Single-cell CRISPR screening characterizes transcriptional deregulation in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia caused by accumulation of multiple genetic alterations in T-cell progenitors. However, for many genes it remains unknown how their mutations contribute to disease development. Therefore, we performed two single-cell CRISPR screens in primary pro-T cells ex vivo to study the transcriptional impact of loss-of-function alterations in T-ALL and correlate this with effects on cell fitness. The various perturbations were clustered based on their effects on E2F/MYC or STAT/NOTCH signatures, which play a defining role in driving T-cell proliferation. Many of the perturbations resulted in positive effects on the STAT and NOTCH signatures and were predicted to behave as haploinsufficient tumor suppressors in T-ALL. Additionally, Spi1 was identified as an essential gene for pro-T cell survival, associated with deregulation of the MYC signature and epigenetic consequences. In contrast, Bcl11b was identified a strong tumor suppressor gene in immature T lymphocytes, associated with deregulation of NF-kB and JAK/STAT signaling. We found a correlation between BCL11B expression level and JAK/STAT pathway mutations in T-ALL patients and demonstrated oncogenic cooperation between Bcl11b inactivation and JAK3 hyperactivation in pro-T cells. Altogether, these single-cell CRISPR screens in pro-T cells provide fundamental insights in the mechanisms of transcriptional deregulation caused by genetic alterations in T-ALL.

CRISPR screening in hematology research: from bulk to single-cell level.

The CRISPR genome editing technology has revolutionized the way gene function is studied. Genome editing can be achieved in single genes or for thousands of genes simultaneously in sensitive genetic screens. While conventional genetic screens are limited to bulk measurements of cell behavior, recent developments in single-cell technologies make it possible to combine CRISPR screening with single-cell profiling. In this way, cell behavior and gene expression can be monitored simultaneously, with the additional possibility of including data on chromatin accessibility and protein levels. Moreover, the availability of various Cas proteins leading to inactivation, activation, or other effects on gene function further broadens the scope of such screens. The integration of single-cell multi-omics approaches with CRISPR screening open the path to high-content information on the impact of genetic perturbations at single-cell resolution. Current limitations in cell throughput and data density need to be taken into consideration, but new technologies are rapidly evolving and are likely to easily overcome these limitations. In this review, we discuss the use of bulk CRISPR screening in hematology research, as well as the emergence of single-cell CRISPR screening and its added value to the field.

Outcomes of Acute Pancreatitis in Hospitalized Patients With Generalized Anxiety Disorder.

Introduction Acute pancreatitis (AP) is a common cause of hospitalization in the United States. There is evidence that chronic stress increases the risk for more severe AP episodes. One common form of chronic stress is generalized anxiety disorder (GAD). The purpose of this research was to investigate the impact of GAD on the outcomes of adult patients admitted to the hospital with AP. Methods Utilizing the 2014 National Inpatient Sample database and International Classification of Diseases, Ninth Edition Revision (ICD) codes, AP patients were selected. Common inpatient outcomes of AP patients with and without GAD were examined. The outcomes studied were acute renal failure, acute respiratory failure, sepsis, acute deep vein thrombosis, myocardial infarction, intestinal perforation, and inpatient mortality. A multivariate logistic regression analysis was conducted to assess if GAD was an independent predictor for these outcomes. Results Among 82,156 adult patients hospitalized for AP during the 2014 year, 10,611 of them had coexisting GAD. AP patients with comorbid GAD were found to have an increased likelihood of acute renal failure (aOR = 1.19, 95% confidence interval (CI) = 1.11-1.28, p < 0.001), sepsis (aOR = 1.09, 95% CI = 1.01 -1.19, p = 0.037), acute deep vein thrombosis (aOR = 1.63, 95% CI = 1.06-2.50, p = 0.025), and inpatient mortality (aOR = 1.62, 95% C = I 1.27-2.08, p < 0.001). There was no statistically significant difference found between the two cohorts for the outcomes of myocardial infarction and intestinal perforation. Conclusion In patients hospitalized with AP, those with coexisting GAD were found to have an increased risk of developing acute renal failure, sepsis, acute deep vein thrombosis, and inpatient mortality. There may be benefits to identifying AP patients with comorbid GAD at the time of admission and monitoring them more carefully during their hospitalization to help identify early signs of complications or prevent the negative outcomes seen in this study.

