Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary.

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study.

BACKGROUND: Hepatic encephalopathy (HE) is a brain disorder that often results from cirrhosis due to viral hepatitis, metabolic and alcohol-related liver disease, and is characterised by cognitive, psychiatric and motor impairments. Recurrent bouts of overt HE negatively impact daily functioning and quality of life. AIM: To evaluate the effect of rifaximin on health-related quality of life (HRQL) in cirrhotic patients with HE. METHODS: Patients with cirrhosis in remission from HE (Conn score = 0 or 1) and a documented history of recurrent HE episodes (≥2 within 6 months of screening) were randomised to rifaximin 550 mg twice daily (N = 101) or placebo (N = 118) for 6 months. Concomitant lactulose was permitted during the study. The Chronic Liver Disease Questionnaire (CLDQ) was administered every 4 weeks, and time for occurrence of HE breakthrough was recorded. A longitudinal analysis using time-weighted averages of the CLDQ scores normalised by days on study therapy was used to evaluate the effect of treatment on HRQL, and between HE outcomes (HE recurrence, yes/no) irrespective of treatment. RESULTS: The time-weighted averages of the overall CLDQ score and each domain score were significantly higher in the rifaximin group vs. placebo (P-values ranged from 0.0087 to 0.0436); and were significantly lower in patients who experienced HE breakthrough compared to those who remained in remission (P-values were <0.0001). CONCLUSION: Rifaximin significantly improved HRQL in patients with cirrhosis and recurrent hepatic encephalopathy. A lower HRQL may predict recurrence of hepatic encephalopathy.

Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.

We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5-year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1- and 5-year recurrence-free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1- and 5-year recurrence-free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under-staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1- and 5-year recurrence-free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under-staging when compared to the Milan criteria.

Review article: the current pharmacological therapies for hepatic encephalopathy.

Effective treatment options for hepatic encephalopathy are limited. Based on the principle that intestinal-derived ammonia contributes to the pathogenesis of hepatic encephalopathy, current therapeutic approaches are directed at reducing bacterial production of ammonia and enhancing its elimination. Non-absorbable disaccharides are first-line therapy for hepatic encephalopathy, but published clinical studies evaluating their safety and efficacy are limited. Alternative therapies such as benzodiazepine receptor antagonists, branched-chain amino acids, and l-ornithine-l-aspartate also have limited clinical data supporting their use. Studies of antibiotics indicate that they are effective in the treatment of hepatic encephalopathy, but adverse effects and concerns about long-term safety have limited the widespread use of most. Rifaximin is a minimally absorbed antibiotic that concentrates in the gastrointestinal tract and is excreted mostly unchanged in faeces. It has been studied extensively in the treatment of hepatic encephalopathy and appears to confer therapeutic benefits greater than those of placebo and non-absorbable disaccharides and at least comparable with those of systemic antibiotics. Rifaximin was also well tolerated in patients with hepatic encephalopathy and is not associated with clinical drug interactions or clinically relevant bacterial antibiotic resistance. In conclusion, non-absorbed antibiotics such as rifaximin offer a favourable benefit-risk ratio in the treatment of hepatic encephalopathy and may help to improve patient outcomes.

A randomized trial of exercise and dietary counseling after liver transplantation.

We report results of a randomized clinical trial of a combined intervention of exercise and dietary counseling (ExD) after orthotopic liver transplantation (OLT). Of the 151 patients randomized into ExD or usual care (UC), 119 completed testing 2, 6 and 12 months post-OLT. Testing included assessment of exercise capacity (VO(2peak)), quadricep muscle strength, body composition (DXA), nutritional intake (Block 95) and health-related quality of life (SF-36). The intervention consisted of individualized counseling and follow-up to home-based exercise and dietary modification. Repeated measure ANOVA was performed to determine differences over time between ExD and UC with a secondary analysis to determine differences over time between adherers (Adh), nonadherers (Nadh) to the intervention and UC. The ExD group showed greater increases in VO(2peak) (p = 0.036), and self-reported general health (p = 0.038) compared to UC. Both groups demonstrated increases in muscle strength, body weight, body fat and other SF-36 scale scores. Adherence to the intervention was 37% with positive trends in VO(2peak) and body composition observed in Adh compared to Nadh and UC. These data suggest improvements in exercise capacity and body composition are achieved with nutrition and exercise behavior modifications initiated early after OLT and with regular follow-up.

