Liver Flashcards
1
Q
What percentage of liver tumors are metastasis?
- where is the metastases from
A
90%
- breast, bronchus, GI
2
Q
What is the most common type of liver cancer?
A
hepatocellular carcinoma
3
Q
What is the incidence of hepatocellular carcinoma and who does it most often affect?
A
- Incidence rising in Europe and USA
- Males> females
- average age = 66 years old
4
Q
What are the symptoms of hepatcellular carcinoma?
A
General: fatigue, loss of appetite, weight loss
RUQ pain - due to stretching of liver capsule
Ascites
Jaundice - usually in late cancer
Haemobilia - bleeding into biliary tree
5
Q
Causes of hepatcellular carcinoma
A
- HBV (leading cause worldwide)
- HCV, auto-immune hepatitis
- cirrhosis (alcohol, hemochromatosis, Primary biliary cholangitis)
- NAFLD
6
Q
Investigations in hepatcellular carcinoma
A
Serum markers
- AFP produced in 60%
- increased levels with increasing size, but can also arise in active Hep B & C infection
- if very high, consider acute hepatic necrosis
3 phase CT (delayed wash out of contrast in tumour)
US
MRI
Biopsy
- advised in large tumors who do not have cirrhosis or Hep B –> confirm diagnosis & exclude metastatic tumour
- Avoid in those eligible for transplantation or surgical resection due to small risk of tumour seeding along needle tract
- reserved for inconclusive cases
7
Q
What is the screening for hepatcellular carcinoma in high risk patients?
A
Screen by US and AFP
High risk: cirrhosis, Hepatitis B/C, haemachromatosis, alcohol, NASH
8
Q
Treatment for hepatcellular carcinoma?
A
Resecting solitary tumours <3cm across
- 50% have recurrence by 3 years
Liver transplant
- Single tumours <5cm or ≤3 nodules ≤3cm (Milan criteria), unsuitable for resection
- 5 year survival of 70%
Percutanous ethanol injection into tumour under US guidance
- 80% cure rate for tumours <3cm
- Recurrence rate similar to resection
Trans-arterial chemo-embolisation
- Hepatocellular carcinoma – not radiosensitive
- Response rate to chemo = 30%
- Hepatic artery embolization with absorbable gelatin powder and doxorubicin
Chemotherapy = sorafenib
- Multikinase inhibitor, active against Raf, VEGF, PDGF signalling
Palliative
- Transarterial chemoembolisation (TACE) – cytotoxic and ischaemic; delays progression; often repeated
- Sorafenib and other molecular therapies (Childs A, advanced/ progressing); Clinical trials
9
Q
Pathology behind cirrhosis
A
Liver injury -> Kupffer cells and hepatocytes produce cytokines -> activates stellate cells in space of Disse
Stellate cells transform into mho-fibroblast like cells -> produce collagen, pro-inflammatory cytokine mediate -> promote hepatocyte damage and fibrosis
10
Q
Aetiology of cirrhosis
A
Drugs and toxins; Alcohol, methotrexate
Infective; Hepatitis viruses, schistosomiasis
Biliary; primary (PBC) or secondary biliary cirrhosis, primary sclerosing cholangitis (PSC)
Autoimmune Hepatitis
Metabolic; non-alcoholic steatohepatitis (NASH), Haemochromatosis, Wilsons disease, Alpha-1- antitrypsin deficiency
Vascular; Budd-Chiari syndrome, veno-occlusive disease
Cryptogenic
MAJOR
A -> alcohol/ NAFLD
B -> Hep B
C -> Hep C
MINOR
A -> autoimmune hepatitis
B -> biliary causes, cystic fibrosis
C -> chronic venous obstruction / Copper (Williams disease), Cryptogenic
11
Q
What is the hepatic venous pressure gradient used for?
A
Prediction of clinical deterioration in cirrhosis
12
Q
What is the presentation of cirrhosis?
A
Variable
Some may be asymptomatic with abnormal liver functions.
May have systemic cutaneous signs:
- weakness
- fatigue
- muscle cramps
- weight loss
- anorexia
- nausea
- vomiting
- upper abdominal discomfort
Liver failure - jaundice, encephalopathy, ascites, bacterial peritonitis
Portal hypertension; bleeding varices
Hepatocellular carcinoma
13
Q
FBC results in cirrhosis?
A
May have anaemia (macrocytic), thrombocytopenia
Prolonged prothrombin time
14
Q
UandE results in cirrhosis?
