Gastroenterology Flashcards
1
Q
What drugs cause a mixed LFT derangement with a R factor 2-5?
A
Carbamazepine
Lamotrigine
Phenytoin
Sulphonamides
2
Q
What drugs cause a hepatocellular pattern of LFT derangement with R factor > 5?
A
Paracetamol
Statins
Isoniazid
Rifampicin
Lamotrigine, diclofenac, disulfram, pyrazinamide
3
Q
What are the causes of an acute transaminitis which would result in ALT / AST rise >1000?
A
- Ischaemic hepatitis - typically associated pre-renal AKI and elevated LDH
- Viral hepatitis
- Drug induced hepatitis - paracetamol
- Hepatic vein thrombosis
4
Q
How is the R factor calculated and what does it indicate?
A
R factor = ALT / ULN divided by ALP / ULN
Ratio <2 suggests a cholestatic pattern of injury
Ratio > 5 suggests hepatocellular injury
Ration 2-5 - mixed
5
Q
What causes an AST: ALT ratio of 2:1?
A
AST: ALT ratio >2 suggestive of alcoholic liver disease, especially if GGT also elevated. If ratio >3, highly suspicious for alcoholic liver disease.
AST : ALT ratio occassionally also elevated in patients with non-alcoholic steatohepatitis
AST: ALT ratio elevated (although not greater than 2) in patients with hepatitis C who develop cirrhosis
Patients with Wilson’s disease or cirrhosis due to viral hepatitis may also have AST > ALT (although ratio not typically >2)
6
Q
What drugs cause a cholestatic pattern of LFT derangement with R factor <2?
A
Augmentin
Flucloxacillin
Penicillins
Cephalosporins
Androgens
OCP
Erythromycin
7
Q
Fibroscan scores
A
High negative predictive value
8
Q
Survival by Child Pugh Score
A
9
Q
MELD components
A
- Creatinine, bilirubin, INR, haemodialysis
- Used for transplant waitlisting
Used for mortality stratification prior to TIPS
10
Q
Pathophysiology of cirrhosis
A
Hepatocellular injury -> activation of hepatic stellate cells (liver cells) -> replacement of matrix with collagen I -> fibrosis & nodule formation
Platelet derived growth factor (PDGF) and TNF cause hepatic stellate cells to proliferate & become contractile
Endothelin-1 -> contraction
TGF beta -> fibrogenesis -> replacement of matrix with collagen I
PDGF and monocyte chemotactic protein-1 (MCP-1) => chemotaxis
11
Q
Pathophysiology of portal hypertension
A
12
Q
What are the effects of carvedilol in portal hypertension / cirrhosis?
A
Alpha 1 blockade - reduces intrahepatic resistance by inducing vasodilatation.
Beta 1 blockade - reduces hyperdynamic state by reducing CO and HR
Beta 2 blockade - induces splanchnic vasoconstriction and reduces portal blood flow / portal pressures.
13
Q
What does the hepatic venous pressure gradient indicate?
A
14
Q
Causes of ascites by SAAG
A
SAAG > 11 => portal hypertension
SAAG <11 - other cause
15
Q
What organisms cause SBP?
A
Culture negative in 60% cases
Gut organisms - E.coli & Klebsiella
Strep & Staph also possible
16
Q
What does the ascitic fluid show in SBP?
A
≥ 250 PMN’s/mm3
17
Q
Management of SBP including prevention
A
- Broad spectrum antibiotics - IV ceftriaxone 2g daily OR cefotaxime 2g TDS. Use tazocin if already on prophylactic antibiotics
- Duration of Abx - 5 days
- IV conc albumin - 1.5g / kg day 1 and 1g/kg day 3 (> 2 bottles per day for > 3 days)
- Repeat ascitic tap within 48 hours to ensure WCC is falling
- Referral for transplantation
- discontinue non-selective beta b,ockers - use of nonselective beta blockers associated with decreased transplant-free survival, increased rates of hepatorenal syndrome & increased length of hospitalisation
SBP prophylaxis if required if
- previous episode of SBP (recurrence rate is 70%)
- cirrhosis and GI bleeding
- ascites with <10g/L ascitic protein concentration if hospitalised for other easons
- ascites with <15g/L ascitic protein with impaired renal function or liver failure (impaired renal function = creatinine > 106, urea > 8.9, sodium <120; liver failure is Child Pugh score 9 or higher and bili 51 microl or higher)
Use daily Bactrim or cipro or norflox for prophylaxis
18
Q
What are the types of hepatorenal syndrome?
A
- Hepatorenal syndrome type 1 = HRS-AKI
- acute deterioration in renal function
- doubling of creatinine (stage 2 AKI or higher) with no resolution despite 48 hrs of withdrawing diuretics and volume expansion with albumin
- pathophys: progressive portal HTN & splanchnic vasodilation with systemic vasodilatation and hypotension -> compensatory increase in cardiac output. When heart can no longer compensate -> decline in CO -> HRS-AKI
Absence of hypovolemic shock or infection
No nephrotoxins
No parenchymal disease - no proteinuria or haematuria
- HRS type 2 = HRS-CKD
- chronic deterioration
- eGFR <60 for 3 months with no other cause
19
Q
What are the effects of terlipressin in hepatorenal syndrome?
A
- if diagnosis of HRS-AKI with no improvement despite 48 hrs of withdrawing diuretics & volume expansion => commence vasoconstrictor therapy with Terlipressin
- long acting vasopressin analogue -> V1 receptor on vascular smooth muscle in the splanchnic bed -> vasconstriction (i.e. reverse splanchnic vasodilation)
- increases MAP -> improves renal perfusion
- increases CO & HR
- increases systemic vascular resistance
Improves chances of HRS reversal
Studies do not show survival benefit, but probably does
10-30% recurrence once terlipressin stopped
Increased risk of cardiac ischaemia (caution IHD), arrhythmia, HTN, pulmonary oedema
Terlipressin boluses has similar efficacy but more side effects than infusion
20
Q
How does lactulose & rifaximin work in the prevention & treatment of hepatic encephalopathy?
