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Liver Flashcards

1
Q

What percentage of liver tumors are metastasis?

- where is the metastases from

A

90%

- breast, bronchus, GI

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2
Q

What is the most common type of liver cancer?

A

hepatocellular carcinoma

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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
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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

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5
Q

Causes of hepatcellular carcinoma

A
  • HBV (leading cause worldwide)
  • HCV, auto-immune hepatitis
  • cirrhosis (alcohol, hemochromatosis, Primary biliary cholangitis)
  • NAFLD
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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
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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

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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
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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

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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

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11
Q

What is the hepatic venous pressure gradient used for?

A

Prediction of clinical deterioration in cirrhosis

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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

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13
Q

FBC results in cirrhosis?

A

May have anaemia (macrocytic), thrombocytopenia

Prolonged prothrombin time

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14
Q

UandE results in cirrhosis?

A

HypoNa
Low Urea
Rising creatinine

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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

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16
Q

Four complications due to portal hypertension

A

Encephalopathy

Acites

Varicoceal bleeding

Liver cancer

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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

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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

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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

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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

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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

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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
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23
Q

What should you always consider in ascites?

A

Portal vein thrombosis

Hepatocellular carcinoma

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24
Q

SE spironolactone

A

painful gynaecomastia, hyperkalaemia

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25
Q

What is the blood supply to the liver?

A

Hepatic portal vein

Hepatic artery

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26
Q

Function of the liver

A

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

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27
Q

Bilirubin metabolism pathway

A

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)
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28
Q

Causes of Unconjugated hyperbilirubinaemia

A

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
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29
Q

Causes of Conjugated hyperbilirubinaemia

A

(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)
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30
Q

Kupffer cells

A

clearance of microorganisms, cell debris and aged erythrocytes from the blood (product = bile)
- Resident macrophages

Present in sinusoidal lumen near gaps between endothelial cells

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31
Q

Stellate cells

A

storage and transport of retinoids (Vitamin A compounds)

activated turn into myo-fibroblast like cells -> produce collage and may lead to fibrosis and cirrhosis

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32
Q

Liver blood supply

A

2 blood supplies: hepatic portal vein 80% (blood from spleen and GI tract) ; hepatic artery 20%

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33
Q

What lobe is gallbladder found on?

A

Quadrate lobe

THINK - GQ magazine

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34
Q

Function of liver

A

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
Q

LFTs - aminotransferases

A

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
Q

LFTs - ALP

A

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
Q

LFTs - GGT

A

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
Q

LFTs - bilirubin

A

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
Q

Albumin

A

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
Q

Prothrombin time

A

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
Q

Three main causes of jaundice

A

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
Q

Causes of jaundice in previously stable patients with cirrhosis

A

Sepsis (UTI, pneumonia, peritonitis)

Malignancy – hepatocellular carcinoma

Alcohol, drugs

GI bleeding

43
Q

Jaundice - drugs that cause haemolysis

A

antimalarials - dapsone

44
Q

Jaundice - drugs that cause hepatitis

A 
Paracetamol overdose
Isoniazid, rifampicin, pyrazinamide (RIPE = TB treatment)
Monoamine oxidase inhibitors
Sodium valproate
Halothane
Statins
45
Q

Jaundice - drugs that cause cholestasis

A

Flucloxacillin (may be weeks after treatment)
Fusidic acid, co-amoxiclav, nitrofurantoin
Steroids (anabolic, the Pill)
Sulfonylureas
Prochlorperazine
Chlorpromazine

46
Q

Viral hepatitis

A

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
Q

Paracetamol overdose

A

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
Q

Alcohol liver disease - pathology

A

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
Q

ALD - investigations

A

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
Q

ALD - 4 major syndromes

A

Alcoholic steatosis
Alcoholic hepatitis
Cirrhosis
Alcoholic cholestasis

May coexist

51
Q

Alcoholic steatosis

A

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
Q

Alcoholic hepatitis

A

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
Q

Alcoholic cholestasis

A

Rare - Usually associated with hepatitis

Requires imaging; Liver biopsy may be necessary

Exclude pancreatitis or gall stones

54
Q

Alcoholic liver cirrhosis

A

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
Q

NAFLD

  • what is it?
  • pathophysiology?
A

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 &amp; 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
Q

NAFLD

  • presentation
  • diagnosis
  • treatment
A

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
Q

NASH - RF

A

> 45 years old
obesity (BMI>31)
Diabetes

58
Q

Acute cholangitis

A

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
Q

Primary sclerosing cholangitis

A

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
Q

Primary sclerosing cholangitis

  • presentation
  • symptoms
A

Presentation

  • Usually male
  • Incidental findings - Raised ALP – may have UC

Symptoms

  • Pain, fever, jaundice
  • Pruritis +/- fatigue
  • Advanced – ascending cholangitis, cirrhosis, liver failure
61
Q

Primary sclerosing cholangitis

  • diagnosis
  • treatment
A

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
Q

What is cholangitis?

A

inflammation of bile duct

63
Q

Primary biliary cholangitis

  • what is it?
  • causes and RFs?
A

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
Q

Primary biliary cholangitis

  • presentation
  • signs
  • complications
A

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
Q

Primary biliary cholangitis

  • diagnosis
  • treatment
A

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
Q

Autoimmune hepatitis

  • what is it?
  • symptoms?
  • diagnosis?
  • treatment?
A

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
Q

Haemochromatosis

A

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
Q

What food to avoid in hemochromatosis?

A

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
Q

Alpha-1-antitrypsin deficiency

A

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
Q

Budd-Chiari syndrome

A

Thrombosis of hepatic veins

Acute liver failure - Ascites/ exudate

Cirrhosis if chronic

Imaging; Thrombosis screening; JAK2 mutation

Rx anticoag, TIPSS Shunting

71
Q

Wilson’s disease

  • what is it?
  • symptoms (child, young adults, general)
  • diagnosis
  • treatment
A

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
Q

Wilson’s disease

- symptoms (child, young adults, general)

A

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
Q

Wilson’s disease

- diagnosis

A

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
Q

Wilson’s disease

- treatment

A

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
Q 
LFT results:
Haemolysis
Gilberts
Alcohol
Cirrhosis
Metastases
Hepatitis
A

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
Q

Kernicterus

A

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
Q

Ciclosporin

A

inhibits production and release of lymphokines, therefore suppresses cell-mediated immune response

Given prior and as maintenance post transplant

78
Q

Tacrolimus

A

Macrolide calcineurin inhibitor

Inhibits T-lymphocyte signal transduction and IL2 transcription

79
Q

Signs of viral hepatitis

A 
Loss of appetite
Jaundice
Nausea
Vomiting
Fever
Weakness
Abdominal pain
Joint pain
Dark urine
Clay-coloured stool
80
Q

Hep A

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
Q

Hep B

A 
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
Q

Hep C

A 
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
Q

Hep D

A 
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
Q

Hep E

A

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

GI (7 decks)

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