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cirrhosis suspected of having encephalopathy have normal or
slightly elevated ammonia levels, which adds little diagnostic information. Generally, hepatic encephalopathy is a clinical diagnosis based on history, physical exam, and exclusion of
other possibilities. Psychometric testing is becoming increasingly available to assist in conrming this diagnosis. Recent articles have questioned the value of checking ammonia levels in
terms of their utility in guiding therapy.
22
Some recent studies have suggested that ammonia levels may
have more signicance in the setting of acute liver failure (eg,
due to overwhelming infection of the liver by viral hepatitis).
In these patients, the degree of ammonia elevation correlates
with the severity of hepatic encephalopathy and the likelihood
of death, and it may be a useful marker for predicting which
patients may require emergent liver transplant.
23
Ammonia concentration may also be elevated in patients with
Reye syndrome, inborn disorders of the urea cycle, various medications (most notably valproic acid), impaired renal function,
ureterosigmoidostomy, or urinary tract infections with bacteria that convert urea to ammonia. In patients with cirrhosis or
mild liver disease, elevated ammonia and hepatic encephalopathy may be precipitated by such factors as increased dietary protein, GI bleeding, constipation, and H pylori infection. Patients
with vascular shunts or bypass procedures in which blood ow
is directed from the portal circulation directly into the systemic
circulation (as in transjugular intrahepatic portosystemic shunt)
are more likely to develop hepatic encephalopathy.
VIRAL HEPATITIS
e onset of acute viral hepatitis may be dramatic and present
as an overwhelming infection, or it may pass unnoticed by the
patient. In the usual prodromal period, the patient oen has
a nonspecic u- like illness that may include nausea, vomiting, fatigue, or malaise. is period may be followed by clinical
hepatitis with jaundice. During this time, the most abnormal
laboratory results are usually the aminotransferases, which can
be in the thousands. Bilirubin may be quite elevated, while ALP
only mildly so.
e major types of viral hepatitis are reviewed here, but they
are oen clinically indistinguishable. us, serologic studies of
antibodies, molecular assays to detect viral genetic material, and
knowledge of the epidemiology and risk factors for these dierent viruses (Table15-6) are central to diagnosis.
TABLE 15-6. Groups at Higher Risk of Infection by
Various Hepatitis Viruses
Hepatitis A virus
Persons in contact with infected persons
Daycare workers and attendees
Institutionalized persons
Travelers to countries with high rate of hepatitis A infections
Military personnel
Men who have sex with men
IV drug users
Hepatitis B virus
Persons in contact with infected persons
Unvaccinated healthcare professionals and morticians
Hemodialysis patients
Men who have sex with men
IV drug users
Multipartner heterosexuals
Tattooed/bodyNewborns of HBsAg- carrier mothers
Hepatitis C virus
Dialysis patients
Healthcare professionals
IV drug use (primary cause)* (even once)
Intranasal drug use
Recipients of clotting factors before 1987
Recipients of transfusion or organ transplant before
July 1992
Tattooed/bodyChildren born to HCV- positive mothers
Hepatitis D virus
Only individuals with chronic HBV infection
Hepatitis E virus
Travelers to Latin America, Egypt, India, and Pakistan
Persons in contact with infected persons
*Even one isolated incident of injection drug use can lead to
Hepatitis C.
pierced persons
pierced persons
Type A Hepatitis
Hepatitis A virus (HAV) is spread primarily by the fecal–oral
route by contaminated food or water or by person- to- person
contact. It has an incubation period of 3 to 5 weeks with a
several- day prodrome (preicteric phase) before the onset of
jaundice and malaise, or the icteric phase. e icteric phase generally lasts 1 to 3 weeks, although prolonged courses do occur.
Hepatitis A is responsible for about 50% of acute hepatitis in
the United States (more than all other hepatotropic viruses
combined), generally due to person- to- person contact within
community- wide outbreaks. Between 2016 and 2018, reports
of hepatitis A infections in the United States increased by 294%
compared with 2013 to 2015; this increase reects outbreaks
involving individuals who report drug use or homelessness, men
who have sex with men, and contaminated food items.
24
Unlike types B, C, and D hepatitis virus, HAV does not cause
chronic disease, and recovery usually occurs within 1 month.
Many patients who get type A hepatitis never become clinically
ill. Perhaps 10% of all patients become symptomatic, and only
10% of those patients become jaundiced. Fulminant hepatic failure occurs in <1% of cases. Most patients have a full recovery,
but there is a substantial mortality risk in elderly patients and
very young patients, in patients with chronic hepatitis B or C,
and in patients with chronic liver disease of other etiologies.
