CHOLESTASIS

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CHOLESTASIS

• Dr Allister Grant
• Consultant Hepatologist
• 7.2.12

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Cholestasis

• Cholestasis is an impairment of bile formation
  and/or bile flow
• Symptoms of fatigue, pruritus and in its most
  overt form, jaundice.
• Early biochemical markers in often asymptomatic
  patients
• increases in serum alkaline phosphatase (ALP)
• ? -glutamyltranspeptidase (?GT)
• Conjugated hyperbilirubinaemia at more advanced
  stages.
• Cholestasis
• classified as intra-hepatic or extra-hepatic.

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Chronic Cholestasis

• gt6mo
• Most chronic cholestasis is intra-hepatic
• Asymptomatic patients are usually picked up by
  routine blood tests
• ALP iso-enzymes
• ?GT is too sensitive and not specific for liver
  disease

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?-Glutamyl transpeptidase

• The high sensitivity and very low specificity
  seriously hampers the usefulness of this test
• If ALP is elevated and GGT is elevated then the
  raise in ALP is likely to be hepatic in origin
• Elevated in
• a whole host of liver diseases
• Drugs/Alcohol
• Obesity/ dyslipidaemia/ DM
• CCF
• Kidney, Pancreas, Prostate

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Investigation of Cholestasis
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• Hepatocellular cholestasis
• Sepsis-, endotoxaemia-induced cholestasis
• Cholestatic variety of viral hepatitis
• Alcoholic or non-alcoholic steatohepatitis
• Drug- or parenteral nutrition-induced cholestasis
• Genetic disorders e.g., BRIC, PFIC, ABCB4
  deficiency
• Intra-hepatic cholestasis of pregnancy (ICP)
• Erythropoietic protoporphyria
• Malignant infiltrating disorders e.g.,
  hematologic diseases, metastatic cancer
• Benign infiltrating disorders e.g., amyloidosis,
  sarcoidosis hepatitis and other granulomatoses,
  storage diseases
• Paraneoplastic syndromes e.g., Hodgkin disease,
  renal carcinoma
• Ductal plate malformations e.g., congenital
  hepatic fibrosis
• Nodular regenerative hyperplasia
• Vascular disorders e.g., BuddChiari syndrome,
  veno-occlusive disease, congestive hepatopathy
• Cirrhosis (any cause)

• Cholangiocellular cholestasis
• Primary biliary cirrhosis (AMA/AMA-)
• Primary sclerosing cholangitis
• Overlap syndromes of PBC and PSC with AIH
• IgG4-associated cholangitis
• Idiopathic adulthood ductopenia
• Ductal plate malformations biliary hamartoma,
  Caroli syndrome
• Cystic fibrosis
• Drug-induced cholangiopathy
• Graft vs. host disease
• Secondary sclerosing cholangitis e.g., due to
  various forms of cholangiolithiasis, ischemic
  choangiopathies (hereditary haemorragic
  telangiectasia, polyarteritis nodosa and other
  forms of vasculitis),
• infectious cholangitis related to AIDS and other
  forms of immunodepression, etc.

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Drug Induced Cholestasis

• Intrahepatic Hepatocellular Cholestasis
• Intrahepatic Cholangiocellular Cholestasis
• Ductopenic
• Granulomatous

• AllopurinolAntithyroid agents
• AugmentinAzathioprineBarbituratesCaptoprilCar
  bamezepineChlorpromazineChlorpropamideClindamyc
  in
• ClofibrateDiltiazem
• Erythromycin Flucloxacillin
• Isoniazid
• LisinoprilMethyltestosterone
• Oral contraceptives (containing estrogens)Oral
  hypoglycemics PhenytoinTrimethoprim-sulfamethoxa
  zole

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Mr S

• 62yr old
• 25 yr history of UC/PSC
• Limited details due to frequent movement around
  the country

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Mr S

• 1990s Seen at Royal Free- ?Listed for OLTx and
  then removed from list
• Ampullary stenosis 1994
• Recurrent pancreatitis
• Recurrent cholangitis
• 1998 ERCP lower CBD narrow, no dominant
  strictures

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Mr S

• 2000 Inverness- Recurrent cholangitis, short
  attacks
• Ciprofloxacin (PRN at home)
• 2003 Seen in Hemel Hempstead- cholangitis,
  ERCPs
• Severe post ERCP pancreatitis

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Mr S

• Leicester Aug 2003
• Gastro referral from GP 2004
• Feels bad most weeks
• Has a cocktail of Ciprofloxacin, Hyoscine,
  Pethidine, DHC to take when feels bad

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Mr S

• Had been having colonoscopic surveillance, but
  not for 2 years
• Ex Smoker
• Appendicectomy, Depression
• Olsalazine 500mg bd, Omeprazole 10mg od
• UDCA 150mg tds FeSO4

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Mr S

• OPD Nov
• Hx of severe post ERCP pancreatitis obtained
• LFT's persistently ALP 400-700
• Referred to Hepatology
• Advised rotating ABx

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Mr S

• What next?

