A Review on Global Burden of Liver Diseases

Abstract

Liver disease represents a significant global health challenge, contributing substantially to morbidity, mortality, and economic burden. It encompasses a spectrum of conditions, including viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC). These diseases collectively account for millions of deaths annually, with disproportionate impacts in low- and middle-income countries. Viral hepatitis remains a leading cause, despite the availability of vaccines and antiviral therapies, while NAFLD is emerging as a major concern due to the global rise in obesity and diabetes. Alcohol abuse and environmental factors further compound the burden in many regions. Addressing liver disease requires coordinated efforts in prevention, early diagnosis, and effective management. Public health interventions, including vaccination, harm reduction strategies, and lifestyle modifications, are critical for reducing incidence and progression. Additionally, increasing access to advanced diagnostics, liver transplantation, and targeted therapies can improve patient outcomes. Comprehensive, global strategies are essential to alleviate the burden of liver disease and achieve sustainable health equity. This review highlights the epidemiology, risk factors, and challenges in combating liver disease, emphasizing the urgent need for collaborative action at the national and international levels.

Keywords

Introduction

Liver disease, a prevalent condition, is the ninth-largest cause of death in Western countries and accounts for 4% of all deaths globally. It includes cirrhosis, viral hepatitis, and liver cancer, causing approximately two million fatalities annually and accounting for 4% of all deaths globally. Women account for one out of every three liver-related deaths, with 600,000 to 900,000 fatalities attributable to liver cancer. Liver deaths may be underreported, with men accounting for almost two-thirds of liver-related deaths. The four main causes of liver disease associated with CLD are chronic hepatitis C virus (CHC), chronic hepatitis B virus (CHB), alcohol-related liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD). NAFLD, linked to obesity, is on the rise and is expected to do so in the future due to the pandemic of obesity. Liver illness has the greatest effect on the young, ranking as the 12^th most common cause of disability-adjusted life-years (DALYs) among individuals aged 25 to 49. Prompt diagnosis is essential in cases of serious illness, as it affects both the mother and the unborn child. NAFLD includes a wide range of medical conditions, with up to 75% of patients with type 2 diabetes (T2D) having NAFLD. ^[1]

Liver Diseases: Chronic liver disease (CLD) is a common condition resulting from severe alcohol use disorders, non-alcoholic fatty liver disease (NAFLD/NASH), chronic viral hepatitis, genetic causes like alpha-1 antitrypsin deficiency, hereditary hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing chollangitis (PSC), and autoimmune hepatitis (AIH). Genetic causes include alpha-1 antitrypsin deficiency, hereditary hemochromatosis, and Wilson disease. Autoimmune hepatitis destroys the liver parenchyma, with females more often affected. PBC causes inflammation and scarring in portal veins, while PSC reduces the size of intrahepatic and extrahepatic bile ducts. Autoimmune hepatitis is more prevalent in females and is identified by increased autoantibodies. Other causes include drugs like amiodarone, isoniazid, methotrexate, phenytoin, and nitrofurantoin, Vascular Budd-Chiari syndrome, and idiopathic/cryptogenic diseases. Treatment options include lifestyle changes, medication, and lifestyle changes. ^[2]

Alcohol Associated Liver Disease: Alcohol-associated liver disease is a progressive, inflammatory condition linked to prolonged alcohol use. It is not exclusive to heavy drinkers but can also affect moderate drinkers. Severe symptoms include subacute fever onset, hepatomegaly, leukocytosis, jaundice, coagulopathy, and impairment of liver function. Portal hypertension symptoms include ascites, hepatic encephalopathy, and variceal hemorrhage. If high alcohol consumption continues, the condition often worsens and eventually leads to cirrhosis. Alcoholic liver disease heals gradually over weeks to months if consumption is stopped. The prevalence of alcoholic liver disease is highest in European countries. Daily consumption of 30 to 50 grams of alcohol for over five years can cause the disease. At-risk drinking definitions include men over 14 drinks per week, women and those over 65 years, and significant drinking from a liver toxicity standpoint. ^[3]