Outcomes of Gastroparesis in Hospitalized Patients With Generalized Anxiety Disorder.

Background   Gastroparesis is a common gastrointestinal pathology that has been increasing in prevalence and represents a significant cost to the United States healthcare system. Gastroparesis is associated with psychological dysfunction, including generalized anxiety disorder (GAD). GAD is known to be a prevalent and chronic manifestation of anxiety, which has been increasing in prevalence since the year 2020. Despite the association between gastroparesis and GAD, there has been limited research on the possible impact GAD may have on the morbidity and mortality of patients hospitalized for gastroparesis, which is further evaluated in this study.   Methods   Using the Nationwide Inpatient Sample from the year 2014, a retrospective study was conducted to assess the outcomes of hospitalized gastroparesis patients with and without a history of GAD. In this study, the analyzed outcomes included acute kidney injury (AKI), acute respiratory failure, sepsis, acute deep vein thrombosis, myocardial infarction, intestinal obstruction, and inpatient mortality. To assess whether GAD is an independent risk factor for the outcomes, a multivariate logistic regression analysis was used.   Results   There were 22,150 patients with gastroparesis assessed in this study; GAD was found to be a comorbid diagnosis in 4,196 of those patients. In the GAD cohort, there was an elevated risk for AKI (adjusted odds ratio 1.24, p < 0.001). The adjusted odds ratios for acute respiratory failure, sepsis, acute deep vein thrombosis, myocardial infarction, intestinal obstruction, and inpatient mortality did not meet the threshold for statistical significance.   Conclusion   In hospitalized gastroparesis patients, GAD is a risk factor for AKI. This finding may be attributed to prerenal azotemia due to an increased risk of nausea and vomiting associated with GAD, as well as the medications used to treat GAD such as escitalopram and duloxetine. In addition, the dual inflammatory states caused by the co-existence of both GAD and gastroparesis may also have a role in increasing the risk for AKI. The results of this study may become increasingly relevant given the increasing prevalence of GAD. .

Outcomes of Patients Hospitalized for Acute Diverticulitis With Comorbid Generalized Anxiety Disorder.

Introduction Diverticular disease and anxiety disorders are common in the general population. Prior research on diverticular disease showed that these patients have an increased frequency of anxiety and depression. The objective of this study was to explore the impact of generalized anxiety disorder (GAD) on the outcomes of adult patients admitted with acute diverticulitis. Methods Using the National Inpatient Sample database from the year 2014 and International Classification of Diseases, Ninth Edition Revision, Clinical Modification (ICD-9 CM) codes, acute diverticulitis patients were selected. The outcomes of diverticulitis patients with and without GAD were explored. The outcomes of interest included inpatient mortality, hypotension/shock, acute respiratory failure, acute hepatic failure, sepsis, intestinal abscess, intestinal obstruction, myocardial infarction, acute renal failure, and colectomy. A multivariate logistic regression analysis was performed to determine if GAD is an independent predictor for the outcomes. Results Among 77,520 diverticulitis patients in the study, 8,484 had comorbid GAD. GAD was identified as a risk factor for intestinal obstruction (adjusted odds ratio (aOR) 1.22, 95% CI: 1.05-1.43, p<0.05), and intestinal abscess (aOR 1.19, 95% CI: 1.10-1.29, p<0.05). GAD was found to be a protective factor for hypotension/shock (aOR 0.83, 95% CI: 0.76-0.91, p<0.05) and acute respiratory failure (aOR 0.76, 95% CI: 0.62-0.93, p<0.05). The aORs of sepsis, inpatient mortality, myocardial infarction, acute renal failure, and colectomy were not statistically significant. Conclusions Patients with acute diverticulitis who are also diagnosed with GAD are at increased risk for intestinal obstruction and intestinal abscess, which may be due to the influence GAD has on the gut microbiota as well as the impact of GAD pharmacotherapy on gut motility. There was also a decreased risk for acute respiratory failure and hypotension/shock appreciated in the GAD cohort which may be attributable to the elevated healthcare resource utilization seen generally in GAD patients, which may allow for presentation to the emergency department, hospitalization, and treatment earlier in the diverticulitis disease course.

Outcomes of Patients Who Developed Clostridioides difficile Infection During Hospitalization and Had a History of Comorbid Post-Traumatic Stress Disorder.

