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A generation ago hepatitis A (infectious hepatitis or yellow jaundice) was the commonest recognised form of viral hepatitis, presenting usually with an abrupt onset of fever, anorexia, nausea and vomiting. It usually occurred in epidemics and hence was common in overcrowded institutions and camps. Now hepatitis B and C are the most commonly reported types of viral hepatitis with an onset that is more insidious and with a longer incubation period.4,7 Symptoms include malaise, anorexia, nausea and polyarthritis. Acute hepatitis C is often subclinical.
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The various forms of hepatitis are summarised in TABLE 58.6. All forms of hepatitis are common in developing countries and travellers are at risk of contracting these infections: hepatitis A and E from faeco-oral transmission; and hepatitis B, C, D and G from intravenous drugs and bodily fluids (from sexual transmission, in particular, for hepatitis B).
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Evidence points to more viruses causing non-ABC hepatitis.8 Hepatitis F virus has been claimed to be transmitted enterically while the newly designated hepatitis G virus (HGV) is transmitted parenterally. It does not appear to cause a severe illness in recipients. It can be predicted that the hepatitis alphabet will continue to expand.
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In hepatitis A, liver damage is directly due to the virus, but in hepatitis B and C it is due to an immunologic reaction to the virus.
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Other infections that can present with jaundice as part of a systemic disease are malaria, Epstein–Barr mononucleosis, cytomegalovirus, Q fever, toxoplasmosis, leptospirosis and, rarely, measles, varicella, yellow fever, rubella, herpes simplex, dengue fever, Lassa fever and Marburg and Ebola virus.
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Hepatitis A is becoming relatively less prevalent in developed countries. It is enterically transmitted and arises from the ingestion of contaminated food, such as shellfish, or water. There is no carrier state and it does not cause chronic liver disease. Hepatitis A most often causes a subclinical or self-limited clinical illness.
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Pre-icteric (prodromal) phase:
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anorexia, nausea ± vomiting
malaise
headache
distaste for cigarettes in smokers
mild fever
± diarrhoea
± upper abdominal discomfort
++
Icteric phase (many patients do not develop jaundice):
++
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Recovery usually in 3–6 weeks.
++
Fulminant hepatitis with liver coma and death may occur but is rare.
++
LFTs and viral markers confirm the diagnosis. The antibodies to HAV are IgM, which indicates active infection, and IgG antibodies, which means past infection and lifelong immunity and which is common in the general population. Ultrasound is useful to exclude bile duct obstruction, especially in an older patient.
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Outcome and treatment
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Hepatitis A has an excellent prognosis with most patients making a complete recovery, and patients should be reassured. The mortality is less than 0.5%. Admission to hospital is not usually necessary. There is no specific treatment, so management is as follows.
++
Provide appropriate reassurance and patient education.
Rest as appropriate.
Follow a fat-free diet.
Avoid alcohol, smoking and hepatotoxic drugs (until recovery).
Advise on hygiene at home to prevent spread to close contacts and family members. Recent evidence indicates that it can be spread sexually and by IV drugs.
Wash hands carefully after using the toilet and disinfect them with antiseptic.
Do not handle food for others with your fingers.
Do not share cutlery and crockery during meals.
Do not use tea-towels to dry dishes.
++
Simple health measures such as good sanitation, effective garbage disposal and hand washing are probably responsible for the major decrease in the disease. Immune serum globulin (0.03–0.06 mL/kg IM) confers satisfactory passive immunity for close contacts (within 2 weeks of contact) and for travellers to endemic areas for up to 3 months. An active vaccine consisting of a two-dose primary course is the best means of prevention.
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Hepatitis B has protean clinical manifestations. Transmission is by blood spread, percutaneous, sexual transmission, perinatal spread or by close prolonged family contact. Infection may be subclinical or self-limited acute hepatitis. Fulminant hepatitis is rare. Five per cent of subjects go on to become chronic carriers of the virus. Most are ‘healthy carriers’ but some may develop chronic active hepatitis, cirrhosis and hepatoma. The serology of hepatitis B involves antibody responses to the four main antigens of the virus (core, DNA polymerase, protein X and surface antigens). Passive and active vaccines are available, and should be used freely in groups at risk, including babies of infected mothers. High-risk groups are presented in TABLE 58.7. The clinical features are the same as those found in hepatitis A infection but may be less abrupt in onset but more severe in the long term.7 A serum sickness-like immunological syndrome may be seen with transient rashes (e.g. urticaria or a maculopapular rash), and polyarthritis affecting small joints in up to 25% of cases in the prodromal period.
