Module 1.3: Liver + Pancreas

Question 1

Summarise the reasoning for the research interest in alcohol

Answer 1

• 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

Question 2

Summarise the most effective way of addressing the issues with alcohol

Answer 2

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

Question 3

Summarise the metabolism of alcohol

Answer 3

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

Question 4

Summarise the variation in acetaldehyde dehydrogenase

Answer 4

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

Question 5

Describe the pathogenesis of alcoholic liver disease

Answer 5

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

Question 6

Briefly describe the disease progression in ALD

Answer 6

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

OR

fatty liver –> cirrhosis (8-20%)

Question 7

Describe and exlpain the risk factors of ALD

Answer 7

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

Question 8

Decribe the alcoholic steatosis stage of ALD

Answer 8

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

Question 9

Decribe the alcoholic hepatitis stage of ALD

Answer 9

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

Question 10

Decribe the alcoholic fibrosis/cirrhosis stage of ALD

Answer 10

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

Question 11

define FIBROSIS of the liver

Answer 11

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

Question 12

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

Answer 12

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

Question 13

Screening for alcoholism

Answer 13

CAGE

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

Question 14

Tx of ALD

Answer 14

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

Question 15

Tx of alcoholic hepatitis

Answer 15

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

Question 16

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

Answer 16

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%

Question 17

Describe normal iron metabolism

Answer 17

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

Question 18

Describe the results of excess iron in the body

Answer 18

Liver: cirrhosis, HCC

Heart: CCF, conducting deficits, arrhythmias, constrictive pericarditis

Endocrine: diabetes, panhypopituitarism, hypogonadotrophism

Joints: chondrocalcinosis

Question 19

How does excess iron lead to cellular damage?

Answer 19

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

Question 20

What are the two forms of iron found in the body

Answer 20

Haem - 10% - Fe2+ - ferrous

non-haem - 90% - Fe3+ - ferric

Question 21

Explain the process of iron absorption in the body

Answer 21

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)

Question 22

Explain the importance of TfR1 in iron absorption

Answer 22

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

Question 23

Explain how iron absorption is controlled

Answer 23

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

Question 24

Give examples to causes of excess iron

Answer 24

Dietary: bantu siderosis
erythropoietic siderosis
multiple transfusions
genetic: haemochromatosis

Question 25

What are the types of haemachromatosis

Answer 25

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

Question 26

Summarise the relevance of HFE mutations in haemochromatosis

Answer 26

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

Question 27

Describe the function of Hepcidin

Answer 27

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

Question 28

Describe the regulation is hepcidin

Answer 28

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

Question 29

Describe the role of hepcidin in immunity

Answer 29

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

Question 30

Describe the diagnostic criteria for haemochromatosis

Answer 30

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

Question 31

Describe the Tx of haemochromatosis

Answer 31

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

Question 32

Define hepatic steatosis

Answer 32

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

Question 33

Define NAFLD

Answer 33

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

Question 34

Define metabolic syndrome

Answer 34

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

Question 35

Describe the NAFLD spectrum

Answer 35

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 ```

Question 36

Describe the magnitude of NAFLD

Answer 36

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

Question 37

Describe the pathogenesis of NAFLD

Answer 37

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

Question 38

Environmental factors contributing to NAFLD

Answer 38

DIETARY - high saturated fat content - high fructose content - reduced antioxidants OBESITY - energy intake > output - lack of exercise - increased portions T2DM SMALL BOWEL INTESTINAL OVERGROWTH

Question 39

Genetic factors contributing to NAFLD

Answer 39

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

Question 40

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

Answer 40

increased hepatic TAG for PNPLA3 gene

Question 41

Describe the role of PNPLA3 in NFALD

Answer 41

aka adiponutrin On Chr22 Associated with severity of lipid accumulation May sensitise the liver to environmental stressors exact mechanisms unknown

Question 42

Describe how NAFLD can be diagnosed

Answer 42

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%

Question 43

Describe the non-invasive scoring systems used in NAFLD

Answer 43

BARD - BMI > 28 - AST/ALT ration > 1 - Diabetes NAFLD Fibrosis Score - age - BMI - hyperglycaemia - AST/ALT - PLT - albumin FIB4 - age - AST - ALT - PLT

Question 44

Summarise the treatment studied for pts with NAFLD

Answer 44

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

Question 45

What is copper found in?

Answer 45

Nuts, mushrooms

Question 46

What is copper required for?

Answer 46

Enzyme function e.g. ``` Superoxide dismutase - free radical detoxification Lysyl oxidase Dopa-B-hydroxylase Tyrosinase Cytochrome C oxidase ```

Question 47

Describe normal copper mechanism

Answer 47

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

Question 48

What are the types of APSase transporters in the body?

Answer 48

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

Question 49

Describe the genetics of Wilson's disease

Answer 49

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

Question 50

Describe the pathophysiology of Wilson's disease

Answer 50

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

Question 51

Describe the presentation of Wilson's disease

Answer 51

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

Question 52

Indicate the biochemical features of Wilson's

Answer 52

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

Question 53

How can Wilson's be diagnosed?

Answer 53

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

Question 54

How is Wilson's screened for?

Answer 54

Siblings screened via haplotype analysis - requires two siblings and one parent Homozygous treated even if asymptomatic Heterozygotes not treated

Question 55

Tx of Wilson's

Answer 55

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

Question 56

Define chronic pancreatitis

Answer 56

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

Question 57

Symptoms of chronic pancreatitis

Answer 57

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

Question 58

What are causes of chronic pancreatitis

Answer 58

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

Question 59

Describe the pathogenesis of chronic pancreatitis

Answer 59

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

Question 60

what are the forms and causes of familial chronic pancreatitis?

Answer 60

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

Question 61

Describe the role of PRSS1 in chronic pancreatitis

Answer 61

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

Question 62

Describe the role of SPINK1 in chronic pancreatitis

Answer 62

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

Question 63

Describe the role of CFTR in chronic pancreatitis

Answer 63

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

Question 64

Give examples to the genetic factors identified in sporadic chronic pancreatitis

Answer 64

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

Question 65

How can chronic pancreatitis be diagnosed?

Answer 65

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

Question 66

Describe the management of chronic pancreatitis

Answer 66

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

Question 67

Prognosis in chronic pancreatitis

Answer 67

highest risk of pancreatic cancer in PRSS1 reduced life expectancy if pancreatic cancer develops Otherwise unaffected QOL - pain, opiates, exocrine/endocrine insufficiency

Question 68

Summarise general info re: CF

Answer 68

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

Question 69

Groups of CFTR mutations

Answer 69

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

Question 70

Describe the pathogenesis of CF

Answer 70

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

Question 71

Manifestations of CF organ damage

Answer 71

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

Question 72

Describe the pancreatic involvement in CF

Answer 72

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

Question 73

Chronic liver disease in CF

Answer 73

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

Question 74

Distal Intestinal Obstruction Syndrome in CF

Answer 74

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