Acute Renal Failure

1.6.07

• Broadly defined as rapid deterioration of renal function resulting in accumulation of waste products such as urea and creatinine.
• Pre-renal, renal, post-renal.

Pre-renal - causes of renal hypoperfusion
• Intravascular volume depletion e.g. through vomiting, diarrhoea.
• Trauma/burns/crash injury.
• Haemorrhage.
• Pancreatitis.
• Diabetic ketoacidosis.
• Addison's disease.

Pre-renal
• Decreased CO2.
• Changes in renal vascular resistance.
• Renovascular obstruction.
• Microvascular obstruction.
• Increased blood viscosity.
• Interference with renal autoregulation.

Intrinsic ARF
• Persistent pre-renal failure of any cause.
• Nephrotoxins.
• Haemoglobinuria/myoglobinuria e.g. from any crush injury.
• Radiological contrast material.
• Acute glomerulonephritis e.g. from Goodpasture's syndrome, Wegener's granulomatosis.
• Acute renal vasculitis.
• Obstetric causes e.g. ATN from severe hypovolaemia.

Obstructive uropathy
• Bilateral urinary tract calculi.
• Single urinary tract calculus.
• Retroperitoneal fibrosis.
• Crystal nephropathy.
• Cancer of bladder/cervix.
• Urethral stone.
• Following pelvic surgery.

Clinical features of urinary tract obstruction
• Anuria.
• Polyuria.
• Alternating anuria and polyuria.
• Pain.
• UTI.
• Uraemia of no apparent cause.

Golden clinical rules
• Assess volume status.
• Search to diagnose urinary tract obstruction:
-History.
-PR.
-Ultrasound.
• If pre-renal, fill up (with saline - isotonic to plasma).
• If renal, remove cause or treat condition.
• If obstructive, relieve obstruction.

Management
• Support renal failure.
-Fluids/CVP.
-Electrolytes e.g. high plasma K+.
-Insulin/dextrose.
-Ca2+ resonium.
-Haemodialysis for uraemia.
• Look for and fight infection.
• Don't forget nutrition - enteral/parenteral.
• Remember dangers of blood-borne agents e.g. HBV, HCV, HIV.
• Renal biopsy, if indicated.
• Treat any underlying treatable condition e.g. arteritis, myeloma, hypercalcaemia.

Acute or acute-on-chronic renal failure?
• Pre-existing renal disease suggested by:
-PMH of proteinuria, Nocturia, renal stones, DM or hypertension.
-Analgesic abuse.
-FH of polycystic kidneys, hereditary nephritis.
-Normochromic normocytic anaemia.
-Secondary hyperparathyroidism.
-Stunting of growth or failure of secondary sexual characteristics.
• Palpable or history of polycystic kidneys.
• Bilaterally small kidneys.

Complications
• Fluid/volume.
• Metabolic.
• Infection.
• Nutritional.
• Related to underlying problem.
• Stressful situation for patient and family.

Prognosis
• ~40% mortality.
• Worse if:
-Post-surgery.
-Infection.
-Catabolic.
-Increase in age and multiple diseases.
-Delay in referral and commencing dialysis.
-Complications.

Survivors
• If patient survives ARF, majority recover renal function to become dialysis independent.

Pathology Of Renal Failure

25.5.07

Renal function
• Blood supply 1250ml/min.
• GFR 150ml/min.
• Urine output 1ml/min.
• Filtration (glomerulus).
• Modification (PCT).
• Concentration (loop and DCT).
• Active processes.

Acute renal failure (ARF)
• Pre-renal - pump failure, volume loss, microvascular damage.
• Renal.
• Post-renal.

ARF: renal causes
• Ischaemia - worsened by crush injury.
• Toxins.
-Heavy metals.
-Solvents.
-Antibiotics.
-Venoms and mycotoxins.
-Bence Jones protein.

ARF: post-renal causes
• Obstruction from:
-Stones.
-Prostatic enlargement.
-Tumours.
-Ureteric stricture.
-[+Rarer causes.]

Features of ARF
• Anuria/Oliguria.
• Na+ <20mEq/L.
• High osmolality (ratio u/p >1.5).
• High urea and creatinine.
• May go on to acute tubular necrosis (ATN).

