Gastroenterology Flashcards
What drugs cause a mixed LFT derangement with a R factor 2-5?
Carbamazepine
Lamotrigine
Phenytoin
Sulphonamides
What drugs cause a hepatocellular pattern of LFT derangement with R factor > 5?
Paracetamol
Statins
Isoniazid
Rifampicin
Lamotrigine, diclofenac, disulfram, pyrazinamide
What are the causes of an acute transaminitis which would result in ALT / AST rise >1000?
- Ischaemic hepatitis - typically associated pre-renal AKI and elevated LDH
- Viral hepatitis
- Drug induced hepatitis - paracetamol
- Hepatic vein thrombosis
How is the R factor calculated and what does it indicate?
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
What causes an AST: ALT ratio of 2:1?
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)
What drugs cause a cholestatic pattern of LFT derangement with R factor <2?
Augmentin
Flucloxacillin
Penicillins
Cephalosporins
Androgens
OCP
Erythromycin
Fibroscan scores
High negative predictive value
Survival by Child Pugh Score
MELD components
- Creatinine, bilirubin, INR, haemodialysis
- Used for transplant waitlisting
Used for mortality stratification prior to TIPS
Pathophysiology of cirrhosis
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
Pathophysiology of portal hypertension
What are the effects of carvedilol in portal hypertension / cirrhosis?
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.
What does the hepatic venous pressure gradient indicate?
Causes of ascites by SAAG
SAAG > 11 => portal hypertension
SAAG <11 - other cause
What organisms cause SBP?
Culture negative in 60% cases
Gut organisms - E.coli & Klebsiella
Strep & Staph also possible
What does the ascitic fluid show in SBP?
≥ 250 PMN’s/mm3
Management of SBP including prevention
- 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
What are the types of hepatorenal syndrome?
- 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
What are the effects of terlipressin in hepatorenal syndrome?
- 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
How does lactulose & rifaximin work in the prevention & treatment of hepatic encephalopathy?
- 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
Risk factors for variceal bleeding
- 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
Who should be screened for varices?
- 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
Outline primary prophylaxis of variceal haemorrhage
Variceal banding OR non-selective beta blocker (carvedilol 6.25mg BD preferred as greater alpha blockade leads to bigger decrease in HVPG)
Secondary prophylaxis of variceal haemorrhage
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
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
Haemostatic abnormalities in CLD
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
- Hepatic vein thrombosis / Budd Chiari syndrome
- Diuretic refractory ascites or hepatic hydrothorax
TIPS procedure associated with improved survival and reduced rebleeding
What are the contraindications to TIPS?
- Heart failure - TIPS increases pre-load & increases R) sided pressures by shift in volume from splanchnic to systemic circulation
- Severe TR
- Severe pulmonary hypertension
- Polycystic liver disease
- 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
What are the complications of a TIPS procedure?
- 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 - Increased pre-load -> can worsen R) sided heart failure
- TIPS stenosis
- Technical complications - arrhythmias, traversal of liver capsule
What is the leading cause of death in NAFLD?
Cardiovascular disease
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
- Pioglitazone
- improves fibrosis as well as inflammation and steatosis
- BUT- weight gain, fluid overload, osteoporosis and bladder Ca
- 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
- Vitamin E (antioxidant)
- For non-diabetic patients
- Improves NASH
- BUT- risk of haemorrhagic stroke, prostate cancer
- Bariatric surgery
- Post of improvement in liver histology
- 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
- Cenicriciroc
- CCR5 antagonist à reduced macrophage recruitment à anti-fibrotic agent
- Elafibrinor
- PPAR agonist
- Increases lipid oxidation à decreases steatosis
Inhibits macrophages à decreased inflammation à decreased fibrosis
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
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
Biopsy features with NASH
- > 5% hepatic steatosis
- Lobular inflammation
- Hepatocellular ballooning
NAFLD = >5% hepatic steatosis
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
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%
Diagnostic criteria for ETOH hepatitis
- ETOH consumption - in last 2 months, >50g / day, minimum 6 months
- Bili >30
- AST : ALT ratio > 1.5
- No other cause of acute hepatitis
Where is iron absorbed?
Mainly in duodenum & jejunum
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
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
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
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.
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
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
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%
Natural history of hepatitis B
- Acute infection - mostly symptomatic (70%).
- <0.1% patients develop fulminant hepatitis B
3.. <5% adults with acute infection progress to chronic infection. > 90% infected adults progress to chronic infection - 30% of patients with chronic Hep B infection progress to cirrhosis
- 5-10% of patients with chronic Hep B progress to HCC without cirrhosis
What are the phases of chronic hepatitis B infection? Which phases should treatment be started in?
- 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 - 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. - Immune control
- seroconversion from HBeAg to HBeAb
- normal LFTs. Low viral load.
- Monitor every 6-12 months with LFTs & viral load - 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.
What are the two different types of treatment available for hepatitis B?
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
What are the extrahepatic manifestations of hepatitis C?
- 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) - Porphyria cutanea tarda
- bullous skin disease
- 50% with PCT have HCV - Lichen planus
20% pts have lichen planus
all patients with lichen planus should be assessed for HCV
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
Drug induced liver injury - cholestatic vs hepatitic pattern
What is the differential diagnosis of LFT derangement in pregnancy?
What are the maternal & foetal risks associated with intrahepatic cholestasis of pregnancy?
Management of perianal disease
Truelove & Witt’s criteria for severity of UC
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
