Development Of Hepatic Dysfunction Research Articles

Liver transplantation in acute liver failure: a challenging scenario

Acute liver failure is a critical medical condition defined as rapid development of hepatic dysfunction associated with encephalopathy. The prognosis in these patients is highly variable and depends on the etiology, interval between jaundice and encephalopathy, age, and the degree of coagulopathy. Determining the prognosis for this population is vital. Unfortunately, prognostic models with both high sensitivity and specificity for prediction of death have not been developed. Liver transplantation has dramatically improved survival in patients with acute liver failure. Still, 25% to 45% of patients will survive with medical treatment. The identification of patients who will eventually require liver transplantation should be carefully addressed through the combination of current prognostic models and continuous medical assessment.

The Role of Ferritin in Assessing COVID-19 Severity

Ferritin is one of the biomarkers requiring special attention; its blood level increases significantly especially in the severe course of COVID-19. Information on the effect of hyperferritinemia on the disease outcome is very contradictory as are the ideas about the causes of its development.The objective: to study the effect of hyperferritinemia on the disease outcome and analyse the possible causes of its development in severe COVID-19.Subjects and Methods. Data on 479 patients with severe course of coronavirus infection treated in intensive care units (ICU) were retrospectively analyzed. Of them, the proportion of patients with a favorable outcome (Group 1) was 51.0% (n = 241), and with an unfavorable outcome (Group 2) - 49.0% (n = 235). The following parameters were assessed: the levels of ferritin, C-reactive protein, fibrinogen, IL-6, IL-10, IL-18, procalcitonin, complement C5a, total, direct and indirect bilirubin, ALT, AST, and the blood level of lactate dehydrogenase (LDH). The changes of erythrocyte count and hemoglobin blood level were also monitored. In order to form a clear view of iron metabolism, free iron, transferrin, and myoglobin levels were assessed in several patients with high ferritin values (more than 1,500 pg/L).Results. In the unfavorable outcome, ferritin levels increase very significantly, reaching maximum by day 6 of patients' stay in ICU. The difference in the level of ferritin between the groups of survivors and deceased during this period is clear and significant (p = 0.0013). The association of ferritin values with the outcome is detected as early as day 1, but by day 4 it becomes highly significant (the cut-off point is 1,080 pg/l). No data have been obtained that would indicate the association of hyperferritinemia with impaired iron metabolism, the development of hepatic dysfunction, or cellular destruction. In contrast to survivors, those who died on day 6 had elevated IL-6 while C5a level remained unchanged. Conclusions. The rapid increase in ferritin blood levels to 1,000 pg/L or higher is an unfavorable prognostic sign indicating a high probability of a lethal outcome. When assessing genesis of hyperferritinemia in COVID-19, the crucial significance should be attributed to the cytokine storm rather than disorders of iron metabolism or hemotoxic effects of the virus. The persistent increase of ferritin level in blood during 4-6 days of stay in ICU should be considered as a reason to intensify anticytokine therapy.

The Role of Parenteral Lipids in the Development of Hepatic Dysfunction and Hepatic Steatosis in a Mouse Model of Total Parenteral Nutrition.

Parenteral nutrition-associated liver disease, a common and life-threating complication among people who require long-term parenteral nutrition, has been associated with abnormal liver function, cholestasis, steatosis and fibrosis. Intravenous soybean lipids may be associated with the development of liver disease. We therefore examined whether different doses of parenteral lipids would affect the development of liver disease, and further investigated the possible pathogenesis of it. C57BL/6J mice with a central catheter placed in the right jugular vein were divided into three groups. The control group received normal mouse chow with intravenous normal saline; The lipids group received parenteral nutrition solution (0.14 g lipids per day); the H-lipids group received parenteral nutrition solution with twice the amount of lipids (0.3 g lipids per day). Changes in body weight, serum biochemical parameters, liver histology and farnesoid X receptor gene expression in the liver were assessed. The values of serum direct bilirubin, total bilirubin and cholesterol were markedly increased in the H-lipids group at day 7. The predominant histologic finding in the H-lipids group was steatosis, and the steatosis score in the H-lipids group was much higher than in the other two groups at either day 5 or day 7. Hepatic expression of farnesoid X receptor mRNA decreased after 7 d of parenteral nutrition. High doses of parenteral lipids are more likely to develop liver disease in a mouse model of parenteral nutrition. Farnesoid X receptor may play a key role in the development of parenteral nutrition-associated liver disease.

