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Sign or symptom | Pathological basis |
---|---|
Jaundice | Haemolysis (increased formation of bilirubin), liver disease (impaired conjugation and/or excretion) or biliary obstruction |
Dark urine | Conjugated hyperbilirubinaemia (water-soluble) due to failure of bile excretion |
Pale faeces | Bile duct obstruction causing lack of bile pigments in faeces |
Spider naevi, Gynaecomastia | Secondary to hyperoestrogenism, failure of hormone metabolism |
Oedema | Reduced plasma oncotic pressure due to hypoalbuminaemia |
Xanthelasma | Cutaneous lipid deposits due to hypercholesterolaemia in chronic biliary disease |
Steatorrhoea | Malabsorption of fat due to lack of bile (e.g. biliary obstruction) |
Pruritus | Biliary obstruction resulting in bile salt accumulation |
Ascites | Combination of hypoalbuminaemia, portal hypertension and secondary hyperaldosteronism |
Bruising or bleeding | Impaired hepatic synthesis of clotting factors |
Hepatomegaly | Increased size of liver due to inflammation (e.g. hepatitis), infiltration (e.g. amyloid, fat) or tumour (primary or secondary) |
Splenomegaly | Enlargement of spleen due to congestion in portal hypertension |
Haematemesis | Ruptured oesophageal varices due to portal hypertension |
Encephalopathy | Failure of liver to remove exogenous or endogenous substances mimicking or altering balance of neurotransmitters |
Forming the interface between the gastrointestinal tract and the rest of the body, the liver is a chemical factory of crucial importance in metabolising, storing or excreting the absorbed products of digestion. It makes and excretes bile, synthesises proteins, metabolises hormones and drugs, and mounts an immune response to portal pathogens. The clinical consequences of severe liver disease are therefore wide-ranging and can be life-threatening, either suddenly as a result of overwhelming acute liver injury or gradually at the end stage of chronic liver disease. However, because there is considerable functional reserve and reparative capacity, lesser degrees of liver injury cause few symptoms and often go unnoticed unless specifically investigated.
This wedge-shaped organ, weighing approximately 1.5 kg in the adult, is situated in the right hypochondrial region of the abdominal cavity. The segmental anatomy divides the liver into eight segments centred on vascular supply, and without external anatomical landmarks. These map to the conventional four lobes of the liver: right (segments 4–8), left (segments 2 and 3), caudate (segment 1) and quadrate (part of segment 4), and form the basis of liver resection for tumours.
The liver receives blood from two sources:
arterial blood from the right and left hepatic arteries, which are branches of the coeliac axis (accounts for 10% volume and 30% oxygen, high-pressure flow into peribiliary capillaries then into sinusoids)
venous blood from the hepatic portal vein, which drains the alimentary tract from the stomach to the rectum, and the spleen (accounts for 90% volume and 70% oxygen, low-pressure flow into sinusoids).
Because of this dual blood supply, the liver is much less affected by vascular disease than other major organs in the body. Blood leaves the liver through the hepatic veins, which drain into the inferior vena cava close to the right atrium.
Most of the liver comprises liver cells ( hepatocytes ). These are arranged in plates or cords one to two cells thick, separated by vascular sinusoids ( Fig. 16.1 ). The blood flowing through the sinusoids is separated from the liver cells by sieve-like endothelial cells and a web of basement membrane which allows free exchange of molecules at the liver cell surface. The other cells in the sinusoids comprise Kupffer cells (the liver's resident macrophages), and Ito cells, which in disease states transform to myofibroblasts that synthesise collagen. Blood flowing through the vascular sinusoids drains into hepatic vein branches (called central veins or terminal hepatic venules).
Bile is produced by hepatocytes and is excreted into tiny canaliculae between abutting hepatocytes. It is propelled towards the portal tracts in the opposite direction to the sinusoidal blood flow. It is carried via the canals of Hering and ductules into the small interlobular bile ducts in the portal tracts. From these, it drains via a tree of increasingly large septal and segmental ducts into the right and left hepatic ducts at the porta hepatis . These fuse to form the common hepatic duct which leaves the liver.
The portal tracts each contain three tubular structures, which are branches of:
the bile duct
the hepatic artery
the portal vein.
These constitute the portal triad . Collagen in the normal liver is restricted to the portal tracts and terminal hepatic veins. An increase in fibrous tissue in the liver is a key feature of chronic liver disease. The perimeter of the portal tract is normally smooth, and the first row of hepatocytes around it is known as the limiting plate . This boundary is disrupted in chronic inflammatory diseases. From the portal tracts, oxygenated blood enters the sinusoidal system and flows slowly past hepatocytes, allowing the various metabolic functions to take place before leaving via the terminal hepatic venule. Although hepatocytes all look the same on light microscopy, they can be considered as arranged in three zones: periportal hepatocytes are in zone 1, and perivenular hepatocytes zone 3. The zone 3 hepatocytes are furthest from the incoming blood supply and vulnerable to ischaemic injury. They also are most active in detoxification and susceptible to injury from metabolites.
