Liver conditions Flashcards
1
Q
Describe the architecture of a liver lobule
A
Histologically, the liver is composed of hepatocytes, bile canaliculi, and hepatic sinusoids:
- Hepatocytes are arranged in chords, with blood flowing inbetween in sinusoids from the portal triads → central vein
- Endothelial cells form space of Disse between hepatocytes and sinusoids
2
Q
Describe the roles of the several vessels entering or leaving the liver
A
- Portal vein bringing food-rich blood from the gut.
- Hepatic artery bringing oxygenated arterial blood. Liver has dual blood supply.
- Heptic veins taking away processed blood into the vena cava.
- Lymphatics taking away some lymph and some by-products.
- Hepatic ducts removing bile to the gallbladder & gut (biliary system).
3
Q
Describe the general anatomical features of the liver
A
- Large, lobated exocrine/blood-processing gland, with vessels/ducts entering/leaving at the porta
- Enclosed by a thin collagen tissue capsule, mostly covered by mesothelium.
- Collagen tissue of the branching vascular system provides gross support.
- Parenchymal cells are supported by fine reticular fibres.
4
Q
Describe the hepatic lobular flow
A
Blood flows:
- From branches of the portal vein and hepatic artery; from the periphery towards the centre;
- in the sinusoids, between the cell plates (blood flows slowly from portal triad to central vein, allowing exchange of nutrients for the enrichment of blood)
- Blood collected in central veins → sublobular veins → collecting veins → hepatic veins leaving the liver.
5
Q
Describe the liver acinus
A
The territory of an acinus (as its axis) has one final branch
of the portal vein, and is subdivided into:
- Periportal zone – roughly spheroid, isolated from periportal zones of adjacent acini
- Intermediate zone
- Perivenous zones – near the central vein
6
Q
What does this slide show?
A
Normal liver
No fatty infiltration
No inflammation
No fibrosis or cell plate thickening
7
Q
What types of cells are found within the sinusoids of the liver?
A
Kuppfer (stellate) cells- resident liver macrophages
Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections
8
Q
Roughly speaking, what do the 3 main LFTs measure?
A
LFTs measure liver enzymes which can leak from damaged liver cells- so they reflect liver injury
- ALT + AST = liver parenchymal damage (hepatocellular)
- ALP = obstructive cause (cholecystatic)
Gamma-GT = mirrors ALP (unlike ALP, only produced by liver so good way of discerning hepatic pathology)
9
Q
State the sources of ALT, AST, ALP
A
ALT = hepatocytes ONLY
AST = liver, heart, skeletal muscle, kidneys, pancreas
ALP = biliary ducts, bone, placenta, small intestine, kidneys
10
Q
What is the correct way of assessing ALT and AST levels? Explain which pathologies would affect assessment of AST:ALT
A
must look at AST:ALT ratio
High AST:ALT >2.5 = alcoholic damage/cirrhosis, metastases
Low AST:ALT <1 = paracetamol OD (toxin-induced hepatitis), viral hepatitis (hep A/B/E, EBV, CMV), hepatic obstruction
SALT
11
Q
Compare the likely diagnoses for a:
- Marked
- Moderate
- Mild
increase in ALT
A
Marked increase (1000s):
- Toxin/drug induced hepatitis e.g. paracetamol
- Acute viral hepatitis e.g. hep A/B/E, EBV, CMV
Moderate increase (300-500):
- chronic/alcoholic/autoimmune hepatitis
- biliary obstruction
MIld increase (<300):
- Cirrhosis
- Haemachromotosis
- hepatocellular carcinoma
- Wilson’s
- NASH
12
Q
State some non-hepatic causes for raised ALP
A
- placenta: pregnancy
- small intestine: fatty meals
- kidney: CKD
- bone: paget’s, bony metastases, fractures, osteomalacia, renal bone disease
13
Q
Which marker can be measured to determine whether ALP is hepatic in origin?
A
Gamma-glutamyl transferase (Gamma-GT)
Mirrors ALP but specific to liver
14
Q
And isolated rise in Gamma-GT is suggestive of what?
A
alcoholic liver disease
15
Q
What is a high ALP with high gamma-GT suggestive of?
A
bile duct disease
liver metastases
16
Q
Summarise the production of bilirubin
A
reticuloendothelial cells metabolise Hb into haem and globin
haem → iron and bilviderin
bilviderin → unconjugated bilirubin (binds to albumin and travels to liver)
conjugated bilirubin excreted into bile
in colon: conjugated bilirubin → urobiligen (20% absorbed via enterophepatic circulation)
80% urobiligen → stercobilin
17
Q
How can jaundice be categorised? For each, state the underlying cause and the type of bilirubin that is in excess
A
Pre-hepatic = increased haemolysis = ^UNCONJUGATED
Heptic =liver impairment = ^UNCONJUGATED+CONJUGATED
Post-hepatic = biliary tree obstruction = ^CONJUGATED
18
Q
EXPLAIN the causes of pre hepatic jaundice
A
Caused by increased haemolysis.
This results in the increased presence of unconjugated bilirubin in the blood as the liver is unable to conjugate it all at the same rate.
This is caused by:
- Tropical disease, e.g. malaria, yellow fever
- Genetic disorders, e.g. sickle-cell anaemia, Gilbert’s syndrome
- Haemolytic anaemias
19
Q
EXPLAIN the causes of hepatic jaundice
A
Hepatic jaundice is caused by liver impairment.
This causes the decreased ability of the liver to conjugate bilirubin, resulting in the presence of conjugated and unconjugated bilirubin in the blood. Liver damage can result from:
- Viral hepatitis
- Hepatotoxic drugs, e.g. paracetamol overdose, alcohol abuse
20
Q
EXPLAIN the causes of post hepatic jaundice
A
Post-hepatic jaundice is caused by the blockage of bile ducts.
This results in backflow of conjugated bilirubin into the blood as it cannot move past the obstruction.
Bile duct obstruction can be caused by:
- Gallstones
- Hepatic tumours
- Pancreatic tumours
21
Q
What is the key liver protein and what is a specific outcome of not having enough
A
Albumin
When albumin is low, there is reduced oncotic pressure so water leaks out of cells contributing to ascites.
