Lecture 11: Tumors & Gallbladder

Three general categories of cholestasis

↑ serum concentrations of Conjugated bilirubin, Bile Acids/salts, Cholesterol

Pre-Hepatic: ↑ Unconjugated

Hepatic: ↑ Mixed

Post-Hepatic: ↑ Conjugated

Conjugated → Dark urine

Causes:

Mechanical obstruction of bile ducts: of EXTRAHEPATIC DUCTS or smaller INTRAHEPATIC DUCTS

Hepatocellular/metabolic: conjugated bilirubin, bile acids still made, but excretion by liver cells into the bile canaliculi is impaired

Acholuric jaundice

Jaundice due to unconjugated Bilirubin

Extrahepatic Obstructive (large ducts)

Adults : Gallstones in common bile duct (Choledocholithiasis), tumors (head of pancreas adenocarcinoma, cholangiocarcinoma), Primary Sclerosing Cholangitis (UC), iatrogenic bile duct strictures

Kids: Biliary Atresia, CF, Choledochal cysts (bile stasis → recurrent infections → inflammatory strictures)

Intrahepatic Obstructive (small ducts)

Adults: Hepatitis, Alcoholic cirrhosis, autoimmune (Primary Biliary Cholangitis)

Kids: Rare Alagille Syndrome (paucity of intrahepatic bile ducts)

No benefit from surgery

Hepatocellular (non-obstructive/metabolic)

Drugs (anabolic steroids, chlorpromazine); often due to inhibition of Bile Salt or Conjugated Bilirubin Export Pumps

↑ Conjugated Bili and/or ↑ Bile Acids

Sepsis, Transplant rejection

Genetic: Dubin-Johnson, Rotor syndromes

Do not benefit from surgery

Hepatocellular + Intrahepatic Obstructive

Grouped clinically as “Intrahepatic Cholestasis”

Common clinical manifestations of Cholestasis

Jaundice from ↑conjugated Bilirubin

Pruritus from ↑ Bile salts

Skin Xanthomas from ↑ Cholesterol

Clinical Complications of Cholestasis

Intestinal malabsorption of fats: Due to lack of Bile acids

Chronic cholestasis → deficiency of fat-soluble vitamins (A,D,E,K)

Secondary/Obstructive Biliary Cirrhosis: Bile acids hepatotoxic “detergents” & injure or kill hepatocytes

Chronic uncorrected obstruction incites fibrosis of the portal tracts

Ascending Cholangitis: large duct partial/intermittent obstructions ↑ risk of ascending bacterial infection

Fever, chills, abdominal pain, jaundice; often leads to Sepsis/Shock

Ascending Cholangitis

Subtotal or intermittent large duct obstruction predisposes to secondary bacterial infection

Agents: Coliforms; enterococci common

Fever & chills, RUQ abdominal pain, & Jaundice; suppurative cholangitis, septic shock

Cholestasis plus ductular reaction; stromal neutrophils; neutrophils infiltrate bile duct epithelium & lumens

Strictures (scarring) of large ducts that may lead to Secondary Sclerosing Cholangitis or Secondary Biliary Cirrhosis

Labs in Cholestasis

Hyperbilirubinemia: ↑ Conjugated Bilirubin

GGT: ↑ in biliary obstruction (more than AST & ALT)

Alkaline Phosphatase (ALP): ↑ 3-5 X in extrahepatic & usually < 3 X, for intrahepatic cholestasis

Hypercholemia: ↑ serum Bile Acids

Hyperlipidemia: ↑ Total serum Cholesterol

5’-Nucleotidase: ↑ in parallel with ALP (used like GGT to confirm liver origin of ALP)

Microscopic morphology of Cholestasis

in all causes:

Centrilobular cytoplasmic Bile pigmentation of Hepatocytes & Kupffer cells

dilated bile canaliculi with retained bile (Canalicular bile plugs)

if large extrahepatic duct obstruction also see:

Ductular Reaction: portal tract bile ductular proliferation, edema & neutrophilic inflammation

Ductular bile lakes

Cholate stasis: periportal hepatocyte feathery degeneration due to Bile Acid toxicity

Cholestasis (Zone 3, Centrilobular)

Cholestasis

Canalicular bile plugs

Large Extrahepatic Duct Cholestasis

Portal tract Ductular reaction with bile lakes

Large Extrahepatic Duct Cholestasis

Cholate stasis of periportal hepatocytes

Primary Biliary Cirrhosis

End stage Primary Biliary Cholangitis

Small duct obstruction

Autoimmune; Anti-mitochondrial Ab

Fibrosis/Cirrhosis with "Florid Duct Lesions" (Granulomas & mostly non-suppurative inflammation, destruction of ductular epithelium with focal pseudo stratification & papillary infoldings)

