Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

Shiffman, Mitchell L.; Diago, M.; Tran, Albert; Pockros, Paul J.; Reindollar, Robert; Prati, Daniele; Rodrı́guez-Torres, Maribel; Lardelli, Pilar; Blotner, Steven; Zeuzem, Stefan

doi:10.1016/j.cgh.2006.02.002

Cited by 75 publications

(65 citation statements)

References 27 publications

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“…These results were consistent with a clinical observation, in which up to 0.54% hepatocytes in chronic hepatitis C liver biopsies were found to be TUNEL-positive (Calabrese et al, 2000). Furthermore, the cell deaths observed in these animals were not readily detectable by the routine serum ALT test, a finding reminiscent of that seen in a subset of patients who have active HCV disease, as assessed by HCV RNA levels and liver histopathology, but who also exhibit persistently normal serum ALT values (Calabrese et al, 2000;Rodrigues et al, 2000;Shiffman et al, 2006).…”

Section: Discussionsupporting

confidence: 90%

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

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Sun

Chan

et al. 2007

Journal of Virological Methods

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Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.

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Section: Discussionsupporting

confidence: 90%

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Tumurbaatar

Sun

Chan

et al. 2007

Journal of Virological Methods

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“…Nevertheless, it is generally accepted that individuals with PNALT have more mild hepatic histology when compared to patients with persistently abnormal ALT. In a retrospective study, the necroinflammatory activity was negligible and the stage of fibrosis in 480 patients with PNALT was significantly lower compared to a large cohort of patients with abnormal ALT 4 (Table). It should be noted that 10% of the PNALT cohort had stage 3 bridging fibrosis on liver biopsy 4 .…”

Section: Natural History Of Chronic Hepatitis C With Persistently Normentioning

confidence: 98%

“…In a retrospective study, the necroinflammatory activity was negligible and the stage of fibrosis in 480 patients with PNALT was significantly lower compared to a large cohort of patients with abnormal ALT 4 (Table). It should be noted that 10% of the PNALT cohort had stage 3 bridging fibrosis on liver biopsy 4 . Other cross sectional studies have shown that cirrhosis was present in 0-11% of patients with PNALT.…”

Section: Natural History Of Chronic Hepatitis C With Persistently Normentioning

confidence: 98%

Hepatitis C Infection With Normal Liver Chemistry Tests

Fried¹

2008

Clinical Gastroenterology and Hepatology

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A 50 y/o man was recently diagnosed with chronic hepatitis C after a life insurance physical. He was very surprised by the diagnosis since he led an active lifestyle, exercised regularly, and did not smoke nor drink any alcohol, except a glass of wine once or twice per month. He had experimented with injecting drugs during his freshman year at college. Over the last 5 years, he had undergone regular physicals and never was told of any "liver problems". In reviewing laboratory data from his referring provider, liver enzymes had been checked on two previous annual physicals with serum ALT activities of 44 and 41 U/L. Physical examination shows a healthy male, BMI =24, without any stigmata of chronic liver disease. Currently, serum ALT activity is 44 U/L and HCV RNA is >700,000 IU/mL with genotype 1. Platelet count was 244,000 cells/mm 3 . The DilemmaThis patient is a generally healthy man who was likely infected with chronic hepatitis C for over 30 years prior to the consultation. Despite the prolonged duration of infection, he had no signs or symptoms of hepatitis C or advanced liver disease. There is historical evidence that his serum ALT activities have been persistently within the normal range. When confronted with such an individual, clinicians may speculate that aggressive treatment of hepatitis C in this vigorous patient is unwarranted. However, further evaluation and management can be planned only after considering the natural history of chronic hepatitis C infection with persistently normal ALT levels and the outcome of therapy in these patients. Defining normal serum ALT activityElevations of serum alanine amontransferase (ALT) and aspartate aminotransferases (AST) activity serve as important markers for liver injury. The finding of an abnormal ALT in a patient, even in the absence of clinical signs or symptoms, should prompt further evaluation for occult liver disease. Hereditary hemochromatosis, chronic viral hepatitis, and nonalcoholic steatohepatitis are frequently overlooked causes of asymptomatic ALT abnormalities that could have serious consequences over time. In order to define "abnormal ALT" which would prompt clinical investigation, healthcare providers must be confident in the definition of "normal" ALT, a value below which they can be secure that liver disease is unlikely. However, despite the importance of these definitions to general medical care and the seemingly simple dichotomy that should be represented by a laboratory test above or

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“…Chronic HCV infection is often clinically silent for years, with up to 50% of patients having normal transaminase levels at any given time, and 20-30% having normal transaminase levels for prolonged periods. However, transaminase levels do not accurately reflect liver damage as a significant number of patients with normal transaminase levels will develop hepatic fibrosis [Armstrong et al 2006;Shiffman et al 2006] Extrahepatic manifestations are seen in patients with chronic HCV infection. These are primarily rheumatologic or lymphoproliferative, including arthralgias or arthritis, cryoglobulin-related vasculitis and glomerulonephritis, Sjogren-like sialadenitis, and non-Hodgkins lymphomas.…”

Section: Epidemiology and Natural History Of Hepatitis C Virus Infectionmentioning

confidence: 99%

Treatment of rheumatoid arthritis in patients with concomitant chronic hepatitis C infection

Joseph¹

2011

Therapeutic Advances in Musculoskeletal

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Hepatitis C virus (HCV) infection is present in 1.8% of the general US population and its prevalence worldwide is estimated at 2-3%. HCV infected patients with concomitant rheumatoid arthritis (RA) pose a particular challenge to the rheumatologist because of the risks of treatment with disease-modifying medications in patients with chronic liver infection. In this paper the difficulties of diagnosing RA in HCV patients and the safety of RA treatment in patients with both conditions are discussed.

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Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

Cited by 75 publications

References 27 publications

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Hepatitis C Infection With Normal Liver Chemistry Tests

Treatment of rheumatoid arthritis in patients with concomitant chronic hepatitis C infection

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