Mrs Sumana Mrs Sumana Kumarihamy Kumarihamy

58yrs58yrsHouse wifeHouse wife

82, Pol-ambakotuwa, Walala, 82, Pol-ambakotuwa, Walala, MenikhinneMenikhinne

DOA- 23/5/02DOA- 23/5/02 DOA-17/06/02DOA-17/06/02BHT: 55618/2002BHT: 55618/2002

Presenting complaintsPresenting complaints Progressive yellowish discoloration Progressive yellowish discoloration

of eyes for one monthof eyes for one month Loss of appetite, loss of energy and Loss of appetite, loss of energy and

itching of the body for 3/12itching of the body for 3/12

H/O presenting H/O presenting complaintscomplaints

Was apparently well 3/12 backWas apparently well 3/12 back Developed vague ill health with loss of Developed vague ill health with loss of

eneergy, LOA, and generalised itching of eneergy, LOA, and generalised itching of the body which progressively increased.the body which progressively increased.

No significant LOWNo significant LOW Since one month back noticed yellowish Since one month back noticed yellowish

discoloration of eyes which increased in discoloration of eyes which increased in intensity and passing dark urine and intensity and passing dark urine and pale stoolspale stools

No fever/Abd. pain or Back painNo fever/Abd. pain or Back pain

H/O presenting H/O presenting complaintscomplaints

No joint pain or skin rashNo joint pain or skin rash No history of bloody diarrhoea or No history of bloody diarrhoea or

malaenamalaena No dyspnoea or chest painNo dyspnoea or chest pain No previous history of jaundice/No No previous history of jaundice/No

contact history of hepatitiscontact history of hepatitis No H/O foreign travelNo H/O foreign travel Mild tremor + , increased sweating +Mild tremor + , increased sweating +

Past medical and surgical Past medical and surgical historyhistory

Taken treatment for thyroid disease Taken treatment for thyroid disease from THP for 5 years from 1995from THP for 5 years from 1995

Diagnosed Thyrotoxicosis and Diagnosed Thyrotoxicosis and Hypertention in July 2000 and treated Hypertention in July 2000 and treated with Propranolol and carbimazole for with Propranolol and carbimazole for one month and discontinued Rxone month and discontinued Rx

I131 given in august 2000I131 given in august 2000 Defaulted Rx as she felt better and Defaulted Rx as she felt better and

since then not on any drugssince then not on any drugs

Past medical and surgical Past medical and surgical historyhistory

Not taken any ayurvedic treatmentNot taken any ayurvedic treatment Denies alcohol intakeDenies alcohol intake No blood transfusionsNo blood transfusions No tattooingNo tattooing No surgeries No surgeries No P/H of hepatitisNo P/H of hepatitis No past episodes of haemetemisis or No past episodes of haemetemisis or

melaenamelaena No DM/IHDNo DM/IHD

Family HistoryFamily History Youngest in a family fiveYoungest in a family five No F/H of jaundice or any other No F/H of jaundice or any other

significant illnesssignificant illness Parents expiredParents expired

Social historySocial history Married with 3 childrenMarried with 3 children Husband retired Grama sevakaHusband retired Grama sevaka Son and elder daughter married and Son and elder daughter married and

employedemployed Younger daughter living with them Younger daughter living with them

awaiting university admissionawaiting university admission All the children are in good healthAll the children are in good health Sanitation and hygeine satisfactorySanitation and hygeine satisfactory Denies any sexual promisquisityDenies any sexual promisquisity

ExaminationExamination General:General:

Looks illLooks ill Extensive vitiligo Extensive vitiligo Rest of the skin is hyperpigmentedRest of the skin is hyperpigmented Not wastedNot wasted Deeply ictericDeeply icteric Not paleNot pale Grade IIb diffuse goitre + (Grade IIb diffuse goitre + (