ATN
• Biochemical/laboratory features:
-Not anuric (may be polyuric).
-Urine Na+ >40mEq/L.
-Osmolality u/p <1.1:1.
-Numerous granular and cellular casts.

Chronic renal failure (CRF)
• Leakage of proteins (damage to filter).
• Na+ and water retained.
-Oedema and hypertension.
• Haematuria.
• Decrease in GFR.
-<20% abnormal (<5% = ESRF).
• Raised urea, creatinine, K+.
• Decreased Ca2+.

CRF: syndromes
• Nephritic:
-Decreased urine output.
-Modest proteinuria.
-Hypertension.
-Retention of Na+ and water.
-Haematuria.
• Nephrotic:
-Protein loss>3.5g/day.
-Hypoalbuminaemia.
-Oedema.
• Rapidly progressive renal failure.
-Generally with crescentic glomerulonephritis.

Membranous glomerulonephritis
• Nephrotic syndrome.
• Drugs, tumours, infections, SLE, DM.
• Thickened glomerular basement membrane diffusely and universally.
• Spikes (complexes) on silver stain.

Immune complex glomerulonephritis
• Circulating complexes trapped in glomeruli.
• Injury mainly due to complement binding.
• Tend to cause Membranoproliferative pattern of injury.
• See in e.g.
-SLE.
-HBV.
-HCV.
-HIV.
-Endocarditis.
-Chronic infections.
-Parasitic invasions.

Amyloidosis
• Abnormal amount of polymerised protein (β-pleated sheet).
• Plasma cell and inflammatory types.
• Trapped in glomeruli in filtration.
• Result in nephrotic syndrome.
• Stains brick red with Congo red dye.
• Apple green birefringence with Congo red.

Interstitial nephritis
• Pyelonephritis.
• Drug induced.
-NSAIDs.

Renal papillary necrosis
• Osmotic stress.
• DM.
• NSAIDs.
-Australia.
-Vultures.

Systemic hypertension
• Benign hypertension tends to have minimal effects on GFR.
• Risk increased in black people in USA.

Summary
• ARF.
• CRF.
-Polycystic.
-Systemic.
§DM, SLE, hypertension.
-Glomerular.
-Interstitial.
-Obstruction.

Glomerulonephritis

21.5.07

Definition
• Disease affecting kidneys - classified according to changes seen in glomerulus on light, immunofluorescence and electron microscopy.

Clinical presentation
• Persistent microscopic haemuturia.
• Persistent proteinuria.
• Nephrotic syndrome.
• Recurrent macroscopic haemuturia.
• Acute nephritic syndrome.
• Acute/subacute renal failure.
• Chronic renal failure.

Proteinuria
• Normal range <0.2g/24 hours.
• Nephrotic syndrome.
• Definition: proteinuria >5g/24 hours.
• Oedema.
• Hypoalbuminaemia.
• Hypercholesterolaemia.
• Persistent proteinuria: above normal range, but not nephritic and usually asymptomatic.

Types of glomerulonephritis
• Based on histology.
• Although patients may share same histological type, clinical presentation may be variable.
• Some clinical presentations more characteristic of certain types.

Minimal change glomerulonephritis
• Usually presents as nephritic syndrome.
• Commonest cause of nephritic syndrome in children.
• Usually responds to oral steroids, if not cyclophosphamide/cyclosporin may be used.

Focal segmental glomerulonephritis
• Usually presents as nephritic syndrome.
• Responds less well to immunosuppression than minimal change glomerulonephritis.
• May be found in association with AIDS and with IVDU.
• ~50% will progress to ESRF.
• Focal segmental changes may be found late in course of patients whose initial biopsy showed minimal change glomerulonephritis.

Membranous glomerulonephritis
• Accounts for 20-30% adult nephritic syndrome and up to 5% children.
• May also present as asymptomatic proteinuria/chronic renal failure.
• In 20-30% cases, secondary to another cause.
• Up to 30% may develop ESRF.
• Up to 30% will resolve spontaneously.
• Immunosuppression reserved for those with intractable nephritic syndrome/progressive renal failure.
• Regimes include:
-Prednisolone.
-Cyclophosphamide.
-Azathioprine.
-Chlorambucil.
-Cyclosporin A.
-Mycophenolate.