INTRODUCTION: Clostridioides difficile (C. difficile), is a common cause of nosocomial diarrhea. Antibiotic use is a risk factor for developing C. difficile infection (CDI). Clinical presentations of CDI range from mild diarrhea to fulminant colitis. A history of anxiety increases the risk of developing irritable bowel syndrome following CDI. Post-traumatic stress disorder (PTSD) is a common form of anxiety and is associated with several medical comorbidities. This study explores the impact PTSD has on the outcomes of adult patients who develop CDI while hospitalized. METHODS: Hospitalized adults who had developed CDI were selected from the 2014 National Inpatient Sample database using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. The outcomes of CDI patients with and without comorbid PTSD were explored. The outcomes assessed in this study were inpatient mortality, sepsis, hypotension/shock, acute renal failure, acute respiratory failure, megacolon, colonic perforation, and intestinal abscess. Independent t-tests and chi-squared tests were used to compare means and proportions, respectively. A multivariate logistic regression analysis was utilized to determine whether PTSD is an independent predictor of the outcomes. RESULTS: Among 72,383 hospitalized adults who developed CDI in the year 2014, 465 also had a diagnosis of PTSD. PTSD was found to be an independent risk factor for inpatient mortality (adjusted odds ratio {aOR} 2.93, 95% confidence interval (CI): 1.39-6.21, p = 0.005), and sepsis (aOR 1.61, 95% CI: 1.24-2.07, p = 0.001). However, PTSD was not a risk factor for hypotension/shock (aOR 1.26, 95% CI: 0.97-1.63, p = 0.080), acute renal failure (aOR 1.02, 95% CI: 0.81-1.28, p = 0.895), or acute respiratory failure (aOR 1.15, 95% CI: 0.83-1.58, p = 0.412) in patients with CDI. Due to small sample sizes of patients who developed megacolon, colonic perforation, and intestinal abscess, further analysis of these outcomes was not performed. CONCLUSION: Inpatients who develop CDI with comorbid PTSD are at increased risk for sepsis and inpatient mortality. These findings may be due to the impact of PTSD's dysregulation of the hypothalamic-pituitary axis leading to low cortisol production, increased serum cytokine concentrations, and/or increased intestinal inflammation. Awareness of these increased risks when triaging CDI patients with PTSD and possibly increased psychiatric interventions to treat PTSD may be necessary to help reduce the risk of sepsis and inpatient mortality in this subgroup of patients.

Outcomes of Inflammatory Bowel Disease in Hospitalized Patients With Generalized Anxiety Disorder.

Background The development of inflammatory bowel disease (IBD), which encompasses ulcerative colitis and Crohn's disease, is multifactorial. Stress from anxiety is a risk factor for IBD. Generalized anxiety disorder (GAD) is twice as likely in IBD patients. This study explores the outcomes of patients hospitalized for IBD with comorbid GAD. Methods A retrospective analysis utilizing the 2014 USA National Inpatient Sample database was performed to assess the outcomes of hospitalized IBD patients with and without GAD. The outcomes analyzed were sepsis, acute hepatic failure, hypotension/shock, acute respiratory failure, acute deep vein thrombosis, acute renal failure, intestinal obstruction, myocardial infarction, ileus, inpatient mortality, colectomy, intestinal abscess, intestinal perforation, and megacolon. A multivariate logistic regression analysis was employed to explore whether GAD is a risk factor for these outcomes. Results Among 28,173 IBD hospitalized patients in the study, GAD was a comorbid diagnosis in 3,400 of those patients. IBD patients with coexisting GAD were found to be at increased risk for acute hepatic failure (adjusted odds ratio (aOR) 1.80, p = 0.006), sepsis (aOR 1.33, p < 0.001), acute respiratory failure (aOR 1.24, p = 0.018), inpatient mortality (aOR 1.87, p < 0.001), intestinal abscess (aOR 2.35, p = 0.013), and intestinal perforation (aOR 1.44, p = 0.019). The aORs for the remaining outcomes were not statistically significant. Conclusions In hospitalized IBD patients, GAD is a risk factor for sepsis, acute hepatic failure, acute respiratory failure, intestinal abscess, intestinal perforation, and inpatient mortality. IBD and GAD are becoming increasingly common, which will likely lead to a larger number of complications among inpatients with these comorbidities.

Outcomes of Hospitalized Acute Alcoholic Hepatitis (AH) in Patients With Bipolar 1 Disorder (B1D).