ExaminationExamination General examinationGeneral examination

No Keisher Fleisher ringsNo Keisher Fleisher rings Corneal arcus and xanthelasmaCorneal arcus and xanthelasma No tendon or planar xanthomataNo tendon or planar xanthomata No LNENo LNE No parotid enlargementNo parotid enlargement No clubbing/Leukonychia or palmar erythemaNo clubbing/Leukonychia or palmar erythema Fine tremors +Fine tremors + No bruising or purpuraNo bruising or purpura No spider naevi/ no ankle oedemaNo spider naevi/ no ankle oedema

Cardiovascular systemCardiovascular system Pulse – 110/min, regular, good volume Pulse – 110/min, regular, good volume

and non collapsing and non collapsing BP – 160/70BP – 160/70 JVP – Not elevatedJVP – Not elevated Apex – 5ht IC space, mid clavicular lineApex – 5ht IC space, mid clavicular line S1, S2 – NormalS1, S2 – Normal Systolic murmur + at apex, no radiationSystolic murmur + at apex, no radiation

Respiratory systemRespiratory system Trachea – MidlineTrachea – Midline Movements equalMovements equal Vesicular breathing Vesicular breathing No added soundsNo added sounds

AbdomenAbdomen Not distendedNot distended No dilated vesselsNo dilated vessels No scarsNo scars No tenderness/Guarding or ridigidyNo tenderness/Guarding or ridigidy Liver not enlargedLiver not enlarged Spleen not palpableSpleen not palpable Gall bladder not palpableGall bladder not palpable Kidneys not ballotableKidneys not ballotable No other palpable masses/No free fluidNo other palpable masses/No free fluid PV/PR normalPV/PR normal

Central nervous systemCentral nervous system Higher functions- conscious and Higher functions- conscious and

orientedoriented Cranial nerves- NormalCranial nerves- Normal Motor/sensory and reflexes- normalMotor/sensory and reflexes- normal

SummarySummary 58 yrs old lady with a P/H of 58 yrs old lady with a P/H of

thyrotoxicositreated with antithyroid drugs thyrotoxicositreated with antithyroid drugs and radio iodin therapy, who has defaulted and radio iodin therapy, who has defaulted treatment for 2 yrs presented with LOA, treatment for 2 yrs presented with LOA, lethargy, itching of the body for 3/12 and lethargy, itching of the body for 3/12 and progressively increasing yellowish progressively increasing yellowish discoloration of eyes for one month.discoloration of eyes for one month.

She is passing dark urine and pale stoolsShe is passing dark urine and pale stools On examination: Ill, deeply icteric, corneal On examination: Ill, deeply icteric, corneal

arcus and xanthelasma+, extensive vitiligo arcus and xanthelasma+, extensive vitiligo increased pigmentation in rest of the skin, Gr increased pigmentation in rest of the skin, Gr IIb diffuse goitre, fine tremor+IIb diffuse goitre, fine tremor+

PR- 110/min reg, BP-160/70, Systolic murmur PR- 110/min reg, BP-160/70, Systolic murmur at apex at apex

Rest of the physical examination normalRest of the physical examination normal

PRIMARY PRIMARY BILIARY BILIARY

CIRRHOSISCIRRHOSIS

IntroductionIntroduction A chronic progressive disease of A chronic progressive disease of

liver primarily affecting women liver primarily affecting women (F:M= 9:1)(F:M= 9:1)

90% women aged 35-6090% women aged 35-60 Progressive destruction of small and Progressive destruction of small and

intrahepatic bile ducts fibrosis intrahepatic bile ducts fibrosis Cirrhosis Cirrhosis

Aetiology and Aetiology and pathogenesispathogenesis

Cause – unknownCause – unknown ? Auto immune aetiology? Auto immune aetiology

Associated with other auto immune diseases Associated with other auto immune diseases CREST syndromeCREST syndrome SICCA syndromeSICCA syndrome Auto immune thyroiditisAuto immune thyroiditis Type I DMType I DM