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The main viral investigation for HBV is HBsAg (surface antigen), which is searched for routinely. If detected, indicating hepatitis B positive or carrier, a full viral profile is then formed.
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HBsAg may disappear or persist. Its presence indicates a current or chronic infection as well as a carrier state (see FIG. 58.4). Chronic hepatitis B (carriage) is defined as the presence of HBsAg for at least 6 months.
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HBeAg is a soluble protein from the pre-core and core. Antibodies develop to both HBsAg and HBeAg.
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Serological patterns
Acute hepatitis B
HBsAg +ve, anti-HBcIgM +ve, anti-HBs −ve
Chronic hepatitis B
HBsAg +ve, anti-HBcIgG +ve, anti-HBs −ve
Resolved hepatitis B
HBsAg −ve, anti-HBcIgG +ve, anti-HBs +ve
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Monitoring and outcome9,10
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The possible course of events is shown in FIGURE 58.5. The majority of patients recover completely with the outcome depending on several factors, including the virulence of the virus and the immune state and age of the patient. Some will develop chronic hepatitis, some will develop a fulminant course, and others will become asymptomatic carriers and present a health risk to others.
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Monitor progress with 6–12 monthly LFTs, HBeAg and HBV DNA.
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Negative HBsAg and HBV DNA (with anti-HBe) = resolving, with anti-HBs = full recovery.
Positive HBsAg and HBV DNA = replicating and infective—refer.
Monitor LFTs every 6 months. Refer if ALT elevated.
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There is no specific treatment initially—being similar to hepatitis A, appropriate reassurance and patient education are necessary. Advise avoidance of alcohol. Avoid certain drugs, e.g. sedatives, NSAIDs, OCP, until recovery (normal LFTs). Advise about prevention of transmission, especially safe sex and sharing needles. Refer to a liver transplantation centre if encephalopathy or severe coagulopathy develop. Treatment of chronic hepatitis B infection (abnormal LFTs) is with the immunomodulatory and antiviral agents—pegylated interferon alpha and entecavir, tenofovir or other agents. This is expensive but it achieves permanent remission in 25% of patients, and temporary remission in a further 25%.7 Liver transplantation has been performed, but is often followed by recurrence of hepatitis B in the grafted liver. Follow up with regular LFTs and alpha-fetoprotein screening. It is appropriate to refer any HBsAg positive patient with an abnormal ALT and/or signs of chronic liver disease to a specialist since the evaluation of chronic hepatitis B can be complex.4
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Serology guidelines
HBsAg = acute or persistent infection
anti-HBs = past infection and immunity
HBeAg = highly infectious
HBV DNA = circulating and replicating virus
anti-HBc IgM = recent and continuing infection
anti-HBc IgG = past infection
anti-HBe = seroconversion
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Active immunisation through hepatitis B vaccination has been a major breakthrough in the management of this serious illness. There is a course of three injections. If there is a negative antibody response after 3 months, revaccinate with a double dose. If the response is positive, consider a test in 5 years with a view to a booster injection.
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For non-immune patients at risk (e.g. after a needle-stick injury), hepatitis B immunoglobin (HBIg), which contains a high level of HBV surface antibody, is appropriate.
++
Prenatal screening of pregnant women and appropriate use of HBIg and HB vaccine is useful in preventing perinatal vertical transmission of HBV.
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Hepatitis C virus is responsible for most cases of viral hepatitis in Australia. It is primarily contracted from intravenous drug use or tattooing. It does not seem to be spread very readily by sexual contact although there is a small risk during heterosexual and homosexual intercourse. It is also not readily spread perinatally.
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Clinical symptoms of hepatitis C are usually minimal (often asymptomatic), and the diagnosis is often made after LFTs are found to be abnormal. An important feature is that there are at least six major genotypes of HCV and treatment decisions are based on the genotype; thus, patients with acute hepatitis C should have HCV genotype testing.
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Hepatitis C infection may be self-limiting, but more commonly (in about 70% of cases) causes a slow, relentless progression to chronic hepatitis, cirrhosis (20%) and also hepatoma.7 See FIGURE 58.6. The severity of hepatic fibrosis can be assessed by liver biopsy or, preferably, by a non-invasive device called a FibroScan that assesses ‘hardness or stiffness’ of the liver via the technique of transient elastography. A raised ALT level that is tested three times over the next 6 months implies disease activity. HCV RNA (a PCR test) is present when the ALT becomes abnormal while the anti-HCV rises more slowly and may not be detectable for several weeks. If the PCR test is negative, the hepatitis C infection has resolved.
