Underlying Liver Dysfunction Research Articles

Portal vein embolization prior to major liver resection

Portal vein embolization (PVE) induces compensatory hypertrophy of the future liver remnant volume (FLRV) to improve the safety of major liver surgery by reducing the risk of post-operative liver failure. The aim was to describe our experience of PVE for patients with large or multifocal malignant liver tumours who initially were deemed unresectable. Perioperative data were retrieved from a prospective database and computed tomographic scans were retrospectively reviewed to calculate volume changes and the degree of liver hypertrophy following PVE. PVE was successful in 23 out of 25 patients and resulted in a change in the mean estimated FLRV from 585 to 788 mL following PVE. This represented a 35% increase in the remnant liver parenchymal volume post-embolization (P < 0.01). The procedure was well tolerated and did not compromise the surgical resection in any patient. Nineteen patients went on to have a liver resection following PVE with an in-hospital mortality of 16% (3 out of 19) and a 42% morbidity rate. After a mean follow-up of 31 months (1-130 months), 32% (6 out of 19) of patients are alive and 4 of these (21%) are completely disease-free. PVE results in an increase in the FLRV prior to major hepatectomy. Failure to develop hypertrophy following PVE is a surrogate marker for underlying liver dysfunction. PVE is safe and may increase the pool of patients suitable for liver resection. Long-term survival is similar to those not requiring embolization prior to liver resection.

Safety and Effectiveness of Gemcitabine in 260 Patients with Biliary Tract Cancer in a Japanese Clinical Practice Based on Post-marketing Surveillance in Japan

Gemcitabine was approved for the treatment of biliary tract cancer in 2006 in Japan. While biliary tract cancer is usually associated with patients 70 years of age or older and/or those who tend to have underlying liver dysfunction, data on this population were limited in the Japanese Phase II study of gemcitabine. Thus, further evaluation of safety and effectiveness in this population was planned. This special post-marketing surveillance was conducted as an observational study on the use of gemcitabine in a clinical practice setting. Gemcitabine-naïve patients with biliary tract cancer were enrolled from 2006 to 2008 and observed over 12 months; one or more doses of gemcitabine were administered during the period. Data such as patient background, treatment details, adverse events occurring during the observational period, laboratory values of liver enzyme and survival status were collected 3 and 12 months after the start of therapy. Of the 285 patients registered for the study, 260 were included in the analysis. The mean age was 66.9 years. There were 120 patients (46.2%) classified as elderly (70 years or older). Haematotoxicities were the most common adverse drug reactions. In the elderly and the non-elderly, adverse drug reactions (serious) occurred in 48.3% (20.8%) and 50.7% (12.9%), respectively. The overall estimated 1-year survival rate was 52.5% (95% confidence interval, 45.9-58.7%). In line with previous clinical and post-marketing studies conducted in Japan, the results of this study suggest that gemcitabine could be used safely and effectively for biliary tract cancer patients including the elderly.

Hepatocellular carcinoma: natural history, current management, and emerging tools

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer.

Icodextrin-associated hepatotoxicity.

