Download Investigation of Cholestasis

CHOLESTASIS
Dr Allister Grant
Consultant Hepatologist
7.2.12
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)
– γ -glutamyltranspeptidase (γGT)
– Conjugated hyperbilirubinaemia at more advanced stages.
• Cholestasis
– classified as intra-hepatic or extra-hepatic.
Chronic Cholestasis
• >6mo
• Most chronic cholestasis is intra-hepatic
• Asymptomatic patients are usually picked up
by routine blood tests
• ALP iso-enzymes
• γGT is too sensitive and not specific for liver
disease
-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
Investigation of Cholestasis
Raised ALP
Check GT
if isolated rise
Dilated
bile ducts
1) Stop alcohol
2) Stop hepatotoxic drugs
3) Advise weight loss if BMI>25
Non-dilated
bile ducts
4) Recheck LFT’s after an interval
Persistently raised ALP
Ultrasound +
Full liver screen
Consider
MRCP
ERCP
Other imaging
Diagnosis madeTreat disease
Non diagnostic Ixconsider
Liver biopsy
Hepatocellular cholestasis
Cholangiocellular 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., Budd–Chiari syndrome,
veno-occlusive disease, congestive hepatopathy
Cirrhosis (any cause)
•
•
•
•
•
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.
Drug Induced Cholestasis
•
Intrahepatic Hepatocellular Cholestasis
•
Intrahepatic Cholangiocellular Cholestasis
•
Ductopenic
•
Granulomatous
•
Allopurinol
Antithyroid agents
Augmentin
Azathioprine
Barbiturates
Captopril
Carbamezepine
Chlorpromazine
Chlorpropamide
Clindamycin
Clofibrate
Diltiazem
Erythromycin
Flucloxacillin
Isoniazid
Lisinopril
Methyltestosterone
Oral contraceptives (containing estrogens)
Oral hypoglycemics
Phenytoin
Trimethoprim-sulfamethoxazole
Mr S
• 62yr old
• 25 yr history of UC/PSC
• Limited details due to frequent movement
around the country
Mr S
• 1990’s 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
Mr S
• 2000 Inverness- Recurrent cholangitis, short attacks
• Ciprofloxacin (PRN at home)
• 2003 Seen in Hemel Hempstead- cholangitis, ERCP’s
• Severe post –ERCP pancreatitis
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
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
Mr S
• OPD Nov
• Hx of severe post ERCP pancreatitis obtained
• LFT's persistently ALP 400-700
• Referred to Hepatology
• Advised rotating ABx
Mr S
• What next?
Mr S
• USS- CBD stone, IHD’s mildly dilated
Thickened ducts
• MRCP
Mr S
Mr S
Mr S
• What next?
Mr S
• Dec 04 Admitted with jaundice and fever
• Had not started Abx
• WCC 19, Bili 52, ALP 614
• Enterococcus species
• ERCP
Mr S
Mr S
Mr S
• Post ERCP ALP >1000
• Gradually settled
• URSO increased to 500mg tds (65kg)
• Started rotating ABx
Mr S
• Free of cholangitic episodes for 18 mo
• Occasional fleeting pain
• ALP 600, Bili 22
Primary Sclerosing Cholangitis
Definition
A chronic inflammatory cholestatic
disease
Progressive destruction of bile ducts
May progress to cirrhosis
Aetiology unknown
Relationship to IBD
• IBD in 60-80% of PSC patients
• UC more common than Crohn’s (2:1)
• PSC in Crohn’s disease almost always involves
the colon
• 2-10% of UC patients have PSC
Survival in PSC Compared to Olmsted County
1.0
Survival
Control population
PSC (no transplant)
0
0
5
10
15
Follow up (Years)
Bamba K et al Gastro 2003
20
Cholangiocarcinoma
• Lifetime prevalence of 10-30%
• Annual risk 1.5% per year
• Difficult to diagnose
• Patients also have late risk of HCC
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
Recurrence of PSC Post Transplant
Alexander J et al Liver transplantation 2008
PSC Clinical Presentation
• Asymptomatic
15-44%
• Symptomatic
•
•
•
•
•
•
•
•
•
•
•
Fatigue
Pruritus
Jaundice
Hepatomegaly
Abdominal Pain
Weight Loss
Splenomegaly
Ascending cholangitis
Hyperpigmentation
Variceal Bleeding
Ascites
75
70
30-69
34-62
16-37
10-34
30
5-28
25
2-14
2-10
Diagnosis
• Cholangiography
– either MRCP or ERCP
– multifocal strictures and dilatation usually
affects both intra and extrahepatic ducts
• Clinical,biochemical and histological
features
PSC Diagnostic Criteria
• Exclude
– HIV cholangiopathy
– Cholangiocarcinoma
– Biliary tract surgery or trauma
– Choledocholithiasis
– Congenital abnormalities
– Ischaemic cholangiopathy
– Stricturing due to TACE
PSC
• Prevalence of auto-antibodies in PSC
• P-ANCA
80%
• AMA
<2%
• ANA
50-60%
• SMA
35%
p-ANCA is not specific for PSC
• PSC
80%
• UC
75%
• AIH
80%
• PBC
30%
Cholangiography
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
Small Duct PSC
• 5% of PSC
• Normal cholangiogram but biopsy showing
PSC
• Can progress to classical PSC (12%)
• May exist with or without UC
Probability of Survival
Survival curves for patients with
small duct and large duct PSC (p<0.05)
Months since diagnosis
Björnsson E et al. Gut 2002;51:731-735
Primary Biliary Cirrhosis
