Monday 28\2\2011
Anatomy , Physiology & Investigations
Dr Monem Alshok
Department of Clinical Medicine
The liver is the largest organ of the body, weighing 1 to 1.5 kg and representing 1.5 to 2.5 % of the lean body mass.
The liver is located in the right upper quadrant of the abdomen under the right lower rib cage against the diaphragm and projects for a variable extent into the left upper quadrant. The liver is held in place by ligamentous attachments to the diaphragm, peritoneum, great vessels, and upper gastrointestinal organs. The liver is the largest internal organ in the body and is situated in the right hypochondrium. Functionally, it is divided into right and left lobes by the middle hepatic vein. The right lobe is larger and contains the caudate and quadrate lobes. The liver is further subdivided into a total of eight segments by divisions of the right, middle and left hepatic veins. Each segment receives its own portal pedicle, permitting individual segment resection at surgery. It receives a dual blood supply; approximately 20% of the blood flow is oxygen-rich blood from the hepatic artery,and 80% is nutrient-rich blood from the portal vein arising from the stomach, intestines, pancreas, and spleen. The blood supply to the liver constitutes 25% of the resting cardiac output and is via two main vessels. The hepatic artery, which is a branch of the coeliac axis, supplies 25% of the total blood flow. Autoregulation of blood flow by the hepatic artery ensures a constant total liver blood flow. The portal vein drains most of the gastrointestinal tract and the spleen. It supplies 75% of the blood flow. The normal portal pressure is 5-8 mmHg; flow increases after meals. Both vessels enter the liver via the hilum (porta hepatis). The blood from these vessels is distributed to the segments and passes into the sinusoids via the portal tracts. Blood leaves the sinusoids, entering branches of the hepatic vein which join into three main branches before entering the inferior vena cava. The caudate lobe is an autonomous segment as it receives an independent blood supply from the portal vein and hepatic artery, and its hepatic vein drains directly into the inferior vena cava. Lymph, formed mainly in the perisinusoidal space, is collected in lymphatics which are present in the portal tracts. These small lymphatics enter larger vessels which eventually drain into the hepatic ducts.
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 reticuloendothelial system), stellate (Ito or fat-storing) cells, endothelial cells and blood vessels, bile ductular cells, and supporting structure. 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 lymphatics organized in a loose stroma 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”).
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 fenestrae of variable size, allowing the free flow of plasma but not cellular elements. The plasma is thus in direct contact with hepatocytes in the subendothelial space of Disse
: Hepatocytes have distinct polarity
The basolateral side of the hepatocyte lines the space of Disse and is richly lined with microvilli; it demonstrates endocytotic and pinocytotic activity, with passive and
active uptake of nutrients, proteins, and other molecules. 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 cells usually lie within the sinusoidal vascular space and represent the largest group of fixed macrophages in the body.
The stellate cells are located in the space of Disse but are not usually prominent unless activated, when they produce collagen and matrix. Red blood cells stay in the sinusoidal space as blood flows through the lobules, but white blood cells 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 lymphatics.
Stellate cells store retinoids in their resting state and contain the intermediate filament, desmin. When activated (to myofibroblasts) they are contractile and probably regulate sinusoidal blood flow.Endothelin and nitric oxide play a major role in modulating stellate cell contractility. Stellate cells, after activation, produce collagen types I, III and IV
Evaluation of patients with liver disease should be directed at:
(1)establishing the etiologic diagnosis, (2) estimating the disease severity (grading), and (3) establishing the disease stage (staging). Diagnosis should focus on the category of disease, such as hepatocellular, cholestatic, or mixed injury, as well as on the specific etiologic diagnosis Grading refers to assessing the severity or activity of disease—active or inactive, and mild, moderate, or severe. Staging refers to estimating the place in the course of the natural history of the disease, whether acute or chronic; early or late; precirrhotic, cirrhotic, or end-stage.
Functional unit of the liver is the acinus
This consists of parenchyma supplied by the smallest portal tracts containing portal vein radicles, hepatic arterioles and bile ductules.
The hepatocytes near this triad (zone 1) are well supplied with oxygenated blood and are more resistant to damage than the cells nearer the terminal hepatic (central) veins (zone3).The sinusoids lack a basement membrane and are loosely surrounded by specialist fenestrated endothelial cells and Kupffer cells (phagocytic cells). Sinusoids are separated by plates of liver cells (hepatocytes). The subendothelial space that lies between the sinusoids and hepatocytes is the space of Disse, which contains a matrix of basement membrane constituents and stellate cells
The biliary system
Bile canaliculi form a network between the hepatocytes. These join to form thin bile ductules near the portal tract, which in turn enter the bile ducts in the portal tracts. These then combine to form the right and left hepatic ducts that leave each liver lobe. The hepatic ducts join at the porta hepatis to form the common hepatic duct. The cystic duct connects the gall bladder to the lower end of the common hepatic duct. The gall bladder lies under the right lobe of the liver and stores and concentrates hepatic bile; it has a capacity of approximately 50 mL. The common bile duct is formed by the combination of the cystic and hepatic ducts and is approximately 8 mm in diameter, narrowing at its distal end to pass into the duodenum. The common bile duct and pancreatic duct open into the second part of the duodenum through a common channel at the ampulla of Vater.The lower end of the common bile duct contains the muscular sphincter of Oddi, which contracts rhythmically and prevents bile from entering the duodenum in the fasting state.
