Hepatology - Infections and the liver

Question 1

When should viral hepatitis be considered?

Answer 1

This must be considered in anyone presenting with hepatic liver blood tests (high transaminases). Hepatitis viruses are the most common cause, with cytomegalovirus, EBV, herpes simplex and yellow fever giving rise to occasional cases.

Question 2

What are the clinical features of acute viral hepatitis infection?

Answer 2

Prodromal symptoms (headache, myalgia, arthralgia, nausea and anorexia) usually precede jaundice by a few days to 2 wks. Vomiting and diarrhoea may follow and abdominal discomfort is common. Dark urine and pale stools may precede jaundice. There are usually few physical signs. The liver is often tender but only minimally enlarged. Occasionally, mild splenomegaly and cervical lymphadenopathy are seen. Jaundice may be mild and the diagnosis may be suspected only after finding abnormal liver blood tests in the setting of non-specific symptoms. Symptoms rarely last longer than 3–6 wks, and complications such as liver failure or chronic liver disease are rare.

Question 3

What is chronic hepatitis?

Answer 3

Chronic hepatitis is de ned as sustained inflammatory disease of the liver lasting for more than 6 months. Chronic viral hepatitis is the principal cause of chronic liver disease, cirrhosis and hepatocellular carci- noma (HCC) world-wide.

Question 4

What are the causes of chronic hepatitis?

Answer 4

Viral:

• Hep B
• Hep C

Autoimmune

Drugs:

• methyldopa
• nitrofurantoin
• isoniazid
• ketoconazole

Hereditary:
- Wilson’s disease

Others:

• IBD
• Alcohol

Question 5

What are hepatitis A and E? How are they transmitted?

Answer 5

These are both single stranded RNA viruses that cause acute hepatitis without progression to chronic carriage. They are BOTH transmitted by the faecal-oral route.

Question 6

What is the pathogenesis of hepatitis A and E infection?

Answer 6

Both viruses replicate in hepatocytes and are secreted into bile. Liver inflammation and hepatocyte necrosis is caused by the immune response, with targeting of infected cells by CD8þ T cells and natural killer cells. Histology shows inflammatory cell infiltration (neutrophils, macrophages, eosinophils and lymphocytes) of the portal tracts, zone 3 necrosis and bile duct proliferation.

Question 7

Where is hepatitis A and E infection most common?

Answer 7

HAV is endemic in the developing world infection often occurs sub- clinically. In the developed world, better sanitation means that seroprevalence is lower, age of exposure increases and hence is more likely to be symptomatic. Annual UK incidence is 5000 cases (seroprevalence 5%).

HEV is endemic in Asia, Africa and Central America.

Question 8

What is the history of hepatitis A and E infection?

Answer 8

Incubation period for HAV or HEV is 3-6 weeks.
Prodromal period: Malaise, anorexia (distaste for cigarettes in smokers), fever, nausea and
vomiting.

Hepatitis: Prodrome followed by dark urine, pale stools and jaundice lasting 3 weeks.
Occasionally, itching and jaundice last several weeks in HAV infection (owing to cholestatic hepatitis).

Question 9

What are the important examination findings in hepatitis A and E infection?

Answer 9

Pyrexia, jaundice, tender hepatomegaly, spleen may be palpable (20%). Absence of stigmata of chronic liver disease, although a few spider naevi may appear, transiently.

Question 10

How do I investigate suspected cases of hepatitis A or E?

Answer 10

1) Blood:
- LFTs (incr. AST and ALT, mild incr. bilirubin and AlkPhos)
- ESR is raised
- In severe cases, albumin is decreased and platelets are increased

2) Viral serology:
i) HAV
- Anti-HAV IgM (during acute illness, disappearing after 3-5 months)
- Anti-HAV IgG (recovery phase and lifelong persistance)
ii) HEV
- Anti-HEV IgM (incr. 1-4 weeks after onset of illness), anti-HEV IgG
- Hepatitis B and C serology is also needed to rule out these infections

3) Urinalysis
- positive for bilirubin
- increased urobilinogen

Question 11

How do I manage hepatitis A and E infection?

Answer 11

No specific management.
Bed rest and symptomatic treatment (e.g. antipyretics and antiemetics). Colestyramine for severe pruritis.

