Features Of Advanced Liver Disease Research Articles

Role of uremic toxins in vascular disease—the end of nihilism?

The liver and kidneys are the main organs involved in the metabolism and elimination of carbohydrates, fats, and proteins, as well as their breakdown products. When kidney or liver function is impaired, these metabolites accumulate and contribute to the clinical features of advanced liver disease or end-stage kidney disease (ESKD). The term “uremic toxins” was coined decades ago to describe the compounds that accumulate in ESKD. In 2003, the European Uremic Toxin Work Group listed 90 such solutes.

S1019 Indirect Bilirubin Predominates in Hyperbilirubinemia Due to Cirrhosis: Comparison With Alcoholic Hepatitis

INTRODUCTION: Research done in the 1950’s and 60’s described the occurrence of extravascular hemolysis in a subset of patients with alcoholic cirrhosis. Subsequent studies suggested that hemolysis in this setting is the result of acquired red blood cell abnormalities in the setting of hypersplenism. In the decades since, this phenomenon and its potential clinical significance have received little attention. The objective of this study was to examine levels of indirect hyperbilirubinemia in patients with different forms of advanced liver disease. METHODS: Clinical and laboratory data were compared among 3 groups of patients admitted to the University of Iowa Hospital between January 2010 and January 2018. Fifty subjects each with alcoholic hepatitis (AH), decompensated alcoholic cirrhosis (AC) and decompensated cirrhosis due to causes other than alcohol (N-AC) in whom fractionated bilirubin had been obtained at admission were selected for study. Statistical analysis was done using Excel. RESULTS: As would be expected, total bilirubin was significantly higher in AH versus AC and N-AC. Absolute levels of direct bilirubin were also highest in AH but the indirect bilirubin comprised only about a quarter of the total in this group. Conversely, the indirect bilirubin comprised nearly half of the total bilirubin in AC and about 60% in N-AC. Hemoglobin levels were similar among the groups, but RBC counts were slightly lower in AH versus N-AC. MCV, MCH, and MCHC were highest in AH, perhaps reflecting the effects of recent heavy alcohol ingestion. Spleen sizes were similar among the groups. CONCLUSION: Our data show that, in contrast to AH, hyperbilirubinemia in decompensated cirrhosis is characterized by a large indirect fraction. Indirect bilirubin in cirrhotic patients seems unlikely to be a direct consequence of the severity of the underlying liver disease, given that direct bilirubin predominates in severe AH, which indicates that the ability to conjugate bilirubin is preserved even in conditions of severe hepatocellular dysfunction. Extravascular hemolysis due to acquired red cell membrane abnormalities and/or hypersplenism may contribute to elevations in indirect bilirubin. Hemolysis markers (LDH, haptoglobin) were not routinely obtained in the patients in this study, limiting our ability to evaluate this possibility. Further study is needed to determine the cause and clinical significance of indirect hyperbilirubinemia in cirrhosis.Table 1.: Comparison of variables with features of advanced liver disease among three study groups; 1. alcoholic hepatitis (AH) 2. decompensated alcoholic cirrhosis (AC) and 3. decompensated non-alcoholic cirrhosis (N-AC)Table 2.: Comparison of clinical and laboratory data among the three study groups i.e. 1. alcoholic hepatitis (AH) 2. decompensated alcoholic cirrhosis (AC) and 3. decompensated non-alcoholic cirrhosis (N-AC)Figure 1.: Comparing the proportion of indirect bilirubin between three study groups.

Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C

As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events. A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events. Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM ≥12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM ≥12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001). The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events. The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver-related adverse events.

Testosterone in men with advanced liver disease: abnormalities and implications.

