Mild Thrombocytopenia, a Predictor of Outcomes After Laparoscopic Cholecystectomy: Assessment of Surgical Risk in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: A common cause of mild thrombocytopenia is chronic liver disease, the most common etiology being metabolic dysfunction-associated steatotic liver disease (MASLD). Mild thrombocytopenia is a well-defined, independent marker of hepatic fibrosis in patients with chronic liver disease. Currently, there is a paucity of information available to characterize perioperative risk in patients with MASLD; therefore, the characterization of perioperative morbidity is paramount. We used a platelet threshold of 150×10 9 as a surrogate for fibrosis in patients undergoing laparoscopic cholecystectomy to study its effect on perioperative complications and mortality. PATIENTS AND METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for laparoscopic cholecystectomies occurring from 2005 through 2018. Demographic differences between patients with and without thrombocytopenia were evaluated using the t test or the χ 2 test, whereas adjusted and unadjusted differences in outcome risk were evaluated using log-binomial regression models. RESULTS: We identified 437,630 laparoscopic cholecystectomies of which 6.9% included patients with thrombocytopenia. Patients with thrombocytopenia were more often males, older, and with chronic disease. Patients with thrombocytopenia and higher Aspartate Aminotransferase to Platelet Ratio Index scores had 30-day mortality rates risk ratio of 5.3 (95% CI: 4.8-5.9), with higher complication rates risk ratio of 2.4 (95% CI: 2.3-2.5). The most frequent complications included the need for transfusion, renal, respiratory, and cardiac. CONCLUSIONS: Perioperatively, patients with mild thrombocytopenia undergoing laparoscopic cholecystectomy had higher mortality rates and complications compared with patients with normal platelet counts. Thrombocytopenia may be a promising, cost-effective tool to identify patients with MASLD and estimate perioperative risk, especially if used in high-risk populations.

In nonalcoholic fatty liver disease, a diet of freshwater fish vs. freshwater fish plus red meat reduced liver fat.

SOURCE CITATION: He K, Guo LL, Tang H, et al. A freshwater fish-based diet alleviates liver steatosis by modulating gut microbiota and metabolites: a clinical randomized controlled trial in Chinese participants with nonalcoholic fatty liver disease. Am J Gastroenterol. 2022;117:1621-3135973188.

The top 10 research priorities in psoriatic arthritis: a James Lind Alliance Priority Setting Partnership.

OBJECTIVES: To identify and prioritize the top 10 research questions for PsA. METHODS: The British Psoriatic Arthritis Consortium (BritPACT) formed a Priority Setting Partnership (PSP) comprising of people living with PsA, carers and clinicians, supported by the James Lind Alliance (JLA). This PSP followed the established three-stage JLA process: first, an online survey of people living with PsA, carers and clinicians to identify PsA questions, asking, 'What do you think are the most important unanswered questions in psoriatic arthritis research?' The questions were checked against existing evidence to establish 'true uncertainties' and grouped as 'indicative questions' reflecting the overarching themes. Then a second online survey ranked the 'true uncertainties' by importance. Finally, a workshop including people living with PsA and clinician stakeholders finalized the top 10 research priorities. RESULTS: The initial survey attracted 317 respondents (69% people living with PsA, 15% carers), with 988 questions. This generated 46 indicative questions. In the second survey, 422 respondents (78% people living with PsA, 4% carers) prioritized these. Eighteen questions were taken forward to the final online workshop. The top unanswered PsA research question was 'What is the best strategy for managing patients with psoriatic arthritis including non-drug and drug treatments?' Other top 10 priorities covered diagnosis, prognosis, outcome assessment, flares, comorbidities and other aspects of treatment (https://www.jla.nihr.ac.uk). CONCLUSION: The top 10 priorities will guide PsA research and enable PsA researchers and those who fund research to know the most important questions for people living with PsA.

Mixed methods study of clinicians' perspectives on barriers to implementation of treat to target in psoriatic arthritis.

