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412 SECTION VI Gastrointestinal Disease
with a sensitivity for the diagnosis of chronic pancreatitis of 71% to
93% and a specificity of 89% to 100%. The major limitation of ERCP is
the development of procedure-related acute pancreatitis in up to 5% of
patients. Thus, ERCP should not be used for diagnostic purposes but
instead be reserved for patients with established chronic pancreatitis
when endoscopic therapy is recommended (discussed later).
Endoscopic ultrasound (EUS) as a diagnostic imaging study for
chronic pancreatitis relies on quantitative and qualitative parenchymal
tissue and ductal findings. EUS appears to be equally or more sensitive
than other tests of structure and function. An international consensus panel proposed the Rosemont criteria for diagnosing chronic pancreatitis. Major criteria include hyperechoic foci with shadowing that
indicates pancreatic duct calculi and parenchymal lobularity with honeycombing. Minor criteria include cysts, a dilated main duct (≥3.5 mm
in diameter), irregular pancreatic duct contour, dilated side branches
(≥1 mm in diameter), hyperechoic duct wall, parenchymal strands,
nonshadowing hyperechoic foci, and lobularity with noncontiguous
lobules. In the absence of any of these criteria, chronic pancreatitis is
unlikely, whereas with detection of four or more criteria, the disease is
likely, even when other imaging and pancreatic function tests may still
be normal.
Treatment
Malabsorption
Treatment of PEI is best achieved with pancreatic enzyme replacement
therapy (PERT). Most commercial preparations consist of pancreatin,
which is the shock-frozen powdered extract of porcine pancreas containing lipase, amylase, trypsin, and chymotrypsin.
In order to treat malabsorption due to PEI, it is necessary to provide approximately 10 percent of the normal pancreatic enzyme output. This translates into approximately 30,000 international units (IU)
or the equivalent 90,000 United States Pharmacopeia units (USP) of
lipase per meal. For most patients, the recommended dose depends on
the size and nature of the meal (i.e., fat content), residual pancreatic
function, and therapeutic goals (i.e., elimination of steatorrhea, reduction in the abdominal symptoms of maldigestion, or improvement in
nutrition). Due to residual pancreatic lipase secretion and physiologic
gastric lipase secretion, it is appropriate to begin therapy with 40,000 to
50,000 USP of lipase with each meal and one half of that amount with
snacks. Administration of acid-stable, encapsulated microspheres or
microtablets filled with pancreatic enzymes has greatly increased the
efficacy of enzyme supplementation. Enzyme preparations should be
taken with meals. If more than one capsule/tablet per meal must be
taken, it may be beneficial to take one part of the dose at the beginning
and the rest during the meal.
Other factors may accentuate steatorrhea, including concomitant
small bowel bacterial overgrowth, which can occur in up to 25% of
patients with chronic pancreatitis. Bacterial overgrowth may be caused
by hypomotility due to pancreatic inflammation or chronic use of narcotic analgesics.
Pain
The greatest challenge in treating chronic pancreatitis is controlling
abdominal pain. Pain may improve over time, but the course is not
predictable and improvement may take years. Therapy targets the
mechanisms responsible for pancreatic pain, including pancreatic
hyperstimulation, ischemia, obstruction of ducts, inflammation,
and neuropathic hyperalgesia. Pain can develop in the early stages of
chronic pancreatitis before morphologic changes can be demonstrated
on imaging studies. Patients with chronic pancreatitis are at increased
risk for pancreatic cancer, which may cause a change in the pain pattern, and extrapancreatic causes of pain must always be considered.
Pain management should proceed in a stepwise fashion and begin
with lifestyle modifications such as alcohol and tobacco abstinence, a
low-fat diet, and pancreatic enzyme supplementation, followed by a
sequentially more aggressive and invasive approach for symptomatic
failures, although it should be recognized that placebo alone is effective
for up to 30% of patients. Several approaches can be considered for
chronic pain relief.
1. Tobacco and alcohol abstinence. Abstention may decrease the fre-
quency of painful attacks and reduce the likelihood of pancreatic
function deterioration and development of pancreatic cancer.
2. Analgesics. Most patients with chronic pain require analgesics.
Nonopioid analgesics such as acetaminophen and nonsteroidal
anti-inflammatory drugs are used as initial treatment. If possible,
the use of opioids should be avoided due to the risk of abuse, tol-
erance, and addiction. When deemed necessary, weak opioids (e.g.,
tramadol or codeine) are initially prescribed before escalation to
stronger opioids (e.g., morphine, oxycodone, fentanyl) for poorly
controlled pain. The risk of dependence to opioids is not known
in this setting; however, patients with previous addictive behaviors
such as substance use with alcohol or tobacco are at greater risk for
analgesic dependence and addiction. Safe opioid prescribing prac-
tices are necessary with close monitoring of patients’ symptoms and
adherence to a well-defined plan that includes a patient agreement,
regular follow-up, urine drug testing, and query of the state’s online
prescription monitoring program.
3. Secretion suppression. Oral pancreatic enzyme replacement, soma-
tostatin analogue, and enteral nutrition are proposed treatments to
blunt pain by reducing pancreatic secretion. These therapies are of
unproven benefit and not routinely recommended as adjuncts to
pain therapy. When PERT is initiated for pain management, the
non–enteric-coated pancrelipases (i.e., pancreatic enzyme prepara-
tions) are preferred because the enteric-coated preparations the-
oretically release their enzymes further down the intestine, away
from the stimulatory cholecystokinin (CCK) enterocytes.
4. Neural transmission modification. Gabapentinoids, including pre-
gabalin, have been used effectively to treat neuropathic pain disor-
ders, including diabetic neuropathy and neuropathic pain of central
origin. Based on the finding that pancreatic pain is accompanied by
similar alterations of central pain processing, studies suggest a ben-
efit with pregabalin as an adjuvant treatment to decrease pain asso-
ciated with chronic pancreatitis. Similarly, tricyclic antidepressants,
selective serotonin reuptake inhibitors, and serotonin-norepineph-
rine reuptake inhibitors can be administered on a trial basis.
5. Neuroablative techniques such as celiac plexus blockade can be
performed by injection of a local anesthetic and a steroid into the
region of the celiac ganglia. This can be accomplished through
endoscopic (i.e., EUS) or percutaneous radiologic guidance. The
results are disappointing with a pain reduction in a minority of
individuals (15% to 50%) that is not durable with pain reduction
or relief of up to 1 to 6 months.