Serum testosterone is reduced in up to 90% of men with cirrhosis, with levels falling as liver disease advances. Testosterone is an important anabolic hormone, with effects on muscle, bone, and hematopoiesis. Many of the features of advanced liver disease are similar to those seen in hypogonadal men, including sarcopenia, osteoporosis, gynecomastia, and low libido. However, the relative contribution of testosterone deficiency to the symptomatology of advanced liver disease has not been well established. More recently, it has been demonstrated that low testosterone in men with cirrhosis is associated with increased mortality, independent of the classically recognized prognostic factors, such as the Model for End-Stage Liver Disease score. Only several small clinical trials have examined the role of testosterone therapy in men with cirrhosis, none of which have resolved the issue of whether or not testosterone is beneficial. However, in men with organic hypogonadism due to structural hypothalamic-pituitary-testicular axis disease, testosterone therapy has been shown to improve muscle mass and bone mineral density, increase hemoglobin, and reduce insulin resistance. Despite initial concerns linking testosterone with hepatocellular carcinoma, more recent data suggest that this risk has been overstated. There is, therefore, now a strong rationale to assess the efficacy and safety of testosterone therapy in cirrhosis in well-designed randomized controlled trials.

Prevalence and Indicators of Portal Hypertension in Patients With Nonalcoholic Fatty Liver Disease

Little is known about the prevalence and severity of portal hypertension in patients with nonalcoholic fatty liver disease (NAFLD). We investigated the prevalence and noninvasive predictors of portal hypertension in patients with NAFLD. Signs of portal hypertension, including esophageal varices, splenomegaly, portosystemic encephalopathy, and ascites, were investigated in 354 patients with NAFLD. One hundred patients had portal hypertension at the time of NAFLD diagnosis (28.2%), 88 of these patients had septal fibrosis or cirrhosis (88%). Fibrosis stage correlated with presence (r = 0.41, P < .0001) and number of findings (r = 0.48, P = .006) of portal hypertension. Of the 204 patients with no or mild fibrosis (stages, 0-2), 12 patients had portal hypertension (6%); they had a significantly higher grade of steatosis, based on biopsy analysis, compared with the 192 patients without portal hypertension (94%). Thrombocytopenia, hyperbilirubinemia, cirrhosis, and obesity were associated independently with portal hypertension. Esophageal varices were found in 57 of the 128 patients undergoing endoscopic screening (44.5%) and were associated independently with thrombocytopenia, type 2 diabetes, and splenomegaly. Signs of portal hypertension were present in 25% of patients at the time of diagnosis of NAFLD; most had advanced fibrosis or cirrhosis. Portal hypertension can occur in a small proportion of patients with mild or no fibrosis and is associated with the extent of steatosis. Features of advanced liver disease and insulin resistance might identify patients with NAFLD and portal hypertension, and those expected to derive the most benefit from endoscopic screening for esophageal varices.

Accelerated and Progressive and Lethal Liver Fibrosis in Mice That Lack Interleukin (IL)-10, IL-12p40, and IL-13Rα2

Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis. IL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni. Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection. IL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.

Non‐invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can you avoid liver biopsy?

Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non-invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1). To estimate liver fibrosis in haemophilia patients infected with hepatitis C (HCV) using non-invasive biomarkers without liver biopsy. One hundred and thirty-two haemophilia patients (124 male, mean age 38 +/- 14 years) with anti-HCV antibodies were evaluated. These patients were stratified into several groups: patients with features of advanced liver disease - seven, persistently HCV RNA-negative - 21, persistently normal liver function tests (LFTs)- 24, HCV/HIV co-infected - 27. The following biomarkers of fibrosis were used: FT, AST-to-platelet ratio index (APRI), Forns index, age-platelet index and hyaluronic acid. The obtained scores were correlated with the clinical features of the patients. Estimated by the FT, the distribution of the stage of fibrosis in the 132 patients was F0F1 = 65% (86/132), F2 = 5% (7/132), F3 = 13% (17/132) and F4 = 17% (22/132). Using FT, all patients with clinical suspicion of advanced liver disease were classified as F3F4, whereas patients with persistently HCV RNA-negative were all classified as F0F1. Twenty-one per cent (5/24) of the patients with persistently normal LFTs had fibrosis stage F3F4. The proportion of F3F4 among HCV/HIV co-infected patients was significantly higher than among HCV mono-infected (52% vs. 33%; P = 0.05). Concordance of three or more biomarkers was present in 43% (57/132) of the patients. Liver biopsy could be avoided in 70% (92/132) using a practical assumption that if FT is in concordance with APRI and/or Forns, then we may confidently rely on the biomarker. Concordance rate for patients with presumably advanced or minimal liver disease was excellent (100% and 95% respectively). In our HCV-infected haemophilia patients, FT correctly identified clinically advanced or minimal liver disease. Discordance among the various biomarkers of fibrosis was considerate; nevertheless, practical combination of FT, APRI, and Forns may predict stage of fibrosis with accuracy, potentially avoiding liver biopsy in the majority of the patients.

