Severe End-stage Liver Disease Research Articles

Chronotropic incompetence in end-stage liver disease.

BackgroundCirrhosis causes alterations in the cardiovascular and autonomic nervous systems and leads to cirrhotic cardiomyopathy (CCM). CCM is defined as cardiac dysfunction characterized by an impaired systolic responsiveness to stress or exercise, and/or impaired diastolic function, as well as electrophysiological abnormalities, including chronotropic incompetence (CI), in the absence of other known cardiac disease. CI is a common feature of autonomic neuropathy in cirrhosis. The aim of the study is to assess the role of cardiac exercise stress test in the diagnosis of CCM.MethodsThe analysis included 160 end-stage liver disease (ESLD) patients who underwent a cardiac exercise stress test prior to the orthotopic liver transplantation. CI was defined as the inability to achieve the heart rate reserve (HRR). Pertaining to the therapy with beta-blockers: 80% of HRR was achieved in patients not taking beta-blockers and 62% in patients taking beta-blockers.ResultsIn the analyzed population, 68.8% of patients met the criteria for CI. CI was more frequent in the more severe ESLD (with a higher MELD score and in a higher Child-Pugh class). In comparison to the viral hepatitis and other etiologies of ESLD, patients with alcoholic cirrhosis had a significantly lower rest heart rate (HR), lower maximal HR, lower median achieved percentage of maximal predicted HR (MPHR), a smaller percentage of patients achieved ≥ 85% of MPHR and a lower heart rate reserve. No significant relationship between the survival of OLT recipients and presence of chronotropic incompetence regarding to class of Child-Pugh scale, MELD score and etiology of ESLD were found.ConclusionsThe prevalence of CI is higher among liver transplant candidates than previously described. The altered chronotropic response may differ in regard to the severity of liver disease correlating with both the Child-Pugh and MELD scores, however CI does not seem to influence the long-term survival post OLT. Exercise stress test is a reliable, safe and useful tool for the diagnosis of CCM in liver transplant candidates and should be included in the standard cardiovascular assessment prior to OLT.

Establishment of Functional Liver Spheroids From Human Hepatocyte-Derived Liver Progenitor-Like Cells for Cell Therapy.

Globally, about two million people die from liver diseases every year. Liver transplantation is the only reliable therapy for severe end-stage liver disease, however, the shortage of organ donors is a huge limitation. Human hepatocytes derived liver progenitor-like cells (HepLPCs) have been reported as a novel source of liver cells for development of in vitro models, cell therapies, and tissue-engineering applications, but their functionality as transplantation donors is unclear. Here, a 3-dimensional (3D) co-culture system using HepLPCs and human umbilical vein endothelial cells (HUVECs) was developed. These HepLPC spheroids mimicked the cellular interactions and architecture of mature hepatocytes, as confirmed through ultrastructure morphology, gene expression profile and functional assays. HepLPCs encapsulated in alginate beads are able to mitigate liver injury in mice treated with carbon tetrachloride (CCL4), while alginate coating protects the cells from immune attack. We confirmed these phenomena due to HUVECs producing glial cell line-derived neurotrophic factor (GDNF) to promote HepLPCs maturation and enhance HepLPCs tight junction through MET phosphorylation. Our results display the efficacy and safety of the alginate microencapsulated spheroids in animal model with acute liver injury (ALF), which may suggest a new strategy for cell therapy.

Part 2: Disease of the Heart and Liver: A Relationship That Cuts Both Ways.

Diseases known to affect both the heart and liver include a variety of infectious, autoimmune, and metabolic disorders, as well as toxins: most commonly alcohol. As damage to both the heart and liver progresses, transplantation is a reasonable therapeutic option. Heart failure patients with underlying congestive hepatopathy receiving cardiac transplant have demonstrated improved liver enzyme levels posttransplant. Patients with severe end-stage liver disease requiring a liver transplant must undergo careful preoperative evaluation as surgical stress exposes the myocardium to high levels of catecholamines. Clinicians must consider both cardiac and hepatic complications when evaluating heart failure, cirrhosis, and nonalcoholic fatty liver disease. In Part 2 of this review, we discuss new noninvasive techniques for assessing liver fibrosis in the preoperative stage. Both serum and radiologic studies, such as transient elastography, have begun to take the place of liver biopsy due to their decreased morbidity. Last, we explore the current research examining the benefit of combined heart-liver transplant, although more longitudinal outcome studies are needed.

