Articles on Medical Diseases and Conditions

Blog

  • Reye’s Syndrome

    Reye’s syndrome usually begins a few days after onset of a viral illness, most often one of the influenza viruses or varicella. The disease predominantly affects children and young adolescents, with a peak incidence between ages 5 and 15 years. Onset of the disease is manifested by symptoms of encephalitis (e.g., confusion, lethargy, or aggressive behavior), without focal neurologic signs, that accompany or follow onset of protracted or recurrent vomiting. Temperature is usually normal. There is laboratory evidence of liver cell injury, with AST or ALT more than 3 times the upper limit of the reference range, with some patients exceeding 20 or even 25 times the upper limit. Serum total bilirubin is usually normal, and clinical jaundice is rare. Nevertheless, the PT is usually elevated, and blood ammonia level is frequently elevated. Routine CSF test results are usually normal. Creatine phosphokinase level is markedly abnormal, and phosphorus level is decreased, indicating muscle involvement. Fatty liver is frequently found on biopsy or autopsy. Although exact etiology is not known, influenza A and B, especially B, have been associated with the majority of cases, with chickenpox next most frequent and other viruses also implicated on occasion. There is also very strong association with aspirin use during a viral infection.

    Conditions that may simulate Reye’s syndrome and that can be ruled out by assay of serum levels or other tests include salicylate or acetaminophen overdose, valproic acid toxicity, encephalitis from other causes (e.g., herpes simplex virus) with superimposed creatine phosphokinase elevation due to intramuscular injection, denatured alcohol poisoning, and acute lead poisoning. Certain rare inborn errors of metabolism (e.g., deficiency of ornithine transcarbamylase) may be manifested by symptoms that suggest Reye’s syndrome.

  • Congenital Hyperbilirubinemias

    There are five major groups of inherited defects in bilirubin metabolism: Gilbert’s syndrome, Crigler-Najjar syndrome (type I), Arias syndrome (Crigler-Najjar syndrome type II), Dubin-Johnson syndrome, and Rotor syndrome.

    Gilbert’s syndrome. Gilbert’s syndrome is a congenital partial defect in unconjugated bilirubin clearance due to decreased function of the enzyme bilirubin uridine diphosphate-glucuronate glucuronyl transferase (UDP-GT). Males are affected 1.5-7.3 times more than females. In one study 27%-55% of the siblings of persons with Gilbert’s disease also had mild features of the syndrome. The disorder clinically consists entirely of elevated total bilirubin level, usually less than 3 mg/100 ml (4 mg in some reports) (SI 51.3-68.4 µmol/L). Ninety percent or more of the bilirubin is nonconjugated. The bilirubin level can fluctuate, with about 25% of patients having values within reference range at some time. Patients may or may not have mild jaundice. Liver function tests or liver biopsy does not show significant abnormality. The problem is differentiating the benign bilirubin level elevation of Gilbert’s syndrome from more serious conditions such as a hemolytic process or active liver disease.

    There is no really satisfactory diagnostic test at present. Some physicians follow the patient for only 12-18 months and feel that persistent nonconjugated hyperbilirubinemia without development of other abnormal liver function tests is diagnostic of Gilbert’s syndrome. The other method being used (to some extent) is bilirubin response to caloric deprivation. If caloric intake is restricted to 400 calories for 24 hours, persons with Gilbert’s syndrome usually have a rise in total bilirubin greater than 0.8 mg/100 ml (13.7 µmol/L), whereas non-Gilbert’s syndrome patients have increases less than this. However, 8%-13% of Gilbert’s syndrome patients do not have increases greater than 0.8 mg. Most investigators agree there is considerable overlap between Gilbert’s and non-Gilbert’s syndrome persons both in baseline bilirubin and in response to provocative tests such as fasting or caloric restriction.

    Crigler-Najjar syndrome (type I). In Crigler-Najjar syndrome type I, the unconjugated bilirubin is increased due to absence of the liver cell microsomal enzyme bilirubin UDP-GT, which adds glucuronide to unconjugated bilirubin to form bilirubin monoglucuronide. Newborns and infants display marked hyperbilirubinemia with jaundice, and death may occur. There is autosomal recessive inheritance. The jaundice does not respond to phenobarbital therapy.

