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SURGICAL WEBSITES BREAST DISEASE LIVER ABSCESS Anatomy of liver SURGICAL WEBSITES KIDNEY SURGERY POSTGRADUATE SURGERY LINKS
BREAST DISEASE Breast cancer Breast lump Breast awareness Breast calcifications Breast cysts Breast pain Duct ectasia Fat necrosis Fibroadenoma Hyperplasia Intraductal papilloma Phyllodes tumour Sclerosing adenosis
LIVER ABSCESS Anatomy of liver Physiology of liver Method of examination of liver Haematology of liver disease. Amoebic liver abscess .Pyogenic liver abscess. Percutaneous needle aspiration of liver abscess. Case study. Result Result continued Discussion
CHOLECYSTECTOMY Introduction Historical Review Anatomy of Gallbladder Physiology of Gallbladder Physiologic effects of pneumoperitoneum Pathology of Gallbladder Investigations Pre- operative preparation of laparoscopic cholecystectomy Contraindications Treatment modalities for gallstones. Anaesthesia
INGUINAL HERNIA HOW SURGICAL OPERATION IS DONE THYROID EXAMINATION MANAGEMENT OF SEVERELY INJURED PATIENT SEPSIS AND MULTIPLE ORGAN FAILURE CHEST TRAUMA BRONCHOGENIC CARCINOMA TETANUS AND ANAEROBIC INFECTIONS
METHOD OF EXAMINATION OF LIVER METHOD OF EXAMINATION OF LIVER.
The lower edge should be determined by palpation just lateral to the right rectus muscle. This avoids mistaking the upper intersection of the rectus sheath for the liver edge.
The liver edge moves 1-3 cm downward with each inspiration. It is usually palpable in normal subjects inspiring deeply. The edge may be tender, regular or irregular, firm or soft, thickened or sharp. The lower edge may be displaced downwards by a lower diaphragm, for instance in emphysema. Movements may be particularly great in athletes or in singers. Common causes of liver palpable below umbilicus are malignant deposits, Polycystic or Hodgkin’s disease, amyloidosis, congestive cardiac failure, and grossly fatty change. Rapid change in live size may occur when congestive cardiac failure is corrected, cholestatic jaundice relieved or when fat is dispersed. The surface can be palpated in epigastrium and any irregularity or tenderness noted. An enlarged lobe in Budd-Chiari syndrome or with some cases of cirrhosis may be palpated as epigastric mass.
Pulsation of the liver, usually associated with tricuspid valvular incompetence, is felt by manual palpation with one hand over the right lower ribs posteriorly and the other anteriorly on the abdominal wall.
Fairly heavy percussion passing downward from the nipple line may determine the upper end. The lower edge is recognised by very light percussion passing upwards from the umbilicus towards the costal margin. Percussion is a valuable method for determining the liver size and is the only clinical method for determining small liver.
The anterior liver span is obtained by measuring the vertical distance between the uppermost and the lower most points of the hepatic dullness by percussion in the right mid-clavicular line. This is usually 12- 15 cm. Direct percussion is as accurate as ultrasound in estimating liver span.
Friction may be palpable and audible, usually due to recent biopsy, tumour or peri-hepatitis. The venous hum of the portal hypertension is audible between the umbilicus and the xiphisternum. An arterial murmur over the liver may indicate a primary liver cancer or acute alcoholic hepatitis.
LABORATORY INVESTIGATIONS AND LIVER FUNCTION TESTS
Most of the laboratory investigations for the diagnosis of the liver abscess are non specific. However in many underdeveloped regions where no sophisticated investigations are available, they do have some place in the diagnosis of the liver abscess. Although the liver can be affected in a wide range of disorders, the differential diagnosis of abnormal liver function tests can be substantially narrowed by a comprehensive history and physical examination and by the recognition of relatively distinct biochemical patterns of liver injury 13. Liver function tests are valuable preoperative investigations not only in liver disease but also in various other disorders 14.
The objectives of performing liver function tests are assessment of intensity and type of jaundice, estimation of damage to liver cells, assessment of synthetic and metabolic functions of liver, monitoring of drug therapy of hepatotoxic drugs, follow up of liver disorders 15.
