Liver and Friends Flashcards
What are the normal Functions of the Liver?
Protein Synthesis - albumin
Glucose and Fat metabolism
Detoxification and Excretion - drugs, hormones, bilirubin
Defense against infection - complement factors, clotting factors
Bile synthesis
What can chronic liver disease lead to?
Liver cirrhosis
Subsequent Liver failure
What does Acute Liver disease lead to?
Recovery - ability to regenerate
Acute Liver Failure
What is Acute Liver injury?
severe acute liver injury from a primary liver aetiology. It is characterised by liver damage (i.e. elevated transaminases) and impaired liver function (e.g. jaundice and coagulopathy with INR > 1.5). Hepatic encephalopathy is absent.
What are some causes of acute liver injury?
Viral A, B, EBV
Drugs - Paracetamol
Alcohol
Vascular – ischaemia (Budd Chiari Syndrome)
Obstruction – usually bile
Congestion – from heart failure
What are some causes of chronic liver disease?
Alcohol
Viral infection - Hepatitis (B/C)
Autoimmune liver disease
Metabolic dysfunction - iron/copper overload
NAFLD
What is a typical presentation of acute liver injury?
Non-specific signs:
Malaise
Nausea
Anorexia
Jaundice
GI Upset
Jaundice
Hepatomegaly
What are some common presentations of chronic liver disease?
Ascites
Oedema
Haematemesis (varices) – vomiting blood
Malaise
Anorexia
Wasting
Easy bruising
Itching
Erythema nodosum
Spider naevi
Hepatomegaly
Abnormal LFTs
Jaundice (rarer)
Confusion rarer)
What are the key liver function tests?
Serum Albumin - decreases in injury
Serum Bilirubin - increases in injury
Prothrombin time - increases in injury
Serum Liver Enzymes:
Hepatocellular - Transaminases (AST, ALT)
Cholestatic - Alkaline, Phosphatase Gamma GT
What LFT markers assess the livers synthetic function?
(what would happen to these markers in disease?)
Bilirubin (increase)
Albumin (decrease)
Prothrombin Time (increase)
What LFT markers would be raised in hepatocellular injury?
ALT
AST
What would the Ratio of AST/ALT suggest?
ALT>AST - chronic liver disease
AST>ALT - cirrhosis or acute alcoholic hepatitis
What LFT makers would be raised in cholestatic injury?
Alkaline Phosphatase (ALP/AP)
Gamma-glutamyltransferase (GGT)
What causes the yellow colour in jaundice?
The accumulation of bilirubin in the blood
What are the different classifications of jaundice?
Pre-hepatic - haemolysis, gilberts
Hepatic - liver damage/disease
Post hepatic - obstruction/biliary
What would be the colour/changes to urine and stools in pre hepatic jaundice?
Urine - Normal
Stools - Normal
Itching - None
Liver Tests - Normal
What would be the colour/changes to urine and stools in Intra hepatic/ Post Hepatic jaundice?
Urine - Dark
Stools - May be pale
Itching - Maybe
Liver Tests - Abnormal
What should be considered asking when a Px presents with Jaundice?
- Dark urine/ Pale stools, Itching
- Symptoms - Biliary pain, Rigors, abdo swelling, weight loss
- PHx - biliary disease, malignancy, HF, Autoimmune
- Drug Hx
- Social Hx - alcohol, Recent travel, IVDU
- FHx
What Tests would be wanted in a Px with Jaundice?
Liver enzymes - Very high AST/ALT suggests liver disease
Ultrasound - dilation of hepatic bile ducts in biliary obstruction
CT, MRCP, ERCP
What are MRCP/ERCPs?
Magnetic Resonance cholangiogram
Endoscopic Retrograde Cholangiogram
Where do Gallstones most commonly form?
In the gall bladder
What are the components of Gallstones?
70% cholesterol
30% pigment +/- Calcium
What are the risk factors for gallstones development?
4Fs
Female,
Fat
Fertile
Forty
(but can affect anyone)
What is the presentation of a Px with Gallstones?
Biliary Pain
Obstructive jaundice
What is the management of gallstones present in the gall bladder?
Laparoscopic cholecystectomy
Bile acid dissolution therapy
What is the management of gallstones present in the Bile Duct?
ERCP w/ Sphincterotomy (opening of sphincter of Oddi)
Followed by removal of stones, crushing of stones and stent placement
Surgery - remove larger stones
What is a typical time frame for drug induced liver injury?
From 5 days after starting it
To 3-6 months whilst on it.
What accounts for 50% of the causes of drug induced acute liver failure?
Paracetamol overdose
What proportion of acute liver failure is drug induced?
> 65%
What are the different types of Drug induced Liver Injury?
Hepatocellular
Cholestatic
Mixed
What are the common drugs that are hepatotoxic? (2 mnemonics)
VAMPIRES:
V - Valproate
A - Amiodarone
M - Methyldopa
P - Pyrazinamide
I - Isoniazid
R - Rifampicin
E - PhenYtoin
S - Statins
FAT PINK CARS:
F - Fe salts
A - Amiodarone
T - Tetracyclines
P - Pyrazinamide
I - Isoniazid
N - Nitrofurantoin
K - Ketoconazole (and other antifungals)
C - CCL4
A - Anaesthetic Agents (Halothane)
R - Rifampicin
S - Statins
What is Liver Failure?
The liver loses its regenerative capacity due to hepatocyte death/necrosis causing decompensated liver injury and irreversible damage.
What are the different types of Liver Failure?
Acute Liver Failure
Fulminant Liver Failure
Acute-on-Chronic Liver Failure
Chronic Liver Failure
What is Acute Liver Failure?
Rapid decline of hepatic functions characterised by the development of hepatic encephalopathy and coagulopathy (>1.5 INR) in a patient who previously had a normal healthy liver
What is Fulminant Liver Failure?
What are the different categories of Fulminant liver failure?
Rare syndrome of massive hepatocyte necrosis causing acute liver failure
Hyperacute - HE (Hepatic Encephalopathy) within 7 days of jaundice
Acute - HE within 8-21 days of Jaundice
Subacute - HE within 5-26 weeks of Jaundice??????????
What is the most common cause of Fulminant Liver Failure?
Paracetamol Overdose
50% of the cause in the UK
What is Acute-On-Chronic Liver Failure?
The acute and rapid decline of a Px with Chronic Liver failure Sx
What is Chronic Liver Failure?
Patient with progressive Hx of liver disease over 6+ months of constant liver injury
What is the Pathogenesis of Liver Failure?
Liver injury
Causes liver hepatitis
Chronic hepatitis leads to fibrotic liver
Leads to Liver cirrhosis
and then Decompensated Cirrhosis (End stage liver failure)
What are the main causes of acute liver failure?
Viral infection - Hep A/E/B, EBV, CMV
Autoimmune Hepatitis
Drugs - Paracetamol OD, Alcohol, Ectasy, Isoniazid
Metabolic Causes - Wilsons disease, A1AT, Haemachromotosis
Budd-Chirai syndrome
What is Budd Chiari Syndrome?
Hepatic vein thrombosis usually seen in the context of other haematological disease
This blocks the hepatic vein from draining leading to a backflow of blood into the liver causing liver damage
What are the symptoms of acute liver failure?
Chronic pain
Abdominal pain - RUQ
Nausea and vomiting
Malaise
What are the clinical signs of Acute Liver Failure?
Jaundice
Coagulopathy
Hepatic Encephalopathy
+:
Confusion
Asterixis - sign of HE
Hepatomegaly
Ascites
Bruising
What are the diagnostic investigations of Acute Liver Failure?
Bloods:
FBC - Infection/Bleeds
LFTs - Inc bilirubin, Inc PT/INR, Dec Albumin
Serum AST/ALT Inc, NH3 Inc, Dec Glucose
U&Es - Hepatorenal Syndrome
Imaging:
EEG - Grades HE (absent in Acute liver injury)
Abdo Ultrasound - Check for Budd Chiari
CT
Microbiology:
Blood culture, Urine culture, Ascitic tap - rule out infection
What is the treatment for acute Liver failure?
ICU,
ABCDE
Fluids
Analgesia
Tx underlying Cause and Tx complications
What is the treatment of paracetamol Overdose
<1 hour - Activated Charcoal + N-acetyl Cysteine
> 1 hour - N-acetyl Cysteine
What are some complications and their treatments of Acute Liver Failure?
Raised ICP - Mannitol
Hepatic Encephalopathy - Lactulose - increases NH3 excretion/ Rifaximin
Ascites - Diuretics (furosemide/spironolactone)/ paracentesis
Haemorrhage - Vitamin K
Sepsis - Sepsis 6
GI Bleeding - beta blockers
SBP - prophylactic Abx
What are the most common causes of Chronic Liver disease?
Alcoholic Liver Disease (ALD)
Non-Alcoholic Fatty Liver Disease (NAFLD)
Viral Hepatitis (B/C)
+ Metabolic, Autoimmune, PSC, PBC, Drugs, Budd Chiari
What is the main cause of Liver death in the UK?
Alcoholic Liver disease
What are the Major Risk factors for Chronic Liver failure?
Alcohol
Obesity
T2DM
Drugs
Inherited Metabolic Disease
Existing Autoimmunity
What is the Pathogenesis of Chronic Liver Failure?
Hepatitis chronic inflammation leads to scarring
Liver Fibrosis (reversible)
Liver Cirrhosis (barely Reversible/irreversible)
Compensated Liver cirrhosis - Some extent of liver function
Decompensated Liver cirrhosis - End stage liver disease
What are the key clinical signs of Liver cirrhosis?
