Alcoholism and Hepatitis

8/7/2019 Alcoholism and Hepatitis

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Alcoholism and HepatitisAlcoholism and HepatitisAlcoholism and HepatitisAlcoholism and HepatitisHistory of Presenting Illness

- Anorexia- Nausea and Vomiting- Weight loss

- Fever

- Generalized Abdominal Pain

ASK ABOUT:- Tattoos- Blood trasnfusions- Needlestick injury- Injecting drug use- Sexual practices- recent contacts- Travel

- MEDICATIONS ( see below)

Differential DiagnosesNonalcoholic steatohepatitis (NASH)Drug-induced liver disease(valproic acid, tetracycline,antiviral agents such as zidovudine)Viral hepatitis

Examination- Tender Hepatomegaly (80-90% of cases)- Jaundice

- Ascites

- Splenomegaly

- Spider naeviEpidemiologyAlcoholic Hepatitis seen in 33% of chronic alcoholics

JAUNDICE- The eyes are first to go.ASK ABOUT THE COLOUR OF URINE AND STOOL:

JAUNDICE WITHOUT DARK URINE OR PALE STOOL

means HAEMOLYSIS (unconjugated bilirubin released@ circulation, thus not water soluble and cannot beexcreted by kidneys)

JAUNDICE WITH DARK URINE AND PALE STOOLSmeans OBSTRUCTIVE JAUNDICE

Acute fatty liver of pregnancyMetabolic liver disease and inbornerrors of metabolismReye syndromeCongestive Heart failure

- Malaise

- Diarrhoea- Ankle swelling- Abdomen distension

- Yellow eyes

- Itching- Bruising- Black tarry stools

Acute fatty liver of pregnancy

Metabolic liver disease and inbornerrors of metabolismReye syndromeCongestive Heart failure


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Tests and InvestigationsFBC + blood microscopy:

looking for macrocytic anaemia of alcoholism

alpha-fetoprotein: very specific marker of hepatocellular carcinomaLIVER FUNCTION TESTS:

ALT= the necrosis enzymeAST = alcoholic heptitis enzymeSAP/ALP = cholestasis enzymes (with GGT)GGT =induceable acoholism enzymeBilirubin:

Conjugated = hemolysis or liver dysfunctionUnconjugated= biliary obstruction or liver failure

SERUM ALBUMINwill be low; trying to explain ascitesPROTHROMBIN Time low due to reduced rate of cloting factor synthesisThiamine =low mainly due to malnutritionRBC Folate (alcohol inhibits the gut tranbsporter of folate)

HEPATITIS VIRUS SEROLOGY:HBsAg -earliest ACUTE marker, may persist chronicallyHBeAg -ACTIVE INFECTION, virus is replicating (25% dont have this)HBV DNA

Ascites Fluid Aspiration: Looking for malignant cellsAbdominal ultrasound

Looking for cysts, focal lesions, biliary tree stones etc.

Abdominal CT scanLooking for masses, enlarged lymph nodes, vascular malformations

Liver Biopsy: only way to objectively diagnose alcoholic liver disease

MANAGEMENT:Limit progression to cirrhosis:

Stop drinking.Antiviral drugs:

- nucleoside analogue lamivudinefor hepatitis B- interferon-alpha plus ribavirin for hepatitis C

Immune suppression may work for autoimmune diseaseControl lipid vitamin deficiencies: A, D, E, KFor ascites:

- salt restriction,- aldosterone antagonist (first choice)- loop diuretic (second choice) diuretics

control variceal bleedingby means of endoscopic surgery (banding or adrenaline injection)

by reducing portal pressure pharmacologically(eg by somatostatin analogues (octreotide) and b-adrenergic blocking agents).

Screen for hepatocellular carcinoma

LOOK FOR LIVER TRANSPLANT DONORSurvival rates are about 80% in adults and 90% in children

AST to ALT ratio = 2:1


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An Occupational Hazard 7.10 by Eleanor Curtin

Problem summary Seok Kim is a 52-year-old importer. He migrated to Australia with his family fromKorea in 1995.Mr Kim has noticed dark urine and yellow eyes for the past threeweeks. For about three months he has noticed a poor appetite and decreasingenergy . He is known to have a history heavy alcohol intake and hypertension. Hehas a past history of hepatitis. There is no history of blood transfusion, tattoos or

injecting drug use but his mother had liver disease.

Diagnosis & defn PROLONGED ALCOHOL INTAKE and infection with HEPATITIS B VIRUSresulted in damage to the liver parenchyma, inflammation, fatty infiltration andcirrhosis.

