Mrs Sumana Kumarihamy 58yrs

House wife 82, Pol-ambakotuwa, Walala, Menikhinne DOA- 23/5/02 DOA-17/06/02 BHT: 55618/2002

Presenting complaints

Progressive yellowish discoloration of eyes for one month Loss of appetite, loss of energy and itching of the body for 3/12

H/O presenting complaints

Was apparently well 3/12 back Developed vague ill health with loss of eneergy, LOA, and generalised itching of the body which progressively increased. No significant LOW Since one month back noticed yellowish discoloration of eyes which increased in intensity and passing dark urine and pale stools No fever/Abd. pain or Back pain

H/O presenting complaints

No joint pain or skin rash No history of bloody diarrhoea or malaena No dyspnoea or chest pain No previous history of jaundice/No contact history of hepatitis No H/O foreign travel Mild tremor + , increased sweating +

Past medical and surgical history

Taken treatment for thyroid disease from THP for 5 years from 1995 Diagnosed Thyrotoxicosis and Hypertention in July 2000 and treated with Propranolol and carbimazole for one month and discontinued Rx I131 given in august 2000 Defaulted Rx as she felt better and since then not on any drugs

Past medical and surgical history

Not taken any ayurvedic treatment Denies alcohol intake No blood transfusions No tattooing No surgeries No P/H of hepatitis No past episodes of haemetemisis or melaena No DM/IHD

Family History

Youngest in a family five No F/H of jaundice or any other significant illness Parents expired

Social history

Married with 3 children Husband retired Grama sevaka Son and elder daughter married and employed Younger daughter living with them awaiting university admission All the children are in good health Sanitation and hygeine satisfactory Denies any sexual promisquisity

Examination

General:
Looks ill Extensive vitiligo Rest of the skin is hyperpigmented Not wasted Deeply icteric Not pale Grade IIb diffuse goitre + (

Examination

General examination

No Keisher Fleisher rings Corneal arcus and xanthelasma No tendon or planar xanthomata No LNE No parotid enlargement No clubbing/Leukonychia or palmar erythema Fine tremors + No bruising or purpura No spider naevi/ no ankle oedema

Cardiovascular system

Pulse 110/min, regular, good volume and non collapsing BP 160/70 JVP Not elevated Apex 5ht IC space, mid clavicular line S1, S2 Normal Systolic murmur + at apex, no radiation

Respiratory system

Trachea Midline Movements equal Vesicular breathing No added sounds

Abdomen

Not distended No dilated vessels No scars No tenderness/Guarding or ridigidy Liver not enlarged Spleen not palpable Gall bladder not palpable Kidneys not ballotable No other palpable masses/No free fluid PV/PR normal

Central nervous system

Higher functions- conscious and oriented Cranial nerves- Normal Motor/sensory and reflexes- normal

Summary

58 yrs old lady with a P/H of thyrotoxicositreated with antithyroid drugs and radio iodin therapy, who has defaulted treatment for 2 yrs presented with LOA, lethargy, itching of the body for 3/12 and progressively increasing yellowish discoloration of eyes for one month. She is passing dark urine and pale stools On examination: Ill, deeply icteric, corneal arcus and xanthelasma+, extensive vitiligo increased pigmentation in rest of the skin, Gr IIb diffuse goitre, fine tremor+ PR- 110/min reg, BP-160/70, Systolic murmur at apex Rest of the physical examination normal

PRIMARY BILIARY CIRRHOSIS

Introduction

A chronic progressive disease of liver primarily affecting women (F:M= 9:1) 90% women aged 35-60 Progressive destruction of small and intrahepatic bile ducts fibrosis Cirrhosis

Aetiology and pathogenesis

Cause unknown

? Auto immune aetiology

Associated with other auto immune diseases

CREST syndrome SICCA syndrome Auto immune thyroiditis Type I DM

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

Aetiology and pathogenesis

A circulating IgG antimitochondrial antibody (AMA) in >90% of patients Of the mitochondrial protiens involved Ag M2 is specific Finding of M4 and M8 Ag in patients with M2 may be associated with more progressive disease Five M2 specific Ag defined using immuno blot technique of which E2 component of PDC is the major M2 auto antigen Their role in pathoenesis is unclear Increased serum IgM and cryoprotiens consisting of immune complexes capable of activating altrenative complement pathway in 80-90%

Incidence

Relatively common N.Europe and N. America Uncommon in Africa and Indian subcontinent In UK prevalence 240/million Incidence 4-30/million/yr Prevalence seems to be increasing

Patterns of clinical disease

Historically middle aged women with jaundice, itching and lethargy But it has a wider spectrum

Presymptomatic AMA +ve No symptoms LFTs is normal Most- liver histology normal Symptomatic in 10-15 yrs

