complex cirrhosis results. A true cardiac cirrhosis is extremely rare. Mechanism (fig. 11.20) Hypoxia causes degeneration of the zone 3 liver cells, dilatation of sinusoids and slowing of bile secretion. Endotoxins diffusing through the intestinal wall into the portal blood may augment this effect [27]. The liver attempts to compensate by increasing the oxygen extracted as the blood flows across the sinusoidal bed. Collagenosis of Disse’s space may play a minor role in impairing oxygen diffusion. Necrosis correlates with a low cardiac output [1]. The hepatic venous pressure increases and this correlates with zone 3 congestion [1]. Thrombosis begins in the sinusoids and may propa- gate to the hepatic veins with secondary local, portal vein thrombosis, ischaemia, parenchymal loss and fibrosis [30]. Clinical features Mild jaundice is common but deeper icterus is rare and associated with chronic congestive failure. In hospital inpatients, cardio-respiratory disease is the commonest cause of a raised serum bilirubin level. Oedematous areas escape, for bilirubin is protein-bound and does not enter oedema fluid with a low protein content. Jaundice is partly hepatic, for the greater the extent of zone 3 necrosis the deeper the icterus (fig. 11.21) [26]. Bilirubin released from infarcts or simply from pul- monary congestion, provides an overload on the anoxic liver. Patients in cardiac failure who become jaundiced with minimal hepato-cellular damage usually have pul- monary infarction [26]. The serum shows unconjugated bilirubinaemia. The patient may complain of right abdominal pain, probably due to stretching of the capsule of the enlarged liver. The firm, smooth, tender lower edge may reach the umbilicus. A rise in right atrial pressure is readily transmitted to the hepatic veins. This is particularly so in tricuspid incompetence when the hepatic vein pressure tracing resembles that obtained from the right atrium. Palpable systolic pulsation of the liver can be related to this trans- mission of pressure. Pre-systolic hepatic pulsation occurs in tricuspid stenosis. The expansion may be felt bimanually. This expansibility distinguishes it from the palpable epigastric pulsation due to the aorta or a hyper- trophied right ventricle. Correct timing of the pulsation is important. In heart failure, pressure applied over the liver increases the venous return and the jugular venous pres- sure rises due to the inability of the failing right heart to handle the increased blood flow. The hepato-jugular reflux is of value for identifying the jugular venous pulse and to establish that venous channels between the hepatic and jugular veins are patent. The reflux is absent if the hepatic veins are occluded or if the main mediastinal or jugular veins are blocked. It is useful for diagnosing tri- cuspid regurgitation [19]. Atrial pressure is reflected all the way to the portal system. Doppler sonography shows increased pulsa- tility in the portal vein depending on the severity of the heart failure [13]. Ascites is associated with a particularly high venous pressure, a low cardiac output and severe zone 3 necro- sis. In patients with mitral stenosis and tricuspid incom- petence or constrictive pericarditis, the ascites may be out of proportion to the oedema and symptoms of con- gestive heart failure. The ascitic fluid protein content is 202 Chapter 11 Bilirubin release from infarcts and tissue congestion Zone 3 congestion and necrosis Bilirubin overload JAUNDICE Fig. 11.20. Mechanisms of hepatic jaundice developing in patients with cardiac failure. Rise right atrial pressure Rise hepatic venous pressure Zone 3 sinusoidal distension and haemorrhage CARDIAC FAILURE Low cardiac output Low liver blood flow Low liver oxygen supply Zone 3 necrosis Zone 3 reticulin collapse and fibrosis Cardiac cirrhosis Fig. 11.21. Possible mechanisms of the hepatic histological changes in heart failure. raised to 2.5g/dl or more, similar to that observed in the Budd–Chiari syndrome [25]. Confusion, lethargy and coma are related to cerebral anoxia. Occasionally the whole picture of impending hepatic coma may be seen. Splenomegaly is frequent. Other features of portal hypertension are usually absent except in very severe cardiac cirrhosis associated with constrictive pericarditis. Contrast-enhanced CT shows retrograde hepatic venous opacification on the early scans and a diffusely mottled pattern of hepatic enhancement during the vas- cular phase [22]. Cardiac cirrhosis should be suspected in patients with prolonged, decompensated mitral valve disease with tri- cuspid incompetence or in patients with constrictive pericarditis. The prevalence has fallen since both these conditions are relieved surgically. Biochemical changes The biochemical changes are small and proportional to the severity of the heart failure. In congestive failure the serum bilirubin level usually exceeds 1mg/dl and in about one-third it is more than 2mg/dl [26]. The jaundice may be deep, exceeding 