May 7, 2013

Alcohol consumption as a cofactor for other liver diseases†‡

Clinical Liver Disease

Special Issue: Alcoholic Liver Disease

Volume 2, Issue 2, pages 72–75, April 2013

Jose Altamirano*, Javier Michelena

Article first published online: 24 APR 2013

DOI: 10.1002/cld.197

Copyright © 2013 the American Association for the Study of Liver Diseases

CIBERehd is funded by Instituto de Salud Carlos III. Javier Michelena received “Formación del Profesorado Universitaro” grant from the Ministerio de Educación of the Spanish Goverment.

Potential conflict of interest: Nothing to report.


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Alcohol has been shown to cause synergistic injury in combination with other chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis B and C, hemochromatosis, and autoimmune liver diseases. Abusive alcohol consumption rapidly accelerates the development of hepatic fibrosis and cirrhosis and also increases the risk of liver cancer and death from liver disease. The negative impact of alcohol consumption is dose- and time-dependent and varies depending on the underlying liver disease and may occur at much lower alcohol intake compared with an alcohol dose necessary to initiate alcoholic liver disease itself. There is not a clear “safe” limit for alcohol consumption in the setting of chronic liver disease. Thus, alcohol consumption should be avoided or at least limited in any patient with underlying liver disease.

Abusive alcohol intake is a major risk factor for chronic liver disease (CLD). In addition, alcohol consumption in the presence of other liver diseases may result in progression of the disease. Alcoholic liver disease is prevalent among patients with chronic hepatitis C (HCV) and B (HBV) virus infection, influences the progression of the disease and has a stimulation effect on viral replication.1, 2 Alcohol may negatively impact the course of NAFLD increasing the fibrosis rate in patients with non-alcoholic steatohepatitis3 and of hereditary hemochromatosis (HH).4 Finally, alcohol may interact with the metabolism of certain drugs5 and can also contribute to the development and worsening of some autoimmune liver diseases.6

Alcohol and Chronic Hepatitis C

Chronic HCV infection is the leading cause of advanced liver disease in the United States; an estimated 3.2 million people have active chronic HCV infection.7 Alcohol consumption is a common comorbidity in these patients, and multiple studies have shown that it may result in synergistic injury, with accelerated rates of fibrosis and the development of cirrhosis and liver cancer.8–11 Various mechanisms have been proposed, including: alcohol's effect on HCV viral replication, HCV-related cytotoxicity, hepatic oxidative stress, and immune modulation.

There is evidence that HCV RNA levels increase in concert with a more pronounced alcohol intake (Fig. 1a).12 Conversely, it has been shown that serum HCV RNA decreases with a reduction in alcohol intake (Fig. 1b).2 Alcohol consumption is also associated with HCV progression, and there is extensive evidence showing that chronic alcohol consumption leads to disease progression (Table 1). Even small doses of alcohol intake (below 30 g/day) can promote liver fibrogenesis.13 Thus, it appears that there is no “safe alcohol consumption” among patients with HCV infection. Chronic alcohol consumption in HCV-infected patients stimulates not only fibrogenesis but also hepatocarcinogenesis. Patients with chronic HCV infection who actively consume alcohol have a higher relative risk of hepatocellular carcinoma (HCC) compared with abstainers (54 versus 19, respectively).14 This risk also appears to be dose-dependent. In one study, alcohol consumption >80 g/day increased the risk for HCC significantly by a factor of 7.3 when compared with <40 g/day.11 Finally, there are data showing that alcoholics have inferior rates of response to HCV therapy.15 However, the question about a possible inhibitory effect of alcohol on therapy rather than patient noncompliance requires further research.


Figure 1. Impact of alcohol consumption and effect of alcohol reduction on serum HCV RNA levels. Abbreviations: HCV, hepatitis C virus; SRAC, self-reported alcohol consumption. (a) Adapted with permission from Hepatology.12 Copyright 1998, Wiley. (b) Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Table 1. Effect of Alcohol Consumption in the Progression of HCV Infection
Study Alcohol Intake Evaluation No. of Patients Results
Roudot-Thoraval et al.33 Excessive alcohol intake defined as >5 drinks/day for women and 6 drinks/day for men for >1 year 6,664 Excessive alcohol intake was also associated with a higher risk of cirrhosis (34.9% versus 18.2%; P < 0.001).
Poynard et al.34 Abstinent/Moderate, <50 g/day; high, ≥50 g/day 2,235 Fibrosis rate progression increased from 0.125 to 0.167 in patients with consumption ≥50 g/day
Pessione et al.12 Weekly self-reported alcohol consumption 233 Significant correlation between self-reported alcohol consumption and serum HCV RNA levels (r = 0.26; P = 0.001)
Corrao et al.35 Lifetime daily alcohol intake 702 Alcohol intake + HCV infection multiplies the alcohol-associated risk of cirrhosis (odds ratio: 9.0 for 50 g/day, 26.1 for 100 g/day, 133 for >125 g/day)
Harris et al.36 Heavy drinking defined as >80 g/day 836 Heavy drinking exacerbates the risk for cirrhosis among patients with HCV infection (odds ratio: 7.8 versus 31.1 in HCV and HCV heavy drinkers, respectively)
Alcohol and Chronic Hepatitis B

The interaction of alcohol consumption with HBV infection has been studied less extensively. Alcohol stimulates carcinogenesis in patients with HBV. This effect was shown in the seminal study of Ohnishi et al.,16 in which patients with HBV infection and active alcohol consumption developed HCC approximately 10 years earlier than patients who did not drink at all. Additionally, a dose-dependent effect of alcohol consumption has been demonstrated. Patients with heavy alcohol consumption (>80g/day) had a significantly increased risk of HCC in HBV-related cirrhosis.17

