Assessment of Advanced Liver Fibrosis and the Risk for Hepatic Decompensation in Patients With Congestive Hepatopathy.

Congestive hepatopathy (CH) arises from chronically elevated right-sided heart pressures transmitted to the liver by passive venous congestion. Over time, CH can lead to hepatic bridging fibrosis, decompensated cirrhosis, and hepatocellular carcinoma. Currently, there are no evidence-based guidelines to direct appropriate screening or management of patients with CH, partly because of the inability of current clinical tools (serum tests, imaging studies, liver stiffness measurements, and liver biopsy) to accurately estimate hepatic fibrosis or the risk for hepatic decompensation. The Model for End-Stage Liver Disease excluding international normalized ratio (MELD-XI) score is the only validated serum-based test to predict clinical outcomes in CH. Noninvasive liver stiffness measurements are proving to be of minimal utility as all patients with CH have elevated values that currently cannot differentiate between congestion and fibrosis. In addition, fibrosis staging by liver biopsy is difficult to standardize because of heterogeneous collagen deposition in CH. Moreover, liver biopsy results have little predictive value for post-heart transplant hepatic outcomes in patients with CH. Evaluating liver nodules and masses is also complicated in CH as the finding of delayed venous washout in nodules is not specific for hepatocellular carcinoma in the background of a congested liver, and these lesions may require biopsy to confirm the diagnosis. The lack of effective clinical tools for predicting liver fibrosis and liver function suggests the need for the development of novel biomarkers in patients with CH to assist in the management of this complicated disease. (Hepatology 2018; 00:000-000).

Neurological disorders in liver transplant candidates: Pathophysiology and clinical assessment.

Compromised liver function, as a consequence of acute liver insufficiency or severe chronic liver disease may be associated with various neurological syndromes, which involve both central and peripheral nervous system. Acute and severe hyperammoniemia inducing cellular metabolic alterations, prolonged state of "neuroinflammation", activation of brain microglia, accumulation of manganese and ammonia, and systemic inflammation are the main causative factors of brain damage in liver failure. The most widely recognized neurological complications of serious hepatocellular failure include hepatic encephalopathy, diffuse cerebral edema, Wilson disease, hepatic myelopathy, acquired hepatocerebral degeneration, cirrhosis-related Parkinsonism and osmotic demyelination syndrome. Neurological disorders affecting liver transplant candidates while in the waiting list may not only significantly influence preoperative morbidity and even mortality, but also represent important predictive factors for post-transplant neurological manifestations. Careful pre-transplant neurological evaluation is essential to define severity and distribution of the neurological impairment, to identify the abnormalities still responsive to current treatment, and to potentially predict the inherent post-operative prognosis. The preferred specific indices of neurological pre-transplant assessment may vary among centers, however, even with the aid of the current biochemical, neurophysiological, neuropsychological and neuroimaging diagnostic tools, the correct diagnosis and differential diagnosis of various syndromes may be difficult. In this article the relevant pathophysiological and clinical aspects of the most frequent brain and peripheral nervous system diseases affecting liver transplant candidates with acute or advanced chronic liver failure are briefly reported. The practical diagnostic findings useful for the preoperative assessment and treatment, as well as the expected neurological evolution after liver transplantation are also evaluated.

Treatment of patients waitlisted for liver transplant with all-oral direct-acting antivirals is a cost-effective treatment strategy in the United States.