5mg/dl and even up to 26.9mg/dl. Patients with advanced mitral valve disease and a normal serum bilirubin concentration have a normal hepatic bilirubin uptake but diminished capacity to eliminate conjugated bilirubin related to reduced liver blood flow [4]; this con- tributes to post-operative jaundice. Serum alkaline phosphatase is usually normal or slightly increased. Serum albumin values may be mildly reduced. Protein loss from the intestine may contribute. Serum transaminases are higher in acute than chronic failure and are proportional to the degree of shock and the extent of zone 3 necrosis. The association of very high values with jaundice may simulate acute viral hepatitis. Prognosis The prognosis is that of the underlying heart disease. Cardiac jaundice, particularly if deep, is always a bad omen. Cardiac cirrhosis per se does not carry a bad prognosis. If the heart failure responds to treatment, the cirrhosis compensates. The liver in constrictive pericarditis The clinical picture and hepatic changes are those of the Budd–Chiari syndrome. Marked thickening of the liver capsule simulates sugar icing (zuckergussleber). Microscopically, the picture is of cardiac cirrhosis. Jaundice is absent. The liver is enlarged and hard and may pulsate [8]. Ascites is gross. Diagnosis must be made from ascites due to cirrhosis or to hepatic venous obstruction [17]. This is done by the paradoxical pulse, the venous pulse, the calcified pericardium, the echocardiogram, the electrocardio- gram and by cardiac catheterization. Treatment is that of the cardiac condition. If peri- cardectomy is possible, prognosis as regards the liver is good although recovery may be slow. Within 6 months of a successful operation, liver function tests improve and the liver shrinks. The cardiac cirrhosis will not resolve completely, but fibrous bands become narrower and avascular. References 1 Arcidi JM Jr, Moore GM, Hutchins GM. Hepatic morphol- ogy in cardiac dysfunction. A clinicopathologic study of 1000 subjects at autopsy. Am. J. Pathol. 1981; 104: 159. 2 Batts KP. Ischemic cholangitis. Mayo Clin. Proc. 1998; 73: 380. 3 Berger ML, Reynolds RC, Hagler HK et al. Anoxic hepato- cyte injury: role of reversible changes in elemental content and distribution. Hepatology 1989; 9: 219. 4 Bohmer T, Kjekshus E, Nitter-Hauge S. Studies on the eleva- tion of bilirubin preoperatively in patients with mitral valve disease. Eur. Heart J. 1994; 15: 10. 5 Carrico JC, Meakins JL, Marshall JC et al. Multiple-organ failure syndrome. Arch. Surg. 1986; 121: 196. 6 Chu C-M, Chang C-H, Liaw Y-F et al. Jaundice after open heart surgery: a prospective study. Thorax 1984; 39: 52. 7 Collins JD, Bassendine MF, Ferner R et al. Incidence and prognostic importance of jaundice after cardiopulmonary bypass surgery. Lancet 1983; i: 1119. 8 Coralli RJ, Crawley IS. Hepatic pulsations in constrictive pericarditis. Am. J. Cardiol. 1986; 58: 370. 9 Doctor RB, Dahl RH, Salter KD et al. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischaemia. Hepatology 1999; 29: 1364. 10 Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am. J. Gastroenterol. 1992; 87: 831. 11 Henrion J, Descamps O, Luwaert R et al. Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J. Hepatol. 1994; 21: 696. 12 Hickman PE, Potter JM. Mortality associated with ischaemic hepatitis. Aust. NZ J. Med. 1990; 20: 32. 13 Hosoki T, Arisawa J, Marukawa T et al. Portal blood flow in congestive heart failure: pulsed duplex sonographic find- ings. Radiology 1990; 174: 733. 14 Kamiyama T, Miyakawa H, Tajiri K. Ischemic hepatitis in cirrhosis. Clinical features and prognostic implications. J. Clin. Gastroenterol. 1996; 22:126. 15 Klatt EC, Koss MN, Young TS et al. Hepatic hyaline globules associated with passive congestion. Arch. Pathol. Lab. Med. 1988; 112: 510. 16 Lefkowitch JH, Mendez L. Morphologic features of hepatic injury in cardiac disease and shock. J. Hepatol. 1986; 2: 313. The Hepatic Artery and Hepatic Veins: the Liver in Circulatory Failure 203 17 Lowe MD, Harcombe AA, Grace AA et al. Restrictive- constrictive heart failure masquerading as liver disease. Br. Med. J. 1998; 318: 585. 18 Ma TT, Ischiropoulos H, Brass CA. Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion. Gastroenterol- ogy 1995; 108: 463. 19 Maisel AS, Atwood JE, Goldberger AL. Hepatojugular reflux: useful in the bedside diagnosis of tricuspid regurgi- tation. Ann. Intern. Med. 1984; 101: 781. 20 Mathurin P, Durand F, Ganne N et al. Ischemic hepatitis due to obstructive sleep apnea. Gastroenterology 1995; 109: 1682. 21 Motoyama S, Minamiya Y, Saito S et al. Hydrogen peroxide derived from hepatocytes induces sinusoidal cell apoptosis in perfused hypoxic rat liver. Gastroenterology 1998; 114: 153. 22 Moulton JS, Miller BL, Dodd GD III et al. Passive hepatic congestion in heart failure: CT abnormalities. Am. J. Roentgenol. 1988; 151: 939. 23 Nouel O, Henrion J, Bernuau J et al. Fulminant hepatic failure due to transient circulatory failure in patients with chronic heart disease. Dig. Dis. Sci. 1980; 25: 49. 