A
- Lactulose
-synthetic, non-absorbable sugar
-catabolised by colonic flora -> produces acidic pH which favors formation of non-absorbable ammonium NH4+ from NH3 ammonia leading to decrease NH3 absorption
-alters gut flora -> favors non-urease producing lactobacillus
-hyperosmolar load -> decreased GI transit time -> decreased NH3 absorbtion
-increased NH3 excretion via increase in faecal volume
- aim 3-4 soft stools per day - daily dose 35-40mL lactulose - Rifaximin - dose 550mg BD
- locally acting antibiotic
- eliminates ammonia producing colonic bacteria
- use if no improvement in 48 hours or cannot take lactulose
- do not continue if no recurrence in 3 months due to concerns with resistance
21
Q
Risk factors for variceal bleeding
A
- Large varices
- Child pugh C > B > A
- Endoscopic features - red sign, red wale sign
- Ongoing ETOH intake
- High hepatic venous pressure gradient > 12mmHg
- Previous bleeding - recurrence rate 60-70%, mainly within first 2 years
22
Q
Who should be screened for varices?
A
- liver stiffness 15-25 kPa with platelets <150 OR score > 25kPa
- cirrhotics without known varices - screen every 2 years
- cirrhotics with small varices - scope every 12 months
Fibroscan <20 kPa and normal platelets do not need variceal surveillance
23
Q
Outline primary prophylaxis of variceal haemorrhage
A
Variceal banding OR non-selective beta blocker (carvedilol 6.25mg BD preferred as greater alpha blockade leads to bigger decrease in HVPG)
24
Q
Secondary prophylaxis of variceal haemorrhage
A
Variceal banding until eradicated AND non-selective beta blockers
Consideration of TIPS for recurrent variceal bleeding
Aims to reduce HVPG <12mmHg. Associated risk of encephalopathy
25
Hepatopulmonary syndrome
Caused by intrapulmonary diltataion & shunting
Platypnoea & orthodexia i.e. hypoxia & SOB worsened by sitting up, better when supine
Clubbing is a very sensitive physical sign
Diagnostic study is bubble study
Only treatment is transplant
26
Haemostatic abnormalities in CLD
27
What are the indications for TIPS?
TIPS = transjugular intrahepatic portosystemic shunt. Involves creation of a low-resistance channel between an intrahepatic branch of the portal vein & the hepatic vein, to decrease portal pressures.
Indications:
1. Bleeding secondary to portal hypertension
- active oesophageal variceal bleeding
- bleeding refractory to 1st line Mx or re-bleed within 120 hours
- gastric varices
- ectopic varices
- portal hypertensive gastropathy
2. Hepatic vein thrombosis / Budd Chiari syndrome
3. Diuretic refractory ascites or hepatic hydrothorax
TIPS procedure associated with improved survival and reduced rebleeding
28
What are the contraindications to TIPS?
1. Heart failure - TIPS increases pre-load & increases R) sided pressures by shift in volume from splanchnic to systemic circulation
2. Severe TR
3. Severe pulmonary hypertension
4. Polycystic liver disease
5. Uncontrolled systemic infection or sepsis
Relative contraindications
1. HCC - especially if central
2. brittle encephalopathy
3. portal vein thrombosus
4. severe thrombocytopenia / coagulopathy
5. malnourishment
6. very sick liver - bili > 60
29
What are the complications of a TIPS procedure?
1. Hepatic encephalopathy in 30-50%
- chronic encephalopathy may occur in 25%
- increased risk if older, previous encephalopathy, ETOH induced cirrhosis
- if refractory encephalopathy, shunt can be made smaller or occluded
2. Increased pre-load -> can worsen R) sided heart failure
3. TIPS stenosis
4. Technical complications - arrhythmias, traversal of liver capsule
30
What is the leading cause of death in NAFLD?
Cardiovascular disease
31
Available pharmacotherapies for NAFLD
Pharmacotherapy
* for biopsy proven NASH and fibrosis
Options for pharmacologic, liver-targeted therapy for NAFLD are limited, and we do not use them in all patients. We reserve pharmacologic therapy for patients who do not achieve their weight loss goals and who have biopsy-proven NASH with fibrosis stage ≥2. The approach also depends on whether the patient has diabetes mellitus
NASH with diabetes
1. Metformin
* Improves LFTs
* Doesn’t change liver histology
2. Pioglitazone
* improves fibrosis as well as inflammation and steatosis
* BUT- weight gain, fluid overload, osteoporosis and bladder Ca
3. GLP1 agonist: Liraglutide
NASH without diabetes
1. GLP1 agonist: Semaglutide (NEJM 2021) improves and in some cases can resolve NASH. However no effect on fibrosis if this has already occurred
* Semaglutide has a mechanism of action that is similar to that of liraglutide but with more pronounced metabolic effects
* Studied in patients with and without T2DM
2. Vitamin E (antioxidant)
* For non-diabetic patients
* Improves NASH
* BUT- risk of haemorrhagic stroke, prostate cancer
Surgery
1. Bariatric surgery
* Post of improvement in liver histology
2. Liver transplant
* 3rd most common indication for liver transplant
* NAFLD may recur
Future therapies
1. Obeticholic acid
* FXR (bile acid receptor) agonist
* This receptor is a major modulator of lipid metabolism and insulin sensitivity
* Improves NASH and fibrosis
2. Cenicriciroc
* CCR5 antagonist à reduced macrophage recruitment à anti-fibrotic agent
3. Elafibrinor
* PPAR agonist
* Increases lipid oxidation à decreases steatosis
Inhibits macrophages à decreased inflammation à decreased fibrosis
32
Causes of hepatic steatosis other than NAFLD
Other Causes of Hepatic Steatosis
* Alcoholic liver disease
* Hepatitis C (particularly genotype 3)
* Wilson disease
* Lipodystrophy
* Starvation
* Parenteral nutrition
* Abetalipoproteinemia
* Medications (amiodarone, methotrexate, tamoxifen, glucocorticoids, valproate, anti-retroviral agents for HIV)
* Reye syndrome
* Acute fatty liver of pregnancy
* HELLP (haemolytic anaemia, elevated liver enzymes, low platelet count) syndrome
* Inborn errors of metabolism (LCAT deficiency, cholesterol ester storage disease, Wolman disease)
Drug-induced liver disease
33
NAFLD fibrosis score
Components of NAFLD fibrosis score - age, BMI, presence of diabetes, AST / ALT ratio, platelet count, albumin
Has a high negative predictive value
Low scores <-1.45 = absence of signifciant fibrosis (F0-2). Repeat in 2 yrs.
