Living-donor versus cadaveric liver transplantation for non-resectable small hepatocellular carcinoma and compensated cirrhosis: a decision analysis.

BACKGROUND: Cadaveric liver transplantation is effective for nonresectable early hepatocellular carcinoma. However, the scarcity of cadaveric organs has prompted some centers to use living donors, which guarantees transplantation, but entails a risk to the donor. In the absence of controlled trials, decision analysis can be used to help explicate the tradeoffs involved when considering living donor versus cadaveric liver transplantation for nonresectable early hepatocellular carcinoma. METHODS: Using a Markov model, a hypothetical cohort of patients with Child's A cirrhosis and a single 3.5-cm tumor received one of three strategies: 1) no transplant; 2) intent to perform cadaveric liver transplantation; or 3) living donor liver transplantation. Data were obtained from natural history and retrospective studies. All probabilities in the model were varied simultaneously using a Monte Carlo simulation. RESULTS: Living-donor liver transplantation was the best strategy, improving life expectancy by 4.5 years compared with cadaveric liver transplantation. This strategy remained dominant even when varying severity of cirrhosis, age, tumor doubling time, tumor growth pattern, blood type, regional transplant volume, initial tumor size, and rate of progression of cirrhosis. CONCLUSIONS: Living-donor liver transplantation should confer a substantial survival advantage for patients with compensated cirrhosis and non-resectable early stage hepatocellular carcinoma.

Radioiodine uptake and thyroid scintiscanning.

This article reviews the technical aspects and clinical applications of the radioactive iodine uptake test and thyroid scintiscanning. The choice of radionuclide for the tests is discussed. The main uses of the radioactive iodine uptake test are to identify the cause of hyperthyroidism and to aid in the selection of the I-131 dose in the treatment of hyperthyroidism. Factors other than thyroid diseases that alter uptake results are identified. Thyroid scintiscanning is used in the identification of normal and ectopic thyroid tissue, in the diagnosis of the cause of a patient's hyperthyroidism, and as part of the evaluation of selected patients with thyroid nodules.

Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: the molecule versus the mimic.

The 2-oxo-acid dehydrogenase complexes and, in particular, the E2 component of the pyruvate dehydrogenase complex (PDC) are the target of antimitochondrial antibodies (AMA). More than 95% of primary biliary cirrhosis (PBC) patients have detectable levels of autoantibodies to PDC-E2 and in general these react with a region of the molecule that contains the prosthetic group lipoic acid (LA). LA is vital to the function of the enzyme, although there is conflicting evidence as to whether its presence is required for PDC-E2 recognition by AMA. Some, but not all, monoclonal antibodies (mAbs) to PDC-E2 produce an intense staining pattern at the apical surface of bile duct epithelial cells (BEC) in patients with PBC, and it has been argued that the molecule at the apical surface of PBC bile duct cells is a modified form of PDC-E2 or a cross-reactive molecule, acting as a molecular mimic. Herein, we characterize the epitopes recognized by 4 anti-PDC-E2 mAbs that give apical staining patterns (3 mouse and 1 human). In particular, by using a combination of recombinant antigens, competitive inhibition assays, and a unique peptide-on-bead assay, we determined that these apically staining mAbs recognize 3 or 4 distinct epitopes on PDC-E2. More importantly, this suggests that a portion spanning the entire inner lipoyl domain of PDC-E2 can be found at the BEC apical surface. In addition, competition assays with patient sera and a PDC-E2-specific mAb showed significant epitope overlap with only 1 of the 3 mouse mAbs and showed a differential response to the peptide bound to beads. These findings further highlight the heterogeneous response of patient autoantibodies to the inner lipoyl domain of PDC-E2.

A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis.

BACKGROUND & AIMS: The aim of this study was to determine if colchicine or methotrexate improves blood test results, symptoms, and/or liver histology in patients with primary biliary cirrhosis. METHODS: Patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase (ALP) levels were at least 2 times above normal and who were not yet candidates for liver transplantation received colchicine or methotrexate and were followed up for 2 years. RESULTS: In patients receiving colchicine (n = 43), mean pruritus score decreased from 1.63 to 1.12 (P = 0.04), ALP level from 494 to 355 U/L (P < 0.0001), and alanine aminotransferase (ALT) level from 79 to 61 U/L (P < 0.0001). In patients receiving methotrexate (n = 42), pruritus score decreased from 1.25 to 0.44 (P = 0.0001), ALP from 478 to 235 U/L (P < 0.0001), and ALT from 96 to 61 U/L (P = 0.0001). Methotrexate but not colchicine significantly improved liver histology (P = 0.005) and serum immunoglobulin G levels (P = 0.0002). Methotrexate improved most blood test results more than colchicine. Serum bilirubin levels increased slightly with each drug, and albumin levels decreased slightly. CONCLUSIONS: Both colchicine and methotrexate improved biochemical test results and symptoms in primary biliary cirrhosis, but the response to methotrexate was greater.

Clinical perspectives in the diagnosis of thyroid disease.