Stigmata of chronic liver disease
Jaundice - Caused by raised bilirubin
Hepatomegaly
Splenomegaly - Caused by portal HTN
Spider Naevi - telangiectasia with central arteriole and small vessels radiating away
Palmer Erythema - Hyper dynamic circulation
Gynaecomastia - endocrine dysfunction
Bruising - abnormal clotting
Ascites
Dupytrens Contracture
Caput Medusae - distended paraumbilical vein due to Portal HTN
Asterixis - Flapping Tremor
What are the stigmata of chronic liver disease?
Caput medusa: distended and engorged superficial epigastric veins around the umbilicus.
Splenomegaly: enlarged spleen.
Palmar erythema: red discolouration on the palm of the hand, particularly over the hypothenar eminence.
Dupuytren’s contracture: thickening of the palmar fascia. Causes painless fixed flexion of fingers at the MCP joints (most commonly ring finger).
Leuconychia: appearance of white lines or dots in the nails. Sign of hypoalbuminaemia.
Gynaecomastia: development of breast tissue in males. Reduced hepatic clearance of androgens leads to peripheral conversion to oestrogen.
Spider naevi: type of dilated blood vessel (i.e. telangiectasia) with central red papule and fine red lines extending radially. Due to excess oestrogen. Usually found in the distribution of the superior vena cava.
What are the major Complications of Decompensated Liver Cirrhosis?
Malnutrition
Hepatic Encephalopathy
Ascites
Coagulopathy
Portal Hypertension
SBP - spontaneous bacterial peritonitis
Hepatorenal Syndrome
Oesophageal Varices
Hepatocellular Carcinoma
How does liver cirrhosis lead to malnutrition?
Increased use of muscle tissue as fuel and reduces amount of protein in the body.
Cirrhosis affects liver metabolism of protein and disrupts glucose and glycogen storage/release
leads to increased muscle used as fuel causing malnutrition.
What is the management of Liver cirrhosis induced malnutrition?
Regular meals
Low sodium - minimise fluid retention
High protein and high calorie
Avoid alcohol
How does Liver cirrhosis lead to portal hypertension and subsequent varices?
Liver cirrhosis leads to increased resistance of blood flow in the liver.
Increased pressure back into portal system
Causes pressure at anastomoses with systemic venous system
these swell and become tortuous causing varices
What are the most common sites for varices to occur as a result of portal HTN?
Gastro-oesophageal junction (GOJ)
Ileo-caecal junction
Rectum
Anterior abdominal wall via umbilical vein (caput Medusae)
What is a treatment for stable varices (non bleeding)
Propranolol - reduce portal HTN
Elastic band ligation
Injection of sclerosant
How does Liver Cirrhosis lead to Ascites?
Increased pressure in portal system leads to portal HTN
fluid leaks of of capillaries into the peritoneal cavity
A drop in circulating volume reduces BP entering kidneys. This activates RAAS - can exacerbate issue.
Lack of synthesis of albumin also lowers the oncotic pressure of the vasculature leading to fluid leakage
What is the management of Ascites?
Low sodium diet
Spironolactone
Paracentesis - ascitic tap/drain
Prophylactic Abx
What s SBP?
Spontaneous Bacterial Peritonitis that occurs secondary to ascites caused by cirrhosis.
This is an infection that develops in ascitic fluid without a clear cause
What is the presentation of SBP?
Can be ASx
Fever
Abdominal pain
Deranged bloods - Raised WBC, CRP, Creatinine
Ileus
Hypotension
What are the most common organisms in SBP?
E.coli
Klebsiella pneumoniae
Gram +tve cocci - Staphly/enterococci
What is the management of SBP?
Take an ascitic culture (paracentesis) prior to giving Abx
Often treated with IV Cephalosporin - Cefotaxime
How does Liver Cirrhosis lead to Hepato-Renal Syndrome?
Portal HTN decreases circulating volume in other areas such as kidneys.
Activates RAAS
Causes vasoconstriction (added to low blood supply to kidneys) starves kidneys of blood
Rapid deterioration of kidney function - Hepatorenal syndrome
What is hepatic encephalopathy?
Cirrhosis leads to increased ammonia build up in the blood which can be transported to the brain.
This can lead to reduced consciousness, confusion, personality changes, memory impairment and mood swings.
How is Hepatic Encephalopathy treated?
Laxatives (lactulose) - increase excretion of ammonia.
Abx (rifaximin) reduce bacterial production of ammonia
Nutritional support - potentially by NG tube
What is the Child Pugh Score?
What is involved?
Assess prognosis and Extent of required Tx for chronic liver failure:
Bilirubin
Ascites presence
Serum Albumin
PT/INR
HE
What is Decompensated Liver Cirrhosis a major risk factor for?
Hepatocellular Carcinoma
What is the Presentation of Chronic Liver Failure?
Jaundice
Ascites
HE
Portal HTN
Oesophageal Varices
Caput Medusae
What are the Diagnostic Investigations for Chronic Liver Disease?
Liver Biopsy - Gold standard - Determines Extent of CLD
LFTs,
Imaging - Ultrasound, CT for secondary findings
Ascitic Tap
What investigations are done in chronic liver disease (cirrhosis) to determine condition/cause?
Non-invasive Liver Screening:
Bloods:
LFTs - Hepatocellular/cholestatic
FBC - inflammation/infection
Electrolytes - Hyponatraemia (Fluid retention)
U&Es - hepatorenal syndrome (Urea + creatinine are deranged)
viral markers/autoantibodies - virus/autoimmune cause
Alpha-Fetoprotein - HCC
Fibroscan - elasticity of the liver
Ultrasound - Splenomegaly, Ascites, Enlarged portal veins
Endoscopy - Oesophageal varices
CT/MR - HCC, Hepatosplenomegaly, ascites
Liver Biopsy - confirm cirrhosis.
What is the Treatment of Chronic Liver Disease?
Tx underlying pathology
Prevent Progression - lifestyle modification
Consider Liver transplant - If decompensated liver
Manage complications
What is Alcoholic Liver Disease?
Progressive damage to the liver from long term excessive Alcohol Consumptions.
What is the Progression of Alcoholic Liver Disease?
Alcohol related Fatty liver (steatosis):
Build up of fat in the liver (reversible in a few weeks)
Alcoholic Hepatitis:
Liver inflammation - Mallory Bodies
Alcoholic Cirrhosis
Liver becomes largely fibrotic - Micronodular
What is the recommended alcohol intake per week?
14 units
How do you calculate the number of units in an alcoholic drink?
Strength (ABV) x Vol/ml / 1000
What is 1 UNIT of alcohol?
8g OR 10ml
What are the symptoms of Alcoholic Liver disease?
Early stages may show little signs/Sx
Jaundice
Fever: important to rule out infection
Anorexia
Abdominal pain
Abdominal distention (ascites)
Muscle wasting
Confusion: seen in encephalopathy and alcohol withdrawal
What are the signs of ALD?
Jaundice
Tender hepatomegaly
Ascites
Asterixis: flapping tremor secondary to encephalopathy
Tremor: seen in alcohol withdrawal
Bruising (coagulopathy)
Stigmata of chronic liver disease
What are the CAGE Questions?
C – CUT DOWN? Ever thought you should?
A – ANNOYED? Do you get annoyed at others commenting on your drinking?
G – GUILTY? Ever feel guilty about drinking?
E – EYE OPENER? Ever drink in the morning to help your hangover/nerves?
What investigations should be done for all patients with suspected Hepatitis?
Full blood count
Urea & electrolytes
Liver function tests
Bone profile
C-reactive protein
Magnesium
Coagulation (INR)
Non-invasive liver screen
Liver ultrasound
+/- septic screen (e.g. blood cultures, urines, ascitic cultures, chest x-ray)
What are the Diagnostic investigations for ALD?
Bloods:
LFTs - Raised GGT, AST/ALT ratio >2
FBC - Macrocytic non-megaloblastic anaemia
Hx of Alcohol
Biopsy - confirm extent of hepatitis/cirrhosis
What Laboratory findings may be indicative of ALD?
Moderately elevated transaminases (< 300 IU/L)
AST/ALT ratio >2 (other liver diseases rarely cause this ratio)
Elevated bilirubin (usually > 86 umol/L)
Elevated gamma-glutamyl transferase (GGT)
Elevated neutrophil count (typically < 20.0 x10^9/L)
Elevated INR
What may be found in ALD on histology?
Mallory Cytoplasmic Inclusion Bodies
What are the treatments of ALD?
STOP ALCOHOL - Tx withdrawal if present
Healthy Diet / BMI
Pharmacological - Consider steroids short term
B1 & folate supplements
Surgical - Consider Liver transplant in ESLF
What can be given to treat withdrawal Sx of ALD?
Chlordiazepoxide
Diazepam
To be eligible for a liver transplant, how long must you have abstained from alcohol for?
3+ months
What are the complications of Alcoholic Liver disease?
Pancreatitis
HE
Ascites
HCC
Mallory Weiss Tear
WERNICKE KORSAKOFF SYNDROME
What is Wernicke Korsakoff Syndrome?
A memory disorder that results from Vitamin B1 (thiamine) deficiency caused by alcoholism as this is poorly absorbed in the presence of alcohol.
Wernickes Encephalopathy comes before Korsakoffs syndrome
What are the symptoms of Wernicke Encephalopathy and Korsakoff syndrome?
