Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis

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IN THE NAME OF GOD
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Primary Billiary Cirrhosis

• Dr. Nasser Ebrahimi Daryani
• Professor of Gastroenterology
• Tehran University of Medical Sciences

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PBC

• T-lymphocyte-mediated attack on small
  intralobular bile ducts that leads to their
  gradual destruction and eventual disappearance.
• 95 are women
• onset is usually between 30 to 65 y
• Incidence 2.7 per 100,000 person years
• Prevalence 65.4 for women and 12.1 for men per
  100,000 persons

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Laboratory tests

• AMA are the serologic hallmark of PBC
  ELIZA 95 sensitive and 98 specific
• Direct immunofluorescence less sensitive
• 13 of first-degree relatives of patients with
  PBC have AMA suggesting they are susceptible to
  developing PBC
• Elevation of 5'-nucleotidase and GGT parallel
  those of ALP.
• ALTlt 5 UNL
• Bili elevates as the disease progresses
• Eosinophils in the blood liver

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AMAs may be found in patients with
other syndromes, particularly overlap syndromes
and autoimmune hepatitis (AIH), but also
occasionally in primary sclerosing cholangitis
(PSC) and drug-induced liver disease.
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• Hyperlipidemia (50)
•  In early PBC LDL ? and VLDL ? and striking
  elevations of HDL ? ? .
• IgM ?
• ceruloplasmin ?
• bile acids ?
• hyaluronate ?(correlate with the serum bilirubin
  and histologic worsening of PBC)

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• incidence of PBC appears to be increasing
• - 23 cases per million in 1987 to 32
  cases per million in 1994
• possibly due to better detection rather than a
  true change in disease incidence
• Asymptomatic (up to 60)
• Symptoms signs
• at presentation
• Fatigue (85)
• Pruritus (55)
• Jaundice (10)
• RUQ pain (8)
• Hepatosplenomegaly (25)
• Metabolic bone disease (20)
• Xantholasma (10)

Associated disorders Sicca syndrome
(72-100) RTA (60) Arthritis (42) Gall stone
(33) Thyroid dysfunction (15-20) Scleroderma
(19) CREST (7) Raynaud's syndrome
(8) Hepatocellular carcinoma (2) Celiac disease
(rare)
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Symptoms Signs

•  Pruritus may occur initially during pregnancy
  and be mistaken for the pruritus of pregnancy.
• Hyperpigmentation of skin(25-50)
• Arthropathy(42)
• RA(5-10)
• hypercholesterolemic arthropathy
• Hepatic decompensation(rarely)
• Advanced disease
• Spider nevi,
• muscle wasting,
• ascites,
• Edema
• Kayser-Fleischer rings

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PROGNOSIS

• Patients with PBC who are asymptomatic at
  diagnosis may have a better prognosis than those
  who have symptoms.
• Good prognosis in patients initially diagnosed
  with mild disease who achieve a biochemical
  response to UDCA .
• UDCA in stage III or IV disease did not improve
  survival or development of complications.

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Poor Prognosis

• Coexisting disorders related to PBC
• thyroiditis,
• sicca syndrome,
• Scleroderma
• Antinuclear antibodies
• Cigarette smoking

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DIAGNOSIS

•   The diagnosis of PBC should be considered in
  the patient, particularly a woman, who complains
  of
• Itching ,
• fatigue,
• jaundice,
• unexplained weight loss,
• with RUQ discomfort,
• and/or whose serum ALP is elevated.

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Liver biopsy

• PBC should be confirmed by percutaneous liver
  biopsy when the diagnosis is first considered.
• The biopsy will also provide information about
  the stage of the disease and prognosis .
• Exceptions are
• gt75y (or have a short life expectancy due to
  comorbidities)
• contraindications to liver Bx.

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Ursodeoxycholic Acid for the Treatmentof Primary
Biliary Cirrhosis

• The use of UDCA has been recommended for patients
  with PBC who have positive tests for AMA and
  elevated liver biochemical markers.
• Some patients with PBC have positive tests for
  AMA but have normal liver enzyme levels these
  patients may eventually have clinical
  manifestations of PBC (including histologic
  changes)but are not considered candidates for any
  therapy.

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• A liver biopsy is not essential for either the
• diagnosis of PBC or the initiation of
  treatment. Although therapy with UDCA is most
  effective in patients with stage I or II disease,
  patients at any stage of disease are candidates
  for such therapy.
• At present, many patients do not undergo liver
  biopsy before starting treatment with UDCA.