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FIGURE 15-5. Temporal relationships of serologies for type A hepatitis with onset of jaundice and infectious
status. Anti-HAV IgM is the IgM antibody against HAV. HAAg is the hepatitis A antigen (virus). Total anti-HAV is
primarily IgG antibodies (and some IgM in acute phase) against HAV. Source: Adapted with permission from Abbott
Laboratories, North Chicago, IL.
A vaccine for HAV is available. It is recommended for those
from or traveling to endemic regions (ie, Central and South
America), men who have sex with men, users of street drugs,
those with occupational exposure, patients requiring clotting
factor concentrates, and patients with chronic liver diseases. is
vaccine is increasingly being recommended as a universal vaccine for pediatric patients. Although this vaccine is generally
preferred for postexposure prophylaxis, use of immunoglobulin
should be considered in the very young (<12 months) or patients
who cannot receive the vaccine.
Presently, the only two tests available to measure antibodies
to HAV are immunoglobulin M (IgM) or total (all isotypes of)
antibody. Detection of IgM is the more clinically relevant test as
it reveals acute or recent infection. ese antibodies are present
at the onset of jaundice and decline within 12 (but usually 6)
months. Total antibody, which is comprised of antibody of all
isotypes against HAV, indicates present or previous infection or
immunization (Figure15-5).
Type B Hepatitis
Hepatitis B virus (HBV) is a DNA virus spread by bodily uids, most commonly as a sexually transmitted disease, but also
via contaminated needles (as with parenteral drug abuse or
needle stick accidents), shared razor blades or toothbrushes,
nonsterile tattooing or body piercing, blood products, or vertical transmission (transmission from mother to child, generally at birth). is disease is 50 to 100 times more contagious
than HIV. e incubation period of HBV varies from 2 to
4months, much longer than that of HAV. Geographically,
there is a markedly increased prevalence of hepatitis B in
Southeast Asia, China, and sub-Saharan Africa, with 10% to
20% of the populations being hepatitis B carriers. In contrast,
the incidence of hepatitis B carriers in the United States is
approximately 0.4%.
e clinical illness is generally mild and self- limited but can
be quite severe. Unfortunately, up to 5% of infected adults and
90% of infected neonates develop a chronic illness. Chronic
HBV infection is oen mild but may progress to cirrhosis, liver
failure, or hepatocellular carcinoma, thereby contributing to premature death in 15% to 25% of cases.
Viral Antigens and Their Antibodies
ree HBV antigens and antibody systems are relevant to diagnosis and management: surface antigen (HBsAg), core antigen (HBcAg), and e antigen (HBeAg). HBsAg is present on the
outer surface of the virus, and neutralizing hepatitis B surface
antibodies (anti-HBs) directed against this protein are central
to natural and vaccine- induced immunity (Figure15-6). Neither HBcAg nor HBeAg are on the surface of the virion, and
thus antibodies against these antigens are not protective. Nevertheless, antibodies are directed against these proteins and may
serve as markers of infection. Of these antigens, only HBsAg
and HBeAg can be detected in the serum by conventional techniques. HBsAg is detected for a greater window of time during
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FIGURE 15-6. Hepatitis B virus and its antigenic
components. The complete and infectious virus (1),
originally known as the Dane particle, is composed of
the outer layer (HBsAg) and inner nucleocapsid core.
The inner core is comprised of HBcAg intermeshed with
HBeAg and encapsulates the viral DNA. HBeAg may be
an internal component or degradation product of the
nucleocapsid core. An incomplete and noninfectious
form (2) is composed exclusively of HBsAg and is
cylindrical in shape.
TABLE 15-7. Interpretation of Common Hepatitis B
Serological Test Results
HBsAg ANTI-HBs ANTI-HBc INTERPRETATION
Positive Negative Positive Acute infection or
chronic hepatitis B
Negative Positive Positive Resolving hepatitis B
or previous infection
Negative Positive Negative Resolving or
recovered hepatitis B
or patient after
vaccination
In addition to serological tests, sensitive molecular assays may
be used to detect HBV DNA, revealing active viral replication
in either acute or chronic infection. ese assays may be useful
for early detection, as in screening blood donors, because DNA
is detectible an average of 25 days before seroconversion. Additionally, some assays allow the quantication of serum viral load,
which may be used in the decision to treat and, subsequently,
monitor therapy. Presently, eight genotypes of HBV have been
identied, which can be of real value in terms of determining
appropriate therapy for chronic infection. For example, genotype A— most prevalent in the United States— seems to respond
better to interferon than the others, and patients with this genotype might benet from starting with interferon as opposed to
the oral agents available. Genotype C is more prevalent in Asia.
For the details of these assays (PCR, RNA:DNA hybrid capture assay, nucleic acid cross- linking assay, and branched DNA
assay), refer to a review by Pawlotsky etal.
