Hepatology PDF

9 Hepatology KEY POINTS Alcoholic liver disease is increasing, as are deaths from liver disease Liver Stomach Viral hepatitis is common, increasing and transmissible in health-care facilities...

9 Hepatology KEY POINTS Alcoholic liver disease is increasing, as are deaths from liver disease Liver Stomach Viral hepatitis is common, increasing and transmissible in health-care facilities Left hepatic Health-care professionals must be immunized against hepatitis B virus Right hepatic duct duct Common Liver disease can lead to bleeding and drug intolerance Cystic duct hepatic Gallbladder duct Pancreas Common bile Life is impossible without the liver. The liver (hepar) consists of duct Pancreatic hepatocytes, organized for optimal contact with sinusoids (blood ves- Duodenum duct sels) and bile ducts. It makes and breaks down sugar, proteins and fats; stores nutrients; produces bile; and removes metabolic products and Fig. 9.1 Liver anatomy. other toxins from the blood. Bile drains to the gallbladder and, via the bile duct, to the small intestine, at which point it is intimately associ- ated with the head of the pancreas, swelling of which may cause biliary obstruction and jaundice (Fig. 9.1). Table 9.1 Some drugs metabolized by the liver The liver, through the function of the Kupffer cells (mononuclear Local anaesthetics Bupivacaine, lidocaine, mepivacaine, prilocaine, phagocytes) that line the sinusoids forms part of the lymphoreticular articaine system (along with macrophages in the lymphoid tissue and spleen) Analgesics Paracetamol (acetaminophen), aspirin, codeine, ibuprofen, meperidine and plays an important role by capturing and digesting bacteria, Antimicrobials Ampicillin, azole antifungals, clindamycin, fungi, parasites, effete blood cells, and cellular debris. The liver turns metronidazole, tetracyclines, vancomycin glucose into glycogen (stored in the liver). This is converted back Sedatives Diazepam into glucose when required, maintaining stable blood glucose levels. Excess carbohydrates and protein are converted to fat. The liver also makes proteins – blood proteins (e.g. most blood-clotting factors using vitamin K metabolites), and albumin, hormones, transporter intestine back into the blood (enterohepatic recirculation). Conjugated proteins and complement. The liver underlies normal haemostasis, bilirubin can also be excreted in the urine, which it darkens. Increased since it produces blood clotting factors I, II, VII, IX, X and XI; bile levels of bilirubin in the blood can cause the body, especially the scle- salts which aid vitamin K absorption (needed for clotting factors); rae of the eyes, to appear yellow (jaundice). and the hormone thrombopoietin which stimulates the bone marrow Water-soluble toxins and waste products can be eliminated via the megakaryocyte production of platelets. The liver also forms bile essen- kidneys in the urine, but non–water-soluble toxins need to be chemi- tial for fat digestion and absorption of fat-soluble vitamins (A, D, E cally modified by the liver to allow this process to occur. Digested and K), and produces or stores these vitamins and vitamin B12; it also proteins in the form of amino acids are broken down further in the stores minerals (e.g. copper and iron). Bile (gall) is made up of water, liver, a process known as deamination. Nitrogenous products such as cholesterol, phospholipids, bicarbonate, bile pigments and bile salts; it ornithine and arginine are converted to urea, which is excreted into the is a bitter yellow or green fluid secreted by hepatocytes, stored in the urine by the kidneys. Sex steroids, such as the masculinizing hormone gallbladder between meals, and discharged into the duodenum upon testosterone and the feminizing hormone oestrogen, are inactivated in eating, being required for fat and fat-soluble vitamin absorption. The the liver. bile salts sodium glycocholate and sodium taurocholate are produced Most drugs, including alcohol, are metabolized/excreted via the by the liver from cholesterol; they help emulsify fats for their absorp- liver (Table 9.1). In particular, oral drugs are absorbed by the gut and tion and facilitate the activity of pancreatic lipase. transported via the portal circulation to the liver. In the liver, these The breakdown of