Selection of biochemical tests
Tests are needed to detect disease, to direct the diagnostic work up, to estimate the severity to assess prognosis and to evaluate therapy. There is no magic test and it is unnecessary to use a large number of methods. The more investigations are multiplied, the greater chance there is of a biochemical deficiency being demonstrated. This type of ‘shotgun’ investigation adds to the confusion. A few simple tests of established value should be used. If an abnormality is found it may need to be confirmed by repeat estimation to show that it is real and not a laboratory error.
The severity of liver damage is assessed by serial measurement of serum total bilirubin, albumin transaminase and prothrombin time after vitamin K. The pattern of conventional test (bilirubin, enzymes) indicates which most specialist tests are likely to be valuable Imaging by ultrasonography and CT are important link in the diagnostic pathway as is liver biopsy.
The liver is central to the metabolism of protein, carbohydrate and fat as well as being important in drug metabolism. Quantitative methods of assessment of liver function using substrates for a specific hepatic pathway, including galactose, caffeine and lignocaine, have been developed to give a better measure of hepatic function rather than damage.
BILE PIGMENTS BILIRUBIN
The incidence of hyperbilirubinaemia as reported by different worker showed a wide variation. Jaundice is comparatively frequent and deep when a left lobe abscess perforates in the lesser sac. Rarely a patient with liver abscess can present as a case of obstructive jaundice. This may be due to compression of common bile duct by liver abscess. Clinical jaundice with serum bilirubin of 5 to 10 mg or more often in patients with multiple abscesses.
Jaundice in a case of liver abscess may be due to hepato cellular dysfunction or intra hepatic biliary obstruction. An enlarging abscess may compress upon or distort a large hepatic duct and produce obstructive jaundice. Compression of common bile duct or involvement of the gallbladder may be responsible in few cases. An inferior surface abscess is more likely to be associated with such complication.
On analysis of the results of liver function tests in liver abscess, it has been found by many workers, that the most frequent abnormal finding is elevation of serum alkaline phosphatase. In a large number of these cases, elevation of serum alkaline phosphatase was not accompanied by corresponding degree of jaundice. Such a disparity in the liver function test can be explained by obstruction to portions of intrahepatic biliary system, without diffuse hepatocellular damage. This situation is comparable to that produced by ligation of portions of intrahepatic biliary system in experimental animals. In these serum alkaline phosphatase was found to be elevated without corresponding elevation of serum bilirubin. While conjugated bilirubin is readily excreted by kidney and cleared from the blood, serum alkaline phosphatase accumulates in the blood and produces this disparity. The alteration in other parameters of liver function tests in relation to Bilirubin suggests a more severe disease 16.
In further attempts to study the jaundice in patients with liver abscess the following observations were made:
The survival of the chromium labelled red blood cells was normal in these patients and there was no evidence of haemolysis and increased bilirubin load.
There was significant elevation of the conjugated bilirubin fraction.
- Bilirubin UDP-glucuronyl transferase enzyme activity was normal in patients of amoebic liver abscess with or without jaundice.
- Activity of BSP-glutathione conjugating enzyme was reduced in patients with amoebic liver abscess regardless of the presence of jaundice.
BSP- excretion studies showed that the storage capacity which represents the ability of uptake and storage of BSP excretion by hepatic parenchymal cells into the biliary system was significantly reduced.
On the basis of these observations they concluded that jaundice in the liver abscess is a result of defective excretion of bilirubin by the hepatic cells into the biliary tree.
There have been other reports explaining on the basis of hepatocellular dysfunction
Role of other factors in the pathogenesis of jaundice in liver abscess:
A. Site of abscess:
An abscess near the inferior surface of the liver is more likely to distort or compress a major hepatic duct and produce jaundice.
B. Size and number of abscesses:
In case of a large abscess or multiple abscesses there is a greater destruction of the liver parenchyma and corresponding degree of impairment of the liver function. Hence the reported incidence of the jaundice is higher in the large abscesses, similarly a higher degree of jaundice in patient s having multiple abscesses.