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Mr S

• USS- CBD stone, IHDs mildly dilated
• Thickened ducts
• MRCP

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Mr S
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Mr S
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Mr S

• What next?

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Mr S

• Dec 04 Admitted with jaundice and fever
• Had not started Abx
• WCC 19, Bili 52, ALP 614
• Enterococcus species
• ERCP

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Mr S
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Mr S
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Mr S

• Post ERCP ALP gt1000
• Gradually settled
• URSO increased to 500mg tds (65kg)
• Started rotating ABx

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Mr S

• Free of cholangitic episodes for 18 mo
• Occasional fleeting pain
• ALP 600, Bili 22

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Primary Sclerosing Cholangitis
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Definition

• A chronic inflammatory cholestatic disease
• Progressive destruction of bile ducts
• May progress to cirrhosis
• Aetiology unknown

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Relationship to IBD

• IBD in 60-80 of PSC patients
• UC more common than Crohns (21)
• PSC in Crohns disease almost always involves the
  colon
• 2-10 of UC patients have PSC

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Survival in PSC Compared to Olmsted County
Bamba K et al Gastro 2003
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Cholangiocarcinoma

• Lifetime prevalence of 10-30
• Annual risk 1.5 per year
• Difficult to diagnose
• Patients also have late risk of HCC

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PSC and Bowel Cancer

• 25 PSC develop cancer or dysplasia cf 5.6 with
  UC alone
• Cancers associated with PSC tend to be more
  proximal, are more advanced at diagnosis and more
  likely to be fatal
• Need yearly colonoscopic surveillance

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Recurrence of PSC Post Transplant
Alexander J et al Liver transplantation 2008
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PSC Clinical Presentation

• Asymptomatic 15-44
• Symptomatic
• Fatigue 75
• Pruritus 70
• Jaundice 30-69
• Hepatomegaly 34-62
• Abdominal Pain 16-37
• Weight Loss 10-34
• Splenomegaly 30
• Ascending cholangitis 5-28
• Hyperpigmentation 25
• Variceal Bleeding 2-14
• Ascites 2-10

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Diagnosis

• Cholangiography
• either MRCP or ERCP
• multifocal strictures and dilatation usually
  affects both intra and extrahepatic ducts
• Clinical,biochemical and histological features

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PSC Diagnostic Criteria

• Exclude
• HIV cholangiopathy
• Cholangiocarcinoma
• Biliary tract surgery or trauma
• Choledocholithiasis
• Congenital abnormalities
• Ischaemic cholangiopathy
• Stricturing due to TACE

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PSC

• Prevalence of auto-antibodies in PSC
• P-ANCA 80
• AMA lt2
• ANA 50-60
• SMA 35

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p-ANCA is not specific for PSC

• PSC 80
• UC 75
• AIH 80
• PBC 30

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Cholangiography
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Role of Liver Biopsy in PSC

• Can help to confirm diagnosis
• May help to exclude an overlap syndrome
• If cholangiogram is normal then may help to
  exclude small duct PSC
• For staging and prognostication
• Not always needed

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Small Duct PSC

• 5 of PSC
• Normal cholangiogram but biopsy showing PSC
• Can progress to classical PSC (12)
• May exist with or without UC

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Survival curves for patients with small duct and
large duct PSC (plt0.05)
Probability of Survival
Months since diagnosis
Björnsson E et al. Gut 200251731-735
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Primary Biliary Cirrhosis
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PBC Epidemiology

• Femalemale ratio of 91
• Most common during middle age
• Presentation similar between genders, races, and
  sexes
• Prevalence 19-150 cases/million
• Incidence 4-15 cases/million/yr
• Incidence/prevalence rates increasing?
• Familial clustering

Kaplan et al. NEJM 2005353(12)1261
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PBC-Asymptomatic Disease

• 50-60 of patients (earlier diagnosis)
• 36-89 of asymptomatic patients develop symptoms
  within 4.5-17 years
• Elevated AMA (M2)
• Liver biopsy
• Liver chemistry tests
• Normal
• Cholestatic
• 50-70 10 year survival in asymptomatic patients
• UDCA associated with better survival when
  compared to pre-UDCA era

Balasubramaniam et al. Gastroenterology
199098(6)1567
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PBC Symptomatic Disease

