Symptoms and Syndromes 13 Cholestasis Page: 1 Definition 228 2 Pathogenesis 228 2.1 Obstructive cholestasis 228 2.2 Non-obstructive cholestasis 229 3 Morphological changes 229 4 Forms of cholestasis 230 5 Causes of cholestasis 230 5.1 Extrahepatic obstructive cholestasis 230 5.2 Intrahepatic obstructive cholestasis 230 5.3 Intrahepatic cholestasis 230 5.4 Genetically determined cholestasis 232 5.4.1 Primary storage diseases 232 5.4.2 Recurrent intrahepatic cholestasis in pregnancy 232 5.4.3 Benign recurrent intrahepatic cholestasis (BRIC) 233 Ϫ Aagenaes syndrome 5.4.4 Progressive familial cholestasis (PFIC) 233 Ϫ Byler’s disease/syndrome 5.4.5 Zellweger’s syndrome 234 5.4.6 Infantile Refsum’s syndrome 234 6 Diagnosis 235 6.1 Anamnesis 235 6.2 Clinical findings 235 6.2.1 Fatigue 235 6.2.2 Pruritus and scratch marks 235 6.2.3 Xanthelasmas and xanthomas 235 6.2.4 Changes in biotransformation 236 6.3 Laboratory diagnostics 236 6.4 Imaging procedures 237 6.4.1 Sonography 237 6.4.2 CT and MRI 238 6.4.3 ERC, PTC and EUS 238 6.5 Liver biopsy and laparoscopy 238 7 Clinical sequelae 240 7.1 Abdominal complaints 240 7.2 Steatorrhoea and diarrhoea 240 7.3 Malabsorption 240 7.4 Osteopathy 240 7.5 Renal dysfunction 240 8 Therapy 240 8.1 Mechanical cholestasis 240 8.2 Functional cholestasis 241 ț References (1Ϫ80) 241 (Figures. 13.1Ϫ13.8; tables 13.1Ϫ13.11) 227 13 Cholestasis 1 Definition 2 Pathogenesis Cholestasis is defined as a disorder of cholepoiesis The liver cell is a polar unit. • The resorptive processes and bile secretion as well as a mechanical or func- take place at the sinusoidal and lateral membrane, the tional stoppage of the bile flow in intrahepatic or secretory processes on the surface of the canaliculi. The extrahepatic bile ducts Ϫ with bile components pass- cytoskeleton (microfilaments, microtubules, intracellu- ing into the blood. • Cholestasis can occur both with lar membranes) maintains the polar orientation of the and without jaundice. hepatocyte. (24, 33, 42, 44, 71, 80) (s. fig. 13.1) Morphology: The morphologist uses the term cholestasis BM CM to describe the presence of bile in the hepatocytes as well + as in hypertrophic Kupffer cells (ϭ cellular bilirubino- 3Na Na+/K+ TJ 2 K+ } ATPase stasis), particularly in the form of inspissated bile droplets Na+ BSEP BS } NTCP BST BS ϭ BS- and copper within the more or less dilated canaliculi ( Phospholipids - MDR2 (= flippase) canalicular bilirubinostasis). • In extrahepatic cholestasis, OA MRP 1 - - AE2 CI HCO3 bile is additionally found within the likewise mostly di- BS- + OA-/OC+ } OATP1 MDR1 OC lated interlobular bile ducts (ϭ ductular bilirubinostasis) GSH - BS HCO3 MRP2 - as well as in the parenchyma in the form of “bile infarcts” (=MOAT) OA ,GSH - Epoxide TJ or “bile lakes”. BS hydrolase Pathophysiology: The biochemist defines cholestasis as BM CM a decrease in the secretion of bile as well as a reduction in the proportion of water, together with a respective Fig. 13.1: The hepatocyte as a polar unit. • Major hepatocellular effect on the substances dissolved in it. transport systems: CM ϭ canalicular membrane, BM ϭ basolateral membrane, TJ ϭ tight junctions, BSϪ ϭ bile salts, OAϪ ϭ organic Clinical aspects: ϩ The clinician diagnoses cholestasis by anions, OC ϭ organic cations, GSH ϭ reduced glutathione, AE2 ϭ Ϫ ϭ the increase in bile acids, special enzymatic markers and ATP-dependent anion exchange (Cl/HCO3 ; GSH), BST ATP- dependent bile acid transporter, NTCP ϭ sinusoidal Naϩ-depend- cholesterol in the serum. ϩ ent taurocholate cotransporting protein, OATP1 ϭ sinusoidal Na - ᭤ The principal biochemical symptom of cholestasis is independent organic anion (and cation) transporter protein, ϭ ϭ the rise in bile acids in serum (as well as changes in its BSEP bile salt export pump for monovalent bile salts, MRP2 canalicular multispecific organic anion transporter (ϭ MOAT), spectrum) in combination with an increase in enzymatic MDR ϭ ATP-dependent organic cation transporter, MDR ϭ γ Ј 1 2 markers of cholestasis (AP, LAP, -GT, 5 -nucleo- ATP-dependent phospholipid transporter (ϭ flippase), MRP1 ϭ tidase). Cholestasis is directly related to the metabolism sinusoidal multidrug resistance-associated protein of bile acids. • In clinical terms, the subsequent rise in activity of enzymatic markers of cholestasis may be attributed to cholestasis, yet these enzymes are not 2.1 Obstructive cholestasis necessarily specific to this condition. (s. p. 89) Obstructive cholestasis Ϫ initially often without jaun- ᭤ Dysfunction in the metabolism of bile acids (ϭ chole- dice, thereafter generally with jaundice Ϫ is caused by a stasis) is often combined with an additional dysfunction mechanical impediment of the bile flow. Because of this, in bilirubin metabolism (ϭ jaundice). The rise in biliru- the bile flow is reduced and biliary stasis is generated, bin is the main biochemical and clinical symptom of which, depending on the localization of the impediment, jaundice; it is based on a disorder of bilirubin metab- subsequently affects the bile ducts of (1.) the entire liver olism. Thus cholestasis is related not directly but in- or (2.) only certain subzones of the liver. directly to jaundice. • Depending on the constellation of Even in cases of a total obstruction with jaundice, there is no total the biochemical and clinical findings, the term “jaundice stoppage of bile secretion due to the residual function of the hepa- with cholestasis” or “cholestasis with jaundice” can be tocytes. What happens, in fact, is that a certain form of circulation applied. (s. tabs. 12.1, 12.2, 12.4; 13.1) • The main clin- of intrahepatic bile acids is maintained by way of resorption pro- ical sign of advanced cholestasis is pruritus. cesses taking place in the bile capillaries and mechanisms of regur- gitation occurring at the tight junctions. This circulation of bile acids mainly runs via the periportal sections of the hepatic lobules, Various hepatobiliary diseases remain unchanged as so that biliary thrombi are only rarely detectable here Ϫ even in either cholestasis or jaundice. • Often, however, a com- cases of prolonged cholestasis. • In obstructive cholestasis, with bination of both disorders is present from the very be- its secondary repercussions on bile capillaries and hepatic cells, ginning or appears during the course of disease. including morphological changes, it is probable that functional dis- orders in the polarity of the hepatocytes will ultimately appear. 228 Cholestasis 2.2 Non-obstructive cholestasis Endotoxins generated in the body are broken down in the RES. Given inadequate clearance (e.g. in chole- Pathogenetically, non-obstructive cholestasis is a multi- stasis) or when they are formed to excess, the state of factorial process. • The factors that cause intrahepatic cholestasis is reinforced. Endotoxins also lead to inflam- cholestasis lead to biochemical dysfunctions and/or matory reactions in the liver and are possibly the cause damage to subcellular structures, with changes in the of complications in cases of prolonged cholestasis. (51) metabolism of bile acids. (1.) Various substances (taurolithocholate, ethinyl oestradiol, The mechanisms of disorder leading to cholestasis drugs, toxins) cause increased retention of cholesterol in cellular are based on many different aetiopathological membranes. As a result, the permeability of hepatocellular mem- factors. One single cause of cholestasis generally dis- branes, including the tight junctions, is decreased. Hypothermia turbs several subprocesses in the metabolism of bile and hypoxia also disturb membrane fluidity. The osmotic pressure acids, which in turn may trigger additional chole- gradient, necessary for biliary secretion, is no longer maintained because of decreased membrane permeability. static mechanisms. Such disorders result in damage to cellular and biliary structures, leading to further (2.) Considerable dysfunction of membrane lipids is caused by a change in the double-bonding of their unsaturated fatty acids due dysfunctions and reinforcing cholestasis. Thus patho- to lipid peroxidation. More pronounced lipid peroxidations are genic mechanisms, acting in a synergy of addition or found particularly in alcohol-induced liver damage Ϫ often ac- potentiation, set up a vicious circle culminating in a companied by cholestasis. cholestatic condition. (15, 18, 22, 33, 44, 71, 80) (3.) Naϩ/Kϩ-ATPase localized in the sinusoidal and lateral hepa- tocyte membrane is inhibited by cholestasis factors (chlorpro- mazine, oestrogens, atypical bile acids, protoporphyrin, etc.) as well as by a change in the viscosity and fluidity of the membrane. Naϩ/Kϩ-ATPase activity works like a metabolic pump and sup- plies the energy needed for the cellular uptake of bile acids (along 3 Morphological changes with bicarbonate and chloride). In the development of morphological damage to hepa- (4.) Mg2ϩ-ATPase activity can likewise be inhibited in the cana- licular side of the membrane by cholestatic factors (in particular tocytes and bile capillaries, lipid peroxidations as well as bile acids). This metabolic pump transports bicarbonate and chlor- the formation of leukotrienes (C4, D4, E4) play a key ide into the canaliculi and is probably closely associated with the role, with prostaglandin E2 having a reinforcing effect. function of the microfilaments. ᭤ After only a few days, cholestasis causes potentially (5.) Transmembranous transport of biliary acids requires the func- ultrastructural changes: tional competence of the carrier proteins in