6. Antioxidants. Oxidative stress can cause direct pancreatic acinar
cell damage through several pathways. Supplementation with anti-
oxidants, such as selenium, vitamins C and E, and methionine, may
relieve pain and reduce oxidative stress. In a randomized trial, the
reduction in the number of painful days per month was higher for
the patients who received antioxidants compared with those who
received placebo (7.4 vs. 3.2 days). Patients who received antioxi-
dants also were more likely to become pain free (32% vs. 13%).
7. Endoscopic decompression. Endoscopic decompression of the
pancreatic duct is an option for obstruction caused by strictures,
stones, or sphincter of Oddi dysfunction. Endoscopic thera-
pies include pancreatic sphincterotomy, stricture dilation, stone
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413
removal with intracorporeal or extracorporeal shock wave lithotripsy, and temporary plastic stent placement. Complete or partial
pain relief is reported for approximately 50% to 80% of carefully
selected patients during follow-up extending as long as 3 to 4 years.
8. Surgery. Surgical pancreatic ductal drainage, usually with lateral
pancreaticojejunostomy (i.e., Puestow procedure), can be offered
to those with a dilated (>6 mm in diameter) main pancreatic duct.
Pain reduction is reported by approximately 80% of patients.
This procedure is safe and has an operative mortality rate of less
than 5%; however, only 35% to 60% of patients are free of pain
at the 5-year follow-up. Individuals with nonobstructed, nondilated pancreatic ductal systems with disease predominating in the
pancreatic head may be offered resection of the focally diseased
portion of the gland with a pancreaticoduodenectomy or a duodenum-preserving pancreatic head resection also referred to as
a Frey or Beger procedure. Highly selected patients with diffuse
pancreatic parenchymal disease refractory to other forms of therapy may benefit from a total pancreatectomy with islet cell autotransplantation.
Management of Complications
The complications of chronic pancreatitis include pseudocysts, pancreatic fistulas, biliary obstruction, pancreatic cancer, small bowel
bacterial overgrowth, and isolated gastric varices due to splenic vein
thrombosis.
Pancreatic fistulas. Pancreatic fistulas occur as a result of duct
disruption resulting in localized fluid collections, ascites, or pleural
effusions. Treatment consists of bowel rest, endoscopic pancreatic
duct stenting, and administration of a somatostatin analogue.
Surgical intervention may be needed if this conservative approach is
unsuccessful.
Vascular complications. The splenic vein courses along
the posterior surface of the pancreas, where it can be affected by
inflammation from pancreatitis or malignancy that leads to thrombosis.
Splenic vein thrombosis can result in isolated fundal gastric varices.
Splenectomy is usually curative for patients who develop bleeding
from gastric varices.
Pseudoaneurysm formation is a complication of acute and chronic
pancreatitis. Affected vessels, including the hepatic, splenic, pancreaticoduodenal, and gastroduodenal arteries, lie close to the pancreas.
CT or MR imaging shows the pseudoaneurysm as a cystically dilated
vascular structure in or adjacent to the pancreas. EUS with Doppler
imaging can show blood flow within the pseudoaneurysm. Mesenteric
angiography permits confirmation of the diagnosis and provides a
means of therapy because selective embolization of the pseudoaneurysm can be accomplished during the procedure. Surgery for bleeding
pseudoaneurysms is difficult and associated with high morbidity and
mortality rates.
Biliary and duodenal obstruction. Symptomatic obstruction
of the bile duct or duodenum, or both, develops in a few patients
with chronic pancreatitis. Postprandial pain and early satiety
are characteristic of duodenal obstruction, whereas pain and
cholestasis (sometimes with resultant cholangitis) suggest a bile
duct stricture. These complications most commonly result from
inflammation or fibrosis in the head of the pancreas or an adjacent
pseudocyst.
Endoscopic stenting may be attempted for bile duct strictures, but
they are often refractory and typically require prolonged treatment.
Endoscopic failures can be treated with surgical biliary decompression.
The importance of decompression is underscored by the observation
that it can reverse secondary biliary fibrosis associated with bile duct
obstruction.
CARCINOMA OF THE PANCREAS
Definition and Epidemiology
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause
of cancer-related death in the United States, with approximately 45,000
new cases diagnosed annually (see also Chapter 58). The peak incidence of PDAC occurs in the seventh decade of life. There is a modest
male-to-female predominance (relative risk of 1.4:1), and blacks have
a 30% to 40% higher incidence of PDAC than white individuals in the
United States.
Many environmental factors have been implicated as increasing
the risk for pancreatic cancer. Cigarette smoking is the most consistent factor, with the increased risk attributed to the aromatic amines
found in cigarette smoke. Other risk factors include obesity, lack of
physical activity, and diabetes mellitus. Studies evaluating the relationship between diet and pancreatic cancer are inconclusive. A Western
diet (i.e., high intake of fat and meat, particularly smoked or processed
meats) has been linked to the development of pancreatic cancer in
many studies. Chronic pancreatitis also increases the risk of PDAC
(relative risk as high as 13-fold), particularly in those individuals with
hereditary pancreatitis and tropical pancreatitis. Epidemiologic studies
have failed to find a consistent association between alcohol or coffee
consumption and the development of pancreatic cancer.
Up to 10% of patients with pancreatic cancer have a family history of the disease, but most cannot be identified with a known genetic
disorder. Recognized genetic disorders that predispose to pancreatic cancer include hereditary pancreatitis (PRSS1 gene), hereditary
nonpolyposis colorectal cancer, familial adenomatous polyposis,
hereditary breast and ovarian cancers (PALB2 and BRCA2 genes),
Peutz-Jeghers syndrome (STK11 gene), familial atypical mole melanoma syndrome (CDKN2A gene), ataxia telangiectasia (ATM gene),
and the Von Hippel–Lindau syndrome (VHL gene). Screening to
detect precancerous lesions or early cancers should be considered for
individuals with a cumulative predicted risk of PDAC greater than 5%
or relative risk (RR) of 5 or greater (having ≥2 relatives with PDAC
including ≥1 a first degree, or having a germline mutation of a predisposing gene and ≥2 relatives with PDAC or ≥1 a first degree, or
Peutz–Jeghers syndrome even in the absence of a family history) and
eligible for a possible pancreatic resection after discussion of the risks
and benefits of such screening. Although imaging surveillance of highrisk family cohorts is practiced at some centers of expertise, there is
no consensus about the optimal methods or frequency of pancreatic
cancer screening. Screening with EUS and/or MRI can be considered
but has not been shown to improve survival rates.