In Vitro Hepatic Differentiation of Adult, Embryonic, Induced Pluripotent and Perinatal Stem-Cells

Globally regenerative medicine is considered as one of the rapidly growing biomedical industry have objective to substitute damaged cells. Cell transplantation is less intrusive than whole-organ transplantation, and has been used to provide an alternative for patients to whole-organ transplantation. The End-stage liver disease comprises a subgroup of patients with cirrhosis who have signs of decompensation that is irreversible with medical treatment. The only restorative therapy for severe end-stage liver disease is orthotropic liver transplantation. However, liver transplantation has several limitations such as scarcity of organ donors, immunosuppressive drugs, and several postoperative complications. Thus, cell transplantation can be used for the treatment of end stage liver disorders to decrease the mortality in acute liver failure. Therefore, stem cells can be used for cellular therapy, development of liver disease models, and tissue-engineering applications. This review involved the studies conducted on the stem cells potential of hepatic differentiation, isolated from different sources. The PubMed and Google Scholar were searched for scientific studies reported the sources of stem cells based on their origin and their potential of hepatic differentiation in-vitro by using different tools of differentiation. All the research articles were selected in which solely hepatic differentiation in combination with different tools is reported. Keywords: Adult Stem Cells, Embryonic Stem Cells, Induced Pluripotent Stem Cells, In-vitro, Mesenchymal Stem Cells.

Induced pluripotent stem cells for the treatment of liver diseases: challenges and perspectives from a clinical viewpoint.

The only curative treatment for severe end-stage liver disease (ESLD) is liver transplantation (LT) but it is limited by the shortage of organ donors. The increase of the incidence of liver disease has led to develop new therapeutic approaches such as liver cell transplantation. Current challenges that limit a wider application of this therapy include a limited cell source and the poor engraftment in the host liver of cryopreserved hepatocytes after thawing. Induced pluripotent stem cells (iPSCs) that can be differentiated into hepatocyte-like cells (HLCs) are being widely explored as an alternative to human hepatocytes because of their unlimited proliferation capacity and their potential ability to avoid the immune system. Their large-scale production could provide a new tool to produce enough HLCs for treating patients with metabolic diseases, acute liver failure (ALF), those with ESLD or patients not considered for organ transplantation. In this review we discuss current challenges for generating differentiated cells compatible with human application as well as in-depth safety evaluation. This analysis highlights the uncertainties and deficiencies that should be addressed before their clinical use but also points out the potential benefits that will produce a great impact in the field of hepatology.

The diagnostic value and limits of diagnostic parameters for Wilson's disease

Wilson disease (WD) is a rare and treatable genetic disorder. This paper describes the new advances and author's long-term experiences in the diagnosis of WD. The characteristics in clinical and routine tests are: the age of presentation can be quite broad, the WD could not be excluded based on age only; the patients usually have mild digestive symptoms but obvious chronic liver disease signs; liver function tests may reveal normal or a mild elevation in bilirubin, ALT and AST, but quite abnormal in serum albumin and prothrombin time in most patients; Coombs-negative hemolytic anemia, normal or markedly subnormal serum alkaline phosphatase (typically < 40 IU/L) are useful for the diagnosis of fulminant WD. In china, Kayser-Fleischer rings are present in 72.2% of patients at the time of diagnosis, the positive rate is significantly higher in patients with a neurological presentation (93.4%) than patients presenting with liver disease (63.3%), however, they are usually absent in children under 6 years old, occasionly present in patients with chronic cholestatic liver disease. The mean serum ceruloplamin level in WD patients is 71.1 ± 48.7 mg/L, the level is < 200 mg/L in 98.9% of patients, < 100 mg/L in about three fourths patients, < 50 mg/L in about half patients, but it may be low in 50% of patients with severe end-stage liver disease of any etiology too, and even lower than 50 mg/L in patients with nephritic syndrome. Basal 24-hour urinary copper excretion may be≥100 g at presentation in 86.7% of patients with WD, but also in 22% of Patients with certain chronic liver diseases, the sensitivity of penicillamine challenge test is lower than basal urinary copper excretion, however, the specificity is significantly higher than former (97% versus 78%). Hepatic copper determination remains the gold standard for the diagnosis of WD. We have designed a standard method for hepatic copper determination. The most useful cut-off value is 209 g/g dry wt using our method, with the sensitivity of 99.4%, and specificity of 96.1%. However, long-standing hepatic failure and or obstruction can cause heptic copper elevations into the WD area. In recent years, direct complete DNA sequencing has become easy, rapid, less expensive and commercially available. Currently reported mutation detection rate is 90%, the specificity is almost 100%. The limitation to the method has been the ability to identify all the affected alleles in suspected individuals. If no mutation is identified, the diagnosis of WD could not be excluded. None of the laboratory parameters alone allows a definite diagnosis of WD. The WD diagnostic scoring system based on a composite of key parameters helps clinicians to gauge the degree of certainty of the diagnosis: WD scores greater than 4, the diagnosis of WD is highly likely; score 0 or 1, the diagnosis is unlikely. However, the WD diagnosis could not be excluded in suspected patients who do not perform genetic test and hepatic copper determination. Patients with chronic cholestatic liver disease may have scores more than 4.

