Proton beam stereotactic body radiotherapy and hypofractionated therapy with pencil beam scanning is safe and effective for advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A single center experience.

Background: Proton beam therapy (PBT) is a non-surgical treatment that spares adjacent tissues compared to photon radiation and useful for Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). We present a single center experience in HCC and iCCA treated with Pencil Beam Scanning (PBS) PBT. Methods: Forty-four consecutive patients (22 patients in each group) receiving PBT were included and reviewed. PBT was delivered with hypofractionated or stereotactic body radiation therapy (SBRT) using PBS. Tumor size was approximated by clinical target volume (CTV). Outcomes were evaluated with Kaplan-Meier and liver toxicity was determined by MELD-Na and albumin-bilirubin (ALBI) grade. Results: Median follow up was 38.7 months, fourteen (35%) had multifocal disease and median CTV was 232.5cc. Four (9%) and 40 (91%) patients received SBRT and hypofractionated radiation, respectively. Two year overall survival was statistically higher for HCC (entire group: 68.9% months [95% CI: 61.3 - 76.3%]; iCCA: 49.8% [95% CI: 38.5% - 61.1%]; HCC: 89.4% [95% CI: 82.3 - 96.5%]; P <0.005). There was no statistical difference in progression-free survival or freedom from local failure. Biologically Equivalent Dose (BED) was greater than or equal to 80.5Gy in 37 (84%) patients. All iCCA patients had stable or improved ALBI grade following treatment. ALBI grade was stable in 83% of HCC patients and average MELD-Na score remained stable. Tumor size, pretreatment liver function, and total radiation dose were not associated with liver toxicity. Conclusions: PBT for unresectable HCC and iCCA is safe and effective, even for large and multifocal tumors. Liver function was preserved even in those with baseline cirrhosis in this advanced population with large tumors.

Impact of Inflammatory Bowel Disease Subtypes on the Post-liver Transplant Outcomes of Patients with Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Liver transplant patients with primary sclerosing cholangitis often present with concurrent inflammatory bowel disease. The effect of comorbid conditions on post-transplant prognosis was evaluated. METHODS: The 2005-2019 United Network of Organ Sharing Standard Transplant Analysis and Research database was used to identify patients with primary sclerosing cholangitis. Patients were categorized as having Crohn's Disease, ulcerative colitis, unclassified inflammatory bowel disease, or no inflammatory bowel disease. Baseline characteristics were assessed between cohorts, and outcomes were examined using Cox regression. Outcomes included all-cause mortality, graft failure, infection-induced mortality, and organ system-delineated mortality. Supplementary analyses with unique exclusion and stratification criteria were also performed. RESULTS: Among 2829 patients undergoing transplant, 1360 were considered to have ulcerative colitis, 372 were considered to have Crohn's Disease, and 69 were considered to have an unclassified form of inflammatory bowel disease. Primary sclerosing cholangitis patients with some form of inflammatory bowel disease had no increased risk for any outcomes. However, patients with ulcerative colitis had lower risks of general infectious (aHR 0.65 95%CI 0.44-0.95) and sepsis-induced (aHR 0.56 95%CI 0.35-0.91) mortality, whereas patients with Crohn's Disease had higher risks of sepsis-induced mortality (aHR 2.13 95%CI 1.22-3.70). Supplementary analyses showed effect modification by abdominal surgery history and era. CONCLUSION: The type of inflammatory bowel disease in liver transplant patients with primary sclerosing cholangitis was found to portend risk difference for infection-induced mortality, with ulcerative colitis found to be protective and Crohn's Disease predictive of increased mortality secondary to infectious etiologies. These associations warrant further investigation.

A Systematic Review of Crohn's Disease Case Definitions in Administrative or Claims Databases.