Pathology
More than 95% of malignant neoplasms of the pancreas arise from the
exocrine pancreas. The term pancreatic cancer usually refers to ductal
adenocarcinoma of the pancreas, representing 85% to 90% of all pancreatic neoplasms. Exocrine pancreatic neoplasm is a more inclusive term
that includes neoplastic pancreatic ductal and acinar cells and their stem
cells (e.g., pancreatoblastoma). Other, less common exocrine cancers
include adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, and undifferentiated carcinomas. Neoplasms
arising from the endocrine pancreas (i.e., islet cell or neuroendocrine
tumors) comprise no more than 5% of pancreatic neoplasms.
Pancreatic cancers are composed of several distinct elements,
including pancreatic cancer cells, tumor stroma, and stem cells. The
precursor lesion of pancreatic cancer is pancreatic intraepithelial neoplasia, which progresses from mild dysplasia (PanIN grade 1) to more
severe dysplasia (PanIN grades 2 and 3) and eventually to invasive
carcinoma.
414 SECTION VI Gastrointestinal Disease
TABLE 39.4 Definitions of Pancreatic Ductal Adenocarcinoma Treatment Categories
Resectable No evidence of tumor spread outside the pancreas
No involvement of the superior mesenteric artery (SMA), celiac, or common
hepatic artery (CHA)
No invasion of the superior mesenteric vein (SMV) or portal vein (PV)
Metastatic Evidence of spread to other organs (typically liver, lung, or peritoneum)
Borderline resectable Tumor abutment (<50% of vessel circumference) of celiac, SMA or CHA
Involvement but patent SMV or PV or short-segment occlusion with option for
reconstruction
Locally advanced Arterial encasement (>180 degrees or 50% of vessel circumference) of SMA,
celiac or CHA
SMV/PV occlusion without ability to surgically reconstruct
Clinical Presentation
The clinical manifestations of pancreatic carcinoma may be nonspecific and are often insidious. The clinical presentation is dependent
to a great extent on tumor location and stage. PDAC localized to the
head of the pancreas (70% to 80%) are more frequently symptomatic
than those located in the body or tail (20% to 30%). Most PDAC has
reached an advanced stage by the time of diagnosis. Common presenting signs and symptoms of pancreatic cancer include jaundice, weight
loss, and abdominal pain. The pain is usually constant, with radiation
to the back. Because most cancers begin in the pancreatic head, patients
may exhibit obstructive jaundice or a large, palpable gallbladder (i.e.,
Courvoisier’s sign).
Painless jaundice is the most common manifestation in patients
with a potentially resectable and curable lesion. Anorexia, nausea, and
vomiting may also occur, along with emotional disturbances such as
depression. Less common manifestations include superficial thrombophlebitis (i.e., Trousseau sign), acute pancreatitis, diabetes mellitus,
ascites, paraneoplastic syndromes (e.g., Cushing’s syndrome), hypercalcemia, gastrointestinal bleeding, splenic vein thrombosis, and a palpable abdominal mass.
Diagnosis and Staging
The goal of imaging in the evaluation of suspected pancreatic carcinoma is to establish the diagnosis with a high degree of certainty and
to determine resectability in patients who are otherwise candidates for
operative resection. The diagnosis of pancreatic cancer is frequently
suggested by a pancreatic mass seen on imaging studies. Evidence of
a dilated pancreatic duct, hepatic metastases, invasion of vessels, or
a dilated common bile duct in the setting of biliary obstruction may
also be found. The imaging appearance may be impossible to distinguish from benign causes of pancreatic masses such as focal pancreatitis or autoimmune pancreatitis. Pancreas protocol triple phase (i.e.,
arterial, late arterial, and venous phases) cross-sectional multidetector
CT scanning is the best initial study to diagnose and stage pancreatic
cancer by identifying a mass lesion and assessing for liver metastasis or
vascular invasion. CT is reported to have a sensitivity of 90% to 97%
for identifying PDAC, although it is less sensitive for diagnosing small
(<2 cm) lesions, with a sensitivity of 65% to 75%. CT is not sensitive
for detecting nodal metastases. MRI is an alternative imaging modality
that has similar accuracy to CT scanning for the diagnosis and staging
of PDAC. EUS is superior to CT and MRI for detecting small lesions of
the pancreas and should be performed when there is strong suspicion
of PDAC despite the absence of a mass lesion by other imaging modalities. EUS-guided fine-needle aspiration (sensitivity of 85% to 90%
and specificity approaching 100%) is recommended when histologic
confirmation will alter management such as confirming malignancy
in unresectable disease prior to initiating palliative care, confirming
a potentially resectable tumor prior to neoadjuvant therapy, and for a
suspected mass not visible on cross-sectional imaging.
The imaging techniques are highly accurate for recognizing unresectable disease, but they are somewhat limited for identifying resectable disease because occult metastases (<1 cm in diameter) may be on
the surface of the liver or peritoneum. Staging laparoscopy may reduce
morbidity and cost from open surgical tumor resection; it should be
considered for patients with the highest likelihood of occult metastatic
disease (i.e., those with tumors of the body or tail of the pancreas) who
appear to have potentially resectable disease by CT (one half of whom
have occult peritoneal metastases), those with large (>3 cm) primary
tumors, those for whom imaging suggests occult metastatic disease,
and those with a very high initial CA 19-9 level (>1000 units/mL).
The use of tumor markers to diagnose carcinoma of the pancreas
has yielded disappointing results. The tumor marker CA 19-9 has a
sensitivity of 70% to 80% and a specificity of 85% to 95% for diagnosing selected patients already exhibiting signs and symptoms that
suggest pancreatic cancer. However, for early-stage cancers, CA 19-9
has limited sensitivity. Use of CA 19-9 requires the Lewis blood group
antigen, which is absent in 5% to 10% of the population. The greatest utility for CA 19-9 is to identify occult metastasis in patients with
seemingly resectable tumors, for monitoring patients after apparently
curative surgery, and for following those receiving chemotherapy for
advanced disease. Rising CA 19-9 levels suggest recurrent disease even
in the absence of radiographically detectable lesions.
Treatment
Dividing patients with PDAC into resectable, borderline resectable, locally advanced, and metastatic categories is clinically useful
(Table 39.4).
Resectable Disease
Unfortunately, only 10% to 20% of carcinomas in the head of the
pancreas and rare cancers of the body and tail are resectable for cure.
Current criteria for resectability include the absence of distant metastases and the absence of tumor involvement of major arteries (superior
mesenteric, celiac, and common hepatic). Venous involvement requires
vascular patency and criteria for resectability will depend on the surgeon’s experience and ability to perform vascular reconstruction.