A
HypoNa
Low Urea
Rising creatinine
15
Q
Signs of cirrhosis
3 general 5 face 6 hands 2 legs 3 trunk 5 abdomen
A
General
- Weight loss → advanced – not early
- Jaundice
- Unkempt → May be due to alcohol or encephalopathy
Face
- Xanthelasma → Yellow plaques on upper eyelids - cholesterol deposits
- Paper dollar skin
- Rhinophyma
- Seborrheic dermatitis
- Parotid swelling → Stones in parotid ducts → swell
Hands
- Clubbing
5 stages
1. Increased fluctuation of nail bed
2. Loss of angle
3. Increase in curvature of long axis of nail
4. Drumsticking
5. HPOA – hypertrophic pulmonary osteoarthropathy
- Polished nails → Appear shiny
- Leukonychia → Seen in any cause of low albumin
- Dpuytrens contracture
- Palmar erythema → Mainly alcoholic cirrhosis
- Tremor - Flapping tremor – asterixis → dorsiflex hands and flap every few secs
Legs - Bruising, ankle oedema
Trunk
- Reduced body hair
- Gynaecomastia (Common due to abnormal testosterone metabolism, higher oestrogen) / Often on spirolactone
- Spider naevi
Common in alcoholic cirrhosis / Press down, take finger off → fill in
Can have 3 – always occur in upper part of body
>3 → cirrhosis or pregnant
Abdomen
- Hepatomegaly; Splenomegaly
- Ascites
Sign of liver failure → NEED liver transplant
Fluid pushes belly button out
Leakage of fluid out of portal system, made worse due to low albumin
Once have ascites – 50% chance of death in next year
- Dilated veins
- Testicular atrophy
- Umbilical hernia
16
Q
Four complications due to portal hypertension
A
Encephalopathy
Acites
Varicoceal bleeding
Liver cancer
17
Q
What is portal hypertension?
A
Scarred liver - increased intra-hepatic vascular resistance
- Venous pressure is insufficient to push through liver
Increased portal inflow as liver increases blood supply to portal system by increasing supply to intestines
18
Q
Varices
- Presentation
- History, RF
- Examination
A
Presentation: Hypotension, haematemesis, malaena
History: RF for chronic liver disease, recent NSAIDs, abdominal sepsis/ surgery, pancreatitis/umbilical vein sepsis
Examination: stigmata of chronic liver disease, cardiovascular compromise, hepato-splenomegaly/ascites, hepatic bruits
Bleeding oesophageal varices → Usually vomit lots and lots of blood
19
Q
Treatment for variceal
A
Self-expandable (Danis) stent
- Removable
- Haemostasis through direct compression of varices
TIPSS (transjugular intrahepatic portosystemic stent shunt)
- Uncontrolled/recurrent variceal bleeding, gastric variceas, refractory ascites
- Stent placed between portal vein and hepatic vein within liver to provide a portosystemic shunt and therefore reduce portal pressure
- Carried out under radiological control via internal jugular vein
- Coagulation deficiencies must be corrected & antibiotic prophylaxis is given
Primary prophylaxis (prevention of initial bleed) - Grade 2/3 varices or any with red signs
Beta-blocker
- Reduce portal venous pressure
- Propranolol 80-160mg/day
- Nadolol 40-240mg/day
- Non-selective beta blocker – cardalol/ carvedilol
Variceal band ligation
Secondary prophylaxis – band ligation and propranolol
20
Q
Encephalopathy
A
Spectrum of neuropsychiatric abnormalities in patients with acute or chronic liver dysfunction
- May be subtle / may need ventilation
- Accumulation of gut-derived neurotoxic substances (Biochemical toxin)
E.g. ammonia, glutamin/glutamate ratio
- Astrocyte damage, impaired neurotransmitter function
Test: name 20 animals – patient will get stuck after about 3
Diagnosis
- Blood ammonia, EEG, critical flicker frequency
DD: intracranial lesions, infection, alcohol withdrawal
Exclude non-hepatic causes of altered mental function (alcohol, hypogly)
Treatment
- Identify and treat precipitating factors - Lactulose SE and non compliance, UGI bleed, constipation, sepsis, diuretics, TIPSS
- Maintain energy, fluid, and electrolyte balance
- Fall precautions
- Avoid CNS depressants; ICP monitoring
- Consider prophylactic intubation for grade 3 or 4 HE (aspiration) & transfer to ITU
Specific treatment:
- Lactulose 1st line
- Oral, NG, enema (aim for 2-4 BO/24h)
Cathartic (reduces colonic bacterial load), acidifies gut lumen and inhibits ammoniagenic bacteria
- PEG lavage solutions via NG in severe HE
- Low protein diet not recommended
- Rifaximin 400mg tds PO (gut sterilisation) is 2nd line
- Secondary prophylaxis – prevents recurrence, ↑ QoL
- Primary prophylaxis?
- Assess for transplant
21
Q
Signs of encephalopathy
A
Tremor
Apraxia
- asked to do something but is unable to do it
- issue with motor planning to perform task
Incoordination
Asterixis
- “flapping temor”
- Dorsiflex hands - flap every few seconds
Ataxia
- lack of coordination of muscle movements
Dysarthria
- difficulty speaking
Decerebration
22
Q
Ascites
- What % cirrhotics have it?
- Pathophysiology?
- Diagnosis
- Treatment
A
10% of cirrhotics - 50-70% develop within 10 years
Decreased QoL and survival - 2 yr mortality 50%
Complex pathophysiology
- Na/water retention, portal hypertension, splanchnic vasodilatation
Diagnostic tap (albumin, WCC, micro, cyto) - High serum ascites albumin gradient >11 mmol/l = 96% predictive for ascites
Diagnosis: US; Paracentesis obtain fluid for analysis
Treatment
- Restrict Na & diuretics
- No added salt diet (90mmol/l)
- Combination – aldosterone antagonist + loop diuretic
Spironolactone (slow-acting aldosterone antagonist) & furosemide (100:40) ratio
Adjust dose every 3-5 days
Max. spironolactone 400mg / furosemide 160mg
No more than 0.5kg/day weight loss
SE spironolactone: painful gynaecomastia, hyperkalaemia
SLOW
Large volume paracentesis (LVP)
- Good for reccurent ascites
- > 5L; Fast; High rate of recurrence
- Requires albumin infusion to prevent post paracentesis circulatory dysfunction (renal failure)
- 100ml of 20% albumin/ 3L ascites drained
23
Q
What should you always consider in ascites?