25
infection and reveals active infection. Detection of HBeAg indicates large amounts of circulating HBV; these patients are 5to 10
times more likely to transmit the virus than are HBeAg- negative
persons.
In response to infection with HBV, the body may produce
anti-HBs, hepatitis B core antibody (anti-HBc), and hepatitis B e- antibody (anti-HBe). All of these antibodies can
be detected in clinical laboratories, and in the case of antiHBcAg, separate tests are available to detect IgM or total antibody (all isotypes). Anti-HBs are associated with resolved
type B hepatitis or patients who have responded to vaccination for HBV. Anti-HBc is a bit more challenging to interpret, as it can be seen in acute type B hepatitis, aer recovery
from type B hepatitis (oen in concert with anti-HBs), and in
chronic infection (oen with HBsAg and HBeAg), and there
can be false- positive results as well. As shown in Table 15-7
and Figure15-7, levels of antigens and antibodies show complex patterns in the course of HBV infection and thus can
yield considerable information about the infection’s course
and chronology.
Acute Type B Hepatitis
HBsAg titers usually develop within 4 to 12 weeks of infection
and may be seen even before elevation of aminotransferases or
clinical symptoms (Figure15-7). Subsequently, HBsAg levels
decline as anti-HBs titers develop, which indicates resolution
of the acute symptomatic infection and development of immunity. In between the decline of HBsAg and the rise of anti-HBs,
there is oen a window when neither is present during which
time anti-HBc may be used to diagnose infection. IgM antiHBc may be used to reveal acute infection as opposed to a are
of chronic HBV.
Chronic Type B Hepatitis
e development of chronic hepatitis B is suggested by the persistence of elevated LFTs (aminotransferases) and is supported
by persistence of HBsAg for >6 months. Persistence of HBeAg
also suggests chronic infection, but some chronically infected
patients produce anti-HBe and, subsequently, clear HBeAg well
aer the acute phase is over (late seroconversion; Figure15-8).
Clearance of HBeAg is associated with a decrease in viral
DNA and some degree of remission in chronic hepatitis B.
However, this can be confusing because HBeAg is a precore
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FIGURE 15-7. Serological prole, including temporal relationships integrated with infectious status and symptoms,
in 75% to 85% of patients with acute type B hepatitis. Source: Adapted with permission from Abbott Laboratories,
North Chicago, IL.
FIGURE 15-8. Serological proles of patients who chronically carry HBV. Source: Reproduced with permission from
Abbott Laboratories, North Chicago, IL.
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protein, and in patients infected with certain mutations developed during the course of the disease (precore and core promoter), HBeAg may not be produced. Yet even in the face of
anti-HBe, there may be active disease with ongoing brosis and
development of cirrhosis. Although chronically infected individuals usually lack anti-HBs, in some cases low levels of nonneutralizing antibodies may be present. Additionally, low levels
of IgM anti-HBc may persist.
Hepatitis B Vaccine
e HBV vaccine consists of recombinant HBsAg, which,
although not infectious, stimulates the production of protective
anti-HBs. Generally, this is a safe vaccine, with ecacy of >90%.
Presently, it is recommended as a standard vaccine for neonates.
e hepatitis B vaccine is administered in a total of three doses,
given at 0, 1, and 6 months. In those who were not vaccinated at
birth, it is indicated for people at high risk of acquiring type B
hepatitis or its complications including neonates of mothers
with hepatitis B, men who have sex with men, injection drug
abusers, dialysis patients, healthcare workers, patients with HIV,
family and household contacts of patients with type B hepatitis,
sexually active people with multiple partners, and patients with
chronic liver disease. It should also be considered in patients
about to undergo chemotherapy or other forms of immunosuppression. More recent eorts, especially in endemic countries,
are leading to this being accepted as a universal vaccine. is
vaccine, for example, is oen required for students in the United
States before entering the public school system.
A vaccine product directed against both HAV and HBV is
available. In analyzing serologic data, successful vaccination
may be distinguished from previous infection by the presence
of anti-HBs and absence of antibodies against other antigens (eg,
HBcAg, HBeAg). Testing for antibodies aer vaccination is not
generally recommended, with exceptions including healthcare
workers, dialysis patients, and the spouses or sexual partners of
infected patients. Although some patients fail to develop antibodies for a number of reasons, including anergy, these patients
should be evaluated for the possibility of occult chronic HBV
infection if antibody tests are negative aer the second vaccine
series. e vaccine has a prolonged duration of action. Routine
booster injections are not recommended except, perhaps, for
dialysis patients when their titers of anti-HBs are <10 International Units/L.
