Assessment of the Visual Analogue Score in the Evaluation of the Pruritus of Cholestasis.

Background and Aims: A visual analogue score (VAS), based on application of a visual analogue scale, has been widely used to assess pruritus in clinical studies of patients with cholestatic liver disease. A VAS is a numerical score of the severity of the perception of pruritus, and, hence, is inherently subjective. The objective of this study was to assess the reliability of a VAS as an index of pruritus in cholestatic patients. Methods: In 8 patients with chronic pruritus due to primary biliary cholangitis, values for a VAS of pruritus were compared with corresponding measurements of scratching activity, which were generated by a monitoring system specifically designed to quantitate this activity. The relationship between individual values for the VAS and corresponding values for scratching activity during a specific interval immediately preceding the recording of the VAS was examined by determining the Spearman's rank correlation coefficient. Results: The mean Spearman's rank correlation coefficient between individual values for the VAS and corresponding mean values for scratching activity was 0.072; the range of these coefficients was -0.04 to 0.26. A VAS of pruritus is an unreliable index of scratching activity, and, hence, of the pathophysiological process responsible for the pruritus of cholestasis. Conclusions: It is concluded that the use of a VAS as a primary quantitative endpoint in trials of the efficacy of potential therapies for the pruritus of cholestasis may be inappropriate.

Theories of the pathogenesis of hepatic encephalopathy.

The earliest hypothesis of the pathogenesis of HE implicated ammonia, although effects of appreciable concentrations of this neurotoxin did not resemble HE. Altered eurotransmission in the brain was suggested by similarities between increased GABA-mediated inhibitory neurotransmission and HE, specifically decreased consciousness and impaired motor function. Evidence of increased GABAergic tone in models of HE has accumulated; potential mechanisms include increased synaptic availability of GABA and accumulation of natural benzodiazepine receptor ligands with agonist properties. Pathophysiological concentrations of ammonia associated with HE, have the potential of enhancing GABAergic tone by mechanisms that involve its interactions with the GABAa receptor complex.

Liver disease and erythropoietic protoporphyria: a concise review.

The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme. In erythropoietic protoporphyria (EPP), in the majority of cases an autosomal dominant disease, there is a mutation of the gene that encodes ferrochelatase (FECH). FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver. The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000. Clinical manifestations of EPP appear in early infancy upon first exposure to the sun. Nevertheless, approximately 5%-20% of patients with EPP develop liver manifestations. Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity, such as cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease with end-stage liver disease and acute liver failure. Liver damage is the major risk in EPP patients, so surveillance and frequent clinical and biochemical liver follow-up is mandatory. The diagnostic approach consists in detecting increased levels of protoporphyrin, decreased activity of FECH and genetic analysis of the FECH gene. A variety of non-surgical therapeutic approaches have been adopted for the management of EPP associated with liver disease, but none of these has been shown to be unequivocally efficacious. Nevertheless, some may have a place in preparing patients for liver transplantation. Liver transplantation does not correct the constitutional deficiency of FECH. Consequently, there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin. Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.

Spectrum of anemia associated with chronic liver disease.

Anemia of diverse etiology is a common complication of chronic liver diseases. The causes of anemia include acute or chronic gastrointestinal hemorrhage, and hypersplenism secondary to portal hypertension. Severe hepatocellular disease predisposes to hemorrhage because of impaired blood coagulation caused by deficiency of blood coagulation factors synthesized by hepatocytes, and/or thrombocytopenia. Aplastic anemia, which is characterized by pancytopenia and hypocellular bone marrow, may follow the development of hepatitis. Its presentation includes progressive anemia and hemorrhagic manifestations. Hematological complications of combination therapy for chronic viral hepatitis include clinically significant anemia, secondary to treatment with ribavirin and/or interferon. Ribavirin-induced hemolysis can be reversed by reducing the dose of the drug or discontinuing it altogether. Interferons may contribute to anemia by inducing bone marrow suppression. Alcohol ingestion is implicated in the pathogenesis of chronic liver disease and may contribute to associated anemia. In patients with chronic liver disease, anemia may be exacerbated by deficiency of folic acid and/or vitamin B12 that can occur secondary to inadequate dietary intake or malabsorption.

Pruritus and fatigue associated with liver disease: is there a role for ondansetron?

BACKGROUND: Complications of liver disease include pruritus and fatigue. Increased central opioidergic tone, which is modulated by serotoninergic pathways, contributes to the former; increased central serotoninergic tone may contribute to the latter. OBJECTIVE: To examine non-clinical and clinical data relevant to the hypothesis that ondansetron, a 5-HT(3) receptor subtype antagonist, ameliorates pruritus and fatigue in liver disease. METHODS: Non-clinical findings supporting the hypothesis are discussed and all trials of ondansetron for pruritus or fatigue in liver disease are reviewed. CONCLUSION: That ondansetron ameliorates pruritus in liver disease is strongly supported by subjective observations, but is not confirmed by objective findings in two controlled trials. Anecdotal observations also suggest that ondansetron ameliorates fatigue in liver disease, but in only one of two randomized controlled trials, that used subjective end points, is a similar conclusion possible.

Ondansetron and pruritus in chronic liver disease: a controlled study.

