Biliary Disorders Will Gelson Consultant Hepatologist Addenbrookes Hospital

Biliary Disorders Will Gelson Consultant Hepatologist Addenbrooke’s Hospital April 2020

Anatomy and physiology Stones Neoplasia and cysts Biliary Diseases https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Biliary Anatomy https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Biliary Anatomy https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Biliary Physiology • Liver produces 500 -1500 m. L of bile/day • Major physiologic role of biliary tract and GB is to concentrate bile and conduct it in welltimed aliquots to the intestine • In the intestine: – Bile acids participate in normal fat digestion – Cholesterol and other endogenous/exogenous compounds in bile excreted in faeces • Also has an excretory role https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Biliary Physiology • Complex fluid secreted by hepatocytes • 97% water, 0. 7% bile salts, 0. 2% bilirubin, 0. 51% fats (cholesterol, fatty acids, and lecithin) • Passes through hepatic bile ducts into common hepatic duct • Tonic contraction of sphincter of Oddi during fasting diverts ~1/2 of bile through the cystic duct into the GB – stored and concentrated. https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Biliary Physiology • CCK – released after food ingestion – GB contracts, sphincter of Oddi relaxes – Allows delivery of timed bolus of bile into intestine. • Bile acids – detergent molecules – Bile acids solubilize dietary fat and promote its digestion and absorption • Enterohepatic circulation: – Bile acids efficiently reabsorbed by SI mucosa (terminal ileum) recycled to liver for re-excretion https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts AF 78 y o man https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Stone Disease • Gallstones (cholelithiasis): – 20 -35% by age 75 – 2 types: • Cholesterol (75%) • Pigment – Calcium bilirubinate and other calcium salts • Bile duct stones (choledocholithiasis) – 15% of patients with GS have CBD stones – Usually secondary https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Predisposing Factors • Factors that increase biliary cholesterol saturation: – – – Oestrogens Multiparity OCPs Obesity Rapid weight loss Terminal ileal disease (decreases bile acid pool) • Factors that increase bile stasis: – – – Bile duct strictures Parenteral hyperalimentation Fasting Choledochal cysts Pregnancy – (GB hypomotility) https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Clinical Manifestations Asymptomatic • 60 -80% patients with gallstones in US – Over 20 -year period: • 18% of these develop biliary pain • 3% require cholecystectomy https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Clinical Manifestations https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Clinical Manifestations Both • Pain/colic • Infection • Obstruction https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Clinical Manifestations Gallbladder • Pain/colic • Infection – Acute cholecystitis • Perforation • Sepsis • Empyema – Chronic cholecystitis • Obstruction https: //easternliver. net – Mucocoel

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Clinical Manifestations Bile duct • Pain/colic • Infection – Acute cholangitis • Sepsis – Chronic • Obstruction – Jaundice – Pancreatitis https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Clinical Manifestations Mirizzi’s Syndrome • Causes all of the above (except pancreatitis) https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Radiological Diagnosis • AXR/CT (15 -20% radio-opaque) https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Radiological Diagnosis • Ultrasound scan (transabdominal/EUS) https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Radiological Diagnosis • MRCP https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Treatment Gallstones • For symptomatic stones, ultimate treatment is cholecystectomy • In the face of complications the situation is usually temporized (antibiotics and occasionally percutaneous drainage) https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Treatment Bile duct stones • ERCP and stone removal before prophylactic cholecystectomy is the most common approach • Antibiotics often required to temporise the situation • Stents sometimes required for temporisation or palliative measure • Large stones can now be blasted using Spyglass and lithotripsy • Some surgical units favour on table biliary clearance at the time of cholecystectomy https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts FR 61 y o male https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Pancreatic Lesions • Pancreatic adenocarcinoma • Workup includes CT and EUS guided tissue diagnosis • Treatment includes: – Biliary decompression – Curative intent: operative and chemotherapy – Palliative care https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Pancreatic Lesions • Other solid pancreatic lesions – Secondary deposits – Lymphoma – Neuroendocrine tumours https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Pancreatic Cystic Lesions https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Biliary Malignancies Cholangiocarcinoma https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Benign Biliary Lesions • • Choledochal cysts Biliary cystadenomas Biliary adenomas Gallbladder polyps https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Benign Strictures Post-inflammatory Ischaemic • Pancreatitis • Post radiation Bile duct injury at • Stones surgery • Cholangitis • Cholecystectomy • AIDS cholangiopathy • Choledochotomy • Biliary parasites • Gastrectomy • Autoimmune/Ig. G 4 Hepatic resection • Primary sclerosing cholangitis • (PSC) • Transplantation https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts PSC and PBC https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Primary Biliary Cholangitis (PBC) • Chronic disease of liver with autoimmune destruction of intrahepatic bile ducts and cholestasis • Insidious onset – Often detected by chance finding of ALP • Women aged 40 -60 • Disease is progressive and complicated by: – Steatorrhea, xanthomas, xanthelasma, osteoporosis, osteomalacia, and portal hypertension • Associated with Sjögren’s syndrome, scleroderma, hypothyroidism, and celiac disease https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts PBC: Clinical Findings Asymptomatic with normal blood tests Asymptomatic with cholestatic blood tests Itch/fatigue Extrahepatic manifestations Portal hypertension Jaundice/chronic liver failure https: //easternliver. net Inflammatory conditions

