Hepatic Disease Severity Research Articles

Intrahepatic recurrence after percutaneous radiofrequency ablation of hepatocellular carcinoma: Analysis of the pattern and risk factors

Purpose To evaluate the pattern and risks for intrahepatic recurrence after percutaneous radiofrequency (RF) ablation for hepatocellular carcinoma (HCC). Materials and methods We studied 62 patients with 72 HCCs (≤4 cm) who were treated with percutaneous RF ablation. The mean follow-up period was 19.1 months (6.0–49.1). We assessed the incidence and cumulative disease-free survival of local tumor progression (LTP) and intrahepatic distant recurrence (IDR). To analyze the risk factors, we examined the following, for the LTP: (1) tumor diameter, (2) contact with vessels, (3) degree of approximation to hepatic hilum, (4) contact with hepatic capsule, (5) presence of ablative safety margin, (6) degree of benign periablational enhancement and (7) serum alpha-fetoprotein; for the IDR: (1) severity of hepatic disease, (2) presence of HBsAg, (3) serum alpha-fetoprotein, (4) whether RF ablation was the initial treatment and (5) multiplicity of tumor for IDR. Results The incidence of overall recurrence, LTP and IDR was 62.9%, 26.4% and 53.2%, respectively. The cumulative disease-free survival rates were 52%, 82% and 56% at 1 year, 26%, 63% and 30% at 2 years, respectively. Univariate analysis showed that the significant risk factors for LTP were: a tumor with a diameter >3 cm, contact of HCC with a vessel and an insufficient safety margin ( p < 0.05). A multivariate stepwise Cox hazard model showed that the measurement of a tumor diameter >3 cm and insufficient safety margin were independent factors. Only the increased serum alpha-fetoprotein was a significant risk factor for IDR ( p < 0.05). Conclusion Intrahepatic recurrence after percutaneous RF ablation is common. Large HCC (>3 cm) with high serum alpha-fetoprotein should be treated more aggressively because of higher risk for recurrence.

The Importance of Predicting the Prognosis in Patients With Hepatopulmonary Syndrome: A Simple Scoring System

Hepatopulmonary syndrome (HPS) is a pulmonary vascular disorder, complicating hepatic diseases, and is responsible for an increased morbidity and mortality among patients awaiting liver transplantation. Nowadays, it is recognized as an independent risk factor for death in this patient population. The severity of hypoxemia and the advanced stage of the liver dysfunction are determinants for the prognosis. Therefore, the possibility to be successful, thus improving survival, consists of addressing HPS at an earlier stage, giving more attention to moderate evidences of this pathology instead of the severe ones. On the basis of scientific evidence, we suggest a simple scoring system to predict prognosis among patients with HPS, founded on the integration of two main factors: the severity of hepatic disease, expressed as class of Child-Pugh, and the severity of the hypoxemia. This model of prognostic evaluation has the objective of estimating the additional risk of these patients, thereby avoiding a deleterious underestimate of risk and an arbitrariness of management.

Relationship between matrix metalloproteinase-2 activity and cystatin C levels in patients with hepatic disease

Objectives: A direct relationship between cystatin C levels and the severity of hepatic disease has been revealed in our previous study. This study was aimed to consider whether a correlation exists between matrix metalloproteinases (MMPs), which have been proven to be involved in liver cirrhosis, and cystatin C to reflect the severity of hepatic disease. Design and Methods: A total of 154 consecutive patients with various liver diseases were recruited to determine their serum levels of cystatin C, MMP-2 and-9, together with other hepatic parameters. These were compared with 40 normal controls. Results: Average levels of MMP-2 and cystatin C were significantly higher in patients while MMP-9 was significantly lower, as compared to controls. A linear regression analysis has revealed a direct relationship between cystatin C and MMP-2 ( Y = 83.39 + 270.56 X, R = 0.38, P < 0.001), as well as between MMP-2 and the severity of liver diseases. Conclusion: This is the first study to demonstrate a correlation between cystatin C and MMP-2, suggesting that there may be certain interactions between cystatin C and MMP-2 in patients with hepatic diseases.

