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Gastro BSc > Module 1.3: Liver + Pancreas > Flashcards

Module 1.3: Liver + Pancreas Flashcards

1
Q

Summarise the reasoning for the research interest in alcohol

A
  • Sheron, 2010
    causes >50% of violent crime + domestic violence
    2000 homicides/year
    200000 deaths
    4x more deaths and disability risk than illicit drugs
    cause of 7% of all ill health + early death
  • BMJ 2013
    drinking doubled compared to 40 years ago
    1/4 adults in UK drink dangerous amounts
    total cost of misuse 21b pounds/year in social/economic harm
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2
Q

Summarise the most effective way of addressing the issues with alcohol

A

difficult to change social beliefs

MIN UNIT PRICING

  • 45p/unit would lead to 220m pounds average annual savings to NHS over 10y
  • prevent 714 deaths and 25k hospital admissions

according to Home Office Impact assessment

Organ donations - if swapped to ‘opt out’ system, % of donors would increase

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3
Q

Summarise the metabolism of alcohol

A

MAJOR PATHWAY

ethanol –> acetaldehyde (enzyme: alcohol dehydrogenase, NAD->NADH)

acetaldehyde –> acetate (enzyme: acetaldehyde dehydrogenase, NAD->NADH)

only occurs in hepatocyte cytosol

MINOR PATHWAY

ethanol –> acetaldehyde (enzyme: cytochrome P4502E1, NAPDH->NAPD)

occurs in smooth ER

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4
Q

Summarise the variation in acetaldehyde dehydrogenase

A

some people have forms of acetaldehyde dehydrogenase that work faster - THEY ARE ISOENZYMES

ALDH2 is present in 75% of oriental-origin Asian populations –> works slowly –> Acetaldehyde buildup –> unpleasant reactions + FLUSHING

Natural aversion to alcohol –> lower rate of alcoholism in Chinese subject with ALDH2

This is the basis of Disulfiram - inhibits acetaldehyde dehydrogenase –> unpleasant symptoms such as flushing, nausea, tachycardia, dyspnoea, hypotension

BACLOFEN –> GABA receptor agonist –> used as anti-spasmodic –> reduces cravings

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5
Q

Describe the pathogenesis of alcoholic liver disease

A

Incompletely understood

Risk of alcoholic liver disease related to amount and duration of consumption of alcohol

Only minority of chronic alcohol abusers develop liver disease –> presumably genetic drivers that influence liver disease development

  1. CENTRILOBAR HYPOXIA
    - alcohol metabolism consumes O2 via the NAD pathway
  2. NEUTROPHIL INFILTRATION AND ACTIVATION
  3. INFLAMMATORY CELL INFILTRATION AND ACTIVATION
  4. ANTIGENIC ADDUCT FORMATION
    - adduct: causes DNA and protein damage by binding to DNA
    - acetaldehyde and hydroxylethyl radicals bind to proteins and damage them
  5. INJUROUS PRO-INFLAMMATORY CYTOKINES
    - TNF and IL6
    - scarring and liver damage
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6
Q

Briefly describe the disease progression in ALD

A

Normal liver –>/ alcoholic hepatitis (10-35%) –> cirrhosis (?40%)

OR

fatty liver –> cirrhosis (8-20%)

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7
Q

Describe and exlpain the risk factors of ALD

A

Amount and duration of ethanol ingestion

  • for cirrhosis 80g/day for 10-20y required
  • – 1 litre wine, 8 cans of beer

Coexisting HepB/HepC infection

  • accelerates disease in alcoholics
  • 30% prevalence of HeCV in ALD

Malnutrition

  • all money spent on alcohol or because alcohol is filling
  • worsens severity

Genetic factors

  • FEMALE GENDER
  • – increased disease risk for a given amount/duration of alcohol intake independent of weight
  • STRONG CANDIDATE GENES:
    — PNPLA3 - role in hydrolysis of triglycerides
    — TM6SF2 - role in VLDL production and secretion
    — MBOAT7 - role in neutrophil activation
    (Stickel et al 2016)

