Liver diseases: A major, neglected global public health problem requiring urgent actions and large- scale screening

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1 Received: 19 December 2017 Accepted: 24 December 2017 DOI: /liv REVIEW ARTICLE Liver diseases: A major, neglected global public health problem requiring urgent actions and large- scale screening Patrick Marcellin Blaise K. Kutala Hepatology Department and INSERM CRI, Hôpital Beaujon, APHP, University Paris Diderot, Clichy, France Correspondence Patrick Marcellin, Service d hépatologie, Hôpital Beaujon, Clichy, France. patrick.marcellin@aphp.fr Handling Editor: Mario Mondelli Abstract CLDs represent an important, and certainly underestimated, global public health problem. CLDs are highly prevalent and silent, related to different, sometimes associated causes. The distribution of the causes of these diseases is slowly changing, and within the next decade, the proportion of virus- induced CLDs will certainly decrease significantly while the proportion of NASH will increase. There is an urgent need for effective global actions including education, prevention and early diagnosis to manage and treat CLDs, thus preventing cirrhosis- related morbidity and mortality. Our role is to increase the awareness of the public, healthcare professionals and public health authorities to encourage active policies for early management that will decrease the short- and long- term public health burden of these diseases. Because necroinflammation is the key mechanism in the progression of CLDs, it should be detected early. Thus, large- scale screening for CLDs is needed. ALT levels are an easy and inexpensive marker of liver necroinflammation and could be the first- line tool in this process. KEYWORDS alcoholic liver disease, ALT, chronic liver disease, cirrhosis, epidemiology, hepatitis B, hepatitis C, hepatocellular carcinoma, NAFLD, NASH, screening 1 INTRODUCTION Chronic liver diseases (CLDs) represent a major world public health problem. The liver is, in many ways, the reflection of a person s health and should play a central role in worldwide public health policies. Current, but probably undervalued, worldwide estimations show that 844 million people have CLDs, with a mortality rate of 2 million deaths per year. 1 This can be compared with other major public health problems related to chronic diseases such as diabetes (422 million, 1.6 million deaths), 2 pulmonary (650 million, 6.17 million deaths) 3 and cardiovascular diseases (540 million, 17.7 million deaths). 3,4 However, unlike other chronic diseases, a large proportion of CLDs can be cured (chronic hepatitis C, CHC) and prevented or treated (chronic hepatitis B, CHB). Indeed, viral (predominantly in Asia, Africa, Latin America), alcohol- induced CLD (ALD) and emergent metabolic CLDs Abbreviations: ALD, alcoholic liver disease; ALT, alanine-amino-transferase; CHB, chronic hepatitis B; CHC, chronic hepatitis C; CLD, chronic liver disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steato-hepatitis. (i.e. non- alcoholic fatty liver disease, NAFLD and non- alcoholic steatohepatitis, NASH), predominant in Western countries, have been essentially neglected as public health problems. 4 Urgent actions are needed for the prevention, diagnosis, appropriate management and treatment of CLDs. To reach this goal, large- scale screening for CLD is needed. Public awareness and participation by healthcare systems and authorities are crucial to reach this goal. 5 2 THE HIGH PREVALENCE OF CLDS The estimated worldwide prevalence of CHB is 3.6%, ranging from 0.5% in European countries to more than 8% in sub- Saharan Africa. 6 The estimated prevalence of CHC is 2.5%, ranging from 1.8% in the United States (US) to 5.6% in Africa. The prevalence of ALD is 8.5% with the highest prevalence (around 12%) found in Europe and the United States. 7 The estimated worldwide prevalence of NAFLD is 25% and of NASH is 3%- 5%. 8 The highest prevalence of NAFLD is observed in John Wiley & Sons A/S. wileyonlinelibrary.com/journal/liv Liver International. 2018;38(Suppl. 1):2 6. Published by John Wiley & Sons Ltd

2 MARCELLIN and KUTALA 3 Western countries (17% to 46%) where it is the most common CLD in adults 9 with a high prevalence of NASH in the United States (16%). However, the accurate respective prevalence of NAFLD and NASH are not well known because of the lack of liver histology information (diagnostic gold standard) in most studies. 3 THE HIGH INCIDENCE OF CLD- RELATED MORBIDITY AND MORTALITY CLDs induce cirrhosis in patients per year with a prevalence of 4.5% to 9% worldwide. 10 The prevalence of cirrhosis is probably underestimated as most patients remain asymptomatic. Indeed, the risk curve for the incidence of cirrhosis is much flatter than the risk curve for mortality from cirrhosis. The exact incidence of decompensated cirrhosis is unknown. If decompensation occurs in an estimated 20% to 25% of patients with cirrhosis, this would represent patients per year. 11 There is a growing incidence of hepatocellular carcinoma (HCC) worldwide. The annual global incidence of HCC is over cases. 12 The highest incidence of HCC is observed in Asia and Africa, associated with the high prevalence of CHB and CHC in these regions (Table 1). 13,14 Decompensated cirrhosis is the 14th most common global cause of death in adults, the fourth in central Europe. It results in one million deaths per year worldwide, per year in Europe. 