Causes of secondary membranous glomerulonephritis
• Cancer: bronchus, breast, GI tract, prostate.
• Infection: hep B, syphilis, leprosy, filiriasis.
• Drugs: gold, penicillamine, captopril.
• Multisystem: SLE, sarcoidosis, RA.

IgA nephropathy
Presentation
• Often with recurrent episodes of macrohaematuria occurring within 12-24 hours of onset of URTI.
• Frequently accompanied by muscle and loin pain and fever out of proportion to severity of URTI.
• Commonest form of idiopathic GN worldwide.
• Typically affects young males M:F = 3:1.

Diagnosis
• Serum polyclonal IgA sometimes increases, but not of prognostic significance.
• On renal biopsy, mesangial deposits of IgA and C3.

Outcome
• Up to 50% adults: slowly progressive renal failure of 15-20 years of often asymptomatic progression.

Treatment
• Depends on presentation and progression.
• Immunosuppression often tried in severe nephritic syndrome/rapid progression of renal failure.

Membranoproliferative glomerulonephritis
• Usually presents as persistent proteinuria/nephritic syndrome/chronic renal failure.
• 3 histological types.
• May be secondary to systemic disease.
• Immunological abnormalities.
• Low serum, C3 complement found in 60-100% type I and 30-40% type II.
• Complement abnormalities indicate activation of alternative pathway.
• Treatment:
-If secondary to another disease, treat underlying disease.
-In idiopathic forms, no specific treatment of consistently proven benefit.

Rapidly progressive glomerulonephritis
• Form of glomerulonephritis causing renal damage - may progress from onset to ESRF within weeks/months.
• Characteristic lesion: focal necrotising glomerulonephritis with crescent formation.
• 3 main causes:
1. Antiglomerular basement membrane disease.
2. Vasculitis.
3. SLE.
• However, many other causes, including systemic disease, drugs, infections, neoplasia.
• Clinical presentation:
-Often dependent on presence/absence of systemic disease.
-If absent, patients may present with non-specific features of renal failure:
§Oliguria.
§Oedema.
§Dyspnoea/uraemic symptoms.
-Macroscopic haemuturia and loin pain sometimes reported.

Antiglomerular basement membrane disease
• Rare: affects M>F.
• May be associated with pulmonary haemorrhage.
• Characterised by presence of circulating antiglomerular basement membrane antibodies and deposition of IgG in basement membrane.

Vasculitis
• Rapidly progressive renal lesion may be seen in variety of systemic diseases, notably polyarteritis nodosa and Wegener's granulomatosis.
• Often associated with circulating anti-neutrophil cytoplasmic antibodies.

Post-streptococcal glomerulonephritis
• Occurs usually between 7 and 21 days after group A streptococcus infection.
• During epidemic, clinically detectable glomerulonephritis occurs in 5-10% after pharyngitis and ~25% after skin infections.
• Young children at highest risk.
• Presentation can vary from microhaematuria to full-blown nephritic syndrome.
• Investigations:
-Throat/skin swab.
-ASO titre.
-C3 and C4 complement may be decreased.

Alport's syndrome
• Inherited as x-linked trait.
• In males, usually progressive form of renal disease causing ESRF commonly between 16-35 years.
• Associated with sensorineural deafness and anterior lenticomus.

Renal Transplantation

21.5.07

History
• In 01/02, Emerich Ullmann reported first case of renal autotransplantation performed in neck of dog.
• In same year, presented first xenotransplantation of kidney (goat with dog's).

First successful human kidney transplantation: Boston (1954) - identical twins.

Treatment options for ESRF
DIALYSIS
(long term)

Peritoneal Haemodialysis

TRANSPLANTATION

Cadaveric Live donor

What life is like on dialysis
• Poor quality of life.
• Usually unable to work.
• Little/no holidays.
• Feel ill most of time.

Transplantation optimum renal replacement therapy for most patients.

Cadaveric donor operation - donor selection criteria
• 2-75 years.
• No infection.
• No DM.
• No cancer except primary brain tumours.
• No HIV.

