ANAESTHESIA AND LIVER DISEASE: UNDERSTANDING BLOOD RESULTS

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1 Vet Times The website for the veterinary profession ANAESTHESIA AND LIVER DISEASE: UNDERSTANDING BLOOD RESULTS Author : Marieke De Vries Categories : Vets Date : September 26, 2011 Marieke De Vries discusses the interpretation of abnormalities in biochemistry that may be found during routine pre-anaesthetic blood work-up on dogs and cats in the first of a two-part article Summary To minimise morbidity and mortality associated with general anaesthesia, and to identify higher risk patients, routine pre-anaesthetic haematology and biochemistry blood tests are often performed. Especially in elderly patients and in patients with, for example, endocrinologic diseases it is not uncommon to find raised liver enzymes. When are these elevations reason for concern? Raised enzymes are not necessarily indicative of liver function impairment. Liver function may be better evaluated by measuring albumin, total proteins, bile acids, bilirubin and ammonia concentrations. Blood results should always be interpreted in conjunction with a thoroughly taken history and clinical examination. Key words anaesthesia, liver enzymes, liver disease, risk THE liver plays a central and essential role in many metabolic processes, metabolism of drugs and xenobiotics, storage of vitamins, glycogen and fat, and in immunoregulation. Because of its enormous reserve capacity, clinical signs of liver insults occur only after 1 / 8

2 substantial damage. Compensated liver disease may be asymptomatic or accompanied by relatively non-specific signs, such as reduced appetite, anorexia, weight loss, depression, vomiting and polyuria/ polydipsia (PU/PD). More specific signs are jaundice ( Figure 1 ), coagulopathies, ascites and central nervous system signs (hepatoencephalopathy). Generally, it is routine practice to perform blood tests before general anaesthesia is undertaken, especially in elderly patients. But when are blood results really abnormal and when should you start to worry? Reference ranges for individual parameters are determined by sampling a number of animals within a population and calculating mean and standard deviation for each parameter. The reference range is derived from two standard deviations at either side of the mean that is 95 per cent of animals within a population are included within this reference range. This means that five per cent (1: 20) of healthy animals are expected to have a value outside the reference interval, and may, therefore, display an abnormal result. The interpretation of abnormal enzyme activity, clinical relevance and the risk-predictive value for general anaesthesia is, therefore, not straightforward and should not be used as a substitute for a thoroughly taken history and physical examination of the patient ( Figure 2 ). Liver enzymes can be divided into two groups: hepatocellular/ leakage enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and biliary/cholestatic enzymes (alkaline phosphatase [AP] and gamma glutamyl transferase [?GT]). Liver disease may result in abnormal values for these enzymes, although increased levels may also be seen with other clinical conditions and with certain drug therapy. Increased liver enzyme levels are, therefore, not pathognomonic for liver disease and single enzyme determinations should never be used as prognostic indicators. Better indicators of hepatic function are total proteins, albumin, bile acids, bilirubin and ammonia concentrations. In cases of hepatic dysfunction, abnormal values may also be found for urea, cholesterol and glucose. Biochemistry ALT is a cytosolic enzyme and leaks into the vascular space during hepatocellular damage. It is considered to be liver-specific though small amounts can be found in erythrocytes, heart and skeletal muscle. Mild elevations are considered non-specific for hepatocellular injury, but moderate 2 / 8

3 to severe elevations are cause for concern and should prompt immediate further work-up. Following hepatocellular injury, serum levels fall slowly, due to increased production by regenerating hepatocytes and altered intrahepatic architecture; serum half-life in dogs is twoand a- half days. A reduction of 50 per cent every three to four days with a return to normal by two to three weeks can be expected and is a good prognostic sign. In cats, the half-life is shorter and the reference range lower; relatively small increases are always significant in this species. End-stage liver disease may result only in small increases or even normal values since there are few hepatocytes to leak from. Mild increases may be seen in hyperthyroid cats, hypothyroid dogs, in patients with Cushing s disease ( Figure 3 ) and dental disease and during phenobarbital therapy. AST is located within the mitochondria rather than in the cytosol, therefore, increased AST levels tend to reflect more serious hepatic damage. This enzyme is not specific to the liver and is also found in high concentrations within muscle and red blood cells. Mild increases may be seen with glucocorticosteroid and phenobarbital therapy and in hyperthyroid cats. AP is not a leakage enzyme and, therefore, does not correlate with hepatocellular damage. AP is found in cells lining bile canaliculi and increases may be seen with impaired bile flow. Isoenzymes of AP are present in the liver, kidneys, intestine, bone and placenta. Due to their short half-life, the placental (with exception in late-term feline pregnancy), intestinal and renal isoenzymes do not contribute to serum AP measurements. Animals with a high bone turnover (young growing patients, and patients suffering from osteosarcoma or major trauma) will have increased levels. Species-specific differences exist, for instance, two liver co-enzymes occur in dogs. Elevations in AP in canine patients may not only be related to biliary disease, but also to increased levels of glucocorticosteroids (endogenous/exogenous) and, for instance, phenobarbital treatment. Measurement of the activity of this isoenzyme to diagnose (steroid) induced hepatopathy is not useful as an increase may also be seen with many primary hepatobiliary diseases, and in disease states including diabetes mellitus, hypothyroidism and acute pancreatitis, and in patients on anticonvulsant therapy. In cats, elevations in AP are more specific for hepatobiliary disease as it is not susceptible to drug induction and, as for ALT, small elevations are more significant than in dogs.?gt is also non-specific for liver disease, although in cats it is more sensitive for liver impairment than in dogs. Increased levels may be found with cholestasis in parallel with AP. The cells containing this enzyme are found lower down the biliary tree and are less affected by primary hepatocellular damage; an increase is more specific for cholestasis. Mild increases (two to three 3 / 8

