DISORDERS OF THE BILIARY TREE Flashcards
1
Q
Which lobes of the liver does the gallbladder lie between?
A
The inferior aspects of the right lobe and quadrate lobe
2
Q
Whats the anatomical structure of the gallbladder?
A
Fundus at the top where it protects into the inferior surface of the liver
Body is the largest part
Neck is where the gallbladder tapers to become continuous with the cystic duct, leading into the biliary tree
3
Q
Whats the Hartmanns pouch?
A
A mucosal fold in the neck of the gallbladder
A common location for gallstones to become lodged, causing cholestasis
4
Q
Whats the storage capacity of the gallbladder?
A
30-50ml
5
Q
Outline the structure of the biliary tree?
A
Bile is initially secreted from hepatocytes and drains from both lobes of the liver via canaliculi, intralobular ducts and collecting ducts into the left and right hepatic ducts. These ducts amalgamate to form the common hepatic duct, which runs alongside the hepatic vein.
As the common hepatic duct descends, it is joined by the cystic duct – which allows bile to flow in and out of the gallbladder for storage and release. At this point, the common hepatic duct and cystic duct combine to form the common bile duct.
The common bile duct descends and passes posteriorly to the first part of the duodenum and head of the pancreas. Here, it is joined by the main pancreatic duct, forming the hepatopancreatic ampulla (commonly known as the ampulla of Vater) – which then empties into the duodenum via the major duodenal papilla. This papilla is regulated by a muscular valve, the sphincter of Oddi.
6
Q
Whats the arterial supply to the gallbladder?
A
The cystic artery (a branch of the right hepatic artery)
7
Q
Whats the venous drainage of the gallbladder?
A
Cystic veins which drain directly to the portal vein
8
Q
What innervates the gallbladder?
A
Coeliac plexus for sympathetic and sensory fibres
Vagus nerve delivers parasympathetic innervation
9
Q
What mediates secretion of bile into the cystic duct?
A
Cholecystokinin
Also parasympathetic stimulation produces contraction of the gallbladder
10
Q
What makes up bile?
A
70% Bile salts and acids
10% Cholesterol
5% Phsopholipids
5% proteins
1% bilirubin
Electrolytes
Water
Bicarbonate
11
Q
What are the 2 main groups of constituents of bile?
A
Bile acid-dependant - produced by hepatocytes e.g. bile acids, bile pigments and cholesterol
Bile acid-independant - produced by ductal cells that line bile ducts - secrete an alkaline solution stimulated by secretin
12
Q
What are the 2 primary bile acids?
A
Cholic acid
Chenodeoxycholic acid
13
Q
What are bile salts?
A
When bile acids are conjugated with the amino acids glycine and taurine they form bile salts
These are more soluble than bile acids and act as detergents to emulsify lipids (they are a amphipathic)
14
Q
What are the bile pigments?
A
Biliverdin (green pigment)
Bilirubin - breakdown product of Hb and is conjugated in the liver and secreted into bile
15
Q
What is the enterohepatic Circulation of Bile Acids?
A
the movement of bile acid molecules from the liver to the small intestine and back to the liver
The enterohepatic circulation allows the liver to recycle and preserve a pool of bile acids.
16
Q
Whats intestinal bacteria’s role in producing bile salts?
A
In the intestine, the primary bile acids are often converted by colonic bacteria to the secondary bile acids, predominantly deoxycholic acid and lithocholic acid.
17
Q
Whats the average total bile flow?
A
600ml a day
18
Q
Outline the production of bilirubin?
A
RBC broken down by Kupffer cells in the liver and reticuloendothelial system
Iron and globin are removed from haem and reused
Haem forms biliverdin which is changes to unconjugated bilirubin via biliverdin reductase
Bilirubin is taken to the liver via albumin where it dissociates and is taken up by hepatic cell membranes and transported to the endoplasmic reticulum by cytoplasmic proteins. Here its conjugated with glucuronic acid and excreted into bile
Conjugated bilirubin is actively secreted into biliary canaliculi and excreted into the intestine within bile
In the terminal ileum, bacterial enzymes hydrolyse the molecule to release free bilirubin
It is then reduced to urobilinogen; some of this is excreted in stool as stercobilinogen and the remainder is absorbed bu the terminal ileum and passes to the liver via the enterohepatic circulation and is re-excreted into bile
Urobilinogen bound to albumin enters circulation and is excreted in urine via the kidneys
19
Q
What is biliary colic?
A
Pain in the RUQ/epigastrium which is associated with the temporary obstruction of the cystic or common bile duct, usually by a stone migrating from the gallbladder
Usually a sudden onset of severe constant pain lasting from 30 minutes to 6 hours. Typically has a crescendo characteristic
Not associated with fever or abdominal tenderness!