Type C Hepatitis
Hepatitis C virus (HCV) is an RNA virus mainly spread parenterally, although it may also be transmitted vertically and sexually.26
Although 70% to 80% of acute infections are asymptomatic, 70%
to 80% of patients develop chronic disease. Given the mildness
of the acute attack and the tendency to develop into chronic hepatitis, it is understandable why many patients with this disease
rst present decades later with cirrhosis or, more commonly,
chronic elevations of aminotransferases. Because chronic HCV
infection is oen asymptomatic and LFT results may be normal
or intermittently elevated, it is recommended that patients at
high risk for HCV be screened appropriately. Patients for whom
screening would be appropriate include those born in the United
States between 1945 and 1965, patients with a history of illegal
drug use. Additionally, patients who received clotting factors
before 1987 or blood products or organ transplants before July
1992, are HIV positive, have a history of hemodialysis, or have
evidence of liver disease (elevated ALT) should be screened.
ese guidelines are rapidly changing. Presently, the U.S. Preventive Services Task Force recommends universal screening for
everyone between the ages of 18 and 79 years.
Acute hepatitis C is oen asymptomatic, and when symptoms
are present, they are mild. Diagnosis of acute hepatitis C, however, is important as evidence suggests that prompt treatment
with antiviral medications can prevent progression to chronic
hepatitis C in most cases.
In chronic hepatitis C infection, the LFT results are usually
minimally elevated, with ALT and AST values commonly in the
60 to 100 International Units/L range. ese values can uctuate and occasionally return to normal for a year or more, only
to rebound when next checked. e primary clinical concern in
chronic HCV is that if untreated, within 20 years 20% to 30%
of patients develop cirrhosis and 1% to 5% develop hepatocellular carcinoma.
e rst screening test used is oen an enzyme- linked
immunosorbent assay (ELISA) assay for anti-HCV, which
detects antibodies against a cocktail of HCV antigens. Positive test results can be seen in patients who have passively
acquired these antibodies (but not the infection), as a result of
blood transfusions, or as children of mothers with hepatitisC.
Because of possible cross- reactivity with one of the antigens
in the assay, this test has a considerable false- positive rate, and
thus positive results need to be conrmed with a more specic
assay. One such assay is the recombinant immunoblot assay,
which is similar to ELISA in principle, but tests antibody reactivity to a panel of antigens individually. Binding to two or more
antigens is considered a positive test. Binding to one antigen
is considered indeterminate. Presently the approach to a positive ELISA is to skip the recombinant immunoblot assay and
go directly to the reverse transcriptase polymerase chain reaction (RT-PCR) assay.
Qualitative RT-PCR, oen referred to as just PCR, detects
viral RNA in the blood. It is a sensitive assay that may be used
in the diagnosis and subsequent management of hepatitis C.
RT-PCR has several advantages compared with serologic tests.
It can detect HCV within 1 to 2 weeks of exposure and weeks
before seroconversion, presentation of symptoms, or the elevation of LFTs. is may be useful because seroconversion only has
occurred in 70% to 80% of patients at the onset of symptoms, and
it may never occur in immunosuppressed patients. Additionally, there is evidence suggesting that treating acute hepatitis C
may be of value. Some immunocompromised patients with
hepatitis C (as described previously) may have false- negative
ELISA studies, and thus RT-PCR is recommended for consideration in patients with hepatitis or chronic liver disease who
are immunosuppressed. Furthermore, unlike serologic assays,
RT-PCR is not confounded by passively acquired antibodies
that may be present in uninfected infants or recipients of blood
products, and RT-PCR can distinguish between resolved and
chronic infection.
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Once a diagnosis of HCV infection is established, various
quantitative molecular assays that monitor viral load may be
useful in following viral titers during treatment or assessing the
likelihood of response to therapy. A major consideration with
these tests is that the methodology is not yet standardized, and
there is laboratory- to- laboratory variability. ese tests are not
preferred for initial diagnosis because they are less sensitive
than qualitative RT-PCR. ey include a quantitative PCR assay
and a branched- chain DNA assay (for more information, see
Pawlotsky etal.25). Presently, most laboratories report HCV PCR
measurements in International Units/milliliter, with pretreatment levels oen in the millions.
ere are at least six major genotypes of the type C virus
and multiple subtypes. Viral genotype determination is useful
because genotype may help direct the antiviral regimen needed,
length of therapy, as well as predict the likelihood of response
to treatment. Recent release of several new oral antiviral agents
has improved treatment in terms of being well tolerated by the
patients and yielding eradication rates >90%. Length of treatment may vary depending not only on genotype but also on
presence of cirrhosis and previous exposure to other medica
tions. Genotype determination may be done via direct sequencing or hybridization of PCR amplication products.
