Function In Cirrhosis Research Articles

Proximal Tubule Secretory Clearance, Injury, and Kidney Viability in Cirrhosis.

Cirrhosis affects all structures of the kidney, in particular the tubules which are responsible for secretion of protein-bound metabolites and electrolyte/water homeostasis. Yet, prevailing assessments of kidney function focus solely on glomerular filtration rate (GFR) which may incompletely reflect these processes. We sought to characterize markers of tubular function, injury, and viability in patients with and without cirrhosis. We recruited outpatients undergoing liver transplantation evaluation for a collection of plasma and 24-hour urine, matching by GFR to control participants without cirrhosis. We measured urinary kidney injury molecule-1 (KIM-1), a marker of proximal tubular injury, as well as epidermal growth factor (EGF), a marker of viability necessary for tubular epithelial cell proliferation after injury. We also estimated secretory clearance by measuring several highly secreted endogenous metabolites in urine and plasma. We recruited 39 patients with cirrhosis (mean MELD-Na 17±4, Child-Pugh 8±2, eGFR 66±20 ml/min/1.73m2) and 58 GFR-matched controls without cirrhosis (eGFR 66±21 ml/min/1.73m2). Urinary KIM-1 was 4.4-fold higher than controls (95% CI:2.9-6.5), and EGF averaged 7.41-fold higher than controls (95% CI:2.15-25.53). We found that of 8 solutes, 5 had significantly greater kidney clearance in cirrhosis (1.3-2.1-fold higher): indoxyl sulfate, p-cresol sulfate, pyridoxic acid, tiglylglycine, and xanthosine. Cirrhosis was characterized by molecular signs of tubular injury in stable outpatients without acute kidney injury, accompanied by largely preserved tubular secretory clearance and greater signs of tubular viability. Within the limitations of the study, this suggests a phenotype of chronic ischemic injury but with initial preservation of tubular function in cirrhosis.

Performance of race-neutral eGFR equations in patients with decompensated cirrhosis.

The 2021 Chronic Kidney Disease Epidemiology Collaboration equation [CKD-EPI 2021] is a race-neutral equation recently developed and rapidly implemented as a reference standard to estimate glomerular filtration rate(GFR). However, its role in cirrhosis has not been examined especially in low GFR. We analyzed the performance of CKD-EPI 2021 compared to other equations with protocol measured GFR(mGFR) in cirrhosis. We analyzed 2090 unique adult patients with cirrhosis undergoing protocol GFR measurements using iothalamate clearance from 1985-2015 when listed for liver transplantation at Baylor University in Dallas and Fort Worth, Texas. Using mGFR as a reference standard, the CKD-EPI 2021 was compared to CKD-EPI 2012, MDRD-4, MDRD-6, RFH and GRAIL overall and in certain subgroups(ascites, mGFR≤30mL/min/1.73 m2, diagnosis, MELD and gender). We examined bias(difference between eGFR and mGFR), accuracy(p30: eGFR within ±30% of mGFR) and agreement between eGFR and mGFR categories. CKD-EPI 2021 had the 2nd lowest bias across the entire range of GFR after GRAIL (6.6 vs. 4.6mL/min/1.73 m2, respectively, p<0.001). Accuracy of CKD-EPI 2021 was similar to CKD-EPI 2012 (p30=67.8% vs. 67.9%, respectively) that was higher than the other equations (p<0.001). It had a similar performance in patients with ascites, by diagnoses, MELD subgroups, by sex and in non-Black patients. However, it had a relatively higher overestimation in mGFR≤30mL/min/1.73 m2 than most equations (18.5mL/min/1.73m2, p<0.001). Specifically, 64% of patients with mGFR≤30mL/min/1.73m2 were incorrectly classified to a less severe CKD stage by CKD-EPI 2021. In Blacks, CKD-EPI 2021 underestimated eGFR by 17.9mL/min/1.73 m2 that was higher than the alternate equations except RFH (p<0.001). The novel race-neutral eGFR equation, CKD-EPI 2021, improves the GFR estimation overall but may not accurately capture true kidney function in cirrhosis specifically at low GFR. There is an urgent need for a race-neutral equation in liver disease reflecting the complexity of kidney function physiology unique to cirrhosis given implications for organ allocation and dual organ transplant.