Pain of <30 mins is less likely to be biliary colic
20
Q
What is cholelithiasis?
A
refers to the development of a solid deposit or ‘stone’ within the gallbladder.
21
Q
What is choledocholithiasis?
A
Gallstones within the biliary tree
22
Q
What is acute cholecystitis?
A
Acute inflammation of the gallbladder, most commonly caused by gallstones
23
Q
What is acute cholangitis?
A
Infection of the biliary tree, commonly due to an obstructing stone in the CBD
24
Q
Outline the epidemiology of gallstones?
A
Prevalence is 10-15% of adults in Europe and the US
Prevalence increases with advancing age before levelling off at 60-70
2-3x more common in women
Tend to affect Caucasians, native Americans and Hispanic ethnicity more (may reflect genetic and dietary factors?)
Rarely seen brefore age 30
25
What are the risk factors associated with the development of cholelithiasis?
Older age >40
Female
Genetic predisposition
Rapdi weight loss/prolonged fasting
Obesity
NAFLD
Diabetes mellitus
Medications - octreotide, ceftriaxone, glucagon-like peptide-1 analogues, HRT
Crohn’s disease
Diet high in triglycerides and refined carbohydrates and low fibre
(Fat, Fair, Female, Fourty)
26
What is cholestasis?
Blockage to the flow of bile
27
What is gallbladder empyema?
Pus in the gallbladder
28
How does cholelithiasis tend to present?
80% may be asymptomatic
Biliary colic - severe colicky epigastric/RUQ pain often triggered by high fat meals and lasts 30 mins-8 hours. May be associated with nausea and vomiting
Alternatively, pt may present with the complications of gallstones e.g. cholecystitis, cholangitis, obstructive jaundice or pancreatitis
29
What are the types of gallstones?
Cholesterol stones - 90% of western world gallstones
Pigmented stones (aka bilirubin stones)
Mixed stones
30
What causes cholesterol gallstone formation?
Cholesterol supersaturation (bile has so much cholesterol that the bile salts/acids/phospholipids can’t hold any more in solution so cholesterol precipitates)
??Accelerate cholesterol crystal nucleation
Not enough bile salts, acids or phospholipids to keep the cholesterol in solution
Impaired gallbladder motility (stasis causes cholesterol to precipitate out)
31
Where does cholesterol come from?
Hepatic uptake from dietary sources
20% - hepatic biosynthesis
32
Outline the cholesterol synthesis pathway?
Acetyl CoA -> HMG-CoA -> mevalonate -> IPP -> FPP
-> squalene -> epoxysqualene -> lanosterol -> cholesterol
33
Whats the rate limiting step in cholesterol synthesis?
HMG coA reductase (catalyses the first step of acetate to mevalonate)
34
What are black pigment stones?
These are dark stones composed primarily of calcium bilirubinate, accounting for around 10-20% of stones. They occur in people with increased amounts of bilirubin in their bile - hyperbilirubinbilia. This occurs in patients with increased haemolysis
35
What are brown pigment gallstones?
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.
36
What are the features of biliary colic?
Intermittent, self-limiting RUQ pain
Normal observations
Normal or mild tenderness
Normal blood tests
USS shows gallstones
37
What are the features of acute cholecystitis?
RUQ pain, fever, malaise
Temperature and haemodynamic instability may occur
Tenderness and localised guarding may be present
Raised WCC, CRP with normal or a mild LFT increase
USS shows gall stones, inflamed thickened gallbladder and pericholecystic fluid
38
What are the features of acute cholangitis?
Charcots triad - fever, jaundice, RUQ pain (+ mental status changes and hypotension to make Reynolds Pentad)
Temperature and haemodynamic instability likely to occur
Tenderness and clinical jaundice may be apparent
Raised WCC, CRP, bilirubin, ALP and ALT
USS shows CBD stone and ducts dilatation
39
What are complications of gallstones?
Biliary colic
Acute cholecystitis
Acute pancreatitis
Obstructive jaundice
Rarer - acute cholangitis, fistula formation, biliary peritonitis, gallbladder mucocele, gallbladder cancer
40
What is Bouveret’s syndrome?
a rare variant of gallstone ileus characterized by a gastric outlet obstruction due to the impaction of a gallstone lodged in the duodenum, resulting from a cholecystoduodenal fistula
41
What is gallstone ileus?
mechanical intestinal obstruction due to impaction of one or more gallstones within the gastrointestinal tract
42
What is Mirizzi syndrome?
A stone located in Hartmanns pouch or in the cystic duct itself can cause compression on the adjacent common hepatic duct.
This results in an obstructive jaundice, even without stones being present within the lumen of the common hepatic or common bile ducts.
43
Why can cholelithiasis lead to acute pancreatitis?
this occurs when a stone that has migrated along the common bile duct becomes stuck in the biliopancreatic duct causing pancreatic outflow obstruction
44
What is Murphy’s sign?
