HCV Research and News

December 29, 2013

Immunological alterations in hepatitis C virus infection

World J Gastroenterol 2013 December 21; 19(47): 8916-8923

Vincenza Calvaruso, Antonio Craxì, Gastroenterologia and Epatologia, DIBIMIS, Università di Palermo, 90127 Palermo, Italy

Author contributions: Both authors contributed equally to this paper.

Correspondence to: Vincenza Calvaruso, MD, PhD, Gastroenterologia and Epatologia, DIBIMIS, Università di Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy. vincenza.calvaruso@unipa.it

Telephone: +39-91-6552280 Fax: +39-91-6552156

Received July 31, 2013; Revised October 23, 2013; Accepted November 12, 2013;

Abstract

A higher prevalence of immunological processes has recently been reported in patients with hepatitis C virus (HCV) infection, focusing the attention of physicians and researchers on the close association between HCV and immune disorders. HCV lymphotropism represents the most important step in the pathogenesis of virus-related immunological diseases and experimental, virologic, and clinical evidence has demonstrated a trigger role for HCV both in systemic autoimmune diseases, such as rheumatoid arthritis, Sjögren syndrome, hemolytic anemia and severe thrombocytopenia, and in organ-specific autoimmune diseases, such as autoimmune hepatitis, thyroid disorders and diabetes. This review will outline the principal aspects of such HCV-induced immunological alterations, focusing on the prevalence of these less characterized HCV extrahepatic manifestations.

Keywords: Hepatitis C virus, Immune disorders, Cytopenia, Extrahepatic manifestation, Autoantibody

Core tip: Hepatitis C virus (HCV)-infected lymphoid tissue of the host represents a site for the persistence of HCV infection which exerts a chronic stimulus to the immune system, facilitating clonal B-lymphocyte expansion and consequent wide autoantibody production, including cryo- and non-cryo-precipitable immune complexes which may lead to organ- and non-organ-specific immunological alterations. This review outlines the principal aspects of such HCV-induced immunological alterations, focusing on the prevalence of these less characterized HCV extrahepatic manifestations.

INTRODUCTION

Autoimmunity and viral infections are closely related, and the hepatitis C virus (HCV), is recognized as one of the viruses most often associated with autoimmune features. For this reason HCV is not only associated with chronic hepatic inflammation but also an array of extrahepatic complications. In the majority of these associated extrahepatic manifestations, the pathogenic mechanism appears to be immunologically driven, with many having features of autoimmunity. HCV infection has been associated with both organ-specific [thyroiditis, diabetes, autoimmune hepatitis (AIH)] and systemic autoimmune diseases and this association has generated growing interest in recent years since it is often observed in patients with chronic HCV infection.

PATHOGENESIS OF HCV RELATED IMMUNE DISORDERS

HCV lymphotropism represents the most relevant step in the pathogenesis of virus-related immunological disorders[¹]. Indeed, infected lymphoid tissue of the host represents a site for the persistence of the HCV infection[²^-⁶]. HCV exerts a chronic stimulus to the immune system, facilitating the clonal B-lymphocyte expansion and consequent wide autoantibody production, including cryo- and non-cryoprecipitable immune complexes[³^,⁷^-⁹] which may lead to organ- and non-organ-specific immunological alterations[³^,⁷^,⁸^,¹⁰]. The first step is translocation, demonstrated in a high percentage of HCV-infected patients, with consequent Bcl-2 proto-oncogene activation, antiapoptotic activity and prolonged survival of lymphocytes[³^,⁷^,⁹^,¹⁰]. Besides, the identification of HCV envelope protein E2 able to bind the CD81 molecule expressed on both hepatocytes and B-lymphocytes seems to be crucial for HCV-driven autoimmunity[³^,⁷^,⁹^,¹⁰].

Dysregulation of cytokine networks skewing regulatory T-cells to a Th2 phenotype, which may be associated with enhanced humoral immune responses and autoantibody production has also been related to the expansion of autoantibody-producing B-cells and chronic lymphoproliferation in HCV infection[¹¹]. HCV infections induce a massive chemokine and cytokine burst and therefore recruit leukocytes to the site of infection with the goal to stop viral spread. This excitation of the human defense system could stimulate a potentially self-reactive lymphocytes inducing autoimmunity in susceptible individuals[¹¹].

Many studies have linked Th1 immune response with HCV infection[¹²], mixed cryoglobulinemia (MC)[¹³] and organ specific autoimmune disorders[¹⁴]. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological base of the association of autoimmunity related HCV infections.

Several studies have shown an increased expression of interferon-gamma (IFN-γ), and IFN-γ inducible chemokines (C-X-C motif chemokine 10 - CXCL10), in hepatocytes and in lymphocytes of HCV-infected patients[¹²^,¹⁵^,¹⁶], which are directly related to the degree of inflammation and an increase in circulating levels of IFN-γ and CXCL10[¹⁷^,¹⁸].

Furthermore, it has been shown that NS5A and core proteins, alone or by a synergistic effect with Th1 cytokines [IFN-γ and tumor necrosis factor-α (TNF-α)], are capable of upregulating CXCL10 and monokine induced by gamma interferon (MIG) gene expression and secretion in cultured human hepatocyte derived cells. These data suggest that CXCL10 produced by HCV-infected hepatocytes could play a key role regulating T-cell trafficking into a Th1-type inflammatory site by recruiting Th1 lymphocytes, that secrete IFN-γ and TNF-α, with a synergistic effect on CXCL10 secretion by hepatocytes, thus perpetuating the immune cascade[¹⁹].

HCV AND SYSTEMIC AUTOIMMUNE DISEASES

Mixed cryoglobulinemia

MC is the most well documented extrahepatic manifestation of HCV infection[²^,²⁰]. MC, which is defined by documenting cryoprecipitates in serum (Ig precipitates from serum at temperatures under 37 °C and dissolves upon re-warming), is characterized by the presence of circulating immunocomplexes produced by a benign proliferation of B-cells. MC represents the link between HCV and various autoimmune and lymphoproliferative disorders. Although serum cryoglobulins (CGs) are frequently present in patients with chronic HCV[³^-⁵^,²¹^,²²], in many of them CGs are present at low levels and symptoms are often absent or very mild. Only about 5% of HCV-infected subjects have clinically overt MC syndrome.

HCV-related arthritis

Chronic oligo-polyarthritis during chronic HCV infection is often associated with MC but can also represent an independent entity. Indeed, it is not rare to observe a simple association between HCV infection and classical rheumatoid arthritis (RA) that can co-exist by chance or can be related to the ability of HCV to act as a trigger of the immune disease in individuals genetically predisposed to RA.

