ENFOQUE DEL PACIENTE ICTERICO
He evaluation of jaundice begins with a thorough review of the history of
presentation, medication usage, medical history, physical examination, and
evaluation of liver function tests. In a diagnostic evaluation for a patient
with jaundice, the key elements initially arise from the patient’s history
and physical examination. The following key questions are to be asked:
1. Is the elevated bilirubin conjugated or unconjugated? In general, most
patients with jaundice do not have isolated unconjugated
hyperbilirubinemia.
2. If the hyperbilirubinemia is unconjugated, is it caused by increased
production, decreased uptake, or impaired conjugation?
3. If the hyperbilirubinemia is conjugated, is the problem intrahepatic or
extrahepatic?
4. Is the process acute or chronic?
Jaundice can appear among patients with both acute hepatitis and
chronic liver disease. The general appearance of the patient may suggest
chronic liver disease with cachexia, muscle wasting, palmar erythema,
Dupuytren’s contracture, abnormal nails, parotid enlargement, or
xanthelasmas. Detection of mild to moderate amounts of ascites is
frequently difficult even by experienced hepatologists. Splenomegaly may
occur among patients with infections, infiltrative diseases, viral hepatitis,
or cirrhosis. A palpable, distended gallbladder suggests malignant biliary
obstruction.
The clinician must differentiate conjugated from unconjugated
hyperbilirubinemia with total and direct bilirubin assays. Patients with
unconjugated hyperbilirubinemia should be examined for evidence of
hemolysis. This includes reticulocyte count, examination of a peripheral
smear, serum level of lactic dehydrogenase, and haptoglobin levels. The
diagnosis of exclusion for unconjugated hyperbilirubinemia is Gilbert’s
disease, which is a benign disease of a partial defect in the enzyme
uridine diphosphoglucuronyl transferase (UDPGT), characterized by mild,
chronic, and intermittent unconjugated hyperbilirubinemia. The following
algorithm suggests an approach to the management of jaundice.
Conjugated hyperbilirubinemia has multiple causes, divided principally
into hepatocellular or vascular events or extrahepatic obstruction.
Hepatocellular causes of a conjugated bilirubinemia include infectious
hepatitis, medication-related hepatitis or cholestasis, autoimmune liver
disease, alcohol injury, total parenteral nutrition, among many other
causes. Further evaluation of these causes should include hepatitis viral
serologic testing and autoimmune markers such as antinuclear antibodies
(ANA) or antimitochondrial antibodies (AMA). Infectious causes of
hyperbilirubinemia are listed in Table 7-1
TABLE 7-1. Infectious Causes Of Hyperbilirubinemia
Bacterial cholangitis
Candida infection
Hepatitis virus A, B, or C infection Bacteroides infection
Cytomegalovirus infection
Syphilis
Epstein-Barr virus infection Toxoplasmosis
Liver abscess
Brucellosis
Sepsis syndrome Q fever
Toxic shock Rickettsia
Escherichia coli infection
Leptospirosis
Klebsiella infection
Malaria
Pseudomonas infection Yellow fever
Shigella infection
Legionella infection
. They range from bacterial and viral to fungal organisms and involve
the liver either directly with an abscess or indirectly through circulating
cytokines or toxins. Medication-related sources of hyperbilirubinemia,
shown in Table 7-2, are divided into hepatocellular, cholestatic, and
mixed causes.
TABLE 7-2. Common Drugs Associated With Hyperbilirubinemia
Hepatocellular causes Cholestatic causes
Mixed causes
Acetaminophen
Amitriptyline
Acetohexamide
Alcohol
Androgenic steroids (B) Allopurinol
Amiodarone Atenolol
Ampicillin
Azulfidine Augmentin Augmentin
Carbenicillin Azathioprine
Cimetidine
Clindamycin Bactrim (D) Dapsone
Colchicine Benzodiazepines Disulfiram
Cyclophosphamide Captopril
Gold
Diltiazem Carbamazole
Hydralazine
Ketoconazole
Chlordiazepoxide (D)
Lovostatin
Methyldopa Clofibrate Nitrofurantoin
Nifedipine Cyclosporin Phenytoin
Propylthiouracil Dapsone
Sulfonamides
Pyridium
Disopyramide
Tetracycline
Pyrazinamide
Erythromycin
Quinidine Estrogens (B)
Rifampin
Ethambutol
Salicylates Floxuridine
Verapamil 5-Flucytosine
Fluoroquinolones
Griseofulvin
Haloperidol (D)
Labetolol
Nicotinic acid
Nonsteroidal antiinflammatory drugs
Penicillins
Phenothiazines (D)
Phenytoin
Tamoxifen
Tegretol
Thiabendazole (D)
Thiazides
Thiouracil
Tolbutamide (D)
Tricyclics (D)
Verapamil
Zidovudine
(B), Bland or noninflammatory cholestasis; (D), ductopenic cholestasis or
vanishing bile duct syndrome.