Intermediate - may require biopsy
High scores > 0.675 suggest advanced fibrosis F3-4
34
Biopsy features with NASH
1. >5% hepatic steatosis
2. Lobular inflammation
3. Hepatocellular ballooning
NAFLD = >5% hepatic steatosis
35
Pathophysiology of alcoholic hepatitis
Acetalaldehyde causes cytoskeletal & mitochondrial damage
Mallory bodies form when cytoskeletal collapses onto itself
Loss of cell shape, cannot transport proteins out, osmotic pressure rises, cell swells up, hepatocyte ballooning
Micro or macrovesicular steatosis
Hepatocellular ballooning with cytoplasmic rarefaction
Infiltration by neutrophils (compared to mononulcear infiltration in other forms of chronic hepatitis)
Mallory Denk bodies (eosinophilic accumulation of intracellular material)
Fibrosis with perivenular, perisinusoidal and pericellular distribution - begins in zone 3 (perivenular) and progresses to perisinusoidal
36
How are Maddrey Score and Lille Score used in the management of alcoholic hepatitis?
Maddrey score - predicts mortality
- incorporates PT and bilirubin
- > 32 suggests poor prognosis (30% 1 month mortality) & role for steroids
Treat with pred 40mg for 28 days, then taper over 3 weeks
Approx 40% do not respond
Lille score calculated on D7 to identify patients that are not responding to steroids
Includes bilirubin (initial & D7), PT, age, albumin, PT
<0.45 predicts 6 month survival 85%
>0.45 predicts 6 month survival 25%
37
Diagnostic criteria for ETOH hepatitis
1. ETOH consumption - in last 2 months, >50g / day, minimum 6 months
2. Bili >30
3. AST : ALT ratio > 1.5
4. No other cause of acute hepatitis
38
Where is iron absorbed?
Mainly in duodenum & jejunum
39
Features of Zieve's syndrome
Acute metabolic condition during withdrawal from prolonged heavy ETOH use
- haemolytic anaemia (acanthocytes & spur cells)
- jaundice (elevated unconjugated bilirubin)
- abdominal pain
- transient hyperlipidaemia
Clinically distinct from alcoholic hepatitis but often occurs concurrently
Underlying mechanism unclear ? delipidisation of liver
Typically after an episode of acutely increased ETOH intake
Resolves with abstinence or return to baseline ETOH intake
40
What gene mutation is involved in hereditary haemochromatosis?
- autosomal recessive HFE gene mutations (chromsome 6). 90% patients are homozygotes for C282Y (base substitution). Less common H63D (less likely to cause severe disease). Only 10-30% penetrance. Heterozygotes (carriers) not at any icnreased risk.
- HFE mutation leads to reduced Hepcidin levels. Hepcidin is an iron regulator that prevents iron absorption from enterocytes.
- Low hepcidine leads to increased intestinal iron absorption
Normal 1-2mg iron absorption per day
In HH, absorb approx 4mg per day - 1g excess iron absorption per year
Clinically manifests when total body iron accumulation is up to 20g
Present in men around 40-50
Present in women 60-70 years
41
Patients with hereditary haemochromatosis are susceptible to infection with certain organisms. What are they?
At risk of infections with siderophilic organisms.
Listeria monocytogenes, Yersinia enterocolitica, Vibrio vulnificus
42
Indications for therapeutic phlebotomy in hereditary haemochromatosis?
- ferritin > 100
- evidence of tissue injury e.g. LFT derangement, reduced EF
- MRI/ imaging evidence of increased tissue iron
Start with weekly venesection - remove 500ml blood (equivalent to 200-250mg iron per day)
Aim ferritin <50
Once target reached - cease phlebotomy & monitor ferritin every 6 months
If increasing - re-start venesections 3-6 times per day
Iron chelation not used
In non-diabetic and non-cirrhotic patients, venesection returns life expectancy to normal.
Arthropathy may or may not improve with venesection
Gonadal failure is irreversible.
43
At what ferritin level would you be suspcicious of HH?
Ferritin > 200 women
Ferritin > 300 men
Ferritin < 1000 - cirrhosis unlikley
Ferritin > 1000 - increased risk of cirrhosis. 80% PPV for C282Y homozygotes
44
Clinical manifestations of hereditary haemochromatosis
- Liver is the most common & earliest to be affected. C282Y homozygote males are at increased risk of HCC than other patients with HH.
- Cardiac - sinus node dysfunction, arrhythmia, cardiac abnormalities. Dilated cardiomyopathy. Diastolic dysfunction
- Endocrine abnormalities - type 1 diabetes, malabsorption due to exocrine pancreas involvement.
Hypopituitarism - secondary hypogonadism, hypothyroidism
- CNS - cognitive impairment, possible increased risk of ALS.
- Skin hyperpigmentation
- Joints - due to iron deposition in joints and reduced bone mineral density. Arthralgia and arthropathy
45
What genetic mutation is associated with Wilson's disease?
Autosomal recessive
Mutation in ATP7B (chromosome 13).
ATP7B important for excretion of excess copper (dietary copper absorption is about double of what is needed - 90% then excreted via bile & 10% via urine).
ATP7B excretes excess copper via binding copper to apocaeruloplasmin which forms caeruloplasmin. Also gathers Cu into vesicles which are exocytosed.
