TOC  | D-Dx    

Hepatitis Differential - Outlines in Clinical Medicine on Physicians' Online 2002

A. Viral Hepatitis

  1. Hepatitis A Virus
  2. Hepatitis B Virus (± Delta Virus)
  3. Hepatitis C Virus
  4. Hepatitis E Virus
  5. Epstein-Barr Virus (EBV, Mononucleosis)
  6. Cytomegalovirus (CMV)

B. Non-viral Infectious Hepatitis

  1. Tuberculosis
  2. Malaria
  3. Amoebiasis
  4. Ascending Cholangitis

C. Inflammatory Hepatitis

  1. Sarcoidosis
  2. Idiopathic Granulomatous Hepatitis
  3. Autoimmune Hepatitis (usually ANA+)
    a. Primary
    b. Secondary - systemic lupus erythematosis
  4. Primary Biliary Cirrhosis
  5. Sclerosing Cholangitis

D. Metabolic Abnormalities

  1. Hemochromatosis
  2. Copper Overload (Wilson's Disease)
  3. Alpha-1 Antitrypsin Deficiency

E. Congestion / Ischemia

  1. Budd-Chiari Syndrome (Portal Vein Thrombosis)
  2. Hepatic Vein Thrombosis
  3. Inferior Vena Cava Thrombosis
  4. Congestive Heart Failure
  5. Shock Liver (Hypotension)

DRUG INDUCED HEPATITIS

  1. Direct Toxicity:  Acetaminophen , Carbon tetrachloride , Phosphorus , Mushrooms , Ethanol
  2. Idiosyncratic:  Isoniazid , Propylthiouracil (PTU) , Disulfiram , HMG-CoA Reductase Inhibitors , Zileuton , Niacin , Carbamazepine , Tacrine , etc.
  3. Toxic-Allergic:  Halothane & Isoflurane
  4. Allergic:  Phenytoin (Dilantin) , Sulfonamides , Amoxicillin-Clavulonate (Augmentin®)
  5. Cholestatic: Chlorpromazine , Erythromycin , Estradiol , Captopril , Sulfonamides
  6. Granulomatous Drug Reaction: Diltiazem , Quinidine , Phenytoin , Procainamide
  7. Chronic Hepatitis: Nitrofurantoin , Methyldopa , Isoniazid , Trazadone
  8. Fatty Liver (Steatohepatitis): Amiodarone , Perhexiline , maleate , Valproate , Alcohol
  9. Microvesicular Steatosis: Tetracycline , Aspirin , Zidovudine (AZT) , Didanosine , Fialuridine
  10. Fibrosis / Cirrhosis: Methotrexate , Vitamin A , Methyldopa
  11. Veno-occlusive Disease (VOD): Cyclophosphamide , Other chemotherapy , Herbal Teas
  12. Ischemia: Cocaine , Nicotinic Acid Sustained Release , Amphetamines

     

Liver Function Tests                                                                      REF: Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 6th ed., 1998

Clinical Significance of Common Liver Tests

TEST (NORMAL RANGE)  

BASIS OF ABNORMALITY  

ASSOCIATED LIVER DISEASES  

EXTRAHEPATIC SOURCES  
Aminotransferases ALT, AST
(0-35 IU/L, 0-0.58 mukat/L for both ALT and AST)		 Leakage from damaged tissue Modest elevations--many types of liver disease

Marked elevations--hepatitis (viral, autoimmune, toxic, and ischemic)

AST/ALT >2 and each less than 300 U suggests alcoholic liver disease or cirrhosis of any cause

 ALT--relatively specific for hepatocyte necrosis

AST--muscle (skeletal and cardiac),kidney, brain, pancreas, red blood cells
Alkaline phosphatase (AP) (30-120 IU/L, 0.5-2.0 mukat/L) Overproduction and leakage into serum Modest elevations--many types of liver disease

Marked elevations--extra- and intrahepatic cholestasis, diffuse infiltrating disease (e.g., tumor, MAI), occasionally alcoholic hepatitis