May be low due to low production or increased loss (nephrotic syndrome)
22
Q
State some pathologies that cause:
- Low albumin + low protein
- Low albumin + normal protein
- Low albumin + high protein
A
-
Low albumin + low protein =
- advanced cirrhosis
- protein malnutrition
- chronic inflammation
-
Low albumin + normal protein =
- infection
-
Low albumin + high protein =
- myeloma
23
Q
State some causes of raised INR
A
- liver disease with impaired function
- vit K deficiency
- consumptive coagulopathy (DIC)
- overdose of oral anticoagulants (VKAs)
- Coagulation factors deficiency (fibrinogen and factors II, V, VII, or X, or a combined deficiency) in the extrinsic pathway
24
Q
Define Liver Abscess and Liver Cyst
A
Localised infection in the liver parenchyma that may be bacterial, fungal, or parasitic in origin…
resulting in a walled off collection of …
- abscess = pus
- cyst = cystic fluid
25
State the common causative oganisms for liver abscesses and cysts
_Pyogenic (producing pus)_
* **E. coli**
* **K. pneumoniae**
* **S. constellatus**
* **Klebsiella** species
* **Streptococcus**
_Anaerobes:_
* **Bacteroides fragilis**
* **Fusobacterium necrophorum**
_Amoebic abscess_
* Following infection by **Entamoeba histolytica**
26
Which antimicrobial agent would be a good choice in treating an amoebic liver abscess?
metronidazole
27
What is the optimal management of a non-amoebic liver abscess?
drainage + antibiotic therapy
28
Liver abscesses form by spread of infection from which sources?
* **Biliary** tree
* **Portal** vein
* **Hepatic** vein
* Penetrating **trauma**
* Extension of **contiguous infection**
29
What is the most common identifiable source of pyogenic liver abscess?
The **biliary tract**
cholecystitis, colangitis, strictures, congenital cysts
30
State the most common causes of liver abscess
**40% of cases = idiopathic**
_Infective abscesses:_
* **Cholecystitis, cholangitis**
* caused by pyelophlebitis:
* **appendicitis**
* **diverticulitis**
* **IBD**
* **pancreatitis**
* **Immunocompromise**
* **diabetes mellitus**
_Malignant/parenchymal abscesses:_
* Primary hepatocellular **cancer** + liver mets
* **Cirrhosis**
_Iatrogenic abscesses_
* Post-**transplant**
* chemoembolisation or percutaneous ablation of hepatic neoplasms
* **Biliary sphincterotomy**
* hepatic **cryotherapy**
31
Summarise the epidemiology of liver abscesses and cysts
**Uncommon**- annual incidence is approximately 3.6/100,000
**Pyogenic** = most common in the **industrialised** world
**Amoebic** liver abscess - most **common WORLDWIDE**
**Hydatid** cysts - common in sheep-rearing countries
32
What are the presenting symptoms of liver abscess?
Acute onset in amoebic abscess, insidious in pyogenic:
* **Fevers** and **chills**
* **RUQ pain**/tenderness
* **weight loss, anorexia**
* **N+V**
* **fatigue**
* **chest symptoms**: cough, SOB, pleuritic chest pain
* due to diaphragmatic inflammation
* may see reactive pleural effusion in right lower lobe
33
Why is it important to ask about travel when taking a history for suspected liver abscess?
Strongly associated risk factor for amoebic liver abscess:
origin in or having visited **endemic areas for amoebiasis.**
34
What are the signs of liver abscesses and cysts on physical examination?
* **Fever** - continuous or spiking
* Pyogenic abscess should be considered in all patients presenting with pyrexia of unknown origin associated with associated abdominal pain or bloating
* **Tender hepatomegaly** (right lobe affected more than left)
* **Signs of reactive pleural effusion:**
* Dullness to percussion (RHS)
* Reduced breath sounds (RHS)
* If the abscess ruptures (a rare complication), then patients may present with **signs of shock.**
35
Identify appropriate investigations for liver abscesses and cysts
1. **Bloods**
* FBC- leukocytosis
* LFTs- raised ALP, ALT and bilirubin
* Blood and fluid cultures
* PTT + APTT - prior to aspiration, check for deranged clotting factors
2. **Liver USS (80-90% sensitive)**
* poor-defined lesions with hypo- and hyper-echoic areas
* guide aspiration
3. **CT abdo contrast (\>95% sensitive)**
* lesion seen with surrounding oedema
* gas within lesion highly sugestive of pyogenic abscess
4. **Gram stain and culture of aspirated abscess fluid**
36
Describe the stages of ALD
Alcoholic liver disease (ALD) has 3 stages of liver damage:
1. fatty liver (**steatosis)**
2. alcoholic **hepatitis** (inflammation and necrosis)
3. alcoholic liver **cirrhosis**
All are caused by **chronic heavy alcohol ingestion**
37
What are the defining and associated histopathological features of alcoholic hepatitis?
defining histological features:
* **hepatocyte degeneration** and necrosis
* **inflammation**
* **fibrosis**
associated histological features:
* fatty change- **steatosis**
* **megamitochondria**
* **Mallory-hyaline inclusions** (eosinophilic intracytoplasmic aggregates of cytokeratin intermediate filaments)
38
What does the following slide show?
Histochemical liver stain- **collagen** staining blue
## Footnote
Shows a **fatty liver** with scarring, inflammation and damage
Swollen **balloon cells, inflammatory** cells
**Mallory hyaline** bodies
39
What does the following slide show?
**Disorganised**- hepatocytes are not arranged in a trabecular fashion- this is a sign of liver damage
clear spaces = **steatosis** = fatty cells
arrows pointing at **mallory hyaline** = hepatocyte damage
40
What is another cause of fatty buildup in the liver apart from alcoholic liver disease?
**Nonalcoholic steatohepatitis (NASH)** is liver inflammation and damage caused by a **buildup of fat** in the liver.
* Newly emerging issue
* Patients with **insulin resistance**
* Due to **obesity epidemic**
41
What is the name of the condition in ALD where bile cannot flow from the liver to the duodenum?
**cholestasis**
red is bile
inflammation/obstruction disturbs bile flow
42
Summarise the epidemiology of alcoholic hepatitis
In the UK, **24-28% of adults** drink in a harmful way.
alcoholic hepatitis occurs in **10-35%** of heavy drinkers
43
What are the presenting signs and symptoms of _chronic_ liver disease?
A **long history of heavy drinking is required** for ALD development (15-20yrs)
Key features:
* **RUQ abdominal pain**
* **Hepatomegaly**
Other features:
* **Haematemesis/melaena**- from oesophageal/gastric varices + coagulopathy
* **caput medusae**
* **splenomegaly**
* **ascites /abdo distention**
* **asterixis**
* **Testicular atrophy**
* **spider naeviae**- cutaneous telaniectasia
* **jaundice**
* **palmar erythema**
* **gynaecomastia**
44
State the 5 primary causes of liver disease
* Alcohol
* Autoimmune
* Drugs
* Viral
* Biliary disease
45
What are the symptoms of acute liver disease?
There may be triggering events (e.g. aspiration pneumonia, trauma)
* **Malaise**
* **Anorexia / N+V**
* **Fever**
* **Jaundice**
46
What are the signs of encaphalopathy, such as that caused by ALD? What is this caused by ?
Signs:
* **asterixis**
* **drowsiness**
* **disorientation**
Cause:
* **Build up of ammonia** in the blood - inadequate hepatic clearance
* This crosses the **BBB**
47
Explain the blood results in alcoholic hepatitis
FBC:
* **Low Hb**- iron / folate deficiency, GI bleeding, haemolysis, hypersplenism
* **High MCV**
* **Leukocytosis**- alcoholic hepatitis-related leukaemoid reaction or associated infection.