A polyarthritis, which is often non-erosive and rarely progressive, and involves small joints is the most common kind of arthritis associated with HCV chronic infection without the coexistence of cryoglobulinemia. Instead, 40%-80% of HCV-infected patients with MC[²³] are reported to have a bilateral and symmetric arthralgia, which is non-deforming and includes mainly the knees and hands, and, more seldom, the elbows and ankles. Rheumatoid factor (RF) activity is found in 70%-80% of MC patients but is not correlated with the presence of articular disease, as patients chronically infected with HCV in the absence of HCV-MC or RF may have prominent articular symptoms. Usually there is no evidence of joint destruction, and antibodies to cyclic citrullinated peptide, which are highly specific to rheumatoid arthritis, are absent[²⁴]. These evidences suggest that HCV infection should be considered in the differential diagnosis of patients with atypical arthritis.

Sjögren syndrome

Another autoimmune condition associated with HCV is a chronic lymphocytic sialoadenitis similar to sialoadenitis associated with idiopathic Sjögren syndrome (SS), which has been reported in approximately 50% of patients with HCV infection[²⁵].

Some authors have distinguished the HCV-related sicca syndrome from Sjogren’s syndrome based on several differences, including absence of anti-SSA and anti-SSB antibodies, pericapillary and non pericanalary lymphocytic infiltration, lack of glandular canal damage, high prevalence of mixed cryoglobulinemia (50%), hypocomplementemia (51%), and systemic vasculitic manifestations (58%)[²⁵^-²⁸]. Moreover, the lymphocytic type of the infiltrate in the minor salivary gland shows a predominance of CD8 lymphocytes which is not observed in primary SS[²⁹]. Although the possible etiopathogenetic role of HCV in SS remains a controversial issue[²⁷], the explanation for this extrahepatic manifestation could be a cross reactivity between the HCV envelope and host salivary tissue which lead to an immune reaction directed against salivary glands[²⁶]. The correct classification of patients with sialoadenitis related to HCV chronic infection have important clinical, prognostic and therapeutic implications since it may evolve into a B cell malignant lymphoma, especially in the presence of MC[¹⁰^,³⁰].

HCV related cardiac disorders

Several observations suggest that HCV infection is an important cause of a variety of otherwise unexplained heart diseases. Indeed, it was reported that (+) or (-) chain HCV-RNAs can be detected in the biopsied myocardial tissue or in the autopsied heart suggesting that HCV might proliferate in the myocardium[³¹], resulting in induction of cardiomyopathy. Frustaci et al[³²] have shown that HCV replicates in myocardial tissue of patients with myocarditis, and that HCV infection may contribute to the development of an autoimmune myocarditis, frequently associated with myocardial antibodies and responsive to immunosuppressive therapy. In 2000, Matsumori suggested that some specific HCV clones with high affinity for the heart can develop and cause cardiomyopathy[³³] and in 2006, in a large study involving more than 1000 patients, the same group identified anti-HCV antibodies, HCV RNA, NT-proBNP, and cardiac troponin I and T in sera stored for up to 17 years, and found the anti-HCV antibodies were more prevalent in patients with myocarditis than in the general US population[³⁴]. These results suggest that in regions where its prevalence is high, HCV infection may be an important cause of myocarditis and heart failure. Moreover, the same authors concluded that NT-proBNP is a more sensitive marker of myocardial injury than cardiac troponins in patients with heart failure from HCV myocarditis. More recently, other studies confirmed that NT-proBNP is a sensitive biomarker for identifying patients with heart failure caused by HCV-related myocarditis[³⁵^,³⁶]. Antonelli et al[³⁶] assessed serum NTproBNP in 50 HCV-positive patients and in 50 sex- and age-matched controls. HCV patients showed significantly higher mean NT-proBNP level than controls[³⁵]. This result was confirmed by the same group in another study where TNF-α was also found to be higher in HCV+ patients with respect to controls, suggesting the presence of subclinical cardiac dysfunction[³⁶].

AUTOIMMUNE CYTOPENIAS IN PATIENT WITH HCV INFECTION

Hemolytic anemia and severe thrombocytopenia were the most frequent cytopenias observed in patients with HCV infection. The different types of immune-mediated cytopenias may be severe and clinically significant.

Hemolytic anemia

Although autoimmune hemolytic anemia (AHA) has frequently been reported in association with HCV in the setting of interferon (IFN) treatment[³⁷^,³⁸], it has also been observed as an isolated extrahepatic manifestation. The existence of AHA in patients with chronic hepatitis was first described in 1951, when Hyman et al[³⁹] described AHA in 3 patients with chronic liver involvement. In 1973, Panush et al[⁴⁰] described a patient with chronic active hepatitis who presented with AHA with a positive Coombs test, who responded to treatment with steroids. In 1982, Portell et al[⁴¹] reported 5 patients with chronic hepatopathy (3 with active chronic hepatitis and 2 with cirrhosis) and a positive Coombs AHA, with positive ANA in 4 and sicca syndrome in 1. In 2001, 2 cases of HCV infection associated with Coombs-positive AHA, in the absence of treatment with IFN, were reported by Srinivasan[⁴²] and Chao et al[⁴³], respectively. In 2003, Ramos-Casals et al[⁴⁴] presented the largest series of cases of HCV-related AHA not treated with antiviral therapy. Seventeen HCV patients, mostly women with a mean age of 56 years, presented a high level of association with autoimmune diseases, with cryoglobulinemia as the most frequent immunologic marker. Most patients had a history of liver cirrhosis and even if they had a good response to corticosteroids, the prognosis was poor (56% mortality).

HCV-associated immune thrombocytopenic purpura

Although thrombocytopenia during the course of chronic liver disease is usually attributed to hypersplenism, an autoimmune mechanism has been suggested as playing a role in some patients with HCV infection. This hypothesis is based on the observation of a greater prevalence of thrombocytopenia and antiplatelet antibodies in HCV patients compared with HBV patients[⁴⁵], and of the frequency of HCV infection seen among patients initially diagnosed with idiopathic thrombocytopenic purpura (ITP)[⁴⁶^-⁴⁸]. The pathophysiology of infection-related ITP involves diverse immunologic pathways as well as nonimmune mechanisms that accelerate platelet destruction and/or decrease platelet production.

High affinity binding of HCV to the platelet membrane with subsequent binding of anti-HCV antibody might lead to phagocytosis of platelets[⁴⁹]. Dysregulation of the host immune system triggering the production of autoantibodies against platelet glycoproteins has also been postulated[⁴⁵^,⁵⁰]. However there have been conflicting data on the presence of specific antibodies in platelets in patients with HCV-related ITP[⁴⁵^,⁵⁰^-⁵²].

