Henryk Dancygier

Hepatic Drug Metabolism and Drug Toxicity

Hepatic biotransformation and metabolic zonation are discussed in Chapters 8 and 9, respectively. The liver plays a central role in the metabolism of endogenous substances and in the degradation and elimination of exogenous compounds. It is placed “strategically” between the intestinal and the systemic circulation. Thus, it is the fi rst organ that comes into contact with enterally absorbed foreign compounds. The liver receives 1,500 ± 300 mL blood/min, corresponding to approximately 25% of the entire blood volume of an adult. Approximately 70% is supplied by the portal vein, the remaining 30% via the hepatic artery. The hepatic microcirculation, the functional heterogeneity of hepatocytes, and the polarized structure of each hepatocyte mirror the division of work of liver cells. The liver plays a major role in biotransformation, i.e. the biochemical degradation of xenobiotics. The processes of biotransformation may be divided into phase I and phase II reactions. The former are nonsynthetic reactions that include oxidation, reduction and hydrolysis of drugs, the latter are usually effected by specifi c transferases and include conjugation of the foreign compound or of its metabolites with activated glucuronic acid, activated acetic acid, active sulfate, aminoacids, methyl residues, glutathione as well as the formation of derivatives of mercapturic acid.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NFLD) denotes liver lesions resembling alcohol induced liver injury in patients consuming less than 20–25 g ethanol daily. NAFLD should be considered part of a multiorgan system derangement and encompasses hepatic steato-sis, steatohepatitis, cirrhosis and in some cases hepa-tocellular carcinoma. Nonalcoholic steatohepatitis (NASH) mimics alcoholic hepatitis and is defined his-tologically by the presence of hepatocellular injury (steatosis, hepatocyte ballooning, cell death), inflam-mation (intralobular neutrophils > mononuclear cells) and fibrosis [56, 95, 105, 120].

Liver Cell Degeneration and Cell Death

(Synonyms: ballooning, ballooning degeneration, toxic cell swelling, vacuolar degeneration, hydropic change). Ballooning denotes a severe, but reversible hepatocellular change. This injury initially is not lethal but may become a precursor of lytic necrosis if the injurious insult continues. Ballooning degeneration is observed in viral, toxic (alcohol), and ischemic liver damage, mainly in centrilobular (zone 3) hepatocytes. Hydropic cell swelling represents an osmotic cell edema due to impaired hepatocellular energy homeostasis and altered permeability of the cell membrane; these alterations affect ion pumps localized in the membrane with subsequent infl ux of sodium and water. The swollen, ballooned hepatocytes are rounded, with cytoplasm that appears clear and stringy (Fig. 23.1). Large segments of the hepatocyte are occupied by clear spaces, the organelles are rarifi ed and irregularly clumped. Peribiliary basophilia, which describes the accumulation of rough endoplasmic reticulum at the apical (biliary) pole of the hepatocyte, is a phenomenon due to cell hydration rather than a distinct feature of hydropic cell swelling (Fig. 23.2). Small, clear cytoplasmic vacuoles represent distended segments pinched-off from the endoplasmic reticulum (vacuolar degeneration). Swelling of mitochondria with rarefaction of their cristae, intramitochondrial accumulation of amorphous material rich in phospholipids, myelin fi gures, loss of intercellular contacts, and disaggregation of granular and fi brillary nucleolar elements are further alterations that may be seen by electron microscopy in hydropic cell swelling. Chapter Outline

Drug-Induced and Toxic Liver Injury

The idiosyncratic mechanisms of liver injury are not completely understood. Both allergic and toxic factors play a role. In hypersensitivity reactions drugs or their metabolic products act as allergens and alter the antigenicity of the hepatocyte membrane. In course of the ensuing immunological reactions the liver is damaged [1–3]. In “idiosyncratic toxicity” altered metabolism by allelic variation and polymorphisms of enzymes are thought to be involved. Classic examples of toxic liver damage are the intoxications with Amanita phalloides and carbon tetrachloride. Two toxins of A. phalloides – phalloidin and amanitin – attack the liver directly. Phalloidin damages the membranes of the smooth endoplasmic reticulum, the cell membrane and the cytoskeleton by inhibiting the polymerisation of actin. Amanitin inhibits the synthesis of RNA and proteins. Chapter Outline

Biliary Ductopenia (Vanishing Bile Duct Syndrome)

Vanishing bile duct syndrome (VBDS) encompasses a group of different cholestatic liver diseases characterized by the destruction and permanent loss of predominantly interlobular bile ducts. If more than 50% of portal tracts in an adequately large biopsy specimen do not contain a bile duct, then VBDS is present. VBDS may be idiopathic or secondary to other causes.

