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  • Published: 03 February 2024

Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019

  • Xiao-Ning Wu 1 , 2 ,
  • Feng Xue 1 ,
  • Nan Zhang 1 , 2 ,
  • Wei Zhang 1 , 2 ,
  • Jing-Jing Hou 1 , 2 ,
  • Yi Lv 1 , 2 ,
  • Jun-Xi Xiang 1 , 2 &
  • Xu-Feng Zhang 1 , 2  

BMC Public Health volume  24 , Article number:  363 ( 2024 ) Cite this article

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This study aimed to assess the global, regional, and national burden of liver cirrhosis and other chronic liver diseases between 1990 and 2019, considering five etiologies (hepatitis B, hepatitis C, alcohol use, NAFLD and other causes), age, gender, and sociodemographic index (SDI).

Data on liver cirrhosis and other chronic liver diseases mortality, incidence, and disability-adjusted life years (DALYs) were collected from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2019.

In 2019, liver cirrhosis and other chronic liver diseases accounted for 1,472,011 (95% UI 1,374,608-1,578,731) deaths worldwide, compared to 1,012,975 (948,941-1,073,877) deaths in 1990. Despite an increase in absolute deaths, the age-standardized death rate declined from 24.43 (22.93–25.73) per 100,000 population in 1990 to 18.00 (19.31–16.80) per 100,000 population in 2019. Eastern sub-Saharan Africa exhibited the highest age-standardized death rate (44.15 [38.47–51.91] per 100,000 population), while Australasia had the lowest rate (5.48 [5.05–5.93] deaths per 100,000 population in 2019). The age-standardized incidence rate of liver cirrhosis and other chronic liver diseases attributed to hepatitis B virus has declined since 1990, but incidence rates for other etiologies have increased. Age-standardized death and DALYs rates progressively decreased with higher SDI across different GBD regions and countries. Mortality due to liver cirrhosis and other chronic liver diseases increased with age in 2019, and the death rate among males was estimated 1.51 times higher than that among females globally.

Liver cirrhosis and other chronic liver diseases continues to pose a significant global public health challenge. Effective disease control, prevention, and treatment strategies should account for variations in risk factors, age, gender, and regional disparities.

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Introduction

Liver cirrhosis and other chronic liver diseases ranks as the 14th most common cause of death globally, contributing significantly to mortalities and disability-adjusted life years (DALYs) [ 1 , 2 ]. It represents an advanced stage of various liver diseases such as hepatitis B and C infections, non-alcoholic fatty liver disease, alcohol consumption, autoimmune disorders, and so on [ 2 , 3 ]. Typically, liver cirrhosis and other chronic liver diseases develops following prolonged inflammation. The mortality and morbidity associated with liver cirrhosis and other chronic liver diseases increase sharply, with a 1-year case-fatality rate reaching up to 80%. Consequently, liver cirrhosis and other chronic liver diseases poses a substantial burden on patients, healthcare systems, and governments worldwide at both global and regional levels [ 2 , 4 ].

In recent years, there has been extensive research analyzing the incidence and mortality trends of liver cancer, highlighting its significant disease burden [ 5 , 6 , 7 , 8 ]. However, compared to liver cancer, reports on the trends of liver cirrhosis and other chronic liver diseases in recent years have been relatively less detailed. The majority of studies on liver cirrhosis and other chronic liver diseases aim to investigate its epidemiology, pathological mechanism and severity based on specific causes [ 9 , 10 , 11 ]. The impact of liver cirrhosis and other chronic liver diseases varies significantly across geographical locations, genders, races, ethnicities, and socioeconomic classes, and this impact has also undergone substantial changes over time. Although there have been some reports on the incidence and mortality rates of liver cirrhosis and other chronic liver diseases, they either lack the most recent data or do not comprehensively analyze the disease burden of liver cirrhosis and other chronic liver diseases by integrating incidence rates, mortality rates, DALYs rates, along with various etiological factors, geographical regions, gender, age, and SDI [ 4 , 9 , 10 , 11 , 12 , 13 ].

To address this gap, we conducted a systematic analysis using the latest available data from the Global Burden of Disease Study (GBD) 2019. This analysis involved calculating the mortalities, incidence cases, and DALYs for liver cirrhosis and other chronic liver diseases across different GBD regions and countries in 2019. Additionally, ASRs and percentage change in ASRs (APC) from 1990 to 2019 were also calculated to facilitate comparisons. Further analysis for liver cirrhosis and other chronic liver diseases was performed by classifying the data according to five specific etiologies (hepatitis B, hepatitis C, alcohol use, NAFLD and other causes), age groups, gender, and sociodemographic index (SDI). This endeavor aimed to provide the most up-to-date and comprehensive insights into the complete details of liver cirrhosis and other chronic liver diseases.

The data used in this study were obtained from the Global Health Data Exchange (GHDx) query tool ( https://ghdx.healthdata.org ), specifically from the Global Burden of Disease Study (GBD) 2019 [ 14 ]. The GBD 2019 was conducted under the coordination of the Institute for Health Metrics and Evaluation (IHME) [ 10 ]. Detailed information on liver cirrhosis and other chronic liver diseases, including mortality, incidence, and DALYs, stratified by region, country, sex, age, and etiology, was extracted from the GBD 2019 database.

The dataset encompassed 204 countries and territories, which were categorized into 21 regions based on the classification used in the GBD study. These regions include Andean Latin America, Australasia, Caribbean, Central Asia, Central Europe, Central Latin America, Central sub-Saharan Africa, East Asia, Eastern Europe, Eastern sub-Saharan Africa, High-income Asia Pacific, High-income North America, North Africa and Middle East, Oceania, South Asia, Southeast Asia, Southern Latin America, Southern sub-Saharan Africa, Tropical Latin America, Western Europe and Western sub-Saharan Africa. The etiologies of liver cirrhosis and other chronic liver diseases were divided into HBV, HCV, alcohol use, NAFLD, and other causes [ 14 , 15 ].

In this study, the trends in global liver cirrhosis and other chronic liver diseases were evaluated using age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) stratified by five different etiologies. The annual percentage change (APC) was calculated to measure the change in each trend over time. A positive APC value indicated an increasing burden, while a negative value indicated a declining burden. The burden of liver cirrhosis and other chronic liver diseases in 21 GBD regions and 204 countries and territories were described statistically based on specific values categorized by different groups of sex and age. The Socio-demographic Index (SDI) is a composite indicator that reflects the development status of a country or region. It is calculated based on the rankings of per capita income, average educational attainment, and fertility rates in the GBD study. SDI ranges from 0 (worst) to 1 (best) [ 14 , 16 ]. The 2.5th and 97.5th centiles were used to determine the 95% uncertainty intervals (UIs). To explore the relationship between the burden of liver cirrhosis and other chronic liver diseases (mortality, incidence, DALYs) and SDIs across the 21 regions and 204 countries and territories, smoothing spline models were employed to examine the shape of the association.

The general linear models are commonly used in statistical analysis, requiring the dependent variables to be normally distributed and independent of each other. These models assume homogeneity of variance and are often utilized for comparing multiple repeated measurements of the same continuous variable. On the other hand, the dependent variable in generalized linear models (GLMs) is not limited to a normal distribution and does not place as much emphasis on homogeneity of variance. A key advantage of GLMs is that the independent variable can be either discrete or continuous, allowing for a broader scope of applications. In this article, GLMs were employed to estimate the mixed effects of gender, SDI, and alcohol use on the age-standardized death rate of liver cirrhosis and other chronic liver diseases [ 17 , 18 ]. The results are presented through a predictive formula derived from this model:

Y = α0 + α1×Gender + α2×SDI + α3×AlcoholUse + α4×SDI&AlcoholUse + α5×Gender&SDI.

In the given model, α0 represents the overall intercept of the predictor variable. α1, α2, α3, α4, α5, and α6 indicate the slopes of the response variable, reflecting the fixed effects. SDI&AlcoholUse denotes the interaction between the two predictor variables, while Gender&SDI represents the same concept. The relative risk (RR) of mortality for males and females can be assessed by calculating with the aforementioned equation. All statistical analyses were conducted using SPSS 26.0 software (IBM SPSS, Chicago, IL, USA). A p-value less than 0.05 was considered statistically significant. Tables and figures were generated using GraphPad 8.0 or Python.

Global burden of liver cirrhosis and other chronic liver diseases

In 2019, there were a total of 1,472,011 deaths (95% UI 1,374,608-1,578,731) caused by liver cirrhosis and other chronic liver diseases worldwide. This marked a significant increase of 45.32% compared to the 1,012,975 deaths (95% UI 948,941-1,073,877) reported in 1990. The ASMR for liver cirrhosis and other chronic liver diseases globally exhibited a notable decrease of 26.32%, declining from 24.43 (22.93–25.73) per 100,000 population in 1990 to 18.00 (16.80-19.31) per 100,000 population in 2019 (Table  1 ; Figs.  1 and 2 ). The incidence of liver cirrhosis and other chronic liver diseases in individuals of all ages witnessed a 62.03% increase, rising from 1,274,022 (1,027,186-1,548,534) cases in 1990 to 2,051,553 (1,661,430-2,478,127) cases in 2019. The global ASIR was 25.66 (20.25–31.63) per 100,000 population in 1990, showing a slight decrease to 25.35 (20.78–30.44) per 100,000 population in 2019 (Table  1 ; Figure S1 and S2 ). In 2019, liver cirrhosis and other chronic liver diseases resulted in a total of 46,189,415 (43,027,109 − 49,551,291) DALYs, representing a 33.00% increase compared to the 34,727,732 (32,382,957 − 37,132,796) DALYs in 1990. Conversely, the global ASDR exhibited a decreasing trend from 766.07 (718.30-813.11) per 100,000 population in 1990 to 560.43 (521.86-602.02) per 100,000 population in 2019 (Table  1 ; Figure S3 and S4 ), indicating a decline of 26.84%.

figure 1

Number of mortality and ASMR at the global level by etiology of liver cirrhosis and other chronic liver diseases, 1990–2019. COHB, liver cirrhosis and other chronic liver diseases due to hepatitis B. COHC, liver cirrhosis and other chronic liver diseases due to hepatitis C. COAU, liver cirrhosis and other chronic liver diseases due to alcohol use. CONA, liver cirrhosis and other chronic liver diseases due to NAFLD. COOC, liver cirrhosis and other chronic liver diseases due to other cause. ASMR, age-standardized mortality rate

figure 2

Age-standardized mortality rate for liver cirrhosis and other chronic liver diseases, by region and etiology, 2019. COHB, liver cirrhosis and other chronic liver diseases due to hepatitis B. COHC, liver cirrhosis and other chronic liver diseases due to hepatitis C. COAU, liver cirrhosis and other chronic liver diseases due to alcohol use. CONA, liver cirrhosis and other chronic liver diseases due to NAFLD. COOC, liver cirrhosis and other chronic liver diseases due to other cause

In 2019, hepatitis B accounted for approximately 22.36% of all liver cirrhosis and other chronic liver diseases-related deaths in individuals of all ages. Hepatitis C was responsible for 26.75% of these deaths, while alcohol use contributed to 24.90%. Non-alcoholic steatohepatitis (NASH) caused 9.20% of the mortalities, and other causes accounted for 16.78% (Fig.  3 ).

figure 3

Contribution of COHB, COHC, COAU, CONA, and COOC to liver cirrhosis and other chronic liver diseases mortality, both sexes, globally and by region, 2019. COHB, liver cirrhosis and other chronic liver diseases due to hepatitis B. COHC, liver cirrhosis and other chronic liver diseases due to hepatitis C. COAU, liver cirrhosis and other chronic liver diseases due to alcohol use. CONA, liver cirrhosis and other chronic liver diseases due to NAFLD. COOC, liver cirrhosis and other chronic liver diseases due to other cause

Specifically, there were 331,266 (278,542 − 392,126) deaths attributed to liver cirrhosis and other chronic liver diseases caused by hepatitis B (COHB) in 2019, representing a 14.36% increase from 1990 [289,682 (249,026–331,355)]. However, the ASMR for liver cirrhosis and other chronic liver diseases caused by hepatitis B decreased by 42.10% during this period, dropping from 6.96 (6.00-7.95) per 100,000 population in 1990 to 4.03 (3.39–4.76) per 100,000 population in 2019, and HBV infection now ranks as the third leading cause for ASMR of liver cirrhosis and other chronic liver diseases. For liver cirrhosis and other chronic liver diseases caused by hepatitis C (COHC), there were 245,022 (208,652 − 282,509) deaths in 1990 and 395,022 (335,832 − 458,584) deaths in 2019. The ASMR for COHC declined by 19.26% from 5.97 (5.09–6.90) per 100,000 population in 1990 to 4.82 (4.09–5.57) per 100,000 population in 2019. Liver cirrhosis and other chronic liver diseases resulting from alcohol use (COAU) caused 232,949 (197,746 − 273,817) deaths in 1990 and 371,964 (314,703 − 438,425) deaths in 2019. The ASMR for COAU decreased by 20.99% worldwide, going from 5.67 (4.80–6.64) per 100,000 population in 1990 to 4.48 (3.81–5.28) per 100,000 population in 2019. In 1990, there were 75,957 (54,215 − 101,590) deaths attributed to liver cirrhosis and other chronic liver diseases due to non-alcoholic fatty liver disease (CONA), and this number increased to 134,240 (96,483 − 176,920) deaths in 2019. The ASMR for CONA decreased by 14.43% from 1.94 (1.39–2.59) per 100,000 population in 1990 to 1.66 (1.20–2.17) per 100,000 population in 2019. Moreover, liver cirrhosis and other chronic liver diseases due to other causes (COOC) resulted in 169,363 (137,356 − 206,849) deaths in 1990 and 239,517 (187,991 − 302,873) deaths in 2019. The ASMR for COOC decreased by 22.37%, declining from 3.89 (3.12–4.83) per 100,000 population in 1990 to 3.02 (3.38–3.78) per 100,000 population in 2019 (Figs.  1 and 2 ).

Geographic burden of liver cirrhosis and other chronic liver diseases

In 2019, the regions with the top two ASMR for liver cirrhosis and other chronic liver diseases were Eastern Sub-Saharan Africa and Central Asia, with rates of 44.15 (38.47–51.91) and 42.86 (38.53–47.51) per 100,000 population respectively. Central Asia experienced a significant burden of liver cirrhosis and other chronic liver diseases, with ranking first in ASIR among all regions (Fig.  2 ; Figure S2 ). It also had the highest ASDR for liver cirrhosis and other chronic liver diseases, with a rate of 1318 (1187–1467) per 100,000 population in 2019 (Figure S4 ). Central Asia and Eastern Europe consistently showed the most significant increases in ASMR, ASIR, and ASDR from 1990 to 2019 compared to other regions, which experienced varying degrees of decline. North Africa and the Middle East had the most dramatic decrease in ASMR over the past 30 years. High-income Asia Pacific had the largest drop in ASIR, while Eastern Sub-Saharan Africa experienced the largest decline in ASDR from 1990 to 2019.

Hepatitis B was the leading cause of liver cirrhosis and other chronic liver diseases in Western Sub-Saharan Africa, Oceania, and South Asia, accounting for 43.96%, 33.85%, and 31.88% of total liver cirrhosis and other chronic liver diseases deaths in 2019 respectively (Figs.  2 and 3 ). The highest ASMR for COHB for all ages was observed in Western Sub-Saharan Africa (16.69 [12.69–21.35]), while the lowest was found in East Asia (2.30 [1.87–2.78]). Eastern Sub-Saharan Africa had the highest ASMR for COHC in 2019 (15.46 [12.52–19.04]), while Western Europe had the lowest ASMR for COHC (1.79 [1.41–2.25]). More than 40% of liver cirrhosis and other chronic liver diseases-related deaths caused by hepatitis C were found in high-income regions such as North America, Australasia, and North Africa and the Middle East (Figs.  2 and 3 ). Central Asia had the highest ASMR for COAU for all ages in 2019 (17.22 [13.83–20.69]), while Australasia had the lowest (1.01 [0.72–1.36]). Mortalities attributed to COAU accounted for over 40% in Central Europe, Tropical Latin America, Western Europe, Eastern Europe, Andean Latin America, Caribbean, and Central Asia (Figs.  2 and 3 ). The proportion of mortalities for liver cirrhosis and other chronic liver diseases due to NAFLD was lower than that due to other causes in most regions in 2019. Andean Latin America consistently had the highest proportions attributable to NAFLD and other causes of liver cirrhosis and other chronic liver diseases (21.17% and 19.88% respectively) in ASMR. The highest ASMR for CONA was in Central Latin America (5.90 [4.32–7.66]), while Eastern Sub-Saharan Africa had the highest ASMR for COOC in 2019 (7.35 [5.23–9.63]) (Figs.  2 and 3 ).