Alcohol and NAFLD

NAFLD is increasingly recognized as the downstream hepatic consequence of the metabolic syndrome. Well-known risk factors for NAFLD include obesity (especially with increased waist circumference), insulin resistance, and hypertriglyceridemia. Small amounts of alcohol may improve peripheral insulin resistance that take place in NAFLD.18 In addition, some studies have shown a paradoxical association between modest alcohol consumption with a lesser degree of severity in NAFLD patients.19, 20 However, additional alcohol consumption worsens NAFLD at various stages of the disease, both in animals5 and in humans.21–23

There is evidence that the impact of alcohol consumption on the development of NALFD is dose-dependent. Studies from Europe have shown that alcohol consumption of more than 60 g/day increases the rate of fatty liver by echography to 46% compared with 16% in control subjects.24 Alcohol consumption has also shown an additive risk for NAFLD development in obese patients. In one study, individuals with a body mass index of more than 25 kg/m2 had a further increase in fatty liver to >70%, and if both alcohol consumption and overweight were factors, steatosis was present in >90%.22

On the other hand, liver fibrosis in NAFLD also increases with alcohol consumption. Patients with high-risk alcohol consumption and obesity have an almost two-fold risk of developing cirrhosis21 (Fig. 2).


Figure 2. Obesity is a risk factor for alcoholic liver disease progression. Abbreviation: BMI, body mass index. Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Finally, recent evidence shows that even social drinking in patients with nonalcoholic steatohepatitis results in a significantly increased risk of HCC.25 This observation is in keeping with animal studies showing that alcohol administration is associated with deterioration of experimentally induced fatty liver disease in rodents and may also enhance the generation of carcinogenic DNA lesions.26

Alcohol Consumption and Hereditary Hemochromatosis

HH is an autosomal recessive gene disorder in which HFE gene mutations cause chronic intestinal hyperabsorption of iron, resulting in iron overload in various organs.27, 28 Iron overload is a negative prognostic factor for the development of liver disease.4 Alcohol consumption increases reactive oxygen species by producing H2O2, which leads to iron hyperabsorption and iron release due to a decrease in hepcidin. This leads to iron accumulation in the liver, resulting in increased toxicity (Fig. 3). One observational study showed that hemochromatosis subjects who drank >60 g/day of alcohol were approximately nine times more likely to develop cirrhosis than those who drank <60 g/day.29 Thus, patients diagnosed with HH should avoid alcohol consumption.


Figure 3. Iron overload due to alcoholic liver disease. Abbreviations: EtOH, ethanol; ROS, reactive oxygen species; TfR1, transferrin receptor 1.

Alcohol, Drug Interactions and Autoimmune Liver Diseases

Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially well known for methotrexate, paracetamol, and antituberculosis drugs. First, prolonged high-dose methotrexate intake results in stellate cell activation leading to zone 3 fibrosis, which is further enhanced by alcohol consumption, since alcohol by itself leads to an activation of stellate cells.30 Second, alcohol consumption induces cytochrome P450 2E, which is also responsible for the metabolism of various drugs (e.g., paracetamol and antituberculosis drugs such as isoniazid). An induction of CYP2E1 by alcohol results in enhanced metabolism of paracetamol with an increased generation of highly toxic intermediates that are not normally detoxified due to the decreased hepatic glutathione levels presented in alcoholic patients. Isoniazid toxicity depends on two factors: (1) the speed of isoniazid acetylation and (2) the speed of the metabolism of the intermediate acetylhydrazine by CYP2E1.31 Finally, it should be pointed out that vitamin A and beta-carotene taken in excess may also lead to hepatic fibrosis and cirrhosis.

The effect of alcohol consumption in patients with autoimmune liver diseases has not been studied extensively, though there is some clinical evidence in patients with primary biliary cirrhosis (PBC). In a study of 274 patients with untreated PBC, moderate alcohol consumption (30 g/day) was an independent predictor of advanced PBC stage.32 In these patients, moderate alcohol consumption was also significantly correlated with increased oxidative stress and steatosis on liver biopsies, which was thought to contribute to worsening of PBC stage.


Alcohol has been shown to cause synergistic injury in combination with other forms of CLD, particularly chronic HCV and HBV infection, NAFLD, HH, and autoimmune liver disease. Alcohol consumption, particularly in high doses, accelerates to liver fibrogenesis and the development of cirrhosis and also increases the risk of HCC and death from liver disease. Despite the effect of light alcohol consumption on decreasing insulin resistance and cardiovascular mortality, there does not seem to be a “safe” limit for alcohol consumption in the setting of combined CLD.



7 May 2013, Vol 158, No. 9>

Original Research | 7 May 2013

Gregory D. Kirk, MD, MPH, PhD; Shruti H. Mehta, PhD, MPH; Jacquie Astemborski, MS; Noya Galai, PhD; Jonathan Washington, BA; Yvonne Higgins, PA; Ashwin Balagopal, MD; and David L. Thomas, MD, MPH

[+-] Article and Author Information

Ann Intern Med. 2013;158(9):658-666. doi:10.7326/0003-4819-158-9-201305070-00604

Background: Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.

Objective: To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.

Design: Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.

Setting: Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.

Participants: 1176 current and former injection drug users with antibodies to HCV.

Measurements: Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.

Results: Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.

Limitation: The process of liver fibrosis began before the study in most persons.

Conclusion: In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.

Primary Funding Source: National Institute on Drug Abuse.


Antivir Ther. 2013 May 3. doi: 10.3851/IMP2614. [Epub ahead of print]

Benito JM, Sánchez-Parra C, Maida I, Aguilera A, Rallón NI, Rick F, Labarga P, Fernández-Montero JV, Barreiro P, Soriano V.

Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

BACKGROUND: Achievement of early viral suppression is important in patients with chronic hepatitis C virus (HCV) infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far.
METHODS: All consecutive individuals that initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV-RNA (<25 IU/mL) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in).

RESULTS: A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, BMI, baseline HCV-RNA, HCV subtype 1a (45% vs 42%), IL28B-CC alleles (29% vs 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% vs 44%). Conversely, more patients on BOC than TLV had previously failed to peginterferon-ribavirin (82% vs 64%). RVR was achieved by 82% of patients on TLV vs 59% on BOC (p=0.001). Multivariate logistic regression analysis (OR [95% CI], p) confirmed that TLV use was the strongest predictor of RVR (3.54 [1.23-10.24], 0.02), being others HCV subtype 1b vs 1a (3.26 [1.17-9.09], 0.02) and low baseline HCV-RNA (0.41 [0.16-1.03], 0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR.

CONCLUSIONS: Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV-RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV-RNA responses.


PLoS One. 2013 Apr 25;8(4):e61568. doi: 10.1371/journal.pone.0061568. Print 2013.

Cozen ML, Ryan JC, Shen H, Lerrigo R, Yee RM, Sheen E, Wu R, Monto A.

Department of Medicine, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America.

BACKGROUND: The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored.

METHODS AND FINDINGS: We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18-4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50-23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients.

CONCLUSION: These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.


Free Full Text Article

Reuters Health Information

May 03, 2013

By Will Boggs, MD

NEW YORK (Reuters Health) May 03 - Patients with hepatitis C virus (HCV) are more likely to have an early response to pegylated interferon alpha-2a than alpha-2b, a new meta-analysis has found.

"The Cochrane meta-analysis about sustained virological response and our meta-analysis taking into account rapid virological response and early virological response (show that) the efficacy of peg-a-2a is superior to peg-a-2b and thus it is the first choice in the management of hepatitis C," Dr. Manuel Romero-Gomez from Valme University Hospital in Seville, Spain, told Reuters Health by email.

Dr. Romero-Gomez and colleagues pooled data from eight randomized trials that compared peginterferon alpha-2a and alpha-2b in 4,566 patients.

A complete early virological response (EVR) was achieved by 53.3% of patients treated with peginterferon alpha-2a and 43.8% of those treated with alpha-2b (p=0.0028), the authors reported April 14 online in Alimentary Pharmacology & Therapeutics.

Results were similar in a sub-analysis of patients infected with HCV genotypes 1 and 4, but the difference fell short of statistical significance.

Crude rates of rapid virological response (RVR) were higher for peginterferon alpha-2a than alpha 2-b (25.0% vs 16.8%; p=0.0056), and results were also significantly better for alpha-2a in a sub-analysis of patients infected with HCV genotypes 1 and 4 (p=0.0048).

"RVR and EVR are crucial in the management of therapy in hepatitis C because they allow us to make decision about futility rules, saving cost and adverse events," Dr. Romero-Gomez said. "Using peg-a-2a we can treat more patients with double therapy if they reach RVR or add boceprevir/telaprevir in patients without RVR."

"We need more data to define which patients have to be treated with peg-a-2a or peg-a-2b," Dr. Romero-Gomez cautioned. "According to baseline characteristics, pega-a-2a seems to be better in very difficult-to-cure patients (genotype 1 with advanced fibrosis and metabolic derangements), but this point needs to be confirmed in further studies."


Aliment Pharmacol Ther 2013.


Beta Blockers Ameliorate GI Permeability in Cirrhosis

Daniel M. Keller, PhD

May 02, 2013

AMSTERDAM, the Netherlands — Nonselective beta-blocker therapy improves gastrointestinal permeability and decreases intestinal bacterial translocation in patients with cirrhosis and esophageal varices, according to a new study.

These effects were associated with a reduction in the risk for variceal bleeding, and appear to be independent of a hemodynamic response, said Thomas Reiberger, MD, associate professor of hepatology at the Medical University of Vienna in Austria.

Dr. Reiberger presented the results here at the International Liver Congress 2013.

Infection and endotoxemia can impair liver function, increase portal pressure, and impair coagulation, which can result in variceal bleeding, he explained.

Antibiotic treatment is one way to reduce endotoxemia and bacterial translocation, but nonselective beta blockers might help by decreasing intestinal permeability.

Dr. Reiberger and colleagues tested this hypothesis in 50 cirrhotic patients with esophageal varices. Exclusion criteria were celiac disease, current infections, antibiotic or lactulose use in the previous 3 months, and consumption of > 6 g of alcohol per day.

Hepatic venous pressure gradient and other physical and laboratory parameters were measured at baseline and at 1 month, and intestinal permeability was assessed with sucrose, lactulose, and mannitol tests. Decompensation, bleeding, and death were assessed at 3-month follow-up.

The patients were predominantly men in their early to mid-50s (range, 18 to 75 years). Fewer patients with a lower hepatic venous pressure gradient (from 13 to 20 mm Hg) had large varices than those with a higher hepatic venous pressure gradient of more than 20 mm Hg (33% vs 66%; P = .002). There was also less portal hypertensive gastropathy with the lower hepatic venous pressure gradient (53% vs 97%; P = .015).

About 20% of patients had normal gastroduodenal and intestinal permeability, 18% had abnormal gastroduodenal permeability, 8% abnormal intestinal permeability, and 54% both abnormalities.