Approach to the Patient with Hepatomegaly

The volume of the normal liver is closely related to body weight. Hepatomegaly denotes a disproportionate increase in liver volume in relation to the normal body weight. Since liver volume is not measured in clinical practice, in practical terms hepatomegaly simply signifi es an increase in liver size. In this chapter we will briefl y discuss some aspects of hepatomegaly as they pertain to the clinical hepatologist. It is not our intention to present a detailed and in-depth scientifi c discussion of the topic; for this, the interested reader is referred to the scientifi c literature.

Effects of Chronic Liver Disease on Other Organs: Tabellary Overview

The outstanding signifi cance of the liver in metabolism and its central anatomical location in the splanchnic circulation explains why acute liver failure and end stage liver disease have far reaching implications for the function of other organs and systems. Table 96.1 summarizes the most important complications of liver cirrhosis [1]. For a detailed discussion the reader is referred to Chapters 32, 33, 78, 79, 80 and 91.

Endoscopic Retrograde and Percutaneous Transhepatic Cholangiography

The direct visualisation of the bile duct with a retrograde (endoscopic) or antegrade (transhepatic) approach has become a successful means for investigating biliary tract disease for more than 30 years. Percutaneous transhepatic cholangiography (PTC) was fi rst reported in the literature in 1937 but did not become popular until the 1950s after it gained attention in the English-speaking literature [6]. Endoscopic retrograde cholangiography (ERC) was fi rst reported in 1968 and spread throughout Europe and Japan to the United States in the early–mid-1970s after improved instruments were developed and the feasibility of therapeutic applications made it more attractive (initially biliary sphincterotomy and biliary stenting) [9] Today, both methods allow for a variety of diagnostic and therapeutic maneuvers, though ERC is preferred over PTC as a fi rst-line procedure as it is less invasive and generally has a lower risk of complications [38]. Indeed, ERC has become an indispensable tool in the practice of modern gastroenterology. Despite providing revolutionary methods for investigating disorders and diseases of the biliary system, PTC and ERC are becoming less commonly used for purely diagnostic purposes, as this role has been taken over by less invasive imaging modalities, such as magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS). Therefore, in the vast majority of cases, ERC is performed with the intention of performing a therapeutic intervention such as bile duct stone removal, biopsy/brushing of a stricture or mass, biliary stenting, and more. This chapter is meant as a general overview of the use of cholangiography (mainly ERC) in the diagnosis and management of patients with hepatobiliary disorders. Pancreatography and exclusively pancreatic disorders will therefore not be discussed, and we refer the interested reader to specialized textbooks for this Chapter Outline

Approach to the Patient with Focal Liver Lesions

The diagnostic evaluation of focal liver lesions represents an interdisciplinary challenge. In this chapter a rational approach to a patient with a liver mass is presented. We would like to emphasize, however, that there is no gold standard in approaching this problem, and different ways are practiced in different centers and countries depending on the availability of imaging technology, the local expertise, and on federal regulations (e.g. contrast enhanced ultrasound has not yet been approved for hepatobiliary imaging in the United States by the Food and Drug Administration). For this reason, a detailed but fi xed algorithm is not presented. The morphologic characteristics of focal liver lesions and the diagnostic accuracy of noninvasive imaging modalities are discussed in Chapters 37–39 (transabdominal ultrasonography, computed tomography, magnetic resonance imaging and nuclear imaging, respectively). Individual disorders are discussed in detail in Chapters 57 (Cystic Liver Diseases), 65 and 66 (Bacterial and Amebic Liver Abscess), 101 and 102 (Benign and Malignant Tumors).

Drug- and Toxin-Induced Liver Injury

The development of a plethora of new agents in the last decades was associated with an increased prevalence of adverse drug-induced hepatic reactions. Although most patients tolerate prescribed drugs well, approximately 2% of all cases of jaundice occurring in the hospital and up to 25% of cases with fulminant hepatitis are ascribed to drugs. A meta-analysis performed in the nineties reported an overall incidence of serious adverse drug reactions (ADRs) in hospitalized patients of 6.7% and of fatal ADRs of 0.32% [21]. Nutritional supplements are frequently considered to be harmless, but indiscriminate use of unlabeled ingredients or supplements containing anabolic steroids may lead to signifi cant ADRs [9, 14, 27]. Also herbal agents may interact with hepatic drug metabolism and potentially are hepatotoxic [7, 16, 19, 20]. The broad clinical and pathologic spectrum of ADRs requires one to always consider drug-induced and toxic lesions in the differential diagnosis of hepatic diseases [11, 15, 21, 22, 30].