National burden of liver cirrhosis and other chronic liver diseases

At the national level, India had the highest number of deaths (270,036 [228,609 − 321,257]) and DALYs (9,635,297 [8,187,694 − 11,300,327]) attributed to liver cirrhosis and other chronic liver diseases. China had the highest number of incident cases (409,693 [308,245–514,354]). In China, the estimated ASMR for liver cirrhosis and other chronic liver diseases ranged from 126.73 to 3.26 per 100,000 population in 2019. In contrast, Singapore had the lowest ASMR and ASDR for liver cirrhosis and other chronic liver diseases, and the lowest ASIR was observed in both Cook Islands and Papua New Guinea (Fig.  4 ). The largest increases in ASMR and ASDR over the past 30 years were seen in Ukraine, and the biggest increase in ASIR was observed in Kazakhstan. Korea showed the most notable decreases in these rates from 1990 to 2019 (Figure S7 ). For India, Indonesia, and Pakistan, three heavily populated countries, the annual percentage of change from 1990 to 2019 in the ASMR was (-17% [-32–2%]), (-17% [-32–1%]), and (-16% [-38–21%]), respectively.

figure 4

The global age-standardized rate of liver cirrhosis and other chronic liver diseases per 100,000 populations in 2019, by country and territory. ( A ) ASMR in 2019; ( B ) ASIR in 2019; and ( C ) ASDR in 2019. ASMR, age-standardized mortality rate. ASIR, age-standardized incidence rate. ASDR, age-standardized DALYs rate

In terms of specific etiologies, Egypt had the highest ASMR of COHB in 2019 (32.67 [20.28–47.58]), while Colombia had the lowest (0.22 [0.14–0.34]). Ukraine had the largest increase in ASMR of COHB from 1990 to 2019 (115% [72–166%]), while Korea had the largest decrease (-82% [-85% to -77%]) (Figure S8 A and S9 A).

Egypt also had the highest ASMR of COHC in 2019 (52.58 [33.36–73.18]), while Iceland had the lowest (0.28 [0.20–0.40]). Ukraine experienced the most significant increase in ASMR of COHC from 1990 to 2019 (231% [168–305%]), while Korea had the largest decrease (-69% [-74% to -61%]) (Figure S10 A and S11 A).

Mongolia had the highest ASMR of COAU in 2019 (29.25 [21.58–38.89]), while Singapore had the lowest (0.52 [0.36–0.73]). The countries with the greatest increase and decrease in ASMR of COAU were the same as those for COHB and COHC, with percent changes ranging from − 68 to 198% (Figure S12 A and S13 A).

Regarding CONA and COOC in 2019, Egypt also had the highest ASMR, while Singapore had the lowest ASMR for CONA, and New Zealand had the lowest ASMR for COOC. Ukraine showed the largest increases in ASMR for CONA and COOC, while Korea had the largest decreases (Figure S14 A, S15 A, S16 A, and S17 A).

For more detailed information on incident numbers, DALYs, ASIR, ASDR, and annual rates of percent change for different etiologies globally, by region, and by country, please refer to supplementary materials (Figure S7 - S17 ).

Age and sex on liver cirrhosis and other chronic liver diseases

In 2019, the global number of deaths due to liver cirrhosis and other chronic liver diseases was higher in males than females across all age groups, except for those aged older than 85 years (Fig.  5 ). This trend was also observed for DALYs, while the incidence of liver cirrhosis and other chronic liver diseases was higher in males only within the age range of 10–49 years (Figure S18 and S19 ).

figure 5

Global liver cirrhosis and other chronic liver diseases mortality by etiology and age for females and males, 2019. For each group, the left column showed case data in female and the right column shows data in male. COHB, liver cirrhosis and other chronic liver diseases due to hepatitis B. COHC, liver cirrhosis and other chronic liver diseases due to hepatitis C. COAU, liver cirrhosis and other chronic liver diseases due to alcohol use. CONA, liver cirrhosis and other chronic liver diseases due to NAFLD. COOC, liver cirrhosis and other chronic liver diseases due to other cause

The number of mortalities from liver cirrhosis and other chronic liver diseases in 2019 exhibited a sharp increase after the age of 20, reaching its peak at the ages of 60–64 years for males and 65–69 years for females. Subsequently, the number of deaths declined in older age groups. The lowest number of deaths occurred in patients younger than 15 years. The development of liver cirrhosis and other chronic liver diseases caused by different etiologies exhibited age-related and gender-specific patterns (Fig.  5 ).

Burden of liver cirrhosis and other chronic liver diseases by sociodemographic index

From 1990 to 2019, there were generally nonlinear relationships between the ASMR of liver cirrhosis and other chronic liver diseases and SDI at both global and regional levels. The expected values based on SDI and ASMR in all locations indicated a gradual decrease in ASMR with improvements in SDI, reflecting general expected trends (Fig.  6 A). At the regional level, Central Latin America, Andean Latin America, Central Asia, Southeast Asia, and North Africa and the Middle East had a higher burden of liver cirrhosis and other chronic liver diseases compared to the expected levels based on SDIs from 1990 to 2019. Conversely, Oceania, East Asia, and Australasia exhibited a significantly lower burden than expected. In regions such as Central Europe, Eastern Europe, Central Asia, and Southern Sub-Saharan Africa, the burden of liver cirrhosis and other chronic liver diseases initially increased and then decreased with the enhancement of SDI over time. On a global scale, the observed burden of liver cirrhosis and other chronic liver diseases was lower than the expected level based on the SDIs from 1990 to 2019 (Fig.  6 A).

figure 6

ASMR of liver cirrhosis and other chronic liver diseases by SDI: ( A ) ASMR in global and 21 GBD regions, 1990–2019. ( B ) ASMR in 204 countries and territories, 2019. Expected values based on sociodemographic index and disease rates in all locations are shown as the black line. ASMR, age-standardized mortality rate; GBD, global burden of diseases, injuries, and risk factors study; SDI, sociodemographic index

At the national level, a nonlinear association was also observed between the ASMR and the SDI value. Countries like Egypt, Mongolia, Cambodia, Zambia, and several others had a higher ASMR than the expected value, while countries like Colombia, Norway, New Zealand, and several others had a lower ASMR than expected based on the SDIs (Fig.  6 B). Nonlinear associations between the SDI and ASIR and ASDR of liver cirrhosis and other chronic liver diseases were also detected at the regional and national levels (Figure S20 and S21 ).

These findings highlight the complex relationships between the ASMR of liver cirrhosis and other chronic liver diseases, SDI, and geographical variations, indicating the need for further investigation into the underlying factors contributing to the observed burdens.

Relative risk estimation of ASMR in males and females

The coefficients and overall intercepts of the various predictors were determined through using of GLMs (Table  2 ). The predictive formula for ASMR is:

Y = 36.663 + 26.315×Gender − 32.187×SDI + 1.725×AlcoholUse − 2.299×SDI&AlcoholUse − 18.273×Gender&SDI (Gender = male).

Y = 36.663–32.187×SDI + 1.725×AlcoholUse − 2.299×SDI&AlcoholUse (Gender = female).

RR for males relative to females in ASMR of liver cirrhosis and other chronic liver diseases was calculated as follows when both males and females without any alcohol consumption:

RR=(36.663 + 26.315–32.187×SDI-18.273)/(36.663–32.187×SDI)=(44.705–32.187×SDI)/(36.663–32.187×SDI)

SDI values exhibited variations across different countries and regions. When considering both males and females without any alcohol consumption, there was a correlation between the relative risk (RR) of death rates for males compared to females and SDI values. In 2019, the global mortality rate among males was 1.51 times higher than that among females (SDI in 2019 was known). This suggests a gender disparity in mortality rates, with males being more vulnerable to certain factors associated with liver cirrhosis and other chronic liver diseases compared to females.

As the major causes of liver cirrhosis and other chronic liver diseases is largely preventable and treatable, it is crucial for policymakers in national health-care systems to have a comprehensive understanding of the incidence, mortality and DALYs associated with each causal factor. This knowledge allows for the implementation of targeted interventions aimed at reducing premature deaths and morbidity related to liver cirrhosis and other chronic liver diseases. Therefore, there is a pressing need for a detailed assessment of the global and regional disease burden, particularly in terms of mortality, incidence, and DALYs attributable to liver cirrhosis and other chronic liver diseases. This study represents an important contribution as it is, to the best of our knowledge, the first comprehensive analysis showcasing the burden of liver cirrhosis and other chronic liver diseases worldwide between 1990 and 2019. It provides a detailed account of the numbers and age-standardized rates of mortality, incidence, and DALYs stratified by five etiologies globally, regionally, and nationally. Across the globe, there has been a steady increase in numbers of mortality, incidence, and DALYs associated with liver cirrhosis and other chronic liver diseases over this period, likely due to population growth and aging. These factors have contributed to a relatively inadequate provision of health care resources, particularly in underdeveloped regions and countries. However, it is worth noting that age-standardized rates of mortality and DALYs have shown a declining trend from 1990 to 2019, indicating some improvements in addressing the disease burden of liver cirrhosis and other chronic liver diseases. Additionally, decreases in ASMR and ASDR suggest potential future improvements in the overall situation. Although the ASIR has remained relatively stable, the declines observed in mortality and DALYs may be associated with increased long-term survival of patients.

The age-standardized rates of liver cirrhosis and other chronic liver diseases varied across the five etiologies studied. It is evident that hepatitis B virus, hepatitis C virus, and alcohol use were still the primary causes of liver cirrhosis and other chronic liver diseases deaths at the global level. In 2019, these three factors accounted for 74.61% of liver cirrhosis and other chronic liver diseases-related mortalities. Notably, the prevalence trends indicated a more significant decline in HBV compared to other factors, with a gradual decrease in the proportion of mortalities attributed to HBV since 2009. This decline can be attributed, in some part, to routine immunization with the hepatitis B vaccine in many regions [ 19 ]. Furthermore, the Western Sub-Saharan Africa region exhibited the highest ASMR for liver cirrhosis and other chronic liver diseases caused by HBV in 2019. This can be attributed to various factors such as high temperatures, a high rate of invisible HBV infection, and inadequate interruption of mother-to-child transmission. These conditions make the population more susceptible to HBV infection, leading to a silent epidemic of the virus in this region [ 20 , 21 , 22 ]. Implementing routine immunization programs targeting HBV transmission and improving healthcare infrastructure have the potential to effectively control the incidence of hepatitis B-related liver cirrhosis and other chronic liver diseases deaths in African and other Asian countries.

Previous studies have indicated that hepatitis C virus is the leading cause of liver cirrhosis and other chronic liver diseases in developed countries and regions [ 1 , 3 , 23 ]. However, our study reveals that HCV remains the predominant etiology not only in high-income regions such as Asia Pacific and North America but also in less developed areas including North Africa, the Middle East, and Southern Latin America. The dominance of HCV as a significant risk factor for liver cirrhosis and other chronic liver diseases in various economic settings highlights the importance of addressing this viral infection on a global scale. While prevention and control efforts have made substantial progress in high-income regions, there is a pressing need to extend these measures to less developed areas where HCV remains a significant public health concern. It is essential to establish robust surveillance networks, strengthen laboratory capacities, and promote information sharing to facilitate a comprehensive understanding of the burden of HCV-related liver cirrhosis and other chronic liver diseases across different regions. Luckily, significant progress has been achieved in the field of hepatitis C virus treatment over the past few decades, culminating in HCV becoming the first chronic viral infection that can be cured [ 24 ]. This remarkable development can be attributed to the introduction of direct-acting antiviral agents (DAAs), which have revolutionized antiviral therapy and cure rates exceeding 98% across various patient populations infected with HCV [ 24 ]. These medications directly target specific viral proteins essential for HCV replication, resulting in rapid suppression of viral replication and ultimately achieving sustained virological response (SVR), which is defined as undetectable levels of HCV RNA in the blood 12 weeks after completion of treatment and serves as a marker for viral eradication. The availability of highly effective and well-tolerated DAA regimens has transformed HCV management, offering the potential to achieve viral eradication and improve patient outcomes.

Noteworthy, we observed that alcohol use is a significant contributor to liver cirrhosis and other chronic liver diseases, as supported by our findings and previous evidence [ 10 ]. Specifically, Mongolia and Moldova emerged as the countries with the highest age-standardized rates of liver cirrhosis and other chronic liver diseases attributed to alcohol use. Excessive alcohol consumption in Mongolia can be attributed to various factors, including geographical location, cultural influences from neighboring Russia, and the economic dependence on the alcohol industry [ 25 , 26 ]. It is evident from our study and previous research that there is a pressing need for a comprehensive approach to reduce alcohol consumption in these countries in order to alleviate the burden of liver cirrhosis and other chronic liver diseases [ 3 , 10 , 27 ].

Furthermore, non-alcoholic fatty liver disease and obesity have been identified as significant risk factors for liver cirrhosis and other chronic liver diseases [ 11 , 12 ]. Our study revealed a global increase in the incident cases of NAFLD-associated liver cirrhosis and other chronic liver diseases from 1990 to 2019. This rising trend was observed not only in economically underdeveloped countries like Kazakhstan and Mongolia but also in developed nations such as the United Kingdom and Finland. The growing prevalence of obesity and metabolic syndrome is closely associated with the increasing incidence of NAFLD. Therefore, it is reasonable to expect a surge in the morbidity rates associated with this condition. Given the lack of effective preventive or therapeutic interventions for NAFLD, maintaining a healthy diet and engaging in regular exercise become particularly important strategies [ 13 ].

Factors such as smoking and aflatoxin B1 were categorized as “other causes” in the Global Burden of Disease (GBD) 2019 study, along with all risk factors not mentioned earlier [ 14 ]. Analyzing the statistical results of age-standardized mortality rates (ASMR), age-standardized death rates (ASDR), and age-standardized incidence rates (ASIR) for liver cirrhosis and other chronic liver diseases from other causes, we discovered that the disease burden associated with these causes was more severe than anticipated, surpassing that caused by non-alcoholic fatty liver disease (NAFLD) over the past three decades. Hence, there is a need for greater implementation of prevention measures to reduce exposure to aflatoxin B1 and smoking.

On a global scale, liver cirrhosis and other chronic liver diseases exhibits a significant sex-based disparity, with the mortality rate in males being 1.51 times higher than in females in 2019 [ 6 , 28 ]. This discrepancy between males and females can be attributed to factors such as sex hormones, sex chromosomes, immunity, and behaviors (particularly alcohol use and smoking) [ 29 , 30 ]. Therefore, it is highly recommended to adopt sex-specific prevention and treatment strategies for liver cirrhosis and other chronic liver diseases [ 31 ].

Furthermore, we investigated the nonlinear associations between mortality, incidence, DALYs of liver cirrhosis and other chronic liver diseases with the SDI values of different regions and countries. In general, higher SDI values were correlated with a lower disease burden of liver cirrhosis and other chronic liver diseases from 1990 to 2019 across most of the 21 GBD regions [ 4 , 32 ]. These findings are expected, as nations with higher income tend to exhibit lower mortality rates related to liver cirrhosis and other chronic liver diseases due to improved healthcare access and strengthened health infrastructure. However, certain regions and countries with higher SDI values still experienced a relatively high burden of liver cirrhosis and other chronic liver diseases, indicating that the disease burden cannot be solely inferred from SDI values. Overall, it is undeniable that better economic development in regions and countries can contribute to mitigating the disease burden associated with liver cirrhosis and other chronic liver diseases.

There are several limitations to consider in this study. Firstly, since this study relied on secondary analysis of data from the Global Burden of Disease 2019, the accuracy of the conclusions is dependent on the quality of the data collected by GBD and the research methods employed in this analysis. Secondly, the classification of risk factors for liver cirrhosis and other chronic liver diseases in GBD 2019 was limited to five etiologies, which means that only a subset of etiologies could be analyzed for their impact on disease burden. Further research is necessary to differentiate the specific factors included under the category of ‘other causes’ in this analysis, including autoimmune hepatitis as a potential sixth factor leading to liver cirrhosis and other chronic liver diseases.