24 Nunes G, Blaisdell FW, Margaretten W. Mechanism of hepatic dysfunction following shock and trauma. Arch. Surg. 1970; 100: 646. 25 Runyon BA. Cardiac ascites: a characterization. J. Clin. Gas- troenterol. 1988; 10: 410. 26 Sherlock S. The liver in heart failure; relation of anatomical, functional and circulatory changes. Br. Heart J. 1951; 13: 273. 27 Shibayama Y. The role of hepatic venous congestion and endotoxaemia in the production of fulminant hepatic failure secondary to congestive heart failure. J. Pathol. 1987; 151: 133. 28 Shibuya A, Unuma T, Sugimoto M et al. Diffuse hepatic cal- cification as a sequela to shock liver. Gastroenterology 1985; 89: 196. 29 te Boekhorst T, Urlus M, Doesburg W et al. Etiologic factors of jaundice in severely ill patients: a retrospective study in patients admitted to an intensive care unit with severe trauma or with septic intra-abdominal complications fol- lowing surgery and without evidence of bile duct obstruc- tion. J. Hepatol. 1988; 7: 111. 30 Wanless IR, Liu JJ, Butany J. Role of thrombosis in the patho- genesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995; 21: 1232. 31 Weisiger RA. Oxygen radicals and ischemic tissue injury. Gastroenterology 1986; 90: 494. 204 Chapter 11 Bilirubin metabolism [37] Bilirubin is the end product of haem, the majority (80–85%) coming from haemoglobin with only a small fraction derived from other haem-containing proteins such as cytochrome P450 (fig. 12.1). Approximately 300mg bilirubin is formed daily. Production from haemoglobin takes place in reticulo-endothelial cells. The enzyme that converts haem to bilirubin is micro- somal haem oxygenase (fig. 12.2). Cleavage of the por- phyrin ring occurs selectively at the a-methane bridge. The a-bridge carbon atom is converted to carbon monoxide and the original bridge function is replaced by two oxygen atoms which are derived from molecular oxygen. The resulting linear tetrapyrrole has the struc- ture of the IX a-biliverdin. This is converted further to IX a-bilirubin by a cytosolic enzyme, biliverdin reduc- tase. Such a linear tetrapyrrole should be water soluble, whereas bilirubin is lipid soluble. The lipid solubility is explained by realignment of the pyrrole ring such that internal hydrogen bonding masks the propionic acid side chains making bilirubin poorly soluble in aqueous solvents. This bonding can be broken by alcohol in the diazo (van den Bergh) reaction converting unconjugated, indirect, bilirubin to direct reacting bilirubin. In vivo the stable hydrogen bonds are altered by esterification of the propionic groups by glucuronic acid. About 20% of circulating bilirubin is not formed from the haem of mature erythrocytes. A small proportion comes from immature cells in the spleen and bone marrow. This component is increased in haemolytic states. The remainder is formed in the liver from haem proteins such as myoglobin, cytochromes and unknown sources. Hepatic transport and conjugation of bilirubin (fig. 12.3) Unconjugated bilirubin is transported in the plasma tightly bound to albumin. A very small amount is dialysable, but this can be increased by substances such as fatty acids and organic anions which compete with bilirubin for albumin binding. This is important in the neonate where such drugs as sulphonamides and salicy- lates facilitate diffusion of bilirubin into the brain and so increase the risk of kernicterus. The liver extracts organic anions including fatty acids and bile acid and non-bile-acid cholephils, such as biliru- bin, despite tight albumin binding. Studies suggest that bilirubin dissociating from albumin in the sinusoid dif- fuses across the unstirred water layer at the surface of the hepatocyte [42]. A previously proposed albumin re- ceptor has not been substantiated. The mechanism for 205 Chapter 12 Jaundice Plasma Bilirubin Haemoglobin catabolism Other haem sources Liver microsomes Bilirubin glucuronide Urobilin Tissues B a c t e r i a l a c t i o n UB Urobilin- ogen Fig. 12.1. The metabolism of bilirubin. UB, unconjugated bilirubin. passage of bilirubin across the plasma membrane into the hepatocyte involves either transport proteins, such as the organic anion transporter [37], and/or bilirubin flip-flop across the membrane [42]. Uptake is highly effective because of the rapid hepatic metabolism by glu- curonidization and excretion into bile, and also because of binding by carrier proteins in the cytosol such as glutathione-S-transferase (ligandin). Unconjugated bilirubin is non-polar (lipid soluble). It is converted to a polar (water soluble) compound by conjugation and this allows its excretion into the bile. The microsomal enzyme responsible, bilirubin uridine diphosphate glucuronosyl transferase (UGT), converts unconjugated bilirubin to conjugated bilirubin mono- and diglucuronide. Bilirubin UGT is a one of several UGT enzyme isoforms that are responsible for the