Inspiratory arrest during deep inspiration when examiner palpates the gallbladder fossa just beneath the liver edge
45
How should you investigate gallstone disease?
Abdominal USS (the absence of stones on scan doesnt exclude their existence)
FBC and CRP - for raised WCC and signs of inflammation
LFTs
Amylase to check for evidence of pancreatitis
Urinalysis + pregnancy test - exclude renal or tubo-ovarian pathology
Consider referral for further investigation if results are normal but clinical suspicion remains high:
MRCP if either LFTs are abnormal or bile duct is dilated even if no stones seen on USS
ERCP can also be done
CT scan may be done to look for any complications
46
What typically causes raised ALP?
Liver (cholestatic picture) or bone problems
Often raised in pregnancy due to production by the placenta
47
What is an obstructive/cholestatic picture on LFTs?
ALT and AST slightly raised
Higher raise in ALP
48
What is an MRCP?
Magnetic resonance cholangio-pancreatography
MRI scan with a specific protocol that produces a detailed image of the biliary system.
It is very sensitive and specific for biliary tree disease, such as stones in the bile duct and malignancy.
49
What is ERCP?
An endoscopic retrograde cholangio-pancreatography (ERCP) involves inserting an endoscope down the oesophagus, past the stomach, to the duodenum and the sphincter of Oddi. This gives the operator access to the biliary system. It combines x-ray and the use of an endoscope
50
What can be done during ERCP?
Cholangio-pancreatography: retrograde injection of contrast into the duct through the sphincter of Oddi and x-ray images to visualise biliary system
Sphincterotomy: making a cut in the sphincter to dilate it and allow stone removal
Stone removal: a basket can be inserted and pulled through the common bile duct to remove stones
Balloon dilatation: a balloon can be inserted and inflated to treat strictures
Biliary stenting: a stent can be inserted to maintain a patent bile duct (for strictures or tumours)
Biopsy: a small biopsy can be taken to diagnose obstructing lesions
51
What are the complications of ERCP?
Excessive bleeding 0.9%
Cholangitis 1.1%
Pancreatitis 1.5%
Duodenal perforation 0.4%
52
How do you manage someone with asymptomatic gallstones found in a normal gallbladder/biliary tree?
Reassure them that they do not need treatment unless they develop symptoms.
Explain that asymptomatic gallstones are very common.
DONT GIVE PROPHYLACTIC TREATMENT - risk of complications from surgical treatment outweighs the potential risk of developing complications from stones
53
How do you manage someone with asymptomatic gallstones found in the CBD?
Offer referral for bile duct clearance and laparoscopic cholecystectomy — although they are asymptomatic, there is a significant risk of developing serious complications such as cholangitis or pancreatitis.
54
How should you manage a person with symptomatic gallstones?
Arrange emergency admission for people who are systemically unwell with a suspected complication of gallstone disease
Refer urgently to gastro or surgery
For severe pain - diclofenac 75mg IM. Second dose after 30 mins if needed
For mild/mod pain - paracetemol or NSAID
Advice people to avoid food and drink that triggers symptoms until they have gallbladder/gallstones removed
Secondary care management is nearly always laparoscopic cholecystectomy - done if symptomatic or there are complications
55
How do you manage gallbladder empyema?
Cholecystectomy
Or
Cholecystostomy (drainage) later followed by cholecystectomy
56
What is a Kocher incision?
A subcostal incision used to gain access for the gallbladder and biliary tree
57
What is post-cholecystectomy syndrome?
A set of symptoms which are similar to the fractures experienced before the cholecystectomy. Its thought to be caused by bile leaking into surrounding area or gallstones being left in bile ducts
In most cases symptoms are mild and short-lived but they can persist for many months
May include - Diarrhoea, indigestion, epigastric or RUQ pain, nausea, intolerance of fatty foods, flatulance
58
Why are females more at risk for gallstones?
As oestrogen increases the activity of HMG-CoA reductase -> elevates serum cholesterol levels
59
In what proportion of cases does acute cholecystitis occur secondary to gallstones?
90% of pt
60
What is acute calculous cholecystitis?
Acute cholecystitis secondary to gallstones
61
What is alcuculous cholecystitis?
an inflammatory disease of the gallbladder without evidence of gallstones or cystic duct obstruction
typically seen in hospitalised and severely ill patients
associated with high morbidity and mortality rates
62
What causes acalculous cholecystitis?
multifactorial pathophysiology: gallbladder stasis, hypoperfusion, infection
in immunosuppressed patients it may develop secondary to Cryptosporidium or cytomegalovirus
One example - patients on long periods of fasting where the gallbladder is not being stimulated by food to regularly empty, resulting in a build-up of pressure.
63
What are the features of acute cholecystitis?