Donor selection - UK code
• Brainstem death.
• Preconditions: irreversible coma.
• Exclusions.

Imaging renal anatomy: angiogram.

Matching of kidney
• ABO.
• HLA.
• Lymphocytotoxic crossmatch.

Surgical complications
• Renal artery thrombosis.
• Renal vein thrombosis.
• Urine leak and ureteric stenosis.
• Lymphocele.

Long-term complications
• Infection.
• Cancer.
• Drug side-effects.
• Rejection.
• Graft loss.

Side-effects of immunosuppression
• Drug-specific.
• Total burden of immunosuppression.
• Additional chronic renal failure.
• Progression of primary disease.

Predictors of long-term graft function
• Factors impacting on graft survival (HLA match, donor type etc).
• Factor impacting on patient survival.

Module 2.14

The Tax Inspector's Appointment.
21.5.07 - 1.6.07.

Drugs In Liver Disease

11.5.07

Liver disease
• Common.
-ALD >20,000 deaths per annum.
• May need treatment.
-For liver disease and complications.
-For concomitant conditions.
• Liver is major site of drug metabolism.
-Can have major effects on drug handling.

Functions of the liver
• Processing digested foods from the intestine.
• Controlling levels of fats, amino acids and glucose.

Clinical signs of liver disease
• Jaundice.
• Ascites.

Drug handling in the body and effect of liver and kidney disease
Lipophilic drugs Hydrophilic drugs
↓ ↓
Liver Kidneys
Phase I metabolism Excretory processes
Phase II metabolism
Phase III metabolism
↓
Reduced hepatic clearance Reduced renal clearance

How are drugs metabolised?
• Phase I (oxidation, reduction, hydrolysis).
-Small chemical changes.
-FUNCTIONALISE molecule for phase II.
• Phase II (glucoronidation, sulphation, acetylation, amino acid conjugation, glutathione conjugation).
-Conjugation reactions.
-Increased water solubility.
-Increased excretion.

Functionalisation
• Addition of reactive group.
• Unmasking of reactive group.

Conjugation
• Addition of large group.
• Often charged.

Phase III: membrane transporters.
P-glycoprotein: an efflux transporter.

Effect of liver disease on drug disposition
• Severity of liver disease.
-Enormous reserve in liver.
-Affected in severe disease.
• Enzymes responsible.
-Phase II affected less than Phase I.
• Type of liver disease.
-Cholestasis (increases in alkaline phosphatase and GGT) - transporters.
-Acute hepatic inflammation (increase in transaminases) - p450 enzymes.

Effect of pharmacokinetic changes on drug effects
Liver disease
↓
Pharmacokinetic changes
↓
Clinical effect of drug
↓
Increased No change Reduced

Other effects of liver disease
• Changes in drug absorption.
-Changes in gut motility.
-Delay in gastric emptying and orocaecal transit.
• Changes in protein binding.
-Hypoproteinaemia.
-Affects drugs with high protein binding.
• Changes in liver blood flow.
-May be decreased/bypass liver.
-Increased bioavailability of certain drugs.
• Changes in renal excretion.
-Affected in severe liver impairment.
-Etc.

Effect of pharmacodynamics changes in liver disease
Liver disease
↓
Pharmacodynamic effects
↓
Exaggerated response Reduced response Increased toxicity
↑ ↑ ↑
Sedation with Decreased diuresis with Nephrotoxicity
benzodiazepines loop diuretics with aminoglycosides

Use of potentially hepatotoxic drugs
• Not an increased risk of further liver damage when administered hepatotoxic drugs.
• Decreased hepatic reserve therefore, more severe clinical consequences of any damage.
• Judicious use.

Using drugs in liver disease
• Careful clinical assessment always important.
• Questions to ask:
-How serious is the condition, and what if the treatment was withheld?
-What drug treatments are available?
-Are efficacies of different treatments equivalent?
-What are the adverse effects of different treatments?
-Is the drug metabolised by the liver?
-Is the drug potentially hepatotoxic?