Comprehensive investigation of platelet function in patients with cirrhosis

Cirrhosis presents with thrombocytopenia and possibly thrombocytopathy. Previous studies exploring platelet function gave conflicting results and most controversies are explained by the variety of methods employed for investigation. We sought to assess in-vitro the overall platelet function in cirrhosis.We investigated 34 patients by using the following tests. (i)Aggregometry. (ii)Measurement of the content of platelet granules. (iii)Cytometric platelet activation. (iv)Plasmatic markers of in-vivo platelet activation. (v)Platelet procoagulant activity by thrombin generation (TG) in platelet-rich plasma (PRP).TG measured in PRP for patients and controls was similar. Platelets from patients with cirrhosis showed reduction of aggregation and secretion of ATP. Similar results were observed for platelet activation parameters such as P-selectin expression and PAC-1 platelet binding. Plasma levels of βeta-thromboglobulin and soluble P-selectin, were increased in patients-vs-controls. In contrast, there were no patients-vs-controls differences for plasmatic platelet-factor-4. Results are consistent with a state of in-vivo platelet activation and decreased in-vitro aggregation. Since bleeding events following invasive procedures are uncommon in cirrhosis, we speculate that in-vitro aggregometry testing does not reflect the situation occurring in-vivo. Results of the study and pathophysiological considerations support the conclusion that platelet function in cirrhosis as determined by aggregometry, although somewhat impaired, may support the overall hemostatic potential, which is needed for most invasive interventions. These conclusions are in line with the recommendations of international guidelines, warning against indiscriminate use of prophylactic preprocedural administration of platelets before invasive procedures. Decision on platelet support should not be made based on in-vitro laboratory testing for platelet function.

Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver.

There are no reliable methods in clinical practice to diagnose adrenal insufficiency (AI) in patients with cirrhosis owing to variable cortisol-binding protein levels. This leads to unreliable results in ACTH stimulated serum cortisol test. We aimed to estimate the long-acting porcine (LA)ACTH-stimulated serum and salivary cortisol levels of patients at different stages of cirrhosis using second generation electrochemiluminescence and to determine the prevalence of true adrenal insufficiency in these patients. We included 135 noncritical patients with cirrhosis (45 each from CHILD A, Band C) and 45 healthy controls. Serum and salivary samples were collected at baseline in the morning and at 1and 2 h after LA-ACTH injection. In healthy subjects, the 2.5th centile of 2 h ACTH stimulated serum and salivary cortisol were 19.8and 0.97 μg/dL, which were used as cut-offs for defining AI based on serum and saliva respectively. The median (interquartile-range) 2-h stimulated salivary cortisol in Child A, B, C categories and controls were 1.36(1.23-2.38), 1.46(1.18-2.22), 1.72(1.2-2.2) and 2.12(1.42-2.72) μg/dLrespectively. Six subjects (4.4%) were diagnosed to have AI based on stimulated salivary cortisol cut-off, whereas 39 (28.9%) cirrhosis subjects had inadequately stimulated serum cortisol. Three patients (symptomatic) required steroid replacement therapy. Hypoalbuminemia was identified as a major risk factor for the misdiagnosis of adrenal insufficiency by serum cortisol-based testing. Long-acting porcine ACTH stimulated salivary cortisol reduces the overdiagnosis of adrenal insufficiency compared to serum cortisol in cirrhosis liver. Stimulated salivary cortisol is a promising investigation for evaluation of adrenal function in cirrhosis and more studies are required for its further validation before clinical use.

Adrenal insufficiency in liver diseases - pathophysiology and underlying mechanisms.