The higher hepatic venous pressure gradient was significantly associated with increased markers of gastroduodenal and intestinal permeability and of bacterial translocation before beta-blocker treatment, compared with lower hepatic venous pressure gradient. Portal pressure was linearly related to gastroduodenal permeability (P = .003) and intestinal permeability (P < .001).

Bacterial translocation was also associated with hepatic venous pressure gradient. Portal pressure was directly correlated with lipopolysaccharide-binding protein level (P < .001) and interleukin-6 level (P = .006).

Beta Blockers Reduce Pressure

"Not surprisingly, we found a decrease in portal pressure [21 mm Hg to 17 mm Hg; P < .05], but we also found a decrease in the sucrose/mannitol ratio and intestinal permeability index, indicating that beta blockers lead to an improvement of gastroduodenal and intestinal permeability," Dr. Reiberger reported. "Also, lipopolysaccharide-binding protein levels and interleukin-6 levels were significantly decreased with the nonselective beta-blocker therapy."

Fifty-one percent of patients had hemodynamic responses to the beta blockers. "Although there was a clear hint that the patients who were hemodynamic responders had better outcomes in these intestinal permeability tests...what's really striking is that the proportion of patients achieving a normal result on the sucrose, lactulose, mannitol tests after beta-blocker therapy is also really high in the nonresponders. That's why I conclude that it's independent of hemodynamic response," Dr. Reiberger explained. In addition, decreases in levels of lipopolysaccharide-binding protein and interleukin-6 were similar in responders and nonresponders.

There was a trend toward a higher risk for variceal bleeding in patients with abnormal gastroduodenal permeability than in those with normal gastroduodenal permeability (log-rank P = .066); the trend was similar for intestinal permeability. There was a significant correlation between higher interleukin-6 level and more variceal bleeding (log-rank P = .038). Intestinal permeability appeared to have no effect on survival.

After the presentation, an audience member asked Dr. Reiberger whether his team had looked at the different effects on the adrenergic system of propranolol and carvedilol. Dr. Reiberger noted that very few patients were on carvedilol but, from what he could see, there was no difference between them in terms of lipopolysaccharide-binding protein level, interleukin-6 level, or change in intestinal permeability.

Session moderator Isabelle Colle, MD, professor of hepatology and gastroenterology and head of the gastroenterology clinic at Gent University in Belgium, explained some of the mechanisms by which beta blockers exert their effects in this setting. By decreasing hepatic venous pressure gradient and portal pressure "the microcirculation in the intestine is better, ameliorate the function of the barrier, which decreases permeability," she explained. In addition, patients with cirrhosis have slow intestinal transit times, which beta blockers speed up, "so you have fewer bacteria, you have less ammonia."

Dr. Reiberger suggested that beta blockers influence immunity because the sympathetic nervous system affects immune function.

Do all nonselective beta blockers have the same effects? A study of nonresponders to propranolol who were switched to carvedilol showed that "carvedilol had a better effect on the portal pressure than propranolol," Dr. Colle told Medscape Medical News. In the future, carvedilol will probably be better than propranolol, she noted.

Dr. Reiberger reports receiving research support from MSD, Roche, Phoenix, and Gilead. Dr. Colle has disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 84. Presented April 26, 2013.


Vitamin D deficiency and vitamin D therapy in chronic hepatitis C

Annals of Hepatology

March-April, Vol. 12 No.2, 2013: 199-204


José M. Ladero,* María J. Torrejón,† Pilar Sánchez-Pobre,‡ Avelina Suárez,§ Francisca Cuenca,† Virginia de la Orden,|| María J. Devesa,† María Rodrigo,¶ Vicente Estrada,¶ Gustavo López-Alonso,† José A. Agúndez**

* Service of Gastroenterology, Hospital Clínico San Carlos, Department of Medicine, Medical School, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. † Clinical Laboratory Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. ‡ Service of Gastroenterology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. § Service of Clinical Microbiology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
|| Genomics Unit, Clinical Laboratory Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. ¶ Infectious Diseases Unit, Service of Internal Medicine, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. **Department of Pharmacology, University of Extremadura, Cáceres, Spain.


Background. Vitamin D has immunomodulatory properties, exerts an anti-hepatitis C virus (HCV) effect in vitro and improves response to interferon-based therapy in patients with chronic hepatitis C (CHC). Low serum levels of 25(OH) vitamin D [25(OH)D] are frequently found in CHC patients and seem to be related to more advanced stages of liver fibrosis. The study aims to establish the incidence of vitamin D deficiency in Spanish patients with CHC, its possible relation with features of liver damage and with the IL28B gene polymorphism, and the immediate effect of vitamin D therapy on CHC-related analytical variables. Materials and methods. Baseline serum 25(OH)D levels were measured in 108 consecutive CHC patients (60 men, age 54.3 ± 10.5 yrs). Results of transient elastography and of IL28B rs12979860C/T genotype were available in 89 and 95 patients, respectively. Forty one patients with insufficient levels of 25(OH)D received vitamin D supplements and were re-evaluated thereafter. Results. Deficiency of vitamin D (< 20 µg/dL) and suboptimal levels (20-30 µg/mL) were detected in 36.1% and 40.9% of patients, respectively. No relationships were found between 25(OH)D levels and biochemical liver tests, fibrosis stage and IL28B genotype. Vitamin D therapy normalized 25(OH)D levels in all treated patients, but did not modify significantly HCV-NA serum levels or biochemical tests. Conclusions. Vitamin D deficiency is common in Spanish patients with CHC but it is related neither to biochemical and virological variables nor with the fibrosis stage and IL28B polymorphism. Vitamin D therapy has no immediate effect on HCV-RNA serum levels.


