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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