OBJECTIVES: In treat to target (T2T), the patient is treated to reach and maintain specified and sequentially measured goals, such as remission or low disease activity. T2T in psoriatic arthritis (PsA) has demonstrated improved clinical and patient-reported outcomes and is recommended in European guidelines. However, most clinicians do not use T2T in PsA. This study examined the barriers and enablers to implementation in practice. METHODS: Sequential mixed methods comprising a qualitative design (interviews and focus group) to inform a quantitative design (survey). Qualitative data were analysed thematically, and quantitative statistics were analysed descriptively. RESULTS: Nineteen rheumatology clinicians participated in telephone interviews or a face-to-face focus group. An overarching theme 'Complexity' (including 'PsA vs Rheumatoid Arthritis', 'Measurement' and 'Resources') and an underpinning theme 'Changes to current practice' (including 'Reluctance due to organisational factors' and 'Individual determination to make changes') were identified. 153 rheumatology clinicians responded to an online survey. Barriers included limited clinical appointment time to collect outcome data (54.5%) and lack of training in assessing skin disease (35%). Enablers included provision of a protocol (86.4%), a local implementation lead (80.9%), support in clinic to measure outcomes (83.3%) and training in T2T (69.8%). The importance of regular audit with feedback, specialist PsA clinics and a web-based electronic database linked to hospital/national information technology (IT) systems were also identified as enablers. CONCLUSIONS: Implementation of T2T in PsA requires an integrated approach to address the support, training and resource needs of individual clinicians, rheumatology teams, local IT systems and service providers to maximise success.

Defining inflammatory musculoskeletal manifestations in systemic lupus erythematosus.

Objective: To define the prevalence and clinical associations of clinical and imaging definitions of synovitis in unselected SLE patients with musculoskeletal (MSK) symptoms. Methods: 112 patients with SLE (excluding RF and CCP positive patients); 88 consecutive with inflammatory MSK symptoms and 24 asymptomatic SLE controls were recruited. Patients had clinical assessment (BILAG, SLEDAI, joint counts, patient and physician visual analogue score), routine laboratory tests and US of two hands and wrists (synovitis and tenosynovitis, OMERACT definitions). Results: Overall, 68% (60/88) of symptomatic patients had US inflammation (grey scale ⩾ 2 and/or PD ⩾ 1 or tenosynovitis) compared with 17% (4/23) of asymptomatic patients. In symptomatic patients, clinical inflammation was seen defined by BILAG A or B in 38% (34/88) or defined by the SLEDAI-MSK criterion in 32% (28/88). BILAG A/B had sensitivity (95% CI) of 56% (41, 69%) and specificity of 89% (72, 96%) for US-confirmed inflammation. SLEDAI-MSK criterion had sensitivity of 44% (31, 59%) and specificity of 89% (72, 96%). In patients with inflammatory symptoms, 27% (24/88) had subclinical inflammation (abnormal US but no clinically swollen joints) and 35% (31/88) had no clinical or US inflammation. Subclinical tenosynovitis and PD were associated with significantly higher IgG, physician visual analogue score, tender joint count. Conclusion: In SLE patients with MSK symptoms, a large proportion of objective, clinically meaningful inflammation is only identifiable by US. The existing classification of MSK SLE using disease activity instruments based on joint swelling is inaccurate to guide patient selection for clinical trials, biologic therapy, or treat-to-target protocols.

Management of Nail Disease in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life. This review updates the previous Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for nail psoriasis. METHODS: This systematic literature review of the PubMed, MEDLINE, Embase, and Cochrane databases examined the updated evidence since the last GRAPPA nail psoriasis treatment recommendations published in 2014. Recommendations are based on preformed PICO (Patient/Population - Intervention - Comparison/Comparator - Outcome) questions formulated by an international group of dermatologists, rheumatologists, and patient panel members. Data from this literature review were evaluated in line with Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: Overall, there is insufficient evidence to make any recommendation for the use of topical corticosteroids, topical calcipotriol, topical tazarotene, topical cyclosporine, dimethyl fumarates/fumaric acid esters, phototherapy, and alitretinoin. There is a low strength of evidence to support the use of calcipotriol and corticosteroid preparations, topical tacrolimus, oral cyclosporine, oral methotrexate, intralesional corticosteroids, pulsed dye laser, acitretin, Janus kinase inhibitors, and apremilast. CONCLUSION: The highest strength of supporting evidence is for the recommendation of biologic agents including tumor necrosis factor inhibitors, and interleukin 12/23, 17, and 23 inhibitors.

