Thiazolidinediones or glitazones specifically target insulin resistance. They have proven efficacy for reducing plasma glucose levels of type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. In addition, they may be associated to some improvement of cardiovascular risk profile. However, troglitazone, the first compound approved by the FDA in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy on blood glucose control of type 2 diabetic patients as compared to troglitazone. In controlled clinical trials, the incidence of significant increases in liver enzyme levels (ALT) was similar with rosiglitazone or pioglitazone as compared to placebo, whereas troglitazone was associated with a threefold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only two cases of severe reversible liver failure have been reported in patients treated with rosiglitazone, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. While regular monitoring of liver enzymes is still recommended and more long-term data are desirable, current clinical evidence supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone. (+info)
Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.
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Although nonalcoholic steatohepatitis (NASH) has generally been considered a benign condition, the increasing prevalence and severity of obesity has heightened concerns about the frequency with which NASH progresses to end-stage liver disease. The aim of this study is to determine the frequency, clinical features, and posttransplantation history of decompensated liver disease secondary to NASH. The frequency of NASH as a cause of end-stage liver disease was prospectively determined in patients evaluated for liver transplantation. NASH was considered to be the primary cause of liver disease in patients who had histological evidence of steatohepatitis and in whom chronic liver diseases other than NASH were excluded. Posttransplantation histological characteristics were also determined in patients with NASH and compared with those of patients with pretransplantation diagnoses of cholestatic liver diseases, alcoholic disease, and hepatitis C. Of 1,207 patients evaluated for liver transplantation during the study period, 31 patients (2.6%) had NASH as the primary cause of liver disease. In the same period, 546 liver transplantations were performed, 16 of which (2.9%) were for end-stage disease secondary to NASH. Posttransplantation steatosis was seen in 60% of transplant recipients with NASH versus 5% of those with cholestatic disease, 15% of those with alcoholic disease, and 15% of those with hepatitis C. Steatohepatitis recurred in 33% of transplant recipients with NASH, with progression to cirrhosis in 12.5%. NASH can progress to end-stage liver disease in a minority of affected patients and was the primary cause of liver disease in 2.9% of patients evaluated for liver transplantation at our center. Recurrence of steatosis and NASH is frequent and can be severe after liver transplantation. (+info)
Heterozygous M3Mmalton alpha1-antitrypsin deficiency associated with end-stage liver disease: case report and review.
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Alpha1-antitrypsin (alpha1AT) deficiency is an autosomal recessive disorder that can cause pulmonary emphysema and liver disease. We report here the case of a 59-year-old woman who was admitted to hospital for evaluation of jaundice. She had no history of hepatitis or childhood liver disease. She had never received a blood transfusion, nor had she abused drugs or alcohol. Transjugular liver biopsy was then performed and revealed a micronodular cirrhosis. Ten months later, because of persistent liver cell failure and ascites, she underwent an orthotopic liver transplantation. Investigation of alpha1AT system in the proband revealed a substantial decrease in serum alpha1AT associated with a low elastase inhibitory capacity. The Pi phenotype revealed a PiM-like profile. Sequencing of exons 1-5 demonstrated the presence of the M3 allele. Moreover, a triple nucleotide deletion was detected in exon 2 of one allele. This caused an "in-phase" frameshift, coding for a protein deficient in a single Phe residue, which corresponded to the Mmalton variant. After liver biopsy, periodic acid-Schiff-positive acidophilic bodies resistant to diastase digestion were observed in the cytoplasm of hepatocytes. These results demonstrated that our patient had a heterozygous M3Mmalton alpha1AT genotype related to a deficiency phenotype. This observation is the first of a patient with heterozygous Mmalton genotype associated with an alpha1AT deficiency that induced severe liver disease requiring orthotopic liver transplantation. (+info)
Sequential changes in the metabolic response to orthotopic liver transplantation during the first year after surgery.
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OBJECTIVE: To quantify the sequential changes in the metabolic response occurring in patients with end-stage liver disease after orthotopic liver transplantation (OLT). SUMMARY BACKGROUND DATA: Detailed quantification of the changes in energy expenditure, body composition, and physiologic function that occur in patients after OLT has not been performed. Understanding these changes is essential for the optimal management of these patients. METHODS: Fourteen patients who underwent OLT for end-stage liver disease had measurements of resting energy expenditure, body composition, and physiologic function immediately before surgery and 5, 10, 15, 30, 90, 180, and 360 days later. RESULTS: Resting energy expenditure was significantly elevated after surgery (24% above predicted), peaking around day 10 after OLT, when it averaged 42% above predicted. A significant degree of hypermetabolism was still present at 6 months, but at 12 months measured resting energy expenditure was close to predicted values. Before surgery, measured total body protein was 82% of estimated preillness total body protein. During the first 10 days after OLT, a further 1.0 kg (10%) of total body protein was lost, mostly from skeletal muscle. Only 54% of this loss was restored by 12 months. Significant overhydration of the fat-free body was seen before OLT, and it was still present 12 months later. Although significant losses of body fat and bone mineral occurred during the early postoperative period, only body fat stores were restored at 12 months. Both subjective fatigue score and voluntary hand grip strength improved rapidly after OLT to exceed preoperative levels at 3 months. At 12 months grip strength was close to values predicted for these patients when well. Respiratory muscle strength improved less markedly and was significantly lower than predicted normal levels at 12 months. CONCLUSIONS: Before surgery, these patients were significantly protein-depleted, overhydrated, and hypermetabolic. After surgery, the period of hypermetabolism was prolonged, restoration of body protein stores was gradual and incomplete, and respiratory muscle strength failed to reach expected normal values. Our measurements indicate that OLT does not normalize body composition and function and imply that a continuing metabolic stress persists for at least 12 months after surgery. (+info)
Cerebral blood flow velocity increases during a single treatment with the molecular adsorbents recirculating system in patients with acute on chronic liver failure.