Prediction of risk factors related to the development of hepatic dysfunction following open heart surgery

Our goal was to investigate the incidence of postoperative jaundice in open heart surgery patients and to determine the risk factors associated with hepatic dysfunction.

Total parenteral nutrition-associated cholestasis and risk factors in preterm infants.

Background/Aim:Development of hepatic dysfunction is a well-recognized complication of total parenteral nutrition in preterm infants. Previous studies reported the incidence of total parenteral nutrition–associated cholestasis and described possible contributing factors to its pathogenesis, but little is done trying to determine its possible predictive risk factors. The aims of this study was to determine the incidence of total parenteral nutrition–associated cholestasis and to develop a possible predictive model for its occurrence.Patients and Methods:A review of medical records of all very low birth weight infants admitted to neonatal intensive care unit at King Khalid University Hospital, Riyadh, Saudi Arabia, between January 2001 and December 2003 was carried out. The infants were divided into two groups: Cholestasis and noncholestasis, based on direct serum bilirubin level >34 μmol/L. A multivariate logistic regression analysis was performed to calculate the statistical significance of risk factors. Receiver–operating characteristic curve was used to determine the optimal cutoff points for the significant risk factors and to calculate their sensitivity and specificity. The level of significance was set at P ≤ 0.05.Results:A total of 307 patients were included in the analysis. The incidence of cholestasis in the whole population was 24.1% (74 patients). Infants with cholestasis had a lower birth weight, 735.4 ± 166.4 g vs. 1185.0 ± 205.6 g for noncholestasis group (P < 0.001), whereas the mean gestational age for the two groups was 25.4 ± 2.1 week and 28.9 ± 2.1 week, respectively (P < 0.001). The significant risk factors for the development of cholestasis were birth weight (P = 0.006) with an odds ratio of 0.99 [95% confidence interval (CI), 0.98, 0.99]; sensitivity of 92%, specificity of 87%; and total parenteral nutrition duration (P < 0.001) with an odds ratio of 1.18 (95% CI, 1.10, 1.27); sensitivity of 96%, specificity of 89%.Conclusions:A lower birth weight and longer duration of total parenteral nutrition were strong predictive risk factors for the development of cholestasis in preterm infants.

Homocysteine Inhibits Hepatocyte Proliferation via Endoplasmic Reticulum Stress

Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21Cip1 in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21Cip1 and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21Cip1 are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.

Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence

Chronic hepatitis B virus (HBV) infection is the key driving force of liver disease progression, resulting in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to suppress or eliminate HBV replication to reduce the activity of hepatitis, thus reducing the risk of, or slowing the progression of, liver disease. Nucleos(t)ide analogues (Nucs) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function, thus increasing survival in patients with hepatic decompensation. Long-term Nuc therapy may result in histological improvement or reversal of advanced fibrosis and reduction in disease progression, including the development of HCC. The long-term benefits of a finite course of interferon (IFN)-α therapy also include a sustained and cumulative response, as well as hepatitis B surface antigen seroclearance and reduction in the development of cirrhosis and/or HCC. Pegylated IFN and newer Nucs may achieve better long-term outcomes because of improved efficacy and a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. Understanding the effects of anti-HBV treatment against HCC incidence and recurrence after hepatectomy or liver transplantation is required for further improvement of outcome.

