on 22-Nov-2021 (Mon)

Serum biochemical tests, also commonly referred to as “liver function tests,” can be used to (1) detect the presence of liver disease, (2) distinguish among different types of liver disorders, (3) gauge the extent of known liver damage, and (4) follow the response to treatment. However, serum biochemical tests have shortcomings. They lack sensi- tivity and specificity; they can be normal in patients with serious liver disease and abnormal in patients with diseases that do not affect the liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest a general category of liver disease, such as hepatocellular or cholestatic, which then further directs the evaluation.

many tests, such as the aminotransferases and alkaline phosphatase, do not measure liver function at all. Rather, they detect liver cell damage or interference with bile flow.

Bilirubin, a breakdown product of the porphyrin ring of heme-containing proteins, is found in the blood in two fractions—conjugated and unconjugated. The uncon- jugated fraction, also termed the indirect fraction, is insoluble in water and is bound to albumin in the blood. The conjugated (direct) bilirubin fraction is water-soluble and can therefore be excreted by the kidney. Normal values of total serum bilirubin are reported between 1 and 1.5 mg/dL with 95% of a normal population falling between 0.2 and 0.9 mg/dL. If the direct-acting fraction is <5% of the total, the biliru- bin can be considered to all be indirect. The most frequently reported upper limit of normal for conjugated bilirubin is 0.3 mg/dL. Elevation of the unconjugated fraction of bilirubin is rarely due to liver disease. An isolated elevation of unconjugated bilirubin is seen primarily in hemolytic disorders and in a number of genetic conditions such as Crigler-Najjar and Gilbert’s syndromes (Chap. 45). Isolated unconjugated hyperbilirubinemia (bilirubin elevated but <5% direct) should prompt a workup for hemolysis (Fig. 330-1). In the absence of hemolysis, an isolated, unconjugated hyperbilirubinemia in an other- wise healthy patient can be attributed to Gilbert’s syndrome, and no further evaluation is required. In contrast, conjugated hyperbilirubinemia almost always implies liver or biliary tract disease. The rate-limiting step in bilirubin metab- olism is not conjugation of bilirubin, but rather the transport of conju- gated bilirubin into the bile canaliculi. Thus, elevation of the conjugated fraction may be seen in any type of liver disease including fulminant liver failure. In most liver diseases, both conjugated and unconjugated fractions of the bilirubin tend to be elevated. Except in the presence of a purely unconjugated hyperbilirubinemia, fractionation of the bilirubin is rarely helpful in determining the cause of jaundice. Although the degree of elevation of the serum bilirubin has not been critically assessed as a prognostic marker, it is important in a number of conditions. In viral hepatitis, the higher the serum bilirubin, the greater is the hepatocellular damage. Total serum bilirubin correlates with poor outcomes in alcoholic hepatitis. It is also a critical compo- nent of the Model for End-Stage Liver Disease (MELD) score, a tool used to estimate survival of patients with end-stage liver disease and assess operative risk of patients with cirrhosis. An elevated total serum bilirubin in patients with drug-induced liver disease indicates more severe injury. Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the kidney. Therefore, any bilirubin found in the urine is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease. A urine dipstick test can theoretically give the same information as fractionation of the serum bilirubin. This test is almost 100% accurate. Phenothiazines may give a false-positive reading with the Ictotest tablet. In patients recovering from jaundice, the urine biliru- bin clears prior to the serum bilirubin.

Serum enzyme tests can be grouped into two categories: (1) enzymes whose elevation in serum reflects damage to hepatocytes and (2) enzymes whose elevation in serum reflects cholestasis

The aminotransfer- ases (transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. They include aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and ery- throcytes in decreasing order of concentration. ALT is found primarily in the liver and is therefore a more specific indicator of liver injury. The aminotransferases are normally present in the serum in low concentra- tions. These enzymes are released into the blood in greater amounts when there is damage to the liver cell membrane resulting in increased permeability. Liver cell necrosis is not required for the release of the aminotransferases, and there is a poor correlation between the degree of liver cell damage and the level of the aminotransferases. Thus, the absolute elevation of the aminotransferases is of no prognostic signifi- cance in acute hepatocellular disorders. The normal range for aminotransferases varies widely among labo- ratories, but generally ranges from 10 to 40 IU/L.