C. Previous status of liver function:
If liver function is previously impaired by alcoholism, an episode of viral hepatitis or any other disease, the super added infection will be associated with a greater degree of jaundice.
D. Secondary infection:
Diffuse ‘toxic’ damage to the liver due to secondary infection has been described as a cause of jaundice in liver abscess.
Serum Bilirubin Estimations are based on the van den Bergh diazo reaction. A direct reaction at 10 minutes gives an estimate of the conjugated bilirubin present. The total bilirubin is determined in the presence of an accelerator such as caffeine benzoate or menthol. An approximate value for conjugated from that for total bilirubin.
These diazo reactions are subjected to error and diagnosis should not be based solely upon them. Other more accurate methods for estimation such as thin layer chromatography, high performance gas liquid chromatography and alkaline methanolysis are available but are too elaborate to be clinically useful.
Inspection of faeces is an important investigation in jaundice. Clay coloured stools indicate biliary obstruction or rarely very severe bilirubin glucuronyl-transferase deficiency.
Bilirubin cannot be detected in urine of normal subjects or patients with unconjugated hyperbilirubinemia. In cholestatic patients a small fraction of the conjugated bilirubin in plasma is dialyzable and filtered by the glomerulus, some is re-absorbed by the tubules and the remainder gives the dark colour to urine.
‘Dipsticks’ are commercially available, easy to use and give satisfactory results for the detection of conjugated bilirubin in urine.
Uses. In acute virus hepatitis bilirubin appears in urine before urobilinogen or before jaundice. In an undiagnosed febrile illness, bilirubinaemia favours the diagnosis of hepatitis.
As a screening test urinary bilirubin has some value in general practice the pre-icteric patient. It is however an insensitive test for patients with enzyme elevation alone.
UROBILINOGEN
Bacterial action converts bilirubin in the colon to a series of colourless tetrapyrroles collectively called urobilinogen. Approximately 20% is absorbed and undergoes an enteric circulation with re-excretion into bile by liver. A small proportion is excreted in the urine. Urinary urobilinogen has been used in evaluation of liver problems. In complete bile duct obstruction where no bilirubin enters the intestine urinary urobilinogen may be absent. However measurement of this substance in the urine has been superseded by more sensitive serum tests as well as imaging, which may give a more direct path to diagnosis. As with urinary bilirubin measurements, spot urinary urobilinogen is a poor predictor of hepatic disease with a high proportion of false negative results.
Indocyanine green
This dye is removed from circulation by the liver. It is not conjugated and there is no extra- hepatic removal of entero-hepatic circulation. It is safer, more expansive and more specific than BPS. It is used for liver blood flow studies.
Serum enzyme tests
These tests will usually indicate the type of liver injury, whether hepato-cellular or cholestatic, but cannot be expected to differentiate one from the hepatitis from another to determine whether cholestasis is intra or extra hepatic. They are valuable in directing the choice of a specific serological test, imaging or liver biopsy to reach the diagnosis. Only a few tests are necessary and the combination of serum aspartate transaminase (AST formerly SGOT) and alkaline phosphatase (with occasionally serum alanine transaminase, formerly SGPT) is adequate.
Alkaline phosphatase
Hepatic function tests in liver abscess exhibit an unusual pattern consisting of elevation of the serum alkaline phosphatase and retention of bromsulphthalein associated with normal bilirubin levels and normal tests of hepatocellular function. Liver abscess exhibit a consistent pattern of elevated serum alkaline phosphatase without a corresponding elevation of serum bilirubin 17.
The level of alkaline phosphatase rises in cholestasis and to a lesser extent when liver cells are damaged. The mechanisms of the increase are complex. Synthesis of the alkaline phosphatase by the hepatocyte is increased and this depends on intact protein and RNA synthesis. Secretion into the serum may rise through leakage from the canaliculus into the sinusoids because of leaky tight junctions. Increased release of phosphatase into sinusoids from the hepatocyte plasma membrane may contribute.