Mehta N. Clin Gastroenterol Hepatol. 2013;11:572-578.

May 7, 2013

Patients with infiltrative hepatocellular carcinoma experienced prolonged survival when treated with transarterial chemoembolization or sorafenib in a recent retrospective cohort study.

Researchers evaluated data from 155 patients with infiltrative hepatocellular carcinoma (iHCC) seen at the University of California, San Francisco Medical Center between 2002 and 2010. Participants had a median age of 60 years, MELD score of 13, maximum tumor diameter of 11.3 cm and alpha-fetoprotein level of 347 ng/mL.

Nearly all patients (95.5%) had died as of Sept. 2011. The survival rate was 63% of patients at 3 months, 30% at 6 months and 8% at 12 months, with a median survival of 4.0 months across the cohort. Median survival was longer among patients who underwent treatment, including transarterial chemoembolization (TACE, 6.0 months), sorafenib (7.5 months) or radiofrequency ablation with or without TACE (9.2 months), than patients who did not receive treatment (3 months).

Survival rates were significantly higher among patients treated with sorafenib (n=11, 73% at 6 and 36% at 12 months) and those who underwent transarterial chemoembolization (TACE, n=18, 45% and 17%) than participants who received no therapy (n=109, 17% and 2%) (P<.01 for all comparisons). No significant difference in survival was observed between those treated with sorafenib or TACE (P=.267).

Multivariate analysis indicated associations between mortality at 6 months and several factors, including: cirrhosis of Child-Pugh class B (HR=2.61, 1.36-4.8 vs. class A) or C (HR=6.12, 2.74-13.76 vs. class A); not having received sorafenib, radiofrequency ablation or transarterial chemoembolization (HR=2.79, 1.60-4.88); MELD score (HR=1.07, 1.03-1.12 per one-point increase); tumor size (HR=1.05, 1.01-1.10 per 1-cm increase) and an alfa-fetoprotein level above 1,000 ng/mL (HR=2.47, 1.56-3.84) (95% CI for all).

“iHCC is a radiographically distinct and advanced form of HCC,” the researchers wrote. “The majority of patients with iHCC have extensive tumor burden as well as macrovascular invasion. … The prognosis of patients who are diagnosed with iHCC is grim, with a median survival of only 4 months. Nonetheless, our results suggest that some patients may still derive survival benefit from liver-directed therapy and/or systemic therapy with sorafenib.”


Only half of those with HCV complete confirmatory RNA test

May 7, 2013

Nearly 50% of people who have ever had hepatitis C virus have received a follow-up RNA test to confirm whether they are still infected, according to new research by the CDC.

“The majority of people who have HCV do not even know they have HCV,” John Ward, MD, director of the CDC’s Division of Viral Hepatitis, said during a media briefing. “People must complete the two-step testing process to accurately identify current infection, so that they can receive the treatment they need. These data give us an idea of the gap between those who are and those who are not receiving the second follow-up test, showing us that we have a substantial challenge in front of us.”

The researchers evaluated surveillance data from eight sites in the United States, obtained from 2005 to 2011. They compared the number of people with a positive HCV antibody test with the number of people with a positive HCV RNA test. They examined the numbers by birth cohort, surveillance site and number of deaths. They also calculated the rates of newly reported HCV infection in 2011.

There were 217,755 people with newly reported HCV, and among those, 107,209 (49.2%) only had a positive antibody test and 110,546 (50.8%) had a positive RNA test. In both groups, people born from 1945 to 1965 comprised most new infections. Across all of the sites, the rate of persons with newly reported HCV infection was 84.7 per 100,000 population.

“HCV affects about 3 million Americans, most of whom are baby boomers,” CDC Director Thomas Frieden, MD, MPH, said during the media briefing. “The bottom line is that if you were born from 1945 to 1965, get tested, and if that test is positive, have follow-up testing. You may not remember everything that happened in the ’60s and ’70s, but your liver does.”

According to Frieden, about half of the people infected with HCV will go on to have serious liver problems and about one-third may die of complications from their infections. HCV also is the leading cause of liver cancer, which is the fastest growing cause of cancer-related death in the United States, he said. If baby boomers are tested and receive care, about 120,000 deaths can be prevented.

The CDC recommends that testing for HCV begins with a rapid or laboratory-conducted assay for HCV antibody. A reactive result should be followed up with nucleic acid testing for HCV RNA.

For more information:

CDC. MMWR. 2013;62(early release):1-5.

CDC. MMWR. 2013;62(early release):1-4.


C. Koh, T. Heller, V. Haynes-Williams, K. Hara, X. Zhao, J. J. Feld, D. E. Kleiner, Y. Rotman, M. G. Ghany, T. J. Liang, J. H. Hoofnagle

Aliment Pharmacol Ther. 2013;37(9):887-894.

Abstract and Introduction

Background Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear.

Aim To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post-SVR.

Methods The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE).

Results Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152–27 U/L), AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), platelet count (209 000–239 000/μL) and AST to platelet count ratio index (APRI: 1.31–0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1–13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P < 0.001).

Conclusions In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.