The aminotransfer- ases (transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. They include aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and ery- throcytes in decreasing order of concentration. ALT is found primarily in the liver and is therefore a more specific indicator of liver injury. The aminotransferases are normally present in the serum in low concentra- tions. These enzymes are released into the blood in greater amounts when there is damage to the liver cell membrane resulting in increased permeability. Liver cell necrosis is not required for the release of the aminotransferases, and there is a poor correlation between the degree of liver cell damage and the level of the aminotransferases. Thus, the absolute elevation of the aminotransferases is of no prognostic signifi- cance in acute hepatocellular disorders. The normal range for aminotransferases varies widely among labo- ratories, but generally ranges from 10 to 40 IU/L.

The aminotransfer- ases (transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. They include aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and ery- throcytes in decreasing order of concentration. ALT is found primarily in the liver and is therefore a more specific indicator of liver injury. The aminotransferases are normally present in the serum in low concentra- tions. These enzymes are released into the blood in greater amounts when there is damage to the liver cell membrane resulting in increased permeability. Liver cell necrosis is not required for the release of the aminotransferases, and there is a poor correlation between the degree of liver cell damage and the level of the aminotransferases. Thus, the absolute elevation of the aminotransferases is of no prognostic signifi- cance in acute hepatocellular disorders. The normal range for aminotransferases varies widely among labo- ratories, but generally ranges from 10 to 40 IU/L.

Any type of liver cell injury can cause modest elevations in the serum aminotransferases. Levels of up to 300 IU/L are nonspecific and may be found in any type of liver disorder. Minimal ALT ele- vations in asymptomatic blood donors rarely indicate severe liver disease; studies have shown that fatty liver disease is the most likely explanation. Striking elevations—that is, aminotransferases >1000 IU/L—occur almost exclusively in disorders associated with exten- sive hepatocellular injury such as (1) viral hepatitis, (2) ischemic liver injury (prolonged hypotension or acute heart failure), or (3) toxin- or drug-induced liver injury. The pattern of the aminotransferase elevation can be helpful diag- nostically. In most acute hepatocellular disorders, the ALT is higher than or equal to the AST. Whereas the AST:ALT ratio is typically <1 in="" patients="" with="" chronic="" viral="" hepatitis="" and="" nonalcoholic="" fatty="" liver="" disease,="" a="" number="" of="" groups="" have="" noted="" that="" as="" cirrhosis="" develops,="" this="" ratio="" rises="" to="">1. An AST:ALT ratio >2:1 is suggestive, whereas a ratio >3:1 is highly suggestive, of alcoholic liver disease. The AST in alcoholic liver disease is rarely >300 IU/L, and the ALT is often normal. A low level of ALT in the serum is due to an alcohol-induced deficiency of pyridoxal phosphate.

The aminotransferases are usually not greatly elevated in obstruc- tive jaundice. One notable exception occurs during the acute phase of biliary obstruction caused by the passage of a gallstone into the com- mon bile duct. In this setting, the aminotransferases can briefly be in the 1000–2000 IU/L range. However, aminotransferase levels decrease quickly, and the biochemical tests rapidly evolve into those typical of cholestasis.

The activities of three enzymes— alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase (GGT)—are usually elevated in cholestasis. Alkaline phosphatase and 5′-nucleotidase are found in or near the bile canalicular membrane of hepatocytes, whereas GGT is located in the endoplasmic reticulum and in bile duct epithelial cells. Reflecting its more diffuse localization in the liver, GGT elevation in serum is less specific for cholestasis than are elevations of alkaline phosphatase or 5′-nucleotidase.

Elevation of liver-derived alkaline phosphatase is not totally specific for cholestasis, and a less than threefold elevation can be seen in almost any type of liver disease. Alkaline phosphatase elevations greater than four times normal occur primarily in patients with cholestatic liver disorders, infiltrative liver diseases such as cancer and amyloidosis, and bone conditions characterized by rapid bone turnover (e.g., Paget’s disease). In bone diseases, the elevation is due to increased amounts of the bone isoenzymes. In liver diseases, the elevation is almost always due to increased amounts of the liver isoenzyme. If an elevated serum alkaline phosphatase is the only abnormal finding in an apparently healthy person, or if the degree of elevation is higher than expected in the clinical setting, identification of the source of elevated isoenzymes is helpful (Fig. 330-1). This problem can be approached in two ways. First, and most precise, is the fractionation of the alkaline phosphatase by electrophoresis. The second, best sub- stantiated, and most available approach involves the measurement of serum 5′-nucleotidase or GGT. These enzymes are rarely elevated in conditions other than liver disease.