Relative adrenal insufficiency (RAI) is common in critically ill patients with cirrhosis, but it has been also documented in non-critically ill patients. Its pathophysiology is complex and not well understood yet. In this review, we aimed to present potential mechanisms and causal pathways implicated in the pathogenesis of RAI in cirrhosis. There is accumulating evidence supporting a suboptimal baseline adrenal function in cirrhosis mainly due to decreased cortisol synthesis and metabolism rates from the adrenal gland. Apart from this peripheral impairment, more recent studies suggest that there is a greater defect in the central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (hypothalamus/pituitary gland). Pro-inflammatory mediators, which are elevated in cirrhosis, have been also implicated through suppression of the HPA axis, decrease in cortisol synthesis and tissue glucocorticoid resistance. All abovementioned support the hepatoadrenal syndrome hypothesis that during episodes of acute decompensation there is suboptimal adrenocortical response that leads to worse outcomes. In conclusion, the complex pathophysiology of adrenal dysfunction in cirrhosis has not been fully elucidated yet and further research is needed in order to better understand this rather common entity in cirrhosis.

Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG &lt; 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]

Опыт противовирусной терапии хронического гепатита D в Кабардино-Балкарской Республике

Objective. To study the results of the application of an innovative strategy for antiviral therapy of chronic hepatitis D (CHD) in real practice. Patients and methods. Evaluation of the efficacy and tolerability of bulevirtide, HBV and HDV entry inhibitor, in 8 patients with CHD: in monotherapy in 3 patients, combined therapy with peginterferon alfa in 5 patients. Results. High virological efficacy of both treatment regimens was demonstrated for 48 weeks: all patients on monotherapy, 4 of 5 patients on combination therapy achieved a virological response. The maximum decline in viral load was 5.8 log10 from baseline with monotherapy, 6.6 log10 with combination therapy. HDV RNA undetectable level was observed in all patients on combination therapy (in 2 patients – by week 12, in 1 – by week 24, in 1 – by week 36) and in 1 patient on monotherapy (by week 24). In 2 patients with undetectable HDV RNA level, the resumption of viremia was noted after interruptions in treatment, which emphasizes the need for adherence to treatment for the formation of a stable virological response. The tolerability of treatment was good, no serious adverse events, cases of withdrawal of treatment, deterioration of liver function in cirrhosis were reported. The number of white blood cells remained stable (3.2–3.4 × 109/l), the number of platelets decreased by week 24 from 104 to 83 thousand cells × 109/l, followed by self-recovery to the baseline by week 48. Conclusion. The data obtained confirm the validity of the choice of an innovative strategy for antiviral therapy of HCD in real practice, indicate the high efficacy and good tolerability of bulevirtide in monotherapy and combination therapy in patients with CHD, including with compensated cirrhosis. Key words: bulevirtide, chronic hepatitis D, combination therapy, monotherapy, peginterferon, real practice

Противовирусная терапия хронического гепатита D в Республике Крым – опыт реальной практики

Objective. The analysis of the results of antiviral therapy of chronic hepatitis D (HDV) in real practice using bulevirtide, an inhibitor of the entry of hepatitis B and D viruses (HDV) into the hepatocyte. Patients and methods. Intermediate treatment results were studied in 6 patients with HDV, including 3 patients with compensated cirrhosis who received bulevirtide in combination with pegylated interferon-α for 48 weeks, as well as in 3 patients who continued treatment (in combination therapy or monotherapy) for up to 60–64 weeks. Results. After 48 weeks of combination therapy, the HDV RNA level decreased from 6.5 log10 to 1.0 log10 ( p = 0.015), the median decrease was 3.4 log10, the frequency of virological response was 83%, and aviremia was 50%. Virological efficacy increased with treatment. In 3 patients, an increase in the initially normal level of alanine aminotransferase (ALT) associated with the use of interferon was noted, followed by a decrease or normalization; in 2 patients with initially moderate and high liver activity, ALT levels decreased by 35 and 354 U/l, respectively. Virological and biochemical response was maintained in all 3 patients who continued treatment up to 60–64 weeks, including aviremia in 1 patient. No serious adverse events, cases of withdrawal of treatment or deterioration of liver function in cirrhosis have been reported. Conclusion. The analysis of the intermediate results of CHD treatment in real practice has demonstrated the effectiveness, safety and good tolerability of bulevirtide, including at the stage of compensated liver cirrhosis. Further study of optimal treatment regimens is needed to achieve treatment goals and improve the prognosis of the disease. Key words: bulevirtide, chronic hepatitis D