• Fatigue (common)
• Pruritus
• Jaundice
• Hepatosplenomegaly
• RUQ pain
• Hyperpigmentation

• Xanthomas and xanthelasmas
• Dyslipidemia
• Extrahepatic autoimmune diseases
• Complications
• Portal hypertension
• Chronic cholestasis

Koulentaki et al. Am J Gastroenterol
2006101(3)541
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PBC Complications

• Chronic cholestasis
• Loss of bone density
• Malabsorption
• Steatorrhea
• Bile salt deficiency
• Pancreatic disease
• Coeliac disease
• Vitamin A, D, E, K deficiency

• Portal hypertension
• Oesophageal and gastric varices
• Ascites
• Encephalopathy
• SBP
• HRS or HPS
• Hepatocellular carcinoma

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PBC Metabolic Bone Disease

• 30-50 of patients
• Classification
• Osteoporosis common
• Osteomalacia rare
• Diagnosis and F/U
• DEXA scan
• Every 2-3 yrs

• Management
• Calcium and vitamin D
• Adequate exercise
• Oestrogen replacement
• Post menopausal
• Other medications
• Bisphosphonates
• Strontium Ranelate
• Transplantation
• Progressive disease

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PBCMetabolic Bone Disease
Compression fractures
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PBC Hypercholesterolemia

• Elevated cholesterol 85 of patients
• Stage I or II disease increased HDL predominates
• Stage III or IV disease increased LDL
• No increased risk for ischemic heart disease
• Lipid-lowering drugs not recommended unless there
  is a separate lipid disorder
• Plasmapheresis for xanthomatous neuropathy and
  symptomatic planar xanthomas

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PBC Dyslipidemia
Xanthomas
Xanthelasmas
Xanthomas
Xanthomas
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PBC Associated Diseases

• Thyroid disease
• Hashimotos thyroiditis
• Graves disease
• Scleroderma
• CREST syndrome
• Sjogrens syndrome
• Arthritis
• Raynauds phenomenon
• Coeliac disease

• Renal tubular acidosis
• Proximal
• Distal
• Gallstones
• Haematologic disorders
• Inflammatory bowel disease (rare)
• Pulmonary interstitial fibrosis (rare)

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PBC Non-Invasive Tests

• Biochemical tests
• Alkaline phosphatase
• ?GT
• 5 nucleotidase
• AST and ALT
• Bilirubin
• Total cholesterol
• Serum IgM
• Prothrombin time
• Albumin

• Serology
• AMA (95)
• ANA (50)
• SMA (50)
• Anti-centromere
• Anti-thyroid
• Medical imaging
• Ultrasound
• CT
• MR or MRCP

Dickson et al. Hepatology 198910(1)1 Muratori
et al. Clin Liver Dis 200812(2)261 Kaplan et
al. N Engl J Med 2005353(12)1261
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PBC Histology

• Stage I (portal)
• Inflammation of interlobular and septal bile
  ducts
• Granulomatous (florid duct) lesion
• Stage II (periportal)
• Inflammation of interlobular and septal bile
  ducts
• Ductular proliferation

• Stage III (septal)
• Inflammation of interlobular and septal bile
  ducts
• Fibrosis
• Bile duct loss
• Cholestasis
• Stage IV (cirrhotic)
• Established cirrhosis

Scheuer et al. Mayo Clin Proc 199873(2)179
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PBCPathology
Cirrhosis
NRH
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PBC Overall Management

• Survival of patients with PBC inferior to that of
  a healthy control population
• Medical treatment warranted in all patients
• No medical therapy has been shown to conclusively
  alter the history of PBC
• Goals of treatment
• Slow disease progression
• Treat complications

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PBC Medical Management

• Ineffective
• Corticosteroids
• Azathioprine
• Cyclosporine
• Penicillamine
• Colchicine
• Chlorambucil
• Possibly effective
• Methotrexate
• Mycophenolate mofetil

• Effective
• Ursodeoxycholic acid
• Improvement in symptoms
• Improvement in LFTs
• Improvement in histology
• Improvement in transplant free survival

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PBC-UDCA

• Effective dose 13-15 mg/kg/day indefinitely
• Mechanism of action
• Promotes endogenous bile acid secretion
• Replacement of hepatotoxic (endogenous) bile
  acids
• Stabilizes biliary epithelial cell membranes
• Alters HLA I-II expression on biliary epithelial
  cell
• Inhibits biliary cell apoptosis
• Improvement in LFTs
• Delays disease progression and improves
  transplant-free survival
• Follow LFTs every 3-6 mo.

