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Management of the major complications of cirrhosis: Beyond guidelines

  • Juan Carlos Garcia-Pagan
    Affiliations
    Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

    Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Spain
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  • Claire Francoz
    Affiliations
    Hepatology and Liver Intensive Care Unit, Hôpital Beaujon, INSERM. Clichy; France
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  • Sara Montagnese
    Affiliations
    Department of Medicine, University of Padova, Italy
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  • Marco Senzolo
    Affiliations
    Gastroenterology, Multi-visceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Italy
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  • Rajeshwar P. Mookerjee
    Correspondence
    Corresponding author. Address: Institute for Liver and Digestive Health, University College London and Royal Free Medical school, Hampstead, London. NW3 2PF, UK; Tel.: +442074332853.
    Affiliations
    Institute for Liver and Digestive Health, University College London, UK

    Department of Hepatology and Gastroenterology, Aarhus University, Denmark
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      Summary

      Along with a growing understanding of the pathophysiology of cirrhosis and its complications, new therapies and management strategies have emerged in recent years. Many of these advances have helped inform the current EASL clinical practice guidelines1 on the management of some of the key complications of cirrhosis, such as ascites, variceal bleeding and infection. However, there are still some aspects of management where the evidence base is less clear, and/or where opinions amongst practitioners remain divided. Some of these more controversial areas are explored in this section, wherein we present evidence culminating in a suggested management approach based on expert opinion and extending beyond the current guidelines.

      Keywords

      Introduction

      Improvements in our understanding of the pathophysiology of cirrhosis and the identification of new therapeutic targets have created new treatment opportunities.
      However, growing pressure on healthcare budgets and a trend by healthcare managers to recourse to clinical guidelines to justify which therapeutic options may or may not be adopted in practice, create barriers to the incorporation of innovative therapies, despite often compelling scientific evidence. Thus, whilst guidelines are clearly important to ensure uniformity of care standards, sometimes one must also use expert opinion to justify a management strategy, which is particularly the case for some aspects of the management of cirrhosis and its complications, for which the evidence is often less definitive. Whilst some management strategies lie beyond the current clinical practice guidelines,
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      they are nonetheless commonly encountered and could be adopted into practice, whilst we await more definitive data. Such topics include the management of refractory ascites, minimal encephalopathy, diabetic care in advanced liver disease, and optimal management of patients discharged from hospital with decompensated cirrhosis.

      How to improve current care pathways to prevent readmission to the hospital with further decompensation and morbidity?

      An estimated 1.5 billion people worldwide have chronic liver disease, with a marked 13% increase in cirrhosis cases noted in the last decade.
      • Moon A.M.
      • Singal A.G.
      • Tapper E.B.
      Contemporary epidemiology of chronic liver disease and cirrhosis.
      This translates into increased cirrhosis-associated morbidity, especially from acute decompensation events, and mortality. Whilst our understanding of the pathophysiological drivers of acute decompensation of cirrhosis has improved considerably over the last decade, the management still remains largely reactive, often necessitating intensive therapies and protracted hospital admissions in response to late presentations.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      Moreover, even after resolution of an acute decompensation event, re-admission to hospital with further complications is common, with 90-day readmission rates estimated at between 21–53%, based on the population and number of cirrhosis complications.
      • Tapper E.B.
      • Halbert B.
      • Mellinger J.
      Rates of and reasons for hospital readmissions in patients with cirrhosis: a multistate population-based cohort study.
      ,
      • Bajaj J.S.
      • Reddy K.R.
      • Tandon P.
      • Wong F.
      • Kamath P.S.
      • Garcia-Tsao G.
      • et al.
      The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis.
      Those with more advanced disease, prior encephalopathy and/or those who have previously received prophylactic antibiotics, have higher readmission rates, generating a substantial health and societal care cost.
      In addition to optimal management of cirrhosis complications per the recent EASL guidelines,
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      patients with advanced liver disease also require support and management for substance/alcohol abuse, nutrition and frailty.
      • Macdonald S.
      • Jepsen P.
      • Alrubaiy L.
      • Watson H.
      • Vilstrup H.
      • Jalan R.
      Quality of life measures predict mortality in patients with cirrhosis and severe ascites.
      This in turn requires a programme of education for patients and carers alike, following discharge from hospital back into the community. In this regard, the delivery of current management protocols is often wanton in ensuring adequate and equitable access to specialist advice, timely follow-up, and sufficient community support, following hospital discharge. This in an era when many other chronic disease management protocols, such as for heart failure, have turned to technology to help improve outcomes and patient engagement. This begs the question, what could aide early recognition of new cirrhosis complications and be used to provide effective community cirrhosis monitoring and management for patients at risk of decompensation? The urgent need to address this question has intensified in light of the COVID-19 pandemic, and the consequent need to streamline healthcare resources and reduce patient footfall, both for emergency admissions and routine out-patient assessments.

       The role of remote monitoring of cirrhosis

      Telemedicine is a terminology encompassing several different practices including teleconsultation (imparting specialist knowledge to another practitioner through case presentation); telemonitoring (adopting technology such as wearables to remotely monitor signs and symptoms), and televisits (where patients can be assessed by a healthcare provider in a remote location). COVID-19 has certainly seen a growth in televisits and telephone consultations, but it is difficult to obtain key metrics of changing clinical status in the absence of hospital tests and assessment. In this regard, the ability to adopt smartphone technology and low-cost sensing equipment to acquire key physiological data remotely, could potentially help differentiate acute decompensation from chronic stable cirrhosis, as shown by a study of continuous heart rate variability (HRV) monitoring; a loss of HRV was associated with decompensation and inflammation, whilst an HRV threshold could identify patients at a high risk of mortality.
      • Jansen C.
      • Chatterjee D.A.
      • Thomsen K.L.
      • Al-Kassou B.
      • Sawhney R.
      • Jones H.
      • et al.
      Significant reduction in heart rate variability is a feature of acute decompensation of cirrhosis and predicts 90-day mortality.
      Indeed, the potential of remote monitoring in cirrhosis has been shown by several studies, including a study of 25 patients with cirrhosis and ascites, where Bluetooth-linked weighing scales and an App, enabled providers to feedback responses over 30 days of monitoring.
      • Bloom P.
      • Wang T.
      • Marx M.
      • Tagerman M.
      • Green B.
      • Arvind A.
      • et al.
      A smartphone app to manage cirrhotic ascites among outpatients: feasibility study.
      The authors reported good compliance with remote weight measurement on >70% of the study days, whilst demonstrating the feasibility of monitoring changes in weight (increase or decrease) where interventions were recommended for more than 50% of alerts. In another example, a “Patient Buddy App” was used to provide education on cirrhosis complications and evaluate the risk of hepatic encephalopathy (HE). This study in 40 patients showed that some HE-related admissions (a potentially reversible cause of hospital admissions) were avoided, albeit the study had no control group.
      • Ganapathy D.
      • Acharya C.
      • Lachar J.
      • Patidar K.
      • Sterling R.K.
      • White M.B.
      • et al.
      The patient buddy app can potentially prevent hepatic encephalopathy-related readmissions.
      The study findings did reveal an expected 40% readmission rate but this was from non-HE causes, raising the question of whether some complications of cirrhosis, such as infection or bleeding, can be prevented or their impact reduced with technological interventions. Such interventions are generally associated with good compliance, going against the dogma that patients always gain most from traditional doctor-patient direct consultations. Further evaluation of such technology is needed and the potential for ‘digital therapies’ to be applied remotely in cirrhosis certainly warrants evaluation.
      Hepatologists need to embrace technology and broader care networks, to deliver high-quality care for patients with decompensated cirrhosis in the community.

