Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation.

Acute liver failure.

Acute liver failure is a rare but often catastrophic illness affecting the liver and multiple organ systems. Patients with acute liver failure require a multidisciplinary approach for adequate management. With improved critical care and the availability of liver transplantation, survival has significantly improved. Hepatic encephalopathy, cerebral edema and infections are the most common complications of acute liver failure. The evaluation requires a diligent search for a specific etiology of the liver failure, since certain causes may respond well to specific pharmacological therapies. Acetaminophen and non-acetaminophen drug-induced hepatotoxicity account for more than 50% of cases of acute liver failure. Assessment of prognosis frequently (at least on a daily basis) by using various prognostic tools, allows the treating team to decide whether or not to proceed with urgent liver transplantation. Artificial liver support devices are still in evaluation and not ready for use in clinical practice. While it is determined whether or not there is sufficient hepatic regeneration, the care of the patient with acute liver failure revolves around managing the dysfunction of multiple extra hepatic systems.

Hepatic encephalopathy.

Hepatic encephalopathy (HE) is a syndrome of neuropsychiatric dysfunction caused by portosystemic venous shunting, with or without intrinsic liver disease. Patients with hepatic encephalopathy often present with the onset of mental status changes ranging from subtle psychologic abnormalities to profound coma. Several hypotheses have been proposed to explain the mental impairment associated with portosystemic shunting and liver disease. Clinicians diagnosing HE frequently have the opportunity to intervene and reverse severe HE, even hepatic coma. The recent advances in understanding and management of HE are the subject of this article.

The hepatorenal syndrome.

The onset of renal failure in a patient with cirrhosis or acute liver failure is alarming because it raises the possibility of the hepatorenal syndrome (HRS). Periodic surveillance of renal function is helpful in patients with severe liver disease to detect HRS early and to help correct reversible contributing factors. Once established, HRS responds relatively poorly to medical management, although recent advances have brought hope for an improved prognosis. In this article the diagnosis, pathophysiology, and management of HRS are discussed in detail, with an emphasis on recent diagnostic and therapeutic advances.

Liver transplantation using an organ donor with HELLP syndrome.

BACKGROUND: The shortage of organs for liver transplantation has forced transplant centers to expand the donor pool by using donors traditionally labeled as marginal. One such example is liver transplantation using a donor with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), a disorder of late pregnancy that involves the liver as one of the target organs. METHODS: Two patients who died from complications of HELLP syndrome were evaluated for attempted multi-organ procurement. Donor characteristics, gross and microscopic liver findings, and procurement and transplant outcomes were reviewed. RESULTS: One of the liver allografts was successfully transplanted; the other was not procured because of poor macroscopic appearance. CONCLUSION: It is possible to successfully transplant the liver from a donor that succumbs to HELLP syndrome, provided there is adequate recovery of liver function before procurement.

Long-term outcome of controlled, non-heart-beating donor liver transplantation.

BACKGROUND: Previous reports have established the feasibility of using livers from controlled, non-heart-beating donors (CNHBD) with good immediate graft function. This has been largely borne out of necessity because of the donor shortage. METHODS: Retrospective database review for the last 7 years (1995-2002), encompassing 19 patients receiving CNHBD, with follow-up period of 1,000 +/- 694 days, median 762 days. Detailed review of recipient characteristics, operative and clinical course, immunosuppression, complications, survival rates, and comparison with the results obtained in patients receiving transplants of allografts procured in standard fashion, from heart-beating donors RESULTS: Kaplan-Meier patient survival rates were 100%, 89.5%, and 83.5% at 30 days, 1, and 2 years, respectively, which is not different from recipients of livers procured from heart-beating cadaveric donors (P=0.74, log-rank test). Five patients died at a mean follow-up time of 492 (range 46-1,103) days. The causes of death were related to secondary sclerosing cholangitis (n=1), cardiac failure (n=1), and sepsis (n=3). Two (10.5%) recipients underwent retransplantation, one for primary graft nonfunction and one because of biliary cast syndrome with cholangitis. Significant preservation damage (ALT>2,000) developed in five patients, but this did not affect survival. The incidence of vascular (15.6% vs. 9.6%, P=0.34) and biliary complications (10.55 vs. 13.8%, P=0.68) was no different than for those recipients receiving standard cadaveric donors. CONCLUSIONS: CNHBD safely expands the donor pool with similar long-term results as those obtained in patients receiving organs from brain-dead donors under standard procurement techniques.