BACKGROUND: We sought to review Crohn's disease (CD) case definitions that use diagnosis, procedure, and medication claims. METHODS: We searched PubMed and Embase from inception through January 31, 2022, using terms related to CD, inflammatory bowel disease, administrative claims, or validity. Each article was scrutinized by 2 authors independently screening and abstracting data. Collected data included participant characteristics, case definition characteristics, and case definition validity. When diagnostic accuracy was provided for multiple case definitions, we extracted the case definition selected by the authors. All diagnostic accuracy characteristics were captured. RESULTS: We identified 30 studies that evaluated a case definition using claims data to identify CD patients. The most common case definition included counts of diagnosis codes (57%) followed by a combination of diagnosis codes and medications (20%). All but 1 study validated the case definition with a medical chart review. In 2 studies, the patient's primary care provider completed a survey to confirm disease status. The positive predictive value of the case definitions ranged from 18% (≥1 code at a single U.S. health plan) to 100% (≥1 code plus a relevant prescription at a U.S. hospital). More complex case definitions (eg, ≥1 code + prescription or ≥2 codes) had lower variability in positive predictive value (≥80%) and specificity (≥85%) than the ≥1 code requirement. CONCLUSIONS: Health services researchers should validate case definitions in their research cohorts. When such validation cannot be performed, we recommend using a more complex case definition. Studies without a validated CD case definition should use sensitivity analyses to confirm the robustness of their results.

This systematic review of Crohn's disease (CD) case definitions identified that complex case definitions such as ≥1 diagnosis code + ≥1 prescription had desirable diagnostic accuracy properties.

The clinical implications of pre-liver transplant diabetes on post-liver transplant outcomes in patients with NASH: analysis of the UNOS database.

BACKGROUND AND AIMS: The presence of perioperative diabetes may lead to increased mortality risks following liver transplant (LT) in patients with non-alcoholic steatohepatitis (NASH). This risk factor was evaluated using a UNOS-STAR national database. METHODS: The UNOS-STAR liver transplant registry 2005-2019 was used to select patients with NASH (including cryptogenic liver disease). The following populations were excluded: those younger than 18 years old and those with living donors/dual transplants. Selected patients were stratified into those with and without pre-LT diabetes and compared to the individual mortality endpoints using iterative Cox analyses. RESULTS: 6324 recipients with and 8251 without diabetes were selected. The median follow-up time was 3.07 years. Those with diabetes were older (58.50 vs. 54.50 years, p < 0.001), were more likely to be Hispanic or Asian, and had higher BMI than the non-diabetics (31.10 vs. 29.70 kg/m2 p < 0.001); however, there was no difference in gender (female 41.9 vs. 43.1% p = 0.170). Compared to non-diabetics, recipients with diabetes had a higher rate of all-cause mortality (61.68 vs. 47.80 per 1000 person-years). In multivariate iterations, pre-LT diabetes was associated with all-cause mortality (aHR 1.19 95% CI 1.11-1.27) as well as deaths due to cardiac (p = 0.014 aHR 1.24 95% CI 1.04-1.46) and renal causes (p = 0.039 aHR 1.38 95% CI 1.02-1.87). CONCLUSION: The presence of pre-LT diabetes is associated with all-cause mortality and deaths due to cardiac and renal causes following LT. The findings warrant an early preoperative screening procedure to ensure that patients with diabetes have their metabolic risk factors optimized prior to LT.

Hepatitis C-positive donor liver transplantation for hepatitis C seronegative recipients.

BACKGROUND: The opioid crisis has led to an increase in hepatitis C virus-positive donors in the past decade. Whereas historically hepatitis C seropositive organs were routinely discarded, the advent of direct-acting antiviral agents has notably expanded the utilization of organs from donors with hepatitis C. There has been growing experience with liver transplantation (LT) from hepatitis C seropositive donors to hepatitis C seropositive recipients. However, data remain limited on LT from hepatitis C seropositive or hepatitis C ribonucleic acid positive donors to hepatitis C seronegative recipients. METHODS: We performed a retrospective study of 26 hepatitis C seronegative recipients who received hepatitis C seropositive donor livers followed by preemptive antiviral therapy with direct-acting antiviral treatment at the Johns Hopkins Hospital Comprehensive Transplant Center from January 1, 2017, to August 31, 2019. RESULTS: Twenty-five of the 26 recipients are alive with proper graft function; 20 of them received livers from hepatitis C nucleic acid testing positive donors. All 12 recipients who completed their direct-acting antiviral courses and have reached sufficient follow-up for sustained virologic response have achieved sustained virologic response. Nine of our recipients have either completed direct-acting antiviral treatment without sufficient follow-up time for sustained virologic response or are undergoing direct-acting antiviral treatment. One patient is awaiting antiviral treatment initiation pending insurance approval. Of note, 11 of 12 patients with sustained virologic response received a hepatitis C nucleic acid testing positive donor liver. CONCLUSION: Hepatitis C seronegative patients who receive a hepatitis C seropositive or hepatitis C nucleic acid testing positive liver allograft can enjoy good short-term outcomes with hepatitis C cure following direct-acting antiviral treatment.

