FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

BACKGROUND: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. METHODS: Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. RESULTS: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. CONCLUSIONS: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

Thrombotic Microangiopathy and Acute Tubular Injury After Diethylene Glycol Ingestion: A Kidney Biopsy Teaching Case.

We present a rare and unusual case of thrombotic microangiopathy (TMA) in a patient who ingested chafing fuel containing diethylene glycol. The patient showed a typical clinical course of initial gastrointestinal symptoms followed by acute kidney injury (AKI) and peripheral sensorimotor neuropathy. A kidney biopsy showed TMA and diffuse acute tubular injury. Diethylene glycol is widely used as a solvent in numerous consumer products, including brake fluid, antifreeze, chafing fuel, and artificial fog solutions. Diethylene glycol has been implemented in mass poisonings, and the incidence of AKI in diethylene glycol poisonings is linked to high-mortality rates. TMA, a pathologic lesion observed in a wide spectrum of diseases, is triggered by endothelial injury. Our case shows that TMA should be considered as a possible life-threatening complication in the setting of acute diethylene glycol poisoning. Direct toxic injury to endothelial cells by diethylene glycol is a possible mechanism. It is therefore plausible that patients with a genetic predisposition to endothelial injury may develop TMA following diethylene glycol exposure.

Interval appendicitis shows histological differences from acute appendicitis and may mimic Crohn disease and other forms of granulomatous appendicitis.

AIMS: While patients presenting with clinical signs and symptoms of acute appendicitis (AA) often receive surgical intervention shortly after presentation, certain patients may instead receive non-operative management initially, with appendectomy later. The histology of such interval appendicitis (IA) has only been described in small series. Also, we have noticed a recent increase in the incidence of IA specimens at our institution. METHODS AND RESULTS: We identified appendectomy specimens in our department during 2018 with available haematoxylin and eosin slides and electronic clinical data, and evaluated multiple histological findings. Cases were then divided into AA and IA, based on clinical history (AA if the patient presented to the hospital within 1 week of symptom onset and underwent appendectomy within 48 h; IA if appendectomy was delayed at least 1 week). Changes between groups were compared. The cohort included 165 cases (125 AA, 40 IA). Findings significantly more common in AA included mucosal acute inflammation, mural acute inflammation and acute serositis. Findings significantly more common in IA included Crohn-like mural inflammation, mural fibrosis, goblet cell hyperplasia, granulomas, xanthogranulomatous inflammation, haemosiderin-laden macrophages and granulation tissue. The rate of IA in 2018 (24%) was noticeably higher than in previous years. CONCLUSION: Acute inflammatory changes are more common in AA but can remain present in IA. Mural fibrosis, serosal adhesions, haemosiderin-laden macrophages and granulation tissue suggest IA. Granulomas and xanthogranulomatous inflammation can also be seen in IA, and Crohn-like mural inflammation is not uncommon. These histological patterns can guide signout and prevent diagnostic errors, particularly when clinical information is unavailable.

EUS imaging for the diagnosis of nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: EUS is increasingly used to evaluate patients with liver disease, but its role in assessing hepatic steatosis has not been reported. The goal of our study was to assess the accuracy of EUS for diagnosing hepatic steatosis. METHODS: We identified all patients who underwent EUS-guided liver biopsy sampling at our institution. All digitally stored EUS liver images were reviewed by a single radiologist, who rated the severity of liver echogenicity using a 4-point US scale. Liver biopsy specimens for all study patients were reviewed by a single liver pathologist, who rated them for steatosis and fibrosis using Nonalcoholic Steatohepatitis Clinical Research Network criteria. Receiver operator characteristic curves were used to assess the diagnostic accuracy of EUS for hepatic steatosis for all patients and in a subgroup analysis for obese and nonobese patients. RESULTS: During the study period, 76 patients underwent EUS-guided liver biopsy sampling. The average age of study patients was 56.5 years, 50% were women, and 43.2% were obese. The accuracy for EUS for the diagnosis of hepatic steatosis was .8 (95% confidence interval [CI], .7-.89). The accuracy of EUS for the diagnosis of hepatic steatosis in obese patients was .93 (95% CI, .8-.99) and in nonobese patients was .69 (95% CI, .54-.83). For obese patients, EUS had a positive predictive value of 89.7% and a negative predictive value of 75%. The finding of course echotexture on EUS had an accuracy of 79% for the diagnosis of grade 3 fibrosis or cirrhosis. CONCLUSIONS: EUS is a useful tool for the diagnosis of hepatic steatosis, particularly in obese patients in whom abdominal US has modest accuracy.

Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry.

