GI & Hepatology JC054: Jaundice After Raw Oysters: Acute Hepatitis

Question 1

Acute + Chronic Viral Hepatitis A-E

Answer 1

Large proportion may not have symptoms at all, esp. young
- ***Exacerbation of Chronic hepatitis B will have symptoms

Clinical features (same for acute hepatitis / exacerbation of chronic hepatitis):

1. Pre-jaundice / Pre-icteric phase:
   - low grade fever (usually <39oC)
   - **severe LOA (smoker may even stop smoking)
   - **severe fatigue, myalgia
   - **diarrhoea (enteric type of viral hepatitis)
   - **RUQ dull ache due to liver capsule distension (if large HCC: occasionally pain)
   - **darkening of urine colour (∵ death of hepatocytes —> leakage of bile into blood)
   - **transient pruritis (∵ transient obstruction of bile ducts —> bile salt in skin)
2. Jaundice / Icteric phase:
   - ***jaundice
3. Convalescent phase:
   - whole cycle 2-4 weeks

Question 2

***Biochemistry of Hepatitis

Answer 2

1. ↑ AST (SGOT)
2. ↑ ALT
   —> reflect amount of ***hepatocyte damage
   —> patients with fulminant hepatitis may have falling AST / ALT as disease progresses

Best index for progress / prognosis:
3. Factor 7 (short t1/2: 12 hours) (not usually done)

4. ***Prothrombin time (check daily / BD)
5. Bilirubin (mainly Conjugated / Direct):
   - may be ↑ for a long time after clinical / essential histological recovery (cholestatic phase)

Question 3

Management of Symptomatic hepatitis

Answer 3

1. None needed
   - no known drugs / herbs will hasten recovery of course of hepatitis —> TCM may cause liver damage / failure
2. Rest (if extremely tired)
   - but do not alter course of hepatitis
3. Diet
   - no alcohol for ***6 months for acute hepatitis / for life for chronic hepatitis
   - eat anything
   - glucose drip does not help (fatty liver if too much glucose)
   - fatty diet harmless

Question 4

***Comparisons of Viral hepatitis A-E

Answer 4

HAV:

• Pico-rna
• 27nm
• SS +RNA
• 7400 nucleotides
• no envelop
• endemic-epidemic
• ***oral-faecal
• ***2-4 weeks incubation
• ***no chronicity (once you get Hep A you will be immune forever)

HBV

• Hepa-dna
• 42nm
• DS DNA (only DNA virus)
• 3200 nucleotides (small)
• have envelop (***i.e. surface Ag HBsAg)
• endemic
• blood
• 4-24 weeks incubation (i.e. need to trace sexual history up to 24 weeks)
• ***chronicity varies with age (>90% if acquired before 2 yo, never if acquired in adult e.g. sexually)

HCV

• Flavi
• 30-60nm
• SS +RNA
• ***9400 nucleotides (largest)
• ***have envelop
• endemic
• ***blood
• 2-25 weeks incubation
• ***70-85% chronicity

HDV

• Satellite (∵ require HBsAg to survive, if no Hep B you cannot have Hep D)
• 35nm
• SS circular RNA
• 1700 nucleotides
• ***no envelop
• endemic
• ***blood
• ***chronicity depends on HBV population (acute / chronic Hep B)

HEV

• Calici
• 27-34nm
• SS +RNA
• 7600 nucleotides
• ***no envelop
• endemic-epidemic
• ***oral
• ***2-7 weeks incubation
• ***no chronicity except in transplant patients

Question 5

Hepatitis A transmission + epidemiology

Answer 5

Oral-Faecal transmission:

• virus shed into faeces during incubation, not excreted 7-10 days after onset of jaundice (i.e. ***dangerous period: incubation period)
• not well-cooked shellfish (bivalve e.g. clamps, oyster X fish / prawns) from infected water (esp. clamps, valves trap HAV)
• ingestion of infected water e.g. uncooked vegetable
• faecal contamination (e.g. children, sex, health care workers)

Parenteral transmission (rare but possible):

• transfusion
• acupuncture, tattoo
• outbreak in Italian haemophiliacs in 1994 (∵ factor 8 concentrate contamination)

Epidemiology:

• low in clean countries (USA, Europe, Australia, NZ)
• high in dirtier countries (Africa, South America)
• intermediate in HK, China
• ***↓ incidence in HK over last decade
• % change of notifications in 2009 over preceding 5 years: -21.3%

Question 6

Hepatitis A clinical course

Answer 6

Clinical course:

• ***Self-limiting
• ***Anicteric (often only mildly symptomatic in children)
• Icteric in some adults
• ***Diarrhoea comparatively common in early stage (∵ enteric viral hepatitis)
• Recovery within 4-6 weeks

Atypical clinical course:
- Prolonged cholestasis
—> **High bilirubin (10x above normal)
—> **AST, ALT ↓
—> Last 12-24 weeks (6 months)
—> **Centrilobular cholestasis with **Periportal inflammation (may mimic CAH: Copper‐Associated Hepatitis)
—> Always complete resolution
—> Steroid quickly “whitewashes” but ↑ relapse (i.e. ***DO NOT give steroids!!!)
(Steroid can reduce jaundice by enhancing liver uptake / storage of bilirubin —> ↓ serum bilirubin concentration)

Relapse (Related to immune reaction of patient):

• 6-10%
• Biphasic (2 attacks) / Polyphasic
• ***AST / ALT ↑↑ (> 1000)
• Last 3-12 months
• ***IgM anti-HAV remains positive
• **HAV in stool, **HAV RNA in serum
• Steroid ↑ relapse
• ***Always resolves