Diagnosis of Alcohol Associated Liver Disease: Alcoholic liver disease (ALD) can be diagnosed through physical examination, laboratory findings, and histopathology. Hepatomegaly is the most common physical examination finding in patients with ALD, and patients with severe ALD may show jaundice, ascites, spider angiomata, splenomegaly, painful hepatomegaly, and a bruit over the liver. Decompensated cirrhosis is more likely to manifest when fibrosis worsens. Laboratory findings are similar to physical manifestations of ALD, but a single test anomaly is insufficient to diagnose alcohol-related liver damage. Most patients with alcoholic steatosis (ASH) will have elevated AST > ALT, but the specificity is reduced in cirrhosis. Histopathology of ALD is well-characterized, with benign steatosis, mallory bodies, sclerosing hyaline necrosis, ballooning hepatocyte degeneration with polymorphonuclear cell infiltration, and increasing fibrosis being common. Micronodular cirrhosis is the most common type caused by alcohol consumption, with mallory bodies found in 95% of biopsies. ^[4]

Treatment of Alcohol Associated Liver Disease:  Alcoholic liver disease management varies depending on the extent of injury. Isolated fatty liver requires abstinence, while alcoholic hepatitis requires supportive care. Treatment for decompensated alcoholic cirrhosis is limited to liver transplantation in a select subgroup. Abstinence from alcohol is crucial for both short-term and long-term survival, with a 7-year survival rate of 50% for those who continue to drink alcohol. Treatment of addiction requires a multidisciplinary approach, including an addiction specialist, primary care physician, and psychiatrist. Nutrition is essential for patients with progressive alcoholic liver disease, as they are malnourished due to factors like poor diet, anorexia, and encephalopathy. Parenteral nutritional support may be necessary in severe cases, but the survival benefit is not established. Portal hypertension may develop in patients with alcoholic cirrhosis and isolated alcoholic hepatitis. Liver transplantation is the second most common indication in the US, but identifying candidates with low risk of recidivism is crucial.Alcoholic hepatitis is an inflammatory liver injury with a high incidence of autoimmune markers. Corticosteroids, which possess potent anti-inflammatory properties, have been investigated for their use in treating alcoholic hepatitis. However, consensus on their use is lacking after over 12 randomized controlled clinical trials. Specific anti-TNF-? therapy has shown promise in initial pilot studies, but larger clinical trials have not yielded the same results. Oxidative stress is believed to contribute to Alzheimer’s disease (ALD), with alcohol mediating this through lipid peroxidation and depletion of antioxidant capabilities. Vitamin E deficiency, a common issue in ALD, has been found to have no significant improvements in liver function or mortality. ^[5]

Non-Alcoholic Fatty Liver Disease: Non-alcoholic fatty liver disease (NAFLD) is a liver condition where fat accumulates in individuals who consume little to no alcohol. It is part of a spectrum of liver conditions, including non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis or liver failure. Despite being the primary cause of chronic liver disease globally, there is limited public knowledge about NAFLD. Over the next decade, treatment options for NAFLD patients are expected to shift. Key studies have shed light on the disease’s natural history, diagnosis, and pathogenesis. NAFLD prevalence in the US is estimated to be 20%, with a range of 11.5% to 46% in the general population. NASH prevalence is between 2% and 3%, higher in white men. Obesity is a risk factor, with up to 90% of patients undergoing bariatric surgery having NAFLD and cirrhosis. ^[6]

Viral Hepatitis: Viral hepatitis, primarily Hepatitis B and C, is a major contributor to liver disease, causing chronic diseases, cirrhosis, and cancer. It affects 296 million people globally, with high endemicity in sub-Saharan Africa and East Asia. Hepatitis A, caused by the Hepatitis A virus, is self-limiting and primarily transmitted through fecal-oral routes. Although the global burden of Hepatitis A has decreased, it remains endemic in low- and middle-income countries. Control efforts focus on vaccination, sanitation, and public health education. Hepatitis B and C are major causes of liver disease globally, with over 296 million people living with chronic HBV infection. HBV is transmitted through blood, sexual contact, and mother-to-child transmission, leading to progressive liver damage, cirrhosis, and liver cancer. HCV, caused by the Hepatitis C virus, is a major contributor to liver disease, with 58 million people living with chronic infection. Addressing these burdens requires sustained efforts in prevention, early detection, and treatment. Hepatitis D, caused by the Hepatitis D virus (HDV), is a significant contributor to liver disease globally, particularly in regions with high Hepatitis B virus prevalence. It affects 15-20 million people, with the highest rates in sub-Saharan Africa, the Mediterranean region, the Middle East, and Central Asia. Chronic HDV infection leads to more severe liver disease, cirrhosis, liver failure, and hepatocellular carcinoma. There is no specific antiviral treatment for HDV, and the management of chronic infection remains challenging. Vaccination against HDV is the most effective strategy for reducing HDV-related liver disease. ^[7]