Oral Surgical Treatment of Patients With Chronic Liver Disease: Assessments of Bleeding and Its Relationship With Thrombocytopenia and Blood Coagulation Parameters

Cirrhotic patients awaiting liver transplantation require eradication of infectious oral foci to prevent septic episodes after transplantation; however, cirrhosis can hinder hemostasis and can result in severe bleeding. The present study assessed the bleeding risk factors connected with the clinical history of these patients and the characteristics of the extractions. We retrospectively analyzed 1183 extractions in 318 patients, including 47 with severe end-stage liver disease who were outside of our intention-to-treat bracket (ie, platelet count [PLT] >40 × 103/μL and international normalized ratio [INR] <2.5). Follow-up examinations included inspection of the oral cavity on the first, third, and seventh days, with reparatory surgery in the case of severe bleeding. Continuous variables were compared using the Mann-Whitney U and Kruskal-Wallis tests, and categorical variables were compared using Fisher's exact test. Binary logistic regression analysis was also performed. Within the intention-to-treat bracket, 1 of the 271 patients (0.4%) required surgical repair. The bleeding rate for an INR of 2.5 or more was significantly greater than that for a PLT of 40 × 103/μL or less (4 of 10 [40%] versus 2 of 34 [6%]; P= .02]. All 3 patients with both an INR of 2.5 or more and a PLT of 40× 103/μL or less exhibited severe bleeding. No significant association between the occurrence of bleeding with either liver disease etiology or the number of molars extracted was found. No patient required hospitalization. Patients with a PLT greater than 40 × 103/μL and an INR of less than 2.5 can be considered relatively low-risk patients. However, an INR of 2.5 or more and, to a minor degree, a PLT of 40 × 103/μL or less represent significant risk factors.

Liver-Regenerative Transplantation: Regrow and Reset.

Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end-stage liver disease. Only one-third of those on the liver transplant waiting list will be transplanted, and the demand for livers is projected to increase 23% in the next 20 years. Consequently, organ availability is an absolute constraint on the number of liver transplants that can be performed. Regenerative therapies aim to enhance liver tissue repair and regeneration by any means available (cell repopulation, tissue engineering, biomaterials, proteins, small molecules, and genes). Recent experimental work suggests that liver repopulation and engineered liver tissue are best suited to the task if an unlimited availability of functional induced pluripotent stem (iPS)-derived liver cells can be achieved. The derivation of iPS cells by reprogramming cell fate has opened up new lines of investigation, for instance, the generation of iPS-derived xenogeneic organs or the possibility of simply inducing the liver to reprogram its own hepatocyte function after injury. We reviewed current knowledge about liver repopulation, generation of engineered livers and reprogramming of liver function. We also discussed the numerous barriers that have to be overcome for clinical implementation.

Poor outcomes with treatment of hepatorenal syndrome type 1 with splancnic vasoconstrictors and albumin: report of seven cases and review of the literature

Treatment of hepatorenal syndrome type 1 (HRS-1) with splanchnic vasoconstrictors and high-dose albumin has been associated with reversal of renal failure in approximately 60% to 80% of the cases in pilot or uncontrolled studies. To evaluate the results of treatment of HRS-1 with terlipressin and high-dose albumin. All patients with HRS-1 that underwent treatment with terlipressin and high-dose albumin at our unit were retrospectively reviewed. Outcomes including reversal of renal failure and death were recorded and compared to baseline clinical and laboratory parameters. Seven subjects (median age 64 [47-69] years, 5 males) with median Child-Pugh and MELD scores of 12 [10-15] and 22 [17-38], respectively, hospitalized with decompensated chronic liver disease secondary to tense ascitis and infections, who exhibited criteria for HRS-1, were submitted to therapy with terlipressin and high-dose albumin according to a predefined standard protocol. Baseline creatinine levels were 2.9 [2.3-4.0] mg/mL. None of the patients achieved reversal of HRS-1 and five subjects died on-treatment due to sudden-death (n = 1), multiple organ dysfunction associated with end-stage liver failure (n = 2) and sepsis (n = 2). Treatment of HRS-1 with terlipressin and high-dose albumin was not associated with reversal of renal failure, but most of the treated subjects had severe end-stage liver disease with high MELD scores as well as high baseline creatinine values, parameters previously associated with bad outcomes.