The rate of syphilis in the United States has been increasing steadily in the past decade, but it remains an uncommon diagnosis in tissue biopsies. Most of the pathology literature on hepatic syphilis consists of older series or case reports. This study aimed to systematically characterize the histologic spectrum of hepatic syphilis in a contemporary cohort. Clinicopathologic features of 14 hepatic syphilis cases between 2012 and 2018 were analyzed to characterize the broad spectrum of histologic changes. Thirteen patients were men (age range: 19 to 59 y); 6 had known human immunodeficiency virus, 7 were men known to have sex with men, and no patient had known prior syphilis. Hepatic syphilis was the primary clinical suspicion in only 1 patient. Common symptoms included jaundice, rash, and abdominal pain. Thirteen had elevated transaminases, and 12 had elevated alkaline phosphatase. Pathologic changes were grouped into 5 histologic patterns: biliary-pattern injury (n=5), acute hepatitis (n=4), autoimmune hepatitis-like (n=1), fibroinflammatory mass-forming lesion (n=2), and no particular pattern (n=2). Nearly all showed portal and lobular lymphocytes and plasma cells; 12 had prominent histiocytes/Kupffer cells, 9 had ductular reaction, and 7 had duct inflammation. Occasional focal findings included dropout (n=7), phlebitis (n=7), and loose granulomata (n=5). Treponeme immunohistochemistry was positive in 10 and negative in 4, though treatment was given before biopsy in 3 of those 4. Thirteen patients had rapid plasma reagin testing either before or after biopsy, with 1:64 or higher titer. All patients who received treatment recovered. Hepatic syphilis is rare but likely underrecognized. It exhibits a variety of histologic appearances and therefore should be considered in several hepatic differential diagnoses, especially in men who have sex with men. Kupffer cells, granulomata, and phlebitis may suggest the diagnosis regardless of predominant histologic pattern. Negative treponeme immunohistochemical staining does not exclude the diagnosis, including in untreated patients.

Case Report: Refractory Cryptosporidiosis after CAR T-Cell Therapy for Lymphoma.

Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post-chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non-HIV-infected immunosuppressed host.

Durable Response to PD-1 Blockade in a Patient With Metastatic Pancreatic Undifferentiated Carcinoma With Osteoclast-Like Giant Cells.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare and potentially aggressive variant of pancreatic ductal adenocarcinoma. Data on this disease are sparse, and despite genetic similarities to pancreatic ductal adenocarcinoma, UCOGC clinical outcomes can be markedly different. We report on a female patient aged 62 years who presented with UCOGC with pulmonary metastases initially treated with 2 lines of cytotoxic chemotherapy. After rapid disease progression with both cytotoxic treatments, the patient's tissue was sent for next-generation sequencing, which revealed a high tumor mutation burden (32 mutations per megabase), as well as somatic mutations in BRAF, NF1, PIK3CA, CDKN2A, TERT, and TP53. Pancreatic cancers have previously demonstrated suboptimal responses to immunotherapeutic approaches. However, given the high tumor mutation burden and distinctiveness of the tumor class, the patient began third-line pembrolizumab monotherapy after palliative radiation to the rapidly progressing and painful abdominal mass from her primary tumor. She had a marked response in her primary UCOGC tumor and metastatic sites, and she remains on pembrolizumab monotherapy with ongoing response after 32 months of therapy. Recent evidence showing significant PD-L1 enrichment on neoplastic cells of undifferentiated carcinomas (including UCOGC) may indicate a role for immunotherapeutic approaches in these patients. Rare cancers such as UCOGC and other undifferentiated carcinomas may benefit from next-generation sequencing to inform treatment decisions when standards of care are absent, as in this report.

Cathelicidin Mediates a Protective Role of Vitamin D in Ulcerative Colitis and Human Colonic Epithelial Cells.

BACKGROUND: Vitamin D plays a protective role in ulcerative colitis (UC) patients through unclear mechanisms. Cathelicidin is an antimicrobial peptide induced by 1,25(OH)D2. Our goal was to evaluate the link between cathelicidin and vitamin D-associated clinical outcomes in UC patients, explore vitamin D induction of cathelicidin in human colon cells, and evaluate the effects of intrarectal human cathelicidin on a murine model of colitis. METHODS: Serum and colonic cathelicidin levels were measured in UC patients and correlated with clinical and histologic outcomes. Human colon cells were treated with 1,25(OH)2D and production of cathelicidin and cytokines were quantified. Antimicrobial activity against Escherichia coli from cell culture supernatants was measured. Mice were treated with intrarectal cathelicidin, and its effects on DSS colitis and intestinal microbiota were evaluated. RESULTS: In UC patients, serum 25(OH)D positively correlated with serum and colonic cathelicidin. Higher serum cathelicidin is associated with decreased risk of histologic inflammation and clinical relapse but not independent of 25(OH)D or baseline inflammation. The 1,25(OH)2D treatment of colon cells induced cathelicidin and IL-10, repressed TNF-α, and suppressed Escherichia coli growth. This antimicrobial effect was attenuated with siRNA-cathelicidin transfection. Intrarectal cathelicidin reduced the severity of DSS colitis but did not mitigate the impact of colitis on microbial composition. CONCLUSIONS: Cathelicidin plays a protective role in 25(OH)D-associated UC histologic outcomes and murine colitis. Cathelicidin is induced by vitamin D in human colonic epithelial cells and promotes antimicrobial activity against E. coli. Our study provides insights into the vitamin D-cathelicidin pathway as a potential therapeutic target.