Wernicke Encephalopathy:
Confusion
Nystagmus
Ataxia
Korsakoff Syndrome:
Memory Impairment
Behavioural changes
How is Wernicke Korsakoff Syndrome treated?
IV Thiamine (Vit B1)
What is NALFD?
Non-alcoholic fatty liver disease:
excess fat with the liver, which is known as hepatic steatosis (i.e. fatty liver). A small amount of fat in the liver is normal, but when this is present in > 5% of hepatocytes we term it NAFLD
What are the risk factors for NAFLD?
Obesity
HTN
Hyperlipidaemia
T2DM
FHx - PNPLA3
Endocrine disorders
DRUGS
What is the Epidemiology of NAFLD?
NAFLD is now the most common cause of abnormal liver blood tests within the UK and estimated to affect > 50% of patients with type 2 diabetes mellitus.
What is Metabolic Syndrome?
The metabolic syndrome refers to a group of risk factors that are associated with an increased risk of cardiovascular disease and stroke. These risk factors have also been associated with the development NAFLD and include:
What are the factors of Metabolic Syndrome?
Abdominal obesity: waist circumference > 94 cm men and > 80 cm women
Hypertension: arterial blood pressure > 130/85 mmHg or treated for
hypertension
Impaired fasting glucose: fasting blood glucose > 5.6 mmol/L or treated for type 2 diabetes mellitus
High triglycerides: serum level > 1.7 mmol/L
Low HDL cholesterol <1mg/dl in Men and 1.3mg/dl in women
What drugs are RFs for NAFLD?
NSAIDS
Amiodarone
What is the pathogenesis of NAFLD?
Accumulation of Fat within the liver promotes inflammatory changes.
Hepatosteatosis (NAFLD)
This can lead to liver injury promoting inflammation
Non-alcoholic steatohepatitis (NASH)
Excessive inflammation and hepatocellular death leads to fibrosis
Fibrosis leading to Cirrhosis
How would a NAFLD Px present?
Often ASx
Any findings are incidental
If severe NAFLD then Sx/signs of Liver failure
What are the diagnostic tests for NAFLD?
Bloods:
Abnormal LFTs - Inc PT/INR, Dec Albumin, Inc Bilirubin
FBC - Thrombocytopenia, Hyperglycaemia
Imaging:
1st line - Abdominal Ultrasound - confirms diagnosis of hepatic steatosis
Enhanced Liver Fibrosis (EFL)
NAFLD fibrosis score
Fibroscan
What investigation would be used to determine the cause of abnormal LFTs if the cause is unclear?
Non-invasive Liver screen:
FBC
LFT
U&E
Ultrasound
Hep B/C serology
Autoantibodies - AIH, PBC,PSC
Immunoglobulins - AIH, PBC
Caeruoplasmin - wilsons disease
Alpha 1 anti trypsin - A1AT Def
Ferritin/Transferrin - HH
How is the risk of fibrosis assessed?
Using FIB-4 (fibrosis score)
Detects stiffness of the liver
What is the Tx for NAFLD?
Lose weight (lower BMI)
Control RFs:
Statins - cholesterol
Metformin - diabetes
ACEi - BP
Vitamins
What are some complications of NAFLD?
HE
Ascites
HCC
Portal HTN
Oesophageal Varices
What is Autoimmune Hepatitis?
Chronic liver inflammation (hepatitis) caused by autoimmune attack via T cells on the Liver.
It has an unknown cause but likely genetics and then an environmental trigger
What are the risk factors for autoimmune hepatitis?
Female
Other autoimmune diseases - SLE
Viral hepatitis
HLA DR3/4
What are the types of Autoimmune Hepatitis?
Type 1 - Adult females (80% of cases):
ANA/ASMA Abs - Very specific for T1 AIH
Type 2 - Young Females:
ALC-1/ALKM1 Abs
Seronegative AIH - 20% of AIH patients are autoantibody negative.
How may patients present with AIH?
25% ASx
40% with acute Hepatitis Sx:
Anorexia
Nausea
Coryzal symptoms
Jaundice
Right upper quadrant pain
Hepatomegaly
30% with Chronic Liver Disease Sx:
Non-specific features
Stigmata of chronic liver disease
Complications of cirrhosis
What are the diagnostic investigations for AIH?
Serology - ANA/ASMA +/- ALC-1/ALKM1
LFTs - Hepatic (ALT/AST Raised)
Liver Biopsy
What may be seen on liver biopsy to aid the diagnosis of AIH?
Interface hepatitis: inflammation and fibrosis at the lobular-portal interface
Lymphoplasmacytic infiltrates: infiltration of lymphocytes and plasma cells
Hepatocyte necrosis: specifically ‘bridging necrosis’.
Hepatic Rosette formation: gland-like formations (Pseudoacini) that develop due to chronic inflammation.
What are the antibodies associated with AIH?
Anti-nuclear (ANA) - Type 1
Anti-Smooth muscle (ASMA) - Type 1
Anti-liver/kidney (ALKM1) - Type 2
Anti-mitochondrial (AMA) - mainly for PBC
Anti-soluble liver and pancrease (SLA/LP) - 75% of Type 1
What Immunoglobulin is associated with AIH?
IgG are raised
How is AIH treated?
Immunosuppressants via Corticosteroids (Prednisolone) + Azathioprine
Hep B vaccination
What is a last resort Tx for AIH?
Transplant consideration (10-20% of Px may have this)
What is the process of RBC breakdown?
RBC Hb is split into Haem and Globin
Haem is split into Iron and Biliverdin (via Haemoxygenase). Globin into amino acids which is recycled for erythrocytes
Biliverdin is converted to Unconjugated Bilirubin via biliverdin reductase
UnC Bilirubin is bound to albumin and transported to the liver
UDP GlucoronylTransferase (UGT) Conjugates Unc biliribin with Glucoronic acid to form Con Bilirubin.
Con Bilirubin enters the small intestine via the CBD and enters at the A.o.V
Con bilirubin is converted to urobilinogen via colonic flora.
5% - sent to kidneys to be oxidised and excreted as urobilin
5% - recycled via enterohepatic circulation
90% - Large intestine and reduced to stercobilin and excreted in faeces
What is Jaundice?
Yellowing of the skin and eyes due to accumulation of conjugated/unconjugated bilirubin in the blood.
What are the different types of Jaundice?
Pre-hepatic - Haemolysis
Intra-hepatic - Liver dysfunction
Post hepatic - Obstruction
What are the causes of Pre-hepatic jaundice?
Haemolytic anaemias:
Sickle cell
Thalassaemia
G6PDH Def
Malaria
What is raised in Pre hepatic jaundice?
Raised Unconjugated bilirubin due to increased RBC breakdown saturating conjugatory mechanisms
What are the causes of intra hepatic jaundice?
Parenchymal disease:
HCC
ALD/NAFLD
Hepatitis
Hepatotoxic drugs - Rifampicin
Gilberts syndrome
Crigler Najjar Syndrome
What is Raised in Intra hepatic jaundice?
Conjugated and unconjugated bilirubin
Can be mixed due to the failure of Hepatocytes to uptake, metabolise and or excrete bilirubin
What is Gilberts Syndrome?
Very common Autosomal recessive mutation of UGT1A1 gene
causes underactive UGT enzyme and therefore decreases CON bilirubin.
How may a Patient with Gilbert Syndrome present?
Young male
Painless jaundice that has sudden onset
What is Crigler Najjar Syndrome?
Autosomal recessive absence of UGT enzyme and therefore has an inability to conjugate bilirubin
What are the causes of Post hepatic Jaundice?
Biliary tree pathology
Choledocholithiasis - bile stone
Pancreatic cancer
cholangiocarcinoma
Mirizzi Syndrome
Autoimmune - PBC/PSC
What is Mirizzi Syndrome?
common hepatic duct obstruction caused by extrinsic compression from an impacted stone in the cystic duct or infundibulum of the gallbladder
What is raised in Post hepatic jaundice?
Conjugated bilirubin is raised due to biliary obstruction.
This causes pale stools and Dark urine.
What is Courvoisier sign and what would it suggest?
Painless jaundice and palpable GB
Likely pancreatic cancer/cholangiocarcinoma
What is the Charcot Triad?
Fever
RUQ Pain
Jaundice
What combination of Charcot Triads symptoms suggest which conditions?
RUQ pain = Biliarycolic
Fever + RUQ pain = Cholecystitis
Fever + RUQ Pain + jaundice = Ascending cholangitis
What is Murphys Sign?
RUQ Tenderness
Ask Px to take a breath in whilst pressing on RUQ
Makes them wince
+tve for Cholecystitis
How can the type of Jaundice be diagnosed?
1st line = Abdominal Ultrasound
Blood tests and LFTs
Urine bilirubin: normally -tve
+tve = Dark urine = post hepatic/intrahepatic
-tve in haemolysis causes
Urobilinogen: normally +tve
Increased in haemolysis - Pre hepatic
Decreased in Intra/post hepatic
What is pancreatic cancer?
Adenocarcinoma of the exocrine pancreas
(99% of cases) of ductal origin.
Typically affects the head of the pancreas
who is typically affected by pancreatic cancer?
Males
60yrs +
What are the risk factors for pancreatic cancer?
Smoking
Alcohol
Diabetes Mellitus
FHx
Chronic pancreatitis
Genetics - PRSS-1 mutation
How would a patient with pancreatic cancer present/ what signs would they have?