Liver cells are rich in organelles, including numerous mitochondria, lysosomes, peroxisomes (microbodies), and rough and smooth endoplasmic reticulum, reflecting their wide range of metabolic functions. Liver cells synthesise albumin, clotting factors including fibrinogen, some complement components, alpha-1 antitrypsin, and so on, and remove many waste products and potentially toxic substances. Liver cells also metabolise or activate drugs. They are important in energy metabolism of carbohydrate and fats, a function which is disturbed in maturity-onset diabetes and obesity.
All cells in the normal liver are capable of regeneration. The liver cells are classified as stable — that is, they normally replicate only very infrequently, but if the liver is injured nearly all surviving hepatocytes can enter the cell cycle and rapidly replace destroyed hepatocytes.
There are numerous causes of liver disease, many of which are mentioned in the general pathology chapters of this book. Genetic, environmental, infectious, metabolic and autoimmune causes can damage hepatocytes. Obstruction to blood vessels or bile ducts also results in liver cell injury, and more than one cause may be present. The clinical effects depend more on the time frame and severity of injury, and effectiveness of repair and regeneration, than the specific cause of liver disease. The common causes of liver disease are listed in Table 16.1 . Most can cause either acute or chronic liver disease.
Cause of liver disease | Acute | Chronic |
---|---|---|
Viral hepatitis | Hepatitis A, B, E Immune response eliminates virus |
Hepatitis B, C (D) Virus persists in hepatocytes, evading immune response |
Alcohol | Acute alcoholic hepatitis — severe toxic injury to hepatocytes from binge drinking (may be superimposed on chronic injury) | Steatosis alone — reversible metabolic alteration in liver cells Steatohepatitis, cell injury and death with progressive fibrous scarring leading to cirrhosis |
Nonalcoholic fatty liver disease | Steatosis alone Steatohepatitis, with risk of progressive fibrosis and cirrhosis |
|
Drugs — intrinsic | Toxic effect of drug on liver cells, causes necrosis, e.g. paracetamol excess | Subclinical injury builds up gradually over time, e.g. methotrexate |
Drugs — idiosyncratic | Allergic reaction to drug or its metabolite — rare, unpredictable, may be severe, e.g. antibiotic including antituberculous, antiepileptic, antidepressant, analgesic | Persistent mild unrecognised chronic inflammation or induces autoimmune hepatitis (e.g. methyldopa) |
Autoimmune — hepatitis | Acute presentation with severe hepatitis (up to 40% cases) | Autoimmune hepatitis — usual presentation detected during investigation of abnormal liver tests |
Autoimmune — biliary | Primary biliary cholangitis Primary sclerosing cholangitis (PSC) |
|
Transplant rejection | Acute cellular rejection — inflammation during first few weeks or with drop in immunosuppression | Ductopenic chronic rejection — gradual destruction of bile ducts |
Bile duct obstruction | Gallstone obstructing common bile duct Presents in infancy: biliary atresia |
Large duct PSC, immunoglobulin G4 disease, tumours |
Genetic inborn error of metabolism | Presents in infancy on weaning (e.g. galactosaemia, tyrosinaemia) | Haemochromatosis Wilson disease Alpha-1 antitrypsin deficiency |
In acute liver injury , regeneration can return the liver to normal once the cause of the damage subsides (e.g. immune response eliminates the virus, drug is discontinued), and if mild may be unnoticed by the patient. Malaise and jaundice (yellowing of the white of the eye and later skin due to the presence of raised serum bilirubin) are the main symptoms. Very rarely, if the liver cell injury is overwhelmingly severe, acute liver failure can develop with coagulopathy, encephalopathy, or even death.
Chronic liver disease develops when the cause of hepatocyte damage persists, for example, alcohol, virus, metabolic, autoimmune and so on. The continuing liver cell damage is associated with inflammation and progressive scarring which gradually disrupts the normal architectural structure of the liver. This, together with regeneration of the surviving hepatocytes between bands of fibrosis, has the potential to result eventually in the development of cirrhosis , the late stage of all chronic liver diseases. Chronic liver disease may be clinically inapparent until the late stage is reached, but if detected sooner can often be successfully treated. Cirrhosis is defined anatomically by the presence throughout the liver of fibrous septa that subdivide the parenchyma into nodules. Perfusion of sinusoids is inefficient, liver cell function impaired, and intrahepatic pressure increased. The patient may present with symptoms and signs of liver failure (ascites, weakness, bruising, jaundice, encephalopathy) or with haemorrhage from bleeding oesophageal varices.
Blood tests commonly used in the investigation of a patient with liver disease are listed in Table 16.2 . They include:
biochemical analysis, for example, bilirubin, liver enzymes, albumin
immunological testing for immunoglobulins, autoantibodies
virology for viral antigens and antibodies and polymerase chain reaction (PCR) for viral nucleic acids.