* **Thrombocytopenia**- 2/2 alcohol-induced bone marrow suppression, folate deficiency, or hypersplenism.
LFTs:
* **Low albumin**
* **Prolonged PT** (longer = more damage)
* High **AST + ALT-** found in hepatocytes
* **High bilirubin**
* **elevated GGT-** more sensitive than ALT/ALP, less specific
U&Es:
* Normal or **low** sodium, potassium, magnesium, phosphorus
* **elevated urea**- suggests active GI bleeding when paired with normal creatinine
48
What does the AST:ALT ratio tell us about the cause of hepatitis?
**Raised AST**= AST\>ALT (ratio \>2) = **alcoholic cause**
**Raised ALT**= ALT\>AST (ratio \<1)= **viral, non-alcoholic fatty live**r
49
In what conditions is AST raised?
present in heart, muscle, kidney and brain
raised in:
* MI
* hepatic necrosis
* muscle injury
* congestive cardiac failure
* ALD
50
In what conditions are ALT and AST raised?
(very raised → mildly raised)
**Indicate hepatocellular injury**
## Footnote
**+++ = viral**, toxic or alcoholic hepatitis (\<50x), **ALT\>AST**
**++ = cirrhosis** and other chronic liver diseases (\<5x) **AST\>ALT**
**+ = obstructive jaundice** (\<3x)
51
State some non-bedside investigations for alcoholic hepatitis
* **Ultrasound** - used to screen for HCC every 6-12 months in ALD patients with cirrhosis.
* **Upper GI Endoscopy** - investigate varices
* **Liver Biopsy** - diagnostic of ALD and/or alcoholic cirrhosis
* **EEG** - slow-wave activity indicates encephalopathy
52
How would you manage acute hepatitis?
* **Thiamine**
* **Vitamin C** and other **multivitamins** (Pabrinex)
* Monitor and correct **K+, Mg2+ and glucose**
* Ensure **adequate urine output**
* **Steroid** therapy for prevention of short-term mortality- prednisolone
* **Glypressin and N-acetylcysteine** for hepatorenal syndrome
53
How would you provide nutrition to those with acute alcoholic hepatitis?
Via oral or **NG feeding** is important
**Protein restriction** if encephalopathic
**Parenteral nutritional** supplementation (B group, thiamine and folic acid)
54
How would you treat ascites and encephalopathy caused by ALD?
_Encephalopathy:_
* oral **lactulose or phosphate** **enemas**
* decrease ammonia generation by bacteria
_Ascites:_
* **diuretics** (spironolactone with/without furosemide)
* therapeutic **paracentesis**
55
What management should be taken to slow the progression of ALD?
* **alcohol abstinence** +/- withdrawal management
* lond-acting **benzodiazepines- oxazepam/diazepam** for seizure prevention.
* May worsen encephalopathy
* **weight reduction and smoking cessation**
56
Explain 2 syndromes arising from live failure caused by activation of RAAS
**portal hypertension**
→ **splanchnic vasodilation** (increased NO)
→ **reduced blood volume** detected in JGA
→ **activation of RAAS**
2 outcomes:
1. vasoconstriction of renal vessels **⇒ HEPATORENAL SYNDROME**
2. Renin stimualtes reabsorption of salt + water **⇒ ASCITES**
57
Identify the possible complications of alcoholic hepatitis
* **hepatic encephalopathy**
* **portal hypertension**
* **hepatorenal syndrome**
* **GI bleeding** 2/2 gastro-oesophageal varices, haemorrhoids, and portal hypertensive gastropathy + **coagulopathy**
* **hepatocellular carcinoma**
* **sepsis**
58
Summarise the prognosis for patients with alcoholic hepatitis
Mortality:
* **First month = 10%**
* **First year = 40%**
If alcohol intake continues, most will progress to cirrhosis within 1-3 years
To calculate prognostic score can use Maddrey’s discriminant function or Glasgow alcoholic hepatitis score
59
Define autoimmune hepatitis
**Chronic inflammatory disease of the liver of unknown aetiology.**
Characterised by:
* presence of **circulating auto-antibodies** with a high serum globulin concentration
* **inflammatory changes** on liver histology
* favourable response to immunosuppressive treatment
60
What are the risk factors for autoimmune hepatitis?
* **female** gender
* **genetic pre-disposition**
* HLA- different for types 1+2
* **immune dysregulation**
* **other autoimmune condtions**
* Viruses:
* measles virus
* cytomegalovirus
* Epstein-Barr virus
* hepatitis viruses A, C, and D
* certain drugs
61
Explain the aetiology of autoimmune hepatitis
1. Genetic predisposition + environmental factor
2. hepatocyte production of **HLA antigens** → **T-cell-**mediated autoimmune attack
3. **Chronic inflammatory changes-** lymphoid infiltration of the portal tracts
4. hepatocyte **necrosis → fibrosis → cirrhosis**
62
Summarise the epidemiology of autoimmune hepatitis
**Type 1 (commonest):** occurs in ALL age groups (but mainly young women)
**Type 2:** generally occurs in girls and young women
63
What are the presenting symptoms of autoimmune hepatitis
**May be asymptomatic** and discovered incidentally through abnormal LFT
_non-acute:_
* **fatigue/malaise**
* **abdominal discomfort**
* **nausea**
* **arthralgia** involving small joints
* **anorexia**
* **spider angiomata**
* **pruritus**
_acute(25):_
* **fever**
* **jaundice**
* **N+V, diarrhoea**
* Some may present with **serum sickness** (e.g. arthralgia, polyarthritis, maculopapular rash)
64
What are the signs of autoimmune hepatitis on physical examination?
Stigmata of chronic disease:
* **spider naevi**
* **palmar erythema**
* **jaundice**
* **hair loss**
* **leuconychia**
* **asterixis**
**Ascites, oedema** and **hepatic encephalopathy** are late features
65
Identify appropriate investigations for autoimmune hepatitis
**_Bloods:_**
* **LFTs**
* high AST, ALT, bilirubin, gamma- GT (not as much as bile duct injury)
* ALP not usually raised much
* hypoalbuminaemia
* **Hypergammaglobulinaemia** is typical with:
* Presence of ANA, ASMA and Anti-LKM antibodies
* increased **PTT**
**_Liver Biopsy:_**
* Needed to establish diagnosis and check whether hepatitis or cirrhosis
**_US, CT or MRI of liver and abdomen_**
* Visualise structural lesions
**_ERCP_**
* To rule out PSC
66
What blood antigens are tested in suspected autoimmune hepatitis to rule out other causes of liver damage?
* Viral serology (hep B/C)
* Urinary copper/caeruloplasmin (Wilson’s disease)
* Ferritin and transferrin saturation (haemochromatosis)
* a-1 antitrypsin (for deficiency)
* Anti-mitochondrial antibodies (PBC)
67
What are the indications for management of autoimmune hepatitis?
