January 7, 2011

Liver Disease a Possible Predictor of Stroke

ScienceDaily (Jan. 7, 2011) — People suffering from fatty liver disease may be three times more likely to suffer a stroke than individuals without fatty liver, according to a study by researchers at St. Michael's Hospital and the London Health Sciences Centre. The study is the first to find a link between nonalcoholic fatty liver disease -- a disease characterized by the accumulation of fat in the liver in non drinkers -- and stroke.

In a research letter to the editor in the journal Epidemiology released January 6, Drs. Joel Ray, Ivan Ying and colleagues explain they found high levels of enzymes known to be markers of liver disease in adults who had an acute stroke. Between 2005 and 2009, they reviewed 103 consecutive adults who had an MRI-proven acute stroke between 2005 and 2009 and compared them to 200 adults with suspected acute stroke, but whose MRI was normal, thereby ruling out acute stroke.

"The risk of stroke in relation to fatty liver disease has never been tested," Dr. Ray says. "Our study shows a strong link between the two and the possibility in future that currently available blood liver enzyme tests, or novel markers of fatty liver, may be used to predict the risk of stroke and help us better care for and treat at risk patients."

Nonalcoholic fatty liver disease is a common condition that often has no symptoms or complications. Risk factors include obesity, high cholesterol, diabetes and, especially, insulin resistance.

While the findings are promising, additional research is needed to validate the study's findings, Dr. Ray said.


Liver Disease in the HIV-Infected Individual REVIEW

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*Division of Gastroenterology and Hepatology and Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

"Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment."

Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART era, liver disease is now the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.

Managing liver disease is an increasingly important component to the care of individuals infected with human immunodeficiency virus-1 (HIV). Since the advent of effective antiretroviral therapy (ART) for HIV, there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS).1, 2, 3 However, liver disease has emerged as the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths.3, 4 In some series, nearly half of deaths among hospitalized HIV-infected patients in the ART era have been attributed to liver disease.5, 6

Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have also changed.7 Before ART, the most common causes of liver dysfunction in HIV-infected patients were opportunistic infections, including cytomegalovirus (CMV) and mycobacterium infections, and AIDS-related neoplasms such as lymphoma and Kaposi's sarcoma (KS).8, 9 Since the ART era, however, the spectrum of liver disease among HIV-infected individuals has shifted to concomitant infection with chronic HCV, chronic HBV, medication-related hepatotoxicity, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD) (Table 1).7, 10, 11 This review will focus on the major causes of liver disease in the HIV-infected population in the ART era and will briefly review liver disease in persons with AIDS.

Viral Hepatitis

Hepatitis C Virus

Most liver disease among HIV-infected individuals is secondary to coinfection with HCV and/or HBV.12 Because of shared risk factors, coinfection with HCV and HIV is common. Reported prevalence rates of HIV-HCV coinfection vary depending on the route of HIV transmission, from 10% among those with high-risk sexual behavior to 90% with injection drug use.13 Overall, approximately 30% of HIV-infected individuals in the United States and Europe are coinfected with HCV.14

HIV infection alters the natural history of HCV in several ways. HIV-infected patients who are acutely infected with HCV are half as likely as HIV-uninfected individuals to clear HCV viremia.15 Coinfected individuals also have higher HCV RNA levels, accelerated progression to hepatic fibrosis, an increased risk of developing cirrhosis, and a higher risk of decompensated liver disease once cirrhotic.16, 17, 18 In a meta-analysis of 8 studies, HIV-HCV coinfected subjects had a 2-fold increased risk of histologic cirrhosis and 5-fold increased risk of decompensated liver disease compared with HCV-monoinfected individuals.19 Studies of the role of HCV on the natural history of HIV have been conflicting. However, in a recent analysis of 1428 HIV-HCV coinfected individuals treated for HCV, patients who achieved sustained virologic response had lower rates of HIV progression and nonliver mortality after adjusting for fibrosis, Centers for Disease Control and Prevention clinical category, and nadir CD4 count.20

Given both the high prevalence of HCV among the HIV-infected population and the impact of HIV on HCV-related liver disease progression, all HIV-infected patients should be tested for chronic HCV infection by using third-generation enzyme immunoassays, followed by quantitative HCV RNA testing if positive. Although third-generation immunoassays are highly sensitive, even in the setting of HIV infection (>99%), HCV RNA should be checked in patients with significant risk factors for HCV and advanced immunosuppression or in whom acute infection is suspected.21 During the past decade, outbreaks of sexually transmitted HCV among noninjection-drug-using men who have sex with men have been reported in Europe, the United States, and Australia; men who have sex with men should therefore be considered at risk for acquiring HCV.22 Because there is no available vaccine to prevent HCV infection, HIV-infected individuals who test negative for HCV should be counseled to avoid risk factors for HCV infection. For individuals who test positive for HCV, the extent of liver disease should be determined. Aminotransferase levels are not sensitive for fibrosis in the setting of HIV infection; therefore, liver biopsy remains the preferred modality for staging disease among coinfected patients.