Solvent–detergent plasma: use in neonatal patients, in adult and paediatric patients with liver disease and in obstetric and gynaecological emergencies

The study was conducted to assess the efficacy and tolerance of solvent-detergent (SD) plasma in neonates, in obstetric and gynaecological patients and in patients with liver disease in three large hospitals in Dublin during the period 1 April 2002 (when SD plasma was introduced) through 31 October 2003. Forty-one neonates received 67 transfusions of SD plasma at a mean dose +/- standard deviation of 18.4 +/- 13.2 mL kg(-1). Thirty-one (75.6%) patients had coagulopathy without haemorrhage (either disseminated intravascular coagulopathy or other coagulopathy); a further eight (19.5%) had clinical haemorrhage (excluding intraventricular haemorrhage), which complicated a coagulopathy. Thirty-eight obstetric and gynaecological patients received 57 SD plasma transfusions at a mean dose of 15.3 +/- 7.7 mL kg(-1). Thirty-six women (94.7%) had haemorrhage with mean blood loss per patient of 3345.8 +/- 2738.1 mL. Fifteen children with liver disease received 33 SD plasma transfusions at a mean volume of 38.0 +/- 41.5 mL kg(-1) body weight. Seventeen adult patients with severe end-stage liver disease were transfused with SD plasma either following liver transplantation or prior to other invasive procedures, at a mean dose of 10.2 +/- 3.4 mL kg(-1). There were statistically significant decreases in mean activated partial thromboplastin time and prothrombin time in neonates, in obstetric and gynaecological patients and in patients with liver disease. Complete correction of coagulation parameters was not achieved in any case in the liver transplant group. No adverse reactions were observed for SD plasma infusion. Use of SD plasma in critically ill neonates, in women with obstetric and gynaecological emergencies and in patients with liver disease appears safe, and improves laboratory indices of coagulopathy.

Solvent-detergent plasma: use in neonatal patients, in adult and paediatric patients with liver disease and in obstetric and gynaecological emergencies

We assessed the efficacy and tolerance of solvent-detergent (SD) plasma in neonates, in obstetric and gynaecological patients, and in patients with liver disease in three large hospitals in Dublin over an 18-month period. Forty-one neonates received 67 transfusions of SD plasma at a mean dose ± standard deviation of 18.4 ± 3.2 ml/kg. Thirty-eight obstetric and gynaecological patients received 57 SD plasma transfusions at a mean dose of 15.3 ± 7.7 ml/kg. Thirty-six women (94.7%) had haemorrhage with mean blood loss per patient of 3345.8 ± 2738.1 ml. Fifteen children with liver disease received 33 SD plasma transfusions at a mean volume of 38.0 ± 41.5 ml/kg body weight. Seventeen adult patients with severe endstage liver disease were transfused with SD plasma either following liver transplantation or prior to other invasive procedures, at a mean dose of 10.2 ± 3.4 ml/kg. There were statistically significant decreases in APTT and PT in neonates, in obstetric and gynaecological patients, and in patients with liver disease. Pre-transfusion and post-transfusion APTT was measured in 40/67 neonatal transfusion episodes, PT in 43/67, fibrinogen in 39/67, and platelets in 49/67. After plasma infusion the mean APTT improved from 68.9 ± 37.4 s to 44.0 ± 15.6 s (t = 4.79; P 0.05). In the group of adult patients with severe end-stage liver disease, precoagulation and postcoagulation test results were available for 14 of 17 transfusion episodes. There was a statistically significant improvement in the PT from 23.2 ± 4.9 s to 18.6 ± 2.9 s (t = 4.46, P < 0.001) and in the APTT from 45.1 ± 8.9 s to 36.4 ± 7.1 s (t = 3.95, P < 0.002). No adverse reactions were observed for SD plasma infusion. Use of SD plasma in critically ill neonates, in women with obstetric and gynaecological emergencies, and in patients with liver disease appears safe, and improves laboratory indices of coagulopathy.

Preoperative imaging in adult-to-adult living related liver transplant donors: what surgeons want to know.

Because of an overwhelming demand for cadaveric livers in the United States that far outstrips supply, living related liver transplantation is increasingly being performed to help treat a cohort of patients with severe end-stage liver disease. This procedure demands careful preoperative evaluation to minimize morbidity to the healthy donor and recipient, however. As a part of the workup, radiologic assessment of the donor hepatic vascular and biliary anatomy, hepatic volume, and hepatic parenchyma (with regard to focal and diffuse liver disease) is essential. In this pictorial essay, the experience of a group of investigators at the University of California at Los Angeles is reviewed, and the essential radiologic components of the preoperative evaluation of hepatic vascular and biliary anatomy, hepatic parenchyma, and lobar volume are described. The roles of high-field magnetic resonance (MR) imaging, MR angiography, MR cholangiopancreatography, multidetector-row computed tomography (CT) angiography, and CT cholangiography in the workup are discussed.

The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine-3 (M3G) and morphine-6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half-life of morphine was 4.2 h (95% CI 3.6-4.8) the mean volume of distribution was 4.1 l kg-1 (95% CI 2.9-5.4) and the mean plasma clearance was 11.4 ml min-1 kg-1 (95% CI 8.1-14.7). The mean oral bioavailability was 101% (95% CI 56-147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half-life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.