Thrombocytopenia in HCV patients may be present even in the absence of clinically evident liver disease or splenomegaly and may be mistakenly diagnosed as primary chronic immune thrombocytopenic purpura (CITP)[⁴⁸^,⁵³]. Six cross-sectional studies have reported serologic evidence of HCV infection in 20% of patients with a clinical diagnosis of CITP[⁴⁸^,⁵³^-⁵⁷], and in the largest series published to date, HCV antibodies were identified in 30% of 250 patients fulfilling the American Society of Hematology criteria for CITP[⁵⁴]. There were significant differences in the demographic characteristics of patients with HCV-positive compared with patients with HCV-negative CITP. Patients positive for HCV were older and the incidence was distributed equally between the sexes compared with the female predominance in HCV-negative CITP.

ORGAN-SPECIFIC AUTOIMMUNE DISEASES

Thyroid disorders and HCV

Autoimmune thyroid involvement and hypothyroidism were significantly more frequent in patients with chronic hepatitis C (CHC) than in comparison groups such as patients with viral hepatitis B or D[⁵⁸^-⁶⁰] or normal subjects[⁶¹^,⁶²]. The most frequent thyroid disorder in this setting is the presence of circulating anti-thyroid antibodies which is more commonly reported in female subjects[⁵⁸]. The prevalence of abnormally high levels of anti-thyroid antibodies observed in these patients ranges from 2% to 48%[⁵⁸^,⁶¹^,⁶³^,⁶⁴], with heterogeneous geographic distribution[⁶⁵]. These discrepancies are related to variable genetic predisposition and environmental co-factors, such as iodine intake or other infectious agents[⁶⁶]. The evidence of a subclinical hypothyroidism was observed in 2%-9% of patients with chronic HCV infection, particularly in those patients with MC[⁵⁹^,⁶⁰^,⁶²^,⁶³^,⁶⁷], and these patients seem to be susceptible to Hashimoto’s autoimmune thyroiditis and Grave’s disease when treated with interferon.

Antonelli et al[²¹] in 2004 analyzed 630 consecutive patients affected by CHC compared with a large control group of subjects from iodine-deficient and sufficient areas and with 86 patients with chronic hepatitis B. They demonstrated that patients with CHC were more likely to have hypothyroidism, anti-thyroglobulin and anti-thyroid peroxidase antibodies than any of the other groups. The same group evaluated thyroid function, the presence of thyroid autoantibodies, thyroid nodules and thyroid cancer, in 93 HCV + MC consecutive patients matched by sex and age to 93 patients with CHC without MC and 93 healthy (HCV-negative) controls. Subclinical hypothyroidism and thyroid autoimmunity were significantly more frequent in HCV + MC patients than in HCV-negative controls. Moreover, serum thyroid peroxidase antibodies were also significantly more frequent in HCV + MC patients than in CHC patients. Finally, the prevalence of thyroid nodules was not significantly different in the three groups[⁶⁸]. In conclusion, pooling all data about HCV-positive patients (with CHC or HCVAb positivity) and using as control healthy subjects and HBV-infected patients, there was a significant increase in the prevalence of both thyroid autoimmune disorders (OR = 1.6; 95%CI: 1.4-1.9) and hypothyroidism (OR = 2.9; 95%CI: 2.0-4.1)[⁶⁹].

Some authors have reported that patients with chronic HCV have a higher prevalence of papillary thyroid carcinoma[⁷⁰^,⁷¹]. In 2002, the prevalence of thyroid cancer in a series of 94 HCV-related mixed cryoglobulinemic patients was investigated[⁷⁰]. A control group was obtained from a sample of the general population (2401 subjects) who had undergone thyroid ultrasonography. The prevalence of thyroid nodules was higher, although not significantly so, in control subjects than in MC patients but 2 patients with papillary thyroid cancer were found in the MC series, while no case was observed among controls.

A more recent study[⁷¹] prospectively investigated the prevalence and features of thyroid cancer in 308 patients with CHC in comparison with 2 large sex- and age-matched control groups from the general population with different iodine intake. Thyroid status was assessed by measurement of circulating thyroid hormones and autoantibodies, thyroid ultrasonography, and, when indicated, fine-needle aspiration cytology. The authors have found that circulating thyrotropin, anti-thyroglobulin, and anti-thyroperoxidase antibodies levels, and the prevalence of hypothyroidism were significantly higher in HCV patients and 6 cases of papillary thyroid cancer were detected among HCV patients, whereas only 1 case was observed in controls, suggesting a high prevalence of thyroid papillary cancer in HCV patients. Because of this high prevalence of thyroid disorders, the guidelines on management of CHC recommend investigation of thyroid function, including free T4 and TSH in all patients, and since interferon-based therapy could exacerbate thyroid dysfunction, thyroid function tests should be fully evaluated prior to initiating HCV treatment.

Diabetes mellitus and HCV

Data from the literature have shown a higher incidence of type 2 diabetes mellitus with chronic HCV when compared with patients with other liver disorders[⁷²^-⁷⁴]. In a large study[⁷⁵] involving 229 consecutively recruited MC-HCV patients compared with 217 sex- and age-matched controls without HCV infection, the prevalence of type 2 diabetes was significantly higher in MC-HCV patients than in controls. Moreover, MC-HCV diabetic patients more often had non-organ-specific autoantibodies than non-diabetic MC-HCV patients.

Another study conducted in 2005 by the same group[²²], established the prevalence and clinical phenotype of type 2 diabetes in a large series of non-cirrhotic HCV patients. The prevalence of type 2 diabetes was significantly higher in HCV patients compared with control subjects or non-cirrhotic HBV patients. Moreover, type 2 diabetic HCV patients had a significantly lower BMI than type 2 diabetic control subjects and significantly higher BMI than non-diabetic HCV patients. In contrast, no association with diabetes mellitus type 1 has been identified[²²^,⁷²^,⁷³^,⁷⁶^-⁷⁸]. The association between chronic HCV and diabetes mellitus seems to be independent of the severity of the liver disease and is associated with insulin-resistance, but not with the presence of pancreatic anti-insulin antibodies[⁷⁹]. In contrast, interferon treatment of HCV has been associated with the appearance of diabetes mellitus type 1 and development of anti-pancreas autoimmunity[⁸⁰^-⁸²].

AIH and HCV infection

Finally, an intriguing, still controversial aspect is the possible etiopathogenetic role of HCV in AIH[³^,⁶^,⁸^,⁹^,⁶⁵]. Patients with AIH may present with mixed cryoglobulins, HCV infection, and extrahepatic manifestations such as thyroiditis, sicca syndrome, and arthritis[⁶], while patients with HCV infection show one or more non-organ-specific auto-antibodies. The antigenic target specificity of HCV-related autoantibodies shows only quantitative differences compared with those associated with “primary” AIH[⁸].