End-stage liver disease (ESLD) due to chronic large or small bile duct obstruction

In fibrotic stage, attempts at repair, result in ductular proliferation

Secondary Biliary Cirrhosis

Large duct obstruction

Mechanical obstruction, Fibrosis/Cirrhosis with "Ductular Reaction" (Portal tract bile ductular proliferation, edema & neutrophilic inflammation with bile lakes, reflecting external blockage)

Jigsaw Puzzle pattern of fibrosis (elongated micro nodules)

Biliary Cirrhosis (Primary or Secondary)

Neonatal Cholestasis

Jaundice in the first 24 hours or after 2 weeks should trigger a work-up for Neonatal Cholestasis (↑ Conjugated Bili)

Two types:

Obstructive

Nonobstructive/Intrahepatic affecting secretion of conjugated bilirubin

Obstructive Neonatal Cholestasis

Extrahepatic Biliary Atresia most commonly develops in first 3 months after birth by progressive obstruction of normally formed extrahepatic bile ducts → intrahepatic tree

If identified before progression proximally into the intrahepatic ducts or development of ascending cholangitis → amenable to surgical correction

Biliary Atresia is most common cause of death from liver disease in early childhood

Inflammation & strictures of Common Hepatic or Common Bile ducts

Present with ↑ Direct Bili in 6-12 range; uncorrected will develop Cirrhosis within 3-6 months; death within 2 years

Rx: If limited to extrahepatic ducts → Surgery (Hepatoportojejunostomy/Kasai Procedure)

50% progress to intrahepatic tree involvement & require Liver Transplantation to survive

Nonobstructive/Intrahepatic affecting secretion of conjugated bilirubin Neonatal Cholestasis

Infections, CF, α-1 Antitrypsin deficiency, some cases of Dubin-Johnson, Alagille Syndrome (portal tract bile duct paucity due to NOTCH mutations), Idiopathic

Non-obstructive cholestasis often shows Neonatal Hepatitis with inflammation, intracanalicular cholestasis & Giant or syncytial cells

Preeclampsia

Toxemia of pregnancy

Hypertension + Proteinuria (+/- edema) or + evidence of other organ involvement (low platelets, renal insufficiency, liver involvement, pulmonary edema, or Cerebral/visual symptoms) developing after 20 weeks gestation

Hepatic Aminotransferases >x2

Very high BP

↓ Platelets

Pulmonary edema

Renal insufficiency

HELLP syndrome

Hemolysis, Elevated Liver enzymes, Low Platelets

preceded by preeclampsia & is life threatening to mother & baby

Typically develops at 28-36 weeks of gestation, but 2nd trimester (27 weeks or less) or postpartum onset is also common (up to 7 days postpartum)

abdominal pain/tenderness in the mid-epigastrium or RUQ, nausea, vomiting, malaise

Disseminated Intravascular Coagulation (DIC), placental abruption, acute renal failure, pulmonary edema, & subcapsular or intraparenchymal liver hematoma

Preeclampsia → HELLP → DIC

Anemia, Thrombocytopenia (<100,000)

Peripheral smear – Schistocytes (Microangiopathic hemolysis)

Liver function tests – ↑ AST & ALT → 2x reference

elevated LDH (≥600 U/L) from hemolysis

Intrahepatic Cholestasis of Pregnancy

Onset, in late 2nd or early 3rd trimester, of generalized itching, often beginning in palms & soles

Hypercholemia (↑ serum Bile Acids) may be X 3 – 100 normal

Mild ↑ in Transaminases, ALP & Conjugated Bilirubin

Generally benign, but ↑ incidence of fetal distress, prematurity & stillbirth

Stillbirth mostly preventable by induced delivery at 37 weeks

Resolves postpartum

Acute Fatty Liver of Pregnancy

Mild subclinical hepatic dysfunction (↑ ALT, ↑ AST only) or rapid progression to acute liver failure & death

Present in 3rd Trimester with N&V, RUQ/epigastric pain, or symptoms of Liver failure (bleeding, jaundice, encephalopathy)

Risk factors: Fetal long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency, Preeclampsia or HELLP syndrome, multiple gestation; low BMI

Dx: Clinically by exclusion; CT may suggest fatty liver

Liver biopsy showing MICROVESICULAR STEATOSIS

Focal Nodular Hyperplasia

result from local alterations of blood flow

usually single nodule with central scar & fibrous septae with ductular reaction resembling focal cirrhosis

fibrotic septae with narrowed vessels; triads present

Most common in adult women

nodule/s in a noncirrhotic liver

Focal Nodular Hyperplasia

Central scar

Hepatic Adenoma

Solitary

women aged 20–45

RUQ or epigastric pain produced by enlargement or hemorrhage; may rupture through liver capsule & bleed, requiring emergency surgery

Risk of spontaneous rupture proportional to size (> 5 CM high risk).