Key issue is that copper cannot be excreted.
Excess copper deposition in tissues -> free radical production -> tissue damage
46
What are the clinical manifestations of Wilson's disease?
1. CLD / cirrhosis - usually in childhood / teenage years
2. Neurologic
Cortex - cognitive changes, labile emotions, personality changes
Basal ganglia - PD, movement disorder / dyskinesias
Cerebellum - ataxia
3. Eye - Kayser Fleischer rings
4. Renal proximal tubule -> nephropathy
5. RBCs -> haemolytic anaemia
6. Grey skin pigmentation, blue nails
47
How to diagnose Wilson's disease?
1. Low serum caeruloplasmin < 200mg/L. Levels <140 are pathognomonic fr Wilson's disease. Not reliable in inflammatory states (acute phase reactant)
2. ALT typically does not exceed 1500
3. Ocular slit lamp - Kayser Fleischer rings
4. 24 hour urinary copper excretion (Usually > 100 microg; normally <40 microg)
5. Gene testing for ATP7B only if unable to establish diagnosis with above
48
Distinguish between type 1 and type 2 autoimmune hepatitis
AIH general points
-bimodal age distribution - 10-30 yrs or > 40 yrs
- chronic hepatitis, unclear underlying etiology, associated with autoantibodies and hypergammaglobulinaemia
- triggering events include drugs, herbs, viruses, immunisation
- ANA is the most sensitive but least specific Ab
- anti-soluble liver antigen is the most specific but least sensitive
- autoantibody neg in 20%
- 40% present as acute hepatitis, 25% cirrhosis at presentation
- biopsy shows mononuclear (plasmacytic) infiltrate with interface hepatitis
Type 1
- better prognosis, better response to immunosuppression
- usually < 40 yrs
- strongly associated with HLA DR3 and DR4
- atypical p-ANCA
- ANA + ASMA are present in 80% and are 99% specific but 40% sensitive
- also AAA (anti actin Ab)
Type 2
- worse prognosis, less likely to respond to immunosuppression
- anti-LKM1 Ab - worst prognosis, 99% specific
- targeted against an epitope of CYP2D6
- also anti ALC-1 (anti-liver cytosol)
49
How is PSC diagnosed?
- Elevated ALP (suspect PSC in patient with UC with persistently elevated ALP 2 x ULN). Elective conjugated bilirubin. Aminotransferases <300.
- often p-ANCA positive
- hypergammaglobulineraemia + elevated IgM
- urine - low urobilinogen, high conjugated bilirubin
- MRCP / ERCP is the gold standard test for diagnosis - shows multifocal strictures with altering normal / dilated segments (beaded appearance)
- involves the entire biliary tract (intrahepatic & extrahepatic)
MRCP has 86% sensitivity, 94% specificty
Biopsy not required if MRCP in keeping with PSC.
Shows fibrous obliteration of small bile ducts, called onion skin fibrosis, which is the most specific finding
Always check IgG4 level in new diagnosis PSC. IgG4 associated cholangitis is a steroid-responsive sclerosing cholangitis with clinical & radiographic features in keeping with PSC.
Check fat-soluble vitamin levels (A,D,E,K)
- PSC is most commonly associated with Vitamin D deficiency (seen in up to 80% patients) - can get night blindness
- Vitamin D & E deficiency common in late stage
DEXA, Ca, vit D - strong association with metabolic bone disease
Annual scope if UC & PSC
Increased risk of cholangiocarcinoma 8-15% - Ca 19-9 elevated in 80%
50
What is the association between PSC and IBD?
PSC is associated with colitis - mainly UC but could also be Crohn's colitis.
- 75-90% patients with PSC have UC; only 5% patients with UC have PSC and only 2% of patients with CD have PSC
- PSC plus UC at increased risk of colorectal Ca -> need annual scopes
- presence of IBD is associated with lower age at presentation, development of serious malignant complications and reduced liver transplnat free survival in pts with UC
51
What is the pathophysiology of PBC?
Non-supportive granulomatous inflammation of bile ducts
T-cell mediated damage - unknown trigger
Bile leaks out of ducts -> causes inflammation
52
How is PBC diagnosed?
ALP > 1.5 x ULN
AMA / Anti-mitochondrial Abs have 98% specificty. Titre > 1:40. Positive in 98%. Titre NOT associated with disease activity.
ANA positive in 70%
Marked hyperlipidaemia - elevated HDL, LDL.
Histology
- periductal granulomas
- Florid duct lesions - pathogonomic - present in > 80%
- Periporrtal inflammation
- Mononuclear cell infiltrate
- High hepatic copper level
53
What is the role of ursodeoxycholic acid for PBC?
13-15mg/kg/day
Naturally occurring hydrophilic bile acid that decreases hepatotoxicity by reducing the hydrophobicity of naturally occurring bile acids
Delays progression, improves survival BUT does not improve symptoms of pruritis & fatigue
Use cholestyramine for itch
Other treatments
- Obeticholic acid
- Elafibranor - PPAR alpha & delta agonist
54
What autoimmune diseases are associated with PBC?
Autoimmune hepatitis
Sjogren's syndrome (40-65%) - xerostomia, keratoconjunctivitis
Hashimoto's thyroiditis 10-15%
CREST syndrome 5-15%
RA 5%
55
What is the incubation period for hepatitis A?
Incubation period is 28 days
Contagious during incubation period
Remain contagious for 1 week after jaundice appears
HAV IgM detectable at time of symptom onset - remains detectable for 3-6 months
56
Natural history of hepatitis B
1. Acute infection - mostly asymptomatic (70%).
2. <0.1% patients develop fulminant hepatitis B
3.. <5% adults with acute infection progress to chronic infection. > 90% infected children progress to chronic infection
4. 30% of patients with chronic Hep B infection progress to cirrhosis
5. 5-10% of patients with chronic Hep B progress to HCC without cirrhosis
57
What is the structure of the hepatitis B virus?