Anorexia
Weight loss
Acute pancreatitis
Body and tail of pancreas:
Epigastric pain that radiates to back
Relieved by sitting forward
Head of pancreas:
Painless jaundice (Courvoisier’s Sign)
Weight loss
What is the characteristic of the pain in a body/tail pancreatic cancer?
Epigastric pain
Radiates to the back
Relieved when sitting forward
What are the diagnostic investigations for pancreatic cancer?
1st line - abdominal ultrasound
GS - Pancreatic CT protocol then bile duct drainage
Ca19-9 tumour marker positive - monitors progression
What is the gold standard diagnostic investigation for pancreatic cancer?
Pancreatic CT
Diagnostic in 97% of cases
+ Biopsy confirmation
What marker indicates progression of pancreatic cancer?
Ca19-9 tumour marker
What is the Treatment of pancreatic cancer?
Very poor prognosis - 5yr survival - 3%
surgery + post op chemo if no mets
Palliative care
What is Hepatocellular carcinoma (HCC)
arise from liver parenchyma
90% all primary liver cancers
What is the epidemiology of HCC?
One of the leading causes of cancer mortality
Highest risk in Asia due to increased burden of Viral Hepatitis
What are the major risk factors of HCC?
Chronic hepatitis - viral infection of Hep C and B
Cirrhosis of the liver - ALD/ NAFLD/ Haemochromatosis
What are some other risk factors for HCC (non major)?
Hepatitis D
Aflatoxin B1
Alcohol
Smoking
NAFLD
Metabolic Liver disease
Where do HCC metastases often travel to?
How do these travel?
Lymph nodes
Bones
Lungs
via haematogenous spread (hepatic/portal veins)
How would a patient with HCC present?
Sx of decompensated liver failure - HE, jaundice, ascites
Cancer signs - tATT, unexplained weight loss
What diagnostic investigations are done for HCC?
Imaging:
1st line - Abdo ultrasound
GS - CT (confirms diagnosis)
May also biopsy and Histology for diagnosis
Raised serum AFP (alpha fetoprotein)
What is the treatment of HCC?
Surgical Resection of the liver
Only cure is Liver transplantation if decompensated
What should be given to prevent HCC?
HBV Vaccination!!
What isa cholangiocarcinoma?
adenocarcinoma that arises from the biliary tree
What percentage of liver cancers are cholangiocarcinomas?
10%
What are the risk factors for cholangiocarcinoma?
Parasitic flukeworms
Biliary Cysts
IBD
PSC
How would a Px with cholangiocarcinoma present?
Abdo pain
jaundice
weight loss
pruritis
fever
Late constellation Sx of tumour since it is slow growing
What diagnostic investigations would be used for a cholangiocarcinoma?
LFT - Inc Bilrubin, Inc Alkaline Phosphates
Inc Ca19-9
Imaging :
1st line - Abdo USS + CT
GS ERCP - imagine of biliary tree
Biopsy
What is the gold standard investigation for cholangiocarcinoma?
ERCP
What is the Tx of cholangiocarcinoma?
Chemo/radiotherapy possibly
Mostly inoperable due to late presentation of Px
What are some benign primary liver tumours?
Haemangioma
Hepatic Adenoma
What is more common, primary or secondary liver tumours?
Secondary are more common
Where can secondary tumours come from?
GI tract
Lungs
Breast
How may a patient with a secondary liver tumour present?
Depends on the site of the primary cancer
What diagnostic investigations may show a secondary liver tumour?
Increased serum ALP(Alkaline Phosphatase)
Imaging:
1st line - Ultrasound
GS - CT/MRI for staging and primary tumour
What is the Treatment of 2’ liver cancer?
Surgical resection if possible
Chemotherapy
What are some different biliary tract diseases
Gallstones
Cholecystitis
Ascending Cholangitis
What are the risk factors for biliary tract disease
5Fs
Fat
Female
Forty (40+)
Fertile
Fair
+ FHx, T2DM, NAFLD
What are gallstones?
Small stones usually made of cholesterol that form in the gall bladder
Define:
Cholelithiasis
Choledocholithiasis
Biliary Colic
Acute Cholecystitis
Acute Cholangitis
Cholelithiasis: refers to gallstones - solid deposits that develop in the gallbladder.
Choledocholithiasis: refers to gallstones within the biliary tree.
Biliary colic: refers to a self-limiting pain in the RUQ/epigastrium associated with gallstones.
Acute cholecystitis: refers to the acute inflammation of the gallbladder, most commonly caused by gallstones.
Acute cholangitis: refers to infection of the biliary tree, commonly due to an obstructing stone in the common bile duct.
What is the epidemiology of gallstones
May be present at any age but unusual <30
Increasing prevalence with age
More common in females
More common in Scandinavians, S. Americans and Native North Americans
Less common in Asian and African groups
Most form in the GB
Present in 10-20% of population
What is the general composition of gallstones?
Phospholipids - lecithin
Bile pigments (broken down haemoglobin)
Cholesterol
What are the 3 types of gallstones?
Cholesterol
Black Pigment
Mixed (brown pigment)
What are the characteristics of cholesterol, Pigment and mixed stones?
Cholesterol:
Large often solitary
Pigment:
Small black and gritty,
calcium bilirubinate
Mixed:
often have multiple
Main component is cholesterol mixed with calcium bilirubinate and calcium salts
How are Cholesterol stones formed?
They occur due to crystallisation of cholesterol in bile (along with other compounds) due to supersaturation of cholesterol and crystillisation promoting factors
How are pigment stones formed?
They occur in people with increased amounts of bilirubin in their bile - hyperbilirubinbilia. This occurs in patients with increased haemolysis
How are Mixed Stones formed?
These stones are a mix of calcium bilirubinate and a calcium salts of fatty acids, accounting for around 5% of stones. They mostly occur in association with infection (bacterial or parasitic) and may develop de novo in the bile duct after cholecystectomy.
What is the cause of gallstones?
Lithogenic bile - Admirand’s triangle
Biliary sepsis
Altered composition of Bile
Gallbladder hypomotility:
- Pregnancy/oestrogen contraceptive pill
- Total parenteral nutrition/fasting
What is Admirand’s triangle?
Low bile salts
Low lecithin
High cholesterol
How are gallstones formed?
Bile is secreted by hepatocytes into the biliary circulation. It is composed of bile acids (or salts), phospholipid, bilirubin, cholesterol and water.
Imbalance in composition and stasis leads to stone formation.
What are the symptoms of gallstones?
Usually ASx but can cause cholic pain upon GB contraction
RUQ biliary colic pain - constant severe pain for 30 mins
Worse after a fatty meal as CCK induced gallbladder contraction against a stone
Pain radiates to right shoulder
Fever
Jaundice - if stone obstructs duct
nausea and vomiting
What investigations are done to confirm gallstones?
Murphy Sign
Ultrasound scan
LFTs - ALT raised due to backpressure. Bilirubin high if blockage.
MRI - stones in bile duct
CT - gallstone complications
cholangiography - assess condition of the gallbladder
What are the complications of gallstones in the gallbladder?
Biliary colic
Acute cholecystitis +- empyema
Chronic cholecystitis
Mucocele
Carcinoma
Mirrizi’s syndrome
What are the complications of gallstones in the common bile duct?
Obstructive Jaundice
Pancreatitis
Cholangitis
What are the symptoms of cholecystitis?
RUQ pain + Fever + Tender gall bladder
Reffered pain to top of right shoulder (phrenic)
Murphy Sign +tve
Vomiting
What is Murphy Sign?
patient to take in and hold a deep breath while palpating the right subcostal area.
If pain occurs when the inflamed gallbladder comes into contact with the examiner’s hand,
Murphy’s sign is positive.
What is the treatment for Cholecystitis?
Abx, Analgesia and fluids
Laparoscopic cholecystectomy
What are the symptoms of Ascending cholangitis?
Reynolds pentad:
RUQ pain
Fever
Jaundice
Altered mental state
Hypotension
What is Reynold’s Pentad
Chartcot’s Triad + Altered Mental State + Hypotension
What is the Diagnostic test for Gallstones
1st line = Abdo ultrasound
What are the investigations for Ascending Cholangitis?
Ultrasound abdomen
FBC
Raised WBCs
Raised ESR and CRP
Raised serum bilirubin (very high if bile duct obstruction) and serum alkaline phosphatase
ERCP
MRCP to locate stone
LFTs
CT
What is the treatment for Ascending Cholangitis?
IV antibiotics e.g. co-amoxiclav
Fluids
ERCP (endoscopic retrograde cholangiopancreatography) to image/stent/remove stone
Shockwave lithotripsy
If this fails 🡪 laparoscopic/open cholecystectomy
What are the treatments for gallstones?
Elective laparoscopic cholecystectomy if Sx
Until then pain management- NSAIDS (mild), Diclofenac (severe)
Lifestyle modifications - low fat in diet
What is Biliary Colic?
Where a patient has cholic pain due to a gallstone often in the gallbladder that has not yet caused inflammation and therefore the patient doesn’t present with aa fever or jaundice. They will likely have RUQ pain (colicky) if Symptomatic
What is acute cholecystitis?
gall bladder inflammation that develops over hours
What is the pathogenesis of acute cholecystitis?
Large fatty meals stimulate CCK which signals bile release from GB
When the GB has a gallstone in it, the squeezing of the GB can get it lodged in the cystic duct
Bile stasis becomes a chemical irritant stimulates mucosa in wall to release mucus and inflammatory enzymes 🡪 inflammation, distension and pressure build up
Bacteria can start to grow e.g. E. coli and invade into gallbladder wall 🡪 Cholecystitis
If they penetrate the GB wall then this can lead to peritonitis
What are the causes of cholecystitis?