-
Type D Hepatitis
Hepatitis D virus (HDV) is caused by a defective virus that
requires the presence of HBsAg to cause infection. erefore,
people only can contract type D hepatitis concomitantly with
HBV infection (coinfection) or if chronically infected with HBV
(superinfection). Coinfection presents as an acute infection that
may be more severe than HBV infection alone. Alternatively,
the picture of superinfection is that of a patient with known or
unknown chronic HBV who develops an acute are with worsening liver function and increases in HBsAg. Acute coinfection
is usually self- limited with rare development of chronic hepatitis, while superinfection becomes chronic in >75% of cases and
increases the risk of negative sequelae, such as cirrhosis. Transmission of HDV is generally by parenteral routes, although no
obvious cause can be determined in some cases.
Testing for HDV is usually only indicated in known cases
of HBV infection. e single, widely available assay detects
anti-HDV antibodies of all isotypes (Figure15-9). is test is
unable to distinguish between acute, chronic, or resolved infection and lacks sensitivity because only about 38% of infected
patients have detectible anti-HDV within the rst 2 weeks of
illness. Because seroconversion may occur as late as 3 months
aer infection, testing may be repeated if the clinical picture suggests HDV. Tests are also available for HDV RNA, and stains are
available to assess the D antigen in hepatocytes.
Type E Hepatitis
Hepatitis E virus (HEV) is generally similar to hepatitis A. It is a hardy, protein- coated RNA virus that is spread
by the fecal–oral route, often by contaminated food or
water. Like HAV, HEV causes an acute illness that is generally self- limited. HEV is endemic in parts of Asia and
has become increasingly detected in the United States.
Unlike HAV, HEV is notable for a predilection for causing life- threatening illness in women who are in their third
trimester of pregnancy. Recently, testing for antibodies to hepatitis E has become available, including HEVAg or hepatitis E
antigen. Work is underway to develop a vaccine for hepatitis E.
PRIMARY BILIARY CHOLANGITIS
Primary biliary cholangitis (PBC), previously called primary biliary
cirrhosis, is a chronic disease involving progressive destruction of
small intrahepatic bile ducts leading to cholestasis and progressive brosis over a period of decades. Ultimately, it can progress to
cirrhosis and liver failure, necessitating transplantation.27 Ninety
percent of aected individuals are women, with onset occurring
in adulthood. e etiology of the disease is unknown, although
it seems to involve an autoimmune component and is associated with a variety of autoimmune disorders, including Sjögren’s
syndrome, rheumatoid arthritis, and scleroderma, and thyroid
diseases. e initial symptoms of the disease are oen those of
progressive cholestasis with fatigue, pruritus, jaundice, and deciencies in fat- soluble vitamins.
e most useful laboratory test in diagnosing PBC is the
detection of antimitochondrial antibodies (AMA), with a sensitivity of 95%. is assay is also highly specic, although patients
with autoimmune and drug- induced hepatitis occasionally have
low antibody titers. PBC usually presents with a predominantly
cholestatic laboratory picture, initially with an elevated ALP and
GGT, and later, with an elevated total bilirubin. Aminotransferases tend to be minimally elevated or normal (Minicase 1).
HEMOCHROMATOSIS
Hemochromatosis is an iron overload state involving the liver
and other organs. If le untreated, hemochromatosis can lead
to cirrhosis, cardiac failure, diabetes, and hepatocellular carcinoma.28 Its presentation is oen subtle, and most cases are
discovered either in patients undergoing evaluation of abnormal aminotransferases or presenting with a positive family
history of hemochromatosis. Iron overload can be either by
a primary or secondary disorder. Hereditary hemochromato
sis (also referred to as classic or primary hemochromatosis) is
inherited in an autosomal recessive fashion and involves dys
regulated handling of iron absorption from the GI tract. Up to
90% of aected individuals have inherited two alleles carrying the mutant C282Y genotype on chromosome 6. Persons of
northern European descent have the highest risk, with a greater
likelihood in men. Secondary hemochromatosis is generally the
result of iatrogenic iron overload from repeated blood transfusions used as therapy for disorders such as thalassemias, sideroblastic anemias, myelodysplastic syndromes, and congenital
dyserythropoietic anemias.
Hemochromatosis remains an underdiagnosed disease entity.
Many patients report nonspecic symptoms leading to a delay in
diagnosis and treatment for up to several years. e classically
reported clinical manifestations of hemochromatosis included the
29
-
-
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FIGURE 15-9. Two serological proles of patients infected with HDV. HDAg = hepatitis D antigen (the virus); anti-
HD = antibodies against HDV. Source: Reproduced with permission from Abbott Laboratories, North Chicago, IL.
triad of bronze skin, diabetes, and cirrhosis but were infrequent
at the time of disease diagnosis. Now more commonly, patients
experience malaise, fatigue, arthralgias, hepatomegaly, and elevated aminotransferase levels when diagnosis is conrmed.