15 Global mortality from HCC is growing. HCC is the third most common cause of cancer- related death ( cases per year) in the world and the seventh most common cause in the United States 16 with an important number of new cases estimated in 2013, associated with a corresponding number of deaths. In Europe, HCC is responsible for deaths per year. 11,15 By 2020, the mortality rates will increase by an estimated 1.5 times. 16 The highest incidence rates of HCC are found in Eastern Asia and sub- Saharan Africa where around 85% of cases occur (Table 1). 4 In the United States, a total of liver transplantations (LTs) were performed between 1992 and Of these, 12.5% were performed in patients with ALD, 5.8% in those with ALD and associated CHC and 54% in those with CHC or CHB. The proportion of patients transplanted for HBV has declined in last decade because of HBV antiviral treatments. The effect of the recent availability of HCV antivirals has not yet been demonstrated. In Europe, 5500 LTs are performed every year. Because the diagnosis is usually made late, HCC accounts for only 5% of all LTs. 15,17 4 THE HIGH COST OF CLDS The cost of CLDs is underestimated because of the lack of data. In 2004, the direct cost of CLDs in the United States including cirrhosis (excluding patients with CHC) was estimated to be $2.5 billion. The estimated cost was $ per patient with HCV- related compensated Key points The worldwide prevalence and incidence of CLDs are high. NAFLD and NASH will still increase. CLDs are a major and increasing cause of morbidity and mortality. Public and health authorities need to be more aware of the significant problem of CLDs. CLDs are silent and under-diagnosed and large-scale screening is needed. Management and access to treatment need to be improved. Liver necroinflammation is the key step to fibrosis. ALT, a marker of liver necroinflammation, is the easiest available tool for large-scale screening. cirrhosis and a total cost of $10.6 billion for CHC (before direct antiviral agents, DAAs, became available). The estimated annual cost of patients with HCV and end- stage CLD was $ In 2010, the average per- patient- per- year cost was found to steadily increase along with disease stage, from $ for Barcelona Clinic Liver Cancer criteria (BCLC) stage 0 and $ for stage A, $ for stage B, $ for stage C, $ for stage D. 19 The estimated annual cost for NASH is $103 billion according to a prevalence model. The estimated average 3- year healthcare cost per patient who underwent LT was $ in 2010 in the United States A NEGLECTED PUBLIC HEALTH PROBLEM The extent of the global public health burden of CLDs, whatever the cause, is not well known and is certainly underestimated. First, an accurate evaluation of the incidence and prevalence in large regions is not available, especially those in which CHB 21 and/or CHC is highly endemic as well as in areas with a high risk of ALD or NASH. 9 Moreover, an accurate global evaluation of the impact of CLDs, in particular the morbidity and mortality related to decompensated cirrhosis and HCC, is needed. 22 Finally, the real cost of CLDs must be assessed according to the specific management in each country. This is true for all causes of CLD, but especially true for NASH, an emerging CLD that is responsible for an increasing rate of cirrhosis and HCC, and for which specific markers for screening are not available. National and international programmes on CLDs are lacking. Although national programmes on CHC have been developed in some countries, 5 programmes do not exist in most, including regions with the highest prevalence. There are HBV vaccination programs worldwide, however their efficacy needs to be assessed. Knowing that

3 4 MARCELLIN and KUTALA Incidence (million) Prevalence (%) Current estimation (million) Future estimation 2030 (million) TABLE 1 The global epidemiology of chronic liver diseases HBV a HCV a ALD Not available 19.3 b NAFLD b NASH 2.5 < b a Estimation according to a prevalence model. b Estimation according to an incidence model. mother- to- infant transmission accounts for almost all cases of CHB in Africa and Asia, the recommended strategy to vaccinate newborns at birth should be extended and applied. So far, there are no national or international programmes for NASH because of the lack of clear screening and management strategy, and the absence of specific treatments. Indeed, the real issue is the limited public and political awareness of the extent of the public health burden of CLDs. Effective actions require appropriate funding. Although it has not been proven, early diagnosis would certainly be cost- effective, since it allows optimal management and/or administration of available drugs that can prevent cirrhosis and HCC. Obviously, increasing easy access to antiviral treatment is crucial for CHB and CHC. 6 URGENT ACTIONS ARE NEEDED One priority should be to increase awareness about CLDs in the public, healthcare professionals and the authorities. Information on the frequency and causes of CLDs should be widely diffused (Table 1). The progression of CLDs is known to depend upon the combination of different causes (i.e. HBV- HCV co- infection, excess alcohol consumption or NASH associated with CHB or CHB). Also co- infection with HIV accelerates the progression of CHB and CHC unless it is effectively treated. Cultural, societal, environmental, as well as psychological and life style factors play an important role, in particular excess alcohol consumption for NASH, but also CHB and CHC. Education of the public about the potential impact of certain behaviours that increase the risk of CLD is crucial. Indeed, the public is not aware of CLDs because they are silent and symptoms develop late. CLDs are not generally recognized by physicians because of the absence of symptoms, a normal clinical examination and limited biochemical abnormalities. Also, physicians knowledge about CLDs, including the interpretation of serological markers of CHB and CHC as well as biochemical markers suggesting NASH is not optimal. Physicians should be made aware of the frequency of NASH in patients with clinical signs (even moderate) and the presence of a metabolic syndrome (often incomplete) in particular patients who have overweight, hypertension, diabetes or dyslipidaemia. Available specific treatments for NASH are needed. 