P-70 Predictors of risk factors related to the development of hepatic dysfunction following open heart surgery

P-70 Predictors of risk factors related to the development of hepatic dysfunction following open heart surgery

Association of circulating osteopontin levels with clinical outcomes in postoperative biliary atresia

Biliary atresia (BA) is one of the most serious liver disorders in children. The aims of the present study were to investigate circulating levels of osteopontin in BA children compared with healthy controls and to evaluate the relationship between circulating osteopontin and therapeutic outcome of BA patients. Fifty-nine BA patients post-Kasai operation and 13 healthy children were recruited. The patients were divided into two groups according to their serum total bilirubin levels (TB<2, jaundice-free vs. TB≥2mg/dL, persistent jaundice) and alanine aminotransferase (ALT<45, normal ALT vs. ALT≥45IU/L, elevated ALT). Plasma osteopontin levels were analyzed using commercial enzyme-linked immunosorbent assay. The circulating osteopontin was higher in BA children compared with that of healthy controls (146.9±19.1 vs. 28.0±8.4ng/mL, P=0.001). The BA patients with persistent jaundice had more increased plasma osteopontin levels than those without jaundice (157.8±47.9 vs. 27.5±6.4ng/mL, P=0.001). Furthermore, plasma osteopontin levels in BA patients with elevated ALT were significantly higher than those with normal ALT (103.2±29.2 vs. 24.5±7.9ng/mL, P=0.01). In addition, circulating osteopontin was positively correlated with serum total bilirubin (r=0.526, P<0.001) and with serum ALT (r=0.575, P<0.001). Subsequent analysis showed that the BA patients with portal hypertension had more elevated plasma osteopontin compared to those without portal hypertension (116.7±31.1 vs. 19.5±9.3ng/mL, P=0.01). Increased circulating osteopontin was associated with the development of hepatic dysfunction and portal hypertension in BA patients. Circulating osteopontin may serve as a possible marker reflecting disease severity and monitoring the disease progression in postoperative BA patients.

Hepatic involvement with tuberculosis-associated immune reconstitution disease

We read with interest the article by Hoffman and colleagues concerning hepatotoxicity in patients receiving antiretroviral therapy (ART) in a South African cohort. Hepatotoxicity is a common problem in resource-limited settings where less costly but more hepatotoxic agents are often used and where patients frequently have comorbidity. Of particular note concurrent treatment for tuberculosis is common; in a cohort in Cape Town South Africa we reported that approximately 30% of patients during the first year of ART receive overlapping tuberculosis treatment. Hoffman and colleagues found that such overlap of tuberculosis treatment with ART was associated with an 8.5-fold increased risk of grade 3 or 4 hepatotoxicity (as defined by the AIDS clinical trials network). Development of hepatic dysfunction during the early weeks of concurrent tuberculosis treatment and ART presents a common clinical challenge which is complicated greatly by the fact that potential causes are multiple. Each of the major classes of antiretroviral agents is hepatotoxic with hypersensitivity reactions to nonnucleoside reverse transcriptase inhibitors being the most commonly implicated cause during early ART. Rifampicin isoniazid and pyrazinamide and co-trimoxazole are all well recognised causes of hepatitis. Moreover patients who also have coinfection with chronic hepatitis infections B or C may develop a transient rise or flare in serum concentrations of hepatic transaminases during early immune recovery with ART. In addition however we suggest that immune reconstitution disease associated with tuberculosis (TB-IRD) is a further under-recognised cause of hepatic disease in this period. (excerpt)

Intestinal Failure–Associated Liver Disease: What Do We Know Today?

Intestinal failure-associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.

Insights into the role of interleukin-6 in the induction of hepatic injury after trauma-hemorrhagic shock.