This panel of blood tests together with liver ultrasound (often referred to as the ‘noninvasive liver screen’, or NILS) is used as a first line in the investigation of patients with liver disease. In addition, imaging techniques and liver biopsy are important. These investigations complement careful history-taking including alcohol, therapeutic and recreational drug use, foreign travel, and a thorough clinical examination.
Test | Deviation from normal | Interpretation |
---|---|---|
Albumin Normal 35–50 g/L |
↓ | Liver failure |
Prothrombin time Normal < 15 s |
↑ | Liver failure |
Alanine aminotransferase (ALT) Normal < 40 IU/L |
↑ | Hepatocellular injury |
Aspartate aminotransferase (AST) Normal < 40 IU/L |
↑ | Hepatocellular injury |
Gamma-glutamyltransferase (GGT) Normal < 50 IU/L |
↑ | Hepatocellular injury, biliary obstruction |
Alkaline phosphatase Normal < 100 IU/L |
↑ | Biliary obstruction Hepatic metastases |
Bilirubin Normal 5–12 µmol/L |
↑ | Hepatocellular injury Biliary obstruction Liver failure Congenital hyperbilirubinaemia Haemolysis |
IgM anti-HAV antibody | Present | Hepatitis A |
HBsAg | Present | Chronic hepatitis B |
HBeAg | Present | Active hepatitis B replication |
HBV DNA | Present | Active hepatitis B replication |
Anti-HBcAb | Present | Previous hepatitis B |
Anti-HCV antibody | Present | Hepatitis C virus exposure |
HCV RNA | Present | Active hepatitis C infection |
Caeruloplasmin | ↓ | Wilson disease |
IgA | ↑ | Alcoholic cirrhosis |
IgG | ↑ | Autoimmune hepatitis |
IgM | ↑ | Primary biliary cholangitis |
Antimitochondrial antibody | Present | Primary biliary cholangitis |
Antismooth muscle, antinuclear or anti-LKM antibodies | Present | Autoimmune hepatitis |
Ferritin | ↑ | Haemochromatosis or acute phase response |
Transferrin saturation | ↑ | Haemochromatosis |
Alpha-1 antitrypsin | ↓ | Alpha-1 antitrypsin deficiency |
Alpha-fetoprotein (AFP) (normally undetectable) | ↑ | Liver cell carcinoma |
Jaundice becomes visible when the serum bilirubin is more than 40 µmol/L and is the most common sign of liver disease. It has several causes. Bilirubin pigment is a breakdown product of haemoglobin ( Fig. 16.2 ). It is normally present in low levels in the blood as an unconjugated water-insoluble form bound to albumin. This is converted to water-soluble conjugated bilirubin by hepatocytes and excreted in bile. If bile outflow is interrupted, conjugated bilirubin is resorbed and excreted in urine, making it appear dark. Once in the intestine, bilirubin is converted by bacteria to faecal urobilinogen (stercobilinogen), and its metabolites account for the brown colour of faeces.
Jaundice may be classified as prehepatic , intrahepatic , or posthepatic , based on the point of abnormality in the pathway of bilirubin metabolism (see Fig. 16.2 ).
Increased breakdown of red blood cells ( haemolysis ) (see Ch. 23 ) can result in production of bilirubin that exceeds the capacity of the liver to conjugate and excrete it; the bilirubin is therefore unconjugated.
Jaundice due to failure of hepatocytes to conjugate and excrete bilirubin is a symptom of:
acute diffuse liver cell injury
liver cell failure in end-stage chronic liver disease
inborn errors of bilirubin conjugation and bile salt excretion, including cholestasis in pregnancy.
The excess bilirubin is predominantly conjugated, reabsorbed into the blood, and is excreted in the urine, causing darkening.
This is due to obstruction of the bile ducts — see ‘ biliary system ’ below. As with intrahepatic causes, the excess bilirubin is conjugated and darkens the urine. Conversely, the patient's faeces are pale because bile pigment does not reach the intestinal contents.
In hepatocyte injury, damage to the membranes of cells and their organelles allows intracellular enzymes to leak into the blood, where the elevated concentrations can be measured. Examples include alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyltransferase. The enzyme alkaline phosphatase is normally present in cells lining bile ducts. A raised level in the blood is seen in biliary obstruction. Many of these enzymes are not specific to the liver; therefore the results of diagnostic serum assays need careful interpretation.
Albumin is a major serum protein synthesised by the liver cells. It has a relatively long half-life, so low levels indicate long-term insufficient liver function. Serum albumin may be low for other reasons such as leakage from glomerulus into urine (nephrotic syndrome) or protein malabsorption.
Liver cells synthesise most clotting factors; therefore a bleeding tendency results from hepatic insufficiency. This can be detected in the laboratory by measuring the prothrombin time. Because the clotting factors have a relatively short half-life, coagulopathy develops in severe acute liver disease as well as the end stage of chronic liver disease.