conju- gation of many endogenous metabolites, hormones and neurotransmitters. The gene expressing bilirubin UGT is on chromosome 2. The structure of the gene is complex (fig. 12.4) [5, 11, 36]. Exons 2–5 at the 3¢ end are constant components of all isoforms of UGT. To complete the gene, one of several first exons can be employed. Exon 1*1 encodes the vari- able region for bilirubin UGT1*1, responsible for virtu- ally all bilirubin conjugation. Another first exon, 1*4, encodes the variable region for another bilirubin UGT but although mRNAcan be detected this appears to play no role in bilirubin conjugation even in the absence of bilirubin 1*1 activity [3, 5, 36]. Other first exons (exon 1*6 206 Chapter 12 + O 2 O Iron Haemoglobin Biliverdin Bilirubin Globin α γ βδ Iron Globin MV M M P N H C C H C H N PM N NN V M P Carbon monoxide C H N H MP O N H MV C H O N H MV C H 2 N H PM C H N H MP O N H MV C H N H MV CHCH Haem oxygenase Biliverdin reductase Fig. 12.2. The metabolism of haemoglobin to bilirubin. M, methyl; P, propionate; V, vinyl. BR – albumin BR + albumin PLASMA SINUSOIDAL MEMBRANE CYTOSOL ENDOPLASMIC RETICULUM CANALICULAR MEMBRANE Carrier proteins BR Mono- and di- glucuronides Transporters (cMOAT) BILE Flip-flop Protein bound (ligandin) Membrane– membrane transfer Conjugation (UGT1) Fig. 12.3. Bilirubin (BR) uptake, metabolism and secretion by the hepatocyte. MOAT, multi-specific organic anion transporter; UGT1, uridine diphosphate glucuronosyl transferase 1. TATAA box Mutation: 1*1 Exon Gilbert's Crigler–Najjar type I/II 23 4 5 3'5' Fig. 12.4. Structure of gene for bilirubin UGT1*1 with five exons and the promoter region (TATAAbox). There are several other possible first exons (not shown) that can be spliced to exons 2–5, and have other substrate specificities. and 1*7) encode the enzyme isoforms for phenol UGTs. Thus selection of one of the exon 1 sequences gives dif- ferent substrate specificity and enzyme characteristics. Expression of UGT1*1 depends further on a promoter region containing a TATAAbox in a 5¢ position relative to exon 1*1. Detail of the gene structure is relevant to the pathogen- esis of the unconjugated hyperbilirubinaemias (Gilbert’s and Crigler–Najjar syndromes; see below), where conju- gating enzyme in the liver is reduced or absent. Levels of UGT are well maintained in hepato-cellular jaundice and even increased in cholestasis. They are reduced in the neonate. The major bilirubin conjugate in human bile is the diglucuronide. A single microsomal glucuronyl system catalyses both the conversion of bilirubin to the monoglucuronide and on diglucuronide. With a high bilirubin load, as in haemolysis, monoglucuronide formation is favoured, whereas if the bilirubin load is low or there is enzyme induction the diglucuronide increases. Although conjugation as a glucuronide remains the most important mechanism, sulphate, xylose and glucose conjugation also occur to a small extent and may be increased in cholestasis. In the late stages of cholestatic or hepato-cellular jaun- dice, despite high serum bilirubin levels, none can be detected in the urine. This is due to a third type of biliru- bin, a bilirubin monoconjugate, covalently bound to albumin. This would not be filtered by the glomerulus and hence would not reach the urine. Biliary canalicular excretion of bilirubin is mediated by the ATP-dependent multi-specific organic anion transporter (cMOAT) also called multi-drug resistance protein-2 (MRP-2) [23]. Biliary excretion of glucuronide is the rate-limiting factor in the transport of bilirubin from plasma to bile. Bile acids are secreted into bile by the bile salt export pump (BSEP). The separate mechanism for bilirubin and bile acid is exemplified by the Dubin–Johnson syndrome where there is a defect in the excretion of conjugated bilirubin, while bile salt excretion is usually normal. A high proportion of the conjugated bilirubin in bile is incorporated into mixed micelles with cholesterol, phos- pholipids and bile salts. Bilirubin diglucuronide in bile is polar (water soluble) and hence is not absorbed from the small intestine. In the colon, bacterial b-glucuronidases hydrolyse the conju- gated bilirubin, which is then reduced to urobilinogens and urobilin which are excreted in the stool (fig. 12.1). Neonates who lack an intestinal flora are at increased risk of absorption of unconjugated bilirubin formed from conjugated bilirubin by intestinal b-glucuronidase. In the presence of bacterial cholangitis some hydrolysis of the bilirubin glucuronide is possible in the biliary tree and unconjugated bilirubin is precipitated. This may be important in the production of bilirubin gallstones. Urobilinogen is non-polar and is well absorbed from the small intestine, but only minimally from the colon. The little that is normally absorbed is re-excreted by the liver (entero-hepatic circulation) and kidneys. With hepato-cellular dysfunction, re-excretion by the liver is impaired and more is excreted in the