Hepatitis B VirusDEFINITIONA. Hepadna virusB. Small double-stranded DNA genome, viral DNA polymerase (DNAP)C. envelope (SURFACE), protein coat (CORE)Incubation: 1-5 months (~ 2m)

Transmission: blood**, vertical**, sexual*, salivaReplication: @ HEPATOCYTE, salivary glands, pancreas, testis(1) ATTACHMENT: unknown receptor(2) UNCOATING: core released, DNAP makes DNA circular - CCC DNA (covalently closed circular DNA)(3) NUCLEUS ENTRY: CCC DNA very stable PERSISTS for life of cell, may also integrate in host DNA(4) VIRAL PROTEIN SYNTHESIS:

ENVELOPE encodes surface antigen HBsAgCAPSID encodes core antigen HBcAg (not found in blood)

encodes circulating peptide HBeAgHost response:THIS CAUSES THE MOST DAMAGE!!!!A. Innate immune response INDUCES APOPTOSIS to clear infxd cells.T-CELL MEDIATED RESPONSE: HBcAg induces cytotoxic Tcell response FIBROSIS (worse with alcohol)***if impaired T-cell immunity less damage to liver but virus never clears & higher cancer risk (high level replication)B. three antibodies: anti-HBs, anti-HBc, anti-HBe.Durable & highly infectious

Stable to temperature, dryness, anti-septicsInactivated by: glutaraldehyde, formulin, urea

INITIAL ACUTE PHASE LATER ACUTE

CHILDHOOD INFXN ASYMPTOMATIC flares in adulthoodSEVERE CHRONIC LIVER DISEASE (high prevalence pattern)ADULT / OLDER CHILD INFXNACUTE HEPATITIS RECOVERY (low prevalence pattern)

HPI ~~MOSTLY ASYMPTOMATICA. TYPICAL ACUTE INFXN

a. FATIGUE, HEADACHEb. FEVER (low grade)

B. GIT a. NAUSEAb. ANOREXIAc. DISTASTE FOR CIGSd. DIARRHOEA

C. ABDO PAIN (right upper quad)peritoneum stretches over big liver

PHYS EXAMA. TENDER LIVERB. CERVICAL LYMPH NODESC. SPLENOMEG (esp. children)D. SERUM SICKNESS (10%)

circulating Ag-Ab complexes deposited

a. ARTHRALGIAb. RASHc. FEVER

A. GIT RESOLVES

A. JAUNDICE SCLERAL DARK URINE

(advancing) PALE STOOLS PALPABLE LIVER

3-6WEEKS

RESOLUTION


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EPIDEMIOLOGYPREVALENCE:Persistent HBV ~ 300 million worldwide-ENDEMIC sub-Saharan Africa, China, SE Asia(different viral genotypes)

vertical transmission (at birth)chronic liver disease 5-20%

acute hep B rare, 10-20% adults are carriers,most non-carriers are immune-LOW prev: acute hepatitis

sexual transmission, IV drugs-AUSTRALIA: 1-2% carriers

HISTORYRISK FACTORSA. IV drug userB. HOMOSEXUAL (male)C. CLOSE CONTACT with infxd individuals

1. mother2. regular sexual partners

D. HAEMODIALYSISE. HEALTHCARE workerF. TRAVEL 1. Asia

2. Pacific Islands3. Eskimo4. India5. Sub-Saharan Africa

6. HaitiG. TATTOOS / ACUPUNCTURE

DIFFERENTIAL DIAGNOSESA. ALCOHOLIC HEPATITISB. MEDICATIONSC. ISCHAEMIAD. BILIARY TRACT

DIAGNOSISA. SEROLOGY - !!GOLD STANDARD!!Antigens:HBsAg -earliest ACUTE marker, may persist chronicallyHBeAg -ACTIVE INFECTION, virus is replicating (25% dont have this)HBV DNADNA polymeraseAntibodies:HBsAb -previous Hep B INFECTION + IMMUNITY

or VACCINATION + IMMUNITYHBcAb -CONVALESCENCE: core windowas surface Ag cleared by surface AbHBeAb -earliest Ab, LOW INFECTIVITY: predicts Hep B resolutionLIVER FUNCTION TESTS* ALBUMIN normal

* BILIRUBIN-URIA early perists to convalescenceFBC*WCC high


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ACUTE HEPATITIS

IMMUNE RESPONSE CAUSES CELL DAMAGE!!(immuno-suppressed & neonates asymptomatic infection)a. immune response against viral Ags damages virus-infxd hepatocytesA. cytotoxic T-cells react to virus Ags or virus-modified cell membrane Ags CELL LYSISB. antibody-dependent cytoxicity circulating immune complexes containing viral Ags and Abs can cause POLYARTHRITIS, VASCULITIS,GLOMERULO-NEPHRITIS

b. strength of immune response determines clinical expressionPROMPT response cell injury & virus clearance ACUTE HEPATITISACCELERATED & EXCESSIVE response fulminant liver necrosis total clearance FULMINANT HEPATITISWEAK response persistence of antigenic hepatocytes continued low-level destruxn CHRONIC HEPATITISFAILED response virus perpetuates, no liver damage CARRIER STATE

