Biopsy-proven Liver Cirrhosis Research Articles

273-OR: Postprandial Dysfunction in Metabolic Associated Fatty Liver Disease (MAFLD)

Metabolic dysfunction in patients with metabolic fatty liver disease (MAFLD) may increase the risk for diabetes development. The liver is essential for the postprandial control of our metabolism and hormonal response, yet most studies focus on fasting conditions. We therefore studied the fasting and postprandial phase in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD, (n = 9, mean age 50 y, mean BMI 35 kg/m2, no/mild fibrosis) , cirrhosis (n = 10, age 62 y, BMI 32 kg/m2, CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2) , randomized 1:1 to fasting or Nutridrink (Nutricia, 300 kcal) . None of the postprandial patients had type 2 diabetes (T2D) . In the NAFLD/cirrhosis groups, 17/classified as MAFLD. Peripheral blood samples were collected at 0, 15, 45, 60, 90 and 120 minutes. At time point 60, a transjugular liver biopsy and liver vein blood were taken. Levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured in peripheral blood, glucagon and FGF21 also in liver vein blood. Postprandial peak glucose and C-peptide was increased in NAFLD and cirrhosis compared with healthy (mean peak glucose (mM) 7, 10, 6; mean peak C-peptide (pM) 2675, 3340, 1689, respectively) . The postprandial incremental AUC for insulin was significantly increased in patients with NAFLD compared to healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia, a phenotype related to prediabetes. FGF21 was increased in NAFLD and cirrhosis and correlated to age (r= .61, P = .001) and fasting glucose (r = .54, P = .006) . Glucagon levels were higher in liver vein compared to peripheral blood, while FGF21 levels were similar in both compartments. In summary, patients with NAFLD and cirrhosis without T2D showed significant metabolic dysfunction after a standardized meal compared to healthy controls. We found impaired glucose tolerance, hyperinsulinemia and hyperglucagonemia in both NAFLD and cirrhosis, suggesting a condition of prediabetes in patients with MAFLD. Disclosure J. Grandt: None. A.H. Jensen: None. M.P. Werge: None. E.B. Rashu: None. A. Junker: None. L. Hobolth: None. C. Mortensen: None. M. Vyberg: None. R. Serizawa: Consultant; Merck Sharp & Dohme Corp. L. Gluud: Advisory Panel; Novo Nordisk. Consultant; Pfizer Inc. Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. N.J. Wewer Albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc. Speaker's Bureau; Merck & Co., Inc., Mercodia AB. Funding Nicolai J. Wewer Albrechtsen was financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.

Evaluation of liver fibrosis and cirrhosis on the basis of quantitative T1 mapping: Are acute inflammation, age and liver volume confounding factors?

PurposeTo evaluate potential confounding factors in the quantitative assessment of liver fibrosis and cirrhosis using T1 relaxation times. MethodsThe study population is based on a radiology-information-system database search for abdominal MRI performed from July 2018 to April 2019 at our institution. After applying exclusion criteria 200 (59 ± 16 yrs) remaining patients were retrospectively included. 93 patients were defined as liver-healthy, 40 patients without known fibrosis or cirrhosis, and 67 subjects had a clinically or biopsy-proven liver fibrosis or cirrhosis. T1 mapping was performed using a slice based look-locker approach. A ROI based analysis of the left and the right liver was performed. Fat fraction, R2*, liver volume, laboratory parameters, sex, and age were evaluated as potential confounding factors. ResultsT1 values were significantly lower in healthy subjects without known fibrotic changes (1.5 T MRI: 575 ± 56 ms; 3 T MRI: 857 ± 128 ms) compared to patients with acute liver disease (1.5 T MRI: 657 ± 73 ms, p < 0.0001; 3 T MRI: 952 ± 37 ms, p = 0.028) or known fibrosis or cirrhosis (1.5 T MRI: 644 ± 83 ms, p < 0.0001; 3 T MRI: 995 ± 150 ms, p = 0.018). T1 values correlated moderately with the Child-Pugh stage at 1.5 T (p = 0.01, ρ = 0.35). ConclusionT1 mapping is a capable predictor for detection of liver fibrosis and cirrhosis. Especially age is not a confounding factor and, hence, age-independent thresholds can be defined. Acute liver diseases are confounding factors and should be ruled out before employing T1-relaxometry based thresholds to screen for patients with liver fibrosis or cirrhosis.

