Primary Biliary Cirrhosis
Content
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
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 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 160/70 BP – JVP – Not elevated Apex – 5ht IC space, mid clavicular line Normal S1, S2 – 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 LFT’s is normal
Most- liver histology normal Symptomatic in 10-15 yrs
Patterns of clinical disease
Asymptomatic AMA +ve LFT’s 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 5’nucleotidase
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 Ursodeoxy cholic acid If ineffective/intolerant – Rifampicin, Naltrexone, plasmapharesis Liver transplantation Severe/intractable –
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
Presenting complaints
Progressive yellowish discoloration of eyes for one month Loss of appetite, loss of energy and itching of the body for 3/12
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 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 160/70 BP – JVP – Not elevated Apex – 5ht IC space, mid clavicular line Normal S1, S2 – 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 LFT’s is normal
Most- liver histology normal Symptomatic in 10-15 yrs
Patterns of clinical disease
Asymptomatic AMA +ve LFT’s 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 5’nucleotidase
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 Ursodeoxy cholic acid If ineffective/intolerant – Rifampicin, Naltrexone, plasmapharesis Liver transplantation Severe/intractable –
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