FUNCTIONS OF THE LIVER Protein metabolism Carbohydrate metabolism Lipid metabolism Formation of bile (Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin. ) Hormone and drug inactivation Immunological function
Immunological function of the Liver :
The reticuloendothelial system of the liver contains many immunologically active cells.
The liver acts as a sieve for the bacterial and other antigens carried to it via the portal tract from the gastrointestinal tract. These antigens are phagocytosed and degraded by Kupffer cells, which are macrophages attached to the endothelium.
Kupffer cells have specific membrane receptors for ligands and are activated by several factors, such as infection. They secrete interleukins, tumour necrosis factor (TNF), collagenase and lysosomal hydrolases.
Antigens are degraded without the production of antibody, as there is very little lymphoid tissue. They are thus prevented from reaching other antibody-producing sites in the body and thereby prevent generalized adverse immunological reactions
INVESTIGATIONS Investigative tests can be divided into
Blood tests
(a) Liver function tests: (i) serum albumin (ii) prothrombin time
(b) Liver biochemistry: (i) serum aspartate and alanine aminotransferases - reflecting hepatocellular damage (ii) serum alkaline phosphatase, ?-glutamyl transpeptidase - reflecting cholestasis (iii) total protein
(c) Viral markers
(d) Additional blood investigations; haematological, biochemical, immunological and genetic
Urine tests - for bilirubin and urobilinogen
Imaging techniques - to define gross anatomy
Liver biopsy - for histology
Useful blood tests for certain liver diseases
Test Disease
Antimitochondrial antibody Primary biliary cirrhosis
Antinuclear, smooth muscle (actin), Autoimmune hepatitis
liver/kidney microsomal antibody
High serum IG IgGAutoimmunehepatitis IgM PBC
Viral markers Hepatitis A, B, C, D andE
?-Fetoprotein Hepatocellular CA
Serum iron, transferrin saturation, serum ferritinHereditary h haemochromatosis
Serum and urinary copper, serum caeruloplasmin Wilson s dise
?1-Antitrypsin Cirrhosis (± emphysema)
Antinuclear cytoplasmic antibodies Primary sclerosing c
Genetic analysese.g. HFE gene (hereditary haemochromatosis)
LFT
Synthetic function: Albumin, PT The International Normalized Ratio (INR) is used in many countries .
Hepatic Enzyme: AST, ALT, LDH
(Aspartate aminotransferase (AST) is primarily a mitochondrial enzyme (80%; 20% in cytoplasm) and is also present in heart, muscle, kidney and brain. High levels are seen in hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure.
Alanine aminotransferase (ALT) is a cytosol enzyme, more specific to the liver so that a rise only occurs with liver disease.
Cholestatic enzymes: Alkaline Phosphatase, ?GT (inducible e.g alcohol,anticonvulsants)
Gamma-GT – 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
Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFT’s become abnormal then investigate
Markers of Cholestasis
ALP –Alkaline Phosphatase : liver and bone (placenta, kidneys, intestines or WCC)
Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its release from cell surface. Takes time for induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week. ALP isoenzymes, 5-NT( Nucleotidase ) or gamma GT may be necessary to evaluate the origin of ALP.
Albumin and Prothrombin time (INR): Useful indicators of liver synthetic function
Acute hepatitis (ALT>10xupper limit of normal seen in :
Viral
Ischaemic
Toxins
Drugs
Autoimmune
What are the PRINCIPLES in investigation of LFTs? :
2.5% of population have raised LFTs , Normal LFTs do not exclude liver disease ,Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity & Physical examination for liver disease If mild abnormalities and no risk factors or suggestion of serious liver disease , repeat LFTs after an interval (with lifestyle modification.
What is the Value of Liver Biopsy in Abnormal LFTs?
The most accurate way to grade the severity of liver disease
Aminotransferase levels correlate poorly with histological activity
Narrows the diagnostic options, if not diagnostic
Radiology:
Abdominal Ultrasound
MRCP
ERCP PTC
CT Abdomen MRI MRA , (DVI), 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)
Ultrasound in Liver Disease
Detects Fatty Liver , Increased echogenicity may not be specific for fat
Unable to detect Inflammation or cirrhosis (unless advanced) Therefore unable to discriminate between NASH and simple fatty liver or identify other types of liver disease (which may include fatty change) Liver biopsy is the only way to make an accurate diagnosis It may be worth treating fatty liver for 6 months before considering referral for biopsy
Abdominal ultrasound is useful in:
a jaundiced patient , hepatomegaly/splenomegaly ,the detection of gallstones ,focal liver disease - lesions > 1 cm ,general parenchymal liver disease ,assessing portal and hepatic vein patency ,lymph node enlargement , Colour Doppler ultrasound will demonstrate the vascularity of a lesion and the direction of blood flow in the portal and hepatic veins
Cholestatic Jaundice
Intracellular:
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Sepsis
Hepatocellular Disease
Drugs
Extracellular:
Gallstones
Cholangiocarcinoma
Biliary Stricture ( Benign/ Malignant)
Carcinoma Head of Pancreas
Enlarged Porta Hepatis.
المادة المعروضة اعلاه هي مدخل الى المحاضرة المرفوعة بواسطة استاذ(ة) المادة . وقد تبدو لك غير متكاملة . حيث يضع استاذ المادة في بعض الاحيان فقط الجزء الاول من المحاضرة من اجل الاطلاع على ما ستقوم بتحميله لاحقا . في نظام التعليم الالكتروني نوفر هذه الخدمة لكي نبقيك على اطلاع حول محتوى الملف الذي ستقوم بتحميله .