Prevention and control:

• public health: safe water, sanitation, food hygeine standards. Both are notifiable diseases
• immunisation (HAV only): passive immunisation with IM human immunoglobulin is only effective for a short period. Active immunisation with attenuated HAV vaccine offers safe and effective immunity for those travelling to endemic areas, high-risk individuals (e.g. residents of institutions).

Question 12

What complications are associated with hepatitis A and E infection?

Answer 12

Fulminant hepatic failure develops in 0.1% of cases of HAV and 1-2% of HEV but up to 20% in pregnant women. Cholestatic hepatitis with prolonged jaundice and pruritis may develop after HAV infection.

Post hepatitis syndrome - continued malaise for weeks to months.

Prognosis is good, with usual recovery in 3-6 weeks.

Question 13

What are hepatitis B and D viruses?

Answer 13

Hepatitis can be caused by hepatitis B virus (HBV), which may follow an acute or chronic infection (defined as viraemia and hepatic inflammation continuing >6 months).

Hepatitis D virus (HDV) a defective virus, may only co-infect with HBV or superinfect persons who are already carriers of HBV.

Question 14

What is the aetiology of hepatitis B and D infection?

Answer 14

HBV is an enveloped, partially double-stranded DNA virus. Transmission is by sexual contact, blood and vertical transmission. Various viral proteins are produced, including core antigen (HBcAg), surface antigen (HBsAg) and e antigen (HBeAg). HBeAg is a marker of “ infectivity.
HDV is a single-stranded RNA virus coated with HBsAg.
Antibody- and cell-mediated immune responses to viral replication lead to liver inflammation
and hepatocyte necrosis. Histology can be variable, from mild to severe inflammation and changes of cirrhosis.

Question 15

What are the risk factors associated with hepatitis B infection?

Answer 15

Hepatitis B infection is associated with IV drugabuse, unscreened blood and blood products, infants of HbeAg-positive mothers and sexual contact with HBV carriers. Risk of persistant HBV infection varies with age, with younger individuals, especially babies, more likely to develop chronic carriage. Genetic factors are associated with increased rates of viral clearance.

Question 16

What are the clinical features of acute hepatitis B infection?

Answer 16

Incubation period 3–6 months; 1- to 2-week prodrome of malaise, headache, anorexia, nausea, vomiting, diarrhoea and RUQ pain.
May experience serum-sickness-type illness (e.g. fever, arthralgia, polyarthritis, urticaria,
maculopapular rash).
Jaundice then develops with dark urine and pale stools.
Recovery is usual within 4–8 weeks. One per cent may develop fulminant liver failure.

This leads to clearance of the infection in 99% of individuals and is marked by the disappearance of HBsAg from the serum.

Examination findings in the acute stage include, jaundice, pyrexia, tender hepatomegaly, splenomegaly and cervical lymphadenopathy in 10–20%. Occasionally, urticaria/maculopapular rash.

Question 17

What defines chronic hepatitis B infection?

Answer 17

Persistance of HBsAg in the serum for more than 6 months after acute infection defines chronic infection. Progression from acute to chronic infection depends on several factors including the virulence of the virus, and the immunocompetence of the individual.

Chronic carriage may be diagnosed after routine LFT testing or if cirrhosis or decompensation develops. Chronic patients may have no findings, or signs of chronic liver disease and decompensation.

Question 18

What is the course of chronic hepatitis infection?

Answer 18

When HBV infection is acquired at birth (vertical transmission) or early childhood there is a high level of immunological tolerance and cellular immune responses to hepatocyte- membrane HBV proteins do not occur and chronic infection is the norm. This immune tolerant phase is characterized by minimal hepatic inflammatory activity and normal or near-normal serum ALT despite positive HBeAg and high levels of HBV replication (reflected by high levels of serum HBV DNA). This phase may persist for 2–3 decades before an immune clearance phase that lasts for a variable period of time and is characterized by high HBV DNA levels as before but now is an active hepatitis (that might lead to fibrosis and cirrhosis) with elevated serum ALT. This phase ends with clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) with a marked decrease in serum HBV DNA and normalization of serum ALT (the inactive HBsAg carrier state). Some patients during the immune clearance phase will develop viral mutations that do not produce HBeAg but continue to replicate at high levels and have progressive liver damage with fluctuating serum levels of aminotransferases (reactivation phase). Acquisition of infection later in life is associated with a very short immune tolerant phase or not at all.

Question 19

What viral serology suggests acute hepatitis B infection?

Answer 19

HBsAg positive

IgM anti-HBcAg

Question 20

What viral serology suggests chronic hepatitis B infection?