Universal preoperative ERCP for patients with biliary obstruction
is not recommended due to lack of proven benefit and the potential
to increase adverse events. Selective use of ERCP with biliary stent
placement is recommended for those patients with biliary obstruction
and a clinical presentation of either cholangitis, intractable pruritus,
marked hyperbilirubinemia, or when surgery is delayed for neoadjuvant therapy. Technical success of ERCP is achieved in over 90% of
such patients with an acceptable complication rate of under 5%. At the
CHAPTER 39 Diseases of the Pancreas
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415
time of stent placement, ERCP tissue sampling techniques can confirm
a diagnosis of pancreatic malignancy (sensitivity of 30% to 60% and
specificity 100%).
The standard operation for pancreatic cancer of the head or uncinate process is the Whipple procedure (i.e., pancreaticoduodenectomy). Whipple resection consists of removal of the pancreatic head,
distal common bile duct, gallbladder, duodenum, proximal jejunum,
gastric antrum, and regional lymph nodes. Reconstruction requires
pancreaticojejunostomy, hepaticojejunostomy, and gastrojejunostomy. The pylorus-preserving version of the Whipple procedure leaves
the stomach intact. The surgical mortality rate for this procedure is
approximately 3% when performed by experienced pancreatic surgeons. Adjuvant therapy is indicated in all patients following resection
of PDAC, irrespective of the pTNM stage, as it improves progression-free and overall survival rates.
Locally Advanced and Borderline Resectable
The term borderline resectable is reserved for patients with focal tumor
abutment of the visceral arteries (celiac, superior mesenteric artery [SMA],
or common hepatic), defined as contact of the tumor with less than one
half circumference of the vessel wall, or short-segment occlusion of the
superior mesenteric vein (SMV) or SMV–portal vein confluence. The latter is considered a relative rather than absolute contraindication to curative resection as some surgeons are performing resection with vascular
reconstruction for selected individuals under these circumstances. Also,
for tumors of the tail of the pancreas, encasement of the splenic vein does
not necessarily obviate resectability. Locally advanced disease refers to
individuals with unresectable cancer due to arterial encasement (>180° or
>50% vessel circumference) of SMA, celiac or common hepatic arteries or
SMV/PV occlusion without an option for reconstruction.
The use of preoperative neoadjuvant chemoradiation therapy in
an effort to convert patients with unresectable borderline or locally
advanced disease to a resectable status has increased the overall resection rate, but no difference in survival has been demonstrated.
Metastatic or Unresectable Disease
Although practice varies across institutions, most surgeons consider
a pancreatic cancer to be categorically unresectable if there is extrapancreatic involvement, including extensive peripancreatic lymphatic
extension, nodal involvement beyond the peripancreatic tissues, or
distant metastases (e.g., liver, peritoneum, omentum, extra-abdominal
sites). Other indications of unresectability include vascular encasement
(i.e., tumor contact with more than one-half of the vessel’s circumference), or direct involvement of the superior mesenteric artery, aorta,
celiac artery, or hepatic artery, as defined by the absence of a fat plane
between the tumor and these structures on CT imaging.
Patients with metastatic or inoperable pancreatic cancer should
be offered treatment with multidisciplinary input based on goals of
care, patient preferences, performance status (PS) and social support
systems. If protocol enrollment is not available or is declined, conventional systemic chemotherapy should be offered because it provides
benefit improving disease-related symptoms and overall survival.
• Patientsunderage75yearswithanECOGPS0to1andbilirubin
less than 1.5 mg/dL should be offered FOLFIRINOX or gemcit-
abine plus nab-paclitaxel;
• PatientswithanECOGPS2andbilirubinlessthan1.5ULNshould
be offered gemcitabine plus nab-paclitaxel or gemcitabine;
• PatientswithanECOGPS0to2andbilirubin1.5ULNorgreater
or comorbidities should be offered gemcitabine; and
• PatientswithanECOGPS3to4shouldbeofferedbestsupportive
care.
For patients with inoperable cancers and poor performance status, palliative interventions to alleviate jaundice, pain, and intestinal
obstruction often become the focus of therapy. When advanced disease is observed operatively, the surgeon must determine whether to
perform additional palliative surgery. Biliary bypass is indicated in
patients with obstructive jaundice. Duodenal bypass is indicated when
features suggest impending gastric outlet obstruction. Alternative palliative endoscopic approaches are available for patients not undergoing
exploratory surgery.
Prognosis
Carcinoma of the pancreas accounts for approximately 5% of cancer
deaths in the United States. The overall prognosis is poor because less
than 20% of patients are alive beyond the first year after diagnosis, and
only 7% survive to the fifth year. Although 15% to 20% of patients
have resectable disease at initial diagnosis, most have locally advanced
or metastatic cancer. Median survival is 8 to 12 months for patients
with locally advanced unresectable disease and 3 to 6 months for those
with metastases at diagnosis.
A Whipple resection for pancreatic head cancers is the only chance
for cure; however, the median survival after surgery is 15 to 20 months.
Five-year survival after margin negative (R0) pancreaticoduodenectomy is approximately 25% to 30% following node-negative resection
and 10% for node-positive disease. The overall 5-year survival rate is
10% to 25%, and up to 50% of those who survive 5 years ultimately
die of recurrent cancer. Poor prognostic factors include a high tumor
grade, a large tumor, high levels of CA 19-9 before and after surgery,
tumor-positive surgical margins, and lymph node metastases.
For a deeper discussion of these topics, please see Chapter 135,
“Pancreatitis,” and Chapter 185, “Pancreatic Cancer,” in Goldman-
Cecil Medicine, 26th Edition.
SUGGESTED READINGS
Baron TE, DiMaio CJ, Wang AY, et al: American Gastroenterological
Association Clinical Practice update: management of pancreatic necrosis,
Gastroenterology 158:67–75, 2020.
Fogel EL, Shahda S, Sandrasegaran K, et al: A multidisciplinary approach to
pancreas cancer in 2016: a review, Am J Gastroenterol 112:537–554, 2017.
Forsmark CE: Management of chronic pancreatitis, Gastroenterology
144:1282–1291, 2013.
Gardner TB, Adler DG, Forsmark CE: ACG clinical guideline: chronic
pancreatitis, Am J Gastroenterol, 2020.
Hidalgo M: Pancreatic cancer, N Engl J Med 362:1605–1617, 2010.
Paulson AS, Cao HS, Tempero MA, et al: Therapeutic advances in pancreatic
cancer, Gastroenterology 144:1316–1326, 2013.
Singh VK, Yadav D, Garg PK: Diagnosis and management of chronic
pancreatitis: a review, JAMA 322:2422–2434, 2019.