In clinical practice, the search for serum autoantibodies should be limited to cases for whom treatment with IFN is planned. An exception may be cases where clinical data (female gender, young age), high biochemical activity (transaminase-globulins) and histological aspects (interfaces hepatitis) of liver disease may suggest the presence of AIH with superimposed HCV infection.

The heterogeneous geographical distribution of HCV-associated AIH[⁶⁵] suggests a possible involvement of various pathogenetic co-factors; among these, HCV might trigger a particular AIH clinico-serological subset, which is prevalent in specific geographical areas.

CONCLUSION

In the case of patients with chronic HCV infection, the possible existence of extrahepatic manifestations should be taken into account and an accurate analysis of clinical and anamnestic data is recommended. Some patients may display the entire complex spectrum of HCV-related disorders which could be mild for many years and progress, generally during a long follow-up, to more severe systemic manifestations. In the last few years, very consistent data have been accumulated through different in vivo and in vitro models, suggesting that a more accurate characterization of the modalities and consequences at the molecular level of HCV infection of lymphatic cells may be of great importance in the future for the clarification of the pathogenesis of several pathological manifestations of HCV.

Footnotes

P- Reviewers: Kato T, Seya T, Tetsuya T S- Editor: Zhai HH L- Editor: Cant MR E- Editor: Liu XM

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68. Antonelli A, Ferri C, Fallahi P, Giuggioli D, Nesti C, Longombardo G, Fadda P, Pampana A, Maccheroni M, Ferrannini E. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM. 2004;97:499-506. [PubMed] [DOI]

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72. Caronia S, Taylor K, Pagliaro L, Carr C, Palazzo U, Petrik J, O’Rahilly S, Shore S, Tom BD, Alexander GJ. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;30:1059-1063. [PubMed] [DOI]

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Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

World J Gastroenterol 2013 December 28; 19(48): 9328-9333

Arvind Reddy, Elizabeth May, Murray Ehrinpreis, Milton Mutchnick, Division of Gastroenterology, Wayne State University, Detroit, MI 48201, United States

Author contributions: All the authors contributed to this manuscript.

Correspondence to: Arvind Reddy, MD, Division of Gastroenterology, Wayne State University, 6-Hudson c/o Milton Mutchnick, MD 3990 John R, Detroit, MI 48201, United States. areddygi@yahoo.com

Telephone: +1-313-5772424 Fax: +1-313-5772233

Received August 9, 2013; Revised August 21, 2013; Accepted September 4, 2013;

Abstract

AIM: To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).

METHODS: This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease. Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-) age, race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC. A subgroup of controls included 118 matched patients with liver cirrhosis. χ² test and ttest were used for data analysis.

RESULTS: Seventy-seven percent of patients in all 3 groups were African Americans. Patients with HCC had a significantly higher body mass index (P = 0.03), a higher rate of co-infection with human immunodeficiency virus (HIV) (P = 0.05) and a higher prevalence of alcohol abuse (P = 0.03) than the controls. More patients with HCC had LHB than controls (78% vs 39%, P = 0.01). Sixty three percent of patients with HCC were both hepatitis B surface antigen (HBsAb)(-) and HBcAb(+) compared to 23% of controls (P < 0.01). When compared to cirrhotic controls, the frequency of HBcAb(+) remained higher in patients with HCC (78% vs 45%, P = 0.02). Patients with HCC were more likely to be both HBsAb(-) and HBcAb(+) than the cirrhotic controls (63% vs 28%, P = 0.01). Although not statistically significant, 100% of CHC and HIV co-infected patients with HCC (n = 11) were HBcAb(+) when compared to controls (44%; n = 9).

CONCLUSION: These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.

Keywords: Hepatocellular carcinoma, Chronic hepatitis C, Latent hepatitis B, Hepatitis C virus

Core tip: Latent hepatitis B (LHB) has recently received significant attention among researchers and clinicians managing chronic liver disease. It is defined as a combination of hepatitis B surface antigen negative and hepatitis B core antibody positive. The potential association of LHB with hepatocellular carcinoma among patients with chronic hepatitis C infection has been studied and reported in this manuscript.

INTRODUCTION

Emerging data suggest that the mortality rate in cirrhotic patients with hepatocellular carcinoma (HCC) is rising whereas the mortality rate from other complications of cirrhosis is either stable or declining[¹]. In the United States, chronic hepatitis C (CHC) accounts for the majority of cases of HCC. Among patients with CHC, factors such as older age, male gender, severity of liver disease, metabolic syndrome and poor response to interferon therapy are established risk factors for hepatocarcinogenesis[¹]. “Latent hepatitis B (LHB)”, defined as the presence of detectable hepatitis B core antibody (HBcAb) with undetectable hepatitis B surface antigen (HBsAg)(-) in serum and usually with detectable HBV DNA in hepatocytes, has not been studied as a risk factor for HCC in the United States[²]. Patients with previous exposure to hepatitis B virus but with no evidence of chronic infection are HBsAg(-) and HBcAb(+). This finding alone is now considered as unrecognized LHB[³]. In a large study, the majority of patients with LHB had detectable hepatitis B DNA (HBV DNA) in serum as well as in liver tissue[⁴]. Various other studies have also confirmed the same findings[⁵^,⁶]. This led to the identification of a unique group of patients who are HBcAb(+) and at risk for latent hepatitis B.

Early studies from the 1990s suggested that patients with HCC in the absence of chronic hepatitis B and C had detectable covalent closed circular hepatitis B DNA (ccc DNA) in liver parenchyma although they were HBsAg(-) in serum. These patients were considered to have “occult hepatitis B”[⁷]. A single prospective study by Squadrito et al[⁸] revealed that among HBsAg(-) patients with CHC, patients with occult hepatitis B with ccc DNA in liver biopsy specimens were at a higher risk for the development of HCC. With the availability of highly sensitive real-time polymerase chain reaction (PCR) assays for the measurement of HBV DNA, tissue analysis for HBV DNA is largely unnecessary to make a diagnosis of latent hepatitis B[²]. Patients with cirrhosis from alcoholic and non-alcoholic fatty liver disease are also at a significantly higher risk for developing HCC when associated with LHB particularly in those who were HBcAb(+) but HBsAg(-)[⁹]. Injection drug users, patients on hemodialysis, patients with CHC and human immunodeficiency virus (HIV)-infected patients are at increased risk for LHB[¹⁰]. In patients with CHC, occult hepatitis B seems to be associated with rapid progression of liver disease[¹¹]. Studies from areas with high prevalence of chronic hepatitis B have associated occult hepatitis B with HCC among patients with CHC[¹²^,¹³]. This association is much stronger among CHC patients who are non-responders to currently available therapy[¹⁴]. Another study reported that although occult hepatitis B may not have a significant impact on response of CHC to interferon, it does increase the risk for HCC among non-responders but not among responders[¹⁵].