Strongly associated with ORAL CONTRACEPTIVES (risk 30-40 x) or use of anabolic steroids

β-catenin mutations are considered to have a high risk of malignant transformation into Hepatocellular carcinoma

“Inflammatory” variant associated with NAFLD affecting both men & women; ↑ risk for malignant transformation

Hepatocytes with little atypia & mitotic activity

No portal tracts or central veins

No fibrosis

↑ blood levels of Alpha Fetoprotein (AFP)

Hepatocellular Carcinoma

malignant transformation of hepatocytes

Most important risk factors: HBV, HCV, Aflatoxins and Alcohol

Secondary risk factors: metabolic diseases

β-catenin activation (mutations that prevent degradation)

Precursor lesions: Dysplastic nodules

Fibrolamellar variant of Hepatocellular Carcinoma

Arises in normal livers of young adults

No association with Cirrhosis, Alcoholism or Hepatitis B/C infection

Does not produce AFP

Strongly associated with fusion gene activating Protein Kinase A

Less aggressive, but fatal if unresectable

Cholangiocarcinoma

Adenocarcinoma arising from the bile ductal epithelial cells of the biliary tree inside the liver

Klatskin Tumors: Cholangiocarcinoma that is perihilar at junction of right & left hepatic ducts with proximal common hepatic duct

Cholangiocarcinoma Risk Factors

Chronic parasitic infestation with LIVER FLUKES

Chronic inflammation of large bile ducts (PSC, stones,)

risk factors of HCC

congenital malformations of biliary tree (Choledochal Cysts, including intrahepatic only Caroli Disease), Congenital Hepatic Fibrosis (assoc. with Renal cystic diseases)

risk factors for cholesterol gallstones

Ethnic/genetic: Navajo, Pima, Hopi

Demographic: living in the West (US, Europe)

Gender: Females 2x males; oral contraceptives; pregnancy

Estrogen:

↑ liver HMG-CoA reductase activity thus ↑ cholesterol synthesis

inhibits hepatocyte Bile Salt Export Pump into the canaliculi (less bile acids)

Age: prevalence increases with age; usually affects middle age & older

Obesity, Hyperlipidemia, Rapid weight loss (post Bariatric surgery)

risk factors for Pigmented (bilirubin) stones

Hemolytic anemias: sickle cell anemia, thalassemia, malaria

Bacterial & parasitic infections ( predispose to bouts of Pyogenic Cholangitis) of biliary tree

Severe ileal dysfunction or bypass- Crohn disease

↑ spillage of bile acids into the colon carrying solubilized unconjugated bilirubin promote its absorption → ↑ re-excretion into the bile & stone formation

Complications of Gallstones

Cholecystitis - gallstones are usually involved

Choledocholithiasis - stones in biliary tree

Acute Cholecystitis

2° to obstruction of neck or cystic duct with a gallstone

Few are Acalculous; occurs in severely ill patients (Ischemia)

RUQ pain that lasts > 6 hours (< 6h = biliary colic)

Anorexia, N&V, mild fever

Murphy’s sign

CBC may see MILD leukocytosis

Best & most sensitive: Ultrasonography shows Cholelithiasis, Ultrasound Murphy’s Sign, wall thickening (> 3 mm), & pericholecystic fluid

if Dx still unclear: HIDA Scan (IV radioactive tracer → secreted into bile ducts by bile ductal cells → image biliary tree)

AST, ALT normal or mildly elevated

ALP & Bilirubin to r/o common duct obstruction

Amylase/Lipase to r/o pancreatitis

Pregnancy test if female

U/A to r/o pyelonephritis

Carcinoma of Gallbladder

Most common malignancy of extrahepatic biliary tract

Adenocarcinomas

Most important risk factor is Gallstones (more common in women, Native Americans)

Symptoms same as Cholelithiasis; most discovered incidentally at cholecystectomy & have already invaded the liver, cystic duct and spread to the liver hilar nodes.

Common driver mutations are in the EGF receptor Her-2/neu or downstream RAS pathway with loss of TP5

Acute Fatty Liver of Pregnancy

Microvesicular Steatosis

Metastasis to liver from

COLON, LUNG, BREAST, PANCREAS