**Aminotransferases** \> 10x the upper limit of normal
**Symptomatic**
**Histology:** significant interface hepatitis, bridging necrosis or multiacinar necrosis
68
How is autoimmune hepatitis managed?
_Immunosuppression:_
* **corticosteroids eg prednisolone**
* maintenance treatment with gradual reduction in dose
* immunosupressive agents eg **azathioprine, mercaptopurine**
* for maintenance phase
* steroid sparing agents
_Monitor_
* **Ultrasound and alpha-fetoprotein level** every 6-12 months in patients with cirrhosis – to detect hepatocellular carcinoma
* Repeat liver **biopsies** to check disease progression
_Hep A and B vaccinations_
_Liver transplant_
* If patient refractory/intolerant to immunosuppression therapy/end-stage of disease
69
What are the possible complications of Autoimmune Hepatitis
* **Fulminant hepatic failure** – severe impairment of hepatic functions in the absence of pre-existing liver disease
* **Cirrhosis**
* **Complications of portal hypertension** – varices, ascites
* **Hepatocellular carcinoma**
* Side-effects of **corticosteroid** treatment
70
What is the prognosis for patients with autoimmune hepatitis?
**80% achieve remission** by 3 years
**35-50% remain in remission** when immunosuppression withdrawn
**50%** require lifelong maintenance
**5 year survival rate:** 85% if treated, 50% if untreated
71
# Define viral hepatitis
for A - E, state whether infection is acute or chronic
hepatitis caused by infection with RNA viruses
* hepatitis **A + E = acute** only
* hepatitis **B + D = acute or chronic** (D requires infection with B)
* hepatitis **C = chronic** only
72
Explain the aetiology of hepatitis A + E
Small non-enveloped single-stranded RNA viruses
1. Transmission = **faecal-oral** route
2. Viruses replicate within hepatocytes and are secreted into **bile**
3. Infected hepatocytes are targeted by **CD8+ T cells** and **NK cells** → **necrosis + liver inflammation**
73
What is the average incubation period for HAV?
28 days.
74
What are the key histological features of viral hepatitis?
* Inflammatory cell **infiltration of portal tracts** (neutrophils, macrophages, eosinophils, lymphocytes)
* **Zone 3 necrosis**
* **Bile duct proliferation**
75
Summarise the epidemiology of HAV/HEV in the developed and developing worlds
_Developing world:_
* HAV is **endemic** - Asia, Africa and Central America
* Infection **often occurs sub-clinically** (asymptomatic in young children)
* **children are key transmission** reservoir
_Developed world:_
* Less common (better sanitation)
* **Age of exposure is higher** → patients = **symptomatic**
* Annual UK incidence: **5000**
76
What are the 3 phases of hepatitis A+ E? For each phase, state the symptoms
_Prodromal phase- abrupt onset pre-jaundice (1 week)_
* **Anorexia**
* **Fever**
* **N+V**
* **Malaise, fatigue**
* Distaste for cigarettes in smokers
* **Headache**
_Icteric phase (1-4 weeks)_
* **Jaundice**
* **Tender hepatomegaly**
* **RUQ pain**
* **Pale stools + dark urine**
* acholic stools = clay coloured
* **Pruritis**
_Recovery/convalescence phase_
* 1-2 weeks after jaundice
* Full recovery takes 4-6 weeks
note the **ABSENCE of stigmata of chronic liver disease** (although some spider naevi may appear transiently)
77
Identify appropriate investigations for viral hepatitis
1. **LFTs**
* high AST, ALT and bilirubin
* ALP mildly raised
* low albumin
2. **FBC, coagulation profile, U+Es**
* microcytic anaemia, thrombocytopaenia
* due to cirrhosis-induced portal hypertension
* other signs of cirrhosis- high PTT, high urea, hyponatraemia
3. **Viral serology**
* **IgM HAV /** **IgM HEV** - shows current infection (IgG shows past)
* Hepatitis B surface antigen -**HBsAg** (HB antibody shows past)
* **HCV antibody test**
* **HEV in stool**
* **Urinalysis**
* Positive for bilirubin
* Raised urobilinogen
78
How is viral hepatitis A+E managed?
Largely supportive:
* **If exposed to HAV - vaccine ASAP** and/or immunoglobulin for high risk - no HEV vaccine
* **avoid alcohol + hepatotoxic drugs** eg paracetamol
* **hospitalisation rarely**- for volume depletion, coagulopathy, encephalopathy, severe prostration
* \<1% need **transplant**
79
Summarise the prognoses for viral hepatitis A+E
* Recovery is usually within **4-8 weeks**
* **85% full recovery** in 3 months
* **10-20% relapse** w/ persistent fever, jaundice etc over several months
* In **pregnancy** HEV can cause **fulminant hepatic failure**- mortality of 80%
* **No chronic** effects
80
What are the possible complications of viral hepatitis A+E?
* **Fulminant hepatic failure** (in a very small proportion of patients but is more common in pregnant women)
* **Cholestatic hepatitis** with prolonged jaundice and pruritus can develop after HAV infection
* **Post-hepatitis syndrome:** continued malaise for weeks to months
81
compare the genomic structure of viral hepatitis B,C,D
**HCV = flavivirus,** single-stranded, enveloped RNA
**HBV = hepadnavirus**, double-stranded, enveloped DNA
**HDV=** **single-stranded RNA virus coated with HBsA**
defective virus, using the HBV surface antigen to enter hepatocytes
82
Which is the most severe form of chronic hepatitis?
**Hepatitis delta virus (HDV)**
HDV-infected individuals are more likely to die from **advanced liver disease** compared with HBV alone
Their risk of developing **hepatocellular carcinoma is 9x higher.**
83
How are hepatitis B and C transmitted?
* **percutaneous blood exposure**
* (unsafe healthcare practices, IV drug use)
* **sexual transmission**
* **perinatally**- permucosal transmission from HB/CV infected mother (vertical transmission)
84
State the risk factors for hepatitis B and C
* **perinatal exposure** in an infant born to an HBV-infected mother
* **high-risk sexual behaviours**
* **unsafe medical practices**
* ****most common worldwide cause is unsafe injection practices
* unscreened blood transfusion
* **IV/intranasal drug use**
* **family history** of HBV, hepatocellular carcinoma, and/or chronic liver disease
* genetic factors are associated with varying rates of viral clearance
younger individuals (particularly babies) are more likely to become chronic carriers
**incarceration** increases risk of the above risk factors
85
Summarise the epidemiology of hepatitis B + C
* **HCV** = 71 million infected. Worldwide endemic
* European and Eastern Mediterranean
* **HBV** = 250-350 million infected. Endemic only in LICs
* Southeast Asia (excluding Japan), China, and Africa
86
What are the 3 viral proteins produced by HBV that can be measured? What does their presence indicate?