INTRODUCTION: Alcoholic hepatitis (AH) is a common cause of hospital admissions and is associated with a high mortality rate. AH occurs frequently in patients with heavy alcohol use. Alcohol use disorder (AUD) commonly presents with comorbid psychiatric disorders such as bipolar disorder. Bipolar disorder patients are also known to be at an increased risk for chronic liver diseases. Bipolar 1 disorder (B1D) is often considered the most severe presentation among different types of bipolar disorder. This study assesses the clinical outcomes of patients admitted for AH with concomitant B1D. METHODS: Adult patients with AH were identified within the 2014 National Inpatient Sample (NIS) database. International Classification of Diseases, Ninth Edition Revision, Clinical Modification (ICD-9 CM) codes were used to select for all of the diagnoses for this study. AH patients were subdivided into those with and without B1D. The outcomes of interest were sepsis, hepatic encephalopathy, acute respiratory failure, acute kidney injury, ischemic stroke, hepatic failure, coagulopathy, and inpatient mortality. A multivariate logistic regression analysis was performed to explore whether B1D is an independent predictor for the outcomes. RESULTS: Among 4,453 patients with AH identified, 166 patients also had B1D. AH patients with comorbid B1D were seen to be younger (42.9 years old vs. 46.2 years old, p < 0.05) and more commonly female (55.4% vs. 36.5%, p < 0.05). The B1D subgroup of AH patients were found to less likely develop acute hepatic failure (adjusted odds ratio (aOR) 0.13, 95% confidence interval (CI): 0.02-0.97, p < 0.05). The adjusted odds ratios for the remaining outcomes were not statistically significant. CONCLUSIONS: Our study indicates that B1D may be an independent protective factor against acute hepatic failure in patients hospitalized with AH. This finding can be explained by frequent laboratory monitoring and psychiatric assessments performed by psychiatrists treating B1D patients, as well as the impact B1D has on cortisol release induced by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis.

Outcomes of Upper Gastrointestinal Bleeding in Hospitalized Patients With Generalized Anxiety Disorder.

Background Upper gastrointestinal bleeding (UGIB) has a high morbidity and mortality. Social deprivation is a risk factor for UGIB and is associated with anxiety. The primary pharmaceutical therapeutic agents for anxiety are selective serotonin reuptake inhibitors. Anxiety is prevalent in the general population and generalized anxiety disorder (GAD) is a common form of anxiety. This study explores the impact of GAD on the outcomes of adult patients hospitalized with UGIB. Methods Adult UGIB patients were selected utilizing the National (Nationwide) Inpatient Sample database from year 2014 and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The outcomes of UGIB patients with and without GAD were investigated. The outcomes explored include inpatient mortality, hypotension/shock, acute renal failure, acute hepatic failure, acute respiratory failure and acute myocardial infarction. A multivariate logistic regression analysis was used to determine if GAD is an independent predictor of the outcomes. Results Among 19,850 UGIB patients studied, 2357 had comorbid GAD. GAD was identified as a risk factor for acute renal failure (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 1.30-1.57, p < 0.05) and inpatient mortality (aOR 1.50, 95% CI 1.01-2.06, p < 0.05). The aORs of hypotension/shock, acute hepatic failure, acute respiratory failure and acute myocardial infarction were not statistically significant. Conclusion UGIB patients with comorbid GAD are at elevated risk of inpatient mortality and acute renal failure. These results may gain increasing relevance as GAD prevalence has increased since the start of the coronavirus disease 2019 (COVID-19) pandemic.

Monitoring of Leukemia Clones in B-cell Acute Lymphoblastic Leukemia at Diagnosis and During Treatment by Single-cell DNA Amplicon Sequencing.