Tenner S, Baillie J, DeWitt J, et al: American College of Gastroenterology
guideline: management of acute pancreatitis, Am J Gastroenterol
108:1400–1415, 2013.
Vege SS, DiMagno MJ, Forsmark CE, et al: Initial medical treatment of acute
pancreatitis: American Gastroenterological Association Institute Technical
review, Gastroenterology 154:1103–1139, 2018.
Whitcomb DC: Genetic risk factors for pancreatic disorders, Gastroenterology
144:1292–1302, 2013.
Yadav D, Lowenfels AB: The epidemiology of pancreatitis and pancreatic
cancer, Gastroenterology 144:1252–1261, 2013.
SECTION VII
Diseases of the
Liver and Biliary System
40 Laboratory Tests in Liver Diseases, 417
41 Jaundice, 420
42 Acute and Chronic Hepatitis, 426
43 Acute Liver Failure, 434
44 Cirrhosis of the Liver and Its
Complications, 437
45 Disorders of the Gallbladder and Biliary
Tract, 448
416
40
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Laboratory Tests in Liver Diseases
Michael B. Fallon, Ester Little
INTRODUCTION
The liver is a large and complex organ, involved in major metabolic,
secretory, and nutritional functions. It plays a central role in glucose
homeostasis, synthesis and secretion of bile, and synthesis of lipoproteins and plasma proteins, including clotting factors and vitamin
storage (vitamins B12, A, D, E, and K). It is also the site of biotransformation, detoxification, and excretion of a multitude of endogenous
and exogenous compounds.
Given the diversity of the liver roles, the clinical manifestation of liver
diseases is varied and can be quite subtle. The first step in evaluating a
patient with liver disease is the clinical history, and signs of liver disease can also be seen on physical exam (e.g., jaundice, dark urine, light
colored stools, gastrointestinal bleeding, spider angiomas, palmar erythema, hepatomegaly, splenomegaly, ascites, and asterixis). The history
and physical findings guide the initial set of laboratory tests ordered.
LIVER CHEMISTRY TESTS
The most widely used tests to evaluate the liver are aspartate and alanine aminotransferases (AST and ALT), alkaline phosphatase (ALP),
gamma glutamyl transpeptidase (GGT), bilirubin, albumin, and prothrombin time. They are commonly referred to as “liver function
tests.” However, this is misleading because (1) they do not accurately
reflect the function of the liver, (2) abnormal levels can indicate diseases affecting other organs, and (3) they may be normal in patients
with advanced liver disease. A better terminology is liver chemistry
tests. These tests reflect patterns of abnormalities seen in liver and biliary cell injury.
Patterns of Abnormalities in Liver Chemistry Tests
There are primarily three patterns of abnormalities in liver chemistry tests: one that reflects damage of the hepatocytes or hepatocellular
damage (AST and ALT), one that reflects cholestasis and damage of
the biliary cells (ALP and GGT), and one when patients have isolated
elevation in bilirubin.
The tests are interpreted based on limits of normality and may vary
between different laboratories. However, for ALT, it is now recognized
that the limit of normality should be the same for all, and many professional societies have included the following levels in their guidelines:
normal ALT ranges from 29 to 33 units/L in adult men and 19 to 25
units/L in adult women. Table 40.1 depicts the most common liver
chemistry tests and the disease processes associated with each set of tests.
Hepatocellular Damage
ALT and AST are intracellular enzymes that catalyze the transfer of
the α-amino group of aspartate or alanine to the α-keto group of
ketoglutaric acid, resulting in formation of pyruvate or oxaloacetic
acid, respectively. Vitamin B6 is required to carry out this reaction. In
the presence of cell injury or death, AST and ALT are released into
circulation. ALT is found predominantly in hepatocytes and is more
specific, whereas AST is also found in the heart, lungs, kidney, pancreas, brain, and skeletal muscle.
In most hepatocellular disorders (i.e., viral hepatitis, autoimmune
hepatitis, hemochromatosis, Wilson’s disease and some drug-induced
liver injury) ALT is higher than or equal to AST. However, in alcoholic
liver disease this ratio is reversed. A ratio greater than 2 is seen in 70%
and greater than 3 in 96% of the patients with known alcoholic liver
disease. Chronic and heavy alcohol consumption leads to vitamin B
deficiency. The effect of vitamin B6 deficiency is more prominent on
ALT than AST activity, causing the increase in AST/ALT ratio. Not
uncommonly, the AST is also higher than ALT in patients with nonalcoholic fatty liver disease (NAFLD), mimicking alcoholic liver disease.
The magnitude of elevation in aminotransferases also helps identify
the possible cause of liver damage. Marked elevation, above 15 times the
upper limit of normality (ULN), is seen in acute viral hepatitis, acetaminophen toxicity, hypoxic hepatopathy (shock, ischemia, hypoxemia)
or acute bile duct obstruction. More modest elevations, usually 10 to 15
times the ULN, are seen in alcoholic hepatitis, autoimmune hepatitis,
Wilson’s disease, Budd-Chiari, and malignant infiltration of the liver
(usually from breast cancer, small cell lung cancer, lymphoma, melanoma). In patients with chronic viral hepatitis, ALT and AST levels are
rarely above 10 times the ULN, except during exacerbations of chronic
hepatitis B. Elevations less than four times the ULN are more commonly
seen in nonalcoholic fatty liver disease, hemochromatosis, α1-antitrypsin deficiency, celiac disease, and thyroid disease. Once the liver damage
has progressed to cirrhosis, the elevation in aminotransferases is mild
and can be normal. Conversely, ALT and AST can be massively elevated in diseases not related to the liver, such as rhabdomyolysis and
heat stroke. In addition to acetaminophen, multiple medications can
cause elevation in the aminotransferases at different levels of magnitude,
including diclofenac, fluoxetine, isoniazid, ketoconazole, lisinopril, phenytoin, rifampin, ritonavir, and statins.
The rate at which the AST and ALT levels decrease as the patient
improves can also help in identifying the cause. More rapid decline
suggests ischemia or resolution of an acute biliary obstruction.