    Arias syndrome (Crigler-Najjar type II). In Arias syndrome (Crigler-Najjar type II), the unconjugated bilirubin level is increased, but the defect is still somewhat uncertain. The usual stated etiology is partial defect of liver cell microsomal enzyme UDP-GT, but others believe it may be due to a deficiency in hepatic cell wall transglucuronide enzyme. Patients have moderate hyperbilirubinemia (6-20 mg/100 ml), and the jaundice responds well to phenobarbital therapy.

    Dubin-Johnson syndrome. In Dubin-Johnson syndrome, both conjugated and unconjugated bilirubin levels are increased, with conjugated type predominating, due to a defect in transport of bilirubin from the liver cells to the bile ducts. Hyperbilirubinemia is usually mild, and jaundice may be precipitated by other illness or by pregnancy. Inheritance is autosomal recessive. Serum BSP excretion levels are normal 45 minutes after injection but characteristically become elevated 90-120 minutes after injection. Serum bile acid levels are normal. The gallbladder usually does not visualize on oral cholecystography.

    Urine coproporphyrin analysis may be helpful for diagnosis. Normally, urine coproporphyrin is predominantly (about two-thirds) type III. In Dubin-Johnson syndrome, the predominant isomer in urine becomes type I, even though total urinary coproporphyrin excretion levels are frequently normal. Some (not all) asymptomatic carriers may also have predominantly type I.

    Rotor syndrome. Rotor syndrome is associated with an increase in conjugated bilirubin levels due to defect in liver cell excretion of bilirubin. Inheritance is autosomal recessive. There usually is mild hyperbilirubinemia; jaundice may be induced by other illness. Liver uptake and storage of BSP is decreased (BSP retention in serum at 45 minutes after injection is increased), and serum bile acid levels are increased.

  • Comments on Selection of Liver Function Tests

    A few comments on the use of liver function tests are indicated. It is not necessary to order every test available and keep repeating them all, even those that give essentially the same information. For example, the ALT is sometimes useful in addition to the AST either to establish the origin of an increased AST value (because ALT is more specific for liver disease) or to obtain the AST/ALT ratio when this ratio might be helpful. However, once the results are available, it is rarely necessary to repeat the ALT because it ordinarily does not provide additional assistance to the AST in following the course of the patient’s illness, nor will repetition add much additional useful information to assist diagnosis. The same is true of an elevated ALP level and the use of ALP test substitutes that are more specific for liver disease (gamma glutamyl transferase [GGT]; 5-nucleotidase [5-NT];). Whichever additional enzyme of this group is used, a normal result suggests that bone rather than liver is the source of the increased ALP level and the ALP level alone can be followed without repeating the other enzyme. If the AST level is moderately or markedly elevated and there are obvious signs of liver disease such as jaundice, it would be useless to assay GGT or 5-NT even once for this purpose, since both of them are likely to be elevated regardless of the cause of the liver disease and regardless of bone contribution to ALP. Therefore, rather than enzyme differentiation, many prefer ALP isoenzyme fractionation, which has the added benefit that concurrent elevation of both bone and liver fractions can be demonstrated. For this purpose, ALP isoenzyme electrophoresis is more reliable.

    Aminotransferases of Liver Origin Elevated Over 6 Months Duration
    Chronic active hepatitis virus hepatitis
    Fatty liver (hepatic steatosis)
    Wilson’s disease
    Hemochromatosis
    Alpha-1 antitrypsin deficiency
    Drug-induced
    Alcohol-associated (“active cirrhosis”)
    Primary biliary cirrhosis
    Autoimmune chronic active hepatitis

    Isolated Elevation of Alkaline Phosphatase
    ALP level increased
    AST level normal
    Total bilirubin level normal
    Liver space-occupying lesions
    Bone osteoblastic activity increased
    Drug-induced (dilantin most common)
    Intrahepatic cholestatic process in advanced stage of resolution
    Pregnancy (third trimester)
    Hyperthyroidism
    Hyperparathyroidism