Simple rules in liver disease
• Determine whether dose needs to be decreased (see appendix in BNF).
• Start at low doses and increase dose slowly, depending on response and adverse effects.
• Carefully monitor patients and review regularly.
• Avoid interacting drugs.
• Provide information for patients.
• Contact in case of problems.
• Consider drugs in differential diagnosis if new symptoms.

Practice points
• Liver disease affects both pharmacokinetics and pharmacodynamics parameters, both of which increase risk of drug toxicity.
• Doses of lipophilic drugs should be decreased, particularly for those with narrow therapeutic index.
• First-pass metabolism of drugs with high hepatic extraction decreased, necessitating decrease in dose of oral formulations.
• Choose hydrophilic drug over lipophilic compound when available.

Blood-Borne Viruses

11.5.07

• HIV.
• Hep B.
• Hep D.
• Hep C.
• Parvovirus etc.

AIDS
• Acquired Immune Deficiency Syndrome.
• First cases recognised in 1979.
• First paper 1981.

Does HIV cause AIDS?
Cons:
1. For each person with AIDS there are 99 who are HIV-infected.
2. HIV-positive AIDS cases (4 in total) - HIV is just another opportunist growing in AIDS patients.
Pros:
1. Cohort studies.
2. Therapy.

"AIDS viruses"
1983: Montagnier - Paris.
LAV (lymphodenopathy associated virus).
IDAV (immune-deficiency associated virus).
1983: Gallo - USA.
HTLV-III (human T-cell leukaemia virus III).
1984: Gallo.
HTLV-III (human T-cell lymphotrophic virus III).
1986: HIV-1 (human immunodeficiency virus-1).
HIV-2.

Retrovirus
Genome: RNA positive sense (2 copies per virion).
Envelope: Yes.
Capsid: Cuboidal.
Size: ~ 100-120 nm.

Classification
1. Spumaviruses.
2. B and D-type oncoviruses.
3. C-type oncoviruses.
4. HTLV-related oncoviruses.
5. Lentiviruses (SIV, HIV etc.).

HIV genes and proteins
GAG (Group specific antigen.)
Encodes capsid proteins. Made as long polyprotein and cleaved to p24,
p17, p15.
Pol (Polymerase.)
Encodes protease, reverse transcriptase, endonuclease/ligase.
Env (Envelope.)
Encodes envelope glycoproteins (gp). Made as gp160, which is cleaved to
gp120 and gp41.

Stages in infection
1. Attachment - 2 receptors.
2. Penetration - fusion/endocytosis.
3. Reverse transcriptase - produces provirus.
4. Integration.
5. Reactivation and new virus production.
6. Maturation - proteolysis.
7. Release - budding.

HIV - receptors
1. Initial binding by gp120 to CD4.
2. Conformational change to gp120 and gp41 exposes new ligand.
3. Ligand binds to chemokine receptors e.g. CCR-5.
4. Viral entry.

Cells infected
1. Lymphocytes (T-helper cells expressing CD4).
2. Monocytes and macrophages.
3. Brain cells (predominantly astrocytes and oligodendrocytes, but also neurones).
4. Enterocytes.
5. Laryngeal cells.

Human infection
1. Initial acquisition (sexual, blood etc).
2. Incubation period (4-6 weeks). Each day 109 - 1010 new virus particles produced (106 - 107 are mutant).
3. Seroconversion illness in only 50% of those infected. Resembles glandular fever.
4. Latent period (virus still excreted).
5. Development of AIDS. Rising viral load, falling CD4 counts.

HIV excretion
1. Semen.
2. Cervical secretions.
3. Blood.
4. CSF.
5. Breast milk.
6. Saliva.
7. Urine.
8. Faeces.

Module 2.13

The Yellow Clerk.
8.5.07 - 18.5.07.

Alcohol's Trip Through The Body

27.4.07

Beer
1. MOUTH: usual ingestion route.
2. STOMACH: little absorption/breakdown here. Most emptied to small intestine.
3. SMALL INTESTINE: uptake into bloodstream.
4. BLOODSTREAM: carries the alcohol.
5. LIVER: oxidises alcohol into water, carbon dioxide and energy at 0.015%/hour.