Pharmacokinetics of Adefovir after Oral Administration of Adefovir Dipivoxil 10 mg in Healthy Japanese Males and Japanese Patients with Chronic Hepatitis B

The pharmacokinetics of adefovir dipivoxil, a novel reverse transcriptase inhibitor for the treatment of chronic hepatitis B, were investigated in healthy Japanese subjects (n=12) and Japanese patients with chronic hepatitis B (n=11).Healthy males received single and multiple doses (once daily for 5 days) of adefovir dipivoxil 10 mg. After the first and final doses, blood and urine samples were collected over 48 hours and concentrations of adefovir, the hydrolysed active metabolite, measured by LC-MS/MS. Adefovir pharmacokinetic parameters (mean±SD) were comparable after single and multiple dosing: Cmax 22.9±3.3 and 24.5±3.8 ng/mL, respectively. The single dose AUC 0-∞ (239.4±35.7 ng·hr/mL) and half-life (6.89±1.21 hr) were also similar to AUC 0-24 (249.3±32.9 ng·hr/mL) and t 1/2 (7.73±0.73 hr) after multiple dosing. The steadystate accumulation ratio was 1.05±0.12, indicating a lack of appreciable accumulation during multiple dosing. Approximately 60% of the dose was recovered in urine as adefovir.Chronic hepatitis B patients with evidence of abnormal liver function associated with YMDD mutant hepatitis B virus and taking lamivudine 100 mg once daily were also studied. The results were similar to those in healthy subjects. Cmax and AUC 0-∞ after the first dose of adefovir dipivoxil 10 mg in chronic hepatitis B patients were 20.1±3.3 ng/mL and 272.8±51.3 ng·hr/mL, respectively. Furthermore, the pharmacokinetics of adefovir were comparable in patients with and without cirrhosis. Adefovir pharmacokinetics in Japanese subjects with normal renal function are therefore not altered by chronic hepatitis B infection, lamivudine co-administration or the severity of hepatic disease. These Japanese results are consistent with those in Western subjects and a major inter-ethnic difference is not observed.

Portopulmonary hypertension and the issue of survival

Can orthotopic liver transplantation (OLT) result in complete resolution of portopulmonary hypertension (POPH)? More specifically, under what conditions will the normal posttransplant normal hepatic/portal physiology cause a resolution of pulmonary artery hypertension and improve long-term survival? OLT, orthotopic liver transplantation; POPH, portopulmonary hypertension; MELD, model for end-stage liver disease. This survival issue is put into some perspective by the article in this month's Liver Transplantation, wherein Kawut and colleagues describe a 38% 3-year survival when POPH complicates liver disease.1 Their series is small (n = 13), retrospective, and burdened by the uncontrolled management interventions that must address consequences of 2 disorders: pulmonary artery hypertension and portal hypertension. Liver transplantation did not appear to be one of the endpoints in Kawut's analysis. These limited data in the era of OLT mirror the discouraging experience from referrals to other major liver centers. Robalino and Moodie2 via a literature review and Cleveland Clinic experience described a 21% 30-month survival in 49 patients with coexistent pulmonary and portal hypertension in the pre-OLT era. Herve et al. from France3 reported a 50% 5-year survival (n = 39; no data on OLT effects), and Swanson et al. documented a Mayo Clinic experience showing a 28% 5-year survival without OLT (n = 66) and 56% 5-year survival with OLT (n = 28).4 These studies and the Kawut contribution beg 2 broad questions that larger series must address. First, why do such patients with POPH have such poor survival? Second, is it hopeless to consider OLT (with long-term survival) when moderate to severe POPH exists? These questions must be considered in the current context of an evolving treatment armamentarium of vasomodulating (not just vasodilating) drugs such as prostacyclins, endothelin receptor antagonists, and phosphodiesterase inhibitors designed to reverse events that obstruct the pulmonary arterial flow (proliferation of endothelium, platelet aggregation with in situ thrombosis, and vasoconstriction due a proliferation of smooth muscle. For the most part, these drugs appear to be safe and effective in POPH.5-13 Regarding the reasons for poor survival, details are crucial.14 What are the specific cardiovascular endpoints described within the Kawut paper? Has death occurred because of an initiating acute gastrointestinal event (bleeding, sepsis, encephalopathy leading to aspiration with hypoxemia) in the setting of stable or even improving pulmonary hemodynamics? Was death directly a consequence of progressive right heart failure unresponsive to aggressive pulmonary vasomodulating drugs? Did sudden cardiovascular collapse occur (hemodynamically intolerable tachydysrhythmia)? Is survival related to current hepatic disease severity measures such as model for end-stage liver disease (MELD) and Child-Turcotte-Pugh classification, as well as severity of POPH? The statistical overview provided by the Kawut paper does not answer these specific queries. Regarding outcome expectations of OLT in the setting of POPH, is pre-OLT or post-OLT POPH survival related to the changing MELD score? Would we dare assign more MELD points to those with moderate POPH who respond “significantly” to pulmonary vasomodulating drugs or their combinations? The most recent multicenter data suggest that pre-OLT mean pulmonary artery pressure greater than 35 mm Hg (n = 30 with increased pulmonary vascular resistance carries a worrisome OLT prognosis (12 deaths or 40% mortality within 18 days of transplant surgery.15 Only one patient had received pre-OLT prostacyclin.15 One could hypothesize a better outcome facilitated by using current drug therapies. Indeed, the major message of the Kawut study relates to the worse prognosis for POPH compared to idiopathic pulmonary artery hypertension (the new term for primary pulmonary hypertension). To me this is not surprising, since we are trying to cope with and treat effects of disease in 2 vascular beds (pulmonary and portal). But we do need to reconsider the effects of modifying cardiac output and pulmonary vascular resistance in the context of a hyperdynamic circulatory state that accompanies portal hypertension. There probably exists a pathologic point of “no return” in the damaged pulmonary arterial bed, whereby pulmonary hemodynamics are no longer responsive to vasomodulating therapy, despite our best efforts. And the stressed right heart can tolerate only so much adverse change in afterload, preload, and downstream effect of “bad humors” arriving from the portal circulation. Following an accurate diagnosis of POPH, our efforts should (as a minimum) focus upon reducing mean pulmonary artery pressure to less than 35 mm Hg prior to the accomplishment of OLT. Additionally, improvement in other parameters such as pulmonary vascular resistance and indices of right heart function may prove to be prognostic. Hopefully, treatment with a protocolized, combined approach of pulmonary arterial vasomodulation and OLT (cadaveric or living donor) will clarify and improve the POPH long-term survival issue.