A
Portal vein thrombosis
Hepatocellular carcinoma
24
Q
SE spironolactone
A
painful gynaecomastia, hyperkalaemia
25
What is the blood supply to the liver?
Hepatic portal vein
| Hepatic artery
26
Function of the liver
Carbohydrate, protein, lipid metabolism
Bile acid synthesis - Needed for fat digestion and removal of cholesterol
Detoxification mechanisms: Hormones, drugs, toxins
LFTs
- Bilirubin metabolism; Enzyme induction & release
- Albumin & clotting factor production
Protein synthesis
- Albumin - HL: 20 days
- Clotting factors
10, 9, 7, 2 (post-translationally modified by Vit K dependent enzymes) , PT, Fibrinogen
- Prothrombin time = 60 hours HL
- Transport proteins: VLDL, thyroid binding globulin, transferrin
27
Bilirubin metabolism pathway
Excreted in bile and urine
Unconjugated bilirubin produced from catabolism of haem
- Lipid soluble, albumin bound, does not pass into urine
Unconjugated converted in liver by UDP-glucuronyl transferase (glucuronic acid added) → conjugated form
- Water soluble, not bound to albumin
Conjugated bilirubin secreted in bile and passes into gut
Some taken up by liver (via enterohepatic circulation), rest converted to urobilinogen by gut bacteria
Urobilinogen reabsorbed and excreted by kidneys or converted to stercobilin (makes poo brown)
Normal findings:
- plasma - unconjugated bilirubin (small amounts)
- urine - bilirubin absent (albumin bound)
28
Causes of Unconjugated hyperbilirubinaemia
Pre-hepatic jaundice
(1) Overproduction: haemolysis, ineffective erythropoeiesis
(2) Impaired hepatic uptake: drugs (paracetamol, rifampicin), ischaemic hepatitis
(3) Impaired conjugation: eponymous syndromes - Gilberts
(4) Physiological neonatal jaundice
Findings
- Plasma - unconjugated hyperbilirubinaemia (not filtered at kidney)
- Urine - bilirubin absent
29
Causes of Conjugated hyperbilirubinaemia
(1) Hepatocellular dysfunction: hepatocyte damage, usually with some cholestasis
- Causes: viruses, drugs, alcohol, cirrhosis, liver mets/abscesses, haemachromatosis, autoimmune hepatitis,
(2) Impaired hepatic excretion (cholestasis)
- Primary biliary cholangitis, primary sclerosing cholangitis, drugs, CBD gallstones, pancreatic cancer
- > no bilirubin = pale stools
Findings
- plasma - mainly conjugated hyperbilirubinaemia
- urine - bilirubin present in urine (strong +ve)
30
Kupffer cells
clearance of microorganisms, cell debris and aged erythrocytes from the blood (product = bile)
- Resident macrophages
Present in sinusoidal lumen near gaps between endothelial cells
31
Stellate cells
storage and transport of retinoids (Vitamin A compounds)
activated turn into myo-fibroblast like cells -> produce collage and may lead to fibrosis and cirrhosis
32
Liver blood supply
2 blood supplies: hepatic portal vein 80% (blood from spleen and GI tract) ; hepatic artery 20%
33
What lobe is gallbladder found on?
Quadrate lobe
THINK - GQ magazine
34
Function of liver
Carbohydrate, protein, lipid metabolism
Bile acid synthesis - Needed for fat digestion and removal of cholesterol
Detoxification mechanisms: Hormones, drugs, toxins
Protein synthesis
- Albumin - HL: 20 days
- Clotting factors
- 10, 9, 7, 2 (post-translationally modified by Vit K dependent enzymes) , PT, Fibrinogen
Prothrombin time = 60 hours HL
Transport proteins: VLDL, thyroid binding globulin, transferrin
35
LFTs - aminotransferases
Aminotransferases = ALT & AST
Cytoplasmic – released in hepatocellular damage/lyse
ALT more liver specific than aspartate transaminases (AST) – in muscle too
ALT (alanine transaminases)
- Half-life hours-days
36
LFTs - ALP
ALP (alkaline phosphatase)
In liver – only 1 of 4 isoenzymes (i.e not specific also produced in gut, bone, placenta) – CHECK GGT
Biliary system – new enzyme production; also found in bone
Reflects bile obstruction
NOT induced by drugs/alcohol
37
LFTs - GGT
Gamma Glutamyltransferase (GGT)
Not just in liver – not specific
Liver and biliary system
- Increases by induction not damage: Alcohol, obesity, drugs (phenytoin, carbamezapine), cholestasis
38
LFTs - bilirubin
Bilirubin
- Reflects function of liver
- NOT sensitive indicator of hepatic dysfunction
- Normally balance between production & hepatic removal
Increased due to overproduction (increased RBC breakdown) OR impaired uptake, conjugation or excretion
39
Albumin
Normal: 35-50 g/L
Important for osmotic effect
Carries non-water soluble substances including unconjugated bilirubin
Increased in dehydration
Decreased due to dilution or reduced synthetic liver function
Often normal in cirrhosis until liver failing