Sir, Abnormal liver function tests can be observed in peritoneal dialysis (PD) patients. The most common cause of these are viral infections, especially hepatitis B and C [1]. Icodextrin-based PD solutions (Extraneal; Baxter, IL, USA) are increasingly used in this patient population [2]. Several adverse reactions have been reported with icodextrin, mainly skin reactions (upto 15%) [3]. In the full prescription catalogue, it is said that it may lead to liver dysfunction, specifically alkaline phospahatase (ALP) and alanine transaminase (ALT) levels. A 26-year-old male PD patient applied to our Transplant Unit to undergo renal transplantation from his mother. He had been on PD for the last 2 months and was treated with a 13 L of 1.36% glucose-containing PD solution and 2 L of Extraneal exchange. He was also on 80 mg/day furosemide. At the time of first visit, he had exfoliative eruptions on his back. Except for high ALT (295 mg/dL, normal <45) and ALP levels (390 mg/dL, normal 35–140), all other liver function parameters were normal. He did not have a history of liver disease and his liver function tests were normal until 2 months ago. His HbsAg, Anti-Hbs, Anti-Hbc, Anti-CMV IgM, Anti-EBV IgM antigen were negative and Anti-CMV IgG and Anti-EBV IgG were positive. Hepatitis C virus was confirmed to be negative by real-time polymerase chain reaction. Alpha-trypsin, ceruloplasmin and autoimmune marker levels were normal. Liver ultrasonography was normal with normal size, paranchyme and echogenity, gall bladder and bile duct was normal. Since there were no evident infectious, metabolic and toxic findings, the decision was made to perform a liver biopsy. However, the patient refused to undergo liver biopsy. After review of the literature on skin lesions and hepatic dysfunction in dialysis patients, we thought that both these signs (eruption and liver dysfunction) may be related to icodextrin use. As a trial and error approach, it was decided to discontinue icodextrin. On Day 3 of discontinuation, ALT levels decreased from 295 to 133 and on Day 11 to normal levels. Similarly, ALP levels decreased from 390 to 260 on Day 11. His previous ALT levels are depicted in Figure 1. Also, exfoliative eruptions disappeared. This trial and error approach showed that the icodextrin-based PD solution was the cause of liver dysfunction. The patient is now transplanted and his liver enzymes continue to be normal. Fig. 1. Serum ALT levels upon icodextrin use and discontinuation. Liver dysfunction was incidentally diagnosed in this case during his preoperative workup for renal transplantation. After exclusion of metabolic disorders, infectious agents, alcoholism and other causes of liver dysfunction, the focus was directed to prescribed drugs. Review of the literature directed us toward icodextrin-based PD solution while it has been linked to skin lesions in PD patients which was also present in our case. However, no valid data exists regarding liver dysfunction with icodextrin-based PD solution. Our trial and error approach showed that it was indeed related to this. Icodextrin is reported as relatively safer compared to glucose-based PD solutions regarding adverse and side effects. The pathophysiological mechanisms underlying liver dysfunction with icodextrin use is unclear. Drug-induced hepatotoxicity can be due to various mechanisms: disturbances in intracellular ion shifts, bile duct injury, apoptosis, mitochondrial dysfunction and direct liver immune injury [4]. Which one/ones of these is responsible for icodextrin-related damage needs to be clarified. As a conclusion, icodextrin may lead to hepatotoxicity, this may be more common than anticipated and shall be taken into account in the differential diagnosis of liver test abnormality in PD patients.

Abstract 2133: Phenylenebis(1,2-ethanediyl)bisisoselenourea (PBISe), a novel selenium drug for the treatment of hepatocellular cancer (HCC)

Abstract Hepatocellular cancer (HCC) is an aggressive tumor that frequently arises in a setting of chronic liver disease and cirrhosis. Appearing 20 to 30 years from initial insult, it is more likely to be discovered in its late stage. The median survival following diagnosis is approximately 6 to 20 months. Although the definitive treatment is tumor resection, most patients are not eligible because of tumor extent or underlying liver dysfunction. Alternative chemopreventive approach in reducing HCC mortality is to be explored. Earlier we have shown the efficacy of PBISe against colon adenocarcinoma and metastatic melanoma with a negligible systemic toxicity in animal studies. In the present study, we intend to demonstrate the chemotherapeutic effects of PBISe on the human HCC. We analyzed the role of PBISe and the underlying mechanism in HCC. PBISe in our study suppressed cell growth, and induce apoptosis. Evaluation of PBISe was performed in vitro on human SK-HEP-1, HepG2, C3A and HUH-7 cells by cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation by Tunnel, cell cycle analysis and AKT, ERK, STAT, SAPK/JNK phosphorylation. PBISe promotes apoptosis by upregulating caspase 3/7, annexin-V, and cPARP. Increased DNA fragmentation was observed with PBISe in all the HCC cell lines tested. PBISe also mediated the cellular proliferation by AKT signaling and downstream pPRAS40 by inducing the cell cycle arrest at G2-M phase. Decreased pERK, pSTAT and pAKT shows that PBISe has a potential to target several signaling pathways. Overall our results suggest that PBISe is a potent chemotherapeutic agent with novel properties for the treatment of HCC. The chemotherapeutic effect of PBISe in the murine HCC model will be discussed. Supported by Penn State Deans Feasibility Grant to H.R.T, NIH RO3 CA 137763-01 to D. D., NIH KO8 417-67HY to K.S.O.C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2011-2133

Safety and efficacy of sorafenib in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is frequently diagnosed in the setting of chronic liver disease and cirrhosis. The median survival after diagnosis is dismal. The treatment options that may offer cure are either resection or liver transplantation. Unfortunately most patients are not eligible for either treatment modality at diagnosis because of advanced stage and underlying liver dysfunction. Until recently, there was no effective systemic therapy for patients with advanced HCC. Sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor and Raf, has shown antitumor activity in patients with advanced HCC in phase III trials. Although objective response is not common, sorafenib promotes disease stabilization and improves overall survival. Sorafenib is well tolerated with a favorable toxicity profile. In this article we review the efficacy and safety data for sorafenib in patients with advanced HCC.