Extrahepatic manifestations:

• ***Rash (Purpuric), Arthralgia, Cryoglobulinaemia
• Apparent triggering of Autoimmune chronic hepatitis (Type 1) in predisposed subjects
• probably related to Immune complex disease
• Usually rare (<15%)
• More common in prolonged disease

Fatality rate:
- variation with age (CDC 1990)
—> <=14 years 0.1%
—> 15-39 years: 0.4%
—> >=40 years: 1.1%

Question 7

***Hepatitis A serology

Answer 7

Pre-icteric phase:

• ***Virus excretion
• Histopathology (damage to hepatocytes)
• ***Symptoms

Icteric phase:

• Jaundice
• ***Viral load ↓
• ***IgM starts to ↑

Convalescent phase:

• ***IgM ↑ (anti-HAV) first (already at high level), after 3-4 months ↓
• IgG ↑ later (last probably for life)
• IgA ↑ (smaller degree)

Question 8

***Hepatitis A diagnosis

Answer 8

**IgM anti-HAV
- for acute infection
- peaks at acute stage / early convalescent stage
- detected:
—> **2-3 weeks after ↑ AST / ALT
—> 1-2 weeks after jaundice
—> occasionally delayed (recheck if IgM anti-HAV negative in first time)

• persists:
  —> **3-4 months (usually)
  —> over 6 months (25%)
  —> over 12 months (very rarely) (i.e. IgM anti-HAV +ve does **not necessarily mean acute infection)

IgG anti-HAV:

• persists for ***decades
• protected probably ***for life from Hep A

Question 9

Hepatitis A prevention

Answer 9

1. Careful cooking of shelled seafood
   - Virus killed by:
   —> Dry heat at 100oC in 1 min
   —> Wet heat at 100oC in 5-10 mins
   —> ***Not killed at 60oC even in 12 hours
2. Chlorination of drinking water
3. Passive immunisation (IVIG)
   - up to 90% efficacy
   - prevent / reduce severity of infection
   - dose-dependent efficacy
   - ***<6 months efficacy
   - mainly for travellers with no time for vaccination
4. Vaccine
   - **Inactivated whole virus from cell cultures
   - 2 doses IM (2nd dose **6 months apart as booster)
   - Effective protection within 3-4 weeks after 1st dose
   - Immunogenicity 99%
   - Protective efficacy 100%
   - Unknown duration of protection (probably ***lifelong)
   - Primary target non-immune adult travellers (HAV occurs 40x more common than typhoid, 800x than cholera)
   - Use in areas of moderate - high endemicity? However:
   —> cost
   —> low mortality of Hep A
   —> no chronic carriers

Question 10

Hepatitis E

Answer 10

• previously known as Enteric NANB hepatitis (Non-A, Non-B)
• commonly affects adults in 3rd decade

Epidemiology:

• known epidemics in India, Burma, Nepal, Pakistan, China, Central Russia, Mexico (dirty areas)
• ***↑ incidence in HK: 26% in 1992, 33.6% in 2016
• % change of notifications in 2009 over preceding 5 years: +39.8% (***記住: Hep A跌, Hep E升)
• slightly higher mortality than Hep A
• now ***more common than Hep A in HK

Question 11

Hepatitis E transmission

Answer 11

4 common genotypes:

• 1, 2 from Humans —> Waterborne
• 3, 4 **Zoonotic —> esp. **Swine (first described in Japan, USA) (ingestion of pig’s liver) (more common in HK) (other animals: Snakes, ***Rats)

Question 12

Hepatitis E clinical course

Answer 12

Almost identical to Hep A

• Incubation 2-7 weeks (slightly longer than Hep A: 2-4 weeks)
• ***~20% prominent cholestasis
• Major difference: ***NO permanent protection against re-infection (∵ many genotypes + Ab probably not long-lasting)

Mortality:
- normal patients 1-2% (vs 0.2% for HAV)
- **pregnant woman up to 20%
—> ∵ HEV damages Kupffer cells —> **endotoxin damage to liver (pregnant woman more sensitive to endotoxin effects)

Post-transplant HEV:

• getting infected with HEV after liver transplantation
• some can become ***chronic with ↑ ALT + +ve HEV RNA
• 5 cases of post-transplant chronic HEV identified as Rat HEV

Question 13

Hepatitis E diagnosis

Answer 13

1. **IgM anti-HEV
   - coincide with symptoms
   - persists for **~3 months
2. IgG anti-HEV
   - follows ↑ of IgM
   - can persists for ***several years
3. PCR assay for **HEV RNA (esp. for **chronic infection)
   - may be important for chronic infection to check whether patient still carrying the virus e.g. transplant patients who are immunocompromised (cannot clear the virus)

Question 14

***Hepatitis E serology

Answer 14

~ Hep A

Pre-icteric phase:

• Virus excretion (mostly before symptoms appear)
• Histopathology (damage to hepatocytes)
• Symptoms

Icteric phase:

• Jaundice
• ***IgM starts to ↑ then after 3 months ↓

Convalescent phase:

• ***IgM ↑ (anti-HEV) first (already at high level)
• IgG ↑ later

Question 15

Hepatitis E prevention

Answer 15

1. Better sanitation
2. Immunoglobulin for passive immunisation
   - efficacy unknown?
3. Vaccine
   - Recombinant vaccine containing genotype 1 + 4 (from China)
   - 3 doses at 0, 1, 6 months
   - protective efficacy 100% after 3 doses
   - not licensed in other places
   - shows protective effects after 4.5 years —> protective efficacy 86.8%