    Serum cholesterol determination is not a very helpful liver function test, although a very high cholesterol level might add a little additional weight to the diagnosis of extrahepatic biliary tract obstruction or biliary cirrhosis. A urine bilirubin determination (“bile”) is not necessary if the serum conjugated bilirubin value is known. Serum protein electrophoresis may help to suggest cirrhosis, but it is not a sensitive screening test, and the pattern most suggestive of cirrhosis is not frequent. The PT as a liver function test is useful only in two situations: (1) an elevated PT not corrected by parenteral vitamin K suggests far-advanced liver destruction, and (2) an elevated PT that is corrected by vitamin K is some evidence for long-standing extrahepatic obstruction in a patient with jaundice. If all test results are normal and inactive cirrhosis is suspected, serum bile acid assay might be useful. The most frequent use for liver scan is to demonstrate metastatic carcinoma to the liver. Ultrasound (or CT scan)—and, in some cases, percutaneous transhepatic cholangiography—are helpful in differentiating extrahepatic from intrahepatic biliary tract obstruction. Liver biopsy can frequently provide a definitive diagnosis, thereby shortening the patient’s stay in the hospital and making lengthy repetition of laboratory tests or other procedures unnecessary. The earlier a biopsy is obtained, the more chance one has to see clear-cut diagnostic changes.

    An initial liver test “profile” might include serum bilirubin, AST, and ALP determinations. If the serum bilirubin level is elevated, it could be separated into conjugated and unconjugated fractions. If the serum bilirubin level is not elevated, determining the GGT may be useful, both to help confirm liver origin for other test abnormalities or to suggest alcoholism if it is elevated out of proportion to the other tests. The PT may be useful if other tests are abnormal to provide a rough idea of the severity of disease. In some cases the results of the initial screening tests permit one to proceed immediately to diagnostic procedures. An AST value more than 20 times normal suggests hepatitis virus hepatitis, and specimens can be obtained for serologic tests diagnostic of acute hepatitis A, B, or C infection (e.g., hepatitis B surface antigen, hepatitis B core antibody-IgM, hepatitis A-IgM, hepatitis C antibody; see Chapter 17). A high bilirubin level or other evidence suggesting biliary tract obstruction can be investigated with biliary tract ultrasound or similar studies. A normal bilirubin level with significantly elevated ALP level not due to bone disease raises the question of metastatic tumor and may warrant a liver scan. If liver screening test results are abnormal but do not point toward any single diagnosis, a liver biopsy might be considered. Liver function tests could be repeated in 2-3 days to see if a significant change takes place, but frequent repetition of the tests and long delays usually do not provide much help in establishing a diagnosis. Also, there are a significant number of exceptions to any of the so-called diagnostic or typical liver function test patterns.

  • Laboratory Test Patterns in Liver Disease

    This section will review several typical patterns of laboratory values found in liver disease, with their differential diagnosis:

    1. An AST value greater than 20 times the upper reference limit.

    If the AST increase is due to liver disease rather than heart or skeletal muscle injury, this suggests acute hepatitis virus hepatitis. Less common etiologies are severe liver passive congestion, active cirrhosis, drug-related liver injury (e.g., acetaminophen), and occasionally atypical early extrahepatic bile duct obstruction. If the ALT level is considerably less elevated than the AST level, this suggests the cause is not hepatitis virus hepatitis. A considerably elevated GGT also would be unusual for hepatitis virus hepatitis A or B and would raise the question of alcohol-related active cirrhosis or early common bile duct obstruction.

    2. An ALP value elevated more than 4 times the upper limit; AST value elevated less than 10 times the upper limit.

    If the ALP is derived from liver rather than bone, this suggests extrahepatic biliary tract obstruction. Serum bilirubin level would be expected to be more than 5 mg/100 ml. Other possible causes are cholestatic drug jaundice, liver space-occupying lesions, primary biliary cirrhosis or primary sclerosing cholangitis, and occasional cases of intrahepatic obstruction of various etiologies.

    3. An ALP value elevated less than 3 times the upper limit; AST value elevated less than 10 times the upper limit.

    This pattern is the most common one seen in patients with liver disease and can be associated with a wide variety of etiologies, including subsiding hepatitis virus hepatitis, chronic hepatitis, infectious mononucleosis, active cirrhosis, alcohol or drug-induced liver injury or dysfunction, acute cholecystitis, acute pancreatitis, severe fatty liver, primary biliary cirrhosis, sepsis, and liver space-occupying lesions. If the AST or ALT level is significantly elevated longer than 6 months, chronic hepatitis virus hepatitis and certain other conditions (see the box) would have to be considered.

