primary tumors associated with metastasis. Overall, the authors discovered significant intratumoral heterogeneity and histomorphologic discordance between primary and metastatic HCCs.
Journal of Gastroenterology and Hepatology
Patients with post-transplant biliary strictures have significantly higher rates of liver transplant failure and rejection: A nationwide inpatient analysis
Kohli DR, Desai MV, Kennedy KF, et al. J Gastroenterol Hepatol. 2021 Jul;36(7):2008-2014.
Post-liver transplant biliary strictures are associated with increased rates of allograft rejection, allograft failure/infections, and readmissions. Compared with patients without strictures, the adjusted odds ratio (OR) for various outcomes in patients with biliary strictures were as follows: 1.46 (1.20, 1.77; P < 0.001) for 30-day non-elective readmission, 2.71 (2.04, 3.59; P < 0.001) allograft rejection, 2.32 (1.61, 3.37; P < 0.001) liver transplant failure, 3.05 (1.39, 6.73; P < 0.01) infection, and 1.41 (1.08, 1.82; P = 0.01) disposition to skilled nursing or intermediate care facility. Compared with ERCP, management of these patients with IR or surgical interventions is associated with significantly higher rates of allograft failure and hospital stay.
The association between non-alcoholic fatty liver disease (with or without metabolic syndrome) and extrahepatic cancer development
Yamamoto K, Ikeya T, Okuyama S, et al. J Gastroenterol Hepatol. 2021 Jul;36(7):1971-1978.
Data were collected from 30 172 participants who underwent health checkups, among whom 4394 (14.6%) had NAFLD. Over the 14-year follow-up period, 2086 participants (6.9%) developed cancer. Participants with NAFLD had a higher incidence of digestive organ neoplasms (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.07–1.67), especially in the stomach (OR: 1.40, 95% CI: 1.02–1.94) and small intestine (OR: 2.80, 95% CI: 0.87–8.96), than did those without NAFLD.
Lindsey Westbrook, MD (Editor); University of Colorado
Vishal Chandan, MBBS; University of California Irvine
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Mojgan Hosseini, MD; University of California San Diego
Meredith Pittman, MD; Maimonides Medical Center
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Heather Stevenson-Lerner, MD, PhD; University of Texas