Very early tracheal extubation without predetermined criteria in a liver transplant recipient population.

This study of all patients undergoing orthotopic liver transplantation (OLT) at our center between January 1997 and December 1999 evaluated the feasibility and safety of very early tracheal extubation without previous selection. Anesthetic management was the same in all cases, and tracheal extubation was performed on the basis of standardized criteria routinely adopted in operating rooms throughout the world, i.e., no residual curarization or anesthetic action, ability to swallow efficiently, and stable hemodynamics. One hundred sixty-nine patients underwent 181 OLTs during the study period. Tracheal extubation was performed within 3 hours of surgery in 115 cases, 8 hours in 19 cases, and 8 to 24 hours in 10 cases. In 36 cases, artificial ventilation was required for more than 24 hours or weaning was not possible. One patient died of primary graft nonfunction within 24 hours and was excluded from the analysis. The feasibility of early extubation was influenced by the amount of intraoperative transfused blood; efficacy of kidney, cardiac, and pulmonary function; and presence of encephalopathy (P <.001). No correlation was found with age or pre-OLT severity of hepatic disease, and the postoperative period was not compromised by early weaning. Very early extubation was feasible and safe in a large number of unselected transplant recipients, thus suggesting that the definition of early tracheal extubation should be changed from 8 to 3 hours after surgery.

Depression, fatigue, and functional disability in patients with chronic hepatitis C

Objective: To examine the extent to which fatigue and functional disability correlate with severity of depressive symptoms in patients with chronic hepatitis C. Methods: Fifty patients with chronic hepatitis C were evaluated using structured psychiatric interviews and standardized rating instruments. Results: Fourteen (28%) of patients had current depressive disorders. Depressed and nondepressed patients did not differ with regard to demographics or hepatic disease severity. Severity of depressive symptoms was highly correlated with fatigue severity while measures of hepatic disease severity, interferon treatment, and severity of comorbid medical illness were not. Severity of depressive symptoms was associated with functional disability and somatization. Conclusions: Disability and fatigue are more closely related to depression severity than to hepatic disease severity. Antidepressant treatment trials in patients with hepatitis C are indicated to determine whether improvement in depressive symptoms leads to improvement in fatigue and functioning.