Alcohol - access to body
• Ingestion.
-Slowly absorbed from stomach.
-Rapidly absorbed from small intestine.
• Other routes of entry:
-Skin.
-Nasal passages/lungs.
-Other epithelia??

How to measure alcohol consumption?
• Units/grams.
• 1 unit = 8g of alcohol.

"Safe limit" for alcohol?
• In healthy male, no more than 28u/week.
• In healthy female, no more than 21u/week.

Ethanol
• Provides "empty" calories - no nutritional benefit.
• 7 cal/g - almost as high as fat in calorific content.
• Water-soluble - does not enter fat.
• Size and body build affect uptake.

Absorption of alcohol
• Rate-dependent on alcohol type and concentration.
• Peaks 1 hour after consumption.
• Faster with carbonated alcohol.
• Greater with empty stomach.
• Increased by drugs enhancing gastric emptying and those drugs that inhibit gastric alcohol dehydrogenase.
• Retarded by food, especially carbohydrate (as much as 75% compared to an empty stomach).

Distribution of absorbed alcohol
• Distribution throughout water in body.
• Most tissues exposed to same concentration of alcohol as blood.
• Liver has higher exposure due to portal system.

Elimination of absorbed alcohol
• 2-5% excreted unchanged in urine, sweat, faeces, milk or breath.
• 95% metabolised by liver.

Alcohol breakdown in liver
• ADH and ALDH2 metabolise ethanol consumed.

ADH ALDH
• Ethanol Acetaldehyde Acetate.
• ADH variants found in most tissues, but highest in liver.

Alcohol metabolism
• 1st step: oxidation of ethanol to acetaldehyde, catalysed by ADH containing NAD+.
• Conversion of acetaldehyde into acetate by ADLH also results in generation of NADH.
• NADH = Hydrogen-transfer chemical enabling oxidative phosphorylation to take place.

ADH
• Up to 50% Japanese people lack ADH.
• Inheritance of high activity ADHb2 enzyme, encoded by ADH2*2 gene, and inactive ALDH202 gene product conclusively associated with decreased risk of alcoholism.

Alcohol metabolism has powerful effects on cellular energy production pathways
• Drinking alcohol warms people up - rapid NADH production from alcohol dramatically increases energy availability and body temperature.

Excess NADH can block other normal metabolic pathways
1. Convert pyruvic acid to lactic acid.
-Hepatic gluconeogenesis inhibited.
-Glucose production decreased.
-Risk of hypoglycaemia.
-Overproduction of lactic acid blocks uric acid excretion by kidneys. Acidosis.
2. Inhibits lipogenesis.
-Accumulated fatty acid converted into ketones and lipids.
-Heavy drinkers ketotic and overweight.
3. Makes excess ATP.
-Inhibits fat oxidation and citric acid cycle.
-Accumulated fatty acids/acetyl coA → ketones and lipids.
-Excess fat in liver and blood.

Metabolism of alcohol faster in heavy drinkers
• Normal metabolism increased, generating high blood concentrations of acetate.
• Microsomal ethanol oxidising system.

Alcohol damages GI tract
• Causes inflammation of tongue, stomach, pancreas, liver and intestines.
• Breakdown products lead to fat deposition, fibrosis and scarring of liver.
• Impairs digestion of food and absorption into blood etc.

Alcoholic hepatitis
• Inflammation induces accumulation of extracellular matrix) collagen - liver fibrosis.
• Scar tissue forms.

Therefore, cirrhosis
• Growth of connective tissue destroys liver cells.

Signs
• Jaundice.
• Fluid in belly.
• Haematemesis.
• Confusion.
• Spider naevi.
• Gynaecomastia.

Oesophageal varices
• Abnormal dilatation of vein due to increase in portal vein pressure.
• Can cause life-threatening bleed.

Alcohol intoxication
• Elation, euphoria, stimulation of pleasure and reward centres in brain.
• Altered behaviour, personality, aggression etc.
• Sedation - mild anaesthetic.

Blood alcohol and brain
• Cerebral impairment at 0.1%.
• Damage of information exchange between cerebellar cortex and cerebrum, at 0.15-0.35%.
• Medulla function depressed - can occur at levels as low as 0.30%.

