Biomedical subjects
Publications and source records attributed to Nickolas Kontorinis.
A 55-year-old Caucasian male developed a well characterized autoimmune hepatitis after completing treatment with pegylated interferon and ribavirin for recurrent hepatitis C. We hypothesize that pegylated interferon triggered a severe form of immune-mediated hepatitis.
Studies have suggested that the use of hepatitis C virus (HCV)-positive (HCV+) donor allografts has no impact on survival. However, no studies have examined the effect that HCV+ donor histology has upon recipient and graft survival. We evaluated the clinical outcome and impact of histological features in HCV patients transplanted using HCV+ livers. We reviewed all patients transplanted for HCV at our institution from 1988 to 2004; 39 received HCV+ allografts and 580 received HCV-negative (HCV-) allografts. Survival curves compared graft and patient survival. Each HCV+ allograft was stringently matched to a control of HCV- graft recipients. No significant difference in survival was noted between recipients of HCV+ livers and controls. Patients receiving HCV+ allografts from older donors (age > or =50 yr) had higher rates of graft failure (hazard ratio, 2.74) and death rates (hazard ratio, 2.63) compared to HCV- allograft recipients receiving similarly-aged older donor livers. Matched case-control analysis revealed that recipients of HCV+ allografts had more severe fibrosis post-liver transplantation than recipients of HCV- livers (P = 0.008). More advanced fibrosis was observed in HCV+ grafts from older donors compared to HCV+ grafts from younger donors (P = 0.012). In conclusion, recipients of HCV+ grafts from older donors have higher rates of death and graft failure, and develop more extensive fibrosis than HCV- graft recipients from older donors. Recipients of HCV+ grafts, regardless of donor age, develop more advanced liver fibrosis than recipients of HCV- grafts.
OBJECTIVES: An increased ammonia level of gut bacterial origin is an important mediator in the pathogenesis of hepatic encephalopathy (HE), and constipation is a frequent precipitant of hepatic coma. Because diabetes mellitus (DM) may be associated with delayed gastrointestinal transit, we speculated that its presence in patients with HCV-related cirrhosis would predispose to and exacerbate HE. METHODS: Sixty-five patients (50 men, 15 women) with HCV-related cirrhosis attending a liver transplantation clinic were assessed for severity of liver disease and presence of DM in a cross-sectional study. A modified Child-Pugh score that excluded HE was calculated. Frequency and severity of HE (absent, mild, and severe) in diabetic and nondiabetic patients were assessed. Clinical severity of cirrhosis and results of neuropsychometric testing in diabetic and nondiabetic patients with mild and severe HE were compared. RESULTS: Fifty-four patients (83%) had HE (33 mild, 21 severe). Twenty patients (31%) had DM. HE was present in 19 (95%) patients with diabetes and 35 (78%) patients without diabetes (p = 0.087). Severity of HE was greater in diabetic (35% mild, 60% severe) than in nondiabetic patients (58% mild, 20% severe) (p = 0.007). In both the mild and severe HE categories, severity of liver disease in diabetic patients was otherwise milder than in the nondiabetic patients. CONCLUSIONS: Diabetic patients with HCV cirrhosis have more severe HE. Diabetic patients have severe HE at earlier stages of biochemical decompensation and portal hypertension compared with nondiabetic patients.
The life expectancy of HIV seropositive persons is approaching the life expectancy of those who are uninfected with HIV. Hepatitis C virus (HCV) infection has emerged as a worldwide epidemic. Given the similar transmission route between HCV and HIV, there has been an explosion in the number of individuals infected with both viruses. Because of the successful introduction of antiretroviral therapy, patients are more susceptible to new opportunistic infections such as HCV. HCV leads to a more rapid progression to end-stage liver disease in patients with HIV, and the morbidity and mortality related to HCV in co-infected patients is on the rise. Therefore, it has become imperative to treat both HIV and HCV in co-infected patients. The primary goal of HCV therapy is permanent eradication of the virus. Secondary goals include reduction in hepatic fibrosis progression, development of decompensated cirrhosis, and hepatocellular carcinoma. Early studies using standard interferon-alfa for the treatment of HCV in co-infected individuals were discouraging, as poor outcomes, high discontinuation rates, and severe adverse events were observed. The current standard of care for treatment of HCV is pegylated-interferon and ribavirin. New studies have recently demonstrated a higher sustained virologic response rate and a better adverse event profile than previously reported in co-infected patients. As a result, we recommend considering all co-infected patients for HCV therapy while watching closely for unique treatment-related toxicities. The treatment of HCV in co-infected patients should be a high priority for all providers.
BACKGROUND: Survival in HIV infection has improved dramatically in the last decade due to antiretroviral therapy (ART). Due to shared routes of transmission, HCV is found in approximately 30% of HIV infected patients. HCV infection has emerged as a major issue in this population as manifest by a major increase in liver-related mortality. ART-associated hepatotoxicity has been demonstrated to occur more frequently in co-infected individuals and may be severe or fatal in some instances. Thus treatment of HCV has become a priority in HIV infected individuals. OBJECTIVES: The main aims of this review are to summarise and illustrate the current evidence based management of anti-HCV therapy in HIV-infected patients. METHODS: A systematic review of the literature was performed using Pubmed and Medline searches. CONCLUSION: All HIV-infected patients should be screened for HCV infection via anti-HCV antibody and HCV RNA polymerase chain reaction. If HCV infection is present, treatment should be considered in those patients with evidence of liver inflammation and fibrosis. Recent studies have demonstrated the safety and efficacy of anti-HCV therapy in HIV-infected individuals with pegylated interferon and ribavirin combination therapy. HCV genotype is predictive of response to therapy and increasing the duration of therapy to 48 weeks has proven to be more effective in patients with genotypes 2 and 3. HCV treatment with interferon based therapy is associated with many unique side effects and toxicities in this population of which the clinician must be aware.