Detection of Graft Nonfunction After Liver Transplantation by Assessment of Indocyanine Green Kinetics

Detection of Graft Nonfunction After Liver Transplantation by Assessment of Indocyanine Green Kinetics

Non-invasive quantitative breath tests for hepatic disease severity: [formula omitted], D.A. Wagner, L. Makowka, J.M. Vierling. Hepatology and Liver Transplantation Programs. Cedars-Sinai Medical Center/UCLA, Los Angeles, CA & Metabolic Solutions Inc., Merrimack, NH

Non-invasive quantitative breath tests for hepatic disease severity: [formula omitted], D.A. Wagner, L. Makowka, J.M. Vierling. Hepatology and Liver Transplantation Programs. Cedars-Sinai Medical Center/UCLA, Los Angeles, CA & Metabolic Solutions Inc., Merrimack, NH

Rates of cancellous bone remodeling and turnover in osteopenia associated with primary biliary cirrhosis

Osteoporosis and fracturing are well-recognized manifestations of primary biliary cirrhosis (PBC), but the abnormalities of bone remodeling and turnover that result in bone loss are poorly understood. We used dynamic histomorphometric techniques to measure tissue level rates of cancellous bone resorption, formation, and turnover in 12 premenopausal women with PBC and in 12 normal premenopausal women. We compared these values with estimates of bone resorption and formation obtained concurrently in the same subjects by radiocalcium kinetics and biochemical markers. Rates of bone turnover were analyzed as a function of a risk score that reflects the severity of hepatic disease and cholestasis (Mayo proportional-hazards model). Positive correlations were observed between tissue level and whole skeletal estimates of bone remodeling. At the remodeling site (bone multicellular unit [BMU]), the depth of eroded lacunae was unaltered by PBC, but wall thickness was decreased. At the level of bone tissues, mean bone turnover was increased in PBC patients but varied widely and increased as hepatic disease and cholestasis worsened. We conclude that PBC causes a reduction in the volume of bone formed at the remodeling site and that the overall level of bone remodeling and turnover in PBC is strongly influenced by the severity of hepatic disease and cholestasis. We hypothesize that the rate of bone loss in PBC may be decreased by therapeutic agents that slow bone turnover, and that further bone loss may be halted by liver transplantation.

Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease

Intrapulmonary vascular abnormalities consiting of arteriovenous malformations and capillary dilatations have been described in patients with severe liver disease. These intrapulmonary vascular abnormalities can result in intrapulmonary right-to-left shunting and hypoxemia. Twenty-five of 53 patients (47%) with end-stage hepatic disease were found to have contrast echocardiographic evidence of intrapulmonary right-to-left shunting. There was no difference in mean age, gender distribution, or severity of hepatic disease in those with and without evidence of such shunting. Although there was no difference in mean partial arterial oxygen pressure (PaO 2) values in the 2 groups (82 ± 11 vs 76 ± 11 mm Hg), the mean PaO 2 value of those with at least 2+ left ventricular opacification (2 to 4+) was significantly lower (66 ± 33 mm Hg, n = 8; p <0.01). Unexpectedly, patients with evidence of intrapulmonary shunting had a lower mortality rate before transplantation (3 of 25, 12%) than those without evidence of shunting (10 of 28, 36%) resulting in a significant difference in actuarial survival (p <0.05) by the end of the follow-up period. It is concluded that intrapulmonary right-to-left shunting occurs frequently in patients with end-stage liver disease and may be a marker of a positive biologic process that, in some way, leads to imptoved short-term survival.

Pharmacokinetics of isoxicam in hepatic disease.

1 The pharmacokinetics of single and repeated oral doses of isoxicam, an extensively metabolized drug, were studied in patients with compensated and decompensated hepatic disease. 2 After a single oral dose, isoxicam was slowly absorbed and eliminated (half-life ranging from 10.5 to 53.9 h). Its pharmacokinetics did not differ from those observed in healthy volunteers and were not significantly influenced by the severity of hepatic disease. However, the t1/2 of isoxicam was found to be inversely (r = -0.700, P less than 0.05 n = 14) related to the log gamma-glutamyl transpeptidase plasma activity. 3 During chronic oral treatment in patients with compensated hepatic insufficiency, steady-state was achieved after 7-9 days of therapy. The mean elimination half-life of isoxicam in five patients was 42.6 +/- 4.5 h, a value which was not statistically different from that obtained in the single dose study. 4 It was concluded that patients with hepatic insufficiency do not require a systematic modification of drug dosage but that long-term treatment should be employed with caution in these patients.

EEA esophageal stapling for control of bleeding esophageal varices

Esophageal transection with the EEA stapler was performed in five patients with bleeding esophageal varices. Bleeding from varices has not recurred in surviving patients during follow-up of up to 27 months. One death occurred during the postoperative period. Esophageal transection with the EEA stapler is an effective means of preventing recurrent variceal hemorrhage. This technique is best suited for patients requiring emergency operation to prevent exsanguination and for those in whom a major shunting procedure is contraindicated because of the severity of hepatic disease or other medical illness.