Targets of immunotherapy for hepatocellular carcinoma: An update.

Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.

Current status of liver transplantation for cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.

Spontaneous bacterial empyema in cirrhosis: A systematic review and meta-analysis.

BACKGROUND: Spontaneous bacterial empyema (SBE) occurs when a hepatic hydrothorax becomes infected and runs a course similar to spontaneous bacterial peritonitis (SBP). It remains underdiagnosed as patients with cirrhosis do not routinely undergo diagnostic thoracentesis. Current understanding is limited by small cohorts, while studies reporting its association with ascites/SBP are conflicting. AIM: To explore the incidence of SBE, to determine its association with ascites, and to summarize what is known regarding treatment and outcomes for patients with SBE. METHODS: Major databases were searched until June 2021. Outcomes include the incidence of SBE in pleural effusions, SBP in peritoneal fluid, and SBE in patients without ascites within our cohort of patients with cirrhosis. We performed a meta-analysis using a random-effects model with pooled proportions and 95% confidence intervals (CI). We assessed heterogeneity using I 2 and classic fail-safe to determine bias. RESULTS: Eight studies with 8899 cirrhosis patients were included. The median age ranged between 41.2 to 69.7 years. The majority of the patients were Child-Pugh B and C. Mean MELD score was 18.6 ± 8.09. A total of 1334 patients had pleural effusions and the pooled incidence of SBE was 15.6% (CI 12.6-19; I 2 50). Amongst patients diagnosed with SBE, the most common locations included right (202), left (64), and bilateral (8). Amongst our cohort, a total of 2636 patients had ascites with a pooled incidence of SBP of 22.2% (CI 9.9-42.7; I 2 97.8). The pooled incidence of SBE in patients with cirrhosis but without concomitant ascites was 9.5% (CI 3.6-22.8; I 2 82.5). CONCLUSION: SBE frequently occurs with concurrent ascites/SBP; our results suggest high incidence rates of SBE even in the absence of ascites. The pleura can be an unrecognized nidus and our findings support the use of diagnostic thoracentesis in patients with decompensated cirrhosis after exclusion of other causes of pleural effusion. Thoracentesis should be considered particularly in patients without ascites and when there is a high suspicion of infection. The need for diagnostic thoracentesis will continue to be important as rates of multi-drug resistant bacterial infections increase and antibiotic susceptibility information is required for adequate treatment.

Over-the-scope clip as first-line therapy for ulcers with high-risk bleeding stigmata is efficient compared to standard endoscopic therapy.

Background and study aims Ulcers with high-risk stigmata have significant rebleeding rates despite standard endoscopic therapy. Data on over-the-scope clip (OTSC) for recurrent bleeding is promising but data on first line therapy is lacking. We report comparative outcomes of OTSC as first-line therapy versus standard endoscopic therapy in ulcers with high-risk stigmata. Patients and methods Consecutive adults who underwent endoscopic therapy for ulcers with high-risk stigmata between July 2019 to September 2020 were included. Patients were grouped into OTSC or standard therapy based on first-line therapy used on index endoscopy. Outcomes measured included: 1) intra-procedural hemostasis based on endoscopic documentation of adequate hemostasis; 2) 7-day rebleeding (> 2 g/dL drop in hemoglobin, hematochezia or hemorrhagic shock); 3) cost of endoscopic interventions; and 4) procedure duration measured as endoscope insertion to removal time. Cost of tools used during the index endoscopy was included. Results Sixty-eight patients were included, 47 were in standard therapy and 21 in the OTSC group. Hemostasis was achieved in 95.2 % in the OTSC group compared to 83.0 % in the standard therapy group ( P  = 0.256, number needed to treat [NNT]: 9). Procedure time was shorter in the OTSC group (23 vs. 16 minutes, P  = 0.002). Cost of endoscopic interventions were comparable, P  = 0.203. Early rebleeding was less often in OTSC group, two (9.5 %) compared to 10 (21.3 %) in standard therapy group, NNT 9. Conclusions Use of OTSCs as first-line treatment for ulcers bleed probably improves hemostasis and decreases early rebleeding. Use of OTSC as first-line therapy shortened procedure duration without increasing the cost of endoscopic interventions.