Secondary hyperparathyroidism and symptomatic hypercalcemia: overlooked complications of chronic liver disease

A 71-year-old female with biopsy-proven liver cirrhosis was brought to the ER due to confusion for 5 days. She was diagnosed with acute decompensated liver disease and hepatic encephalopathy. Investigations also revealed PTH-dependent hypercalcemia. Both of these entities could be causing her symptoms. Neck ultrasound did not reveal any parathyroid lesions. Alteration in mental status persisted even after the management and resolution of hepatic encephalopathy. Symptomatic resolution occurred after normalization of her calcium levels which required normal saline, cinacalcet as well as calcitonin over the course of 7 days. Hypercalcemia secondary to chronic liver disease should be considered in the differential diagnosis of patients with liver cirrhosis presenting with an altered mental status. Hypercalcemia of chronic liver disease is not always transient and managed with normal saline as previously reported; It could necessitate more aggressive therapy with calcitonin and cinacalcet as reported in this case.

Comparative Study of Ultrasound-guided Percutaneous Omental Biopsy in Cirrhotics and Noncirrhotics

To evaluate the safety and efficacy of ultrasound-guided (US-guided) omental biopsy in patients with liver cirrhosis and compare these with the noncirrhotic patients. We retrospectively studied the US-guided omental biopsies (73 males, 14 females with mean age52.71±15.90y) between January 2012 and December 2018. Patients with biopsy-proven liver cirrhosis (n= 31) who underwent omental biopsy were included in Group 1, and patients without any features of the chronic liver disease (n= 56) were included in Group 2. The technical success, diagnostic parameters, complications, imaging appearance, and histopathology spectrum were compared between the two groups. Also, univariate analysis was done to evaluate the association of a parameter with histopathology. The technical success, sample adequacy, diagnostic accuracy of Group 1 were 100%, 96.77%, and 96.77%, respectively, and for Group 2, these were 100%, 98.21%, and 98.21%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value of Group 1 were 95%, 100%, 100%, 91.67%, respectively, and for Group 2, these were 97.92%, 100%, 100%, 88.89%, respectively. There was one complication of abdominal wall hematoma in Group 1 (3.2%), which was managed conservatively. Smudged imaging appearance and nonspecific inflammation on histopathology were more common in Group 1, and there was a significant association of increased omental thickening with specific pathology in Group 1. US-guided omental biopsy in patients with liver cirrhosis is safe and effective with comparable results to noncirrhotic patients.

Cardiac\xa0output Optimisation following Liver Transplant (COLT) trial: study protocol for a\xa0feasibility\xa0 randomised controlled trial

BackgroundPatients with liver cirrhosis undergoing liver transplantation have a hyperdynamic circulation which persists into the early postoperative period making accurate assessment of fluid requirements challenging. Goal-directed fluid therapy (GDFT) has been shown to reduce morbidity and mortality in a number of surgery settings. The impact of GDFT in patients undergoing liver transplantation is unknown. A feasibility trial was designed to determine patient and clinician support for recruitment into a randomised controlled trial of GDFT following liver transplantation, adherence to a GDFT protocol, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate the efficacy of GDFT in patients undergoing liver transplantation.MethodsThe Cardiac output Optimisation following Liver Transplant (COLT) trial is designed as a prospective, single-centre, randomised controlled study to assess the feasibility and safety of GDFT in liver transplantation for patients with cirrhosis. Consenting adults (aged between 18 and 80 years) with biopsy-proven liver cirrhosis who have been selected to undergo a first liver transplantation will be included in the trial and randomised into GDFT or standard care starting immediately after surgery and continuing for the first 12 h thereafter. Both groups will have cardiac output and stroke volume monitored using the FloTrac (EV1000) device. The intervention will consist of a protocolised GDFT approach to patient management, using stroke volume optimisation. The control group will receive standard care, without stroke volume and cardiac output measurement. After 12 h the patient’s fluid management will revert to standard of care. The primary endpoint of this study is feasibility. Secondary endpoints will include a safety assessment of the intervention, graft and patient survival, liver function, postoperative complications graded by Clavien-Dindo criteria, length of intensive care and hospital stay and quality of life across the intervention and control groups.DiscussionThere is a growing body of evidence that the use of perioperative GDFT in surgical patients can improve outcomes; however, signals of harm have also been detected. Patients with liver cirrhosis undergoing liver transplantation have markedly different cardiovascular physiology than general surgical patients. If GDFT is proven to be feasible and safe in this patient group, then a multicentre trial to demonstrate efficacy and cost-effectiveness will be required.Trial registrationInternational Standard Randomised Controlled Trial Registry, ID: ISRCTN10329248. Registered on 4 April 2016.