ЭФФЕКТИВНОСТЬ ИСПОЛЬЗОВАНИЯ СТВОЛОВЫХ КЛЕТОК В ЛЕЧЕНИИ ЦИРРОЗА ПЕЧЕНИ (ЭКСПЕРИМЕНТАЛЬНОЕ ИССЛЕДОВАНИЕ)

Rationale. The need to find the most effective ways to restore liver function in cirrhosis. Goal. To evaluate the effectiveness of using cellular technologies in liver cirrhosis in an experiment.Materials and methods. The experiment included 132 individuals of c57black mice aged 12 to 18 weeks. All individuals are divided into 5 groups (30 individuals in group’s №1– №3, №5 and 12 individuals in group №4). Individuals of group 5 were removed from the experiment before it began in order to determine the normal weight of the liver and spleen. A model of liver cirrhosis was created for individuals of groups 1– 4. Group 4 individuals were removed from the experiment 30 days after the model was formed to confirm the presence of liver cirrhosis. Individuals of group 1 were given intravenous stem cells. Individuals of group 2 were intraportally injected with stem cells. Individuals of group 3 were not injected with stem cells. Changes in all three groups were evaluated 30 days after cell therapy.Results. Against the background of cell therapy, the greatest decrease in liver mass is observed in group 2 (intraportal administration of stem cells), where the liver mass exceeds normal values by 7%. In second place is group 1 (intravenous administration of stem cells), where the liver mass is higher than normal by 17%. In group 3, the liver mass exceeds normal values by 25.3%. The spleen mass 30 days after the application of cell technologies in the second group differed from normal values by 0.01 g; in group 1-by 0.06 g; in group 3-by 0.1 g. The level of total protein 30 days after the introduction of stem cells in group 1 increased by 5.9%; in group 2 by 28.8%; in group 3 by 1.1%. Albumin levels increased by 11% in group 1, 33.8% in group 2, and remained unchanged in group 3. The ALT level in group 1 decreased by 32.3%, in group 2 by 48.1%, and in group 3 remained unchanged. The AST level decreased by 7% in group 1, by 25.9% in group 2, and remained unchanged in group 3. Indicators of alkaline phosphatase decreased by 3.9% in group 1, by 14.3% in group 2, and did not improve in group 3.Conclusion. The use of cellular technologies in liver cirrhosis contributes to a faster recovery of liver function when intraportal introduction of cellular structures.

Assessment of kidney function in cirrhosis: Are we moving closer to accurate estimation of glomerular filtration rate?

Assessment of kidney function in cirrhosis: Are we moving closer to accurate estimation of glomerular filtration rate?

Bedside Tests of Muscle Function are Non-inferior to Skeletal Muscle Index in Predicting Outcomes in Patients with Cirrhosis and Correlate Better with Health-related Quality of Life and Cognitive Function

Presenting Author: Dr. Surender Singh Background: Sarcopenia is an independent predictor of poor outcomes in patients with cirrhosis. Assessment of sarcopenia can be done either by Computer Tomography based skeletal muscle index (SMI) or bedside tests like Handgrip strength or Gait speed. Aims: To compare Handgrip strength and Gait-speed with SMI in predicting mortality and their correlation with Health-related quality of life (HRQOL) and cognitive function in cirrhosis. Methods: 116 outpatients with cirrhosis were included in this prospective cohort study. Assessment for sarcopenia was done by SMI, Handgrip strength and Gait speed and Receiver operative curves (ROC) curves were plotted to compare them as predictors of mortality. HRQOL was assessed using the chronic liver disease questionnaire (CLDQ) and fatigue severity scale (FSS). Cognitive function was assessed by mini-mental state examination (MMSE). Correlations of SMI with Handgrip strength, Gait speed, HRQOL, and cognitive function were analyzed. Results: 100(86.2%) males and 16(13.8%) females with a mean age of 50.2(48.4-51.9, 95%CI) years were included. The most common cause of cirrhosis was alcoholic liver disease (47.4%) followed by hepatitis C (12.9%). Sarcopenia was diagnosed in 64(55.2%) patients using SMI. The AUCs of Gait speed, Handgrip strength, and SMI in predicting mortality were 0.91(0.85- 0.96), 0.86(0.78-0.93), and 0.8(0.71-0.88) respectively (P >0.05). The CLDQ and MMSE scores were significantly lower in the sarcopenic group, whereas the FSS score was higher suggestive of poor HRQOL and cognitive function in comparison to the Not sarcopenic group. Significant correlation was seen between SMI and Handgrip strength (r=0.75) and Gait-speed (r=0.63), (P<0.01). CLDQ(r=0.86) and FSS(r=0.77) showed strongest correlation with Handgrip strength and MMSE with Gait-speed (r=0.71), (P<0.01). Conclusion: The Handgrip strength and Gait-speed are non-inferior to SMI as an independent predictor of mortality, and correlate better with HRQOL and cognitive function, and could replace SMI for assessment of sarcopenia.