DNA virus
Consists of a nucleocapsid (core antigen) and envelope (surface antigen).
HbeAg is a soluble protein that deflects the immune radar to allow chronic infection. Suggests active viral replication. Only occurs in early disease.
Covalently closed circular DNA remains in the nucleus despite treatment - therefore Hepatitis B cannot be cured.
Hep B virus enters the hepatocyte via the NTCP receptor
Circular covalently closed DNA has two transcription pathway
- one leading to viral RNA replication - which can be targeted by antivirals.
- another leading to HbsAg production - this is not targeted by antivirals. This is why HBV antivirals are not effective against HDV which uses HbsAg as its receptor for cell entry via NTCP)
58
What are the extra-intestinal manifestations of hepatitis B?
Polyarteritis nodosa - medium vessel necrotising vasculitis. Typically occurs 4 months after onset of HBV infection
Glomerular disease
- mostly in children - typically spontaneously resolve with seroconversion from HBeAg -> HBeAb
Membranous and membranoproliferative
Aplastic anaemia
59
What are the phases of chronic hepatitis B infection? Which phases should treatment be started in?
1. Immune tolerance
- young patient with low immune response. Normal LFTs. HBsAg positive, HBeAg positive. High viral load. Lasts 10-30 yrs. Monitor with LFTs, viral load, HBeAg, HBeAb every 6-12 months
2. Immune clearance
- 2nd or 3rd decade of life. Abnormal LFTs. HBeAg positive. HBsAg positive. High viral load.
NEEDS CONSIDERATION OF TREATMENT. At risk of progression to HCC / cirrhosis.
3. Immune control
- seroconversion from HBeAg to HBeAb
- normal LFTs. Low viral load.
- Monitor every 6-12 months with LFTs & viral load
4. Immune escape
- virus mutates & escapes the immune system
- HBeAg negative
- high viral load
- abnormal LFTs
- at risk of progression to cirrhosis / HCC. Needs consideration of treatment.
60
What is best indicator of prognosis in acute hepatitis B?
PT / INR
61
What is the DDx for isolated positive HBcAb?
* Distant quiescent HBV
=> i.e. Distantly immune but test not sensitive enough to detect very low anti-HBs
* False positive
* Resolving acute HBV
* Occult HBV
=> i.e. Chronically infected - can detect HBV DNA but have negative HBsAg
=> May or may not have HBcAb
62
What are the indications for antiviral therapy in the acute phase of Hepatits B infection?
Most patients do not have a severe acute phase hepatitis. <5% progress to chronic infection.
Indications for antiviral therapy for acute infection:
- pre-existing chronic liver disease
- concomitant HCV or HDV infection
- fulminant hepatitis
- jaundice or symptoms lasting > 4 weeks
- coagulopathy INR > 1.5
- Elderly
- immunocompromised
Do NOT give interferon for acute infection
63
What are the indications for treatment in chronic hepatitis B infection?
1. Immune clearance - ALT > 2 x ULN, viral load > 20,000, HBeAg positive
2. Immune escape - virus mutates to evade immune system, ALT > 2 x ULN, viral load > 2000, HBeAg negative
3. Acute liver failure
4. Compensated cirrhosis with viral load > 2000
5. Decompensated cirrhosis with positive HBV DNA
6. HCC
7. HCV co-infection - initiate at the same time or before HCV treatment (HCV treatment can flare HBV)
8. Pregnant women
9. Prior to immunosuppression
64
What are the two different types of treatment available for hepatitis B?
65
Who should have HCC surveillance amongst patients with hepatitis B?
Asian males > 40 years
Asian women > 50 years
First degree relative with HCC
Anyone with cirrhosis
ATSI > 50 yrs
African men / women from diagnosis
66
How can hepatitis B transmission from mother to baby be prevented?
- entecavir is teratogenic, use tenofovir in pregnancy.
- Materal high viral load or HBeAg positive has 90% risk of transmission to baby
- give tenofovir in third trimester
- can breastfeed on tenofovir
67
What types of immunosuppression are associated with increased risk of hepatitis B reactivation?
Very high risk reactivation if HBsAg positive
- Anti-CD20 agents (rituximab, obinutuzumab, ofatumumab)
- Haematopoietic stem cell transplantation - high risk reactivation if HBsAg positive
High risk reactivation if HBsAg positive
- High dose glucocorticoids - pred 20mg or higher for at least 4 weeks
- Anti CD52 agnet alemtuzumab - high risk reactivation
Moderate risk reactivation
chemotherapy, anti-TNF, anti-rejection therapy for solid organ transplants
Low risk reactivation if HBsAg positive (<1%)
- MTX or azathiopurine
HBsAg negative and anti-HBcAb positive lower risk
If at high risk of reactivation
- check viral load beginning of immunosuppression
- continue entecavir 0.5mg daily 18-24 months after completing immunosuppression for stem cell transplant or B cell depleting treatment. Otherwise continue for 12 months
- if moderate risk immunosuppression but HBcAb positive but HBsAg negative (quiscent infection) -> no treatment required
68
Is it possible to vaccinate against Hepatitis C?
No vaccine for hepatitis.
RNA virus with a high mutation rate, due to copying errors in viral replication, resulting in viral diversity.
7 genotypes
More than 70 subtypes of main genotypes
69
Which genotype of hepatitis C is most common?
Genotype 1 is most common in Europe & US
Genotype 3 is most common in Australia - most difficult to treat with direct acting anti-virals (85% cure rate)
70
What is the natural history of hepatitis C infection?
75% patients infected with hepatitis C will develop chronic infection
5-20% will develop cirrhosis
>95% non-cirrhotic patients with achieve SVR with DAAs
Decompensated cirrhotics 75-85% will achieve SVR
Genotype 3 cirrhotic - DAAs 85% effective
Risk of HCC remains even after SVR
71
What are the extrahepatic manifestations of hepatitis C?