The Dynamax system: a new orthopaedic appliance and case report.

The Dynamax appliance is a treatment modality for the correction of the Skeletal II malocclusion characterized by a mandibular retrusion. Progressive mandibular advancement, maxillary expansion, control of maxillary growth, incisor torque and control of vertical facial development are incorporated into a two-part appliance. The design facilitates laboratory construction, clinical handling and patient acceptability. A prefabricated spring module forms the basis of the appliance, allowing both maxillary expansion and mandibular advancement. An easily adjustable progressive forward position of the lower jaw makes a construction bite unnecessary. The spring module provides most of the structure of the appliance so that minimal acrylic is required and the appliance is fully contained within the freeway space. Contact between the upper and lower parts of the appliance occurs posteriorly in the lingual sulcus. Here the depth permits an extended vertical contact, to maintain a protrusive mandibular position throughout the range of mandibular opening, including during sleep. The lower portion of the appliance may be fixed or removable and multibracket treatment can be carried out in one or both arches at the same time as the orthopaedics.

Measurement of the profile angle and the aesthetic analysis of the facial profile.

Cephalometric measurement of the face in terms of aesthetics can be difficult and misleading due to the variability of the intra-cranial reference lines. Extra-cranial references are more accurate, but can be time-consuming to apply. The Aesthetic Horizontal is an intuitive datum line related to the 'photographic position' of the head, which is expedient in use and clinically relevant. A new and straightforward technique is presented for transferring the Aesthetic Horizontal directly from the patient to any recent radiograph, which can then be used as the reference line for an aesthetic analysis of the facial profile. The instrument used for measuring the profile angle and the transfer is readily constructed from a protractor and small weight. The technique can also be used to transfer any other orientation (e.g. Natural Head Position or Natural Head Posture) from the patient to a recent radiograph.

Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort.

Uncontrolled studies have suggested a beneficial effect of lamivudine in patients with decompensated cirrhosis caused by replicating hepatitis B virus (HBV). We analyzed the outcome of lamivudine treatment in 23 consecutive patients with severely decompensated HBV-cirrhosis defined as a Child-Pugh-Turcotte (CPT) score of > or =10, and compared with a historical untreated control group of 23 patients matched for age, gender, and baseline CPT score. Significant clinical response, defined as a decrease in the CPT score by > or =3 points, was observed in 14 of 23 (60.9%) treated patients versus none of the controls (P <.0001). The median change in CPT scores was -3.0 (range, -6 to +3) in the treated group versus +1.0 in the controls (range, -1 to +2) (P =.016). Orthotopic liver transplantation (OLT) was performed in 34.8% of treated patients (median, 3.5; range, 1-32 months), versus 73.9% of controls (median, 3.0; range, 1-14 months) (P =.04). Excluding transplanted patients, there were no deaths in the treated group versus 6 deaths in the control group (P =.009). Time to death or OLT was significantly longer in treated patients than in controls (P <.001). Two patients developed lamivudine resistance after 9 and 12 months, respectively. Our results suggest that lamivudine significantly improves hepatic function in over half of the patients with decompensated cirrhosis and replicating HBV, and may confer a survival advantage. However, the small sample size and the use of a retrospective control cohort preclude drawing definitive conclusions. Expedited OLT remains the only viable treatment for lamivudine nonresponders.

Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.

The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P =.87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P =.0001). An alpha-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > or = 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P =.0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT.