In the absence of jaundice or elevated aminotransferases, an elevated alkaline phosphatase of liver origin often, but not always, suggests early cholestasis and, less often, hepatic infiltration by tumor or gran- ulomata. Other conditions that cause isolated elevations of the alkaline phosphatase include Hodgkin’s disease, diabetes, hyperthyroidism, congestive heart failure, amyloidosis, and inflammatory bowel disease. The level of serum alkaline phosphatase elevation is not helpful in distinguishing between intrahepatic and extrahepatic cholestasis. There is essentially no difference among the values found in obstruc- tive jaundice due to cancer, common duct stone, sclerosing cholangitis, or bile duct stricture. Values are similarly increased in patients with intrahepatic cholestasis due to drug-induced hepatitis, primary biliary cirrhosis, rejection of transplanted livers, and, rarely, alcohol-induced steatohepatitis. Values are also greatly elevated in hepatobiliary dis- orders seen in patients with AIDS (e.g., AIDS cholangiopathy due to cytomegalovirus or cryptosporidial infection and tuberculosis with hepatic involvement).

Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage and decreased albumin synthesis. One exception is the patient with ascites in whom synthesis may be normal or even increased, but levels are low because of the increased volume of distribution. However, hypoalbuminemia is not specific for liver disease and may occur in protein malnutrition of any cause, as well as protein-losing enterop- athies, nephrotic syndrome, and chronic infections that are associated with prolonged increases in levels of serum interleukin 1 and/or tumor necrosis factor, cytokines that inhibit albumin synthesis. Serum albumin should not be measured for screening in patients in whom there is no suspicion of liver disease.

A fracture is a break in the continuity of a bone. It can be classified on the basis of aetiology, the relationship of the fracture with the external environment, the displacement of the fracture, and the pattern of the fracture.

A fracture sustained due to trauma is called a traumatic fracture*. Normal bone can withstand considerable force, and breaks only when subjected to excessive force. Most fractures seen in day-to-day practice fall into this category e.g., fractures caused by a fall, road traffic accident, fight etc.

A fracture through a bone which has been made weak by some underlying disease is called a pathological fracture. A trivial or no force may be required to cause such a fracture e.g., a fracture through a bone weakened by metastasis. Although, traumatic fractures have a predictable and generally successful outcome, pathological fractures often go into non-union.

This is a special type of fracture sustained due to chronic repetitive injury (stress) causing a break in bony trabeculae. These often present as only pain and may not be visible on X-rays.

A fracture may be displaced. The factors responsible for displacement are: (i) the fracturing force; (ii) the muscle pull on the fracture fragments; and (iii) the gravity. While describing the displacements of a fracture, conventionally, it is the displacement of the distal fragment in relation to the proximal fragment which is mentioned. The displacement can be in the form of shift, angulation or rotation

If a patient was previously eating but is unable to eat after the evening meal in preparation for a procedure the next morning, oral antihyperglycemic drugs should be omitted on the day of a procedure (surgical or diagnostic). If procedures are arranged as early in the day as possible, antihyperglycemic therapy and food intake can simply then be shifted to later in the day

Overt hyperglycemia (≥180 mg/dL [10.0 mmol/L]) in patients previously treated with oral agents who are not eating can be treated briefly with intermittent, subcutaneous doses of regular (every six hours) or rapid-acting (every four to six hours) insulin, provided the blood glucose is not severely elevated, responds well to the insulin, and the problem lasts only a day or two at most (see 'Correction insulin' above). If eating, rapid-acting insulin is preferred, administered before meals. However, a more formal and comprehensive insulin regimen, including some form of basal insulin, is usually preferred when hyperglycemia persists (algorithm 1 and algorithm 2).