1. Essential mixed cryoglobulinaemia - all patients with HCV must be assessed for EMC. EMC is an indication for prompt treatment
- palpable purpura
- finger / toe necrosis
- renal impairment - MPGN
-leucocytoclastic vasculitis
-arthralgias
-neurological disease, peripheral neuropathy
- Rx of EMC includes combination of antivirals with PLEX (clears the cryoglobulin), rituximab (depletes cryoglobulin producing B cells)
2. Porphyria cutanea tarda
- bullous skin disease
- 50% with PCT have HCV
3. Lichen planus
20% pts have lichen planus
all patients with lichen planus should be assessed for HCV
72
What is the treatment for hepatitis C? How can it be cured ?
Direct acting anti-viral therapy is the treatment of choice in hepatitis C. It achieves sustained virological response (SVR) defined as undetectable HCV RNA for 12 or 24 weeks after completion of antiviral therapy. Uses combination of medications from different classes to avoid resistance and optimsie efficacy (PAN-GENOTYPIC).
Key viral proteins:
NS5A - responsible for viral assembly & release
NS5B - RNA polymerase responsible for viral replication
NS3/4A - protease
Protease inhibitors (target NS3/4A) - inhibition of viral protein production
'evir'. Glecaprevir & Voxilaprevir.
-contraindicated in decompensated cirrhosis
NS5A inhibitors 'asvir'
- Pibrentasvir, Velpatasvir
- associated with long-term resistance
NS5B inhibitors 'uvir'
-Sofobuvir
-can lead to complete heart block with amiodarone
Maviret (Glecaprevir PLUS Pibrentasvir) & Epclusa (Velpatasvir PLUS sofosbuvir) used for ALL genotypes - 1st line therapy
Maviret 8 week course
Epclusa 12 week course
*Epclusa is the treatment of choice in decompensated cirrhotic patients
Vosevi (triple therapy) - sofosbuvir + velpatasvir + voxilaprevir.
12 week course
> 95% cure rate
Common adverse effects - nausea, fatigue, headache
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What are the drug interactions associated with direct acting antivirals?
- PPIs reduce efficacy of DAAs
- Statins can lead to rhabdomyolysis
- Amiodarone plus sofobuvir can result in complete heart block
- Anti-epileptics often interact with DAAs
- interaction with OCPs
- Protease ninhibiitors are contraindicated in decompensated cirrhosis because protease inhibitors accumulate & cause worsening of liver failure / cirrhossi
- DAAs NOT recommended in pregnancy or breastfeeding - small risk of mother to baby transmission 2-5%
- HCV treatment can cause flare of HBV
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What is the relationship between HBV & HDV?
HDV infection is dependent on the presence of HBsAg. HDV is a RNA virus that enters hepatocytes that has a outer lipoprotein envelope made of HBsAg. HBsAg binds to NCTP protein on hepatocytes for cell entry.
HDV has 8 genotypes
5% patients with HBV have HDV.
Acute co-infection with HBV & HDV causes an acute severe hepatitis, with an increased risk of acute liver failure compared to HBV alone. Around 5% with co-infection develop chronic HDV infection, usually recover from both HBV & HDV.
HDV super-infection in a patient with HBV has poor prognosis. More than 80% patients with superinfection develop chronic HDV. Increased risk of cirrhosis & HCC in patients that develop HDV superinfection.
Nucleoside therapy of HBV does not impact HDV viraemia or outcomes
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What is the treatment for HDV?
- Bulevirtide - binds to NTCP (sodium taurocholate co-transporting polypeptide) preventing HBsAg binding and hepatocyte entry
- can be used in combination with pegylated interferon (also a treatment for HBV)
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What is the most common cause of acute viral hepatitis?
Worldwide the most common cause of acute hepatitis is hepatitis E
Significant cause of acute liver failure in India / Bangladesh
Associated with ALF in pregnancy and in older people
Pregnancy mortality 25%
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What are the key genotypes of hepatitis E?
Genotype 1 + 2 - only infect humans. Faecal - oral spread via contaminated water. Large outbreaks. Typically self-limiting & brief. Never chronic. High mortality in pregnancy 25%
Genotype 3 + 4 - endemic in animal species e.g pig & wild board. Zoonotic infections in humans. High income countries.
No chronic infections develop in immunocompetent individuals. But can have unusual neurological manifestations - GBS, meningoencephalitis, mononeuritis multiplex, neurologic amyotrophy, myositis.
Immunosuppressed patients can develop chronic infection
- solid organ transplant receipeints
- haematological disorders
- HIV
- rheumatic disorders with heavy immunosuppression
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What is Ribavirin used for? What are its side effects?
Used for chronic hepatitis E hepatitis - if ongoing HEV viraemia in immunosuppressed patient
12 week course
Adverse effects include haemolytic anaemia, neutropenia, thrombocytopenia, insomnia & irritability
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How is paracetamol normally metabolised?
What is the pathogenesis of paracetamol induced hepatotoxicity?
90% metabolised in liver via the SULT (sulphonyltransferase) and UDP-glucoronyltransferase enzymes - conjugated to non-toxic metabolites & excreted in urine
2% excreted in urine unchanged
8% metabolised via CYP450 enzymes into NAPQI (n-acetyl p benzoquinoneimine). NAPQI conjugated with hepatic glutathione into non-toxic compounds & excreted
In supratherapeutic doses, SULT & UGT pathway becomes saturated. More drug shunted to CYP450 pathway -> more NAPQI -> glutathione stores depleted. Once glutathione stores depleted by 70-80%, NAPQI causes cellular injury
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What are the risk factors for paracetamol induced hepatotoxicity?
1. Multiple supratherapeutic doses - higher rates of severe hepatotoxicity, hepatic coma & death
2. Decreased capacity for glucoronidation or sulfation
3. Depletion of glutathione stores
4. ETOH
-acute ETOH intake may be protective because competes as a substrate for CYP2E1
-chronic heavy ETOH consumption leads to depletion of glutathione synthesis & stores, increased synthesis & activity of CYP2E. No evidence of increased hepatotoxicity in chronic alcoholics with therapeutic doses. Chronic alcoholics are at increased risk of hepatotoxicity after multiple supratherapeutic doses.