Estimating Glomerular Filtration Rate in Cirrhosis Using Creatinine-Based and Cystatin C-Based Equations: Systematic Review and Meta-Analysis.

Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual-organ transplantation. We performed a systematic review/meta-analysis to assess the performance of creatinine-based and cystatin C (CysC)-based eGFR equations compared with measured GFR (mGFR) in patients with cirrhosis. A total of 25 studies (n = 4565, 52.0 years, 37.0% women) comprising 18 equations met the inclusion criteria. In all GFR equations, the creatinine-based equations overestimated GFR (standardized mean difference, SMD, 0.51; 95% confidence interval [CI], 0.31-0.71) and CysC-based equations underestimated GFR (SMD, -0.3; 95% CI, -0.60 to -0.02). Equations based on both creatinine and CysC were the least biased (SMD, -0.14; 95% CI, -0.46 to 0.18). Chronic kidney disease-Epi-serum creatinine-CysC (CESC) was the least biased but had low precision and underestimated GFR by -3.6 mL/minute/1.73 m2 (95% CI, -17.4 to 10.3). All equations significantly overestimated GFR (+21.7 mL/minute/1.73 m2 ; 95% CI, 17.7-25.7) at GFR <60 mL/minute/1.73 m2 ; of these, chronic kidney disease-Epi-CysC (10.3 mL/minute/1.73 m2 ; 95% CI, 2.1-18.4) and GFR Assessment in Liver Disease (12.6 mL/minute/1.73 m2 ; 95% CI, 7.2-18.0) were the least biased followed by Royal Free Hospital (15 mL/minute/1.73 m2 ; 95% CI, 5.5-24.6) and Modification of Diet in Renal Disease 6 (15.7 mL/minute/1.73 m2 ; 95% CI, 10.6-20.8); however, there was an overlap in the precision of estimates, and the studies were limited. In ascites, overestimation of GFR was common (+8.3 mL/minute/1.73 m2 ; 95% CI, -3.1 to 19.7). However, overestimation of GFR by 10 to 20 mL/minute/1.73m2 is common in patients with cirrhosis with most equations in ascites and/or kidney dysfunction. A tailored approach is required especially for decisions regarding dual-organ transplantation.

Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections

Background and AimsBacterial infections are common and severe in cirrhosis, but their pathogenesis is poorly understood. Dysfunction of liver macrophages may play a role, but information about their function in cirrhosis is limited. Our aims were to investigate the specific profile and function of liver macrophages in cirrhosis and their contribution to infections. Macrophages from human cirrhotic livers were characterized phenotypically by transcriptome analysis and flow cytometry; function was assessed in vivo by single photon emission computerized tomography in patients with cirrhosis. Serum levels of specific proteins and expression in peripheral monocytes were determined by ELISA and flow cytometry. In vivo phagocytic activity of liver macrophages was measured by spinning disk intravital microscopy in a mouse model of chronic liver injury.Approach and ResultsLiver macrophages from patients with cirrhosis overexpressed proteins related to immune exhaustion, such as programmed death ligand 1 (PD‐L1), macrophage receptor with collagenous structure (MARCO), and CD163. In vivo phagocytic activity of liver macrophages in patients with cirrhosis was markedly impaired. Monocytes from patients with cirrhosis showed overexpression of PD‐L1 that paralleled disease severity, correlated with its serum levels, and was associated with increased risk of infections. Blockade of PD‐L1 with anti‐PD‐L1 antibody caused a shift in macrophage phenotype toward a less immunosuppressive profile, restored liver macrophage in vivo phagocytic activity, and reduced bacterial dissemination.ConclusionLiver cirrhosis is characterized by a remarkable impairment of phagocytic function of macrophages associated with an immunosuppressive transcriptome profile. The programmed cell death receptor 1/PD‐L1 axis plays a major role in the impaired activity of liver macrophages. PD‐L1 blockade reverses the immune suppressive profile and increases antimicrobial activity of liver macrophages in cirrhosis.

Bowel Movement Frequency Is Not Linked With Cognitive Function in Cirrhosis

The spectrum of hepatic encephalopathy (HE) ranges from overt HE (OHE) to cognitive impairment (ie, covert) HE (CHE).1 The first-line therapy is lactulose, which is titrated to achieve ~2-3 soft/loose daily bowel movements (BM). This metric is considered dogma for practitioners despite erratic results, GI adverse events, and poor tolerance in Western countries.1 There are logistic barriers for the widespread uptake of rifaximin, the second-line therapy. Moreover, although BM frequency-directed dose titration of lactulose is the usual practice, its impact on objective cognitive performance is unclear. Our aim is to determine the impact of BM frequency on cognition in patients with/without prior OHE.

S2381 Evaluating Platelet Quantity in the Presence of Essential Thrombocythaemia With Cirrhosis

INTRODUCTION: Thrombocytopenia is normally a sequela of decompensated cirrhosis. Essential thrombocythaemia (ET), by contrast, is a myeloproliferative disorder involving an elevated platelet count that can manifest as thromboses of microvasculature. The rare concurrence of these two conditions is challenging for providers in that a normal platelet count may not be a proper indication of an adequate synthetic liver function, as a baseline value is unknown. CASE DESCRIPTION/METHODS: 66-year-old female with a history of ET and untreated chronic hepatitis B and C viral infections, who presented with intermittent left upper quadrant pain. On physical exam, the patient’s vital signs were within normal limits, and abdomen was non-tender on palpation. A complete metabolic panel was significant for elevated aminotransferases, with AST 78, ALT 78, and an alkaline phosphatase of 164. Additionally, a complete blood count was significant for thrombocytosis to 879 and hemoglobin of 10.6. Magnetic resonance imaging of the abdomen showed evidence of cirrhosis with sequelae of portal hypertension, including splenomegaly and upper abdominal varices, which were also seen on computed tomography of abdomen. She was diagnosed with new-onset cirrhosis secondary to chronic untreated viral hepatitis. Thrombopoietin (TPO) levels were not assessed as platelet count was markedly elevated. The patient was continued on her home hydroxyurea for continued management of ET. DISCUSSION: Platelet count is an important measure for patients with cirrhosis. Calculation like the AST to Platelet Ratio Index (APRI) score is used to predict disease severity. Assessing platelet production as an indicator of synthetic function in cirrhosis becomes difficult when treating patients with known ET. Prior cases have suggested that the thrombocytosis in ET may be attributed to an abnormality of the normal feedback inhibition responsible for platelet turnover. TPO levels are generally normal in ET and are notably reduced in decompensated cirrhosis. Providers, therefore, should consider direct measurement of TPO levels in patients with normal platelet counts who are diagnosed with ET and cirrhosis in order to assess whether synthetic liver function is impacted by liver disease. Furthermore, patients with cirrhosis have an increased risk of portal vein thrombosis (PVT); given that patients with both cirrhosis and ET may have an even higher risk of PVT, providers may consider prophylactically anticoagulating these patients to prevent such a complication.

