Viral hepatitis causes about 1.3 million deaths a year (2022 estimate), a toll comparable to tuberculosis and making it the second leading infectious cause of death worldwide. Hepatitis B accounts for about 83% of these deaths and hepatitis C for about 17%. Hepatitis B is concentrated in the Western Pacific and African regions, where about 102 million and 64 million people respectively are chronically infected. Hepatitis C is found in every region, with large differences between and within countries.
Causes of chronic liver disease
The mix of causes varies with where you are. The table below compares two hospital populations. They are single-centre series, not national figures, so they show how different the pattern can be rather than giving true population rates.
| Northeastern Malaysia (Hospital Universiti Sains Malaysia, 2023) | East coast USA (Johns Hopkins, 2023) |
|---|---|
| Viral hepatitis 62.1% | Viral hepatitis |
| Metabolic liver disease 25.4% | Alcohol |
| Cryptogenic 5.9% | Metabolic (NAFLD, now MASLD) |
| Alcohol 3.6% | Autoimmune hepatitis |
| Autoimmune hepatitis 2.1% | Biliary disorders |
| Drugs and toxins 0.9% | Drugs and toxins |
Chronic viral hepatitis is caused mainly by hepatitis B and hepatitis C (and hepatitis D, which needs hepatitis B). CMV, EBV and yellow fever can injure the liver but typically cause acute, not chronic, hepatitis.
Metabolic liver disease is mainly what used to be called non-alcoholic fatty liver disease (NAFLD). In 2023 it was renamed metabolic dysfunction-associated steatotic liver disease (MASLD), and non-alcoholic steatohepatitis (NASH) became MASH. It often occurs with diabetes or the metabolic syndrome.
Drugs that more commonly cause chronic liver injury include methotrexate, amiodarone and nitrofurantoin.
Chronic biliary disorders include primary biliary cholangitis (formerly called primary biliary cirrhosis) and primary sclerosing cholangitis.
Less common causes include alpha-1 antitrypsin deficiency, galactosaemia, glycogen storage diseases, cystic fibrosis, porphyria, Wilson disease and haemochromatosis.
From cause to disease
Whatever the cause, chronic liver disease distorts the liver’s normal architecture. Persistent inflammation, repeat regeneration and fibrosis change how blood and bile move through the organ, and with it the pressures inside the vessels and canaliculi. To see why different injuries damage different parts of the liver, it helps to start with how the liver is organised.
The lobule and the acinus
The classic unit of liver structure is the lobule: a hexagon with a central vein in the middle and a portal triad (hepatic artery, portal vein and bile duct) at each corner.
A more functional view uses the acinus, which follows the direction of blood flow. Blood enters the sinusoids from the terminal portal venule and hepatic arteriole, flows past the hepatocytes, and drains into the central vein. This divides the hepatocytes into three zones according to how soon they receive blood:
- Zone 1 (periportal) is nearest the portal triad. It receives blood first, with the most oxygen and nutrients.
- Zone 2 lies in between.
- Zone 3 (pericentral) is nearest the central vein. It receives blood last, with the least oxygen.
Zonation: different zones, different work
Hepatocytes in different zones do different jobs. Zone 1 cells, with the most oxygen, are especially active in gluconeogenesis, fatty acid oxidation and oxidative energy metabolism, and they are the main site of urea synthesis (the ammonia absorbed from the gut is largely cleared here). Zone 3 cells, with the least oxygen, are more active in glycolysis, lipid synthesis, glutamine synthesis and the metabolism of drugs and other xenobiotics. Zone 2 cells show features of both.
Because the zones differ, so does their vulnerability. In a published review of liver zonation, pericentral injury includes MASLD, which begins with fat in zone 3, alcohol and drug toxicity and paracetamol overdose, and periportal injury includes autoimmune hepatitis, primary biliary cholangitis and iron overload. These patterns are general, and real injuries often overlap zones.
Human hepatocyte gene-expression profiles made by bulk RNA sequencing suggest the periportal and pericentral zones are shaped in part by gut-derived toxins and by xenobiotic metabolism, respectively.
Bile as an excretory route
Hepatocytes secrete bile, and the ducts then modify it. It contains bile salts, bilirubin, phospholipids, cholesterol and many other solutes, in a fluid that is about 95% water. Bile is also the main route by which the liver removes lipophilic xenobiotics, drugs and toxins, along with bilirubin and bile salts.
What shapes the zones
The oxygen gradient from the portal to the central side is present in almost all conditions. Hypoxia-inducible factors adapt gene expression to the local oxygen level, and they interact with other zonation pathways: WNT/β-catenin, hormone and growth-factor signalling, Hippo and hedgehog. Some of these depend on ligands made by cells other than hepatocytes. For example, liver endothelial cells contribute WNT ligands, and cholangiocytes and stellate cells secrete hedgehog ligands.
Putting it together
Whether you divide the liver into lobules or acini, the point is the same: blood delivers a gradient of oxygen, nutrients and toxins across the tissue, and hepatocytes at different positions have different jobs and different exposures. A chronic injury therefore tends to start where the exposure or the metabolic stress is greatest, and over time chronic inflammation, regeneration and fibrosis distort the architecture itself.
About the images. The two figures in this post are original schematic diagrams drawn for The Good Doctor. They are not reproductions of any published figure. They are simplified for teaching and not to scale.
References
- World Health Organization. Global hepatitis report 2024 (as summarised by PAHO, 10 April 2024). https://www.paho.org/en/news/10-4-2024-who-sounds-alarm-viral-hepatitis-infections-claiming-3500-lives-each-day
- World Health Organization. Hepatitis B fact sheet. https://www.who.int/news-room/fact-sheets/detail/hepatitis-b
- Abdullah S, Zaleha S, Hassan MN, Ramli M, Abdullah M, Noor NHM. Red blood cell alloimmunization and its associated factors among chronic liver disease patients in a teaching hospital in northeastern Malaysia. Diagnostics. 2023;13(5):886. https://doi.org/10.3390/diagnostics13050886
- Johns Hopkins Medicine. Chronic liver disease/cirrhosis.
- Khalili M, Burman B. Liver disease. In: Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th ed. Lange.
- Cunningham RP, Porat-Shliom N. Liver zonation: revisiting old questions with new technologies. Front Physiol. 2021;12:732929. https://www.frontiersin.org/articles/10.3389/fphys.2021.732929
- Boyer JL. Bile formation and secretion. Compr Physiol. 2013;3(3):1035-1078. doi:10.1002/cphy.c120027
- Kietzmann T. Liver zonation in health and disease: hypoxia and hypoxia-inducible transcription factors as concert masters. Int J Mol Sci. 2019;20(9):2347. https://doi.org/10.3390/ijms20092347
- American Association for the Study of Liver Diseases. New MASLD nomenclature. https://aasld.org/new-masld-nomenclature