A large multicenter Japanese study concluded that CHC patients with LHB are at a significantly higher risk for developing HCC[¹⁶]. In the same study, interferon was less effective in preventing HCC in patients with LHB when compared to those without evidence of previous HBV exposure. This association was independent of the presence of HBV DNA in serum and therefore, LHB is clinically and prognostically more relevant than serum DNA status.

The above referenced studies establishing LHB as a risk factor for development of HCC are from countries with high endemicity for chronic hepatitis B infection. We studied this potential association among predominantly African American patients with CHC and cirrhosis in an area with low endemicity for chronic hepatitis B.

Continue reading full article here …..

Modeling viral kinetics and treatment outcome during alisporivir interferon-free treatment in HCV genotype 2/3 patients

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Jeremie Guedj^1,2, Jing Yu³, Micha Levi⁴, Bin Li³, Steven Kern⁵, Nikolai V. Naoumov⁵, Alan S. Perelson^2,*

DOI: 10.1002/hep.26989

Publication History

Accepted manuscript online: 23 DEC 2013 03:36AM EST
Manuscript Accepted: 19 DEC 2013
Manuscript Revised: 18 OCT 2013
Manuscript Received: 13 JUL 2013

Abstract

Alisporivir (ALV) is a cyclophilin inhibitor with pan-genotypic activity against hepatitis C virus (HCV). Here we characterize the viral kinetics observed in 249 patients infected with HCV genotypes 2 or 3 and treated for six weeks with different doses of ALV with or without ribavirin (RBV). We use this model to predict the effects of treatment duration and different doses of ALV plus RBV on the sustained virologic response (SVR).

Continuous viral decline was observed in 214 (86%) patients that could be well described by the model. All doses led to a high level of antiviral effectiveness equal to 0.98, 0.96 and 0.90 in patients treated with 1000, 800 and 600 mg ALV once-daily, respectively. Patients that received RBV had a significantly faster rate of viral decline, which was attributed to an enhanced loss rate of infected cells, δ (mean δ=0.35 d^-1 vs 0.21 d^-1 in patients +/- RBV, respectively, P=0.0001). The remaining 35 patients (14%) had a suboptimal response with flat or increasing levels of HCV RNA after one week of treatment, which was associated with ALV monotherapy, high body weight and low RBV levels in patients that received ALV+RBV.

Assuming full compliance and the same proportion of suboptimal responders, the model predicted 71% and 79% SVR following ALV 400 mg with RBV 400 mg twice-daily for 24 and 36 weeks, respectively. The model predicted that response guided treatment could allow a reduction in the mean treatment duration to 25.3 weeks and attain a 78.6% SVR rate.

Conclusion: Alisporivir plus ribavirin may represent an effective interferon-free treatment that is predicted to achieve high SVR rates in patients with HCV genotype 2 or 3 infection. (Hepatology 2013;)

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Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Robert J. Wong M.D.^1,2, Ramsey Cheung M.D.^1,2, Aijaz Ahmed M.D.^1,*

DOI: 10.1002/hep.26986

Publication History

Accepted manuscript online: 25 DEC 2013 09:13PM EST
Manuscript Accepted: 18 DEC 2013
Manuscript Revised: 13 NOV 2013
Manuscript Received: 8 OCT 2013

Keywords: fatty liver; hepatitis C virus; liver cancer; UNOS; alcoholic liver disease

Abstract

Nonalcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the U.S. and is predicted to become the leading indication for LT in the near future. The trends in NASH-related hepatocellular carcinoma (HCC) among LT recipients in the U.S. remain undefined. We performed a retrospective cohort study to evaluate trends in the etiology of HCC among adult LT recipients in the U.S. from 2002 to 2012, utilizing national data from the United Network for Organ Sharing registry. From 2002-2012, there were 61,868 adults who underwent LT in the U.S., including 10,061 patients HCC. The total number and proportion of HCC LT recipients demonstrated a significant increase following the implementation of the model for end stage liver disease (MELD) scoring system in 2002 (3.3%, n=143 in 2000 vs. 12.2%, n=714 in 2005 vs. 23.3%, n=1336 in 2012). The proportion of HCV-related HCC increased steadily from 2002 to 2012, and HCV remained the leading etiology of HCC throughout the MELD era (43.4% in 2002 vs. 46.3% in 2007 vs. 49.9% in 2012). NASH-related HCC also increased significantly, and NASH is the second leading etiology of HCC-related LT (8.3% in 2002 vs. 10.3% in 2007 vs. 13.5% in 2012). From 2002 to 2012, the number of patients undergoing LT for HCC secondary to NASH increased by nearly 4-fold, and the number of LT patients with HCC secondary to HCV increased by 2-fold. Conclusion: NASH is the second leading etiology of HCC leading to LT in the U.S. More importantly, NASH is currently the most rapidly growing indication for LT in patients with HCC in the U.S. (Hepatology 2013;)

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HCV+ Died 23 Yrs Earlier Than Persons without HCV. Blacks Have Double the Rate vs Whites-CDC Study

Provided by NATAP

Download the PDF here

"....Our most significant finding, however, was that among decedents with the same cause of death, persons with hepatitis B or C died about 2 decades younger than persons without these infections. Prevention and early treatment of hepatitis B and C will help prevent these early deaths. Evidence suggests that early therapeutic intervention improves all-cause hepatitis B and C mortality; prevention efforts should be expanded to further (1) promote hepatitis A and B vaccination among recommended target groups, (2) increase hepatitis B and C screening to get more people into care and earlier treatment, and (3) treat alcohol- and drug-related disorders......Our study demonstrated racial/ethnic disparities in deaths with hepatitis C, specifically among American Indians/Alaskan Natives, NH blacks, and Hispanics." (from jules: this study was presented this Fall at conference, I think it was IDSA.

"Among decedents with hepatitis C, the highest mortality rates were observed among persons aged 55-64 years; the American Indian/Alaskan Native, NH black, and Hispanic race/ethnic groups; and males. In comparison, among decedents without viral hepatitis, the highest mortality rates were observed among persons aged ≥75 years, NH blacks, and males."

YOU CAN SEE in Table 1 the rates of mortality in HCV among Blacks (7.87), whites (3.97), hispanics (6.9), American Indian/aAlaska Native 10.07).