ЗАСТОСУВАННЯ ПЕРКУТАННОЇ ХІМІЧНОЇ АБЛЯЦІЇ В ЛІКУВАННІ ПАЦІЄНТІВ З ГЕПАТОЦЕЛЮЛЯРНОЮ КАРЦИНОМОЮ

Щороку частота виявлення ГЦК невпинно зростає. У період з 1990 по 2015 рік показник вперше діагностованих випадків ГЦК збільшився на 75%. В Україні за 2018 рік спеці- альним лікуванням охоплено лише 18,0% первинних хворих: тільки хірургічним лікуванням - 4,9%, комбінованим та комплексним лікуванням — 2,0 %. Незадовільні результати з охоплення спеціальним лікування пов'язані з особливостями етіопатогенезу ГЦК, асимптоматичним пе- ребігом та недосконалою системою скринінгу пацієнтів групи ризику, що утруднює діагнос- тику захворювання на ранніх стадіях. Вибір тактики лікування ГЦК асоційованою з вірусним гепатитом і цирозом печінки досі залишається складною клінічною проблемою, оскільки “за- стосування радикального лікування на ранній стадії є наріжним каменем для покращення за- гальної виживаності таких пацієнтів. Пацієнтам з ГЦК на ранніх стадіях з цирозом печінки, що не підлягають радикальному хірургічному лікуванню на момент звернення, показано засто- сування методів перкутанної абляції — радіочастотна абляція, хімічна абляція, кріоабляція, мікрохвильова абляція тощо. Основними показаннями для застосування локальної абляції в лікуванні ГЦК — дуже рання та рання стадія (за BCLC – стадія 0 та А), компенсована або субкомпенсована функція печінки при цирозі (Child - Pugh клас A та B), загальносоматичний статус за ECOG 0–1, діаметр пухлинного вогнища до 5,0 см (найбільш оптимально до 3,0 см), вогнищеве вузлове ураження, солітарне або множинне ураження. Перкутанну абляцію застосо- вують у якості “брідж”-терапії з метою локального контролю пухлинного росту у пацієнтів, що відповідають Міланським критеріям, критеріям UCSFC і знаходяться в списку очікуван- ня на трансплантацію. Також дані методи показали свою ефективність як неоад'ювантна “downstaging”-терапія у хворих, що не відповідають критеріям для трансплантації печінки та/або з первинно нерезектабельним ураженням. Протягом багатьох десятиліть перкутан- на хімічна абляція була “золотим” стандартом мініінвазивного лікування ГЦК. Даний метод простий у виконанні, не потребує спеціального обладнання, добре переноситься пацієнтами, безпечний та економічно вигідний. Основні хімічні агенти - етанол та оцтова кислота. Про- цедура перкутанної хімічної абляції передбачає інтратуморальне введення хімічного агенту “real-time” під контролем методів візуалізації (УЗД або КТ). Хімічна абляція - це метод дру- гої лінії і застосовується лише у випадках, наявності протипоказань до виконання радіочас- тотної абляції. Даний метод не супроводжується тяжкими специфічними ускладненнями та летальністю. Ефективність її клінічного застосування безпосередньо залежить від розміру пухлинного вогнища. Оптимальний розмір пухлинного вогнища становить не більше 3,0 см. Інтратуморальне введення етанолу призводить до некротизації 90% -100% пухлинних вузлів ГЦК діаметром ≤ 2,0 см та 70% при пухлинах 2,0 - 3,0 см.

Dobutamine reverses the cardio-suppressive effects of terlipressin without improving renal function in cirrhosis and ascites: a randomized controlled trial.