Cholestasis
The tests that indicate cholestasis and biliary cell damage are ALP and
GGT. Serum ALP comprises a group of isoenzymes derived from the liver,
intestine, bone, and placenta. The liver isoenzyme (ALP-1) is present in
the mucosal cells lining the bile ducts and increases in response to bile
duct damage from inflammation or obstruction. In these circumstances,
417
418 SECTION VII Diseases of the Liver and Biliary System
TABLE 40.1 Liver Chemistry Tests
Liver Chemistry Test What It Reflects Associated Diseases
Aspartate aminotransferase and
alanine aminotransferase
Alkaline phosphatase and
γ-glutamyl transpeptidase
Isolated bilirubin elevation Increased production and impaired uptake,
Decreased albumin and prolonged
prothrombin time
Hepatocellular damage Viral hepatitis, autoimmune hepatitis (AIH), alcoholic hepatitis, hemochroma-
tosis, ischemic hepatitis, Budd-Chiari syndrome, α1-antitrypsin deficiency,
Wilson’s disease, and drugs
Cholestasis, biliary cell damage, and infiltra-
tive processes
conjugation or excretion of bilirubin
Impaired synthetic liver function Liver failure, severe acute hepatitis, and advanced liver disease with cirrhosis
Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), familial choles-
tatic syndromes, AIDS cholangiopathy, cholestasis of pregnancy, biliary obstruction
by stones or cancer, drugs, sarcoidosis, amyloidosis, and malignancy infiltration
Hemolysis, Gilbert, Crigler-Najjar, Dubin-Johnson, and Rotor syndromes
GGT and 5′-nucleotidase (5′-NT) are simultaneously released. Thus, an
elevation of ALP without elevation of GGT and 5′-NT indicates a nonhepatic cause. Fractionation of the different ALP isoenzymes by electrophoresis can be useful in determining alternative sources.
ALP does not differentiate intrahepatic from extrahepatic cholestasis. Examples of disorders that cause intrahepatic cholestasis are primary
biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), infections (AIDS cholangiopathy), familial cholestatic syndromes, cholestasis of pregnancy, total parenteral nutrition, ischemic cholangiopathy,
liver allograft rejection, congestive hepatopathy (liver congestion secondary to right-sided heart failure), some medications (amiodarone,
anabolic steroids, amoxicillin clavulanate, carbamazepine, estrogens,
naproxen, phenytoin, rifampin), and infiltrative diseases (sarcoidosis,
amyloidosis, malignant infiltration of the liver). Causes of extrahe-
patic cholestasis include bile duct stones or tumors, diverticulum of the
ampulla of Vater, chronic pancreatitis, and pancreatic cancer.
ALP is frequently below normal range in patients with Wilson’s disease, particularly those presenting with acute liver failure, in whom bilirubin is disproportionally elevated compared to alkaline phosphatase.
GGT is very nonspecific, and in addition to liver diseases it can be
elevated in pancreatic diseases, myocardial infarction, renal failure, alcoholism, chronic obstructive pulmonary disease, and from several medications. As noted above, 5′-NT would not be elevated in these conditions.
Isolated Bilirubin Elevation
Patients with both hepatocellular diseases and cholestasis frequently
also have bilirubin elevation secondary to leakage of bilirubin into the
serum. However, some patients have elevated bilirubin with normal
ALT, AST, ALP and GGT, which is termed isolated bilirubin elevation.
In such cases, the first step is to fractionate the bilirubin to determine
if it is caused by an elevation in the unconjugated (indirect) or conjugated (direct) bilirubin. An increase in unconjugated bilirubin results
from overproduction (hemolysis), impaired uptake (Gilbert’s disease) or impaired conjugation (Crigler-Najjar syndrome). An increase
in conjugated bilirubin is due to decreased excretion in the bile ducts
(Dubin-Johnson and Rotor syndromes) or leakage of the pigment
from hepatocytes into serum.
More detailed discussion on cholestasis and isolated elevation of
bilirubin can be found in Chapter 41.
The half-life of albumin in serum is 14 to 20 days. Low albumin is seen
in prolonged liver dysfunction or acute liver impairment, and a decrease
in albumin concentration reflects a reduction in albumin synthesis.
Hypoalbuminemia does not always reflect liver synthetic dysfunction. Several other conditions may decrease albumin, including
malnutrition, nephrotic syndrome, protein losing enteropathy, and
systemic inflammation.
Coagulation Factors and Prothrombin Time
The liver is the major site for the synthesis of 11 coagulation factors,
including factors I, II, V, VII, IX, X, XII, and XIII. Deficiency in clotting factors occurs in more severe or more advanced stages of liver
diseases. These factors can be measured individually or indirectly by
determining the prothrombin time (PT).
The PT is dependent on factors II, V, VII and X, all of which are
synthesized in the liver. Prolonged PT is not specific to liver diseases
and can be seen in several congenital or acquired disorders. When
these conditions are excluded, a prolonged PT is usually secondary to
deficiency of vitamin K (inadequate dietary intake, prolonged obstructive jaundice, intestinal malabsorption or prolonged broad spectrum
antibiotic use) or by poor utilization of vitamin K because of advanced
liver disease. The administration of a single parenteral dose of vitamin
K normalizes the PT in cases of vitamin K deficiency.
The magnitude of the prolongation of PT reflects the severity of the
liver disease; however, PT does not correlate with the coagulation status or the risk of bleeding in patients with cirrhosis. In fact, in patients
with cirrhosis there is also a decrease in synthesis of anti-hemostatic
factors, and some patients become relatively hypercoagulable and have
an increased risk of clot formation, despite having prolonged PT. This
is an important and frequently misunderstood concept.
Gamma Globulins
Elevation of individual gamma globulins can be suggestive of specific
liver diseases. Some examples include elevation of immunoglobulin G
(IgG) in patients with autoimmune hepatitis, elevation of immunoglobulin M (IgM) in PBC, and elevation of immunoglobulin A (IgA)
in patients with alcoholic cirrhosis. IgG4-related disease is an autoimmune phenomenon in which increased IgG4 levels cause dysfunction
in multiple organs, including bile ducts (IgG4-related cholangiopathy).
LIVER SYNTHETIC FUNCTION
Albumin
From 300 g to 500 g of albumin is distributed in body fluids, and the
adult liver synthesizes 15 g of albumin per day. Serum albumin concentration reflects the rate of synthesis, degradation, and volume of distribution. The synthesis of albumin is influenced by several factors including
nutritional status, serum oncotic pressure, hormones, and cytokines.
Specific Markers of Liver Diseases
Specific laboratory tests are required for the diagnosis of some liver
diseases.
• α1-Antitrypsin (α1AT): it can be quantified and, if decreased, the
A1AT phenotype can be determined
• Autoimmune hepatitis: antinuclear antibody (ANA), anti–smooth
muscle antibody (ASMA), anti–liver/kidney microsomal antibody
type 1 (anti-LKM1)
CHAPTER 40 Laboratory Tests in Liver Diseases
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419
• Primary biliary cholangitis: antimitochondrial antibody (AMA)
• Hemochromatosis: iron panel (serum iron, total iron binding
capacity, transferrin saturation and ferritin) and HFE gene mutations
• Wilson’s disease: serum ceruloplasmin and urinary copper levels
• Viruses: different viruses (e.g., hepatitis A, B, C, D, E, Epstein-Barr
virus, cytomegalovirus, and herpes virus) that cause hepatitis are
detected using polymerase chain reaction.