(Click on table to enlarge)

Among the 10 most frequently cited causes, deaths listing hepatitis B and C occurred at an average median age of 22-23 years younger than deaths not listing hepatitis B and C......Our analysis of 2010 MCOD data identified 18 473 deaths reported with viral hepatitis. If ranked as a leading cause of death using NCHS's list [25], viral hepatitis would rank as the 15th leading cause of death......Hepatitis C alone was identified as a cause of nearly 90% of these deaths; the majority of those occurred in persons aged 45-64 years.....The disproportionate burden in this age group is consistent with other studies [4, 7, 18]. As a result, in 2012, the CDC recommended 1-time hepatitis C testing for persons born during 1945-1965 (aged 45-65 years in 2010) [26], especially because birth-cohort screening in primary care settings is cost effective [27]. Our study provides evidence that strengthens this national recommendation. Moreover, the well-demonstrated increased mortality of both liver-associated and nonliver-associated conditions in HBV- and HCV-infected decedents provides key evidence to get more people treated before they develop serious illness.......we did find a significant elevated risk of dying with substance-related mental disorders in HCV-infected decedents aged 0-44 years (data not shown).

The most frequently listed category among deaths with either hepatitis B or hepatitis C was fibrosis, cirrhosis, and other liver diseases (45.3% and 48.4%, respectively; Tables 2 and 3)......The most frequently reported nonliver-associated conditions among decedents with either hepatitis B or C were cardiac arrest and ventricular fibrillation, substance-related mental disorders, diabetes mellitus without complication, essential hypertension, and adult respiratory failure insufficiency arrest (8.9%-14.0%). Septicemia (except in labor) was among the top 10 most frequently reported conditions for hepatitis C but not for hepatitis B.

Among decedents aged 45-64 years, the relative risks for conditions associated with a significantly increased risk of dying with hepatitis B ranged from 14.0 (cancer of liver and intrahepatic bile duct) to 2.6 (acute and unspecified renal failure; Table 4). Coronary atherosclerosis and other heart disease and substance-related mental disorders (relative risk, 0.5 and 0.7, respectively) were the 2 conditions associated with a significantly decreased risk of dying with hepatitis B. .....Among the same age group, the relative risks for conditions associated with a significantly increased risk of dying with hepatitis C ranged from 12.0 (cancer of liver and intrahepatic bile duct) to 1.5 (septicemia, except in labor; Table 5).

Causes of Death and Characteristics of Decedents With Viral Hepatitis, United States, 2010

Abstract

Background. Previous research indicates that the mortality burden from viral hepatitis is growing, particularly among middle-aged persons. To monitor progress toward prevention goals, it is important to continue to document characteristics and comortalities of these deaths. This study sought to examine demographic characteristics and the most frequent causes of death among decedents with a viral hepatitis-related death.

Methods. A cross-sectional study was performed on approximately 2.4 million death records from 2010. We calculated mortality rates for decedents with and without hepatitis A, B, and C virus (HAV, HBV, and HCV) and relative risks for the most frequently cited conditions in decedents with and without HBV and HCV.

Results. In 2010, there were 18 473 (0.7%) deaths with HAV, HBV, and HCV listed among causes of death, disproportionately in those aged 45-64 years. Among the 10 frequent causes of death, decedents listing HBV or HCV died, on average, 22-23 years earlier than decedents not listing these infections. HBV- and HCV-infected decedents aged 45-64 years had an increased risk of having the following conditions reported than decedents without these infections: cancer of liver and intrahepatic bile duct; fibrosis, cirrhosis, and other liver diseases; alcohol-related liver disease; gastrointestinal hemorrhage; human immunodeficiency infection; acute and unspecified renal failure; and septicemia (HCV only).

Conclusions. Decedents with other causes of death that include HBV or HCV died 22-23 years earlier than decedents not listing these infections. These data suggest and support the need for prevention, early identification, and treatment of HBV and HCV.

In the United States, hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are nationally notifiable infectious conditions and are routinely reported and monitored through national surveillance [1]. Hepatitis A and acute hepatitis B and C are reportable by law in all states and the District of Columbia; chronic hepatitis B and C are reportable by law in 43 states and the District of Columbia. Reporting of these conditions is based upon standard case definitions established in collaboration with the Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists [2].

While the incidence of hepatitis A, B, and C is at an all-time low [1]-creating the misconception that further prevention efforts are unnecessary-foodborne outbreaks for hepatitis A and healthcare-associated outbreaks for hepatitis B and C continue to occur each year [1]. For hepatitis A, mortality occurs most frequently among persons aged >45 years [1] and persons with underlying chronic liver disease [3]. For hepatitis B and C, mortality occurs most frequently among persons aged 45-64 years [4], and chronic infection accounts for the majority of the total burden. One reason why mortality occurs disproportionately in this relatively younger age group is because up to 65% [5] of the estimated 730 000 [6] US residents with hepatitis B and up to 75% [5] of the estimated 3.2 million [7] US residents with hepatitis C are asymptomatic; many are unaware of their infection [8]. Still, these prevalence estimates, which were obtained from the National Health and Nutrition Examination Survey, are considered conservative because high-risk groups, specifically homeless and institutionalized persons, were not included. Although important for estimating and describing the total burden of disease and for tracking and targeting prevention activities, an analysis describing hepatitis A, B, and C mortality rates by detailed demographic characteristics has not been performed for the United States. Additionally, while hepatitis B and C are well-recognized causes of liver-related disease [9], understanding the effect of these viruses on other frequently occurring comorbidities that lead to death is becoming appreciated [10-13]. Specifically, studies have concluded that HCV infection significantly increased the risk of dying from all causes and nonliver-related causes [10, 11]. Additionally, all-cause mortality among HCV-infected patients in 4 US healthcare networks was nearly 3 times higher than all-cause mortality among HCV-uninfected persons in the noninstitutionalized US population [13]. However, similar studies for hepatitis B have not been performed in a representative US population. Additionally, to our knowledge, this is the first study to document the most common or frequent causes of death among decedents with hepatitis B and C.

Our goal was to use US multiple-cause-of-death (MCOD) data, mainly for hepatitis B and C, from 2010 to (1) characterize the national burden of mortality associated with and without hepatitis A, B, and C by describing incidence rates for select detailed demographic characteristics; (2) compare the most frequently listed causes of death among persons with and without a death associated with hepatitis B and C; and (3) calculate the risk of dying with the most frequently cited conditions among persons aged 45-64 years with a death associated with hepatitis B and C.

METHODS

MCOD Data

This study used the public-use 2010 US MCOD data file, which contains information on all registered deaths occurring within the calendar year [14]. State vital registration offices house these death certificates and, through a cooperative agreement, compile and share this information with the National Center for Health Statistics (NCHS). NCHS then uses this information to generate the annual national multiple-cause mortality datasets.