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The aim of this uncontrolled pilot study is to determine the effect of treatment with the molecular adsorbents recirculating system (MARS) on cerebral perfusion in patients with acute on chronic liver failure (AOCLF). In 8 patients (median age, 44 years; range, 35 to 52 years) admitted with AOCLF, a single 10-hour MARS treatment was performed. Hepatic encephalopathy (HE) was graded according to the Fogarty criteria. Changes in cerebral perfusion were determined by transcranial Doppler as mean flow velocity (V(mean)) in the middle cerebral artery. Arterial ammonia and bilirubin levels were monitored as a measure of the capability of the MARS to remove water-soluble and protein-bound toxins. During MARS treatment, HE grade improved in 3 patients and remained unchanged in 5 patients (P =.11). V(mean) increased from 42 cm/sec (range, 26 to 59 cm/sec) to 72 cm/sec (range, 52 to 106 cm/sec; P <.05), whereas arterial ammonia level decreased from 88 micromol/L (range, 45 to 117 micromol/L) to 71 micromol/L (range, 26 to 98 micromol/L; P <.05) and bilirubin level from 537 micromol/L (range, 324 to 877 micromol/L) to 351 micromol/L (range, 228 to 512 micromol/L; P <.05). In conclusion, cerebral perfusion is increased and levels of ammonia and bilirubin are reduced during MARS treatment in patients with AOCLF. (+info)
A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients.
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OBJECTIVE: To determine the factors affecting the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV) and to identify models that predict patient and graft survival. SUMMARY BACKGROUND DATA: The national epidemic of HCV infection has become the leading cause of hepatic failure that requires OLT. Rapidly increasing demands for OLT and depleted donor organ pools mandate appropriate selection of patients and donors. Such selection should be guided by a better understanding of the factors that influence the outcome of OLT. METHODS: The authors conducted a retrospective review of 510 patients who underwent OLT for HCV during the past decade. Seven donor, 10 recipient, and 2 operative variables that may affect outcome were dichotomized at the median for univariate screening. Factors that achieved a probability value less than 0.2 or that were thought to be relevant were entered into a stepdown Cox proportional hazard regression model. RESULTS: Overall patient and graft survival rates at 1, 5, and 10 years were 84%, 68%, and 60% and 73%, 56%, and 49%, respectively. Overall median time to HCV recurrence was 34 months after transplantation. Neither HCV recurrence nor HCV-positive donor status significantly decreased patient and graft survival rates by Kaplan-Meier analysis. However, use of HCV-positive donors reduced the median time of recurrence to 22.9 months compared with 35.7 months after transplantation of HCV-negative livers. Stratification of patients into five subgroups, based on time of recurrence, revealed that early HCV recurrence was associated with significantly increased rates of patient death and graft loss. Donor, recipient, and operative variables that may affect OLT outcome were analyzed. On univariate analysis, recipient age, serum creatinine, donor length of hospital stay, donor female gender, United Network for Organ Sharing (UNOS) status of recipient, and presence of hepatocellular cancer affected the outcome of OLT. Elevation of pretransplant HCV RNA was associated with an increased risk of graft loss. Of 15 variables considered by multivariate Cox regression analysis, recipient age, UNOS status, donor gender, and log creatinine were simultaneous significant predictors for patient survival. Simultaneously significant factors for graft failure included log creatinine, log alanine transaminase, log aspartate transaminase, UNOS status, donor gender, and warm ischemia time. These variables were therefore entered into prognostic models for patient and graft survival. CONCLUSION: The earlier the recurrence of HCV, the greater the impact on patient and graft survival. The use of HCV-positive donors may accelerate HCV recurrence, and they should be used judiciously. Patient survival at the time of transplantation is predicted by donor gender, UNOS status, serum creatinine, and recipient age. Graft survival is affected by donor gender, warm ischemia time, and pretransplant patient condition. The authors' current survival prognostic models require further multicenter validation. (+info)
Role of plasmapheresis in the management of acute hepatic failure in children.
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OBJECTIVE: To assess the efficacy of plasmapheresis in the treatment of children with acute hepatic failure. SUMMARY BACKGROUND DATA: Acute liver failure is expressed with severe encephalopathy, coagulopathy, and subsequent multisystem organ failure, resulting in a high death rate. Liver transplantation is considered the best option, with long-term 1-year survival rates exceeding 88%. It has been suggested that plasmapheresis may improve coagulopathy and prevent bleeding complications while maintaining adequate fluid, electrolyte, and acid-base balance. METHODS: Forty-nine patients with acute liver failure underwent a total of 243 therapeutic plasma exchanges (TPE). Indications for treatment included candidacy for liver transplant and prolonged prothrombin time. Pheresis was performed daily until the patient recovered, died, or was transplanted. Four patients were anhepatic during pheresis. RESULTS: Coagulation profiles after TPE significantly improved compared with mean preexchange values while maintaining euvolemia. No bleeding episodes were observed during the course of treatment. There was no sustained improvement in neurologic function. Spontaneous recovery was observed in three patients; the remaining either underwent transplantation (32/49) or were not considered transplant candidates because of irreversible neurologic insults (11/49) or sepsis (3/49). CONCLUSION: For children with acute liver failure, TPE is extremely effective in preventing life-threatening bleeding while maintaining appropriate volume status in small children. This method of treatment has no effect on the neurologic complications of liver failure and has no impact on the ability of the liver to regenerate. (+info)
Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.
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Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (beta(2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn. (+info)