Patterns of clinical disease

Asymptomatic AMA +ve LFTs abnormal No symptoms But upto 50% established cirrhosis at the time of diagnosis Symptomatic Pruritus and lethargy Median tme to death 8-12 yrs Decompensated Variceal haemorrahage, Jaucdice and ascites median time to death 3-5yrs

Patterns of clinical disease

AMA negative PBC (Autoimmune cholangitis)

Clinical, biochemical and histological features of PBC, yet no AMA in serum Anti nuclear and anti smooth muscle Ab present Some particularly those with ALP <2times upper limit of normal may respond to corticosteroids Clinical course/response to therapy resembles classical PBC

Course of the disease

Rate of progression varies Prognosis depends partly on the stage Relentlessly progressive Serum bilirubin best prognostic marker

When it reaches 150mic.mol/l prognosis in the absence of liver transplant is 18/12

Clinical features Signs and symptoms

Many asymptomatic- Detected on basis of high ALP Among symptomatic patients 90% are women aged 35-60 Characteristic features- tiredness and pruritus

Pruritus-generalised/initially limited to palms and soles

Jaundice

Clinical features Signs and symptoms

Gradual darkening of exposed areas (Melanosis) Impaired bile excretion Steatorrhoea and malabsorption of fat soluble vitamins High cholesterol Xanthelasma, Xanthomas Eventually signs of hepatocellular failure and portal hypertension and ascitis Progession may be quit variable

Physical examination

May be entirely normal in early phase Later jaundice of varying intensity Hyperpigmentation Xanthelesma and Xanthomas Moderate to striking hepatomegaly Splenomegaly Clubbing Bone tenderness, Signs of vertebral compression Echymosis Glossitis

Physical examination

Clinical evidence of Sicca syndrome in 75% Clinical evidence of autoimmune thyroid disease in 25% Other associated conditions

RA CREST syndrome Keratoconjunctivitis sicca IgA deficiency Type I DM

Scleroderma Pernicious anaemia RTA

Bone disease Osteomalacia and Osteoporosis

Laboratory findings

Presymptomatic stage:

>2fold increase in ALP Increased Seurm 5nucleotidase Incdreased Gamma GT Serum bilirubin usually normal Aminotransferases minimally increased Diagnosis supported by positive AMA (Titre >1/40) both relatively specific and sensitive

Positive in >90% of symptomatic pts Also present in <5% of pts with other liver diseases

Laboratory findings

As disease evolves
Serum bilirubin rises progressively Aminotransferases rarely exeeds 150-200 units Hyperlipidaemia common Increased PT Increased liver Copper not specific, found in prolonged cholestasis

Serum Igs (particularly IgM and to a lesser extent IgG) increased

Laboratory findings

Many other auto anti bodies are found

Anti nuclear Anti platelets Anti thyroid Anti centromere Ro La

Diagnosis

Middle aged women with unexplained pruritus or high ALP with evidence of cholestasis PBC should be considered +ve AMA important diagnostic evidence, false +ve results do occur. Therefor liver biopsy to confirm diagnosis and for staging

Diagnosis

Liver histology
Non suppurative destructive cholangitis Hallmark Four stages

Stage I Granulomatous cholangitis with granulomas, lymphoid aggregates, destruction of middle sized intrahepatic bile ducts Stage II Inflammation spreading beyond portal tracts, dissapearing bile duct syndrome Stage III- Scarring stage, adjacent portal tracts linked by fibrous septae Stage IV- Cirrhosis

AMA (M2) and Nuclear pore protein (gp 210) specific to PBC

Management

Treatment of symptoms

Pruritus:
Cause unknown ? Retension of opioid agonist substances and upregulation of opioid receptors Mainstay of Rx Cholestyramine 4g tds If ineffective/intolerant Ursodeoxy cholic acid Rifampicin, Naltrexone, plasmapharesis Severe/intractable Liver transplantation

Management

Lethargy
Cause unknown No specific Rx Use of inapropriate medication or failure to diagnose associated conditions

Bone disease
Osteopenia common Calcium, Biphosphonates, HRT Replacement of fat soluble vitamins

Management

Medical treatment

Ursodeoxy cholic acid 10-15mg/kg/day

Improvement in LFT Often improvement in symptoms Prolongation of survival Reduced need for liver transplantation

Reduction in ALP within 6/12 useful predictor of clinical response Immunosuppressive drugs Effects usually limited Current studies evaluating these drugs in combination with ursodeoxy cholic acid

Management

Liver transplantation
The only effective therapy in patients with end stage disease Indications: 1. Symptomatic disease intractable to treatment 2. End stage liver disease Serum bilirubin most effective prognostic marker Results usually excellent 5 yr survival >85% Upto 20% recurrent disease at 10 yrs

Thank you