A randomized trial of two methods to disclose prognosis to surrogate decision makers in intensive care units.

RATIONALE: Surrogate decision makers and clinicians often have discordant perceptions about a patient's prognosis. There is a paucity of empirical data to guide communication about prognosis. OBJECTIVES: To assess: (1) whether numeric or qualitative statements more reliably convey prognostic estimates; and (2) whether surrogates believe physicians' prognostic estimates. METHODS: A total of 169 surrogate decision makers for intensive care unit patients were randomized to view 1 of 2 versions of a video portraying a simulated family conference involving a hypothetical patient. The videos varied only by whether prognosis was conveyed in numeric terms ("10% chance of surviving") or qualitative terms ("very unlikely" to survive). MEASUREMENTS AND MAIN RESULTS: We assessed: (1) surrogates' personal estimates of the patient's prognosis; and (2) surrogates' understanding of the physician's prognostic estimate. Neither surrogates' personal estimates nor their understanding of the physician's prognostication differed when prognosis was conveyed numerically versus qualitatively (surrogates' estimate, 22 ± 23% chance of survival versus 26 ± 24%, P = 0.26; understanding of physician's estimate, 17 ± 22% chance of survival versus 16 ± 17%, P = 0.62). One in five surrogates estimated the patient's prognosis was greater than 20% more optimistic than the physician's prognostication. Less trust in physicians was associated with larger discrepancies between surrogates' personal estimates and their understanding of the physician's estimate. CONCLUSIONS: Neither numeric nor qualitative statements reliably convey news of a poor prognosis to surrogates in intensive care units. Many surrogates do not view physicians' prognostications as absolutely accurate. Factors other than ineffective communication may contribute to physician-surrogate discordance about prognosis.

"It's not just what the doctor tells me:" factors that influence surrogate decision-makers' perceptions of prognosis.

OBJECTIVE: Physicians and surrogate decision-makers for seriously ill patients often have different views of patients' prognoses. We sought to understand what sources of knowledge surrogates rely on when estimating a patient's prognosis. DESIGN: Prospective, mixed-methods study using face-to-face, semistructured interviews with surrogate decision-makers. SETTING: Four intensive care units at the University of California, San Francisco Medical Center in 2006 to 2007. PARTICIPANTS: Participants were 179 surrogate decision-makers for 142 incapacitated, critically ill patients at high risk for death. MAIN RESULTS: Less than 2% (3 of 179) of surrogates reported that their beliefs about the patients' prognoses hinged exclusively on prognostic information provided to them by physicians. The majority cited other factors in addition to physicians' predictions that also contributed to their beliefs about the patients' prognoses, including perceptions of the patient's individual strength of character and will to live; the patient's unique history of illness and survival; the surrogate's own observations of the patient's physical appearance; the surrogate's belief that their presence at the bedside may improve the prognosis; and the surrogate's optimism, intuition, and faith. For some surrogates, these other sources of knowledge superseded the importance of the physician's prognostication. However, most surrogates endeavored to balance their own knowledge of the patient with physicians' biomedical knowledge. CONCLUSIONS: Surrogates use diverse types of knowledge when estimating their loved ones' prognoses, including individualized attributes of the patient, such as their strength of character and life history, of which physicians may be unaware. Attention to these considerations may help clinicians identify and overcome disagreements about prognosis.

Expanding the paradigm of the physician's role in surrogate decision-making: an empirically derived framework.