Epigenetic factors
- how micro-environment within the body affects the genes
- alcohol induced oxidative stress –> histone modification –> altered recruitment of transcriptional machinery and abnormal gene expression –> accelerated cell death and inflammation
(Mandrekar 2011)

Obesity and diabetes
- independent predictors of fibrosis in NASH which has histological similarities to ALD and may share pathogenesis

Concurrent exposure to hepatotoxins
- two hepatotoxins –> greater risk than either alone e.g. paracetamol + alcohol

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8
Q

Decribe the alcoholic steatosis stage of ALD

A

occurs within hours of binge

Direct effect of etOH

90% of heavy drinkers

accummulation of membrane bound fat droplets + proliferation of smooth ER + gradual distorsion of mitochondria

minimal inflammatory changes

Reversible

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9
Q

Decribe the alcoholic hepatitis stage of ALD

A

medical emergency - otherwise patients die within a few months

ESSENTIAL FEATURES:

  • liver cell necrosis
  • mallory bodies (eosinophilic accumulation of cellular material)
  • neutrophil infiltration

periventricular or pericentral (viral is periportal)

Other features: bridging necrosis, fatty change, bile duct proliferation, cholestasis, perivenular fibrosis

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10
Q

Decribe the alcoholic fibrosis/cirrhosis stage of ALD

A

The on-going necrosis of hepatocytes results in regeneration, leading to fibrosis –> nodular, firm liver

Fibrosis - Potentially reversible if abstain from alcohol

TRUE CIRRHOSIS - presence of regenerative nodules –> IRREVERSIBLE

It is worth trying to reverse cirrhosis UNLESS PT HAS DECOMPENSATED

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11
Q

define FIBROSIS of the liver

A

accumulation of scar protein or ECM, including interstitial collagens, glycoproteins and proteoglycans

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12
Q

What is the main cell involved in the scarring of the liver?

A

STELLATE CELLS
main source of ECM
normal function is to store Vit A
activated by platelet derived GF + transforming growth factor-1 + endothelin-127

when activated, they lose vitA, proliferate and become fibrogenic

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13
Q

Screening for alcoholism

A

CAGE

felt the need to cut down
annoyed if criticised
felt guilty about it
eye-opener first thing in the morning

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14
Q

Tx of ALD

A

few specific therapies

most important intervention = ABSTINENCE

Nutritional supplements: fluids, vitamins (pabrinex), human albumin olution

the idea is to prevent relapse

Liver transplantation in decompensated cirrhosis but pts have to show they can be alcohol abstinent

Tx complications
- ascites, portal hypertension, varices, encephalopathy, HCC

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15
Q

Tx of alcoholic hepatitis

A

High mortality (40%)

Tx of alcohol withdrawal - CHLORDIAZEPOXIDE

fluids, calories, vitamins (pabrinex), albumin

exclude and tx sepsis, renal impairment, portal hypertnsion etc.

STEROIDS reduce morality in selected cases of Alcoholic Hepatitis

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16
Q

Describe the use of Child-Pugh classification in chronic liver disease

A

PARAMETERS:

Ascites
Bilirubin
Albumin
PT
Encephelopathy

Score 5-6 - GRADE A - well-compensated
Score 7-9 - GRADE B - significant functional compromise
Score 10-15 - GRADE C - decompensated

1/2 year survival:
A - 100/85%
B - 80/60%
C - 45/35%

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17
Q

Describe normal iron metabolism

A 
dietary intake: 10-20mg/day
Absorbed: 1-1.5 mg/day
Total in body: 4g
Iron in Hb: 3g
Total iron binding capacity: 250-370 ug/dl
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18
Q

Describe the results of excess iron in the body

A

Liver: cirrhosis, HCC

Heart: CCF, conducting deficits, arrhythmias, constrictive pericarditis

Endocrine: diabetes, panhypopituitarism, hypogonadotrophism

Joints: chondrocalcinosis

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19
Q

How does excess iron lead to cellular damage?