RUQ pain that may radiate to the right shoulder (irritates phrenic nerve)
Associated tenderness and guarding
Nausea and vomiting
Fever and signs of systemic upset (tachypnoeic, tachycardia)
Murphys sign positive
LFTs normal (unless Mirizzi syndrome then may be deranged
64
Outline the pathological classification of acute cholecystitis?
Oedematous cholecystitis — occurs after 2–4 days of obstruction. The gallbladder tissue is intact histologically, with oedema in the subserosal layer.
Necrotizing cholecystitis — occurs after 3–5 days of obstruction and is characterized by oedematous changes in the gallbladder, with areas of haemorrhage and necrosis. Necrosis does not involve the full thickness of the gall bladder wall.
Suppurative cholecystitis — occurs after 7–10 days of obstruction and is characterized by thickened gallbladder wall with white cell infiltration, intra-wall abscesses, and necrosis. May result in perforation of the gallbladder and a pericholecystic abscess formation.
Chronic cholecystitis — occurs after repeated episodes of mild attacks and is characterized by mucosal atrophy and fibrosis of the gallbladder wall.
65
How do you investigate acute cholecystitis?
History and exam
abdominal USS
MRCP can be done also
Blood tests. FBC, CRP, serum amylase
Observations
66
what's seen on ultrasound in acute cholecystitis?
gallbladder wall thickening (> 3 mm)
wall edema
gallbladder distention (> 40 mm)
positive sonographic Murphy sign,
pericholecystic and perihepatic fluid
67
How do you manage a pt with acute cholecystitis?
NBM
IV fluids
Antibiotics
Analgesia
ERCP to remove stones
Surgical assessment for cholecystectomy
68
When is lap chole done for acute cholecystitis?
NICE now recommend early laparoscopic cholecystectomy, within 1 week of diagnosis
previously, surgery was delayed for several weeks until the inflammation has subsided
pregnant women should also proceed to early laparoscopic cholecystectomy - this reduces the chances of maternal-fetal complications
69
What are complications of acute cholecystitis?
Gangrenous cholecystitis (necrosis of gallbladder wall)
Perforation of gallbladder
Biliary peritonitis
Pericholecystic abscess
Fistula between gallbladder and duodenum -> gallbladder ileus
Jaundice
Sepsis
Mortality
70
Whats the prognosis of acute cholecystitis?
Without treatment, acute cholecystitis may resolve spontaneously within 1–7 days. However, 25–30% of people will require surgery or develop complications
Mortality rate is 10-50%
71
What is acute cholangitis?
Bacterial infection and inflammation in the bile ducts. It is a surgical emergency and has a high mortality due to sepsis and septicaemia.
72
What are the 2 main causes of acute cholangitis?
Obstruction in the bile ducts stopping bile flow
Infection introduced during an ERCP procedure
73
What are the most common organisms to cause acute cholangitis?
E.coli (most common)
Klebsiella species
Enterococcus species
74
How does acute cholangitis present?
Charcots triad - RUQ pain, fever and jaundice
Hypotension and confusion are also common - make reynolds’ pentad
75
What investigations should you do for acute cholangitis?
Obs
BM
Urine dip and pregnancy test
FBC, U&E, CRP, LFT, amylase
Imaging - US, CT, MRCP and maybe ERCP
(Ultrasound is first line and looks for bile duct dilation and bile duct stones)
76
How do we manage acute cholangitis?
NBM
IV fluids
Blood cultures
IV antibiotics
Analgesia
ERCP after 24-48 hours to relieve any obstruction
Percutaneous transhepatic cholangiography can be done if ERCP fails or is unavailable/inappropriate
Further management depends on underlying cause e.g. elective cholecystectomy is indicated in those with gallstones
77
Whats the other name for acute cholangitis?
ascending cholangitis
78
What is primary sclerosing cholangitis?
a condition where the intrahepatic or extrahepatic ducts become strictured and fibrotic. This causes an obstruction to the flow of bile out of the liver and into the intestines.
Chronic bile obstruction eventually leads to hepatitis, fibrosis and cirrhosis of the liver.
79
Whats the cause of primary sclerosing cholangitis?
The cause is mostly unclear although there is likely to be a combination of genetic, autoimmune, intestinal microbiome and environmental factors.
80
What conditions is primary sclerosing cholangitis associated with?
70% of cases are alongside established UC
Others: Crohn’s and HIV
81
What are the risk factors for primary sclerosing cholangitis?
Male
30-40
Ulcerative colitis
FHx
82
How does primary sclerosing cholangitis present?
Cholestasis - jaundice, pruritus
RUQ pain
Fatigue
Hepatomegaly
83
How do you investigate primary sclerosing cholangitis?
LFTs - ALP very deranged and ALT and AST slightly raised (often become more raised as disease progresses to hepatitis). Raised bilirubin as strictures become more severe and prevent bilirubin from being excreted through the bile duct
P-ANCA raised in up to 94% of cases
Antinuclear antibodies (ANA) raised in up to 77% of cases
ACL raised in up to 63% of cases
Diagnosis gold standard - MRCP
84
What are complications of primary sclerosing cholangitis?
Acute bacterial cholangitis
Cholangiocarcinoma develops in 10-20% of cases
Colorectal cancer
Cirrhosis and liver failure
Biliary strictures
Fat soluble vitamin deficiencies
85
How is primary sclerosing cholangitis managed?
Liver transplant is curative
ERCP can be used to dilate and stent any strictures
Colestyramine to relieve pruritus
Monitoring for complications
86
Whats the moa of cholestyramine?
adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.
87
What is cholangiocarcinoma?
Bile duct cancer
88
What type of cancers are cholangiocarcinoma?
Adenocarcinomas
89
Where does cholangiocarcinoma typically affect?
Most common site is perihilar region (where L + R hepatic ducts join to become the common hepatic duct)
May affect intrahepatic ducts or extrahepatic ducts
90
What are the key risk factors for cholangiocarcinoma?
Primary sclerosing cholangitis 10-20%
Liver flukes - parasitic (found in SE Asia and Europe)
91
How does cholangiocarcinoma present?
Obstructive jaundice - yellow sclera/skin, pale stools, pruritus
Unexplained weight loss
RUQ pain
Palpable ga;bladder
Hepatomegaly
Periumbilical lymphadenopathy and Virchow node
92
What is Courvoisier’s law?
patients with painless jaundice and a palpable gallbladder often have a malignant obstruction of the common bile duct or pancreas
93
What cancer marker is for cholangiocarcinoma?
CA 19-9 (often used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis)
94
What investigations are done for cholangiocarcinoma?
Staging CT thorax, abdomen and pelvis (to look for mets and other cancers)
CA 19-9 may be raised
MRCP to assess biliar system
ERCP to put a stent in, relive obstruction and obtain a biopsy
95
How is a cholangiocarcinoma managed?
Curative surgery may be possible in early cases. It may be combined with radiotherapy and chemotherapy.
In most cases, curative surgery is not possible. Palliative treatment may involve:
Stents inserted to relieve the biliary obstruction
Surgery to improve symptoms (e.g., bypassing the biliary obstruction)
Palliative chemotherapy
Palliative radiotherapy
End of life care with symptom control
96
What is primary biliary cholangitis also known as?
primary biliary cirrhosis
97
What is primary biliary cirrhosis?
a condition where the immune system attacks the small bile ducts within the liver. The first parts to be affected are the intralobar ducts, also known as the Canals of Hering. This causes obstruction of the outflow of bile, which is called cholestasis. The back-pressure of the bile obstruction and the overall disease process ultimately leads to fibrosis, cirrhosis and liver failure.
98
What are the consequences of primary biliary cirrhosis?
Pruritus, jaundice due to build up of bilirubin
Xanthelasma and increased risk of CVD due to cholesterol build up
GI disturbance, malabsorption of fats, greasy stools - bile acids usually help gut digest fat
99
How does primary biliary cholangitis present?
) early: may be asymptomatic (e.g. raised ALP on routine LFTs) or fatigue, pruritus
cholestatic jaundice
hyperpigmentation, especially over pressure points (excess melanin)
around 10% of patients have right upper quadrant pain
Increased cholesterol - xanthelasmas, xanthomata
also: clubbing, hepatosplenomegaly
late: may progress to liver failure
100
Who does primary biliary cholangitis typically affect?
Middle aged women
101
What is primary biliary cirrhosis associated with?
Sjogren's syndrome (seen in up to 80% of patients)
rheumatoid arthritis
systemic sclerosis
thyroid disease
102
How is primary biliary cholangitis diagnosed?
LFTs - ALP will rise first and others bilirubin rise later
ESR raised
IgM raised
Autoantibodies - anti-mitochrondrial antibodies in 98% of cases and ANA in 30%
Imaging typically MRCP or USS to exclude an extrahepatic biliary obstruction
Liver biopsy is used to stage disease
103
How is primary biliary cholangitis managed?
first-line: ursodeoxycholic acid - slows disease progression and improves symptoms by reducing the amount of cholesterol released by your liver
pruritus: cholestyramine
fat-soluble vitamin supplementation
liver transplantation
Immunosuppresson may be considered in some patients
104
What are the complications of primary biliary cholangitis?
cirrhosis → portal hypertension → ascites, variceal haemorrhage
osteomalacia and osteoporosis (vitamin D deficiency)
significantly increased risk of hepatocellular carcinoma (20-fold increased risk)
105
What is von Meyenburg complex?