urine. This accounts for the urobilinogenuria of alcoholic liver disease, pyrexia, heart failure and the early stages of viral hepatitis. Distribution of jaundice in the tissues Circulating protein-bound bilirubin does not easily enter protein-low tissue fluids. If protein levels are higher, jaundice becomes more evident. Thus exudates tend to be more icteric than transudates. Cerebrospinal fluid from jaundiced subjects contains a small amount of bilirubin, the level being one-tenth to one-hundredth of that found in the serum. The cere- brospinal fluid is more likely to be xanthochromic when meningitis is present, the classical example being Weil’s disease with both jaundice and meningitis. In deep jaundice, the ocular fluids are yellow, and this is considered to explain the extremely rare symptom of xanthopsia (seeing yellow). The basal ganglia may be stained yellow in the newborn (kernicterus). This is due to the high concentra- tion of circulating, unconjugated bilirubin having an affinity for neural tissue. Urine, sweat, semen and milk contain bile pigment in the deeply jaundiced patient. Bilirubin is a normal con- stituent of synovial fluid. Paralysed parts and oedematous areas tend to remain uncoloured. Bilirubin is readily bound to elastic tissue. Skin, ocular sclera and blood vessels have a high elastic tissue content, and easily become icteric. This also accounts for the disparity between the depth of skin jaundice and serum bilirubin levels during recovery from hepatitis and cholestasis. Factors determining the depth of jaundice Even with complete bile duct obstruction, the depth of jaundice is very variable. After an initial rapid increase, the serum bilirubin levels off after about 3 weeks although the obstruction persists. The level of jaundice depends on both bile pigment production and the capac- ity of the kidney for its excretion. Rates of bilirubin production may vary and products other than bilirubin, which do not give the diazo reaction, may be formed from haem catabolism. The intestinal mucosa may allow the passage of bilirubin, presumably unconjugated, from the blood. Jaundice 207 In prolonged cholestasis the skin is greenish, possibly due to biliverdin, which does not give the diazo reaction for bilirubin. Conjugated bilirubin, because of its water solubility and penetration of body fluids, produces more jaundice than unconjugated pigment. This accounts for the more intense colour of hepato-cellular and cholestatic rather than haemolytic jaundice. Classification of jaundice Classification is into three types (figs 12.5, 12.6): pre-hepatic, hepatic and cholestatic. There is much overlap, particularly between the hepatic and cholestatic varieties. Pre-hepatic. There is an increased bilirubin load on the liver cell most usually due to haemolysis. The circulating serum bilirubin is largely unconjugated and the serum transaminase and alkaline phosphatase are normal. Bilirubin cannot be detected in urine. This picture of unconjugated hyperbilirubinaemia is also seen when there is failure of bilirubin conjugation as in Gilbert’s and Crigler–Najjar syndrome. Hepatic. This is related to failure of the hepatocyte to excrete conjugated bilirubin into bile, presumably as a result of the failure of transport systems across the hepato- cyte and the canalicular membrane. Conjugation is intact and therefore there is reflux of conjugated bilirubin into 208 Chapter 12 Cholestatic Isolated rise in bilirubin Gilbert's Haemolysis Hepato-cellular Acute Chronic Dilated ducts Undilated ducts JAUNDICE TYPE Pre- hepatic Hepatic Cholestatic CAUSE Bilirubin load Haemolysis Haemoglobin Bilirubin Conjugation – Gilbert's, Crigler–Najjar Canaliculus Ductule Bile duct Pancreas Conjugation Transport Gallbladder Canalicular secretion – Drugs – Sex hormones – Inherited Ductular disease – Primary biliary cirrhosis Bile duct obstruction – Gallstone – Cancer of bile duct or pancreas Transport? – Hepatitis, cirrhosis – Alcohol, drug Fig. 12.5. Classification of jaundice. Fig. 12.6. Classification and causes of jaundice. the circulation. Serum biochemistry shows an increase in liver enzymes according to the underlying cause; being predominantly transaminases in viral and drug hepatitis. The jaundice usually comes on rapidly. Fatigue and malaise are conspicuous. If liver damage is severe there may be evidence of liver failure with encephalopathy, fluid retention with oedema and ascites, and bruising both spontaneous and related to venepunctures due to reduced hepatic synthesis of coagulation factors. In the long- standing case, serum albumin levels are reduced. Cholestatic (Chapter 13). This is due to failure of ade- quate amounts of bile to reach the duodenum, either through failure of canalicular secretion of bile or physical obstruction to the bile duct at any level. The patient is rel- atively well, apart from the causative condition, and pru- ritus is characteristic. The patient becomes increasingly pigmented. The serum shows