7 LIVER INFLAMMATION: THE KEY OF PROGRESSION FIGURE 1 Necroinflammation the key to the progression of chronic liver disease The main mechanism for the progression of CLD, whatever the cause, is liver inflammation. 23 Hepatocyte necrosis is mainly the result of inflammation that is related to the immune response to target cells. Necroinflammation induces the progression of fibrosis to cirrhosis then HCC, causing morbidity and the mortality. 24 In the last two decades, the assessment of CLDs has focused upon the stage of fibrosis. However, fibrosis is a consequence, not the cause. Because of the availability of serum fibrosis tests or scores, which are easier to use than liver biopsy, the central role of necroinflammation, the main step in the progression of CLD, has been nearly forgotten. Necroinflammation is known to be independent of viral load in CHB and CHC and is not correlated with the amount of alcohol intake in ALD or the amount of fat in NASH (Figure 1). Indeed, the presence and grade of necroinflammation was initially used to define the agressivity or activity of disease, differentiating chronic

4 MARCELLIN and KUTALA active hepatitis from chronic persistent hepatitis. Histological scores included the grade of inflammation (activity) in addition to the stage of fibrosis, to determine the prognosis of CLD and the indication for therapy. Also, non- progressive ALD versus progressive ALD is defined by the presence of inflammation (alcoholic hepatitis). Non- progressive NAFLD is differentiated from progressive NAFLD (NASH) by the presence of inflammation. The grade of necroinflammation is known to be correlated with the stage of fibrosis and its prognosis in CLD. Indeed, in large histology studies performed in CHC patients (liver histology was the primary end- point in large pivotal trials of successive drugs), the stage of fibrosis is correlated with the grade of necroinflammation. The progression of CLD is driven by necroinflammation. This is demonstrated by the histological effect of antiviral treatments in CHB and CHC, which are associated with the disappearance of necroinflammation and the regression of fibrosis, even in patients with cirrhosis. 25 Finally, stopping inflammation stops the fibrogenesis process and allows natural fibrolysis to occur. Thus, inflammation should be the target of therapy and better knowledge of the mechanisms responsible for the excessive immune response in different CLDs is needed to develop more effective therapies. 5 9 CONCLUSION CLDs represent an important, and certainly underestimated, global public health problem. CLDs are highly prevalent and silent, related to different, sometimes associated causes. The distribution of the causes of these diseases is slowly changing, and within the next decade, the proportion of virus- induced CLDs will certainly decrease significantly while the proportion of NASH will increase. There is an urgent need for effective global actions including education, prevention and early diagnosis for management and treatment to prevent cirrhosis- related morbidity and mortality. Our role is to increase the awareness of the public, healthcare professionals and public health authorities to encourage active policies for early overall management that will decrease the short- and long- term public health burden of these diseases. CLDs meet all the criteria in favour of systematic screening. Because necroinflammation is the key mechanism in the progression of CLDs, it should be detected early. Thus, large- scale screening for CLDs is needed. ALT levels are an easy and inexpensive marker of liver necroinflammation and they could be the first- line tool in this process. CONFLICTS OF INTEREST The authors do not have any disclosures to report. 8 TRANSAMINASES: AN ALARM AND THE EASIEST AVAILABLE LARGE SCALE SCREENING TEST ORCID Blaise K. Kutala Elevated alanine- amino- transferase (ALT) levels are correlated with the grade of necroinflammation but not with the stage of fibrosis. Even if the correlation is not highly accurate, this is the only easy, inexpensive test available to detect CLD, whatever the cause. Although ALT is not specific, it is an alarm, signalling the presence of liver disorders requiring an etiological and prognostic evaluation. Therefore, measurement of ALT should be part of routine blood testing, such as glycaemia or cholesterolaemia. The prognosis of the CLD is determined by an assessment of the fibrosis stage, based on scores, blood tests or devices such as elastometry, which are not always available and are quite expensive. Liver biopsy is an invasive procedure associated with some morbidity; however, it is currently the only procedure that provides an accurate assessment of the grade of necroinflammation, to help determine the prognosis. The sensitivity of ALT is not perfect. 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