All-oral direct acting antivirals (DAAs) have been shown to have high safety and efficacy in treating patients with hepatitis C virus (HCV) awaiting liver transplant (LT). However, there is limited empirical evidence comparing the health and economic outcomes associated with treating patients pre-LT versus post-LT. The objective of this study was to analyze the cost-effectiveness of pre-LT versus post-LT treatment with an all-oral DAA regimen among HCV patients with hepatocellular carcinoma (HCC) or decompensated cirrhosis (DCC). We constructed decision-analytic Markov models of the natural disease progression of HCV in HCC patients and DCC patients waitlisted for LT. The model followed hypothetical cohorts of 1,000 patients with a mean age of 50 over a 30-year time horizon from a third-party US payer perspective and estimated their health and cost outcomes based on pre-LT versus post-LT treatment with an all-oral DAA regimen. Transition probabilities and utilities were based on the literature and hepatologist consensus. Sustained virological response rates were sourced from ASTRAL-4, SOLAR-1, and SOLAR-2. Costs were sourced from RedBook, Medicare fee schedules, and published literature. In the HCC analysis, the pre-LT treatment strategy resulted in 11.48 per-patient quality-adjusted life years and $365,948 per patient lifetime costs versus 10.39 and $283,696, respectively, in the post-LT arm. In the DCC analysis, the pre-LT treatment strategy resulted in 9.27 per-patient quality-adjusted life years and $304,800 per patient lifetime costs versus 8.7 and $283,789, respectively, in the post-LT arm. As such, the pre-LT treatment strategy was found to be the most cost-effective in both populations with an incremental cost-effectiveness ratio of $74,255 (HCC) and $36,583 (DCC). Sensitivity and scenario analyses showed that results were most sensitive to the utility of patients post-LT, treatment sustained virological response rates, LT costs, and baseline Model for End-Stage Liver Disease score (DCC analysis only). CONCLUSION: The timing of initiation of antiviral treatment for HCV patients with HCC or DCC relative to LT is an important area of clinical and policy research; our results indicate that pre-LT treatment with a highly effective, all-oral DAA regimen provides the best health outcomes and is the most cost-effective strategy for the treatment of HCV patients with HCC or DCC waitlisted for LT. (Hepatology 2017;66:46-56).

Quantified Risk Assessment for Major Hepatectomy via the Indocyanine Green Clearance Rate and Liver Volumetry Combined with Standard Liver Volume.

BACKGROUND: Preoperative risk assessment for post-hepatectomy liver failure (PHLF) is essential for major hepatectomy. We intended to establish a standard liver volume (SLV) formula for Korean patients and validate the predictive power of the indocyanine green clearance rate constant (ICG-K) fraction of future remnant liver (FRL) (FRL-kICG) to total liver volume (TLV). METHODS: This study comprised 2 retrospective studies. Part I established SLV formula and acquired ICG pharmacokinetic data from 2155 living donors. In part II, FRL-kICG cutoff was determined using 723 patients who underwent right liver resection for hepatocellular carcinoma. RESULTS: In part I, the formula SLV (mL) = -456.3 + 969.8 × BSA (m(2)) (r = 0.707, r (2) = 0.500, p = 0.000) was derived with mean volume error of 10.5%. There was no correlation between TLV and ICG retention rate at 15 min. With a cutoff of 0.04 with hepatic parenchymal resection rate (PHRR) limit of 70%, 99.0% of our living donors were permissible for left or right hepatectomy. In part II, 25 hepatocellular carcinoma patients (3.5%) showed an FRL-kICG or SLV-corrected FRL-kICG <0.05. Of these, 4 (16 %) died of PHLF, whereas only 2 (0.3%) died in the other patient group with both an FRL-kICG and SLV-corrected FRL-kICG ≥ 0.05 (P = 0.000). CONCLUSIONS: The FRL-kICG appears to reliably predict PHLF risk quantitatively. We suggest FRL-kICG cutoffs of 0.04 and 0.05 with PHRR limits of 70% and 65% for normal and diseased livers, respectively. Further validation with large patient population in multicenter studies is necessary to improve FRL-kICG predictability.

Usefulness of real-time elastography strain ratio in the assessment of bile duct ligation-induced liver injury and the hepatoprotective effect of chitosan: an experimental animal study.