       Machine learning algorithms to define patients at risk of cirrhosis complications

      The use of machine learning algorithms and potential artificial intelligence are also gaining momentum, although their application in decompensated cirrhosis is limited. However, in 1 study, applying feature selection criteria and several machine learning models to the CANONIC study dataset,
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      demonstrated improved sensitivity and specificity for mortality prediction.
      • Garcia M.S.
      • Agarwal B.
      • Mookerjee R.P.
      • Jalan R.
      • Doyle G.
      • Ranco G.
      • et al.
      An accurate data preparation approach for the prediction of mortality in ACLF patients using the CANONIC dataset.
      This preliminary data does show that agnostic evaluation of variables in patients with cirrhosis may help define a population at risk of new complications and progression, and in the future, generate a risk algorithm that may complement remote monitoring, and guide early intervention when integrated into community-care pathways. However, such methods clearly require rigorous testing and validation, especially in prospective datasets.

       Specialist cirrhosis-care nursing support

      Whilst other chronic conditions such as heart failure have a well-established framework for specialist and community nursing supported by data,
      • Bureau C.
      • Thabut D.
      • Oberti F.
      • Dharancy S.
      • Carbonell N.
      • Bouvier A.
      • et al.
      Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites.
      this is still significantly lacking in liver disease. A study in 47 patients who received dedicated specialist nurse led follow-up, where the nurses had received prior training (including in palliative care), showed significant buy-in from participants and carers, and improved coordination of care and quality-of-life feedback.
      • Albillos A.
      • Banares R.
      • Gonzalez M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites.
      ,
      • D'Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D'Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      Whilst controlled studies are limited in this area, such studies encourage further investment for the delivery of specialist nursing care to patients with cirrhosis, as recently summarised in a Position paper on this subject, as part of the European Horizon 2020 programme, LiverHope.
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      The role of specialist nursing for cirrhosis extends to counselling for nutrition, education of patients and carers on potential complications, awareness of risk of falls, and care of skin fragility. This is in addition to providing support for alcohol use disorders when applicable. Alongside regular follow-up assessment and review of diet and medication compliance, this specialised support would help ensure continuity of high-quality care once patients are discharged from hospital.
      Expert opinion
      • The need for close follow-up of decompensated cirrhosis after hospital discharge is clear, and remote monitoring should be seen as a viable option, supported by technological infrastructure.
      • The use of machine learning and data science to help improve prognostic indicators will help guide triaging of patients to personalised interventions and treatment algorithms.
      • Technology should be supported by increased investment in specialist cirrhosis nursing, to assist with early intervention and thereby reduce need for hospitalisation.

      How to diagnose and manage chronic kidney disease in decompensated cirrhosis?

      Chronic kidney disease (CKD) has become a major global public health problem. The prevalence of CKD in the general population is around 10% in high-income countries, where diabetes mellitus, obesity and hypertension represent the main causes.
      • Chen T.K.
      • Knicely D.H.
      • Grams M.E.
      Chronic kidney disease diagnosis and management: a review.
      Specific conditions such as IgA nephropathies or virus-induced glomerulopathies are well described in cirrhosis.
      • Davis C.L.
      • Gonwa T.A.
      • Wilkinson A.H.
      Pathophysiology of renal disease associated with liver disorders: implications for liver transplantation. Part I.
      However, non-specific causes, associated with ageing and metabolic syndrome, especially diabetes mellitus, may account for the majority of CKD in the population with cirrhosis, especially in patients with NASH (non-alcoholic steatohepatitis). Recent studies have shown that CKD may affect nearly half of such patients.
      • Huelin P.
      • Piano S.
      • Sola E.
      • Stanco M.
      • Sole C.
      • Moreira R.
      • et al.
      Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure.
      ,
      • Wong F.
      • Reddy K.R.
      • O'Leary J.G.
      • Tandon P.
      • Biggins S.W.
      • Garcia-Tsao G.
      • et al.
      Impact of chronic kidney disease on outcomes in cirrhosis.
      The diagnosis and staging of CKD in decompensated cirrhosis remains challenging. Indeed, non-invasive tools used to estimate renal function including serum creatinine or estimates of glomerular filtration rate (GFR), such as creatinine or cystatine-based equations, have poor accuracy in decompensated cirrhosis.
      • Francoz C.
      • Nadim M.K.
      • Baron A.
      • Prie D.
      • Antoine C.
      • Belghiti J.
      • et al.
      Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current recommendations.
      • De Souza V.
      • Hadj-Aissa A.
      • Dolomanova O.
      • Rabilloud M.
      • Rognant N.
      • Lemoine S.
      • et al.
      Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis.
      • Mindikoglu A.L.
      • Dowling T.C.
      • Weir M.R.
      • Seliger S.L.
      • Christenson R.H.
      • Magder L.S.
      Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.
      The present reference standard remains measurement of GFR through clearance of an exogenous marker, which is expensive, time-consuming and only available in select centres.
      • Francoz C.
      • Glotz D.
      • Moreau R.
      • Durand F.
      The evaluation of renal function and disease in patients with cirrhosis.
      In non-liver transplant (LT) candidates, the measure of GFR may be useful to adapt the dosage of drugs which are metabolised by the kidney and for prognostication. In LT candidates, the assessment of GFR is particularly important. Indeed, if measured GFR is below 30 ml/min, combined liver and kidney transplantation rather than LT alone may be proposed.
      • Nadim M.K.
      • Sung R.S.
      • Davis C.L.
      • Andreoni K.A.
      • Biggins S.W.
      • Danovitch G.M.
      • et al.
      Simultaneous liver-kidney transplantation summit: current state and future directions.
      There is a high prevalence of CKD in patients with cirrhosis, and despite limitations in measurement of GFR, this should be determined early for those being considered for transplantation, with renal replacement therapy used as a bridge to transplantation.
      Of note, whilst the current EASL CPG guidelines
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      highlight in detail the new classifications of acute kidney injury (AKI) and the limitations of using tubular damage markers and rarely acquired biopsy information, to distinguish this from hepatorenal syndrome (HRS)-induced AKI, the overlay of HRS on CKD is much more challenging. By definition, if CKD is suspected, a further drop in GFR thought to be related to HRS and systemic inflammation would be hard to attribute as being causal to further kidney injury, beyond the contributions of chronic progression of structural damage and/or comorbidities like diabetes. However, If HRS is suspected, the management should follow the current EASL CPG algorithm for HRS whilst we await better markers of tubular damage.
      There is no specific treatment for CKD. First, risk factors should be screened and treated. Second, the management involves renoprotective strategies to slow kidney deterioration,
      • Chen T.K.
      • Knicely D.H.
      • Grams M.E.
      Chronic kidney disease diagnosis and management: a review.
      based on control of blood pressure (below 130/80 mmHg) and reduction of proteinuria.
      • Chen T.K.
      • Knicely D.H.
      • Grams M.E.
      Chronic kidney disease diagnosis and management: a review.
      Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the drugs of choice.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey Jr., D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      In contrast, beta-blockers (selective) are not first-line drugs and their renoprotective effects are unclear.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey Jr., D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      In decompensated cirrhosis, the use of ACEIs and ARBs is contraindicated given their poor tolerance. Indeed, they increase the risk of developing AKI by inducing arterial hypotension and reducing the GFR.
      • Pariente E.A.
      • Bataille C.
      • Bercoff E.
      • Lebrec D.
      Acute effects of captopril on systemic and renal hemodynamics and on renal function in cirrhotic patients with ascites.
      ,
      • Tandon P.
      • Abraldes J.G.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      • Bosch J.
      Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis.
      Recent EASL guidelines recommend stopping non-selective beta-blockers (NSBBs) in patients with cirrhosis and AKI.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      Whether they should be continued once AKI has resolved has never been investigated.
      At the later stage of end-stage renal disease, patients should theoretically be considered for renal replacement therapy (RRT) and, eventually, transplant evaluation. Several techniques of RRT could be proposed including in-centre haemodialysis or home haemodialysis, requiring arteriovenous fistula placement, or peritoneal dialysis. No large study has evaluated RRT for CKD in decompensated cirrhosis. It may be assumed that initiating RRT in a patient with end-stage cirrhosis and multi-organ failure, who is not a candidate for transplantation, is unreasonable. Conversely, initiation of RRT to treat ascites in a patient without severe liver insufficiency, or starting RRT in the context of AKI superimposed on CKD, should be discussed, especially in patients listed for LT. Arteriovenous fistulas should be avoided because of a high associated risk of complications (bleeding, infection); central venous dialysis catheters are preferred. Continuous RRT may be the safest option.
      Expert opinion
      • Patients with cirrhosis should be screened for CKD given its high prevalence in this population, especially in those with metabolic syndrome.
      • GFR should be measured using clearance of exogenous markers in LT candidates since current estimates of GFR have poor accuracy in decompensated cirrhosis, and these patients may be candidates for combined liver and kidney transplantation.
      • To date, no specific treatment for CKD is available in decompensated cirrhosis, as nephroprotective strategies are contraindicated.
      • When end-stage kidney disease occurs, RRT may be proposed to bridge to transplantation.