Nutritional therapy in cirrhosis

Abstract In recent years increasing interest has been given to nutritional therapy in a variety of chronic diseases, including cirrhosis. Protein/calorie malnutrition is a common feature of advanced liver disease, and considerably affects prognosis. Hence, the need for nutritional support to provide patients with the minimum protein requirements to balance increased catabolism. Although most patients tolerate normal protein supply, in subjects with impending encephalopathy a nutritional support with branched‐chain amino acids (BCAA) was suggested on the basis of neuro‐pharmacological studies. A large, randomized trial has recently provided evidence that BCAA may be superior to equicaloric and equinitrogenous supplements, improving survival and retarding hepatocellular failure. Administration schedules including a late evening supplementation may be particularly helpful. Biochemical studies are providing the rationale for the beneficial effects, showing that leucine may be an important regulator of amino acid/protein metabolism.

Preoperative preparation of patients with advanced liver disease

To review the characteristic features of patients with advanced liver disease that may lead to increased perioperative morbidity and mortality rates. Literature review. Patients with end-stage liver disease are at high risk of major complications and death following surgery. The most common complications are secondary to acute liver failure and include severe coagulopathy, encephalopathy, adult respiratory distress syndrome, acute renal failure, and sepsis. The degree of malnutrition, control of ascites, level of encephalopathy, prothrombin time, concentration of serum albumin, and concentration of serum bilirubin predict the risk of complications and death following surgery. Other determinants of adverse outcome include emergency surgery, advanced age, and cardiovascular disease. Portal hypertension is a prominent feature of advanced liver disease, and it predisposes the patient to variceal hemorrhage, hepatorenal syndrome, hepatopulmonary syndrome, and uncontrolled ascites. Portal hypertension can be ameliorated by percutaneous or surgical portasystemic shunting procedures. If well-defined contraindications are not present, patients with advanced liver disease should be evaluated for orthotopic liver transplantation from a cadaver donor or possible living-related liver transplantation. Optimal preparation, which addresses the common features of advanced liver disease, may decrease the risk of complications or death following surgery. Preparation should include correcting coagulopathy, minimizing preexisting encephalopathy, preventing sepsis, and optimizing renal function.

Addisons’ other disease: primary biliary cirrhosis as a model autoimmune disease

Thomas Addison described three of the classical autoimmune diseases, so can justifiably be regarded as one of the fathers of the study of autoimmunity. The least well recognised of these conditions, the autoimmune liver disease primary biliary cirrhosis (PBC), is in some ways the most interesting. As a result of the relatively advanced state of knowledge of its immunopathogenesis, it represents a good model for the study of autoimmune disease. The classical pathological lesion of PBC is apoptotic damage to the biliary epithelial cells lining the small intrahepatic bile ducts. The disease is typified by two symptom sets:•fatigue and pruritus, which can occur at any stage of the disease process, and•the features of advanced liver disease, which occur when secondary liver damage results from bile retention.Although autoantibodies directed at, in particular, pyruvate dehydrogenase complex (PDC) are almost universally present in PBC (and represent an important diagnostic tool), it appears likely that CD8+ cytotoxic T cells reactive with self-PDC derived epitopes are directly responsible for target cell damage. Recent studies in humans and a novel murine disease model have shed light on the mechanism of breakdown of immune tolerance to self-PDC; they provide important insights into the pathogenesis of PBC in particular and of autoimmunity in general.