Aka multiple bile duct hamartoma
Dilated cystic bile ducts, which are embryologic remnants that failed to involute during the period of embryogenesis. They are typically small (less than 5mm) and present as multiple lesions scattered throughout the liver
Benign!
106
What is polycystic liver disease?
A rare condition that causes cysts to grow throughout the liver making it look like a cluster of very large grapes
The majority of people also have polycystic kidney disease
Most people dont discover it until they are adults.
Most cases disease is not life threatening as liver can function normally
Treatment is only needed if you have symptoms - may include cyst aspiration, cyst fenestration or liver resection
107
What is caroli disease?
a rare genetic condition
Inherited autosomal recessive that causes the bile ducts in the liver to be wider than usual. dilation of the intrahepatic bile ducts can cause bile duct stones to form or infections to occur.
Usually occurs in association with congenital hepatic fibrosis
108
What is biliary atresia?
A congenital anomaly of extrahepatic duct fibrosis = obstruction of bile flow
This presents bile entering duodenum = impaired fat digestion, absorption, cholestasis, distension of gallbladder
109
How does biliary atresia present?
Neonates asymptomatic at first
Stools gradually become acholic, clay-coloured
Persistent jaundice
Dark urine
Portal hypertension - splenomegaly, ascites, Caput medusae
Impaired liver function - bleeding and bruising
110
What are complications of biliary atresia?
Liver cirrhosis
Porta hypertension
Hepatic encephalopathy
Recurrent cholangitis
Metabolic problems e.g. impaired growth associated with malabsorption
111
What will the LFTs show in prehepatic jaundice?
Normal or raised total bilirubin but normal conjugated bilirubin
Elevated LDH, decreased haptoglobin and schistocytes on blood smear - if all this comes back normal then its likely hepatocellular e.g. Gilbert syndrome
Normal ALT/AST
Normal ALP
112
What will the LFTs show in hepatic jaundice?
High bilirubin
Very high ALT/AST
Elevated ALP
113
What will the LFTs show in post-hepatic jaundice?
Very high bilirubin
Moderately high ALT/AST
Very high ALP
114
At what bilirubin level is jaundice visible?
>34 micromols/L
115
Why is jaundice best seen in the sclera?
Sclerae have a high affinity for bilirubin due to their high elastin content
116
What are pre-hepatic causes of jaundice?
Haemolytic disorders - sickle cell disease, thalassaemia major, hereditary spherocytosis, G6PD deficiency, vitamin B12 deficiency, autoimmune haemolytic anaemia, iatrogenic e.g. metallic heart valve
Drugs causing drug-induced liver injury - antibiotics, anti-epileptics. Others include herbal medicines, dietary supplements
Gilbert’s syndrome
Critter-Najjar syndrome
117
What are intra-hepatic causes of jaundice?
Viral infection - hepatitis, Epstein-Barr virus, HIV infection
Alcohol
NAFLD
Autoimmune liver disorders - PBC, PSC, AIH
Metabolic causes of intra-hepatic jaundice - Dubin-Johnson and Rotor’s syndrome, haemochromatosis, Wilson’s disease
Drugs
Malignancy of biliary system - hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer
118
What are post-hepatic causes of jaundice?
Choledocholithiasis
Cholestatic liver disease
Mirizzi’s sundrome
Surgical strictures e.g. following liver transplantation or cholecystectomy
Extra-hepatic malignancy e.g. pancreatic cancer and others
Pancreatitis
Parasitic infection e.g. plasmodium falciparum, fasciola infection and Chlonorchis infection
119
What can cause pseudojaundice?
Excessive ingestion of beta-carotene rich foods e.g. carrot or squash
(Serum bilirubin wont be elevated and sclera icterus does not occur)
120
What characterises pre-hepatic jaundice?
Normocytic anaemia
Unconjugated hyperbilirubinaemia
Markers of haemolysis - raised lactate dehydrogenase, raised reticulocyte and low haptoglobin
121
What are the 2 categories of hepatic causes of jaundice?
Unconjugated hyperbilirubinaemia
Conjugated hyperbilirubinaemia
122
How can you differentiate between hepatic causes of unconjugated hyperbilirubinaemia from pre-hepatic causes?
Unconjugated hyperbilirubinaemia is likely to be pre-hepatic if there is anaemia and low haptoglobin (i.e. markers of haemolysis)
Other wise its mor likely to be hepatic caused
123
Which enzyme is needed for the conjugation of bilirubin with glucuronic acid in the liver?
Uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1)
Often shortened to glucuronosyltransferase
124
What can cause reduced or absent activity of glucuronosyltransferase?
Inherited - Gilbert’s syndrome, crigler-najjar syndrome type 1 and type 2
Acquired - hyperthyroidism, ethinyl estradiol, antibiotics, antiretroviral drugs
125
How do Gilbert syndrome and Crigler-Najjar syndrome present differently?