The purpose of the study described here was to evaluate the usefulness of the elastographic strain ratio in the assessment of liver changes in an experimental animal setting and the hepatoprotective effects of chitosan. Ultrasonography and Strain Ratio calculation were performed before and after bile duct ligation (BDL) in three groups of Wistar albino rats (n = 10 animals per group): (i) rats subjected to bile duct ligation only; (ii) rats subjected to bile duct ligation and administered chitosan for 14 d; (iii) rats subjected to bile duct ligation and administered chitosan for 7 d. The results were compared with the laboratory data and pathologic findings. Strain ratios revealed an increase in liver stiffness after bile duct ligation (p < 0.05), except in the group with chitosan administered for 7 d, and agreed with laboratory and pathology data. In conclusion, strain ratio can be used as an experimental research instrument in the assessment of liver response to injury. To the best of our knowledge, this is the first study reporting on the usefulness of the sonoelastographic liver-to-kidney strain ratio in assessing the effects of experimentally induced liver lesions.

New perspectives in the assessment of future remnant liver.

In order to achieve microscopic radical resection margins and thus better survival, surgical treatment of hepatic tumors has become more aggressive in the last decades, resulting in an increased rate of complex and extended liver resections. Postoperative outcomes mainly depend on the size and quality of the future remnant liver (FRL). Liver resection, when performed in the absence of sufficient FRL, inevitably leads to postresection liver failure. The current gold standard in the preoperative assessment of the FRL is computed tomography volumetry. In addition to the volume of the liver remnant after resection, postoperative function of the liver remnant is directly related to the quality of liver parenchyma. The latter is mainly influenced by underlying diseases such as cirrhosis and steatosis, which are often inaccurately defined until microscopic examination after the resection. Postresection liver failure remains a point of major concern that calls for accurate methods of preoperative FRL assessment. A wide spectrum of tests has become available in the past years, attesting to the fact that the ideal methodology has yet to be defined. The aim of this review is to discuss the current modalities available and new perspectives in the assessment of FRL in patients scheduled for major liver resection.

Critical analysis of the pediatric end-stage liver disease scoring system: a single center experience.

The Pediatric End-Stage Liver Disease (PELD) scoring system is a new nationally utilized formula developed to provide a continuous numerical assessment of the risk of death in order to allocate livers to children for transplantation. A retrospective review of the clinical course of children undergoing liver transplantation at the Mount Sinai Medical Center was performed in order to assess the effectiveness of this scoring system in the first 24 months of its utilization. Forty-eight patients underwent liver transplantation with overall patient and graft survival rates of 98% and 96%, respectively. In 23 cases the PELD scoring system determined waiting time for transplantation. Of these 23 patients, 7 moved to the intensive care unit (ICU). Only 2 of 23 patients underwent transplantation with their actual PELD score. The rest required petition for exception (17) or status 1 listing (4). Significant morbidity occurred while awaiting transplantation: failure to thrive (78%), ascites (73%), hemorrhage (49%), infectious complications (39%), encephalopathy (30%), peritonitis (17%), pathologic bone fractures (13%), and hepatopulmonary syndrome (9%). In patients with PELD scores granted by exception the average score that did not yield a liver offer was 38 with an average waiting time of 55 days. At the time of transplantation actual PELD score averaged 22, while the petitioned score was 40. Based upon our center's initial experience, the current PELD scoring system is not adequate. Actual PELD scores did not lead to timely allocation of livers to children. It appears that this scoring system underestimates the near-term risk of death. Urgent reassessment is required to prevent potential morbidity and mortality in children. In conclusion the United Network for Organ Sharing policy that permits granting of exceptions has circumvented these problems with the PELD scoring system.

Serum sodium predicts mortality in patients listed for liver transplantation.