A

oxygen derived free radicals are produced through the Fenton reaction which damage proteins, DNA and cell membrane

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20
Q

What are the two forms of iron found in the body

A

Haem - 10% - Fe2+ - ferrous

non-haem - 90% - Fe3+ - ferric

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21
Q

Explain the process of iron absorption in the body

A

Ferric iron is reduced to ferrous iron by Duodenal cytochrome b (Dcytb), which is a ferric reductase. Dcytb is expressed in the duodenal brush border.

The ferrous iron is taken up by a divalent metal transporter 1, DMT1

Following uptake iron is either STORED as FERRITIN

or

released by FERROPORTIN 1 (FPN), which is the only exporter that regulates plama iron concs

Once in circulation, iron is oxidised to its ferric form by HEPHAESTIN on intestinal surface or CAERULOPLASMIN in plasma.

Iron binds TRANSFERRIN to be transported

When delivered to a site, it binds to transferrin receptor 1 (TfR1)

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22
Q

Explain the importance of TfR1 in iron absorption

A

highly expressed in erythroid precursors to ensure increased iron uptake for erythropoiesis

Interaction of transferrin-bound iron with TfR1 results in INVAGINATION of cell membrane

The iron is releaed in the cytoplasm and converted back to Fe2+ by STEAP3

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23
Q

Explain how iron absorption is controlled

A

by iron responsive elements (IRE) and IRE-binding-proteins (IRP1 and 2)

IRP1 acts as an iron sensor in high oxygen environments

IRP2 acts at physiological oxygen tensions

LOW intracellular Iron –> IRP binding to IRE –> increased DMT1 synthesis + increased ferroportin in duodenum –> increased absorption

Most important regulator = HEPCIDIN

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24
Q

Give examples to causes of excess iron

A

Dietary: bantu siderosis
erythropoietic siderosis
multiple transfusions
genetic: haemochromatosis

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25
Q

What are the types of haemachromatosis

A

1 - classic

  • – affected protein: HFE
  • – inheritance: AR

2A + 2B - juvenile

  • – affected protein: haemojuvelin and hepcidin respectively
  • – inheritance: AR

3 - Tfr2 haemachromatosis

  • – affected protein: Tfr2
  • – inheritance: AR

4 - African overload Ferroportin disease

  • – affected protein: ferroportin
  • – inheritance: AD

X - 1 human case and mouse models

  • – affected protein: DMT1
  • – inheritance: AR
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26
Q

Summarise the relevance of HFE mutations in haemochromatosis

A

Autosomal recessive
8-10% of Caucasians are carriers
Most common mutations: C282Y and H63D

apprx 85-90% of those with the phenotype are C282Y homozygous

3-5% are C282Y/H63D heterozygous

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27
Q

Describe the function of Hepcidin

A

25aa protein

related to defensins - inflammatory marker

UPREGULATED IN:

  • bacterial infection
  • IL1, IL6
  • iron overload

DOWNREGULATED IN:

  • iron deficiency
  • hypoxia

Hepcidin binds to ferroportin (FPN) and causes DEGRADATION

Results in iron export from enterocytes + macrophages
–> decreased serum iron

When hepcidin expression is decreased, iron absorption and cellular iron export is UPREGULATED resulting in increase in serum iron

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28
Q

Describe the regulation is hepcidin

A

Depends upon signalling through the bone morphogenic protein (BMP)/SMAD pathway

BMP6 highly expressed in liver

high transferrin-Fe complexes in plasma = hepcidin increased

TfR2 senses high conc and forms complex with BMP and other proteins such as haemojuvelin

The complex activates SMAD signalling pathway causing gene transcription for hepcidin

IN IRON OVERLOAD:
- the complex activates SMAD signalling pathway, causing gene transcription for hepcidin

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29
Q

Describe the role of hepcidin in immunity

A

Expressed by macrophages - because bacteria need iron rich environments to grow. When activated by bacteria, immune system increases production of hepcidin as a way of restriction infection