5. CLD / cirrhosis - without chronic ETOH use not an increased risk of paracetamol hepatoxicity. Paracetamol metabolism is decreased in cirrhosis, so elimination half-life is prolonged
CYP450 activity reduced in cirrhosis - may be protective
Cirrhotics, especially decompensated, should have no more than 2g/day
6. Drugs that induced CYP2E1 - colchicine, dexamethasone, isoniazid, phenobarbitol, nicotine
7. Drugs that induce CYP450 - rifampicin, phenytoin, carbamazepine, St John's Wort, high dose omeprazole, barbiturates
8. Malnourishment - increased risk of hepatotoxicity. Hepatic glucuronidation is dependent on hepatic carbohydrate reserves
Depleted glutathione with malnourishment.
9. Age - older patients more likely to develop hepatoxicity than patients < 5 years. However, with repeated overdoses, risk of hepatoxicity equal in children = adults
Adults > 40 yrs at highest risk of live rfailure
10. Tobacco - contains CYP1A2 inducers - independent risk factor for mortality following paracetamol overdose
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What features suggest ischaemic hepatitis rather than other causes of acute marked transaminitis e.g. viral hepatitis or drug or toxin induced liver injury?
1. Early rapid rise in LDH
2. Ratio of ALT: LDH <1.5 early in course of acute hepatitis
3. Rapid fall in aminotransferases is characteristic of ischaemic liver injury
4. Additional evidence of end-organ hypoperfusion - ATN especially
5. Hepatopulmonary syndrome - self-limiting. Due to intrapulmonary vasodilation.
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Drug induced liver injury - cholestatic vs hepatitic pattern
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Methotrexate induced liver injury
- uncommon; NAFLD and DILI is much more likely in these patients
- cumulative dose > 5g
- 15-50% patients have an asymptomatic elevation in transaminases on long term low dose therapy
- significant hepatic fibrosis on MTX is rare 5% and cirrhosis is rarer 1-2%
Mechanism - hepatic accumulation of a polyglutamate metabolite of methotrexate + excess homocysteine + oxidative stress / cytokine mileu -> activation of hepatic stellate cells
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What is the MELD score?
MELD = model for end stage liver disease
Prognostic tool for transplant waitlisting
Includes bilirubin, INR, creatinine, dialysis. May also include sodium
MELD score > 15 - benefits of transplantation outweigh risks
MELD 6-14 - risk of transplantation outweighs benefits
3 month survival post transplant much worse if MELD > 20
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What is the UCSF criteria for HCC?
If meeting this criteria - predicted survival 90% at 1 year and 75% at 5 years
1. 1 x nodule <6.5cm
2. up to 3 nodules, the largest of which <4.5 cm
3. Cumulative tumour size <8cm
4. no evidence of gross vascular invasion or metastases
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What is the King's College Criteria for acute liver failure?
Paracetamol-induced acute liver failure
- arterial pH <7.3 OR all 3 of - INR > 6.5 + Cr > 300 + grade III or IV encephalopathy
Non-paracetamol induced acute liver failure
INR > 6.5 OR
3 of the following:
INR > 4.5
Bilirubin > 300
Time from onset of jaundice to coma > 7 days
Drug toxicity
Age <11 or > 40
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What is the typical immunosuppression post liver transplant & key ADRs?
Usually combination of CNI + mycophenolate + prednisolone
- longer term switch to Everolimus to reduce cancer risk + nephrotoxicity
CNI - usually tacrolimus
- nephrotoxicity, HTN, tremor, neurotoxicity, diabetes, dyslipidaemia, hirsutism
Mycophenolate - GI disturbance and myleosuppression - leukopenia
Prednisolone - aim to wean & cease in 3 months
Combination of mycophenolate, Bactrim & valganciclovir often cause leucopenia
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What are the key early & late complications of liver transplants?
Early:
1. Infection - bacterial, fungal, CMV reactivation (highest risk in donor + / recepient - ; CMV colitis & hepatitis, fever, leucopenia, tissue damage - treat with IV ganciclovir for 7 days)
2. Biliary strictures - esp in DCD due to hypotension
3. Renal ADRs from drugs
4. Diabetic complications
5. Graft failure - rare
Late complications
1. Cancer - skin cancer, PTLD (4%)
2. Vascular cx - AMI
3. Renal disease -esp if tacrolimus
4. Recurrent liver disease - mainly PSC & PBC
5. osteoporosis
Rejection:
1. Acute cellular rejection
- in 30%, at around day 7 - 10
- portal based inflammation - cholestatic LFTs
- managed with steroid boluses & increased background immunosuppression
- usually no chronic sequelae
2. Chronic rejection
- rare, in 3%
- months - year post transplant
- pathophys - vanishing bile duct syndrome - cholestatic LFTs
- management - increase tacrolimus dose, may not be treatable
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What is the differential diagnosis of LFT derangement in pregnancy?
90
What are the maternal & foetal risks associated with intrahepatic cholestasis of pregnancy?
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What is the likely pathophys of intra-hepatic cholestasis of pregnancy?
- 3rd trimester; 80% after 30/40
- presents with unexplained pruritis (hands & soles typically) with raised ALT (up to 30 x ULN) or bile acids > 10
- other LFT abnormalities or imaging abnormalities uncommon
- risk to baby starts when bile acids >40 but only significant when > 100
- bile acids rise 2-5 after eating
- use random NOT fasting bile acids for diagnosis & monitoring
- likely due to mutations in biliary transports (MDR3, MR2, BSEP). Up to 80% recurrence in subsequent pregnancies, also within families
Carriers usually asymptomatic outside pregnancy or oestrogen containing contraception. Oestrogen alters metabolism and excretion of bile acids
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What is the relationship between IBD and NOD2/CARD15 gene variants?
NOD2/CARD15 gene variants are associated primarily with CD, rather than UC.