Mechanisms of iron hepatotoxicity

Mechanisms of iron hepatotoxicity

Reversibility of minimal hepatic encephalopathy following liver transplantation in Egyptian cirrhotic patients.

AIMTo evaluate the reversibility of minimal hepatic encephalopathy (MHE) following liver transplantation (LT) in Egyptian cirrhotic patients.METHODSThis prospective study included twenty patients with biopsy-proven liver cirrhosis listed for LT and twenty age- and sex-matched healthy control subjects. All underwent neuro-psychiatric examination, laboratory investigations, radiological studies and psychometric tests including trail making test A (TMT A), TMT B, digit symbol test and serial dotting test. The psychometric hepatic encephalopathy score (PHES) was calculated for patients to diagnose MHE. Psychometric tests were repeated six months following LT in the cirrhotic patient group.RESULTSBefore LT, psychometric tests showed highly significant deficits in cirrhotic patients in comparison to controls (P < 0.001). There was a statistically significant improvement in test values in the patient group after LT; however, their values were still significantly worse than those of the controls (P < 0.001). The PHES detected MHE in 16 patients (80%) before LT with a median value of -7 ± 3.5. The median PHES value was significantly improved following LT, reaching -4.5 ± 5 (P < 0.001), and the number of patients with MHE decreased to 11 (55%). The pre-transplant model for end-stage liver disease (MELD) score ≥ 15 was significantly related to the presence of post-transplant MHE (P = 0.005). More patients in whom reversal of MHE was observed had a pre-transplant MELD score < 15.CONCLUSIONReversal of MHE in cirrhotic patients could be achieved by LT, especially in those with a MELD score < 15.

Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis.

Because of several limitations and complications of liver transplantation, new alternative treatment modalities are required for patients with liver cirrhosis. Many study results encourage the use of autologous bone marrow-derived mesenchymal stem cells for liver diseases. In this study, we assessed the impact of autologous mesenchymal stem cell transplantation on liver tissue and liver chemistry. Twenty-five patients with biopsy-proven liver cirrhosis were enrolled in the study. Patients received 1×106 autologous mesenchymal stem cells/kg via a peripheral vein. Biochemical parameters were checked monthly. Periodical radiological screening and liver biopsies before mesenchymal stem cell transplantation were performed after 6 months. Liver specimens were assessed by a pathologist. No side effect was observed and the mesenchymal stem cell transplantation procedure was well tolerated. Twelve patients completed the study. In 8 patients, improvements in Model for End-Stage Liver Disease (MELD) scores were observed. Serum albumin levels markedly increased in the third month. In patients with non-responder hepatitis C, HCV RNA levels both became negative after mesenchymal stem cell transplantation. Histopathological examinations of liver tissues before and at 6 months after transplantation revealed no change in liver tissue regeneration or fibrosis. However, in 5 patients, hepatitis activity index scores decreased. Autologous mesenchymal stem cell transplantation via peripheral vein is safe and feasible. Consecutive liver biopsy examinations suggested that mesenchymal stem cells could not reach the liver in a sufficient amount. Improvement in patients and clearance of HCV RNA may have occurred through immunomodulatory mediators secreted by transplanted mesenchymal stem cells, namely the "endocrine" effect.

PTU-137 Pneumococcal Vaccination In Patients With Liver Cirrhosis – Is The Message Being Heard?

IntroductionPatients with liver cirrhosis are immunocompromised and prone to invasive infection where outcomes are usually poor. In particular, cirrhosis is a major risk factor for severe pneumococcal infection which has...

