6 Liver disease
Investigations
Routine serum liver biochemical tests
• Bilirubin is produced from the breakdown of red cells and a raised level indicates jaundice. In the serum, most of the total bilirubin is unconjugated. Gilbert’s syndrome is the most common familial hyperbilirubinaemia, with isolated serum bilirubin levels of 17–102 µmol/L (1–6 mg/dL) (mostly unconjugated). Unconjugated bilirubin is also produced in haemolysis. It is not water-soluble so does not appear in the urine. Conjugated bilirubin is water-soluble and makes the urine dark.
• Serum enzymes
• Elevation of the serum aminotransferases (aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT)) occurs with hepatocellular damage from any cause. Mild elevations are a common finding at routine screening, often due to moderate alcohol consumption. ALT is more specific to the liver and only rises with liver damage, whereas AST is also elevated with muscle damage, e.g. myocardial infarction.
• Alkaline phosphatase is present in the liver and many other tissues, e.g. bone, intestine and placenta. If there is an abnormality of the other liver enzymes, particularly the γ-GT, the alkaline phosphatase can be presumed to arise from the liver. The level is raised in cholestasis of any cause, whether intra- or extrahepatic, with infiltration of the liver, e.g. by metastases, and in cirrhosis, often without jaundice. Serum levels are higher than normal in children and adolescents (bone) and in pregnancy (placenta).
• γ-Glutamyl transpeptidase (γ-GT) increases in the serum in parallel with the serum alkaline phosphatase in liver disease. γ-GT is an inducible enzyme and serum levels are elevated by alcohol and by drugs, e.g. phenytoin; when the liver tests are normal, this elevation does not indicate liver damage.
• Markers of liver fibrosis
• Fibrotest/fibrosure tests measure α2-macroglobulin, α2-haptoglobulin, γ-globin, apoprotein A1, γ-GT and total bilirubin. These results are formulated to determine a fibrosis index. The index is sensitive and specific (> 90%) for the absence of fibrosis, and has 80% sensitivity and specificity for severe fibrosis.
• Liver function
• Serum albumin falls in chronic liver disease and is a useful guide to prognosis. Because of its long half-life (20 days), the albumin level is often normal in acute liver disease.
• Prothrombin time (PT) is a marker of synthetic function if vitamin K deficiency has been excluded by giving a 10 mg IV bolus of vitamin K and then rechecking the PT after 24 hours. The PT is used to predict outcome in fulminant hepatic failure. PT values vary in different laboratories and the International Normalized Ratio (INR), which is corrected by an international sensitivity ratio, is often used.
Box 6.1 shows an interpretation of abnormal liver biochemistry.
Box 6.1 Abnormal liver biochemistry — how to proceed
Always check the history and examine the patient for signs of liver disease.
The role of imaging
• Ultrasound (US) examination is particularly useful in the jaundiced patient. Look for:
US is useful for the detection of gallstones and for evaluation of hepatosplenomegaly and other abdominal masses. In focal liver disease, lesions > 1 cm can be detected and US is used to screen patients for hepatocellular carcinoma. Colour flow Doppler will show the direction of blood flow in the portal and hepatic veins. In endoscopic ultrasound, a small, high-frequency US probe mounted on the tip of the endoscope can accurately stage pancreatic tumours (particularly neuroendocrine) and also chronic pancreatitis.
• Computed tomography (CT) with IV contrast is useful for the evaluation of all liver diseases and can detect smaller lesions than US.
• Magnetic resonance imaging (MRI) avoids the use of irradiation and is very sensitive for the detection of liver masses. It cannot be used in patients with pacemakers, defibrillators and implanted metal objects.
• Magnetic resonance cholangiopancreatography (MRCP) allows non-invasive visualization of the bile and pancreatic ducts, thereby replacing diagnostic ERCP.
• Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are used to outline the biliary tree. ERCP also visualizes the pancreatic duct. Contrast is introduced into the lower bile duct through the ampulla of Vater using an endoscope (ERCP) or injected through the liver (PTC). Via ERCP, the biliary system can be drained by performing a sphincterotomy and inserting a stent. Stones can also be removed from the common bile duct at ERCP. Pancreatitis, with a raised serum amylase, can occur after ERCP (5%); bleeding is seldom serious. A broad-spectrum antibiotic, e.g. oral 500 mg ciprofloxacin ×2, should be given prophylactically to all patients with suspected biliary obstruction or a history of cholangitis. PTC is used when ERCP is not possible but sometimes the two techniques are combined, with PTC showing the biliary anatomy above the obstruction and ERCP showing the distal anatomy.
