- Chronic liver disease (CLD) is a — deterioration of liver functions for more than — , which includes synthesis of clotting factors, other proteins, detoxification of harmful products of metabolism, and excretion of bile.
-The time to disease is a — rather than absolute distinction.
-Acute Liver Injury: — course, usually a more — , — onset of symptoms
-Chronic Liver Disease: — course ( > — ), a more — , — onset of symptoms
-Some causes of liver disease can present with either an acute (eg. — is acute only) or chronic presentation (eg. — ), and some can progress from acute to chronic (acute alcohol-associated hepatitis to chronic alcohol-related liver disease).
progressive
six months
relative
short , rapid , severe
longer > 6 months
more gradual , insidious
hepatitis A
haemochromatosis
Alcohol-associated hepatitis
Paracetamol overdose
Hepatitis A and E
Ischaemic hepatitis
Drugs and toxins
are —- liver injury
Chronic Alcohol Related Liver Disease (ALD)
Fatty liver disease
Hepatitis B and C
Haemochromatosis
are — liver disease
acute
chronic
- Chronic Liver Disease is a — process of — , — , and — of liver — , which can lead to — and — if the underlying cause is not addressed
1-Fibrosis is the deposition of — matrix (ECM) in response to chronic liver injury by any cause. Fibrosis can be — in the initial stage of development. The transition point to irreversible fibrosis is still not completely understood.
2-Cirrhosis is a — stage of chronic liver disease that results in disruption of liver. — , the formation of widespread —- , – reorganization, — , and deposition of an — matrix
continuous provess
inflammation , destruction , regeneration
liver parnhcuma
fibrosis and cirrhosis
extracellular màxtrix
reversible
final
architecture
nodule , vascular , neo-angiogensis , extraceuular
pathophysiology :
The injury pathway is initiated by —-
HSC are usually — cells found in the space between — and —.
While quiescent, they play a role in —- metabolism.
In response to liver injury, HSCs are – , and transform into — and upregulate the expression of — receptors.
This pro-inflammatory phase makesthe liver cells responsive to inflammatory —- , and leads to progressive activation of more HSC cells,resulting in the accumulation of — and — .
hepatic stellate cells (HSC)
dormant
sinusoid and hepatocytes
vitamin a
activated
fibroblast
inflammatory
cytokines
ECM and fibrosis
pathophysiology of portal hypertension :
-The liver receives — % of the cardiac output (between — mls/min).
Hepatic sinusoids are specialised — , which receive this considerable blood volume.
-In cirrhosis, sinusoidal endothelial cells (SECs), which line the — , produce excess — a vasodilator , and — a vasoconstrictor, leading to blood vessel — and — pressures within the liver vascular bed.
This is termed portal hypertension.
-Due to back pressure, the splanchnic (abdominal) circulation also sees an — in NO leading to dilation of blood vessels, activating the — , and resulting in water and sodium — , — blood volume, creating a — circulation.
-Portal hypertension (increased pressure in the — ) and hyperdynamiccirculation (increased — in the portal system)
25%
800-1200
capillaries
hepatic sinusoids
nitric oxide NO
endothelin-1 ET-1
contraction
high
increase
renin-angiotensin-aldosterone system (RAAS)
retention
increase
hyper dynamic
portal vein
blood volume
pathophysiology : portal hypertension
Portal hypertension: As the — toblood flow increases within the portalcirculation (in this case due tothe upstream — ),the pressure backs up and tries tofindalternative routes back tothe heart, around the obstruction.
Due to the venous anatomy, this pressurecan back up into:
Gastro-oesophageal veins: Oesophageal or gastric varices (increasing the risk of life-threatening – bleeding)
Splenic vein: —
Umbilical veins: —
Rectal veins: Rectal —
resistance
fibrosis
variceal bleeding
splenomegaly
capcut medusea
rectal varices
-The natural history of cirrhosis is characterised by a stable ‘ — ‘ period, followed by periods of acute ‘ — ‘.
-A common cause for GI acute medical admissions, complex medical needs, high risk of in hospital death.
-Def: Acute deterioration in liver function in a patient with cirrhosis, characterised by the development of one of the following complications:
1-Jaundice(impaired— of bilirubin leading to accumulation in skin and mucous membranes)
2-Ascites (most common complication of — , accumulation of fluid in the — due to — )
3-Hepatic Encephalopathy: a range of — symptoms, exact mechanism unknown but thought to be secondary to build up of toxins crossing the — , including ammonia
4-VaricealHaemorrhage: — varices can rupture, leading to life-threatening haemorrhage with a high mortality rate.
