Search Results

Hepatic lobule. (A) Depiction of the hepatic lobules. (B) Arrangement of hepatocytes and hepatic sinusoids. (C) Histology of a portal tract. (Source: Figure 26.19 in McKinley & O'Loughlin's Human Anatomy, 2nd ed.)

Blood supply of a liver acinus. Oxygen tensions and nutrient levels within sinusoids continuously decrease as blood flows from zone 1 through zone 3. BD, bile ductule; CV, central vein; HA, hepatic artery; PV, portal vein. (Source: Jones AL. Anatomy of the normal liver. In: Zakim D, Boyer T, eds. Hepatology: A Textbook of Liver Disease. 3rd ed. 1996.)

Acetaminophen toxicity. The major portion of acetaminophen is metabolized to nontoxic metabolites excreted in urine. Only 5–15% is oxidized by cytochrome P450 (CYP 450) enzymes to a potentially toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). The normally small amounts of this metabolite are readily converted to harmless mercapturic acid conjugates by glutathione. When high doses of acetaminophen are consumed, glutathione can be depleted, allowing NAPQI to accumulate and produce hepatic necrosis. Also, normal biotransformation is diminished with compromised liver function, including that associated with malnutrition and alcohol abuse. Toxicity can be further accentuated by ethanol consumption, which induces CYP 450 activity, leading to greater portions of acetaminophen converted to NAPQI. Emergency management of acetaminophen overdose consists of administering high doses of acetylcysteine, which replenishes glutathione.

The coagulation pathway and target sites for anticoagulant drugs.1,4 The coagulation pathway is a cascade of enzymatic conversions, each activating the next enzyme (Factor) in the sequence. The final enzyme in this pathway is thrombin, also called Factor IIa, which catalyzes the conversion of fibrinogen to fibrin strands. Warfarin (W) acts by inhibiting synthesis of factors in the liver. In contrast, heparin (H) acts to inhibit factors that have become activated within the bloodstream. Thrombin can be activated by either of 2 pathways. The intrinsic pathway is initiated within the bloodstream by platelet thromboplastin. H influences this pathway by inhibiting Factor IXa. However, it also inhibits Factors Xa and IIa within the common pathway, and its activity must be monitored using the activated partial thromboplastin time (aPTT). The extrinsic pathway functions outside the bloodstream, initiated by tissue thromboplastin. This pathway is influenced most by W because it inhibits hepatic synthesis of Factor VII, the most essential factor in this pathway. The anticoagulant activity of W is monitored using the prothrombin time (PT), which is now standardized as the international normalized ratio (INR). Newer agents, commencing with the low–molecular-weight Hs (L) have greater specificity for inhibiting Factor Xa and thrombin within the common pathway and generally do not require therapeutic monitoring.

The coagulation pathway and target sites for anticoagulant drugs.^3,18 The coagulation pathway is a cascade of enzymatic conversions, each activating the next enzyme (factor) in the sequence. The final enzyme in this pathway is thrombin (factor IIa), which catalyzes the conversion of fibrinogen to fibrin strands. Warfarin acts by inhibiting synthesis of factors in the liver. In contrast, heparin acts to inhibit factors that have become activated within the bloodstream. Thrombin can be activated by either of 2 pathways. The intrinsic pathway is initiated within the bloodstream by platelet thromboplastin. Heparin influences this pathway by inhibiting factors XIIa, XIa, and IXa, which requires its activity to be monitored using the activated partial thromboplastin time. The extrinsic pathway functions outside the bloodstream, initiated by tissue thromboplastin. This pathway is influenced most by warfarin because it inhibits hepatic synthesis of factor VII, the most essential factor in the extrinsic pathway. Therefore the anticoagulant activity of warfarin must be monitored using the prothrombin time (PT), which is now standardized as the international normalized ratio (INR). Newer agents, commencing with the low-molecular-weight heparins, have greater specificity for inhibiting only factors Xa or IIa (thrombin) within the common pathway and therapeutic monitoring is not required.