Bile acid indices as biomarkers for liver diseases II: The bile acid score survival prognostic model.

BACKGROUND: Cholestatic liver diseases are characterized by an accumulation of toxic bile acids (BA) in the liver, blood and other tissues which lead to progressive liver injury and poor prognosis in patients. AIM: To discover and validate prognostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS: We analyzed urine samples by liquid chromatography-tandem mass spectrometry and investigated the use of the urinary BA profile to develop survival models that can predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in 257 patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, formation of secondary BA, and toxicity of the BA profile. We have developed and validated the bile-acid score (BAS) model (a survival model based on BA indices) to predict the prognosis of cholestatic liver diseases. RESULTS: We have developed and validated a survival model based on BA (the BAS model) indices to predict the prognosis of cholestatic liver diseases. Our results demonstrate that the BAS model is more accurate and results in higher true-positive and true-negative prediction of death compared to both non-BAS and model for end-stage liver disease (MELD) models. Both 5- and 3-year survival probabilities markedly decreased as a function of BAS. Moreover, patients with high BAS had a 4-fold higher rate of death and lived for an average of 11 mo shorter than subjects with low BAS. The increased risk of death with high vs low BAS was also 2-4-fold higher and the shortening of lifespan was 6-7-mo lower compared to MELD or non-BAS. Similarly, we have shown the use of BAS to predict the survival of patients with and without liver transplant (LT). Therefore, BAS could be used to define the most seriously ill patients, who need earlier intervention such as LT. This will help provide guidance for timely care for liver patients. CONCLUSION: The BAS model is more accurate than MELD and non-BAS models in predicting the prognosis of cholestatic liver diseases.

Bile acid indices as biomarkers for liver diseases I: Diagnostic markers.

BACKGROUND: Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM: To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS: We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS: Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION: BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.

Role of betaine in liver disease-worth revisiting or has the die been cast?

Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries due to the epidemic of obesity and insulin resistance. Unfortunately, no medication is approved for NASH and risk factor modification is often advised. Over the last decade, several clinical trials on NASH have been conducted with several ongoing and the future looks promising. Although betaine (trimethyl glycine) was evaluated for NASH, results were mixed in the clinical trials in large part due to the quality of the studies. It seems reasonable to re-evaluate betaine in clinical trials for NASH and alcoholic liver disease due to its low cost, tolerability and mechanism of action.

Treat-to-target in PsA: methods and necessity.

With increasing recognition of the high burden and impact of psoriatic arthritis (PsA) and the growing number of therapeutic options, there has been an intensifying focus on treatment strategy in recent years. In 2015, the Tight Control of Psoriatic Arthritis study confirmed the clinical benefit of using a treat-to-target approach in PsA. This randomised controlled trial found benefits in both arthritis and psoriasis disease activity as well as lower disease impact reported by patients, although participants allocated to tight control experienced a higher rate of serious adverse events. European and international recommendations support the use of a treat-to-target approach in PsA and have offered specific advice on how to do this using outcomes such as the minimal disease activity criteria. However, implementation of this approach in routine practice is low, with real-world data highlighting undertreatment as a result. Recent qualitative work with physicians in the UK has helped researchers to understand the barriers to implementation of treat-to-target in PsA. We now need to address these barriers, provide education and support to non-specialist clinicians in routine practice, and aid the translation of optimal care to the clinic.

Controversies in liver transplantation for hepatitis C.