Comparative Studies of Early Liver Dysfunction in Senescence-accelerated Mouse Using Mitochondrial Proteomics Approaches

The liver is a complex and unique organ responsible for a breadth of functions crucial to sustaining life, especially for various metabolic processes in its mitochondria. Senescence-accelerated mouse prone/8 (SAMP8), a widely used aging model, exhibits an oxidative stress-induced aging phenotype and severe mitochondria-related liver pathology that are not seen in senescence-accelerated mouse resistant/1 (SAMR1). Here we used both two-dimensional electrophoresis- and ICAT-based mitochondrial proteomics analysis to view the liver mitochondrial protein alterations between SAMP8 and SAMR1. Compared with SAMR1, decreased expression and activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase were detected in SAMP8 at 6 months old (SAMP8-6m). As the key enzyme of ketogenesis, 3-hydroxy-3-methylglutaryl-CoA synthase is well known to be transcriptionally regulated by peroxisome proliferator-activated receptor alpha, which was also expressed at lower levels in SAMP8-6m livers. In addition, down-regulation of two peroxisome proliferator-activated receptor alpha target gene products (acyl-CoA oxidase and enoyl-CoA hydratase), elevation of triglyceride, and reduction of acetyl-CoA were observed, indicating abnormal fatty acid metabolism in SAMP8-6m livers. In addition eight proteins (NDUAA, NDUBA, NDUB7, NDUS1, NDUS3, NDUV1, ETFA, and UCRI) of mitochondrial complexes were down-regulated in SAMP8-6m, resulting in mitochondria-related liver dysfunction characterized by enhanced oxidative stress-induced molecular damage (lipid peroxide and oxidized protein) and depressed energy production (ATP). Glutamine synthetase and ornithine aminotransferase involved in glutamine synthesis were up-regulated in SAMP8 livers at both 1 and 6 months old that may be related to the accumulation of glutamate and glutamine. Our work provided useful clues to understanding the molecular mechanism underlying liver dysfunction in senescence-accelerated mouse.

Systemic Therapy for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer-related death. Eighty percent of new cases occur in developing countries, but the incidence is rising in economically developed regions including Japan, Western Europe, and the United States. More than 80% of patients present with advanced or unresectable disease, and for those patients who do undergo resection, the recurrence rates can be as high as 50% at 2 years. Thus, a large number of patients will seek systemic therapy. Systemic cytotoxic chemotherapy is largely ineffective and can have significant toxicity in patients with underlying liver dysfunction. Newer biologic agents that target molecular abnormalities common to HCC may improve the clinical outcome in patients with HCC.

Loop-mediated isothermal amplification (LAMP) 法を用いた &lt;I&gt;Vibrio vulnificus&lt;/I&gt; の迅速検出

Vibrio vulnificus is found in marine waters near the coast around the world. Infection with this gram-negative rod, via ingestion of raw seafood or via a skin wound following contact with contaminated estuarine or marine water, can cause necrotizing fasciitis and sepsis. Most of patients with Vibrio vulnificus infection have underlying liver dysfunction or diabetes mellitus. Due to the high mortality and short latent periods, control of this infection depends on early identification of the bacterial species and prompt initiation of intensive care. Accordingly, the development of a technique that can identify this microbe quickly and accurately is of great importance. Loop-mediated isothermal amplification (LAMP) is a novel nucleic acid amplification method to detect specific genes with rapidity and high sensitivity. In this study, we developed LAMP for the detection of Vibrio vulnificus. Using 28 Vibrio vulnificus strains and 53 other bacterial strains, we confirmed the high specificity of this method. Moreover, our LAMP method also showed high sensitivity, with a minimum detection level of one colony-forming unit per test. Furthermore, we developed simplified and conventional pretreatments for the method using experimental animal models. All of these attempts have lod to our non being able to detect Vibrio vulnificus within 1 hour.