Terbinafine-associated hepatotoxicity.

Terbinafine, an orally and topically active agent licensed for treatment of dermatophytic infection, has gained rapid worldwide acceptance in medical practice. Despite its fairly benign profile of adverse reactions, liver toxicity has occasionally been linked to terbinafine. This report describes a patient with severe cholestatic hepatitis associated with use of terbinafine. The patient was treated successfully with corticosteroids after partial response to ursodeoxycholic acid and cholestyramine. We attempt to identify risk factors for terbinafine-induced hepatotoxicity by an analytical review of all relevant literature. The mechanism underlying terbinafine hepatotoxicity could be more than just an idiosyncratic reaction. 7,7-dimethylhept-2-ene-4-ynal (TBF-A), the allylic aldehyde metabolite of terbinafine, may play a role in the pathogenesis of its hepatotoxicity. Our analysis supports monitoring patients clinically and measuring liver biochemistry through periodic blood tests, after confirming normal liver function at the onset of therapy with terbinafine. Early detection of abnormal hepatic function should prompt immediate discontinuation of this drug along with further evaluation.

Management of autoimmune and cholestatic liver disorders.

The management of autoimmune and cholestatic liver disorders is a challenging area of hepatology. Autoimmune and cholestatic liver diseases represent a comparatively small proportion of hepatobiliary disorders, yet their appropriate management is of critical importance for patient survival. In this article, management strategies are discussed, including the indications and expectations of pharmacologic therapy, endoscopic approaches, and the role of liver transplantation.

Coagulopathy of acute liver failure.

Coagulopathy is an essential component of the acute liver failure (ALF) syndrome and reflects the central role of liver function in hemostasis. ALF is a syndrome characterized by the development of hepatic encephalopathy and coagulopathy within 24 weeks of the onset of acute liver disease. Coagulopathy in this setting is a useful prognostic tool in ALF and a dynamic indicator of the hepatic function. If severe, it can be associated with bleeding and is commonly a major obstacle to the performance of invasive procedures in patients with ALF. This review focuses on the epidemiology, pathophysiology, presentation, evaluation, and management of coagulopathy in ALF.

The coagulopathy of acute liver failure and implications for intracranial pressure monitoring.

INTRODUCTION: The development of coagulopathy in acute liver failure (ALF) is universal. The severity of the coagulopathy is often assessed by determination of the prothrombin time and International Normalized Ratio (INR). DISCUSSION: In more than 1,000 ALF cases, the severity of the coagulopathy was moderate in 81% (INR 1.5-5.0), severe in 14% (INR 5.0-10.0), and very severe in 5% (INR > 10.0). Certain etiologies were associated with more severe coagulopathy, whereas ALF caused by fatty liver of pregnancy had the least severe coagulopathy. METHODS: Management consisted of transfusions of FFP in 92%. Overall, FFP administered during the first week of admission amounted to 13.7 +/- 15 units. RESULTS: Patients who received an ICP monitor had significantly more FFP transfused than those managed without ICP monitor (22.7 +/- 2.4 vs. 12.3 +/- 0.8 units FFP; P < 0.001). Only a minority of patients developed gastrointestinal bleeding or had an intracranial pressure monitor installed. CONCLUSION: Further research is necessary to explore the reasons clinicians transfuse ALF patients with large amounts of FFP in the absence of active bleeding or invasive procedures.

Driving with minimal hepatic encephalopathy: real world consequences?