Chronic hepatitis C virus (HCV) infection is estimated to affect 180 million persons worldwide and at least 3.2 million Americans.[1, 2] This disease is the most common cause of chronic hepatitis and cirrhosis, end-stage liver disease and hepatocellular carcinoma in the United States and the developed world.[3, 4] It is also the single most common reason for liver transplantation.[4] Therapy for HCV has evolved during the last 20 years from use of interferon alone to the combination of interferon and ribavirin followed by the combination of peginterferon with ribavirin.[5–7] Recently direct-acting antiviral agents have been developed for HCV that have increased the response rate substantially.[8–13] The endpoint for assessing efficacy of antiviral therapy has been the loss of HCV RNA from serum which, if sustained for at least 6 months after stopping treatment, is referred to as a sustained virological response (SVR).[14] The durability of a 6-month SVR is above 95%, but the long-term clinical benefits of this outcome have not been well defined.[15, 16]

Although achievement of an SVR has been associated with clinical, laboratory and histological improvements in chronic HCV, this endpoint is a surrogate for the ultimate aim of therapy, which is prevention of progression to cirrhosis, end-stage liver disease, hepatocellular carcinoma and death from liver disease.[17–26] These 'hard' endpoints, however, generally take years or decades to evolve and following patients randomised to treatment or observation with these dire outcomes has not been practical and has been considered ethically untenable. Thus, while SVR is associated with improvements in serum aminotransferase levels and liver histology, its role in preventing progression of disease and disability or death from chronic liver disease is uncertain and currently controversial.

At the Clinical Center of the National Institutes of Health (NIH), we have conducted a series of prospective controlled and uncontrolled studies of therapy of chronic HCV beginning in 1984.[26–31] All patients who achieved an SVR as a part of these studies have been followed on a long-term basis to assess the natural history and outcome of this virological response. As a consequence, we have a cohort of SVR patients that have been followed up for up to 23 years. We report the follow-up of the initial 103 patients who achieved an SVR between the years 1986 and 2003.

Materials and Methods

All patients who achieved a 6-month post-treatment SVR in clinical research protocols conducted by the Liver Diseases Branch, NIDDK between 1984 and 2003 were included in this analysis. Of the 262 patients enrolled, 103 achieved an SVR. Thereafter, many patients were followed on a regular basis. Starting in 2007, patients who had not returned in the previous 2 years were asked to return for a medical evaluation, blood tests, abdominal ultrasound and ultrasound transient elastography. The initial protocols included studies of interferon alfa-2b alone for 6 or 12 months,[26–29] escalating doses of interferon alfa-2b for 12 months, and the combination of standard interferon alfa-2b or peginterferon alfa-2a with ribavirin for 6–12 months.[29–31] All patients gave written informed consent for the initial trials as well as for long-term follow-up and transient elastography in a protocol, which was approved by the NIDDK Institutional Review Board and registered in (#NCT00001971). All authors had access to the study data and had reviewed and approved the final manuscript.

Laboratory Tests

At the time of last follow-up, patients were tested for liver biomarkers including alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase, gamma glutamyl-transpeptidase (GGT), immunoglobulin levels (IgG, IgA, IgM), rheumatoid factor, alpha-fetoprotein and platelet counts. Results of these markers before therapy were available from most patients. Serum HCV RNA was tested by quantitative and qualitative reverse transcriptase polymerase chain reaction (Amplicor; Roche Molecular Systems, Pleasanton, CA, USA) with a lower limit of sensitivity of 100 viral copies/mL (50 IU/mL). HCV genotyping was done using reverse hybridisation (INNO-LiPA; Innogenetics, Ghent, Belgium). HCV RNA testing before, during and immediately after therapy was performed using assays that were available at the time and were not always of similar specificity and sensitivity. Virological testing from the initial studies (done between 1984 and 1992) was done on serum samples, stored at −80 °C.[29] In patients who relapsed, stored serum samples (−80 °C) were retrieved and retested for HCV RNA at the time of SVR using the Amplicor system to confirm the absence of HCV RNA.

All except three patients underwent a pre-treatment liver biopsy with interpretation by one hepatopathologist (DEK) using the Ishak modification of the HAI scoring system for activity and fibrosis.[32]

Transient Elastography

Patients evaluated after 2007 underwent ultrasound transient elastography (TE) performed via FibroScan (Echosens, Paris) after informed consent.[33] Elastography was done by individuals specifically trained in the technique. At least 10 determinations were made and median results were expressed in kilopascals (kPA). Values range from 2.5 to 75 kPA with values of <7.0 being normal and suggesting no or mild hepatic fibrosis, values of 7.1–13.7 suggesting moderate to advanced fibrosis and values of >13.8 suggesting cirrhosis.

Statistical Analysis

Continuous variables were reported as mean (±standard deviation), and categorical variables as percentages. Mean and proportion of abnormal values, differences of baseline ALT, AST, GGT, alkaline phosphatase, total and direct bilirubin, IgG, albumin, alpha-fetoprotein, rheumatoid factor and platelets and the most recent follow-up values were compared via paired student's t-test for continuous variables or McNemar's test for categorical variables. As a sensitivity analysis, regression analysis was used to explore the effect in time between baseline to follow-up and mean differences between baseline and follow-up values. Cumulative incidence of relapse was plotted using the Kaplan–Meier method. In comparing pre-treatment liver biopsy scores with follow-up TE, the McNemar's exact test for association was used. Significance was accepted at a P-value of less than 0.05. Data analysis was performed using sas, Version 9.1.3 (SAS Institute Inc., Cary, NC, USA) software.


Among 262 patients treated in five clinical research protocols between 1984 and 2003, 103 had an SVR and comprised the analysis cohort for this study. These patients were followed up for a median time of 7.5 years (6 months to 23 years) after SVR and 89 were seen and evaluated after 2007. The duration of follow-up after SVR was less than 5 years in 27 patients, 5–10 years in 58 patients, and greater than 10 years in 12 patients. Of this cohort, three patients were found to be HCV RNA positive at the time of follow-up and were considered late relapsers. The estimated time to relapse was 0.67, 6.3 and 6.5 years after stopping therapy. Thus, the relapse free rate was 96% at an average of 7.6 years after therapy (Figure 1). The three HCV RNA positive patients appeared to have suffered a relapse rather than re-infection, as the recurrent virus was almost identical to the pre-treatment sequence strains (Supplemental Table S1, published online).[34] None had ongoing risk factors for hepatitis C or a clear predisposition for relapse (i.e. corticosteroids, chemotherapy or immunosuppression).