Acute kidney injury and hepatorenal syndrome (HRS) are frequent complications in patients with cirrhosis and ascites. First-line treatment is terlipressin, which reverses HRS in ~40% of patients but also lowers cardiac output (CO). We aimed to investigate whether reversing the cardio-suppressive effect of terlipressin with the β-adrenoceptor agonist dobutamine would increase CO and thereby increase the glomerular filtration rate (GFR). We randomized 25 patients with cirrhosis, ascites, and impaired renal function (2:2:1): group A received terlipressin followed by the addition of dobutamine; group B received dobutamine and terlipressin as monotherapies; and group C received placebo. Renal and cardiac functions were assessed during 8 clearance periods of 30 min, and concentrations of vasoactive hormones were measured. Dobutamine as a monotherapy increased CO (1.03 L/min, P < 0.01) but had no significant effects on GFR. Renin (P < 0.05), angiotensin II (P < 0.005), and aldosterone (P < 0.05) increased after dobutamine infusion. Terlipressin as a monotherapy improved GFR (18.9 mL·min-1·m-2, P = 0.005) and mean arterial pressure (MAP) (14 mmHg, P = 0.001) but reduced CO (-0.92 L/min, P < 0.005) and renin (P < .005). A combined treatment of dobutamine and terlipressin had a positive effect on CO (1.19 L/min, P < 0.05) and increased renin (P < 0.005), angiotensin II (P < 0.005), and aldosterone (P < 0.05), but it had no significant effects on MAP or GFR. Dobutamine reversed the cardio-suppressive effect of terlipressin in cirrhosis, ascites, and impaired renal function. However, dobutamine reduced peripheral vascular resistance, activated renin-angiotensin-aldosterone system, and did not improve GFR compared with terlipressin as a monotherapy. Therefore, dobutamine cannot be recommended in cirrhosis and ascites.NEW & NOTEWORTHY This study shows that the cardio-suppressive effects of the vasopressin receptor agonist terlipressin can be reversed by dobutamine. This is a novel observation in patients with decompensated cirrhosis. Furthermore, we show that dobutamine reduced the peripheral vascular resistance and activated the renin-angiotensin system, whereas renal function was not further improved by terlipressin alone.

Causes and Consequences of Innate Immune Dysfunction in Cirrhosis.

Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.

Pharmacokinetic and Pharmacodynamic Properties of L-Ornithine L-Aspartate (LOLA) in Hepatic Encephalopathy.

l-Ornithine l-aspartate (LOLA), a stable salt of l-ornithine and l-aspartate, readily dissociates into its constituent amino acids that are readily absorbed by active transport, distributed, and metabolized. l-ornithine serves as an intermediary in the urea cycle in periportal hepatocytes in the liver and as an activator of carbamoyl phosphate synthetase, and, like l-aspartate, by transamination to glutamate via glutamine synthetase in perivenous hepatocytes as well as by skeletal muscle and brain. By way of these metabolic pathways, both amino acids participate in reactions whereby the ammonia molecule is incorporated into urea and glutamine and it is the nature, cellular, and biological location of these pathways that underpins the application of LOLA as an effective ammonia-lowering strategy widely used for the management and treatment of hepatic encephalopathy. These metabolic pathways were elucidated based upon studies in experimental animals and were confirmed by studies in patients with severe liver diseases. More recent studies suggest that LOLA may have additional direct hepatoprotective properties. Moreover, its use may result in improvements in skeletal muscle function in cirrhosis.

Renal Function in Cirrhosis: A Critical Review of Available Tools.

Patients with cirrhosis have a high prevalence of renal dysfunction. The susceptibility to renal dysfunction is due to both the severe splanchnic arterial vasodilation and the systemic inflammation observed in these patients. An accurate assessment of renal function is recommended in all patients with cirrhosis. Indeed, the renal function assessment guides the management of patients, helps to refine prognosis and to define transplant strategies. Despite its limitations, serum creatinine is still the most used biomarker for the estimation of glomerular filtration rate (GFR) and the assessment of acute kidney injury (AKI) in patients with cirrhosis. New biomarkers of GFR such as cystatin C may improve the assessment of GFR and the prognostic stratification in these patients. AKI is a life-threatening complication and needs a timely management. The differential diagnosis between hepatorenal syndrome (HRS) and acute tubular necrosis (ATN) is tricky in clinical practice. New biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin and interleukin-18, represent useful tools in refining the discrimination between HRS and ATN. Patients with HRS need a prompt treatment with vasoconstrictors and albumin and a rapid evaluation for liver transplant eligibility. In this article, the authors reviewed the available tools in the diagnosis and management of renal dysfunction in cirrhosis.