Gallstones
Tumour
Bile duct blockage
Infection
Blood vessel problems
What investigations are done for acute cholecystitis?
Urine tests - bilirubin and urobilinogen raised
FBC - Inc WCC
Imaging - abdominal USS
What test is ordered if dilated bile ducts are found on ultrasound in suspected acute cholecystitis?
MRCP
What are the differential diagnoses for acute cholecystitis?
Main:
Biliary Colic
Cholangitis
Others:
Peptic ulcer disease
Liver disease
Pancreatitis
Cardiac disease
What is the management for Acute Cholecystitis?
Conservative: if ASx
Nil by mouth
Fluid resuscitation
Abx - Gentamicin
analgesia - Paracetamol/NSAIDS
If Symptomatic:
Laparoscopic cholecystectomy
Analgesia and fluids and Abx (gentamicin)
What is Ascending Cholangitis?
Inflammation of the bile duct caused by bacteria ascending from the duodenum through the ampulla of Vater
What is the pathophysiology of ascending cholangitis?
Normally, bacteria can’t go up CBD as bile and pancreatic juices travel down and flush bacteria out
Obstruction of common bile duct 🡪
stasis of bile 🡪 invasion of bacteria from duodenum
High pressure on the CBD (due to the obstruction) can cause spaces between the cells do widen which allows the bacteria and the bile access to the blood stream 🡪 bacteraemia and jaundice
Can be obstructed by stone, cancer, stricture, parasite (ascaris). Also, infection can be introduced through intervention e.g. ERCP
What causes ascending cholangitis?
Gallstones
Iatrogenic - ERCP
Cholangiocarcinoma
Ascending infection from duodenum junction
What are the risk factors of ascending cholangitis?
History of gallstones (5Fs)
Sclerosing cholangitis
HIV
Narrowing of common bile duct
What are the blood tests done for suspected or known ascending cholangitis?
FBC - WCC raised
CRP - Raised
LFT - Hyperbilirubinaemia
What imaging tests are ordered for ascending cholangitis?
Transabdominal ultrasound
What is the management of ascending cholangitis
Antibiotics
ERCP - bile duct clearance
How can Sepsis occur in ascending cholangitis?
Biliary obstruction causes backflow of biliary sludge.
This causes stasis
Bacteria from the intestines can enter the biliary duct and colonise the biliary tree
What are the differential diagnoses for a patient who has:
1. RUQ pain, No fever , No jaundice.
2. RUQ pain, Fever, no jaundice
3. RUQ pain, Fever and Jaundice
- Biliary Colic
- Acute Cholecystitis
- Cholangitis
What is Primary Biliary Cholangitis
Autoimmune system attacks the small bile ducts in the liver.
This causes obstruction of the outflow of the bile (cholestasis)
The back pressure of bile obstruction can lead to fibrosis and liver disease
What is the pathophysiology of PBC?
PBC is characterised by T-cell mediated attack to small bile ducts within the liver.
Autoreactive T cells seem to target the E2 subunit of the pyruvate dehydrogenase complex, which is expressed on the luminal surface of bile duct epithelial cells in PBC.
Chronic inflammation leads to bile duct destruction and loss.
This leads to cholestasis (poor bile flow), which causes the build-up of potentially toxic substances at high concentrations, such as bile acids, that can lead to damage to hepatocytes.
Over time, this leads to chronic liver disease.
What autoantibodies are associated with PBC?
Anti-Mitochondrial (AMA) - 95% of patients.
Also ANA, Anti-gp210 and anti-sp100
What ducts are affected in PBC?
Intralobar ducts
(Canals of Hering)
What are the symptoms of PBC?
Fatigue
Pruritus
GI disturbance and abdominal pain
Signs of chronic liver disease
What are the signs of PBC?
Hepatomegaly
Excoriation marks
Xanthomas (deposition of cholesterol in the skin causing a nodule)
Xanthelasmas (deposition of cholesterol in the skin causing a papule or plaque)
Xerosis (dry skin)
Hyperpigmentation of skin: due to melanin deposition but reason unknown
Jaundice: more common as disease advances
Features or chronic liver disease (advanced disease)
What is PBC associated with?
Middle aged women >50 years
Other autoimmune diseases (e.g. thyroid, coeliac)
Rheumatoid conditions
What is Xanthoma and Xanthelasma?
Xanthomas (deposition of cholesterol in the skin causing a nodule)
Xanthelasmas (deposition of cholesterol in the skin causing a papule or plaque)
What are some complications of PBC?
Cirrhosis
Malabsorption of Fats + ADEK
steatorrhoea
osteomalacia
How is the diagnosis for PBC made?
Diagnosis of PBC is based on the presence of cholestatic liver enzymes and positive anti-mitochondrial antibodies.
What are the diagnostic tests for PBC?
LFTs:
Raised AP
Raised Con Bilirubin
Dec Albumin
Antibodies:
AMA (anti mitochondrial) - specific to PBC (95%)
ANA (anti nuclear)
Liver Biopsy
Imaging:
1st Line - Abdo USS to exclude extrahepatic cholestasis
Blood tests:
ESR Raised
IgM Raised
What is the Treatment of PBC?
Ursodeoxycholic acid - reduces intestinal absorption of cholesterol
Sx Treatment:
Colestyramine - for Pruritus
Rifampicin - Abx
SSRI (sertraline)
Vit ADEK Supplements
Liver Transplant - in ESLF
What is the most important disease progression of PBC?
Advanced liver cirrhosis
Portal Hypertension
What is Primary Sclerosing Cholangitis?
Autoimmune attack on the intrahepatic and/or extrahepatic ducts causing them to become strictured and fibrotic.
This causes an obstruction to bile outflow from the liver eventually resulting in cholangitis, hepatitis and Liver cirrhosis (Same pathology as PBC)
What are the risk factors for PSC?
Male
Northern Europeans
Aged 30-40
Ulcerative colitis
FHx
What is the aetiology of PSC?
Largely Unknown.
PSC is considered a progressive autoimmune disorder that is strongly associated with inflammatory bowel disease (IBD)
How would PSC Present?
Early stages may be ASx
Sx:
Fatigue
Pruritus
Features of cholangitis - Fever, malaise, night sweats, RUQ pain, Rigors
Signs:
Hepatomegaly
Splenomegaly
Excoriations
Stigmata of chronic liver disease
What are the diagnostic tests for PSC?
LFTs:
Cholestatic - ALP and GGT is raised
Then later bilirubin may become raised later in disease
Antibodies are not sensitive or specific for PSC (sometimes pANCA)
GS - MRCP imaging showing bile duct lesions/strictures
What is the treatment of PSC
Conservative Sx management
Liver transplant is only effective Tx (curative)
Colestyramine - help pruritus
How does Colestyramine help with pruritus?
Bile acids can bit itchy.
Colestyramine binds to bile acids and prevents their absorption (Bile acid Sequestration).
What does PSC have a strong link to?
IBD - Ulcerative Colitis
What are some complications of PSC?
Acute bacterial cholangitis
Cholangiocarcinoma
Colorectal cancer
Cirrhosis and liver failure
What are some differential Diagnoses for PSC?
It is important to exclude secondary causes of sclerosing cholangitis before making the diagnosis.
Causes of Sclerosing Cholangitis:
Inflammatory: IgG4-sclerosing cholangitis, pancreatitis
Malignancy: cholangiocarcinoma, hilar lymphadenopathy, head of pancreas tumour
Infection: recurrent pyogenic cholangitis, biliary infestation (e.g. flukes)
Stones: choledocholithiasis
Other: drugs, papillary stenosis
What is Acute Pancreatitis?
Acute inflammation of the pancreas
What are the causes of Acute Pancreatitis?
I GET SMASHED:
Idiopathic
Gallstones - 50% of all acute causes
Ethanol - 80% of chronic causes
Trauma
Steroids
Mumps
Autoimmune
Scorpion Sting/Spider Bite
Hypercalcaeima/Hyperlipidaemia
ERCP
Drugs - Azathioprine, NSAIDs, ACEi
What drugs can cause Acute Pancreatitis?
Azathioprine
NSAIDs
ACEi
What is the pathogenesis of Acute pancreatitis?
Obstruction of pancreatic secretions/damage to pancreas causes accumulation of digestive enzymes in the pancreas
Zymogens become activated within the pancreas
Leads to autodigestion of the pancreas creating inflammation and enzymes leak into the blood. Can lead to retroperitoneal haemorrhage
Oedema, fluid shift and vomiting leads to hypovolaemic shock
What are the risk factors for acute pancreatitis?
Alcoholism
Smoking
Obesity
Family history
What are the symptoms associated with acute pancreatitis?
Abdominal pain (may radiate to the back)
Nausea
Vomiting
Anorexia
Diarrhoea
What are the signs of Acute pancreatitis?
Abdominal tenderness
Abdominal distention
Cullen’s Sign
Grey-Turner’s Sign
Signs of Shock:
Tachycardia
Tachypnea
Pyrexia
What are the Eponymous signs for pancreatitis?
Cullen’s sign: peri-umbilical bruising (first described in ruptured ectopic pregnancy)
Grey-Turner’s sign: flank bruising
What is a DDx of acute pancreatitis based on the pain experienced by Px?
AAA
What diagnostic investigations would be performed in acute pancreatitis?