In summary, this study confirms that liver cirrhosis and other chronic liver diseases is a significant global health issue, necessitating the attention of primary care physicians, specialists, and health policymakers to implement appropriate preventive measures and enhance awareness regarding early detection, diagnosis, and treatment. From 1990 to 2019, the global ASMR and ASDR for the five specified causes of liver cirrhosis and other chronic liver diseases demonstrated a decline. However, among the five ASIRs, only the incidence rate for hepatitis B showed a decreasing trend. Given that liver cirrhosis and other chronic liver diseases can be prevented and its progression slowed through appropriate interventions, variations among risk factors, age and gender groups, as well as different regions and countries should be taken into account in disease control, prevention, and treatment strategies for liver cirrhosis and other chronic liver diseases.

Data availability

The datasets analyzed during the current study are publicly available from the Global Health Data Exchange query tool ( https://ghdx.healthdata.org/gbd-results-tool ). The datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request.

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This work was supported by the National Natural Science Foundation of China (82170608), and Shaanxi Science Foundation for Distinguished Young Scholars (2021JC-36), the Natural Science Basic Research Program of Shaanxi (2021JM-268) and Innovation Capability Support Program of Shaanxi Province (2023KJXX-030).

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Xiao-Ning Wu and Feng Xue performed data analysis, and wrote the initial draft of the article; Nan Zhang, Wei Zhang, Jing-Jing Hou, and Yi Lv have collected the data and approved the final version of the manuscript; Xu-Feng Zhang and Jun-Xi Xiang conceived and designed the study, and revised the article. All authors have read and approved the manuscript.

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Wu, XN., Xue, F., Zhang, N. et al. Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019. BMC Public Health 24 , 363 (2024). https://doi.org/10.1186/s12889-024-17948-6

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  • Liver cirrhosis
  • Chronic liver disease
  • Global burden of disease 2019

BMC Public Health

ISSN: 1471-2458

case study about liver disease

ORIGINAL RESEARCH article

The burden of liver cirrhosis in mortality: results from the global burden of disease study.

\nFei Ye

  • 1 Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
  • 2 Xiangya Nursing School, Central South University, Changsha, China
  • 3 Department of Respiratory, Beijing Tiantan Hospital, Capital Medicine University, Beijing, China
  • 4 Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, China
  • 5 Department of General Surgery, The Huaihua Second People's Hospital, Huaihua, China

Background: Liver cirrhosis-related death is a serious threat worldwide. The number of studies exploring the mortality trend of cirrhosis caused by specific etiologies was limited. This study aimed to demonstrate the pattern and trend based on the data of global burden of disease (GBD).

Methods: The data of cirrhosis mortality were collected from the GBD 2017. The Age standardized mortality rate (ASR) and estimated annual percentage changes (EAPC) were used to estimate the temporal trend of liver cirrhosis mortality by etiologies, regions, sociodemographic index (SDI), and sexes.

Results: Globally, mortality cases of cirrhosis increased by 47.15%. Although the global ASR of cirrhosis mortality remained stable during this period, the temporal trend varied in etiologies. The ASR of mortality caused by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis (NASH) increased with an EAPC of 0.17 (95% CI, 0.14–0.20), 0.20 (95% CI, 0.16–0.24), 1.00 (95% CI, 0.97–1.04), respectively. A decreasing trend of ASR was found among the causes of hepatitis B virus (BV) and other causes. The increased pattern was heterogeneous worldwide. The most pronounced increase trend was found in middle-high SDI regions and Eastern Europe. Contrarily, the most pronounced decrease trend was found in low SDI regions and Western Sub-Saharan Africa.

Conclusion: Cirrhosis is still a public health problem. The growth trend of cirrhosis mortality caused by HCV was slowed by promoting direct-acting antiviral therapy. Unfortunately, we observed an unfavorable trend in etiologies for alcohol consumption and NASH, which indicated that more targeted and specific strategies should be established to limit alcohol consumption and promote healthy lifestyles in high-risk countries, especially in middle-high SDI regions and Eastern Europe.

Introduction

Cirrhosis is the end stage of chronic liver disease ( 1 ). It has become one of the top 10 leading causes of death ( 2 ). More than 160 million people suffered from cirrhosis in 2017 around the world, and more than 0.8 million patients with cirrhosis died every year ( 3 , 4 ). Among the etiologies, more than half of the patients were attributed to hepatitis B (HBV) and hepatitis C virus (HCV) ( 5 , 6 ). Although the antiviral therapy has been continuously improved, the burden of cirrhosis caused by hepatitis is still quite large. Additionally, the decompensation rate and the survival of patients are also affected by the underlying etiologies ( 7 ).

Nowadays, the epidemiological distribution of cirrhosis etiologies varies worldwide due to socioeconomic development and antivirus therapy application. However, the detailed information was poorly described. Previous studies have indicated that HCV and alcohol were the major causes of cirrhosis in the United States, most European countries, and Japan. HBV caused cirrhosis mainly occurred in Asian-Pacific and African countries ( 8 ). As the morbidity and the mortality of cirrhosis are rising, it is important to study the epidemiological distribution of cirrhosis.

The Global Burden of Disease (GBD) is the most comprehensive worldwide observational epidemiological study. By exploring the trends from 1990 to 2017, we can find the challenges in health. Since Mokdad studied the burden of cirrhosis from 1980 to 2010 ( 6 ), there was no other study found in the database. Due to data additions, improvements, and methodological refinements made by GBD study 2017, it is now possible and timely to study the burden of cirrhosis in mortality and underlying etiologies. In the study, we discussed the mortality and the burden of cirrhosis worldwide from 1990 to 2017. For the first time, we demonstrated trends of cirrhosis mortality and provided estimates of annual sexual, geographical, and social liver cirrhosis rates for countries and territories.

In the study, the data of cirrhosis from 1990 to 2017 were collected from the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool) ( 9 ). The sociodemographic index (SDI) was used in our study. SDI used log lag-dependent income per capita , average educational attainment in the population over age 15, and the total fertility rate. Using SDI, the 195 countries and territories were divided into the low-SDI region, the low-middle-SDI region, the middle-SDI region, the high-middle-SDI region, and the high-SDI region. According to the geographical location, they were classified as 21 regions, including East Asia, Central Europe, North America-high income, etc. The analysis and estimated methods for studying the trend and burden of cirrhosis were mentioned by Liu et al. study ( 3 ). In brief, the “GBD compare,” a GBD visualization tool, was used to estimate the levels and trends of cirrhosis mortality. Additionally, human development index (HDI) was also used. It was a summary measure indicative of a long and healthy life, being knowledgeable and having a decent standard of living. In our study, HDI was collected and used in the study to match GBD data.

Statistical analysis

The age-standardized mortality rate (ASR) and estimated annual percentage change (EAPC) were used to explore the trend of cirrhosis mortality ( 3 ). Using ASR, we can obtain the mortality of liver cirrhosis and changes in etiology. EAPC was also used to evaluate the changes of ASR during the period ( 10 , 11 ). ASR increase was defined as a value of 95% CI of EAPC greater than 0. ASR decline was defined as a value of the 95% CI of EAPC <0. The ASR stability was defined as a value of the 95% CI of the EAPC containing 0. To explore the trend of ASR in etiologies, a complete linkage clustering in hierarchical clustering was used for EAPCs. Class spacing is defined as the maximum distance between two elements. In this complete linkage clustering, the two clusters with the smallest class spacing are combined preferentially, and the iteration ends when the result is unchanged. In our study, the end result was that 195 countries and territories were grouped into 4 categories, including significant increase, minor increase, remained stable or minor decrease, and significant decrease. By using hierarchy cluster analysis in the study, EAPC ≤ −1.34 was defined as a significant decrease group, −1.3 ≤ EAPC ≤ 0.92 was define as remained stable or a minor decrease group, 0.99 ≤ EAPC ≤ 3.38 was defined as a minor increase group, and EAPC≥ 3.87 was defined as a significant increase group. Additionally, a correlation analysis between EAPC and ASR–HDI was conducted to study the influential factors of EAPC. The R software (R 3.5.1, Institute for Statistics and Mathematics) and STATA/MP (STATA 13.1, StataCorp LLC) were used to analyze data. p <0.05 was considered to be statistically significant.

Mortality burden of global cirrhosis

Globally, the mortality of cirrhosis increased 47.15% from 1990 to 2017. India had the highest number of deaths in 2017 ( Figure 1A ). The highest growth of mortality was found in the United Arab Emirates (UAE), followed by Qatar and the Philippines. The mortality cases dropped the most in Hungary, with a decrease of 45.67%. During this period, the growth rate of mortality in China was 2.02% ( Figure 1B ).

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Figure 1 . The overall mortality cases of liver cirrhosis in 195 countries and territories. (A) The mortality cases in 2017 across the world. (B) The change in mortality cases from 1990 to 2017 across the world.

The ASR of liver cirrhosis mortality varied over the world. It was 16.66 per 100,000 in 1990 and 17.31 per 100,000 in 2017 ( Figures 2A,B , Table 1 ). In 1990, the ASR was higher in Western Sub-Saharan Africa and Central Europe, especially in Moldova ( Figure 2A ). In 2017, the ASR in Europe was higher ( Figure 2B ). Globally, the trend of ASR remained stable with an EAPC of 0.02 (95% CI, −0.01–0.06). Additionally, the ASR increased in male patients and decreased in female patients ( Table 1 ). Higher EAPCs were found in European countries, including Lithuania, Belarus, and Russia. The lowest EAPC is in Mali ( Figure 2C ). Based on the results of cluster analysis, 6 countries (3.08%) were grouped into a significant increase group, such as Lithuania, Belarus, and Armenia. Forty-one countries (21.03%) were classified as the minor increase group. In contrast, 30 countries (15.38%) were classified as the significant decrease group, including South Korea, Spain, Italy, and Qatar. Additionally, most of the 195 countries (60.51%) were grouped into the remained stable or minor decrease group ( Figure 3 ).

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Figure 2 . The global burden of liver cirrhosis mortality in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis from 1990 to 2017.

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Table 1 . The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis.

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Figure 3 . The temporal ASR trends clusters in etiologies related with liver cirrhosis for countries and territories.

For SDI regions, the mortality cases increased across the 5 SDI regions ( Figure 4 ). However, the ASR decreased in the low, low-middle, and high-SDI regions ( Table 1 ). For geographical regions, mortality cases increased in most of the regions except for Asia Pacific–high income and Western Europe ( Figure 5A ). During this period, the ASR in 11 of 21 regions demonstrated an increased trend, especially in Eastern Europe with the EAPC of 4.08 (95% CI, 3.41–4.75) ( Figure 6A ). In contrast, the most significant decrease of ASR was found in Western Sub-Saharan Africa ( Figure 6A , Table 1 ).

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Figure 4 . The liver cirrhosis mortality cases caused by different etiologies and SDI regions from 1990 to 2017.

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Figure 5 . The liver cirrhosis mortality cases and its proportion in different countries and SDI regions by etiologies. (A) The mortality cases of liver cirrhosis in different SDI regions and geographical regions by different etiologies. (B) The proportion of liver cirrhosis mortality for different etiologies in different SDI regions and geographical regions.

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Figure 6 . The EAPC of liver cirrhosis mortality at global and national levels. (A) The EAPC of liver cirrhosis mortality by regions and etiologies from 1990 to 2017. (B) The correlation between EAPC and ASR in 1990 and HDI in 2017.

For etiologies, HBV (29.03%) was the most important cause of cirrhosis in 2017, followed by HCV (25.87%) ( Figure 5B ). During the period, the proportion of HCV remained relatively stable. The proportion of HBV decreased from 31.93% in 1990 to 29.03% in 2017 ( Figure 5B ), but significant changes occurred in some regions. For instance, in the middle-high-SDI region, it decreased from 34.31 to 27.52%. Additionally, the proportion dropped from 41.93 to 38.14% in North Africa and the Middle East ( Figure 5B ).

Influential factors for EAPC in mortality of liver cirrhosis

The ASR in 1990 demonstrated the disease reservoir at the baseline. The HDI in 2017 demonstrated the level of available medical resources. A significant negative association was found between EAPC and ASR in 1990 when the ASR was limited to below 45 per 100,000 ( Figure 6B ). On the contrary, the association disappeared when the ASR was >45 per 100,000 ( Figure 6B ). Additionally, EAPC was positively correlated with HDI in 2017 when HDI was < 0.77. The relationship between EAPC and HDI disappeared when HDI was >0.77 ( Figure 6B ).

Mortality burden of liver cirrhosis due to HBV

Globally, ~29.03% of the mortality cases were caused by HBV in 2017 ( Figure 5B ). The proportion decreased from 31.93% in 1990 to 29.03% in 2017 ( Figure 5B , Table 1 ). The highest mortality case was found in India ( Supplementary Figure 1A ). The mortality rate in the United Arab Emirates increased the most ( Supplementary Figure 1B ). The ASR caused by HBV was significantly heterogeneous across the world, and the highest ASR was observed in Southeast Asia ( Supplementary Figures 2A,B , Supplementary Table 1 ). Contrary to the increasing trend of mortality cases, the ASR showed a downward trend with an EAPC of −0.35 (95% CI, −0.41– −0.29) ( Supplementary Table 1 ). The highest EAPC was found in Lithuania, and the lowest EAPC was observed in Mali ( Supplementary Figure 2C ). The mortality cases increased in 4 SDI regions except for the high-SDI region, while the ASR decreased in all 5 SDI regions ( Figure 4 , Supplementary Figure 2C , Supplementary Table 1 ). For geographical regions, the mortality cases caused by HBV increased in 16 regions. In parallel, the greatest EAPC was found in Eastern Europe, and the lowest EAPC was found in Southern Sub-Saharan Africa and Western Sub-Saharan Africa ( Supplementary Figure 2C , Supplementary Table 1 ).

Mortality burden of liver cirrhosis due to HCV

In 2017, the mortality cases increased 51.92% from 1990 to 2017 ( Supplementary Table 2 , Supplementary Figure 3A ). The proportion of mortality caused by HCV remained stable during the period ( Figure 5 ). But the number of deaths increased dramatically in the United Arab Emirates ( Supplementary Figure 3B ). In China, mortality cases increased 9.20% during the period ( Supplementary Figure 3B ). The mortality caused by HCV was under 10 per 100,000 in most countries ( Supplementary Figures 4A,B ). The highest ASR was found in Moldova in 2017, followed by Cambodia and Egypt ( Supplementary Figures 4A,B ). The ASR was on the rise with the EAPC of 0.17 (95% CI, 0.14–0.20) ( Supplementary Table 2 ). Among all countries, Lithuania had the highest EAPC, followed by Belarus and Armenia. Contrarily, the lowest EAPC was found in Mali ( Supplementary Figure 4C ). For SDI regions, the decrease trend of mortality caused by HCV was only observed in the low-SDI region with the EAPC of −0.65 (95% CI, −0.72– −0.59), and the most significant increase was found in the middle-high SDI region ( Supplementary Table 2 ). Among the 21 geographical regions, 12 regions displayed an increase trend, and the most significant increase was found in Eastern Europe, followed by Central Asia. Contrarily, the most significant decrease was observed in Western Sub-Saharan Africa ( Supplementary Table 2 ).

Mortality burden of liver cirrhosis due to alcohol consumption

In 2017, ~25.12% of deaths caused by cirrhosis were ascribed to alcohol consumption ( Supplementary Figure 5A , Table 1 ). The United Arab Emirates had the highest increase of mortality cases (434.87%), and China showed a 15.76% increase ( Supplementary Figure 5B ). The ASR minor increased from 1990 to 2017 ( Supplementary Figures 6A,B , Supplementary Table 3 ). The higher ASR was found in Moldova, Romania, and Ukraine in 2017. The highest increase in ASR was found in Lithuania. Contrarily, the highest decrease in ASR was found in Mali ( Supplementary Figure 6C ). The ASR decreased in low- and high-SDI regions, but it increased in low-middle, middle, and middle-high regions ( Supplementary Table 3 ). For geographical regions, ASR in nine regions was on the rise. Contrarily, 10 of 21 regions indicated a downward trend ( Supplementary Figure 6C , Supplementary Table 3 ).

Mortality burden of liver cirrhosis due to NASH

Globally, NASH precipitated nearly 8.92% of the total number of deaths from liver cirrhosis ( Table 1 ). The proportion of NASH-induced deaths increased in all 5 SDI regions ( Figure 5B ). In 2017, India had the largest number of deaths ( Supplementary Figure 7A ). The mortality cases in the United Arab Emirates increased most significantly, while the mortality of China increased 39.87% during the same period ( Supplementary Figure 7B ). Hungary demonstrated the highest decrease ( Supplementary Figure 7B ). The ASR increased significantly with the EAPC of 1.00 (95% CI, 0.97–1.04) ( Supplementary Figures 8A–C , Supplementary Table 4 ). The highest EAPC was found in Lithuania. In contrast, the most pronounced decrease in ASR was detected in Afghanistan ( Supplementary Figure 8C ). The ASR increased in 4 SDI regions, except for the low-SDI region ( Supplementary Table 4 ). Moreover, the significantly increased ASR was found in the middle-high region with EAPC of 1.81 (95% CI, 1.66–1.95) ( Supplementary Figure 8C , Supplementary Table 4 ). For geographical regions, most of the region (66.67%) showed an increase trend, especially in Eastern Europe. In contrast, Asia Pacific–high income and Sub-Saharan Africa demonstrated a decrease trend ( Supplementary Table 4 ).