haemoglobin, cholesterol, proteins, sex steroids drugs may undergo first-pass metabolism, in which they are modified, and many drugs occurs, at least partly, in the liver. The enzyme haem activated or inactivated before they enter the systemic circulation. oxygenase acts on haem to form biliverdin, which in turn is converted The diagnosis of liver disease depends on the history, physical into bilirubin. Biliverdin and bilirubin are termed bile pigments. examination and evaluation of liver function tests (Table 9.2). Apart Bilirubin is not water-soluble (unconjugated bilirubin) and needs a from bilirubin, liver enzyme levels may also be increased in the blood carrier (albumin) to be transported. In the liver, bilirubin is conjugated in various disorders. Aminotransferase levels are sensitive indicators of by combining with glucuronic acid and becomes water-soluble conju- liver-cell injury (Table 9.3). gated bilirubin. This then enters the bile, and flows into the bile duct Alkaline phosphatase levels may be raised if there is biliary obstruc- and finally the intestine, where it can be excreted in, and colours, the tion, but also vary with age. Rapidly growing adolescents can have stool after being changed into urobilinoids. Alternatively, the process serum alkaline phosphatase levels that are twice those of healthy of conjugation can be reversed by beta-glucuronidase, which converts adults as a result of the leakage of bone alkaline phosphatase into the conjugated bilirubin back into unconjugated bilirubin. Unlike con- blood. Also, serum alkaline phosphatase levels normally increase jugated bilirubin, unconjugated bilirubin can be reabsorbed from the gradually between the ages of 40 and 65 years, particularly in women.  HEPATOLOGY 277 Table 9.2 Liver function testsa Table 9.3 Causes of raised aminotransferase levels Serum test Comments Causes Examples Bilirubin Positive in urine in most patients with jaundice, Hepatic Alcohol abuse except unconjugated hyperbilirubinaemia. Alpha-antitrypsin deficiency Bilirubin rises in serum because of overproduction or obstruction. In liver disease, the total serum Autoimmune hepatitis bilirubin may rise (hyperbilirubinaemia). The Chronic hepatitis B total bilirubin includes that which has undergone Chronic hepatitis C conjugation (the direct or conjugated bilirubin) plus the portion of bilirubin that has not been Drugs metabolized (unconjugated bilirubin). When the Haemochromatosis direct bilirubin fraction is elevated, the cause is Steatosis and non-alcoholic steatohepatitis typically gallstones. If the direct bilirubin is low Wilson disease while the total bilirubin is high, this reflects liver cell damage or bile duct damage within the liver Non-hepatic Acquired muscle diseases itself Coeliac sprue Hyaluronic Raised serum levels in liver fibrosis; marker of pre- Inherited disorders of muscle metabolism acid (HA) cirrhosis Strenuous exercise Alanine Leaks from damaged liver. Most sensitive marker Drugs aminotransferase of any form of hepatocyte damage. Also known (ALT) as serum glutamic–pyruvic transaminase (SGPT) Antibiotics Aspartate Leaks from damaged liver, heart or muscle. Rises Synthetic penicillins aminotransferase in liver, heart or muscle damage. Also known as Ciprofloxacin (AST) serum glutamic–oxaloacetic transaminase (SGOT) Nitrofurantoin 5′-Nucleotidase Found in liver, thyroid and bone. Rises in biliary Ketoconazole and fluconazole obstruction Isoniazid Gamma-glutamyl Found in liver, kidneys, pancreas, prostate. transferase Rises in obesity, alcoholism, most liver diseases, Antiepileptic drugs (GGT or GGTP) pancreatitis, diabetes, myocardial infarct and with Phenytoin some drugs. Medications commonly cause GGT to Carbamazepine be elevated but alcohol is the main drug cause of an increase in the GGT Inhibitors of hydroxymethylglutaryl– coenzyme A reductase Alkaline Found in biliary canaliculi, osteoblasts, intestinal phosphatase mucosa and placenta. Rises in pregnancy, liver Simvastatin disease, gallstones and bone disease Pravastatin Renal or intestinal damage can also cause the Lovastatin alkaline phosphatase to rise. One way to assess Atorvastatin the aetiology of a raised level is to examine Non-steroidal anti-inflammatory drugs isoenzymes (NSAIDs) Albumin Low albumin (hypoalbuminaemia) may indicate Sulphonylureas