Poupon et al. N Engl J Med. 1994330(19)1342 Heat
hcote et al. Hepatology 199419(5)1149
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PBCIncomplete Responders to UDCA

• 66 of patients
• Definition
• Failure to normalize LFTs
• Development of cirrhosis on therapy
• Predictors of incomplete response
• High alkaline phosphatase or GGT
• Advanced disease prior to UDCA initiation
• Assess patient compliance, UDCA dose, overlap
  syndrome

Combes et al. Hepatology 199522(3)759 Poupon et
al. J Hepatolol 200339(1)12
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PBC Liver Transplantation

• Patient and graft survival
• 1 yr 83-92
• 5 yr 75-85
• Higher risk of rejection
• PBC recurrence
• 15 to 25 of patients at 10 years
• Granulomatous bile duct injury
• AMA does not define recurrence
• Exclude other post transplant disorders
• Intermediate term patient and graft survival are
  good
• Use of UDCA for recurrent disease uncertain

Liermann et al. Hepatology 200133(1)22
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PBC Pruritus

• Antihistamines
• 50 response rate
• Cholestyramine
• 90 response rate
• UDCA
• Inconsistent results

• Rifampin
• Rapid onset of action
• Can cause liver injury
• Other medications
• Opiate antagonists
• Sertraline
• Ondansetron?
• Other
• Extracorporeal support
• OLT

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PBC Vitamin Deficiency

• Vitamin A
• 20 of patients
• Night blindness
• Replace as appropriate
• Can cause liver injury
• Vitamin D
• Replace as appropriate
• Can cause liver injury
• Supplemental calcium

• Vitamin E
• Rarely seen in adults
• Neurologic sequelae
• Reduced proprioception
• Ataxia
• Replace as appropriate
• Vitamin K
• Risk of hemorrhage
• Replace as appropriate

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Natural History and Prognosis

• PBC progresses over 15-20 yrs
• Median survival
• Asymptomatic disease 10-16 yrs
• Symptomatic disease 7.5-10 yrs
• Bilirubin (80µg/L) 2 yrs

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PBCSummary

• Important cause of chronic cholestatic liver
  disease
• Middle-aged females predominate
• Immune pathogenesis favored
• Other autoimmune diseases frequently coexist
• PBC progresses in most patients

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PBCSummary

• Complications of portal hypertension and chronic
  cholestasis associated with progressive disease
• UDCA is standard medical therapy for all patients
• Transplantation reserved for patients with
  marginal liver reserve and complications

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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
vs.
Age Gender Assocd Dx
40-60 Female RA, CREST Scleroderma Sjogrens
10-30 Male Ulcerative Colitis Crohns Disease
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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
vs.
Age Gender Assocd Dx
40-60 Female RA, CREST Scleroderma, Sjogrens
10-30 Male Ulcerative Colitis Crohns Disease
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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
vs.
Age Gender Assocd Dx
40-60 Female RA, CREST Scleroderma, Sjogrens
10-30 Male Ulcerative Colitis Crohns Disease
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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
vs.
Age Gender Assocd Dx Ducts Affected
40-60 Female RA, CREST Scleroderma, Sjogrens
Small to medium
10-30 Male Ulcerative Colitis Crohns
Disease All ducts
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Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)
vs.
Age Gender Assocd Dx Ducts Affected Method
of Dx
40-60 Female RA, CREST Scleroderma, Sjogrens
Small to medium ?Biopsy
10-30 Male Ulcerative Colitis Crohns
Disease All ducts MRCP/ERCP
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Mr Y

• 53 year old married man presented at GGH -end
  Aug 09
• Chest Pain/Abdo pain and loose stools
• Troponin negative
• Abnormal LFTs
• ALT 212
• ALP 522
• Bili 21
• ALB 37
• Amylase 33

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Initial liver screen

• IgG slightly elevated
• IgM slightly elevated
• Caeruloplasmin
• A1AT level
• Ferritin
• TFT

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Imaging

• USS-
• echogenic mass in left lobe -5x4x2cm
• Probably complex haemangioma- some doppler flow
  and some other small similar lesions
• By week later ALPgt1000
• Transferred to Liver Unit

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• CT
• Multiple haemangiomata
• Multiple enlarged nodes at porta 12mm
• ? SB polyp
• RMZ consolidation

• HBsAg neg
• HCV ab neg
• EBV IgG pos
• CMV neg
• Autoantibodies neg
• Tumour markers neg

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Rash on palms and soles biopsied 9/9/09- non
specific Liver biopsy arranged and done
17/9/08- periductal fibrosis and biliary
inflammation
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• VDRL/TPHA Positive
• Commenced on penicillin
• Referred to GUM
• LFTs completely normalised in 2 months

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