With the implementation of the model for end-stage liver disease (MELD), refractory ascites, a known predictor of mortality in cirrhosis, was removed as a criterion for liver allocation. Because ascites is associated with low serum sodium, we evaluated serum sodium as an independent predictor of mortality in patients with cirrhosis who were listed for liver transplantation and whether the addition of serum sodium to MELD was superior to MELD alone. This is a single-center retrospective cohort of all adult patients with cirrhosis listed for transplantation from February 27, 2002, to December 26, 2003. Listing laboratories were those nearest the listing date +/-2 months. Of the 513 patients meeting inclusion criteria, 341 were still listed, while 172 were removed from the list (105 for transplantation, 56 for death, 11 for other reasons). The median serum sodium and MELD scores were 137 mEq/L (range, 110-155) and 15 (range, 6-51), respectively, at listing. Median follow-up was 201 (range, 1-662) days. The risk of death with serum sodium <126 mEq/L at listing or while listed was increased, with hazard ratios of 7.8 (P < .001) and 6.3 (P < .001), respectively, and the association was independent of MELD. The c-statistics of receiver operating characteristic curves for predicting mortality at 3 months based upon listing MELD with and without listing serum sodium were 0.883 and 0.897, respectively, and at 6 months were 0.871 and 0.905, respectively. In conclusion, serum sodium <126 mEq/L at listing or while listed for transplantation is a strong independent predictor of mortality. Addition of serum sodium to MELD increases the ability to predict 3- and 6-month mortality in patients with cirrhosis.

When is a patient too well and when is a patient too sick for a liver transplant?

1. Liver transplantation is currently offered as a therapeutic option for patients with a wide range of end-stage liver diseases. 2. Conventional wisdom suggests that patients who receive a liver transplant have a greater expected lifetime when compared to comparable candidates on the waiting list. 3. The model for end-stage liver disease (MELD) scoring system is an excellent predictor of mortality on the waiting list and also predicts mortality after liver transplantation. 4. The combination of waiting list mortality risk and posttransplant mortality risk assessed by MELD and other factors can be used to estimate whether candidates are likely to derive a survival benefit from a liver transplant.

Retransplantation for recurrent hepatitis C in the MELD era: maximizing utility.

1. Retransplantation (re-LT) for hepatitis C virus (HCV) recurrence is controversial. Although re-LT accounts for 10% of all liver transplants (LTs), the number of patients requiring re-LT is expected to grow as primary LT recipients survive long enough to develop graft failure from recurrent disease. 2. Utility, as applied to the medical ethics of transplantation, refers to allocating organs to those individuals who will make the best use of them. The utility function (U) of liver transplantation is represented by the product of outcome (O = 1-year survival with LT) times emergency (E = 3-month mortality without LT), i.e., U = O x E. 3. For primary LT, maximal U is achieved by allocating organs at the highest model for end-stage liver disease (MELD) score (i.e., "sickest first"). No significant differences exist between HCV and non-HCV diagnoses. 4. For re-LT, maximal utility for HCV and non-HCV diagnoses are achieved at MELD scores of 21 and 24, respectively. Utility starts to decline at MELD scores above 28. 5. The current allocation system (MELD) fails to maximize utility with regard to re-LT.

Organ allocation for liver-intestine candidates.

1. Patients listed for combined liver and intestine transplantation have the highest waitlist mortality of any transplant candidates. 2. Liver-intestine candidates have higher mortality rates than other patients listed for liver transplantation at all model for end-stage liver disease (MELD) and pediatric end-stage liver disease (PELD) scores, sepsis rather than liver failure being the major cause of death in this group. 3. Increasing PELD scores appear to correlate with increasing waitlist mortality in patients awaiting combined liver and intestinal transplantation. 4. Present policy to increase MELD / PELD scores for liver-intestine patients by an additional estimated 10% mortality risk is an attempt to bridge the difference in waitlist mortality while maintaining the principle of allocating organs on the basis of disease severity. 5. Scheduled reevaluation of present allocation practices is essential to refine Organ Procurement and Transplantation Network United Network for Organ Sharing policy as it relates to patients in need of combined liver and intestinal transplantation.

How will patients be selected for transplantation in the future?

1. The model for end-stage liver disease has become a selection tool for recipients for liver transplantation. 2. The present selection / allocation system does not recognize distinctions in "donor organ quality." 3. Many studies have shown that donor factors such as age, gender, fat content, and heart beating versus non-heart beating status influence outcome of the liver transplantation. 4. Efforts to increase organ donation are likely to provide more "expanded-criteria donors." 5. Future selection practices may attempt to match specific recipients to specific donors.

Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA.