BACKGROUND: The wide array of available thyroid diagnostic tests can help provide accurate diagnoses for most cases of thyroid disease but can be confusing and costly when used inappropriately. METHODS: Published articles were reviewed and combined with the author's clinical experience and data collected from patients. RESULTS: The discussions focus on confusing aspects of thyroid diagnostic tests, the use and limitations of the thyrotropin test to screen for thyroid dysfunction, biological factors that complicate the interpretation of this and other thyroid diagnostic tests, and a combined clinical and laboratory approach to (a) thyroid diseases with only one important dimension ("simplex" conditions) and (b) thyroid diseases with several important dimensions ("multiplex" conditions). CONCLUSION: The optimal use of thyroid diagnostic tests is patient-specific and depends on the patient's specific thyroid disease, the stage of disease, and coexisting medical conditions.

The efforts of WHO and Pugwash to eliminate chemical and biological weapons--a memoir.

The World Health Organization and the Pugwash Conferences on Science and World Affairs (Nobel Peace Prize 1995) have been involved in questions concerning chemical and biological arms since the early 1950s. This memoir reviews a number of milestones in the efforts of these organizations to achieve the elimination of these weapons through international treaties effectively monitored and enforced for adherence to their provisions. It also highlights a number of outstanding personalities who were involved in the efforts to establish and implement the two major treaties now in effect, the Biological Weapons Convention of 1972 and the Chemical Weapons Convention of 1993.

Treatment of primary biliary cirrhosis and primary sclerosing cholangitis: use of ursodeoxycholic acid.

Considerable progress has been made in the management of cholestatic liver diseases during the past decade. Various therapeutic agents have been proposed and evaluated for treatment of patients with primary biliary cirrhosis and primary sclerosing cholangitis. These treatments include ursodeoxycholic acid plus immunosuppressive and anti-inflammatory drugs such as glucocorticoids, azathioprine, colchicine and methotrexate. Although these two diseases are grouped together as chronic cholestatic liver diseases, there are important differences between them, particularly with respect to response to treatment. Primary biliary cirrhosis responds much better to medical treatment. Ursodeoxycholic acid has emerged as the most commonly used medication in the treatment of these diseases. Ursodeoxycholic acid therapy is safe and has been associated with improvement of biochemical test results for liver function in patients with primary biliary cirrhosis and primary sclerosing cholangitis. However, questions remain about the long-term efficacy of the drug in halting histologic progression, although ursodeoxycholic acid does improve survival without the need for liver transplantation after 4 years of treatment in patients with primary biliary cirrhosis. Ursodeoxycholic acid is unproven in the treatment of primary sclerosing cholangitis.

Medical treatment of primary sclerosing cholangitis.

Until 1970, primary sclerosing cholangitis (PSC) was considered to be a medical curiosity. With the development of endoscopic cholangiography, PSC is now recognized more frequently and is a common indication for liver transplantation. PSC is usually progressive, leading to cirrhosis, portal hypertension, and liver failure. The manifestations of disease may be clinically similar to those of other causes of bile duct obstruction and must be distinguished from gallstone disease, bile duct carcinoma, primary biliary cirrhosis, and secondary biliary cirrhosis due to bile duct stricture. Medical management of PSC must take into account the likelihood that destroyed bile ducts do not regenerate as hepatocytes do. Hence, PSC should be treated early in its course. The goal of therapy is to prevent further damage and destruction of bile ducts. In this article, we will present relevant data concerning the medical management of primary sclerosing cholangitis.

Analysis of impaired exercise capacity in patients with cirrhosis.

Exercise limitation in cirrhosis is typically attributed to a cirrhotic myopathy (without impaired oxygen utilization) and/or a cardiac chronotropic dysfunction. We performed symptom-limited cardiopulmonary exercise testing in 19 cirrhotics without confounding variables (cardiopulmonary disease, beta blockade, anemia, smoking). Twelve concurrently exercised patients without cirrhosis and with normal resting pulmonary function were controls. Oxygen consumption (VO2) at peak exercise, at anaerobic threshold (VO2-AT), work rate (WR), and heart rate (HR) were measured. Cirrhotics had significantly lower peak WR (73+/-4 vs 107+/-7% predicted, p < 0.001), VO2 (72+/-4 vs 98+/-5% predicted, P < 0.001), VO2-AT (53+/-4 vs 71+/-5% predicted peak VO2, P < 0.01), HR (83+/-2 vs 91+/-2% predicted, P < 0.01) and were more likely to have chronotropic dysfunction (peak HR < 85% predicted). Six cirrhotics had normal aerobic capacity (peak VO2 > 80% predicted), while 13 were abnormal. The abnormals had an earlier AT (46+/-2 vs 67+/-3% predicted peak VO2, P < 0.05) but no difference in peak HR percent predicted was found. In conclusion, two thirds of cirrhotics, without confounding factors, have significantly reduced aerobic capacity. Cirrhotic myopathy (without impaired O2 utilization) and cardiac chronotropic dysfunction do not adequately account for the observed decrease in aerobic capacity.

