1. Lecture 6 Toxic Response of the liver

3. The Liver
Liver resides on the right side of the abdomen腹部 just below the diaphragm横膈膜 .
Receives blood from hepatic artery肝动脉 and the portal vein门静脉 .
Hepatic artery contain highly oxygenated blood含氧血 from systemic circulation.
The portal vein carries less oxygenated, nutrient-rich营养丰富 blood from the stomach and intestines.
The first organ to encounter potentially toxic chemicals ingested.
Has well-developed detoxification戒毒 mechanisms.

4. pancreas胰腺
胆囊管

5. Liver functions
Maintenance of nutrient levels in the blood including glucose and cholesterol胆固醇
Synthesis of proteins such as albumin清蛋白 and factor VIII凝血因子 which are important in blood clotting凝血and other blood functions.
Formation and excretion of bile胆汁 via the gall bladder胆囊
Biotransformation and detoxification of endogenous内生的 and exogenous外因的 agents such as bilirubin胆红素 , ammonia, steroid hormones甾体激素 and foreign chemicals

6. Liver structure
肝小叶
肝细胞

7. Liver structure (II)
Anatomical structural subunit is the liver lobule:肝小叶
A hexagon六边形 has a portal triad at each corner and the central vein at the center.
Portal triad contains branches of the portal vein and hepatic artery and a bile duct
Blood from hepatic artery and portal vein  portal triad  mix in penetrating vessels  flows between hepatocytes  central vein  hepatic vein  exit from liver.

8. Liver structure (III)
Functional structural subunit of the liver is liver acinus肝腺泡 .
Acinus is divided into three zones:
Zone 1: closest to the portal triad, highly oxygenated and nutrient-rich blood.
Zone 3: closest to the central vein, oxygen-poor, nutrient depleted blood.
Zone 2: between zone 1 and 3

10. Bile formation Synthesis of bile
Bile is a yellowish mixture of many compounds including bile acids, glutathione, phospholipids, cholesterol, bilirubin, organic anions, proteins, metals, ions, and detoxified foreign chemicals.
Hepatocytes肝细胞  produce bile  bile canaliculi胆小管  bile ductules小叶内胆管  bile ducts胆管  gall bladder  bile is secreted into a small intestine after a meal.
Bile acids are complexed with lipids and fat-soluble vitamins before absorption
Many xenobiotics are excreted from hepatocytes in bile after their metabolism  into faeces.

11. 胆石

12. Type of Hepatotoxicity肝中毒
Fatty liver脂肪肝
Hepatic Death
Cholestasis胆汁阻塞
Liver cirrhosis肝硬化
Inflammation炎症
Toxic effects on blood vessels and blood flow
Liver cancer

13. Nonalcoholic Steatohepatitis
Non-alcoholic fatty liver disease非酒精性脂肪性肝病
Nonalcoholic Steatohepatitis
非酒精性脂肪性肝炎 疤痕

15. Fatty Liver
Occur through excess fat synthesis, decreased fat degradation, impaired fat secretion.
Common and reversible acute toxic response to many hepatotoxicants such as carbon tetrachloride四氯化碳 and ethanol乙醇.
An excess accumulation of lipid in the parenchymal tissue薄壁组织
Microscopically, the numerous lipid droplets push aside other cellular components in the hepatocytes.

17. Hepatic Death
Hepatocyte death is the end-result of excessive or prolonged exposure to hepatotoxic agents.
Often preceded by fatty liver
Due to toxic effects on the ATP-producing mitochondria  decrease ATP
 inactivation of many ATP-dependent functions of the cell  alter the balance of ions and water  accumulation of excess calcium and water in the cells  swelling and bursting of cells  cell dead

18. Hepatic Death (II)
Most toxic agents cause Zone 3 hepatocyte death while fewer agents induce Zone 1 or 2 death.
Higher levels of cytochrome P450 mixed function oxidase enzymes in Zone 3  can produce more toxic components
Higher levels of cytoprotective molecule, glutathione in zone 1

20. Cholestasis胆汁阻塞
Is defined as a reduction of bile formation or impaired secretion of specific bile components.
Occurs following injury to bile duct cells or blockage of bile ducts.
Several toxic agents can induce cholestasis through the above mechanism e.g. Methylenedianiline
 jaundice –skin and eyes of the affected individual appear yellowish due to the accumulation of bilirubin

22. Liver Cirrhosis肝硬化
Is the result of chronic toxic injury or inflammation of the liver parenchyma
Damaged tissue is replaced with fibrous scar tissue.
Due to repetitive exposure to hepatotoxic chemicals e.g. ethanol
Or chronic inflammation caused by viral hepatitis病毒性肝炎