Pseudomembranous colitis: Not always Clostridium difficile.

Although Clostridium difficile infection is the cause of most cases of pseudomembranous colitis, clinicians should consider less common causes, especially if pseudomembranes are seen on endoscopy but testing remains negative for C difficile or if presumed C difficile infection does not respond to treatment. Histologic review of colonic mucosal biopsy specimens can provide clues to the underlying cause.

Data regarding M1 muscarinic receptor-mediated modulation of hepatic catalase activity in response to oxidative stress.

We recently demonstrated the role of M1 muscarinic receptors (M1R) in modulating oxidative stress in liver and hepatocytes (Urrunaga et al., 2015) [1]. Here we provide data regarding the effect of a novel M1R agonist, VU0357017 (Lebois et al., 2010) [2], on H2O2-mediated hepatocyte injury, the effect of an M1R antagonist VU0255035 (Sheffler et al., 2009) [3] on catalase and super oxide dismutase (SOD) activities in H2O2-treated hepatocytes in vitro, and finally, the effect of M1R ablation on hepatic catalase activity in acetaminophen (APAP)-treated mice.

Prevalence, Severity, and Impact of Renal Dysfunction in Acute Liver Failure on the US Liver Transplant Waiting List.

BACKGROUND AND AIMS: Although renal dysfunction is a known complication of acute liver failure (ALF), its frequency, severity, and impact among patients with ALF on the US liver transplant list are not well defined. METHODS: Organ Procurement and Transplantation data for ALF patients listed as status 1/1A from 2002 to 2012 were analyzed. The frequency and severity of renal dysfunction at the time of listing [the latter was categorized in 5 stages using estimated GFR (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration creatinine 2009 equation] were determined and the association between renal dysfunction and waiting list mortality was assessed using Cox proportional hazard regression analysis. RESULTS: There were a total of 2280 adult patients with ALF, including 56 % with renal dysfunction (defined as eGFR < 60 ml/min/1.73 m(2)) at listing. The highest proportion of patients with renal dysfunction was among those with ALF caused by hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, fatty liver disease of pregnancy, heat stroke/hyperthermia, hepatitis A virus, and drug-induced liver injury due to acetaminophen APAP, phenytoin, trimethoprim-sulfamethoxazole, and macrolides. Despite the fact that 69 % (468/674) of patients with APAP-induced ALF listed as status 1/1A had renal dysfunction, only 0.9 % underwent simultaneous liver-kidney transplantation. Six-week survival probabilities in patients with ALF on the liver transplant waiting list were 71, 59, 56, 59, and 42 % with renal dysfunction stages of 1, 2, 3, 4, and 5, respectively. Multivariate analysis showed that after controlling for age, etiology of ALF, INR, total bilirubin, and region, the relative risk of death increased progressively as eGFR declined (P < 0.0001). CONCLUSIONS: Among patients with ALF on the liver transplant waiting list, renal dysfunction was common (overall prevalence of 56 %). Most importantly, severe renal dysfunction was associated with significantly increased mortality.

M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice.