Serum hepatic alkaline phosphatase may be distinguished from bony phosphatase by fractionation into iso-enzymes, but this is not routinely carried out. Arise in g-glutamyl transpeptidase confirms the likely source of alkaline phosphatase as being hepato biliary. Raised levels are sometimes observed with primary or secondary tumours, even without jaundice or involvement of bone. Increased values without a rise in serum bilirubin are also found other space occupying lesions or infiltration, such as amyloid, abscess, leukemia or granulomas. Non-specific mild elevations are seen in a variety of conditions including Hogkin’s disease and heart failure. The cause is presumably focal, intra-hepatic bile duct obstruction caused by these lesions.
Gamma glutamyl transpeptidase (g-GT)
Serum values are increased in cholestasis and hepato-cellular disease. Levels parallel serum alkaline phosphatase in cholestasis and may be used to confirm that a raised serum phosphatase is of hepato-biliary origin. Levels are increased with hepatic metastasis, not consistently but more so than for alkaline phosphatase.
As isolated rise in serum g-GT is seen in patients with alcohol abuse, even without liver disease, perhaps because of microsomal enzyme induction. More often there is steatosis. In fibrosis, cirrhosis and hepatitis due to alcohol, other liver enzymes are elevated in conjunction with g-GT.
Other factors may influence the level. Disorders include hepato-biliary disease, alcoholism and concomitant drug administration for instance with barbiturates or phenytoin. Screening g-GT may have led to more alcohol abusers being identified although in a third of such individuals the serum g-GT does not rise. The finding of increased levels, however often leads to over investigation of an elevated level in an innocent person who has never had taken alcohol or a social drinker who has never abused alcohol.
Amino transferases
Serum Glutamic oxaloacetic transaminase (SGOT, aspartate transaminase) is a mitochondrial enzyme present in large quantities in heart, liver, skeletal muscle and kidney and the serum level increases in when ever these tissues are acutely destroyed, presumably due to release from damaged cells.
Serum Glutamic pyruvic transaminase (SGPT, alanine transaminase) is a cytosolic enzyme also present in liver. Although the absolute amount is less than SGOT, a greater proportion is present in liver compared with heart and skeletal muscles. A serum increase is therefore more specific for liver damage than SGOT.
A mild rise in SGOT and SGPT, although non specific may be an aid in the diagnosis of the liver abscess in conjunction with the clinical and other laboratory findings. However many workers have found hepatic transaminases to be usually with in normal limits. In liver abscess there is significant elevation of SGOT with a slight to moderate elevation of SGPT.
Transaminase determinations are useful in the early diagnosis of viral hepatitis. Measurements must be made early, for normal values may be reached within a week of onset. The patient may develop fatal acute hepatic necrosis in spite of falling transaminase values. Serial estimations are essential.
Very high levels may be seen in the early stages of acute cholestasis particularly choledocholithiasis and with circulatory failure.
Routine screening may show unexpectedly raised aminotransferase levels. These are also due to obesity, diabetes mellitus, alcohol abuse, hepatic drug reaction or circulatory failure. Rarer causes include a1-antitrypsin deficiency and haemochromatosis. Liver biopsy is usually necessary to make the diagnosis. However, it should be delayed if the patient is asymptomatic and the increase in transaminase is modest. The value should be monitored.
Results vary in cirrhosis, and are particularly high in chronic active hepatitis. Very high levels are unusual in alcoholic liver disease. A high ratio of SGOT to SGPT (greater than two) may be useful in diagnosing alcoholic hepatitis and cirrhosis. This is due not only to hepatocyte damage but also to pyridoxal 5 phosphatase (vitamin B6) deficiency.
Other serum enzymes
LACTIC ACID DEHYDROGENASE
This enzyme was found to be significantly elevated in most of cases. The elevated levels return to normal with in a month following complete cure of the disease. Thus LDH enzyme determination is a useful index for cure of invasive hepatic amoebiasis.
Lactic dehydrogenase (LDH) is relatively insensitive index of hepato-cellular injury, but marked increases are found in patients with neoplasm especially with hepatic involvement.
