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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
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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
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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 (
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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
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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
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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