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Diagnosis and progress
++
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HCV Ab (anti-HCV) +ve = exposure (current or past)
CD4/HCV = viral load
ALTs on LFTs indicate disease activity (tested 3 times over next 6 months)
ALT persistently normal = good prognosis
ALT ↑ ↑ = requires referral for treatment
If PCR +ve + significant viral load + ALT ↑ perform HCV genotype—determines treatment
PCR −ve, ALT −ve = infection clear
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The current standard treatment for chronic hepatitis C is direct-acting antivirals (DAAs) taken daily by mouth. These agents are now supplanting interferonbased therapy. The determination of genotype and viral load, as well as hepatic status, will identify those most likely to respond to therapy.
++
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protease inhibitors, e.g. simeprevir
nucleotide polymerase inhibitors, e.g. sofosbuvir
non-nucleotide inhibitors, e.g. dasabuvir
NS5A inhibitors, e.g. daclatasvir, ledipasvir
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These agents are given in combination according to the genotype. Cure rates are in the order of 95%. Treatment can be managed within general practice, in collaboration with a specialist gastroenterologist.13
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The recommended steps for pretreatment assessment are:13,14
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Confirm the diagnosis of chronic HCV infection.
Test for hepatitis C virus genotype and viral load.
Document the HCV treatment history.
Evaluate comorbidity and liver status, especially cirrhosis (refer if present), FBE, APRI, LFTs, blood glucose, creatinine U and E, HIV, HBV.
Discuss contraception and pregnancy (if applicable).
Consider concomitant medication.
Assess adherence to treatment.
Select treatment regimen (8 or 12 weeks) and review potential drug interactions.
Consult with a specialist.
Treat and monitor.
++
Cure is defined as undetectable plasma HCV RNA at least 12 months after treatment.
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Those at increased risk of having hepatitis B and C
++
Blood transfusion recipients (prior to HBV and HCV testing)
Intravenous drug users (past or present)
MSM who have practised unsafe sex
Kidney dialysis patients
Sex industry workers
Those with abnormal LFTs with no obvious cause
Tattooed people/body piercing
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Prevention of transmission of hepatitis B and C viruses
++
Advice to those who are positive for HCV:
++
Do not donate blood or any body organs or tissues.
Do not share needles.
Advise health care workers, including your dentist.
Do not share intimate equipment such as toothbrushes, razors, nail files and nail scissors.
Wipe up blood spills in the home with household bleach.
Cover up cuts or wounds with an adequate dressing.
Dispose of bloodstained tissues, sanitary napkins and other dressings safely.
Use safe sex practices such as condoms.
Avoid tattooing.
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Hepatitis D is a small defective virus that lacks a surface coat. This is provided by hepatitis B virus, and so hepatitis D infection occurs only in patients with concomitant hepatitis B.
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It is usually spread parenterally and if chronic is usually associated with progressive disease with a poor prognosis. Treatment with interferon has a variable success rate. Antibodies to the delta virus, both anti-HDV and anti-HDV IgM (indicating a recent infection) as well as HDV Ag can be measured.15 Referral to a specialist is recommended.
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Hepatitis E is an enterically transmitted virus that occurs in outbreaks in certain countries with a poor water supply, such as some Asian subcontinent countries. Epidemiologically, HEV behaves like HAV, with well-documented water-borne epidemics in areas of poor sanitation. There is a high case fatality rate in endemic areas (10–20%) and in pregnant females.
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Researchers claim to have identified HGF virus, which is spread enterically.16 Treatment can be comfortably managed within general practice.
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HGV has been identified as a transfusion-spread virus. It has subsequently been found to be prevalent among Queensland blood donors.10,17
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Cholestasis refers to the syndrome of biliary obstructive jaundice whereby there is obstruction to the flow of bile from the hepatocyte to the duodenum, thus causing bilirubin to accumulate in the blood. It is classified into two main groups:
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The significant causes are listed in TABLE 58.8.
++
++
Jaundice (greenish tinge)
Dark urine and pale stools
Pruritus—worse on palms and soles
Pain varies from nil to severe
+++
Gallstones and jaundice
++
Gallstones can be found in the following (see FIG. 58.7):
++
++
gall bladder (asymptomatic up to 75%)—the majority remain here
neck of gall bladder (biliary ‘colic’ or acute cholecystitis)
cystic duct (biliary ‘colic’ or acute cholecystitis)
common bile duct—may cause severe biliary ‘colic’, cholestatic jaundice or cholangitis
++
Acute cholecystitis is accompanied by mild jaundice in 25% of cases, due to accompanying common duct stones.15
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Common bile duct stones may be asymptomatic or may present with any one or all of the triad of abdominal pain, jaundice and fever. The jaundice varies, depending on the amount of obstruction. The liver is moderately enlarged if the obstruction lasts for more than a few hours.