Diagnosis typically begins with laboratory assessment of
serum ferritin and transferrin iron saturation levels in patients
found to have chronically elevated liver enzymes and clinical
suspicion of hemochromatosis.30 A transferrin iron saturation level of >60% in men or 50% in women may suggest this,
although the American Association for the Study of Liver Diseases guidelines suggests 45% as a cuto.31 Ferritin levels tend
to be elevated as well, >200 ng/mL in men and 150 ng/mL in
women. Hemochromatosis gene testing can then be performed
on these patients or individuals at risk for hereditary hemochromatosis based on family history. is diagnosis can be suggested in patients who are homozygous for the C282Y gene or
compound heterozygote with a copy of the C282Y gene and a
copy of the H63D gene. Early diagnosis of hereditary hemochromatosis is important so that therapy can be started before end
organ involvement is evident and is associated with improved
outcomes.32 erapeutic phlebotomies to decrease serum ferritin levels may result in a normal life expectancy. Management of
secondary hemochromatosis is usually through chelation therapy, but life expectancy may be shorter and related to the need
for continued transfusion therapy to treat the primary disorder
(Minicases 2 through 11).
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MINICASE 1
Cholestasis in a Middle-Aged Woman
Gwen V., a 52- year- old woman, presents for her routine annual
medical examination. She has no new medical complaints. In
the past, she was diagnosed with osteoporosis and started
on alendronate as well as supplemental vitamin D. She denies
alcohol use, illicit drug use, or use of other vitamins or herbal
supplements. Her physical examination is entirely normal. Routine
laboratory evaluation includes a normal CBC, lipid profile, and renal
function. Her liver profile is abnormal, with an elevated ALP of 330
International Units/L. Her AST, ALT, and bilirubin are normal.
An ultrasound of her liver and biliary system is normal. Additional
bloodwork shows that her GGT is abnormally elevated at 562
International Units/L. Additional workup demonstrates negative
serologies for viral hepatitis, negative ANA, and ASM. Her AMA titer
is positive at 1:280. She is told she has primary biliary cirrhosis,
needs a liver biopsy, and seeks another opinion.
QUESTION: What disease does she have, and how do we diagnose
her? Does she need a liver biopsy?
DISCUSSION: Gwen V. has a cholestatic picture with elevations
in ALP and GGTP. Her negative ultrasound helps exclude biliary
MINICASE 2
obstruction. Her positive AMA is a further clue to her diagnosis. Prior
to 2014, the diagnostic term was indeed primary biliary cirrhosis.
This was an unfortunate term because many of these patients do not
have cirrhosis at all. Currently, the correct diagnostic term is primary
biliary cholangitis (PBC), which is classified as an autoimmune
disease of the liver. Over the course of decades there can be
continued inflammation of the small bile ducts in the liver, leading to
scarring and ultimately cirrhosis. The disease is much more common
in women and is often associated with other autoimmune diseases,
especially thyroid disease.
Diagnosis requires two out of the three criteria:
1. Cholestatic liver tests
2. Abnormal serum AMA over 1:40
3. Characteristic findings on liver biopsy
Thus, our patient does not need a liver biopsy because she meets the
criteria for PBC. Management would include treatment with ursodiol
and following up with her lab results. If her ALP remains elevated, a
newer treatment with obeticholic acid might be considered. Patients
with PBC may have a higher incidence of osteoporosis, as our
patient does. Additionally, lipids may be abnormal.
Case of a Prolonged International Normalized Ratio and Low Serum Albumin
Jane M., a 50- year- old woman, presents to her physician with reports
of increasing fatigue and a 20- lb weight loss over the past 4 months.
Initial evaluation shows an albumin of 2 g/dL and an INR of 2.3. Jane M.
is referred for evaluation of possible cirrhosis. On further questioning,
she denies any history of hepatitis, exposure to hepatotoxins, alcohol
use, family history of liver disease, or liver disease.
Jane M.’s physical examination does not suggest liver disease; there
is no evidence of ascites, palmar erythema, asterixis, hepatomegaly,
splenomegaly, or spider angiomata. It is noted that she has pedal
edema. Liver function studies are otherwise normal: ALT 12
International Units/L, AST 20 International Units/L, total bilirubin
1mg/dL, and ALP 56 International Units/L.
An IM dose of vitamin K 10 mg corrects the INR within 24 hours.
Workup shows that Jane M. has malabsorption due to sprue, a
disease of the small bowel. With proper dietary management,
PANCREATIC INFLAMMATION/
PANCREATITIS
Pancreatitis refers to inammation of the pancreas (either acute
or chronic) and is the most common disease associated with
this gland.33 Although there are multiple causes of pancreatitis,
the clinical presentation is oen the same. Acute pancreatitis
her symptoms resolve and she gains weight. At a follow- up visit
3weeks later, her albumin concentration is 3.7 g/dL and her edema
has resolved.