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• MECHANISM OF ACTION 
• Inhibits absorption of toxic hydrophobic
  endogenous bile salts
• Stabilizes hepatocyte membranes against toxic
  bile salts
• Replaces endogenous hepatotoxic bile acids with
  non toxic UDCA
• Reduces expression of MHC class 12 antigens
• Reduces proliferation of colonocytes recurrence
  of adenoma

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• UDCA appears to improve biochemical tests , but
  its effect on the natural history of recurrent
  PBC is uncertain.
• UDCA was not associated with improved patient
  and graft survival compared with untreated
  patients in a retrospective study involving 52
  patients with recurrent PBC

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• A dose of 13 - 15 mg /kg/d
• should be provided, with slow initiation( 250-mg
  tablet given daily for 3 to 4 days, with
  successive tablets added at intervals of 3 to4
  days).
• Monitoring of LFT( at 3-month intervals).

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• Drugs interactions with UDCA
• Clofibrate, cholestyramine, and other
  cholesterol-binding or bile acidbinding
  sequestrants.
• Estrogens may increase biliary cholesterol
  levels, whereas charcoal and some antacids may
  bind bile acids.
• The dose of UDCA does not have to be adjusted
  for renal or other hepatic diseases.

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Liver transplantation in primary biliary cirrhosis
associated morbidity costly the optimal time
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Prognostic Models

• MELD 3.78Ln serum bilirubin (mg/dL) 11.2Ln
  INR 9.57Ln serum creatinine (mg/dL) 6.43
• Risk score 0.87 log( Bilirubin in mg/dl)
• -2.53 log( Albumin
  in mg/dl)
• 0.039 log( Age in
  years)
• 2.38 log( PT in
  seconds)
• 0.859 edema score
  
• Log Risk 1.68( bleeding 0.25)
• 2.03 log ( Bilirubin
  30.3)

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Predictors of Survival
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transplantation

• Bilirubin gt5 mg/dL
• Albumin lt2.8 g/dL
• Decompensation or portal hypertension ascites,
• variceal bleeding,
• coagulopathy
• malnutrition,
• or encephalopathy
• Intractable pruritus
• Recurrent, nontraumatic bone fractures

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• Liver transplantation is the only option for
  patients with PBC with
• life-threatening end-stage liver disease and its
  complications
• severe intractable symptoms (severe pruritus,
  profound fatigue, and severe bone disease)
• patients with PBC are good candidates for
  transplantation and
• have a better long-term prognosis compared to
  those with other common

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OUTCOME

• relieves symptoms
• improves survival
• complications of end-stage liver disease,
  (encephalopathy, variceal bleeding and
  hepatorenal syndrome) are reversed
• Jaundice and ascites (over a period of days to a
  few months).
• Splenomegaly (usually persists although the
  enlarged spleen may decrease slightly in size)
• Skin xanthomas (within a few weeks)

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Recurrence

• In a report of 421 patients from Pittsburgh
• 8 percent of patients after five years,
• 22 percent after 10 years.
• in a series of 400 patients from Birmingham
• 18 percent at five years
• and 30 percent at 10 years.

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diagnosis of recurrent

• .Transplant for PBC and
• . Persistence of AMA and
• . Liver histology showing the characteristic
  portal tract lesions
• mononuclear inflammatory infiltrate,
• lymphoid aggregates,
• epithelioid granulomas,
• bile duct damage.
• Definite recurrent PBC when three of the four
  portal tract lesions are present
• probable recurrence when two are present.

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• A cholestatic pattern of liver biochemical
  abnormalities is neither sensitive nor specific
  for recurrence.
• and can arise from multiple causes
• The presence of AMA does not establish that
  recurrence is present or will develop.
• AMA persist in most patients following
  transplantation usually with a small and
  transient fall in their titer.

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Risk factors for recurrence

• older recipient age,
• longer cold ischemia time,
• treatment with tacrolimus
• younger donor age.

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• azathioprine may have a protective effect
• recurrence is not typically associated with graft
  loss
• Although (UDCA) is the mainstay of treatment of
  PBC pretransplant, its role in treatment of
  recurrent PBC has not been defined

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Retransplantation

• Although there was initially some controversy,
  recurrence of primary biliary cirrhosis (PBC)
• has been reported and is estimated at about
  10 to 20, occurring on an average 3 to 6
• years after transplantation. Progression of
  recurrent PBC is often slow and may not
• necessitate retransplantation

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• ADMINISTRATION 
• The biliary enrichment with UDCA is the same
  whether it is taken in divided doses or as a
  single dose . Compliance is likely better with
  the latter regime.
• van de Meeberg PC Wolfhagen FH Van
  Berge-Henegouwen GP Salemans JM Tangerman A
  van Buuren HR van Hattum J van Erpecum KJ. J
  Hepatol 1996 Dec25(6)887-94.

