Chronic Liver Disease

Viral hepatitis caused 1.34 million deaths in 2015, a number comparable to deaths caused by tuberculosis and higher than those caused by HIV. The epidemic caused by Hepatitis B (HBV) affects mostly the African and Western Pacific regions. The epidemic caused by Hepatitis C (HCV) affects all regions, but with major differences between and within countries. The Eastern Mediterranean Region and the European Region have the highest reported prevalence of HCV.¹

Causes of chronic liver disease in order of frequency according to geographical location, here Malaysia² vs USA.³

Northeastern Malaysia2	East coast USA3
viral hepatitis 62.1%	viral hepatitis
metabolic liver disease 25.4%	alcohol
cryptogenic 5.9%	NAFLD
alcoholic 3.6%	autoimmune hepatitis
autoimmune hepatitis 2.1%	biliary disorders
drugs / toxins 0.9%	drugs / toxins
other –	other –

Other less common causes include alpha-1 antitrypsin deficiency, high blood galactose levels, glycogen storage diseases, cystic fibrosis, porphyria, Wilson disease, and hemochromatosis. The causes of chronic viral hepatitis are primarily hepatitis B and hepatitis C but also cytomegalovirus (CMV), Epstein Barr virus (EBV), and Yellow Fever. Metabolic liver disease is primarily non-alcoholic fatty liver disease often seen coexistent with conditions like diabetes mellitus or the metabolic syndrome. The drugs that more commonly can cause chronic liver disease are methotrexate, amiodarone, and nitrofurantoin. The chronic biliary disorders include primary biliary sclerosis and sclerosing cholangitis.

---

To the pathophysiology of liver disease

The pathophysiology of chronic liver disease relates to a distortion in its histo-architecture from chronic inflammation, regeneration, and fibrosis affecting intravascular and intracanalicular pressure dynamics.⁴ Recall the structure of the functional unit of the liver, the lobule, with its central vein and portal triads.:

Physiologically, it may be more useful to think of liver architecture in terms of washout zones in the liver lobule (i.e., in a portal-to-central direction of the blood flow) so to arrive at the conception of the acinus, crossing two lobules with both triads and central veins at polarised peripheries of paracentral zones:

Blood entering the sinusoids from a terminal portal venule or hepatic arteriole flows past hepatocytes closest to those vessels first (termed zone 1 hepatocytes) and then percolates past zone 2 hepatocytes (so called because they are not the first hepatocytes reached by blood entering the hepatic parenchyma). The last hepatocytes reached by the blood before it enters the central vein are termed zone 3 hepatocytes. Thus, the microscopic organization of the liver can be viewed in terms of functional zones. A liver acinus is defined as the unit of liver tissue centred around the portal venule and hepatic arteriole whose hepatocytes can be imagined to form concentric rings of cells in the order in which they come into contact with portal blood, first to last. Hepatocytes at either extreme of the acinus (zones 1 and 3) appear to differ in both enzymatic activity and physiologic functions. Zone 1 hepatocytes, exposed to the highest oxygen concentrations, are particularly active in gluconeogenesis and oxidative energy metabolism. They are also the major site of urea synthesis (because freely diffusible substances such as ammonia absorbed from protein breakdown in the gut are largely extracted in zone 1). Conversely, zone 3 hepatocytes are more active in glycolysis and lipogenesis (processes requiring less oxygen). Zone 2 hepatocytes display attributes of both zone 1 and zone 3 cells.⁵

But this conception has again been turned on its head to accommodate the concept of zonation, which again is based on the washout through the liver lobule. This understanding of liver zonation is considered now the essential understanding of the pathophysiology of chronic liver disease. As impressed by Cunningham and Porat-Schliom, “using bulk RNA-seq, human hepatocyte gene expression profiles have been created showing that periportal and pericentral zones are regulated in part, by gut derived toxins and xenobiotic metabolisms, respectively”.⁶

Whichever way you look at, or want to divide the liver architecture, acinus or lobule, the essential point is to appreciate the gradation of nutrients and toxins that lie across this architecture; the respective perfusion and washout which exposes certain parts of the liver architecture to greater or lesser metabolic and oxidative stress.

Bile is a complex secretion of the hepatocytes modified as it traverses along the bile duct canaliculus to achieve a mixed concentration of dissolved endogenous solid constituents—including bile salts, bilirubin phospholipid, cholesterol, amino acids, steroids, enzymes, porphyrins, vitamins, and heavy metals—as well as exogenous drugs, xenobiotics and environmental toxins, in 95% water. So, bile necessarily is the major excretory route for potentially harmful exogenous lipophilic substances, but also endogenous bilirubin and the bile salts.⁷

Interplay of major zonation signalling pathways.

The sinusoids facilitate free exchange of nutrients, metabolites, and various substrates, such as oxygen. Although the gradient may vary, the periportal to perivenous oxygen gradient (in blue) exists inevitably under almost all conditions. Hypoxia-inducible factors (HIFs) may be major orchestrators since they adapt the gene expression profile in response to changing oxygen tensions. The HIF system in hepatocytes but also in the other sinusoidal cells can undergo cross-talks with other major zonation regulating pathways such as the WNT/β-catenin pathway and associated components, hormone and growth factor signaling pathways, the Hippo pathway and the hedgehog (HH) pathway. All these pathways and factors exempt the oxygen gradient; depend, to the more or lesser extent, on the presence of specific ligands which are secreted from other cells than the hepatocytes, e.g., liver endothelial cells which contribute to the synthesis of certain WNTs, whereas cholangiocytes and stellate cells can secrete hedgehog ligands. PT, portal tract consisting of branches from the hepatic artery (HA), portal vein (PV) and a bile duct; CV, central vein.⁸

Putting it all together:

References:

1. Cliona O’Farrelly, Robert H Pierce, Nicholas Crispe, “Hepatic immunology,” in H. C. Thomas, Stanley M. Lemon, and Arie J. Zuckerman, Viral hepatitis, 3rd ed. ed. (Malden, Mass: Blackwell Pub., 2005), 15-6.
2. S. Abdullah, Siti Zaleha, Mohd Nazri Hassan, Marini Ramli, Marne Abdullah, and Noor Haslina Mohd Noor. 2023. “Red Blood Cell Alloimmunization and Its Associated Factors among Chronic Liver Disease Patients in a Teaching Hospital in Northeastern Malaysia” Diagnostics 13, no. 5: 886. https://doi.org/10.3390/diagnostics13050886.
3. Chronic Liver Disease/Cirrhosis | Johns Hopkins Medicine.
4. image
5. Mandana Khalili, and Blaire Burman. Liver Disease – Pathophysiology of Disease: An Introduction to Clinical Medicine (Lange Medical Books), 7th Ed. (doctorlib.info)
6. Cunningham Rory P., Porat-Shliom Natalie. Liver Zonation – Revisiting Old Questions With New Technologies. Frontiers in Physiology 12 (2021): https://www.frontiersin.org/articles/10.3389/fphys.2021.732929. DOI=10.3389/fphys.2021.732929.
7. Boyer, James L. “Bile formation and secretion.” Comprehensive Physiology vol. 3,3 (2013): 1035-78. doi:10.1002/cphy.c120027.
8. Kietzmann, Thomas. 2019. “Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters” International Journal of Molecular Sciences 20, no. 9: 2347. https://doi.org/10.3390/ijms20092347