for hyperglycemia that the synthetic function of the liver has been markedly diminished, such as in cirrhosis. Glipizide Falls in malnutrition, nephrotic syndrome and Herbs and homeopathic treatments gastrointestinal disease Alchemilla (lady’s mantle) Prothrombin time Prolonged in liver disease, malnutrition (decreased Chaparral (and international vitamin K ingestion) normalized ratio [INR]) Chinese herbs Ephedra (ma huang) a Statins and other drugs can disturb liver function tests. Gentian Germander Jin bu huan Raised levels of gamma-glutamyl transferase (GGT) have been Scutellaria (skullcap) reported in a wide variety of clinical conditions, including pancreatic Senna disease, myocardial infarction, renal failure, chronic obstructive pul- Shark cartilage monary disease, diabetes and alcoholism. High serum GGT levels are Drugs and substances of abuse also found in patients who are taking medications such as phenytoin Anabolic steroids and barbiturates. Chloroform Cocaine Ecstasy CONGENITAL LIVER DISEASE Phencyclidine Glues and solvents General and clinical aspects Glues containing toluene Trichloroethylene Transient neonatal jaundice is common, usually due to the normal breakdown of haemoglobin around birth, and is of little consequence. Severe neonatal jaundice can be caused by prematurity, or haemolysis Dental aspects such as in rhesus incompatibility, biliary atresia or hepatic disease; it can lead to kernicterus (damage to the brain basal ganglia), which can Disorders associated with an early rise in serum levels of conjugated be fatal, or cause epilepsy or choreoathetosis (with or without learning bilirubin (mainly biliary atresia and haemolysis, such as in rhesus impairment) and deafness. Rare familial liver enzyme disorders that disease) can cause a greenish discolouration of the teeth and dental can cause jaundice are shown in Appendix 9.1. hypoplasia.  278 Hepatology Excessive alcohol intake, viral hepatitis and drugs also account for the ACQUIRED LIVER DISEASE majority of cases of cirrhosis (Box 9.1). Liver diseases can have many Liver disease is increasing, due especially to alcohol use, obesity and effects, according to the degree of liver damage – including jaundice, a infections; in the decade to 2009 in the UK, liver-associated deaths bleeding tendency, and impaired drug and metabolite degradative and increased by one-fifth. A bleeding tendency, dangers from certain excretory activities (Table 9.5). Many patients with liver disease are drugs, liability to infections and sometimes infectious hazards are fac- asymptomatic and the problem frequently remains subclinical for years tors to consider in the dental patient with liver disease. or decades. Malaise, anorexia and fatigue are common, sometimes with low-grade fever and upper abdominal discomfort. Bilirubin ester is normally excreted in bile and is one of the factors that colour the faeces. If bilirubin is not conjugated (enzyme defect HEPATITIS or parenchymal liver disease) or excreted (biliary obstruction), it accumulates in the body and colours the skin and mucous membranes The liver has some powers of regeneration but this capacity can be (jaundice) and the whites of the eyes (icterus); it is detectable clinically exceeded by repeated or extensive damage by infective agents, alcohol, at levels greater than 40 micromol/L, and the urine darkens. drugs or poisons. The word ‘hepatitis’ means inflammation of the liver Jaundice is often caused by liver disease but may also result from and also often refers to a group of viral infections that affect the liver, haemolysis, abuse of alcohol or other drugs, or infection (Table 9.6). but hepatitis can also be caused by drugs or autoimmune disorders. The Pale, fatty faeces and malabsorption result from failure of bile salts most common types of viral infection are hepatitis A, hepatitis B and to reach the intestine (obstructive diseases), causing malabsorption hepatitis C. Alcohol abuse is the major drug causing acute hepatitis. of fats, and of the fat-soluble vitamins (e.g. vitamin K) needed for Chronic hepatitis is the term for hepatitis that persists longer than 6 clotting-factor synthesis. Bile salts accumulating in the blood may months; it may follow acute hepatitis (or appear without warning) and cause itching, nausea, anorexia and