Some forms of chronic liver disease have an autoimmune pathogenesis and are associated with nonorgan-specific autoantibodies in the blood, providing useful diagnostic markers. Examples include:
antimitochondrial antibodies in primary biliary cholangitis
antinuclear antibodies (ANA) and antismooth muscle antibodies in autoimmune hepatitis.
Polyclonal immunoglobulin (Ig) elevations also occur:
raised IgG in autoimmune hepatitis
raised IgM in primary biliary cholangitis
raised IgA in alcoholic cirrhosis.
Acute and chronic viral hepatitis is diagnosed by detection of specific antibodies together with PCR testing for nucleic acids of hepatitis B and C.
Techniques used to identify intrahepatic masses, assess liver blood flow and visualise the biliary tract include the following:
Ultrasonography — focal lesions, dilated ducts, blood flow. Transient elastography is a new technique that measures liver ‘stiffness’, a noninvasive estimate of liver fibrosis.
CT — tumours.
MRI — tumours, biliary tree (MR cholangiopancreatography [MRCP]).
Endoscopic retrograde cholangiopancreatography (ERCP)—cannulation of the ampulla of Vater and injection of contrast. This also gives an opportunity for brush cytology and removal of gallstones, but has a risk of inducing pancreatitis.
Needle core biopsy enables the nature of the tissue damage in liver disease to be directly analysed and is often performed during the course of investigation of chronic liver disease. Percutaneous needle biopsy has a small risk of haemorrhage and biliary leakage from the biopsy site, and is contraindicated if imaging shows biliary obstruction. In patients with severe liver disease and coagulopathy, liver biopsy is obtained through the hepatic vein via the transjugular route under image guidance to avoid the risk of bleeding.
Most liver diseases produce diffuse abnormalities in the organ; a biopsy from any part of it will therefore be representative. For patients in whom imaging shows a focal abnormality (e.g. tumour or abscess) biopsy is targeted using imaging. Liver biopsies are examined by light microscopy after sectioning and staining; when performed to diagnose medical liver diseases, additional stains are generally used to demonstrate:
collagen — fibrosis, cirrhosis — van Gieson or Masson trichrome stain
iron storage — Perls stain
copper-binding protein or copper — Shikata orcein or rhodanine stain
glycogen — periodic acid–Schiff (PAS) stain
glycoprotein — for example, active Kupffer cells and alpha-1 antitrypsin deficiency — PAS with diastase.
The purpose of obtaining a liver biopsy is:
to diagnose the type or specific cause of the liver disease
to assess the severity of the injury (including grade of inflammation)
to evaluate the degree of architectural alteration in the progression from normal to cirrhosis (stage of fibrosis)
to assess any change over time, including in response to treatment, by comparing with previous biopsies.
When patients present with clinical features of acute liver disease (usually malaise and jaundice) the cause can usually be diagnosed by clinical history, blood tests and imaging, and biopsy is performed only when the disease is severe or the diagnosis uncertain. The biopsy may show features of acute hepatitis (see below) or a previously unrecognised chronic liver disease including alcoholic liver disease, or (rarely) diffuse infiltration by malignancy.
Causes of acute hepatitis include:
viral (hepatitis A, B, E)
drug-induced liver injury (DILI)
autoimmune hepatitis
‘seronegative’ when no cause can be identified.
In acute hepatitis, there is hepatocyte injury with cell death, inflammation and regeneration without structural change to the liver. The normally uniform liver cell plates are transformed into ‘ lobular disarray’ characterised by gaps in the liver cell plates, swollen surviving hepatocytes, apoptotic bodies, small regenerated hepatocytes, inflammatory cells and active Kupffer cells ( Fig. 16.3 ). Histological features are similar in acute hepatitis whether it is due to hepatotrophic viruses, drugs or autoimmune hepatitis.
The extent of liver cell destruction seen in the biopsy is classified as ( Fig. 16.4 ):
death of individual liver cells by apoptosis (spotty necrosis, hepatocyte drop-out)
death of adjacent hepatocytes, for example, in the zone around the hepatic vein (zone 3) ( zonal necrosis )
death of a swathe of hepatocytes between a portal tract and hepatic vein ( bridging necrosis ); the supporting reticulin framework of the liver collapses. Care is needed to avoid mistaking the resulting condensation of reticulin fibres for scar tissue of chronic liver disease
liver cell death affecting all hepatocytes between adjacent portal tracts ( panacinar and multiacinar necrosis ); when extensive ( massive necrosis ), this can result in liver failure and death.
Resolution — the cause does not persist and the liver returns to normal (e.g. hepatitis A, E, most cases of hepatitis B, most drug-induced hepatitis)
acute liver failure — with risk of death (rare, any cause)
chronic hepatitis, may progress to cirrhosis — the cause persists (e.g. autoimmune hepatitis, chronic hepatitis B and C, some drugs); the initial acute hepatitis may have been mild and unrecognised.