Primary biliary cirrhosis: from induction to destruction.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly affects middle-aged women; fatigue and pruritus are the most common symptoms at presentation. Liver function tests are consistent with cholestasis and reveal an elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase with or without elevation of aminotransferase levels. Histologically, PBC is characterized by the destruction of the intrahepatic small bile ducts and subsequently fibrosis. The serological hallmark of the disease is the presence of antimitochondrial antibodies, which are found in 95% of patients with PBC. The antimitochondrial antibodies are directed against the 2-oxo-acid dehydrogenase complexes located on the inner membrane of the mitochondria. PBC generally slowly progresses, even over decades, and may lead to liver failure. In symptomatic patients, advanced age, elevated serum bilirubin levels, decreased serum albumin levels, and cirrhosis each correlate with shortened survival. Immunosuppressive and anti-inflammatory drugs have been used in the treatment of PBC based on the presumed autoimmune pathogenesis, but satisfactory agents leading to complete reversal or cure of the disease are not available. At present ursodeoxycholic acid appears to be the only effective therapy in preventing or delaying the need for liver transplantation and improving survival. However, a number of patients receiving ursodeoxycholic acid still develop progressive disease and require transplantation; transplantation is the only effective therapy at the end stage of the disease.

The role of the interventional radiologist. Transjugular procedures.

The transjugular route provides a convenient and safe approach for the interventional radiologist to access the hepatic parenchyma and hepatic vascular structures. The transjugular intrahepatic portosystemic shunt has revolutionized the management of the complications of portal hypertension, allowing the establishment of a side-to-side shunt without recourse to surgery and general anesthesia. On a smaller scale, the transjugular approach to obtaining a liver biopsy has also proven its worth in allowing the histologic diagnosis and staging of liver disease in patients in whom such information is required for appropriate management but major contraindications to percutaneous biopsy exist. This article reviews the current techniques, indications, and complications of these interventional procedures and their role in the management of patients with end-stage liver disease.

Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast.

BACKGROUND: In registration trials, zafirlukast, an asthma medication, caused asymptomatic elevated aminotransferase levels in up to 5% of participants. Until now, however, no cases of severe hepatitis attributed to zafirlukast have been reported. OBJECTIVE: To report the clinical characteristics of three patients with severe hepatitis due to zafirlukast. DESIGN: Case report. SETTING: One community hospital and two university hospitals. PATIENTS: Three middle-aged women taking zafirlukast, 20 mg twice per day. INTERVENTION: Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient. MEASUREMENTS: Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis other than drug toxicity, and liver biopsy in two patients. RESULTS: Patient 1 recovered spontaneously, had a severe relapse after inadvertent rechallenge with the medication, and ultimately made a complete recovery. Patient 2 developed subfulminant hepatic failure and required liver transplantation. Patient 3 developed severe hepatitis that improved after treatment with corticosteroids. Liver tissue was available from two patients and showed histologic changes commonly associated with drug reactions. CONCLUSION: Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis.

Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection.

BACKGROUND/AIMS: Lamivudine is highly effective in suppressing hepatitis B viral replication and hepatic necroinflammatory activity. The potential for recovery of hepatic decompensation in patients with chronic hepatitis B infection treated with lamivudine has not been established. The aim of this study was to evaluate the effectiveness of lamivudine treatment in severely decompensated cirrhosis due to chronic hepatitis B. METHODS: Thirteen consecutive patients with chronic hepatitis B infection, Child's-Pugh-Turcotte (CPT) score of > or =10 (median score=11) and detectable circulating hepatitis B DNA (range 15 to 9634 pg/ml) were included and treated with lamivudine 150 mg once daily. Hepatitis B envelope antigen (HBeAg) was positive in 9 of 13 patients pre-treatment. RESULTS: Two patients underwent liver transplantation at 4 and 6 weeks after starting lamivudine treatment. The remaining 11 patients were followed for a mean of 17.5 months without liver transplantation (range 3 to 39 months). Significant improvement of liver function, defined as a decrease in CPT score of > or =3, was observed in 9 of 13 patients (69%). In five patients, CPT score improved to <7 and they were placed on the inactive status (UNOS status 7) for liver transplantation. Hepatitis B DNA remained negative in all except one patient who developed breakthrough viral replication 12 months after starting lamivudine treatment, while maintaining stable liver function. Three of seven HBeAg-positive patients who did not undergo liver transplantation lost HBeAg during follow-up, but none had sustained seroconversion to hepatitis B e antibody. CONCLUSION: Lamivudine appears highly effective in reversing severe hepatic decompensation due to replicating hepatitis B infection.

Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group.

The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.