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30
Q

Describe the diagnostic criteria for haemochromatosis

A

RAISED SERUM IRON: 220ug/dL

RAISED TRANSFERRIN SAT: 90% (normal 45%)

RAISED TRANSFERRIN: 50-200 is normal

STAINABLE IRON ON LIVER BIOPSY

HEPATIC IRON INDEX

FERROUS SCAN VIA MRI

31
Q

Describe the Tx of haemochromatosis

A

VENESECTION

  • 500ml blood = 250 mg Fe
  • removal of 10-40g Fe needed

Weekly venesection until transferrin saturation below 50% and ferritin below 50ug/ml

Venesection every 3 months afterwards for maintenance

32
Q

Define hepatic steatosis

A

presence of vesicles of fat, predominantly triglycerides, accumulating within hepatocytes

33
Q

Define NAFLD

A

presence of hepatic steatosis as part of the metabolic syndrome

steatosis affecting >5% of hepatocytes in the absence of excessive significant alcohol consumption, other liver disease or the consumption of steatogenic drugs

PRIMARY:

  • associated with metabolic syndrome
  • Obesity
  • T2DM
  • Dyslipidaemia

SECONDARY:

  • alcohol
  • drugs
  • – steroids, amiodarone, HAART, MTX, tamoxifen
  • HepC infection
  • parenteral nutrition
34
Q

Define metabolic syndrome

A

3+ of

waist circumference > 102cm/88cm M/F
TRG > 150 mg/dl
HDL<40/50 mg/dl M/F
BP >/= 135/85 mmHg
fasting glucose >/= 100 mg/dl

INSULIN RESISTANCE is the main pathophysiology

35
Q

Describe the NAFLD spectrum

A

statosis –12-40%—> NASH –15%—> Cirrhosis –1%/yr–> HCC

cirrhosis and HCC —-> liver transplantation or death

NAFL = steatosis without hepatocellular injury
NASH = steatosis with inflammation and hepatocyte ballooning degeneration
36
Q

Describe the magnitude of NAFLD

A

4-34% of population has fatty liver

80% of severely obese

70% of T2diabetics

16% prevalence in normal weight individuals with no metabolic risk factors

Prevalence of NAFLD increases with age - 40% in over 60

Obesity has tripled since 1975 - WHO 2016

37
Q

Describe the pathogenesis of NAFLD

A

complex interplay between diet, environment and liver and adipose tissues

poorly understood

Visceral ectopic fat accumulation causes INSULIN RESISTANCE and hepatic necro-inflammation with activation of HEPATIC STELLATE CELLS and increased production of collagen matrix and progression of liver disease

38
Q

Environmental factors contributing to NAFLD

A

DIETARY

  • high saturated fat content
  • high fructose content
  • reduced antioxidants

OBESITY

  • energy intake > output
  • lack of exercise
  • increased portions

T2DM

SMALL BOWEL INTESTINAL OVERGROWTH

39
Q

Genetic factors contributing to NAFLD

A

FAMILIAL AGGREGATION
- present in 17% in siblings, 37% of parents of overweight children without NAFLD - SCHWIMMER 2009

TWIN STUDIES

  • significantly higher in identical twins
  • MAKKONEN 2009
40
Q

What genes were identified as a result of candidate-gene disease association studies in NAFLD?

A

increased hepatic TAG for PNPLA3 gene

41
Q

Describe the role of PNPLA3 in NFALD

A

aka adiponutrin

On Chr22

Associated with severity of lipid accumulation

May sensitise the liver to environmental stressors

exact mechanisms unknown

42
Q

Describe how NAFLD can be diagnosed

A

Transaminases

  • ALT>AST
  • both <3x normal
  • normal in 20% of cases although similar liver damage
  • ALP/GGT not discriminatory

Components of MS

  • raised triglycerides, glucose
  • decreased HDL

Ferritin

  • raised in 20%, no correlation with Fe overload
  • advanced disease

Autoantibodies

  • ANA in 20-34%, SMA in 3-6%
  • associated with fibrosis

Imaging

  • US first line
  • enlarged bright liver
  • only sensitive when steatosis >33%
43
Q