Recurrent Hepatitis C-Related Membranoproliferative Glomerulonephritis in a Simultaneous Liver-Kidney Transplant Recipient With Atypical Presentation and Clinical Course

Hepatitis C virus (HCV) infection is known to be associated with membranoproliferative glomerulonephritis (MPGN) with or without coexistent cryoglobulinemia. We report a patient with end-stage liver and renal disease caused by HCV infection (biopsy-proven liver cirrhosis and MPGN, respectively). Approximately 10 months after simultaneous liver-kidney transplantation, patient developed severe acute kidney injury (AKI) with tripling of the baseline serum creatinine level. Allograft biopsy showed recurrent HCV-related cryoglobulinemic MPGN. However, urinalysis done immediately prior to biopsy did not suggest MPGN (lack of proteinuria and microscopic hematuria). Subsequent clinical course was also atypical in that the severe AKI resolved spontaneously and completely over 2 weeks without any change in maintenance post-transplant immunosuppressive medications, or use of plasmapheresis or HCV-antiviral therapy. Three months after resolution of recurrent MPGN-related AKI, institution of interferon-free anti-HCV therapy (sofosbuvir + ribavirin) resulted in clearance of HCV viremia over 18 weeks while liver and kidney transplant function remained stable/good. This patient illustrates the following: HCV-related MPGN may recur in the kidney transplant without typical urinary findings, and the resultant (even severe) AKI may resolve spontaneously without specific treatment and the excellent outcome that can be achieved with the newer anti-HCV therapies. World J Nephrol Urol. 2014;3(4):157-161 doi: http://dx.doi.org/10.14740/wjnu185e

Feasibility of semiquantitative liver perfusion assessment by ferucarbotran bolus injection in double-contrast hepatic MRI

To evaluate the feasibility of semiquantitative measurement of liver perfusion from analysis of ferucarbotran induced signal-dynamics in double-contrast liver MR-imaging (DC-MRI). In total 31 patients (21 men; 58 ± 10 years) including 18 patients with biopsy proven liver cirrhosis prospectively underwent clinically indicated DC-MRI at 1.5 Tesla (T) with dynamic T2-weighted gradient-echo imaging after ferucarbotran bolus injection. Breathing artefacts in tissue and input time curves were reduced by Savitzky-Golay-filtering and semiquantitative perfusion maps were calculated using a model free approach. Hepatic blood flow index (HBFI) and splenic blood flow index (SBFI) were determined by normalization of arbitrary perfusion values to the perfusion of the erector spinae muscle resulting in a semiquantitative perfusion measure. In 30 of 31 patients the evaluated protocol could successfully be applied. Mean HBF was 7.7 ± 2.46 (range, 4.6-12.8) and mean SBF was 13.20 ± 2.57 (range, 8.5-17.8). A significantly lower total HBF was seen in patients with cirrhotic livers as compared to patients with noncirrhotic livers (P < 0.05). In contrast, similar SBF was observed in cirrhotic and noncirrhotic patients (P = 0.11). Capturing the signal dynamics during bolus injection of ferucarbotran in DC-MRI of the liver allows for semiquantitative assessment of hepatic perfusion that may be helpful for a more precise characterisation of liver cirrhosis and focal liver lesions.

Left Atrial Volume: A Novel Predictor of Hepatopulmonary Syndrome

We studied patients with hepato-pulmonary syndrome (HPS). We found that HPS is frequently present in patients with left atrial enlargement. The aim of this prospective study was to evaluate the possible correlation between left atrial volume and HPS. Adult patients (>18 yr old) with biopsy proven liver cirrhosis who were referred for liver transplantation were enrolled in the study. Diagnosis of HPS was established when the following points were fulfilled: (a) the presence of chronic liver disease, (b) increased alveolar-arterial difference (AaDO(2)), (c) intrapulmonary vascular dilatation, and (d) absence of primary cardiac or pulmonary disease. We enrolled 41 patients (mean age 47.1 +/- 10.6 yr) diagnosed with HPS. Also 108 Child-Pugh score matched cirrhotic patients (mean age 49.2 +/- 9.3 yr) who have negative contrast echocardiography and normal age-related AaDO(2) were selected as a control group for the purpose of comparison of left atrial volume (LAV). LAV was significantly greater in patients with HPS compared to the control group (55.1 +/- 7.5 mL vs 37.1 +/- 9.3 mL, P < 0.05). The area under the receiver-operating characteristic (ROC) curve for LAV was 0.903 (Cut point >/= 50 mL, sensitivity 86.3%, specificity 81.2%). In the context of liver cirrhosis, LAV >/= 50 mL is a simple and feasible parameter to detect HPS.