compensated
decompensation
excretion
cirrhosis
abdomen
portal hypertension
neurological
BBB
oesophageal
symptoms and causes:
1-Fatigue and weakness:
Catabolic state given inflammation, malnutrition, poor diet of ALD
2-Nausea and Vomiting:
Poor gastric emptying, increased acid production, ascites causing mechanical nausea
3- — :
Excess bilirubin deposited in skin
4- — :
Circulating conjugated/unconjugated bilirubin
5- Bleeding:
Reduced clotting factors produced, platelets consumed due to splenomegaly
5- Weight gain:
Fluid retention and third spacing, given hyperdynamic state, reduced albumin production
6-Confusion:
Encephalopathy due to reduced — excretion, — deficiency due to alcohol Wernicke’s
7- Fever/ Abdominal pain:
8-Subacute bacterial peritonitis due to –
Upper GI Bleed: Haematemesis, malaena
Oesophageal Varices due to portal hypertension
prutitis
jaundice
ammonia
b12
ascites
signs and causes:
Reduced GCS/Asterixis:
Hepatic Encephalopathy due to reduced excretion of ammonia
Jaundice:
Hepatocyte damage reducing conjugation of bilirubin
Bruising/Petechiae:
Reduced clotting factor synthesis, consumptive thrombocytopaenia
Ascites:
Due to RAA system activation, salt and fluid retention, splanchnic arterial dilation, portal hypertension, reduced oncotic pressure due to reduced albumin synthesis
Splenomegaly/Caput medusae:
Portal hypertension
Peripheral oedema:
Reduced albumin production
Pallor:
Anaemia of chronic disease, B12 deficiency, iron deficiency
causes of chronic liver disease:
1- fatty liver: non alcoholic fatty liver , metabolic dysfunction , most common cause in west , associated w —
2- alcohol liver : ALD , major cause of liver disease and major kill
3- viral hepatits : hep — and — harv a chornic cource causing cirrhosis , hepatits— and —cause acute liver injury , hep E rarely cause anyhting but found in immunocompromised
4- haemchromatosis: highest rate in Ireland
5- autoimmune : autoimmune hepatitis , primart biliary cholangitis , primary sclerosis cholangitis
6- heredity : — disease and —- dificny
diabetes
b , c
a , e
wilson , alpha 1 trypsin
Metabolic dysfunction-associated steatotic liver disease - leading cause of chronic liver in Ireland and west ( 1/3 )
Steatosis: accumulation of — droplets within hepatocytes
Metabolic Syndrome: A cluster of conditions which indicate a high risk of —- disease:
—- resistance
—- Obesity ‘apple shaped’
Hypertension
Hyperlipidaemia
Associated Conditions:
MASLD
Sleep apnoea
Gout: Hyperuricaemia
PCOS: Polycystic Ovarian Syndrome
Erectile Dysfunction
Causes a mild chronic disease, i.e. the majority of deaths are secondary to — and —.
lipid
cardiovascular
insulin
central
MI and stroke
Metabolic dysfunction-associated steatotic liver disease:
Nomenclature:
Previously termed ‘Non-Alcoholic Fatty Liver Disease’ or NAFLD.
While out ruling alcohol is a key component of making this diagnosis, the name is stigmatising, and therefore has been recently changed.
Other terms:
NASH: Non-Alcoholic Steatohepatitis
Infers inflammation secondary to the —-
MASLD is a diagnosis of exclusion:
— liver on ultrasound
Absence of — excess
Features of — syndrome
Need to out-rule all other potential causes
Treatment:
— modification: diet, exercise,
weight loss. — analogues
fatty infiltration
fatty liver
alchohol
metabolic
lifestyle
GLP-1
alcohol related liver disease:
Ethanol:
CNS —- which produces euphoria and behavioural excitation at low levels, drowsiness, ataxia, slurred speech, stupor, and coma at higher intoxication levels.
Impact of Alcohol on Liver:
-Ethanol is metabolised by —- (alcohol—) in hepatocytes
-ADH-catalyzed ethanol oxidation uses nicotinamide adenine dinucleotide (NAD+) as a — , generating reduced —(NADH) and —-. The latter compound is highly — and —.
Impact of Alcohol on Brain:
Alcohol use leads to cerebellar dysfunction,resulting in classic intoxifcation symptoms of —, broad based — , — speech.
Chronic use: cerebellar wasting can lead to chronic cerebellar ataxia and can be seen on neuroimaging in chronic alcoholism.
Acute Withdrawal: due to changes to —- channels that occur in alcoholism, abrupt withdrawal can lead to —-.
depressants
adh ( alcohol dehydrogenase )
cofactor
NAD+ and acetahyde
highly toxic and reactive
ataxia , gait , slurred
neurotransmitters
seizures
1- Clinical features of Alcohol-related Liver Disease: Features of CLD
Extra-hepatic manifestations:
-Nervous system: Symmetric peripheral — . Withdrawal: — deficiency complications: Wernicke’s — , korsakoff’s — .