Because of the limitations and invasiveness of liver biopsy, noninvasive methods to determine liver disease are being actively investigated and are becoming a viable alternative to liver biopsy. A variety of laboratory markers have been studied as potential surrogates for hepatic fibrosis; most were derived from studies in individuals without HIV infection. A meta-analysis of studies of the markers in the HIV-HCV coinfected population suggested that they might be useful in excluding cirrhosis if used at their most sensitive thresholds; however, their diagnostic odds ratios were suboptimal.23 Transient elastography (TE) uses ultrasound technology to estimate liver stiffness by measuring elastic shear wave velocity through the liver. In a study of 169 HIV-HCV coinfected patients, TE accurately detected significant fibrosis and cirrhosis but was less accurate in discriminating mild from significant fibrosis.24

The decision to treat HCV in the HIV-infected patient should be made on an individual basis, because the benefits must be weighed against safety and efficacy concerns. HCV treatment should be prioritized in coinfected patients without decompensated cirrhosis who have a liver biopsy revealing portal fibrosis or more advanced disease.25 Women of child-bearing age might desire treatment before becoming pregnant, because pregnancy must be avoided during and 6 months after anti-HCV therapy because of ribavirin teratogenicity. Because they usually have favorable treatment responses, patients with HCV genotype 2 or 3 who are motivated and can tolerate treatment should be offered it regardless of liver disease stage. Certain IL28B genotypes respond well to treatment and so might also become an indication to treat without liver disease staging.26 Early treatment of acute HCV infection has also been associated with improved response rates in HIV-infected individuals.27 Patients with decompensated cirrhosis should be referred to a liver transplant center with experience in transplantation with HIV infection.

The current Food and Drug Administration-approved treatment for HCV in the setting of HIV infection is pegylated interferon alfa and ribavirin, which is the standard of care based on 4 large randomized trials.28, 29, 30, 31 This regimen is less effective in HIV-infected patients, with sustained virologic response rates ranging from 14%-38% among those with HCV genotype 1 infection and 44%-73% among genotype 2 and 3 infections. Similar to HCV-monoinfected individuals, genotype, baseline HCV RNA, and early response to therapy are predictors of treatment response.28 In patients receiving HCV treatment, didanosine (ddI) is contraindicated and zidovudine is not recommended, because ribavirin potentiates the risk of mitochondrial toxicity and anemia, respectively.32 Stavudine should also be avoided in patients receiving HCV treatment because of the risk of steatosis.33 Abacavir has been associated with decreased SVR, possibly as a result of competition with ribavirin because both are guanosine analogues.34, 35, 36 However, this competitive interaction appears to be insignificant when weight-based ribavirin dosing is used.37, 38

Although HCV-infected patients have a higher incidence of ART-related liver toxicity, this infrequently leads to ART discontinuation, and the benefits of ART for HIV treatment are profound; therefore, ART should not be withheld in the coinfected population. In addition, ART might have beneficial effects on the progression of liver disease in HIV-HCV coinfection, because improvement in CD4 count might decrease fibrosis progression, although studies investigating this have been inconsistent. A recent systematic review of 11 studies examined the impact of ART on liver disease in HIV-HCV coinfection; 3 associated ART with less severe fibrosis, 6 failed to show a link, 1 associated protease inhibitors (PIs) with decompensated liver disease, and 1 showed varied effects depending on drug class.39 In other studies, HIV viral suppression has been linked to slower fibrosis progression, and ART has been associated with decreased liver-related mortality.40, 41

Individuals with HCV infection and cirrhosis have an increased risk of developing hepatocellular carcinoma (HCC). The American Association for the Study of Liver Disease recommends screening these patients every 6-12 months with alpha-fetoprotein measurement and imaging.42 Although separate recommendations for HIV-HCV coinfection do not exist, screening remains important in this population because HCC incidence has been increasing among HIV-infected individuals.43 Finally, HIV-HCV coinfected patients without immunity to HAV should receive vaccination, because HAV can cause fulminant hepatitis in patients with underlying liver disease.

Hepatitis B Virus

Although the prevalence of HIV-HBV coinfection varies by geographic location, approximately 10% of HIV-infected individuals worldwide are also chronically infected with HBV.44 Like HIV-HCV coinfection, HIV alters the natural history of HBV. Individuals with HIV infection are 3-6 times more likely to develop chronic HBV after an acute exposure than individuals without HIV infection, and hepatitis B surface antibody (anti-HBs) development is improved with higher CD4 cell counts.45, 46 In addition, HIV-infected patients have a lower rate of spontaneous clearance of HBeAg, increased HBV replication, and a higher rate of loss of anti-HBs and reactivation of HBV.47 Coinfected individuals also experience an increased progression to cirrhosis and higher liver-related mortality compared with HBV monoinfected individuals.48, 49 The impact of HBV infection on the natural history of HIV is less clear.

