Disease of the Liver & Biliary

System 4th year 2017

Sunday 4/3/2017

Dr Monem Alshok .

Liver Lectures include :

Anatomy , Physiology & Investigations

Acute Paranchymal liver diseases

Chronic Paranchymal liver diseases

Cirrhosis & portal hypertension

Immunological LD& Intrahepatic Cholestasis

Vascular LD

Pregnancy & liver

NASH & ALD

Liver tumors & focal liver lesion

Metabolic & inherited LD

Liver Transplantation

Drugs, Toxins & liver

Structure of Liver

Liver largest internal organ.( 1 - 1.5 Kg ) Hepatocytes form hepatic plates that are 1–2 cells

thick.Arranged into functional units called lobules.

Plates separated by sinusoids.More permeable than other capillaries.

Contains phagocytic Kupffer cells. Secretes bile into bile canaliculi, which are drained

by bile ducts.

Structure of Liver (continued)

Insert fig. 18.20

Liver Cells

The majority of cells in the liver are

hepatocytes, which constitute two-thirds of the

mass of the liver. The remaining cell types are

Kupffer cells (members of the RES ), stellate

(Ito or fat-storing) cells, endothelial cells and

blood vessels, bile ductular cells, and

supporting structures

Under L\M

Viewed by light microscopy, the liver appears to

be organized in lobules, with portal areas at the

periphery and central veins in the center of each

lobule. However, from a functional point of view, the

liver is organized into acini, with both hepatic

arterial and portal venous blood entering the acinus

from the portal areas (zone 1) and then flowing

through the sinusoids to the terminal hepatic veins

(zone 3); the intervening hepatocytes constituting

zone2

Portal areas of the liver

Consist of small veins, arteries, bile ducts, and lymphatic organized in a loose Struma of supporting matrix and small amounts of collagen. Blood flowing into the portal areas is distributed through the sinusoids, passing from zone 1 to zone 3 of the acinus and draining into the terminal hepatic veins (“central veins”).

Bile : Secreted bile flows in the opposite direction, in a counter current pattern from zone 2 to zone 1. The sinusoids are lined by unique endothelial cells that have prominent fenestrate of variable size, allowing the free flow of plasma but not cellular elements. The plasma is thus in direct contact with hepatocytes in the sub endothelial space of Disse

Hepatocytes have distinct polarity

The basolateral side of the hepatocyte

lines the space of Disse and is richly lined with

microvillus; it demonstrates endocytotic and

pinocytotic activity, with passive and

active uptake of nutrients, proteins, and other

molecules

Hepatocytes

The apical pole of the hepatocyte forms the

cannicular membranes through which

bile components are secreted. The canniculi of

hepatocytes form a fine network, which fuses

into the bile ductular elements near the portal

areas.

Kupffer

Kupffer cells usually lie within the sinusoidal

vascular space and represent the largest

group of fixed macrophages in the body

The stellate cells

The stellate cells are located in the space of Disse

but are not usually prominent unless activated, when

they produce collagen and matrix. RBC stay in the

sinusoidal space as blood flows through the lobules,

but WBC can migrate through or around endothelial

cells into the space of Disse and from there to portal

areas, where they can return to the circulation through

lymphatic

Liver

Location at R. Hypochondrium &Epigastric region

4 Lobes( L lobe & R lobe by falciform ligament ). The right and left hemiliver are further subdivided into 8 segments in accordance with subdivisions of the hepatic and portal veins

Left

Quadrate

Caudate

Right

Each lobe has lobules – Contains hepatocytes –Surround sinusoids – Feed into central vein

12

Glisson’s capsule: the peritoneal lining that

surrounds the liver.

Bare area: posterior surface of the liver not covered.

Coronary ligaments: reflections of peritoneum on the

posterior surface

Triangular ligaments: lateral extensions of the

coronary ligaments.

Falciform: from umbilicus to diaphragm, contains

obliterated umbilical vein.

Ligamentum teres, extends from falciform on

undersurface of liver

Ligaments of the Liver

Anatomy

• Eight segments, based on arterial and portal venous inflow.

• Segment 1 is the caudate lobe of the liver.