Gilbert syndrome is characterised by isolated unconjugated hyperbilirubinaemia and typically presents around the time of puberty (since bilirubin production increases then). Crigler-Najjar syndrome has a more severe presentation in the neonatal period due to severely reduced or absent activity.
126
What proportion of the population have Gilbert’s syndrome?
3%
127
What is Gilbert’s syndrome?
Gilbert's syndrome is an autosomal recessive* condition of defective bilirubin conjugation due to a mild deficiency of UDP glucuronosyltransferase - 10-30% activity of glucuronosyltransferase. = causes excess unconjugated bilirubin
Typically, it presents as an incidental finding on blood tests, with slightly raised serum bilirubin levels, while other routine liver function tests and reticulocyte count remain within normal limits.
Plasma bilirubin concentrations can rise in people with Gilbert’s syndrome during intercurrent illness, periods of stress, when dehydrated or fasting, or during menstruation. Frank jaundice may occur.
No treatment is required
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What is crigler-Najjar syndrome?
a rare autosomal recessive disorder causing defects in UDP-glucuronosyltransferase due to a genetic defect in the UGT1A1 gene= leading to unconjugated hyperbilirubinaemia.
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What are the 2 types of Crigler-Najjar syndrome?
Type 1 Crigler-Najjar syndrome presents in neonates with progressive jaundice in the first few days of life. If untreated it leads to kernicterus and death. Absolute deficiency of UDP-glucuronosyl transferase. Dont survive to adulthood
Type 2 Crigler-Najjar syndrome is less severe and brain damage does not occur. May improve with phenobarbital (<10% UDP-glucuronosyltransferase activity)
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What is kernicterus?
A rare neurological disorders characterized by hyperbilirubinemia during infancy
It can cause athetoid cerebral palsy and hearing loss. Kernicterus also causes problems with vision and teeth and sometimes can cause intellectual disabilities.
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How can HIV infection cause jaundice?
Extra-hepatic obstruction due to AIDS cholangiopathy (biliary tract strictures caused by infection)
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What is post-hepatic jaundice characterised by?
Elevated conjugated bilirubin
Cholestatic liver enzyme elevation - predominant rise in ALP and GGT
Evidence of obstruction on imaging
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What causes the dark urine and pale stools in jaundice?
Patients with biliary obstruction
Dark urine occurs because conjugated bilirubin is water-soluble and easily excreted by the kidneys leading to discolouration.
Pale stools occur because the breakdown products of bilirubin, once they enter the intestines, gives faeces its characteristic brown colour. The absence of bilirubin passing into the intestines leads to a pale appearance.
While suggestive of post-hepatic jaundice, these features may also be seen in acute hepatic disorders so they are not a reliable marker to differentiate between the causes of jaundice.
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What is Dubin-Johnson syndrome?
A rare, benign, autosomal recessive condition that is relatively common in Iranian Jews
There is a mutation in the canalicular multi drug resistance protein 2 (transporter protein that usually moves bilirubin into the bile) = defective hepatic excretion of bilirubin
This results in a grossly black liver
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What is Rotor’s syndrome?
A benign, automatic recessive disorder where there is a defect in the hepatic uptake and storage of bilirubin
Causes a mixed hyperbilirubinaemia
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What is Fasciola?
a liver fluke common in sheep and cattle in many areas of the world.
Human infection occurs when Fasciola larvae are ingested in contaminated water or on water plants such as raw watercress.
After ingestion, the parasites migrate from the intestines to the liver and then settle in the bile ducts.
In the biliary system, the parasites can cause inflammation and blockage.
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What is Chlonorchis?
a liver fluke found across parts of Asia.
Infection occurs when the larvae are ingested in raw or undercooked fish, crabs, or crayfish.
The juvenile parasites migrate from the duodenum to the biliary tract where they mature to adult flukes and can cause inflammation and intermittent obstruction.
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What should you ask a a person with jaundice?
Duration and previous episodes
Colour of urine and stools
Pain
Pruritus
Systemic features - anorexia, weight loss, fever, rigors, arthralgia, rash, fatigue
Alcohol intake
Travel abroad to areas endemic for viral hep and parasites
IV drug use, tattoos, body piercings, blood transfusions, multiple sexual partners, sex between men or with sex workers
PMHx - biliary surgery, gallstones, hepatis, AIH, thyroid sdisease, NAFLD
Comorbidities - IBD, obesity, diabetes, metabolic syndrome
Drugs - prescribed and OTC. Always ask about ?paracetenok overdose
Occupation - exposure to viral hepatitis, HIV, hepatotoxic chemicals
FHx - inherited anaemias, haemoglobinopathies
Pregnancy possibility
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How should you examine a person with jaundice?