Comment on Mackenzie and Woodhouse: C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction

Sir: With interest we read Mackenzie and Woodhouse's paper about serum C-reactive protein (CRP) levels in patients with and without liver dysfunction during bacteraemia [1]. The authors concluded that patients with biochemical evidence of liver disease show significantly lower serum CRP levels during bacteraemia than patients without liver dysfunction. This remarkable result was only achieved when patients with biopsy-proven liver cirrhosis were included in the analysis. When cirrhotic patients were excluded, however, and patients with liver dysfunction, defined as an elevated plasma bilirubin level and increased prothrombin time, were compared with controls, between-group differences did not reach statistical significance. Therefore, we feel that from the available data it cannot be concluded that patients with liver diseases, in general, generate lower serum CRP levels during bacteraemia. As multiple studies have shown greater CRP production in cirrhotic non-infected patients than in healthy controls [2, 3], it could be argued that cirrhotic patients produce less CRP during periods of infection. However, a recent large study in critically ill subjects reported that CRP levels during infection in cirrhotic patients did not significantly differ from CRP levels in non-cirrhotic patients [4]. Also, no differences were found in relation to the severity of the cirrhosis. Because interleukin-6 stimulates hepatocytes to produce CRP, an interesting study to aid the understanding of these apparently conflicting results would be to relate the interleukin-6 to CRP levels in cirrhotic patients. However, as far as we know, this has not been done. Finally, we believe that the use of CRP as a valuable screening test for infection in the ICU has certain limitations. The decision on starting antibiotics must be individualized and not be based on a certain CRP level. It should be based on suspicion of the presence of infection, the stability of the patient's clinical condition, the presence of comorbidity and the risk of death or complications.

Effect of Chronic Viral Hepatitis on Graft Survival in Saudi Renal Transplant Patients

Background: In Saudi Arabia the prevalence of hepatitis C among hemodialysis patients is very high ranging from 60 to 80%. A large number of these dialysis patients go for renal transplant, resulting into a higher prevalence of hepatitis C virus (HCV) infection in renal transplant patients. Yet no current systematic report is available on the influence of hepatitis C status on patient and graft survival. The present study was therefore undertaken to address this objective. Methods: Retrospective analysis of data of 448 renal transplantation subjects was undertaken. The mean follow-up period was 5.85 ± 2.7 (median 5.3) years. The factors associated with renal graft survival were reviewed and these include: age, sex, and type of donor, immunosuppressive medication, episodes of infection, blood pressure, serum creatinine, and status of hepatitis. The primary end-points were renal graft function and patient survival. Logistic regression, COX regression analysis, and Kaplan-Meier survival estimates were used to evaluate the influence of hepatitis C on the above parameters. Results: Among 448 recipients of first kidney transplant patients, 286 (63.8%) were positive for HCV infection. In the HCV-positive group, 204 (71.32%) were males. Kaplan-Meier survival analysis showed a significantly better graft survival for HCV-negative patients than HCV-positive patients (p < 0.001; log-rank test). Logistic regression analysis and COX regression analysis have shown different grades of graft dysfunction were present in HCV-positive patients after adjustment for covariates: age, sex, blood pressure, type of donor, and immunosuppressive medication; the presence of HCV was a major predictor of bad outcome and significantly influenced graft survival (odds ratio = 4.37; 95% Cl = 1.81–4.77). Significant deterioration of liver function was noted in HCV-positive patients at the last follow-up, taking ALT as a marker (ALT level 80.6 ± 5.8 U/l at the last follow-up versus 49.5 ± 32 U/l at baseline p ≤ 0.0001). Sixteen patients had a chronic active course and 1 patient developed biopsy-proven liver cirrhosis and portal hypertension. A serious and significantly greater incidence of fatal chest infections was seen in HCV-positive patients. Although mortality was greater in HCV-positive versus HCV-negative patients (20 vs. 7), the difference did not attain statistical significance (p = 0.23) and none of the patients died as a result of hepatic failure. Conclusion: The presence of HCV infection greatly influenced graft survival in renal transplant patients and a higher proportion of infected patients had renal and hepatic dysfunction. A significant increase in fatal chest infections was noted in HCV-positive patients. Overall mortality was higher in HCV-positive patients, but it was not statistically significant. All measures should be taken to prevent HCV transmission in the dialysis population. Renal transplant recipients with HCV infection need close monitoring for both graft and liver function.