INCUBATION

DNA Viral replicationACUTE preicteric

Immune response causing liver celldestruction

ACUTE icteric

Bile canaliculi obstruction &damage cholestasis

CONVALESCENCEViral replication stops, LIVERarchitecture restores,inflammatory exudate clears

asymptomatic usually mild illnessSYMPTOMS

malaise, nausea, anorexia serum sicknessPHYS EXAM

tender LIVER

Non-specific symptoms intensify(or cessation = anicteric)

high fever, chills, headacheabdo pain

big, tender LIVER jaundice pale stools (cholestasis)

pruritis (bile salt irritation)

Clinical & chemical recovery in 12-16wks

(late stage) HBsAg

ALT, AST

early acute markers HBsAg, HBeAg

Bilirubin (conjugated) serum urine DARK

as acute phase ends, HBcAbrises and e Ag falls

(1) HBcAb (2)HBeAb(3)HBsAb(gives immunity)antigens no longer detectable

ACUTE HEP B LIVER(gross)A. NECROSIS, LOBULE COLLAPSE(pale yellow areas)

ACUTE HEP B LIVER (micro)

Ballooningdegeneration

Councilman

body

ACUTE HEP B LIVER(low power)A. portal MONONUCLEAR INFLAMM EXUDATE:limited to hepatocyte plate PIECEMEAL NECROSIS

HISTOLOGY ACUTE HEPATITISGROSSA. enlargedB. pigmented: red, greenish(if cholestasis)MICRO

A. CELL INJURY lobular disarrayBALLOON DEGENERATION: cytoplasm swelling (E.R., MITO)

B. NECROSIS single cells / sml clusters(1) Cytolysis: cells disappear from framework(2) Apoptosis: condensation & fragmentation COUNCILMAN BODIES

C. INFLAMMATORY S(1) KUPFFER CELL HYPERTROPHY

(2) MONONUCLEAR INFLAMMATORY INFILTRATE from portal regionD. BILE DROPLETS

@ ballooned cells, Kupffer cells, within canaliculi

E. REGENERATION (in recovery phase)(1) nuclei enlargement & mitosis(2) hepatocyte plates 2 cells thick

NORMAL LIVER

Portal tract

Central vein


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FULMINANT HEPATITIS (1-4%)

MASSIVE LIVER NECROSISCan supervene any type of hepatitis, often kills the patientAcute hepatitis deteriorates within TWO WEEKS of symptom onsetA. LIVER FAILURE: coagulopathyB. ENCEPHALOPATHY

(submassive necrosis lasts several months, same outcome)PROGNOSIS 70-90% mortality if you survive, life is good!

A. lifelong immunityB. no liver damageC. not carriers

HISTOLOGY GROSSShrunken, red, soft, flabby

MICROA. liver cells almost all goneB. little inflammation

CARRIER STATE

CHRONIC INFXN, INFECTIOUSClinically either ASYMPTOMATIC or CHRONIC HEPATITISVERTICAL TRANSMISSION responsible for high carrier rates

(transplacental / perinatal). Persistence of virus in infxd infantssuggests TOLERANCE produced by early exposure.DIAGNOSIS: HBsAg, AST, ALT (detects early stage disease)HISTOLOGY of asymptomatic carrier

- GROUND GLASS hepatocytesCytoplasm filled with HBsAg particles

CHRONIC HEPATITIS

LASTS LONGER THAN 6 MONTHSWeak immune response. HB X antigen incorporated into hostgenome allowing chronic infxn and expresses oncogeneinactivating p53.NON-VIRAL CAUSES:

a.DRUGS (methotrexate) & ALCOHOLb.AUTO-IMMUNE WILSONS Cu overload HAEMOCHROMATOSIS Fe overload-1 ANTI-TRYPSIN defic

ONSET A. follows ACUTE orB. develop independently INSIDIOUS ONSET

DIAGNOSISAll antigen markers + anti-HBc but NO anti-HBeHIGH RISK GROUP male renal dialysis very young & elderly Downs immunodeficient2 COURSES either-A.BETTER -persistent hepatitis with little damage

a. usually ASYMPTOMATICb. maybe episodic MALAISE, ANOREXIA, NAUSEAc. LIVER ENZYMES

HISTO: LIMITING PLATE PRESERVED(row of cells adj to portal tract)A. INFLAMMATION +/- necrosis

B. OMINOUS -chronic ACTIVE hep with progressive liverdestruxn CIRRHOSIS liver failure deathvariable presentation, either-a. asymptomaticb. PERSISTENCE of acute symptomsc. CIRRHOSISunpredictable course can improve or deteriorate***HEPATOCELLULAR CARCINOMA risk***