Describe the non-invasive scoring systems used in NAFLD

A

BARD

  • BMI > 28
  • AST/ALT ration > 1
  • Diabetes

NAFLD Fibrosis Score

  • age
  • BMI
  • hyperglycaemia
  • AST/ALT
  • PLT
  • albumin

FIB4

  • age
  • AST
  • ALT
  • PLT
44
Q

Summarise the treatment studied for pts with NAFLD

A

Lifestyle interventions - reduction in caloric intake

Weight loss therapies

  • orlistat
  • bariatric surgery

Insulin sensitisers

  • metformin
  • thiazolidinediones
  • incretin based therapies
  • DDP4 inhibigofx

Hypertension
- angitension II receptor blockers

Dyslipidaemia

  • statins
  • fibrates
  • Ezetebime

Antioxidants

45
Q

What is copper found in?

A

Nuts, mushrooms

46
Q

What is copper required for?

A

Enzyme function

e.g.

Superoxide dismutase - free radical detoxification
Lysyl oxidase
Dopa-B-hydroxylase
Tyrosinase
Cytochrome C oxidase
47
Q

Describe normal copper mechanism

A

Dietary intake: 4mg/day

2mg absorbed, 2mg excreted in bile

absorbed from gut bount to albumin

In circulation, bound to CAERULOPLASMIN or ALPHA-2-GLOBULIN

Transported by transmembrane cation ATPase that has 6 copper binding units

Each binding site is formed from 2 cystin residues linked by two other aa’s

3 ATPases on extracellular domain of the protein

48
Q

What are the types of APSase transporters in the body?

A

ATP7a and ATP7b

Normally copper enters the blood from guy via ATP7a

At the liver it is released from albumin and enters the liver sinusoid through CTR1

In hepatocytes, it binds intracellular caeruloplasmin and is transported to the Golgi

At the golgi, it accumulates in vesicles and buds off

Binds to ceruloplasmin to allow transport into bile canaliculi via ATP7b

49
Q

Describe the genetics of Wilson’s disease

A

Autosomal recessive

1/90 are carriers

1 in 30k monozygotic frequency –> INCOMPLETE PENETRANCE hence not all are phenotypic

Mutation on 13q - transmembrane cation channel ATPase transporter - ATP7B

250 mutations identified

50
Q

Describe the pathophysiology of Wilson’s disease

A

Mutation on ATP7B –> copper enters from guy to hepatocytes FREELY

CANNOT BE SECRETED IN BILE –> accumulation in hepatocytes

lysis and release of free copper

ATP7A is still functional –> can accumulate in BRAIN and EYE

Attempt to excrete causes TOXICITY and renal failure

accumulation in liver causes cholestatic liver disease

51
Q

Describe the presentation of Wilson’s disease

A

children and young adults - presents by 30

earlier presentation (<20) likely to present with neuro features

May present as fulminant hepatitis - jaundice, ascites, hepatic/renal failure, hepatocyte necrosis secondary to copper toxicity. Most pts cirrhotic

May present as chronic hepatitis (10-30y)

  • jaundice, high transaminases, raised IgG
  • neuro changes 2-5y later

Renal changes
- Cu deposited in tubules

KAYSER-FLEISHER RINGS

  • Cu accumulation in Descemet’s membrane around the eye
  • Requires slit-lamp to visualise
  • Seen in older pts
  • indicates neuro involvement
52
Q

Indicate the biochemical features of Wilson’s

A

High serum Cu

High urinary Cu excretion - 1mg/d

Low biliary copper expression

Low caeruloplasmin (marker, not cause)

Increased Cu deposition in liver, basal ganglia, eye

Low ALP:bilirubin ratio - highly suggestive

53
Q

How can Wilson’s be diagnosed?

A

Biochemical markers

MRI - Cu in basal ganglia

Penicillamine trial

  • normal urinary copper <38ug/d
  • Wilson’s >1mg/d
  • – after penicillamine, should drop to 25ug/d

Electron microscopy

Histology on liver biopsy

Quantitative assay of Cu conc on liver biopsy

  • Over 250ug/g dry weight = WILSONS
  • Under 40ug/d dry weight = EXCLUDED
54
Q

How is Wilson’s screened for?