    4. An ALP value elevated; AST value not elevated.

    If the ALP elevation is due to liver rather than bone and if other nonhepatic causes (such as phenytoin therapy) for the elevated ALP value can be eliminated, this suggests a space-occupying lesion or lesions in the liver. Other possibilities are primary biliary cirrhosis and resolving phase of previous active liver disease.

  • Metastatic Carcinoma

    Metastatic tumor to the liver may be completely occult or may produce a clinical or laboratory picture compatible with hepatomegaly of unknown origin; normal liver with elevated ALP levels simulating bone disease; active cirrhosis; or obstructive jaundice. The liver is a frequent target for metastases, some of the most common primary sites being lung, breast, prostate, and both the upper and lower GI tract. Earlier reports frequently stated that metastases to a cirrhotic liver were rare, but later studies have disproved this. By far the most frequently noted abnormality is hepatic enlargement. About 25% of patients with metastatic tumor to the liver become jaundiced, and another 25% have elevated bilirubin levels (usually with the conjugated fraction predominating) without clinically evident jaundice. Occasionally patients develop jaundice with relatively little hepatic tissue replacement. In about 10% of patients the bilirubin levels are high enough (>10 mg/100 ml; 170 µmol/L) to simulate obstruction of the common bile duct. A significant minority of patients with tumor in the liver may have physical findings compatible with portal hypertension or cirrhosis.

    In 50%-60% of patients with metastatic carcinoma to the liver the serum bilirubin level is normal, whereas ALP levels are elevated in about 80% of patients (range, 42%-100%) and GGT in about 88% (45%-100%). Therefore, ALP or GGT levels are frequently elevated in nonjaundiced patients with liver metastases, and ALP elevation may occur in some instances when only a relatively few tumor nodules are present. The most typical pattern for metastatic carcinoma to the liver is a normal bilirubin level, normal AST level, and elevated GGT and/or ALP level of liver origin. If the serum bilirubin level is elevated, the typical metastatic tumor pattern becomes less typical or is obscured, because many of these patients develop mildly abnormal AST values suggestive of mild acute hepatocellular damage in addition to the elevated ALP level. Diagnosis is much more difficult when liver function test results other than ALP or GGT are abnormal since these other test results can be elevated (at least temporarily) from any of a considerable variety of etiologies. Unfortunately, only about one third (or less) of metastatic tumor cases have elevated ALP or GGT levels and normal AST levels. Finally, whether or not a patient has elevated bilirubin, ALP or GGT may be elevated due to nonhepatic etiology (i.e., phenytoin therapy, sepsis). Some investigators report that carcinoembryonic antigen (CEA) is more sensitive in detecting colon cancer metastasis to the liver than is ALP, but this is a minority opinion.

    As mentioned previously, a liver scan (radionuclide, CT, or ultrasound) is very useful. Liver biopsy is usually necessary for definite diagnosis. Biopsy sometimes may demonstrate tumor when other tests are normal, equivocal, or conflicting, or when the biopsy is performed because of some other preliminary diagnosis.

  • Cirrhosis

    The most common etiologies of portal cirrhosis are alcohol, hepatitis virus, or unknown (cryptogenic) cause. Less common causes are primary biliary cirrhosis and genetically related cirrhosis (Wilson’s disease, hemochromatosis, and alpha-1 antitrypsin deficiency). Cirrhosis exhibits a wide spectrum of test results, depending on whether the disease is active or inactive and on the degree of hepatocellular destruction. In patients with early or moderate degrees of inactive cirrhosis, there are usually no abnormalities in bilirubin or enzyme test results. Bile acid assay may be abnormal. In more pronounced degrees of inactive cirrhosis there may be minimal or mild elevations of AST, serum gamma-globulin, ALP, and serum bilirubin levels, although no definite pattern can be stated. In advanced cases the PT begins to rise, and mild abnormalities on other liver function tests are more frequent.