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The investigations of choice for cholestatic jaundice are ultrasound and ERCP.
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This is due to bacterial infection of the bile ducts secondary to abnormalities of the bile duct, especially gallstones in the common duct. Other causes are neoplasms and biliary strictures.
++
Charcot triad (present in 70%) is shown in the diagnosis box.
++
DxT fever (often with rigor) + upper abdominal pain + jaundice ➜ acute cholangitis
++
Older patients can present with circulatory collapse and Gram-negative septicaemia. Urgent referral is necessary.
+++
Carcinoma of head of the pancreas
++
Pancreatic cancer is the fourth commonest cause of cancer death in the UK and US.15
++
++
Weight loss, malaise, diarrhoea
Migratory thrombophlebitis
Palpable hard, fixed mass
Metastases (e.g. left supraclavicular gland of Virchow—Troisier sign)
Occult blood in stool
Glycosuria
++
++
DxT jaundice + constitutional symptoms (malaise, anorexia, weight loss) + epigastric pain (radiating to back) ➜ pancreatic cancer
++
Prognosis is very poor: 5-year survival is 5%.
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Cirrhosis of the liver
++
Cirrhosis is accompanied by jaundice as a late and serious manifestation with the exception of primary biliary cirrhosis, where jaundice appears before advanced liver failure. The development of jaundice usually indicates that there is minimal hepatic reserve and is therefore found in conjunction with other signs of liver failure (see FIG. 58.8).
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alcohol excess
chronic viral hepatitis (esp. HBV, HCV)
Others:
autoimmune chronic active hepatitis
primary biliary cirrhosis (autoimmune)
haemochromatosis
Wilson disease
drugs (e.g. methotrexate)
cryptogenic (no cause found)
++
Anorexia, nausea ± vomiting
Swelling of legs
Abdominal distension
Bleeding tendency
Drowsiness, confusion or coma (if liver failure)
++
Spider naevi (distribution of superior vena cava)
Palmar erythema of hands
Peripheral oedema and ascites
Jaundice (obstructive or hepatocellular)
Enlarged tender liver (small liver in long-term cirrhosis)
Ascites
Gynaecomastia
± Splenomegaly (portal hypertension)
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Autoimmune chronic active hepatitis (ACAH)5
++
Also termed idiopathic ACAH, this usually affects young females (10–40 years) who present insidiously with progressive fatigue, anorexia and jaundice. Diagnosis is made by abnormal LFTs (which should raise suspicion), positive smooth muscle antibodies, a variety of other autoantibodies and a typical liver biopsy. If untreated, most patients die within 3–5 years. Treatment is with prednisolone orally, monitored according to serum alanine aminotransferase levels, and supplemented with azathioprine or mercaptopurine. About 80% respond, while 20% develop chronic liver disease. Specialist referral is advisable.
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Primary sclerosing cholangitis5
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This uncommon inflammatory disorder of the biliary tract presents with progressive jaundice and other features of cholestasis such as pruritus. It is often associated with ulcerative colitis. Diagnosis is based on characteristic cholangiopancreatography findings. There is no specific therapy, but refer for possible ERCP. Ursodeoxycholic acid may benefit some patients. Patients have an increased risk of colorectal cancer.
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Primary biliary cirrhosis5
++
This is an uncommon cause of chronic liver disease that often presents with pruritis, malaise and an obstructive pattern of liver biochemistry. Found mainly in women. Treatment is with ursodeoxycholic acid orally.
+++
Alcoholic liver disease
++
The main effects of alcohol excess on the liver are:
++
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If diagnosed, patients are advised to stop drinking alcohol for life except for fatty liver when small amounts can be drunk later.
++
Alcohol can cause hepatic steatosis (fatty liver), which is almost universal in obese alcoholics. Non-alcoholic causes include obesity, diabetes mellitus, hypertriglyceridaemia and corticosteroids. A significant number with this very common condition (one in five Australians) will develop cirrhosis. Fatty liver is usually asymptomatic but some complain of malaise and tiredness. Serology is unhelpful. Diagnosis is by liver biopsy and perhaps CT scan. The treatment is weight loss through diet, which improves liver function and reduces fatty deposits.
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