FBC:
High WCC
GS - Liver enzymes: Serum Amylase and Lipase High
LFTs:
Cholestatic - High AST, LDH
High Conc bilirubin
Low Urobilinogen
Imaging;
CXR - Exclude duodenal ulcer
USS Gallstones
What is the first line/Gold standard test for acute pancreatitis?
A serum amylase elevated 3 times above the reference range is considered diagnostic.
What is required for Dx of Acute pancreatitis?
Px must have at least 2 of:
Characteristic Signs and Symptoms
Increased Amylase/Lipase
Radiological Evidence (USS)
How is pancreatitis severity scored?
APACHE 2 - assess severity in 24hrs
Glasgow Criteria - Prediction of severe attack (only after 48hrs)
What is the Glasgow criteria in assessing acute pancreatitis severity?
PANCREAS:
PaO2
Age
Neutrophils
Ca2+
Renal Function
Enzymes
Albumin
Sugar
What is the Treatment of acute pancreatitis?
Emergency:
Nil By mouth
IV fluid
Analgesia - morphine
Catheterise
Abx prophylaxis
What is a major complication of acute pancreatitis?
SIRS (systemic Inflammatory Response Syndrome)
Tachycardia
Tachypnoea
Pyrexia
Increase WCC
What are some complications of Acute pancreatitis and how are they managed?
ARDS - Give O2
Hyperglycaemia - Insulin
Shock - Hypovolaemic give fluids, Septic - Abx
What Ig is Raised in a patient with autoimmune chronic pancreatitis?
IgG4
How is autoimmune Chronic pancreatitis treated?
With steroids
What is Chronic Pancreatitis?
3+ month history of pancreatic deterioration leading to irreversible pancreatic damage, inflammation and fibrosis.
Give the pathophysiology of Chronic Pancreatitis
Progressive loss of lobular morphology and structure of pancreas due to necrosis/apoptosis, inflammation and/or duct obstruction
Deformation of the large ducts and severe changes in arrangement and composition of islets
Irreversible morphological and structure changes - impair exocrine and endocrine functions
What are the causes of chronic pancreatitis?
AGITS:
Alcohol - Most common
Genetics - CF, Haemochromatosis
Immune
Triglycerides
Structural - Duct obstruction
CDK, Trauma, Recurrent acute Pancreatitis
What are the risk factors for chronic pancreatitis?
Male sex
Alcohol misuse
Smoking
Obesity
Recurrent acute pancreatitis
CKD
Gallstones
⍺1-antitrypsin deficiency
How might a patient present with chronic pancreatitis?
Epigastric pain
Steatorrhoea (increased levels of fat in stool) and weight loss
Endocrine Dysfunction - Diabetes mellitus - polyuria, polydipsia
Epigastric mass - pseudocyst
What are the characteristics of pain in chronic pancreatitis?
Bores through the back
Relieved by sitting forward or hot water bottle
Exacerbated by fatty foods/alcohol
What Diagnostic Investigations would be used for Chronic Pancreatitis?
Hx
Bloods:
Lipase + amylase
Faecal Elastase
Transabdominal Ultrasound + CT - detects pancreatic calcification + dilated pancreatic ducts
What is the management of Chronic Pancreatitis?
Alcohol Cessation
Abdo Pain Sx - NSAIDs
Pancreatic Enzyme supplements
Surgical:
Endoscopic stenting
Whipple - Distal pancreatectomy
What forms the Hepatic Portal Vein?
Union of the SMA and Splenic Veins
What is Portal Hypertension?
Pathological high pressure in the portal vein commonly caused as a complication of other conditions such as liver cirrhosis and alcoholism
What is the normal pressure range in the portal venous system and in portal HTN?
5-10 mmHg
When Pressure in portal vein is >10mmHg = Bad / >12mmHg = V.bad
What is the pathophysiology of Portal Hypertension?
Increased vascular resistance in portal venous system
Causes splanchnic dilations and compensatory Increase in CO
Results in fluid overload in portal vein
This opens venous collaterals - connecting portal and systemic venous systems.
Venous collaterals shunt blood to gastroeosophageal veins causing varices
Where would varices tend to develop in portal HTN?
Lower oesophagus and gastric cardia
What are Varices?
A dilated vein that is at risk of rupture causing haemorrhage in the GI Tract
How is Portal HTN Classified?
Site of the obstruction:
Pre-hepatic - blockage of PV before the liver
Intrahepatic - Distortion of liver architecture (pre/post sinusoidal)
Post hepatic - Venous blockage outside the liver.
What are some causes of Pre hepatic Portal HTN?
Portal Vein Thrombosis
What are some causes of Intra hepatic portal HTN?
Cirrhosis - most common in UK
Schistosomiasis - Commonest world wide
What are some causes of post hepatic portal HTN?
Budd Chiari (hepatic vein obstruction by tumour/thrombus)
RHF
Constrictive Pericarditis
What are the Sx of Portal HTN?
Mostly ASx
Associated with LF and therefore Sx of LF may be present
Present when oesophageal varices rupture
What investigations are required for portal HTN?
Abdominal Ultrasound - Dilated portal vein
Doppler US - slow PV velocity
Oesophagealgastroduodenoscopy (OGD) check for presence of oesophageal varices
What are the complications of portal HTN?
Bleeding from gastric/oesophageal varices
Ascites
Pulmonary HTN
LF
Hepatopulmonary Syndrome
What is the Treatment of Portal HTN?
Tx underlying Cause
Salt reduction and Diuretics
Beta blockers/Nitrates to reduce BP.
What causes oesophageal varices?
Portal HTN
When are Gastro-oesophageal varices prone to rupture?
When portal pressure exceeds 12mmHg
This will lead to GI bleeding.
What are the Sx of a patient who’s oesophageal varices have ruptured?
Haematemesis - coughing blood.
Abdo pain
Shock - if large blood loss
Hypotension and tachycardia
Ascites
What is the management of oesophageal varices?
Resus until haemodynamically stable
Consider blood transfusion - get Hb to 80g/L
Stop the bleed:
IV Terlipressin (give IV Somatostatin if CI in IHD) - causes vasoconstriction
Variceal banding
TiPPS - Transjugular intrahepatic portosystemic shunt
Prevent Bleed:
Propranolol and Nitrates
Prophylactic Abx
What is Ascites?
Accumulated free fluid in abdominal cavity commonly as a complication of Cirrhosis
What is the epidemiology of Ascites?
10-20% survival 5-years from onset
Signifies other serious illness
Common post op
What are the main causes of Ascites?
Local Inflammation - peritonitis, TB, Abdo cancer
Low protein - Nephrotic Syndrome, Hypoalbuminaemia (LF)
Flow Stasis - Liver cirrhosis, Budd Chiari, Congestive HF
What is the pathophysiology of Ascites?
Local inflammation - Fluid accumulation
Low protein - Lower osmotic potential of intravascular space
Low flow - Fluid cannot move forwards (i.e. due to clot) - Raises pressures in vessels
What are the symptoms & signs of Ascites?
Abdominal Distension/swelling
Abdominal pain - severe suspect SBP
Shifting Dullness
Fluid in flanks
Fluid thrill
May have jaundice and Pruritus
What are the risk factors for ascites?
High sodium diet
Hepatocellular carcinoma
Splanchnic vein thrombosis resulting in portal hypertension
What investigations are done for Ascites?
Shifting Dullness Exam
Ascitic Tap - Aspiration of ascitic fluid:
- Cytology - WCC
- Protein Measurement (serum ascites albumin gradient (SAAG))
What would the different results of protein measurement suggest in an Ascitic tap?
Transudate:(raised portal pressure)
<30g/l
Low protein
Serum Albumin ascitic gradient (SAAG) ,11g/l
Clear fluid - due to increased hydrostatic pressure
Exudate: (Normal portal pressure)
>30 g/L
High Protein
SAAG >11g/L
cloudy fluid - due to inflammation mediated exudation
What would a Transudate ascitic tap suggest the cause of Ascites is?
Portal HTN
ALF, cirrhosis
Budd Chiari
Constrictive pericarditis
Congestive HF
Nephrotic Syndrome
What would an Exudate ascitic tap suggest the cause of Ascites is?
Malignancy
Peritonitis
Pancreatitis
Bowel Obstruction
What is the management for ascites?
Tx underlying cause
Reduce Sodium - help live
Diuretics - increase Na excretion - Spironolactone
Paracentesis - fluid drain
Liver transplant
What are some complications of ascites?
Spontaneous Bacterial Peritonitis
What is Peritonitis?
Inflammation of peritoneum
Can be primary (inflammation on its own i.e. bacterial infection/ascites)
Can be secondary (i.e. bile - treat underlying cause to manage peritonitis)
What is peritonism?
Tensing of muscles to prevent movement of peritoneum
What are the causes of peritonitis?
AEIOU:
A – Appendicitis – umbilicus to RIF pain
E – Ectopic pregnancy – low abdominal pain, sudden onset, tachycardia, low BP
I – Infection with TB
Bacterial – most common
Gram-negative e.g. E. Coli and Klebsiella
Gram-positive staphylococcus e.g. S. Aureus
O – Obstruction – colicky pain, history of abdominal surgery
U – Ulcer – epigastric pain radiating to shoulder
Peritoneal dialysis
What are the different pathways of infection for peritonitis?
GI perforation
Transmural translocation - from pancreatitis etc
Exogenous contamination - drains, surgery etc,
UTI
Haematogenous spread - septicaemia
What are the Sx of Periotonitis?
Sudden onset severe abdominal pain
General collapse
fever
malaise
Nausea and vomiting
+ Ascites / Septic Shock
What are the characteristics of the abdominal pain in peritonitis?