    In “active” cirrhosis (florid cirrhosis or alcoholic hepatitis), liver function tests show evidence of mild to moderate acute hepatocellular damage but occasionally there may be marked AST level elevation. The serum bilirubin level may be normal or elevated; if elevated, it is usually elevated only to a mild extent, but occasionally it may rise quite high. ALP levels are often less than 3 times normal, although occasionally they may be higher; and AST levels usually are less than 10 times normal. Active cirrhosis may have a clinical and chemical pattern simulating the minimal changes of advanced fatty liver, the moderate abnormalities of chronic hepatitis, occasionally the marked abnormalities of acute hepatitis with intrahepatic cholestasis, or infrequently the picture of obstruction with secondary liver damage. A history of chronic alcoholism, physical findings of spider angiomata and splenomegaly, AST level disproportionately elevated compared to ALT level, and GGT level disproportionately elevated compared to AST level help point toward alcohol-associated active cirrhosis. Liver biopsy is the best diagnostic test.

    In childhood cirrhosis, the possibility of Wilson’s disease (see Chapter 34) should be considered. Primary biliary cirrhosis would be likely in a 30- to 50-year-old woman with pruritus, slow onset of jaundice, protracted clinical course, liver biopsy showing bile duct destruction, and an abnormal antimitochondrial antibody test.

  • Fatty Liver

    Fatty liver is a common cause of hepatomegaly of unknown etiology. In uncomplicated fatty liver, function tests are variable. There may be no abnormality at all. ALP levels in one series were elevated in nearly 48% of patients but usually were less than twice normal. An elevated AST level is found in 40% of patients, usually less than 5 times normal, and more often with severe degrees of fatty metamorphosis. The serum bilirubin level may be elevated in 35% of patients, but most have minimal abnormality, usually less than twice normal and without jaundice. Severe fatty liver may present clinically with jaundice, but this is very uncommon.

  • Primary Biliary Cirrhosis

    Primary biliary cirrhosis is an uncommon type of biliary obstruction that should be briefly mentioned. It occurs predominantly in young or middle-aged women and typically is a slow process. On liver biopsy there is inflammation and destruction of small bile ducts within liver portal areas. Clinically there is pruritus with or without mild jaundice. Steatorrhea is sometimes present. Biochemically, there usually is an ALP and GGT increase more than 3 times the normal limit, increased serum cholesterol level, and normal or mildly increased AST levels. Serum antimitochondrial antibodies are elevated in 90% or more patients. Diagnosis is made on the basis of the clinical and biochemical pattern plus the presence of antimitochondrial antibodies. Liver biopsy may be necessary to differentiate the disease from chronic hepatitis, liver tumor, drug-induced cholestasis, or some other conditions associated with cholangitis.

  • Biliary Obstruction

    Obstruction may be complete or incomplete, extrahepatic or intrahepatic. Extrahepatic obstruction is most often produced by gallstones in the common bile duct or by carcinoma of the head of the pancreas. Intrahepatic obstruction is most often found in the obstructive phase of acute hepatocellular damage, as seen in “active” alcoholic cirrhosis, hepatitis virus hepatitis, in liver reaction to certain drugs such as chlorpromazine (Thorazine), and occasionally in patients with other conditions such as metastatic carcinoma. In one series, 12% of patients with liver metastases had a total bilirubin level more than 10 mg/100 ml (170 µmol/L). Serum bilirubin levels may become markedly elevated with either intrahepatic or extrahepatic obstruction. Although extrahepatic obstruction typically is associated with considerable bilirubin elevation, bilirubin values may be only mildly elevated in the early phases of obstruction, in persons with incomplete or intermittent obstruction, and in some persons with common duct obstruction by stones. In addition, occasional patients with intrahepatic cholestasis have considerably elevated serum bilirubin levels. Thus, the degree of bilirubinemia is not a completely reliable diagnostic point. Patients with extrahepatic obstruction typically have ALP elevation more than 3 times the upper reference limit, normal or minimally elevated AST levels, and moderately or considerably elevated total bilirubin levels, with 75% or more consisting of the conjugated fraction. In contrast, intrahepatic obstruction due to hepatocellular injury usually is associated with a considerably elevated AST level and a conjugated bilirubin/nonconjugated bilirubin ratio close to 1:1. Unfortunately, as time goes on, the serum bilirubin level in extrahepatic obstruction demonstrates a progressive decline in the conjugated bilirubin/nonconjugated bilirubin ratio, until a ratio not far from 1:1 is reached. Also, the AST level may increase somewhat as liver cells are damaged by distended biliary ductules. Therefore, differentiation of long-standing extrahepatic obstruction from intrahepatic obstruction may not always be easy. Metastatic tumor to the liver has the typical laboratory picture of extrahepatic obstruction without jaundice. Occasionally, however, it is accompanied by jaundice. Finally, some drugs such as chlorpromazine, anabolic steroids, or oral contraceptives may occasionally produce liver dysfunction that has a predominantly cholestatic-type biochemical pattern.