? Triggered by infection (an environmental ? Triggered by infection (an environmental factor acting on a genetically predisposed factor acting on a genetically predisposed individual)- remains unprovenindividual)- remains unproven

Aetiology and Aetiology and pathogenesispathogenesis

A circulating IgG antimitochondrial antibody (AMA) A circulating IgG antimitochondrial antibody (AMA) in >90% of patientsin >90% of patients

Of the mitochondrial protiens involved Ag M2 is Of the mitochondrial protiens involved Ag M2 is specificspecific

Finding of M4 and M8 Ag in patients with M2 may Finding of M4 and M8 Ag in patients with M2 may be associated with more progressive diseasebe associated with more progressive disease

Five M2 specific Ag defined using immuno blot Five M2 specific Ag defined using immuno blot technique of which E2 component of PDC is the technique of which E2 component of PDC is the major M2 auto antigenmajor M2 auto antigen

Their role in pathoenesis is unclearTheir role in pathoenesis is unclear Increased serum IgM and cryoprotiens consisting of Increased serum IgM and cryoprotiens consisting of

immune complexes capable of activating altrenative immune complexes capable of activating altrenative complement pathway in 80-90%complement pathway in 80-90%

IncidenceIncidence Relatively common N.Europe and N. Relatively common N.Europe and N.

AmericaAmerica Uncommon in Africa and Indian Uncommon in Africa and Indian

subcontinentsubcontinent In UK prevalence 240/millionIn UK prevalence 240/million

Incidence – Incidence – 4-30/million/yr4-30/million/yr

Prevalence seems to be increasingPrevalence seems to be increasing

Patterns of clinical Patterns of clinical diseasedisease

Historically middle aged women with Historically middle aged women with jaundice, itching and lethargyjaundice, itching and lethargy

But it has a wider spectrumBut it has a wider spectrum PresymptomaticPresymptomatic AMA +veAMA +ve No symptomsNo symptoms

LFT’s is normalLFT’s is normal Most- liver histology normalMost- liver histology normalSymptomatic in 10-15 yrsSymptomatic in 10-15 yrs

Patterns of clinical Patterns of clinical diseasedisease

AsymptomaticAsymptomatic AMA +veAMA +ve LFT’s abnormalLFT’s abnormal No No symptomssymptoms But upto 50% established cirrhosis at But upto 50% established cirrhosis at the the time of diagnosis time of diagnosis

SymptomaticSymptomatic Pruritus and lethargyPruritus and lethargy Median Median tme to death 8-12 yrstme to death 8-12 yrs

DecompensatedDecompensated Variceal haemorrahage, Jaucdice Variceal haemorrahage, Jaucdice and ascitesand ascites median time to death 3-5yrs median time to death 3-5yrs

Patterns of clinical Patterns of clinical diseasedisease

AMA negative PBC (Autoimmune AMA negative PBC (Autoimmune cholangitis)cholangitis) Clinical, biochemical and histological features Clinical, biochemical and histological features

of PBC, yet no AMA in serumof PBC, yet no AMA in serum Anti nuclear and anti smooth muscle Ab presentAnti nuclear and anti smooth muscle Ab present Some particularly those with ALP <2times Some particularly those with ALP <2times

upper limit of normal may respond to upper limit of normal may respond to corticosteroidscorticosteroids

Clinical course/response to therapy resembles Clinical course/response to therapy resembles classical PBCclassical PBC

Course of the diseaseCourse of the disease Rate of progression variesRate of progression varies Prognosis depends partly on the stagePrognosis depends partly on the stage Relentlessly progressiveRelentlessly progressive Serum bilirubin best prognostic Serum bilirubin best prognostic

markermarker When it reaches 150mic.mol/l prognosis When it reaches 150mic.mol/l prognosis

in the absence of liver transplant is 18/12in the absence of liver transplant is 18/12