40
Prothrombin time
Good marker of synthetic function of liver; Indicates severity of hepatitis
Rarely very abnormal in cirrhosis
Rarely >25 seconds – if is consider acute liver failure
41
Three main causes of jaundice
Pre-hepatic
- Increased bilirubin production (e.g. haemolytic disease – sickle cell anaemia, internal haemorrhage)
- Congenital hyperbilirubinaemia
Hepatocellular
- Hepatocyte damage (toxins, viruses)
- Inability to transport bilirubin into bile
Cholestatic
- Obstruction of bile flow
Intra-hepatic – block canaliculus (cirrhosis, tumour, drugs)
Post-hepatic – block in bile duct (e.g. gall stones)
- Failure of hepatocytes to initiate bile flow
42
Causes of jaundice in previously stable patients with cirrhosis
Sepsis (UTI, pneumonia, peritonitis)
Malignancy – hepatocellular carcinoma
Alcohol, drugs
GI bleeding
43
Jaundice - drugs that cause haemolysis
antimalarials - dapsone
44
Jaundice - drugs that cause hepatitis
```
Paracetamol overdose
Isoniazid, rifampicin, pyrazinamide (RIPE = TB treatment)
Monoamine oxidase inhibitors
Sodium valproate
Halothane
Statins
```
45
Jaundice - drugs that cause cholestasis
Flucloxacillin (may be weeks after treatment)
Fusidic acid, co-amoxiclav, nitrofurantoin
Steroids (anabolic, the Pill)
Sulfonylureas
Prochlorperazine
Chlorpromazine
46
Viral hepatitis
Non-specific prodromal illness (headache, myalgia, arthralgia, nausea, anorexia) usually precedes jaundice by few days → 2 weeks
Vomiting, diarrhoea and abdominal discomfort may follow
47
Paracetamol overdose
Paracetamol broken down by cytochrome p450 system into NAPQI (toxic metabolite - binds cell constituents & destroys mitochondrial function → hepatotoxicity & nephrotoxicity)
Glutathione required to convert NAPQI to non-toxic compound
If too much taken glutathione stores run out and NAPQI builds up
- Cells become necrotic and lyse
Fasting (anorexic), heavy drinking - reduce glutathione store
Binge drinking = protective (Ethanol competes at CYP2E1)
Treatment: N-acetylcysteine
48
Alcohol liver disease - pathology
80% metabolised by alcohol dehydrogenase to acetaldehyde
- Acetaldehyde forms adducts with cellular proteins in hepatocytes → activates immune system → cell injury
- Acetylaldehyde → (by aldehyde dehydrogenase) →acetyl-CoA & acetate
- Creates NADH – changes redox potential of cell
20% metabolised by microsomal ethanol-oxidising system (MEOS)
- Cytochrome CYP2E1 oxidises ethanol to acetate - releases oxygen free radicals → lipid peroxidation and mitochondrial damage
49
ALD - investigations
History most important
Blood alcohol levels
FBC
- Macrocytosis (>110 in absence of folate deficiency, anaemia or other cause highly suspicious)
- Thrombocytopaenia
Gamma glutyl transferase (GGT)
- 60g/day
- Prolonged intake; 1-2 months to fall once stop
- Usually 4x but may be up to 20x
- Many other causes
AST
- Transaminase, less specific than ALT for liver injury
- Ratio AST/ALT >2 suggests ALD
50
ALD - 4 major syndromes
Alcoholic steatosis
Alcoholic hepatitis
Cirrhosis
Alcoholic cholestasis
May coexist
51
Alcoholic steatosis
Often symptomless
Tender hepatomegaly
Occasionally massive and associated with features of liver failure and/or portal hypertension
GGTP and MCV increased, mild increases of ALT and ALP
Prognosis:
- Increased risk of cirrhosis (2-5x) over 10 years
- 2x mortality rate v normal population
52
Alcoholic hepatitis
Presentation: Jaundice, malnutrition, hepatomegaly, features of portal hypertension (ascites, encephalopathy)
- Anorexia, vomiting, RUQ pain, bruising, alcohol withdrawal
1/3 die in acute episode
High bilirubin; But normal AST/ALT
Malnutrition, jaundice, ascites & encephalopathy, prolonged prothrombin time = poor prognosis
BEWARE not biochemical hepatitis
Treatment
- Nutritional support
- Corticosteroids (1 month)
- Pentoxifylline
53
Alcoholic cholestasis
Rare - Usually associated with hepatitis
Requires imaging; Liver biopsy may be necessary
Exclude pancreatitis or gall stones
54
Alcoholic liver cirrhosis
Stigmata of chronic liver disease: ascites, varices, encephalopathy
Liver may be large, normal or small
Risk of hepatocellular carcinoma
Treatment:
- Treat abuse - Self-help groups; Counselling; Pharmacological agents
- Nutritional support
- Treat complications
- Consider transplantations in selected patients
Prognosis
- Abstinence may lead to significant improvement
- Associated with degree of liver failure
- CHECK for varices
- Prophylaxis of ascites infection (cotrimoxazole)
- Screen for HCC (USS and AFP)
55
NAFLD
- what is it?
- pathophysiology?