HISTO: A. INFLAMMATORY infiltrate, portal region

Spill-over into parenchymaB. NECROSIS despite regenerationdrop out necrosis ** high mortality

D. FIBROSIS - PORTALMANAGEMENTHEP B VACCINE: recombinant HBsAg. Effective & affordable WHO policy to provide neo-natal vaxANTI-VIRAL DRUGS limited success, resistant virus commonA. LAMIVUDINE: targets viral enzyme (reverse trasncriptase)B. PEGYLATED IFN: mimics innate immune responseLIVER TRANSPLANTReinfection from extra-hepatic reservoir prevention withHepB specific Ig + lamivudineAcute support BED-REST until signs & symptoms disappeared DRUG AVOIDANCE until recovery (incl alcohol, OCP)

COMPLICATIONS

PROGNOSIS acute hepatitisLow mortality ~0.5%Higher if

over-60s other serious disease hep E in pregnancy


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Alcoholic Liver Disease

ALCOHOL METABOLISM @ LIVERABSORPTION@ STOMACH: some metabolized here (first pass metabolism)**bulk of Alcohol metabolism @ LIVERbut also @ STOMACH: fasting increases gastricemptying, decreases first pass metabolism, gets into blood quicker.@ PROX INTESTINE2 MAIN METABOLIC PATHWAYS @ LIVER CELL

BOTH OXIDIZE ETHANOL TO PRODUCE TOXIC ACETALDEHYDE

(1) ADH-mediated (MAJOR PATHWAY STANDARD)

EXCESS H+ IONS produced impairs FATTY ACID [o] FFAs accumulate

esterified to 3-GLYs FATTY CHANGE(REVERSIBLE)enhanced by FATTY DIET ( flux FFAs to LIVER), LIVER DISEASE (impaired

lipoprotein synth)

(2) MEOS & CYP2E1 (INDUCED BY CHRONIC DRINKING)

MEOS microsomal ethanol-oxidising system. Involves cytochrome P450 2E1(key enzyme in alcohol toxicity). INDUCIBLE ENZYMEthus the more you drink,the more you produce, the more damage it causesa)OXYGEN RADICALS producedlipid peroxidationcell membrane damageb)chronic alcohol UPREGULATES P4502E1other metabolic actionsupregulated (with toxic products) thus, toxicity of certain drugs & chemicals isgreaterHow does ACETALDEHYDE cause problems?A. MITOCHONDRIA DAMAGE impaired cellular respirationB. IMPAIRED MICROTUBULAR CELL TRANSPORTC. protein-acetaldehyde ADDUCTSimmunogenic!

Incite B-cell & cytotoxic T-cell response Associated with COLLAGEN DEPOSITION in ALD (fibrosis pathogenesis)

D. OXIDATIVE STRESS: cell membrane damage, fat cant exit fatty accumulationenhanced free radical activitylipid peroxidation**P4502E1 contributes directly to this damageGLUTATHIONE (GSH) = Major cellular anti-oxidant @ LIVER, decreasedwith chronic alcohol exposure

E. CYTOKINE RELEASE (TNF, TGF-) from KUPFFER CELLS

HEPATITISA. ADDUCTS incite immune response

B. ENDOTOXIN = a LPS (lipopolysaccharide) found in wall of gram ve bacteria.High levels in ALD (increased gut bacteria?)- induces TNF-apoptosis / necrosis of hepatocyteC. N-PHIL & MONONUCLEAR INFILTRATE

CIRRHOSISA. FIBROSIS STARTS AROUND CENTRAL VV (home of P4502E1major site ofoxidative stress) STELLATE (ITO) CELLS COLLAGEN depositionB.NODULES: hepatocyte regeneration confined with FIBROUS BANDS disruptsvasculature and bile channels (twists & squashes) PORTAL HT

Ethanol Acetaldehyde AcetateADH ALDH

NAD NADH NAD NADH

@ CYTOPLASM @ MITOCHONDRIA

ADH-alcoholdehydrogenaseALDH-aldehydedehydrogenase

Ethanol AcetaldehydeCYP2E1

@ EndoplasmicReticulum

(centrilobular)NADP NADPH

(1) FATTY CHANGEdamaged hepatocytes take up FATTY ACIDS,convert to 3-GLYs but lipoprotein synthprevents exit FAT ACCUMULATION

(2) ALCOHOLIC HEPATITIS-INFLAMM. INFILTRATE lymphocytes (top R)-HEPATOCYTE NECROSIS-COLLAGEN deposition

(3) CIRRHOSIS-NODULE FORMATION: hepatocyte regenerationconfined within FIBROUS CT BANDS

!! MOST COMMON CAUSE OF LIVER DISEASE IN WESTERN SOCIETIES!!