Clinical features – Signs Clinical features – Signs and symptomsand symptoms

Many asymptomatic- Detected on basis Many asymptomatic- Detected on basis of high ALPof high ALP

Among symptomatic patients 90% are Among symptomatic patients 90% are women aged 35-60women aged 35-60

Characteristic features- tiredness and Characteristic features- tiredness and prurituspruritus Pruritus-generalised/initially limited to Pruritus-generalised/initially limited to

palms and solespalms and soles JaundiceJaundice

Clinical features – Signs Clinical features – Signs and symptomsand symptoms

Gradual darkening of exposed areas Gradual darkening of exposed areas (Melanosis)(Melanosis)

Impaired bile excretion Steatorrhoea Impaired bile excretion Steatorrhoea and malabsorption of fat soluble vitaminsand malabsorption of fat soluble vitamins

High cholesterol Xanthelasma, High cholesterol Xanthelasma, XanthomasXanthomas

Eventually signs of hepatocellular failure Eventually signs of hepatocellular failure and portal hypertension and ascitisand portal hypertension and ascitis

Progession may be quit variableProgession may be quit variable

Physical examinationPhysical examination May be entirely normal in early phaseMay be entirely normal in early phase Later jaundice of varying intensityLater jaundice of varying intensity HyperpigmentationHyperpigmentation Xanthelesma and XanthomasXanthelesma and Xanthomas Moderate to striking hepatomegalyModerate to striking hepatomegaly SplenomegalySplenomegaly ClubbingClubbing Bone tenderness, Signs of vertebral Bone tenderness, Signs of vertebral

compressioncompression EchymosisEchymosis GlossitisGlossitis

Physical examinationPhysical examination Clinical evidence of Sicca syndrome in 75%Clinical evidence of Sicca syndrome in 75% Clinical evidence of autoimmune thyroid Clinical evidence of autoimmune thyroid

disease in 25%disease in 25% Other associated conditionsOther associated conditions

RARA SclerodermaScleroderma CREST syndromeCREST syndrome Pernicious anaemiaPernicious anaemia Keratoconjunctivitis siccaKeratoconjunctivitis sicca RTARTA IgA deficiencyIgA deficiency Type I DMType I DM

Bone disease – Osteomalacia and Bone disease – Osteomalacia and OsteoporosisOsteoporosis

Laboratory findingsLaboratory findings Presymptomatic stage:Presymptomatic stage:

>2fold increase in ALP>2fold increase in ALP Increased Seurm 5’nucleotidaseIncreased Seurm 5’nucleotidase Incdreased Gamma GTIncdreased Gamma GT Serum bilirubin usually normalSerum bilirubin usually normal Aminotransferases minimally increasedAminotransferases minimally increased Diagnosis supported by positive AMA (Titre Diagnosis supported by positive AMA (Titre

>1/40) both relatively specific and sensitive>1/40) both relatively specific and sensitive Positive in >90% of symptomatic ptsPositive in >90% of symptomatic pts Also present in <5% of pts with other liver diseasesAlso present in <5% of pts with other liver diseases

Laboratory findingsLaboratory findings As disease evolvesAs disease evolves

Serum bilirubin rises progressivelySerum bilirubin rises progressively Aminotransferases rarely exeeds 150-200 Aminotransferases rarely exeeds 150-200

unitsunits Hyperlipidaemia commonHyperlipidaemia common Increased PT Increased PT Increased liver Copper – not specific, Increased liver Copper – not specific,

found in prolonged cholestasisfound in prolonged cholestasis Serum Igs (particularly IgM and to a Serum Igs (particularly IgM and to a

lesser extent IgG) increasedlesser extent IgG) increased

Laboratory findingsLaboratory findings Many other auto anti bodies are Many other auto anti bodies are

foundfound Anti nuclearAnti nuclear Anti plateletsAnti platelets Anti thyroidAnti thyroid Anti centromereAnti centromere RoRo LaLa

DiagnosisDiagnosis Middle aged women with Middle aged women with

unexplained pruritus or high ALP unexplained pruritus or high ALP with evidence of cholestasis with evidence of cholestasis PBC should be consideredPBC should be considered

+ve AMA important diagnostic +ve AMA important diagnostic evidence, false +ve results do occur. evidence, false +ve results do occur.