 Bone growth or disease (e.g., tumor, fracture, Paget's disease), placenta, intestine, tumors
gamma-Glutamyl transpeptidase (GGT) (0-30 IU/L, 0-0.50 mukat/L) ?Overproduction and leakage into serum Same as for alkaline phosphatase; induced by ethanol, drugs. GGT/AP > 2.5 suggests alcoholic liver disease. Kidney, spleen, pancreas, heart, lung, brain
Bilirubin (conjugated or direct)
(0.1-1.0 mg/ dL, 2-18 mumol/L)

Unconjugated/indirect  Hyperbilirubinemia  - most commonly from hemolysis
Decreased hepatic clearance Modest elevations--many types of liver disease

Marked elevations--extra- and intrahepatic bile duct obstruction, lcoholic, drug-induced or viral hepatitis, inherited hyperbilirubinemia

 Increased breakdown of hemoglobin (due to hemolysis, ineffective erythropoiesis, resorption of hematoma) or myoglobin (due to muscle injury)
Prothrombin time
(10.9-12.5 sec)		 Decreased synthesis Acute or chronic liver failure (unresponsive to vitamin K)

Biliary obstruction (usually responsive to vitamin K administration)

 Vitamin K deficiency (secondary to malabsorption, malnutrition, antibiotics), consumptive coagulopathy
Albumin
(4.0-6.0 g/dL, 40-60 g/L)		 Decreased synthesis
?Increased catabolism		 Chronic liver failure

Liver failure of at least several weeks' duration

 Decreased in nephrotic syndrome, protein-losing enteropathy, vascular leak, malnutrition, malignancy, and inflammatory states

ALT (alanine aminotransferase) formerly called serum glutamic pyruvic transaminase [SGPT]
AST (aspartate aminotransaminase) formerly called serum glutamic oxaloacetic transaminase [SGOT]

The AST/ALT Ratio may be useful in the differential diagnosis.  

Modest elevations of the aminotransferases AST & ALT (<500 IU) are found in a wide variety of liver diseases. In the absence of other disorders, the aminotransferases are typically less than 300 IU in patents with alcoholic hepatitis or biliary obstruction. There are exceptions, however.
AST/ALT ratio is usually preserved. Extreme aminotransferase elevations (>2000 IU) have a relatively restricted differential diagnosis.
Surprisingly, the degree of aminotransferase elevation correlates poorly with the extent of hepatocyte necrosis, as determined by liver biopsy, and is not predictive of outcome in acute hepatitis. Indeed, a rapid fall in aminotransferases in association with a rising bilirubin level and prothrombin time (PT) portends a poor prognosis in the setting of fulminant liver disease.

The AST & ALT  are frequently normal or near normal in patients with advanced cirrhosis in the absence of significant ongoing liver injury, as sometimes seen with hereditary hemochromatosis, methotrexate use, or jejunoileal bypass. Moreover, azotemia may falsely lower serum AST concentration, whereas certain drugs (e.g., erythromycin and p-aminosalicylic acid) and other factors (e.g., diabetic ketoacidosis and high sucrose diets) can falsely increase the AST.

Lactate Dehydrogenase (LDH)
Lactate dehydrogenase (LDH) has a wide tissue distribution, and elevated serum levels are seen with skeletal or cardiac muscle injury, hemolysis, stroke, and renal infarction, in addition to acute and chronic liver disease. Because of this nonspecificity, LDH rarely adds useful information to that obtained from the aminotransferases alone. Uncommon situations in which serum LDH levels may be diagnostically useful include the massive but transient serum elevation of LDH characteristic of ischemic hepatitis and the sustained LDH elevation, accompanied by elevation of the alkaline phosphatase (AP), that suggests malignant infiltration of the liver.

Markers of Cholestasis

Alkaline Phosphatase
Alkaline phosphatase (AP) comprises a group of enzymes present in a variety of tissues, including liver, bone, intestine, kidney, placenta, leukocytes, and various neoplasms. AP production tends to increase in tissues undergoing metabolic stimulation. Thus, AP serum activity during adolescence is up to three times that of adults due to rapid bone growth and also rises during late pregnancy due to placental growth and metabolism. Bone and liver are the major sources of serum AP, although individuals with blood groups O and B may have a significant serum AP level derived from the small bowel, particularly after a fatty meal. This is the rationale for obtaining fasting measurements of AP. Patients with chronic renal failure may also have elevations of the intestinal isoform of AP.
Elevation of AP in the setting of liver disease results from increased synthesis and release of the enzyme into serum rather than from impaired biliary secretion. Bile acids, which are retained in cholestatic liver disease, may solubilize the hepatocyte plasma membrane and facilitate the release of AP. Because serum elevation of AP requires synthesis of new enzyme, AP may not become elevated for one or two days after acute biliary obstruction. Moreover, because the half-life of serum AP is approximately one week, the level in serum may remain elevated for several days to weeks after resolution of biliary obstruction.