The conditions on the cause of death section of the death certificate are reported by the decedent's physician, hospital residents, medical examiner, or coroner. The types of causes of death are the underlying, immediate, intermediate, and contributing causes of death that, together, are called the multiple causes of death. In MCOD files, these conditions are translated into International Classification of Diseases, Tenth Revision (ICD-10) [15], codes by highly skilled nosologists at NCHS using 2 schemes: entity axis and record axis. The entity axis represents a direct transcription of each disease entity listed on the cause of death section of the death certificate. The record axis represents a modified version of the entity axis in which repetitive conditions and inconsistencies are removed, related conditions are joined, and coding rules are followed [16]. An example of how conditions are coded is as follows: a death certificate with cirrhosis of liver and alcoholism as causes of death would be directly transcribed to ICD-10 codes K74 (cirrhosis of liver without mention of alcohol) and F10 (alcohol dependence syndrome) as entity axis conditions. These conditions represent separate entities for the same death record. Searching for death records with ICD-10 code K74 would, on the surface, seem that such records had no mention of alcohol. Therefore, a preferable record axis code would be K70.3 (alcoholic cirrhosis of liver), which would encompass both ICD-10 codes K74 and F10.

Definitions

For the purpose of this study, hepatitis A-, B-, and C-related deaths were defined using 2 definitions. First, deaths citing HAV (ICD-10: B15), HBV (ICD-10: B16, B17.0, B18.0, and B18.1), or HCV (ICD-10: B17.1 and B18.2) as the underlying cause or associated cause of death in the record axis was counted. Second, any death with HIV (ICD-10: B20-B24) as the underlying cause and HAV, HBV, or HCV as an associated cause of death in either the record or entity axis was counted. The second definition was implemented to ensure that deaths where coinfection with HIV and viral hepatitis occurred were not excluded due to the frequent reassignment of HIV as the underlying cause of death and the tendency for viral hepatitis to be excluded when translation from entity to record axis occurs [4, 18, 19]. For hepatitis B and C, the decision to combine acute and chronic ICD-10 codes was based on a study that found that chronic hepatitis B and C deaths were often incorrectly coded as acute [20]. The term "viral hepatitis" refers to hepatitis A, B, and C, collectively. The terms "with hepatitis" and "without hepatitis" are used for decedents who had and did not have hepatitis listed as a cause of death, respectively.

Statistical Analyses

Demographic information on age, race/ethnicity, and sex were examined, and mortality rates were calculated from this information. For this analysis (Table 1), deaths listing more than 1 hepatitis infection were assigned a single infection based on a mutually exclusive hierarchy: hepatitis A > hepatitis B > hepatitis C. The hierarchy was based on the need to fully describe characteristics of deaths with hepatitis A and B as hepatitis C carried the highest mortality burden and the degree of co-hepatitis infection was small. Age was divided into the following categories: 0-34, 35-44, 45-54, 65-74, and ≥75 years. Race/ethnicity was classified as Asian/Pacific Islander, American Indian/Alaska native, non-Hispanic (NH) white, NH black, and Hispanic. Mortality rates were calculated using the 2010 US bridged-race approximations [21] and were standardized to the age distribution of the 2000 US standard population [22]. The Poisson distribution was used to estimate the variance for rates and to calculate 95% confidence intervals (CIs) [23].

To determine the most frequently reported causes of death (Tables 2 and 3), ICD-10 codes among deaths with and without hepatitis B and C were isolated from the record axis and classified according to the Clinical Classifications Software (CCS) for ICD-10; this is a well-developed categorization scheme that collapsed approximately 32 000 ICD-10 codes into 260 clinically meaningful and manageable categories [24]. For the CCS category labeled "Other Liver Diseases" in decedents with hepatitis B or hepatitis C, liver fibrosis and cirrhosis (ICD-10, K74) was the most frequently listed; therefore, we renamed this category with the more descriptive label of "Fibrosis, Cirrhosis, and Other Liver Diseases." Liver-associated conditions included the following CCS categories: fibrosis, cirrhosis, and other liver diseases; other hepatitis infections; cancer of the liver and intrahepatic bile duct; alcohol-related liver disease; and gastrointestinal hemorrhage. The median age at death for each of the top 10 CCS categories was examined. Then, the difference was determined by calculating the average of the median ages for the 10 most frequently cited causes among decedents with and without hepatitis B and C and subtracting these 2 averages.

Relative risks were calculated to quantify the risk of dying with the 15 most frequently cited conditions among decedents aged 45-64 years who had hepatitis B and C listed among causes of death. The comparison group was decedents belonging to the same age group who did not have hepatitis B and C listed. For this analysis, we included deaths with either hepatitis B alone or hepatitis C alone (but not those who were coinfected) to remove the effect of potential confounders on the results of deaths with hepatitis B, which accounted for 30% of hepatitis B deaths. We separately compared the relative risks of all deaths with hepatitis B together (hepatitis B alone plus hepatitis B/C coinfected) with hepatitis B alone and found that the magnitude of association of liver-associated and HIV-associated conditions with hepatitis B would be more similar to those of hepatitis C had hepatitis B/C coinfected deaths been included, therefore justifying the removal of the coinfected.

The 95% CIs were used to determine the variance and statistical significance of each relative risk estimate. Data were analyzed using SAS software, version 9.2 (SAS Institute, Cary, NC).

RESULTS

In 2010, 2 472 542 deaths were registered in the United States, of which 18 473 (0.7%) listed hepatitis A, B, or C among causes of death. This implied an age-adjusted mortality rate of 5.2 deaths per 100 000 population (Table 1). Hepatitis A was listed as the underlying cause of 30 deaths (<0.01%) and as any cause of 96 deaths (<0.01%; Figure 1). Hepatitis B was listed as the underlying cause of 589 deaths (0.02%) and as any cause of 1875 deaths (0.08%). Hepatitis C was listed as the underlying cause of 6857 deaths (0.28%) and as any cause of 17 113 deaths (0.69%). Among deaths with hepatitis A, B, or C, 92.6% were with hepatitis C, 10.1% were with hepatitis B, and 0.5% was with hepatitis A. Among deaths with hepatitis C, 3.4% had hepatitis A and/or B. Among deaths with hepatitis B, 1.7% had hepatitis A.

Among decedents with hepatitis A, the highest mortality rates were observed among persons aged ≥45 years and accounted for 89.6% of hepatitis A-related deaths (Table 1). Among decedents with hepatitis B, the highest mortality rates were observed among persons aged 55-64 years, Asians/Pacific Islanders, and males. Among decedents with hepatitis C, the highest mortality rates were observed among persons aged 55-64 years; the American Indian/Alaskan Native, NH black, and Hispanic race/ethnic groups; and males. In comparison, among decedents without viral hepatitis, the highest mortality rates were observed among persons aged ≥75 years, NH blacks, and males.