Answer 20

HBsAg positive
IgG anti-HBcAg
HBeAg positive or negative (latter in precore mutant variant)

HBeAg persists in chronic infection and correlates with increased severity and infectivity and the development of chronic liver disease. When anti-HBeAg develops (seroconversion) the Ag disappears and there is a rise i ALT.

Question 21

What serology would a patient who is clear of hepatitis B show?

Answer 21

Anti-HBsAg positive

IgG anti- HBcAg (if due to natural infection NOT vaccination)

Question 22

Other than viral serology, what other investigations are important in cases of viral hepatitis?

Answer 22

PCR: for detection of HBV DNA is the most sensitive measure of ongoing viral replication

LFTs: increased ALT and AST, mild increase in bilirubin and ALP

Clotting: increased PT in severe disease

Biopsy: percutaneous or transjugular if clotting is deranged or ascites present

HIV screen (same routes of transmission)

Question 23

How can hepatitis B infection be prevented?

Answer 23

Blood screening, instrument sterilisation, safe sex practices.

Passive immunisation: Hepatitis B immunoglobulin (HIBG) following acute exposure and to neonates born to HBeAg positive mothers (in addition to active immunisation)

Active immunisation: Recombinant HBsAg vaccine for individuals at risk and neonates born to HBV positive mothers. Immunisation against HBV protects against HDV.

Question 24

How is active hepatitis B infection treated?

Answer 24

There is no treatment for active infection. Symptomatic treatment with bed rest, antiemetics, antipyretics and cholestyramine for pruritis. Notification of a consultant in communicable diseases.

Question 25

What are the indications for treatment with anti-retrovirals in chronic hepatitis B infection?

Answer 25

HBsAg-positive, HBeAg positive or HBeAg-negative chronic
hepatitis (depending on ALT and HBV DNA levels), compensated cirrhosis and HBV DNA
>2,000 IU/mL, decompensated cirrhosis and detectable HBV DNA by PCR.

Antiviral treatment is not used for inactive HBV carries (normal ALT and HBV DNA <2000IU/mL), who have a lower risk of progressive disease. However, they should be assessed annually for hep B serology and liver biochemistry, since some will develop progressive disease and require treatment.

Question 26

What antiviral medication can patients with chronic hep B infection be treated with?

Answer 26

Patients may be treated with interferon alpha (standard or pegylated, which has “ half-life), or nucleos/tide analogues (adefovir, entecavir, telbivudine, tenofovir, lamivudine). The role of lamivudine as primary therapy has diminished due to high rates of drug resistance. Interferon alpha is a cytokine which augments natural antiviral mechanisms. Side-effects include flu-like symptoms, fever, chills, myalgia, headaches, bone marrow suppression and depression, necessitating discontinuation in 5–10% of patients.

Question 27

What are the complications of HBV infection? What is the prognosis?

Answer 27

Fulminant hepatic failure (1%), chronic HBV infection ( 10% adults, much higher in neonates), cirrhosis and hepatocellular carcinoma, extrahepatic immune complex disorders including glomerulonephritis, polyarteritis nodosa. Superinfection with HDV may lead to acute liver failure or more rapidly progressive disease.

In adults, 10% infections become chronic, and of these, 20–30% will develop cirrhosis. Factors predictive of a good response to interferon include high serum transaminases, low HBV DNA, active histological changes and the absence of complicating diseases.

Question 28

What is the aetiology of hepatitis C infection?

Answer 28

HCV is a small, enveloped single stranded RNA virus of the flavivirus family. Because it is an RNA virus, fidelity with replication is poor and mutation rates are high resulting in different HCV genotypes, even in a single patient.

Transmission occurs by the parenteral route and at-risk groups include recipients of blood and blood products prior to blood screening, IV drug users, non-sterile acupuncture and tattooing, those on haemodialysis and health care workers. Sexual and vertical trans- mission is uncommon (1–5%, “ risk in those co-infected with HIV).

Question 29

What is the pathogenesis of HCV infection?

Answer 29

Although HCV is hepatotropic, it is not thought that the virus is directly hepatotoxic, rather that the humoral and cell-mediated response leads to hepatic inflammation and necrosis. On liver biopsy, chronic hepatitis is seen and a characteristic feature is lymphoid follicles in the portal tracts. Fatty change is also common and features of cirrhosis may be present.

Question 30

What is the history of HCV infection?