Rigidity helps pain - Pain relieved by resting hands on abdomen - stops abdominal movement
Localised guarding and rebound tenderness
Well localised - more inflamed as it has reached parietal layer and overlying dermatome
Poorly localised - less inflammation pressing only on visceral nerves
What are the signs of Peritonitis?
Pain relieved by resting hands on abdomen – stops movement of peritoneum and therefore pain
Guarding/rebound tenderness
Absence of bowel sounds
Rigid abdomen
Pain worse on coughing or moving
Patient wants to lie still
Sepsis/septic shock – hypotension, tachycardia, oliguria, fever
What region of the abdomen is innervated by which nerves?
T5-9 = Epigastric (greater splanchnic - foregut to 2nd part of duodenum)
T10-11= Umbilical (lesser splanchnic - 2nd part of duodenum to 2/3 transverse colon)
T12 = Hypogastric (least splanchnic - 2/3 transverse colon to upper rectum)
How is peritonitis diagnosed?
Ascitic Tap shows Neutrophilia
Blood test and culture
Increased ESR/CRP
Urine dipstick for UTIs
Bloods:
U&Es
FBC
Serum amylase - rule out acute pancreatitis
Erect CXR - rule out perforated colon if no free air under diaphragm
CT Scan
AXR - bowel obstruction
hCG - rule out pregnancy
What is the Treatment of Peritonitis?
ABCDE
Tx underlying cause
Analgesia + urinary catheterisation +/- GI decompression
IV fluids + Electrolytes (fluid resus)
IV Abx - Cefotaxime, Metronidazole
Surgery
- Remove/divert cause of peritonitis
- Peritoneal Lavage (cleaning of peritoneum)
What are the main complications of peritonitis?
Septicaemic if not Tx early (suspect if BP is low)
Local Abscess formation
Kidney Failure
What are the differential diagnoses for peritonitis?
Bowel Obstruction
Give 3 causes of iron overload.
- Genetic disorders e.g. haemochromatosis.
- Multiple blood transfusions.
- Haemolysis.
- Alcoholic liver disease.
What is Hereditary Haemochromatosis?
Autosomal recessive mutation of the HFE gene on chromosome 6 that results in excess Iron uptake by transferrin 1 leading to increased iron storage and deposition of iron in tissues.
Who is typically affected by Haemochromatosis?
Males
50yrs old +
Why are women less likely to be affected by haemochromatosis?
They will lose iron in blood during menstruation
What is the pathophysiology of Hereditary Haemochromatosis?
Excess iron uptake by transferrin 1 and decreased Hepcidin synthesis (loss of iron homeostasis regulatory protein)
Iron accumulation into the liver
Causes fibrosis of Liver and can lead to iron deposition in other organs
What organs can iron be deposited in in haemochromatosis?
Pancreas
Kidney
Heart
Skin
Ant. Pituitary
What are the risk factors for hereditary haemochromatosis?
Genetic
Alcohol
What are the Sx of Haemochromatosis?
Males in 40-50s (women often present later)
Chronic tenderness
Joint pain
Pigmentation - Slate grey statue
Hair loss
Erectile dysfunction
Amenorrhoea
Cognitive Sx - memory/mood
What is the Gross iron overload triad?
Bronze statue skin
Hepatomegaly
T2DM
What are the diagnostic investigations for Haemochromatosis?
Iron studies:
Inc serum Fe
Inc Ferritin
Inc Transferrin sat
Dec TIBC
Genetic test - HFE gene mutation
Liver biopsy to quantify Fe and assess degree of damage
What are some complications of hereditary haemochromatosis?
T1DM - iron affects pancreatic function
Liver cirrhosis
Endocrine issues - Iron deposits in pit.
Cardiomyopathy - iron in heart
HCC
Hypothyroidism - Iron in thyroid
Arthritis
What is the management of Haemochromatosis?
1st Line - Venesection - remove blood to reduce iron
Use Deferoxamine (chelation therapy) if CI
Low iron diet.
90% of people with haemochromatosis have a mutation in which gene?
HFE.
What protein is responsible for controlling iron absorption?
Hepcidin.
Levels of this protein are decreased in haemochromatosis.
Name 3 metabolic disorders that can cause liver disease.
- Haemochromatosis - iron overload.
- Alpha 1 anti-trypsin deficiency.
- Wilson’s disease - disorder of copper metabolism.
What is Wilsons Disease?
Autosomal Recessive mutation of ATP7B gene on chromosome 13 leading to excess body copper accumulation
Who is typically affected by Wilsons Disease?
Young patient
20 yrs
FHx
Has RF
What is the pathophysiology of Wilsons Disease?
Mutation of copper transporting ATPase
Impairs ability of hepatocyte to incorporate copper into caeruloplasmin and excrete into bile
Copper accumulates in liver and later on in other organs (CNS)
What are the clinical features of Wilsons Disease?
CLANKAH:
Cornea - Kayser Fleischer Rings - Cu deposits in cornea)
Liver disease - Jaundice etc
Arthritis
Neurological - Parkinsonism, Memory issues
Kidney - Fanconi’s Syndrome
Abortions
Haemolytic Anaemia
What are Kayser Fleischer rings?
Copper deposits in the cornea of the eyes that are symptomatic in Wilsons Disease
What investigations are required for Wilsons Disease?
Blood tests:
Low serum Copper - copper is deposited in tissues so not in blood
Low Caeruloplasmin - protein thta carries copper
Liver Biopsy - high Hepatic Copper
MRI - Basal ganglia degeneration
What is the management of Wilsons Disease?
1st Line - D-Penicillamine (copper chelation)
Trientene
Diet - avoid high copper foods
What are the side effects of Penicilamine?
Skin rashes
Fall in WCC, Hb and Platelets
haematuria
Renal Damage
What is ⍺-1 antitrypsin deficiency?
Inherited autosomal recessive condition where there is a deficiency of alpha 1 anti-trypsin enzyme due to a mutation in the SERPINA-1 gene on chromosome 14
What is the pathophysiology of Alpha 1 anti-trypsin?
alpha 1 anti-trypsin normally inhibits neutrophil elastase (an enzyme that degrades elastic tissue)
Therefore in Deficiency there is increased Neutrophil Elastase that targets:
Lungs - degrades Elastic tissue causing alveolar duct collapse and panacinar emphysema
Liver - Unprotected elastic degeneration leads to liver becoming fibrotic and at increased risk of cirrhosis and HCC
Where is Alpha 1 anti-trypsin synthesised?
In the liver and therefore A1AT deficiency causing damage to the liver is made worse due to a loss of synthetic function.
What are the symptoms of a patient with A1AT deficiency?
Young/middle aged male
Often present COPD like symptoms with no smoking Hx:
Dyspnoea, chronic cough, sputum production
Potentially Liver Sx too
What is the Diagnostic investigations for A1AT deficiency?
Serum A1AT is low <20mm/dl
Barrel chest exam - CXR shows hyperinflated lungs - pulmonary emphysema
Liver Biopsy
CT - panacinar Emphysema
Genetic testing +tve SERPINA mutation
What would be found on liver biopsy in A1AT Deficiency?
Acid schiff positive staining globules in hepatocytes
Break down produces due to the action of proteases
What is the management of A1AT deficiency?
No definitive Tx
Stop smoking
manage emphysema - inhales (SABAs, LABAs)
Consider liver transplantation in hepatic decompensation
What amount of paracetamol is ingested for overdose?
75mg/Kg
What is paracetamol overdose responsible for in the UK?
50% of all fulminant liver failures
What are the Sx of paracetamol overdose?
Acute severe RUQ pain
Severe Nausea and Vomiting
What is the normal metabolism of paracetamol?
Metabolised by the liver:
90% by phase 2 metabolism - glucoronidation to then be excreted
10% by phase 1 CYP 450 to create NAPQI (toxic metabolite) which is then conjugated with glutathione before being excreted.
What happens to paracetamol metabolism in overdose?
Phase 2 pathway becomes saturated and therefore there is increased shunting down phase 1 metabolism.
This increases NAPQI (toxic) production. Over time glutathione is depleted leading to accumulation of NAPQI in the liver.
NAPQI is hepatoxic and will cause liver damage and fulminant liver failure
How is Paracetamol overdose treated?
Activated charcoal if within 1hr of ingestion + N-acetylcysteine
N-acetylcysteine if >1hr after ingestion.
What is the purpose of Treating paracetamol overdose with N-acetylcysteine?
Increases availability of glutathione to remove NAPQI
What is Gilberts Syndrome?
+ crigler Najjar
Most common cause of hereditary jaundice where you are deficient or produce abnormal UGT.
Gilberts - Deficiency
CN - Absence
Therefore you cannot conjugate bilirubin and this leads to increased unconjugated hyperbilirubinaemia
What is the Treatment of Gilberts/Crigler Najjar syndrome?
Gilberts - should be ok w/out Tx
CN - Phototherapy to break down unconjugated bilirubin.
What is a hernia?
Protrusion of a viscus/part of viscus through a defect in the wall of its containing cavity into an abnormal position
What is a reducible hernia?
Can be pushed back into abdominal cavity with manual manoeuvring
What is an irreducible hernia?
Cannot be pushed back into place
What is an obstructed hernia?
I.e. intestine
Intestine obstructed due to pressure from edges of hernia, but blood flow is maintained
What is an incarcerated hernia?
Contents of the hernial sac are stuck inside by adhesions
What is a strangulated hernia?