CHOLINESTERASE
Cholinesterase is a non-specific esterase synthesised by liver. Significant depression of serum cholinesterase in liver abscess has been reported, also decreases in hepato-cellular disease, especially cirrhosis, reflect diminished synthesis and also poor nutrition. In malnutrition, the serum levels parallel that in liver. Decreases may be useful in detecting hepatotoxicity due to chemicals.
QUANTITATIVE ASSESSMENT OF THE HEPATIC FUNCTION
Chronic liver diseases pass through a long period of minimum non specific symptoms (‘compensated’) until the final stage of ascites, jaundice, encephalopathy and pre-coma (‘decompensated’). Serum albumin and prothrombin time give some indication of the synthetic function of the liver, but this is usually maintained until late disease. Serial estimates of quantitative liver function in the early stages would be helpful both in monitoring treatment and in prognosis but are of no value in diagnosis. Such tests however suffer from the draw back of their complexity.
Expression of platelet-derived growth factor and its receptor is found in liver of patients with chronic liver disease. Platelet-derived growth factor contributes to liver fibrosis in chronic liver disease. The B-chain of platelet-derived growth factor is released mainly by macrophages involved in inflammatory reactions. This cytokine probably acts on myofibroblast-like mesenchymal cells, and may be implicated in liver fibrosis in chronic liver disease 18.
Galactose elimination capacity
Galactose is pharmacologically safe and can be injected intravenously in a dose sufficient to saturate the enzyme system responsible for its elimination. The rate-limiting step is the initial phosphorylation by galactokinase. Account must be taken of the substantial fraction of the dose eliminated extrahepatically. This test seems to reflect hepato-cellular function fairly accurately but requires multiple determinations over a 2-hour period.
Breath tests
Aminopyrine is metabolised (N-demethylated) by cytochrome P450 (microsomal) system to carbon dioxide. It has many of the characteristics of an ideal breath test substance for the measurement of hepatic function. The aminopyrine is labelled with 14C and given by mouth. Samples of 14CO2 are collected from the breath for intervals of 2 hours. The expired 14CO2 correlates with the rate of disappearance of radioactivity from the plasma. The tests reflect the residual functional microsomal mass and viable hepatic tissue. Results in cirrhotic rats suggest that reduced N-demethylation be due to loss of liver cell volume. 14C-caffeine and phenacetin have been used as breath test substances. The 14C-galactose breath test measures cytosolic function. All breath tests are complex and costly. They are unlikely to achieve general popularity.
Salivary caffeine clearance
Caffeine (1,3,7 trimethylxanthine) is metabolised exclusively by N-demethylation in the hepatic microsomal enzymes system (cytochrome P448). The methylxanthines are excreted in urine. Serum and salivary caffeine levels can be assayed simply using an enzyme multiplied immuno-assay technique. Overnight caffeine clearance in saliva correlates with the serum clearance in saliva correlates well with serum clearance and also with aminopyrine breath tests. Salivary caffeine clearance is a simple method to measure hepatic functional impairment.
Lignocaine metabolite formation
Lignocaine is metabolised by oxidative N-demethylation by cytochrome P450 system. Monoethylglycinexylidide (MEGX) is formed and correlates with the rate of lignocaine clearance. Serum MEGX can be measured easily and the concentration 15 minutes after intravenous injection of lignocaine gives a quantitative assessment of liver function. In children, MEGX formation decreases with increased severity of liver disease. MEGX formation in donors correlates with graft survival in recipients following liver transplantation. MEGX formation showed a stepwise decline corresponding to worsened liver disease 19.
Bromsulphthalein test
This test is of particular value in assessing liver dysfunction in the absence of Jaundice. Bromsulphthalein (BSP) is infused at two different rates and the plasma BSP level is estimated at intervals, later. The subsequent calculations allow the measurement of two independent processes of BSP in the liver and its active secretion in the bile The intravenous bromsulphathlein disappearance technique allowed an estimate of the storage capacity of the hepatocytes (S) and the excretory function (Tm) and is measured in mg/min.
In liver abscess, there is retention of bromsulphthalein and a lowering of its transport maximum (without alteration of storage or conjugation of the dye) due to an excretory defect following intrahepatic cholestasis. High BSP retention was found in liver abscess.