increases in conjugated bilirubin, biliary alkaline phosphatase, g-glutamyl transpeptidase (g-GT), total cholesterol and conjugated bile acids. Steatorrhoea is responsible for weight loss and malabsorption of fat-soluble vitamins A, D, E and K, and calcium. Diagnosis of jaundice (tables 12.1, 12.2; fig. 12.7) A careful history and physical examination with routine biochemical and haematological tests are essential. The stool should be inspected and occult blood examination performed. The urine is tested for bilirubin and uro- bilinogen excess. The place of special tests such as ultra- sound, liver biopsy and cholangiography will depend on the category of jaundice. Clinical history Occupation should be noted; particularly employment involving alcohol or contact with rats carrying Weil’s disease. Place of origin (Mediterranean, African or Far East) may suggest carriage of hepatitis B or C. Family history is important with respect to jaundice, hepatitis and anaemia. Positive histories are helpful in diagnosing haemolytic jaundice, congenital hyperbiliru- binaemia and hepatitis. Contact with jaundiced persons, particularly in nurs- eries, camps, hospitals and schools, is noted. Close contact with patients on renal units or with drug abusers is recorded, as is any injection in the preceding 6 months. ‘Injections’ include blood tests, drug abuse, tuberculin testing, dental treatment and tattooing as well as blood or plasma transfusions. The patient is asked about previous drug treatment with possible hepato-toxic agents. Consumption of shellfish and previous travel to areas where hepatitis is endemic should be noted. Previous dyspepsia, fat intolerance and biliary colic suggest choledocholithiasis. Jaundice 209 Table 12.1. First steps in the diagnosis of the jaundiced patient Clinical history and examination Urine, stools Serum biochemical tests bilirubin transaminase (AST, ALT) alkaline phosphatase, g-GT albumin quantitative immunoglobulins Haematology haemoglobin, white cells, platelets Blood film Prothrombin time (before and after i.v. vitamin K) X-ray of chest ALT, alanine transaminase; AST, aspartate transaminase; g-GT, g-glutamyl transpeptidase. Vascular spider Purpura Scratch marks Gallbladder Liver Pigmentation Ulcers Depth jaundice Xanthelasma Fetor hepaticus Nutrition Anaemia Signs of primary tumour Lymphadenopathy Body hair Spleen Veins Ascites Erythema xanthomas 'Flapping' tremor Nails: white, clubbed Bruise Oedema Fig. 12.7. Physical signs in jaundice. Jaundice after biliary tract surgery suggests resid- ual calculus, traumatic stricture of the bile duct or hepatitis. Jaundice following the removal of a malignant growth may be due to hepatic metastases. Jaundice due to sepsis and/or shock is common in hospital practice and is often assumed due to viral or drug liver injury [41]. Alcoholics usually have associated features such as anorexia, morning nausea, diarrhoea and mild pyrexia. They may complain of pain over the enlarged liver. Progressive failure of health and weight loss favour an underlying carcinoma. The onset is extremely important. Preceding nausea, anorexia and an aversion to smoking (in smokers), fol- lowed by jaundice a few days later, suggest viral hepa- titis or drug jaundice. Cholestatic jaundice develops 210 Chapter 12 Table 12.2. General features of the common types of acute jaundice Gallstones in Carcinoma in Acute viral Cholestatic drug common bile duct peri-ampullary region hepatitis jaundice Antecedent history Dyspepsia, previous Nil Contacts, injections, Taking drug attack transfusion or nil Pain Constant epigastric, Constant epigastric, Ache over liver or none None biliary colic or none back or none Pruritus ±+Transient + Rate of development of jaundice Slow Slow Rapid Rapid Type of jaundice Fluctuates or persistent Usual but not always Rapid onset, slow fall Variable, usually mild with recovery Weight loss Slight to moderate Progressive Slight Slight Examination Diathesis Frequently female, Over 40 years old Young usually Often older female, obese psychotic Depth of jaundice Moderate Deep Variable Variable, rash sometimes Ascites 0 Rarely with metastases If severe and prolonged 0 Liver Enlarged, slightly Enlarged, not tender Enlarged and tender Slightly enlarged tender Palpable gallbladder 0 + (sometimes) 0 0 Tender gallbladder area + 00 0 Palpable spleen 0 Occasionally About 20% 0 Temperature ≠ Not usually ≠ onset only ≠ onset Investigations Leucocyte count ≠ or normal ≠ or normal Ø Normal Differential leucocytes Polymorphs ≠ — Lymphocytes ≠ Eosinophilia at onset Faeces colour Intermittently pale Pale Variable, light to dark Pale occult blood 0 ± 00 Urine: urobilin(ogen) + Absent - Early - Early + Late Serum bilirubin (mmol/l) Usually 50–170 Steady rise to 250–500 Varies with severity Variable Serum alkaline phosphatase >3¥>3¥<3¥>3¥ (times normal) Serum aspartate transaminase <5¥<5¥>10¥>5¥ (times normal) Ultrasound and CT Gallstones ± dilated duct Dilated ducts ± mass Splenomegaly