23. Liver Cirrhosis (II)
Normally, residual hepatocytes divide and regenerate the parenchymal tissue following a hepatotoxic injury. If this process is impaired  cirrhosis
The scar tissue courses through the liver and appears as tough, fibrous bands
This reduces blood and bile flow  impairs the metabolic capacity of the liver.
Common occurrence in alcoholics
Irreversible  liver failure and death of the person

25. 肝纤维化

26. Viral Hepatitis 病毒性肝炎 (甲、乙型病毒性肝炎 )

27. Inflammation发炎
Can occur in response to chemically-induced hepatic cell injury or as a result of viral infection.
Characterized by the activation of Kupffer cells枯否细胞 and the presence of other inflammatory and immune system免疫系统 cells e.g. neutrophils中性粒细胞 , macrophages巨噬细胞 , lymphocytes淋巴细胞 , and plasma血浆 cells  produce toxic oxygen free radicals to destroy foreign organisms
But at excessive levels  also damage parenchymal cells of the liver

28. Toxic effects on blood vessels and blood flow
Certain industrial agents can directly damage liver endothelial cells内皮细胞 impairing损害 blood flow and secondarily affecting many hepatic functions.
Dacarbazine氮烯唑胺 a cancer chemotherapeutic drug化疗药 , is more toxic to the sinusoidal endothelial cells肝窦内皮细胞 than hepatocytes  occlusion of the sinusoid.
Microcystin微囊藻毒素 a component of blue-green algae, damages hepatocytes causing them to swell and block sinusoid blood flow.

32. Hepatitis B virus carrier

35. Liver Cancer
Many occupational chemicals (e.g. dyes, metals, solvents), pesticides (e.g. DDT, aldrin, lindane), dietary factors and contaminants (e.g. alcohol, aflatoxin, nitrosamines), and pharmaceutical agents (e.g. phenobarbital, diazapam, clofibrate) induce liver cancer.
Most hepatic cancers develop from hepatocytes  known as hepatocellular carcinomas原发性肝细胞癌
Some cause the formation of liver tumors from other cells.
Tumors from endothelial cells (hemangiosarcomas血管瘤 )
Tumors from hepatocytes and biliary cells (cholangiocarcinomas胆管癌 )

37. 淋巴结

39. Factors that influence Hepatotoxicity
Biotransformation : activation pathways
Biotransformation : Detoxification pathways
Potentiation增强 of Hepatotoxicity

40. Activation Pathways
Generally, absorbed toxic chemicals is metabolized in the liver to form less toxic products  excreted in the bile and urine.
However, some chemicals enter the liver as nontoxic entities but are metabolized to potent hepatotoxic products.
Biotransformation is mediated by Cytochrome P450 system
Toxic products of biotransformation include electrophilic derivatives of the parent compound or free radicals  bind to or degrade protein or DNA

41. Detoxification Pathways
Enzyme systems, cofactors, and vitamins also exist in the liver to detoxify the toxic metabolites and free radicals generated by biotransformation.
generation of toxic moieties > detoxificatyion  hepatotoxicity
Glutathione is a very important detoxification molecule; glutathione transferase attached glutathione onto toxic electrophiles  polar  easily excreted.
Glutathione peroxidase  detoxifiy peroxides generated by free radical reactions
Other hepatic enzymes include Glucuronyl transferase and sulfotransferase
Vitamin C and E  antioxidants to protect liver cells

42. Potentiation of Hepatotoxicity
Certain chemical agents can modify the activation or detoxification of other chemicals by
 enzyme levels,
inactivating enzymes
 cofactor or antioxidants
For example, isopropanol pre-exposure or ethanol consumption can enhance the toxicity of carbon tetrachloride because
Alcohols  levels of activation enzymes of carbon tetracholoride   hepatotoxicity

43. Measurement of Hepatic Toxicity
Human hepatic toxicity may be assayed by the analysis of hepatic enzymes released into the blood from damaged liver cells.
serum glutamate pyruvate transaminase (SGPT谷氨酸丙酮酸转氨酶 ) and serum glutamate oxaloacetate transaminase (SGOT谷氨酸草酰乙酸氨基转移酶 ) are often seen following liver toxicity, e.g. obstructive jaundice, hepatitis, metastatic carcinoma of the liver.
Noninvasive radiographic techniques
Invasive techniques such as biopsy活组织检查 of the liver –for the diagnosis of hepatocellular damage.

44. 活组织检查