Intestinal transplantation for gut failure

In recent years, we have witnessed increasing clinical experience with intestinal transplantation at selected centers. Although early results with this therapy were poor, several important advances have led to improved outcomes. These improvements prompted the Centers for Medicare and Medicaid Services to issue a memorandum on October 4, 2000, according federal reimbursement for intestinal transplantation at selected centers and for selected indications.1 The Centers for Medicare and Medicaid Services stipulated that, to qualify for transplantation, patients must meet a specific definition of intestinal failure and have experienced failure of parenteral nutrition (Table 1). In addition, the Centers for Medicare and Medicaid Services set forth centerspecific criteria for reimbursement, including 1-year patient survival rates of at least 65% and minimum center volume of at least 10 transplants performed per year. Only 4 centers in the United States currently meet these criteria (Mount Sinai Medical Center, University of Pittsburgh Medical Center, University of Miami, and University of Nebraska Medical Center). Thus, intestinal transplantation is currently at a crossroads, transitioning from its historical status as an experimental therapy to standard care for patients with appropriate indications. Presently, appropriate indications, timing of referral, and outcomes of intestinal transplantation are not well recognized among physicians caring for patients who may be candidates for this therapy. Definitions of terms such as “intestinal failure” and “failure of parenteral nutrition” are not standard, and there is no accepted algorithm for integrating parenteral nutrition, intestinal rehabilitation, and transplantation for patients with intestinal failure. Herein we review (1) the applicability of intestinal transplantation for patients with intestinal failure, (2) the current state of medical practice in intestinal transplantation with an emphasis on recent improvements, and (3) current results of this therapy. We also offer for the general gastroenterologist or gastrointestinal surgeon a rational approach to managing intestinal failure and integrating intestinal rehabilitation, parenteral nutrition, and transplantation.2 Brief History

Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease

GP73 is a novel type II Golgi membrane protein of unknown function that is expressed in the hepatocytes of patients with adult giant-cell hepatitis (Gene 2000;249:53-65). Its expression pattern in human liver disease and the regulation of its expression in hepatocytes have not been systematically studied. The aims of the present study were to compare GP73 protein levels in viral and nonviral human liver disease and in normal livers, to identify its cellular sources, and to study the regulation of its expression in hepatoma cells in vitro. GP73 protein levels were quantitated in explant livers of patients with well-defined disease etiologies and compared with the levels in normal donor livers. GP73-expressing cells were identified immunohistochemically. GP73 expression in vitro was studied by Western blotting and immunofluorescence microscopy in HepG2 and SK-Hep-1 cells and in the HepG2-derived, hepatitis B virus (HBV)-transfected HepG2215 and HepG2T14.1 cell lines. Whole organ levels of GP73 were low in normal livers. Significant increases were found in liver disease due to viral causes (HBV, HCV) or nonviral causes (alcohol-induced liver disease, autoimmune hepatitis). In normal livers, GP73 was constitutively expressed by biliary epithelial cells but not by hepatocytes. Hepatocyte expression of GP73 was dramatically up-regulated in diseased livers, regardless of the etiology, whereas biliary epithelial cell expression did not change appreciably. GP73 was present at high levels in HepG2215 cells (a cell line that supports active HBV replication), but was absent in HepG2T14.1 cells (an HBV-transfected cell line that does not support HBV replication) and in HBV-free HepG2 cells. In SK-Hep-1 cells, GP73 expression was increased in response to interferon gamma (IFN-γ), and inhibited by tumor necrosis factor α (TNF-α). In conclusion, increased expression of GP73 in hepatocytes appears to be a general feature of advanced liver disease, and may be regulated via distinct pathways that involve hepatotropic viruses or cytokines. (H EPATOLOGY 2002;35:1431-1440.)

Systemic arteriovenous malformations: a feature of advanced liver disease.

Arterial and arteriovenous abnormalities are reported in association with advanced liver disease, those most commonly recognised are spider naevi, pulmonary arteriovenous shunts, and generalised vasodilatation. The first two cases of peripheral systemic arteriovenous malformations in association with cirrhosis are reported. After liver transplantation in one of these patients the vascular malformation regressed. A review of published works shows that other vascular complications of advanced liver disease such as pulmonary shunts and generalised vasodilation also regress after orthotopic liver transplantation.