Spectrum of liver disease – simple fatty infiltration of hepatocytes (steatosis), fatty infiltration with inflammation (NASH = non-alcoholic steatohepatitis) & cirrhosis in absence of excessive alcohol consumption
Normal liver -> steatosis -> steatohepatitis -> fibrosis/cirrhosis
Outcomes: hepatocellular carcinoma (7%)/ liver related death (20%)/ liver transplants (50%)
Associated with dyslipidaemia, insulin resistance, T2DM, obesity → metabolic syndrome
```
Pathophysiology
- Obesity & insulin resistance → increased free fatty acid reflux
- Two hit hypothesis
1st hit = steatosis
2nd hit = progresses to NASH
```
Hepatocellular injury
- Oxidative stress due to free radicals produced during fatty acid oxidation
- Direct lipotoxicity from fatty acids and other metabolites
- Endoplasmic reticulum stress
- Cytokine release (TNF-alpha) and immune-mediated
Cell death & inflammation → stellate cell activation → fibrosis
Genetics – may determine disease progression – PNPLA3
56
NAFLD
- presentation
- diagnosis
- treatment
Presentations
- Often asymptomatic – may have fatigue, RUQ discomfort
- 40-50 years old
Diagnosis:
- Exclude excess alcohol, other liver disease and confirm NAFLD
- Mild increase ALT ; increased GGT; increased Alk P (moderately increased in 1/3)
- increased ferritin (50%); increased transferrin
- increased fasting glucose, triglycerides and increased HDL with insulin resistance
- increased PT and low albumin
Normal results do not rule out NAFLD
Imaging
Ultrasound – most often used
- Assessment of hepatic fat content – appears bright
CT/ MRI – better sensitivity
Biopsy = Gold standard for diagnosis, assess inflammation and fibrosis
Treatments
Only thing that will work = lose weight
- At least 10%
- Medications associated with weight loss – exendin-4, orlistat, Rimonabant -> reduce levels of free fatty acids
Screening + treatment of associated conditions + complications
- High BP, diabetes, cholesterol
- Dyslipidaemia - statins, hypertension
- Insulin sensitizer – metformin reduced hepatic glucose production & increased insulin sensitivity
Liver transplant if have severe cirrhosis
Amiodarone – damages liver – causes steatohepatitis
- Not distinguishable from that seen in people with sick liver from alcohol or obesity
57
NASH - RF
>45 years old
obesity (BMI>31)
Diabetes
58
Acute cholangitis
Caused by bacterial infection of bile ducts
Occurs in patients with other biliary problems
Jaundice, fever, RUQ pain (Charcot’s triad)
Treatment: antibiotics, relief of biliary obstruction, removal of underlying cause
59
Primary sclerosing cholangitis
Progressive cholangitis with bile duct inflammation and strictures
- Diffuse inflammation and fibrosis
- Can involve entire biliary tree and leads to gradual obliteration of intra & extra-hepatic bile ducts
- Eventually may lead to biliary cirrhosis, portal hypertension, hepatic failure
60
Primary sclerosing cholangitis
- presentation
- symptoms
Presentation
- Usually male
- Incidental findings - Raised ALP – may have UC
Symptoms
- Pain, fever, jaundice
- Pruritis +/- fatigue
- Advanced – ascending cholangitis, cirrhosis, liver failure
61
Primary sclerosing cholangitis
- diagnosis
- treatment
Cholestatic LFTs - high ALP, then high bilirubin
Elevated IgM
+ve ANCA, SMA or ANA (IMPORTANT -ve AMA)
Management
- no cure
- UDCA - may reduce risk of colon carcinoma
Treatment:
- URSO
- acute attacks of cholangitis = broad spectrum antibiotics
(ciproflaxacin)
- Liver transplant = end stage disease (important to asses IBD as prognosis worse post transplant - 5-10% develop colorectal cancer)
Prognosis:
- 75% symptomatic survive 15 years or more
- most die from liver failure
62
What is cholangitis?
inflammation of bile duct
63
Primary biliary cholangitis
- what is it?
- causes and RFs?
Interlobular bile ducts are damaged by chronic autoimmune granulomatous inflammation causing cholestasis
- May lead to fibrosis, cirrhosis, portal hypertension
Cause:
- Unknown environmental triggers? (pollutants, xenobiotics, non-pathogenic bacteria)
- Genetic predisposition – IL12A locus – loss of immune tolerance to self-mitochondrial proteins
RF: FH, many UTIs, smoking, past pregnancy, other autoimmune diseases, use of nail polish/hair dye
64
Primary biliary cholangitis
- presentation
- signs
- complications
Presentation
- >30 years old; Usually female
- Often asymptomatic, diagnosed after incidental finding increased ALP
- Itch, fatigue may precede jaundice for many years
- Pruritis may be due to upregulation of opioid receptors & increased endogenous opioids
- Fatigue – exclude hypothyroidism; depression; coeliac disease (increased incidence in PBC)
Signs
- Jaundice
- Skin pigmentation
- Xanthelasma
- Xanthomata
- Hepatosplenomegaly
Complications
- Cirrhosis complications
- Osteoporosis common
- Malabsorption of fat-soluble soluble vitamins (A, D, E, K) - cholestasis
65
Primary biliary cholangitis
- diagnosis
- treatment
Diagnosis
- Cholestatic LFTs: increased ALP and GGT; mildly increased AST and ALT
- Late disease - increased bilirubin, low albumin, increased Prothrombin time
- Elevated IgM
+ve AMA (antimitochondrial antibodies)
- Granulomatous inflammation of portal tracts → progressive damage → eventual loss of small and middle-sized bile ducts
May do US to exclude extrahepatic cholestasis
- Would show no signs of biliary obstruction
Treatment
- Pruritis – 1st line = colestyramine = Binds potentials pruritogens in gut & excreted
SE: may bind other drugs (esp. UDCA) in gut so space drugs out
If fail try: naltrexone or rifampicin
Fat-soluble vitamin prophylaxis (Vit A, D K)
Consider high-dose ursodeoxycholic acid (UDCA/URSO)
- Hydrophilic bile acid – replaces bile acids, reduces apoptosis of biliary epithelium
SE: weight gain
If fail to respond – consider obeticholic acid
- Agonist for nuclear farnesoid X receptor
- Reduced hepatic synthesis of bile acid
66
Autoimmune hepatitis
- what is it?