4 times) may be seen in canine patients receiving glucocorticosteroid or anticonvulsant treatment. Bilirubin is formed in the reticuloendothelial cell system by the enzymatic processing of haem. In cases of hepatic disease, concentrations may be increased, due to abnormal uptake, conjugation and/or release by the liver. Obstruction of the biliary tree will result in marked elevations. Mild increases (up to 30µmol/L) may be seen in cats with normal to mildly elevated liver enzymes following periods of prolonged anorexia, gut stasis or intraabdominal inflammation. This may be due to a temporary stasis in the bile canaliculi and will resolve when the underlying cause is treated. Jaundice may persist long after liver function returns to normal, as a proportion of the conjugated bilirubin may irreversibly bind to albumin (known as delta-bilirubin), which is not excreted by the kidneys or taken up by hepatocytes. It will only be removed from the circulation when the albumin, to which it is bound, is broken down. Due to its long half-life, albumin remains in the circulation and extravascular tissues for an extensive time; the finding of jaundice without bilirubinuria may, therefore, be an indicator of improved hepatic function. Albumin, total proteins and globulins The liver is the major production site of proteins such as albumin, and clotting factors. Decreased hepatic function may result in low total protein and albumin concentrations, but as the liver has an enormous reserve capacity, normal albumin and protein levels may still be seen with the liver working at 25 per cent to 33 per cent of its maximal capacity. Because of its long half-life (eight days in dogs and cats), hypoalbuminaemia is a hallmark of chronic liver dysfunction. Many drugs are transported in blood bound to proteins, classified as: high more than 85 per cent; moderate 50 per cent to 85 per cent; and low less than 50 per cent bound. This affinity of drugs for plasma proteins is species-dependent. Theoretically, low concentrations of proteins may result in an increased, free fraction of highly protein-bound drugs. As it is this unbound fraction of the drug that is active, this could result in increased (side) effects. However, the clinical significance is of little or no importance in veterinary patients. 4 / 8

5 Most highly protein-bound drugs, given at doses resulting in clinically appropriate concentrations, may only occupy 10 per cent of the available protein sites. Therefore, changes in plasma protein concentrations that occur with disease are unlikely to impinge on total binding capacity of plasma proteins for drugs. Transient and usually small increases in free-drug concentrations are offset by redistribution and increased rate of metabolism and excretion that occurs with most drugs. New equilibrium conditions are reached very quickly. The disease state (impaired liver function) is far more likely to influence the clearance of the drug from the system, and to be of clinical significance, than is the change in plasma proteinbinding capacity. Albumin contributes 80 per cent of plasma oncotic pressure, and is generally recommended to treat patients with an albumin concentration of 15g/L or less before commencing anaesthesia. Levels below 20g/L have been positively correlated with increased morbidity and mortality in human patients. Anaesthesia will result in haemodilution, especially when intravenous fluids are administered, which will reduce albumin concentration even more. If low albumin and low oncotic pressure are of concern, colloids, (fresh) frozen plasma or (human) albumin may be administered. Almost all clotting factors are produced by the liver, with the exception of factor VIII and von Willebrand factor (vwf), but especially vitamin K-dependent factors II, VII, IX and X may be affected. If liver impairment is suspected, it is important to check the patient s coagulation profile, especially if procedures with an increased risk of bleeding are going to be undertaken (liver biopsies, nasal biopsies or invasive surgery). Generally, coagulation disorders are seen when the concentration of plasma coagulation factors is decreased to between 30 per cent and 35 per cent of normal. Clotting function can be assessed by measuring clotting times prothrombin time (PT) and activated partial thromboplastin time (aptt), although these may be poor predictors of the patient s tendency to bleed. In acute liver disease, both PT and aptt may be prolonged; in chronic liver disease states PT may be normal. In humans, PT may especially be prognostically useful in evaluating hepatocellular function and is the most powerful predictor of intraoperative and postoperative bleeding. Coagulation times of more than oneand a-quarter to one-and-a-half times normal are reason for concern and should be addressed. Globulins are commonly increased in liver disease, due to inflammation, acute phase responses and decreased clearance of antigen by Kupffer s cells, resulting in a systemic immune response. In chronic, severe liver disease globulines may be decreased due to reduced synthesis. Bile acids 5 / 8