LIPID AND PROTEIN METABOLISM
LIPIDS
Several types of lipid are carried in plasma in relatively large amounts-cholesterol and cholesterol esters, phospholipids and triglycerides. Cholesterol is found in cell membranes and is a precursor of bile acids and steroid hormones. It is synthesised in the liver, small intestine and in other tissues. Synthesis takes place mainly from acetyl CoA in the microsomal fraction and in cytosol. Hepatic synthesis is inhibited by cholesterol feeding and by fasting and is increased by biliary fistula and bile duct ligation and also by an intestinal lymph fistula. Esterification is carried out in plasma by the enzyme lecithin cholesterol acryl transferase (LCAT) which is synthesised in liver.
Triglycerides are simpler compounds than phospholipids. They have a backbone of glycerol, the hydroxyl group of which have been esterified with fatty acids. Naturally occurring triglycerides contain a variety of fatty acids. Naturally occurring triglycerides contain a variety of fatty acids; they act as a store of energy and also a method of transport of energy from the gut and liver to peripheral tissues.
LIPOPROTEINS
Cholesterol, phospholipids and triglycerides are insoluble in water and would not exist in plasma in free solution. Three major groups of lipoproteins are involved in lipid transport. One migrates in electrical field with a1-globulins (high-density lipoprotein-HDL) and another with b-globulin (low-density lipoprotein-LDL). A third fraction, very low-density lipoprotein (VLDL), is also recognised. It is rich in triglycerides and is synthesised by liver. The fourth type of lipoprotein is the chylomicron, which is a large triglyceride rich particle originating from the gut and appearing in the plasma after the ingestion of a fatty meal. The chemical and the physical difference between the various lipoproteins are due partly to their differing lipid composition and partly to variation in their protein. The liver removes LDL and VLDL remnants. The fate of HDL is uncertain.
A number of different protein sub-units are present in plasma lipoproteins; in their delipidated form they are called apoproteins. Apoprotein Apo A-1 activates plasma LCAT; apoprotein Apo C-11 activates lipoprotein lipase.
Changes in liver disease
The increase in total serum cholesterol in cholestasis is not simply to the retention of cholesterol normally excreted in the bile. The mechanism is uncertain. Four factors have been implicated: regurgitation of biliary cholesterol into the circulation; increased hepatic synthesis of cholesterol into the circulation; increased hepatic synthesis of cholesterol; reduced plasma LCAT activity; and regurgitation of biliary lecithin, which produces a shift of cholesterol from pre-existing tissue cholesterol into the plasma.
Where as slight increase to 1.5-2 times normal are sometimes seen in acute cholestasis, very high values are found in chronic conditions, very high values are found in chronic conditions, especially postoperative stricture and primary biliary stricture. Values of over five times the upper limit of normal are associated with skin xanthomas. Malnutrition lowers the serum cholesterol so that the values may be normally in carcinomatous biliary obstruction. Increased values are seen during recovery from viral hepatitis, in fatty liver and in some patients with gallstones.
In cirrhosis total serum cholesterol values are usually normal. Low results indicate malnutrition or decompensation.
In hepato-cellular disease and in obstructive jaundice the plasma triglycerides tend to be increased, the excess being found in the LDL fraction. In both conditions the percentage of cholesterol ester is decreased due to LCAT deficiency related to impaired formation and, in obstructive jaundice, due to marked increase in cholesterol. Lipoprotein electrophoresis shows absence of pre-b and a wide, deeply staining b band.
In cholestasis an abnormal lipoprotein, lipoprotein X, is very rich in free cholesterol and lecithin, is found which appears on electron microscopy as bilamellar discs.
Bile acids
Bile acids are synthesised only in the liver, 250-500mg being produced and lost in the faeces daily. Synthesis is under negative feedback control. The primary bile acids, cholic acid and chenodeoxycholic acid, are formed by cholesterol. Synthesis is controlled by amount of bile acid returning to the liver in the entero-hepatic circulation. On contact with colonic bacteria the primary bile acids undergo 7a-dehydroxilation with production of secondary bile acids, deoxycholic acid and a very little lithocholic acid. Tertiary bile acids, largely ursodeoxycholic acid, in human bile the amount of the trihydroxy acid (cholic acid) roughly equals the sum of the two dihydroxy acids (chenodeoxycholic and deoxycholic acids).