BACKGROUND: Little is known about what role physicians take in the decision-making process about life support in intensive care units. OBJECTIVE: To determine how responsibility is balanced between physicians and surrogates for life support decisions and to empirically develop a framework to describe different models of physician involvement. DESIGN: Multi-centered study of audio-taped clinician-family conferences with a derivation and validation cohort. SETTING: Intensive care units of four hospitals in Seattle, Washington, in 2000 to 2002 and two hospitals in San Francisco, California, in 2006 to 2008. PARTICIPANTS: Four hundred fourteen clinicians and 495 surrogates who were involved in 162 life support decisions. RESULTS: In the derivation cohort (n = 63 decisions), no clinician inquired about surrogates' preferred role in decision-making. Physicians took one of four distinct roles: 1) informative role (7 of 63) in which the physician provided information about the patient's medical condition, prognosis, and treatment options but did not elicit information about the patient's values, engage in deliberations, or provide a recommendation about whether to continue life support; 2) facilitative role (23 of 63), in which the physician refrained from providing a recommendation but actively guided the surrogate through a process of clarifying the patients' values and applying those values to the decision; 3) collaborative role (32 of 63), in which the physician shared in deliberations with the family and provided a recommendation; and 4) directive role (1 of 63), in which the physician assumed all responsibility for, and informed the family of, the decision. In 10 out of 20 conferences in which surrogates requested a recommendation, the physician refused to provide one. The validation cohort revealed a similar frequency of use of the four roles, and frequent refusal by physicians to provide treatment recommendations. CONCLUSIONS: There is considerable variability in the roles physicians take in decision-making about life support with surrogates but little negotiation of desired roles. We present an empirically derived framework that provides a more comprehensive view of physicians' possible roles.

Surrogate decision-makers' perspectives on discussing prognosis in the face of uncertainty.

RATIONALE: Many physicians are reluctant to discuss a patient's prognosis when there is significant prognostic uncertainty. OBJECTIVES: We sought to understand surrogate decision makers' views regarding whether physicians should discuss prognosis in the face of uncertainty. METHODS: We conducted semi-structured interviews with 179 surrogates for 142 incapacitated patients at high risk of death in four intensive care units at an academic medical center. The interviews explored surrogates' attitudes about whether physicians should discuss prognosis when they cannot be certain their prognostic estimates are correct. We used constant comparative methods to analyze the transcripts. Validation methods included triangulation by multidisciplinary analysis and member checking. MEASUREMENTS AND MAIN RESULTS: Eighty-seven percent (155/179) of surrogates wanted physicians to discuss an uncertain prognosis. We identified five main reasons for this, including surrogates' belief that prognostic uncertainty is unavoidable, that physicians are their only source for prognostic information, and that discussing prognostic uncertainty leaves room for realistic hope, increases surrogates' trust in the physician, and signals a need to prepare for possible bereavement. Twelve percent (22/179) of surrogates felt that discussions about an uncertain prognosis should be avoided. The main explanation was that it is not worth the potential emotional distress if the prognostications are incorrect. Surrogates suggested that physicians should explicitly discuss uncertainty when prognosticating. CONCLUSIONS: The majority of surrogates of patients that are critically ill want physicians to disclose their prognostic estimates even if they cannot be certain they are correct. This stems from surrogates' belief that prognostic uncertainty is simultaneously unavoidable and acceptable.

Hope, truth, and preparing for death: perspectives of surrogate decision makers.

BACKGROUND: Although many physicians worry that openly discussing a poor prognosis will cause patients and families to lose hope, surrogate decision makers' perspectives on this topic are largely unknown. OBJECTIVE: To determine surrogate decision makers' attitudes toward balancing hope and telling the truth when discussing prognosis. DESIGN: Prospective, mixed-methods cohort study. SETTING: 4 intensive care units at the University of California, San Francisco, Medical Center, San Francisco, California. PARTICIPANTS: 179 surrogate decision makers for incapacitated patients at high risk for death. MEASUREMENTS: One-on-one, semistructured interviews with surrogates were conducted on the patients' 5th day of receiving mechanical ventilation. Constant comparative methods were used to inductively develop a framework to describe participants' responses. Validation methods included multidisciplinary analysis and member checking. RESULTS: Overall, 93% (166 of 179) of surrogates felt that avoiding discussions about prognosis is an unacceptable way to maintain hope. The main explanatory theme was that timely discussion of prognosis is essential to allow family members to prepare emotionally and logistically for the possibility of a patient's death. Other themes that emerged included surrogates' belief that an accurate understanding of a patient's prognosis allows them to better support the patient and each other, a moral aversion to the idea of false hope, the perception that physicians have an obligation to discuss prognosis, and the notion that some surrogates look to physicians primarily for truth and seek hope elsewhere. A few surrogates (6 of 179) felt that physicians should withhold prognostic information because of a belief that discussing death could be emotionally damaging to the family or could negatively affect the patient's health. LIMITATION: The authors did not longitudinally assess whether early disclosure about prognosis predicts fewer adverse bereavement outcomes. CONCLUSION: Most surrogates of critically ill patients do not view withholding prognostic information as an acceptable way to maintain hope, largely because timely discussions about prognosis help families begin to prepare emotionally, existentially, and practically for the possibility that a patient will die.