The most frequently listed category among deaths with either hepatitis B or hepatitis C was fibrosis, cirrhosis, and other liver diseases (45.3% and 48.4%, respectively; Tables 2 and 3). Cancer of the liver, including hepatocellular carcinoma, and intrahepatic bile duct and alcohol-related liver disease were also frequently reported in deaths with hepatitis B and C (11.6%-22.8%). The most frequently reported nonliver-associated conditions among decedents with either hepatitis B or C were cardiac arrest and ventricular fibrillation, substance-related mental disorders, diabetes mellitus without complication, essential hypertension, and adult respiratory failure insufficiency arrest (8.9%-14.0%). Septicemia (except in labor) was among the top 10 most frequently reported conditions for hepatitis C but not for hepatitis B.

For deaths without hepatitis B or C, liver-associated conditions were not among the top 10 categories. Further, the top causes occurred at a lower frequency for any 1 category (7.2%-15.1%) than the top causes among deaths with hepatitis B or C (8.9%-48.4%; Tables 2 and 3). Among the 10 most frequently cited causes, deaths listing hepatitis B and C occurred at an average median age of 22-23 years younger than deaths not listing hepatitis B and C.

Among the same age group, the relative risks for conditions associated with a significantly increased risk of dying with hepatitis C ranged from 12.0 (cancer of liver and intrahepatic bile duct) to 1.5 (septicemia, except in labor; Table 5). The relative risks for conditions associated with a significantly decreased risk of dying with hepatitis C ranged from 0.6 (all external causes of injury and poisoning) to 0.9 (respiratory failure, insufficiency, arrest-adult).

DISCUSSION

Our analysis of 2010 MCOD data identified 18 473 deaths reported with viral hepatitis. If ranked as a leading cause of death using NCHS's list [25], viral hepatitis would rank as the 15th leading cause of death.

Hepatitis C alone was identified as a cause of nearly 90% of these deaths; the majority of those occurred in persons aged 45-64 years. The disproportionate burden in this age group is consistent with other studies [4, 7, 18]. As a result, in 2012, the CDC recommended 1-time hepatitis C testing for persons born during 1945-1965 (aged 45-65 years in 2010) [26], especially because birth-cohort screening in primary care settings is cost effective [27]. Our study provides evidence that strengthens this national recommendation. Moreover, the well-demonstrated increased mortality of both liver-associated and nonliver-associated conditions in HBV- and HCV-infected decedents provides key evidence to get more people treated before they develop serious illness. In our comparative cause-of-death analysis, hepatitis B- or C-related deaths most frequently also had liver-associated conditions, which supports the established literature on outcomes of chronic hepatitis infection. Our most significant finding, however, was that among decedents with the same cause of death, persons with hepatitis B or C died about 2 decades younger than persons without these infections. Prevention and early treatment of hepatitis B and C will help prevent these early deaths. Evidence suggests that early therapeutic intervention improves all-cause hepatitis B and C mortality [28-30].

Illicit drug use is associated with an increased likelihood of HBV and HCV infection [7]. In this study, while we showed that substance-related mental disorders were reported frequently among causes of death in persons aged 45-64 years, regardless if HBV and HCV infections were present, the relative risk of dying with a substance-related mental disorder, however, was less likely in deaths with hepatitis B and was not significant in deaths with hepatitis C. For hepatitis B, the decreased likelihood of dying may be explained by the fact that the majority of HBV-infected decedents in the 45-64 year age group were Asians/Pacific Islanders, who most likely acquired their infection during birth or early childhood. For hepatitis C, the insignificant relative risk of dying may be explained by the fact that most persons aged 45-64 years may have used illicit drugs infrequently during their youth, and the behavior is more common among adolescents and young adults. To support this assumption, we did find a significant elevated risk of dying with substance-related mental disorders in HCV-infected decedents aged 0-44 years (data not shown).

Our study demonstrated racial/ethnic disparities in deaths with hepatitis C, specifically among American Indians/Alaskan Natives, NH blacks, and Hispanics. While health disparities in minorities with chronic HCV infection have been documented since as early as 1999 [4, 31, 32], we and others [4] showed that this trend, unfortunately, has not improved.

Although we could not obtain vaccination status from death certificates, our data showed that 3.4% of decedents with hepatitis C had hepatitis A and/or hepatitis B and 1.7% of decedents with hepatitis B had hepatitis A, indicating vaccination was probably not received. Even though hepatitis A and B vaccination is recommended for HCV-infected patients [33], this recommendation had the lowest quality-of-care indicator score in an evaluation study of HCV-infected patients-only 22% received hepatitis A vaccination and only 26% received hepatitis B vaccination or had documented immunity [34].

Although the results of this study are population based, the findings should be interpreted with caution. First, the inaccuracy of cause-of-death coding on death certificates is a significant problem that can lead to underestimates in the viral hepatitis mortality burden [35, 36]; therefore, the hepatitis death estimates in this analysis likely represent only a small fraction of the true burden. Despite having guidelines and training in place, a study at Johns Hopkins Medical Institutions found that more than 40% of causes of death were improperly filled out [36]. In addition to the variability in completeness of recording viral hepatitis deaths, there are data from studies that used medical records to validate hepatitis B and/or C as causes of death in healthcare networks (Mahajan et al, unpublished data) [37]. Investigators found that for patients who had a known HBV [37] or HCV [37, 38] infection associated with chronic liver disease at death, this information was often not reported on death certificates, even when end stage liver disease or hepatocellular carcinoma were listed as the main cause of death. The viral hepatitis mortality burden is even further underestimated by undiagnosed hepatitis infections and deaths unrelated to the decedent's hepatitis infection, such as those that resulted from a suicide or vehicle accident. Because death certificate data imperfectly collect cause of death information, this analysis can only provide data for which viral hepatitis is or is not mentioned on the death certificate. Despite these limitations, MCOD data are invaluable in that they capture all registered deaths in the United States, providing an insightful view into the national burden of viral hepatitis mortality.

In summary, viral hepatitis was listed as a cause of more than 18 000 recorded US deaths in 2010, and there are many who are likely not diagnosed or recorded as having these hepatitides [37]. Because these data demonstrated that death occurred 22-23 years earlier among persons with an HBV- or HCV-related death, prevention efforts should be expanded to further (1) promote hepatitis A and B vaccination among recommended target groups, (2) increase hepatitis B and C screening to get more people into care and earlier treatment, and (3) treat alcohol- and drug-related disorders [26].

Source