* **Core antigen (HBcAg)**
* test looks for antibody to the antigen rather than antigen itself
* **Surface antigen (HBsAg)**
* indicates active infection
* detected an average of 4 weeks post-exposure
* usually becomes undetectable after 4-6 months of infection.
* **e antigen (HBeAg)**
* acute phase protein
* presence ≥3 months after onset = high likelihood of development of chronic infection
* indicates greater infectivity, with a high level of viral replication
**ANTIBODIES TO ANY OF THESE ANTIGENS INDICATE CLEARED/ACTIVE/CHRONIC INFECTION**
87
How is HDV detected?
Presence of anti-HDV antibodies using PCR
88
Other than serology tests can be done in suspected/diagnosed viral hepatitis?
**Abo USS- all patients**
* evaluate for fibrosis, cirrhosis, portal hypertension + HCC
**Liver biopsy**
* patients with chronic infection to grade and stage liver disease before initiating therapy
* rule out other causes
**Non-invasive tests of liver fibrosis**
* liver elastography uses ultrasound and low-frequency waves to measure liver elasticity
89
How is hepatitis B and C managed?
_Immunisation_
* **active = recombinant HBsAg** (at risk individuals, neonates with HBV+ mothers)
* **passive = HB immunoglobulin**/antibodies (post-exposure)
_Symptomatic Tx_
* acutely eg antipyretics, antiemetics and cholestyramine
_Antiviral therapy_
* **entecavir, TDF, TAF, interferon-alpha**
* see algorithm for indications
* usually life-long
* Nucleoside/nucleotide analogues. entecavir is a cytokine
90
Identify the possible complications of viral hepatitis B + C
* 1% get **fulminant hepatic failure**
* Massive immune-mediated lysis of infected hepatocytes
* **Chronic HBV infection** (10% of adults, much higher in neonates)
* **Cirrhosis**- 20% of chronic patients, exacerbated with alcohol
* **HCC** (HBV accounts for 50% HCC worldwide)
* results from chronic inflammation and cellular regeneration
_Extrahepatic immune complex disorders_
* **rheumatological complications**
* myalgia, fatigue, arthralgias, and arthritis.
* **skin complications**
* porphyria cutanea tarda and lichen planus.
* **cryoglobulinaemia**
* Cryoglobulins deposit in the skin, kidney, and joints
* **glomerulonephritis**
* **eye complications**
91
Define hepatocellular carcinoma
**Primary malignancy arising from hepatocytes** in predominantly **cirrhotic liver.**
However, some patients may not have cirrhosis before developing HCC (esp chronic HBV)
92
What is the prognosis for hepatitis B?
1. **‘Full recovery’.**
* Majority, HBV is a self-limiting condition with full clinical recovery.
* Virus is rarely cleared completely but kept in check by cytotoxic T-cells.
* (immunosuppresion can lead to reactivation)
2. **Carrier status.**
* 10% will become asymptomatic carriers (virus still detectable in the blood)
* Long-term prognosis is good
* risk of long-term complications \<1%.
3. **Chronic hepatitis B. (symptomatic)**
* 5–10%
* Rates are 90% if the infection was acquired at birth from the mother.
* Of the patients who develop chronic infection, about 20% will develop cirrhosis and 6% HCC
4. **Fulminant hepatitis.**
* 0.5%
* mortality rate of 80%
93
What are the risk factors for HCC?
Chronic liver damage
* **cirrhosis**
* chronic **hepatitis** **B and C**
* chronic **heavy alcohol use** \>80 g/day for more than 10 years
* **Diabetes and obesity**- insulin resistance
* **FHx**
* **Aflatoxin**
* **Haemachromotosis** (iron overload in liver)
94
Summarise the epidemiology of hepatocellular carcinoma
* COMMON- 6th most common worldwide
* average age = **60**
* LESS common than **liver metastases**
* High incidence in regions where **hepatitis B and C are endemic**
* 44% of HCC cases worldwide are attributable to chronic HBV infection
95
What are the presenting symptoms of HCC?
_Symptoms of Malignancy_
* Malaise
* Weight loss
* Loss of appetite
_Symptoms of chronic liver disease (cirrhosis):_
* **RUQ pain**- enlarged liver, liver inflammation, and stretching of the liver capsule.
* **early satiation**- compression of ascites on stomach
* **abdominal distension** - ascites
* **jaundice**
* **oesophageal or gastric variceal bleeding**
* **leg oedema**
* **cachexia**
* **asterixis, palmar erythema, spider naevi, caput medusae**
96
What management options are available for HCC?
* **Hepatic resection**
* **Liver transplantation**
* **Radiofrequency ablation (RFA)**- destroys the tumour by modifying the temperature
97
How would bloods would you do to investigate HCC? What would they show?
* **FBC**- microcytic anaemia, thrombocytopaenia
* due to variceal bleeding and portal hypertension (splenic sequestration + pooling of blood)
* **U+Es**- hyponatraemia, high urea due to renal injury
* **LFTs-** elevated AST/ALT, ALP, and bilirubin; low albumin
* **Clotting**- eleveated PTT
* **AFP**- elevated in 60% HCC patients.
* Tumour marker
98
What other investigations other than bloods would you do for HCC?
* **Abdo USS**- initial staging test + cirrhosis screening every 6 months
* sensitive but not specific
* see irregular echos and poorly defined margins
* **CT/MRI abdo w/contrast**
* more specific than USS
* used if AFP raised/abnormal USS
* **Liver biopsy**
* not required in majority- radiological diagnosis
* see central necrosis, multinucleated giant cells, poorly differentiatd hepatocytes
99
Define NASH
Clinico-histopathological entity that includes a **spectrum of conditions**
characterised histologically by **macrovesicular hepatic steatosis** in those who do not consume alcohol in amounts generally considered harmful to the liver
100
Explain the pathophysiology of NASH
_HIT 1_
**insulin resistance** → **excessive triglyceride accumulation** → hepatic steatosis
_HIT 2_
**additional oxidative injury/stress** **→ necroinflammatory changes** → steatohepatitis (inflammation and fibrosis)
*multifactorial causes, including dysregulated cytokine production, hormones, deficiencies and intestinal bacteria*
101
What does NASH increase the risk of?
diabetes mellitus
MI
stroke
102
What are the risk factors for NASH?
* **obesity**
* **insulin resistance or diabetes**
* **hyperlipidaemia**
* **hypertension**
* **metabolic syndrome**
* history of **rapid weight loss**
* **hepatotoxic medications**- oestrogens (tamoxifen), corticosteroids, methotrexate
* **total parenteral nutrition**
* **increasing age**
103
Summarise the epidemiology of NASH
Difficult to ascertain- need biopsy (not USS) in order to make the diagnosis.
**MOST COMMON liver disorder in developed countries**
**1/3** people in the UK have the early stages of NASH
104
What are the signs and symptoms of NASH?