AETIOLOGY who is at risk?ALCOHOL TOXICITY DEPENDS ON HOSTRESPONSE no dose response, unpredictableA. HAZARDOUS DRINKINGYet only 10% alcoholics develop cirrhosis!!>60g / day -male>30g / day -female(without 2 alcohol free days)B. FEMALE:A. body weight fat contentB. smaller 1

stpass metabolism (less able to metabolize

alcohol in gastric mucosamore delivered to blood)C. NUTRITIONHighsat fats & lowcarbo dietD. OTHER LIVER INSULTS: co-toxins, drugs, diseaseE. ORIENTAL ETHNICITYInactive ALDEHYDE DEHYDROGENASEaccumulation of toxic ACETALDEHYDE

CIRRHOSIS micronodular(gross)

Stellate cells producecollagen & ECM

PDGFStellate cell growth factorTGF for ECM production


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TREATMENTSYMPTOMATIC & SUPPORTIVEA. STOP ALCOHOLbeat craving with naltrexoneB. NUTRITION: B12, protein control etc.C. PREDNISALONE (severe hepatitis)D. BLOCK TNF with PENTOXYFILLINE

DIAGNOSISA. HISTORYB. MACROCYTOSIS: vit B12 deficiency

C. LFTS: AST > ALThigh GGT

PROGNOSISA. FATTY LIVER: disappears after 3 months abstinenceB. HEPATITIS: one third die in acute phase (esp if poorliver function), if keep drinkingC. CIRRHOSIS:(only 10% alcoholics get this)serious complications : ascites, varicesif keep drinking: 35% survive 5yif quit: 70% survive beyond 5y


9/15

LIVER: ANATOMY

SITUATION: upper abdo (R) cavity,inside thoracic cage but midline covered byabdo mm.

SURFACES:DiaphragmaticA. SUPERIOR: peritoneum covering,DIAPHRAGMabove, FALCIFORMLIGAMENTdivides into R & L lobes.B. POSTERIOR: R lobe connects toDIAPHRAGMvia CORONARY LIGAMENT(folds of peritoneum, in between is theBARE AREA: direct contact withdiaphragm). Behind are R ADRENAL, IVC,AORTA, OESOPHAGUS.C. ANTERIOR: contact with DIAPHRAGM,ANT ABDO WALL.D. RIGHT

Visceral!!H-SHAPED!! UPRIGHTS: fissures forligamentum venosum & teres (L), fossaefor IVC, GALL BLADDER(L). CROSSBAR:

porta hepatis. Contacts OESOPH,STOMACH, DUO, TRANSVERSE COLON,R COLIC FLEX, R KIDNEY, ADRENAL,GALL BLADDER.

LIGAMENTS: (mostly deflections ofperitoneum)A. FALCIFORM: attaches to DIAPHRAGMand UMBILICUS, divides into RIGHT & LEFTLOBESB. TRIANGULAR:continuous with-C. CORONARY: attaches POSTERIORsurface to DIAPHRAGMD. ROUND: remnant of left umbilical vein,

enclosed by inferior FALCIFORM LIGAMENTLOBES:A. LEFT (sml) & RIGHT (big): separated byFALCIFORM(anterior) & FISSURES(visceral). FUNCTIONAL LOBES: divided byline betw fossae for GALLBLADDERandIVC. Separate blood supply & bile drainage.B. QUADRATE & CAUDATE

BLOOD SUPPLY ~~ DUAL SUPPLY~~ highly vascularized, easily ruptured (1.5L blood/min)

OXY-blood

DEOXY-blood &digestion prodsfrom GIT,RBC breakdownprods fromSPLEEN (for bile

pigments)

R

Cystic A.GALL-

BLADDER

PORTA PORTAHEPATIS sinusoids HEPATIS

LUNGS

STOMACH

SPLEEN

PANCREAS/

DUODENUM

SMLINTEST

COLON

AORTAcoeliac

R, L Gastric veins

R,L Gastroepiploic vv

Pancreatico-duodenal v

Sup mesenteric vein

Inf mesenteric vein

Proper hepatic A(30%)

Portal vein

(70%)

Hepatic vvIVC

BILE DUCTS

HEPATICTRIAD: travelthroughoutliver together

Lymphatic vesselsthoracicduct

Common hepatic duct

Visceral surface

THE LOBULE: the functional unit= hexagonal unit, 1mm diameter.BLOOD FLOW:At each corner of hexagon = HEPATIC TRIADAt centre = CENTRAL VEINBlood flows from triad mixed in SINUSOIDS (large, leakycapillaries) drains thru central vein hepatic veins

IVC**Cells near central vein most vulnerable to O2 depletion**Cells near portal triad most vulnerable to poisonsSINUSOIDS:DISCONTINUOUS (leaky) EPITHELIUM lined withMPHAGES (KUPFFER CELLS): remove debris and oldRBCs**beneath endothelium = PERISINUSOIDAL SPACE (ofDisse)drains interstitial fluid: much of bodys lymphsite of HAEMATOPOIESIS for anaemics, foetus.BILE FLOW:Sheets of HEPATOCYTES (1 cell thick) radiate from centralvein = PARENCHYMA. Bile made in hepatocytessecretedinto BILE CANALICULI (betw h-cytes) drain to PORTALTRIAD DUCTSBLOOD & BILE TRAVEL OPPOSITE DIRECTIONS!!!