The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future)

Over the past quarter-century, liver transplantation (LT) has been established as a durable therapy for all forms of end-stage liver disease. LT appears ideally suited for hepatocellular carcinoma (HCC), as it involves complete oncologic resection and correction of the underlying liver dysfunction. Since LT based on the Milan criteria has been shown to provide good disease-free survival, LT is considered the optimal treatment for small HCC, especially in patients with underlying chronic liver disease. However, because there is a severe shortage of organ donors, not all patients in need can be offered LT. Transplant listing criteria must simultaneously determine the greatest number of suitable candidates for LT while rejecting the smallest number of those who could benefit from LT. The amended model for end-stage liver disease allocation policy has had a positive effect on liver transplant candidates with HCC, and their number has been increasing significantly over the past several years. To minimize dropout from the waiting list, the treatment of HCC with procedures such as chemoembolization, radiofrequency ablation, or ethanol injection in patients awaiting LT have become widespread. It is currently accepted that liver resection is the best option for the treatment of small HCC when liver function is well preserved, and that LT is preferred when liver function is severely impaired (Child-Pugh class B or C). However, the question arises as to what is the best option for Child-Pugh class A patients with early HCC eligible for both resection and LT, especially in Western countries. HCC is a major indication for living donor liver transplantation (LDLT), because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of LDLT may offer more patients a potentially curative treatment without reducing the donor pool of organs for patients on the waiting list with nonmalignant liver disease. However, imprudent expansion of the selection criteria may result in more patients with HCC being cured at the expense of a higher incidence of recurrence.

Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma

Sorafenib is an orally active multikinase inhibitor that targets serine and threonine, and tyrosine kinases that are involved in tumor-cell signal transduction and tumor angiogenesis. This phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and preliminary efficacy of sorafenib in Japanese patients with hepatocellular carcinoma (HCC) with underlying liver dysfunction. Patients with unresectable HCC, Child-Pugh status A or B, and adequate organ functions were treated. A single dose of sorafenib was administered, followed by a 7-day wash-out period, after which patients received either sorafenib 200 mg (cohort 1) or 400 mg (cohort 2) twice daily. The PK were investigated after a single dose and during steady state. The efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. A total of 27 patients were evaluated for PK, safety, and efficacy. Although both area under the concentration-time curve for 0-12 h and maximal concentration at steady state were slightly lower in Child-Pugh B patients than in Child-Pugh A patients, the difference was not considered to be clinically relevant. Common adverse drug events included elevated lipase, amylase, rash or desquamation, diarrhea, and hand-foot skin reaction. A dose-limiting toxicity of hand-foot skin reaction was observed in one patient (cohort 2). Among the 24 patients evaluable for tumor response, one patient (4%) achieved a partial response, 20 (83%) had stable disease, and three (13%) had progressive disease. Sorafenib demonstrated a favorable tolerability and safety profile in Japanese HCC patients. Moreover, promising preliminary antitumor activity has been observed. Finally, there were no clinically relevant differences in PK between Child-Pugh A and B patients.

Pattern of Platelet Recovery in Predicting Outcome in Heparin-Induced Thrombocytopenia and Thrombosis.

Heparin-induced thrombocytopenia and thrombosis (HITT), a severe immune-mediated drug reaction, is often underdiagnosed. Early management of HITT with alternative anticoagulants can result in a favorable outcome. However, the morbidity and mortality associated with HITT remain high, posing challenges for patient management. We describe the clinical profile and pattern of platelet count recovery in a cohort of 34 patients diagnosed with HITT. This retrospective study consists of 164 patients screened for HITT over 18 months at our institution based on positive platelet factor 4 (PF4) IgG antibodies in the proper clinical setting. Patients who tested positive were divided on the basis of recovery of platelet count (increase to >100 × 109/L or by 1.5-fold by day 5 of diagnosis) into two groups: delayed and normal recovery. Of the 164 patients screened, 107 were admitted with cardiac diseases while 57 non-cardiac conditions. A total of 34 patients (21%) were tested positive for PF4 antibodies. Patients with underlying cardiac conditions were more likely to be diagnosed with HITT than non-cardiac patients (28% versus 7%, p=0.0012). The male to female ratio was 1:1.1, and the median age was 65 years. Nineteen of 34 patients (56%) had delayed platelet recovery, while the remaining 15 patients (44%) had normal platelet recovery by day 5. The mortality rate was 68% (13 of 19) in the delayed recovery group, compared to only 7% (1 of 15) in the normal recovery group (p=0.0004). Twelve of the 34 patients with liver dysfunction had delayed platelet recovery and died (figure 1). There were 6 venous and 5 arterial thrombotic episodes. A total of 13 patients (38%) were treated with Argatroban, a direct thrombin inhibitor (DTI) indicated for the treatment of HITT, but it did not seem to improve platelet recovery (Table 1). Eight of the 13 treated patients (62%) and 11 of the 21 untreated patients (52%) showed no platelet recovery by day 5. In conclusion, early diagnosis of HITT is critically important for patient management, and yet, diagnosis is often elusive due to a general lack of awareness of this condition. Underlying cardiac diseases appear to predispose patients to HITT, probably due to previous exposure and sensitization to heparin. Despite the availability of new anticoagulants, HITT remains an undertreated and highly fatal condition with overall mortality of 38% in our series. Underlying liver dysfunction appears to be associated with delayed platelet recovery and poor survival. Affect of DTI on platelet recovery needs to be further investigated. Optimal response to therapy requires early diagnosis and intervention. Further studies are necessary to enhance our understanding of this devastating condition to facilitate early diagnosis and proper treatment.Treatment and Survival of HITT PatientsOutcomeTreated with DTINot treatedTotalDead6713Alive71421Total132134 [Display omitted] [Display omitted]