Liver failure is present when the liver can no longer function sufficiently to maintain the body's homeostasis. This includes:
inadequate synthesis — albumin, clotting factors, glucose from glycogen
inadequate metabolism and elimination of endogenous products such as bilirubin, nitrogenous waste, hormones, and so on.
The presentation of liver failure depends on the rate at which the insufficiency in liver function develops.
Acute liver failure — as a result of acute severe liver cell injury with insufficient regeneration ( massive necrosis ). This results in vomiting, hypoglycaemia, encephalopathy, very high ALT and AST, jaundice and bruising.
Chronic liver failure — as a result of decompensation of liver function, occurs late in the course of chronic liver disease, and is covered in the section on cirrhosis .
Precirrhotic chronic liver disease usually causes no symptoms other than malaise, and is detected by abnormalities in routine ‘liver function tests’. This is further investigated by a ‘liver screen’ of diagnostic tests, and usually liver biopsy, so that the appropriate treatment that aims to halt progression and avoid cirrhosis can be given.
The histopathological abnormalities include specific features of particular diseases and nonspecific effects of injury, including some inflammation, fibrous scarring and liver cell regeneration.
Examples of specific patterns of liver disease include:
fatty liver disease — seen in alcoholic liver disease and liver disease associated with obesity and diabetes (known as nonalcoholic fatty liver disease, NAFLD)
chronic hepatitis with inflammation and injury to hepatocytes, especially those surrounding portal tracts — known as interface hepatitis — the pattern seen in chronic viral and autoimmune hepatitis
liver injury consequent on diseases of the bile ducts — includes intrahepatic ducts and effects of large (extrahepatic) bile duct obstruction
inborn errors of metabolism where substances accumulate in liver cells — for example, iron in haemochromatosis, copper in Wilson disease, alpha-1 antitrypsin deficiency
vascular abnormalities, for example, consequences of thrombosis of portal or hepatic veins.
Those with biochemical and serological features are listed in Table 16.3 .
Disease | Distinctive features | ||
---|---|---|---|
Serological | Biochemical | Biopsy | |
Autoimmune hepatitis | Antismooth muscle antibody and antinuclear factor | Raised IgG and transaminases | Prominent interface hepatitis. Abundant plasma cells, liver cell rosettes |
Chronic hepatitis B | HBsAg, HBeAg, HBV RNA | Raised transaminases | Ground-glass hepatocytes |
Chronic hepatitis C | Anti-HCV, HCV RNA | Raised transaminases | Fatty change and portal lymphoid aggregates |
Primary biliary cholangitis | Antimitochondrial antibody | Raised IgM and alkaline phosphatase | Bile duct granulomas, then loss of interlobular bile ducts |
Alcoholic cirrhosis | Raised IgA and GGT | Steatosis, Mallory-Denk bodies, pericellular fibrosis | |
Wilson disease | Low caeruloplasmin | Excess copper | |
Alpha-1 antitrypsin deficiency | Low alpha-1 antitrypsin | Hyaline globules in liver cells | |
Haemochromatosis | Raised ferritin and transferrin saturation | Haemosiderin in liver cells |
Acute fatty liver disease is a very rare condition, causing acute liver failure and characterised histologically by hepatocytes with pale foamy cytoplasm ( microvesicular steatosis ) that is confirmed by a frozen section stained for fat (which dissolves out during routine tissue processing). The causes include acute fatty liver of pregnancy, inherited mitochondrial defects (Reye syndrome), DILI and occasionally alcohol.
Fatty liver disease with macrovesicular steatosis is the most common pattern of liver pathology in developed countries, and is increasing worldwide. Normal liver can contain occasional (<5%) steatotic hepatocytes. Fatty liver disease encompasses a spectrum from bland steatosis, through steatohepatitis, to cirrhosis and hepatocellular carcinoma (HCC). The most common causes are alcoholic liver disease, and NAFLD, the liver disease associated with insulin resistance (i.e. the metabolic syndrome, p. 109 ). Either can progress to steatohepatitis and cirrhosis. Both alcohol and insulin resistance may be synergistic in causing liver injury. Other rarer causes of fatty liver include drugs, hepatitis C, industrial solvent exposure and genetic inborn errors of metabolism.
Common cause of chronic liver disease, may present acutely
Liver may show steatosis or steatohepatitis
Continued consumption leads to fibrosis and cirrhosis
Mechanisms include: toxic effects of acetaldehyde (the metabolite of alcohol), oxidative stress, impaired carbohydrate and fat metabolism, and stimulation of collagen synthesis
Genetic susceptibility to liver damage varies
Alcohol (ethyl alcohol, ethanol) is the most common cause of chronic liver disease and cirrhosis in many countries. Epidemiologically, the prevalence of cirrhosis correlates with alcohol consumption per head of population. Both of these increased in the UK until 2008, after which there has been a slight fall. Public health measures aimed at reducing alcohol consumption and obesity are important, since most chronic liver disease is avoidable.
