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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

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CHOLESTASIS

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  1. CHOLESTASIS Dr Allister Grant Consultant Hepatologist 7.2.12

  2. 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.

  3. 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

  4. -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

  5. Investigation of Cholestasis Raised ALP CheckGT if isolated rise Consider MRCP ERCP Other imaging Dilated bile ducts 1) Stop alcohol 2) Stop hepatotoxic drugs 3) Advise weight loss if BMI>25 4) Recheck LFT’s after an interval Non-dilated bile ducts Diagnosis made- Treat disease Non diagnostic Ix- consider Liver biopsy Ultrasound + Full liver screen Persistently raised ALP

  6. 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.

  7. Drug Induced Cholestasis • Intrahepatic Hepatocellular Cholestasis • Intrahepatic Cholangiocellular Cholestasis • Ductopenic • Granulomatous • AllopurinolAntithyroid agents AugmentinAzathioprineBarbituratesCaptoprilCarbamezepineChlorpromazineChlorpropamideClindamycin ClofibrateDiltiazem Erythromycin Flucloxacillin Isoniazid LisinoprilMethyltestosterone Oral contraceptives (containing estrogens)Oral hypoglycemics PhenytoinTrimethoprim-sulfamethoxazole

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

  9. 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

  10. Mr S • 2000 Inverness- Recurrent cholangitis, short attacks • Ciprofloxacin (PRN at home) • 2003 Seen in Hemel Hempstead- cholangitis, ERCP’s • Severe post –ERCP pancreatitis

  11. 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

  12. 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

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

  14. Mr S • What next?

  15. Mr S • USS- CBD stone, IHD’s mildly dilated Thickened ducts • MRCP

  16. Mr S

  17. Mr S

  18. Mr S • What next?

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

  20. Mr S

  21. Mr S

  22. Mr S • Post ERCP ALP >1000 • Gradually settled • URSO increased to 500mg tds (65kg) • Started rotating ABx

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

  24. Primary Sclerosing Cholangitis

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

  26. 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

  27. Survival in PSC Compared to Olmsted County 1.0 0 Control population Survival PSC (no transplant) 0 5 10 15 20 Follow up (Years) Bamba K et al Gastro 2003

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

  29. 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

  30. Recurrence of PSC Post Transplant Alexander J et al Liver transplantation 2008

  31. 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

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

  33. PSC Diagnostic Criteria • Exclude • HIV cholangiopathy • Cholangiocarcinoma • Biliary tract surgery or trauma • Choledocholithiasis • Congenital abnormalities • Ischaemic cholangiopathy • Stricturing due to TACE

  34. PSC • Prevalence of auto-antibodies in PSC • P-ANCA 80% • AMA <2% • ANA 50-60% • SMA 35%

  35. p-ANCA is not specific for PSC • PSC 80% • UC 75% • AIH 80% • PBC 30%

  36. Cholangiography

  37. 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

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

  39. Survival curves for patients with small duct and large duct PSC (p<0.05) Probability of Survival Months since diagnosis Björnsson E et al. Gut 2002;51:731-735

  40. Primary Biliary Cirrhosis

  41. 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

  42. 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

  43. Fatigue (common) Pruritus Jaundice Hepatosplenomegaly RUQ pain Hyperpigmentation Xanthomas and xanthelasmas Dyslipidemia Extrahepatic autoimmune diseases Complications Portal hypertension Chronic cholestasis PBC Symptomatic Disease Koulentaki et al. Am J Gastroenterol 2006;101(3):541

  44. 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 Complications

  45. 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

  46. PBCMetabolic Bone Disease Compression fractures

  47. 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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