6 Bile acids are metabolites of cholesterol degradation and are formed and conjugated in the liver and secreted in the bile. They are highly conserved: approximately 90 per cent to 95 per cent are reabsorbed from the intestines and returned via the portal vein to the liver to be reutilised. Approximately 75 per cent to 95 per cent of the bile acids are extracted by the liver during their first pass, and small concentrations may be detectable in healthy cats and dogs serum. A small increase in concentration after ingestion of a meal may be expected, with the peak concentration approximately two hours after food intake. When hepatic function is significantly impaired, extraction of bile acids from portal blood by the liver becomes less efficient and both pre and postprandial concentrations increase. An increased total serum bile acid concentration can be seen in patients with hepatic parenchymal disease (reduced uptake/ excretion by hepatocytes), cholestasis and shunts (disruption of enterohepatic cycle). In patients with portosystemic shunts, preprandial concentration may only be slightly increased, while postprandial concentrations are often severely raised. Paradoxical results may be seen in patients in which the gallbladder contracts without food intake. Transiently increased levels (up to 40µmol/L to 50µmol/L) may be seen 24 hours following seizuring. Increased levels may also be seen with secondary reactive hepatopathies (up to 40ìmol/L), with Cushing s syndrome and gastrointestinal disease. Ammonia Ammonia is derived 25 per cent directly from portal blood, the remainder comes from the catabolism of proteins, peptides and aminoacids. After uptake by hepatocytes, it is either converted to urea or used in the synthesis of glutamine. The urea cycle in the liver normally operates at only 60 per cent of its capacity, hence hepatic failure must be fairly advanced before increased concentrations in ammonia will be seen. However, shunting portal blood away from the liver results in ammonia directly derived from the gastrointestinal tract entering the systemic circulation, with hyperammonaemia as a result. Increased levels may be used as an indicator for the presence of hepatoencephalopathy, although concentrations within the normal range do not exclude the condition. Urea Urea is formed by the liver out of ammonia. Low levels may be seen in cases of liver failure and portosystemic shunts, and may be exacerbated by PU/PD. Cholesterol 6 / 8

7 Cholesterol is not a very useful marker in liver disease because it may be increased, decreased or normal depending on the type of condition and dietary intake. Cholesterol may be increased in cases of biliary obstruction, hypothyroidism, hyperadrenocorticism, steroid therapy, diabetes mellitus, postpandrial, pancreatitis and hyperlipidaemia. Decreased levels may be seen with portosystemic shunts and cirrhosis. Glucose The liver is the major production site for glucose, and hypoglycaemia may occur in patients with severe liver disease. Glucose measurement is prudent in animals with (suspected) portosystemic shunts, especially in young patients of toy breeds that already have an increased susceptibility to hypoglycaemia. Glucose levels below 3.5mmol/L should be treated with glucose supplement either intravenously or orally. The glucose concentration for peripheral intravenous administration should not be higher than 10 per cent to avoid thrombophlebitis. Secondary hepatic disease/reactive hepatopathy As already mentioned, increased liver enzyme levels may also be the result of primary non-hepatic disease processes. Examples are severe anaemia and heart failure (resulting in hypoxia), gastrointestinal disease, pancreatic disease, endocrine conditions (hypo and hyperadrenocorticism, hypo and hyperthyroidism, diabetes mellitus), bacterial infections, shock and septicaemia. In conclusion Increased liver enzymes are not necessarily indicative of hepatic dysfunction, and values outside normal reference ranges should be interpreted in conjunction with a thoroughly taken history and well-performed clinical examination. Increased concentrations may also be the result of primary non-hepatic disease conditions and drug therapy. Better indicators of potential hepatic dysfunction may be abnormal values found for albumin, total proteins, bile acids, bilirubin and ammonia. In part two, the effects of anaesthesia on the liver will be discussed, together with drug-induced liver diseases, and anaesthesia for liver diseaserelated procedures. References Charles J A (2007). An update on serum bile acids, Proceedings of the WSAVA, Sydney, Australia accessed March 14, / 8

8 Powered by TCPDF ( Elliott J (2007). Displacement of plasma protein-bound drugs: are there significant interactions? Veterinary Times 37 (26): Steiner J M (2006). Which diagnostic test to use for liver disease? NAVC Proceedings, accessed March 14, Webster C R L (2005). History, clinical signs, and physical findings in hepatobiliary disease. In Ettinger S J and Feldman E C (eds), Textbook of Veterinary Internal Medicine. Diseases of the dog and cat (sixth edn), 225: 1,422-1, / 8