Cholinergic nervous system regulates liver injury. However, the role of M1 muscarinic receptors (M1R) in modulating chronic liver injury is uncertain. To address this gap in knowledge we treated M1R-deficient and WT mice with azoxymethane (AOM) for six weeks and assessed liver injury responses 14 weeks after the last dose of AOM. Compared to AOM-treated WT mice, M1R-deficient mice had attenuated liver nodularity, fibrosis and ductular proliferation, α-SMA staining, and expression of α1 collagen, Tgfß-R, Pdgf-R, Mmp-2, Timp-1 and Timp-2. In hepatocytes, these findings were associated with reductions of cleaved caspase-3 staining and Tnf-α expression. In response to AOM treatment, M1R-deficient mice mounted a vigorous anti-oxidant response by upregulating Gclc and Nqo1 expression, and attenuating peroxynitrite generation. M1R-deficient mouse livers had increased expression of Trail-R2, a promotor of stellate cell apoptosis; dual staining for TUNNEL and α-SMA revealed increased stellate cells apoptosis in livers from M1R-deficient mice compared to those from WT. Finally, pharmacological inhibition of M1R reduced H2O2-induced hepatocyte apoptosis in vitro. These results indicate that following liver injury, anti-oxidant response in M1R-deficient mice attenuates hepatocyte apoptosis and reduces stellate cell activation, thereby diminishing fibrosis. Therefore, targeting M1R expression and activation in chronic liver injury may provide therapeutic benefit.

Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice.

Withaferin-A (WA) has anti-oxidant activities however, its therapeutic potential in acetaminophen (APAP) hepatotoxicity is unknown. We performed a proof-of-concept study to assess the therapeutic potential of WA in a mouse model that mimics APAP-induced liver injury (AILI) in humans. Overnight fasted C57BL/6NTac (5-6 wk. old) male mice received 200 mg/kg APAP intraperitoneally (i.p.). After 1 h mice were treated with 40 mg/kg WA or vehicle i.p., and euthanized 4 and 16 h later; their livers were harvested and serum collected for analysis. At 4 h, compared to vehicle-treated mice, WA-treated mice had reduced serum ALT levels, hepatocyte necrosis and intrahepatic hemorrhage. All APAP-treated mice had reduced hepatic glutathione (GSH) levels however, reduction in GSH was lower in WA-treated when compared to vehicle-treated mice. Compared to vehicle-treated mice, livers from WA-treated mice had reduced APAP-induced JNK activation, mitochondrial Bax translocation, and nitrotyrosine generation. Compared to vehicle-treated mice, WA-treated mice had increased hepatic up-regulation of Nrf2, Gclc and Nqo1, and down-regulation of Il-6 and Il-1ß. The hepatoprotective effect of WA persisted at 16 h. Compared to vehicle-treated mice, WA-treated mice had reduced hepatocyte necrosis and hepatic expression of Il-6, Tnf-α and Il-1ß, increased hepatic Gclc and Nqo1 expression and GSH levels, and reduced lipid peroxidation. Finally, in AML12 hepatocytes, WA reduced H2O2-induced oxidative stress and necrosis by preventing GSH depletion. Collectively, these data show mechanisms whereby WA reduces necrotic hepatocyte injury, and demonstrate that WA has therapeutic potential in AILI.

Renal dysfunction in cirrhosis.

PURPOSE OF REVIEW: Renal dysfunction causes significant morbidity in cirrhotic patients. Diagnosis is challenging because it is based on serum creatinine, which is used to calculate estimated glomerular filtration rate, which itself is not an ideal measure of renal function in patients with cirrhosis. Finding the exact cause of renal injury in patients with cirrhosis remains problematic due to the limitations of the current diagnostic tests. The purpose of this review is to highlight studies used to diagnose renal dysfunction in patients with renal dysfunction and review current treatments. RECENT FINDINGS: New diagnostic criteria and classification of renal dysfunction, especially for acute kidney injury (AKI), have been proposed in hopes of optimizing treatment and improving outcomes. New biomarkers that help to differentiate structural from functional AKI in cirrhotic patients have been developed, but require further investigation. Vasoconstrictors are the most commonly recommended treatment of hepatorenal syndrome (HRS). Given the high mortality in patients with type 1 HRS, all patients with HRS should be evaluated for liver transplantation. When renal dysfunction is considered irreversible, combined liver-kidney transplantation is advised. SUMMARY: Development of new biomarkers to differentiate the different types of AKI in cirrhosis holds promise. Early intervention in cirrhotic patients with renal dysfunction offers the best hope of improving outcomes.