      Should we screen for type 2 diabetes mellitus in patients with decompensated cirrhosis? And how to manage it?

      Abnormalities in glucose metabolism are frequent in patients with cirrhosis, with glucose intolerance affecting 30–50% of patients, and type 2 diabetes mellitus (T2DM) affecting 30%.
      • Bianchi G.
      • Marchesini G.
      • Zoli M.
      • Bugianesi E.
      • Fabbri A.
      • Pisi E.
      Prognostic significance of diabetes in patients with cirrhosis.
      • Elkrief L.
      • Rautou P.E.
      • Sarin S.
      • Valla D.
      • Paradis V.
      • Moreau R.
      Diabetes mellitus in patients with cirrhosis: clinical implications and management.
      • Moreau R.
      • Delegue P.
      • Pessione F.
      • Hillaire S.
      • Durand F.
      • Lebrec D.
      • et al.
      Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.
      • Nishida T.
      • Tsuji S.
      • Tsujii M.
      • Arimitsu S.
      • Haruna Y.
      • Imano E.
      • et al.
      Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis.
      Diabetes and cirrhosis are closely interconnected, cirrhosis inducing insulin-resistance and, conversely, diabetes worsening liver disease and increasing the risk for complications of cirrhosis as well as mortality.
      • Elkrief L.
      • Rautou P.E.
      • Sarin S.
      • Valla D.
      • Paradis V.
      • Moreau R.
      Diabetes mellitus in patients with cirrhosis: clinical implications and management.
      ,
      • Holstein A.
      • Hinze S.
      • Thiessen E.
      • Plaschke A.
      • Egberts E.H.
      Clinical implications of hepatogenous diabetes in liver cirrhosis.
      Diabetes mellitus should be screened for in decompensated cirrhosis and insulin therapy used as the first-line option, albeit, under careful supervision and cautiously to avoid precipitating hypoglycaemia and metabolic encephalopathy.
      Management of patients with T2DM is based on lifestyle changes and pharmacological therapies.
      • American Diabetes A.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020.
      Such strategies may be challenging in patients with decompensated cirrhosis. Firstly, poor nutritional status is frequently associated with end-stage cirrhosis and contraindicates hypocaloric diets. Secondly, ascites, oedema and fatigue frequently hamper physical exercise programmes.
      Most pharmacological treatments of diabetes are difficult to manage in patients with impaired liver function and/or altered kidney function, a common state in decompensated cirrhosis. For instance, metformin increases the risk of lactic acidosis and should not be used in this population. Other drugs (thiazolidindiones, insulin secretagogues, alpha-glucosidase inhibitors or dipeptyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) have yet to be studied in depth in decompensated cirrhosis. However, given most are eliminated either by the liver or the kidney, their use is not recommended in patients with decompensated cirrhosis.
      • American Diabetes A.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020.
      ,
      • Gangopadhyay K.K.
      • Singh P.
      Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment.
      Insulin remains the only drug that can be recommended in decompensated cirrhosis. However, one must be mindful that its hepatic metabolism is reduced in decompensated cirrhosis, thus decreasing the need for it. Because of patients’ highly variable insulin requirements and the risk of hypoglycaemia, treatment should be initiated during hospitalisation, with close monitoring of blood glucose levels.
      The main objective of T2DM treatment is tight glucose control, which has been shown to decrease both micro- and macrovascular complications of diabetes, and to increase survival.
      • American Diabetes A.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020.
      Self-monitoring of blood glucose and/or continuous glucose monitoring facilitate optimal glycaemic control. Glycated haemoglobin (HbA1c) enables long-term glycaemic status to be assessed. A level below 7% is usually considered as the optimal target.
      • American Diabetes A.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020.
      In decompensated cirrhosis, monitoring HbA1c is not accurate as its levels may be decreased by several mechanisms, including anaemia, portal hypertension, poor nutritional status and shortened erythrocyte life span.
      • Lahousen T.
      • Hegenbarth K.
      • Ille R.
      • Lipp R.W.
      • Krause R.
      • Little R.R.
      • et al.
      Determination of glycated hemoglobin in patients with advanced liver disease.
      Therefore, self-monitoring of blood glucose is the only means to evaluate glucose control. In patients with encephalopathy, continuous glucose monitoring may represent the best option.
      The benefit of tight glycaemic control in cirrhosis, especially in decompensated patients, has never been demonstrated. Detrimental effects of diabetes on survival could be more pronounced in patients with model for end-stage liver disease (MELD) scores below 10 than in patients with MELD scores over 10,
      • Elkrief L.
      • Chouinard P.
      • Bendersky N.
      • Hajage D.
      • Larroque B.
      • Babany G.
      • et al.
      Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C.
      as the latter are more likely to die from complications of cirrhosis than from complications of T2DM. If glycaemic control is too tight, patients may be exposed to hypoglycaemia, which can precipitate metabolic encephalopathy. Conversely, blood glucose levels over 10 mmol/L may increase the risks of diabetic ketoacidosis and hyperosmolar hyperglycaemic complications.
      Expert opinion
      • Patients with decompensated cirrhosis should be screened for diabetes given its high prevalence in this population.
      • HbA1c should not be used, neither for the diagnosis, nor for assessing glycaemic control over the preceding 3 months.
      • Insulin therapy is the only evidence-based option for treating T2DM. It should be initiated in hospital due to high variations in glucose levels and risks of hypoglycaemia, which may alter mental function and be confused with HE, thereby complicating management. Optimal fasting blood glucose levels should not exceed 10 mmol/L to avoid hyperglycaemic complications.

      How best to classify and manage hepatic encephalopathy in decompensated cirrhosis?