Acute lymphoblastic leukemia (ALL) is characterized by the presence of chromosomal changes, including numerical changes, translocations, and deletions, which are often associated with additional single-nucleotide mutations. In this study, we used single cell-targeted DNA sequencing to evaluate the clonal heterogeneity of B-ALL at diagnosis and during chemotherapy treatment. We designed a custom DNA amplicon library targeting mutational hotspot regions (in 110 genes) present in ALL, and we measured the presence of mutations and small insertions/deletions (indels) in bone marrow or blood samples from 12 B-ALL patients, with a median of 7973 cells per sample. Nine of the 12 cases showed at least 1 subclonal mutation, of which cases with PAX5 alterations or high hyperdiploidy (with intermediate to good prognosis) showed a high number of subclones (1 to 7) at diagnosis, defined by a variety of mutations in the JAK/STAT, RAS, or FLT3 signaling pathways. Cases with RAS pathway mutations had multiple mutations in FLT3, NRAS, KRAS, or BRAF in various clones. For those cases where we detected multiple mutational clones at diagnosis, we also studied blood samples during the first weeks of chemotherapy treatment. The leukemia clones disappeared during treatment with various kinetics, and few cells with mutations were easily detectable, even at low frequency (<0.1%). Our data illustrate that about half of the B-ALL cases show >2 subclones at diagnosis and that even very rare mutant cells can be detected at diagnosis or during treatment by single cell-targeted DNA sequencing.

A Case of False-positive Amphetamine Results on Urine Toxicology Testing Secondary to Imatinib.

In this case report, we describe a case of imatinib leading to a false-positive amphetamine result on urine drug testing. A 21-year-old female with chronic myelocytic leukemia and in recovery from opioid use disorder reinitiated imatinib maintenance therapy in her third trimester, after previous discontinuation at the beginning of pregnancy. Subsequently, she had multiple presumptive immunoassay-based urine drug tests that resulted positive for amphetamines. The infant's meconium testing was negative for amphetamines, as was maternal definitive testing using urine gas chromatography-mass spectrometry. She had no history of stimulant use and denied any substance use during her pregnancy. Imatinib and/or its metabolites may be responsible for cross-reactivity with urine drug immunoassays leading to a false-positive result for amphetamine.

A Comparison of Coronary Artery Stenosis Estimates Made by Forensic Pathologists and Medical Students.

Previous studies suggest cardiovascular pathologists are less accurate than noncardiovascular pathologists (e.g., clinical pathologists) in estimating the degree of coronary artery stenosis. To further investigate the effect of training on accurate estimation of coronary artery stenosis, we designed a study to compare the accuracy of estimates made by forensic pathologists versus medical students. Six forensic pathologists and twelve medical students each independently examined 24 images of coronary artery cross sections and gave an estimate of the degree of stenosis. When comparing all 24 images, the forensic pathologists had a median difference between the estimated percentage of stenosis and actual percentage of stenosis of -12.380 and the medical students had a median difference of -16.50 (p-value of 0.08542). In estimating the percentage of stenosis, training in forensic pathology does not guarantee significantly improved accuracy compared with medical students. Our study showed no consistent statistically significant difference between estimates given by forensic pathologists and by medical students.

Educational Case: Death Certification and the Role of the Medical Examiner/Coroner.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

The Elephant in the Room: Outbreak of Carfentanil Deaths in Minnesota and the Importance of Multiagency Collaboration.

Over a three-month period in early 2017, the Hennepin County Medical Examiner's Office investigated nine apparent opioid toxicity deaths that occurred in three separate urban, suburban, and rural counties in our jurisdiction. All decedents were known substance abusers and had reportedly recently used heroin; most were found with drug paraphernalia. Complete autopsies variably showed classic stigmata of opioid overdose with no significant injury or natural disease to explain death. Initial toxicology screens failed to identify heroin or other narcotic substances. Several cases were presumptively positive for fentanyl by immunoassay, yet failed to confirm positive for fentanyl. Following American Board of Forensic Toxicology reporting standards, these cases were reported as negative for fentanyl by the laboratory. Due to the discrepant scene and toxicology findings suggestive of an opioid toxicity death, further discussion between the medical examiners and toxicologists prompted additional testing at a referral laboratory. This resulted in quantifiable blood carfentanil in all cases (mean 0.26 ng/mL, range 0.12 - 0.64 ng/mL). Cointoxicants included ethanol (n=2), methamphetamine (n=3), benzodiazepines (n=3), and cocaine (n=1). No case had definitive evidence of acute heroin intoxication, but two cases had low concentrations of morphine present (0.03 and 0.06 ng/mL), and two others had 6-monoacetyl morphine in the urine without morphine in the blood, suggesting recent use. All deaths were certified as accidental acute or mixed carfentanil toxicity. These cases present additional information about carfentanil-related deaths and highlight the importance of collaboration between forensic pathologists and toxicologists.

Therapeutic effects of the euglenoid ichthyotoxin, euglenophycin, in colon cancer.

Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and the 3rd leading cause of cancer-related mortality. The emergence of drug resistance poses a major challenge in CRC care or treatment. This can be addressed by determining cancer mechanisms, discovery of druggable targets, and development of new drugs. In search for novel agents, aquatic microorganisms offer a vastly untapped pharmacological source that can be developed for cancer therapeutics. In this study, we characterized the anti-colorectal cancer potential of euglenophycin, a microalgal toxin from Euglena sanguinea. The toxin (49.1-114.6 µM) demonstrated cytotoxic, anti-proliferative, anti-clonogenic, and anti-migration effects against HCT116, HT29, and SW620 CRC cells. We identified G1 cell cycle arrest and cell type - dependent modulation of autophagy as mechanisms of growth inhibition. We validated euglenophycin's anti-tumorigenic activity in vivo using CRL:Nu(NCr)Foxn1nu athymic nude mouse CRC xenograft models. Intraperitoneal toxin administration (100 mg/kg; 5 days) decreased HCT116 and HT29 xenograft tumor volumes (n=10 each). Tumor inhibition was associated with reduced expression of autophagy negative regulator mechanistic target of rapamycin (mTOR) and decreased trend of serum pro-inflammatory cytokines. Together, these results provide compelling evidence that euglenophycin can be a promising anti-colorectal cancer agent targeting multiple cancer-promoting processes. Furthermore, this study supports expanding natural products drug discovery to freshwater niches as prospective sources of anti-cancer compounds.

Acute Low-Dose Hydralazine-Induced Lupus Pneumonitis.

A 35-year-old female was started on hydralazine 10 mg orally three times a day for treatment of postpartum hypertension. Three months later, after multiple unsuccessful courses of prednisone and antibiotics for presumed pneumonia and asthma exacerbations, her respiratory symptoms progressed in severity and she developed resting hypoxia. Previous diagnostic work-up included spirometry with a restrictive pattern, chest CT showing bilateral basilar consolidation, negative BAL, and nonspecific findings on lung biopsy of mild inflammatory cells. Review of systems was positive for arthralgia, lymphadenopathy, paresthesia, and fatigue that began four weeks after starting hydralazine. A clinical diagnosis of hydralazine-induced lupus (HIL) with pneumonitis was made. Antihistone antibodies were positive supporting a diagnosis of HIL. Management included cessation of hydralazine and a prolonged steroid taper. Within days, patient began improving symptomatically. Six weeks later, CT chest showed complete resolution of infiltrates. Genetic testing revealed she was heterozygous for N-acetyltransferase 2 (intermediate acetylator). Drug-induced lupus should be considered in patients with lupus-like symptoms taking medications with a known association. While the majority of HIL cases occur with high doses and prolonged treatment, cases of low-dose HIL have been reported in patients who are slow acetylators.

Subarachnoid Hemorrhage Related to Ruptured Berry Aneurysm.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Addison Disease: The First Presentation of the Condition May be at Autopsy.

Addison disease is chronic primary adrenal insufficiency, which, in developed countries, is most commonly due to autoimmune destruction of the cortex (termed autoimmune or idiopathic Addison disease). Although the disease process has some classic features, such as increased pigmentation, salt craving, and signs and symptoms related to decreased blood pressure, the initial clinical presentation may be vague and/or insidious. Following an acute stressor such as a gastrointestinal (GI) infection, the patient may experience an adrenal crisis, which can cause sudden death. As such, knowledge of this disease process and the diagnostic criteria in the postmortem period is essential for the practicing forensic pathologist. The diagnosis of autoimmune Addison disease at autopsy is aided by several factors including 1) history, including salt craving, features consistent with orthostatic hypotension, and GI complaints including nausea, vomiting and pain, 2) physical examination findings of increased pigmentation and small or unidentifiable adrenal glands, 3) serologic testing for 21-hydroxylase antibodies, 4) serum cortisol concentrations, and 5) vitreous electrolyte testing. While the listed historical information, the increased pigmentation, decreased serum cortisol concentrations, and evidence of hyponatremia may be found in all forms of Addison disease, small or unidentifiable adrenal glands and 21-hydroxylase antibodies are found exclusively in the autoimmune form of Addison disease. While other causes of Addison disease, such as tuberculosis, metastatic tumor, or other infiltrative processes would have enlarged adrenal glands, these diseases would lack 21-hydroxylase antibodies. The purpose of this paper is to focus on the diagnosis of autoimmune Addison disease.