Mounting evidence suggests that minimal hepatic encephalopathy of cirrhosis may compromise driving performance. A study now reveals that patients with minimal hepatic encephalopathy had a greater self-reported frequency of motor vehicle accidents and traffic violations. There are still numerous issues to be resolved before this increasingly recognized variant of hepatic encephalopathy can be firmly linked to hazardous driving. Minimal hepatic encephalopathy affects a substantial proportion of patients with otherwise well-compensated cirrhosis, and because therapies are effective in reversing this type of encephalopathy, its role in motor vehicle accidents deserves further attention.

Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States.

UNLABELLED: Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women; there are limited data on the clinical presentation and disease severity among non-Caucasian patients with this disease. The goal of this study was to examine differences in the severity of liver disease between Caucasian and non-Caucasian patients with PBC screened for enrollment in a large national multicenter clinical trial. Demographic features, symptoms, physical findings, and laboratory tests obtained during screening were examined in 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic). Non-Caucasians were more likely than Caucasians to be ineligible for participation in the clinical trial (46.5% versus 25.1%, P = 0.0001), primarily because of greater disease severity. African Americans and Hispanics were also more likely to have a lower activity level, more severe pruritus, and more advanced disease. However, the mean age, male-to-female ratio, and seroprevalence of AMA positivity were similar between the 2 groups. CONCLUSION: Liver disease severity at clinical presentation is higher among non-Caucasians than Caucasians with PBC, and this cannot be explained by demographic or serologic features alone. Possible mechanisms underlying this health discrepancy are not clear, but increased awareness of PBC as a cause of chronic cholestatic liver disease is critical in evaluating non-Caucasian patients in the United States.

Cardiovascular risk factors after liver transplantation.

1. Yearly screening of liver recipients with serum cholesterol, triglycerides, and lipoproteins, and assessment for risk factors for atherosclerotic cardiovascular disease, is an important component of comprehensive post transplant care. 2. Revised guidelines and target levels of LDL-cholesterol levels specific for moderate and high cardiovascular risk patients have been recently revised. 3. Transplant physicians should be aware of advances in the management of post transplant arterial hypertension, diabetes mellitus, obesity, and nicotine dependence.

Extended survival by urgent liver retransplantation after using a first graft with metastasis from initially unrecognized donor sarcoma.

A 58-year-old man underwent orthotopic liver transplantation for polycystic liver disease. Shortly after the procedure, it was discovered that the donor harbored a sarcoma of the aortic arch that had metastasized to the spleen, and bilateral renal cell carcinomas. The two sole organ recipients, our liver recipient and a lung recipient at another institution, were both listed for urgent retransplantation, which they received from the same second donor. The liver explant contained metastatic sarcoma. Twenty-four months survival following lung retransplantation has been previously reported. We report the 76-month disease-free survival in the liver recipient.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Use of hepatitis B core antibody-positive donors for liver transplantation.

1. Livers from donors previously exposed to hepatitis B virus (HBV) can fail after transplantation as a result of severe HBV reactivation in the transplant recipient. 2. Antibody against hepatitis B core antigen (HBcAb) in the donor is a marker for risk for transmission of HBV and reactivation after liver transplantation. 3. Recipient HBcAb positivity and antibody to hepatitis B surface antigen (HBsAb) positivity are associated with less risk for HBV reactivation. Conversely, the absence of HBcAb and/or HBsAb in the transplant recipient, higher Child-Pugh score, and presence of HBV DNA in the donor liver may be risk factors for HBV reactivation in the transplant recipient. 4. Recipients of HBcAb-positive (HBcAb(+)) livers at high risk for HBV reactivation should be treated prophylactically with lamivudine alone or a combination of hepatitis B immunoglobulin (HBIg) and lamivudine. The value of monoprophylaxis with HBIg has not been established in this setting. 5. Until data from larger studies are available, for low-risk recipients of HBcAb(+) livers, no prophylaxis, with very close serological and virological monitoring, appears to be a potential alternative to lamivudine monoprophylaxis. 6. Recipients of HBcAb-negative livers should be investigated for HBV infection when an episode of allograft dysfunction is not readily explained by the usual causes (rejection, ischemia, or hepatitis C recurrence).