Although systemic interleukin-6 (IL-6) level is elevated, hepatocellular function is impaired and liver injury occurs after trauma-hemorrhage (T-H), it remains unknown whether a causal relationship exists between elevated IL-6 levels and liver injury after T-H. We hypothesized that IL-6 is causative in the development of hepatic dysfunction and injury after T-H. To examine this, adult male Sprague-Dawley rats underwent a 5-cm midline laparotomy and were subjected to hemorrhagic shock (blood pressure = 35 mmHg for approximately 90 min), followed by resuscitation (Ringer lactate, 4 times the shed blood volume). At 2, 5, and 24 h thereafter, blood samples were collected and the liver isolated and perfused for 60 min. Portal inflow pressure was measured, and perfusate samples were collected to measure IL-6, alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. A significant positive correlation between plasma levels of IL-6 and ALT and perfusate levels of IL-6 and LDH levels was observed. In a second series of experiments, rats were treated with immunoglobulin G (IgG) or antibodies against rat IL-6 (anti-IL-6) at the onset of resuscitation. At 5 h after resuscitation, anti-IL-6 treatment attenuated the T-H induced increases in plasma ALT and thromboxane B(2) (a thromboxane A(2) metabolite) levels, and bile flow was normalized to sham levels. Perfusion of livers from normal rats with IL-6 did not alter portal pressure; however, perfusion of a stable thromboxane A(2) analog dose dependently increased portal pressure. Thus IL-6 plays a significant role in the induction of hepatic dysfunction and liver injury after T-H that appears to be in part mediated by increased thromboxane A(2) levels.

Serum cytokine profiles in patients with Plasmodium vivax malaria: A comparison between those who presented with and without hepatic dysfunction

The aim of this study was to compare the serum cytokine profiles of Plasmodium vivax malaria patients who presented with and without hepatic dysfunction. This is a retrospective analysis of 74 consecutive cases of P. vivax malaria seen at 3 military hospitals near the Demilitarized Zone in South Korea from 1999 to 2000. All patients studied were adult active duty servicemen. On admission, the mean (± SEM) age of the patients who presented with ( n = 36) and without hepatic dysfunction ( n = 38) was 21.6 ± 0.24 and 22.5 ± 0.44 years, respectively ( P = 0.72). On admission, there was no significant difference between the 2 patient populations in terms of mean temperature, haemoglobin level, haematocrit, total white blood cell count, platelet count, parasite index, and serum concentration of transforming growth factor-β. Plasmodium vivax malaria patients who presented with hepatic dysfunction had significantly higher mean serum concentrations of soluble Fas ligand, interleukin (IL)-l, IL-4, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ than those without hepatic dysfunction, suggesting the involvement of these cytokines in the development of hepatic dysfunction. The mean serum concentration of IL-12 was significantly lower in patients with hepatic dysfunction. The mean body temperature was not significantly different between the 2 patient populations.

Contribution of IL-18 and its related cytokines on the development of hepatic dysfunction in non-biliary acute pancreatitis

Background: Interleukin-18 (IL-18) production is the main mechanism of hepatic injury in several animal models via further gamma interferon (IFN-γ) release. IL-18 also functions as an inducer of proinflammatory cytokines as TNF-α, which are also shown to induce organ injuries in many severe inflammatory conditions. To clarify the mechanism of hepatic injury developed in acute pancreatitis, plasma concentrations of IL-18 and its related cytokines were analyzed. Patients and methods: Plasma levels of IL-18, IL-12, IFN-γ, TNF-α, soluble TNF receptor (sTNF-R) and soluble Fas ligand (sFas-L) were measured by ELISA. Results: Plasma concentrations of IL-18 in patients with hepatic injury increased during the first few days apparently and remained so to some extent thereafter. However, IFN-γ showed no apparent increase in plasma concentrations. Those of TNF-α and sTNF-R remained increased in the hepatic injury group. Conclusion: These results suggest that IL-18 may act as a pro-inflammatory cytokine, which provokes the cytokine storm and eventually hepatic injury.