• Segments 2-4 are segments of the left lobe resected during left hepatic lobectomy.

• Segments 5-8 are segments of the right lobe resected during right hepatic lobectomy.

Segments

Falciform ligament does not divide right and left lobes of

liver, the portal fissure or Cantlies line is a plane passing

from the left side of the gallbladder fossa to the left side of

the IVC. It defines the physiologic division between left

and right lobes of liver . It does separate medial and lateral

segments of left lobe

A right trisegmentectomy includes a resection of the right

lobe plus segment 4.

A left lateral segmentectomy includes resection of segments

2 and 3 to the left of the falciform.

Resection of 80% of parenchyma is compatible with life.

Liver

• Dual blood supply

– Hepatic portal vein

• Direct input from

small intestine

– Hepatic artery/vein

• Direct links to heart

19

LIVER BLOOD FLOW

HEART

LIVER

STOMACH

AND

SMALL INTESTINE

HEPATIC

PORTAL

VEIN

HEPATIC

VEIN

IVCAORTA

HEPATIC

ARTERY

ARTERIES TO

DIGESTIVE TRACT

Portal vein: drains blood from the small and large

intestines, stomach, spleen, pancreas,and gallbladder.

The portal trunk divides in to 2 lobar veins, the right drains

the cystic vein, the left receives umbilical and paraumbilical

veins that enlarge to form the caput medusae. The

coronary vein: drains the distal esophagus, which also

enlarge in PHTN.

Common hepatic artery: arises from the celiac artery and becomes the proper hepatic artery after the GD branches. Passes medial to the bile duct and anterior to portal vein. Bifurcates into right and left hepatics in liver parenchyma.Can come off SMA (right) or Left gastric (left).Pringle maneuver.(In 1908, Pringle first described a technique to minimize blood loss

during hepatic surgery by clamping the vascular pedicle. [1] The inflow of blood to the liver is via the hepatic artery and portal vein. Surgeons must be able to isolate and control these sources of blood flow to control bleeding not only in traumatic injuries to the liver but also in elective hepatic resections.)

Hepatic Portal System

• Products of digestion that are absorbed

are delivered to the liver.

• Capillaries drain into the hepatic portal

vein, which carries blood to liver.

– ¾ blood is deoxygenated.

– Hepatic vein drains liver.

Enterohepatic Circulation

• Compounds that recirculate between liver and intestine.– Many compounds can

be absorbed through small intestine and enter hepatic portal blood.

– Variety of exogenous compounds are secreted by the liver into the bile ducts.

• Can excrete these compounds into the intestine with the bile.

Insert fig. 18.22

Major Categories of Liver Function

1 .Immunological & detoxification; Phagocytosis by Kupffer cells, Chemically alteration of biologically active molecules e.g. drugs & hormones , production of less toxic compounds e.g. urea, uric acids , excretion of molecules in bile ,

Detoxifies/removes Drugs &Alcohol

Liver Function

2 .Carbohydrate metabolism

3 . Lipids metabolism

4 . Proteins ( albumin , transport proteins, clotting factors )

production (Produce blood clotting factors I, II, III, V, VII, IX,

XI.)

5 . Secretion of bile : synthesis of bile salts , conjugation & excretion

of bile pigments ,Bile is (Detergent – emulsifies fats & Release

promoted by Vagus n. , CCK , Secretin) , Bile contains : (Water

Bile salts Bile pigments Electrolytes Cholesterol Lecithin)

6 . Stores { Gycolgen , Vitamins (A, D, E, K) Fe and other minerals

,Cholesterol Activates vitamin D}

7 . Fetal RBC production

Bile Production and Secretion

• The liver produces and secretes 250–1500 ml of bile/day.

• Bile pigment (bilirubin) is produced in spleen, bone marrow, and liver.

– Derivative of the heme groups (without iron) from hemoglobin.

• Free bilirubin combines with glucuronic acid and forms conjugated bilirubin. Secreted into bile.

• Converted by bacteria in intestine to urobilinogen. , Urobilogen is absorbed by intestine and enters the hepatic vein. Recycled, or filtered by kidneys and excreted in urine.