Mortality burden of liver cirrhosis due to other causes

In 2017, deaths caused by other causes accounted for 11.06% (146.36 thousand) of total number of cirrhosis deaths ( Supplementary Figure 9A , Supplementary Table 5 ). In North America–high income, the proportion exceeded 20%, albeit the ASR was at a relatively low level ( Figure 5B , Supplementary Table 5 ). The mortality cases increased by 33.49% at the global level, and the most pronounced increase was observed in the United Arab Emirates ( Supplementary Figure 9B ). The global ASR decreased by an average 0.33% (95% CI, −0.37– −0.28). The highest ASR was observed in Moldova in 2017, while the highest increase of ASR was found in Armenia, followed by Lithuania ( Supplementary Figures 10A–C ). The ASR increased in middle-high, high-SDI regions and Australasia ( Supplementary Figure 10C , Supplementary Table 5 ). Contrarily, a decrease trend of ASR was observed in low, low-middle, middle SDI regions and Western Sub-Saharan Africa ( Supplementary Table 5 ).

Cirrhosis has been regarded as a major cause of the global health burden. The mortality caused by liver cirrhosis is gradually increasing ( 6 ). However, due to the heterogeneous pattern in risk factors of different countries, the mortality was obviously different ( 12 ). In the study, we demonstrated the key findings on cirrhosis mortality from GBD 2017. For the first time, we comprehensively estimated the trends of cirrhosis mortality for 195 countries and 5 SDI regions from 1990 to 2017. In general, mortality of cirrhosis increased by 47.15%. The trends were mainly dominated by an increase of HCV-caused cirrhosis, with a smaller contribution from alcohol use and NASH. Notably, the mortality cases induced by NASH increased 90.74%. Thus, the global health community should recognize the risk factors and pay more attention to the cirrhosis caused by alcohol consumption and NASH ( 6 ).

Cirrhosis caused by HBV was a major health burden worldwide. A previous study has indicated that about 248 million people were infected with HBV in 2010 ( 13 ). The mortality widely varied among countries. In some countries, HBV is the leading cause of cirrhosis, especially in East Asia and South Asia ( 13 ). Our study demonstrated that the ASR in Eastern Europe increased 3.69% per year. Contrarily, the ASR in Western Sub-Saharan Africa decreased 2.02% per year. This amazing variation might be partly explained by varying risk factors and transmission routes across countries. Additionally, our study showed that India and China had the highest number of deaths from HBV-related cirrhosis. However, mortality in India increased 102.6% from 1990 to 2017, while mortality in China decreased 7.6%. This might be related to the promoting HBV vaccine, screening of blood products, and obtaining safe injection methods in China. Moreover, socioeconomic development and improvement in people's cognition might also be related to the number of deaths. Unfortunately, despite the availability of effective vaccines and potent antiviral treatments, 76 countries out of 195 demonstrated an increased trend of ASR. This might be related to national HBV prevention policy, national immigration policy, national medical insurance policy, and national blood transfusion and blood donation policy ( 14 , 15 ). Consequently, these countries should be advised to readjust their HBV prevention strategies ( 16 ). Additionally, ensuring blood safety and medical device safety were also important to reduce mortality ( 14 , 17 ). Finally, the development of anti-HBV drugs might provide another way to reduce mortality of HBV-related cirrhosis ( 18 ).

Similar to previous studies, HCV was still the most important risk factor ( 19 , 20 ). Compared with the cirrhosis mortality caused by HBV, the ASR of cirrhosis mortality caused by HCV increased in most regions. Although the prevalence remained low in most European countries and America, the ASR had a more significant increase in Eastern Europe, Central Asia, and North America–high income ( 21 , 22 ). This might be due to the lack of effective vaccines. Moreover, a lack of treatment and poor efficacy were also closely related to the rising trend of mortality. Fortunately, direct-acting antiviral therapy has been on the market since 2014, and it was effective in more than 90% patients with HCV ( 23 ). Moreover, ensuring the safety of blood transfusion, injection drug use and therapeutic injections were also important for blocking HCV transmission ( 24 ). Now, the EAPC of HCV-related cirrhosis is significantly lower than other causes. Therefore, we predicted a possible downward trend in ASR of HCV-related liver cirrhosis.

The overall ASR of liver cirrhosis mortality caused by alcohol slightly increased, but decreased in low- and high-SDI regions. In our study, the increase was more significant in Eastern Europe, Central Asia, and North America–high income. This result was similar to a previous global survey ( 25 ). In our study, the ASR of cirrhosis mortality caused by alcohol decreased in Sub-Saharan Africa, although it increased in most regions. According to a previous global survey, the alcohol consumption was 17.1 liters per drinker in 2005, and the alcohol consumption was lowest in Africa ( 25 ). This result obtained by Liu et al. was consistent with our result ( 25 ). This might be related to the living habits, beliefs, and economic development of local people. Therefore, it might be necessary to formulate policies to limit alcohol consumption to reduce mortality and improve population-health outcomes. Moreover, we need to pay more attention to the drinking problem of young people and formulate relevant policies ( 26 ).

Although the mortality of cirrhosis caused by hepatitis decreased, the ever-increasing mortality of cirrhosis caused by NASH posed a continuing threat. In our study, the EAPC of cirrhosis mortality caused by NASH was highest among all etiologies. Moreover, the ASR increased in 4 SDI regions, and significantly increased in Asia. The increasing trend might be related to heavy and salty meat diet and westernized lifestyle ( 27 ). Similar results also demonstrated that a higher prevalence rate was found in China and other Asian countries in males and obese population ( 28 ). Based on a research, which indicated that the prevalence of NAFLD was higher in regions with a GDP <50,000 yuan and more than 100,000 yuan in China, the burden also might be closely related with national and personal economic levels ( 27 ). Thus, systemic treatment of metabolic diseases and loss of weight might effectively reduce the cirrhosis mortality caused by NASH. Additionally, we should closely monitor the patients suffering with cirrhosis caused by multiple causes, especially those who suffered with NASH and hepatitis ( 29 ).

In addition, our study showed that EAPC was negatively related with baseline ASR (<45/100,000), which indicated that countries with lower ASR had higher mortality of cirrhosis. This might be explained as follows. Firstly, the smaller the ASR, the more significant impact on the EAPC induced by ASR change. Secondly, countries with lower ASR might pay less attention to cirrhosis. Finally, with the focus on cirrhosis, EAPC increased with the increase of ASR, although there was no statistical significance. The HDI (< 0.77) was positively correlated with EAPC. This may be related to the improvement of living standards and medical technology; patients who were missed in the past had been diagnosed. As the HDI gradually increased, people became more aware of cirrhosis and invested more money and time in prevention and treatment, so the EAPC decreased.

In summary, cirrhosis remains a huge threat to public health. Although the ASR of liver cirrhosis mortality caused by HBV decreased, the number of patients who died from cirrhosis due to HBV was high, especially in developing countries. The ASR of cirrhosis mortality caused by HCV still increased, although the direct-acting antiviral therapy for patients with HCV has been used since 2014. Additionally, cirrhosis due to alcohol consumption and NASH was a global health concern that cannot be ignored. Thus, developing policies to limit alcohol consumption and advocate healthy living were important to reduce the mortality, especially in several “high-risk” regions. By conducting this study, we can roughly illustrate the disease burden of cirrhosis mortality worldwide and formulate more reasonable and effective prevention strategies.

Limitations

Although the GBD estimates demonstrated the burden of cirrhosis mortality, several limitations should be noted. First, some patients with cirrhosis were not included in the GBD database, and it might affect the results. Second, due to the data scarcity of GBD data, multi-etiological cirrhosis was not considered in this study. The interaction of several etiologies might play a role in promoting cirrhosis. For instance, alcohol consumption could worsen cirrhosis caused by hepatitis ( 30 ). Additionally, obesity and diabetes also increased the risk of cirrhosis caused by HCV ( 31 ). Therefore, further studies were needed to improve understanding of cirrhosis burden.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Author contributions

FY, MZ, and SL: study design. FY, JL, and SL: data collection. MZ, JL, and CR: data analysis. YG, XL, and DZ: figures. FY, MZ, and JL: manuscript writing. MZ and SL: manuscript proofing. All authors contributed to the article and approved the submitted version.

This study was supported by Chen Xiaoping Science and Technology Development Foundation (CXPJJH11900001-2019334) and Hunan Provincial Natural Science Foundation of China (No. 2018JJ3715) in collection and analysis of the data.

Acknowledgments

We are indebted to individuals who have participated in this study or have helped with this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2022.909455/full#supplementary-material

Supplementary Figure 1. The overall mortality cases of liver cirrhosis caused by HBV in 195 countries and territories. (A) The mortality cases of liver cirrhosis caused by HBV in 2017 across the world. (B) The change in mortality cases of liver cirrhosis caused by HBV from 1990 to 2017 across the world.

Supplementary Figure 2. The global burden of liver cirrhosis mortality caused by HBV in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality caused by HBV in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis caused by HBV from 1990 to 2017.

Supplementary Figure 3. The overall mortality cases of liver cirrhosis caused by HCV in 195 countries and territories. (A) The mortality cases of liver cirrhosis caused by HCV in 2017 across the world. (B) The change in mortality cases of liver cirrhosis caused by HCV from 1990 to 2017 across the world.

Supplementary Figure 4. The global burden of liver cirrhosis mortality caused by HCV in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality caused by HCV in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis caused by HCV from 1990 to 2017.

Supplementary Figure 5. The overall mortality cases of liver cirrhosis caused by alcohol consumption in 195 countries and territories. (A) The mortality cases of liver cirrhosis caused by alcohol consumption in 2017 across the world. (B) The change in mortality cases of liver cirrhosis caused by alcohol consumption from 1990 to 2017 across the world.

Supplementary Figure 6. The global burden of liver cirrhosis mortality caused by alcohol consumption in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality caused by alcohol consumption in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis caused by alcohol consumption from 1990 to 2017.

Supplementary Figure 7. The overall mortality cases of liver cirrhosis caused by NASH in 195 countries and territories. (A) The mortality cases of liver cirrhosis caused by NASH in 2017 across the world. (B) The change in mortality cases of liver cirrhosis caused by NASH from 1990 to 2017 across the world.

Supplementary Figure 8. The global burden of liver cirrhosis mortality caused by NASH in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality caused by NASH in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis caused by NASH from 1990 to 2017.

Supplementary Figure 9. The overall mortality cases of liver cirrhosis caused by other causes in 195 countries and territories. (A) The mortality cases of liver cirrhosis caused by other causes in 2017 across the world. (B) The change in mortality cases of liver cirrhosis caused by other causes from 1990 to 2017 across the world.

Supplementary Figure 10. The global burden of liver cirrhosis mortality caused by other causes in 195 countries and territories. (A,B) The ASR of liver cirrhosis mortality caused by other causes in 1990 (A) and in 2017 (B). (C) The ASR trend of liver cirrhosis caused by other causes from 1990 to 2017.

Supplementary Table 1. The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis caused by HBV.

Supplementary Table 2. The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis caused by HCV.

Supplementary Table 3. The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis caused by alcohol consumption.

Supplementary Table 4. The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis caused by NASH.

Supplementary Table 5. The mortality cases, age-standardized mortality, and temporal trend of liver cirrhosis caused by other causes.

Supplementary Table 6. The mortality cases and temporal trend of liver cirrhosis caused by each etiology in 195 countries and territories.

Abbreviations

GBD, global burden of disease; HBV, hepatitis B virus; HCV, hepatitis C virus; SDI, sociodemographic index; HDI, human development index; ASR, age-standardized mortality rate; EAPC, estimated annual percentage changes; CI, confidence interval; NASH, non-alcoholic steatohepatitis.

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Keywords: liver cirrhosis, global burden of disease study, mortality, ASR, EAPC

Citation: Ye F, Zhai M, Long J, Gong Y, Ren C, Zhang D, Lin X and Liu S (2022) The burden of liver cirrhosis in mortality: Results from the global burden of disease study. Front. Public Health 10:909455. doi: 10.3389/fpubh.2022.909455

Received: 31 March 2022; Accepted: 12 July 2022; Published: 11 August 2022.

Reviewed by:

Copyright © 2022 Ye, Zhai, Long, Gong, Ren, Zhang, Lin and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sushun Liu, surun9566@126.com ; surun9566@csu.edu.cn

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Clinical presentation of alcoholic liver disease and non-alcoholic fatty liver disease: spectrum and diagnosis

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are commonest causes of chronic liver disease in developing as well as developed countries. Their incidence has increased due to widespread easy availability of alcohol and sedentary life style of people. NAFLD is a spectrum which includes fatty liver (NAFL) which is considered benign disease, steatohepatitis (NASH) which indicates ongoing injury to liver and cirrhosis of liver. Similarly, ALD spectrum comprises simple steatosis, alcoholic hepatitis, and cirrhosis and its complications. Most of the time there is significant overlap between these diseases and clinical presentation depends upon the stage of liver disease. Most of the NAFLD patients are asymptomatic and diagnosed to have fatty liver while undergoing routine health check up. ALD requires significant history of alcohol intake which is supportive by radiological and biochemical tests. In both NAFLD and ALD patients, liver enzymes are seldom raised beyond five times the upper limit of normal. Liver biopsy is required for diagnosis of NASH as it is a histological diagnosis and sometimes in alcoholic hepatitis for confirmation if diagnosis is in doubt. Non-invasive markers and prognostic scores have been developed for avoiding liver biopsy in assessment and treatment response of NASH and alcoholic hepatitis patients.

Alcoholic (ALD) and non-alcoholic (NAFLD) liver disease are one of commonest etiologies of chronic liver disease all over the world ( 1 , 2 ). Easy accessibility to food and sedentary life style has led to obesity and associated problems in many countries. Alcohol consumption has increased in all countries which have led to increased morbidity, hospital admission and mortality from ALD. NAFLD spectrum includes fatty liver (NAFL), steatohepatitis (NASH) and cirrhosis. Similarly, ALD spectrum includes simple steatosis, alcoholic hepatitis (AH), combination of AH and cirrhosis and cirrhosis. These pathologic processes often overlap in NAFL and ALD. This review highlights the clinical spectrum and diagnosis of ALD and NAFLD ( 3 , 4 ).

The diagnosis of ALD is made based on reliable history of significant alcohol intake, clinical examination and laboratory features suggestive of significant alcohol intake. Definition of one standard alcoholic drink is any alcoholic beverage that contains 14 g of alcohol. In men consuming more than 4 standard drinks in any single day (or more than 14 drinks per week) is considered significant alcohol intake, similarly in women more than 3 standard drinks in any single day (or more than 7 drinks per week) is considered significant to cause alcohol-related problems ( 3 ).

However reliable history of significant alcohol intake is clinically challenging in many patients and making a diagnosis of ALD need assessment by screening tools and laboratory tests. Several screening tools are available that are validated in many studies and can be easily administered during a clinical visit are available to identify patients at risk for alcohol abuse. Off the many tools available alcohol use disorders identification test (AUDIT), AUDIT-consumption (AUDIT-C) and single question screening tool are the common screening tools in primary care setting. AUDIT is the most widely studied for detecting alcohol use disorders by many physicians ( 5 , 6 ).

No single laboratory or imaging study can confirm the diagnosis of ALD. A detailed history from relatives is crucial in suspecting liver disease due to alcohol. Furthermore, in the initial stages of disease most of the patients are completely asymptomatic, have no clinical signs of liver disease or early cirrhosis and these patients also have normal or slightly raised liver enzymes. Alcoholic patients may have co-existing risk factors for NAFLD such as obesity, diabetes and hepatitis C in patients with ALD. In these patients, significant amount of alcohol varies as even smaller amount of alcohol can cause significant liver injury ( 7 , 8 ).