PBC Epidemiology
• Female:male ratio of 9:1
• 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 2005;353(12):1261
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 preUDCA era
Balasubramaniam et al. Gastroenterology 1990;98(6):1567
PBC Symptomatic Disease
•
•
•
•
•
•
Fatigue (common)
Pruritus
Jaundice
Hepatosplenomegaly
RUQ pain
Hyperpigmentation
Koulentaki et al. Am J Gastroenterol 2006;101(3):541
• Xanthomas and
xanthelasmas
• Dyslipidemia
• Extrahepatic
autoimmune diseases
• Complications
– Portal hypertension
– Chronic cholestasis
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
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
PBC
Metabolic Bone Disease
Compression fractures
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
PBC Dyslipidemia
Xanthelasmas
Xanthomas
Xanthomas
Xanthomas
PBC Associated Diseases
• Thyroid disease
– Hashimoto’s thyroiditis
– Grave’s disease
•
•
•
•
•
•
Scleroderma
CREST syndrome
Sjogren’s syndrome
Arthritis
Raynaud’s phenomenon
Coeliac disease
• Renal tubular acidosis
– Proximal
– Distal
• Gallstones
• Haematologic disorders
• Inflammatory bowel
disease (rare)
• Pulmonary interstitial
fibrosis (rare)
PBC Non-Invasive Tests
• Biochemical tests
–
–
–
–
–
–
–
–
–
Alkaline phosphatase
γGT
5’ nucleotidase
AST and ALT
Bilirubin
Total cholesterol
Serum IgM
Prothrombin time
Albumin
Dickson et al. Hepatology 1989;10(1):1
Muratori et al. Clin Liver Dis 2008;12(2):261
Kaplan et al. N Engl J Med 2005;353(12):1261
• Serology
–
–
–
–
–
AMA (95%)
ANA (50%)
SMA (50%)
Anti-centromere
Anti-thyroid
• Medical imaging
– Ultrasound
– CT
– MR or MRCP
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
Scheuer et al. Mayo Clin Proc 1998;73(2):179
• Stage III (septal)
– Inflammation of
interlobular and septal
bile ducts
– Fibrosis
– Bile duct loss
– Cholestasis
• Stage IV (cirrhotic)
– Established cirrhosis
PBC
Pathology
Cirrhosis
NRH
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
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
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. 1994;330(19):1342
Heathcote et al. Hepatology 1994;19(5):1149
PBC
Incomplete 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 1995;22(3):759
Poupon et al. J Hepatolol 2003;39(1):12
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 2001;33(1):22
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
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
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
PBC
Summary
• Important cause of chronic cholestatic liver
disease
• Middle-aged females predominate
• Immune pathogenesis favored
• Other autoimmune diseases frequently coexist
• PBC progresses in most patients
PBC
Summary
• 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
Primary
Biliary
Cirrhosis
(PBC)
Age
Gender
Assoc’d Dx
vs.
Primary
Sclerosing
Cholangitis
(PSC)
40-60
10-30
Female
Male
RA, CREST
Scleroderma
Ulcerative Colitis
Crohn’s Disease
Sjogren’s
Primary
Biliary
Cirrhosis
(PBC)
Age
Gender
Assoc’d Dx
vs.
Primary
Sclerosing
Cholangitis
(PSC)
40-60
10-30
Female
Male
RA, CREST
Scleroderma,
Sjogren’s
Ulcerative Colitis
Crohn’s Disease
Primary
Biliary
Cirrhosis
(PBC)
Age
Gender
Assoc’d Dx
vs.
Primary
Sclerosing
Cholangitis
(PSC)
40-60
10-30
Female
Male
RA, CREST
Scleroderma,
Sjogren’s
Ulcerative Colitis
Crohn’s Disease
Primary
Biliary
Cirrhosis
(PBC)
Age
Gender
Assoc’d Dx
vs.
Primary
Sclerosing
Cholangitis
(PSC)
40-60
10-30
Female
Male
RA, CREST
Scleroderma,
Sjogren’s
Ulcerative Colitis
Crohn’s Disease
Ducts Affected Small to medium
All ducts
Primary
Biliary
Cirrhosis
(PBC)
Age
Gender
Assoc’d Dx
40-60
10-30
Female
Male
RA, CREST
Scleroderma,
Sjogren’s
Ulcerative Colitis
Crohn’s Disease
Ducts Affected Small to medium
Method of Dx
vs.
Primary
Sclerosing
Cholangitis
(PSC)
?Biopsy
All ducts
MRCP/ERCP
Mr Y
• 53 year old married man presented at GGH -end Aug 09
• Chest Pain/Abdo pain and loose stools
• Troponin negative
• Abnormal LFT’s
ALT 212
ALP 522
Bili 21
ALB 37
Amylase 33
Initial liver screen
• IgG slightly elevated
• IgM slightly elevated
•
•
•
•
Caeruloplasmin
A1AT level
Ferritin
TFT
Imaging
• USS– echogenic mass in left lobe -5x4x2cm
– Probably complex haemangioma- some doppler
flow and some other small similar lesions
By week later ALP>1000
Transferred to Liver Unit
•
•
•
•
•
•
HBsAg neg
HCV ab neg
EBV IgG pos
CMV neg
Autoantibodies neg
Tumour markers neg
• CT
– Multiple
haemangiomata
– Multiple enlarged nodes
at porta 12mm
– ? SB polyp
– RMZ consolidation
Rash on palms and soles biopsied 9/9/09- non specific
Liver biopsy arranged and done 17/9/08periductal fibrosis and biliary inflammation
• VDRL/TPHA Positive
• Commenced on penicillin
• Referred to GUM
• LFT’s completely normalised in 2 months
Suggested reading