Biomarkers of Liver Fibrosis
Liver biopsy is the “gold standard” for evaluation of liver histopathology. Although the complications are few, it is an invasive test and the
need for less invasive means to evaluate fibrosis led to several studies in
search of surrogate markers for hepatic fibrosis. Many such tests combine clinical and serum markers and have been validated in specific
populations, particularly chronic hepatitis C and nonalcoholic fatty
liver disease. Caution is needed when using the results in other patient
populations. In addition, serum markers are not liver specific and concurrent sites of inflammation may contribute to deranged serum levels.
These tests are used to differentiate patients with more significant stages of fibrosis and cirrhosis (stages 3 and 4), from those with
minimal or no fibrosis (stages 0 and 1). The stages are based on the
METAVIR score and range from 0 to 4, where stage 4 corresponds to
cirrhosis.
Examples of such tests include the following:
• APRI Score is based on the AST and platelet count (AST eleva-
tion/platelet count) × 100. It has been mostly studied in patients
with HCV, HCV and HIV co-infection, alcoholic liver disease, and
NAFLD.
• FibroSure or FibroTest uses the measurement of α2-macroglob-
ulin, α2-globulin, γ-globulin, apolipoprotein A1, GGT, and total
bilirubin. It also utilizes the patient’s age and sex. The results clas-
sify the patients as having mild fibrosis, indeterminate fibrosis or
significant fibrosis. It has been better studied in patients with HCV
and has a better specificity than sensitivity.
• HepaScore utilizes the combination of bilirubin, GGT, hyaluronic
acid, α2-macroglobulin, age, and sex. Its performance is similar to
the FibroTest.
• FIB 4 index combines platelet count, ALT, AST, and age. Better
studied in HCV and NAFLD.
• NAFLD fibrosis score considers the patient’s age, body mass index,
blood glucose, aminotransferases, platelet count, and albumin.
Other panel tests have included products of collagen synthesis or degradation, enzymes involved in matrix biosynthesis or degradation,
extracellular matrix glycoproteins, and proteoglycans/glycosaminoglycans.
The routine use of these panels in clinical practice is not clearly
established and some suggest their use in combination with image
modalities.
Image tests applying mechanical waves and measuring their propagation speed through liver tissue using ultrasound and MRI have
become more readily available. They have been studied in a broader
spectrum of liver diseases and have better sensitivity and specificity
than the serologic tests. Nevertheless, at this point none of these tests
fully substitute for liver biopsy.
SUGGESTED READINGS
Gao Y, Zheng J, Liang P, et al: Liver fibrosis with two-dimensional US shear-
wave elastography in participants with chronic hepatitis B: a prospective
multicenter study, Radiology 289:407–415, 2018.
Newsome PN, Cramb R, Davison SM, et al: Guidelines on the management of
abnormal liver blood tests, Gut 67:6–19, 2018.
Northup PG, Caldwell SH: Coagulation in liver disease: a guide for the
clinician, Clin Gastroenterol Hepatol 11:1064–1074, 2013.
Poynard T, De Ledinghen V, Zarski JP, et al: Relative performances of
FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver
fibrosis in patients with chronic hepatitis C: a step toward the truth in the
absence of a gold standard, J Hepatol 56:541–548, 2012.
Rockey D, Caldwell SH, Goodman ZD, et al: AASLD position paper: liver
biopsy, Hepatology 49:1017–1044, 2009.
Sebastiani G, Halfon P, Castera L, et al: Comparison of three algorithms of
non-invasive markers of fibrosis in chronic hepatitis C, Aliment Pharmacol
Ther 35:92–104, 2012.
Tapper EB, Saini SC, Sengupta N: Extensive testing or focused testing of
patients with elevated liver enzymes, J Hepatol 66:313–319, 2017.
41
Jaundice
Mohanad T. Al-Qaisi, Mashal Batheja, Michael B. Fallon
INTRODUCTION
Jaundice is the condition of yellowish pigmentation of the skin, the
conjunctival membranes over the sclera, and other mucous membranes that is caused by elevated serum bilirubin levels (hyperbilirubinemia). The term jaundice is derived from jaune, the French word
for “yellow,” and the condition is also known as icterus (Greek for
“yellow”). Normal serum bilirubin levels range from 0.5 to 1.0 mg/dL,
and plasma bilirubin concentrations typically must exceed 2.5 mg/dL
before jaundice becomes evident clinically.
Although jaundice is commonly due to liver and biliary tract disease, it has many causes, so it is not surprising that the diagnosis and
management of jaundice have challenged clinicians for centuries. In
most cases, jaundice or hyperbilirubinemia per se is not a pathologic
condition but rather a sign of one or more illnesses originating from
or affecting the liver and blood. However, there is one notable exception: In newborns, high bilirubin levels can lead to pathologic cerebral
changes. In this condition, which is known as kernicterus (kern is the
German word for “nucleus”), persistent elevation of unconjugated bilirubin leads to its deposition in the cerebral basal ganglia (or nuclei).
This process can be prevented and treated and therefore merits special
recognition to prevent damage to the developing brain.
BILIRUBIN METABOLISM
Hyperbilirubinemia can be classified based on the three phases of
hepatic bilirubin metabolism: uptake, conjugation, and excretion into
the bile (the rate-limiting step). In addition, jaundice can be classified into prehepatic, hepatic, and posthepatic causes (Table 41.1).
Although the approaches are complementary, the latter classification
may be more useful for the practicing clinician.
The main source of bilirubin is the hemoglobin released from senescent red blood cells, and the liver serves as its primary site of metabolism
and excretion. Abnormalities at any step in bilirubin production, metabolism, or excretion can lead to an increase in the serum bilirubin and
clinical jaundice. Under normal conditions, human red blood cells have
a lifespan of about 120 days. As they age, erythrocytes are broken down
and removed from the circulation by phagocytes. Most bilirubin (80%) is
derived from the breakdown of hemoglobin released from these cells; the
remainder is derived from ineffective erythropoiesis in the bone marrow
and from catabolism of myoglobin and hepatic hemoproteins such as the
cytochrome P-450 isoenzymes. The normal rate of bilirubin production is
approximately 4 mg/kg body weight per day (E-Fig. 41.1).