Alcohol on the brain
• Increased dopamine release to cause euphoria.
• Inhibits glutamate receptor function - when blocked, results in cognitive impairment and amnesia.
• Potentiates GABA receptor function - site of action of sedation and anaesthesia.
• Increased release of 5-HT (serotonin), causing one to become sleepy.

Physiological changes accompanying alcohol consumption
• Sweating, flushing, bruising.
-Body can suffer from heat loss and hypothermia.
• Tachycardia and increase in blood pressure.
• Kidneys secrete more urine.

Alcohol and sex
• Decreased sexual performance.
• Loss of libido.
• Can lead to impotence/less sperm.
• Atrophy of testicles.
• Decreased vaginal lubrication.
• Poor decision increase risk of STDs.
• Menstrual abnormalities.
• Alcohol during pregnancy causes complication for fetus.
• Breast cancer risk factor for females who engage in even moderate drinking.

Alcoholic Pancreatitis

23.4.07

Alcoholic pancreatitis
Epidemiology
• 40 per 100,000/year.
• Associated with alcohol abuse - binge drinking.
• Increasing incidence.
• Severe in 20-30%.
• Mortality up to 10%.
• Management variable.
• Treatment inadequate.

Aetiology
• Alcoholic.
• Biliary - gallstones.
• Idiopathic.
• Others, including hypercalcaemia and hyperlipidaemia.

Alcohol consumption
Binge drinking
• People living in north of England more likely to die earlier through alcohol abuse than anywhere else.

The problem
• Rates of acute pancreatitis increased from 4.9-9.8/100,000.
• Particularly large increase in younger people.

Alcoholic pancreatitis
Clinical signs
• Upper abdo pain.
• Epigastric/diffuse abdo tenderness.
• Serum amylase activity (4X normal).
• Cullen's sign.
• Grey-Turner's sign.

Complications
• Pancreatic necrosis.
• Infected necrosis.
• Pseudocyst.
• Haemorrhage.
• Multiorgan failure.
• Death.

Non-surgical therapy
• Resuscitation.
• Analgesia.
• Stone extraction.
• Ventilation.
• Inotropes.
• Dialysis.
• Nutrition.

Major intervention
• Open necrosectomy.
• Minimal access necrosectomy.
• Pancreatic stenting etc.

Limitations to current management
• Prophylaxis restricted to removing precipitating factors after onset.
• No significant impact on course of disease made by medical treatment.

Pathogenesis
• Autolysis precipitated by known factors.
• Activated digestive enzymes within and subsequently around acinar cells.
• Co-localisation of granules and Lysosomes.
• Vacuolisation etc.

Premature digestive enzyme activation critical
• Mutations in cationic trypsinogen render trypsin resistant to inactivation.

Ca2+ hypothesis
• Abnormal, prolonged elevation of cytosolic Ca2+ initiates pancreatitis.

Alcohol-induced injury theory
• Spasm of sphincter of Oddi.
-Duodenal-pancreatic reflux.
• Formation of protein-rich secretory plugs.
• Duct obstruction causes pancreatic damage and altered Ca2+ signalling.
• Generation of free radicals.
• Sensitisation of acinar cell to CCK on zymogen conversion in vitro.
-Ethanol may sensitise CCK-induced zymogen conversion in pancreatic acinar cells.
• Toxic metabolites.

High ethanol/unsaturated fatty acid diet induces pancreatitis in rats.

Fatty acid ethyl esters induce:
• Direct pancreatic damage in vivo.
• Prolonged abnormal increase of Ca2+ concentration.

Alcohol Dependence: Approach To Detection And Treatment

23.4.07

Definitions
1. Hazardous drinker: heavy/binge drinkers with drinking patterns that pose considerable risks to their own and others' health.
2. Harmful drinker: clear evidence that alcohol use is responsible for (or substantially contributes to) physical/psychological harm - may lead to disability or have adverse consequences for interpersonal relationships.
3. Dependent drinker:
-SADQ.
-DMS IV-R.
-ICD-10 - used in all hospital admissions.
-?AUDIT.