Bile duct

Portal V

Disse space

Bile caniculusbetw hepatocytes

hepatocyte

Hepaticsinusoids

fenestrae

Kupffercell

Centralvein


10/15

SMLINTESTINE

BILECHANNELS

HEP-CYTEPLASMAMACROPHAGES@ LIVER, SPLEEN

LIVER FUNCTIONA. KUPFFER CELLS (2%)-reticular endothelial MACROPHAGE-endocytosis: Ag-Ab, toxins, microparticles-killer function: release superoxide-TNF- releaseB. ENDOTHELIAL CELLS (3%)

-barrier-endocytosis: receptor-mediated (lipids)-pinocytosis possible-FENESTRATED = PERMEABLE!!!LIVER = MAJOR PRODUCER OF BODY PROTEINS-standard fns (eg factor VIII synth)C. ITO CELLS (1.5%)-FAT STORAGE-vit A storage-contractile: can adjust blood flow in response tolocal immune eventsD. PIT CELLS (


11/15

LIVER FUNCTION TESTS COLLECTIVE PATTERN IMPORTANT, individual tests often varyUSE: disease progress (not cause, prognosis, liver function)SPECIMEN: serum sample

ALT, AST (serum TRANSFERASES / TRANSAMINASES)Neither specific to LIVERbut higher [ALT] there (constant low levels in plasma 10x normal significant)

@ CYTOPLASM & MITOCHONDRIA leak out with cell damage.ALT: [alanine aminotransferase] - MORE SPECIFIC FOR LIVERAST: [aspartate aminotransferase]

HIGH [ALT], [AST] NECROSIS of LIVER CELLS

ALT > AST LIVER DISEASEAST > ALT ALCOHOLIC HEPATITIS (rarely 10xN)

CHRONIC HEPATITIS @ Cirrhosis stage

SAP, GGT (Biliary Enzymes)@ CELL MEMBRANES Bile salts damage membranes in bile obstruction (cholestasis)NB/ increase much less with cell damageSAP: [Alkaline Phosphatase] : also @ BONE, INTESTINE, PLACENTAGGT: [Gamma-glutamyl transpeptidase) : everywhere but sensitive to LIVER

HIGH [GGT], [SAP] CHOLESTASISGGT may be normal EARLY in course of acute hepatocellular damage

HIGH [GGT] ALCOHOL / DRUGS (eg. anti-convulsants)Induce synthesis & release of enzymes in absence of diseasealcohol > 60g / d

PANCREATITIS / PROSTATITIS

SERUM BILIRUBINHIGH A. increased production

B. impaired uptake & conjugation @ hepatocyte C. impaired secretion into BILE UNCONJUGATED Bilirubin production(no un-Br in urine as - haemolysisbindsto Albumin) - ineffxive erythropoiesis

Conjugation prob @ LIVER

Transport prob @ LIVER Gilberts

CONJUGATED bile duct obstruction(rare, c-Br in urine)

ALBUMINSpecific: made only in LIVER

LOW chronic disease (long half-life 3-4 wks: no changes with acute disease)

A. synthesis @ LIVER

B. excretion @ KIDNEY

C. malnutritionD. dilution due to ascites

GLOBULINS( = total protein albumin)

HIGH dysregulation of protein synth in liver disease

immune cells?

IgA alcoholic liver diseaseIgM 1 biliary cirrhosisIgG autoimmune hepatitis

COAGULATION FACTORSLIVER makes all factors. Prothrombin Time (I, II, V, VII, X) = good indicator of acute liver disease since short half-life of factors(5-72h). 30% reduction in coags will increase PT.