NOD2/CARD15 is involved in the innate immune system in recognising bacterial peptidoglycans.
NOD2 / CARD15 associated with early age of onset, stricturing phenotype, small bowel involvement & need for early surgery, disease recurrence post surgery
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What are the protective factors for IBD?
1. Smoking protects against UC. UC often occurs in patient's who have recently quit smoking. Smoking is associated with an increased risk of CD.
2. Appendicectomy protects against UC
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What extra-intestinal manifestations of IBD do not correlate with disease activity?
<10% patients have EIMs at presentation, but 25% will develop EIMs
Most EIMs correlate with intestinal disease activity except
1. PSC
2. Ankylosing spondylitis
3. Pyoderma gangrenosum
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What are some key histological findings in CD vs UC?
CD - transmural, patchy disease. Non-caseating granulomas seen in 30% patients but typically pathognomonic
UC - confluent mucosal disease, paneth cell metaplasia
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What ANCA & ASCA status is typically associated with IBD?
CD - ASCA pos / ANCA neg
UC - ASCA neg / ANCA pos
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What risk factors increase the risk of colorectal Ca in IBD?
UC is associated with increased risk of CRC. CD has a less established associated - but this is particularly for Crohn's colitis
The following factors are associated with increased risk
1. Prolonged disease duration
2. Extensive disease
3. High inflammatory burden
4. PSC
5. Family history of CRC
6. Presence of dysplasia
7. Long term AZA + anti-TNF agent use associated with increased risk of hepatosplenic T cell lymphoma, especially in people > 65 years and males who are EBV positive
Colorectal Ca in patients with IBD occurs at a younger age & is associated wth increased mortality
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What are some low risk vs high risk features of CD?
Low risk / mild CD:
- diagnosis > 30 yrs
- absence of penetrating / fistulising disease
- absence of perianal / stricturing disease
- short disease duration
- mild symptoms
- normal or mildly elevated inflammatory markers (CRP / FCP)
- limited distribution of bowel inflammation
- superficial or no ulceration on colonoscopy
- no prior intestinal resections
High risk / mod-severe CD
- perianal disease
- stricturing & penetrating disease
- multiple resections
- severe symptoms
- elevated inflammatory markers
- deep ulcers on scopes
- active / recent tobacco use
- long segments of small and/or large bowel involvement
- glucocorticoid refractory
- relapse after clincial remission with steroid induction
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Why is sulfasalazine less effective in CD?
Sulfasalazine is a pro-drug containing its active component 5 ASA & sulphonamide component.
Requries colonic bacteria to cleave it to release active 5-ASA, so only effective for colitis
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What are the non TNF biologic options for induction & maintanence of remission in CD?
Vedolizumab - anti- alpha 4 beta 7 integrin. Gut specific, less effective for extra-intestinal manifestations, especially if they do not correlate with disease activity.
Ustekinumab - anti IL-12/23. Helpful if comorbid psoriasis.
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What are the risk factors for post-operative disease recurrence in CD? How can post-operative recurrence of CD be prevented?
- Surgery for CD is non-curative. Clinical recurrence occurs in 20-37% at 1 year, up to 85% at 3 yrs.
- Risk factors for disease recurrence;
1. Smoking
2. Disease duration
3. Extensive disease
4. Penetrating or fistulising disease
- Need ileocolonoscopy 6-12 months post-op. Endoscopic recurrence precedes clincial recurrence.
Low risk
Non-smoker, > 50 yrs., first CD operation, long history of CD, short stricturing CD
3 month metronidazole
Ileo-colonoscopy at 6-12 months - start Rx if endoscopic recurrence
High risk
smokers, < 30 yrs., perforating / fistulising / long segment disease, previous resections, short diseae duration
Start thiopurine 2-8 weeks post op if treatment naive
Start ant-TNF 4-8 weeks post op if previous treatment
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Frequency of colorectal Ca screening in IBD
1. High risk patients need annual colonoscopies
Extensive colitis UC OR > 50% CD colitis WITH
- PSC or
- FH CRC <50 yrs
- dysplastic polyp in colon in last 5 yrs
- colonic stricture
2. Intermediate risk - 2-3 years colonoscopy
Extensive colitis UC or > 50% CD colitis WITH
-inflammatory polyps
-FH CRC <50
3. Low risk - colonoscopy every 5 yrs.
- none of the above but more than one segment colitis
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What are some of the side effects of azathioprine?
Azathioprine metabolites:
6-MMP - toxic
6-TGN - therapeutic
Pancreatitis, lymphoma, myelosuppression, skin cancer
Combination of AZA + anti-TNF inhibitor associated with increased risk of hepatosplenic T cell lymphoam
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Management of perianal disease
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What is the typical distribution of UC?
- Pancolitis most common - 50%
- proctitis 28%
- left-sided 25%
- pancolitis with backwash ileitis 7-15%
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What is the definition of toxic megacolon?
Second daily AXR during ASUC to ensure toxic megacolon has not developed
- colonic dilatation 6cm or more OR
- caecal dilatation > 9cm
WITH systemic toxicity
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What are the key endoscopic & histologic features of ulcerative colitis?
Endoscopy
- continuous disease involving the rectum & colon with a sharp cut off point
- loss of vascular markings due to mucosal oedema -> erythematous appearance
- friability & spontaneous bleeding
- erosions & ulcers
- pseudopolyps
-petechiae
- granularity of mucosa
Histology
- crypt abscesses, branching, shortening, disarray
- crypt atrophy
- mucin depletion
- paneth cell metaplasia
- increased lamina propia cellularity
- basal plasmacytosis
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Truelove & Witt's criteria for severity of UC
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What is a key contraindication for anti-TNF therapy?
History of melanoma
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What is the role of TPMT testing?
TPMT (Thiopurine S-methyltransferse) metabolises Azathioprine to its inactive metabolites. HGPRT converts azathioprine into its active metabolites.
Patients with TPMT deficiency are at increased risk of toxicity especially myelosuppression
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