In outpatient or inpatient department a diagnosis of ALD should be suspected in patients with a significant alcohol abuse who present with abnormal serum transaminases, level of aspartate aminotransferase (AST) which is greater than that of alanine aminotransferase (ALT), clinical finding of hepatomegaly with signs of chronic liver disease, and radiological evidence of liver steatosis or fibrosis/cirrhosis. Liver biopsy if done shows macrovesicular steatosis, fibrosis or cirrhosis or combination of these findings ( 3 ).

Liver enzymes in the diagnosis of ALD

Liver enzymes are not very useful for the diagnosis of patients with ALD as liver enzymes may or may not be elevated and the elevation does not correlate with severity of disease. However, the pattern of elevation is helpful in making a diagnosis of liver injury due to alcohol as AST is typically two to three times greater than ALT in these patients. Majority of times the levels of AST and ALT will not increase 5 times the upper level of normal and in any patient if liver enzymes level are more than 8-10 times the upper level of normal a second diagnosis should be considered ( 3 , 9 ). Another clue to diagnosis is elevated serum gamma-glutamyltranspeptidase (GGT) which is more than serum alkaline phosphatase level. If a patient has low serum albumin, low platelet and high prothrombin time then advanced fibrosis or cirrhosis need to be considered. However, it is pertinent to exclude other etiologies before making a definitive diagnosis of ALD, and relevant tests to exclude chronic viral hepatitis (hepatitis B and C), autoimmune hepatitis, hemochromatosis, Wilson disease and drug related hepatotoxicity be done. When the diagnosis is unclear, a liver biopsy may be considered to exclude other causes of liver disease.

Common hematological finding

Common findings include low platelet count, anemia with high mean corpuscular volume (MCV), low lymphocyte with raised neutrophil count, elevated erythrocyte sedimentation rate and an elevated prothrombin time (international normalised ration, INR). Elevated INR with low albumin suggests advanced liver disease. Patients with ALD frequently have evidence of iron overload which is reflected by elevated serum iron indices (ferritin and transferrin saturation) ( 10 ). Many biochemical markers have been evaluated for chronic alcohol consumption in these patients and include serum GGT, AST/ALT ratio, MCV and carbohydrate-deficient transferrin (CDT). CDT combined with GGT has sensitivity of about 80–90% in identifying patients with alcohol abuse. However, CDT levels may be fallacious with increasing disease severity and active smoking ( 11 ). Newer biomarkers such as ethyl glucuronide (metabolites of alcohol) can identify alcohol use up to 3–4 days after the last alcohol drink ( 12 ). However, till date no single biomarker has both high sensitivity and specificity for detecting chronic alcohol abuse. But a combination of markers may provide better diagnostic yield in the diagnosis for example, CDT in combination with other biomarker like GGT and/or MCV, improves sensitivity significantly ( 13 , 14 ).

Role of liver biopsy in diagnosis of spectrum of ALD

Liver biopsy is not necessary for the diagnosis of ALD except when other concomitant diseases are associated like viral disease or NAFLD or diagnosis in doubt due to unreliable history and laboratory findings. Significant history of alcohol intake along with radiological, biochemical and clinical findings are sufficient for diagnosis of ALD. Van Ness et al . ( 15 ) evaluated patients with raised liver enzymes and biopsy was done in them. Clinical findings and history of significant alcohol use have been found to be comparable to liver biopsy for the diagnosis of ALD with sensitivity of 91% and specificity of 97% ( 15 ).

AH is categorised in three terminologies. Definite AH is diagnosed on the basis of compatible clinical diagnosis and liver biopsy confirming the diagnosis; probable AH is defined as compatible clinical symptoms in absence of any confounding serology for another concomitant disease but without any liver biopsy and possible AH is defined as clinically suspicious for AH, presence of any confounding factors such as positive serology for virus, ischemic hepatitis, possible drug-induced liver injury, or uncertain alcohol abuse. It is proposed that patients with possible AH should undergo liver biopsy to confirm the diagnosis for any definitive pharmacologic interventions like steroids ( 3 , 16 ).

ALD is a broad spectrum of disease and it can range from totally asymptomatic disease (as fatty liver) to AH and advanced ALD which includes complications of cirrhosis like jaundice, ascites, variceal bleeding, hepatic encephalopathy, and hepatocellular carcinoma (HCC). Clinical features of ALD will vary according to disease severity in patient and is tabulated in Table 1 . Amount and pattern of alcohol intake strongly influences the clinical outcome of the patients. The clinical course of ALD is strongly influenced by alcohol abstinence and total abstinence is recommended at all stages of ALD ( 17 ). Even patients with decompensated cirrhosis have poor prognosis in those who continue to take alcohol compared to those who abstain from alcohol Most of the patients show frequent overlap of clinical and pathologic findings of ALD.

RUQ, right upper quadrant; USG, ultrasonography; CT, computed tomography; LAI, liver attenuation index; MRI, magnetic resonance imaging; CAP, controlled attenuation parameter; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyltranspeptidase; ULN, upper limit of normal; INR, international normalised ration; SOL, space occupying lesions.

Hepatic steatosis (HS) (fatty liver)

Fatty liver is a common finding in two third of heavy alcohol drinkers and it can be assessed radiologically as early as 7 days of initial alcohol consumption of more than 4 standard drinks per day ( 18 ). Fatty liver is asymptomatic in majority of patients or presents with mild right upper quadrant discomfort (RUQ). Liver function tests (LFTs) are either normal with normal liver enzymes or mildly increased serum aminotransferase levels and GGT. Liver enzymes (AST and ALT) never rise five times of upper normal value in majority of patients. Ultrasound of the abdomen shows steatosis of various grades (grade 1 to 3). Clinical history along with laboratory findings are sufficient to diagnose this condition and liver biopsy is not required in majority of these patients.

Liver biopsy if done shows macro vesicular steatosis predominantly in the centrilobular zone. There will be no significant inflammation or necrosis in fatty liver disease alone ( 19 ). However, the presence of steatosis on liver biopsy is no longer considered a benign condition. In a study by Teli et al . ( 20 ), patients with a histologic diagnosis of alcoholic fatty liver without AH were enrolled (n=88) and analysed retrospectively. Of these patients 18% progressed to fibrosis or cirrhosis when followed for a median of 10 years. Continued alcohol intake, female gender and histological features of megamitochondria and perivenular fibrosis and mixed macro and micro vesicular steatosis on liver biopsy were associated with development of fibrosis or cirrhosis. Similarly, in a systemic review by Parker et al . ( 21 ) mortality was 6% per year in patients with steatosis and hence steatosis no longer considered as benign condition.

AH is a severe form of liver injury with features of both hepatocellular injury and cholestasis that results from significant amount of alcohol consumption during a prolonged period of time. One should always keep a high suspicion for AH in a patient who presented with recent onset or worsening of jaundice in the setting of significant alcohol use in the past 8 weeks. Clinical diagnosis of AH is defined as rapid development or worsening of jaundice and liver-related complications like serum total bilirubin >3 mg/dL; ALT and AST elevated >1.5 times the upper limit of normal but less than five times the upper limit of normal with the AST/ALT ratio >1.5. Patient should be investigated for other concomitant liver disease to confirm the diagnosis of AH ( 3 ).

Symptoms of patients vary according to severity of AH and vary from mild and nonspecific in some patients to more severe like deep jaundice and hepatic encephalopathy in some patients. The diagnosis of AH can be made with good sensitivity and specificity thorough good reliable history, physical examination, and laboratory results. Liver biopsy is confirmatory if diagnosis is in doubt, but generally not required in day to day management of these patients. However liver biopsy (transjugular liver biopsy) is required in clinical trials or when diagnosis is in doubt.

Patient with mild AH may be asymptomatic or mildly symptomatic. Clinical examination of abdomen shows hepatomegaly and laboratory tests shows increased serum aminotransferase levels with the AST level twice or greater than the ALT level. Severe disease is associated with various grades of malnutrition, jaundice, fever, malaise, tender hepatomegaly with or without hepatic bruit. These patients with severe AH may develop or presents with ascites, hepatic encephalopathy, and acute kidney injury. Features of systemic inflammatory response syndrome (SIRS) are defined as presence of ≥2 of the following: heart rate >100 beats per minute, temperature >38 °C or <36 °C, respiratory rate >12 breaths per minute, and white blood cell count >12,000 or <4,000 mm syndrome (SIRS) may be present in these patients even when all relevant test for infections are negative ( 3 ).

AH has got poor short-term survival, need admission and constant monitoring with good nutrition. Many prognostic models have been developed which includes Maddrey’s discriminant function [MDF], Model for End-stage Liver Disease (MELD); age, serum bilirubin, INR, creatinine [ABIC], Glasgow Alcoholic Hepatitis Score [GAHS] and Lille’s score. These scores predict short-term mortality with varied sensitivity and specificity. Lille’s score also guides the physicians to stop steroid therapy if there is no significant benefit after one week of therapy to avoid side effects of it.

MDF score is commonly used by most of the physician due to ease at bedside, robust data in studies and can be calculated easily. MDF score of >32 predict short-term mortality of 30% at 1 month and 40% within 6 months. Higher the MDF means higher mortality. The GAHS has shown higher accuracy of 81% to predict 28-day overall survival compared to MDF score at day 1 of presentation. ABIC score classifies patients of AH in three groups as risk of mortality (based on 3 months) into low risks (0%), intermediate risk (30%), and high risk (75%). A MELD score >20 which defines severe AH predicts 20% mortality in few studies ( 22 - 24 ). In a study by Daswani et al . ( 25 ), 183 patients with severe AH was enrolled and median MELD score of 26 and had a 90-day mortality of 44% and outscores other severity scores.

Liver biopsy will show neutrophil predominant inflammatory infiltrate, Mallory hyaline, ballooned hepatocytes and varied degree of fibrosis or cirrhosis as overlap of these pathological findings are common. Perisinusoidal chicken-wire fibrosis and perivenular fibrosis is a distinctive feature of steatohepatitis.

More than half of the individuals admitted with AH have underlying cirrhosis and have a significantly increased risk of developing cirrhosis. In a study by Park et al . ( 21 ) progression of pre-cirrhotic disease to cirrhosis were 1% in patients with normal histology, 3% in patients with HS, 10% in patients with biopsy suggestive of steatohepatitis and 8% (3–19%) in patients with significant fibrosis. Mortality was significantly higher in patients with cirrhosis compared to those with steatosis.

Alcoholic cirrhosis

Alcohol is most common hepatotoxic agent and excess and continued intake of alcohol consumption increases the risk of developing cirrhosis. Different studies have shown different dosages as the cause of cirrhosis, however there is no clear dose-dependent relationship between alcohol dosage and risk of development of alcoholic cirrhosis as different factors which include genetic predisposition play a significant role ( 26 ). Various associated factors like viral hepatitis, obesity and various metabolic factors like diabetes also add to hepatotoxicity of alcohol and hence risk of cirrhosis ( 7 ). Patients with cirrhosis and portal hypertension may be completely asymptomatic in compensated cirrhosis or have peripheral signs of chronic liver disease if hepatic decompensation exists like ascites, peripheral edema, asterixis and/or mental confusion, jaundice, malnutrition features like reduced muscle mass and easy fatigability.

Patients with alcoholic cirrhosis may have jaundice as well as tender hepatomegaly if associated AH is present. These patients may or may not have ascites. If their hepatitis is severe patient will have asterixis and exhibit mental confusion on examination. On examination these patients may have ascites, splenomegaly, parotid enlargement, testicular atrophy, loss of pubic hairs and palmer erythema. In addition, patients with ALD typically have co-morbidities due to the concomitant toxic effects of alcohol on other organ systems and may have signs of peripheral neuropathy, muscle wasting and heart failure.

Liver biopsy is normally not required for the confirmation of alcoholic cirrhosis. However, if there is any doubt, no definitive history of significant alcohol intake in the recent past, associated AH which require steroid treatment or associated co infection with viral disease, one may need to do transjugular liver biopsy for proper evaluation of aetiology of liver cirrhosis. Alcoholic cirrhosis liver is characterized by small regenerative nodules (micronodular). Absolute abstinence of alcohol significantly improves long-term prognosis and hence should be reinforced in every patient ( 27 ).

ALD is one of the commonest causes of liver disease. ALD comprises spectrum which include fatty liver, AH, cirrhosis with or without AH with its complications like ascites, hepatic encephalopathy and HCC. Diagnosis of ALD requires good reliable history of significant alcohol abuse and excluding other causes of liver disease. AH with alcoholic cirrhosis is one of commonest of acute on chronic liver failure with associated organ failure and high short-term mortality. These patients present with rapid onset jaundice, ascites, hepatic encephalopathy and acute kidney injury. Liver biopsy is generally not required in majority of patients except when history of alcohol intake is not reliable, associated infection with viral disease, obesity or other hepatotropic or non-hepatotropic insult and treatment protocols under trials when definitive diagnosis of AH is required.

NAFLD is a spectrum that ranges from simple steatosis, steatohepatitis with or without fibrosis, cirrhosis and ultimately cirrhosis with HCC. NAFLD is characterised as presence of fat in the liver in the absence of significant alcohol use and other causes of fat in the liver like drugs, lipodystrophy, Wilson disease, parenteral nutrition, starvation and viral disease ( 28 ). The definition of significant alcohol consumption that has been used in various NASH clinical trials is ongoing or recent consumption of >14 standard drinks/week (14 gm alcohol is one standard drink) per week in women and >21 standard drinks/week in men. However according to European Association for the Study of the Liver, diagnosis of NAFLD requires the exclusion of both secondary causes and of a daily alcohol consumption ≥30 g for men and ≥20 g for women. NAFLD is often diagnosed incidentally on imaging and is asymptomatic in majority of the patients. NAFLD is currently considered as hepatic manifestation of metabolic syndrome ( 28 ).

Common terms used in spectrum of NAFLD

NAFLD: whole spectrum of fatty liver disease in persons without significant alcohol consumption and it includes fatty liver to steatohepatitis with or without fibrosis to cirrhosis.

NAFL: diagnosed when liver has ≥5% HS without ballooning of the hepatocytes or fibrosis on liver biopsy. The risk of cirrhosis and liver failure is considered minimal during follow-up.

NASH: diagnosed when liver has ≥5% HS with inflammation and ballooning of hepatocyte which indicate liver injury with or without fibrosis. NASH can progress to advanced fibrosis, cirrhosis and its complication like HCC.

NASH cirrhosis: is diagnosed when cirrhosis is diagnosed in a patient with current or previous histological evidence of steatosis or steatohepatitis.

Majority of patients with NAFLD have only liver steatosis which has benign course with no overall increase in liver related mortality. However, follow-up of fatty liver disease, 10–30% have the potential to progress to NASH and risk of further progression of liver disease and its complications. Patients with NASH cirrhosis are at risk (3% per year) of developing HCC and should be screened for HCC as patients with cirrhosis of other etiology ( 29 - 31 ). Multiple long-term studies suggest that patients with NAFLD with advanced fibrosis have 60% liver-related mortality compared with 9% in NAFLD without advanced fibrosis ( 31 , 32 ). Only 25–40% of patients with NASH will develop progressive liver fibrosis during follow up and of this only 20–30% will develop cirrhosis and its complications. The development of cirrhosis is associated with a poor prognosis as 10-year mortality rate is 20% for Child-Pugh A disease. Of these compensated cirrhosis patients 45% will decompensate within 10 years of diagnosis which further increase the mortality rate ( 31 ).

A meta-analysis of patients with suspected NAFLD (based on either radiological imaging or histology) and NASH with or without fibrosis found that patients with NAFLD and NASH were at higher risk of fatal and nonfatal cardiovascular events than those without NAFLD (random effect odds ratio 1.64; 95% CI, 1.26–2.13) and (odds ratio 2.58; 95% CI, 1.78–3.75) respectively ( 33 ).

Risk factor for fatty liver

Many risk factors are associated with NAFLD and include obesity, advanced age, male, ethnicity, genetics, composition of the diet like high sucrose and fructose), insulin resistance and recently gut flora dysbiosis and associated inflammation. Many components of metabolic syndrome (insulin resistance and dyslipidemia) are associated with NAFLD and NAFLD is now considered as one of the hepatic manifestations of Metabolic syndrome ( 34 - 36 ).

Spectrum of NAFLD

Insulin resistance and its interaction with adipose tissue and associated metabolic syndrome are considered as a key step in the pathogenesis of HS. Insulin resistance leads to dysregulation of many hepatic transcription factors and nuclear receptors, leads to alteration of lipid and glucose metabolism which in turn result in fatty liver. Singh and colleagues ( 37 ) enrolled biopsy-proven NAFLD (150 with NAFL and 261 with NASH). Patients with NAFL and no fibrosis at baseline progressed to stage 1 of fibrosis over 14.3 years whereas patients with NASH and no fibrosis at baseline had accelerated rate of progression to stage 1 of fibrosis over 7.1 years.