The spectrum of alcoholic liver injury which can be seen in liver biopsies includes ( Fig. 16.5 ):
fatty change ( steatosis ) fat globules in the cytoplasm of liver cells, a disturbance of energy metabolism which on its own is reversible when alcohol consumption stops
alcoholic steatohepatitis — a combination of fatty change with cell swelling (ballooned hepatocytes), Mallory-Denk bodies and inflammation. In contrast to pure fatty change, steatohepatitis leads to liver cell death and fibrosis
progressive architectural damage ranging from pericellular fibrosis to cirrhosis.
Alcohol produces liver injury by a variety of mechanisms.
Alcohol metabolism disturbs other metabolic pathways, such as carbohydrate and fat metabolism, so fat accumulates in the liver cells.
Acetaldehyde, the main product of alcohol metabolism, is toxic to liver cell proteins, resulting in injured hepatocytes and an inflammatory reaction.
Alcohol stimulates collagen synthesis in the liver, leading to fibrosis and eventually cirrhosis.
Sustained alcoholic liver injury in genetically susceptible people who continue to drink results in irreversible end-stage cirrhosis. Because the fibrosis is pericellular and abundant, the cirrhosis is micronodular, although if abstinence is maintained after cirrhosis has developed, this may evolve into inactive macronodular cirrhosis as a result of regeneration of hepatocytes.
Recommended safe limits for alcohol continue to be debated. Currently men and women in the UK are advised not to regularly drink more than 14 units of alcohol per week. (One unit of alcohol is 10 mL by volume, equivalent to: half a pint, or c . 300 mL, of beer; or 25 mL of spirits. A small glass of wine contains 1.5 units.)
The metabolic syndrome is recognised clinically by the association of central obesity, dyslipidaemia and hypertension. Excess calorie intake, especially of refined carbohydrate, and little exercise results in insulin resistance, raised levels of insulin and glucose in the blood, and eventually type II diabetes when pancreatic islets fail to keep pace with the increasing requirements for insulin.
NAFLD is present in most patients with metabolic syndrome. It is usually asymptomatic, but is now recognised to be the most common cause of persistent mild elevation of liver enzymes, and in a proportion of patients it progresses to cirrhosis. This has been recognised only in recent years, and the epidemiology and risk factors for progression are still being investigated. Since steatosis disappears in late-stage cirrhosis, these patients were previously diagnosed with ‘cryptogenic’ cirrhosis.
Liver biopsy may show:
steatosis without additional features of steatohepatitis or fibrosis
nonalcoholic steatohepatitis — similar to alcoholic steatohepatitis, but generally less inflammation, Mallory-Denk bodies and fibrosis
cirrhosis — steatosis disappears in late-stage disease.
Patients have increased mortality from chronic liver disease but a greater risk of death from associated cardiovascular disease and cancer.
‘Chronic hepatitis’ refers to chronic liver disease with a predominantly inflammatory pattern on biopsy, characterised by ( Fig. 16.6 ):
portal tract inflammation
interface hepatitis
portal-based fibrosis, bridging fibrosis or cirrhosis
usually also lobular inflammation and apoptosis.
The main causes of this pattern of chronic liver disease are viral hepatitis and autoimmune hepatitis; a rare cause is drug-induced chronic hepatitis. Similar histological features may be seen in patients with autoimmune biliary disease, and Wilson disease. Clinicopathological correlation with other investigations is necessary to determine the cause.
Liver biopsy is used to determine the cause of liver injury, especially if clinical history/blood tests suggest more than one possible cause, and to assess its severity. The results are used to guide decisions about clinical management, and semiquantative scoring systems are used to describe the stage of fibrosis and grade of inflammation and liver cell injury.
Hepatitis viruses A, B, C and E, and delta agent
Acute infection may cause jaundice or be subclinical
Other viruses causing liver damage include Epstein–Barr virus, herpes simplex virus and cytomegalovirus
Viruses transmitted by oral (A, E) or blood-borne route (B, C)
Blood-borne viruses can cause chronic infection (B, C)
The hepatotrophic viruses specifically infect and injure hepatocytes. The initial infection may result in a clinically acute hepatitic illness, or go unnoticed. Hepatitis B and C (and hepatitis E in immunocompromised adults) can establish chronic infection. The hepatotrophic viruses ( Table 16.4 ) are:
hepatitis A virus (HAV)
hepatitis B virus (HBV)
hepatitis C virus (HCV)
hepatitis E virus (HEV)
delta agent, a defective virus which only infects people with hepatitis B.
The liver may also become infected by many other viruses, but these are not regarded as ‘hepatotrophic viruses’ because the infection is not confined to the liver; clinically significant hepatitis is usually seen only in immunocompromised patients. Examples include:
infectious mononucleosis due to Epstein–Barr virus
herpes simplex virus 1
cytomegalovirus.