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• Treatment with UDCA reduces the rate of
  development of esophageal varices, but it does
  not reduce the rate of bleeding from varices
• .
• Lindor KD Jorgensen RA Therneau TM Malinchoc
  M Dickson ER. Mayo Clin Proc 1997
  Dec72(12)1137-40.

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• Treatment does not seem to benefit the symptom
  of fatigue and has a variable effect on pruritus.
• Heathcote EJ Cauch-Dudek K Walker V Bailey RJ
  Blendis LM Ghent CN Michieletti P Minuk GY
  Pappas SC Scully LJ et al. The Canadian
  Multicenter Double-blind Randomized Controlled
  Trial of ursodeoxycholic acid in primary biliary
  cirrhosis. Hepatology 1994 May19(5)1149-56.
• Treatment does not seem to benefit on
  osteoporosis.
• Lindor KD Janes CH Crippin JS Jorgensen RA
  Dickson ER. Bone disease in primary biliary
  cirrhosis does ursodeoxycholic acid make a
  difference? Hepatology 1995 Feb21(2)389-92.

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• Treatment with UDCA has some benefit on the
  development of portal hypertension.
• Huet, PM, Huet, J, Deslauriers, J. Portal
  hypertension in patients with primary biliary
  cirrhosis. In Lindor, KD, Heathcote, EJ, Poupon,
  R (Eds), Primary biliary cirrhosis From
  pathogenesis to treatment. Kluwer Academic
  Publishers, London 1998. p.87.
• Small trials of combination therapy using UDCA
  with methotrexate, colchicine, or prednisolone,
  have been reported but have not shown any
  increased efficacy over UDCA therapy.

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• An initial response will be seen within a month
  to 6 weeks.
• Approximately 80 - 90 of full improvement
  within 3 months.
• Normalization of biochemical values 2 years in
  20 of patients and additional 15 of patients
  after 5 years.
• No other followup testing needs to be done, and
  liver biopsy is not routinely repeated to assess
  the effect of therapy.

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prediction of life expectancy

• The patients age
• Total levels of bilirubin
• Albumin
• The prothrombin time
• The presence or absence of edema and ascites
• Response of alkaline phosphatase

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Adverse Effects

• most common diarrhea
• Weight gain (averages 2.3 kg during the first1 to
  2 years and not progressive)
• Thinning of the hair
• Loose stools have been reported infrequently.

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MANAGEMENT OF COMPLICATIONS OF PBC

• Pruritus 
• Cholestyramine is the drug of first choice (III
  C).
• In patients who fail or are intolerant to the
  side effects of cholestyramine, rifampicin should
  be used as a second line therapy (III C).
• Opioid antagonists can be considered in
  resistant cases (III C).
• Liver transplantation is indicated for
  uncontrollable pruritus (IV).

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• Sicca syndrome
• All patients should be asked directly about dry
  eyes, dry mouth, dysphagia, and a dry vagina in
  women, because patients often do not volunteer
  these symptoms (III C).
• If symptoms are present, appropriate therapy
  should be offered.

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• Raynaud's syndrome 
• prevent exposure of their hands and feet to the
  cold and to stop smoking .
• Calcium channel blockers may relieve symptoms in
  the extremities but worsen esophageal
  dysmotility.
• Fat soluble vitamin deficiency
• In patients with hyperbilirubinemia, fat soluble
  vitamin replacement is likely best given using
  the water soluble form of the fat soluble
  vitamins (III C).

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• Osteoporosis
• BMD should be assessed with dual X-ray
  absorptiometry when the diagnosis of PBC is first
  made and every two years thereafter.
• Education regarding the importance of lifestyle
  changes and vitamin D and calcium supplementation
  should be given (III C).
• HRTis recommended where appropriate (III C).
• If osteoporosis is evident, therapy with a
  biphosphonate is advised (III D).

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• Portal hypertension 
• PBC patients should be screened for the presence
  of varices when first diagnosed and every three
  years until found (III B, C).
• If and when varices are found, standard
  prophylactic measures should be taken.

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• Pregnancy 
• It is currently recommended that any specific
  therapy (eg, UDCA) be withheld in women with PBC
  contemplating pregnancy (first trimester) .
• UDCA therapy during the last trimester of
  pregnancy appears to be safe and may be
  beneficial in mothers with cholestasis (III C,
  D).
• Patients who are pregnant should undergo an
  esophagogastroduodenoscopy to check for varices
  and given nonselectiveb-blocker therapy if
  varices are found. The obstetricianshould be
  advised to minimize the duration of the second
  stage of labor (III C)