• Scintiscanning using an IV injection of 99m-technetium colloid is less commonly used. In chronic liver disease most of the colloid is taken up by the spleen and bone marrow instead of the liver. Scintiscanning can also detect focal lesions. IV technetium-labelled iododiethyl IDA is excreted into the biliary system and can be used in the diagnosis of acute cholecystitis.
Liver pathology
• Percutaneous liver biopsy can be performed with or without US guidance for histological diagnosis. It is a safe procedure that can be carried out as a day case. Bleeding is the most common problem but is rarely serious. Biliary leaks occur rarely. Contraindications include ascites and extrahepatic cholestasis. If the PT is raised (by > 3 secs) or there is thrombocytopenia (< 80 × 109/L), a biopsy can be performed by the transjugular route, if this is really necessary.
Jaundice
Jaundice (Fig. 6.1) is due to intra- or extrahepatic cholestasis.
Fig. 6.1 Approach to the patient with jaundice. CBD, common bile duct; MRCP, magnetic resonance cholangiopancreatography; US, ultrasound.
Approach to the patient
• History — risk factors for hepatitis, drugs (hepatotoxic), pain (biliary tract disease), weight loss (malignancy).
• Examination — signs of chronic liver disease (e.g. spider naevi, gynaecomastia, liver palms), hepatosplenomegaly, other abdominal masses.
Viral hepatitis
• Viral hepatitis (Table 6.1) is caused by hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and hepatitis E virus (HEV).
• In addition, 1–2% of viral hepatitis is due to non-A–E viruses, i.e. so far unidentified viruses, and occasionally is a feature of a recognized viral illness such as infectious mononucleosis (Epstein–Barr virus, EBV), cytomegalovirus (CMV), yellow fever or herpes simplex. Toxoplasmosis can also produce a similar picture to infectious mononucleosis.
• Hepatitis B, C and D may progress to chronic viral hepatitis, which implies the presence of persistent liver inflammation for at least 6 months.
Hepatitis A
Management
• Vaccination. Vaccination is recommended to all people travelling to endemic areas. Patients with chronic liver disease, people with haemophilia and workers in frequent contact with hepatitis cases should also be vaccinated. A formaldehyde-inactivated HAV vaccine is available and 0.5 mL is given into the upper arm, followed by a booster dose 6–12 months later. Immunity can then last for up to 10 years.
Hepatitis B
HBV spread also occurs by the IV route (e.g. by transfusion of infected blood or blood products, or by contaminated needles used by drug users, tattooists or acupuncturists) or by close personal contact, such as during sexual intercourse, particularly in men having sex with men (25% of cases in the USA). The virus can be found in semen and saliva.
Clinical features
• Acute. The symptoms are similar to those of hepatitis A and can vary from mild symptoms to a fulminant hepatic failure. Serum transferases are raised and jaundice occurs. Extrahepatic manifestations include cryoglobulinaemia, glomerulonephritis and polyarteritis nodosa.
Viral markers
• Acute infection (Fig. 6.2)
• Antigens:
– HBsAg appears in the blood from about 6 weeks to 3 months after an acute infection and then disappears.
• Antibodies:
– Anti-HBc (HB core) is the first antibody to appear and high titres of IgM anti-HBc suggest an acute and continuing viral replication. It persists for many months. IgM anti-HBc may be the only serological indicator of recent HBV infection in a period when HBsAg has disappeared and anti-HBs is not detectable in the serum. IgG anti-HBc is seen in chronic stages, along with anti-HBs, and indicates past infection.
– Anti-HBe (i.e. seroconversion) appears after the anti-HBc and its appearance relates to a decreased infectivity and low DNA, i.e. a low risk. It is also seen in carriers with no HBV DNA in their serum.
Treatment
HBV infection is mainly asymptomatic and the majority recover completely. Patients should have their HBV markers monitored. If HBcAg is persistent beyond 12 weeks, refer to experts, who may treat patients with nucleoside analogues. Around 1% of patients with acute hepatitis develop fulminant hepatitis (p. 187).