Massive Oral Ingestion of Elemental Mercury

A 42 year old male, while repairing a sphygmomanometer, intentionally ingested an estimated 3 kg (220 mL) of metallic mercury. During admission, only tremor, irritability, forgetfulness and fatigue were noted. There were no obvious gastrointestinal or hepatic complications. Blood and urine mercury levels were significantly elevated. Most of the metallic mercury was cleared from the gut within 10 days. A few months later, hepatic dysfunction with jaundice developed. Serial investigations did not suggest a viral etiology or alcoholism. Liver function tests and blood and urine mercury levels returned to normal over the next 10 months. The observation suggests that massive and prolonged retention of metallic mercury may facilitate the conversion of metallic, elemental mercury to divalent mercury and its subsequent absorption with development of hepatic dysfunction.

Photosensitized oxidation of tryptophan and hepatic dysfunction in neonatal gerbils.

Hepatic dysfunction is a common metabolic complication of parenteral nutrition. Studies in animals have suggested that several amino acids, especially tryptophan, may play a role in the development of hepatic dysfunction. Further, photoirradiation of amino acids in the presence of photosensitizers, such as riboflavin, causes photooxidative changes in several amino acids. The present study was undertaken to determine the effect of tryptophan, after photoirradiation in the presence of riboflavin, on hepatic function in neonatal gerbils. Two-week-old suckling gerbils received approximately 4 mmol/kg/day of light-exposed or nonlight-exposed tryptophan or received saline intraperitoneally for 4 days. An increase in the activity of serum gamma-glutamyl transpeptidase was found in gerbils receiving both light-exposed and nonlight-exposed tryptophan compared to control. Concentrations of tryptophan were significantly higher in animals receiving saline than in the other two groups. There were no significant differences in the major tissue amino acids among the three groups of animals. Our data suggest the role of photosensitized oxidation of tryptophan in the pathogenesis of hepatic dysfunction in neonatal gerbils. It is possible that similar photooxidation occurring during infusion of parenteral amino acid solutions containing vitamins exposed to constant illumination in the newborn nursery is responsible for the observed hepatic dysfunction in parenterally fed neonates.

Monitoring hepatic dysfunction during intravenous hyperalimentation

Abnormalities of routine biochemical liver function tests may occur during intravenous hyperalimentation (IVH) with hypertonic dextrose and amino acid solutions. The mechanisms are uncertain but it has been proposed that cyclic hyperalimentation may protect against abnormalities at high calorie: nitrogen ratios. Four dogs received IVH at a calorie: nitrogen ratio of 162:1, 288:1 (continuous), and 288:1 (cyclic). Each regimen was given for 3 weeks, was isonitrogenous, and maintained body weight and nitrogen equilibrium. Hepatic function was assessed at the beginning and end of each regimen using routine liver function tests, and in addition, indocyanine green clearance and amino acid molar ratio (AAMR). Cyclic hyperalimentation did not protect against the development of hepatic dysfunction. No changes occurred in total bilirubin concentration. Glutamic pyruvate transaminase and AAMR may give an earlier indication of subclinical deterioration of hepatic function than glutamic oxaloacetic transaminase, alkaline phosphatase, and indocyanine green clearance during IVH regimen, and may be the most useful indices for sequential monitoring of hepatic dysfunction.

Salicylate Hepatitis

Two patients developed acute hepatic injury as a result of salicylate therapy. In each patient serum salicylate levels were below 25 mg per 100 ml during the development of hepatic dysfunction. Liver biopsies, obtained a few days after the peak abnormalities in serum transaminases, revealed nonspecific acute hepatitis. Normal liver tissue was found before the beginning of salicylate treatment in 1 patient, who had systemic lupus erythematosus and drug rechallenge was not attempted. In the other patient, who had rheumatoid arthritis, rechallenge with salicylate evoked hepatic dysfunction and recurrent symptoms. Salicylate-induced liver injury should be considered in the differential diagnosis of hepatic disease occurring in patients receiving high dose salicylate therapy, regardless of serum salicylate levels.