Figure 1.

Kaplan–Meier analysis of proportion of patients without virological relapse. Three of 103 patients became HCV RNA positive after having achieved an SVR after interferon-based therapy. At 7.2 years, the relapse free rate was 96%.

The remaining 100 patients included 56 men and 44 women, 88 whites, 4 African Americans and 8 Asians, with an average age of 55.6 years (). Twenty-one received standard interferon alone, 55 interferon and ribavirin and 24 peginterferon and ribavirin.

Table 1. Clinical features of 100 patients with sustained virological response

Feature Number
Number of men/women (%) 56(56%)/44(44%)
Median duration of follow-up in years (range) 7.5 (0.6–23.0)
Mean age at last visit (range) in years 55.6 (16.7–84.2)
Number of deaths/liver-related deaths 6/1
Number of Caucasians (%) 88 (88%)
Number of African Americans (%) 4 (4%)
Number of Asians (%) 8 (8%)
Number of patients with HCV genotype (%)
1 45 (45%)
2 35 (35%)
3 18 (18%)
Others 2 (2%)
Number of patients with pre-treatment Ishak fibrosis score (%)
0–2 62 (64%)
3–4 25 (26%)
5–6 10 (10%)
Number of patients undergoing treatment (1985–2003) (%)
Interferon alfa-2b 21 (21%)
Interferon alfa-2b & Ribavirin 55 (55%)
Peginterferon alfa-2a & Ribavirin 24 (24%)

In follow-up, six of the 100 patients died but only one died of a HCV-related cause, hepatocellular carcinoma resulting in death 12.5 years after SVR. This patient had biopsy proven cirrhosis before the course of therapy with interferon and ribavirin that led to an SVR. The causes of death in the remaining five patients included Huntington's chorea, cerebrovascular disease, septicaemia from chronic osteomyelitis, pneumonia and cardiac arrest all of which occurred more than a year after therapy and none of which were considered related to hepatitis C or its treatment. No patient developed decompensated liver disease, jaundice, ascites, variceal haemorrhage, hepatic encephalopathy or required liver transplantation.

Follow-up testing was available from all patients 12–264 months after completion of therapy. Serum ALT levels were normal in 90% and the average value was 27 U/L, which was significantly less than before therapy (152 U/L) ( and ). Of the remaining 10% of patients with abnormal follow-up ALT levels, values were minimally or modestly elevated and were less than twice the upper limit of the normal range in nine. All 10 patients with ALT elevations had gained weight; four were overweight and five were obese. Abdominal ultrasound demonstrated steatosis in all six who underwent imaging during follow-up (Supplemental Table S2, published online).

Table 2. Mean results of routine laboratory values taken before therapy and at the time of last follow-up evaluation

Laboratory test Initial value (range) Final value (range) P-value
ALT (U/L) 152 (16–459) 27 (10–72) <0.0001
AST (U/L) 87 (18–296) 24 (14–44) <0.0001
GGT (U/L) 47 (11–176) 28 (5–91) <0.0001
ALP (U/L) 78 (37–237) 69 (28–238) <0.0001
Total bilirubin (mg/dL) 0.7 (0.3–2.3) 0.8 (0.1–2.7) 0.055
Albumin (g/dL) 4.2 (3.0–5.0) 4.1 (3.1–5.2) 0.016
Alpha-fetoprotein (ng/mL) 4.6 (1.2–26.6) 2.9 (1.2–9.0) <0.0001
IgG (mg/dL) 1463 (518–2580) 1113 (605–2090) <0.0001
Platelets (×1000/μL) 209 (73–384) 239 (56–457) <0.0001

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.

Analysis by paired student's t-test.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test Percentage abnormal P-value
Initial Final
ALT 83 10 <0.0001
AST 79 5 <0.0001
Direct bilirubin 47 26 0.048
Rheumatoid factor 38 19 0.0043
Platelet count 24 10 0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.

At the time of final follow-up there were also significant improvements in mean AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), alpha-fetoprotein (4.6–2.9 ng/mL), GGT (47–28 U/L), platelet count (209 000–239 000/μL) and rheumatoid factor (38–19% positive). Based on sensitivity analysis using regression models, patients with longer duration of follow-up had greater mean changes of ALT, AST, total and direct bilirubin, IgG and albumin values between baseline and follow-up (data not shown). Serum total bilirubin and albumin levels did not change appreciably, but were largely normal even before therapy. Direct bilirubin improved slightly although not significantly overall. Before therapy, 47% of patients had a direct bilirubin level of greater than 0.2 mg/dL (range: 0.0–0.4 mg/dL); at the time of last follow-up testing, only 26% had abnormal values (range: 0.1–0.4 mg/dL) (). On follow-up evaluation, no patient had an abnormal prothrombin time. Because the methodology and normal range for the prothrombin time varied over the period of observation, a comparison of initial and final values was not possible.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test Percentage abnormal P-value
Initial Final
ALT 83 10 <0.0001
AST 79 5 <0.0001
Direct bilirubin 47 26 0.048
Rheumatoid factor 38 19 0.0043
Platelet count 24 10 0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.