• Chronic hepatitis
• Inactive chronic HBV infection. Approximately 1–10% of patients will not clear the virus following an acute HBV infection and develop an inactive chronic HBV infection. This occurs more in neonatal (90%) or childhood (20–50% below the age of 5 years) infection than when HBV is acquired in adult life (< 10%). There is a vast geographic variation in the incidence of inactive chronic hepatitis B. These patients have HBsAg in their serum and are HBeAg-negative, HBe antibody-positive with lower levels of HBV DNA in their serum. They have no evidence of active liver disease (normal or only slightly raised transferases) and are not highly infective. Most remain HBsAg-positive, but do not develop progressive liver disease. The spontaneous clearance rate of HBsAg is 1–2% per year.
• Active chronic HBV infection. These patients have raised serum aminotransferases with evidence of HBV replication. This means that they have high levels of HBV DNA in their serum and are HBe antigen-positive (wild-type infection) or HBe antigen-negative (mutant strain). A liver biopsy shows chronic hepatitis. Histologically, there is a full spectrum of changes from near normal with only a few lymphocytes and interface hepatitis to a full-blown cirrhosis. HBsAg may be seen as a ‘ground-glass’ appearance in the cytoplasm on haematoxylin and eosin staining, and this can be confirmed on orcein staining or more specifically with immunohistochemical staining. HBcAg can also be demonstrated in hepatocytes by appropriate immunohistochemical staining.
• Chronic hepatitis — who to treat?
– Patients who are positive for HBeAg, HBsAg and HBV DNA (> 20 000 U/mL — for copies multiply by 5.6) with abnormal serum ALT (> 2 × normal) should be treated. Liver biopsy is not essential in this group.
– Similar patients with HBV DNA levels > 20 000 U/L who have ALT values < 2 × normal should not be treated because the efficacy of therapy is low. A liver biopsy may help, as treatment is sometimes given if inflammation is marked.
The aim of treatment is the seroconversion of HbeAg (when present), i.e. the development of anti-HBe and the reduction of HBV DNA to undetectable levels by PCR. In addition, normalization of the serum ALT level and histological improvement in inflammation and fibrosis reflects a good response.
• Patients with compensated cirrhosis with HBV DNA > 2000 U/L should be treated and those with a DNA < 2000 should only be treated if the ALT is high.
• Patients with decompensated cirrhosis can also be treated but liver transplantation may be required.
• In patients in whom HBeAg disappears, remission is usually sustained. The patient remains a carrier with HBsAg present, although some will eventually become HBsAg-negative.
• Hepatitis B mutants. In hepatitis B associated with a mutant virus, HBeAg is not produced but the synthesis of HBcAg is unaffected. The presence of HBV DNA in the serum indicates viral replication. This must be measured, as e antigen cannot be used to indicate viral replication as the prevalence of mutant viruses increases. DNA polymerase mutants can also occur, particularly after lamivudine therapy.
Antiviral agents (Table 6.2)
• Pegylated α-2a interferon (180 mcg once a week SC) gives response rates of 25–65% (depending on genotype — A and B respond best) after 12 months of treatment. Side-effects of interferon treatment are many, occurring in up to 30% of patients, and the dose may have to be lowered; in 10% the treatment has to be discontinued.
• Nucleoside and nucleotide analogues
• Adefovir 10 mg/day orally is also effective in HBeAg-positive and HBeAg-negative naive patients. Adefovir mutants are less frequent (20% at 4 years).
• Entecavir 0–5 mg orally is more effective than lamivudine and reduces HBV DNA more quickly; there is much less viral resistance. Serum HBV DNA becomes negative in 67% (HBeAg-positive patients) and 90% (HBeAg-negative patients) by 48 weeks. It has been shown to reverse fibrosis in one study.
• Lamivudine 100 mg/day given orally is well tolerated. It appears more effective than interferon, particularly in HBV DNA-positive individuals who have acquired the infection perinatally or in childhood. At 1 year, 50–70% of patients have normalization of their serum ALT and 30% have lost their HBe antigen with seroconversion in 15–20%. However, by 4 years, 80% develop viral resistance due to YMDD mutant (tyrosine (Y), methionine (M), aspartate (D)), which in itself causes hepatitis, but usually less severe than that due to the wild-type infection.
• Tenofovir 300 mg per day orally is effective against lamivudine-resistant virus and, as monotherapy, has a similar potency to entecavir.
Choice and duration of treatment
The duration of all treatment, and which combination of antivirals is optimal, are still being assessed. In general, current treatment for HbeAg-positive disease is with pegylated interferon or tenofovir or entecavir. Interferon should be given for 1 year. HbeAg-negative disease requires long-term (many years of) oral therapy. Older patients respond poorly to interferon and should be treated with nucleoside and nucleotide analogues.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
