Pathophysiology and management of liver cirrhosis: from portal hypertension to acute-on-chronic liver failure.

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.

Tadalafil improves erectile dysfunction and quality of life in men with cirrhosis: a randomized double blind placebo controlled trial.

BACKGROUND AND AIMS: Patients with cirrhosis have high prevalence of erectile dysfunction (ED). The aim of this study was to study the efficacy and safety of tadalafil for ED in patients with cirrhosis. METHODS: 140 cirrhotic males with ED were randomized into tadalafil 10 mg daily (n = 70) or placebo (n = 70) for 12 weeks. ED was diagnosed if erectile function (EF) domain score was < 25 in International Index of Erectile Function (IIEF) questionnaire. The erectile function domain consists of six questions concerning erection frequency, erection firmness, frequency of partner penetration, frequency of maintaining erection after penetration, ability to maintain erection to completion of intercourse and confidence in achieving and maintaining erection. Primary outcome was proportion of patients having an increase in > 5 points in EF domain of the IIEF. Generalized Anxiety Disorder 7 (GAD-7) questionnaire was used for screening and severity measuring of GAD. The presence of depression was screened using the Patient Health Questionnaire (PHQ-9) and the assessment of health related quality of life was done using the Short Form (36) Health Survey. RESULTS: At the end of 12 weeks, more patients in tadalafil group achieved > 5 points increase in the EF domain of the IIEF when compared with the placebo group [44(62.9%) vs. 21(30%), p < 0.001]. At the end of 12 weeks, patients receiving tadalafil had significantly more change in scores on the erectile function domain, orgasmic function domain, intercourse satisfaction domain, overall satisfaction domain, erection vaginal penetration rates and successful intercourse; significantly more decline in the GAD-7 and PHQ-9 scores; significantly more improvement in scores of five of the eight domains of SF-36 (general health perception, vitality score, social functioning, role emotional and mental health) and the mental component summary rates when compared with placebo. The development of side effects and the changes in HVPG were not significantly different between the two groups. CONCLUSIONS: Tadalafil therapy may enhance erectile function, improve anxiety, depression and quality of life; and is well tolerated by men with cirrhosis (CTP score < 10) and ED. However, further larger and long-term studies are needed to confirm these results and look for rarer side effects of using tadalafil in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03566914; first posted date: June 25, 2018.

Influence of shunt occlusion on liver volume and functions in hyperammonemic cirrhosis patients having large porto-systemic shunts: a randomized control trial.

BACKGROUND AND AIMS: Spontaneous-portosystemic-shunts (SPSS) in cirrhosis deprive the liver of nutrient-rich portal blood and contribute to recurrent hepatic encephalopathy (HE). We evaluated the effects of shunt occlusion and redirecting portal blood to liver on its volume and functions. METHODS: Cirrhosis patients presenting with recurrent HE and having SPSS were randomized to receive standard medical treatment (SMT) or shunt occlusion (SO). The later was performed by plug-assisted or balloon-occluded retrograde transvenous obliteration. The primary endpoint was change in liver volume after a minimum follow-up of 3 months. Secondary objectives included clinical course, liver disease severity indices, arterial ammonia levels and bone density. RESULTS: Of 40 enrolled patients, 4 in SMT and 2 in SO group were lost to follow-up. The SO was complete in 17 and partial in one, achieving non-recurrence of HE in 17 (94.4%). In these patients, the mean liver volume increased (baseline 1040 ± 335 ml to 1132 ± 322 ml, 8.8% increase, p < 0.001) and was observed in 16/18 (88.89%) patients. In the SMT group, the liver volume decreased (baseline 988 ± 270 ml to 904 ± 226 ml, 8.6% reduction, p = 0.009) during the same period. Serum albumin increased in SO group (2.92 ± 0.40 g/dl to 3.30 ± 0.49 g/dl, p = 0.006) but reduced in SMT group (2.89 ± 0.43 g/dl to 2.59 ± 0.65 g/dl, p = 0.047). After SO, the patients showed a reduction in serum-ammonia levels (181.06 ± 86.21 to 107.28 ± 44.53 µ/dl, p = 0.001) and an improvement in MELD-Na and bone density compared to SMT group. There were no major adverse events following shunt occlusion. CONCLUSION: Occlusion of large SPSS results in improving the volume and synthetic functions of the liver by restoring hepato-petal portal flow besides reducing serum-ammonia level and recurrence of HE. CLINICALTRIALS: gov number, NCT03293459.

Sexual dysfunctions and their treatment in liver diseases.

Sexual dysfunction (SD) is a prevalent but very commonly ignored aspect in the treatment of liver diseases and cirrhosis. The etiology of SD is multifactorial and therefore treatment strategies are complex, especially in females. Phosphodiesterase inhibitors are useful and effective in erectile dysfunction in males but in females, no single drug is available for SD, therefore multimodal treatment is required depending upon the cause. The foremost and fundamental requirement in both genders is to be stress-free and have adequate control of liver diseases. Improved quality of life is helpful in improving SD and vice versa is also true. Therefore, patients suffering from liver diseases should come forward and ask for treatment for SD, and physicians should actively enquire about SD while history taking and evaluating these patients. SD results in deterioration of quality of life, and both are modifiable and treatable aspects of liver diseases, which are never addressed actively, due to social taboos and fears of SD treatment in the presence of liver diseases. The diagnosis of SD does not require costly investigations, as the diagnosis can be established based on validated questionnaires available for both genders, therefore detailed targeted history taking using questionnaires is essential. Data are emerging in this area but is still at an early stage. More studies should be dedicated to SD in liver diseases.

Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure.