vomiting. may progress to cirrhosis. The most important causes of chronic hepati- A bleeding tendency results from depressed synthesis of blood- tis are hepatitis C virus, alcohol, drugs and autoimmune hepatitis (Table clotting factors and excess fibrinolysins. Prothrombin time (PT), 9.4). Chronic liver disease includes chronic hepatitis, and cirrhosis. the international normalized ratio (INR) and activated partial Box 9.1 Causes of chronic liver disease Table 9.4 Causes of chronic hepatitis Alcoholic and drug-induced liver disease Autoimmune hepatitis Inflammatory Hepatitis Drugs Autoimmune bowel disease Metabolic Gaucher disease Hepatitis Alcohol Alpha1- Haemochromatosis B or C virus Aspirin antitrypsin Portal hypertension deficiency Primary biliary cirrhosis Cytotoxics Wilson Primary sclerosing cholangitis Halothane disease Isoniazid Sarcoidosis Methyldopa Viral hepatitis Nitrofurantoin Wilson disease Paracetamol Zellweger syndrome (cerebrohepatorenal syndrome; a rare congenital (acetaminophen) leukodystrophy) Table 9.5 Manifestations of liver diseases Impaired Main causes Consequences Clinical features Bilirubin metabolism Congenital hyperbilirubinaemia Hyperbilirubinaemia Jaundice Bilirubin excretion Hepatocellular disease Hyperbilirubinaemia Jaundice Extrahepatic obstruction Bilirubinuria Dark urine Pale stools Excretion of bile salts Extrahepatic obstruction Rise in serum alkaline phosphatase and 5′-nucleotidase Pruritus Hepatocellular disease Malabsorption of fats and fat-soluble vitamins (especially Fatty stools vitamin K), causing prolonged prothrombin time Bleeding tendencies Liver cell function Hepatocellular disease Impaired clotting factor synthesis and prolonged Bleeding tendencies prothrombin time Oedema Impaired albumin synthesis Coma or neurological disorders Impaired drug metabolism Bleeding from oesophageal varices Rise in serum transaminases Portal venous hypertension Disorganized liver structure Cirrhosis  Hepatitis 279 Table 9.6 Causes of jaundice Acquired Hepatocellular disease Congenital (parenchymal liver disease) Extrahepatic biliary obstruction Haemolysis Haemolysis, such as in rhesus incompatibility Viral hepatitis Gallstones Malaria Prematurity Drug-induced hepatitis Carcinoma of pancreas Yellow fever Gilbert syndrome (Appendix 9.1) Cirrhosis (often alcoholic) Biliary atresia Sickle cell diseases Various rare syndromes (Appendix 9.1) Primary biliary cirrhosis Others Incompatible transfusion Others Chronic hepatitis Others thromboplastin time (APTT) are all increased. Chronic bleeding may can also cause chronic hepatitis, in which the infection is prolonged – cause anaemia. sometimes lifelong – and may be associated with virus carriage, chronic Drugs (e.g. alcohol and barbiturates) that can induce the hepatic liver disease and liver cancer (hepatoma; hepatocellular cancer); they cytochrome P450 system can lead to diminished effects of other drugs, can also be responsible for aplastic anaemia and other extrahepatic such as the contraceptive pill, phenytoin or warfarin. By contrast, manifestations. The clinical and laboratory features of viral hepatitis some drugs (e.g. cimetidine, omeprazole, sulphonamides and val- are summarized in Table 9.10. proate) impair P450 activity, causing enhanced activity of drugs such as carbamazepine, ciclosporin, phenytoin or warfarin (Table 9.7). Cirrhosis chiefly affects the middle-aged or elderly, and is frequently Hepatitis A (‘infectious hepatitis’) asymptomatic in its earlier stages. Anorexia, malaise and weight loss General aspects are common, and effects can be widespread (Box 9.2; Fig. 9.2). Hepatitis A is caused by HAV and is rarely serious. Hepatitis A is endemic throughout the world, seen particularly where socioeconomic VIRAL HEPATITIS and living conditions are poor and, in those areas, infection (and Many viruses cause hepatitis (Table 9.8). The term ‘viral hepatitis’ consequent immunity) is common in childhood (Fig. 9.5). In the devel- used in health care usually refers to infection by hepatitis B, D or oped world, many people reach adulthood without infection and have C viruses (HBV, HDV, HCV), which are transmitted parenterally no immunity, and therefore are at risk from infection if they travel to (Table 9.9). Jaundice during childhood is often caused by hepatitis endemic