All HIV-infected patients should be screened for HBV with HBsAg, anti-HBs, and hepatitis B core antibody (anti-HBc). Individuals without immunity to HBV should be vaccinated; however, response to vaccination is poor, especially in patients whose CD4 cell count is <200 cells/mm.3,50 Patients should therefore also be counseled to avoid risk factors for HBV transmission. Individuals with persistent HBsAg for a period of 6 months have chronic HBV and should be evaluated for treatment. Isolated anti-HBc is more common in HIV infection than in the general population; in one study, 42% of HIV-infected patients were only positive for anti-HBc.51 Occult HBV, defined as positive HBV DNA in the setting of negative HBsAg, has also been described in HIV-infected subjects, although prevalence estimates range widely.52 The clinical implications of isolated anti-HBc positivity and occult HBV are still unclear, but reactivation of inactive or occult HBV and reverse seroconversion (reappearance of HBsAg and HBV DNA in a patient with evidence of previously resolved infection) have been reported in HIV-infected individuals.53

Once HIV-HBV coinfection is diagnosed, staging of liver disease is important but challenging. Although serum alanine aminotransferase levels are lower in coinfected patients, this correlates poorly with liver disease.48 Noninvasive measures of hepatic fibrosis have not been well-studied in HIV-HBV coinfection; therefore, liver biopsy remains the gold standard for disease staging.

The decision to initiate HBV treatment depends on whether the patient meets indications to treat either the HIV or HBV. Treatment regimens for either virus must consider both infections, because many antiviral agents have dual activity, including tenofovir, lamivudine, emtricitabine, entecavir, and adefovir at doses >10 mg.54 Treatment for HBV is indicated in any patient with cirrhosis and detectable HBV DNA. Although a specific HBV DNA threshold for treatment in the absence of cirrhosis has not been determined, treatment should be considered in patients with HBV DNA ≥2000 IU/mL and more than mild liver disease on biopsy.54

If there is no indication to treat either infection, the patient should be monitored closely. If treatment is indicated for either HIV or HBV, ART should be initiated and should include the combination of tenofovir and emtricitabine (Truvada) or tenofovir and lamivudine.55 If tenofovir is contraindicated, entecavir can be used with the ART regimen, but then lamivudine or emtricitabine should be avoided because of overlapping resistance patterns.47 For patients requiring treatment for HBV but in whom ART is not feasible, options are limited by the need to avoid agents with anti-HIV activity to prevent development of drug-resistant HIV. In these patients, pegylated interferon alfa and adefovir 10 mg can be considered. Telbivudine is also a consideration, but some in vivo studies show declines in HIV RNA without emergence of drug-resistant HIV.56 Elevated ALT and AST during the course of ART might be due to a variety of potential causes including medications, drug-resistant HBV, HBV reactivation in the setting of medication withdrawal (especially with lamivudine withdrawal due to HIV resistance via the M184V mutation), loss of HBeAg, or the immune reconstitution inflammatory syndrome (IRIS).

Screening for HCC among individuals with HIV-HBV coinfection should follow American Association for the Study of Liver Disease guidelines recommending screening for all cirrhotic HBV carriers and for certain groups of noncirrhotic carriers.42 The hepatitis A vaccine should also be provided to individuals without hepatitis A immunity.

Medication Toxicity

Antiretroviral Therapy-Related Medication Toxicity

Liver toxicity is one of the most common serious adverse events associated with ART.57 The clinical presentation can range from mild asymptomatic increases in serum transaminases to overt liver failure.58 In retrospective studies, the incidence of ART-related severe hepatotoxicity is approximately 10%, and life-threatening events occur at a rate of 2.6 per 100 person-years.59, 60

There are 4 primary mechanisms by which ART can lead to liver damage: direct drug toxicity and/or drug metabolism, hypersensitivity reactions, mitochondrial toxicity, and IRIS.60, 61 IRIS is characterized by the paradoxical worsening of preexisting infectious diseases as a result of rapid immune restoration in the setting of successful HIV RNA suppression. The syndrome generally manifests within the first 2 months of ART initiation and is accompanied by a precipitous decline in HIV RNA and rise in CD4 count. In patients with viral hepatitis, immune restoration can lead to clinical hepatitis as a result of the immune response to the virus. There have been case reports of clinical flares of HBV in the setting of ART initiation, even with regimens including anti-HBV activity, and of rapidly progressive HCV-related cirrhosis associated with ART-related immune restoration.62, 63

Coinfection with HBV or HCV has consistently been associated with increased risk of ART-related hepatotoxicity.57, 60 Other risk factors associated with ART-related liver injury include preexisting advanced fibrosis, pretreatment elevated ALT or AST, alcohol abuse, older age, female gender, first exposure to ART, significant increase in CD4 cell count after ART initiation, concomitant tuberculosis medications, and cocaine use.60, 61, 64

Although all antiretroviral drugs have some risk of hepatotoxicity, some are implicated more than others, and classes of drugs have characteristic patterns of injury (Table 2). The non-nucleoside reverse transcriptase inhibitors (NNRTIs) typically cause either hypersensitivity reactions or direct drug toxicity and therefore have 2 peaks of onset, within days to weeks or several months after initiation.60 Nevirapine (NVP) is the NNRTI most associated with hepatotoxicity, although hypersensitivity reactions resulting in liver failure have been reported with the newer NNRTI etravirine.55 Efavirenz can also cause hepatotoxicity but does so less frequently than NVP or etravirine.