Bile Production and Secretion (continued)

• Bile acids are derivatives

of cholesterol.

– Major pathway of

cholesterol breakdown in

the body.

• Principal bile acids are:

– Cholic acid.

– Chenodeoxycholic acid.

• Combine with glycine or

taurine to form bile salts.

– Bile salts aggregate as

micelles.

• 95% of bile acids are

absorbed by ileum.

Insert fig. 18.25

Liver Function Tests

LFT( 1/3rd have abnormal LFT , only 1%

have significant LD )

Liver function tests can be divided into 3parts :

1) Markers of acute hepatocyte injury and death.

SGPT or AST, SGOT or ALT and AP

2) Measures of hepatocyte synthesis function

Prothrombin time and Albumin

3) Indicators of hepatocyte catabolic activity

e.g. Ammonia production

Liver Function Tests

Liver Enzymes

• How does the location of liver enzymes (specifically AST, ALT,

alkaline phosphatase) affect their blood levels in certain diseases?

• The locations of these enzymes are related to their functions. AST

(the enzyme formerly known as SGOT) and ALT (the enzyme

formerly known as SGPT) allow the liver to utilize amino acids for

energy by transferring an amino group from the amino acid to

alpha-ketoglutarate to form glutamate. AST and ALT are integral

enzymes of the hepatocyte, are located in the cytosol (although

some AST is found in mitochondria), and spill into blood when there

is damage to hepatocytes.

• While ALT is highly specific to the liver, remember that AST is

found in other tissues including brain, kidney, heart, muscle,

pancreas, and red blood cells and will therefore be found in blood

when there is damage to these tissues.

Liver enzymes

Alkaline phosphatase, gamma-glutamyl transpeptidase(GGT), and 5'-nucleotidase are membrane proteins located along the canalicular surface of the hepatocyte.

In the liver, alkaline phosphatase is also synthesized by bile duct epithelial lining cells. Alkaline phosphatase actually refers to a family of enzymes that catalyze hydrolysis of phosphate esters at alkaline pH. Like AST, alkaline phosphatase is nonspecific to liver, being also located in bone, placenta, kidney, and intestine.When there is blockage of bile flow, the response of the epithelial lining cells is to increase synthesis and release of alkaline phosphatase, leading to increased levels in the serum. These enzymes are released into blood when bile flow is blocked and there is bile backing up into the liver and causing cell membrane damage. Therefore, elevation of these enzymes in blood is suggestive of cholestasis.

Liver Enzymes

It is sometimes helpful to think of liver function tests in terms of pairs of enzymes, with one member of the pair (e.g. AST) being sensitive but not specific for liver processes, and the other member of the pair (e.g. ALT) usually being specific and confirming that the dysfunction is related to the liver.

Alkaline phosphatase can be thought of as paired with GGT or 5'-nucleotidase in this way (although neither of these latter two enzymes are specific to liver, they are sometimes used as confirmatory tests for hepatobiliary origin of alkaline phosphatase

AST (20% activity is cytosolic and 80% mitochondrial , Half-life 17hrs , ALT mainly Cytosolic and Half-life 47hrs )

Stellate cell • The stellate cell (Ito cell) is the principal source of

fibrosis in cirrhosis. In normal liver, stellate cells are

perisinusoidal cells distributed throughout the liver

which are important for storing the bulk of hepatic

Vitamin A. With liver injury, these cells undergo a

characteristic "activation" (by neighboring cell

paracrine cytokines and lipid aldehydes) in which they

lose vitamin A, proliferate, and become fibrogenic

How to assess the jaundiced

patient? History & Examination : with attention to history, physical

exam and diagnostic tools.

The student shall be able to describe normal bilirubinmetabolism and physiologic consequences associated with it. The student shall be able to understand the clinical classification of jaundice as unconjugated or conjugated, and discuss the various etiologies associated with each.

The student shall be able to explain all the factors necessary in evaluating the jaundiced patient, with attention to obtaining important history from the patient, looking for specific clinical signs on exam, and ordering the appropriate diagnostic laboratory tests and imaging studies.

Signs of Liver Disease

• The student should be able to know about

20 stigmata of CLD .