Oral agents should never be administered to patients who are not eating. In addition, many oral agents have specific contraindications that may occur in hospitalized patients

Metformin is contraindicated in situations in which renal function and/or hemodynamic status is either impaired or threatened, due to the increased risk of lactic acidosis. Examples would include patients with acute cardiac or pulmonary decompensation, acute renal failure, dehydration, sepsis, urinary obstruction, or in those undergoing surgery or radiocontrast studies.

Sulfonylureas (eg, glyburide, glipizide, glimepiride) are associated with hypoglycemia that can be severe and prolonged. Although they may be continued during the hospitalization in stable patients who are expected to eat regularly, unexpected alterations in meal intake will increase the risk for hypoglycemia

On balance, sulfonylureas should usually be discontinued, at least temporarily, in the hospitalized patient. In particular, sulfonylureas should be discontinued in the patient with acute myocardial infarction (MI) because there is some concern that they may adversely affect ischemic preconditioning

Non-sulfonylurea secretagogues (meglitinides [eg, repaglinide, nateglinide]) work similarly to the sulfonylureas but have a shorter duration of action. As a result, these prandial-administered drugs may have a theoretical advantage in hospitalized patients but should also be used cautiously, including in those with acute ischemic heart disease events.

GLP-1 receptor agonists (eg, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide) may result in nausea and are also mainly effective for postprandial glucose management. As a result, their use should probably be avoided in the acute setting. They are also not usually included on most hospital formularies, in part due to high cost.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin) promote the renal excretion of glucose. They increase calorie losses, risk of dehydration and volume contraction, and genitourinary tract infections. In addition, euglycemic diabetic ketoacidosis has been reported in patients with both type 1 (during off-label use) and type 2 diabetes who were taking SGLT2 inhibitors. These drugs should therefore generally not be used in the inpatient setting

The thiazolidinediones (eg, pioglitazone, rosiglitazone) are associated with peripheral edema and should be avoided in patients with heart failure.

Insulin therapy should be continued in all patients already taking it to maintain a reasonably constant basal level of circulating insulin. Failing this, severe hyperglycemia or even ketoacidosis can occur, even in patients labeled as having type 2 diabetes but who have become significantly insulin deficient over a prolonged disease course.

In the non-acute hospital setting and when the patient is eating regularly, basal insulin (NPH or detemir twice daily or glargine, detemir, or degludec once daily [or nightly]) in combination with short- or rapid-acting prandial (bolus) insulin (regular, lispro, aspart, glulisine) is generally effective for patients receiving insulin at home or for patients with poorly regulated blood glucose previously managed with diet or oral agents (algorithm 1)

If the glucose was well managed with the outpatient insulin regimen, we typically reduce the dose by 25 to 50 percent because, in the more controlled environment of the hospital (where the amount of food consumed may be less than at home and blood glucose levels are checked regularly), patients may need considerably less insulin than they were taking in the outpatient setting

In some studies, treatment with such a basal-bolus insulin regimen was associated with better glycemic outcomes than sliding-scale insulin [23-26].

In some [25,26], but not all [23,24], trials, better glycemic management with basal-bolus versus sliding-scale insulin was associated with more hypoglycemia (glucose <70 mg/dL [3.9 mmol/L] in 23.1 and 4.7 percent of patients, respectively, and <40 mg/dL [2.2 mmol/L] in 3.8 and 0 percent, respectively).

Patients treated with U-500 regular insulin at home may continue U-500 (with a 50 percent dose reduction since glucose values often improve substantially in the hospital in patients previously requiring large doses of insulin at home, due to more restrictive hospital diets), if it is available from the hospital formulary. Because the high concentration of insulin delays absorption, the pharmacologic profile of U-500 regular insulin is most similar to that of NPH [27]. Thus, if U-500 is not available, U-100 NPH insulin twice daily should be substituted (again, with a 50 percent dose reduction).

We would also caution that errors are common with U-500 administration, and clear communication among patient, clinician, nursing staff, and pharmacy is imperative to ensure proper dosing. Although in the past U-500 insulin was dispensed using Tuberculin or U-100 syringes, a dedicated U-500 insulin syringe is available and U-500 insulin should be dispensed with the U-500 insulin syringe, if possible [28].