Treatment of hyperthyroidism with radioactive iodine.

Treatment of hyperthyroidism with RAI has been performed for more than a half century with efficacy and safety. For its optimal use, the physician must employ appropriate patient selection criteria and clinical judgment concerning pretreatment patient preparation. The dose of the 131I needed remains an area of uncertainty and debate; thus far, it has not been possible to resolve the trade-off between efficient definitive cure of hyperthyroidism and the high incidence of post-therapy hypothyroidism. Early side effects are uncommon and readily manageable. Other than the need for long-term monitoring and, in most cases, lifelong L-T4 treatment, late adverse consequences of this treatment remain only conjectural. The available follow-up studies support the current majority opinion of North American thyroid specialists that RAI treatment is an excellent choice for most hyperthyroid patients.

Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment.

Cirrhosis occurs in 20-50% of patients with hepatitis C and is thought to be irreversible. We describe two patients with cirrhosis secondary to hepatitis C in whom the extensive fibrosis and cirrhosis appeared to regress in response to treatment with interferon-alpha (IFN-alpha). Both patients were in the early stages of cirrhosis, class A in the Child-Pugh classification, total score 5 for each patient. Both responded fully to IFN-alpha and had normalization of all liver function tests and disappearance of hepatitis C viral RNA. Liver biopsies, performed before and after treatment, were coded unpaired by patient, combined with 21 liver biopsies from eight other patients with chronic hepatitis, and read independently by two pathologists using the Knodell scoring system. Knodell scores decreased from 14 to 3.5 and from 13.5 to 4 in these two patients. Cirrhosis and extensive fibrosis, present at baseline, were not present on follow-up liver biopsies, which were of sufficient size to reduce the likelihood of sampling error. We conclude that hepatic fibrosis and clinically early cirrhosis may be reversible in some patients with hepatitis C who respond to treatment with IFN-alpha.

Reversibility of hepatic fibrosis in autoimmune hepatitis.

BACKGROUND: Hepatic fibrosis and cirrhosis occur in many types of chronic liver injury and generally seem to be irreversible. OBJECTIVE: To determine whether cirrhosis caused by autoimmune hepatitis can be reversible. DESIGN: Retrospective study. PATIENTS: Eight patients with autoimmune hepatitis and cirrhosis who responded to medical therapy and had follow-up liver biopsy while in clinical and biochemical remission. MEASUREMENTS: Biopsy specimens were randomly coded in an unpaired manner according to patient and were read independently by two pathologists using the Knodell scoring system. RESULTS: The median alanine aminotransferase level decreased from 10.30 mukat/L to 0.37 mukat/L, the median serum bilirubin level decreased from 70 mumol/L to 10 mumol/L, and the median serum albumin level increased from 34 g/L to 43 g/L. Cirrhosis, extensive fibrosis, or both were present in all patients at diagnosis but were not present on follow-up liver biopsy. The median Knodell score decreased from 14.0 to 1.3, and the median fibrosis score decreased from 3.3 to 0.8. CONCLUSION: Hepatic fibrosis and cirrhosis may be reversible in some patients in whom autoimmune hepatitis responds to treatment.

Plasma vitamin K1 level is decreased in primary biliary cirrhosis.

OBJECTIVE: To measure directly plasma vitamin K1 in patients with primary biliary cirrhosis (PBC) and to examine the relationship between vitamin K1 level, prothrombin time, other fat-soluble vitamin levels, and severity of cholestasis. METHODS: We directly measured levels of vitamin K1 (phylloquinone) in the plasma of 77 patients with PBC using reverse-phase high-performance liquid chromatography, along with serum levels of vitamins A, E, and 25-OH vitamin D. RESULTS: Median plasma vitamin K1 level was significantly lower in PBC patients compared with 255 normal subjects (0.65 nmol/L; range, 0.05-4.13, vs 0.95 nmol/L; range, 0.2-4.92; p < 0.0001). Of 77 PBC patients, 18 (23%) patients had levels below the normal range for plasma vitamin K1 (<0.3 nmol/L). Only 1 of the 18 patients with decreased vitamin K1 had a prolonged prothrombin time. There was no correlation between vitamin K1 level and prothrombin time in the PBC patients (p = 0.75); there was also no difference in prothrombin time between PBC patients with low vitamin K1 level and PBC patients with normal vitamin K1 level (10.3 vs 10.0 seconds; p = 0.28). PBC patients with decreased vitamin K1 levels had significantly lower vitamin A and vitamin E levels, and significantly higher serum bilirubin levels than those with normal vitamin K1 levels. CONCLUSION: Decreased plasma vitamin K1 level is common in PBC, and is associated with decreased serum levels of vitamins A and E. However, the majority of PBC patients with decreased plasma vitamin K1 levels have normal prothrombin times. Although the prothrombin time is an insensitive marker of vitamin K1 status in PBC patients, clinically important vitamin K deficiency seems uncommon.