9/30/2016

Disclosures Update on Cholestatic Liver Diseases

I have no COI to disclose I shall discuss experimental therapies including limited offlabel use of drugs

Nathan M Bass, MD, PhD Professor Emeritus Department of Medicine, UCSF

Bile Formation & Function

Cholestasis “Impairment in the production of bile or its flow to the intestine.” Manifestations and Consequences:

Nutritional – impaired digestion & absorbtion of fat and fat-soluble vitamins

Two Major Roles:

Excretory Elimination of cholesterol, bilirubin, drugs, hormones, xenobiotics that are metabolized in the liver Nutritional Normal digestion and absorbtion of fat and fat-soluble vitamins (A, D, K, E)

Increase in serum of substances normally excreted in bile [bilirubin, cholesterol, bile acids, drugs] leading to jaundice, pruritus, fatigue, hypercholesterolemia, Toxic injury to liver

Elevated serum alkaline phosphatase (AlkP), γ-GT, ALT, conjugated bilirubin Progressive liver injury, fibrosis, cirrhosis

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Autoimmune Cholangiopathies

Causes of Cholestatic Liver Disease Bile duct obstruction

PBC

Acute or chronic hepatitis

Malignancy

Alcoholic hepatitis

Biliary

Acute or chronic viral hepatitis

Pancreatic

Autoimmune hepatitis

Gallstones

Cirrhosis

Benign strictures

Autoimmune cholangiopathies

Infiltrative liver disease Amyloidosis

Primary biliary cholangitis (PBC) Primary sclerosing cholangitis (PSC)

Drug-induced liver injury Chronic hepatic allograft rejection

30,000 patients in USA

F:M=9:1; middle age onset

M:F ~2:1; onset from childhood on

Microscopic intrahepatic bile ducts

Intra- and extrahepatic bile ducts

Autoantibody AMA + (95%)

ANCA, ANA

Associated autoimmune diseases

Associated inflammatory bowel disease (UC, Crohn’s)

Thyroiditis Sjögren’s (sicca) syndrome

Genetic disorders BRIC PFIC

Bacterial cholangitis

PSC

Jaundice variable onset, fluctuating

Jaundice late in course

Progression to ESLD

Progression to ESLD Portal hypertension

Cholangiocarcinoma (CCA)

Liver failure

HCC

HCC (males>>>females)

PBC & PSC Histology PBC

RUQ sx, fatigue, pruritus

CREST syndrome

Fatigue, pruritus

Sepsis Cholestasis of pregnancy

Alloimmune GVHD

Malignancy

PSC

60,000 patients in USA

Spectrum of PBC and PSC Overlaps Genetic susceptibility Environmental trigger

Autoimmune hepatitis

PBC IgG4-SC

PSC Sarcoidosis

Inflammatory Bowel Disease

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PBC Genetic predisposition plus environmental triggers (smoking, nail polish, UTI, HRT…...)

Diagnosis: Female ≥45Y, Elevated AlkP, IgM, AMA+ Not all need liver biopsy

AMA autoantibody recognizes E2 subunit of mitochondrial enzyme, PDC. Role in pathogenesis? AMA + in