Hepatotoxicity associated with PIs generally occurs weeks to months after drug initiation. Full-dose ritonavir (RTV) was strongly associated with hepatotoxicity but is no longer used. The low-dose RTV used to boost levels of other PIs does not appear to increase the risk of hepatotoxicity.65 However, clinical hepatitis and liver failure have been reported with the newer PI tipranavir in combination with RTV boosting.55, 60 Atazanavir and indinavir both commonly cause an indirect hyperbilirubinemia, which is not associated with liver injury and does not require treatment discontinuation.66

The nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicity as a result of their ability to inhibit mitochondrial polymerase y. Clinically this presents with hepatic steatosis and lactic acidosis from weeks to months after initiation. Stavudine, ddI, and zidovudine are the most frequently implicated. Prolonged ddI use has also been associated with cryptogenic liver disease and recently has been linked to noncirrhotic portal hypertension and esophageal varices.67, 68 Although less associated with mitochondrial toxicity, abacavir might cause hypersensitivity reactions especially in HLA-B*5701 positive patients. Finally, lamivudine, emtricitabine, and tenofovir can lead to HBV reactivation and severe acute hepatitis if withdrawn in an HBV-infected patient or if resistance develops.

The fusion inhibitor enfuvirtide has been rarely associated with hypersensitivity reactions, and the newer drug maraviroc, a CCR5 inhibitor, carries a black box warning for hepatotoxicity as a result of hypersensitivity.

Given the relatively high incidence of ART-related hepatotoxicity, all patients should have baseline ALT and AST checked, followed by regular monitoring every 3 months. Patients should be educated regarding symptoms of hepatitis and hypersensitivity reactions. If an adverse liver event occurs, ART should be discontinued in patients with symptoms, jaundice and elevated direct hyperbilirubinemia, grade 4 hepatotoxicity (ALT/AST >10 times upper limit of normal), or severe lactic acidosis.55 Mild asymptomatic ALT or AST elevations usually spontaneously resolve without drug discontinuation (Table 3).

Non-Antiretroviral Therapy-Related Medication Toxicity

HIV-infected patients are often prescribed a number of non-ART medications that can have adverse liver effects either alone or in combination (Table 4).

Alcoholic Liver Disease

Although alcoholic liver disease is responsible for nearly half of all deaths due to chronic liver disease in the United States, the role of alcohol abuse on liver disease in HIV-infected populations has not been well-defined. In one study of 2864 HIV-infected adults in the United States, 8% of the entire cohort and 15% of current alcohol drinkers were classified as heavy drinkers, which is almost twice as prevalent as in the general population.69

Active alcohol intake is known to be associated with faster liver disease progression in HCV monoinfection.70 In one study of HIV-HCV coinfected patients, excessive alcohol use was associated with elevated HCV RNA levels.71 In another study of 1358 HIV-infected individuals at an urban center, 10% reported hazardous drinking, which was independently associated with an elevated surrogate for hepatic fibrosis.72 These results suggest that alcohol abuse is prevalent among HIV-infected individuals and can independently contribute to liver disease progression. As a modifiable risk factor for liver disease, it is important that physicians provide counseling regarding alcohol consumption in this population.

Nonalcoholic Fatty Liver Disease

NAFLD refers to fat deposition in hepatocytes, or steatosis, in individuals with little or no alcohol use. When accompanied by inflammation and fibrosis, it is referred to as nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD in the U.S. population ranges from 17%-33%, and risk factors include obesity, hyperglycemia, diabetes mellitus, and hypertriglyceridemia.73 Recently, mounting evidence suggests that the prevalence of hepatic steatosis in HIV-infected patients is high, especially in patients with chronic HCV or on NRTIs.61 Most of the prevalence data come from studies in HIV-HCV coinfected individuals, with rates of steatosis in this population ranging from 40%-69%.33, 74 However, in a recent study of 216 HIV-infected patients without viral hepatitis coinfection, 31% had NAFLD diagnosed, although most were diagnosed with ultrasound rather than the gold standard of liver biopsy.75

Metabolic abnormalities are extremely common in HIV-infected persons on ART, especially NRTI-PI combinations. These include insulin resistance, dyslipidemia, hypertriglyceridemia, and lipodystrophy, a disorder of peripheral fat distribution resulting in lipotrophy and visceral adiposity.76 NRTIs can also lead to hepatic steatosis via inhibition of mitochondrial DNA replication, resulting in triglyceride accumulation in the liver.77 Hypertriglyceridemia, low high-density lipoprotein, and low total cholesterol have also been independently associated with HIV infection and might be mediated by cytokines like interferon alfa.78 These metabolic abnormalities have been associated with the development of NASH in HIV-infected patients.79

The natural history of NAFLD in HIV infection is unknown. In the general population, approximately 10%-15% of patients with simple steatosis progress to NASH, and 15%-20% of these patients progress to cirrhosis.80 In general, steatosis alone is not concerning for liver damage, but it might exacerbate underlying chronic liver disease. In HCV-monoinfected patients, steatosis is associated with faster progression of fibrosis and decreased response to treatment.81 Similarly, in cohorts of HIV-HCV coinfection, hepatic steatosis has been associated with more advanced liver fibrosis.33, 74 With continued investigation and research into NAFLD, its impact on liver disease progression in HIV-infected individuals will likely be further elucidated.

Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia (NRH) is a rare condition characterized by multiple small regenerative nodules in the liver parenchyma. NRH has recently become increasingly recognized in HIV-infected patients with cryptogenic liver disease.82 Although the etiology is unclear, both ddI use and thrombophilia have been associated with the disease.82, 83 NRH should be considered in HIV-infected patients with portal hypertension of unclear etiology, especially those on ddI.

Acquired Immunodeficiency Syndrome-Related Liver Disease

Acquired Immunodeficiency Syndrome Cholangiopathy

AIDS cholangiopathy occurs when infection-related strictures in the biliary tract lead to biliary obstruction. It typically presents with right upper quadrant (RUQ) pain and a markedly increased alkaline phosphatase level, with less elevated bilirubin and normal or slightly increased transaminase levels. Patients might also have fever, nausea, vomiting, and diarrhea; jaundice is uncommon.84 It is usually seen in low CD4 counts (<100/mm3). Consequently, although previously relatively common among HIV-infected patients, it is much less common in the ART era. Indeed, in a recent retrospective study of 94 patients diagnosed with AIDS cholangiopathy at an urban hospital between 1983 and 2001, only 13 were diagnosed after 1996.85

The most common infection associated with AIDS cholangiopathy is Cryptosporidium parvum, followed by CMV. Microsporidia, Cyclospora cayetanensis, Mycobacterium avium-intracellulare, and Histoplasma capsulatum have all been reported with AIDS cholangiopathy as well.84 Ultrasound or magnetic resonance cholangiopancreatography might reveal intrahepatic and common bile duct dilation with terminal stenosis. However, endoscopic retrograde cholangiopancreatography remains the gold standard for diagnosis. Biopsies of the papilla and bile duct as well as bile duct brushings might help identify the infectious cause. Sphincterotomy improves the abdominal pain but does not extend survival, and the alkaline phosphatase level often remains elevated.85, 86 The most important aspect to treatment of AIDS cholangiopathy is ART administration, because survival after diagnosis is poor without ART.85

Acalculous Cholecystitis

Acalculous cholecystitis has been well-documented in HIV infection and is usually associated with CMV or Cryptospordium, although other infections, including Isospora and microsporidia have been implicated.87, 88 Patients typically present with RUQ abdominal pain and fever with cholestasis; leukocytosis is often not present. Imaging reveals a thickened, distended, acalculous gallbladder, and HIDA scan often shows a nonfunctioning gallbladder.88 Cholecystectomy is the treatment of choice.

Acquired Immunodeficiency Syndrome-Related Neoplasms

The AIDS-defining malignancies non-Hodgkin lymphoma (NHL) and KS involve the liver in 33% and 9% of cases, respectively.89, 90 Hepatic involvement of NHL might present with asymptomatic liver function test abnormalities, although patients might develop abdominal pain or jaundice. Hepatic involvement of KS rarely causes symptoms or death.90

Opportunistic Infections

Several opportunistic infections have been associated with hepatic involvement in advanced AIDS (Table 5). Of these, Mycobacterium avium complex is the most common. It is usually characterized histologically by acid-fast bacilli-containing poorly formed granulomas, although mass lesions have been described.90, 91 Patients often present with nausea, diarrhea, and abdominal pain. Alkaline phosphatase is usually disproportionately increased.92 Hepatic involvement of Mycobacterium tuberculosis, including liver abscesses, has been reported in approximately 8% of patients with extrapulmonary tuberculosis and HIV infection.91, 93 CMV is one of the most common opportunistic infections involving the liver detected on autopsy of patients with advanced AIDS but rarely results in clinical hepatitis.90, 92 When CMV presents as hepatitis, patients usually have mild transaminitis, fever, malaise, weight loss, and hepatomegaly.

Hepatic involvement of fungal infections, including Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis, can be seen in patients with AIDS and is usually detected on liver biopsy or autopsy. Although liver function test results are often abnormal, the liver involvement is usually asymptomatic.94, 95 Extrapulmonary Pneumocystis jiroveci involving the liver has been described and might be seen in the setting of inhaled pentamidine for prophylaxis of Pneumocystis jiroveci pneumonia.96 Bacillary peliosis hepatis is a rare disease characterized by multiple blood-filled cavities in the liver parenchyma; it has been reported in patients with AIDS and Bartonella henselae infection.97 Other reported opportunistic infections involving the liver of patients with AIDS include disseminated herpes simplex virus, human herpesvirus 6, varicella-zoster virus, Epstein-Barr virus, adenovirus, Candida albicans, Aspergillus fumigatus, Toxoplasma gondii, and Strongyloides stercoralis.90, 91, 92

Vanishing Bile Duct Syndrome

The vanishing bile duct syndrome (VBDS) is an acquired disease resulting in loss of small and medium-sized intrahepatic bile ducts. Multiple causes have been identified, and there have been case reports of VBDS associated with advanced AIDS, with cases attributed to CMV viremia and medication toxicity.98, 99 The presentation is variable and often related to cholestasis. Diagnosis is based on histology, although the work-up should include imaging to rule out extrahepatic biliary obstruction. The outcome of reported AIDS-associated VBDS cases is very poor, with progression to liver failure and death.98, 99


Liver disease among HIV-infected individuals is a common and important cause of non-AIDS-related morbidity and mortality. In the ART era, the spectrum of liver disease among patients with HIV infection has changed dramatically, shifting from opportunistic infections to sequelae of chronic infections, medication toxicities, alcohol use, and fatty liver. Management of HIV-infected patients requires recognition of these conditions and targeted diagnosis and treatment.


Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3

Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3

This study is currently recruiting participants.

First Received: December 13, 2010 Last Updated: December 21, 2010

To assess safety and tolerability of PSI-7977 400 mg and ribavirin (RBV) with and without pegylated interferon alfa 2a (PEG-IFN) in treatment naive subjects with hepatitis C (HCV) genotypes 2 or 3

Further study details as provided by Pharmasset:

Primary Outcome Measures:

· Safety and Tolerability [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]To assess the safety and tolerability of PSI-7977 400 mg and ribavirin for 12 weeks, administered with and without pegylated interferon alfa-2a (PEG-IFN) in treatment naïve subjects with HCV genotypes 2 or 3

Secondary Outcome Measures:

· HCV RNA [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]To evaluate the change in circulating HCV RNA in subjects over 12 weeks of dosing with PSI-7977 and ribavirin administered with and without PEG-IFN in treatment-naïve subjects with HCV genotypes 2 or 3

· HCV RNA [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the proportion of subjects who have HCV RNA below the limit of quantitation (LOQ) and below the limit of detection (LOD) at various time points in the study

· Sustained Virologic Response (SVR) [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To evaluate the sustained virologic response at 12 (SVR12) and 24 (SVR24) weeks following completion of all treatment

· Resistance [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To evaluate the emergence of HCV resistance against PSI-7977

· Duration of PEG-IFN therapy [ Time Frame: SVR 12 and SVR 24 ] [ Designated as safety issue: No ]To explore the effects of the duration of PEG-IFN therapy on safety, tolerability, emergence of resistance, viral kinetics, SVR12, and SVR24

· Pharmacokinetics [ Time Frame: Ongoing ] [ Designated as safety issue: No ]To characterize the steady-state plasma pharmacokinetics of the PSI-6206 metabolite of PSI-7977


Fatty Liver Disease Soars in U.S.

January 7, 2011

There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease.

Fatty liver disease isn't confined to any one group, and there don't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible.

Plumped-up liver cells

The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood.

Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not involved, the condition is called nonalcoholic steatohepatitis (steato- for fat and –hepatitis because the liver is inflamed). Fortunately, that unwieldy name boils down to a handier acronym, NASH. Estimates vary quite a bit, but it seems that 5% to 10% of people with fatty liver disease go on to develop NASH.

NASH is often a relatively stable, low-grade condition that people live with for years, with few if any symptoms. But it can also start a cascade of serious damage to the liver and attempts by the organ to regenerate itself that culminate in an abundance of scar tissue and impaired liver function — a condition called cirrhosis. Cirrhosis is irreversible and can lead to total failure of the liver. It also is associated with an increased risk for developing liver cancer.

Some studies have shown as few as 3% of people with NASH developing cirrhosis, while others have shown as many as 26% doing so. There's no test or risk factor that predicts who will develop cirrhosis and who won't, although one study did find that people who are older or whose initial liver biopsies showed more inflammation were at greater risk. It's clear, though, that the prognosis for NASH is far better than it is for steatohepatitis that's the result of heavy alcohol consumption. Perhaps as many as half of all those with alcoholic steatohepatitis (which lacks a handy acronym) go on to develop cirrhosis.

It's just a theory at this point, but people with fatty liver disease and NASH may need to be more worried about heart disease and stroke than about serious liver problems. An article published in The New England Journal of Medicine in late 2009 argued that the inflammatory and other factors pumped out by a fat-afflicted liver promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot, a combination that can lead to heart attack or stroke. The evidence the authors cited is intriguing, if circumstantial. They pointed to a study showing that people with NASH are twice as likely to die from heart attack or stroke as people without it. And NASH seems to add to the risks that come with excess weight. Overweight men with NASH have higher levels of C-reactive protein, an inflammatory factor, and fibrinogen, a clotting factor, than overweight men without NASH. Moreover, the levels of those and other factors go up as NASH gets more severe.

Diagnosis requires a biopsy

Most people with fatty liver disease don't have symptoms, and that's true even if it has developed into NASH. Only occasionally do people feel run-down, or they have an achy feeling in the upper right side of the abdomen, where the liver is located. So, more often than not, fatty liver disease and NASH are discovered incidentally, starting with higher than normal levels of liver enzymes on a routine blood test. Ultrasound imaging, the same technology used to get pictures of developing fetuses, can be informative: the liver looks bright because the fat shows up as white on the image. But neither an ultrasound nor a CT or MRI scan is completely reliable for making a diagnosis. The fat in the liver is visible, but not the NASH-related inflammation. Some researchers have developed formulas that use a simple blood test and measurements of various hormones, inflammatory factors, and liver enzymes to arrive at a diagnosis, but this work is at a preliminary stage.