Reasons for detecting alcohol dependence
• Failure to detect may lead to:
-Unnecessary investigations.
-Alcohol withdrawal syndrome.
-Recurrent harm (end-organ damage).
-Recurrent hospital attendance.
• Liver deaths have increased eight-fold in 3- years.
• 50% subjects die before they have a chance to stop drinking.
• Prevention of unexpected alcohol withdrawal.

Methods of detection
• History and examination.
• Clinical investigations.
• Screening/assessment questionnaires.

History and examination
• Clinical findings often completely normal.
• Clinical findings poor as early indicators of alcohol - WHO, 1987.

Clinical investigations - laboratory markers
• Blood/urine/breath alcohol:
-No information regarding severity.
-Objective evidence of recent drinking.
-Low sensitivity.
• Serum gamma glutamyl transferase (GGT).
• MCV.
• Carbohydrate-deficient transferring (CDT).
• Conventional lab tests of no use for detecting alcohol abuse/dependence. Also, %CDT cannot be used as screening instrument - Br J Gen Pract 2001 Mar.
• Lab tests useless as screening tools with sensitivities between 10% (%CDT) and 52% (GGT) - Acta Clin Belg 2002 Sep-Oct.

Screening questionnaires
• Paddington Alcohol Test (PAT):
-Staged approach.
-1 min to complete.
-A+E departments.
-Detect hazardous and harmful drinkers.
-46% of detected and referred patients re-attend.
-Constant audit and feedback improves use.

PAT staged approach
• Fall.
• Assault.
• Psychiatric.
• Repeat attender.
• Collapse.
• GI.
• Cardiac.
• Head injury.
• Unwell.
• Self-neglect.

Triggers - AAFs
• Gastritis.
• Hypertension.
• Depression.
• Stroke.
• TB.
• DM.
• Falls.

FAST alcohol screening test
• Staged approach.
• 1 min to complete.
• Sensitivity of 91%.
• Used in wide variety of settings, mainly research.

CAGE questionnaire
• 4 questions.
• More sensitive than routine lab markers.
• Insensitive to milder alcohol abuse.

Alcohol use disorders
• 10-item questionnaire.
• 10 min to complete.
• Score >8 highest sensitivity.
• Identifies hazardous drinking earlier and with greater sensitivity than:
-FAST/CAGE questionnaires.
-Routine history taking.

Screening questionnaire
• Drinking risky amounts was common (17%) in medical inpatients. Most drinkers of risky amounts had dependent (77%), but not the broad spectrum of unhealthy alcohol use anticipated.
• AUDIT reliable tool in detecting dependency.
• AUDIT cut-off of >16-19.

Assessing dependence
• DSM IV.
• ICD-10.
• Severity of alcohol dependence questionnaire (SADQ).

Assessing withdrawal
• Alcohol withdrawal symptom checklist:
-Nervousness.
-Sweating.
-Tremor.
-Nausea.
-Vomiting.
-Abdo pain.
-Seizures.
-Poor appetite.
-Hallucinations.
-Irritation.
-Confusion.
-Chill.
-Headache.
-Craving etc.

Risk factors for progression to severe withdrawal
• High alcohol intake.
• High levels of anxiety.
• Sweating (palms).
• History of severe withdrawal including seizures/delirium tremens.
• Hypoglycaemia.
• Insomnia.
• Concomitant use of other psychotropic drugs.
• Hypokalaemia.
• Tachycardia etc.

Aim for treatment
• Give support and advice for detox.
• Deliver brief interventions.
• Develop and maintain timely, effective, safe interventions.
• Train/support contemporaneous treatment.
• Referral to specialist services.
• Liaison with GPs.

Drugs of choice
• Chlordiazepoxide.
-Oxazapam if liver damage.
• Thiamine - oral/parenteral.

AWS - stages
Usual time from stopping drinking to onset Most common features
Stage 1 6-8 hours Autonomic hyperactivity, manifest in sweating, anxiety and tremor. Tremor and anxiety.
Stage 2 10-30 hours Neural excitation, including hallucinations, hyperactivity and insomnia.
Stage 3 36-70 hours Grand mal seizures
Stage 4 36-70 hours Progression to delirium tremens

Module 2.12

Hitting The Bottle.
23.4.07 - 4.5.07.