Effectiveness of Pegylated Interferon and Ribavirin in Patients With Liver HCV Cirrhosis

Clearance of HCV before transplantation could avoid recurrence of hepatitis C in the liver allograft, thereby improving graft and patient survival. We report our experience with combined therapy for patients with HCV cirrhosis, including 12 patients with biopsy-proven liver cirrhosis (n = 7) or previous cirrhotic complications (n = 5). The Child–Pugh score was A in eight patients and B in four. Two patients had hepatocellular carcinoma. Genotype distribution was 1a (n = 2), 1b (n = 8) or 3 (n = 1). Patients received peginterferon α2b (1.5 μg/kg once weekly) and ribavirin (10.6 g/kg per day) for 48 weeks (genotype 1) or 24 weeks (genotype 3). Twenty-one months after beginning therapy all the patients remained alive; three have undergone liver transplantation. In one patient treatment was discontinued after 2 months due to cachexia. End-of-treatment virologic response was achieved in five patients (41.7%) and sustained virologic response in three patients (25%). Patients who cleared the virus had negative PCR 4 weeks after beginning therapy. All patients had adverse events. The most common clinical events were asthenia, weight loss, fever, and anorexia. Infectious complications resolved in three patients (25%). Hematologic events were common. Seven of 11 patients (63.6%) who completed therapy required dose reduction. We conclude that therapy with peginterferon and ribavirin in patients with HCV cirrhosis has a similar effectiveness to previous treatments. A virologic response 1 month after the beginning of therapy could be a main predictor of a sustained response.

P0381 ENDOGENOUS NITRIC OXIDE IN EXHALED AIR FROM CHILDREN WITH LIVER CIRRHOSIS

Introduction: Endogenous pulmonary nitric oxide production may be increased in severe liver cirrhosis and contribute to pulmonary vasodilatation and hepatopulmonary syndrome. This study is to assess if pulmonary nitric oxide production by measuring exhaled nitric oxide (eNO) is increased in children with liver cirrhosis. Methods: A total of 23 children were enrolled in the study. Nine patients with biopsy-proven liver cirrhosis, eight patients with (non-cirrhotic) chronic liver disease and eight healthy children served as control, were enrolled. Exhaled nitric oxide was measured with multiple breath technique by a chemiluminescence analyzer (Analyzer CLD 88sp, Eco Medics AG, Switzerland), adapted for online recording of NO concentration, at a sample gas flow 50mL/Ds-1 according to the American Thoracic Society and European Respiratory Society recommendations. Exhaled NO was considered as derived from the lower airways when end-expiratory concentrations reached a plateau. The mean value of the end-expiratory NO levels was calculated by spiroWare software. Data are expressed as mean ± ó standard error of the mean. Differences between groups were compared using Kruskal-Wallis one-way analysis of variance (ANOVA) followed by the Dunn’s method. Statistical significance was defined as P < 0.05. Results: Children with liver cirrhosis had higher levels of eNO concentration (22.4 ± ó 3.9 ppb) than healthy children (8.3 ± ó 0.9 ppb; P<0.05) and children with chronic liver disease (9.0 ± ó 1.0 ppb; P<0.05). In liver cirrhotic group, there were no significant correlations between eNO concentration and liver function test (bilirubin, aspartate and alanine aminotransferase, albumin, and prothrombin time). Elevation of exhaled eNO concentration was found in 2 patients with liver cirrhosis and moderate intrapulmonary shunting (17.6, 11.3 ppb). Conclusion: Our finding is in agreement with previous studies in adults that demonstrate eNO value significantly higher in patients with severe cirrhosis. The present data show an increased eNO concentration is correlated with development of liver cirrhosis and hepatopulmonary syndrome in children with liver disease.

Hepatic iron deposition on magnetic resonance imaging: correlation with inflammatory activity.

To define the relation between pathologic inflammatory activity and magnetic resonance imaging (MRI) grades of iron deposition in patients with liver cirrhosis. In 53 patients with biopsy-proven liver cirrhosis, T2*-weighted gradient echo MRI (echo time > or =6 milliseconds) was reviewed. Grading of parenchymal iron deposition and siderotic nodules in the liver and liver-to-skeletal muscle signal intensity ratios were compared with pathologically defined inflammatory activity. The MRI grade of hepatic siderotic nodules correlated significantly with the grade of periportal inflammation (r = 0.301, P < 0.05) but not with the grade of piecemeal necrosis. The grade of parenchymal iron deposition was not correlated with the grade of periportal inflammation or piecemeal necrosis. There was a nonsignificant trend toward correlation between the histologic grade of hepatic iron content and the grades of periportal inflammation and piecemeal necrosis. MRI grading of siderotic nodules correlates with inflammatory activity in cirrhotic patients.