Currently, a liver biopsy is the only way to make a definitive diagnosis of fatty liver or NASH. Liver biopsies involve inserting a long needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren't entirely free of risk and complications, but they're also fairly routine these days and can be done on an outpatient basis.

Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.

Weight loss is the treatment

There's been a fair amount of research into using diabetes drugs to treat NASH, even in people who don't have diabetes. Rosiglitazone (sold as Avandia) and pioglitazone (sold as Actos) have been the leading candidates because they reduce insulin resistance, the root cause of fatty livers. They're not looking so promising these days. The FDA has moved to sharply curtail the use of Avandia because it seems to cause heart problems. The results of an important trial published in 2010 in The New England Journal of Medicine showed Actos to be no better than a placebo in improving NASH in people without diabetes.

Another diabetes drug, metformin (Glucophage), might prove to be an effective treatment, but there isn't enough evidence yet. Vitamin E is a possibility: the same trial that showed Actos wasn't effective showed some improvement in the livers of people who took large doses (800 IU daily) of the vitamin. But many doctors are wary about prescribing large doses of vitamin E because they've been associated with an increased risk of bleeding. Besides, the improvements in the liver were limited. Fish oil has produced some favorable results, and clinical trials are under way, but it can't be endorsed yet.

These setbacks and uncertainties have left weight loss (ideally from changes in diet and an increase in physical activity) as the only recommended treatment for most cases of fatty liver disease and NASH. In many cases, weight loss seems to have a very direct effect: as people lose weight, the fatty liver becomes less fatty. Crash dieting is a bad idea, though, because rapid weight loss (losing 4 pounds a week or more) can wind up damaging the liver. Of course, if sustained weight loss were easy, a lot of today's health problems would be solved, not just fatty liver disease and NASH.

In addition to encouraging people to lose weight, doctors will often advise people with diabetes who have fatty liver disease or NASH to be vigilant about controlling their blood sugar.

The bottom line Many parts of the body come to grief once people become obese or develop diabetes. It's not surprising that our livers do too, given how central they are to a whole suite of metabolic processes. There's some evidence that a fatty liver may add to the already high risk of heart disease among people who are obese or have diabetes. Fatty livers can also develop into cirrhotic ones if the inflammatory processes take off.

But there are two bright spots in the take-home message about fatty livers. First, most cases stay relatively stable and don't result in serious liver disease. Second, the treatment is not an expensive drug with side effects, but losing weight — and that will benefit many other parts of the body besides the liver.

Source: Harvard Univ.

Natural Compound Blocks Hepatitis C Infection

ScienceDaily (Jan. 6, 2010) — Researchers have identified two cellular proteins that are important factors in hepatitis C virus infection, a finding that may result in the approval of new and less toxic treatments for the disease, which can lead to liver cancer and cirrhosis.

An estimated 270 to 300 million people worldwide are infected with hepatitis C and the conventional treatments -- interferon and ribavirin -- can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, said Samuel French, an assistant professor of pathology and senior author of the study.

French and his team set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but HSP 40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.

"This is an important finding because we can block these proteins with the idea of reducing the level of the virus in people and, ideally, completely eliminate it," said French, who also is a researcher at UCLA's Jonsson Comprehensive Cancer Center.

The study appeared in the most recent issue of the journal Hepatology.

Since Quercetin has been shown to inhibit hepatitis C infection, French said, a Phase I clinical trial will be launched at UCLA to determine if the compound is safe and effective.

Quercetin is a plant-derived bioflavonoid, and is used by some people as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Currently, there are early-stage clinical trials testing quercetin for safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes.

"Because Quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral resistance," French said. "Cellular proteins cannot change like viral proteins can."

Many patients in the United States have a type of hepatitis C virus that does not respond to the standard treatments. In these cases, if the virus can't be blocked, end-stage liver disease and, ultimately, death may occur. Once HSP 40 and 70 were identified, French and his team used Quercetin in an attempt to block the proteins and found that the compound "reduced infectious particle production at non-toxic concentrations," according to the study.

"Quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity," the study states.

The UCLA clinical trial will most likely target those with type 1 hepatitis C, which is the non-responsive type prevalent in this country. Only about 50 percent of those with type 1 hepatitis C respond to treatment, French said.

Volunteers with type 1 hepatitis C who opt not to undergo conventional therapies would be recruited for the study. In other studies in other diseases, Quercetin has resulted in no significant side effects, French said.

"A non-toxic treatment for chronic hepatitis C would be great because our current therapies have significant side effects and only a certain percentage of the patient population responds," French said.

The three-year study was funded by the National Institutes of Health, the Cure Digestive Diseases Research Center and the Stein Oppenheimer Endowment Award.


Nanogen Launches Advanced Hepatitis C Medicine

January 2011

BMI Core View: Drugmakers based in emerging markets will increasingly produce hard-to-manufacture pharmaceuticals. Firms in developing countries enjoy low operating costs, but have traditionally lacked the expertise and equipment to make advanced therapeutics such as biologics. As economies in these non-traditional markets grow, capital will be released for the establishment of modern production facilities, with output destined for both domestic consumption and export.