Alcoholic hepatitis (AH) is a common disease associated with significant morbidity and mortality. Most often the diagnosis is suggested by a history of heavy alcohol excess in a patient with features of hepatic decompensation. In its purest form, AH is a histologic diagnosis of acute hepatic inflammation in response to alcohol. The primary objective of treatment for AH is to support long-term alcohol abstinence and to achieve adequate nutrition with lifestyle modification; goal setting and education are integral to long-term medical management. Severity at presentation (calculated by way of the Maddrey score) determines outcome. Patients with AH represent a heterogeneous group with regard to severity and pathogenesis, with various therapeutic interventions assessed in patients with severe AH. To date, corticosteroids have been studied most, and despite remaining controversial, warrant a place in the treatment of selected patients. Recent advances in unraveling the aspects of disease pathogenesis in AH have raised the possibility of targeted therapies, such as anti-tumor necrosis factor-a monoclonals and pentoxifylline. Orthotopic liver transplantation is not recommended for patients with severe acute AH, as most have an unclear long-term prognosis in the context of ongoing excess alcohol ingestion at presentation.
Azathioprine and 6-mercaptopurine (6 MP) are commonly used as immunosuppression postsolid organ transplantation. Recently, a better understanding of the metabolism of these drugs has developed. 6 Mercaptopurine is metabolized by thiopurine methyl transferase (TPMT) which is under the control of a common genetic polymorphism. Genetic testing and measurement of levels of 6 MP metabolites allow identification of patients at risk of toxicity. We report two cases of cholestatic hepatocellular injury associated with 6 MP toxicity occurring after orthotopic liver transplantation. Cholestasis developed after the introduction of 6 MP. Patients underwent extensive investigation and 6 MP toxicity was considered only after all other causes had been excluded. Thiopurine methyl transferase alleles identified on genetic testing were normal as were the 6 thioguanine levels. However, 6-methyl mercaptopurine levels were significantly elevated into the toxic range. Cholestasis resolved within a few weeks of drug withdrawal. 6 Mercaptopurine hepatotoxicity can present with a variety of clinical, biochemical and histological manifestations post OLT and should be considered as a cause of liver enzyme elevation. Monitoring of 6 MP metabolite levels in addition to TPMT allele testing is useful to prevent 6 MP toxicity and to help guide therapy.
Hepatitis C virus (HCV) is the most common chronic infection in the United States, affecting almost 3.9 million Americans. The most effective treatment for chronic HCV infection is combination antiviral therapy with peginterferon and ribavirin. However, combination therapy is also associated with significant adverse effects and is contraindicated in certain patient populations. Hematological adverse effects are common and are a frequent cause of dose reduction and interruption or discontinuation of therapy. Currently there are no approved treatments for the hematological adverse events associated with HCV therapy. However, emerging data suggest that utilization of hematopoietic growth factors can provide a useful adjunct to treatment and optimize sustained virologic response rates.
Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) frequently co-exist due to shared routes of transmission. In the past, the impact of HCV on overall morbidity and mortality of coinfected patients was minimal due to the poor prognosis of HIV. However, since the introduction of highly active antiretroviral therapy (HAART), HCV has become a significant pathogen in this population. HIV clearly exacerbates HCV infection and accelerates progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. There is debate over whether HCV influences the natural history of HIV. Given the high prevalence of coinfection and the accelerated liver damage, HCV treatment has become a priority in these patients. There are new data on pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for HCV in coinfected patients. The therapy is well tolerated and safe, although it appears to be slightly less effective than in monoinfected patients. The risk of HAART-related hepatotoxicity is greater in coinfected patients and therefore requires special consideration and close monitoring.
The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.
Hepatotoxicity is a serious complication in patients taking HAART. Coinfection with hepatitis viruses increases the risk of liver toxicity while taking antiretroviral therapy. Baseline transaminases should be checked before beginning antiretorviral therapy and all patients should be screened for pre-existing liver disease, most notably hepatitis B and C infections. Regular monitoring of transaminases is mandatory when commencing antiretroviral therapy. In patients with normal liver function, transaminases may be checked monthly after commencing HAART for the first 3 months. If stable this can be broadened to 3 month intervals. In patients with pre-existing liver disease monitoring should be performed more frequently (every 2 weeks) when initiating therapy. Once stable liver enzymes should be checked monthly. The less hepatotoxic drugs such as lamivudine and abacavir should be preferred in patients at high risk for hepatotoxicity. Risks include co-infection with hepatitis B and C viruses, a previous record of hepatotoxicity, cirrhosis, obesity and female gender. Minor enzyme elevations (< 5-fold upper normal limit) are generally safe to tolerate and usually resolve. Patients must be closely observed with regular liver function tests and a hypersensitivity type drug reaction should be excluded. The onset of clinical symptoms, elevated serum lactate or evidence of severe hepatic dysfunction (coagulopathy or elevation of ammonia levels) are suggestive of severe toxicity and HAART should be withheld. Treatment of suspected HAART related hepatotoxicity should first involve withdrawal of therapy. Hypersensitivity reactions may be treated with corticosteroids. Nucleoside-induced mitochondrial damage may improve with riboflavin or thiamine therapy.