- —
- —
2- Diagnosis:
Documentation of regular alcohol consumption
Clinical or biochemical features suggestive of liver injury
LFT pattern:
AST: ALT ratio > —
Elevated –
Exclusion of alternative causes of liver disease
Liver biopsy: Histology shows —, hepatocellular injury, fibrosis or cirrhosis
Management:
Alcohol cessation and avoidance of risks (Alcohol withdrawal seizures, Wernicke’s, Korsakoffs)
Addiction support
Screening for and management of cirrhosis complications (variceal bleeding, ascites, SBP, hepatic encephalopathy, HCC)
Nutritional support
Avoidance of other causes of liver injury
neuropathy
thiamine deficiency
Wernicke’s encephalopathy, korsakoff’s psychosis.
pancreatitis and cardiomyopathy
1.5
GGT
steatosis
( ast > alt )
alcohol withdrawal :
1- Thiamine AKA. Vitamin — . Key role in — metabolism.
Deficiency can cause neuronal — , classically seen in the — bodies ( — ).
Deficiency is classically associated with alcohol use disorder, poor dietary intake, impaired intestinal absorption, reduced hepatic storage.
2- Wernicke-Korsakoff syndrome is a disease spectrum, with Wernicke’s representing the — phase, progressing to Korsakoff in the — stage, if the thiamine deficiencyis not reversed.
3-Wernicke’s encephalopathy is—- , life-threatening — condition caused by — deficiency characterized by a clinical triad:
–> — with —
–> —
—> —
4-Korsakoff Psychosis
Neuropsychiatric disorder associated with — disturbances, — , — disturbances.
Management:
Thiamine supplementation: Intravenous — (vit B+C), switching to oral thiamine tablets for — term management.
vit b1
cerebral metabolism
cell death
mamillary bodies ( hypothalamus )
acute
chronic
acute life threatening
neurological
thiamine deficiency
Ophthalmoplegia with nystagmus
Ataxia
Confusion
memory , confabulation , emotions;
iv pabrinex
long term
Hepatitis C:
ssRNA virus
80-90% of infections become chronic
Risk of — and —
Curable
Risk Factors (key questions on history taking):
Intravenous drug injectors
Approximately 70% of people who inject drugs in Ireland have HCV
Sexually transmitted: multiple sexual partners/unprotected sex
Tattoos
Blood transfusion (Irish Blood Transfusion Scandal)
Haemodialysis
Vertical transmission (mother to baby)
Travel to endemic areas: —
Health care workers
Preventable? –
No vaccine currently exists
Curable: —
Direct Acting — , eg. sofosbuvir
99% chance of cure with an — course of – tablets
cirrhosis and HCC
Egypt
no
yes
antivirals
8 week DDA
hept b :
Modes of transmission:
Similar to HCV
Highly —
Very environmentally — : can remain active on surfaces for up to one week. Hygiene practices are essential
Preventable? —
Vaccination exists
Curable? —
Managed by viral — with — analogues: eg. Entecavir, tenofovir
Goals of therapy:
Prevent disease progression to cirrhosis or HCC
Prevent mother to child transmission
Prevent reactivation
Prevent HBV-associated extra-hepatic manifestations
infectious
stable
yes
no
viral suppression w nucleoside
Haemochromatosis
- ‘ – DIABETES’
Named in 1800’s
‘Chrom’ meaning pigmentation, in the ‘haem’ meaning blood
- Excess — is absorbed via the intestine, leading to total-body ironoverload.
-Iron accumulates in multiple organs: — (cirrhosis and HCC), — (cardiomyopathy), — (diabetes), pituitary (pituitary hypogonadism, skeletal (arthralgias/arthritis/osteoporosis).
-Chronic picture: Manifestsyears laterafter significant iron deposition
-Onset in premenopausal women can be — by menstrual loss ofblood
-Symptoms: cirrhosis, diabetes, arthralgias/arthritis/osteoporosis, fatigue, erectile dysfunction/loss of libido/amenorrhoea, ECG abnormalities, bronze skin hyperpigmentation (epidermal iron deposition).
bronze
iron
liver
heart
pancreas
delayed
Ireland has the highest prevalence ofhereditary haemochromatosis(HH) in the world
1/5 people in Ireland are gene carriers.