Objective: The monocyte-macrophage system is central to the host's innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes' functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF. Design: Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration. Results: Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals. Conclusion: Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

Soluble factors and suppressive monocytes can predict early development of sepsis in acute-on-chronic liver failure.

Patients with acute-on-chronic liver failure (ACLF) have a high probability of developing systemic inflammation and sepsis due to immune dysregulation. Fifty-nine patients with ACLF (12 without and 19 with systemic inflammation, and 28 with sepsis) were serially monitored for clinical and immunological changes at baseline, 6 hours, 24 hours, day 3, and day 7 following hospitalization. Ten healthy controls were also included. At all time points, soluble plasma factors and monocyte functions were studied. Patients with ACLF and systemic inflammation showed higher interleukin (IL)-6, vascular endothelial growth factor-a, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1ß than patients with no systemic inflammation. Patients with ACLF with sepsis had raised (p < 0.001) levels of IL-1Ra, IL-18, and triggering receptor expressed on myeloid cells 1 (TREM1) compared to patients with ACLF-systemic inflammation. Five of the 19 (26.3%) patients with systemic inflammation developed sepsis within 48-72 hours with a rapid rise in plasma levels of IL-1Ra (1203-35,000 pg/ml), IL-18 (48-114 pg/ml), and TREM1 (1273-4865 pg/ml). Monocytes of patients with ACLF with systemic inflammation and sepsis showed reduced human leukocyte antigen-DR but increased programmed death ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) (p < 0.04) expression with increased ETosis by monocytes at baseline and until day 7. Conclusion: High and rising levels of plasma IL-1Ra, IL-18, TREM1 soluble factors, and increased suppressive monocytes (PDL1+ve , TIM3+ve ) at baseline can stratify patients with ACLF at high risk of developing sepsis within 48-72 hours of hospitalization.

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial.

BACKGROUND: High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS: In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS: ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) µg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION: In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL: gov (identifier: NCT02718079).

Higher circulating natural killer cells and lower lactate levels at admission predict spontaneous survival in non-acetaminophen induced acute liver failure.

Massive cellular necrosis in acute liver failure (ALF) is dominantly immune mediated and innate immune cells are major pathophysiological determinants in liver damage. In fifty ALF and fifteen healthy, immune cells phenotyping by flow-cytometry, DAMPs using ELISA were analysed and correlated with clinical and biochemical parameters. ALF patients (aged 27 ± 9 yr, 56% males, 78% viral aetiology) showed no difference in neutrophils and classical monocytes, but significantly increased intermediate monocytes (CD14+CD16+) (p < 0.01), decreased non-classical monocytes (CD14-CD16+) and CD3-veCD16+CD56+ NK cells compared to HC. ALF patients who survived, showed higher NK cells (9.28 vs. 5.1%, p < 0.001) among lymphocytes and lower serum lactate levels (6.1 vs. 28, Odds ratio 2.23, CI 1.27-3.94) than non- survivors had higher. Logistic regression model predicted the combination of lactate levels with NK cell percentage at admission for survival. In conclusion, Combination of NK cell frequency among lymphocytes and lactate levels at admission can reliably predict survival of ALF patients.

Albumin in Advanced Liver Diseases: The Good and Bad of a Drug!

Human serum albumin is the most abundant plasma protein, and it regulates diverse body functions. In patients with advanced and decompensated cirrhosis, serum albumin levels are low because of a reduction in the hepatocyte mass due to disease per se and multiple therapeutic interventions. Because of their oncotic and nononcotic properties, administration of human albumin solutions (HAS) have been found to be beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis. Albumin also improves the functionality of the immune cells and mitigates the severity and risk of infections in advanced cirrhosis. Its long-term administration can modify the course of decompensated cirrhosis patients by reducing the onset of new complications, improving the quality of life, and probably providing survival benefits. There is, however, a need to rationalize the dose, duration, and frequency of albumin therapy in different liver diseases and stages of cirrhosis. In patients with acute-on-chronic liver failure, potentially toxic oxidized isoforms of albumin increase substantially, especially human nonmercaptalbumin and 2, and nitrosoalbumin. The role of administration of HAS in such patients is unclear. Determining whether removal of the pathological and dysfunctional albumin forms in these patients by "albumin dialysis" is helpful, requires additional studies. Use of albumin is not without adverse events. These mainly include allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements. Considering their cost, limited availability, need for a health care setting for their administration, and potential adverse effects, judicious use of HAS in liver diseases is advocated. There is a need for new albumin molecules and economic alternatives in hepatologic practice.

Bisphosphonates use in Pachydermoperiostosis.

Pachydermoperiostosis is a rare genetic disorder which commonly presents with clubbing, bone pains and skin changes. The treatment is mostly unsatisfactory. We tried bisphosphonates in our case with encouraging results. We suggest that parenteral bisphosphonates should be tried early in treatment of Pachydermoperiostosis.

Sarcopenia: Ammonia metabolism and hepatic encephalopathy.

Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy.

Unravelling the NERDS syndrome.

A 22-year-old man presented with symmetric polyarthritis, pruritus and deviation of angle of mouth to the right side since the last 7 years. His symptoms were persistent despite receiving ayurvedic medications and symptomatic therapy. Examination revealed dry skin, cutaneous nodules, xanthelasma, periarticular non-tender swellings, pitting oedema of hands and feet and lower motor neuron type right facial palsy. Haematological investigations revealed eosinophilia and skin biopsy had cutaneous eosinophilic infiltration. The constellation of above findings comprises the nodules, eosinophilia, rheumatism, dermatitis and swelling syndrome. It a rare syndrome with few reported cases in literature. The patient was started on oral corticosteroids which was subsequently tapered and methotrexate therapy. His polyarthritis and skin rashes resolved with therapy. He has been followed-up for 2 years and is presently asymptomatic for the last 1 year.