Combination therapy of percutaneous ethanol injection and radiofrequency ablation against hepatocellular carcinomas difficult to treat

Radiofrequency ablation (RFA) is an effective modality for the treatment of hepatocellular carcinoma (HCC), because it can induce large coagulated necrosis in a few sessions. We have recently reported that the combination therapy of percutaneous ethanol injection (PEI) with RFA (PEI-RFA) created enhancement of coagulated necrosis compared with RFA alone. In the present study, we adopted PEI-RFA for the treatment of HCCs located in the regions that are difficult to treat with RFA alone. Five patients with biopsy-proven HCC and liver cirrhosis underwent PEI-RFA therapy. In these patients, HCCs were located beside the gallbladder, inferior vena cava or portal vein or kidney, or immediately under the diaphragm. Prior to RFA, 99.5% ethanol was injected into the region of HCC located in the regions where RFA energy appears to be difficult to reach. In all cases, HCC was totally coagulated by PEI-RFA. Injecting ethanol prior to RFA therapy caused no major side effects. These results indicate that PEI-RFA may be effective for the treatment of HCCs located in the regions that are difficult to treat with RFA alone as well as large-sized HCCs.

Hypermetabolism in clinically stable patients with liver cirrhosis

Hypermetabolism has a negative effect on prognosis in patients with liver cirrhosis. Its exact prevalence and associations with clinical data, the nutritional state, and beta-adrenergic activity are unclear. We investigated resting energy expenditure (REE) in 473 patients with biopsy-proven liver cirrhosis. This was a cross-sectional study with a controlled intervention (beta-blockade) in a subgroup of patients. Mean REE was 7.12 +/- 1.34 MJ/d and correlated closely with predicted values (r = 0.70, P < 0.0001). Hypermetabolism was seen in 160 patients with cirrhosis (33.8% of the study population). REE was > 30% above the predicted value in 41% of the hypermetabolic patients with cirrhosis. Hypermetabolism had no association with clinical or biochemical data on liver function. REE correlated with total body potassium content (TBP; r = 0.49, P < 0.0001). Hypermetabolic patients had lower than normal body weight and TBP (P < 0.05). About 47% of the variance in REE could be explained by body composition whereas clinical state could maximally explain 3%. Plasma epinephrine and norepinephrine concentrations were elevated in hypermetabolic cirrhotic patients (by 56% and 41%, respectively; P < 0.001 and 0.01). Differences in REE from predicted values were positively correlated with epinephrine concentration (r = 0.462, P < 0.001). Propranolol infusion resulted in a decrease in energy expenditure (by 5 +/- 3%; P < 0.05), heart rate (by 13 +/- 4%; P < 0.01), and plasma lactate concentrations (by 32 +/- 12%; P < 0.01); these effects were more pronounced in hypermetabolic patients (by 50%, 33%, and 68%, respectively; each P < 0.05). Hypermetabolism has no association with clinical data and thus is an extrahepatic manifestation of liver disease. Increased beta-adrenergic activity may explain approximately 25% of hypermetabolism.

Doppler ultrasound evaluation of advanced portal vein pulsatility in patients with normal echocardiograms

The hypothesis tested that mechanisms other than retrograde transsinusoidal fluid wave transfer reported in patients with right heart failure are responsible for the ultrasonographic sign of advanced portal vein pulsatility (APP). Within a time-period of 3 years we have seen 13 patients with APP, defined as temporary portal flow reversal in the face of a normal echocardiogram. Nine of these patients had biopsy-proven liver cirrhosis and four with liver disease were without cirrhosis or cardiac pathology. A randomly selected control group of 18 healthy subjects was studied. Doppler ultrasound evaluation of the hepatic veins as well as the intra and extrahepatic portal vein territories was performed in both groups. Hepatopetal portal flow with APP reversed to hepatofugal flow in follow up studies in two patients. In another two hepatopetal flow with APP in the main portal vein and hepatofugal flow in the intrahepatic portal radicles was recorded during the same examination. The remaining group displayed APP in the intra and extrahepatic portal vein territories. None of the normal subjects presented with APP. Hepatic venous outflow obstruction associated with excessive arterioportal shunting is likely to account for APP of all of our patients. Based on a causal link between angiographic ‘to-and-fro’ flow pattern and the sonographic APP sign in patients with sinusoidal outflow obstruction we suggest, that APP expresses a short, transitional period of portal hypertension just before the occurence of flow reversal.