Liver function tests other than specific viral or autoimmune markers
can be helpful in the determination of causes or outcomes of liver disease.
Aminotransferases are representative of the parenchymal hepatic injury
that occurs with viral, autoimmune, and ischemic hepatitis, with values
typically in the several hundred range. Aminotransferase values of 1000
U/L or more can represent severe acute viral hepatitis, fulminant hepatic
failure, or liver disease induced by drugs such as acetaminophen or toxins
from ischemic necrosis. Hyperbilirubinemia can arise from both
parenchymal hepatic injury or obstructive disease. The level of alkaline
phosphatase may be disproportionately elevated in patients with partial
obstruction, multiple intrahepatic lesions, granulomatous disease, or
primary biliary cirrhosis. If the alkaline phosphatase and bilirubin levels
are markedly elevated, the presence of a common bile duct stone should
be excluded. An elevation alkaline phosphatase level with a normal bilirubin
level may occur in the presence of partial extra- or intrahepatic
obstruction. Therefore, alkaline phosphatase level is a more sensitive test
for biliary obstruction than is bilirubin level.
If tumors of the liver are suspected on the basis of a history of
extrahepatic primary tumor or the sudden decompensation of cirrhosis,
additional testing by means of serum -fetoprotein (AFP),
carcinoembryonic antigen (CEA), or CA19-9 levels or computed
tomographic (CT) scanning of the liver is necessary. Ultimately, the
diagnosis of liver tumor, whether primary or metastatic, derives from
adequate radiographic imaging or histologic examination. In the algorithm
for such an evaluation, metastatic disease, hepatocellular carcinoma,
adenoma, and hemangioma all can be suggested with the appropriate
radiographic test. Ultrasonography of the liver can be a helpful starting
point if an abnormal AFP level suggests a tumor, but CT scanning with
dual-phase contrast or magnetic resonance imaging is most helpful in the
diagnosis.
Vascular events in the liver (see algorithm) can result from hepatic
ischemia either from ischemic hepatitis in acute hypotensive shock or left
ventricular dysfunction. Passive congestion to the liver can arise from
right ventricular dysfunction, pulmonary hypertension, or tricuspid
regurgitation. Hepatic outflow obstruction, traditionally known as BuddChiari syndrome, usually involves hepatic venous obstruction or a vena
caval web. However, functional Budd-Chiari syndrome can derive from the
sources of passive congestion to the liver just mentioned. The diagnosis of
Budd-Chiari sydrome is heightened by a history of thrombotic disorders
and polycythemia vera and suggested by findings at Doppler
ultrasonography of the hepatic vein. The hepatic vein, however, can be
the Achilles’ heel of the liver vasculature at Doppler ultrasonography,
because this vein can have thrombosis missed or overdiagnosed because of
its small size, because the liver is firm and cirrhotic, or because of the
passive flow of severe tricuspid regurgitation. Use of diuretics, surgical
shunting, and liver transplantation are treatments for the symptoms and
complications of Budd-Chiari syndrome.
Ultrasonography is the first study used to detect biliary obstruction.
Despite some caveats about missing intraductal stones without biliary
dilation and the fact that ultrasonography is operator dependent, there
are few false-positive test results, and ultrasonography remains the initial
screening test for the evaluation of biliary obstruction in most instances.
CT scanning has a sensitivity similar to that of ultrasonography, but the
results rely less on operator proficiency. In 60% to 90% of instances,
obstructions are found where they are indicated to be on the CT scan,
and CT scanning is not impeded by fat, as is ultrasonography. However,
CT scanning is more expensive than ultrasonography, requires intravenous
administration of contrast medium in many instances, and is not more
sensitive.
Invasive tests include endoscopic retrograde cholangiopancreatography
(ERCP), percutaneous transhepatic cholangiography (PTC), and liver biopsy.
ERCP is 90% successful regardless of the presence or absence of ductal
dilation and can help localize the site of obstruction in more than 90% of
patients. It is particularly helpful in diagnosing common duct stones.