Answer 30

Ninety per cent of acute infections are asymptomatic with <10% becoming jaundiced with a mild ‘flu-like’ illness.
May be diagnosed after incidental abnormal LFT or in older individuals with complications of cirrhosis.

Question 31

What are the important examination findings in HCV infection?

Answer 31

There may be no signs or may be signs of chronic liver disease in long-standing infection. Less common extra-hepatic manifestations include:

• skin rash, caused by mixed cryoglobulinaemia causing a small-vessel vasculitis; and
• renal dysfunction, caused by glomerulonephritis.

Question 32

How do I investigate HCV infection?

Answer 32

1) Bloods
i) HCV serology: Anti-HCV antibodies, either IgM (acute) or IgG (past exposure or chronic).
ii) Reverse-transcriptase PCR: Detection and genotyping of HCV RNA. Used to confirm antibody testing; also recommended in patients with clinically suspected HCV infection but negative serology.
iii) LFT: Acute infection causes “ AST and ALT, mild “ bilirubin. Chronic infection causes 2–8 times
elevation of AST and ALT, often fluctuating over time. Sometimes normal.

2) Liver biopsy: To assess degree of inflammation and liver damage as transaminase levels bear little correlation to histological changes. Also useful in diagnosing cirrhosis as patients with cirrhosis will require monitoring for hepatocellular carcinoma.

Question 33

How can HCV infection be prevented?

Answer 33

Screening of blood, blood products and organ donors, needle exchange schemes for IV drug abusers, instrument sterilization. No vaccine available at present.

Question 34

How should I manage HCV infection?

Answer 34

Medical:
Acute: No specific management and mainly supportive (e.g. antipyretics, antiemetics,
cholestyramine). Specific antiviral treatment can be delayed for 3–6 months.

Chronic: Combined treatment with pegylated interferon-a (cytokine which augments natural antiviral mechanisms) and ribavirin (guanosine nucleotide analogue) is the treatment strategy of choice:
- HCV genotype 1 or 4: 24–48 weeks
- HCV genotype 2 or 3: 12–24 weeks
Monitoring of HCV viral load is recommended after 12 weeks of treatment to determine efficacy of treatment. Regular ultrasound of liver may be necessary if the patient has cirrhosis.

Question 35

What complications are associated with HCV infection?

Answer 35

Fulminant hepatic failure in acute phase (0.5%), chronic HCV carriage, cirrhosis and hepatocellular carcinoma. Less common are porphyria cutanea tarda, cryoglo- bulinaemia and glomerulonephritis.

Question 36

What bacteria causes ascending cholangitis?

Answer 36

Ascending cholangitis is infection and inflammation of the common bile duct, usually secondary to gallstones. It is life threatening and characterised by the triad of RUQ pain, fever and jaundice (Charcot’s triad). It is the most common cause of multiple liver abscesses.

It is caused by E.coli.
Treatment is with decompression and drainage plus tazocin.

Question 37

What causes granulomatous hepatitis?

Answer 37

This is caused by mycobacterium tuberculosis or Histoplasma capsulatum. It is a sign of miliary spread.

Question 38

What causes spontaneous bacterial peritonitis?

Answer 38

E.coli in adults or streptoccocus pneumoniae in children.

It develops during ascites (e.g. cirrhosis, nephrotic syndrome) and is treated with cefotaxime.

Question 39

What is leptospirosis? How is it transmitted?

Answer 39

Infection caused by Leptospira interrogans, a gram negative tightly wound spirochete that has a reservoir in rats and dogs (most common) and is excreted in urine.

It is transmitted by swimming in contaminated water, farmers, miners, people who work with sewage.

Question 40

What are the clinical features of leptospirosis?

Answer 40

The disease is biphasic (where it is called Weil’s disease)

1) Speticaemic phase:
- fever, jaundice, haemorrhagic diatheses, renal failure (intestinal nephritis) conjunctivitis and photophobia, meningitis, phase is terminated by the appearance of antibodies (beginning of immune phase)

2) Immune phase:
- presence of numerous organisms in urine, urine is best examined by dark field microscopy

Question 41

How is leptospirosis diagnosed and treated?

Answer 41

Diagnosis is by serum immunoassay (90% sensitive); urine testing for detecting antigen is also available

Treatment is with penicillin G.

Question 42

What is Clonorchiasis?