PT prolonged SEVERE LIVER DAMAGE

PROLONGED BILE OBSTRUCTION

prevents fat absorption VIT K absorption vit-K dependent factors inactivated (TV)**give Vit K suppts & repeat to distinguish

OTHER TESTS

FERRITIN A. haemochromatosis B. Alcoholic Liver disease

Caeruloplasmin : copper-containing globulin, made @ LIVER

serum LOW Wilsons

LIVER fulminant failure / severe disease

malabsorption

serum HIGH inflammation

neoplasm

BILE obstruction1-antitrypsin : made by LIVER, a protease inhibitor

serum LOW LIVER / LUNG disease-fetoprotein: made by FOETAL LIVER: falls after birth

sig HIGH HEPATOCELLULAR CARCINOMA

URINE BILIRUBINNEGATIVE A. normal

B. (if jaundice) unconjugated hyper-

bilirubinaemia: Albumin-boundPOSITIVE conjugated hyperbilirubinaemia

SEROLOGICAL TESTSHep A (HAV)anti-HAV (of IgM type): acute infection (lasts 1-2wks post onset)

(of IgG type): lasts years, implies immunityHep B (HBV) - ACUTEHBsAg (surface Ag): acute infection (days-wks post onset)anti-HB: (antibody) previous infxn / vaccination (3-6months post infxn)anti-HBc (antibody to core Ag) acute (early marker, subsides & persists)HBeAg (e Ag): active replication in LIVER (transient at onset)anti-Hbe: follows HBeAg

- CHRONICHbsAg and anti-HBc (IgG)

AUTOANTIBODIESIMAGINGBIOPSY


12/15

CHRONIC LIVER DISEASE~~HEPATOCYTE DAMAGE~~ usually CHRONIC HEPATITISCAUSES:

A. ALCOHOLB. VIRUSES (hep B, C, D)C. DRUGS & TOXINS

D. FATTY LIVER (NASH) assoc with METABOLIC E. AUTOIMMUNE

-autoimmune chronic hepatitis:

genetic, mostly female, associated with other AID, IgG & AUTO-ANTIBODIES

-Wilsons toxic Cu overloadCONSIDER IF UNKNOWN CAUSE OF LIVER DISEASE IN


13/15

LIVER FAILURE 7.10either ACUTE - massive hepatocyte destruction VIRAL HEPATITIS, DRUGS (paracetamol), idiopathic

or CHRONIC CIRRHOSIS

CHRONICHepatocyte loss + portal HTA. PORTAL HT=increased pressure on PORTAL VEIN from blockage higher up:

(1) VARICES

FIBROSIS and REGENERATIVE NODULES squash vasculature.Since flow cant pass thru liver -- EXITS THE WAY IT CAME IN causing high pressure flow thru COLLATERAL veins @:

a. OESOPHAGUSb. ANT. ABDO WALL (caput medusae)c. RECTAL VVd. VERTEBRAL VV

(2) SPLEEN THRMBOCYTOPENIA(3) ASCITES & OEDEMA(also ALBUMIN deficiency)

risk SPONTANEOUS BACTERIAL PERITONITISB. GYNAECOMASTIA & hypogonadism

Impaired OESTROGEN breakdownC. WASTING & MALNUTRITION

Metabolic disturbances: gluconeogenesisD. PALMAR ERYTHEMAE. SPIDER NAEVI (upper body)

both from OESTROGEN

in GENERALA. ENCEPHALOPATHY ++ metabolic flap

toxic METABOLITES now able to reach brain because(1) un-toxified blood shunted into systemic circulation(2) loss of detox function with hepatocyte death

ATTENTION BEHAVIOURAL SLEEP COMANEUROLOGIC RIGIDITY / SEIZURES

B. JAUNDICEAltered BILIRUBIN metabolism

C. COAGULOPATHY clotting factors

D. LOW BP

ACUTEMassive loss of hepatocytes causes:

A. FEVER

B. ACIDOSIS

C. RENAL FAILURE

Mechanism unclear but evidence for DECREASED RENALBLOOD FLOW due to vasoconstriction from:(1) gut flora endotoxins not cleared(2)thomboxane A2 by platelets(3) renin & aldosterone from effective blood volume

(ascites)D. HAEMORRHAGE

Liver necrosis

BILIRUBIN FX

bilirubin metabolismhyperbilirubinemiajaundice

bile in GITpale stools

vit K absorptionbleeding

urobilinogendark urine

PROTEIN metabolism metabolism of proteins, carbos,fats

hypoglycaemia plasma proteins

ascites & oedema

Liver failure

encephalopathy coma Death

Liverinflammation

pain fever

Nausea, vomiting,anorexia

fatigue

HORMONE metabolism

androgens & oestrogensgynaecomastialoss of body hairmenstrual dysfnspider naevipalmar erythema

ADH & aldosterone

oedema

Liver fibrosis & scarring

PORTALHYPERTENSION

-ascites-oedema-splenomegaly

anaemiathrombocytopenialeukopenia

-varices

BIOCHEMISTRY

- ASR, ALT- SAP- bilirubin-low albumin- PT

Hepatorenal failure

Liver failure of CIRRHOSIS

CIRRHOSIS GRADINGSYSTEM exists affectsPROGNOSIS significantly.Based on:

- ascites- bilirubin- encephalopathy

- serum albumin-I NR


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ASCITES

= accumulation of free fluid in peritoneal cavityCAUSES:

A. CIRRHOSIS (high pressure in mesenteric circulation) >11g/LB. MALIGNANCY < 11C. INFECTION < 11D. BILIARY COMMUNICATIONE. LYMPHATIC OBSTRUCTION

CLINICAL:A. ABDO DISTENSION & FLANK FULLNESSB. SHIFTING DULLNESS(only if fluid > 1L)C. UMBILICUS EVERSIOND. HERNIAEE. STRIAE**pleural effusion in 10% people (RHS, if LHScheck out)INVESTIGATIONS:

ULTRASOUND diagnosisPARACENTESIS (fluid analysis) causeSerum-ascitic fluid albumin gradient cirrhosis / infxn / malig

PATHOGENESIS:Arterial vasodilation theory

MANGEMENT:(1) low salt diet(2) diuretics(3) drain + IV albumin(4) shunt peritovenous(5) liver transplant

COMPLICATIONS: - !!! OMINOUS !!!

A. SPONTANEOUS BACTERIAL PERITONITIS(1) Portal HT gut wall oedema(2) bacteria translocate from gut lumen circulation(3) poor Retic Endo System fn bacteraemia(4) ascitic fluid poor antimicrobial defences infxn

a. ASCITESb. FEVER, CHILLSc. SUDDEN ABDO PAINd. ENCEPHALOPATHY worse

ASYMPTOMATIC (30%)Diagnosis:

Ascitic WCC > 500/LPMN > 250/L

(no need to culture but MOSTLY single organism,---E.COLI--- 70% gram negative bacteria

if multiple organisms & HUGE protein levelthink 2 BACTERIAL PERITONITISCauses:BOWEL PERFORATIONABSCESSISCHAEMIAPrognosis:NOT GOOD!!!only 25% survival after 5y

high recurrence but NORFLOXACIN v.fxive

CIRRHOSIS

Portal HT hepatocyte function& endotoxaemia

Splanchnic & systemic vasodilation

effective blood vol

Renin-angiotensin system activation(symp NS, ADH)

Na & water retention

plasma vol

Continuous Na & water retention

ASCITES

endogenous vasodilators (NO)

Inadequate for homeostasis

PHYSIOLOGY OF ASCITES

Hydrostatic P Oncotic P

Na+/water retentionLiver lymphatics work overtime but cant fullycompensate fluid escapes liver capsule jailinto peritoneal cavity

B. HEPATORENAL !!! OMINOUS !!!= progressive renal failure with advanced CIRRHOSISand ASCITES (no actual renal disease)

Diagnosis:CREATININE rises & URINE reduces LIVER DISEASE + portal HT low GFR no obvious trigger:

-shock-sepsis-nephrotoxic drugs-XS fluid losses

no other renal (no proteinuria) no improvement with volume expansionPrognosis:50-95% mortality

Liver failure

Vasodilationfollowed by SNSvasoconstriction

BP thusperfusionpressure

toxic waste-endotoxin-free radicals-shear stresstriggerVASOACTIVEMEDIATORS

GFR

renal blood flow

He atorenal

COMPLICATIONS OF LIVER FAILURE

WHAT FAVOURS OEDEMA??A. hydrostatic P (high pressure flow)

-venous obstruxn-Na/water retention

B. oncotic P (low plasma protein)ALBUMIN defic-liver disease-malnutirition-renal disease-wounds / haemorrhage

C. capillary membranepermeability

-inflammation-immune response-neoplasm-allergic response

D. lymphatic obstrxn-inflammation-tumour-surgical removal


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PORTAL HYPERTENSION

= INCREASED PRESSURE on PORTAL VEIN leavingliver from any cause:intrahepatic obstructionpre-hepatic obstructive thrombosispost-hepatic Heart failure

since cant pass thru liver, EXITS THE WAY IT CAME IN causingVARICES @:(1) OESOPHAGUS(2) ANT. ABDO WALL (caput medusae)(3) RECTAL VV (haemorrhoids)(4) VERTEBRAL VVFOUR MAJOR CLINICAL CONSEQS:A. ascitesB. varicesC. splenomegalyD. hepatic encephalopathy

GI BLEEDSA. VARICESB. PEPTIC ULCER C. CLOTTING DYSFN

clotting factors @ LIVER platelets @ SPLEEN

high risk of VARICES??CLINICAL: cirrhosis, severe diseaseBLOOD PRESSURE: HVPG >12mmHg (portal venous P)

** higher it gets, less chance of survivalvariceal >15

ENDOSCOPY: diameter >5mmULTRASOUND: portal flowOTHER:(1) bacterial infxn

(2) NSAIDS(3) alcohol

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Alcoholism and Hepatitis