- symptoms?
- diagnosis?
- treatment?
Up to 40% present with acute hepatitis and signs of auto-immune disease (fever, malaise, urticarial rash, polyarthritis, pleurisy, pulmonary infiltration
Two types
1 – 80%; female, <40 years old; ASMA +ve in 80%; ANA+ve 10%; increased IgG in 97%; Good response to immunosuppression in 80%
2 – commoner in Europe than USA; more often in children; commonly progresses to cirrhosis; less treatable; Typically anti-liver/kidney microsomal type 1 (LKM1) antibodies +ve.
Symptoms
- May have signs of jaundice, pain, fatigue
- 60% asymptomatic; diagnosis = incidental finding of chronic liver disease
- Young or middle aged women: 10-30 years or >40years
- Amenorrhoea common; disease tends to attenuate with pregnancy
Diagnosis
- Depends on excluding other diseases: IgG levels, autoantibodies, histology in absence of viral disease
- Hepatic LFTs: raised bilirubin, AST, ALT, ALP
- Raised IgG; +ve ASMA, ANF
- Signs of hypersplenism – anaemia, low WCC and platelets
- Liver biopsy – mononuclear infiltrate of portal and periportal areas and piecemeal necrosis+/- fibrosis
Treatments
- Prednisolone 30mg/d PO for 1 month, down by 5mg/month to maintenance dose of 5-10mg/d
May be stopped after 2 years but relapse rates high
- Azathioprine may be used as steroid-sparing agent
- Remission achievable in 80% within 3 years
- May need liver transplant
67
Haemochromatosis
Inherited disorder of iron metabolism - increased intestinal iron absorption leads to iron deposition in joints, liver, heart, pituitary, adrenals and skin
Middle aged men
Genes
- Commonest genetic disorder in celtic population
- HFE gene commonly affected
Symptoms
- Early – none, fatigue, arthralgia
- Later – slate-grey skin, signs of chronic liver disease, hepatomegaly, cirrhosis, dilated cardiomyopathy
- Endocrinopathies – DM, hypogonadism
Diagnosis
- Increased LFT, Ferritin
- Transferrin saturation should trigger suspicion
Confirm by HFE genotyping; can also do MRI scanning and biopsy
```
Management
- Venesection (blood is taken)
May take up to 2 years
Iron will continue to accumulate so need to continue for life
To avoid development of liver cirrhosis
```
Diet: no need to avoid iron rich food. Avoid alcohol, uncooked seafood –may contain bacteria that thrive on increased plasma iron – listeria monocytogenes, Vibro vulnificus
Screen 1st degree relatives
68
What food to avoid in hemochromatosis?
No need to avoid iron rich food.
Avoid alcohol, uncooked seafood –may contain bacteria that thrive on increased plasma iron – listeria monocytogenes, Vibro vulnificus
69
Alpha-1-antitrypsin deficiency
Inherited disorder affecting lung (emphysema), liver (cirrhosis and HCC)
A1AT = glycoprotein; family of serine protease inihibitors made in liver that control inflammatory cascades Deficiency = serpinopathy
Common cause of liver disease in children / adults = lung disease
Symptoms: PiZZ genotype
- Dyspnoea from emphysema, cirrhosis, cholestatic jaundice
Cholestasis often remits in adolescence
Tests:
- Serum A1AT low
Part of acute-phase response; inflammation may hide low level
- Liver biopsy
- Lung function – slow reduction in FEV1 with obstructive pattern
- Phenotyping
Treatment – currently no treatment
- Stop smoking
- Prompt treatment/ preventative vaccination for lung infections
- Liver transplantation – if decompensated cirrhosis
70
Budd-Chiari syndrome
Thrombosis of hepatic veins
Acute liver failure - Ascites/ exudate
Cirrhosis if chronic
Imaging; Thrombosis screening; JAK2 mutation
Rx anticoag, TIPSS Shunting
71
Wilson's disease
- what is it?
- symptoms (child, young adults, general)
- diagnosis
- treatment
Very rare – 3/100,000
Impaired copper excretion; Excess deposition in liver & CNS (basal ganglia)
AR disorder of copper transporting ATPase, ATP7B
Total body copper – 125mg.