Hepatitis C is one of the most common indications for liver transplantation in the United States, accounting for approximately 40%-45% of all liver transplants. Unfortunately, recurrent disease is universal in patients who are viremic before transplantation. This can lead to cirrhosis in at least 25% of patients 5 years after liver transplantation, and recurrent hepatitis C is now emerging as an important but occasionally contentious indication for retransplantation. Several attempts have been undertaken to identify patients at high risk for severe recurrent disease who may benefit from treatment, but unfortunately antiviral therapy frequently is ineffective and often is associated with numerous side effects. Although we have made significant strides in understanding the natural history of this disease in nontransplant patients, this does not hold true for the transplant population in which several uncertainties covering virtually the entire spectrum of liver transplantation persist. Despite these concerns, on a more practical level, it is usually only in the postoperative setting that clinicians truly can assess the impact of their interventions on the natural history of recurrent hepatitis C, for example, by adjusting immunosuppression or prescribing antiviral therapy. Preoperative and perioperative (including donor) factors often are outside the control of hepatologists and transplant surgeons. This review is not an inclusive review of the literature but summarizes what we believe are the more controversial topics of this disease.

Major hereditary gastrointestinal cancer syndromes: a narrative review.

Gastrointestinal cancer is one of the major causes of death worldwide. Hereditary gastrointestinal cancer syndromes constitute about 5-10% of all cancers. About 20-25% of undiagnosed cases have a possible hereditary component, which is not yet established. In the last few decades, the advance in genomics has led to the discovery of multiple cancer predisposition genes in gastrointestinal cancer. Physicians should be aware of these syndromes to identify high-risk patients and offer genetic testing to prevent cancer death. In this review, we describe clinical manifestations, genetic testing and its challenges, diagnosis and management of the major hereditary gastrointestinal cancer syndromes.

Addition of chromosomal microarray and next generation sequencing to FISH and classical cytogenetics enhances genomic profiling of myeloid malignancies.

Comprehensive genetic profiling is increasingly important for the clinical workup of hematologic tumors, as specific alterations are now linked to diagnostic characterization, prognostic stratification and therapy selection. To characterize relevant genetic and genomic alterations in myeloid malignancies maximally, we utilized a comprehensive strategy spanning fluorescence in situ hybridization (FISH), classical karyotyping, Chromosomal Microarray (CMA) for detection of copy number variants (CNVs) and Next generation Sequencing (NGS) analysis. In our cohort of 569 patients spanning the myeloid spectrum, NGS and CMA testing frequently identified mutations and copy number changes in the majority of genes with important clinical associations, such as TP53, TET2, RUNX1, SRSF2, APC and ATM. Most importantly, NGS and CMA uncovered medically actionable aberrations in 75.6% of cases normal by FISH/cytogenetics testing. NGS identified mutations in 65.5% of samples normal by CMA, cytogenetics and FISH, whereas CNVs were detected in 10.1% cases that were normal by all other methodologies. Finally, FISH or cytogenetics, or both, were abnormal in 14.1% of cases where NGS or CMA failed to detect any changes. Multiple mutations and CNVs were found to coexist, with potential implications for patient stratification. Thus, high throughput genomic tumor profiling through targeted DNA sequencing and CNV analysis complements conventional methods and leads to more frequent detection of actionable alterations.

Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria.

In Plasmodium falciparum, var genes encode adhesive proteins that are transported to the surface of infected erythrocytes and act as major virulence determinants for infected erythrocyte binding and immune evasion. Var genes are highly diverse and can be classified into five major groups (UpsA, B, C, D, and E). Previous serological studies have suggested that the UpsA var group may contain common antigenic types that have important roles in severe childhood malaria. Here, our analysis found that UpsA vars are highly diverse between 22 world-wide parasite isolates, although they could be grouped into two broad clusters that may be separately recombining. By comparison, orthologs of the UpsA-linked Type 3 var and UpsE-linked var2csa were detected in nearly all parasite isolates, and a var2csa ortholog was also present in a chimpanzee malaria P. reichenowi that diverged from P. falciparum approximately 5-7 million years ago. Although the specific function of Type 3 var genes is unknown, var2csa is a leading candidate for a pregnancy associated malaria vaccine. Compared to typical var genes, var2csa is unusually conserved but still had only 54-94% amino acid identity in extracellular binding regions. However, var2csa alleles have extensive gene mosaicism within polymorphic blocks that are shared between world-wide parasite isolates and recognizable in P. rechenowi suggesting a high rate of self-self recombination and an ancient and globally-related pool of var2csa polymorphism. These studies aid our understanding of the evolutionary mechanisms that shape var diversity and will be important to the development of vaccines against pregnancy associated malaria and severe malaria.