Management of hepatocellular cancer

The nearly ubiquitous association of hepatocellular cancer (HCC) with underlying liver dysfunction portends a dismal prognosis. At the time of presentation with HCC, many patients have advanced cirrhosis that precludes effective therapy. Important prognostic factors include characteristics of the tumor (size, location, involvement of major blood vessels) and the functional state of the liver (quantified by synthetic function and portal hypertension). Localized tumors in a noncirrhotic liver may be treated successfully with surgical resection. In the setting of mild to moderate cirrhosis, localized therapy such as radiofrequency ablation, percutaneous ethanol ablation, chemoembolization, or Yttrium 90 microsphere infusion may be options, depending on the liver reserve and resources available. In the setting of advanced cirrhosis, treatment of the tumor may exacerbate liver decompensation, resulting in a shortened survival. In all of these instances, regardless of the therapy pursued, the underlying field defect with malignant potential remains in place. Liver transplantation has been employed to resolve both life-threatening problems, but it is fraught with many barriers. Appropriate patient selection and the use of adjuvant therapies are being pursued to improve the outcome of transplantation for HCC. Patients may have limited therapy options if they have poor performance status, are not surgical candidates, have a tumor that extends into the main portal vein, or have metastases to distant lymph nodes or organs. Chemotherapy is of marginal efficacy. Emerging therapies exploiting molecular targets are being explored with some promise.

Comparison of Survival Rates after Bland Arterial Embolization and Ablation Versus Surgical Resection for Treating Solitary Hepatocellular Carcinoma up to 7 cm

The vast majority of hepatocellular carcinomas (HCC) occur in patients with underlying liver dysfunction, making surgical resection available to only a subset of patients with adequate hepatic reserve. This study analyzes the authors' results with bland arterial embolization combined with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEIT) compared with surgical resection for the treatment of solitary HCC up to 7 cm in size. A retrospective review of all patients undergoing either surgical resection or bland embolization combined with local ablation for solitary HCC between January 1996 and August 2002 was performed. Progression-free survival rate and overall survival rate were calculated by the Kaplan-Meier method. There were 40 patients who underwent surgical resection and 33 patients who underwent embolization and ablation. Age, gender, and size of the treated lesion were not significantly different between the groups. The embolization/ablation group had more patients classified as Okuda stage II (P<.001). The surgical group had a longer median recurrence-free survival rate (53.1 vs 25.1 months). With a median follow-up of 23 months, the 1-, 3- and 5-year actuarial overall survival rates were 97%, 77%, and 56% for the embolization/ablation group and 81%, 70%, and 58% for the surgical group, respectively. There was no statistical difference in overall survival rates (P=.20). Bland arterial embolization in combination with ablation is effective in treating solitary HCC lesions up to 7 cm and achieves similar overall survival rates to surgical resection in selected patients.

Hepatocellular Carcinoma: The Need for Progress

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Critical Care Myopathy in a Child

Critical care myopathy (CCM) is an important, often unrecognized cause of weakness in the intensive care unit (ICU). We report a child who developed severe myopathy in the ICU. Our patient was newly diagnosed to have autoimmune hepatitis that may have predisposed her to toxicity from corticosteroids and neuromuscular-blocking agents, but she recovered her strength completely. Risk factors that may have predisposed this patient to CCM include underlying liver dysfunction, presence of acute lung injury, use of corticosteroids, and use of neuromuscular blockade. Given the apparent prevalence and underreporting of CCM in the ICU, it is important for rheumatology consultants to include this entity in their differential diagnosis of weakness in critically ill children and adults, and to recommend appropriate evaluation.