      Recognition and screening for mild HE using easily accessible tests, such as animal naming, is important and may help identify those at risk of progression to overt HE. Moreover, ammonia-lowering strategies may treat progression and help clinch a diagnosis in those with high functional capacity.
      HE has been traditionally split into overt (with neurological and/or psychiatric abnormalities that can be detected clinically) and minimal (with abnormalities that are detected on neuropsychological or neurophysiological tests).
      • Ferenci P.
      • Lockwood A.
      • Mullen K.
      • Tarter R.
      • Weissenborn K.
      • Blei A.T.
      Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.
      As the clinical diagnosis of mild forms of overt HE is operator-dependent, it has been suggested that HE is called overt when at least temporal disorientation (for example, 3 mistakes out of 5 questions exploring orientation to time, according to Italian guidelines
      • Montagnese S.
      • Russo F.P.
      • Amodio P.
      • Burra P.
      • Gasbarrini A.
      • Loguercio C.
      • et al.
      Hepatic encephalopathy 2018: a clinical practice guideline by the Italian Association for the Study of the Liver (AISF).
      ) and/or flapping tremor are present (≥grade II according to the West Haven criteria). By contrast, grade I HE changes, which are usually detected by caregivers or physicians who are well acquainted with the patient’s normal personality and behaviour, are grouped with abnormalities on tests (minimal HE) and collectively named covert HE.
      American Association for the Study of Liver D
      European association for the study of the L. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases.
      Whichever their denomination or exact classification, mild forms of HE are common, they can affect quality of life, social and family relations, earning capacity, and the ability to drive. In addition, they are associated with a higher likelihood of developing overt HE over time.
      • Hartmann I.J.
      • Groeneweg M.
      • Quero J.C.
      • Beijeman S.J.
      • de Man R.A.
      • Hop W.C.
      • et al.
      The prognostic significance of subclinical hepatic encephalopathy.
      Over recent years, screening for mild HE has become easier, with bedside tools becoming available and their use more widespread. For example, the animal naming test is universally and rapidly applicable (requiring no equipment and only 60 seconds of time), can be performed by physicians, nurses and caregivers, and has limited spontaneous variability, making it useful for follow-up/monitoring.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      By contrast, attributing neuropsychiatric abnormalities to liver failure and defining neuropsychiatric status within a transplant work-up process remains challenging, with adequate differential diagnosis requiring experience, equipment/personnel that are not routinely available to standard gastroenterology/hepatology wards, and time, including that needed to evaluate response to treatment.

      Controversies in management

      Current management guidelines indicate that non-absorbable disaccharides should be used as secondary prophylaxis after an episode of overt HE, and rifaximin should be added if a second episode occurs within 6 months (recurrent overt HE).
      American Association for the Study of Liver D
      European association for the study of the L. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases.
      Indications for the treatment of milder forms of HE are less stringent.
      American Association for the Study of Liver D
      European association for the study of the L. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases.
      While treatment has been shown to revert neuropsychological abnormalities, it remains to be established if it also affects the likelihood of developing overt HE over time. The expert opinion here would be to consider treatment of minimal HE also as prophylaxis to prevent more severe overt HE. It should also be added that in situations where experience in the diagnosis of minimal HE is scarce, a response to a course of ammonia-lowering treatment solves the problem while also confirming the diagnosis at the same time. This is of particular relevance to high-functioning individuals with jobs of responsibility, in whom the diagnosis may be more difficult because they place themselves at the top end of neuropsychological performance, thus producing “normal” performances (with reference to healthy population norms) even when they are functissoning considerably below their baseline .
      • Montagnese S.
      • De Rui M.
      • Angeli P.
      • Amodio P.
      Neuropsychiatric performance in patients with cirrhosis: who is "normal"?.
      Shunt-related minimal HE poses even more diagnostic challenges, as its persistence may make it more difficult to distinguish from other forms of neuropsychiatric impairment, especially dementias and extrapyramidal syndromes.
      As the pathophysiology of minimal HE is identical to that of more severe forms, treatment is the same. Virtually all agents shown to be effective for overt HE have also been shown to be effective for milder forms. Of interest, one randomised controlled trial (RCT) also showed that a 6-month nutritional intervention (30–35 kcal/kg of body weight/day, 1.0–1.5 g vegetable protein/kg of body weight/day) improved neuropsychiatric performance and also decreased the risk of developing overt HE over time compared to no intervention.
      • Maharshi S.
      • Sharma B.C.
      • Sachdeva S.
      • Srivastava S.
      • Sharma P.
      Efficacy of nutritional therapy for patients with cirrhosis and minimal hepatic encephalopathy in a randomized trial.
      Within the context of milder forms of HE, “ecological” solutions such as nutritional interventions, vegetable/dairy diets (with extreme attention being paid not to compromise overall protein-energy intake), prebiotic fibre, probiotics and symbiotics (taking into account the great heterogeneity in the content of probiotic species and their vitality in various products and brands) may play a relevant role, despite formal evidence in their favour being less stringent than that available for non-absorbable disaccharides and non-absorbable antibiotics. Finally, ammonia-lowering strategies can obviously be associated with simple, direct vigilance modulation, for example with timed coffee administration.
      • Casula E.P.
      • Bisiacchi P.S.
      • Corrias M.
      • Schiff S.
      • Merkel C.
      • Amodio P.
      • et al.
      Acute hyperammonaemia induces a sustained decrease in vigilance, which is modulated by caffeine.
      Of interest, trials with psychoactive drugs modulating vigilance are underway, together with several others targeting inflammation, general and specific nutritional deficits, the microbiota, the intestinal barrier, and the urea cycle.
      Expert opinion
      • Minimal forms of HE are common, and may affect quality of life and independence, and over time, are associated with a higher likelihood of developing overt HE.
      • Screening tools for minimal HE are readily available, do not require specialist equipment and may help with follow-up and disease monitoring.
      • Minimal HE should be treated as ‘prophylaxis’ to prevent more severe overt HE, and treatment challenge may help confirm the diagnosis.

      What is the role for “acute” hepatic venous pressure gradient response to NSBBs in the management of clinically significant portal hypertension?