Diagnosis of Non-Alcoholic Fatty Liver Disease: Diagnosis of non-alcoholic fatty liver disease (NAFLD) involves a medical history, physical examination, blood tests, imaging studies, and liver biopsy. Medical history includes risk factors like obesity, type 2 diabetes, hypertension, dyslipidemia, and lifestyle habits. Physical examination may detect signs of fatty liver disease or metabolic syndrome. Blood tests, such as liver function tests, fasting blood glucose, lipid profile, and HbA1c, help identify metabolic risk factors. Imaging studies, such as ultrasound, CT scan, MRI, and FibroScan, can detect fatty infiltration and liver stiffness. Liver biopsy, considered the gold standard, assesses fat accumulation, inflammation, and liver damage, distinguishing between simple fatty liver and non-alcoholic steatohepatitis. ^[8]

Treatment of Non-Alcoholic Fatty Liver Disease: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the US, with no FDA approved pharmacologic medications or guidelines. Treatment of steatosis and insulin resistance involves managing obesity, dyslipidemia, and oxidative stress. Treatment targets antioxidants, probiotics, glutathione precursors, and anti-cytokines to reduce inflammation and oxidative stress. Weight loss can improve fibrosis, necroinflammatory alterations, and liver chemistries, while progressive weight reduction can reduce insulin levels and improve quality of life. Bariatric surgery is recommended for non-cirrhotic NAFLD patients who are morbidly obese, but it raises the possibility of liver failure. Pharmacologic therapy includes thiazolidinediones (TZDs), which increase plasma adiponectin levels, improving hepatic and peripheral insulin sensitivity. Metformin, a hypoglycemic medication used to treat type 2 diabetes, lowers both peripheral and hepatic insulin resistance by reducing hepatic gluconeogenesis, lipogenesis, and glucose reabsorption from the gut. However, there is conflicting evidence about biopsy-guided improvement in steatosis and NASH activity score. NAFLD is linked to obesity and metabolic syndrome, making lipid lowering agents beneficial. Gemfibrozil and statins have shown improvement in ALT levels in NAFLD patients. Ezetimibe, a drug that reduces serum TNF-? and hepatic lipid content, is being studied for human use. Liver transplantation is considered for NAFLD patients with end-stage decompensated liver disease, but it is not a permanent cure. Therapy should focus on weight management, diet, and glucose control. ^[9]

Primary Biliary Cholangitis: Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic autoimmune liver disease primarily affecting women. It causes progressive destruction of small bile ducts in the liver, leading to cholestasis, liver fibrosis, cirrhosis, and potentially liver failure. PBC is most common in middle-aged women, with higher prevalence in regions like Northern Europe and North America. The exact cause is not fully understood, but it is believed to involve genetic susceptibility and environmental factors. The global burden of PBC is rising, particularly in countries with improved diagnosis and awareness of autoimmune liver diseases. However, access to specialized care and newer therapies remains a challenge. ^[10]

Autoimmune Hepatitis: Autoimmune hepatitis (AIH) is a chronic, inflammatory liver disease caused by the body's immune system attacking its own liver cells, leading to liver damage, fibrosis, and potentially cirrhosis. Although the global burden is lower than viral hepatitis or alcohol-related liver disease, AIH remains a significant cause of liver disease, particularly in women. It is most commonly diagnosed in young women aged 15-40 and is generally higher in Western countries. AIH is treatable with immunosuppressive therapies like corticosteroids and azathioprine, but long-term use can have side effects and requires ongoing management. The global burden of AIH is impacted by factors such as delayed diagnosis, lack of access to specialized care, and healthcare system differences. ^[11]