    Some Etiologies for Aspartate Aminotransferase Values Over 1000 IU/ml
    Liver origin
    Acute hepatitis virus hepatitis
    Chronic active hepatitis (occasional patients; 16% in one study)
    Reye’s syndrome
    Severe liver passive congestion or hypoxia (with or without acute MI, shock, or sepsis)
    Drug-induced (e.g., acetaminophen)
    HELLP syndrome of pregnancy (some patients)
    Other
    First 2-3 days of acute common bile duct obstruction
    Acute myocardial infarct (occasional patients)
    Severe rhabdomyolysis

    If extrahepatic obstruction is a possibility, it can be investigated with ultrasound on the biliary tract. If results of the ultrasound study are normal or equivocal and extrahepatic obstruction is strongly suspected, one of the other studies discussed previously can be attempted.

  • Acute Hepatitis Virus Hepatitis

    Hepatitis virus B will be used as a model here. After an incubation period, acute viral hepatitis most often begins with some combination of GI tract symptoms, fever, chills, and malaise, lasting 4-7 days. During this phase there is no clinical jaundice. Leukopenia with a relative lymphocytosis is common, and there may be a few atypical lymphocytes. Hemoglobin values and platelet counts usually are normal. Liver function tests reflect acute hepatocellular damage, with AST and ALT values more than 10 times the upper reference limit and usually more than 20 times the upper limit. ALP is usually elevated; values typically are less than 3 times the upper reference limit, but some patients may have elevation even higher than 5 times the upper limit. Lactic dehydrogenase (LDH) is usually less than 3 times normal. Serum bilirubin values begin climbing toward the end of this initial phase. The next development is visible jaundice; during this period, clinical symptoms tend to subside. The serum bilirubin level continues to rise for a time, then slowly falls. Both conjugated and unconjugated fractions are increased. The ALP level often begins to fall shortly after clinical icterus begins. The AST level begins to decrease about 1-2 weeks after it reaches its peak. A convalescent phase eventually ensues, with return of all test values to normal, beginning with the ALP. Some patients continue to manifest a low-grade hepatitis (chronic persistent or chronic active), reflected by variable and intermittent AST abnormalities (usually mild or moderate in degree) with or without ALP elevation. The majority of patients (75%-80%) never develop jaundice during viral hepatitis; this condition is known as “anicteric hepatitis.” In such situations, function tests reveal mild to moderate acute hepatocellular damage with a minimal obstructive component.

    The textbook picture of AST more than 20 times (especially when over 25 times) the upper reference range limit (see the box), an ALT level greater than or equal to AST; with ALP mildly elevated and GGT mildly or moderately elevated, is strongly suggestive of hepatitis virus hepatitis. Other liver disorders that may be associated with an AST level over 20 times the upper reference limit include a small minority of patients with drug-induced liver injury (especially acetaminophen overdose), active alcoholic cirrhosis, a few cases (2%) of infectious mononucleosis, and some cases of severe liver passive congestion, as well as a few patients with early “atypical” extrahepatic obstruction. In addition, there are nonhepatic etiologies for markedly elevated AST, such as acute myocardial infarct and severe skeletal muscle injury. The patient may not be seen until the early convalescent phase, or the patient may have a mild anicteric episode. If so, the AST level may have decreased to less than 20 times the upper reference limit, and the differential diagnosis includes a wide variety of conditions, such as subsiding hepatitis, chronic hepatitis, alcoholic and active cirrhosis, infectious mononucleosis or cytomegalovirus infection, liver congestion, drug-induced liver dysfunction, liver space-occupying lesions, and severe fatty liver.

    Chronic hepatitis is usually associated with AST values less than 20 times the upper reference limit and usually less than 10 times the upper limit. However, one study reported that about 15% of persons with the category of chronic hepatitis known as “chronic active hepatitis” had AST values at some time greater than 20 times the upper reference limit.