      Patients with clinically significant portal hypertension (CSPH) on primary prophylaxis are protected from acute variceal bleeding (AVB) if HVPG decreases to values ≤12 mmHg,
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      or if HVPG decreases by >10%,
      • Hernandez-Gea V.
      • Aracil C.
      • Colomo A.
      • Garupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers.
      and HVPG-guided therapy has been shown to reduce portal hypertension-related decompensations and mortality.
      • Villanueva C.
      • Graupera I.
      • Aracil C.
      • Alvarado E.
      • Minana J.
      • Puente A.
      • et al.
      A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.
      Whilst HVPG response to therapy clearly differentiate patients’ future risk, the ‘gold standard’ is to measure HVPG at baseline, and then to repeat the measurement after chronic NSBB administration. HVPG responses appear to be maintained over a long period of time.
      • Augustin S.
      • Gonzalez A.
      • Badia L.
      • Millan L.
      • Gelabert A.
      • Romero A.
      • et al.
      Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal bleeding.
      Measurement of acute HVPG can guide management of primary and secondary variceal bleeding risk and may have prognostic value for other complications including ascites.
      To date, 6 studies evaluating the role of acute HVPG responses have been published, as outlined in Table 1. A reduction of HVPG between 10% to 12% with intravenous propranolol (followed by 0.2 mg/hour) protected against AVB at 2 years. Interestingly, studies demonstrating a prognostic value for acute HVPG response in primary bleeding prophylaxis, also demonstrated a reduction in the occurrence of ascites and cirrhosis complications in HVPG responders.
      • Hernandez-Gea V.
      • Aracil C.
      • Colomo A.
      • Garupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers.
      ,
      • Kirnake V.
      • Arora A.
      • Gupta V.
      • Sharma P.
      • Singla V.
      • Bansal N.
      • et al.
      Hemodynamic response to carvedilol is maintained for long periods and leads to better clinical outcome in cirrhosis: a prospective study.
      ,
      • Villanueva C.
      • Albillos A.
      • Genesca J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • et al.
      Beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension [PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      However, there was only a moderate correlation between acute and chronic HVPG response, with the prognostic value of the chronic response having a greater correlation with the development of ascites.
      • Hernandez-Gea V.
      • Aracil C.
      • Colomo A.
      • Garupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers.
      In 1 study evaluating acute response after oral carvedilol administration, 92% of patients had maintained a haemodynamic response at 6 months.
      • Kirnake V.
      • Arora A.
      • Gupta V.
      • Sharma P.
      • Singla V.
      • Bansal N.
      • et al.
      Hemodynamic response to carvedilol is maintained for long periods and leads to better clinical outcome in cirrhosis: a prospective study.
      Table 1The role of acute HVPG responses.
      StudyNumber of patientsInterventionsPatient characteristicsFindings
      Villanueva et al. Gastroenterology 2009
      • Villanueva C.
      • Aracil C.
      • Colomo A.
      • Hernandez-Gea V.
      • Lopez-Balaguer J.M.
      • Alvarez-Urturi C.
      • et al.
      Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding.
      n = 105“Acute” HVPG response to i.v. propranolol (0.15 mg/kg followed by 0.2 mg/h); Nadolol (titrated according to HR)Primary prophylaxis (all high-risk varices); HVPG ≥12 mmHg; Definition of HVPG response: ≤12 mmHg/≥20%AVB: HVPG response: 4% vs. non-response: 46% at 2 years (independently predictive); Ascites: decreased; Mortality: trend towards decrease, moderate correlation between “acute” and “chronic” HVPG response
      La Mura et al. J Hepatol 2009
      • La Mura V.
      • Abraldes J.G.
      • Raffa S.
      • Retto O.
      • Berzigotti A.
      • Garcia-Pagan J.C.
      • et al.
      Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.
      n = 166“Acute” HVPG response to i.v. propranolol (0.15 mg/kg); Propranolol or nadolol (titrated according to HR/SAP)Primary (n = 78; small: 22%; large: 78% varices, red wale marks: 29%) and secondary prophylaxis (n = 88); HVPG ≥12 mmHg; Definition of HVPG response: ≥12%AVB: HVPG response: 7%/16% vs. non-response: 21%/40% at 1/2 years (independently predictive); AVB (primary prophylaxis): trend towards decrease; AVB (secondary prophylaxis): decreased (independently predictive); Mortality: HVPG response: 5%/5% vs. non-response: 13%/35% at 1/2 years (independently predictive);
      Hernández-Gea et al. Am J Gastroenterol 2012
      • Hernandez-Gea V.
      • Aracil C.
      • Colomo A.
      • Garupera I.
      • Poca M.
      • Torras X.
      • et al.
      Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers.
      n = 83;

      n = 78 with information on HVPG response
      “Acute” HVPG response to i.v. propranolol (0.15 mg/kg);

      Nadolol (titrated according to HR);

      “Chronic” HVPG response (1–3 months)
      Primary prophylaxis (all large varices);

      HVPG ≥12 mmHg;

      Definition of HVPG response: ≥10%
      Bleeding: “chronic” HVPG response: 5% vs. non-response: 17% at 2 years (independently predictive);

      AVB: “chronic” HVPG response: 5% vs. non-response: 14% at 2 years;

      Ascites: “chronic” HVPG response: 27% vs. non-response: 89% (independently predictive); “acute” HVPG response: 17% vs. non-response: 49% at 2 years;

      Refractory ascites: decreased if “chronic” haemodynamic response; “acute” HVPG response: 5% vs. non-response: 18% at 2 years;

      SBP: comparable;

      HRS: decreased if “chronic” HVPG response; trend towards decrease if “acute” HVPG response;

      HE: trend towards decrease if ‘chronic’ hemodynamic response;

      Mortality: decreased if “chronic” HVPG response
      Kirmake et al. J clinical and Experimental Hepatology 2016
      • Abraldes J.G.
      • Villanueva C.
      • Banares R.
      • Aracil C.
      • Catalina M.V.
      • Garci A.P.J.C.
      • et al.
      Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy.
      n = 69“Acute” HVPG response to oral carvedilol (25 mg).

      Carvedilol 12.5 mg/day
      Primary or secondary prophylaxis (large varices or history of variceal bleeding).

      Response defined as a decrease ≥10% or <12 mmHg.
      AVB: “acute” HVPG response: 6% vs. non-response: 26% at 6 months;

      Worsening ascites: “acute” HVPG response: 26% vs. non-response: 74% at 6 months
      Fortea et al. WJCC 2018
      • Fortea J.I.
      • Puente A.
      • Ruiz P.
      • Ezcurra I.
      • Vaquero J.
      • Cuadrado A.
      • et al.
      Impact of an acute hemodynamic response-guided protocol for primary prophylaxis of variceal bleeding.
      n = 76Acute” HVPG response to i.v. propranolol (0.15 mg/kg); nadolol or propranolol (titrated according to HR).

      Non responders were treated with carvedilol (titrated according to HR)
      Primary prophylaxis Response defined as a decrease ≥10% or <12 mmHg.Acute decompensation in compensated cirrhosis. “acute” HVPG response 12.7% vs. non-response receiving carvedilol 20% at 1 year (NS)

      Acute decompensation in decompensated cirrhosis: “acute” HVPG response: 21% vs. non-response receiving carvedilol 21% (NS)
      Villanueva et al. Lancet 2019
      • Villanueva C.
      • Albillos A.
      • Genesca J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • et al.
      Beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension [PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      n = 201Acute” HVPG response to i.v. propranolol (0.15 mg/kg)

      Responders were randomly assigned to propranolol (up to 160 mg twice a day) vs. placebo and non-responders to carvedilol (≤25 mg/day) vs. placebo
      Compensated cirrhosis and CSPH without high-risk varices.Cirrhosis decompensation (ascites, bleeding, or HE) or death: 16 (16%) in the β blockers group vs. 27 (27%) in the placebo group.