A national conference was held to review and assess data gathered since implementation of MELD and PELD and determine future directions. The objectives of the conference were to review the current system of liver allocation with a critical analysis of its strengths and weaknesses. Conference participants used an evidence-based approach to consider whether predicted outcome after transplantation should influence allocation, to discuss the concept of minimal listing score, to revisit current and potential expansion of exception criteria, and to determine whether specific scores should be used for automatic removal of patients on the waiting list. After review of data from the first 18 months since implementation, association and society leaders, and surgeons and hepatologists with wide regional representation were invited to participate in small group discussions focusing on each of the main objectives. At the completion of the meeting, there was agreement that MELD has had a successful initial implementation, meeting the goal of providing a system of allocation that emphasizes the urgency of the candidate while diminishing the reliance on waiting time, and that it has proven to be a powerful tool for auditing the liver allocation system. It was also agreed that the data regarding the accuracy of PELD as a predictor of pretransplant mortality were less conclusive and that PELD should be considered in isolation. Recommendations for the transplant community, based on the analysis of the MELD data, were discussed and are presented in the summary document.

Health status versus utilities of patients with end-stage liver disease.

BACKGROUND: Health-related quality of life (HRQL) in patients with end-stage liver disease (ESLD) can be evaluated using either health-status questionnaires or utility assessment techniques. The two approaches have never been compared in terms of the values they assign to health prior to liver transplantation. STUDY DESIGN: We assessed health status of patients with ESLD using validated disease-specific instruments covering multiple domains (measures of disease, psychological status, personal function, social/role function, and general health perception). We also elicited utilities using formal approaches (standard gamble [SG] and time tradeoff [TTO]) and a simpler alternative (visual analog scale [VAS]). PATIENTS: Outpatients and inpatients at a single center prior to liver transplantation (n = 78). PRINCIPAL FINDINGS: Health status was generally poor (median physical symptoms score on a 0-1 [worst to best] scale, 0.33; psychological symptoms, 0; happiness, 0.50; personal function, 0; social/role function, 0.40; and general health perception, 0.40). The median VAS score was 0.50. The median TTO was 0.79, indicating that half of the patients in our sample chose healthier life in return for a 21% shorter life expectancy. The median SG score was 0.50, indicating that half of the patients were willing to take up to a 50% risk of death in exchange for perfect health. CONCLUSIONS: Both health status measures and utility assessments indicate that HRQL is compromised in patients awaiting liver transplantation. Despite the overall consistency between the two approaches, however, health status measures do not serve as reasonable proxies for utilities. For formal economic evaluations such as cost effectiveness analyses, only direct measures of utility can be used to quantify health states.

Standardization of ischemic hepatic failure in pigs as a model for bioartificial liver assessment.

PURPOSE: A standard protocol of ischemic liver failure in pigs was examined to establish a system for assessing the efficacy of a bioartificial liver, based on clinical practice. METHODS: The portal blood flow was extracorporeally bypassed into the cervical jugular vein, using a centrifugal blood pump. The portal vein and hepatic artery were then ligated. RESULTS: The maintenance protocol was established as follows: (1) the concentration of the inhaled anesthetic was decreased by 0.2% when the systolic blood pressure was <100 mmHg; (2) the volume of an infusion containing 5% glucose was increased to 10 ml/kg per hour when central venous pressure was <5 mmHg; (3) 20 ml of 50% glucose was injected intravenously when the blood glucose was <50 mg/dl; (4) 2000 units of heparin was injected intravenously when the activated clotting time was <150 s; (5) sodium bicarbonate was given when the blood pH was <7.3; (6) tidal volume was increased by 1 ml/kg when the pCO(2) was >80 mmHg; (7) oxygen was increased by 25% when the pO(2) was <100 mmHg. No vasopressors were used in the experiment. CONCLUSION: Our protocol reduced the operating time and minimized the risk of data deviation that can arise from variations in operating techniques and individual animal conditions. This experimental model is also easy to use as a bridge to transplantation.

Body composition and components of energy expenditure in children with end-stage liver disease.