areas. A virus (HAV) and typically is of little consequence; hepatitis B and C Spread of hepatitis A is largely faeco–oral, by consumption of are the most relevant to health care, since the delivery of health care contaminated water or food, particularly raw shellfish. For example, has the potential to transmit viral hepatitis to both health-care profes- nearly 300 000 persons were infected in one outbreak in Shanghai, sionals (HCPs) and patients. Outbreaks have occurred in outpatient originating from contaminated clams. Hepatitis A can also be trans- settings, haemodialysis units, long-term care facilities, and hospitals, mitted sexually and by close person-to-person contact, and in body primarily as a result of unsafe injection practices; reuse of needles, fluids including saliva. Persons in the armed forces, food handlers, fingerstick devices and syringes; and other lapses in infection control. HCPs, sewage workers, travellers to areas of high endemicity, children Jaundice in the teenager or young adult may be due to viral hepatitis and employees at day-care centres, promiscuous individuals who do A, B, C, D or E. Several of these viruses, particularly HAV and hepati- not practise safe sex, and injecting drug users are at greatest risk. tis E virus (HEV), are transmitted faeco–orally. Some, especially HAV and HBV, and probably HCV, can be spread sexually. Hepatitis A and E are more of a problem in resource-poor areas and are transmitted Clinical features faeco–orally; hepatitis E is more severe among pregnant women, espe- The incubation period is 2–6 weeks. The disease is frequently subclini- cially in the third trimester. cal or anicteric, but clinical features are similar to those of other forms Hepatitis B has long been of greatest importance but, in the absence of viral hepatitis (though muscle pains, rashes and arthralgia are rare); of a vaccine, hepatitis C has become a more serious problem. Standard they include fatigue, nausea and vomiting, abdominal pain or discom- (universal) precautions against transmission of infection must always fort, loss of appetite, low-grade fever, jaundice and itching. Recovery be employed, since these viruses, particularly HBV, HCV and HDV is usually uneventful. Blood and faeces become non-infective during or can be transmitted in blood and blood products and in other body shortly after the acute illness. There is no evidence of either a carrier fluids; they may be passed on by practices in which infection control state or progression to chronic liver disease. About 15% have relapses is lacking, particularly in intravenous drug use where there is needle- over a 6–9-month period but the mortality is less than 0.1%. Hepatitis or syringe-sharing. Any practice in which there is a skin breach, such A can be lethal, however, if the patient is also infected with HBV/HCV. as body-piercing or tattooing (Fig. 9.3), can also constitute a risk. Hepatitis A gives long-lasting immunity. Co-infection with other blood-borne agents, such as the human immu- nodeficiency virus (HIV), is common, particularly in intravenous drug users. General management All hepatitis viruses can cause acute, or short-term, illness, and jaun- dice is common (Fig. 9.4). Some hepatitis viruses, particularly HCV The diagnosis of hepatitis A can be confirmed if necessary by demon- and HBV, also have a small acute mortality. HBV, HCV and HDV strating serum antibodies to the virus (HAAb). No specific treatment 280 Hepatology Table 9.7 Drugs contraindicated and alternatives in liver disease Box 9.2 Cirrhosis: clinical features Type of drug Drugs contraindicated Alternatives to use Jaundice Analgesics Aspirin Oxycodone Oedema Codeine Paracetamol Ascites (acetaminophen)a Dextropropoxyphene Swollen ankles Indometacin Gastrointestinal haemorrhage Mefenamic acid Mental confusion Meperidinea Hepatomegaly Non-steroidal anti- Splenomegaly inflammatory drugs (NSAIDs) Opioids Finger-clubbing Pentazocine Skin manifestations Antimicrobials Aminoglycosides Amoxicillin Spider naevi Azithromycin Ampicillin, cephalosporins Palmar erythema Azole antifungals Nystatin, fluconazole Opaque nails (miconazole, Sparse hair ketoconazole, itraconazole) Other occasional manifestations Clarithromycina Erythromycin stearate Parotid swelling (sialosis) Clindamycina Imipenem Gynaecomastia