      Ascites: 9 (9%) in the β blockers group vs. 20 (20%) in the placebo group

      AVB: 4 (4%) in the β blockers group vs. 3 (3%) in the placebo group

      Mortality did not differ according to randomisation
      AVB, acute variceal bleeding; CSPH, clinically significant portal hypertension; HE, hepatic encephalopathy; HR, heart rate; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; SBP, spontaneous bacterial peritonitis.
      Observational studies suggest that HVPG monitoring might be useful to stratify risk and to guide choice of therapy. In the PREDESCI trial and in a retrospective study, carvedilol was used in HVPG acute non-responders to intravenous propranolol.
      • Villanueva C.
      • Albillos A.
      • Genesca J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • et al.
      Beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension [PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Fortea J.I.
      • Puente A.
      • Ruiz P.
      • Ezcurra I.
      • Vaquero J.
      • Cuadrado A.
      • et al.
      Impact of an acute hemodynamic response-guided protocol for primary prophylaxis of variceal bleeding.
      In these patients, carvedilol facilitated further HVPG reduction and improved clinical outcomes long term, even in this high-risk group.
      Whilst some may consider HVPG assessment a specialist investigation, the practicality is well within the means of any interventional radiology unit, and if following standard procedures for evaluating pressure measurements, is a highly reproducible and safe test. Indeed, its risks (and costs) are significantly lower than transjugular biopsy alone, which is routinely performed. As such, acute HVPG response after AVB in those who are not deemed candidates for pre-emptive transjugular intrahepatic portosystemic shunt (TIPS), may best guide the medical strategy for secondary prophylaxis, albeit, further evidence is required to strongly recommend this approach.
      • Nicoara-Farcau O.
      • Han G.
      • Rudler M.
      • Angrisani D.
      • Monescillo A.
      • Torres F.
      • et al.
      Effects of early placement of transjugular portosystemic shunts in patients with high-risk acute variceal bleeding: a meta-analysis of individual patient data.
      Expert opinion
      • Assessment of “acute” HVPG response is feasible and safe in patients with cirrhosis and CSPH and it has an acceptable correlation with chronic response.
      • Acute HVPG response has a good correlation with all clinical outcomes, not only bleeding risk but also the occurrence of ascites and its complications.
      • HVPG-guided therapy could improve the management of patients with CSPH, both for primary and secondary prophylaxis of AVB, reducing costs and adverse effects by identifying ineffective therapy.

      What are the limitations of NSBB therapy in decompensated cirrhosis?

      Current guidelines recommend NSBBs for primary and secondary prophylaxis of AVB
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • de Franchis R.
      • Baveno V.I.F.
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      based on high-quality RCTs that usually exclude patients with decompensated liver disease, particularly those with refractory ascites. Some studies investigating the issue of safety in this group of patients suggested that NSBBs were associated with increased mortality,
      • Serste T.
      • Melot C.
      • Francoz C.
      • Durand F.
      • Rautou P.E.
      • Valla D.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      and higher post paracentesis circulatory dysfunction.
      • Serste T.
      • Francoz C.
      • Durand F.
      • Rautou P.E.
      • Melot C.
      • Valla D.
      • et al.
      Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study.
      These observations led to the hypothesis that worsening cardiac function in some patients with cirrhosis exposes them to the detrimental effects of NSBBs.
      • Krag A.
      • Wiest R.
      • Albillos A.
      • Gluud L.L.
      The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease.
      ,
      • Ferrarese A.
      • Zanetto A.
      • Germani G.
      • Burra P.
      • Senzolo M.
      Rethinking the role of non-selective beta blockers in patients with cirrhosis and portal hypertension.
      Further studies
      • Bang U.C.
      • Benfield T.
      • Hyldstrup L.
      • Jensen J.E.
      • Bendtsen F.
      Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers.
      ,
      • Reiberger T.
      • Mandorfer M.
      Beta adrenergic blockade and decompensated cirrhosis.
      and a recent post hoc analysis of 3 RCTs where vaptans and NSBBs were co-administered in patients with ascites, did not show an increase in mortality.
      • Bossen L.
      • Krag A.
      • Vilstrup H.
      • Watson H.
      • Jepsen P.
      Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: post Hoc analysis of three randomized controlled trials with 1198 patients.
      Moreover, NSBBs have been shown to decrease the risk of spontaneous bacterial peritonitis (SBP),
      • Senzolo M.
      • Cholongitas E.
      • Burra P.
      • Leandro G.
      • Thalheimer U.
      • Patch D.
      • et al.
      beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.
      despite a prior study suggesting an increased risk of AKI,
      • Mandorfer M.
      • Bota S.
      • Schwabl P.
      • Bucsics T.
      • Pfisterer N.
      • Kruzik M.
      • et al.
      Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      albeit this was refuted on subgroup analysis.
      • Bang U.C.
      • Benfield T.
      • Hyldstrup L.
      • Jensen J.E.
      • Bendtsen F.
      Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers.
      ,
      • Bossen L.
      • Krag A.
      • Vilstrup H.
      • Watson H.
      • Jepsen P.
      Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: post Hoc analysis of three randomized controlled trials with 1198 patients.
      ,
      • Tergast T.L.
      • Kimmann M.
      • Laser H.
      • Gerbel S.
      • Manns M.P.
      • Cornberg M.
      • et al.
      Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis.
      Additionally, lower dose NSBBs (≤80 mg) are associated with reduced mortality after SBP.
      • Madsen B.S.
      • Nielsen K.F.
      • Fialla A.D.
      • Krag A.
      Keep the sick from harm in spontaneous bacterial peritonitis: dose of beta blockers matters.
      In patients with sepsis and septic shock, the prior use of NSBBs does not seem to be associated with worse outcome,
      • Galbois A.
      • Das V.
      • Thabut D.
      • Maury E.
      • Ait-Oufella H.
      • Housset C.
      • et al.
      Beta-blockers have no effect on outcomes in patients with cirrhosis and severe infections.
      and this is similarly the case for acute-on-chronic liver failure (ACLF).
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • Mehta G.
      • Macnaughtan J.
      • Bendtsen F.
      • et al.
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      Recently, Tergast et al. observed a significant increase in 28-day transplant-free survival with NSBB use on multivariate analysis in an ACLF subgroup. However, this advantage was completely lost in patients with mean arterial pressure <65 mmHg.
      • Tergast T.L.
      • Kimmann M.
      • Laser H.
      • Gerbel S.
      • Manns M.P.
      • Cornberg M.
      • et al.
      Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis.
      Patients with refractory ascites have a more pronounced hyperdynamic state, and reduced cardiac output compared to those without refractory ascites,
      • Giannelli V.
      • Roux O.
      • Laouenan C.
      • Manchon P.
      • Ausloos F.
      • Bachelet D.
      • et al.
      Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation.
      which is further exacerbated in patients with azotemia and HRS.
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Gines P.
      • Moreira V.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      Indeed, it has been shown that patients treated with NSBBs have significantly lower left ventricular performance
      • Giannelli V.
      • Roux O.
      • Laouenan C.
      • Manchon P.
      • Ausloos F.
      • Bachelet D.
      • et al.
      Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation.
      and that this is correlated with impairment of autoregulation of renal flow and the occurrence of AKI.
      • Tellez L.
      • Ibanez-Samaniego L.
      • Perez Del Villar C.
      • Yotti R.
      • Martinez J.
      • Carrion L.
      • et al.
      Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
      However, not all patients develop impairment of cardiac autoregulation with NSBBs, as shown by a prospective study in patients with refractory ascites undergoing large volume paracentesis (LVP).
      • Ferrarese A.
      • Tikhonoff V.
      • Casiglia E.
      • Angeli P.
      • Fasolato S.
      • Faggian D.
      • et al.
      Hemodynamic evaluation of nonselective beta-blockers in patients with cirrhosis and refractory ascites.
      Furthermore, dosing and type of NSBB are also important considerations. Clinical studies showing a detrimental effect with NSBBs used higher doses of propranolol (160 mg).
      • Serste T.
      • Melot C.
      • Francoz C.
      • Durand F.
      • Rautou P.E.
      • Valla D.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      By contrast, lower doses between 40 mg and 80 mg seem to confer an advantage. Current EASL guidelines recommend propranolol at a daily dose of ≤80 mg.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      However, carvedilol was not recommended in the guidelines for patients with refractory ascites because of concerns related to its potential hypotensive effects. Recent studies have suggested carvedilol is safe at low doses (6.25–12.5 mg), provided that patients maintain systolic pressures ≥90 mmHg.
      • Rodrigues S.G.
      • Mendoza Y.P.
      • Bosch J.
      Beta-blockers in cirrhosis: evidence-based indications and limitations.
      Moreover, carvedilol has a role in reducing inflammation and mitochondrial dysfunction.
      • Araujo Junior R.F.
      • Garcia V.B.
      • Leitao R.F.
      • Brito G.A.
      • Miguel Ede C.
      • Guedes P.M.
      • et al.
      Carvedilol improves inflammatory response, oxidative stress and fibrosis in the alcohol-induced liver injury in rats by regulating kuppfer cells and hepatic stellate cells.
      These are common events in decompensated cirrhosis, and importantly, carvedilol has since been demonstrated to improve survival in patients with ascites.
      • Sinha R.
      • Lockman K.A.
      • Mallawaarachchi N.
      • Robertson M.
      • Plevris J.N.
      • Hayes P.C.
      Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites.
      Expert opinion
      • NSBBs are not absolutely contraindicated in decompensated cirrhosis. However, high doses of NSBBs should be avoided.
      • NSBBs should be temporarily discontinued or titrated in patients with progressive hypotension (systolic pressure <90 mmHg), during acute conditions such as sepsis, SBP or AKI, which can further impair cardiovascular function.
      • Carvedilol should be considered as a beta-blocker option in decompensated cirrhosis at low doses.