Ho Chi Minh City-based Nanogen Biopharmaceutical has launched Pegnano (peginterferon alfa-2a) in Vietnam for the treatment of hepatitis C. The complex biologic has Good Manufacturing Practice (GMP) accreditation and is generally used in combination with ribavirin.

However, Swiss multinational Roche has demanded the de-registration of Pegnano because the medicine infringes intellectual property protection for Pegasys (peginterferon alfa-2a), specifically patent No. 2611. Granted in 2002 by the National Office of Intellectual Property of Vietnam, the Pegasys patent is effective until 2017.

Nanogen's Director, Ho Nhan, is assured of Pegnano 's legitimacy. According to the 2009 revision of article 7 of Vietnam's Intellectual Property Law, the government can ban or limit the application of intellectual property rights in cases where such rights harm national defence, the welfare of people or badly affect other crucial national interests.

The company has ...

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NICUs May Be Source of Donor Organs

By Todd Neale, Staff Writer, MedPage Today
Published: January 06, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Organs from infants who die of cardiac reasons in the neonatal intensive care unit may represent a new donor source for patients awaiting transplantation, a retrospective study showed.
Of 192 infants who died over a three-year period in one of three Boston NICUs, 16 (8%) were deemed candidates for organ donation after cardiac death, according to Anne Hansen, MD, MPH, of Children's Hospital Boston, and colleagues.

Based on warm ischemic time -- the interval between the withdrawal of life support and death -- and other factors, the candidate donors had the potential to provide 18 kidneys, 14 livers, and 10 hearts, the researchers reported in the January issue of the Journal of Pediatrics.

"The need to increase the pool of organ donors is clear," they wrote, noting that through the end of October 2009, there were 441 infants added to the waiting list for organs, compared with just 109 donors.

"The discrepancy between the number of possible recipients and donors underscores the importance of understanding the potential role of an infant donation-after-cardiac-death program in maximizing the donor pool for this population," Hansen and her colleagues wrote.

Historically limited to brain-dead patients, organ donation after cardiac death has gained more attention in recent years as a way to expand the donor pool. In 1997, the Institute of Medicine approved the practice as ethically acceptable and medically useful. In 2007, the Joint Commission required all of its accredited hospitals to develop a donation-after-cardiac-death policy.

To see how many deaths in a level III NICU would be theoretically eligible for donation after cardiac death, the researchers performed a retrospective study of all deaths in three Harvard Program in Neonatology NICUs -- at Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Children's Hospital Boston -- between 2005 and 2007.

Over the study period, there were 192 deaths in infants who had reached at least 23 weeks of gestation.

Eligibility criteria for donation after cardiac death were developed by transplant surgeons in collaboration with the New England Organ Bank. Exclusion criteria were as follows:

• Postmenstrual age at death of less than 37 weeks
• Weight at death of less than 3 kilograms
• Active infection
• Known HIV-positive status
• Active malignancy, excluding a primary brain tumor
• Encephalopathy of unknown etiology
• Brain death
• No requirement for mechanical ventilation when life support is withdrawn

After those exclusions, 31 infants who died during the study were considered eligible for organ donation. Only 16, however, had a warm ischemic time of less than one hour and were classified as potential donor candidates for kidney and liver transplantation. Of those, 14 had an interval of less than 30 minutes, and also qualified as donors for heart transplantation.

In an accompanying editorial, Lainie Friedman Ross, MD, PhD, of the University of Chicago, and Joel Frader, MD, of Northwestern University in Chicago, wrote that the study raises important clinical controversies, including whether organs can be collected in infants as small as those deemed eligible by the study authors.

Ethical controversies around procuring organs from infants who die of cardiac causes remain as well, they said.

Many pediatricians are not confident that infants who are candidates for organ donation after cardiac death are really dead, "a problem not helped by the variability in practices on how long one waits to certify death after circulatory arrest or subsequently how long surgeons must wait to ensure lack of 'auto-resuscitation' after the pronouncement of death," they wrote.

Also, the editorialists wrote, tension exists between the delivery of optimal end-of-life care and the preparations necessary for efficiently procuring organs.

"Donation after cardiac death almost always challenges standard, even when unproven, end-of-life practices that allow families to have substantial time alone with the patient immediately after death."

Two issues must be addressed before implementing newborn donation-after-cardiac-death programs, Ross and Frader argued.

"First, we need to ensure that donation-after-cardiac-death protocols conform to quality end-of-life care for all concerned: patients, parents, and healthcare professionals," they wrote.

"Second, allocation policies should be designed to promote broader geographic sharing of infant organs so these small-size organs are distributed to children who might otherwise die on the deceased donor wait list."

The study authors reported that they had no conflicts of interest.

Editorialist Ross was funded in part by a grant from the National Library of Medicine on Ethical and Policy Issues in Living Donor Transplantation. Editorialist Frader reported that he had no conflicts of interest.

Primary source: Journal of Pediatrics
Source reference:
Labrecque M, et al "Donation after cardiac death: The potential contribution of an infant organ donor population" J Pediatr 2011; 158: 87-92.

Additional source: Journal of Pediatrics
Source reference:
Ross L, Frader J "Are we ready to expand donation after cardiac death to the newborn population?" J Pediatr 2011; 158: 6-8.