Acetaminophen Overuse in the Ohio Medicaid Population

ObjectiveTo examine patterns of use of acetaminophen in patients with and without risk factors for hepatotoxicity in the Ohio Medicaid population. DesignRetrospective, cross-sectional analysis of claims data. SettingOhio. PatientsOhio Medicaid patients (n=22,496) who received at least 6 prescriptions for acetaminophen from November 1998 through April 1999. Main Outcome MeasureOveruse of acetaminophen, defined as an average daily dose (ADD) greater than or equal to 4 grams/day or an ADD of greater than or equal to 3 grams/day along with diagnosis codes suggesting underlying liver dysfunction. ResultsWe identified 687 patients (3.05%) who received either greater than or equal to 4 grams/day or greater than or equal to 3 grams/day and had diagnosis codes suggesting underlying liver dysfunction (n=128). ConclusionAlthough the number is relatively small, some Ohio Medicaid patients are receiving acetaminophen doses that exceed safety recommendations. Because acetaminophen overuse is the leading cause of liver failure, health care professionals should be alert to the possibility of acetaminophen overuse.

Surgery and ablative therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, responsible for an estimated one million deaths annually. The incidence in the United States has steadily increased over the past two decades. Although HCC has historically had a dismal prognosis, it is now being detected earlier as a result of improved radiologic imaging and surveillance. This affords the opportunity to treat patients with curative intent, and may improve survival. Partial hepatectomy and transplantation each provide potentially curative therapy for selected patients with HCC. Transplantation is indicated when there is severe underlying liver dysfunction. Local ablative therapy, such as ethanol injection, hepatic artery embolization, and radiofrequency ablation, offer palliation for patients when surgery is not feasible. The rational application of the myriad of therapies to a patient with HCC is designed to maximize both quality of life and survival.

This month in J Lab Clin Med: Issue highlights for December 2000

This month in J Lab Clin Med: Issue highlights for December 2000

Conversion from sandimmune to neoral in renal allograft recipients

Although cyclosporine (CsA) has been clearly established as an effective immunosuppressant in reducing rejection in solid organ transplantation, intraindividual and interindividual variability in its pharmacokinetics (PK) are major limiting factors in its optimal use. The development of the microemulsion formulation of CsA, Neoral (NEO) (Sandoz, East Hanover, NJ), with better bioavailability and more predictable PK parameters offers the promise of a more reliable immunosuppressant for use in clinical transplantation and has prompted conversion of many stable renal allograft recipients formerly on the conventional formulation. Sandimmune (SIM) (Sandoz, East Hanover, NJ), to NEO therapy. In the present study, 125 stable renal allograft recipients were converted from SIM to NEO therapy in three phases and underwent evaluation of renal function and trough CsA levels and abbreviated pharmacokinetic parameters with conversion. Conversion from twice daily SIM to twice daily NEO led to increased trough CsA levels (14.3%) and a 26.3% increase in CsA exposure as measured by area under the time curve and average CsA levels, (AvCsA), without any adverse impact on renal function. On the other hand, conversion from once daily SIM to twice daily NEO was associated with a 4.9% rise in serum creatinine and was associated with a 58.5% rise in trough CsA levels after conversion. In a third cohort of patients with underlying liver dysfunction and at risk for CsA nephrotoxicity following conversion to NEO, conversion from once daily SIM to once daily NEO was not associated with renal dysfunction despite a 27.2% increase in trough CsA levels. Patients experiencing high AvCsA levels and the greatest rise in trough CsA and AvCsA levels after conversion were at highest risk for renal dysfunction from CsA nephrotoxicity. Thus, conversion protocols designed to maintain trough CsA levels at the preconversion level with subsequent NEO dose adjustments to achieve optimal AvCsA levels are likely to avert CsA nephrotoxicity secondary to increased CsA exposure. Despite the increase in CsA levels after conversion, the prospect of more reliable immunosuppression with NEO is an adequate impetus for conversion of patients from the conventional formulation. Nevertheless, NEO dose adjustments based on trough CsA levels and/or abbreviated PK profiles, as used in the present study, are likely to be necessary in optimizing NEO therapy in clinical transplantation.