A

Siblings screened via haplotype analysis
- requires two siblings and one parent

Homozygous treated even if asymptomatic

Heterozygotes not treated

55
Q

Tx of Wilson’s

A

D-Penicillamine

  • Cu chelator
  • promotes safe urinary excretion up to 100 mg/d
  • Lifelong maintenance needed
  • FLTs improve
  • neuro complications are PERMANENT

ZINC

  • 50 mg
  • blocks dietary Cu absorption by inducing cellular methionine
  • used once stabilised

Liver transplantation
- in fulminant liver disease

56
Q

Define chronic pancreatitis

A

progressive inflammatory changes in the pancreas that results in permanent structural damage which can lead to impaired endocrine or exocrine function

57
Q

Symptoms of chronic pancreatitis

A

abdominal pain, features of exocrine (steatorrhoea) or endocrine (diabetes) insufficiency or can be asymptomatic.

Symptoms do not correlate with the rate of structural damage.

Exocrine insufficiency comes first

58
Q

What are causes of chronic pancreatitis

A

Most common cause is alcohol

Smoking is a factor

Remaining factors (hypercalcaemia, hypertriglyceridaemic) tend to cause recurrent aculte pancreatitis which eventually results in chronic pancreatitis

Genetics

59
Q

Describe the pathogenesis of chronic pancreatitis

A

occurs due to mis-activation of pancreatic enzymes leading to autodigestion

This early activation is influenced by a number of mutations that lead to increased or decreased function of certain proteins

  • premature activation of trypsinogen OR its deactivation by chemotrypsin CTRC

SPINK1 is another enzyme that cleaves activated trypsin preventing the pancreas from being autodigested. SPINK1 mutations can lead to increased trypsin activity

60
Q

what are the forms and causes of familial chronic pancreatitis?

A

Autosomal Dominant Hereditary Pancreatitis
- PRSS1

Autosomal Recessive Pancreatitis

  • CFTR
  • SPINK1

Complex genetic risk in sporadic chronic pancreatitis

  • Multiple hits
  • CFTR, CTRC, SPINK1 heterozygosity
  • SPA1 in children
  • CLDN2 in adults
61
Q

Describe the role of PRSS1 in chronic pancreatitis

A

primary catalysts of zymogen to active enzymes

> 20 mutations recognised

either increase activation of trypsinogen to trypsin (majority) OR confer resistance to breakdown by CTRC

Present by early 20s -> recurrent acute or chronic pancreatitis symptoms

1/3 become exocrine insufficient

40% cumulative risk of pancreatic cancer at 70y

Exacerbated by smoking and DM

Genetic screening recommended

High penetrance (80%)

No Tx but risk can be minimised by lifestyle changes

62
Q

Describe the role of SPINK1 in chronic pancreatitis

A

encodes pancreatic secretory trypsin inhibitor

SPINK mutations in 2% of population

Only 1% of carriers have chronic pancreatitis

  • need to be homozygous
  • require genetic/environmental co-factor
63
Q

Describe the role of CFTR in chronic pancreatitis

A

required for excretion of pancreatic enzymes into duodenum

In CF - decreased flushing of enzymes –> more activated in pancreas –> autodigestion

> 2000 polymorphisms

Unlikely to lead to chronic pancreatitis in heterozygous form BUT will do with an environmental or genetic co factor

e.g. CFTR + SPINK heterozygotes

64
Q

Give examples to the genetic factors identified in sporadic chronic pancreatitis

A

CTRC - chymotrypsin C gene - produces digestive enzyme that cooperates with active trypsin to degrade trypsin. Can confer moderate risk. Usually found in conjunction with other heterozygous pancreatitis susceptibility variants e.g. CFTR or SPINK1

CLDN2 - co-factor in pts with an alcohol aetiology. Risk dominant in men. Recessive in women

CPA1 - linked to non-alcoholic pancreatitis. Childhood onset

65
Q

How can chronic pancreatitis be diagnosed?