- Intake 3mg/day – absorbed in proximal small intestine
Liver – copper incorporated into Caeruloplasmin and excreted in bile
Signs
- Children – liver disease (hepatitis, cirrhosis, fulminant liver failure)
- Young adults – CNS signs (tremor, dysarthria, dysphagia, dyskinesia, dystonias, dementia, parkinsonism, ataxia/clumsiness
- Mood – depression/mania, labile emotions, libido change
- Cognition – reduced memory and IQ, slow to solve problems
- Kayser-Fleischer rings – copper in iris
- Haemolysis, blue lunulae (nails), arthritis, hypermobile joints, grey skin
Diagnosis
1. Urine: 24hr copper excretion high
2. Increased LFT: non specific but ALT>1500 not part of picture
3. Serum copper: typically <11umol/l
4. Low serum caeruloplasmin: <200mg/l – may have low incidental finding in protein deficiency states – nephrotic syndrome, malabsorption)
5. Molecular genetic testing can confirm diagnosis
6. Slit lamp exam: KF rings
7. Liver biopsy: increased hepatic copper, hepatitis, cirrhosis
8. MRI: degeneration of basal ganglia, fronto-temporal cerebellar and brainstem
Treatable – screen all with cirrhosis
- Avoid foods with high copper content (chocolate, liver, nuts, mushrooms, legumes, shellfish)
- Check water sources
- Lifelong penicillamine
SE: nausea, rash, low WCC, low Hb & platelets, haematuria, nephrosis, lupus
- if do not tolerate peniciliiamine - try tridentine
- ZN
Screen siblings: asymptomatic still need treatment
Urinary Cu following penicillamine
Gene testing?
72
Wilson's disease
| - symptoms (child, young adults, general)
Very rare – 3/100,000
- Impaired copper excretion; Excess deposition in liver & CNS (basal ganglia)
- AR disorder of copper transporting ATPase, ATP7B
- Total body copper – 125mg.
- Intake 3mg/day – absorbed in proximal small intestine
- Liver – copper incorporated into Caeruloplasmin and excreted in bile
Signs
- Children – liver disease (hepatitis, cirrhosis, fulminant liver failure)
- Young adults – CNS signs (tremor, dysarthria, dysphagia, dyskinesia, dystonias, dementia, parkinsonism, ataxia/clumsiness
- Mood – depression/mania, labile emotions, libido change
- Cognition – reduced memory and IQ, slow to solve problems
- Kayser-Fleischer rings – copper in iris
- Haemolysis, blue lunulae (nails), arthritis, hypermobile joints, grey skin
73
Wilson's disease
| - diagnosis
Diagnosis
1. Urine: 24hr copper excretion high
2. Increased LFT: non specific but ALT>1500 not part of picture
3. Serum copper: typically <11umol/l
4. Low serum caeruloplasmin: <200mg/l – may have low incidental finding in protein deficiency states – nephrotic syndrome, malabsorption)
5. Molecular genetic testing can confirm diagnosis
6. Slit lamp exam: KF rings
7. Liver biopsy: increased hepatic copper, hepatitis, cirrhosis
8. MRI: degeneration of basal ganglia, fronto-temporal cerebellar and brainstem
74
Wilson's disease
| - treatment
Treatable – screen all with cirrhosis
- Avoid foods with high copper content (chocolate, liver, nuts, mushrooms, legumes, shellfish)
- Check water sources
- Lifelong penicillamine
SE: nausea, rash, low WCC, low Hb & platelets, haematuria, nephrosis, lupus
- if do not tolerate peniciliiamine - try tridentine
- ZN
Screen siblings: asymptomatic still need treatment
Urinary Cu following penicillamine
Gene testing?
75
```
LFT results:
Haemolysis
Gilberts
Alcohol
Cirrhosis
Metastases
Hepatitis
```
Haemolysis - raised bilirubin
Gilberts - raised bilirubin
Alcohol - raised ALT; very raised GGT
Cirrhosis - raised ALT, Alk P, GGT; low albumin
Metastases - raised Alk P, GGT; low albumin
Hepatitis - raised bilirubin, Alk P, GGT; very raised ALT
76
Kernicterus
Premature babies may not be able to conjugate bilirubin until UDP glucuronyl transferases are expressed
May get severe unconjugated hyperbilirubinaemia
Very high bilirubin = toxic to brain of neonate
Treated with phototherapy → breaks down bilirubin → urinary excretion
77
Ciclosporin
inhibits production and release of lymphokines, therefore suppresses cell-mediated immune response
Given prior and as maintenance post transplant
78
Tacrolimus
Macrolide calcineurin inhibitor
Inhibits T-lymphocyte signal transduction and IL2 transcription
79
Signs of viral hepatitis
```
Loss of appetite
Jaundice
Nausea
Vomiting
Fever
Weakness
Abdominal pain
Joint pain
Dark urine
Clay-coloured stool
```
80
Hep A
```
Picornavirus - ss+ve RNA
incubation: 25-30 days
spread: faecal-oral, saliva, shell-fish
NO chronic
children; young adults
Treatment supportive
Vaccine
```
Acute disease and asymptomatic infection
- Highly infectious
Most infections: childhood; overcrowding and poor sanitation
Clinical features: Fever, malaise, anorexia, nausea, arthralgia THEN jaundice, hepatosplenomegaly, adenopathy
- ALT rises but falls in later weeks
Rare complications
- Fulminant hepatitis
- Cholestatic hepatitis
Pathophysiology