QUESTION: Why did Jane M. develop a low albumin and a prolonged
PT? What caused her pedal edema?
DISCUSSION: This case demonstrates that although low albumin and
a prolonged PT suggest advanced liver disease, other causes need
to be considered. Administration of vitamin K promptly corrected
Jane M.’s INR, suggesting malabsorption of vitamin K. If she had
cirrhosis, her PT would not have corrected with the vitamin K.
Similarly, her hypoalbuminemia was not due to her liver’s inability
to synthesize albumin but to the malabsorptive disorder that was
interfering with protein absorption. Therefore, Jane M. had a low
albumin and elevated INR in the absence of liver disease. Her pedal
edema was due to hypoalbuminemia secondary to malabsorption.
generally presents with severe midepigastric abdominal pain
developing over an hour, oen radiating to the back. e pain
tends to be continuous and can last for several days.
is condition is oen associated with nausea and vomiting;
in severe cases, fever, ileus, and hypotension can occur. Ultimately, there can be progressive anemia, hypocalcemia, hypoglycemia, hypoxia, renal failure, systemic inammatory response
334 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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MINICASE 3
Jaundice Caused by Oral Contraceptives
Amber S., a 16- year- old girl, is found by her pediatrician to be slightly
jaundiced during a routine school physical. She denies any history
of liver disease, abdominal pain, illicit drug abuse, alcohol use, or
abdominal trauma. Laboratory evaluation shows a moderately elevated
bilirubin of 2.3 mg/dL along with ALP and GGT concentrations about
four times normal. Her AST is 23 International Units/L.
Amber S. denies being on any medications (except for vitamins)
or being exposed to toxins. Nothing suggests the possibility of a
neoplastic or infectious process (temperature of 98.9°F and WBC
count of 7.5 × 103 cells/mm3). Ultrasound of the liver and biliary
system is normal with no evidence of biliary dilation.
Her parents take her to a pediatric hepatologist. After much
discussion (and threat of a liver biopsy), Amber S. tearfully reveals
that she went to a local family planning clinic and is using birth
control pills.
MINICASE 4
Abnormal Liver Function Tests
QUESTION: How might oral contraceptives cause a cholestatic
picture? What is the importance of the ultrasound? What is the
usual outcome of patients who develop jaundice while taking oral
contraceptives?
DISCUSSION: This case demonstrates that oral contraceptives,
primarily because of their estrogen content, can cause alterations
in cholestatic test results (manifested by an elevated bilirubin, GGT,
and ALP) with relatively normal aminotransferases. The ultrasound
helps to distinguish between intrahepatic and extrahepatic
cholestasis. The absence of biliary dilation suggests intrahepatic
cholestasis. The normal AST suggests that jaundice is not due to
hepatitis.
Cholestasis from oral contraceptives is generally benign and
reverses promptly when the medication is withdrawn. Patients often
omit mentioning use of birth control pills.
Dana D., a 36- year- old executive, is referred to a prominent medical
center for a second opinion. Her physician finds an elevated AST of
180 International Units/L on a routine screening exam. Dana D. has
no symptoms; her physical examination has been normal, without
any signs of liver disease or hepatomegaly.
Additional studies show an ALT of 60 International Units/L, a
markedly elevated GGT of 380 International Units/L, and a minimally
elevated ALP of 91 International Units/L. Her WBC count is elevated
at 20 × 103 cells/mm3. After much discussion, she reveals that she
has been drinking 1 pint of vodka a day.
Dana D. enrolls in Alcoholics Anonymous and stops drinking. Three
months later, her test results are normal: ALT 28 International Units/L,
GGT 54 International Units/L, and ALP 54 International Units/L.
QUESTION: What findings suggest alcoholic liver disease? Why did
all of Dana D.’s laboratory test results return to normal? What else
might have happened in this situation?
DISCUSSION: This case demonstrates several aspects of alcoholic
liver disease. The diagnosis is suggested by an elevated AST out of
proportion to the ALT (generally an AST/ALT ratio of ≥2), as well as by
a markedly elevated GGT with a normal (or virtually so) ALP. AST and
ALT levels generally are <300. An elevated mean corpuscular volume
(MCV), if present, also would support this diagnosis. Patients with
alcoholic liver disease may have markedly elevated WBC counts.
Alcoholic liver disease tends to have several different stages.
The earliest manifestation may be just a “fatty liver,” which is
generally reversible with cessation of alcohol intake. Alcoholic
hepatitis and cirrhosis can follow with continued excessive alcohol
intake. Unfortunately, alcoholic cirrhosis can develop without any
warning signs. If Dana D. had alcoholic cirrhosis, stopping alcohol
consumption probably would not have significantly altered her
abnormal test results.