Sepsis signs
Signs of CLD
Signs of liver failure
Lymphadenopathy - troisiers sign
Hepatomegaly, splenomegaly, palpable gallbladder
Abdominal tenderness
Visible veins e.g. caput medusae
Ascites
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What investigations should you consider in a person with jaundice?
FBC
U&Es
LFTs
Clotting screen
Amylase
Hep A, B and C if risk factors are present
Urine dipstick
CA19-9 if pancreatic cancer indicated
If LFTs show a non-obstructive picture then do a viral hepatitis screen, immunoglobulins, autoantibody profile, ferritin, alpha-1-antitrypsin, alpha-fetoprotein, caeruloplasmin in people <40, HbA1c and TFTs
Consider arranging an abdominal USS or CT
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In those presenting with jaundice, who needs same-day emergency assessment?
Hepatic encephalopathy signs - confusion, alteration in mental state, altered neuromuscular function
Sever hepatic dysfunction - bruising, purpura, petechial
Signs of GI blood loss - haematemesis, melaena
Sepsis signs - fever, hypotension, tachycardia
Signs of ascending cholangitis - jaundice, RUQ pain, fever, hypotension and altered mental status
Marked abdominal tenderness or pain
Vomiting
Suspected paracetemol overdose
Bilirubin >100
Abnormal clotting profile and signs of coagulopathy
Abnormal renal function
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What does an isolated raised bilirubin often indicate?
Pre-hepatic cause (haemolytic anaemia, Gilbert’s syndrome etc)
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What does low serum albumin with jaundice indicated?
chronic liver disease
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Which anatomical site of the biliary tree can be obstructed and is least associated with jaundice?
Cystic duct and gallbladder - this is because bile can still flow from the liver down the common hepatic duct and common bile duct to the sphincter of oddi
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Why is cholecystitis only rarely associated with jaundice?
Because bile can still flow down the common hepatic duct and CBD TPO the sphincter of Oddi where its secreted into the duodenum
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What does jaundice with RUQ mass suggest?
Hepatocellular disease
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What is Prussian blue staining used for?
Highlighting iron deposition within hepatocytes in pt with haemochromatosis
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What will lab results show in Dubin-Johnson syndrome?
Conjugated hyperbilirubinaemia
No elevated of liver enzymes
Non-Pruritis jaundice
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What does primary sclerosing cholangitis look like on radio graphic imaging with contrast?
Localized areas of dilatation proximal to biliary strictures produces a characteristic beaded appearance
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What are the differences in primary biliary cholangitis and primary sclerosing cholangitis?
PSC - damage of medium to large extrahepatic and intrahepatic bile ducts. Pre-malignant. More common in men. Beaded appearance of bile ducts on MRCP or ERCP. Typically also have UC
PBC - damage to small intrahepatic bile ducts. Not pre-malignant. Raised AMA. More common in women (“B” for women). Typically also have Sjögren’s syndrome.
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Whats the M rule for primary biliary cholangitis?
Raised IgM
anti-Mitochondirla antibodies - M2 subtype
Middle aged feMales
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How does biliary atresia present?
Patients typically present in the first few weeks of life with:
Jaundice extending beyond the physiological two weeks
Dark urine and pale stools
Appetite and growth disturbance, however, may be normal in some cases
Signs:
Jaundice
Hepatomegaly with splenomegaly
Abnormal growth
Cardiac murmurs if associated cardiac abnormalities present
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Which antibodies are raised in primary sclerosing cholangitis?
P-ANCA raised in up to 94% of cases
Antinuclear antibodies raised in up to 77% of cases
ACL raised in up to 63% of cases
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Which antibodies are raised in primary biliary cholangitis?
Anti mitochondrial antibodies M2 subtype in 98% of pt
Smooth muscle antibodies in 30%
Raised serum IgM
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What are the 2 types of cholestasis?
Hepatocellular cholestasis - not making enough bile (intra hepatic)
Obstructive cholestasis - physical blockage to path of bile
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Why do the oral contraceptive pill, pregnancy and anabolic steroids cause cholestasis?
Oestrogen inhibits the export pump in hepatocytes which means that the bile acids cannot be secreted into the bile canaliculi
Bile acid production and synthesis actually drives bile production which means that when the cells can transport bile acids, they start to build up inside the hepatocytes = signals to down regulate bile acid synthesis
Alongside this a build up of conjugated bilirubin occurs
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What are hepatocellular causes of cholestasis?
Drugs that increase oestrogen - oral contraceptives, pregnancy, anabolic steroids (similar in structure to oestrogen)
Viral hepatitis
Alcoholic hepatitis
CLD
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What are obstructive causes of cholestasis (extra hepatic)?
Gallstone
primary sclerosing cholangitis
Biliary atresia
Pancreatic head carcinomas
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why does jaundice cause pruritus?
Bile salts deposit in the skin and cause itching