Levels of AP up to three times normal are relatively nonspecific and occur in a variety of different liver diseases.
Striking elevations of AP are seen predominantly with infiltrative hepatic disorders (e.g., primary or metastatic tumor) or biliary obstruction, either within the liver (e.g., primary biliary cirrhosis [PBC]) or in the extrahepatic biliary tree.   Although fairly sensitive, the serum AP concentration is occasionally normal despite extensive hepatic metastasis or, rarely, despite documented large duct obstruction. The level of AP cannot be used to distinguish between intrahepatic and extrahepatic duct obstruction or hepatic infiltration.  Another explanation for elevation of AP in the cancer patient is a nonspecific hepatitis; this has been reported in association with Hodgkin's lymphoma and renal cell carcinoma.

Gamma Glutamyl Transpeptidase (Gamma GT)
Like AP, gamma glutamyl transpeptidase (GGT) is found in many extrahepatic tissues, including the kidney, spleen, pancreas, heart, lung, and brain. However, it is not found in appreciable quantities in bone, and it is thus helpful in confirming the hepatic origin of an elevated AP.  Certain rare hepatic disorders, however, are characterized by elevation of AP without GGT, including benign recurrent intrahepatic cholestasis (BRIC) and Byler disease. In addition, GGT is a microsomal enzyme, and as such it is inducible by alcohol and drugs, including most anticonvulsants and warfarin. Indeed, a ratio of GGT/AP greater than 2.5 has also been reported to be very suggestive of alcohol abuse . However, over one third of habitual consumers of alcohol (>80 g/day) have normal serum GGT levels and the enzyme level often does not rise during alcohol binges.

Bilirubin
Bilirubin is formed from breakdown of hemoglobin molecules by the reticuloendothelial system. Newly formed (unconjugated) bilirubin circulates in blood bound nonpermanently to serum albumin and is carried to the liver, where it is extracted by hepatic parenchymal cells, conjugated first with one and then with a second glucuronide molecule to form bilirubin diglucuronide, and then excreted in the bile.   The 1-minute van den Bergh color reaction is also called the "direct reaction" and the conjugated bilirubin it measures is known as "direct-acting bilirubin," whereas the 30-minute alcohol measurement of unconjugated bilirubin is called the "indirect reaction" and its substrate is "indirect bilirubin."
* the terms "direct" and "conjugated" bilirubin were used interchangeably, & the terms "indirect" and "unconjugated" bilirubin were used interchangeably.

Serum bilirubin normally exhibits a concentration of less than 1 mg/dL (18 mumol/L), is almost entirely unconjugated, and reflects a balance between the rates of production and hepatobiliary excretion.

Unconjugated/indirect Hyperbilirubinemia  - most commonly from hemolysis
Unconjugated hyperbilirubinemia results either from increased bilirubin production, most commonly from hemolysis, or from inherited or acquired defects in hepatic uptake or conjugation. The diagnosis of hemolysis rests on a careful history (e.g., recent transfusions, medications) and straightforward screening tests (i.e., the peripheral blood smear, reticulocyte count, LDH, and haptoglobin). If hemolysis is suggested by these screening tests, a specific cause may be ascertained by more specialized testing (e.g., Coombs' test, glucose-6-phosphate dehydrogenase assay, hemoglobin electrophoresis). Of note, chronic hemolysis cannot account for a sustained elevation of serum bilirubin to concentrations greater than 5 mg/dL in the presence of normal hepatic function..

Conjugated Hyperbilirubinemia -  as a result of inherited or acquired defects in hepatic excretion  
Conjugated hyperbilirubinemia occurs as a result of inherited or acquired defects in hepatic excretion, the rate-limiting step in bilirubin metabolism, and subsequent regurgitation of conjugated bilirubin from hepatocytes into the serum .   Although measurement of the conjugated fraction is not reliable in distinguishing biliary obstruction from parenchymal liver disease, the magnitude of bilirubin elevation may be prognostically useful in alcoholic hepatitis, PBC, and fulminant hepatic failure.  Because of renal clearance of conjugated bilirubin, serum concentrations of bilirubin rarely exceed 30 mg/dL in the absence of hemolysis or renal failure.