A

IMAGING

  • CT
  • MRI/MRCP
  • EUS

LAB

  • amylase, fecal elastase (not affected by Creon)
  • note that any cause of diarrhoea can cause a drop in fecal elastase

GENETIC

  • CFTR
  • PRSS1
  • SPINK1
66
Q

Describe the management of chronic pancreatitis

A

avoid alcohol and tobacco

antioxidants and analgesics

Pancreatectomy in refractory pain with autologous islet cell retransplant

Surveillance for pancreatic cancer

  • Ca19-9 - tumour marker
  • EUS - most sensitive
  • CT can (repeats –> high exposure to radiation
  • MRI - annual/every two years
  • — possible to alternate bw MRI and EUS

Family Screening

67
Q

Prognosis in chronic pancreatitis

A

highest risk of pancreatic cancer in PRSS1

reduced life expectancy if pancreatic cancer develops
Otherwise unaffected

QOL - pain, opiates, exocrine/endocrine insufficiency

68
Q

Summarise general info re: CF

A

autosomal recessive

1:2500 caucasians

abnormality of chloride efflux
- Basis of diagnosis - sweat chloride (>60mmol/L)

CFTR is found on chr7

1000 mutations, 200 polymorphysms

70% of cases are due to a DELETION of phenylalanine at 508th position

69
Q

Groups of CFTR mutations

A

Class 1

  • 7% of pts in Europe
  • shortened CFTR protein, sequence prematurely stopped

Class 2

  • 85%
  • protein fails to reach cell membrane

Class 3

  • <4%
  • channel not regulated properly

Class 4

  • <3%
  • reduced chloride conductance

Class 5

  • <3%
  • reduced synthesis due to incorrect splicing

Class 6
- reduced half-life of Cl-

CLASSES 1-3 –> complete loss of function –> SEVERE

CLASESS 4-5 –> reduction –> MILDER

70
Q

Describe the pathogenesis of CF

A

decreased hydration of epithelial cell secretion, leading to increased viscosity of secretion

causes secondary obstructive organ damage

AFFECTS:

  • lungs
  • pancreas
  • liver & biliary
  • GI
  • sweat glands
  • Vas Deferens
71
Q

Manifestations of CF organ damage

A

pulmonary - organ damage

pancreases - insufficiency

  • endocrine - insulin -diabetes
  • exocrine - enzymes - nutrition defs - malnutrition

liver - cirrhosis

biliary - gallstones

GI - obstruction/motility disturbance

Vas deference - sterility

95% of mortality pulmonary related but GI/pancreato-biliary important factors in mobidity

72
Q

Describe the pancreatic involvement in CF

A

85% are pancreatic insufficient

Most present in first year of life

Managed by pancreatic enzyme replacement

30% become diabetic later in life

15% are pancreatic SUFFICIENT

  • these carry class 4/5 muation
  • present in older age
  • less severe pulmonary disease
73
Q

Chronic liver disease in CF

A

Biliary epithelial cell CFTR leads to ABNORMAL DUCTULAR SECRETION

this leads to

INSPISSATED BILE –> OBSTRUCTION

hydrophobic bile acid retention and immune response to obstruction causes FOCAL BILLIARY CIRRHOSIS

Bile salt metabolism and gut microflora may be involved

Progression to cirrhosis occurs in the first 2 decades

Complications: ascites, variceal haemorrhage, porto-systemic encephalopathy

74
Q

Distal Intestinal Obstruction Syndrome in CF

A

Right iliac fossa pain

Associated palpable mass

Evidence of partial or complete SB obstruction

Thickened mucofaeculant material in terminal ileum and right colon

in 15-20% of CF cases

Partial/complete obstruction in 2-3%

Predisposing factors

  • dehydration
  • poor control of pancreatic insufficiency
  • gut motility dysfunction
  • low intestinal pH

Gastro BSc (13 decks)

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