The calculated APRI was elevated (>0.8) in 53% of patients before treatment and averaged 1.31. In follow-up, the APRI was normal in all patients and averaged 0.33, which was significantly less than pre-treatment values (P < 0.001) (Figure 2).


Figure 2.

Mean platelet counts (a) and AST-to-platelet ratio index values (APRI: b) before therapy (Pre-Tx) and at the time of last follow-up evaluation in 100 patients with a sustained virological response stratified by degree of hepatic fibrosis on pre-treatment liver biopsy. Patients were categorised into three groups based upon pre-treatment Ishak fibrosis scores of 0–2 (no fibrosis to portal fibrosis only), 3–4 (bridging hepatic fibrosis) and 5–6 (early and complete cirrhosis).

Transient elastography was attempted in 75 patients at follow-up, but was successful in only 69 (). In this group, 59% had stiffness scores of ≤7.0 kPA (considered normal), 32% had values between 7.1 and 13.8 (suggestive of moderate to advanced fibrosis), and 9% had values above 13.8 kPA (suggestive of cirrhosis).

Table 4. Association of initial Ishak fibrosis score from initial, pre-treatment liver biopsy and transient elastography stiffness score at the time of final follow-up evaluation

Baseline Ishak score Number of patients Fibroscan on follow-up P-value
≤7.0 7.1–13.8 >13.8
0–2 45 28 (62%) 16 (36%) 1 (2%) 0.0006
3–4 17 12 (71%) 4 (23%) 1 (6%)
5–6 7 1 (14%) 2 (29%) 4 (57%)
Total 69 41 (59%) 22 (32%) 6 (9%)

Analysis by McNemar's test.

Liver biopsy had been performed on 97 patients before therapy and demonstrated cirrhosis (Ishak fibrosis 5–6) in 10, bridging fibrosis (Ishak 3–4) in 25 and no fibrosis or portal fibrosis only (Ishak 0–2) in 62. Analysis of TE stiffness values by initial hepatic fibrosis scores demonstrated that most patients (6 of 7) with pre-treatment cirrhosis had high TE values at follow-up 3.1–23 years after an SVR. In contrast, abnormal TE values were found in only 38% of those with minimal fibrosis and 29% with bridging fibrosis before treatment.

Platelet counts were low (<160 000/μL) in 24% of patients before therapy including 80% of those with cirrhosis. In follow-up, the average platelet count in the 100 patients increased (from 209 000 to 239 000/μL) and was in the normal range in 90% ( and ). Platelet counts were generally normal in patients with no or mild fibrosis before therapy but even in these individuals, the average platelet count increased after SVR. Improvement in platelet count was most marked in patients with cirrhosis (123 000–164 000/μL) and also increased similarly in those with moderate to advanced fibrosis (204 000–241 000/μL) (Figure 2a). Importantly, the platelet count at the time of TE evaluation correlated with liver stiffness scores. Thus, the average platelet count in patients with normal TE scores was 219 902/μL, compared with 212 455/μL in those with TE scores between 7.1–13.8 and 147 333/μL in those with TE scores in the cirrhotic range of >13.8 kPA (P = 0.0248). In contrast, the APRI values correlated with the degree of hepatic fibrosis as assessed by liver biopsy before treatment, but were within the normal range in all patients at the time of follow-up evaluation regardless of initial Ishak scores or follow-up TE values (Figure 2b).

Table 2. Mean results of routine laboratory values taken before therapy and at the time of last follow-up evaluation

Laboratory test Initial value (range) Final value (range) P-value
ALT (U/L) 152 (16–459) 27 (10–72) <0.0001
AST (U/L) 87 (18–296) 24 (14–44) <0.0001
GGT (U/L) 47 (11–176) 28 (5–91) <0.0001
ALP (U/L) 78 (37–237) 69 (28–238) <0.0001
Total bilirubin (mg/dL) 0.7 (0.3–2.3) 0.8 (0.1–2.7) 0.055
Albumin (g/dL) 4.2 (3.0–5.0) 4.1 (3.1–5.2) 0.016
Alpha-fetoprotein (ng/mL) 4.6 (1.2–26.6) 2.9 (1.2–9.0) <0.0001
IgG (mg/dL) 1463 (518–2580) 1113 (605–2090) <0.0001
Platelets (×1000/μL) 209 (73–384) 239 (56–457) <0.0001

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.

Analysis by paired student's t-test.

Table 3. Proportion of patients with abnormal laboratory results before therapy and at the time of last follow-up evaluation

Laboratory test Percentage abnormal P-value
Initial Final
ALT 83 10 <0.0001
AST 79 5 <0.0001
Direct bilirubin 47 26 0.048
Rheumatoid factor 38 19 0.0043
Platelet count 24 10 0.001

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Analysis by McNemar's test.


The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment.[26] These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.[28] Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some.[35] After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease. These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease.

Similar findings after SVR in chronic HCV have been published in other cohorts.[15–20, 36–39] However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C.[19, 20, 36, 37] Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment.

A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation.[27] However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy.

Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis.[5–7, 27] For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions.

Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment. This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment.

In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.

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Guarantor of the article
Christopher Koh.

Author contributions
Study concept & design: CK, TH, JHH; Acquisition of data: CK, TH, VH, JJF, YR, MGG, TJL, JHH; analysis/interpretation: CK, DEK, KH, TH, JHH; Drafting: CK; Critical revision: TH, VH, KH, JJF, XZ, DEK, JHH, MGG, YR, TJL; Statistical analysis: CK, XZ; Technical Support: None; Supervision: JHH, TH, TJL.

All authors approved the final version of the manuscript.

Aliment Pharmacol Ther. 2013;37(9):887-894. © 2013 Blackwell Publishing