Answer 42

This is a helminth infection caused by the intestinal fluke (trematode) Clonorchis sinensis.
The toad has a non schistosomal life cycle –> infects snails, then 2nd intermediate host (usually fish) and infects humans who ingest 2nd intermediate host.

It is contracted by ingesting encysted larvae in fish, larvae enter the CBD and become adults. It can cause cholangiocarcinoma. Treatment is with praziquantel.

Question 43

How does schistosmiasis affect the liver?

Answer 43

The liver is affected by a helminth, schistosoma mansoni.
Larvae in the superior mesenteric vein enter into the portal vein, where they develop into adult worms that deposit eggs to which the host develops an inflammatory response marked by concentric fibrosis (“pipestem cirrhosis”) in the vessel wall; S. japonicum also produces pipestem cirrhosis, though it more commonly invades the urinary bladder vessels and produces squamous cancer of the bladder.
Complications of cirrhosis: portal hypertension, ascites, oesophageal varices. Treatment: praziquantel.

Question 44

What are the three types of liver abscesses?

Answer 44

Liver abscesses can be classified as:

1) Pyogenic
2) Hydatid
3) Amoebic

Question 45

How does a pyogenic liver abscess develop?

Answer 45

Pyogenic liver abscesses are uncommon but important because they are potentially curable but carry significant risk if untreated.

Infection reaches the liver through the hepatic or portal circulation, up the biliary tree, via injury or by direct spread from adjacent organs. Abscesses most commonly occur in older patients through ascending infection due to biliary obstruction (cholangitis) or contiguous spread from an empyema of the gallbladder. Immuno- compromised patients are particularly likely to develop liver abscesses. E. coli and various streptococci, particularly Strep. milleri, are the most common organisms; anaerobes, including streptococci and Bacteroides, may be found when infection has spread from large bowel pathology via the portal vein.

Question 46

What are the causes of pyogenic liver abscesses?

Answer 46

Majority are in the right lobe; majority are solitary.
Causes: ascending cholangitis (most common), intra-abdominal infection (e.g., spread via
the portal vein, diverticulitis, bowel perforation), direct extension (e.g., empyema of
gallbladder, subphrenic abscess), hematogenous spread (e.g., bacterial endocarditis).

Question 47

What are the clinical features of pyogenic liver abscess?

Answer 47

Spiking, intermittent fever; RUQ or right costovertebral angle tenderness. Jaundice is uncommon. Tender hepatomegaly.

Question 48

How do I investigate suspected liver abscesses?

Answer 48

USS reveals 90% or more of symptomatic abscesses and is also a guide for FNA of pus for culture.
Leucocytosis
Plasma ALP activity usually increased
Serum albumin often low
CXR may show raised right diaphragm and lung collapse or an effusion at the base of the right lung
Blood cultures positive in 50-80%
Colonic pathology should be excluded

Question 49

How should I manage a pyogenic liver abscess?

Answer 49

Pending the results of culture of blood and pus from the abscess, treatment should commence with a combination of antibiotics such as ampicillin, gentamicin and metronidazole. Aspiration or drainage with a catheter placed in the abscess under USS guidance is required if the abscess is large or if it does not respond to antibiotics. Surgical drainage is rarely required.
The mortality of liver abscesses is 20–40%; failure to make the diagnosis is the most common cause of death. Older patients and those with multiple abscesses also have a higher mortality.

Question 50

What causes amoebic liver abscesses?

Answer 50

Entamoeba histolytica
Protozoan (amoeba)
Most common cause of a liver abscess worldwide (not in the United States). Usually produces a right lobe abscess.
Treatment: metronidazole followed by paromomycin.

Question 51

What causes a hydatid abscess of the liver?

Answer 51

Echinococcus granulosus (sheepherder’s disease)
Intestinal tapeworm (cestode)
Single or multiple cysts contain larval forms; cysts often present in the liver (most common site), lungs, and brain

Question 52

How is Echinococcosis transmitted?

Answer 52

The infected sheep is the intermediate host (larval form is in the liver cyst); dog eats the liver of a dead sheep and becomes the definitive host, because the larvae develop into adults, which produce eggs; the human who accidentally ingests the embryonated eggs from the dog becomes the intermediate host, because the eggs develop into larvae; the larvae in humans penetrate the bowel and they enter the liver (most common) or other sites to produce the hydatid cyst.
Disease also contracted by children eating grass contaminated with dog excreta containing the eggs.
Rupture of cysts can produce anaphylaxis. Treatment: percutaneous drainage + albendazole.