Normal more slowly, often with persistent pruritus. Pyrexia with rigors suggests cholangitis associated with gall- stones or biliary stricture. Dark urine and pale stools precede hepato-cellular or cholestatic jaundice by a few days. In haemolytic jaun- dice the stools have a normal colour. In hepato-cellular jaundice the patient feels ill; in cholestatic jaundice he may be inconvenienced only by the itching or jaundice, any other symptoms being due to the cause of the obstruction. Persistent mild jaundice of varying intensity suggests haemolysis. The jaundice of compensated cirrhosis is usually mild and variable and is associated with normal stools, although patients with superimposed acute ‘alcoholic hepatitis’ may be deeply jaundiced and pass pale stools. Biliary colic may be continuous for hours rather than being intermittent. Back or epigastric pain may be asso- ciated with pancreatic carcinoma. Examination (fig. 12.7) Age and sex. A parous, middle-aged, obese female may have gallstones. The incidence of type A hepatitis decreases as age advances but no age is exempt from type B and C. The probability of malignant biliary obstruction increases with age. Drug jaundice is very rare in childhood. General examination. Anaemia may indicate haemoly- sis, cancer or cirrhosis. Gross weight loss suggests cancer. The patient with haemolytic jaundice is a mild yellow colour, with hepato-cellular jaundice is orange, and with prolonged biliary obstruction has a deep green- ish hue. A hunched-up position suggests pancreatic car- cinoma. In alcoholics, the skin signs of cirrhosis should be noted. Sites to be examined for a primary tumour include breasts, thyroid, stomach, colon, rectum and lung. Lymphadenopathy is noted. Mental state. Slight intellectual deterioration with minimal personality change suggests hepato-cellular jaundice. Fetor and ‘flapping’ tremor indicate impend- ing hepatic coma. Skin changes. Bruising may indicate a clotting defect. Purpuric spots on forearms, axillae or shins may be related to the thrombocytopenia of cirrhosis. Other cuta- neous manifestations of cirrhosis include vascular spiders, palmar erythema, white nails and loss of sec- ondary sexual hair. In chronic cholestasis, scratch marks, melanin pig- mentation, finger clubbing, xanthomas on the eyelids (xanthelasmas), extensor surfaces and palmar creases, and hyperkeratosis may be found. Pigmentation of the shins and ulcers may be seen in some forms of congenital haemolytic anaemia. Malignant nodules should be sought in the skin. Mul- tiple venous thromboses suggest carcinoma of the body of the pancreas. Ankle oedema may indicate cirrhosis, or obstruction of the inferior vena cava due to hepatic or pancreatic malignancy. Abdominal examination. Dilated peri-umbilical veins indicate a portal collateral circulation and cirrhosis. Ascites may be due to cirrhosis or to malignant disease. A very large nodular liver suggests cancer. A small liver may indicate severe hepatitis or cirrhosis, and excludes extra-hepatic cholestasis in which the liver is enlarged and smooth. In the alcoholic, fatty change and cirrhosis may produce a uniform enlargement of the liver. The edge is tender in hepatitis, in congestive heart failure, with alcoholism, in bacterial cholangitis and occasionally in malignant disease. An arterial murmur over the liver indicates acute alcoholic hepatitis or primary liver cancer. In choledocholithiasis the gallbladder may be tender and Murphy’s sign positive. A palpable, and sometimes visibly enlarged, gallbladder suggests pancreatic cancer. The abdomen is carefully examined for any primary tumour. Rectal examination is essential. Urine and faeces. Bilirubinuria is an early sign of viral hepatitis and drug jaundice. Persistent absence of uro- bilinogen suggests total obstruction of the common bile duct. Persistent excess of urobilinogen with negative bilirubin supports haemolytic jaundice. Persistent pale stools suggest biliary obstruction. Positive occult blood favours a diagnosis of ampullary, pancreatic or alimentary carcinoma or of portal hyper- tension. Serum biochemical tests Serum bilirubin confirms jaundice, indicates depth and is used to follow progress. Serum alkaline phosphatase values more than three times normal strongly suggest cholestasis if bone disease is absent and g-GT is elevated; high values may also be found in patients with non- biliary cirrhosis. Serum albumin and globulin levels are little changed in jaundice of short duration. In more chronic hepato- cellular jaundice the albumin is depressed and globulin increased. Electrophoretic analysis shows raised a 2 - and b-globulins in cholestatic jaundice, in contrast to g- globulin elevation in hepato-cellular jaundice. Serum transaminases increase in hepatitis compared with variable but lower levels in cholestatic jaundice. High values may sometimes be found transiently with acute bile duct obstruction due to a stone. Haematology A low total leucocyte count with a relative lymphocyto- sis suggests hepato-cellular jaundice. A polymorph leu- cocytosis may be found in alcoholic and severe viral hepatitis. Increased leucocyte counts are found with acute cholangitis or underlying malignant disease. If Jaundice 211 [...]