NASH is a histological diagnosis and required liver biopsy for its diagnosis. Presence of steatosis, lobular inflammation and hepatocyte ballooning is the histological feature that distinguishes NASH from simple steatosis. NASH risk factors and its progression to fibrosis and cirrhosis have been evaluated in many studies. NAFL advanced to NASH in 23% of cases over a period of 3 years based on histological diagnosis and follow up biopsies of 52 patients in a study by Wong et al . ( 38 ).

Risk factors which increase the likelihood of NASH in patients with NAFL include obesity, older age, female sex, non-African American race, diabetes mellitus, and hypertension ( 39 ).

Advanced fibrosis and cirrhosis

Long-term outcomes studies on natural history of advanced fibrosis and cirrhosis due to NAFLD are limited. In a meta-analysis the global incidence of advanced fibrosis in NASH patients was 67.9 in 1,000 person-years, with 41% of NASH patients experienced fibrosis progression (average annual progression rate of 0.09%). NAFLD patients progressed to cirrhosis in 25% of patients and 7% to end-stage liver disease ( 39 ). Study comparing patient of chronic liver disease due to viral hepatitis patients and HCC, patients with HCC due to NASH related cirrhosis tend to be older and are likely to be females ( 40 ). HCC in NAFLD patients has been associated with increasing age, obesity, diabetes, the PNPLA3 I148 M polymorphism ( 39 ).

Diagnosis and staging of NAFLD/NASH

Clinical features.

NAFLD is diagnosed based on clinical history, laboratory and radiological tests and confirmed on histological biopsy findings. However, in clinical practise abdominal imaging which reveals HS is sufficient for diagnosis of NAFLD if other diseases have been rule out. Most of the patient and physician have apprehension about liver biopsy for the diagnosis of NAFL and may not be required in each case after relevant blood tests. However liver biopsy is needed in differentiating NASH from simple steatosis as NASH is a diagnosis based on histology ( Figure 1 ). Diagnosis of NASH is important as NASH has a higher risk of disease progression as compared to simple steatosis and hence helps in treatment plan and prognostication of disease to the patient ( 39 ).

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Chart to follow for diagnosis of NAFLD. DM, diabetes mellitus; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; FIB-4, fibrosis-4 score; MR, magnetic resonance.

Most of patients with NAFLD are asymptomatic or have non-specific symptoms before the diagnosis is made. Fatigue and right upper abdominal discomfort are common presenting symptoms. Other symptom includes abdominal bloating, irregular bowel habits and decreased sleep. NAFLD is incidentally diagnosed in majority of the patients with abnormal liver enzymes or abnormalities on imaging performed for other reasons or are identified based on clinical features of the metabolic syndrome ( 41 , 42 ). Early diagnosis is often made by physician or hepatologist based on high index of suspicion in patients with metabolic syndrome or subtle elevations of liver enzymes. However liver enzymes may not be raised in many patients irrespective of severity of liver disease. People who develop decompensation of liver disease due to NAFLD may have symptoms of jaundice, ascites, variceal bleed or hepatic encephalopathy.

As NAFLD is considered as hepatic counter part of metabolic syndrome and. It has been seen in imaging that 70–80% of subjects with central obesity and 50–80% of patients with type 2 diabetes ( 43 , 44 ). NAFLD has also been reported in patients with dyslipidemia, obstructive sleep apnea syndrome, polycystic ovarian disease, hypopituitarism, vitamin D deficiency, hypopituitarism, hypothyroidism and hyperuricemia. These factors should also be assessed simultaneously while ordering the blood tests for the evaluation of NAFLD ( 45 , 46 ).

Most of the patients with NAFLD has normal or near normal LFTs. Patients may show mildly raised transaminases (ALT > AST) and/or GGT and even if elevated, the ALT typically falls (and AST may rise) as fibrosis progresses to cirrhosis. ALT level correlation with histological findings has poor sensitivity and specificity for the diagnosis of NASH ( 47 , 48 ).

Patients with abnormal LFTs, should be simultaneously evaluated for alcohol abuse, drug-induced liver injury, viral hepatitis, autoimmune liver disease, haemochromatosis, celiac disease and Wilson’s disease (in patients <45 years old). Autoantibodies may be detected in low titre in subjects with NAFLD [antinuclear antibody (ANA) <1:100 and/or anti-smooth muscle antibody (ASMA) <1:40] but these patients are associated with normal IgG levels. Few patients may have high ferritin levels and usually reflect underlying inflammatory activity or insulin resistance ( 49 ). Liver biopsy should be considered if there is any doubt in diagnosis.

Scoring symptoms: NAFLD is common symptomatic problem and liver biopsy for the diagnosis and follows up after treatment is not a preferred choice by many patients. To overcome this problem non-invasive scoring systems for the assessment and treatment follow up of fibrosis in NAFLD have been evaluated in many studies. Transient elastography, fibrosis-4 score (FIB-4), NAFLD fibrosis score (NFS), BARD (BMIAST/ALT-Diabetes), enhanced liver fibrosis panel (ELF), Fibro Meter, Fibro Test are few of the commonly used non-invasive scoring system. Of these scoring system NFS and FIB-4 have shown good sensitivity and specificity compared to liver biopsy in predicting advanced fibrosis in patients with NAFLD. These non-invasive scoring system like NFS and FIB-4 have been recommended by American Association for the Study of Liver Diseases (AASLD) in the diagnosis of fibrosis for NAFLD patients ( 28 , 50 - 53 ).

NAFLD is characterised by presence of hepatic fat accumulation after the exclusion of other causes of HS like hepatitis B and C, excessive alcohol consumption, drugs and parenteral nutrition and prolonged starvation. NAFLD clinical spectrum ranges from NAFL to NASH, advanced fibrosis, cirrhosis, and finally HCC in some patients. NAFLD is increasing all over the world so the NASH related cirrhosis and its complications. NASH related cirrhosis has become a common indication for liver transplantation. Most of the patients with NAFLD have associated metabolic comorbidities like obesity, type II diabetes, dyslipidemia, and metabolic syndrome. NAFLD patients are asymptomatic in majority of cases and are diagnosed on tests done for some other reason. Few patients with NAFLD may present with fatigue, dyspepsia, dull pain in right upper abdomen and hepatosplenomegaly. Morbidity and mortality in patients with NALFD correlate with fibrosis stage. In view of invasive nature of liver biopsy and reluctance from the patients to undergo repeated such procedure, non-invasive methods are commonly used. Non-invasive scoring systems are helpful at extremes of fibrosis but have poor sensitivity and specificity in diagnosis less advanced fibrosis. Liver biopsy is usually done for such cases to accurately determine the degree of fibrosis.

Acknowledgments

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of Interest: The authors have no conflicts of interest to declare.

Clinical Trials

Liver disease.

Displaying 82 studies

The purpose of this study is to evaluate an ultrasound technology that may be used to evaluate liver fibrosis.

The purpose of this study is to report the proportion of thiamine deficiency (as defined by the Mayo Clinic Laboratory reference range) in liver transplant patients.

The primary aim of this study is to use an MRI-based Muscle Assessment Score (MAsS), which includes both muscle volume and fat infiltration, at the transplant candidacy evaluation and other follow-up MRI examinations as clinically indicated, as an objective, standardized, and quantitative measure of muscle health and explore the link between muscle composition and adverse outcomes and mortality. In addition, there are growing numbers of high-risk donor livers, such as presenting with steatosis or exposed to prolonged ischemia time.

A secondary aim is to gather information on the association between transplant recipient muscle composition and donor liver characteristics ...

Will adult liver transplant patients who are provided with physical activity (walking) instructions increase their physical activity and perceive an improved quality of life?

The purpose of this study is to compare the accuracy of non-invasive MRE (Magnetic Resonance Elastography) with the results of liver biopsy and/or MRI (Magnetic Resonance Imaging).

Skeletal muscle abnormalities (sarcopenia) and frailty are common complications seen in patients with end-stage liver disease. The presence of these complications portends poor prognosis. The purpose of this study is to assess the impact of a formal home based video strengthening program (REST) on sarcopenia and frailty. We also want to assess the impact of this exercise program on complication rates, hospitalization, on quality of life (QOL) and on survival.

The purpose of this study is to improve international patient's understanding of the primary diagnosis and recommended treatment program, by reducing social, cultural and religious barriers that may hinder in our nursing education

 The purpose of this study is to implement a free-breathing hepatic MRE technique capable of being performed in as little as 0.8 seconds per slice which could significantly reduce the breath-hold requirements for typical MRE exams, establish a rapid imaging protocol, and improve clinical patient throughput.

The purpose of this study is to assess the impact of exercise on sarcopenia and frailty. The exercise that will be performed in this study will include either pulmonary rehabilitation or a formal home based video strengthening program

This Pilot study will enable development & assessment of a Polycystic Liver Disease-specific patient reported outcomes questionnaire (PLD-Q). Polycystic liver disease (PLD) is characterized by the formation of numerous cysts in the liver, and can lead to severe symptomatic hepatomegaly. It is common in patients with autosomal dominant polycystic liver disease (ADPLD) and autosomal dominant polycystic kidney disease (ADPKD).

The purpose of this study is to develop stem cells from cells within patients’ skin. Stem cells are a unique type of cell capable of converting into multiple other adult cell types. The stem cells will later be converted to liver cells and used to better understand liver disease and help develop treatments.

The primary purpose of this study is to develop an understanding of the prevalence, characteristics, and outcomes of major bleeding and clinically relevant non-maor bleeding in hospitalized patients with cirrhosis undergoing invasive procedures.

The purpose of this study is to evaluate the effects of plasma exchange using human serum albumin 5% (PE-A 5%) in acute-on-chronic liver failure (ACLF) subjects.

This study is being done to collect and store samples of blood from patients with liver disease for a research study to be able to find a new and better way to detect liver cancer.

The purpose of this study is to compare the incidence and frequency of elevated liver enzymes or parenteral (IV) nutrition-associated liver disease, in adult patients who are receiving daily versus three time per week soybean based intravenus (IV) fat emulsions.

The purpose of this study is to evaluate the diagnostic performance of Endoscopic Ultrasound (EUS) shear wave elastography in the assessment of liver fibrosis compared to magnetic resonance (MR) elastography.

Phase 2a, dose-ranging Study with PF-05221304 in Nonalcoholic Fatty Liver Disease (NAFLD)

Single arm, open-label study to provide Defibrotide to patients diagnosed with VOD. Defibrotide is no longer available though the Emergency Use IND mechanism (also known as compassionate use, or single patient named use). This protocol is the only mechanism by which Defibrotide can be made available to patients in the U.S.

The purpose of this trial is to evaluate the effectiveness and safety of 2 treatment regimens of CAM2029 versus placebo in patients with Polycystic Liver Disease (PLD). 

This research study will help us to improve our understanding of normal liver and gallbladder function. Additionally, this research study will be used to try to discover new therapies for treating liver disease using gallbladder cells.

This study is being done to better understand the relationship between inflammation in your AT, abnormal deposition of fat around your liver and how this affects its appearance and function and ultimately insulin resistance.

The purpose of this study is to determine if extracellular (EV) counts and content can differentiate Alcoholic Hepatitis (AH) from alcoholic liver disease as well as end stage liver disease due to other causes.

The goal of this study is to examine the current and (potential) future therapeutic relevance of PGx testing in established patients with liver disease seen in the Division of Gastroenterology/Hepatology, in order to improve patient clinical care at Mayo Clinic with more effective and efficient prescribing of medications.

The purpose of this study is designed to evaluate the effectiveness and safety of intravenous Lucassin® (terlipressin) versus a placebo for the treatment of type 1 hepatorenal syndrome in patients receiving standard of care albumin therapy.

The purpose of this study is to assess the repeatability and reproducibility of a set of specified MRI quantitative biomarkers.  The imaging biomarkers will cover an array of methods that could be applicable to non-alcoholic fatty liver disease (NAFLD), including liver fat, liver stiffness, corrected T1 relaxation time and body composition assessments. The data collected will be used to inform a decision of which of these biomarkers has sufficient precision to be advanced to NIMBLE Stage 2.

NIMBLE is a comprehensive, five-year collaborative effort to standardize, compare, validate, and advance the regulatory qualification of imaging and circulating biomarkers to diagnose and stage nonalcoholic ...

The study plans to follow three groups of cirrhotic patients from the time of hospital dismissal randomly divided into either receiving standard of care, using devices through which they can communicate with the clinical teams and using devices and structured follow-up over thirty days. The study aims to develop these devices so as to learn quickly about issues that patients and their caregivers are facing so that clinicans can intervene to stop unnecessary re-hospitalizations in this population.

The purpose of this study is to observe participants with hemophilia A and B who have and have not undergone liver transplantation. Participants will be asked to complete health related quality of life questionnaires and provide medical history.

About this study

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and a major public health issue in the US. It is estimated to affect 1 in 4 adults and it is most commonly found in people who are overweight or obese. Because it is a silent disease (without symptoms until end stage) and the lab tests can be normal, it can be missed in early stages. The fat in the liver can lead to inflammation and eventually scar deposition, which can progress to cirrhosis, liver cancer and ...

This is an Open Label, Multicenter, pilot clinical trial to assess the efficacy and safety of an oral selective Endothelin Receptor Antagonist (ambrisentan) in patients with portopulmonary hypertension.

Preliminary evidence suggests that ambrisentan is safe and effective in patients with portopulmonary hypertension. The goal of therapy for these patients is to improve symptoms of dyspnea and to improve pulmonary hemodynamics to a mean pulmonary artery pressure <35 mm Hg in order to make patients eligible for liver transplantation. Therefore, the primary endpoints for this study will include 6 minute walk distance (6MWD) and pulmonary vascular resistance (PVR).

Eligible subjects ...

The purpose of this study is to compare the frequency of occurance of kidney stone formation in liver disease patients compared to the general population.

The purpose of this study is to validate the Disease Severity Index (DSI) from the HepQuant SHUNT Liver Diagnostic Kit (Test) for likelihood of large esophageal varices.

This is a phase 3, multicenter, randomized, controlled, parallel-group, and open-label clinical study to evaluate the efficacy of standard medical treatment (SMT) + Albutein 20% administration versus SMT alone in subjects with decompensated cirrhosis and ascites. The study population will consist of subjects being discharged after hospitalization for acute decompensation of liver cirrhosis with ascites (or with prior history of ascites requiring diuretic therapy) with or without acute-on-chronic liver failure (ACLF) at admission or during hospitalization but without ACLF at discharge.

The purpose of this study is to determine the safety and efficacy of IDN-6556 compared to placebo in patients with diagnosed fat deposits in their liver (not caused by alcohol) and with abnormal liver tests

The purpose of this study is to identify clinical parameters that may help to predict clinical outcomes prior to the evolution of the admitting diagnosis for cirrhosis, a very important clinical observation for the long-term. We are not participating in optional blood collection. 

The primary objectives of this study are to evaluate the effect of Obeticholic Acid treatment compared to placebo on 1) histological improvement and 2) liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.

The primary purpose of this study is to collect and analze data evaluating the effectiveness of the alfapump to control ascites as determined by the reduction in the need for repeated paracentesis compared to baseline

TARGET-NASH is a longitudinal observational cohort study of patients being managed for NAFLD or NASH in usual clinical practice. TARGET-NASH will create a research registry of patients with NAFLD or NASH within academic and community real-world practices in order to assess the safety and effectiveness of current and future therapies.

The purpose of this study is to evaluate the safety, tolerability, and effectiveness of GS-9674 in adults who have primary sclerosing cholangitis.

This research study is being done to create a collection of biospecimens (blood, urine, cyst fluid, bile, kidney or liver tissue, etc.) that can be used to facilitate the conduction of research on polycystic kidney and/or liver disease.

This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study using avatrombopag to treat adults with thrombocytopenia associated with liver disease. The study will evaluate avatrombopag in the treatment of thrombocytopenia associated with liver disease prior to an elective procedure to reduce the need for platelet transfusions or any rescue procedure for bleeding due to procedural and post-procedural bleeding complications. Participants will be enrolled into 2 cohorts according to mean baseline platelet count and, within each baseline platelet count cohort will be further stratified by risk of bleeding associated with the elective procedure (low, moderate, or high) and hepatocellular ...

The purpose of this study is to examine the safety, tolerability, and efficacy of daily dosing with vidofludimus calcium over a 6-month period on the clinical course and progression of primary sclerosing cholangitis.