A fraction of circulating conjugated bilirubin found in the setting of prolonged cholestasis (the delta fraction) is tightly bound to albumin and thus does not appear in the urine but still reacts directly with the diazo reagent used for bilirubin measurement .  This may explain the occasional paradox of the patient with parenchymal liver disease who has modest elevation of direct-reacting serum bilirubin level but little or no bilirubinuria, as well as the tendency of bilirubinuria to disappear before hyperbilirubinemia in patients with resolving liver disease. It may also contribute to the tendency of hyperbilirubinemia to resolve more slowly than other biochemical parameters of liver injury.

Markers of Hepatic Synthetic Capacity

Prothrombin Time ( PT)
The liver plays a crucial role in hemostasis.  All of the major coagulation factors are synthesized in the hepatocytes except factor VIII, which is made in vascular endothelium and reticuloendothelial cells.  The PT measures the activity of several of these factors involved in the extrinsic coagulation pathway, including factors I, II, V, VII, and X.  Vitamin K is required for the gamma-carboxylation of factors II, VII, IX, and X, which is essential for their normal function.

The differential diagnosis of an elevated PT includes

  1. vitamin K deficiency due to malnutrition, malabsorption, or antibiotic use,

  2. warfarin administration (which interferes with the vitamin K-dependent gamma-carboxylation),

  3. consumptive coagulopathy (e.g., disseminated intravascular coagulation  DIC), and

  4. liver disease

Disseminated intravascular coagulation can usually be distinguished from liver disease as a cause of a prolonged PT by measuring the level of factor VIII, which is decreased in disseminated intravascular coagulation and normal or increased with liver disease.  Prolongation of the PT may occur both in decompensated parenchymal disease with hepatocellular dysfunction and in chronic cholestatic disease with concomitant fat malabsorption and vitamin K deficiency. Parenteral vitamin K replacement (10 mg SQ) should reduce a prolonged PT secondary to vitamin K deficiency by at least 30% within 24 hr. Because of the short half-life of some of the coagulation factors measured by the PT (e.g., approximately 6 hr for factor VII), changes in PT, and factor VII in particular, are extremely useful in monitoring hepatic synthetic function in patients with acute liver disease. For example, prolongation of the PT and elevation of serum bilirubin levels are both predictive of early mortality in patients with alcoholic hepatitis

Albumin
Approximately 10 g of albumin is synthesized and secreted by hepatocytes each day. With progressive parenchymal liver disease, albumin synthetic capacity decreases and its serum concentration falls. However, the serum albumin concentration reflects a variety of extrahepatic factors, including nutritional and volume status, vascular integrity, catabolism, and loss in the urine or stool. In addition, because the serum half-life of albumin is approximately 20 days, serum albumin measurements are less useful than PT in assessing hepatic synthetic function in patients with acute liver disease.

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Hepatocellular Necrosis

The hallmark of hepatocellular necrosis is elevation of the aminotransferase  AST & ALT levels. The magnitude and tempo of the elevation may be diagnostically useful. This is especially true with dramatic elevations, for which the differential diagnosis is quite narrow.

Marked Aminotransferase AST & ALT Elevation (i.e. >2000 IU) are seen almost exclusively with

There are exceptions to this rule. For example, a rare patient with acute obstructing choledocholithiasis may present with extreme aminotransferase elevations, sometimes greater than 2000 IU, associated with minimal elevations of serum AP and bilirubin. However, the presenting clinical features (e.g., right upper quadrant pain often associated with nausea and vomiting) and evolving biochemical pattern (e.g., precipitous fall in aminotransferase levels over one to two days accompanied by a rise in AP and bilirubin levels) usually suggest the diagnosis of acute biliary obstruction. In addition, autoimmune hepatitis and giant cell hepatitis may also rarely be associated with massive aminotransferase elevations. Extreme aminotransferase elevations in autoimmune hepatitis are associated with aggressive disease and poor prognosis without treatment.

        

10052002