Co-amoxiclav Penicillin Bleeding (liver failure) Co-trimoxazole Nystatin Doxycycline Penicillin Portal hypertension and varices Erythromycin estolate Tetracycline Flucloxacillin Penicillin Metronidazolea Minocycline Moxifloxacin Encephalopathy Roxithromycin Talampicillin Tetracyclines Corticosteroids Prednisone Prednisolone Antidepressants Monoamine oxidase Selective serotonin Jaundice inhibitors (MAOIs) reuptake inhibitors (SSRIs) Oesophageal Tricyclicsa varices Muscle relaxants Suxamethonium Atracurium, cisatracurium, Gynaecomastia pancuronium, vecuronium Liver cancer Spider naevi Local Lidocainea Articaine, prilocaine anaesthetics Ascites General Halothane Desflurane Peritonitis anaesthetics Methohexitone Isoflurane Propofola Sevoflurane Palmar erythema Thiopental Leukonychia Dupuytren contracture Clubbing Anxiolytics/ Barbiturates Lorazepama sedatives Diazepama Oxazepama Midazolama Pethidinea (and flumazenil) Testicular atrophy Phenothiazines Promethazine Anticonvulsants Carbamazepine Lamotrigine Phenytoin Others Anticoagulants Biguanides Diuretics Etretinate Liquid paraffin Co-phenotrope (Lomotil) Fig 9.2 Cirrhosis. Methyldopa Oral contraceptives Pilocarpine Sumatriptan a Or given in lower doses than normal. In a variety of liver diseases there is no evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, paracetamol/acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.  Hepatitis 281 is usually needed; normal human immunoglobulin may prevent or Hepatitis B attenuate the clinical illness and is used mainly in sporadic outbreaks. General aspects HAV vaccine is available, especially for prophylaxis in travellers to high-risk endemic areas such as Asia, South America and Africa. A Hepatitis B (serum hepatitis; homologous serum jaundice) is caused combined vaccine against HAV and HBV may also be used. by HBV and is a serious disease. Genotype A is most common in the UK. HBV can cause lifelong infection, cirrhosis (scarring) or cancer of the liver, liver failure and occasionally fulminant hepatitis and death. Dental aspects Hepatitis B affects one-third of the world population, and one-quarter Patients are unlikely to seek dental treatment during the acute phase. of those infected at birth die from liver disease. There appears to be no risk of transmission of hepatitis A during den- Hepatitis B infection is endemic throughout the world, especially tistry that is conducted properly. in institutions (such as those for custodial care), in cities and in poor socioeconomic conditions. It is especially common in the developing world; sub-Saharan Africa, the Pacific Basin, South-East Asia, Central Asia, parts of the Middle East, South America’s Amazon Basin and Table 9.8 Viral causes of hepatitis some Eastern European countries are the areas of highest endemicity. Over 75% of some populations such as Australian aboriginals (hence Hepatitis viruses Herpesviruses Others the older term ‘Australia antigen’) are carriers. In parts of sub-Saharan Hepatitis A virus Cytomegalovirus Coxsackie B virus Africa, Asia and the Pacific, nearly all children are infected. The preva- Hepatitis B virus Epstein–Barr virus Yellow fever lence is low (under 2%) in north-western Europe, North America and Hepatitis C virus Herpes simplex virus Hepatitis D virus the Antipodes. Intermediate levels (2–8%) are found in Mediterranean Hepatitis E virus countries, the Middle East, the Indian subcontinent and Japan. Hepatitis G virus Spread of HBV is mainly parenteral (via unscreened blood or blood SEN viruses products, particularly by intravenous drug abuse and by tattooing/ Transfusion-transmitted body-piercing), sexual (especially among promiscuous individuals virus (torque teno virus; TTV) who do not practise safe sex) and perinatal. HBV is a robust virus, surviving for a week or more in dried blood on surfaces, and has been Table 9.9 Comparative features of more common forms of viral hepatitis Hepatitis virus A B C D E G Alternative Infectious Serum Non-A non-B Delta agent Non-A non-Ba Non-A non-Ba terminology Prevalence Common Uncommon; Uncommon; In countries with low Rare except in Uncommon; about 1–2% of in developed about 5–10% about 1–5% prevalence of chronic HBV endemic areas general population world infection, HDV prevalence is in Far East low among both HBV carriers (