Special Considerations: The global burden of liver disease is influenced by unique challenges and disparities in healthcare access, particularly in low- to middle-income countries. In low-resource settings, liver diseases like Hepatitis B, Hepatitis C, and liver cirrhosis often go undiagnosed and untreated, leading to higher rates of liver failure and mortality. Healthcare infrastructure disparities also contribute to uneven access to vaccines and therapies, resulting in persistent high rates in endemic regions. Socioeconomic factors, cultural and behavioral factors, and migration patterns further exacerbate the prevalence of liver diseases. Health equity is crucial in reducing the global burden of liver disease, requiring global efforts to improve healthcare infrastructure, increase access to vaccines and therapies, and implement targeted public health initiatives. ^[12]

Complications of Liver Disease: Liver diseases, including Hepatitis B, Hepatitis C, NAFLD, alcoholic liver disease, and autoimmune liver diseases, significantly contribute to global morbidity, mortality, and healthcare costs. These diseases often result in severe complications, such as cirrhosis, liver failure, and hepatocellular carcinoma (HCC), which are major contributors to liver-related mortality. Cirrhosis, characterized by the replacement of healthy liver tissue with scar tissue, increases the risk of portal hypertension, ascites, variceal bleeding, and hepatic encephalopathy. Liver failure, either acute or chronic, can lead to rapid deterioration in liver function and require urgent medical intervention. Hepatocellular carcinoma (HCC), a major complication and cause of liver-related death, is often diagnosed at advanced stages due to the lack of early symptoms. Hepatic encephalopathy, resulting from the liver’s inability to detoxify harmful substances, leads to neurological symptoms. These complications disproportionately affect individuals in lower-income regions and those with limited access to care, exacerbate health inequalities, and make early diagnosis, preventive care, and treatment critical to reducing the global burden of liver disease. ^[13]

Burden of Liver Disease In Africa: Liver disease in Africa is a significant burden due to both infectious and non-infectious causes. Hepatitis B is a major contributor, with sub-Saharan Africa having one of the highest global prevalences of chronic Hepatitis B infection. Hepatitis C is prevalent in parts of Africa, particularly in Egypt, due to mass treatment campaigns with unsterilized needles. Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease are also contributing to the burden, driven by increasing rates of obesity, diabetes, and urbanization. Limited access to healthcare impacts prevention and treatment, with specialized care, screening programs, and essential medications and treatments. Liver disease is often diagnosed at advanced stages, with limited treatment options and poor prognosis. Hepatitis E is a significant cause of acute viral hepatitis outbreaks in areas with poor sanitation and water quality. ^[14]

Projection And Challenges: The global burden of liver disease is growing, causing around 2 million deaths annually. Key drivers include hepatitis, cirrhosis, and liver cancer, which is projected to become the third leading cause of cancer-related deaths worldwide by 2040. Non-Alcoholic Fatty Liver Disease (NAFLD) is the leading cause, with a global prevalence of 25%-30% and rising in low- and middle-income countries. Viral hepatitis B and C continue to contribute, and alcohol-associated liver disease is also increasing. Challenges include delayed diagnosis and treatment, insufficient public awareness, limited access to antiviral therapies, and inconsistent implementation of prevention strategies. ^[15]

CONCLUSION:

Liver diseases constitute a significant global health burden, contributing to high rates of morbidity, mortality, and economic strain worldwide. The increasing prevalence of modifiable risk factors such as obesity, harmful alcohol consumption, and viral hepatitis, compounded by genetic predispositions, underscores the need for urgent and comprehensive action. Despite advancements in medical research and public health initiatives, disparities in access to care, early diagnosis, and treatment remain substantial, particularly in low- and middle-income countries. This calls for a renewed focus on prevention, including lifestyle interventions, vaccination programs for hepatitis, and effective policies to curb alcohol misuse and the obesity epidemic.

Addressing the global burden of liver disease demands a collaborative, multi-disciplinary approach involving governments, healthcare systems, researchers, and communities. Enhanced funding for research, equitable access to healthcare, and public health campaigns to raise awareness are critical to achieving meaningful progress. Furthermore, the development of affordable diagnostic tools and innovative therapeutics can significantly reduce disease progression and improve outcomes. By prioritizing equity and fostering international cooperation, it is possible to reduce the disparities in liver disease outcomes and move toward achieving the World Health Organization’s vision of eliminating viral hepatitis by 2030, ultimately improving global health and well-being.

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