      TIPS in patients with decompensated cirrhosis and an elevated MELD: Is there a ‘safe’ threshold to improve management of refractory ascites in non-transplant candidates?

      Refractory ascites is a severe complication of cirrhosis that is associated with poor survival.
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Badalamenti S.
      • Cassara L.
      • Maggi A.
      • et al.
      Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients.
      Therefore, patients without contraindications should be promptly evaluated for LT. If there is a short waiting period or a high MELD score which can lead to a LT in less than 3–6 months, LVP with albumin infusion (LVP+A) is a safe and effective treatment and the best bridge to LT.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      The scenario changes when a longer waiting time is expected or the patient has absolute contraindications for LT. In this situation, it is extremely important to tease apart refractory ascites (either diuretic-resistant or diuretic-intolerant) from recurrent/recidivant ascites (defined as ascites that recurs at least on 3 occasions within 12 months, despite adequate diuretic treatment). In those with recurrent/recidivant ascites, an RCT showed that TIPS using polytetrafluoroethylene (PTFE)-covered stents improved 1-year transplant free-survival without increasing the incidence of HE compared to LVP+A, and it is in our expert opinion, the best treatment approach provided patients do not have absolute contraindications for TIPS (Box 1).
      • Hebert P.L.
      • Sisk J.E.
      • Wang J.J.
      • Tuzzio L.
      • Casabianca J.M.
      • Chassin M.R.
      • et al.
      Cost-effectiveness of nurse-led disease management for heart failure in an ethnically diverse urban community.
      TIPS should be considered in patients with refractory ascites, especially in those being considered for liver transplantation, using smaller size stents, and with due consideration of prophylactics for HE. MELD, whilst an indicator of risk, should be used in conjunction with a holistic review of the patient including age, frailty and comorbidities.
      Contraindications for TIPS placement.

       Absolute

      • -
        Overt Recurrent/Chronic Hepatic encephalopathy
      • -
        Severe Pulmonary artery hypertension: meanPAP>35mmHg and PVR >240 dyn.cm-5
      • -
        Heart failure