Because it has therapeutic capabilities, ERCP allows some patients to avoid
surgical treatment. ERCP is helpful if a stricture due to chronic
pancreatitis is suspected. The main reasons for lack of visualization of
the biliary tree during ERCP are prior operations (e.g., Roux-en-Y
anastomosis) and an inability to cannulate the sphincter of Oddi. The
morbidity rate is 2% to 3%, somewhat less than with PTC. The most
common complications are pancreatitis and cholangitis. The rate of sepsis
is less than 1% if prophylactic antibiotics are given when obstruction is
suspected. The decision to pursue ERCP or PTC depends on the presumed
site of obstruction, the presence of coagulopathy or ascites, and the
expertise of the radiologists and gastroenterologists. PTC and ERCP are
sometimes used together, especially if ultrasound examination reveals
ductal dilation, and a cytologic specimen is needed for determining the
presence of malignant growth. Strictures should be differentiated from
cholangiocarcinoma. This often necessitates cytologic analysis or biopsy of
the lesion. If one of the invasive tests is unsuccessful, the complementary
test can be attempted. PTC depicts the biliary tree in 90% to 100% of
patients with dilated ducts. PTC is the preferred modality when in the
setting of proximal biliary or intrahepatic ductal dilation the area of
stenosis within the bile duct cannot be adequately accessed by means of
ERCP.
Common bile duct dilation is represented in Fig. 7-1 with ERCP
demonstration of two obstructive stones. Therapeutic removal of
obstructive stones can be accomplished with basket retrieval (Fig. 7-2).
The diagnosis of pancreatic cancer is shown in Fig. 7-3 with cutoff of the
pancreatic duct and incomplete filling or drainage. Enlargement of the
head of the pancreas by a mass can result in obstruction of the biliary
and the pancreatic duct (Fig. 7-4), the so-called double-duct sign.
Intrahepatic ductal dilation can exist in multiple conditions, such as distal
bile duct obstruction or both intrahepatic and extrahepatic biliary
disease, such as primary sclerosing cholangitis. The intrahepatic duct
dilation of primary sclerosing cholangitis is shown in Fig. 7-5, which has
scattered areas of narrowing or beading. ERCP can also be useful in
demonstrating bile leakage or fistula, as in this image (Fig. 7-6) of a
patient with fistula formation and complete common bile duct transection
after cholecystectomy.
The diagnosis and management of pancreatic or bile duct cancer
involves the pivotal role of ERCP. Pancreatic cancer with biliary
obstruction can lead to common bile duct and intrahepatic duct dilation
(Fig. 7-7). Proximal hepatic duct dilation in the same patient with
pancreatic cancer as in Fig. 7-7 is shown in Fig. 7-8 after balloon
dilation. The therapeutic role of ERCP in alleviating obstruction caused by
pancreatic cancer in this patient is demonstrated in Fig. 7-9. Use of a
Wallstent prosthesis through the strictured site decreased the biliary
dilation. Biliary dilation from an obstructive lesion of ampullary carcinoma
is shown in Fig. 7-10. Recurrent cholangiocarcinoma after liver
transplantation can be demonstrated by means of ERCP (Fig. 7-11). The
therapeutic role of ERCP in common bile duct stricture is shown in Fig. 712 in the case of a patient with a biliary stricture after liver
transplantation. An endoscopic view of a stent placed to manage
obstructive ampullary adenocarcinoma is shown in Fig. 7-13. A Wallstent
prosthesis traversing the ampulla for bile duct carcinoma is shown in Fig.
7-14.
The histologic features of cholestasis are defined as either
intrahepatic cholestasis marked by bile duct pigment within hepatocytes or
extrahepatic cholestasis with bile duct pigment within the bile ducts. The
presence at liver biopsy of bile duct plugs or bile duct proliferation with
or without dilation is further supportive of extrahepatic obstruction.
Figure 7-15 is a representative liver biopsy specimen at low power from a
patient with extrahepatic obstruction. Figure 7-16 shows a specimen from
a patient with intrahepatic cholestasis. The role of liver biopsy in the
treatment of a patient with jaundice is most important in identifying the
cause of cholestasis but not merely to confirm its presence.
The performance of a liver biopsy is essential in the diagnosis of
hepatocellular diseases such as autoimmunity, worsening abnormal liver
function tests of unclear causation, some types of viral hepatitis,
cholestatic diseases of primary biliary cirrhosis, Wilson disease, or the
establishment of occult cirrhosis. Complications after liver biopsy occur
with an incidence ranging from 0.1% to 3.0%. Overall, liver biopsy is a
safe procedure, as is ERCP. However, liver biopsy is invasive, and careful
consideration is needed in the care of a person at risk for complications.
Patients with coagulopathy, thrombocytopenia, or ascites may need blood
products or an alternative route of biopsy, such as a transjugular
approach. Transjugular liver biopsy is a well-established alternative for
obtaining liver tissue. For patients with renal insufficiency or taking
warfarin, however, ultrasound-guided liver biopsy can be performed with
desmopressin (DDAVP) or a gelatin foam plug.