M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury.

The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age-matched wild-type (WT) and M1R-deficient (Chrm1(-/-)) male mice were injected intraperitoneally with 200mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36h later. Biochemical and histological parameters indicated that liver injury peaked within 16h after APAP treatment and resolved by 24h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1α, Il-1ß, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP-induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1(-/-) and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury.

Pseudomembranous Colitis: Not Always Caused by Clostridium difficile.

Although classically pseudomembranous colitis is caused by Clostridium difficile, it can result from several etiologies. Certain medications, chemical injury, collagenous colitis, inflammatory bowel disease, ischemia, and other infectious pathogens can reportedly cause mucosal injury and subsequent pseudomembrane formation. We present the case of a middle-aged woman with vascular disease who was incorrectly diagnosed with refractory C. difficile infection due to the presence of pseudomembranes. Further imaging, endoscopy, and careful histopathology review revealed chronic ischemia as the cause of her pseudomembranous colitis and diarrhea. This case highlights the need for gastroenterologists to consider non-C. difficile etiologies when diagnosing pseudomembranous colitis.

Portal hypertensive gastropathy and colopathy.

Portal hypertensive gastropathy (PHG) and colopathy (PHC) are considered complications of portal hypertension. Both entities are clinically relevant because they may cause insidious blood loss or even acute massive gastrointestinal hemorrhage. Endoscopic evaluation is necessary for the diagnosis of PHG and PHC. The existence of different endoscopic criteria for PHG and PHC makes consensus difficult and results in a broad range of reported prevalence. Therapy targeted at reduction of portal pressure and mucosal blood flow has been used to treat acute bleeding; nonselective ß-blockers are the most frequently used agents. Further studies are needed to clarify the natural history, pathogenesis, and treatment of PHG and PHC.

Hemorrhagic ascites. Clinical presentation and outcomes in patients with cirrhosis.

BACKGROUND & AIMS: Hemorrhagic ascites can pose diagnostic and therapeutic dilemmas in patients with cirrhosis. We aimed at exploring the characteristics and outcomes of patients with cirrhosis and hemorrhagic ascites. METHODS: The records of all patients with cirrhosis and ascites, who underwent paracentesis between 2003 and 2010 at Parkland Memorial Hospital, were retrospectively reviewed. Hemorrhagic ascites was defined as an ascitic fluid red blood cell (RBC) count ≥ 10,000/µl. We compared each patient with 3 age- and gender-matched controls (cirrhotic patients with ascites and an ascitic RBC count <10,000/µl). Survival curves were generated using Kaplan-Meier plots and compared using the log rank test. RESULTS: 1113 cirrhotic patients underwent paracentesis; 214 (19%) had hemorrhagic ascites. Patients with hemorrhagic ascites had higher rates of spontaneous bacterial peritonitis (p <0.001), acute kidney injury (AKI, p <0.001), and were more likely to require intensive care unit (ICU)-level care (p=0.01) compared to patients without hemorrhagic ascites. Patients with hemorrhagic ascites had a higher mortality than controls at one month (87% vs. 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%). Using multivariate regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 1.34, 95% CI 1.07-1.68) after adjusting for the model for end-stage liver disease score (HR 1.04, 1.03-1.05), ICU-level care (HR 2.02, 1.63-2.51) and presence of hepatocellular carcinoma (HR 2.27, 1.61-3.19). CONCLUSIONS: Patients with hemorrhagic ascites had a significantly higher rate of ICU care, AKI, and mortality than patients with portal hypertension and ascites but without hemorrhagic ascites. We conclude that hemorrhagic ascites is a marker of advanced liver disease and poor outcome.