Early stages are usually asymptomatic
* **fatigue and malaise**
* **heptosplenomegaly**
* **truncal/central obesity**
* **RUQ discomfort** (dull, aching)
Symptoms of cirrhosis will be experienced in the most advanced stages of NASH
105
What investigations are undertaken for NASH?
**LFTs-**
* mildly elevated ALT/AST 1-4x normal
* AST:ALT ratio = \<1 (in acute alcoholic, usually \>2)
* mildly elevted/normal bilirubin, ALP, GGT
**FBC-**
* anaemia, thrombocytopaenia in advanced disease (due to hypersplenism)
**Metabolic panel**
* hyperglycaemia- due to insulin resistance
* hyperlipidaemia in lipid panel
**Liver Ultrasound**
* specific and sensitive
* diffuse hyperechoic echotexture (bright liver)
**Liver Biopsy**
* ultimately required for diagnosis
**Abdo MRI/CT**
* Show decreased liver attenuation and increased fat content
106
How is NASH managed?
CONSERVATIVE- need to control risk factors
* **diet and exercise**
* reduced alcohol
* reduced cholesterol
* stop smoking
* **vitamin E- improve liver function**
* alpha tocopherol
* **weight loss therapy**
* orlistat
* gastric bypass
* **for diabetics- insulin sensitiser**
* metformin
* **antihyperlipidaemic drugs**
* gemfibrozil
* if end stage liver disease- transplant
107
What is the prognosis for patients with NASH?
NASH is a progressive form of non-alcoholic liver disease
Therefore NASH has worse prognosis- **10-20% of patients progress to fibrosis**
1/3rd of these will progress to liver failure and transplant
Recurrent NASH following liver transplantation is common
108
Define cirrhosis
**Diffuse pathological proces**s arising from a variety of causes , characterised by:
1. **fibrosis**
2. conversion of normal liver architecture to structurally abnormal **regenerative nodules**
Cirrhosis is the **final stage of any chronic liver disease.**
**IRREVERSABLE**
109
What is meant by decompensated cirrhosis?
**Acute deterioration in liver function** with portal hypertension in a patient with cirrhosis
*Characterised by:*
* **jaundice**
* **ascites**
* **hepatic encephalopathy**
* **variceal haemorrhage**
110
List some factors that can trigger decompensated cirrhosis
* infection
* GI bleeding
* constipation
* high-protein meal
* electrolyte imbalances
* alcohol and drugs
* tumour development
* portal vein thrombosis
111
List the most common causes of cirrhosis in the Western world:
* **alcohol-related** liver disease
* **non-alcoholic fatty liver disease (**NAFLD and associated steatohepatitis)
* chronic **viral hepatitis B/C** (with or without coexisting hepatitis D)
112
List the causes of cirrhosis
1. **chronic viral heptatitis B/C**
2. **NASH**
3. **alcoholic liver disease**
4. **autoimmune hepatitis**
5. **metabolic disorders**: haemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency
6. **cholestatic disease:** primary sclerosing and primary biliary cholangitis
7. **Biliary obstruction-** mechanical, atresia, CF
8. **Hepatic venous outflow obstruction**- right HF, Budd-Chiari
9. **Drugs/toxins**- amiodarone, methotrexate
10. **Cryptogenic cirrhosis** = unknown cause
113
List some inherited causes of cirrhosis
* **a1-antitrypsin deficiency**
* **Haemochromatosis**
* **Wilson's disease** – autosomal recessive condition characterised by excess copper
* **Galactosaemia**
* **Cystic Fibrosis**
114
Summarise the epidemiology of cirrhosis
Liver disease = 3rd biggest cause of mortality worldwide
115
What are the presenting signs and symptoms of cirrhosis?
* **abdominal distension w/shifting dullness-**
* ****from ascites due to portal hypertension
* **Haematemesis + meleana** -
* from GO varices
* skin features:
* **jaundice and pruritus**
* impaired hepatic secretion of conjugated bilirubin and bile
* hand and nail features:
* **leukonychia, palmar erythema, spider naevi, dupuytrens contracture**
* facial features:
* **telangiectasia, jaundiced sclera**
* abdominal features:
* **collateral circulation (caput medusae), hepatosplenomegaly, hair loss**
* peripheral features:
* **sarcopenia**
* **peripheral oedema**
116
What blood/serological investigations would be done for cirrhosis?
_Bloods_
* FBC- **microcytic anaemia, thrombocytopaenia** ( due to hypersplenism)
* LFT- **high ALT, AST, ALP, gamma-GT + bilirubin, low albumin**
* U+Es- **hyponatraemia**
* Clotting- **increased PTT,**
* Tumour markers- **AFP**
_Investigating cause_
* **Iron, TIBC, transferrin saturation**, ferritin (haemachromotosis)
* **HBsAg + IGg antibodies to HCV** - viral hepatitis
* **ANA + anti smooth muscle antibodies-** autoimmune hepatitis
* **plasma alpha 1 antitrypsin**
117
What imaging investigations would you do for cirrhosis?
**Abdo USS**- signs of advanced cirrhosis, PH, ascites, increased portal vein diameter
**Abdo CT/MRI**- as above.
**Gastroesophageal duodenoscopy-** for varices
**Biopsy**- most specific + sensitive diagnostic test- confirmatory
*With strong clinical evidence, imaging alone is sufficient for diagnosis of cirrhosis*
118
Explain 2 grading systems to estimate the prognosis in cirrhosis
Child-Pugh score + end stage liver disease :
_Stage 1_
* **without GO varicies or ascites**
* **1**% mortality p/a
_Stage 2_
* **GO varices** but **no bleeding** + **no ascites**
* **4**% mortality p/a
_Stage 3_
* **ascites +/- GO varices but no bleeding**
* **20%** mortality p/a
_Stage 4_
* **GI bleeding** due to portal hypertension +/- ascites
* **57**% mortality p/a
119
How is cirrhosis managed?
* **Resuscitation - ABC**
* **Treat underlying cause** of liver failure and prevent further hepatic damage- alcohol, drugs, good nutrition
* **Monitor** - vital signs, PT, pH, creatinine, urine output, encephalopathy
_Manage:_
* **Encephalopathy**: lactulose and phosphate enemas
* **Antibiotic and antifungal prophylaxis**
* **Hypoglycaemia treatment**
* **sodium restriction for ascites**
* spironolactone + furosemide
* **Coagulopathy treatment** - IV vitamin K, FFP, platelet infusions
* **Gastric mucosa protection** - PPIs or sucralfate
* **AVOID sedatives** or drugs metabolised by the liver
120
What are the possible complications of cirrhosis?