Virus | Type of virus | Incubation period (days) | Acute hepatitis | Chronic hepatitis | Serological markers | Patient susceptibility | Transmission |
---|---|---|---|---|---|---|---|
HAV | ssRNA enterovirus | 15–40 | Usually mild ± jaundice; very low mortality | No | IgM anti-HAV antibody | Young | ‘Faecal–oral’ |
HBV | dsDNA | 50–180 | Varies — mild in patients who develop chronic hepatitis | Yes — if impaired immune response | HBsAg, HBeAg | Any age | Blood and blood products; needles; venereal |
HCV | ss + RNA flavivirus | 40–55 | Usually unrecognised | Yes in around 70% | Anti-HCV antibody, HCV RNA | Any age | Blood and blood products; needles; possibly venereal |
HEV | ssRNA virus | 30–50 | Endemic countries; jaundice, high mortality in pregnancy | No | Anti-HEV antibody | Any age | ‘Faecal–oral’ |
+ , Positive sense; dsDNA , double stranded DNA; HAV , hepatitis A virus; HBV , hepatitis B virus; HBeAg , hepatitis E antigen; HBsAg , hepatitis B surface antigen; HCV , hepatitis C virus; HEV , hepatitis E virus; Ig , immunoglobulin; ssRNA , single stranded RNA.
The main characteristics of hepatitis A are:
‘faecal–oral’ spread
relatively short incubation period
sporadic or epidemic
does not cause chronic hepatitis
mild illness, full recovery usual.
In most countries, infection by the virus is common, usually in youth; the resulting illness is often very mild and jaundice absent or slight. Very rarely, it causes severe hepatitis; death is extremely rare.
HAV passes from one individual to another by ‘faecal–oral’ transmission — usually indirectly, such as by the contamination of food and drinking water with sewage. Specific diagnosis is made by detecting IgM-class antibody to HAV in the patient's serum; this indicates recent infection.
The main characteristics of hepatitis B are:
spread from people with chronic hepatitis B by blood, blood-contaminated instruments, blood products and venereally
relatively long incubation period
liver damage by antiviral immune reaction
chronic infection when immune system fails to eradicate the virus.
Infection by HBV is transmitted by blood and blood products from people with chronic hepatitis B. In developed countries, HBV is most often transmitted by contaminated needles, such as may be used for tattooing or by drug addicts. Other routes are sexual contact, and spread from mother to child. This is a common route of infection in parts of the world where hepatitis B is prevalent. Protective vaccination against hepatitis B is given to people at risk of infection, for example, health care workers or to populations in high-incidence countries.
Diagnosis is by virology, using serological tests for hepatitis B antigens and antibodies and for the DNA of circulating viral particles detected by PCR test. IgM antibodies against hepatitis B are produced in acute hepatitis, followed by IgG antibodies against hepatitis B core and surface antigen if the acute infection is cleared. Persistent hepatitis B surface antigen (HBsAg) in the patient's serum indicates that chronic hepatitis has developed, and if accompanied by the ‘e’ antigen (HBeAg), indicates active viral replication and high infectivity of the blood.
The liver cell damage in hepatitis B is caused by the body's immune reaction to viral antigens expressed by the infected liver cells, and the outcome of hepatitis B infection depends on the immune response.
In most cases, a strong immune response results in acute hepatitis with eradication of the virus. Patients with an impaired immune response insufficient to clear the virus develop chronic hepatitis with production of excess HBsAg by hepatocytes; this is visible as inclusions with a ‘ground-glass’ appearance in the hepatocyte cytoplasm. The suppressed virus may mutate and develop altered antigens, resulting in flares of inflammation. Over time, there is progressive scarring, cirrhosis and risk of HCC.
In perinatal infection, there is tolerance to the viral antigens, and hepatitis B can proliferate in hepatocytes to release high levels of viral particles into the blood without any liver injury. Eventually, a limited immune reaction develops, resulting in chronic hepatitis
The main characteristics of hepatitis C are:
spread by blood, blood-contaminated instruments, blood products, and possibly venereally
usually asymptomatic and unrecognised initial infection
fluctuating liver biochemistry
chronic hepatitis in around 70% cases.
Hepatitis C was identified in the early 1990s; prior to this, patients having blood transfusion and the administration of clotting factor concentrates were at risk of infection. In developed countries, donors are now screened for HCV, and most cases are acquired by needle sharing among users of intravenous drugs. In developing countries, the prevalence of infection may be high (>10% in some areas) and routes of infection unclear. Most infections are clinically silent and in around 70% the initial immune response fails to eliminate the virus, resulting in chronic hepatitis. Progression to cirrhosis in untreated cases is on average about 10% per decade but is very variable; factors associated with progression are older age at acquisition, male, alcohol consumption, and coinfection with other viruses (hepatitis B, HIV). Biopsies often show steatosis as well as features of chronic hepatitis.
Hepatitis E is a water-borne virus, distinct from HAV, which is endemic in some developing countries where it can cause severe hepatitis during pregnancy. It has recently been recognised in developed countries (genotype 3) where it can be acquired from poorly cooked meat. It can cause acute hepatitis with jaundice in adults, and can cause chronic hepatitis in immunocompromised hosts (liver transplant recipients).