Clinicians should remember that a patient does not need to be an
“obvious” alcoholic to develop alcoholic cirrhosis. Women are more
susceptible to the hepatotoxic effects of alcohol than men, and as
few as two or three drinks a day can cause significant liver disease
in susceptible persons, this being due to differences in alcohol
metabolism. Of note, 12 oz of beer, 5 oz of wine, and 1.5 oz of
“spirits” all have about 14g of alcohol and thus are equivalent in
terms of risk of alcoholic liver disease.
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 335
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MINICASE 5
A Jaundiced College Student
Jacob N., a 19- year- old college student, anxiously reports to the
infirmary when his girlfriend notices that he has become yellow. He
feels well and has a normal physical examination. On discussion,
he indicates that he has recently embarked on a rigorous crash diet
in anticipation of winter break in Florida.
The evaluation shows an elevated total bilirubin of 4.8 mg/dL,
with a direct bilirubin of 0.48 mg/dL. The absence of hemolysis is
established by microscopic examination of a blood smear, normal
reticulocyte count, and lactate dehydrogenase (LDH), which is
112International Units/L. Jacob N.’s other LFT results are normal:
ALT 21 International Units/L and ALP 76 International Units/L.
QUESTION: What was the most likely cause of Jacob N.’s signs
and symptoms? How should his condition be managed? What is
his prognosis?
MINICASE 6
Hepatic Encephalopathy
DISCUSSION: Elevated bilirubin concentrations do not necessarily
indicate severe liver disease. In this case, the unconjugated bilirubin
was substantially elevated. The normal ALT and ALP rule out
hepatocellular and cholestatic liver diseases. If done, AST would
have been normal. The normal LDH, red blood cell microscopic
exam, and reticulocyte count rule out hemolysis as a cause of the
elevated unconjugated bilirubin. The normal LDH is also consistent
with a lack of intrinsic liver disease.
Jacob N. should be reassured that he has Gilbert syndrome and
might become somewhat jaundiced with fasting or acute or chronic
illness. Gilbert syndrome is not associated with any symptoms, is
totally benign, and requires no treatment. When a patient has an
elevated bilirubin, a practitioner should always obtain LFTs before
providing a diagnosis or performing unnecessary tests.
Stephen F., a 47- year- old man with alcoholism, is admitted to a
hospital after being found on a park bench surrounded by empty
beer bottles. Known to have cirrhosis, Stephen F. is thought to be
showing signs of hepatic encephalopathy as he slowly lapses into
a deep coma over the first 4 days of hospitalization. His physical
examination is significant in that he has hepatomegaly and
splenomegaly.
Laboratory evaluation shows a negative urine drug screen for
central nervous system (CNS) depressants with serum glucose
mildly elevated at 120 mg/dL. All serum electrolytes are normal:
sodium, 140 mEq/L; potassium, 4 mEq/L; chloride, 98 mEq/L; carbon
dioxide, 25 mEq/L; and magnesium, 1.5 mEq/L. Stephen F.’s blood
alcohol concentration on admission is 150 mg/dL (normal: 0 mg/dL).
His serum GGT is 321 International Units/L, and his AST is
87 International Units/L.
Unfortunately, efforts at treating hepatic encephalopathy do not
reverse his coma. Further examination and testing are undertaken
when it is noted that his ammonia concentration is normal at
48 mcg/dL. Then, a large bruise is noticed on the side of Stephen
F.’s head, and a CT scan reveals a large subdural hematoma. With
surgical treatment of the hematoma, he promptly awakes and asks
for more beer.
QUESTION: How does one establish the diagnosis of hepatic
encephalopathy for this patient? What is the role of the serum
ammonia concentration in the diagnosis?
DISCUSSION: This case demonstrates that the diagnosis of
hepatic encephalopathy is not always straightforward. Hepatic
encephalopathy is only one cause of altered mental function in
patients with advanced liver disease. Other causes may include
accumulation of drugs with CNS depressant properties, head trauma,
hypoglycemia, delirium tremens, and electrolyte imbalances. The
diagnosis of hepatic encephalopathy is suggested by the following:
• Elevated ammonia concentrations
• Presence (in early stages) of asterixis or a flapping tremor of the
• Absence of other causative factors
• Characteristic electroencephalographic findings (rarely used)
The response to therapy (usually correction of electrolyte imbalances,
rehydration, and lactulose and/or rifaximin) further supports this
diagnosis. Serum ammonia concentrations, therefore, are just one
piece of this puzzle. An elevated concentration suggests, but does
not establish, this diagnosis. Furthermore, although normal ammonia
concentrations may cause one to question the diagnosis of hepatic
encephalopathy, they can occur in this condition.
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