The purpose of this study is to to assess the effects of different Oral Vancomycin (OV) doses on the clinical and biochemical course in adult patients with Primary Sclerosing Cholangitis (PSC).

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood. Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms. Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual ...

The primary objectives of this study are to evaluate the safety and effectiveness of obeticholic acid treatment compared to placebo on both tissue structure improvement and liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.

The purpose of this study is to investigate the effectiveness of ultrasound imaging for staging liver steatosis, using liver fat content measured by MRI as the reference standard.

The purpose of this study is to demonstrate the safety and effectiveness of BMS-986036.in participants with NASH and stage 3 liver fibrosis.

A Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT-450/Ritonavir and Dasabuvir in Adults with Genotype 1b Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis.

The purpose of this study is to evaluate the safety and effectiveness of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

This is a research trial testing DUR-928 (an experimental medication). The purpose of the trial is to assess whether treatment with DUR-928 has any effect on the treatment of Primary Sclerosing Cholangitis (PSC). This trial will also assess safety (side effects).

The purpose of this study is to create a clinical database and bio-repository by obtaining blood, urine, and stool samples (e.g., biological samples) and personal health information from patients to use in future research studies related to alcoholic hepatitis or other diseases.

The first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related events).

The purpose of this study is to evaluate the effectiveness and safety of three treatment doses of CC-90001 (100 mg, 200 mg and 400 mg PO QD), compared with placebo, in NASH subjects with Stage 3 and Stage 4 fibrosis. This study is designed to assess response to treatment on measures of fibrosis and other efficacy parameters. It will also assess dose response and overall safety.

The purpose of this study is to evaluate the usefulness of combining a core liver biopsy guided by endoscopic ultrasound and stomach balloon placement by endoscope for the diagnosis and treatment of fatty liver disease and obesity.

The purpose of this study is to determine if there are differences in the metabolites (enzymes and other proteins) found in portal venous blood (blood in the portal vein, which delivers blood from the intestines to the liver), peripheral venous blood, and bile between individuals with liver disease undergoing liver transplantation and healthy donors. With this information, we may be able to better understand the importance and nature of the relationship between the gut (i.e. intestines) and the liver in the context of liver disease and identify pathways which may lead to the development of new and improved therapies for ...

The purpose of this study is to determine the impact of foam sclerotherapy of large, dominant kidney/liver cysts on quality of life outcomes and kidney/liver cyst volumes at up to 12 months of follow-up in patients with autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD).  

The purpose of this study is to investigate the potential effectiveness of dupilumab in the treatment of moderate-to-severe, chronic hepatic pruritus.

The purpose of this study is to assess a new drug to decrease liver fat in subjects with Non-Alcoholic Steatohepatitis or Non-Alcoholic Fatty Liver Disease.

The purpose of this study is to evaluate the safety and effectiveness of BMS-986036 in adults with nonalcoholic steatophepatitis (NASH) and compensated liver cirrhosis.

The purpose of this study is to facilitate discovery and development of novel biomarkers of risk and early detection, etiologic factors relating to liver disease, and novel targeted therapeutic and chemopreventive strategies for liver disease such as PSC, PBC, PLD, NAFLD, NASH, ASH, HCC, donors (non-diseased and diseased) for liver transplant or non-liver diseased subjects scheduled for surgery will serve as controls.

The primary aim of this study is to define a comprehensive digital phenotype that predicts risk for near-future relapse or relapse in alcohol use in patients with alcohol-associated liver disease.

The secondary aim of this study is to assess the relationship between this digital phenotype and markers of disease severity outcome, including MELD score and readmission rates.

The purpose of this study is toexamine whether increased sphingosine 1 phosphate : ceramide ratio and circulating bile acids are associated with HPS in patients with advanced liver disease.

This study is to evaluate the safety and efficacy of simtuzumab (GS-6624) in adults with compensated cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). It will consist of 2 phases:

  • Randomized Double-Blind Phase
  • Open Label Phase (optional)

A variety of liver insults lead to pathological changes in liver architecture that culminate in cirrhosis. While invasive liver biopsy was required to detect cirrhosis, the development of magnetic resonance elastography (MRE) has revolutionized our ability to detect liver fibrosis through non-invasive means that involve measurement of liver stiffness. However, a number of pathological findings occur in liver in response to various insults that precede cirrhosis and are clinically important to identify such as steatosis associated with NASH, inflammation associated with viral hepatitis, and congestion associated with cardiac hepatopathy. Detection of such entities provides essential diagnostic, prognostic, and treatment information ...

The purpose of this study is to investigate the effectiveness and safety of three dose levels of subcutaneous semaglutide for the treatment of patients who have fatty-liver disease not caused by alcoholism.

This study will evaluate whether simtuzumab (formerly referred to as GS-6624) is effective at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in participants with non-alcoholic steatohepatitis (NASH). It will consist of 2 phases: - Randomized Double-Blind Phase - Open Label Phase (optional)

The purpose of this study is to identify risk factors and potential predictors for NAFLD and NASH recurrence after liver transplantation.

We purpose of this study is to evaluate the diagnosis accuracy of the Controlled Attenuation Parameter (CAP) measured by FibroScan® (both with M and XL probes) in all patients who are undergoing liver biopsy for any liver disease.  

The purpose of this study is to identify the clinical characteristics, the management and the outcomes of acute kidney injury (AKI) in patients with cirrhosis worldwide. Additionally, to establish the severity of AKI across different regions, to identify precipitants of AKI across different centers, to identify the phenotypes of AKI across different centers, to evaluate differences in the management of AKI across different centers and their impact on clinical outcomes, and to assess outcomes of acute kidney injury (resolution of AKI, in-hospital mortality, 28-day mortality, 90-day mortality).

This study is a biobank of specimens and clinical data for use in current and future research to better understand the cholestatic liver diseases primary biliary cirrhosis/cholangitis (PBC) and primary sclerosing cholangitis (PSC).

The purpose of this study is to evaluate the effectiveness of 2 mg/kg and 4 mg/kg lean body mass (LBM) of belapectin (GR-MD-02) compared to placebo in preventing the development of esophageal varices.

The purpose of this study is to evaluate the safety of acamprosate in individuals with alcohol-use disorder (AUD) and alcohol-related liver disease.

The purpose of this study is to define the prevalence and impact of cognitive impairment and their impact on HRQOL in elderly patients with cirrhosis compared to elderly patients without cirrhosis.

This study is being conducted to evaluate the efficacy, safety and tolerability of GSK2330672 administration for the treatment of pruritus (itch) in participants with primary biliary cholangitis (PBC). Participants will be treated with either placebo or one of the 4 dose regimens of GSK2330672 (20 milligram [mg], 90 mg or 180 mg taken once daily or 90 mg twice daily). Subjects on GSK2330672 will also receive placebo tablets to maintain blinding. The total duration of a subject's participation will be up to 45 days of screening and 24 weeks of study including follow-up.

The purpose of this study is to determine if vasodilators for the lungs can decrease liver stiffness, shown by Magnetic resonance elastography (MRE).  The study also aims to identify any clinical, laboratory, echocardiographic, imaging, and hemodynamic parameters that connect with improved outcomes of cardiac and liver status after starting the pulmonary vasodilators.

The purose of this study is to assess the effectiveness, safety, and tolerability of LPCN 1148 in men with cirrhosis of the liver and sarcopenia.

The overall objective of this proposal is to conduct a systematic approach to dissect both genetic underpinnings and non-genetic factors in the development of adult autoimmune liver diseases including autoimmune hepatitis (AIH), overlap AIH with Primary Biliary Cirrhosis (AIH-PBC), overlap AIH with Primary Sclerosing Cholangitis (AIH-PSC), and drug-induced autoimmune-like hepatitis (DIAIH).

The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes ...

RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Giving everolimus together with lenalidomide may be an effective treatment for lymphoma.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving everolimus and lenalidomide together and to see how well they work in treating patients with relapsed or refractory non-Hodgkin or Hodgkin lymphoma.

The purpose of this study is to sequence patient germline and tumor samples, and nominate top neoantigen candidates using an in-house developed bioinformatics pipeline, and to validate the neoantigen candidates by laboratory assays using patient peripheral blood immune cells or serum.

GRAIL is using deep sequencing of circulating cell-free nucleic acids (cfNAs) to develop assays to detect cancer early in blood. The purpose of this study is to collect biological samples from donors with a new diagnosis of cancer (blood and tumor tissue) and from donors who do not have a diagnosis of cancer (blood) in order to characterize the population heterogeneity in cancer and non-cancer subjects and to develop models for distinguishing cancer from non-cancer.

The purpose of this study is to evaluate the challenges, behavioral patterns, and preferences of minority patient participation in clinical trials. Also, to develop and validate a personalized clinical trial educational platform to boost participation among underserved cancer patients.

Falls are common and catastrophic in cancer patients. Cancer patients are vulnerable to falls due to muscle loss. In prescribing exercise in a data driven manner to cancer patients, our hypothesis is this "prescription" for exercise will eventually be demonstrated to reduce the occurrence of injurious falls.

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Severe Acute Liver Injury: First Manifestation of Systemic Lupus Erythematosus

Affiliations.

  • 1 Department of Gastroenterology, GB Pant Hospital (GIPMER), New Delhi, India.
  • 2 Department of Pathology, GB Pant Hospital (GIPMER), New Delhi, India.
  • PMID: 38264573
  • PMCID: PMC10801300 (available on 2025-05-01 )
  • DOI: 10.1016/j.jceh.2023.101339

Systemic lupus erythematosus (SLE) is a common multisystem disease characterised by a wide variety of presentation patterns and complex manifestations. As a lymphoid organ, the liver plays an important role in the immune response and is a target of autoimmune responses. 1 SLE can affect the liver in approximately 25-60 % of patients during their disease course. 2,3 Liver dysfunction and SLE can present with complicated differential diagnoses. Liver dysfunction in SLE is usually mild and rarely leads to advanced liver diseases such as cirrhosis and liver failure. 4,5 Liver dysfunction in SLE is usually caused by non-SLE-related causes such as drug toxicity, fatty liver, alcoholism, and associated autoimmune hepatitis. However, primary liver involvement in SLE is also well-recognised. Patients with SLE who present with acute liver failure are rare. We report a rare case of SLE-associated acute severe liver injury along with a literature review.

Keywords: SLE; acute liver injury; liver dysfunction.

© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Case Based Question & Answer Session: Liver Diseases

Case Based Question & Answer Session: Liver Diseases

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Case Based Question & Answer Session on Liver Pathology, Abnormal LFTs and Jaundice, Hepatitis B, Hepatitis C, Autoimmune Hepatitis, Alcoholic and Nonalcoholic Liver Disease, Cholestatic Liver Disease, Liver Tumors, Cirrhosis, Portal Hypertension Bleeding, Ascites, Hepatorenal syndrome and Spontaneous Bacterial Peritonitis, Acute Liver Failure, Liver Transplant, Liver Disease in Pregnancy, Drug-induced Liver Injury, Vascular and Infectious Complications

October 13, 2020

Physician's Channel - Mount Sinai New York

Case Reports in Gastroenterology

Introduction

Case report, disclosure statement, a 25-year-old woman with type 2 diabetes and liver disease.

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Anders Ellekær Junker , Lise Lotte Gluud , Jens Pedersen , Jill Levin Langhoff , Jens Juul Holst , Filip Krag Knop , Tina Vilsbøll; A 25-Year-Old Woman with Type 2 Diabetes and Liver Disease. Case Rep Gastroenterol 1 December 2014; 8 (3): 398–403. https://doi.org/10.1159/000369968

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A 25-year-old female nurse was referred to our diabetes outpatient clinic with poorly controlled type 2 diabetes, obesity and elevated liver function tests (LFTs). Following a liver biopsy she was diagnosed with non-alcoholic steatohepatitis (NASH) and liver fibrosis. Treatment with subcutaneous injections of the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was initiated. After 46 weeks of treatment the patient had lost 16 kg, glycemic control was excellent and LFTs had normalized. Repeat liver biopsy and ultrasound showed reduction in hepatic fat content and inflammatory cells. The biopsy no longer fulfilled the criteria for NASH. The liver biopsies did not express hepatic GLP-1Rs using quantitative polymerase chain reaction. Our case suggests that liraglutide may benefit patients with NASH.

Elevated liver function tests (LFTs) in obese patients either with or without diabetes are a common clinical problem. The most frequent cause is non-alcoholic fatty liver disease (NAFLD), which represents both a diagnostic and therapeutic challenge. NAFLD is defined as a total liver fat content of more than 5%. The diagnostic gold standard is histology. The diagnostic criteria also include absence of significant alcohol intake (women: >20 g per day; men: >30 g per day) and use of steatogenic drugs (e.g. amiodarone and glucocorticoids) [ 1 ]. NAFLD is associated with an increase in mortality due to cardiovascular disease, irrespective of diabetes [ 2 ]. The prevalence is closely associated with obesity and type 2 diabetes. Up to 70% of patients with type 2 diabetes have NAFLD. The underlying pathophysiology of the development from simple steatosis to non-alcoholic steatohepatitis (NASH) is not fully understood. Excess hepatic fat infiltration seems to cause lipid-induced mitochondrial dysfunction and oxidative stress (lipotoxicity), which result in inflammation and fibrosis [ 3 ]. Studies have shown that NASH is associated with cirrhosis and hepatocellular carcinoma and is predicted to be the leading cause of liver transplantation by 2020 in the US [ 1 ].

Weight loss is an effective treatment of NASH, but is difficult to maintain for a majority of patients [ 2 ]. Current medical interventions are limited and seem to be associated with risk of side-effects. We present a case of severe liver disease in a young woman with type 2 diabetes. She was treated with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide with remarkable results on glycemic control, LFTs and liver histology.

A 25-year-old female nurse was referred to our diabetes outpatient clinic with poorly controlled type 2 diabetes, obesity and elevated LFTs. Her general practitioner had initiated treatment with metformin (1,000 mg twice-daily) and simvastatin (40 mg once-daily), but compliance was limited. At her first visit to our outpatient clinic her body weight was 90 kg and her body mass index 32.6 kg/m 2 . She was asymptomatic and clinical examination, fundus photography, filament testing and albumin/creatinine ratio revealed no signs of complications related to type 2 diabetes. Blood samples showed a glycated hemoglobin A 1c (HbA 1c ) of 8.9% (74 mmol/mol) and a fasting plasma glucose of 7.3 mmol/l. LFTs showed an alanine aminotransferase (ALT) of 196 U/l (reference range 10-45 U/l), an aspartate aminotransferase (AST) of 132 U/l (reference range 15-35 U/l) and an alkaline phosphatase (ALP) of 127 U/l (reference range 35-105 U/l). Lipids were elevated: total cholesterol 4.5 mmol/l, high-density lipoprotein 0.84 mmol/l, low-density lipoprotein 2.4 mmol/l and triglycerides 2.86 mmol/l. Bilirubin, international normalized ratio and albumin were within normal ranges. The patient had no history of alcohol abuse nor did she take any herbal drug. Abdominal ultrasound revealed increased echogenicity and poor visualization of the intrahepatic vessel walls, suggesting diffuse hepatic steatosis.

Statins were discontinued and the patient was strongly encouraged to be compliant with her metformin treatment (1,000 mg twice-daily). In addition neutral protamine Hagedorn insulin was initiated. The daily dose of basal insulin was gradually increased to 30 IU once daily.

After 8 weeks on metformin and insulin, HbA 1c had markedly improved to 6.3%, but LFTs except for ALP remained elevated (ALT 133 U/l, AST 76 U/l, ALP 69 U/l). The patient was then scheduled for a liver biopsy, which showed hepatic fat infiltration involving more than 66% of hepatocytes, ballooned hepatocytes, lobular inflammation as well as pericellular and periportal fibrosis. The histological diagnosis was NASH with a NAFLD activity score of 5 (score range 0-8) and a fibrosis score of 2 (score range 0-4) (fig. 1 a). Treatment with subcutaneous injections of the GLP-1R agonist liraglutide was initiated. The initial dose was 0.6 mg once daily subcutaneously. The dose was increased with weekly increments of 0.6-1.8 mg once daily during the following weeks. Liraglutide was well tolerated with no side effects such as nausea or vomiting. Insulin was gradually reduced and discontinued after 7 weeks.

