Post on 01-Feb-2016
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CHOLESTASIS
Dr Allister GrantConsultant 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
Dilated bile ducts
Non-dilated bile ducts
Ultrasound +Full liver screen
Raised ALP
Check GT if isolated rise
1) Stop alcohol
2) Stop hepatotoxic drugs
3) Advise weight loss if BMI>25
4) Recheck LFT’s after an interval
Persistently raised ALP
ConsiderMRCPERCP
Other imaging
Diagnosis made-Treat disease
Non diagnostic Ix-consider
Liver biopsy
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., Budd–Chiari 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.
Drug Induced Cholestasis• Intrahepatic Hepatocellular Cholestasis
• Intrahepatic Cholangiocellular Cholestasis
• Ductopenic
• Granulomatous
• AllopurinolAntithyroid agentsAugmentinAzathioprineBarbituratesCaptoprilCarbamezepineChlorpromazineChlorpropamideClindamycinClofibrateDiltiazemErythromycin FlucloxacillinIsoniazidLisinoprilMethyltestosteroneOral contraceptives (containing estrogens)Oral hypoglycemics PhenytoinTrimethoprim-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
• 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 odUDCA 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
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
0
Sur
viva
l
0 5 10 15 20 Follow up (Years)
PSC (no transplant)
Control population
Bamba K et al Gastro 2003
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 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
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
Survival curves for patients with small duct and large duct PSC (p<0.05)
Björnsson E et al. Gut 2002;51:731-735
Months since diagnosis
Prob
abili
ty o
f Sur
viva
l
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 pre-UDCA era
Balasubramaniam et al. Gastroenterology 1990;98(6):1567
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 2006;101(3):541
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
PBCMetabolic 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
• Serology– AMA (95%)– ANA (50%)– SMA (50%)– Anti-centromere– Anti-thyroid
• Medical imaging– Ultrasound– CT – MR or MRCP
Dickson et al. Hepatology 1989;10(1):1Muratori et al. Clin Liver Dis 2008;12(2):261Kaplan et al. N Engl J Med 2005;353(12):1261
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 1998;73(2):179
PBCPathology
NRH
Cirrhosis
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):1342Heathcote et al. Hepatology 1994;19(5):1149
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 1995;22(3):759Poupon 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
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
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
PrimaryBiliary
Cirrhosis(PBC)
PrimarySclerosingCholangitis
(PSC)vs.
Age
Gender
Assoc’d Dx
40-60
FemaleRA, CREST
Scleroderma
Sjogren’s
10-30
MaleUlcerative ColitisCrohn’s Disease
PrimaryBiliary
Cirrhosis(PBC)
PrimarySclerosingCholangitis
(PSC)vs.
Age
Gender
Assoc’d Dx
40-60
FemaleRA, CREST
Scleroderma, Sjogren’s
10-30
MaleUlcerative ColitisCrohn’s Disease
PrimaryBiliary
Cirrhosis(PBC)
PrimarySclerosingCholangitis
(PSC)vs.
Age
Gender
Assoc’d Dx
40-60
FemaleRA, CREST
Scleroderma, Sjogren’s
10-30
MaleUlcerative ColitisCrohn’s Disease
PrimaryBiliary
Cirrhosis(PBC)
PrimarySclerosingCholangitis
(PSC)vs.
Age
Gender
Assoc’d Dx
Ducts Affected
40-60
FemaleRA, CREST
Scleroderma, Sjogren’s
Small to medium
10-30
MaleUlcerative ColitisCrohn’s Disease
All ducts
PrimaryBiliary
Cirrhosis(PBC)
PrimarySclerosingCholangitis
(PSC)vs.
Age
Gender
Assoc’d Dx
Ducts Affected
Method of Dx
40-60
FemaleRA, CREST
Scleroderma, Sjogren’s
Small to medium
?Biopsy
10-30
MaleUlcerative ColitisCrohn’s Disease
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’sALT 212ALP 522Bili 21ALB 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>1000Transferred to Liver Unit
• 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
Rash on palms and soles biopsied 9/9/09- non specific
Liver biopsy arranged and done 17/9/08-
periductal fibrosis and biliary inflammation
Rash on palms and soles biopsied 9/9/09- non specific
Liver biopsy arranged and done 17/9/08-
periductal fibrosis and biliary inflammation
• VDRL/TPHA Positive
• Commenced on penicillin
• Referred to GUM
• LFT’s completely normalised in 2 months
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