The bile acids are conjugated in the liver with amino acids glycine or turine. This prevents absorption in biliary tree and small intestine but permits conservation by absorption in the terminal ileum. Sulphation and glucuronidation (as detoxifying mechanism) may be increased with cirrhosis or cholestasis when these conjugates are found in excess bile salts to bile acids and glycine or turine.
Bile salts are excreted into the biliary canaliculus against an enormous concentration gradient between liver and bile. They are intimately concerned with the digestion and absorption of lipids. When the terminal ileum and proximal colon are reached, absorption takes place by an active transport process found only in the ileum. Oral administration of ursodeoxycholic acid interferes with the small intestinal absorption of both chenodeoxycholic and cholic acid.
The absorbed bile salts enter portal venous system and reach the liver where they are taken up with great avidity by hepatocytes. This depends upon a sodium coupled co-transport system using the sodium gradient across the sinusoidal membrane as a driving force. Chloride ions may be involved. The most hydrophobic bile salts (unconjugated and dihydroxy bile acids) probably enter the hepatocytes by simple diffusion (‘flip-flop’) across the lipid membrane.
The mechanism of the bile acid passage across the liver cells form sinusoid to bile canaliculus is controversial. Cytosolic bile acid binding protein, for example 3-a-hydroxy steroid dehydrogenase, are involved. The role of microtubules is uncertain. Vesicles seem to play a role but only at higher bile acids concentrations. The bile acids are reconjugated and re-excreted into bile. Lithocholic acids are not excreted 20.
The entero-hepatic circulation of bile salts takes place 2-15 times daily. Because the absorption efficiency varies among the individual bile acids they have different synthesis and fractional turnover rates.
In cholestasis bile acids are excreted in the urine by active transport and passive diffusion. They tend to be sulphated and these conjugates are actively secreted by the renal tubules.
Changes in disease
Bile salts increase the biliary excretion of water, lecithin, cholesterol and conjugated bilirubin. Ursodeoxycholic acid produces a much larger choleresis than chenodeoxycholic acid or colic acid.
Altered biliary excretion with defective biliary micelle formation is important in pathogenesis of gallstones. It also leads to steatorrhoea of cholestasis.
Bile salts form a micellar solution with cholesterol and phospholipid and this way help to emulsify dietary fat and also play a part in mucosal phase of absorption. Diminished secretion leads to steatorrhoea. They assist pancreatic lipolysis. They release gastrointestinal hormones.
Disordered intra-hepatic metabolism of bile salts may be important in pathogenesis of cholestasis. They may have a role in the causation of the pruritus of cholestasis.
Serum bile acids
Gas-liquid chromatography allows individual bile acids to be distinguished. Enzymatic assays are based on the use of bacterial 3-hydrosteroid dehydrogenase. The use of bio-luminance assay, capable of detecting bile salts in the picomole range, has improved the sensitivity of the enzymztic technique up to that of radio-immunoassay.
The serum concentration of total bile acids reflects the extent to which bile acids reabsorbed from the intestine have escaped extraction of first passage through the liver. The value reflects the instantaneous balance between intestinal absorption and hepatic uptake. Intestinal load is more important than hepatic extraction in regulating peripheral serum bile acids levels.
Raised levels of serum bile acids are specific for hepato-biliary disease. Sensitivity of serum bile acid estimation is less than originally thought for detecting hepato-cellular damage in viral hepatitis or chronic liver disease. Estimations of individual bile acids are not diagnostic. In cholestasis the ratio of serum trihydroxy to dihydroxy acid increases. Patient with hepato-cellular failure usually have a low ratio, the main bile acid being chenodeoxycholic acid. This is due to reduction in activity of the 12a-hydroxylase enzyme in the hepatocytes.
Amino acid conjugation is preserved even with severe hepatocyte damage.