As erythrocytes are destroyed within the reticuloendothelial system, free hemoglobin is ingested by macrophages and then split into
heme and globin moieties. The heme ring is cleaved by the enzyme
microsomal heme oxygenase to form biliverdin (verde = “green”),
which is then converted to the tetrapyrrole pigment bilirubin by the
cytosolic enzyme biliverdin reductase. This unconjugated (or “indirect”) bilirubin is released into the plasma, where it is tightly bound
to albumin. Because unconjugated bilirubin is insoluble in water, it
cannot be excreted in urine or bile. However, it is permeable across
lipid-rich environments and therefore can traverse the blood-brain
barrier and the placenta.
The unconjugated bilirubin-albumin complex is transported to the
liver. Once in the space of Disse, this complex dissociates; unconjugated bilirubin is transported across the basolateral plasma membrane
of liver cells and attaches to intracellular binding proteins (ligandins). It is then conjugated with glucuronic acid by the enzyme uridine diphosphate glucuronyl transferase (UDP-GT) to form bilirubin
monoglucuronide and diglucuronide, making the molecule water soluble. This conjugated (or “direct”) bilirubin is excreted into bile via
active transport across the canalicular membrane by means of a multispecific canalicular transport protein. In healthy persons, most bilirubin circulates in its unconjugated form with less than 5% of circulating
bilirubin appearing in its conjugated form. If biliary excretion of conjugated bilirubin is impaired, it can exit the basolateral membrane and
reenter the circulation, causing an increase in plasma levels. Because
conjugated bilirubin is water soluble and less tightly bound to albumin than its unconjugated form, it is readily filtered by the glomerulus
and appears in the urine, giving it a dark color (choluria). Once in
bile, bilirubin enters the intestine, where bacteria convert it to colorless
tetrapyrroles (urobilinogens) that are excreted in feces. Up to 20% of
urobilinogen is reabsorbed and undergoes enterohepatic circulation or
excretion in urine.
LABORATORY MEASUREMENT OF BILIRUBIN
The van den Bergh reaction, which is the most commonly used test for
detecting bilirubin in biologic fluids, combines bilirubin with diazotized sulfanilic acid to form a colored compound. The direct-reacting
fraction is roughly equivalent to conjugated bilirubin and the indirect-reacting fraction (total minus direct fraction) to unconjugated
bilirubin. This characteristic provides a means for classifying jaundice
into two categories: unconjugated hyperbilirubinemia and conjugated
hyperbilirubinemia.
UNCONJUGATED HYPERBILIRUBINEMIA
Mechanisms that cause unconjugated hyperbilirubinemia include
overproduction, impaired hepatic uptake, and decreased conjugation
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CHAPTER 41 Jaundice
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TABLE 41.1 Classification of Jaundice and Representative Causes
Prehepatic Causes
Predominantly unconjugated hyperbilirubinemia
Hemolysis (e.g., sickle cell disease, autoimmune hemolytic anemia, mechanical cardiac valve with accelerated red cell destruction)
Microbe-induced hemolysis (malaria, leptospirosis)
Ineffective erythropoiesis (e.g., megaloblastic anemias)
Hematoma resolution
Hepatic Causes
Unconjugated hyperbilirubinemia
Decreased hepatic uptake
Therapeutic drugs that interfere with bilirubin uptake (e.g., rifampin, metformin, methimazole, propylthiouracil, clopidogrel, sulfamethoxazole/trimethoprim)
Herbal medicines (e.g., Teucrium viscidum, kava-kava, chaparral, greater celandine)
Hyperthyroidism
Diminished uptake and decreased cytosolic binding proteins (e.g., newborn or premature infants)
Shunting of blood away from the liver (portal hypertension or surgical shunt)
Decreased conjugation due to limited glucuronyl transferase activity
Gilbert syndrome
Crigler-Najjar syndrome types I and II
Neonatal jaundice
Breast-milk jaundice
Drug-induced inhibition (e.g., chloramphenicol)
Predominantly conjugated hyperbilirubinemia
Impaired hepatic excretion
Familial cholestasis (Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis, cholestasis of pregnancy)
Hepatocellular injury from infiltrative disorders, hemochromatosis, α1-antitrypsin deficiency, lymphoma, sarcoidosis, extensive metastases)
Liver cirrhosis
Hepatitis
Drug-induced cholestasis (chlorpromazine, erythromycin estolate, isoniazid, halothane, and many others)
Primary biliary cirrhosis
Congestive heart failure
Sepsis
421
Posthepatic Causes
Extrahepatic biliary obstruction
Common bile duct obstruction from gallstones
Benign and malignant tumors of the pancreas
Tumors of bile ducts (cholangiocarcinoma) and ampulla of Vater
Biliary strictures (postsurgical, gallstone-related, primary sclerosing cholangitis)
Congenital disorders (biliary atresia, cystic fibrosis)
Infectious cholangiopathy
Chronic pancreatitis (fibrosis of the head of the pancreas)
of bilirubin. These disorders are not usually associated with significant
hepatic disease.
Etiology of Hyperbilirubinemia
There are many potential causes of hyperbilirubinemia, and the major
categories are summarized in Table 41.1. It is helpful to consider them
mechanistically as conditions affecting the balance of bilirubin production, liver metabolism, and excretion. The classic cause of bilirubin overproduction is hemolysis, whereas the most common cause of
impaired bilirubin uptake and metabolism is cirrhosis or other liver
disease (viral hepatitis, drugs, hepatotoxins or ischemia). Bile duct
obstruction due to cancer (classically cholangiocarcinoma or pancreatic head cancer), stones, or strictures is the most common cause of
obstructive jaundice. Because multiple mechanisms are often involved
in an individual patient, the evaluation of jaundice can be complex.
Prehepatic Jaundice
Prehepatic jaundice is associated with excessive bilirubin production
(Fig. 41.1), which most often results from hemolysis (intravascular or
extravascular), resolution of large hematomas, or mechanical injury
to red cells, as in disseminated intravascular coagulation (see Chapter
48). Certain genetic diseases can lead to increased red cell lysis and
therefore hemolytic jaundice. Sickle cell anemia is the classic cause,
but others include glucose 6-phosphate dehydrogenase deficiency and
hereditary spherocytosis. Infectious diseases also can cause hemolysis,
either directly (e.g., malaria) or indirectly (e.g., autoimmune injury).
Jaundice resulting from hemolysis is characteristically mild in degree,
and serum bilirubin levels rarely exceed 5 mg/dL in the absence of
coexisting hepatic disease. Ineffective erythropoiesis, which may be
significantly increased in megaloblastic anemia, also leads to mild
jaundice.
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