Hereditary haemochromatosis is an —- condition due to — (ie. 2 copies) mutations in the — (H: High, Fe:Iron) gene on chromosome –
-C282Y (Cysteine to Tyrosine at 282nd amino acid)
-H63D (Histidine to Aspartic Acid at amino acid 63)
-85% of HH due to C282Y homozygosity
Diagnosis:
1. Iron Studies
Pre-menopausal women: Transferrin saturation >45%, ferritin >200 µg/L
Men/ post-menopausal women: Transferrin saturation >50%, ferritin >300µg/L
2. AND genetic testing: HFE genotyping
Treatment:
1st line: —-
2nd line: — (inaccessible veins, needle phobia, concomitant anaemia)
:Deferasirox
autosomal recessive
homogenous
HFE
c/some 6
venesection
iron chelator
Wilsons disease : rare condition
Wilsons disease (hepatolenticular degeneration) is an — genetic disorder of — metabolism due to — mutations on chromosome —
Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the — , – , and — .
-Ocular: Kayser fleisher — (brown-yellow ring at corneo-scleral junction, due to copper deposition in Descemet’s membrane).
Liver:Cirrhosis, can progress to fulminant liver failure
Neurological: Dysarthria,parkinsonism,cerebellar ataxia, dystonia,tremor etc.
Psychiatric: mood disorders,psychosis,cognition
Other organs: Kidney, heart,joints,endocrine
Can present at any age, but the vast majority between ages —
autosomal recessive
CIPPER
ATP7B
c/some 13
liver brain and cornea
rings
5-35
Wilsons disease:
Investigations:
Serum copper (high, >1.6µmol/L) , caeruloplasmin (low, <0.1g/L)
24-hour urine collection for copper (high, >1.6µmol/L/24hours)
Slit lamp ophthalmology exam
Treatment:
—- : promotes urinary excretion of copper
— : interferes with uptake of copper from GI tract
— : chelator
D-Penacillamine: promotes urinary excretion of copper
Zinc: interferes with uptake of copper from GI tract
Trientine: chelator
primary billary chonagitis aka primary biliary cirrhosis which is a form of —- liver disease
- Characterized by a — -mediated attack on small — bile ducts. Continuous assault on bile duct epithelial cells leads to their gradual — and eventual — . This leads to a cycle of — and liver — .
Associations:
— (95%)
Sjogren’s syndrome
Autoimmune thyroid disease
Rheumatoid arthritis
Coeliac disease
Inflammatory bowel disease
symptoms : fatigue , pruritis , sick , signs and symptoms of cld
The disease is — and can be — , resulting in — liver disease
50% of people are — at time of diagnosis
autoimmune
t lymphocyte
interlobular bile ducts
destruction
disappearance
cholestasis and liver fibrosis
female
chronic and progressive
end stage
asymptomatic
primary biliary colangitis :
Diagnosis:
Cholestatic LFT picture:
Alkaline Phosphatase /GGT almost always elevated (generally 3-4x normal)
AST, ALT < 200 U/L
Raised — in later stages of disease
Antimitochondrial Antibody: — (hallmark of diagnosis)
Raised — (leading to xanthoma and xanthelasma)
Liver biopsy and histology: chronic non-suppurative, granulomatous, lymphocytic small bile duct cholangitis
Treatment
1st line: Ursodeoxycholic Acid
Benzafibrate
Obeticholic acid
Budesonide
bilirubin
AMA
cholesterol
primary scleorisng cholangitis is a form of — liver disease
Primary sclerosing cholangitis
A — progressive disorder of — aetiology that is characterized by — , — , and — of — and — ducts in the intrahepatic and/or extrahepatic biliary tree
Associations:
- —
- —- is present in 50-80% of people with PSC
autoimmune
chronic
unknown
inflammation , fibrosis and structuring
medium and large
UC
IBD
-
Physiology of Mastication & Swallowing22
-
principles of nutrition16
-
Aerobic gram -ve bacili GNB29
-
enteric GI infections28
-
Digestion and Absorption of Macromolecules32
-
upper GI pathology37
-
gastric functions25
-
case control17
-
gastric function: git hormones22
-
Tetanus, botulism and other anaerobic bowel infections34
-
colorectal cancer17
-
pathology: small bowel disorders21
-
pathology of inflammatory disease of bowel38
-
GI pharmacology38
-
functions of the colon20
-
Viral Infections of the Bowel32
-
acute abdomen18
-
bacterial pretonitis22
-
lower GI pharmacology34
-
irritable bowel syndrome14
-
Post-absorption Processing of Carbohydrate22
-
malabsoprtion17
-
gram -ve bacili35
-
gallstones and jaundice22
-
post absorption of lipids26
-
acute appendicitis20
-
Inflammatory bowel disease31
-
tumours of large bowel37
-
histology of liver dysfunction28
-
enviromental healthcare24
-
malignancies38
-
pancreatitis and pancreatic ca20
-
post absorption processing of proteins23
-
chronic liver32
-
biosynthetic function of the liver21
-
drug metabolism25
-
viral hepatitis27
-
Pathological Evaluation of Hepatitis34
-
bile and jaundice23
-
Non alcoholic and alcoholic fatty liver disease33
-
liver failure34