       Relative

      • -
        Age >70 years
      • -
        MELD >18
      MELD, model for end-stage liver disease; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; TIPS, transjugular intrahepatic portosystemic shunt.
      Guidance regarding the best treatment option for patients with refractory ascites is more controversial. Several meta-analyses based on aggregate data of RCTs comparing TIPS using bare stents vs. LVP+A, showed that TIPS was more effective than LVP+A in controlling ascites but patients had a higher incidence of HE, without an improvement in survival.
      • Kimbell B.
      • Murray S.A.
      • Byrne H.
      • Baird A.
      • Hayes P.C.
      • MacGilchrist A.
      • et al.
      Palliative care for people with advanced liver disease: a feasibility trial of a supportive care liver nurse specialist.
      In contrast, 1 specific meta-analysis using the individual data of previous RCTs, which allowed the authors to analyse survival as a time-dependent event, demonstrated a survival benefit for patients receiving TIPS in comparison to those treated with LVP+A.
      • Fabrellas N.
      • Carol M.
      • Palacio E.
      • Aban M.
      • Lanzillotti T.
      • Nicolao G.
      • et al.
      Nursing care of patients with cirrhosis: the LiverHope nursing project.
      Interestingly, the benefit of TIPS was observed for all MELD risk categories and no relationship between MELD and the treatment received (TIPS or LVP+A) was observed. So, does this mean that regardless of the MELD value, TIPS is a better option than LVP+A? The answer is no; it is clear that there is a degree of liver insufficiency beyond which TIPS is likely to be harmful. Unfortunately, the available information about what is the “safe” MELD threshold value for TIPS is scarce and outdated.
      Although different studies attempted to find predictors of poor outcome in patients with refractory ascites treated with TIPS, most of these have several weaknesses that likely explain why the variables and defined cut-offs are difficult to reproduce. These studies only included patients in whom initially strict exclusion criteria for TIPS were applied and, therefore, this induces bias with a highly preselected population. For instance, excluding patients from studies with a MELD, bilirubin, creatinine or age above a given value (not always the same in the different studies) may underestimate the potentially poor outcome of TIPS in patients with higher MELD, bilirubin, creatinine or age. In addition, most prognostic studies are based on old cohorts of patients treated with TIPS for variceal bleeding or for refractory ascites. Although the MELD score was initially shown to predict prognosis after elective TIPS for either prevention of variceal rebleeding or for treatment of refractory ascites,
      • Malinchoc M.
      • Kamath P.S.
      • Gordon F.D.
      • Peine C.J.
      • Rank J.
      • ter Borg P.C.
      A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.
      at the same MELD value, prognosis is worse in patients with refractory ascites.
      • Ferral H.
      • Gamboa P.
      • Postoak D.W.
      • Albernaz V.S.
      • Young C.R.
      • Speeg K.V.
      • et al.
      Survival after elective transjugular intrahepatic portosystemic shunt creation: prediction with model for end-stage liver disease score.
      Therefore, MELD cut-off values are different for patients with variceal bleeding or with refractory ascites.
      • Allegretti A.S.
      • Frenk N.E.
      • Li D.K.
      • Seethapathy H.
      • Vela Parada X.F.
      • Long J.
      • et al.
      Evaluation of model performance to predict survival after transjugular intrahepatic portosystemic shunt placement.
      In addition, a remarkable number of studies assessing prognosis in patients treated with TIPS used bare stents, while current evidence shows that prognosis is better with covered stents, a fact that may also influence the applicability of prognostic markers.
      • Maleux G.
      • Perez-Gutierrez N.A.
      • Evrard S.
      • Mroue A.
      • Le Moine O.
      • Laleman W.
      • et al.
      Covered stents are better than uncovered stents for transjugular intrahepatic portosystemic shunts in cirrhotic patients with refractory ascites: a retrospective cohort study.
      • Tan H.K.
      • James P.D.
      • Sniderman K.W.
      • Wong F.
      Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion.
      • Gaba R.C.
      • Parvinian A.
      • Casadaban L.C.
      • Couture P.M.
      • Zivin S.P.
      • Lakhoo J.
      • et al.
      Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis.
      In addition, a better general management of patients with refractory ascites, which includes prophylaxis and treatment of HE,
      • Bureau C.A.I.T.D.
      • Dharancy S.
      • Perarnau J.M.
      • Oberti F.
      • Borentein P.
      • et al.
      Rifaximin for the prevention of hepatic encephalopathy in patients treated by TIPS: a multicentric randomized placebo-controlled trial.
      and the use of smaller stent sizes,
      • Schepis F.
      • Vizzutti F.
      • Garcia-Tsao G.
      • Marzocchi G.
      • Rega L.
      • De Maria N.
      • et al.
      Under-dilated TIPS associate with efficacy and reduced encephalopathy in a prospective, non-randomized study of patients with cirrhosis.
      likely improves the overall prognosis of patients with refractory ascites treated with TIPS. The implementation of these therapeutic strategies could modify the prognosis of patients with refractory ascites currently treated with covered TIPS. Thus, it is plausible that a certain MELD value, platelet count, or bilirubin level, among other prognostic factors evaluated that were previously associated with a poor prognosis, may no longer be so.
      Despite all these considerations, and until new evidence is available, MELD is still the most used prognostic factor when considering a TIPS in patients with refractory ascites. In most centres an MELD value ≥18–20
      • Ferral H.
      • Gamboa P.
      • Postoak D.W.
      • Albernaz V.S.
      • Young C.R.
      • Speeg K.V.
      • et al.
      Survival after elective transjugular intrahepatic portosystemic shunt creation: prediction with model for end-stage liver disease score.
      ,
      • Miraglia R.
      • Maruzzelli L.
      • Tuzzolino F.
      • Petridis I.
      • D'Amico M.
      • Luca A.
      Transjugular intrahepatic portosystemic shunts in patients with cirrhosis with refractory ascites: comparison of clinical outcomes by using 8- and 10-mm PTFE-covered stents.
      is considered a contraindication. There is no question that TIPS in such patients is associated with a poorer outcome than in patients with a lower MELD value. However, the prognosis of these patients with poor liver function who undergo other therapies such as LVP+A or AlfaPumpTM instead of TIPS, remains unanswered.
      • Choe W.H.
      Do cirrhotic patients with a high MELD score benefit from TIPS?.
      Therefore, when evaluating patients for TIPS with refractory ascites, the expert opinion is to use scores such as MELD as a guide but not as a definitive rule. The decision should also include a holistic and evidence-based approach taking into consideration, among other factors, age, frailty measures,
      • Shoreibah M.G.
      • Mahmoud K.
      • Aboueldahab N.A.
      • Vande Lune P.
      • Massoud M.
      • Bae S.
      • et al.
      Psoas muscle density in combination with model for end-stage liver disease score can improve survival predictability in transjugular intrahepatic portosystemic shunts.
      bilirubin, platelet count
      • Bureau C.
      • Metivier S.
      • D'Amico M.
      • Peron J.M.
      • Otal P.
      • Pagan J.C.
      • et al.
      Serum bilirubin and platelet count: a simple predictive model for survival in patients with refractory ascites treated by TIPS.
      and comorbidities of the patient, as well as the expertise of the centre, as mortality is lower in centres that perform ≥20 TIPS per year.
      • Sarwar A.
      • Zhou L.
      • Novack V.
      • Tapper E.B.
      • Curry M.
      • Malik R.
      • et al.
      Hospital volume and mortality after transjugular intrahepatic portosystemic shunt creation in the United States.
      Patients with refractory ascites and severe liver dysfunction in whom TIPS is contraindicated are usually treated with LVP+A. In these patients, the use of AlfaPump has been shown to reduce the number and volume of paracentesis.
      • Bureau C.
      • Adebayo D.
      • Chalret de Rieu M.
      • Elkrief L.
      • Valla D.
      • Peck-Radosavljevic M.
      • et al.
      Alfapump(R) system vs. large volume paracentesis for refractory ascites: a multicenter randomized controlled study.
      ,
      • Lepida A.
      • Marot A.
      • Trepo E.
      • Degre D.
      • Moreno C.
      • Deltenre P.
      Systematic review with meta-analysis: automated low-flow ascites pump therapy for refractory ascites.
      That said, AlfaPump does not improve survival and is associated with frequent and potentially serious adverse effects.
      • Bureau C.
      • Adebayo D.
      • Chalret de Rieu M.
      • Elkrief L.
      • Valla D.
      • Peck-Radosavljevic M.
      • et al.
      Alfapump(R) system vs. large volume paracentesis for refractory ascites: a multicenter randomized controlled study.
      ,
      • Lepida A.
      • Marot A.
      • Trepo E.
      • Degre D.
      • Moreno C.
      • Deltenre P.
      Systematic review with meta-analysis: automated low-flow ascites pump therapy for refractory ascites.
      Although only tested in a non-randomised observational study, patients with refractory ascites treated with covered TIPS dilated to only 6–7 mm, had the same efficacy controlling ascites but with significantly less HE than those patients in whom the stent was dilated to 8–10 mm.
      • Schepis F.
      • Vizzutti F.
      • Garcia-Tsao G.
      • Marzocchi G.
      • Rega L.
      • De Maria N.
      • et al.
      Under-dilated TIPS associate with efficacy and reduced encephalopathy in a prospective, non-randomized study of patients with cirrhosis.
      Therefore, it could well be that using smaller stents may expand the indication of TIPS in patients with refractory ascites and compromised liver function.
      • Bosch J.
      Small diameter shunts should lead to safe expansion of the use of TIPS.
      This should obviously be evaluated in adequate clinical studies.
      Expert opinion
      • In patients with recurrent ascites, and no contraindications to TIPS, PTFE-covered stents are the best treatment option to improve 1-year transplant free-survival without increasing the incidence of HE.
      • When evaluating patients for TIPS with refractory ascites, scores such as MELD <18 can be used as a guide but not as a definitive rule, and should be considered alongside other factors such as age, frailty and patient comorbidities.
      • Smaller stents may expand the indication for TIPS in patients with refractory ascites and compromised liver function.

      Conclusions

      Whilst the above sections are by no means an exhaustive list of controversial areas in cirrhosis management, they do address many commonly encountered areas of practice and provide a suggested management approach based on current evidence, even if this is limited. Many of these areas are topics of considerable research interest, particularly those where new biomarkers are being tested (e.g. surrogates of portal hypertension or kidney injury), or where modelling of large data sets will potentially inform new prognostic stratification. This research will undoubtedly help address such controversies and lead to updates of the current practice guidelines.

       Abbreviations

      ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; AVB, acute variceal bleeding; CKD, chronic kidney disease; CO, cardiac output; CSPH, clinically significant portal hypertension; GFR, glomerular filtration rate; HbA1c, glycated haemoglobin; HE, hepatic encephalopathy; HRV, heart rate variability; HVPG, hepatic venous pressure gradient; LT, liver transplantation; LVP, large volume paracentesis; NSBBs, non-selective beta blockers; RCT, randomized controlled trials; RRT, renal replacement therapy; T2DM, type 2 diabetes mellitus; TIPS, transjugular intrahepatic portosystemic shunt.

      Financial support

      There is no financial support relevant to the preparation of this manuscript.

      Authors’ contributions

      All authors contributed equally from their respective Institutions (below).

      Conflict of interest

      The authors collectively have no specific conflicts of interest to declare pertaining to the work in this review.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      Transparency declaration

      This article is published as part of a supplement entitled New Concepts and Perspectives in Decompensated Cirrhosis. Publication of the supplement was supported financially by CSL Behring. The sponsor had no involvement in content development, the decision to submit the manuscript or in the acceptance of the manuscript for publication.

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