BACKGROUND: Better understanding of body composition and energy metabolism in pediatric liver disease may provide a scientific basis for improved medical therapy aimed at achieving optimal nutrition, slowing progression to end-stage liver disease (ESLD), and improving the outcome of liver transplantation. METHODS: Twenty-one children less than 2 years of age with ESLD awaiting liver transplantation and 15 healthy, aged-matched controls had body compartment analysis using a four compartment model (body cell mass, fat mass, extracellular water, and extracellular solids). Subjects also had measurements of resting energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry. Nine patients and 15 control subjects also had measurements of total energy expenditure (TEE) using doubly labelled water. RESULTS: Mean weights and heights were similar in the two groups. Compared with control subjects, children with ESLD had higher relative mean body cell mass (33 +/- 2% vs 29 +/- 1% of body weight, P < 0.05), but had similar fat mass, extracellular water, and extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body weight respectively). Compared with control subjects, children with ESLD had 27% higher mean REE/body weight (0.285 +/- 0.013 vs 0.218. +/- 0.013 mJ/kg/24h, P < 0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05). Mean TEE of patients was 4.70 +/- 0.49 mJ/24h vs 3.19 +/- 0.76 in controls, (P < 0.01). CONCLUSIONS: In children, ESLD is a hypermetabolic state adversely affecting the relationship between metabolic and nonmetabolic body compartments. There is increased metabolic activity within the body cell mass with excess lipid oxidation during fasting and at rest. These findings have implications for the design of appropriate nutritional therapy.

Application of a continuous disease severity score to the OPTN liver waiting list.

In a move to establish measurable, objective criteria for cadaveric liver allocation, the United Network for Organ Sharing OPTN will implement the Model for End Stage Liver Disease (MELD) system in early 2002 as a replacement for the current Child-Turcotte-Pugh (CTP)-based Status 2A, 2B, and 3 categories for patients waiting for a cadaver donor liver transplant. The MELD is a continuous mortality risk score based on serum creatinine, bilirubin, and INR. Although originally developed in patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure, analysis of OPTN data shows that the components of MELD (in particular, bilirubin) have a very strong correlation with mortality in liver transplant candidates. Univariate analyses showed that pretransplant mortality significantly increased when the MELD score was > 1.8. In the study cohort, 25% of the patients had a MELD score > 1.8. Multivariate analysis showed that the MELD score was an independent predictor of mortality, with a 2-unit increase multiplying the risk of mortality by a factor of 5.6. The MELD and CTP scores were correlated, but MELD scores varied widely for any given CTP score, indicating that some patients could be disadvantaged with the status-based system. The MELD score was validated in an independent dataset; concordance with 3-month mortality was 0.88. We conclude that the MELD score is a good indicator of disease severity and that implementation of this system should direct more livers to those patients in greatest need of transplantation.

Assessment of serial changes of bone mineral density at lumbar spine and femoral neck before and after liver transplantation.

OBJECTIVE: To assess serial changes of bone mass before and after orthotopic liver transplantation (OLT). METHODS: Consecutive bone mineral density (BMD) of lumbar spine (L2-L4) and femoral neck in 38 patients with chronic liver failure within 2 months before OLT, 6, 12 and 24 months after OLT was determined using dual energy X-ray absorptiometry. RESULTS: 29% of 38 patients before OLT had osteoporosis (BMD below 2 standard deviate). BMD levels at L2-L4 and femoral neck decreased and incidence of osteoporosis increased in the first 6 months after OLT. Over beyond 6 months post-OLT BMD levels at L2-L4 increased to just slightly above the pretransplant level and incidence of osteoporosis decreased from 36.8% (6 months after OLT) to 7.9% (24 months after OLT). Although BMD levels at femoral neck by 12 and 24 months after OLT gradually increased, BMD levels at femoral neck were still lower than those before OLT. CONCLUSIONS: There was already a low bone mass in patients with chronic liver disease before OLT and liver transplantation induced a marked and rapid bone loss.