... hypertrophied; all these changes are non-specific for the aetiology of the cholestasis Changes in other organs The spleen is enlarged and firm due to reticulo-endothelial hyperplasia and increase in mononuclear cells Later, cirrhosis results in portal hypertension and splenomegaly The intestinal contents are bulky and greasy; the more complete the cholestasis, the paler the stools The kidneys are swollen and bile... is the first bile channel to be accompanied by a branch of the hepatic artery and portal vein These are also found in the portal triad These channels unite with one another to form septal bile ducts and so on until the two main hepatic ducts emerge from the right and left lobes of the liver at the porta hepatis Small bile ducts distal to the canals of Hering are lined by four to five cholangiocytes There... microvilli increase the surface area The organelles include the Golgi apparatus and lysosomes Vesicles carry proteins such as IgA from the sinusoid to the canaliculus, and newly synthesized cholesterol and phospholipid, and possibly bile acid membrane trans- Fig 13.1 Scanning electron micrograph of the canalicular biliary system porters, from the microsomes to the bile canalicular membrane The peri-canalicular... [79] There are also water channels (aquaporins) in the apical and basolateral membrane of the cholangiocyte Secretin triggers the insertion of aquaporin 1 into the apical membrane of the cholangiocyte and this facilitates transport of water into bile [56] Aquaporin 4, in the basolateral membrane subserves entry of water into the cell [57] Thus ductular bile formation depends upon the regulation of both... uptake and secretion by the liver are reduced [87] Cytoskeleton Integrity of the canalicular membrane may be altered by disruption of either the micro-filaments responsible for canalicular tone and contraction, or the tight junctions Cholestasis due to phalloidin is related to depolymerization of the actin of micro-filaments Chlorpromazine also affects polymerization of actin Cytochalasin B and androgens... microscopy The biliary canaliculi show changes irrespective of the cause These include dilatation and oedema, blunting, distortion and sparsity of the microvilli The Golgi apparatus shows vacuolization Peri-canalicular bile-containing vesicles appear and these represent the ‘feathery’ hepatocytes seen on light microscopy Lysosomes proliferate and contain copper bound as a metalloprotein The endoplasmic... Disruption of the tight junction leads to free passage of solute and larger molecules into the canaliculus with loss of the osmotic gradient and cholestasis Canalicular bile may also regurgitate into the sinusoid The bile canaliculi empty into ductules sometimes called cholangioles or canals of Hering (fig 13.3) These are found largely in the portal zones of the liver The ductule passes into the interlobular... the biliary canaliculus is the most important factor promoting bile formation This is the bile salt dependent fraction Water follows the osmotically active bile salts and there is a tight relationship between bile flow and bile salt secretion The entero-hepatic cycling of conjugated bile salts depends upon their reabsorption by the ileal Na+-dependent bile salt transporter into the circulation and then... has had time to develop Biliary cirrhosis is associated with partial biliary obstruction due, for instance, to benign biliary stricture or primary sclerosing cholangitis 226 Chapter 13 In biliary cirrhosis the liver is larger and greener than in non -biliary cirrhosis Margins of nodules are clear-cut rather than moth-eaten If the cholestasis is relieved the portal zone fibrosis and bile retention disappear... ions across the basolateral (sinusoidal) membrane, transport through the hepatocyte and excretion across the canalicular membrane This is followed by osmotic filtration of water from the hepatocyte and along the paracellular pathway The secretory process depends upon the presence of one set of carrier proteins in the basolateral membrane and another in the canalicular membrane (fig 13.5) Driving the whole . over the liver increases the venous return and the jugular venous pres- sure rises due to the inability of the failing right heart to handle the increased blood flow. The hepato-jugular reflux is of. filtration of water from the hepa- tocyte and along the paracellular pathway. The secretory process depends upon the presence of one set of carrier proteins in the basolateral membrane and another in the. characterization of these and other biochemical defects. The liver, macroscopically, is greenish-black (black- liver jaundice) (fig. 12.12). In sections the liver cells show a brown pigment which is neither