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Laboratory findings in PBC • Signs of cholestasis – Alk. Phos, cholesterol (HDL), later bilirubin • Anti-mitochondrial Antibodies (95%) – Directed against PDH in mitochondria • Serum Ig. M • Newer Abs: – gp 120, sp 100, anti-centromere https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Treatment of PBC • Ursodeoxycholic Acid – Preferred medical treatment – slows progression, improves long-term survival, ↓risk of esophageal varices • Symptomatic Treatment – Cholestyramine or Colestipol - for pruritis • Can aggravate steatorrha leading to vitamin A, D, K deficiency – Rifampin inconsistently beneficial – Opiod antagonists • Naloxone, naltrexone – show promise for treating pruritis – 5 -HT 3 antagonists • Ondansetron – Calcium supplementation • Helps prevent osteomalcia • Liver transplant – Treatment of choice for advanced disease https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Options for non-responders • Off-licence – Fenofibrate – Budesonide • Licensed – Obeticholic acid (OCA) • Experimental – Novartis • LJN 452: FXR agonist – Cyma. Bay • MBX-8025: PPARδ agonist – Genfit • ELAFIBRINOR: PPARαδ • MOA: choleresis

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Prognosis of PBC • Without transplant, survival = 7 -10 years once symptoms develop • Adverse prognostic indicators: – – – – Older age High serum bilirubin Non-response to urso Oedema Low serum albumin Prolonged PT Variceal hemorrhage • The Mayo risk score • UK PBC risk score (BIL 12, ALT 12, ALP 12, alb, plt) https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Primary Sclerosing Cholangitis (PSC) • Uncommon disease characterized by diffuse inflammation of biliary tract leading to fibrosis and strictures of biliary system. • Most common in men age 20 -40 and closely associated with ulcerative colitis (present in ~2/3 of pts with PSC) – Only 1 -4% of patients with UC develop PSC. – Like UC, smoking is associated with a ↓risk of PSC • Associated with HLA-B 8 and DR 3 or DR 4 • p. ANCA (70%), with fluorescent staining characteristics and target antigens distinct from those in Wegener’s • Large duct PSC is usually progressive, leading to cirrhosis, portal hypertension, and liver failure (median 13 yrs to death, cholangiocarcinoma or liver transplantation) • Small duct PSC has a much better prognosis https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Symptoms and Signs • Progressive obstructive jaundice – Frequently associated with malaise, pruritus, anorexia, and indigestion • Complications of chronic cholestasis – Osteoporosis – Malabsorption of fat soluble vitamins • Ultimately portal hypertension then liver failure https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Laboratory Diagnosis of PSC • ALP or GGT – MC abnormality • Serum transaminases can be normal or • serum bilirubin – in advanced PSC • Hepatic synthetic tests (albumin, PT, etc) – abnormal in advanced PSC • p-ANCAs – in 60 -82% of patients with PSC. (Frequency in UC is similar. ) https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Imaging Diagnosis of PSC • Cholangiography (MRCP/ERCP) – Irregularly distributed, multifocal strictures and dilatations of the intrahepatic and extrahepatic bile ducts = beading https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Treatment of PSC • No effective medical therapies exist – Antibiotics • Episodes of acute bacterial cholangitis – Ursodeoxycholic acid (UDCA) • improves symptoms and LFTs in adult patients with PSC. • ERCP – Balloon dilation of localized strictures. Repeated procedures improves survival. – If major stricture – short term stent relieves symptoms and improves LFTs • Liver transplantation https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Prognosis of PSC • 13 years to death, cholangioca or liver transplantation with large duct PSC • Adverse prognostic markers: – – – Older age Higher serum bilirubin, AST, ALP Lower albumin levels History of variceal bleeding Large duct disease • Complications: – Cholangiocarcinoma (10 -15%) of adults with PSC – GB cancer – Colon CA/dysplasia • In patients with ulcerative colitis, PSC is independent risk factor • Strict adherence to colonoscopic surveillance programme advised https: //easternliver. net

Anatomy and physiology Stones Neoplasia and cysts Inflammatory conditions Questions and “Wiki” • william. gelson@addenbrookes. nhs. uk • Hepatology “wiki” • Power point files https: //easternliver. net