Blood supply is cut off
Ischaemia +- gangrene/perforation of the hernial contents
Patient becomes toxic and requires urgent surgery
What is an inguinal hernia?
Protrusion of abdo contents through inguinal canal
What is a femoral hernia?
Bowel moves through the femoral canal below the inguinal ligament
What is an incisional hernia?
Through weak surgical scar
What is a sliding hiatus hernia?
Gastro-oesophageal junction and part of stomach roll ups into the chest via the hiatus so it lies above the diaphragm
Normally leads to gastric reflux
What is the pathophysiology of inguinal hernias?
The inguinal canal is a short passage that extends medially and inferiorly, through the inferior part of the abdominal wall
From deep inguinal ring to superficial ring
Pathway through which structures can pass from abdominal wall to external genitalia
Common site for herniation - potential site of weakness
What is the pathophysiology of femoral hernias?
Bowel enters femoral canal, presenting as a mass in the upper medial thigh or above the inguinal ligament (points down the leg)
Likely to be irreducible and to strangulate (canal’s borders rigid)
Neck of the hernia is felt inferior and lateral to the pubic tubercle
What are some risk factors for hernias?
Male - inguinal
Heavy lifting
Coughing
Surgery
What are some symptoms of a hiatal hernia?
Gastro oesophageal reflux
Dysphagia
What are some symptoms of a femoral hernia?
Swelling in upper thigh pointing down
What are some symptoms of an inguinal hernia?
Painful swelling in groin
Points along groin margin.
What diagnostic tests can be done to investigate:
Hiatus hernias
Inguinal Hernias
Femoral Hernias
Hiatus Hernias - CXR, Barium swallow (diagnostic)
Inguinal Hernias - usually clinical but potentially USS
Femoral Hernias - Usually clinical but potentially USS
What is the curative treatment for hernias?
Surgery.
What are the 5 viruses that cause hepatitis?
Hepatitis A (HAV) - RNA
Hepatitis B (HBV) - DNA
Hepatitis C (HCV) - RNA
Hepatitis D (HDV) - RNA
Hepatitis E (HEV) - RNA
How are hepatitis A and E transmitted?
Via Faecal-oral transmission
How are hepatitis B,C and D transmitted?
Blood to blood transmission
What is acute hepatitis?
What Hepatitis viruses cause acute hepatitis?
A sudden illnesss with a mild to severe course followed by complete resolution
All hepatitis Viruses
What is chronic hepatitis
What Hepatitis viruses cause acute hepatitis?
A prolonged course of active disease or silent asymptomatic infection.
HBV, HCV, HDV
Outline Acute hepatitis
Variable incubation period
-Systemic symptoms first:
-**Fatigue, low-grade fever, muscle/joint aches, cough, runny nose, and
pharyngitis. **
Jaundice (1-2 weeks after infection)
LFTs (rise through hepatocyte death from virus)
**ALT and AST to elevate to very high **
levels, while GGT, ALP, and bilirubin are only mildly elevated
Outline Chronic Hepatitis
More difficult to Diagnose
Patient is often asymptomatic
Clinical manifestations are the same regardless of virus causing hepatitis.
Describe the transmission of hepatitis A
Ingesting contaminated drinking water or food (shellfish)
Associated with Recent Travel Hx - Africa
Close person to person contact
Often infects young children
What is the pathogenesis of HAV?
-Initial immune response consists IgM antibody; important in the laboratory
diagnosis of hepatitis A.
-1 to 3 weeks later IgG antibody is produced→ lifelong protection
What are the clinical findings of HAV?
Incubation of 2-4 weeks
Usually symptomatic in adults - constitutional Sx + abdo pain.
Rarely causes fulminant hepatitis
What Ix are required for HAV diagnosis?
Serology - Detection of anti-HAV IgM confirms the diagnosis and remails for 3-6 months.
Also:
LFTs: High AST and ALT.
Bilirubin and ALP usually only mild.
Bloods - Inc ESR, Leukopenia
What is the treatment for HAV infection?
Self limiting - no chronic disease
Supportive therapy
Primary prevention - travellers vaccine
100% immunity after infection
What is Hepatitis B virus?
DNA virus that lives in all human body fluids in an infected individual.
Semen, urine, saliva, blood, breast milk
What are HBV markers?
HBsAg - surface antigen - active infection
HBsAg Ab - implies vaccination or past/current infection
HBV DNA - direct count of viral load
HBeAg - viral replication marker - high infectivity
HBcAg - Core antigen - implies past or current infection
How can HBV be transmitted and give examples?
Blood to blood transmission - parenteral transmission.
Needle sharing,
accidental medical exposures,
sexual contact
Blood transfusions
Where is HBV prevalent
ASIA
How does HBV present?
3 clinical states:
Acute hepatitis
Fulminant hepatitis - severe acute hepatitis with rapid destruction of the liver
Chronic Hepatitis
How do you diagnose HBV infection?
HBsAg antigen means there is LIVE virus and infection.
Anti - HBsAg antibodies - patient is protected and immune
HBcAg - exposure to HBV at some point.
HBcAg IgG - chronic fection/carrier
How is HBV infection prevented?
Antenatal screening - HBsAg of pregnant mothers
Universal childhood vaccination
PrEP - tenofovir + emtricitabine
What are the complications of HBV infection?
HDV co-infection
Hepatocellular carcinoma
End-stage liver disease/cirrhosis
How is HBV infection managed?
Pegylated Interferon 2A
Oral nucleoside analogues - Tenofovir, entecavir (better tolerated than PEG IFN)
What is Hepatitis C virus
RNA virus
Incubation period 6-12 weeks
What is the clinical signs of HCV infection?
Acute infection is usually asymptomatic - some patients will present with classic acute hepatitis symptoms
Up to 85% of patients of HCV will develop chronic hepatitis
HCV strongly predisposes HCC.
Outline HCV transmission
Blood-to-blood contact via blood transfusions, injecting drug use, nosocomial (needle sticks, dialysis, inadequate sterilisation of colonoscopes
What is the most common indication for liver transplantation?
Liver cirrhosis resulting from chronic HCV infection
What comorbidities arise with HCV infection?
HCV infection can lead to significant autoimmune reactions:
vasculitis, arthralgias, purpura, membranoproliferative glomerulonephritis
How is HCV diagnosed?
Testing for antiHCV antibodies
(detectable within 6-8 weeks after exposure and remain positive thereafter)
Measure HCV viral RNA
An ELISA antibody test for detectable viral RNA is positive for at least 6 months.
HCV Genotype - Genotype governs Tx
What is the treatment for HCV infection
Direct acting Anti-virals (DAAs)
No vaccine currently exists.
Liver Transplantation for End stage liver disease
What are the different targets of DAAs?
NSE3/4A Protease inhibitors (suffix = previr)
NS5A Inhibitors (Suffix = Asvir)
NS5B Inhibitors (Suffix = buvir)
Give some examples of DAA combination therapy?
Glecaprevir/Pibrentasvir
Sofosbuvir/Velpatasvir
Triple Therapy:
Sofosbuvir/Velpatasvir/Voxilaprevir
Can HCV be cured?
Yes
however that does not confer immunity and there is still a risk of re-infection
What is Hepatitis D virus?
An RNA virus
It is a defetive virus an it cannot replicate itself due to not having the genes to envelop protein.
HDV can only be replicated in cells co-infected with HBV.
HDV uses HBsAg to evelope its protein.
Outline the transmission of HDV?
Transmitted in the same way as HBV
Coinfection of HBV and HDV is more severe than those infected with HBV alone.
What is the presentation of a HDV infection?
Can range from asymptomatic to fulminant liver failure
Simultaneous co-infection with HBV/HDV - causes acute hepatitis.
HDV superinfection of a carrier of HBV can cause liver flare.
What diagnostic tests are required for HDV infection?
Detecting delta antigen or IgM antibody against delta antigen in the patient’s serum.
What is the treatment for HDV infection?
PegINF alpha can mitigate chronic effects but does not eradicate the carrier state.
no vaccine against HDV but a person immunized against HBV will not get HDV infection.
What is Hepatitis E infection?
RNA virus similar to HAV.
How is HEV transmitted?
Via the faecal oral route
Waterborne transmission is most common.
What is the clinical presentation of HEV infection?
Clinically similar to HAV infection.
Often Asymptomatic (95% cases) - usually self limiting
Chronic infection can be caused in immunocompromised individuals.
How is HEV diagnosed?
Detecting IgM antibodies to HEV.
What is the treatment to HEV infection?
Self limiting
No antiviral drug available for acute infection in immunocompetent patients. (consider ribavirin if really ill)
Treatment is supportive.
What are some complications of hereditary haemochromatosis?
T1DM - iron affects pancreatic function
Liver cirrhosis
Endocrine issues - Iron deposits in pit.
Cardiomyopathy - iron in heart
HCC
Hypothyroidism - Iron in thyroid
Arthritis
How are gallstones formed?
he formation of cholesterol crystals and gallstones in lithogenic bile is promoted by factors that favour nucleation such as mucus and calcium
Gallstone formation further promoted by reduced GB motility and stasis
What is SBP?
Spontaneous bacterial peritonitis:
infection of ascitic fluid that cannot be attributed to any intra-abdominal, ongoing inflammatory, or surgically correctable condition.
It is one of the most frequently encountered bacterial infections in patients with cirrhosis.
How is SBP diagnosed?
Ascitic tap and analysis via paracentesis.
Asses fluid appearance, cell count and culture.
Also FBC, LFT, blood cultures