When food intake is diminished or stopped completely in a patient treated with insulin (eg, in preparation for surgery or other procedures), planned pre-meal rapid-acting insulin is discontinued, and the dose of intermediate- or long-acting insulin is reduced. If an episode is clearly short lived (eg, a procedure done in the early morning), subcutaneous insulin (usual dose of short acting and intermediate or long acting) and breakfast can simply be delayed until after the episode.

Insulin can be given either subcutaneously or intravenously. Algorithms for glycemic management of nonfasting and fasting patients with type 1 diabetes who are not critically ill are shown for subcutaneous dosing regimens (algorithm 1 and algorithm 2) [13].

For a patient treated with a continuous insulin infusion via a pump, the basal insulin can be continued at the usual rate, or the overnight basal rate may be reduced by 20 percent to minimize the risk of hypoglycemia the next morning. No boluses would be administered until the patient is able to eat.

Catheters may inadvertently be dislodged during transfers in the operating room or in bed, and if the patient is not alert enough to provide self-care, the health care providers should consider changing to conventional injection therapy until the patient is able to manage pump therapy again.

For a patient who usually takes 20 units of glargine every evening and short-acting insulin before each meal (dose based upon prevailing blood glucose and carbohydrate content of meal), the usual dose of glargine can be continued. An alternative approach is to reduce the dose of glargine by 20 percent (eg, give 16 units) to minimize the risk of hypoglycemia that might require oral ingestion of calories and thereby delay the planned procedure. Short-acting insulin should not be given, unless significant hyperglycemia is noted, as described above.

For a patient who usually takes 24 units of NPH and 4 units of regular insulin in the morning, one-half to two-thirds (12 to 16 units) of the usual morning dose of NPH insulin can be given (if the morning blood glucose value is not too low, ie, is at least 120 mg/dL [6.7 mmol/L]). Short- or rapid-acting insulin should not be given, except if significant hyperglycemia (>200 to 250 mg/dL [11.1 to 13.9 mmol/L]) is found in the morning. In such cases, only small doses (1 to 4 units) should be given with the goals of reducing the blood glucose level to <180 mg/dL (10 mmol/L) and avoiding hypoglycemia during the ongoing fast.

In all of these cases, blood glucose is measured every two to three hours until the meal is eaten. Small amounts of short- or rapid-acting insulin can be administered every six hours to correct hyperglycemia (ie, glucose >150 to 200 mg/dL [8.3 to 11.1 mmol/L]). Intravenous glucose (at approximately 3.75 to 5 g/hour, eg, 5 percent dextrose at 75 to 100 mL per hour) should be given to limit the metabolic changes of starvation.

For example, if the intravenous insulin infusion at steady state was set at 1 unit per hour (or 24 units per day), around 80 percent of this amount (20 units) should be added to the TPN solution by the pharmacy to be given over the course of the day. The amount of insulin can then be titrated every one to two days, based upon glucose monitoring. Since more frequent adjustments are impractical and costly, the concurrent use of rapid- or short-acting insulin as correction every six hours will help to fine-tune glycemic management.

Because of the potential for inadvertent discontinuation of insulin therapy if TPN is interrupted, some clinicians recommend giving a portion of the basal insulin as an injection (eg, 50 percent) in patients with type 1 diabetes. In the example above (patient receiving 24 units of regular insulin a day, 80 percent of this amount [19 units] added to the TPN solution), approximately 10 units of regular insulin can be added to the TPN solution and 9 units of NPH, glargine, or detemir administered as a basal injection. This approach can also be used in insulin-requiring patients with type 2 diabetes.

In patients receiving continuous enteral feeds, the total daily dose of insulin could be administered as basal insulin alone (once-daily glargine, detemir, or degludec, or twice-daily detemir or NPH). However, if the enteral feeds are unexpectedly discontinued, hypoglycemia may occur. Thus, a safer approach may be to administer approximately 50 percent of the total daily insulin dose as basal insulin and 50 percent as prandial (short- or rapid-acting) insulin, which is given every four (rapid-acting insulin) to six (short-acting insulin) hours [30].

If the enteral feeds (continuous or bolus) are unexpectedly discontinued, an intravenous 10 percent dextrose solution, providing a similar number of carbohydrate calories as was being administered via the enteral feeds, should be infused in order to prevent hypoglycemia, especially if the blood glucose concentration falls below 100 mg/dL.