Fig. 1. a Microscopic view of liver tissue (hematoxylin-eosin, ×100). Liver tissue with hepatic fat infiltration including >66% of hepatocytes, ballooning cells and lobular inflammation (NAFLD activity score 5) consistent with NASH. Pericellular and periportal fibrosis (fibrosis score 2). b Microscopic view of liver tissue (hematoxylin-eosin, ×100). Liver tissue with hepatic fat infiltration including 40-50% of hepatocytes, sparse lobular inflammation and no ballooning cells (NAFLD activity score 2) consistent with simple steatosis. Pericellular and periportal fibrosis (fibrosis score 2).

a Microscopic view of liver tissue (hematoxylin-eosin, ×100). Liver tissue with hepatic fat infiltration including >66% of hepatocytes, ballooning cells and lobular inflammation (NAFLD activity score 5) consistent with NASH. Pericellular and periportal fibrosis (fibrosis score 2). b Microscopic view of liver tissue (hematoxylin-eosin, ×100). Liver tissue with hepatic fat infiltration including 40-50% of hepatocytes, sparse lobular inflammation and no ballooning cells (NAFLD activity score 2) consistent with simple steatosis. Pericellular and periportal fibrosis (fibrosis score 2).

After 46 weeks of treatment with liraglutide, total weight loss was 16 kg, LFTs were in the lower normal range (ALT 29 U/l, AST 25 U/l, ALP 67 U/l), glycemic control was excellent (HbA 1c 5.6%) and the lipid profile was normalized without statin treatment. Repeat abdominal ultrasound showed diminished echogenicity, suggesting an overall reduction in steatosis. A repeated liver biopsy confirmed decreased hepatic fat infiltration (involving 40-50% of hepatocytes), no ballooned hepatocytes and only distinct lobular inflammation (fig. 1 b). The histology was no longer consistent with NASH, but pericellular and periportal fibrosis were still present (NAFLD activity score 3, fibrosis score 2).

To investigate the expression of hepatic GLP-1Rs in the present case, the baseline and the post-treatment liver biopsy were compared to liver tissue from another patient with type 2 diabetes but without steatosis, using quantitative polymerase chain reaction. No biopsies showed expression of GLP-1Rs.

The prevalence of obesity and type 2 diabetes is increasing, and obese patients with type 2 diabetes and elevated LFTs are regularly referred to outpatient clinics. This case illustrates the necessity for both diabetologists and hepatologist to be aware, and together take part in the diagnosis and treatment of NAFLD.

Abdominal ultrasound is recommended as a first-line evaluation if LFTs are elevated, but has high inter-observer variability and hepatic fat infiltration fat must exceed 20-30% to be detected. Magnetic resonance spectroscopy is expensive and not widely available, but can identify >5.5% hepatic fat infiltration. Transient elastography enhanced with controlled attenuation parameter can quantify liver steatosis, but has not been validated in large trials [ 4 ]. Imaging techniques cannot distinguish between simple steatosis and NASH. The final diagnosis requires histological assessment of a representative liver biopsy. The NAFLD fibrosis score can help identify patients with a high risk of NASH and fibrosis and, thus, eligible for liver biopsy. The score is based on body mass index, age, presence of diabetes and blood levels of ALT, AST, platelets and albumin [ 5 ]. If coexisting liver diseases to NASH are suspected, liver biopsy should always be considered [ 2 ].

The distinction between simple steatosis and NASH is of both prognostic and therapeutic value. The natural history of simple steatosis is benign from a ‘liver standpoint' and should be managed by treating comorbidities such as obesity, hyperlipidemia and insulin resistance. On the other hand, NASH per se increases the risk of liver-related death [ 6 ] and management should include liver specific treatment(s). In patients with NASH the primary goal is to reverse oxidative stress and reduce hepatic fat infiltration, thereby reducing insulin resistance and further reverse hepatic inflammation [ 2 ]. Weight loss and glycemic control are effective measures in NASH, but can be difficult to achieve and maintain for a majority of patients. Nevertheless, if weight loss can be obtained it improves insulin sensitivity and reduces LFTs. A weight loss of 3-5% improves steatosis and a 10% decrease in body weight reduces hepatic inflammation. In line with these considerations, bariatric surgery should be considered in patients who are overweight and have type 2 diabetes as well as NASH [ 7 ].

Metformin increases hepatic and muscular insulin sensitivity, but does not improve LFTs or liver histology in NASH. Pioglitazones reduce hepatic steatosis but are rarely used due to adverse events including heart failure, bladder cancer and loss of bone density [ 2 ]. One trial suggests that vitamin E 800 IU per day improves LFTs, steatosis, ballooning and inflammation, and vitamin E is recommended for NASH in non-diabetic subjects. However, emerging evidence suggests that vitamin E may increase mortality [ 2 ].

The use of GLP-1R agonists for patients with type 2 diabetes is increasing. These drugs are based on the incretin hormone GLP-1, which is released from enteroendocrine cells in response to food ingestion. Native GLP-1 acts via the GLP-1R (a G protein-coupled receptor expressed in several tissues) and plays an essential role in the maintenance of normal glucose homeostasis and regulation of appetite and food intake. The effects of the native hormone have been exploited through the development of stable GLP-1R agonists. These drugs have sustained effects on glucose levels, increase insulin secretion and reduce glucagon secretion, satiety, food intake and body weight [ 8 ]. Furthermore, a recent post hoc analysis concluded that liraglutide was well tolerated and safe to use in patients with type 2 diabetes and elevated LFTs [ 9 ]. In rodents, GLP-1R agonists reduce hepatic steatosis by suppressing enzymes involved in hepatic lipogenesis through activation of the 5′ adenosine monophosphate-activated protein kinase, and have been suggested to reduce hepatic expression of pro-inflammatory mediators [ 10 ]. Nevertheless, initial observations of the GLP-1R on human hepatocytes [ 11 ] have not been confirmed in subsequent studies [ 12,13 ]. As previously described, no liver biopsies from this case had expression of GLP-1R.

The patient in this report showed remarkable results after 46 weeks of treatment with a GLP-1R agonist. She lost 16 kg of body weight (from a baseline of 90 kg) and achieved normalized LFTs and lipid profile. Her hepatic fat infiltration was reduced by ∼30%, a decreased number of inflammatory cells were observed and, thus, she no longer fulfilled the criteria for NASH. Since no GLP-1Rs were found in the liver tissue, these improvements may be explained by indirect results of glucose metabolic improvement and weight loss induced by treatment with the GLP-1R agonist. In spite of the fact that we were unable to identify GLP-1Rs in liver tissue in the present case, some evidence suggests that GLP-1R agonists may have direct effects on hepatic steatosis (in vitro models) [ 10,11 ]. Furthermore, one other paper has investigated the effect of GLP-1R agonist on liver histology in NAFLD. Kenny et al. [ 14 ] presented a case series with eight biopsy-proven NAFLD patients who received exenatide 10 mg twice daily for 26 weeks. Repeat liver biopsies showed improved NAFLD activity scores of 1-2 in four patients, but no changed in fibrosis score. The patients also lost body weight and glycemic control improved. Cuthbertson et al. [ 15 ] treated 19 patients with exenatide 10 mg twice-daily and 6 patients with liraglutide 1.2 mg once daily for 6 month. Patients had a 42% relative reduction in intrahepatic lipid content assessed by magnetic resonance spectroscopy, independent of body weight loss but in correlation with a decrease in HbA 1c . However, the study was open-labeled, without a control group, and did not asses liver histology. Thus, there is some evidence suggesting that there may be a direct effect of GLP-1R agonists on hepatocytes, but this case does not allow for any conclusion regarding the potential direct or indirect effect of GLP-1 on the liver.

Options for the treatment of NASH are limited and hold risk of severe side effects. In this case, the GLP-1R agonist liraglutide was well tolerated and markedly improved LFTs and histology in this patient with type 2 diabetes and NASH. Randomized controlled trials are needed to evaluate whether the present findings hold promise for the treatment of NASH.

The authors declare no conflict of interest regarding this paper. There were no funding sources.

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Liver disease case studies: Case study level 1 – Alcoholic cirrhosis; alcohol withdrawal

In this chapter Case studies levels 1–3 explore the management of a patient with alcoholic liver disease. The patient has alcoholic liver cirrhosis and first presents with alcohol withdrawal (Case study level 1), then the patient’s risk of bleeding and treatment for the maintenance of alcohol abstinence are considered (Case study level 2). The patient then goes on to develop encephalopathy (Case study level 3). Case studies levels Ma and Mb consider two patients: one presents with TB and the other liver failure.

Case study level 1 – Alcoholic cirrhosis; alcohol withdrawal

Learning outcomes Level 1 case study: You will be able to:

  • describe the risk factors
  • describe the disease
  • describe the pharmacology of the drug
  • outline the formulation, including drug molecule, excipients, etc. for the medicines
  • summarise basic social pharmacy issues (e.g. opening containers, large labels).

Mrs MW, 59 years old, is divorced and unemployed. She was admitted to an acute medical ward at the hospital presenting with general malaise, a grossly distended abdomen, swollen ankles, and jaundice. It was also noted that she smelt of alcohol and was showing signs of alcohol withdrawal.

1. What is cirrhosis of the liver?

2. List possible causes of cirrhosis.

3. What other clinical signs and symptoms may Mrs MW present with?

4. What drug treatment, including dose, would you recommend for Mrs MW’s alcohol withdrawal? What recommendations would you make if the patient was unable to take the medication orally?

1       What is cirrhosis of the liver?

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury. It is an advanced stage of liver fibrosis that is accompanied by distortion of the hepatic vasculature.

2        What are the risk factors for developing primary dysmenorrhoea?

Causes of cirrhosis can usually be identified by the patient’s history combined with serological and histological investigation. Alcoholic liver disease and hepatitis C and B are the most common causes of cirrhosis.

The association of excessive alcohol consumption with liver disease has been recognized for centuries. After the identification of the hepatitis C virus and of non-alcoholic steatohepatitis in obese patients with diabetes, the diagnosis of cirrhosis without an apparent cause (cryptogenic cirrhosis) is rarely made. Genetic causes of cirrhosis include hemochromatosis and Wilson’s disease.

Epidemiological studies have identified a number of factors that contribute to the risk of developing cirrhosis. Regular (moderate) alcohol consumption, age older than 50 years, and male gender are examples that increase cirrhosis risk in chronic hepatitis C infection, and older age, obesity, insulin resistance or type 2 diabetes, hypertension and hyperlipidemia in non-alcoholic steatohepatitis.

3        What other clinical signs and symptoms may Mrs MW present with?

Cirrhosis is often asymptomatic until complications of liver disease are present. Mrs MW may present with itching, jaundice, dark urine, pale fatty stools, abdominal pain, nausea, fatigue, bleeding – such as nosebleeds, hepatic encephalopathy, hepatomegaly, ascites, distended abdominal veins, spider angiomata, palmar erythema and asterixis. She may also present with the signs and symptoms of alcohol withdrawal, which include irritability, anxiety, tachycardia, tremor, sweating, confusion, and hallucinations.

4        What drug treatment, including dose, would you recommend for Mrs MW’s alcohol withdrawal? What recommendations would you make if the patient was unable to take the medication orally?

Long-acting benzodiazepines (e.g. diazepam and chlordiazepoxide) are used to attenuate alcohol withdrawal symptoms but they also have a dependence potential. To minimize the risk of dependence, administration should be for a limited period only (e.g. chlordiazepoxide 20 mg 4 times daily, gradually reducing to zero over 7–14 days). Mild alcohol withdrawal symptoms may be treated with a lower starting dose, such as 15 mg four times a day. In all cases, the patient should be counseled about the proposed length of the treatment course . Benzodiazepines should not be prescribed if the patient is likely to continue drinking alcohol.

In patients unable to take medication by the oral route, diazepam may be administered by intramuscular or slow intravenous injection (into a large vein, at a rate of not more than 5 mg/min), at a dose of 10 mg, repeated if necessary after not less than 4 hours. Alternatively, diazepam may be administered via the rectal route as a rectal solution or suppository. The intramuscular route should only be used when both the oral and intravenous routes are not possible.

General references

  • Schuppan D and Afdhal NH (2008) Liver cirrhosis. Lancet 371: 838–851.
  • Heidelbaugh JJ and Sherbondy M (2006) Cirrhosis and chronic liver failure: Part II. Complications and treatment. American Family Physician 74: 767–776.
  • Joint Formulary Committee (2008) British National Formulary 55. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, March.
  • Vincent WR, Smith KM, Winstead PS and Lewis DA (2007) Review of alcohol withdrawal in the hospitalized patient: management . Orthopedics 30: 446–449.

Author: Caron Weeks [BPharm (Hons), MRPharmS, DipPharmPrac. Lead pharmacist – Medicine, Southampton University Hospitals NHS Trust] and Mark Tomlin [BPharm, MSc, MRPharmS (IPresc) Consultant Pharmacist, Critical Care, Southampton General Hospital]

  • Alcohol withdrawal
  • Case study for pharmacist
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  • liver disease
  • Pharmacy case study

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Cardiovascular Case Studies: Case study level Mb – Myocardial infarction

case study about liver disease

Noakhali Science and Technology University (NSTU)

ScienceDaily

Researchers use the eye as a window to study liver health

Researchers at Karolinska Institutet in Sweden have developed a method to study liver function and disease without requiring invasive procedures. After transplanting liver cells into the eye of mice, the cornea can be used as a window into the body to monitor liver health over time. The study is published in the journal Nature Communications .

Imagine if it were possible to study liver cells in a living organism without the need for invasive procedures. Researchers have now shown that this is possible in mice by transplanting small 3D cell cultures of liver cells, known as spheroids, into the anterior chamber of the eye. The cornea of the eye is then used as a window into the body to get clues about changes in the liver during the mouse's lifetime.

A marker for fatty liver disease

The researchers were able to show that the liver cells attach to the iris of the eye and are supplied with blood vessels and nerves necessary for their function and survival. They also retain their typical liver characteristics and appear to reflect the health of the animal's liver. For example, the spheroids in the eye were found to store fat in a similar way to the liver of the same animal when fed a high-fat diet, meaning that the implant could act as a marker for fatty liver disease.

"This is a unique approach that opens up new opportunities to study the role of the liver in metabolic diseases such as obesity, type 2 diabetes and fatty liver disease," says Noah Moruzzi, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and corresponding author of the paper. "In order to stop or delay disease progression, we need to identify early disease mechanisms, but it has previously been difficult to study the liver without using invasive methods."

Test different treatments

Metabolic diseases have increased dramatically in recent years and were previously associated with old age, but today they increasingly develop in younger individuals and obese children. These disorders share similar risk factors and are often presented together in patients with metabolic syndrome. Fatty liver and type 2 diabetes are characterised by dysfunctional lipid metabolism and blood sugar regulation, controlled by the liver and pancreas, respectively.

"Therefore, continuous and detailed monitoring of functional changes in these organs is essential to identify disease mechanisms," says first author Francesca Lazzeri-Barcelo, PhD student at the same department. "With the new platform, we can now monitor the development of fatty liver at the cellular level and we are excited to start using it to test different drugs and treatment strategies."

Powerful research tool

Professor Per-Olof Berggren's research group at Karolinska Institutet has been transplanting cells and mini-organs to the anterior chamber of the eye in mice since 2008.

"In recent years, our method has proven to be a powerful research tool for monitoring the insulin-producing pancreatic islets during the development of type 2 diabetes," he says. "Now the platform has been extended to liver research, which shows that there is potential to use the tool also in other medical areas."

The study was financed by, among others, the European Research Council (ERC), the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Jonas and Christina af Jochnick Foundation, the Swedish Diabetes Association, the Swedish Research Council and the Novo Nordisk Foundation.

Per-Olof Berggren is the co-founder and CEO of Biocrine AB. Coauthors Ingo Leibiger and Barbara Leibiger are consultants for the same company. Volker Lauschke is a co-founder, CEO, and shareholder of HepaPredict AB, as well as a co-founder and shareholder of PersoMedix AB. The remaining authors declare no competing interests.

  • Liver Disease
  • Chronic Illness
  • Diseases and Conditions
  • Today's Healthcare
  • Cholesterol
  • Liver transplantation
  • Hepatitis C
  • Hepatocellular carcinoma
  • High density lipoprotein

Story Source:

Materials provided by Karolinska Institutet . Note: Content may be edited for style and length.

Journal Reference :

  • Francesca Lazzeri-Barcelo, Nuria Oliva-Vilarnau, Marion Baniol, Barbara Leibiger, Olaf Bergmann, Volker M. Lauschke, Ingo B. Leibiger, Noah Moruzzi, Per-Olof Berggren. Intraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-45122-4

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  3. Case Study on Liver Cirrhosis || Case Presentation/ Nursing Care Plan #

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