- HAV replicates in liver, excreted in bile and shed in stool
- Peak infectivity occurs during 2 week period before onset of jaundice/ elevation of liver enzymes
- Concentration of virus in stool declines after jaundice appears
- Investigations
- IgM anti-HAV generally present 5-10 days before onset of symptoms
- No longer detectable 6 months later
Acute infection: IgG anti-HAV appears early on in course of infection
- Remains detectable for lifetime
- Indicates immunity to HAV (previous HAV infection or vaccine)
HAV RNA in blood - Present at onset of symptoms
- As infection proceeds – HAV rises in stool
Treatment
- Supportive – avoid alcohol
- Rarely – interferon alpha for fulminant hepatitis
Vaccination
- Inactivated viral protein- IM
- Consider if have chronic hep B, C infections
- Travel to endemic areas
81
Hep B
```
Hepadnavirus, ds DNA
Enveloped
incubation: 60-90 days
Spread: blood, saliva, sex, vertical (most common and highest risk)
Chronic infection possible - associated with HCC
Babies, young adults
Insidious onset, pyrexia common
Vaccine
```
Treatment:
- Interferon alpha and/or antivirals (Tenofovir, entecavir)
Immune competent individual clear virus in >95% cases
Acute infection – often asymptomatic
No good evidence for use of antivirals
Clinical features like HepA, but arthralgia and urticaria more common
Investigations
Hep B surface antigen (HBsAg)
- Indicates active infection
- Found in acute and chronic (carrier state) infection
- Negative in acute liver failure as liver damage mediated by viral clearance. Evidence of recent infection – Hep B core IgM
Antibody to HBsAg – appears after 3-6 months, persists for many years/permanent
- Indicates previous infection (would also have anti-HBc) or previous vaccination (no anti-HBc)
Hep B core antigen (HBcAg)
- Not found in blood but antibody (anti-HBc) appears early
- Initially IgM, then IgG (persists for life)
Hep B e antigen (HBeAG)
- Indicates active HBV infection
- Indicator of viral replication → implies high infectivity
Serology
Acute
1st- IgM anti-HBc
2nd – Anti-HBs
Chronic
1st – IgM anti-HBc
Marker of disease: (1) HBeAg (2) HBV DNA (3) ALT
Management
Acute
- Supportive treatment
- Full recovery 90%, remaining = chronic hep B infection
- More likely to be chronic: vertical transmission; immunodeficient
Chronic
- Goals: HBeAg serconversion, reduction in HBV-DNA, normalisation of LFTs
- Treat if have high viral load and active hepatitis
Pharma treatment
- Direct-acting nucleoside/nucleotide antiviral agents
- Concern: selection of antiviral-resistant mutations
Lamivudine
- Long term treatment complicated by development of HBV-DNA polymerase mutants → viral resistance.
- Develops after 9 months
- Rarely used – Prophylaxis of “inactive carriers” with lamivudine before significant immunosuppression
(Rituximab for anti-HBc +ve, HBsAg –ve)
Cyclopentone
- Adefovir, Tenofovir, Entecavir
- Monotherapy more effective than lamivudine in reducing viral load
- Contraindicated in HIV+ve patients – may lead to HIV anti-viral drug resistance
Interferon-alpha
- Contraindicated: cirrhosis – precipitate liver failure
Vaccine
- Offered to those at risk : IVDU, men who have sex with men, close contact with infected (newborn of infected mothers, regular sexual partners), chronic liver disease or on chronic hemodialysis. Medical staff
Can also give immunoglobulin
- IM injection of HBIg
- Babies born to HepB infected mothers given immunoglobulin
- Check HepB serology at 12 months
82
Hep C
```
Flavivirus ss+ve RNA
enveloped
incubation 50 days
spread: blood, saliva
Chronic - 70-90%, associated with HCC
Adults
insidious onset, pyrexia common
```
Treatment: Interferon alpha + ribavirin and/or protease inhibitors (e.g. boceprevir, telaprevir and/or polymerase inhibitors - sofosbuvir)
Diagnosis
Anti-HCV antibodies – confirms exposure
- Indicates recent and/or past HCV infection
- Takes up to 3 months to develop
HCV antigen
- Reflect viraemia (active infection)
HCV-PCR = confirms ongoing infection/chronicity
- Detects viraemia
IL28B - Determines susceptibility to antiviral therapy
83
Hep D
```
incomplete virus; ss-ve RNA
enveloped
incubation: 6-9 weeks
Spread: blood, sex, vertical
Chronic infection
Prevented by Hep B vaccine
```
Co-infection with HBV
- Severe acute disease
- Low risk of chronicity
Super-infection on chronic HBV infection
- Chronic HDV infection
- High risk of severe chronic liver disease
May cause acute liver failure/cirrhosis
Diagnosis
- If HBsAg +ve – ask for anti-HDV antibody
Treatment
- Interferon alpha – little success
- Often require liver transplant
84
Hep E
Calicivirus, ss+ve RNA
incubation 40 days
spread: faecal-oral
NOT chronic
Most cases – acute self-limiting hepatitis
Case fatality – 1-3%, pregnant women more susceptible
Illness severity: increases with age
Serology: IgM anti-HEV; IgG anti-HEV