Caput Medusa

Gamma-GT• Located in hepatocytes and biliary epithelial cells,

pancreas, renal tubules and intestine

• Very sensitive but Non-specific

• Raised in ANY liver discease hepatocellular or

cholestatic

• Usefulness limited

• Confirm hepatic source for a raised ALP

• Alcohol & drugs

• Isolated increase does not require any further

evaluation, suggest watch and rpt 3/12 only if other

LFT’s become abnormal then investigate

ALKALINE PHOSPHATASE

AP is 3 to 4 times raised in children .

AP level doubles in PREGNANCY.

Isolated elevation of AP without marked

hyperbilirubinemia AP:Bil ratio of 1000:1 suggests

Lymphoma, Fungal infections, Sarcoidosis , TB

involvement

PROTHROMBIN TIME

Prolongation of PT in liver diseases relects decreased synthesis of Vitamin K dependent coagulation factors

2,7,9 & 10 and as such serves as a real measure of liver function

Vit. K deficiency can be distinguished from liver synthesis dysfunction by adminstration of Vit.K (10mg IM).

A 30% reduction in PT within 24 hrs should occur in Vit K. Deficiency states.

AMMONIA

• It’s a metabolite of nitrogen containing

products.

• Its metabolised to urea in liver via Krebs

cycle.

• Very high levels are seen in fulminant liver

failure,signifying poor prognosis.

Patterns of liver enzyme alteration

• Hepatic vs cholestatic

• Magnitude of enzyme alteration (ALT >10x vs minor abnormalities)

• Rate of change

• Nature of the course of the abnormality (mild fluctuation vs progressive increase)

Patterns of liver enzyme alteration

• Acute hepatitis –transaminase > 10x ULN

• Cholestatic

• Mild rise in ALT

Acute hepatitis (ALT>10xULN)

• Viral

• Ischaemic

• Toxins & drugs

• Autoimmune

• Early phase of acute obstruction& chalangitis

Cholestasis

• Isolated ALP 3rd trimester, adolescents

• Bone – exclude by raised GGT, 5-NT or isoenzymes

• May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour

• Liver USS/CT most important investigation-dilated ducts

• Ca pancreas, CBD stones, cholangioca or liver mets

Cholestasis – non-dilated ducts

Cholestatic jaundice – Drugs- Antibiotics, Nsaids, Hormones, ACEI

PBC – anti- mitochondrial Ab, M2 fraction, IgM

PSC – associated with IBD 70%, p-ANCA, MRCP and liver biopsy

Chronic liver disease

Cholangiocarcinoma – beware fluctuating levels

Primary or Metastatic cancer, lymphoma

Infiltrative – sarcoid, inflammatory-PMR, IBD

Liver biopsy often required

Investigations

Radiology:

Abdominal Ultrasound

MRCP ;ERCP PTC

CT Abdomen MRI MRA , CT – PET scan

Radionuclide Imaging

Endoscopy Upper GI endoscopy is used for the diagnosis and treatment of varices, for the detection of portal hypertensive gastropathy, and for associated lesions such as peptic ulcers. Colonoscopy may show portal hypertensive colopathy.

Endoscopic ultrasound (EUS)

Black S et al PIDJ 2002 21 810-815

Acute Pancreatitis

Black S et al PIDJ 2002 21 810-815

CMO letter March 31st 2005

* It is important that immunisation does not delay cochlear implantation

CMO letter March 31st 2005

CMO letter March 31st 2005

PET with 18F- FDG

CMO letter March 31st 2005 Liver Adenoma with sponteneous H

MMWR 2000 49 RR-9 1-38Pancreatic Ca

Whitney CG et al NEJM 2003 348 1737-1746

Moxon R International Congress and Symposium Series No 210

London Royal Society of Medicine Press Limited 1995 31-38

Black S et al PIDJ 2000 19 187-195

Whitney CG et al NEJM 2003 348 1737-1746

Black S et al. PIDJ 2000; 19: 187-195

Choo S et al PIDJ 2000; 19: 854-862

Eskola J et al. NEJM 2001; 344: 403-409

Abscess

Varices on EGD

Varix Banding

Thank you