* **Portal hypertension** with ascites
* **Hepatic encephalopathy**
* **Variceal haemorrhage**
* **SBP**- spontaneous bacterial peritonitis
* **HCC**
* **Renal failure** (hepatorenal syndrome)
* **Pulmonary hypertension** (hepatopulmonary syndrome)
* **Hepatic hydrothorax**
121
Summarise the prognosis for patients with cirrhosis
Depends on aetiology and complications
Generally poor prognosis
* Overall **5 year survival = 50%**
* If **ascites**, **2 year survival = 50%**
Poor prognostic indicators:
* encephalopathy
* serum Na+ \<110 mmol/L
* serum albumin \<25g/L
* high INR
122
Define portal hypertension
Abnormally **high pressure within the hepatic portal vein.**
Clinically significant portal hypertension is defined as a hepatic venous pressure gradient **\> 10 mmHg**
123
Explain the aetiology/pathophysiology of portal hypertension due to cirrhosis
Pressure within portal venous system is dependent on:
1. **input from blood flow** **in the portal vein**
* sodium retention + vasoactive NO increase (buildup of toxic metabolites)
* → increased plasma volume + splanchnic vasodilation
2. **hepatic resistance to outflow**
* Vascular channels go smooth → tortuous + irregular (collagen depositions and fibrosis)
* → increased resistance to flow
* → increased pressure → varices and dilations
124
State the pre-hepatic cuases of portal hypertension
* **Splenic/ portal vein thrombosis** (sepsis, trauma)
* Congenital **stenosis**
* **Extrinsic compression** eg by tumour
125
State the hepatic causes of portal hypertension
* **CIRRHOSIS**
* **Schistomiasis**
* **Sarcoidosis** + hepatic **granulomas**
* **Myeloproliferative disease** (CML/polycythaemia vera/essential thrombocytaemia)
126
State some post-hepatic causes of portal hypertension
Anything causing HEPATIC VENOUS OUTFLOW OBSTRUCITON
* **Budd-Chiari syndrome** (obstructing lesions of the hepatic veins and IVC)
* **Constrictive pericarditis**
* **Tricuspid regurgitation**
* **Right heart failure (congestive cardiac)**
127
What are the presenting symptoms of portal hypertension?
* **splenomegaly, hepatomegaly**
* **ascites**
* **jaundice**
* stigmata- **spider naevi, caput medusae, umbilical hernia**
* **peripheral oedema**
* **gynaemcomastia**
* GI varices - **malaena, haemetemesis** (may present with this)
* **Encephalopathy**- lethargy, irritability, disturbed sleep
128
What investigations would you do for portal hypertension?
In advanced disease, **diagnosis can be clinical** (ascites, varices)
_Bloods_
* **LFTs**- thrombocytopaenia, hypoalbuminaemia, microcytic anaemia
* **Clotting**- prolonged PTT- EARLY SIGN
* specific **serological tests for the underlying cause**
_Imaging_
* **Doppler USS**- increased hepatic echogenicity, splenomegaly, HPV dilation, occlusions, gallbladder thickening
* **Endoscopy**- in cases of GI haemorrhage. Visualise varices.
129
How is portal hypertension managed?
Aimed at prevention of complications by decreasing portal pressures.
_Pharmacotherapy_
* **Beta-blockers eg propanolol**
* reduce risk of variceal bleeding- only use if present
* **Somatostatin + vasopressin/terlipressin**
* acute bleeding of varices
* vasoconstrictors of splanchnic beds
* **Prophylactic antibiotics**
_Treating varices/GI haemorrhage_
* **Sclerotherapy**
* **Oesophageal band ligation**
* **Balloon Tamponade**
**_Transjugular Intrahepatic Portosystemic Shunt (TIPSS)_**
Indicated in patients who have had recurrent bleeding despite medical or endoscopic management
Main side effect is **hepatic encephalopathy + thrombosis**
**_Liver transplant_**
Only effective treatment for end-stage liver disease.
130
Explain how varices develop
Varices develop when **portal blood is rerouted** to the **systemic circulation**, through **collateral vessels**
Due to **increased resistance to blood flow** to/through the liver.
The pressure within these irregular vessels is great and they have the **potential to rupture.**
131
How is ascites managed?
* Potassium sparing (spironolactone) and loop (furosemide) **diuretics**
* **sodium restriction**
* **paracentesis** if poorly controlled with above
132
What are the complications of portal hypertension?
* **Variceal bleeding**
* **Ascites**
* **Hepatopulmonary syndrome**
* hepatic dysfunction
* hypoxaemia
* extreme intrapulmonary vasodilation
* **Hepatic hydrothorax**
* pleural effusion for hepatic reasons (i.e. no cardiac, pulmonary, or pleural disease)
* **Hepatorenal syndrome**
* rapid decline in kidney function (see diagram)
* **Complications of liver failure-** encephalopathy,
133
Summarise the prognosis for patients with portal hypertension
Depends on the underlying CAUSE
Variceal haemorrhages have a **1-year mortality of 40%**
134
What are some causes of ascites?
135
Define liver failure (both acute and acute-chronic)
Rapid decline in hepatic function characterised by:
* **jaundice**
* **coagulopathy** (INR \>1.5)
* hepatic **encephalopathy**
* acute/fulminant* = patients with no prior liver disease
* acute-on-chronic* = acute decompensation of chronic liver disease
136
How is liver failure classified?
It is classified based on the **time interval** between the onset of **jaundice** and the development of **hepatic encephalopathy**
* **Hyperacute** = \< 7 days
* **Acute** = 1-4 weeks
* **Subacute** = 4-12 weeks
There is decreasing risk of cerebral oedema with increased delay of encephalopathy
137
State some common causes of acute liver failure
_ALF_
* 66% = **paracetamol hepatotoxicity**
* 11% = **idiosyncratic drug reactions** e.g. antimicrobials
* **Hepatitis** B, A, autoimmune, ischaemic
_Acute on Chronic_
* Anything **condition causing liver injury, in combination with precipitating factors** eg infection, GI bleeding, constipation
* eg Budd Chiari, ALD, NASH, HCC
138
Explain the pathogenesis of hepatic encephalopathy
1. **Ammonia** is absorbed in the gut and enters the **enterohepatic** circulation
2. Impaired liver function leads to **impaired ammonia clearance** + cirrhosis leads to **portosystemic shunting** → absorbed into blood
3. **Hyperammonaemia** causes brain dysfunction as NH3 crosses the BBB and acts as a **neurotoxin**
4. **NH3 converted to glutamine** in astrocytes causing swelling and oedema
139
Explain the pathogenesis of coagulopathy in ALF
Liver plays a central function in haemostasis
Impaired liver function leads to:
* **platelet dysfunction**
* reduced synthesis + increased consumption of **clotting factors**
* reduced clearance of **activated factors**
140
Summarise the epidemiology of liver failure
in UK, **66% paracetamol overdose**
**Worldwide, viral infection** accounts for majority of ALF - HEV + HBV
141
What are the presenting symptoms of ALF?