Therefor liver biopsy – Therefor liver biopsy – to confirm diagnosis and for staging to confirm diagnosis and for staging

DiagnosisDiagnosis Liver histology Liver histology

Non suppurative destructive cholangitis – Non suppurative destructive cholangitis – HallmarkHallmark

Four stages Four stages Stage I – Granulomatous cholangitis with Stage I – Granulomatous cholangitis with

granulomas, lymphoid aggregates, destruction granulomas, lymphoid aggregates, destruction of middle sized intrahepatic bile ductsof middle sized intrahepatic bile ducts

Stage II – Inflammation spreading beyond Stage II – Inflammation spreading beyond portal tracts, dissapearing bile duct syndromeportal tracts, dissapearing bile duct syndrome

Stage III- Scarring stage, adjacent portal Stage III- Scarring stage, adjacent portal tracts linked by fibrous septaetracts linked by fibrous septae

Stage IV- CirrhosisStage IV- Cirrhosis AMA (M2) and Nuclear pore protein AMA (M2) and Nuclear pore protein

(gp 210) specific to PBC(gp 210) specific to PBC

ManagementManagement Treatment of symptomsTreatment of symptoms

Pruritus: Pruritus: Cause unknownCause unknown ? Retension of opioid agonist substances ? Retension of opioid agonist substances

and upregulation of opioid receptorsand upregulation of opioid receptors Mainstay of Rx – Cholestyramine 4g tdsMainstay of Rx – Cholestyramine 4g tds If ineffective/intolerant – Ursodeoxy cholic If ineffective/intolerant – Ursodeoxy cholic

acid Rifampicin, Naltrexone, acid Rifampicin, Naltrexone, plasmapharesisplasmapharesis

Severe/intractable – Liver transplantationSevere/intractable – Liver transplantation

ManagementManagement Lethargy Lethargy

Cause – unknownCause – unknown No specific RxNo specific Rx Use of inapropriate medication or failure Use of inapropriate medication or failure

to diagnose associated conditionsto diagnose associated conditions Bone diseaseBone disease

Osteopenia commonOsteopenia common Calcium, Biphosphonates, HRTCalcium, Biphosphonates, HRT Replacement of fat soluble vitaminsReplacement of fat soluble vitamins

ManagementManagement Medical treatmentMedical treatment

Ursodeoxy cholic acid 10-15mg/kg/dayUrsodeoxy cholic acid 10-15mg/kg/day Improvement in LFTImprovement in LFT Often improvement in symptomsOften improvement in symptoms Prolongation of survivalProlongation of survival Reduced need for liver transplantationReduced need for liver transplantation

Reduction in ALP within 6/12 – useful predictor of Reduction in ALP within 6/12 – useful predictor of clinical responseclinical response

Immunosuppressive drugs – Effects usually limitedImmunosuppressive drugs – Effects usually limitedCurrent studies – evaluating these drugs in Current studies – evaluating these drugs in combination with ursodeoxy cholic acidcombination with ursodeoxy cholic acid

ManagementManagement Liver transplantationLiver transplantation

The only effective therapy in patients with end The only effective therapy in patients with end stage diseasestage disease

Indications: 1. Symptomatic disease Indications: 1. Symptomatic disease intractable to intractable to treatmenttreatment 2. End stage liver disease 2. End stage liver disease

Serum bilirubin – most effective prognostic Serum bilirubin – most effective prognostic markermarker

Results usually excellent – 5 yr survival >85%Results usually excellent – 5 yr survival >85% Upto 20% recurrent disease at 10 yrsUpto 20% recurrent disease at 10 yrs

Thank Thank youyou