Delta agent is an incomplete RNA virus that can only infect hepatocytes in the presence of HBV. Its main effect is to aggravate the consequences of HBV infection, either as more severe acute infection, or a flare of inflammation in chronic HBV infection.
At least 10% of drug reactions involve the liver
May be cholestatic or hepatocellular
Pathogenesis may be dose-related (predictable) or idiosyncratic (unpredictable)
Approximately 10% of all adverse reactions to drugs involve the liver. This is not surprising in view of the central role played by the liver in metabolism and in the conjugation and elimination of toxic substances from the body. A full drug history should therefore be taken from any patient with jaundice or abnormal liver function tests, and liver injury usually subsides when the drug is discontinued. Any suspected or proven association should be reported to the appropriate body (in the UK, the Commission on Human Medicines).
DILI may be predictable or unpredictable. It may be due to injury to the liver cells (hepatocellular) that is pathologically indistinguishable from viral hepatitis, or to bile production or excretion (cholestatic). Predictable reactions will occur in any individual if exposed to a sufficient dose; examples include coagulative centrilobular necrosis due to paracetamol overdose (the most common cause of acute liver failure in the UK), and cholestatic jaundice due to methyl testosterone. Such drugs are intrinsic hepatotoxins.
Idiosyncratic drug reactions unpredictably affect a small proportion of patients taking the drug, and may be severe. They may be a result of a rare genetic pathway for drug metabolism, an allergic response to the drug or its metabolite, or a combination of these, and are not dose-related but recur on repeat exposure to the drug. Examples include cholestatic jaundice due to Augmentin and hepatitic reactions to carbamazepine.
Some examples of other types of DILI without an acute presentation include steatosis and steatohepatitis (e.g. tamoxifen), granulomatous hepatitis (e.g. allopurinol) and nodular regenerative hyperplasia (azathioprine).
There are three chronic liver diseases with an autoimmune basis:
autoimmune hepatitis (AIH)
primary biliary cholangitis (PBC)
primary sclerosing cholangitis (PSC).
Diagnosis is by detecting autoantibodies and elevated Ig in the serum and characteristic changes on liver biopsy in a patient with abnormal liver function tests. The inflammation destroys primarily the hepatocytes (AIH), resulting in histological features of chronic hepatitis, or bile ducts (PBC and PSC), resulting in chronic biliary disease. In around 10% cases, there are clinical features of both AIH and a biliary disease. There is an association with autoimmune diseases affecting other organs.
Females > males
Liver biopsy shows chronic hepatitis, often with plasma cells and liver cell rosettes
Antismooth muscle, antinuclear or anti–liver-kidney microsome (anti-LKM) antibodies, raised IgG and transaminases
AIH occurs more commonly in females, may have an acute onset, and is often a severe form of hepatitis that can cause acute liver failure, or without treatment progress rapidly to cirrhosis. Histologically, it is characterised by extensive interface hepatitis, numerous plasma cells and rosette-like arrangements of swollen liver cells, and there may be bridging and panacinar necrosis. Serum IgG is raised, and autoantibodies to smooth muscle antigen (SMA), nuclear DNA (antinuclear antibody, ANA) or to LKM antigens are also often present. Raised transaminases respond to treatment with steroids, which further supports the diagnosis. Treatment with long-term immunosuppression can prevent progression to cirrhosis.
Bilirubin is just one constituent of bile, a complex excretory product of which bile salts are a major constituent (50% dry weight). Bile salts function in micelle formation and fat absorption from the gut, from which they are reabsorbed into portal blood and then reexcreted several times a day in an enterohepatic circulation. Diseases that damage peripheral branches of the biliary tree result in bile salt accumulation in the surrounding periportal hepatocytes, together with accumulation of copper, also excreted in the bile. Such bile duct injury is associated with raised serum alkaline phosphatase, disturbed serum lipids and characteristic changes on liver biopsy. Bile salt accumulation also causes itching ( pruritus ), a common and troublesome symptom of chronic biliary disease.
Liver biopsy may show bile duct lesions specific to the disease — granulomatous inflammation in PBC and periductal fibrosis in PSC, and these progress to destruction of the intrahepatic ducts ( ductopenia ). In addition, as the disease progresses, there is proliferation of marginal ductules around portal tracts (‘ ductular reaction’ ), followed by portal tract fibrosis, bridging fibrosis and cirrhosis. The periportal hepatocytes show swelling and accumulation of copper bound to copper-associated protein, which can be identified with the Shikata stain and is a useful early sign of chronic biliary disease ( Fig. 16.7 ). Other rare causes of acquired ductopenia include graft-versus-host disease, drug reactions and Hodgkin lymphoma.
Unrelieved large bile duct obstruction (see ‘bile ducts’ below) may result in similar liver biopsy appearances, although associated with bilirubin visible in the canaliculae between hepatocytes only rarely with ductopenia.
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