* **RUQ pain**
* **N+V**
* **jaundice**
* ****defining feature of ALF
* **malaise**
* signs of **hepatic encephalopathy** + cerebral oedema
* defining feature of ALF
* **hepatomegaly** but NO splenomegaly
* NO stigmata of chronic liver disease
* NO ascites
142
What *blood* investigations would you do for ALF?
* **Clotting screen-** increased PTT, INR\>1.5 =DEFINING FEATURE
* **LFTs**- hyperbilirubinaemia, elevated liver enzymes
* **U+Es**- metabolic derangements, high urea and creatine
* **FBC**- leukocytosis (if infection), anaemia, thrombocytopaenia
* **bloodgroup and save**- prepare for transplant
* **ABG-** metabolic acidosis (high lactate) in paracetamol overdose
_identify cause:_
* **toxicology**- if overdose suspected
* **viral serology**- HBcIgM
* **autoimmune markers**- ANA, ASMA
* **Caeruloplasmin** and urinary copper (Wilson's disease)
143
What non-bedside investigations would you do for ALF?
* **Liver US/CT**
* **Ascitic Tap**
* Send for MC&S
* If neutrophils \> 250/mm3 = spontaneous bacterial peritonitis
* **Doppler scan** of hepatic or portal veins - check for Budd-Chiari syndrome
* **EEG +/- CT head** - monitor encephalopathy
144
How is ALF managed?
* *Monitoring-*
* blood **glucose, electrolytes, cultures**
* coagulopathy **- **IV vitamin K, FFP, platelet infusions
* **neurological** status for encephalopathy
* manage = lactulose and phosphate enemas
* decrease ICP with mannitol
* *Treat cause-*
* **acetylcysteine**- paracetamol overdose
* autoimmune heptitis- **methylprednisolone**
* HBV- nucleoside/tide analogue- **TDF, entecavir**
* Budd Chiarri- **anticoagulation (LMWH) + TIPSS**
* **Liver transplant**
145
What are the criteria for a liver transplant?
* \>18yrs
* life expectancy \<7days w/o
* \<8 weeks between onset and encephalopathy
* ITU admission
* plus one of:
* ventilator dependence
* requirement of renal replacement therapy
* INR \>2.0.
146
Identify the possible complications of liver failure
* **rapidly progressing hepatic encephalopathy**
* high risk of cerebral oedema (up to 75%)
* **coagulopathy**
* ****risk of acute bleeding quite low
* **infection**
* primary cause of mortality
* bacterial infections in \>80% ALF cases
* **renal failure and haemodynamic changes**
* **metabolic disorders**
* acid base distrubances
* electrolyte imbalances
* **cerebral oedema**
* ****primary cause of mortality
* **gastrointestinal bleeding**
* ****due to coagulopathy and the requirement for mechanical ventilation
* give PPIs prophylactically
147
what is the prognosis of ALF?
Most important prognostic indicator in ALF is *aetiology*
**ALF 2/2 paracetamol overdose, acute HAV, or ischaemic live**r injury = favourable prognosis
**ALF 2/2 idiosyncratic drug-induced liver injury, acute HBV, Wilsons' or indeterminat**e = lower rate of spontaneous recovery
148
Define haemochromotosis
**Autosomal recessive** multisystem disorder of **dysregulated dietary iron absorption** and **increased iron release** from macrophages.
Leads to **accumulation in multiple organs-** liver, heart, ant. pituitary, joints etc
→ **damage + fibrosis**
149
Explain the aetiology of haemochromotosis
* **Hereditary- HFE gene** = \>90% cases
* Autosomal recessive disorder in white populations
150
What is the epidemiology of haemochromotosis?
**Rare**
**Presents in middle age**- symptoms occur when there has been significant iron accumulation
Presents **later in women**- menstruation is protective
151
What are the symptoms of haemochromotosis?
Early symptoms:
* **malaise**
* **atrophy**
* **ED**
* **heart problems**
Late symptoms:
* **bronzed skin**
* **amenorrhoea**
* **hypogonadism, impotence**
* **cirrhosis**
* **neurological/psychiatric problems**
152
Identify appropriate investigations to diagnose haemochromatosis
Haematinics:
* **serum transferrin saturation- high**. First test to become abnormal
* **serum ferritin- high**
* acute phase protein- raised in inflammation, alcoholism, viral hepatitis, NAFLD
* checks *magnitude* of iron overload
**genetic testing:**
* HFE mutation analysis
* confirm diagnosis
153
Identify appropriate investigations in haemochromatosis to assess degree of iron deposition?
* **Liver MRI-** non-invasive way to estimate liver iron content
* **Liver biopsy-** most sensitive and specific test for measuring liver iron content and evaluate liver injury (fibrosis, cirrhosis)
* **Fasting blood sugar-** to assess damage to the pancreas from iron overload
* **ECG and echocardiogram**: check for cardiomyopathy and conduction abnormalities → arrhythmias
* **Sex hormones-** check for hypogonadism
154
Wilson's disease
An **autosomal recessive** disorder characterised by **reduced biliary excretion of copper** and accumulation of copper in the liver and brain, especially in the **basal ganglia.**
Also known as hepatolenticular degeneration.
155
What is the aetiology of Wilson's disease?
**Mutation in the ATP7B gene, which is part of the biliary excretion of copper by hepatocytes**
## Footnote
Interference with the transport of copper by ATPases into hepatocyte compartments
Therefore no incorporation into **caeruloplasmin or bile excretion**
Excess copper damages the hepatocyte mitochondria → necrosis and copper release into plasma
156
Summarise the epidemiology of Wilson's disease
* **Liver** disease may present in children
* **Neurologica**l disease usually presents in young adults
* The disease does not favour a particular sex and all ethnic groups are affected equally.
157
Recognise the presenting symptoms of Wilson's disease
May present with **hepatitis, liver failure, cirrhosis** (and associated symptoms- jaundice, ascites, oedema)
* **Kayser-Fleischer Rings** – visible to naked eye in late stages, early stages seen by slit lamp
* **behavioural abnormalities**
* ****delusions, loss of emotional control, memory loss, depression
* **dysarthria, dystonia**
* ****speech may be slow/slurred
* **incoordination, dysdiadochokinesis, tremor**
* sloppy or small handwriting
* ****can't alternate hands from prone to supine
* **abnormal extraocular movements**
* ****saccadic movements, esotropia, diplopia
158
Identify appropriate investigations for Wilson's disease
* **LFTs:** high AST, ALT, ALP
* **FBC**- thrombocytopaenia, low WCC
* **Low serum caeruloplasmin**
* acute phase protein- may give false-negatives in inflammation/chronic liver disease/pregnancy
* **Serum copper**
* **24 hour urinary copper** - high
* **Slit-lamp exam**- KF rings
* **Liver biopsy** - increased copper content
* **Genetic analysis** - ATP7B mutations
* **MRI head** – degeneration in basal ganglia, fronto-temporal, cerebellar and brainstem
159
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