Amino acid metabolism
Amino acids are derived from the diet and from tissue break down reach the liver for metabolism. Some are transaminated and some are deaminated to keto-acids, which are then metabolised by many pathways including the TCA cycle. Others are metabolised to ammonia and urea. The maximal rate of urea synthesis in chronic liver disease is markedly reduced. However, experimentally, at least 85% of liver must be removed before this mechanism fails significantly and before blood and urinary amino acid levels increase. A low blood urea concentration is a rare accompaniment of fulminant liver failure. A rise in blood ammonia level also represents a failure of the Kerb’s cycle and this increase has been related to hepatic encephalopathy.
Clinical significance
A generalised or selective aminoaciduria is a feature of hepato-cellular disease. In patients with severe liver disease the usual picture is an increase in the plasma concentration of one or both of the aromatic amino acids tyrosine and phenylalanine, together with methionine, and a reduction in branched chain amino acid valine, leucine and isoleucine. The changes are explained by impaired hepatic function, portal systemic shunting of blood and hyperinsulinaemia and hyperglucagonaemia. Patients with minimal liver disease also show changes, particularly a reduction in plasma proline.
PLASMA PROTEINS
It is interesting to note that there is nearly uniform hypoalbuminaemia, which occurs in the patients with symptoms of a few weeks duration only. There is a fall of serum albumin and rise in certain globulin fractions. Reduction in serum albumin is due to multiple factors. Alper attributed this fall to the negative acute phase reactant property of the albumin. According to him a low albumin level with an elevated gamma globulin would indicate the presence of an abscess of appreciable dimensions and necessitate evacuation of the pus. In fact presence of raised levels of gamma globulins during amoebic dysentery would be evidence of hepatic involvement due to intestinal amoebiasis. After treatment serum protein levels return gradually to normal. Serum immunoglobulins have been studied in patients with amoebic liver abscess. IgE levels are found to be slightly elevated.
The plasma proteins produced by hepatocytes are synthesised on polyribosomes bound to rough endoplasmic reticulum, from which they are discharged into the plasma. Fall in concentration usually reflect decreased hepatic synthesis.
The hepatocyte makes albumin, fibrinogen, a1-antitrypsin, hepatoglobulin, caeruloplasmin, transferrin and prothrombin. Some liver produced proteins are acute phase reactors and rise in response to tissue injury such as inflammation. However, very high values are virtually confined to primary liver cancer. In a hepatitis B positive patient, rising values are of particular significance as an indicator of the development of hepato cellular carcinoma. Alpha-fetoprotein mRNA in peripheral blood is used as a marker of circulating micrometastases from hepatocellular carcinoma, especially in the context of surgical treatment of hepatocellular carcinoma 21.
Electrophoretic pattern of the serum protein
Electrophoresis is used to determine the proportions of the various serum proteins. The a1globulins contains glycoproteins and hormone binding globulins. They tend to be low in hepatocellular disease, falling in parallel with the serum albumin. An increase accompanies acute febrile illness and malignant disease. 90% of a1-globulins consist of a1-antitrypsin and an absent a1-globulin may indicate a1-antitrypsin deficiency. The a2-and b-globulins includes lipoproteins. In cholestasis the increase in a2 and b-globulin component correlates with the height of serum lipids. This pattern may be useful in distinguishing biliary from non biliary cirrhosis. High lipoproteins components strongly support biliary aetiology.
The g-globulins rise in hepatic cirrhosis due to increases. The increased cells in plasma cells in marrow, and in the liver itself, may be the source.
IgG is markedly increased in chronic active hepatitis.
IgM markedly increases in primary biliary cirrhosis and to a lesser extent in viral hepatitis and cirrhosis.
IgA is markedly increased in cirrhosis of liver in alcoholics.
In chronic active hepatitis and in cryptogenic cirrhosis IgG, IgM and to a lesser extent IgA increases.
About 10% of patients with chronic cholestasis due to large bile duct obstruction show increase in all three main immunoglobulins.
PROSTAGLANDINS:
Prostaglandins have been used the diagnosis of liver disease and transplant problems 22.
Washington, DC Registry
Last modified: Monday, 29-Nov-2004 06:39:07 EST |