BACKGROUND/AIMS: Increased central opioidergic neurotransmission, mediated by endogenous opioid peptide agonists, contributes to the pruritus of cholestasis. There are interrelationships between the opioid and serotonin neurotransmitter systems. The serotonin 5-HT3 receptor subtype antagonist, ondansetron, has been reported to ameliorate centrally-mediated pruritus induced by exogenously administered opiates. This study was designed to determine whether long-term oral administration of ondansetron is efficacious in ameliorating pruritus complicating chronic liver disease. METHODOLOGY: Seventeen patients with severe pruritus complicating established chronic liver disease were randomized to receive, double-blind, ondansetron (8 mg) or a placebo orally; each was administered thrice daily for a 4-week period. Endpoints were subjective scores of pruritus and objective 24-hour measurements of scratching activity. Analysable data were generated in 13 of the patients. RESULTS: Ondansetron therapy was associated with ameliorations of pruritus that appeared to be clinically significant in 5 patients (38%); in these 5 patients the mean decrease in a subjective score of pruritus was 27% of the scale of the score. However, these apparent ameliorations were not associated with robust decreases in scratching activity. For the whole group of 13 patients mean scratching activity during ondansetron therapy was not significantly less than that during treatment with placebo (p = 0.19). The total time that patients were not scratching was similar during treatment with ondansetron and placebo (p = 0.57). CONCLUSIONS: The findings suggest that serotoninergic neurotransmission, in neurons bearing receptors of the 5-HT3 subtype, plays no more than a minor role in the mediation of pruritus complicating chronic liver disease. The lack of an association between the results of applying subjective scores of pruritus and scratching activity emphasizes the need to include an objective quantitative efficacy endpoint in the design of trials of new therapies for pruritus.

Fatigue complicating chronic liver disease.

Fatigue is common and can be profound in patients with chronic liver diseases, such as primary biliary cirrhosis (PBC) and chronic hepatitis C. The pathogenesis of fatigue in such patients is unknown; it may be related to infection with the hepatitis C virus or the pathophysiology of cholestasis in PBC, to a psychological reaction to knowledge of the diagnosis, or to the presence of chronic liver disease. A major problem in evaluating a treatment for fatigue in a randomized controlled trial is the inherent subjectivity of fatigue and the lack of a satisfactory objective quantitative primary efficacy endpoint. Experimental studies in rats and male athletes have implicated the serotonin neurotransmitter system in fatigue of central origin. Administration of the 5-HT3 serotonin receptor subtype antagonist, ondansetron, has been associated with substantial sustained clinical ameliorations of profound fatigue in at least some patients with chronic liver disease.

Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis.

BACKGROUND/AIMS: Nitrosative stress resulting from increased nitric oxide (NO) synthesis contributes to the pathogenesis of chronic inflammatory diseases, including chronic viral hepatitis. Our goal was to assess the expression of inducible nitric oxide synthase (iNOS) and the formation of nitrotyrosine (NTY), as a marker of nitrosative stress, in liver biopsies from primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) patients. METHODS: Intrahepatic expression of iNOS and NTY was measured immunohistochemically and compared to histological scores of the severity of liver disease. RESULTS: Hepatocellular iNOS expression was observed in liver sections from PBC patients (with a diffuse lobular distribution) and from AIH patients (marked staining in areas of pronounced inflammation and necrosis), but not in control liver sections, including non-autoimmune cholestatic liver disease. Liver samples from PBC and AIH patients, but not from controls, showed NTY accumulation in clusters of hepatocytes and Kupffer cells. Increased iNOS expression and NTY accumulation correlated with the histological severity of PBC or AIH, especially with the degree of inflammation. CONCLUSIONS: Patients with PBC and AIH showed an enhanced intrahepatic iNOS expression and NTY accumulation, related to the histological severity of liver disease, consistent with NO-mediated nitration of hepatocellular proteins contributing to liver damage in both diseases.

Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: a potential mechanism for increased sensitivity to morphine in liver failure.

Increased GABA-mediated neurotransmission, reported to occur in hepatic encephalopathy (HE), is associated with a decrease in the release of Met-enkephalin and the expression of its coding gene in the brain. Furthermore, patients with cirrhosis and a history of HE exhibit increased sensitivity to the neuroinhibitory effects of morphine. Thus, there is a rationale to study the status of the endogenous opioid system in HE. The aim of this study was to determine whether mu-opioid receptors in the brain are up-regulated in a well characterized model of HE. Binding parameters of mu-opioid receptors were derived by assaying the binding of the opiate agonist [3H]-tyr-D-Ala-Gly-N-Methyl-Phe-Gly-ol (DAMGO) to brain membranes from rats with precisely defined stages of HE and control animals. The mean density of mu-opioid receptor sites (Bmax) in rats with stage II, III, and IV HE was 15, 29, and 33% higher, respectively, than the corresponding control value (p<0.01). In addition, the affinity of mu opioid receptors for the agonist (1/Kd) also increased with progression of HE (mean for stage IV HE vs. corresponding control mean, p<0.01). In conclusion, in liver failure, increased density and affinity of central mu-opioid receptors in the brain may: (i) be the basis for the documented increased sensitivity to opiate agonists; and (ii) occur as a consequence of increased GABAergic tone reducing neuronal synthesis and release of opioid agonist peptides.

Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy.

There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic encephalopathy with a multifactorial pathogenesis. One of the factors considered to be important in the pathogenesis of HE is ammonia. However, the mechanisms by which ammonia contributes to the manifestations of HE remain poorly defined. Ammonia could be more definitively implicated in the pathogenesis of HE if its effects can be shown to lead to an enhancement of inhibitory neurotransmission. In this context the effects of ammonia on the GABA (gamma-aminobutyric acid) neurotransmitter system may be relevant. Ammonia, at the modestly increased concentrations that commonly occur in precoma HE (0.15 mM-0.75 mM), has been shown to increase GABA-induced chloride current in cultured neurons, probably by modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia concentrations also enhanced synergistically the binding of a GABA agonist and a benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which would enhance the neuroinhibitory effects of these ligands. Also, GABA increased the potency of ammonia-induced enhancement of the binding of a BZ agonist to the GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA by 30%-50%, an effect which would increase the synaptic availability of GABA at GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE.