CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

AGAI Educational Review

Manual in Gastroenterology
Fifth Edition - 2009
WEB EDITION 5.00

M. Michael Wolfe, M.D., Editor-in-Chief

Professor of Medicine, Boston University School of Medicine
Chief, Section of Gastroenterology, Boston Medical Center

Robert C. Lowe, M.D., Associate Editor-in-Chief

Associate Professor of Medicine, Boston University School of Medicine
Director of Education, Gastroenterology, Boston Medical Center
 Chapter 8:
Nonviral Liver Disease
Robert C. Lowe, MD

Contents

1. Autoimmune Hepatitis

2. Alcoholic Liver Disease

3. Nonalcoholic Fatty Liver Disease (NAFLD)

4. Primary Biliary Cirrhosis

5. Granulomatous Hepatitis

6. Primary Sclerosing Cholangitis

7. Hemochromatosis

8. Alpha-1 Antitrypsin Deficiency

9. Wilson Disease

10. Vascular Disorders of the Liver

11. References

12. Questions

CHAPTER 8: NON-VIRAL LIVER DISEASE 251

1. Autoimmune Hepatitis

There is a clear genetic predisposition to AIH, with

alleles of the MHC Class II protein determining sus-
Epidemiology

Autoimmune hepatitis (AIH) is a chronic liver dis-
order characterized by hepatic inflammation and
fibrosis, hypergammaglobulinemia, and serum
autoantibodies. It is an uncommon disorder which
occurs with a frequency of roughly 50-200 cases per
million in Northern Europe and North America,
where it accounts for 11%-23% of cases of chronic
hepatitis. It is estimated that there are approximately
200,000 patients with AIH in the United States. The
female-to-male ratio for this disease is estimated at
4:1, and the average age of onset is between 20 and
40 years. A less common form of this disease, desig-
nated Type 2 autoimmune hepatitis, occurs primar-
ily in children, and is uncommonly seen in the
United States.
ceptibility to AIH. These susceptibility alleles are
most common in persons of northern European
descent, but AIH has been described in members of
all ethnic groups. As many as 40% of patients with
AIH also have other autoimmune disorders, most
notably thyroid disease and ulcerative colitis, sug-
gesting that a broader immune dysregulation is pre-
sent in these patients. Several drugs have been
demonstrated to induce an autoimmune hepatotoxic
reaction, and a careful medication history is neces-
sary when evaluating patients with possible AIH
(Table 1).
Table 1

Drugs Associated with Chronic Hepatitis

Pathogenesis and Autoimmune Markers

The etiology of autoimmune hepatitis remains

unknown, but it is speculated that “molecular
mimicry” plays a role. This concept postulates that a
Type 1

patient is exposed to an exogenous antigen that

(Positive ANA, Type 2

shares features with a self-antigen present in or on

ASMA or anti-DNA) (Positive LKM1)

hepatocytes. An aberrant immune response is then

directed at the patient’s own hepatocytes. The trig-
Clometacin Halothane

ger antigen in AIH remains unknown, but antibod-

Methyldopa Iproniazid

ies directed toward the hepatocyte asialoglycopro-

Minocycline Dihydralazine

tein receptor are present in type I AIH, while anti-

Nitrofurantoin Tienilic acid

bodies to a member of the cytochrome P450 system

Oxyphenisatin (ticrynafen)

(CYP2D6) are present in Type II disease. In both

Benzarone

forms of AIH, the damage to hepatocytes is medi-

Diclofenac

ated by cell-mediated cytotoxicity or antibody-

Fenofibrate

dependent cell-mediated mechanisms. The intense

Germander

lymphocytic infiltrate seen in liver biopsies of

Papaverine

patients with AIH is composed mainly of CD4+ T-

Pemoline

cells, with a smaller population of CD8+ cytotoxic

Propylthiouracil

T lymphocytes. As yet, the “triggering” antigen in

AIH remains obscure. Infectious agents have been
long considered to be a possible source of antigens
in autoimmune disease, but no bacterial or viral
Clinical Features

product has been definitively identified. Interest-
ingly, autoimmune hepatitis has been reported to
occur after acute hepatitis A infection, but no spe-
cific antigen-antibody interaction has been eluci-
dated in these cases.
Many patients with autoimmune hepatitis are diag-
nosed in an asymptomatic phase after the discovery
by a primary physician of elevated liver enzymes.
The disease is often insidious and without symp-
toms until late in its course, and approximately 25%
of patients will have progressed to cirrhosis by the
time of presentation. In reported series, up to 85% of
patients with AIH describe fatigue, and up to 48%

252 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

complain of vague discomfort or pain in the right
upper quadrant. Mild pruritus or anorexia is present
in one-third of patients. On physical examination, as
many as 78% have hepatomegaly, and more than
30% have concomitant splenomegaly. Spider
angiomata are seen in up to one-half of patients, and
this physical sign may occur in AIH in the absence
of cirrhosis or portal hypertension.
Although AIH is a chronic disease, it can present as
acute hepatitis in up to 40% of patients, including
rare cases of fulminant hepatic failure. These
patients present with markedly elevated transami-
nases (often >1000 U/mL), hepatic synthetic dys-
function (manifested as an elevated PT) and
encephalopathy. These patients often have underly-
ing cirrhosis, and may have signs of portal hyper-
tension or other signs of advanced liver disease. It is
important to consider autoimmune disease in the
differential of acute liver failure, especially in a
young or middle-aged woman.
Extrahepatic features of autoimmune hepatitis
occur in 10%-50% of patients, and consist primarily
of other autoimmune conditions. The most common
manifestations include autoimmune thyroid disease
(30%-40%), synovitis, and ulcerative colitis (6%).
Rarely, patients may present with frank rheumatoid
arthritis, vitiligo, lichen planus, or features of the
CREST syndrome.
Laboratory testing in chronic AIH demonstrates ele-
vation of the AST and ALT, with only minor eleva-
tion of the ALP. Mild hyperbilirubinemia is com-
mon, but serum bilirubin is >3 in less than half of
patients. Hypergammaglobulinemia is seen in
>90% of patients, with a predominant IgG fraction.
Diagnosis
The diagnosis of autoimmune hepatitis is made on
the basis of several clinical and laboratory criteria,
and a scoring system for diagnosis has been devised
(Table 2). In Type I AIH, the ANA (antinuclear anti-
body) and the ASMA (anti-smooth muscle anti-
body) should be measured, and an ANA titer of
>1:40 or an ASMA titer of >1:80 are characteristic
of this disorder. Perinuclear antineutrophil cytoplas-
mic antibodies are also present in up to 90% of
cases. Clinically, this disease is common in adult
females (70% of cases), with an average age of
onset before 40 years. Type II AIH, in contrast, is
characterized by a positive anti-liver/ kidney micro-
somal antibody (LKM1). It is more common in chil-
dren, but in Europe it accounts for up to 20% of
adult AIH. In the United States, however, it
accounts for only 4% of adult AIH cases. Children
with autoimmune polyendocrine syndrome (APS I)
have a 15% incidence of AIH, usually Type 2. Also
included in the diagnostic criteria are tests to rule
out other forms of liver disease, including viral
serologies, iron studies, and assessment of alcohol
consumption and possible toxic exposures. A third
type of AIH has been reported, with an antibody to
soluble liver antigen (Anti-SLA) as a marker of dis-
ease. This condition, however, is indistinguishable
from Type I disease, and is not thought to be a sepa-
rate clinical entity. Variant forms of AIH exist,
which overlap with both primary biliary cirrhosis
(PBC) and primary sclerosing cholangitis (PSC).
These variants should be suspected in patients with
cholestatic liver enzymes or evidence of bile duct
inflammation on biopsy. A number of patients with
chronic cryptogenic hepatitis, with inflammation
seen on biopsy but with negative serologic workup,
will have autoimmune hepatitis that responds to
immunosuppressive therapy, and patients with sig-
nificant histologic damage should be considered for
therapy directed toward AIH.
Once the diagnosis is made, a liver biopsy is indicated
to assess the grade of inflammation and the stage of
fibrosis. This information is useful both for planning
possible treatment and estimating prognosis. Typical
biopsy findings include a periportal and lobular
mononuclear infiltrate with abundant plasma cells
(Figures 1 and 2). The degree of fibrosis is variable,
but up to 25% of patients have established cirrhosis at
time of initial biopsy. The prognosis of untreated
autoimmune hepatitis depends on the severity of the
inflammatory process within the liver. Patients with
ALT levels >10 times normal, or those with ALT >5
times normal coupled with a serum globulin level >2
times normal, have a three-year mortality of 50%.
Biopsy findings of bridging necrosis or severe lobular
inflammation also portend a poor prognosis, with
over 80% of patients developing cirrhosis within 5
years. However, more mild inflammation (periportal
hepatitis) is associated with a good prognosis and
uncommonly progresses to frank cirrhosis.
CHAPTER 8: NON-VIRAL LIVER DISEASE 253
Table 2

Scoring Criteria for the Diagnosis of Autoimmune Hepatitis

Classification Factors Score

Clinical Female Gender +2

Recent hx hepatotoxic drugs:

Yes -4
No +1

Hx alcohol use:
Yes - <25 gms / day +2
>60 gms / day -2
No +0

Concurrent autoimmune disorder +2

Complete treatment response +2

Relapse +3

Biochemical

Alkaline phosphatase-AST (ALT) ratio:

>3.0 -2
<1.5 +2

Gamma-globulin or serum IgG levels

>2.0 +3
1.5-2.0 +2
1.0 - 1.4 +1

ANA, SMA or anti-LKM1:

>1:80 +3
1:80 +2
1:40 +1

Antimitochondrial Antibodies -4

Viral markers:
Seropositive -3
Seronegative +3

HLA-DR3 or HLA-DR4 +1

Other liver-related autoantibodies +2

continued on next page

254 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Table 2 (continued)

Scoring Criteria for the Diagnosis of Autoimmune Hepatitis

Classification Factors Score

Histologic Interface hepatitis +3

Plasmacytic infiltrate +1

Rosettes +1

No characteristic features -5

Biliary changes -3

Other features (eg, fat granulomas) -3

Adapted from Al-Khalidi JA et al. Mayo Clin Proc. 2001;76:1237-1252.

Pretreatment score: >15, definite diagnosis; 10-15, probable diagnosis.
Posttreatment score: >17, definite diagnosis; 12-17, probable diagnosis.

Treatment Figure 1

The use of immunosuppressive therapy has

markedly improved the prognosis of autoimmune
Autoimmune hepatitis

hepatitis. Current guidelines published by the

AASLD recommend treatment for the following
groups of patients with AIH: those with serum
transaminase levels greater than 10x the upper limit
of normal; those with serum transaminases greater
than 5x the ULN and serum globulin levels at least
twice the ULN; and those with liver biopsies show-
ing bridging necrosis or multi-acinar necrosis.
Patients with milder histologic features or those
with inactive cirrhosis do not require treatment.

The regimens commonly employed consist of either

prednisone alone or a combination of prednisone
and azathioprine. Combination therapy is preferred,
as azathioprine serves as a steroid sparing agent,
A B

allowing prednisone to be tapered off completely or

(Left, A.) Marked chronic necroinflammatory injury with

reduced to a low level that minimizes systemic side

prominent interface hepatitis (piecemeal necrosis) and

effects. Remission induction is possible in approxi-

lymphoplasmacytic inflammatory response. Increased

mately 65% of patients at 18 months, and 80% at 3

fibrous tissue with architectural distortion suggests early

years, with remission defined as improvement in

cirrhosis. (H&E, original mag X 28) (Right, B.) High magni-

liver enzymes (AST <2x ULN) and an improvement

fication of limiting plate area showing interface hepatitis
with many plasma cells and a rare apoptotic body. (H&E

in histology to normal or minimal inflammation.

original mag X 100)

Although transaminases may normalize within 6 to

CHAPTER 8: NON-VIRAL LIVER DISEASE 255

 In addition to immunosuppressive therapies,
patients should receive vitamin D (50,000 units q
Figure 2

week) and calcium supplementation (at least 1 gram

qd) to prevent osteoporosis. If bone disease is docu-
Autoimmune hepatitis

mented, then treatment with bisphosphonates or cal-

citonin is recommended. Patients who develop cir-
rhosis and end-stage liver disease from autoimmune
hepatitis are candidates for orthotopic liver trans-
plantation, with reported 5-year survival rates of
85%-90%. Autoimmune hepatitis may recur in the
graft, however, despite the immunosuppressive reg-
imen used in the post-transplant period. Recurrent
disease, which is seen in approximately 15% of
cases, is usually mild and does not adversely influ-
ence survival.

Masson trichrome preparation showing limiting plate area

with collagen fibers (blue) surrounding many hepatocytes
including rosette formation. (Original mag X 45)

12 months, the inflammatory lesion on biopsy often

lags behind the biochemical improvement. It is rec-
ommended that therapy continue for at least 6
months after the liver enzymes normalize, and a
second liver biopsy is helpful in confirming histo-
logic improvement. Therapy may be discontinued
after 2 years if a complete remission is achieved.
Unfortunately, up to 80% of patients will relapse
within 3 years of cessation of therapy and will
require retreatment and subsequent maintenance
therapy with azathioprine and/or low dose steroids.
In the 10%-15% of patients who fail to respond to
steroids and azathioprine, several other
immunomodulators may be effective, including
cyclosporin and mycophenolate mofetil; however,
these therapies are experimental, and should be
employed in the setting of clinical trials.

Immunosuppressive therapies for AIH are compli-

cated by drug-induced side effects. The effects of
chronic steroid use are well known, including
weight gain, hypertension, diabetes, cataracts, and
osteoporosis. The cosmetic effects, including buf-
falo hump, acne, and hirsutism, may also be signifi-
cant. The adverse effects of azathioprine include
pancreatitis, bone marrow suppression, and a
slightly increased risk of lymphoid malignancy with
chronic use.

256 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

2. Alcoholic Liver Disease
Epidemiology
Alcoholism remains a significant health problem
worldwide; in the United States, it is estimated that
more than 13 million persons currently abuse alco-
hol. The health effects of alcohol are widely recog-
nized, and among the public, liver disease is com-
monly believed to occur frequently in alcoholic
patients, such that the term “cirrhosis” is usually
associated only with alcohol abuse in the minds of
many Americans. Interestingly, only a minority of
alcohol abusers develop significant liver disease,
with 10%-35% of heavy drinkers developing alco-
holic hepatitis, and 8%-20% progressing to cirrho-
sis. Given the prevalence of alcoholism, however,
the burden of liver disease from alcohol use is large.
According to CDC figures, hepatic cirrhosis
accounts for 27,000 deaths per year, making it the
12th most common cause of mortality in the United
States. Approximately one-half of these deaths are
directly attributable to alcoholic liver disease
(ALD).
Pathogenesis
Why only a minority of drinkers develop significant
liver injury is not known, but risk factors for alco-
holic liver disease include female gender, obesity,
and coinfection with hepatitis C. Genetic factors are
also implicated in the pathogenensis of alcoholic
liver disease, but there are no definitive data on the
role of specific genes in the induction of ALD. The
most important factor in the development of ALD is
the quantity of alcohol consumed. It has been esti-
mated that consumption of 80 gm of alcohol per day
for a period of 10-12 years is a threshold for the
development of ALD. The threshold is lower in
women (60 gm/day) for reasons that are incom-
pletely understood. It has been thought that gastric
metabolism of alcohol, which is decreased in
women, is an important factor in the increased sus-
ceptibility to ALD, but this is unproven. It should
also be noted that these figures come from retro-
spective studies that may be flawed, and ALD has
been demonstrated in patients with significantly
lower levels of alcohol consumption.
Alcohol metabolism in the liver is mediated by three
enzyme systems. Alcohol dehydrogenase (ADH) is
the major pathway for ethanol metabolism when
serum ethanol levels are relatively low. This cytoso-
lic enzyme converts ethanol to acetaldehyde, which
is then converted to acetate via mitochondrial alde-
hyde dehydrogenase. At higher serum levels of
ethanol, the cytochrome P450 system (particularly
CYP2E1) participates in metabolism, also convert-
ing ethanol to acetaldehyde. In chronic alcohol use,
CYP2E1 is upregulated as much as 5- to 10-fold and
plays a greater role in alcohol metabolism. The third
enzymatic mechanism, utilizing catalase, is of
minor significance.
Genetic polymorphisms play a role in the clinical
response to alcohol ingestion. Isoforms of ADH exist
with different rates of enzyme activity; Asian indi-
viduals often have an ADH isoform that causes
ethanol to be metabolized 20% faster than Cau-
casians with a different ADH isoform. Variations in
aldehyde dehydrogenase also play an important role,
as up to 50% of Asians have an isoform that slowly
processes acetaldehyde, leading to accumulation and
symptoms including flushing, tachycardia, and nau-
sea. These unpleasant effects lead to decreased alco-
hol consumption among these individuals. The gen-
der difference in gastric ADH activity, mentioned
above, may also play a role in the differential suscep-
tibility to alcohol, but this is unproven.
The toxicity of ethanol to hepatocytes is multifacto-
rial, but oxidative injury appears to play a major role
in this process. Ethanol oxidation leads to the pro-
duction of free radicals such as the superoxide anion
and the hydroxyl radical, which promote lipid per-
oxidation in cellular membranes leading to tissue
inflammation and fibrosis. Oxidants may also cause
mitochondrial dysfunction, which may promote
steatosis by interfering with fatty acid metabolism.
Chronic alcohol use also depletes cellular stores of
antioxidants such as glutathione, making cells more
susceptible to oxidative stress. Ethanol use also
leads to abnormal activation of Kupffer cells, lead-
ing to cytokine production, neutrophil chemotaxis,
and further production of reactive oxygen species.
Clinical Features
The clinical features of alcoholic liver disease vary
greatly among patients, and many remain asymp-
tomatic until cirrhosis and decompensated liver dis-
ease develop. The most important element of the
CHAPTER 8: NON-VIRAL LIVER DISEASE 257
medical history in such patients is the discovery of
potential alcohol abuse. The CAGE questions
(Table 3) are an easy-to-use, relatively accurate
means of ascertaining alcohol abuse during the
medical interview. A patient who responds posi-
tively to two or more of these questions has a high
likelihood of alcohol abuse. Patients with advanced
ALD may complain of easy bruising, increasing
abdominal girth, pedal edema, pruritus, and early
signs of encephalopathy including sleep distur-
bances and difficulty with concentration. The more
obvious signs of jaundice or active gastrointestinal
hemorrhage are easily recognized. Patients with any
of these features usually have cirrhosis, but in some
cases acute alcoholic hepatitis can manifest with
severe, but reversible, signs of liver decompensa-
tion. Acute alcoholic hepatitis may also be accom-
panied by severe right upper quadrant pain, nausea,
and other signs of an acute inflammatory response,
including fever and chills.
Table 3
CAGE Questions
1. Have you ever felt the need to cut down on your
drinking?
2. Have other people annoyed you by criticizing
your drinking?
3. Have you ever felt bad or guilty about your drinking?
4. Have you ever taken a drink early in the morning
(an eye-opener) to steady your nerves or get rid of
a hangover?
Adapted from Schiff, 8th edition
The physical examination may reveal signs of alco-
holic liver disease, though many of these have poor
sensitivity and specificity. Signs usually associated
with decompensated cirrhosis include jaundice,
asterixis, ascites, pedal edema, spider angiomata,
and ecchymoses. In alcoholic liver disease, how-
ever, these signs may appear during an episode of
acute alcoholic hepatitis and resolve during recov-
ery, if the patient remains abstinent from alcohol.
Tender hepatomegaly is often noted in acute alco-
holic hepatitis, and this may resolve with absti-
nence. Other signs of alcoholic liver disease include
258 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
palmar erythema, Dupuytren’s contractures, and the
appearance (in men) of a female escutcheon.
Diagnosis
Laboratory examination in alcoholic liver disease
usually reveals an elevated AST and ALT, with a
characteristic pattern of the AST exceeding the ALT
by a factor of 2 or more. Though not a perfect dis-
criminator, the AST/ALT ratio is reasonably predic-
tive of ALD, especially if the ratio is 3 or greater.
The reason for this AST/ALT ratio is partially
understood; in some patients, it appears that a defi-
ciency in pyridoxal phosphate is responsible for this
phenomenon, and repletion of this vitamin equal-
izes the ratio. However, this is not true in all cases,
so other mechanisms are clearly at work. It should
be noted that the transaminase levels are almost
always <400 mg/dL in pure alcoholic liver disease,
and higher values should spur consideration of
coexistent liver diseases, such as drug-induced hep-
atitis from acetaminophen. Other markers of
chronic alcohol use include elevation of the serum
GGT and elevation of the mean corpuscular volume
(MCV). In acute alcoholic hepatitis, the bilirubin is
often markedly elevated, and may reach levels
greater than 20 mg/dL. Leukocytosis is also com-
mon in alcoholic hepatitis, with typical values of
12,000-15,000/mm3. Prolongation of prothrombin
time is seen both in acute alcoholic hepatitis and in
advanced liver disease, as is thrombocytopenia.
Increased iron stores may also be seen in alcoholic
liver disease, and patients may have elevated ferritin
levels and an elevated transferrin saturation.
Genetic testing for hereditary hemochromatosis
may be necessary to rule out this condition.
Liver biopsy in alcoholic liver disease demonstrates
a variety of findings (Figure 3). The most common
lesion is alcoholic steatosis, with macrovesicular fat
deposition within hepatocytes. This may occur
within days of alcohol exposure, and is reversible
with abstinence. Alcoholic hepatitis, by contrast, is
characterized by neutrophilic infiltration of the hep-
atic lobule and hepatocyte necrosis. Alcoholic hya-
line (Mallory bodies) may also be present. The
lesion is centrilobular, affecting zone 3 predomi-
nantly, although it may involve the entire lobule.
Pericellular and perivenular fibrosis may also be
present. Fibrosis may progress over time, with the

Figure 3
Alcoholic hepatitis
Many hepatocytes containing easily recognizable Mal-
lory bodies. Also note the polymorphonuclear leukocyte
reaction.
development of portal-central and portal-portal
bridges. Eventually, dense fibrous bands form, with
regenerating nodules characteristic of established
cirrhosis.
Therapy
Abstinence from alcohol is the key to therapy in
alcoholic liver disease, as it can reverse symptoms
and prolong life expectancy of patients, including
those who have already progressed to cirrhosis. The
benefit of abstinence cannot be overstated; a study
of patients with established alcoholic cirrhosis
reported 5-year survival rates of 63% in abstinent
patients, compared with 40% in those who contin-
ued to drink. Significant improvement of symptoms,
including jaundice, ascites, and encephalopathy,
may occur with cessation of drinking.
In acute alcoholic hepatitis, patients may benefit
from both rigorous enteral nutrition and the use of
pentoxifylline, an inhibitor of TNF synthesis that
demonstrated a significant survival benefit in a sin-
gle randomized controlled trial. Infliximab, a more
potent inhibitor of TNF-alpha, has been studied in
small trials with inconsistent results. Single agent
infliximab was shown to confer a survival benefit in
a small study, while in another trial, the combination
of infliximab and prednisone resulted in higher
patient mortality, due primarily to increased rates of
infection. More study is needed before these pow-
erful TNF inhibitors can be recommended for the
treatment of acute alcoholic hepatitis.
Corticosteroid therapy is reserved for patients with
poor prognostic indices. The most commonly used
index is the Discriminant Factor (DF), which is cal-
culated as follows:
DF = (4.6x {PT in seconds - control}) +
(serum bilirubin in mg/dL)
Values >32 are associated with >50% mortality in
hospital, and therapy with prednisone or pred-
nisolone has been recommended for such patients. It
should be recognized that the evidence for steroid
therapy is mixed, with recommendations being
based on meta-analysis of pooled data. A recent
ACG guideline recommends a treatment regimen of
prednisolone 40 mg po QD for four weeks, followed
by a tapering regimen. Prednisolone is the recom-
mended agent as it does not require hepatic
metabolism for activation. Treatment is contraindi-
cated in patients with active GI hemorrhage, pancre-
atitis, renal failure and active infection.
Patients with chronic alcoholic liver disease benefit
from abstinence and from maintenance of good
nutrition. Several agents, including colchicine,
PTU, polyunsaturated lecithin, metadoxine, and S-
adenosylmethionine, are being actively studied for
the treatment of chronic ALD, but there are no
definitive recommendations for their use outside of
clinical trials.
Liver transplantation is an option for patients with
advanced alcoholic liver disease. Most transplant
centers require a six-month period of abstinence
before consideration for transplant, and patients
must be involved in an ongoing alcohol cessation
program. Survival after transplant is similar in ALD
and other liver diseases, as long as abstinence is
maintained; recidivism rates are variable, ranging
from 8%-20%, and are associated with adverse out-
comes.
CHAPTER 8: NON-VIRAL LIVER DISEASE 259
3. Nonalcoholic Fatty Liver
Disease (NAFLD)
Nonalcoholic fatty liver disease (NAFLD) is a con-
dition characterized by fatty infiltration of the liver,
with lipid-filled vacuoles within the hepatocyte
cytoplasm. NAFLD encompasses a range of condi-
tions, ranging from simple hepatic steatosis to
steatohepatitis (NASH), in which the steatosis is
accompanied by a significant inflammatory
response with changes on biopsy that mimic those
seen in alcoholic liver disease. This inflammatory
response may lead to the induction of liver fibrosis
and, in a minority of patients, eventual progression
to cirrhosis. A key feature of NAFLD is the exclu-
sion of alcoholic liver disease, with alcohol con-
sumption of less than 40 gm/day a typical cutoff for
the diagnosis of NAFLD.
Epidemiology
NAFLD was initially thought to be a disease with a
female gender predominance, as roughly 75% of
cases in early series were in women. These data,
however, are from retrospective autopsy series, and
recent prospective studies in patients evaluated for
abnormal liver enzymes report a nearly equal gen-
der ratio. Recent epidemiologic studies have
revealed some ethnic differences in the prevalence
of NAFLD, with Latino populations having an
increased risk of NAFLD relative to Caucasians and
African-Americans. Significant risk factors for
NAFLD include diabetes mellitus, obesity, and
hypercholesterolemia, though these factors may be
absent in a significant number of patients with
biopsy-proven NAFLD. These risk factors, which
are components of the metabolic syndrome, are
associated not only with NAFLD, but also with an
increased risk of NASH and its complications.
Drug-induced hepatotoxicity may induce histologic
changes similar to those seen in NAFLD. Among
the common medications that induce this form of
liver injury are amiodarone, tamoxifen, nifedipine,
and diltiazem. A more complete list of drugs caus-
ing steatohepatitis is found in Table 4.
Pathogenesis
The pathogenesis of NAFLD is incompletely under-
stood, and is the subject of active research. Cur-
rently, a “two-hit model of NAFLD” has been
described. It is believed that hepatic steatosis is the
260 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
Table 4
Medications Associated with NAFL
Amiodarone
Corticosteroids
Synthetic estrogens
Tamoxifen
Calcium channel blockers
Chloroquine
Methotrexate
Perhexilene maleate
Tetracycline
Salicylates
initial lesion, and is a result of insulin resistance,
which leads to increased lipolysis and fatty acid
delivery to the liver. The “second” hit is the induc-
tion of oxidative stress with free radical formation,
lipid peroxidation, and resultant cellular damage.
Studies of animal models of NAFLD have identified
several possible etiologic factors, including endoge-
nous ethanol production, elevated hepatic
TNF-alpha levels due to endotoxemia, and mito-
chondrial defects in fatty acid metabolism. It is
likely that the pathogenesis of NAFLD is multifac-
torial, with a combination of metabolic derange-
ments determining the presence of inflammation
and progressive fibrosis.
Clinical Features
The majority of patients with NAFLD are asymp-
tomatic, and the disease is often discovered when an
elevation of serum liver enzymes is detected. A
minority of patients, however, will complain of
fatigue or vague right upper quadrant discomfort.
Physical examination is unremarkable with the
exception of hepatomegaly, which is reported in
12%-75% of cases. Splenomegaly has been reported
in about 25% of patients. Central obesity, which is
associated with insulin-resistance and the metabolic
syndrome, is often present in patients with NAFLD.
Stigmata of portal hypertension are usually absent
unless the disease has progressed to frank cirrhosis.
Diagnosis Figure 4

There is no definitive diagnostic test for NAFLD.

Patients usually manifest elevated serum transami-
Nonalcoholic steatohepatitis (NASH)

nases, with greater elevation of the ALT level com-

pared with AST. This is in contrast to alcoholic liver
disease, in which the AST:ALT ratio is usually 2:1
or greater. A minority of patients with NAFLD have
an AST/ALT pattern similar to that seen in alcoholic
liver disease; these patients tend to have more
advanced disease with established fibrosis on
biopsy. Insulin resistance can also be estimated
using the homeostasis model assessment (HOMA),
calculated by multiplying the fasting insulin level
(U/ml) by the fasting glucose level (mmol/l), and
dividing the product by 22.5. The HOMA is an
imperfect measure of insulin resistance, but may aid
in the evaluation of patients with NASH.
Mixed macrovesicular, mid-sized and microvesicular

Patients with NAFLD may display mild elevations

steatosis, a poorly formed Mallory body (arrow) and a rare
focus of necrosis with polymorphonuclear leukocyte

of alkaline phosphatase and GGT levels (to less than

response. (H&E original mag X 50)

3 times the upper limit of normal), but abnormal

bilirubin, albumin, or prothrombin time is uncom-
mon. Given the association between NAFLD and
Figure 5

both diabetes and hyperlipidemia, it is not surpris-

ing that elevated serum glucose and lipid levels are
NASH

reported in 25%-75% of patients with NAFLD.

Viral serologies and autoimmune markers are nega-
tive, but iron studies may be abnormally elevated in
a minority of patients, and there is some evidence
that these patients may have more severe hepatic
fibrosis than those with normal iron studies. This is
controversial, however, since studies conflict as to
the role of iron in the progression of NAFLD.

Radiologic imaging can identify fatty infiltration of

the liver in some cases, and ultrasound, CT, and
MRI have all been used in this capacity. Unfortu-
nately, these modalities are only moderately sensi-
Centrilobular (Zone 3) fibrosis (blue) in nonalcoholic

tive for diagnosing hepatic steatosis, and more

steatohepatitis. This finding also may occur in alcoholic

important, these imaging studies are unable to dis-

steatohepatitis. (Masson trichrome, original mag X 50)

tinguish simple steatosis from steatohepatitis, and it

is only the latter condition that is associated with
progressive hepatic fibrosis and possible cirrhosis.
Liver biopsy is currently the only definitive method
of diagnosing NAFLD (Figures 4 and 5); in addition
to confirming the presence of steatohepatitis, biopsy
allows assessment of the level of inflammation and
fibrosis in the liver (disease staging). The utility of
biopsy is debated, as there is no effective therapy for
NAFLD at this time except weight loss and control
of hyperglycemia and serum lipids, which can be
recommended for patients with suspected NAFLD
without their undergoing the risk of liver biopsy.
The counter-argument is that patients with cirrhosis
on biopsy (7%-16% in case series) will benefit from
closer follow-up and should have an esophagogas-

CHAPTER 8: NON-VIRAL LIVER DISEASE 261

troduodenoscopy (EGD) to identify and treat
esophageal varices. In addition, such patients
should be screened periodically for hepatocellular
carcinoma with liver ultrasound examination every
6 months and serum alpha-fetoprotein determina-
tion 2 to 4 times per year.
Prognosis
There is controversy over the prognosis of NAFLD,
as definitive natural history studies have not yet been
conducted. Recent studies, however, have suggested
a slightly decreased surivival in patients with
NAFLD. Hepatic steatosis alone is not a progressive
condition, but the presence of steatohepatitis may be
associated with fibrosis and progression to cirrhosis
in a subset of patients. In existing series, severe
fibrosis is seen on initial biopsy in 15%-50% of
patients, and frank cirrhosis in 7%-16%. The time to
development of cirrhosis and the clinical course of
NAFLD-induced cirrhosis are not yet known, but it
is clear that progressive liver disease will occur in a
fraction of patients with steatohepatitis. A recent
study of 103 patients followed with serial biopsies
demonstrated worsening fibrosis in 37% of patients,
with the remainder having stable or improved histol-
ogy over time. Risk factors for progressive fibrosis
in NASH include older age, obesity, and diabetes.
The greater number of risk factors is correlated with
higher degrees of fibrosis on biopsy and presumably
with a greater risk of progression to end-stage liver
disease. Recent data suggest that many patients pre-
viously characterized as having cryptogenic cirrho-
sis may in fact have cirrhosis as a result of NAFLD.
This is an indirect association, since the degree of
steatosis on biopsy may decrease with increasing
amounts of fibrosis, so that a liver specimen demon-
strating cirrhosis with no fatty infiltration may repre-
sent a “burned out” stage of steatohepatitis. The high
frequency of NAFLD risk factors, including obesity,
diabetes, and hypercholesterolemia in patients with
undiagnosed cirrhosis make NAFLD an attractive
possible etiology. Patients with cirrhosis due to
262 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
NAFLD, as with other etiologies of cirrhosis, have
an increased risk of hepatocellular carcinoma. Liver
transplantation is an option for patients with decom-
pensated cirrhosis due to NAFLD, but there is evi-
dence that fatty infiltration and NASH may occur in
the transplanted liver.
Therapy
Currently, therapy for NASH includes treatment of
diabetes and hyperlipidemia, and a program of
weight loss in obese individuals. In some cases, a
loss of as little as 10% of body weight can lead to an
improvement in liver enzyme levels. Unfortunately,
there are no data on whether these therapies change
the natural history of steatohepatitis. It is also evi-
dent that rapid weight loss may induce or worsen
NAFLD, so care must be taken in advising dietary
therapy. Avoidance of alcohol and known hepato-
toxic agents is generally recommended, as obese
patients develop liver disease at a higher rate after
exposure to alcohol than do lean patients.
Presently, there are no proven pharmacologic
agents for NAFLD. Ursodiol had been proposed as
a possible therapeutic agent based on the results of
small studies, but a recent randomized controlled
trial failed to show any benefit. A promising area of
investigation involves the use of agents that
decrease insulin resistance. Metformin has been
shown to improve serum liver enzymes in patients
with NAFLD, and recent studies of rosigitazone
and pioglitazone have demonstrated improvements
in serum enzymes and histologic improvement on
liver biopsy. Randomized controlled trials are
needed to confirm these results before these agents
can be recommended.
4. Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune
disorder affecting primarily women, characterized
by progressive destruction of intrahepatic bile ducts
by an inflammatory process that leads to fibrosis and
eventual cirrhosis.
Epidemiology
PBC is an uncommon disease, with an estimated
prevalence of 4 to 5 cases per 100,000. It is primar-
ily a disease of women, with only 10% of cases
occurring in males. PBC is typically diagnosed in
middle age, with a median age at diagnosis of 50-55
years. There is a clear hereditary component to PBC
such that 4%-6% of first degree relatives of PBC
patients develop the disorder, with a relative risk of
PBC that is greater than 500 times that of the gen-
eral population.
Pathogenesis
The pathogenesis of PBC is only partially under-
stood. Liver biopsy in PBC demonstrates a dense
lymphocytic infiltrate in the portal tracts, with selec-
tive immune destruction of biliary epithelial cells by
CD4 and CD8 lymphocytes. There may also be
granuloma formation from activated macrophages.
The characteristic antibodies in PBC, termed anti-
mitochondrial antibodies (AMA) are directed
toward components of the pyruvate dehydrogenase
complex on the inner mitochondrial membrane.
Immunologic studies have determined that the lym-
phocytes mediating the biliary damage are directed
against these mitochondrial antigens as well. MHC
class 2 molecules are aberrantly expressed on bile
duct epithelium of patients with PBC, and may
function to present antigen to the lymphocytes,
thereby contributing to the aberrant immune
response. The concept of molecular mimicry is
invoked in PBC, as the antimitochondrial antibodies
cross react with a number of highly conserved bac-
terial antigens. There is also evidence that exposure
to xenobiotics may induce the aberrant immune
response seen in PBC.
Clinical Features
The classic description of PBC is that of a middle-
aged woman who presents with fatigue and general-
ized pruritus; however, only 20% of patients present
with this symptom complex. Up to 60% of patients
are asymptomatic at diagnosis, and the disease is
often recognized after an elevated alkaline phos-
phatase level is discovered. In patients who are
symptomatic, fatigue is reported in 65%-78%, and
pruritus is noted in 20%-70%. The pruritus tends to
be intermittent, occurring most often at night, and
can be quite debilitating. It should be noted that the
pruritus does not correlate with severity of disease,
and in fact may lessen over time. A minority of
patients (10%) present with jaundice, a sign of more
advanced disease. Physical examination reveals
hepatomegaly in greater than 50% of patients. The
presence of splenomegaly, ascites, or edema sug-
gests that the disease has progressed to cirrhosis
accompanied by portal hypertension. Skin findings
include hyperpigmentation (25%) and xanthelasma
(10%), and excoriations from frequent scratching.
Several autoimmune diseases are associated with
PBC. Thyroid disorders (most often Hashimoto’s
thyroiditis) are seen in 15% of patients with PBC.
Sjögren syndrome is seen in 50%-75% of cases,
while features of CREST scleroderma are reported
in up to 15% of patients. Ten percent of PBC
patients develop an inflammatory arthritis. Celiac
disease is present in 6% of PBC patients. Interest-
ingly, there appears to be an increased incidence of
autoimmune disorders in family members of
patients with PBC.
Diagnosis
Nearly all patients with PBC have an alkaline phos-
phatase level at least 3 to 4 times normal, with simi-
lar elevations of serum GGT. Serum bilirubin levels
are usually normal at diagnosis, with only 10% of
patients displaying frank jaundice; the presence of
hyperbilirubinemia is a poor prognostic sign in
PBC. Serum transaminase levels are normal or
slightly elevated. Patients with PBC usually have
elevated serum cholesterol levels, and may have an
elevated serum globulin level, with an IgM predom-
inance. Diagnosis is confirmed by determination of
a serum anti-mitochondrial antibody (AMA) level,
which is elevated to a titer of greater than 1:40 in
90%-95% of patients with PBC. This antibody
reacts to antigens of the pyruvate dehydrogenase
complex on the inner mitochondrial membrane. An
elevated AMA level may also be seen in a minority
CHAPTER 8: NON-VIRAL LIVER DISEASE 263
Figure 6 Figure 8

Primary biliary cirrhosis (PBC) PBC

Chronic, nonsuppurative destructive cholangitis with an Extensive portal-portal bridging fibrosis (blue) and duc-
epithelioid granulomatous component. (H&E original topenia. (Masson trichrome. Original mag X 18)
mag X 25)

of patients with autoimmune hepatitis and rarely in

primary sclerosing cholangitis or drug-induced liver
disease. Though very sensitive for the diagnosis of
PBC, the AMA test may be negative in a variant
Figure 7

form of disease with characteristic histologic find-

ings of PBC but with negative serologic testing; this
PBC

entity is called AMA-negative PBC or, more

recently, autoimmune cholangiopathy. It should be
recognized that patients with PBC may manifest
other autoantibodies, including ANA and anti-
smooth muscle antibody (found in up to 50% of
cases of PBC). In several series, an overlap syn-
drome with features of autoimmune hepatitis and
PBC has been described, and may require therapy
aimed at both entities in order to induce remission.

Imaging studies are unrevealing in PBC, with ultra-

sound, CT scanning, and ERCP typically normal.
These studies may be useful early in the diagnostic
evaluation of PBC in order to rule out a mass lesion
A B

or large duct obstruction as a cause for an elevated

Both left (A.) and right (B.) photomicrographs display

alkaline phosphatase level.

the “florid duct” lesion of PBC (chronic nonsuppurative
destructive cholangitis) with chronic inflammatory cells

Liver biopsy in patients with PBC displays charac-

infiltrating and destroying the basement membrane and

teristic findings of bile duct destruction and an

ultimately the interlobular bile duct. (H&E left original

inflammatory infiltrate comprised of mononuclear

mag X 45; right original mag X 60)

cells. Granulomata may be present (Figure 6), but

are not required for the diagnosis. PBC may be
staged according to pathologic findings. Stage 1 (the

264 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

“florid duct lesion”) is characterized by inflamma-
tion and biliary duct destruction (Figure 7). Stage 2
is characterized by proliferation of small bile ducts
in the portal areas. The development of septal fibro-
sis characterizes stage 3, and stage 4 is frank cirrho-
sis (Figure 8). Though useful for staging the disease,
biopsy is not essential in diagnosing PBC, since a
significant alkaline phosphatase elevation, a positive
AMA, and normal imaging studies allow the diagno-
sis to be made with relative certainty. In cases where
the diagnosis is equivocal, a biopsy is still indicated.
Although biopsy findings correlate with the severity
of disease, a number of predictive models exist that
accurately predict the course of disease, making
serial biopsies unnecessary.
Prognosis
Primary biliary cirrhosis is a slowly progressive dis-
ease that leads to hepatic cirrhosis in 10-20 years
after diagnosis. Currently, up to 60% of patients are
diagnosed in an asymptomatic phase, with an ele-
vated alkaline phosphatase as the only clue to under-
lying PBC. Such patients have a good short-term
prognosis, with 5-year survival >90%. The duration
of the asymptomatic period is very variable, but once
symptoms appear, survival rates decrease relative to
the general population. For patients with PBC, a
number of predictive models have been developed to
aid in predicting survival, with most models includ-
ing age, bilirubin level, prothrombin time, and serum
albumin, among other variables (Table 5). These
models are important in making decisions regarding
referral for consideration of liver transplantation in
patients with advanced disease.
Table 5
Mayo Clinic Prognostic Model for PBC
Risk score = 0.871 x log (serum bilirubin in
mg/dL)
-2.53 x log (albumin in g/dL)
+0.039 x (age in years)
+2.38 x log
(prothrombin time in seconds)
+0.859 (if edema is present)
Treatment
Several agents have been evaluated for the treat-
ment of PBC, but only ursodeoxycholic acid (urso-
diol) has been proven effective in retarding the pro-
gression of this disease. At doses of
13-15 mg/kg/day, oral ursodiol induces clinical and
biochemical improvement (decreased levels of
alkaline phosphatase), and significantly increases
survival free of liver transplant, as demonstrated in
three randomized controlled trials. Ursodiol works
as both a cholerrhetic agent, increasing bile flow,
and as an immune modulator. It has been shown to
down-regulate the aberrantly expressed MHC class
II molecules on biliary epithelia, but its impact on
the immune dysregulation in PBC is poorly under-
stood. Other agents, including colchicines and
methotrexate, have been studied for the treatment of
PBC, but the possible benefit of these agents is
inconclusive.
For patients with advanced liver disease due to
PBC, liver transplantation is the treatment of
choice. Prognosis after transplant is excellent, with
5-year survival rates of greater than 80%. PBC
recurs in the transplanted liver in approximately
20% of cases, but recurrence does not appear to
adversely affect survival.
Primary biliary cirrhosis is associated with many
complications common to the cholestatic liver dis-
eases. Osteoporosis is reported in 30%-50% of
patients with PBC, and it is recommended that all
patients with PBC receive supplemental calcium
and vitamin D, in doses similar to those used in
postmenopausal women. When osteoporosis is evi-
dent, bisphosphonate therapy with alendronate
appears to be beneficial. This therapy should be
used with caution in patients with cirrhosis and por-
tal hypertension, as alendronate can induce ulcera-
tion of the esophagus and promote hemorrhage
from esophageal varices.
Pruritus is a significant problem for many patients
with PBC. Ursodiol therapy may reduce symptoms,
but this effect has not been consistent. Agents that
have been used successfully to ameliorate pruritus
include antihistamines, cholestyramine, and
rifampin. Antihistamines are largely ineffective in
PBC, while cholestyramine may ameliorate pruri-
CHAPTER 8: NON-VIRAL LIVER DISEASE 265

tus, but its use is complicated by abdominal bloat-
ing, pain, and diarrhea. Rifampin has been effective
in reducing pruritus, but patients must be monitored
for bone marrow and liver toxicity. Opioid antago-
nists, such as naltrexone and nalmephene, have also
shown promise in the treatment of cholestasis-
induced pruritus.
Hypercholesterolemia is present in 85% of patients
with PBC. Early in the disease, levels of HDL are
elevated, but with time LDL levels also rise. How-
ever, patients with PBC do not appear to have an
increased risk of atherosclerosis or coronary artery
disease. A number of patients will develop xanthe-
lasma as a result of hyperlipidemia. The lipid disor-
der in PBC is often treated with cholestyramine,
which may also ameliorate pruritus in symptomatic
patients. Other cholesterol-lowering agents may be
used in patients with PBC, with the usual recom-
mended monitoring for hepatotoxicity depending
upon the agent used.
Fat soluble vitamin deficiency occurs in up to 20%
of patients with PBC, with deficiencies of vitamins
A, D, and K occurring most commonly. Frank steat-
orrhea, however, is uncommon.
266 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
5. Granulomatous Hepatitis
Introduction
The term “granulomatous hepatitis” refers to the his-
tologic finding of epithelioid granulomas in the liver
parenchyma obtained at biopsy. It is not a diagnosis
in itself, and a careful workup is required to look for
the treatable causes of this pathologic finding. Gran-
ulomatous hepatitis is most often seen in patients
who are evaluated for an elevated alkaline phos-
phatase level, as this enzyme is most often abnormal
in these patients; serum transaminases, however,
may also be elevated. Often, these patients are
asymptomatic, but symptoms may be present,
including fever, malaise, weight loss, and right upper
quadrant discomfort. Once biliary obstruction and
liver masses are excluded by imaging studies, and an
AMA test rules out PBC as the etiology of the ele-
vated ALP, a liver biopsy should be performed.
The biopsy itself, though significant for granuloma-
tous inflammation, is often not diagnostic. Patho-
logic features, however, may suggest a diagnosis.
Caseating granulomas are often seen in mycobacte-
rial infection, while noncaseating granulomas are
more often seen in sarcoidosis or drug reactions.
Fibrin ring granulomas are characterized by a cen-
tral fibrous ring surrounding an empty vacuole, and
are seen in Q fever.
Lipogranulomas have a central lipid-filled vacuole,
and are seen in patients who ingest mineral oil. For-
eign material may also be seen within the granulo-
mata. Talc within granulomas suggests a history of
IVDU, while silica or anthracotic bodies suggest
occupational exposure to silicates or coal products.
Shistosome eggs may be seen within granulomas,
and fungal forms are occasionally noted on silver
staining. Unfortunately, the most common finding is
a nonspecific granulomatous inflammation, making
a thorough search for clinical clues mandatory.
The differential diagnosis of granulomatous liver
disease is outlined in Table 6. In the United States,
sarcoidosis, drug toxicity, and mycobacterial dis-
eases are the most common etiologies of liver gran-
ulomas. Once granulomata are identified on liver
biopsy, workup should include a careful history
with attention to occupational exposures (beryllium,
silica), animal exposures (brucellosis, Q fever) and
travel (to areas endemic for fungal or parasitic dis-
 tuberculosis, but in only 25% of cases with pul-
monary involvement alone. Staining of liver granu-
Table 6

lomas for AFB is not typically diagnostic. Patients

with HIV infection and hepatic granulomas may
Causes of Granulomatous Hepatitis

have TB, atypical mycobacterial infection, viral

infection with CMV or HSV, or fungal diseases.
When infectious agents are suspected, serologic
Common (in United States)

testing, blood and tissue cultures, and direct staining

of the liver biopsy specimen may be revealing.
Sarcoidosis
Tuberculosis

Treatment is aimed at the underlying etiology of the

Primary biliary cirrhosis

liver findings. It should be noted that sarcoid liver

Drug effect

disease, though common in patients with sarcoido-

sis, is usually benign and does not cause progressive
Less Common

liver damage except in a minority of cases. Steroid

Atypical mycobacteria (in immunocompromized

therapy is not recommended unless there is ongoing

patients)

chronic hepatitis and fibrosis in addition to the gran-

Secondary syphilis

ulomatous inflammation.
Fungal infections: histoplasma, coccidioides,
cryptococcus

A subset of patients with no obvious etiology of

Miscellaneous infections: brucellosis, Q fever,

hepatic granulomata are considered to have idio-

schistosomiasis, leprosy, leshmaniasis

pathic granulomatous hepatitis. Corticosteriods and

Exposures: beryllium, copper, talc

methotrexate have been used to treat this condition,

Hodgkin lymphoma

with resolution of symptoms and an improvement in

Viral infection: CMV, EBV

liver biochemical tests and histology. It is impor-

tant, however, to completely rule out infectious eti-
eases). Physical examination is often unrevealing, ologies before embarking on an immunosuppres-
though patients may have hepatomegaly or sive regimen.
splenomegaly. A careful drug history is essential,
with attention to the drugs most often associated
with granulomatous disease, including: allopurinol;
phenytoin; carbamazepine; hydralazine; pro-
cainamide; amoxicillin-clavulinic acid; and sulfon-
amides. A chest x-ray may reveal mediastinal
adenopathy or other signs of sarcoid lung disease.
An ACE level is elevated in 50%-85% of patients
with sarcoidosis, but similar elevations are noted in
other granulomatous diseases, making this serologic
test insensitive and nonspecific. Hepatic granulo-
mas may also be present in patients with Hodgkin
disease, and may occur prior to the onset of classic
symptoms or lymphadenopathy. Thus, patients with
fevers, wasting, and adenopathy, mediastinal or oth-
erwise, need to be evaluated for possible lymphoid
malignancy.

Tuberculosis should always be considered in

patients with hepatic granulomas, especially if there
is evidence of caseation. Liver involvement is seen
in more than 90% of patients with disseminated

CHAPTER 8: NON-VIRAL LIVER DISEASE 267

6. Primary Sclerosing Cholangitis
Epidemiology
Primary sclerosing cholangitis (PSC) is an autoim-
mune condition characterized by inflammation and
fibrosis of medium and large bile ducts, leading over
time to biliary cirrhosis. It is associated most closely
with inflammatory bowel disease, especially ulcera-
tive colitis (UC). Although only 2%-7% of patients
with UC develop PSC, more than 75% of all
patients with sclerosing cholangitis have underlying
UC. Crohn disease is less commonly associated
with PSC, being seen in 10%-15% of cases.
Tobacco use, which has been shown to be protective
against UC, also appears to decrease the incidence
of PSC, though smoking may increase the risk of
bile duct malignancy in patients who already have
PSC. Primary sclerosing cholangitis is twice as
common in males as in females, and the average age
of onset is in the mid-40s.
Pathogenesis
The pathogenesis of PSC is unknown, but it is
believed to be an autoimmune phenomenon, given
its association with ulcerative colitis and its charac-
teristic pathologic findings of lymphocytic infiltra-
tion and destruction of small and large bile ducts.
The associated hypergammaglobulinemia (of the
IgM type) and the frequent finding of autoantibod-
ies (p-ANCA in particular) support this concept.
There has been speculation that bacterial transloca-
tion from the inflamed bowel in UC may induce the
immune response in PSC, but there is no definitive
data to support this conjecture. A lesion similar to
PSC can be caused by cryptosporidial and CMV
infection in patients with AIDS (the so-called
“AIDS cholangiopathy”), but no infectious agent
has been implicated in primary sclerosing cholangi-
tis. An association between PSC and polymor-
phisms of the TNF alpha receptor have been
described, and specific MHC alleles may also be
associated with susceptibility to PSC.
Clinical Features
Patients are usually asymptomatic at the time of ini-
tial diagnosis, with abnormal liver enzymes provid-
ing the only clue to the presence of PSC. An ele-
vated alkaline phosphatase is the most common
manifestation, often with an accompanying mild
268 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
Table 7
Mayo Clinic PSC Risk Analysis
Risk score R = (0.06 x (age in years)) + (0.85 x
(LN (bilirubin value)) - (4.39 x
(LN (hemoglobin
value)) + (0.51 x (biopsy value))
+ (1.59 x (inflammatory bowel
disease value))
R Value Risk Group
≤-5.14 Low
-5.13 to -3.26 Intermediate
≥-3.25 High
elevation of serum transaminases. Serum bilirubin
is normal until late in the course of PSC. A quarter
of patients will have an elevated globulin with an
IgM predominance. Unlike PBC, however, antimi-
tochondrial antibodies are rarely positive. A posi-
tive antineutrophil cytoplasmic antibody (p-ANCA)
is found in up to 80% of patients with PSC, but this
is not a specific marker as it may be present in both
PBC and autoimmune hepatitis. In addition, other
autoimmune markers may be positive in PSC,
including ANA (35%-50%) and ASMA (10%).
The course of PSC is slowly progressive, with the
eventual development of biliary cirrhosis, portal
hypertension, and liver failure. Median survival has
been reported as 12 years in older studies, which
included many patients with advanced disease at
diagnosis. Currently, many patients are identified in
an asymptomatic stage, and median survival is
reported to be approximately 17 years. Clinically,
patients are often asymptomatic at diagnosis, but
within 5-6 years the majority have overt symptoms
of PSC. Nonspecific symptoms of PSC include
fatigue and pruritus, and up to 50% may have an
abnormal physical examination with hepatomegaly
or splenomegaly. Patients with PSC may suffer
repeated episodes of jaundice or cholangitis due to
Figure 9
Primary sclerosing cholangitis
This ERCP image demonstrates the characteristic abnor-
malities of the small bile ducts, with a beaded appearance
due to multiple inflammatory strictures.
bile duct obstruction from strictures. If a “dominant
stricture” of the CBD is seen at ERCP, dilation will
result in symptomatic relief, but the course of PSC
is marked by recurrent symptomatic episodes. A
prognostic model for PSC (Table 7) has been devel-
oped and validated, and it assists clinicians in moni-
toring the progression of disease and in the planning
of liver transplantation when a patient develops
end-stage liver disease. The course of PSC is inde-
pendent of a patient’s underlying IBD, and may
occur or worsen despite effective medical therapy of
IBD. PSC may develop or progress in some patients
even after total colectomy.
In addition to bile duct obstruction, patients with
PSC are prone to gallstone disease, with both
cholesterol gallstones and pigment gallstones.
Patients with prior ileostomy from IBD may
develop peristomal varices and hemorrhage. These
are very difficult to treat locally, and TIPS has been
used to decompress these varices and decrease the
risk of bleeding.
Figure 10
PSC
Marked portal-periportal fibrous expansion and septal
fibrosis. Note the prominent periductal fibrosis of the large
distorted interlobular duct (upper-mid portion of photomi-
crograph) as well as an occasional small duct, chronic
inflammation and a patchy area of cholate stasis. (H&E
original mag X 16)
Cholangiocarcinoma is an important sequela of PSC
that occurs in 7%-15% of cases and is often the
cause of death in these patients. It is difficult to diag-
nose radiologically due to the marked abnormalities
of the biliary tree that characterize PSC. Serum
markers such as CA 19-9 are neither sensitive nor
specific, and ERCP with bile duct brushing and
biopsy have sensitivities of only 40%-70%. Thus,
these tumors often remain undiagnosed until a late
stage and portend a very poor prognosis. In patients
with PSC who undergo liver transplantation, up to
10% of the explanted livers demonstrate occult foci
of cholangiocarcinoma.
Diagnosis
The diagnosis of PSC is made using imaging stud-
ies. Both ERCP and MRCP can make the diagnosis
when the characteristic findings of multiple bile
duct strictures are visible (Figure 9). In 85%-90% of
cases, both the intrahepatic and extrahepatic bile
ducts are affected, with 10% showing only intra-
hepatic duct involvement and a small fraction with
only extrahepatic involvement. These radiologic
findings are not entirely specific, and may be seen in
CHAPTER 8: NON-VIRAL LIVER DISEASE 269
 7. Hemochromatosis

patients with HIV associated cholangiopathy,

cholangiocarcinoma, congenital bile duct disorders,
Epidemiology

and after biliary tract surgery. However, the pres-
ence of the characteristic x-ray findings in a patient
with cholestatic liver enzymes and inflammatory
bowel disease is sufficient for the diagnosis of PSC.
Liver biopsy may show a characteristic lesion with
“onion skin” fibrosis surrounding small bile ducts
(Figure 10). This finding, however, is seen in only
15% of biopsies in patients with PSC, and it is rarely
used to confirm the diagnosis.
Treatment
Hereditary hemochromatosis (HHC) is an inherited
disorder of iron metabolism leading to the deposi-
tion of excess iron in body tissues, including the
skin, liver, pancreas, and heart. It is important to
identify patients with HHC in its early stages, as
phlebotomy can decrease iron stores and prevent
end-organ damage. The HFE gene has recently been
identified as the responsible gene for HHC. Located
on chromosome 6, the HFE gene codes for a protein
similar in structure to the HLA class I molecule.
Mutations in this gene lead to a defective protein
and disordered iron metabolism; the most common

There is currently no proven medical therapy for
PSC, but there are data from small studies suggest-
ing that ursodiol at high doses (20-30 mg/kg/day)
may slow the progression of PSC. A recent random-
ized controlled trial of 219 patients receiving high-
dose UDCA failed to demonstrate a significant
improvement in symptoms, laboratory parameters,
or survival after five years of follow-up. There was,
however, a trend towards improved survival in the
treated group. Other large, randomized controlled
mutations are denoted C282Y, H63D, and S65C;
these form the basis for the current genetic test
available for HHC. The C282Y mutation is the most
common defect, present in 80%-85% of cases of
HHC. The H63D mutant confers a lesser degree of
iron overload in the homozygous state, but the com-
pound heterozygote (C282Y/H62D) may also mani-
Table 8

trials are underway to further evaluate the efficacy

of UDCA in PSC.
Extrahepatic Manifestations of HHC

Other medical therapies, including glucocorticoids,

methotrexate, and penicillamine, have been studied,
but have proven ineffective in the treatment of PSC.
Organ Clinical Manifestation

Endoscopic therapy is only helpful in the 20% of

Pancreas Diabetes mellitus

PSC patients who develop dominant strictures of a

large bile duct. In such cases, dilation and stenting
Heart Cardiac dysrythmias

of narrowed ducts may effectively treat cholangitis,

Dilated cardiomyopathy

and relieve pain and jaundice. Endoscopic treat-

ment, however, does not slow the inexorable pro-
Skin “Bronze” hyperpigmentation

gression of disease.
“Gray” hyperpigmentation

Liver transplantation is the only definitive therapy

Kidneys Diabetic nephropathy

for PSC, with survival rates of 90%-95% at 1 year

and 85%-88% at 5 years. PSC returns in the trans-
Pituitary Hypothyroidism

planted liver, but appears to run a mild course in

Hypogonadism

most patients. Interestingly, patients with UC and

Loss of libido

PSC who undergo transplantation have a signifi-

cantly increased risk of colon cancer and require
Joints Crystalline-induced arthropathy

yearly screening if the colon is not resected. UDCA

therapy has been shown to reduce the risk of colon
cancer in patients with PSC and UC.

270 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

fest clinically significant iron overload. HFE muta-
tions are common in Caucasian persons of Northern
European descent, with an allelic frequency of
1:1020 and a frequency of homozygosity of 1:200-
400. The frequency of clinical iron overload, how-
ever, is significantly lower than this due to incom-
plete phenotypic penetrance. Other genetic iron
overload syndromes, such as African iron overload
and juvenile hemochromatosis, do not manifest
these HFE gene mutations.
Pathogenesis
The role of the HFE protein is becoming clearer as
the mechanisms of intestinal iron absorption are
being elucidated. Total body iron stores are approxi-
mately 3-5 grams, with 1-2 mg absorbed each day to
balance the 1-2 mg lost each day in senescent
intestinal cells. Iron absorption by villus enterocytes
in the proximal small bowel is mediated by apical
(DMT-1) and basal (ferroprotin) iron transporters
that take in iron and excrete it into serum bound to
transferrin. The rate of iron absorption is governed
by the number of transporters on the cell surface.
Recently, the role of hepcidin in the regulation of
iron metabolism has been elucidated. Hepcidin is a
peptide hormone produced in the liver in response
to the presence of iron-bound transferrin in the por-
tal circulation. Hepcidin acts at the basal surface of
enterocytes to reduce the efflux of iron, thereby
increasing intracellular iron stores. These iron-laden
enterocytes are sloughed off in the normal cycle of
enterocyte loss, and their iron stores are not
absorbed into the circulation. There may also be a
concomitant decrease in iron absorption at the villus
surface in response to enterocyte iron loading. The
HFE gene product is expressed on the hepatocyte
surface, and may modulate the response to circulat-
ing iron-bound transferrin. In HFE deficient indi-
viduals, the hepatocyte fails to respond normally to
iron-bound transferrin, and thus produces less hep-
cidin. Without hepcidin to modulate iron absorp-
tion, the villus enterocytes continue to absorb iron
despite sufficient body iron stores, leading to total
body iron overload.
The HFE gene product is also expressed on duode-
nal crypt cells, and there is an alternate hypothesis
that the lack of HFE on these cells leads to deranged
iron sensing in the crypt enterocytes, with a subse-
quent increase in apical DMT-1 transporters on
these cells. When these cells reach the villus sur-
face, they absorb iron at a high rate, despite ade-
quate or excess total body iron stores. The relative
contribution of duodenal versus hepatocyte HFE in
the pathogenesis of hemochromatosis remains an
area of active research.
When these enterocytes mature and reach the villus
apex, they absorb large amounts of iron despite a
total body iron overload. Iron then deposits in tis-
sues throughout the body, and induces tissue dam-
age via the generation of oxygen free radicals. In the
liver, this leads to both inflammation and fibrosis
resulting from the activation of hepatic stellate cells.
Clinical Features
The clinical manifestations of hemochromatosis are
due to iron deposition in various tissues, leading to
eventual organ dysfunction. Early studies of HCC
included only patients with advanced disease, who
commonly have 1 or more symptoms. In recent
studies, however, up to 75% of patients are asymp-
tomatic, identified only by the presence of abnormal
LFTs or abnormal serum iron indices. Symptoms
usually develop between the ages of 40 and 60 years
in untreated patients (Table 8). Women tend to
develop symptoms at a later age, since menstrual
blood loss slows the accumulation of iron stores
during the reproductive years. Diabetes mellitus
secondary to pancreatic infiltration was commonly
seen in earlier studies, as was skin hyperpigmenta-
tion; these 2 symptoms led to the early name
“bronze diabetes” for HHC. Interestingly, the
increased skin pigmentation is not due to visible
iron deposition in the skin, but is in fact due to
increased melanin production by melanocytes,
induced by iron overload. Also common are arthral-
gias and arthritis, often localized to the second and
third MCP joints of the hands. Other symptoms
include impotence and decreased libido (due to
pituitary iron deposition), congestive heart failure
from cardiac iron overload, and signs of advanced
liver disease from hepatic iron deposition. In
patients with HHC and cirrhosis, the incidence of
hepatocellular carcinoma is particularly high, with a
200-fold increased risk compared to the general
population. More recent studies of HHC identify
CHAPTER 8: NON-VIRAL LIVER DISEASE 271
patients on the basis of abnormal serum iron studies
or genetic testing, and the frequency of symptoms
is, as a result, significantly lower. As an example,
the frequency of hepatic cirrhosis at diagnosis was
50%-95% in early studies, but is only reported to be
3%-13% in recent series.
Diagnosis
Currently, asymptomatic patients with an elevated
ferritin and a transferrin saturation (serum Fe/TIBC)
>50% are considered at risk for HHC and require
confirmatory testing. In the past, liver biopsy was
the gold standard for diagnosis. Findings on biopsy
included stainable iron in hepatocytes (Figure 11),
and a hepatic iron index (HII) of >1.9 (the HII = mg
Fe/g liver tissue divided by patient age). Genetic
testing for the common mutations (C282Y, H63D,
and S65C) can provide a noninvasive diagnosis of
HHC. CT and MRI scans of the liver may reveal
iron overload, but these modalites are only helpful
when iron stores are very elevated. Biopsy still has
a role in staging disease, but is reserved for patients
with clinical features that portend a risk of signifi-
cant liver fibrosis. These include: 1.) age >40; 2.)
elevated AST or ALT; 3.) serum ferritin >1000.
Patients who lack these risk factors do not require
biopsy, and may proceed directly to therapy.
Figure 11
Genetic hemochromatosis
Grade 4+ hemosiderosis in cirrhotic liver, predominantly I
hepatocytes and biliary epithelium. When present, iron-
free foci are considered to be precancerous. (Perl’s stain.
Original mag X 18)
272 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
Treatment
Phlebotomy is the mainstay of therapy for HHC, and
effective iron reduction prevents the end-organ com-
plications of the disease. Each unit of blood contains
250 mg of iron and decreases serum ferritin by
approximately 30 ng/mL. Thus, weekly phlebotomy
is carried on for weeks to months until the serum fer-
ritin is <50. The phlebotomy interval is then length-
ened, and most patients are effectively managed with
maintenance phlebotomy 3-6 times per year. Patients
who undergo successful phlebotomy before the
development of hepatic cirrhosis have survival com-
parable to age-matched controls. Patients with cir-
rhosis, despite phlebotomy, have a 10-year survival
of approximately 60%, with liver failure and hepato-
cellular carcinoma being common causes of early
mortality. Liver transplantation for end-stage liver
disease in HCC is effective, but survival rates are
60% and 40%-45% at 1 and 5 years, respectively.
The relatively poor results with transplant are due to
the fact that patients with advanced HCC have other
comorbidities (especially cardiac and endocrine dis-
orders) that shorten survival.
When a patient is diagnosed with HHC, it is neces-
sary to screen family members for the disorder, since
early identification and iron reduction prevents com-
plications. All first-degree relatives of an affected
individual should be offered screening with serum
ferritin and iron saturation. Those persons with ele-
vated markers should undergo genetic testing and
begin phlebotomy. Screening for the genetic defect
is not recommended due to the incomplete pene-
trance of the HHC phenotype. Pooled data from
large studies demonstrate that 25%-58% of C282Y
homozygotes have a normal ferritin and do not have
clinically significant iron overload.
Patients with elevated iron studies may also have
secondary iron overload, either due to chronic
hemolytic anemia (thalassemia, sickle cell disease)
or multiple transfusions. This is usually clinically
apparent, but liver biopsy shows preferential iron
deposition in Kupffer cells rather than hepatocytes,
and HHI is usually <1.9. Elevated ferritin levels are
also seen in other chronic liver diseases, including
NASH, alcoholic liver disease, and hepatitis C. The
degree of hepatic iron overload in these disorders is
usually mild, and the role of iron in the progression

of these disorders is controversial. In patients with
genetic hemochromatosis, however, it is established
that both alcohol use and HCV infection increase
the risk of progression to cirrhosis.
8. Alpha-1 Antitrypsin Deficiency
Epidemiology
Alpha-1 antitrypsin (A1-AT) deficiency is an inher-
ited enzymatic disorder that can result in both seri-
ous lung injury and end-stage liver disease. It is
inherited in an autosomal dominant fashion, and in
Caucasians in the United States, the homozygous
form is believed to occur in 1 in 1800-2000 births.
The incidence is much lower in non-European pop-
ulations. The pulmonary manifestations occur in the
majority of patients, while the hepatic disease is a
less frequent manifestation. Nonetheless, A1-AT is
the most common childhood metabolic disease of
the liver and is responsible for a significant fraction
of pediatric liver transplants.
The enzyme A1-AT is a protease inhibitor that inac-
tivates serine proteases, including neutrophil elas-
tase produced in inflammatory reactions. It serves
an important role in protecting lung tissue from
degradation by elastase. The gene for A1-AT, on
chromosome 14, exists in several allelic forms. The
protein products of the A1-AT gene are identified by
protein electrophoresis, and are given the designa-
tion Pi and the wild type protein is designated
PiMM. Although more than 75 variant forms of A1-
AT have been identified only a small subset have
pathologic significance. In clinical A1-AT defi-
ciency, the most common variant is designated
PiZZ. This protein has less than 15% of the normal
activity, and is associated with both lung and liver
disease. The Z allele of alpha-1 antitrypsin is carried
by 1%-2% of the Caucasian United States popula-
tion, and it is estimated that 80,000-100,000 persons
in the U.S. are homozygous PiZZ. Another allele,
denoted S, is a cause of disease in patients who are
compound heterozygotes with the phenotype PiSZ;
PiSS homozygotes, however, do not appear to
develop organ damage. Other mutations are less
common, and carry a variable risk of disease (Table
9).
Pathophysiology
The pathophysiology of lung disease in A1-AT defi-
ciency is due to an inability to degrade neutrophil
elastase. The enzyme is produced in large quantities
by pulmonary neutrophils, and when unopposed by
A1-AT, it leads to progressive destruction of alveo-
lar tissue and the onset of emphysema. This is par-
CHAPTER 8: NON-VIRAL LIVER DISEASE 273
Table 9

Common ALPHA 1-ATD Mutations

ALPHA 1-AT Plasma Clinical

Mutation Prevalence Concentration Manifestations

Homozygous ZZ 4% Northern Europeans Reduced by 85% Emphysema, cirrhosis

(Glu342Lys) 3% Americans and hepatocellular
carcinoma

Homozygous S 5%-10% in persons Reduced by 40% Generally not

Mutation of European descent disease-producing
(Glu264Val)

SZ mutation <5% in persons of Reduced by 40% Clinically significant,

(Glu342Lys) European descent or more especially in smokers

Siiyama variant Rare Reduced May be clinically

(Ser53Phe) significant

Malton variant Rare Reduced May be clinically

(Phe52) significant

Null variants Rare Reduced Associated with lung

but not liver disease

ticularly true of smokers, and a family history of

COPD in younger individuals should suggest possi-
Clinical Features

ble A1-AT deficiency. The liver disease in A1-AT
deficiency is not caused by the lack of enzyme activ-
ity, but rather by an excess of inactive protein in the
hepatocytes. A1-AT is normally produced in hepa-
tocyte endoplasmic reticulum, and transported to
the Golgi apparatus for final processing and even-
tual secretion. The Z form of A1-AT undergoes
abnormal folding that prevents transport of the
enzyme out of the ER. If the hepatocyte is unable to
degrade the enzyme at a sufficient rate, there is a
buildup of protein in hepatocytes that leads to hepa-
tocyte damage and liver fibrosis by an as yet
unknown mechanism. The misfolded protein is visi-
ble in hepatocytes on light microscopy as intracellu-
lar globules that stain positive with periodic acid
Schiff (PAS) and are resistant to digestion with the
enzyme diastase.
Clinically apparent liver disease occurs in 12%-
15% of patients with PiZZ type A1-AT deficiency,
though autopsy studies demonstrate cirrhosis in
more than 30% of PiZZ patients; this may reflect
mortality due to lung disease in patients with com-
pensated and undetected cirrhosis. The variation in
clinically apparent disease likely represents differ-
ences in the ability of individuals to degrade intra-
cellular A1-AT and prevent excessive accumulation
of protein in hepatocytes. Clinical manifestations of
A1-AT deficiency may occur in early infancy, or
may remain silent until adulthood (Table 10).
Neonatal cholestasis is present in approximately
10% of cases, and an additional 3%-7% develop
clinical disease in early childhood. In later life, A1-
AT deficiency may manifest as a chronic elevation
of AST and ALT in asymptomatic patients, and it

274 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

Table 10

Clinical Manifestations of Alpha 1-ATD

Age at Presenation Clinical Presenation Other Clinical Features

Neonate 8%-12% present with prolonged cholestatic Failure to thrive, irritability,

jaundice (direct reacting bilirubin) acholic stools, bleeding
Up to 50% have elevated AST/ALT from the umbilical,
by age 3 months (often asymptomatic). stump, easy bruising,
Fulminant hepatic failure (rare) hepatomegaly, ascites, pruritus,
hypercholesterolemia

Child/Adolescent 12%-15% develop clinically evident liver

disease with hepatosplenomegaly, ascites
and variceal bleeding

Adult Up to 37% develop cirrhosis from autopsy Emphysema, bronchiectasis,

studies and pulmonary vasculitis
Hepatocellular carcinoma risk is increased may be present
(especially after age 50); may be a presenting (especially among smokers)
feature
May present as unexplained liver enzyme eleva-
tions or complications of portal hypertension

should be considered in patients who are referred
for evaluation of abnormal liver enzymes. Other
patients present with clinical signs of cirrhosis,
including ascites, variceal hemorrhage, or jaundice.
There is also a significantly increased risk of hepa-
tocellular carcinoma in patients with A1-AT defi-
ciency.
the cytoplasm of hepatocytes (Figure 12). These
granules are not pathognomonic of A1-AT defi-
ciency, but their presence should lead to phenotype
analysis of affected patients.
Treatment

Patients with A1-AT deficiency who have pro-

gressed to end-stage liver disease will benefit from
orthotopic liver transplantation, which corrects the
Diagnosis

The diagnosis of A1-AT deficiency is made by mea-
surement of a serum A1-AT level and elec-
trophoretic analysis to identify the mutant alleles of
A1-AT. Decreased serum levels of A1-AT are usu-
ally seen in A1-AT deficiency, but normal levels do
not definitively exclude the diagnosis, as A1-AT is
an acute phase reactant and may reach normal levels
during acute illnesses and inflammatory states.
Liver biopsy demonstrates the accumulation of A1-
AT as PAS-positive, diastase resistant granules in
metabolic defect so that disease will not occur in the
transplanted organ. Outcomes in children after
transplant are good, with 1- and 5-year survivals of
90% and 80%, respectively. There is no other avail-
able therapy for the liver disease in A1-AT, though
there is active research into possible gene therapy
for this condition. The lung disease in this disorder
can be treated with replacement A1-antitrypsin,
which has been shown to ameliorate the pulmonary
disease and improve survival in these patients.

CHAPTER 8: NON-VIRAL LIVER DISEASE 275

 9. Wilson Disease

Figure 12 Epidemiology

Wilson disease (WD) is a rare genetic defect of hep-

atic copper metabolism characterized by copper
Liver biopsy in alpha-1 antitrypsin

deposition in tissues including the liver, cornea, kid-

deficiency

ney, and central nervous system. It is inherited in an

autosomal recessive fashion with the homozygous
state occurring in approximately 1 in 30,000-50,000
The hepatocytes demonstrate the PAS (+) granules

live births. The liver manifestations of WD range

characteristic of this condition

from asymptomatic chronic hepatitis to cirrhosis

12A: low power 12B: high power

and end-stage liver disease. WD may also cause ful-

minant hepatic failure requiring emergency trans-
plantation. It is estimated that 3%-6% of patients
with fulminant hepatic failure requiring transplanta-
tion have WD as the underlying etiology. Wilson
disease should be considered in all patients with
chronically elevated serum transaminases, espe-
cially those with associated symptoms.

Pathogenesis

The Wilson disease gene (designated ATP7B) on

chromosome 13 codes for a P-type ATPase trans-
port protein in the hepatocyte. This protein trans-
ports copper into the bile and facilitates binding to
ceruloplasmin, the serum transporter of copper.
A

Typically, 1-5 mg of copper is absorbed from

dietary sources each day, and 1-2 mg is excreted
daily in the bile. In Wilson disease, copper transport
across the canalicular membrane is impaired, as is
incorporation of copper into ceruloplasmin. As a
result, copper accumulates in hepatocytes, inducing
inflammation and fibrosis, likely via the elaboration
of oxygen free radicals and lipid peroxidation.
Excess copper leaks into the bloodstream and
deposits in other tissues, including the basal ganglia
of the CNS, the cornea, kidney, and heart. More than
60 mutations of ATP7B have been identified, with
varying degrees of activity. This accounts for the
variable presentation of WD, and the large number
of mutations make genetic screening of patients and
family members difficult.

Clinical Features

Patients with Wilson disease are most often between

B

the ages of 8 and 18, but both younger and older

patients have been identified; current guidelines rec-
ommend that WD be considered in patients between
the ages of 3 and 55 with liver abnormalities of

276 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY


Figure 13
Wilson disease with established cirrhosis
Accumulation of copper (brick-red granules) predomi-
nantly along septa of cirrhotic nodules. (Rhodamine. Origi-
nal mag X 25)
unknown etiology. Patients may present with liver
disease, neuropsychiatric disorders, or both, but the
clinical features are quite variable.
Most patients have some degree of hepatic disease,
and liver disease without neurologic symptoms is
seen in 20%-45% of cases. Isolated hepatic disease
is more commonly seen in children, while neuro-
logic and psychiatric symptoms occur more fre-
quently in adolescents and young adults. The onset
of symptoms is rare after age 40. Fulminant WD
presents in a manner similar to other forms of acute
hepatic failure, but several clues may be helpful in
diagnosing WD in this group. Typically, serum AST
and ALT values are less than 10 times the upper
limit of normal, while serum bilirubin values may
be markedly elevated. Serum alkaline phosphatase
is normal or in many cases significantly decreased.
The presence of a Coombs negative hemolytic ane-
mia in a patient with fulminant hepatic failure
(FHF) may be a sign of WD, as free copper released
into the bloodstream may induce severe acute
hemolysis. Serum ceruloplasmin and other serum
copper indices (discussed below) may not be diag-
nostically helpful in fulminant WD, and Kaiser-
Fleischer rings may be absent, so a strong clinical
suspicion of Wilson disease is advised for any
young patient with these features. Interestingly,
although Wilson disease is more common in males
overall, the incidence of FHF is higher in females
with WD.
Diagnosis
WD may manifest as a neuropsychiatric illness with
associated liver abnormalities or as a purely hepatic
disorder. Chronic liver disease in WD may manifest
as abnormal liver enzymes in an asymptomatic
patient. Other patients present with established cir-
rhosis and come to attention because of jaundice,
poor synthetic function, or signs of portal hyperten-
sion. Neurologic disease may be absent in these
patients, and most patients with only hepatic WD
lack the characteristic KF rings on corneal examina-
tion. Neuropsychiatric symptoms, when present,
typically manifest in adolescence or early adult-
hood. The neurologic symptoms of WD include a
progressive movement disorder characterized by
tremor, ataxia, rigidity, and dysarthria/dysphagia.
The inexorable progression of symptoms can leave
patients unable to care for themselves, despite intact
cognitive functioning. Up to one-third of patients
present with psychiatric symptoms, including
depression and psychosis. They are often misdiag-
nosed as having schizophrenia or other primary psy-
chiatric disorders, and liver enzymes should be
obtained in young patients with new onset psychi-
atric symptoms to screen for WD. In patients with
the typical neurologic syndrome, a diagnosis of WD
can be made if KF rings are present (seen in up to
90% of these patients), and the serum ceruloplasmin
level is low. Brain MRI may show evidence of cop-
per deposition in the basal ganglia, but this is not
necessary for diagnosis.
Patients with a purely hepatic presentation of WD,
however, often lack KF rings (<50%), and lack
symptoms specific for WD. The diagnosis of WD is
suggested in these patients by a low serum cerulo-
plasmin level, as ceruloplasmin degrades rapidly
when not bound to copper. However, since cerulo-
plasmin is an acute phase reactant, it may reach low-
normal levels in up to 45% of patients with WD,
especially in acute inflammatory states. A 24-hour
urine copper determination is a more accurate diag-
nostic tool and should be considered when the clini-
cal suspicion of WD is high, even if the serum ceru-
loplasmin is not decreased. A decreased ceruloplas-
CHAPTER 8: NON-VIRAL LIVER DISEASE 277
min is also not specific for WD, and may be seen in
malnutrition, autoimmune liver disease, and in other
genetic disorders of copper metabolism. Serum cop-
per levels are also not sufficiently sensitive or spe-
cific to diagnose WD. Urinary copper levels
(>100 mg in a 24-hour urine collection) have a bet-
ter diagnostic accuracy, and are recommended when
the index of suspicion of WD is high. Liver biopsy
may show nonspecific features of chronic inflam-
mation, steatosis, fibrosis, or established cirrhosis
(Figure 13). An hepatic copper content of
>250 mcg/gram dry weight is usually seen, but there
is great variability in copper deposition in WD and a
single biopsy may not be diagnostic. Thus, a combi-
nation of clinical, laboratory, and histologic features
are needed to make a diagnosis of Wilson disease.
Recent guidelines recommend the use of serum
ceruloplasmin, 24-hour urinary copper excretion,
and a slit lamp exam for KF rings in any patient with
suspected Wilson disease. Patients with both KF
rings and a decreased ceruloplasmin are given a
definitive diagnosis of WD; patients with only a sin-
gle suggestive test should have a liver biopsy with
quantitative copper determination.
Treatment
It is important to confirm the diagnosis of WD, since
therapy can prevent the development of end-stage
liver disease and may ameliorate or reverse the neu-
rologic sequelae. Avoidance of foods rich in copper
is recommended, including shellfish, nuts, choco-
late, mushrooms, and liver. Dietary therapy, how-
ever, is insufficient to prevent copper overload, and
medical therapy is required. Penicillamine is an oral
agent that chelates serum copper and increases uri-
nary copper excretion. At doses of 1-2 g/day, it is
very effective in decreasing total body copper stores
in WD to nontoxic level, and chronic therapy pre-
vents the re-accumulation of toxic levels. Neu-
ropsychiatric symptoms may initially worsen, but
tend to improve steadily with continued therapy.
Unfortunately, up to 20% of patients on chronic
penicillamine therapy develop significant side
effects, including leukopenia, thrombocytopenia,
systemic lupus erythematosus, oral ulcers, and a
number of other immunologic and dermatologic
conditions. Severe side effects necessitate cessation
of therapy.
278 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
Trientine is another chelating agent effective in the
treatment of WD. It is equal in effectiveness to peni-
cillamine with a significantly lower incidence of
side effects. It may be used as a first-line therapy, or
in cases of intolerance to penicillamine. Oral zinc
therapy (150 mg po TID) has also been shown to be
effective in the treatment of WD. Zinc interferes
with intestinal absorption of copper both by com-
peting for transporters in the enterocyte membrane
and by inducing metallothionein production. This
enzyme binds metals such as copper and prevents
their systemic absorption. The copper adducts are
later excreted via shedding of enterocytes into the
intestinal lumen. Zinc therapy appears to be effec-
tive in maintaining total body copper at nontoxic
levels, and it is gaining wider use in patients with
WD after initial chelation therapy reduced copper to
nontoxic levels. Antioxidants such as alpha-toco-
pherol have been advocated as an adjunctive ther-
apy to limit oxidative damage in WD. To date, how-
ever, there have been no controlled studies of
antioxidants in patients with WD.
Patients being treated for WD require twice yearly
liver chemistries, CBC, ceruloplasmin, and serum
copper. A 24-hour urine copper determination
should be performed yearly, with the goal urinary
copper of 200-500 mcg/day in patients on chelation
therapy or <75 mcg/day in patients on zinc therapy.
The prognosis of untreated WD is poor, with an
inexorable progression to end-stage liver disease,
disabling neurologic symptoms, or both. Medical
therapy, if initiated prior to severe liver or neuro-
logic damage, confers a substantial mortality
benefit, with some studies demonstrating a cumula-
tive survival in WD patients that equaled that of
controls. Fulminant WD, however, does not respond
to medical therapy, and orthotopic liver transplanta-
tion is lifesaving in such cases. Liver transplantation
for decompensated cirrhosis in WD is also indi-
cated, with post-transplant survival reported at 80%
at 1 year. Liver transplantation corrects the bio-
chemical defect in WD, so that there is no recur-
rence of disease post-transplant. Neurologic symp-
toms may improve post-transplant as well, but this
is not a universal occurrence.
10. Vascular Disorders of the Liver
Budd-Chiari Syndrome
The Budd-Chiari syndrome (BCS) describes a
diverse set of clinical entities that have in common
an obstruction of hepatic venous outflow. This may
occur at the level of the inferior vena cava (IVC),
hepatic veins, or hepatic venules, and may be due
either to thrombosis or to membranous webs in the
large vessels. The clinical manifestations of Budd-
Chiari syndrome depend not only on the location of
the obstructing lesion, but also the acuity of obstruc-
tion. Thus, BCS is a protean syndrome that requires
a high degree of suspicion if it is to be diagnosed
and treated in a timely fashion.
In the United States and other Western nations, BCS
is largely due to thrombotic obstruction of the hep-
atic veins. Up to 25% of patients with BCS have an
overt myeloproliferative disorder, most commonly
polycythemia vera. Many patients with presumed
idiopathic BCS may have a subclinical hematologi-
cal disorder. Second in frequency are the hyperco-
agulable states, with Factor V Leiden identified as a
common cause of BCS. Other hypercoagulable
states, including Protein C and S deficiency,
antithrombin III deficiency, paroxysmal nocturnal
hemoglobinuria, and antiphospholipid antibody
syndrome, are also known to cause BCS. Oral con-
traceptive use, pregnancy, and the early post-partum
period have also been implicated in up to 20% of
cases of BCS. Up to 10% of cases of BCS are due to
malignancy, especially hepatocellular and renal cell
cancer, though hepatic vein thrombosis has been
reported in patients with a wide variety of tumors.
In India, Africa, and the Far East, however, throm-
botic Budd-Chiari syndrome is uncommon, and
membranous webs in the IVC are the most common
cause of hepatic outflow obstruction. The etiology
of these webs is unclear, and they may be congenital
or acquired.
In prolonged hepatic venous obstruction, regardless
of the etiologic lesion, characteristic pathological
changes occur in the liver. The caudate lobe, which
drains into the IVC directly, often enlarges as blood
is preferentially shunted to this lobe, while the other
portions of the liver atrophy and shrink. The histo-
logic hallmark of BCS is centrilobular congestion,
with hepatocyte necrosis and eventual fibrosis. This
is most marked in zone 3 of the hepatic acinus, but
can spread to encompass the entire liver and lead to
frank cirrhosis.
Clinical Features
Budd-Chiari syndrome typically presents in the
third or fourth decade, and affects women more fre-
quently than men. The clinical features of BCS are
variable, and range from asymptomatic abnormali-
ties of liver enzymes to fulminant hepatic failure. In
acute hepatic venous obstruction (20% of cases),
patients usually present with severe right upper
quadrant pain, hepatomegaly, nausea and vomiting,
and ascites. Jaundice may be present, but is not a
universal finding. Liver enzymes in acute BCS may
be moderately or markedly elevated, with serum
transaminases greater than 1000 IU/mL in some
cases. A small number of patients develop fulminant
hepatic failure in the setting of acute BCS, with
coagulopathy, encephalopathy, and jaundice. These
patients typically do not survive unless they receive
an orthotopic liver transplant.
Budd-Chiari syndrome more commonly presents as
a subacute disease, with weeks of vague right upper
quadrant discomfort, hepatomegaly, and the grad-
ual onset of ascites and splenomegaly. The chronic
form of BCS is insidious and remains asymp-
tomatic until the development of cirrhosis and por-
tal hypertension, when patients present with
variceal bleeding, ascites, coagulopathy, or
encephalopathy. In chronic BCS, transaminases are
usually mildly elevated, but no specific pattern of
liver enzymes is seen.
Diagnosis
The diagnosis of BCS is made using hepatic imag-
ing studies. Doppler ultrasound of the hepatic veins
is 85%-95% sensitive for the diagnosis of BCS, but
its accuracy depends on operator experience. Mag-
netic resonance venography and CT angiography
are also useful in making a diagnosis of BCS. The
gold standard remains angiography, and although
the classic “spider web” patterns of collaterals is not
seen in all cases, this modality is still able to diag-
nose BCS with a high degree of accuracy.
CHAPTER 8: NON-VIRAL LIVER DISEASE 279
Liver biopsy is also helpful in evaluating patients
with BCS. It may confirm the diagnosis by demon-
strating centrilobular congestion, necrosis, and
fibrosis, and, more importantly, biopsy identifies
patients whose BCS has progressed to cirrhosis,
information which has important implications for
therapy.
Treatment
The therapy of Budd-Chiari syndrome is aimed at
relieving the vascular obstruction and preserving
liver function by reducing hepatic venous conges-
tion. Medical therapy consists of anticoagulation,
which is indicated in acute BCS to inhibit further
thrombosis and promote the lysis of existing clot.
Thrombolytic therapy has been used in a limited
number of cases in the acute setting, and may relieve
hepatic obstruction if used early in the course of
BCS. Interventional radiology can play an important
role in the management of BCS. Hepatic vein angio-
plasty has been used successfully in BCS, and
although patency rates are only 50% at 2 years with
conventional balloon angioplasty, the more recent
use of intravascular stents has demonstrated greater
patency rates of 80% at 3 years. Experience with this
technique remains limited, but the results of small
case series are promising. Transjugular intrahepatic
portosystemic shunt (TIPS) has also been used suc-
cessfully in Budd-Chiari syndrome, and clinical
experience with this modality is growing rapidly,
such that TIPS and IVC stenting are reasonable
options in selected patients with BCS.
Surgical vascular shunts have been the standard
treatment for acute or subacute BCS. Side-to-side
portacaval shunts are most commonly performed,
though mesocaval and mesoatrial shunts are also
used when the anatomy is less favorable. Surgical
shunting preserves hepatic function and long-term
survival rates of 85% in selected patients have been
reported. In patients with fulminant BCS or chronic
BCS that has progressed to hepatic cirrhosis and
end-stage liver disease, orthotopic liver transplan-
tation is the treatment of choice, with 5-year sur-
vival reported at 71%. In addition, liver transplan-
tation may cure certain hypercoagulable states,
including Protein C or S deficiency and antithrom-
bin III deficiency.
280 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY
Hepatic Veno-occlusive Disease
Veno-occlusive disease of the liver (VOD), also
known as sinusoidal obstruction syndrome, is a vas-
cular lesion characterized by obstruction of small
hepatic venules by concentric narrowing and con-
nective tissue deposition. Unlike Budd-Chiari syn-
drome, venous thrombosis is not a major component
of VOD, but the clinical sequelae are similar, with
portal hypertension and varying degrees of hepato-
cyte necrosis. It is most often due to a toxic injury to
the hepatic vascular endothelium, with radiation
and chemotherapy the major etiologic agents. Most
cases of VOD are associated with bone marrow
transplantation, due to the combination of high dose
chemotherapy (usually with alkylating agents) and
total body irradiation. Patients with pre-existing
liver disease, and those undergoing allogeneic bone
marrow transplantation are at the highest risk for
VOD; women appear to have a higher incidence of
VOD than men. Rarely, VOD is seen after ingestion
of pyrrolizidine alkaloids, which may be a compo-
nent of herbal teas (Jamaican bush tea) or other
remedies.
Clinical features of VOD are similar to those of the
Budd-Chiari syndrome. In transplant patients, VOD
typically occurs within 3 weeks of transplantation,
and in its acute form is characterized by ascites,
weight gain, abdominal pain, and hepatomegaly.
Serum bilirubin is usually elevated, and the risk of
liver failure and death is 30%-50%. More indolent
forms of VOD are seen with herbal ingestion or
chronic chemotherapeutic toxicity, and may present
as abnormal liver enzymes, portal hypertension, or
established cirrhosis.
As the pathologic process in veno-occlusive disease
is in the terminal hepatic venules, the diagnosis of
VOD is made at liver biopsy rather than at angiogra-
phy. If a biopsy is considered to be too risky, clinical
criteria may allow a presumptive diagnosis to be
made, especially in the bone marrow transplant
patient. There is no established treatment for VOD,
though the antithrombotic drug defibrotide has been
used in uncontrolled trials and was associated with a
35%-55% rate of recovery in moderate-to-severe

VOD. Trials aimed at the prevention of VOD in the
transplant setting have not been definitive, though
there are some data that heparin infusion or low
molecular weight heparin may reduce the incidence
of post-transplant VOD. Ursodiol was demonstrated
to decrease the incidence of VOD in bone marrow
transplant in two studies, but not in a third large ran-
domized controlled trial. Altering the myeloablative
chemotherapy regimens and providing liver shield-
ing during irradiation may also decrease the inci-
dence of VOD after bone marrow transplant.
10. Perlmutter D. Clinical manifestations of alpha
11. Poupon RE, Lindor KD, Cauch-Dudek K, et
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284 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

12. Questions

1. A 34-year-old woman presents to her physician AST 75 WBC 18.1

with a one-month history of malaise and
anorexia. Her physical examination is remark- ALT 30 HCT 33.5
able only for mild nontender hepatomegaly.
Liver enzymes are as follows: ALP 141 MCV 103

AST 245 WBC 8.1 TB 15.5 PLT 98

ALT 280 HCT 33.5 ALB 3.7 PT 19 (control = 12)

ALP 110 MCV 87 GGT 976

TB 2.4 PLT 98 Liver ultrasound reveals normal bile ducts, no

masses, and splenomegaly with perisplenic
ALB 3.0 varices.

TP 9.7 Which of the following statements regarding his

Hepatitis B and C serologies are negative.
Iron studies are normal. Ultrasound shows a
shrunken liver and mild splenomegaly, but no
masses or duct dilation.
Which of the following statements regarding this
condition is true?
A. An antimitichondiral antibody test is usually
positive.
B. Interferon therapy is likely to induce remis-
sion.
C. Liver biopsy demonstrates PAS (+) granules
in hepatocytes.
3. A 41-year-old woman with a history of diabetes
D. Autoimmune thyroid disease is often a con-
comitant illness.
E. Phlebotomy will improve life expectancy.
2. A 57-year-old male presents with 4 days of right
upper quadrant pain, fever, and nausea. Two days
ago he developed frank jaundice. On exam, his
temperature is 100.5F, pulse 99, BP 135/70. He
has tender hepatomegaly 5 cm below the right
costal margin and a palpable spleen tip. He has
frank jaundice and 1(+) pedal edema. He has a
normal mental status and no asterixis. Labora-
tory results are as follows:
condition is true?
A. He meets criteria for corticosteroid therapy.
B. Severity of liver injury correlates directly with
height of ALT elevation.
C. At this stage, abstinence from alcohol will not
affect outcome.
D. Clinical disease is usually due to inherited
deficiency of alcohol dehydrogenase.
E. This condition affects 1%-3% of chronic
alcoholics.
and hypercholesterolemia is referred to you for
evaluation of abnormal LFTs. Her exam is
remarkable for central obesity, and a liver edge
that is 2 cm below the right costal margin and
mildly tender to palpation. She has no other stig-
mata of chronic liver disease. Her liver enzymes
are as follows:
AST 75 WBC 9.1
ALT 80 HCT 39.5
ALP 121 MCV 85

CHAPTER 8: NON-VIRAL LIVER DISEASE 285

 TB 0.5 PLT 256 On further questioning, she reports a decreased
energy level over the past 3-4 months, and
ALB 4.0 PT 12 (control = 12) episodes of pruritus, especially at night.

GGT 100 Hb A1C 9.5%
TP 6.8
An ultrasound reveals a mildly echogenic liver
parenchyma and no other abnormalities.
Hepatitis serologies, iron studies, and autoim-
mune serologies are negative. Serum ceruloplas-
min and alpha-1 antitrypsin levels are normal.
She denies alcohol use, and has been on no new
medications in the past year.
Which of the following statements is correct?
Which of the following statements regarding this
patient is correct?
A. Liver ultrasound will show dilated intrahep-
atic and extrahepatic bile ducts.
B. Ursodiol therapy will likely be indicated for
this patient.
C. She should have a bone scan to determine the
origin of her increased alkaline phosphatase.
D. She will likely have a high titer of anti-smooth
muscle antibody.

A. She most likely has seronegative autoimmune E. Antimitochondrial antibody may be negative
hepatitis. in up to 50% of cases.

B. She will most likely have a positive anti-mito-

chondrial antibody. 5. A 36-year-old male with an eight-year history of
ulcerative colitis has the following liver
C. Better glycemic control may improve her liver chemistries:
chemistries.
AST 63 PLT 98
D. A Doppler ultrasound will reveal the etiology
of her abnormal liver enzymes. ALT 71 PT 12.3 (control = 12)

E. Chelation therapy is indicated for this patient. ALP 811 Serum AMA (-)

TB 0.5
4. A 48-year-old woman is seen for a routine physi-
cal and has liver enzymes drawn. The results are ALB 3.7
as follows:
GGT 1123
AST 53 WBC 9.1
An ultrasound is read as normal, with no masses
ALT 49 HCT 40.5 or ductal dilation.

ALP 645 MCV 86 Which of the following statements regarding this

patient is correct?
TB 0.8 PLT 189
A. Liver biopsy is usually diagnostic in this dis-
ALB 3.9 PT 12.1 (control = 12) order.

GGT 998 B. Serum p-ANCA is usually negative in this dis-

order.

286 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY

 C. An ERCP is indicated to make the diagnosis. E. If his 20-year-old son is found to have the
same condition, there is no benefit to treat-
D. The risk of cholangiocarcinoma in this disor- ment, as the progression of disease is unaf-
der is <1%. fected by therapy

E. This disorder usually has a benign clinical
course.
6. A 58-year-old white male who has not seen a
physician in “many years” is newly diagnosed
with diabetes by his primary care physician. He
has also complained of shortness of breath on
exertion, pedal edema, and decreased sexual
functioning.
7. A 48-year-old man presents with jaundice,
ascites, and pedal edema. Liver ultrasound
reveals a small nodular liver with perisplenic
varices and splenomegaly. Liver enzymes are as
follows:
AST 31 PT 18 (control =12)
ALT 30 Hepatitis serologies negative

His laboratory studies are as follows: ALP 110 ANA (-)

AST 75 WBC 8.1 Serum Iron 234 TB 8.4 Iron studies normal

ALT 81 HCT 49.5 TIBC 288 ALB 2.9 Ceruloplasmin normal

ALP 101 MCV 88 Ferritin 2045 GGT 77 Alpha -1 AT level 30% of normal

TB 2.0 PLT 99 Which of the following statements regarding his

condition is correct?
ALB 2.9 PT 16 (control = 12)
A. Liver damage in this condition is caused by an
GGT 34 enzyme deficiency.

He has negative hepatitis serologies, takes no B. Alpha-1 antitrypsin replacement effectively

medications, and denies alcohol use.
Ultrasound shows a shrunken, nodular liver and
splenomegaly.
Which of the following statements regarding his
condition is correct?
A. His clinical picture and laboratory studies are
most consistent with autoimmune hepatitis.
B. Genetic testing is unlikely to be revealing in
this patient.
treats the liver and lung disease in patients
with this condition.
C. If the patient receives a liver transplant, the
disease will most likely recur in the trans-
planted organ.
D. The majority of patients with this condition
develop end stage liver disease.
E. Liver biopsy will show characteristic granular
deposits in hepatocytes.

C. Orthotopic liver transplant for this disorder is 8. A 25-year-old woman with a history of
associated with >90% 5-year survival rates. schizophrenia is admitted to the hospital with
jaundice and confusion. Her liver chemistries are
D. There is a high rate of hepatocellular carci- as follows:
noma associated with this condition.
AST 45 WBC 10.1

CHAPTER 8: NON-VIRAL LIVER DISEASE 287

 ALT 55 HCT 28.5 9. A 38-year-old woman is seen by her physician
for complaints of fatigue and mild shortness of
ALP 34 MCV 99 breath on exertion. She has a clear chest exam,
but on abdominal exam is found to have mild
TB 15.5 PLT 110 nontender hepatomegaly, but no other signs of
chronic liver disease. She is also noted to have
ALB 3.1 PT 19 (control = 12) cervical and axillary lymphadenopathy. She
takes no medications or supplements.
GGT 25 Haptoglobin undetectable
Liver enzymes are as follows:
Doppler ultrasound reveals an echogenic liver
parenchyma, no ductal abnormalities, and nor- AST 48 WBC 9.1
mal flow in the hepatic and portal veins.
ALT 51 HCT 37.5
Which of the following statements regarding the
most likely diagnosis is correct? ALP 422 MCV 88

A. Orthotopic liver transplant is the only effec- TB 1.1 PLT 199

tive treatment for this presentation.
ALB 4.4 PT 12.2 (control = 12)
B. The hemolytic anemia seen in this condition is
an autoimmune phenomenon. GGT 922

C. Acute chelation therapy is indicated and will
improve outcome.
D. A normal serum ceruloplasmin in this patient
rules out Wilson disease.
Chest x-ray reveals bilateral hilar adenopathy.
Liver ultrasound is read as normal.
Serum AMA is negative.

E. She likely has fulminant autoimmune Which of the following statements regarding the
hepatitis. likely diagnosis is true?

A. This condition is most likely due to drug

toxicity.

B. Her liver biopsy is likely to reveal caseating

granulomas.

C. Liver disease in this condition usually runs a

benign course.

D. Stool ova and parasite exam is likely to be

diagnostic.

E. The patient most likely has AMA-negative

PBC.

288 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY


Answers
1. D.
The presence, in a young woman, of abnormal
transaminases, a normal alkaline phosphatase, and an
elevated globulin fraction suggest autoimmune hep-
atitis. The negative viral serologies indicate that inter-
feron will not be used to treat this patient. The normal
iron studies make hemochromatosis unlikely, so phle-
botomy is not indicated. PAS(+) granules on liver
biopsy are seen in alpha-1 antitrypsin deficiency,
which does not elevate serum globulin levels. Antim-
itochondrial antibodies are present in a small fraction
of patients with autoimmune hepatitis, but are more
characteristic of primary biliary cirrhosis. The best
answer is D., since a large number of patients with
autoimmune hepatitis have a personal or family his-
tory of autoimmune disorders, with autoimmune thy-
roiditis the most commonly associated condition.
2. A.
The patient in question has severe alcoholic hepatitis,
with the characteristic mild transaminitis with a 2:1
ration of AST to ALT, marked elevation of bilirubin,
and synthetic dysfunction with an elevated INR. The
height of the transaminase elevation is NOT a marker
of disease severity in this condition. Abstinence from
alcohol is a key element in the treatment of alcoholic
hepatitis, which occurs in 10%-35% of heavy alcohol
users. The action of alcohol dehydrogenase is to con-
vert ethanol to acetaldehyde, a toxic metabolite; thus,
ADH deficiency is not a factor in alcoholic hepatitis.
The severity of alcoholic hepatitis is determined using
the Discriminant Factor (DF), defined as [(4.6 x
PTPATIENT - PTCONTROL) + Total bilirubin].
When this factor is >32, steroid therapy should be
considered. The DF in this patient is 47.7, meeting the
criteria for steroid use.
3. C.
This clinical scenario is most consistent with nonalco-
holic fatty liver disease (NAFLD). Chelation therapy
is useful in Wilson disease, but the patient’s normal
ceruloplasmin and clinical picture suggest against this
diagnosis. Doppler ultrasound may reveal portal
hypertension, but it is diagnostic only in cases of
Budd-Chiari syndrome, which is unlikely given this
clinical picture. AMA is diagnostic of primary biliary
cirrhosis, which would present with a high alkaline
phosphatase and a normal ultrasound. Seronegative
autoimmune hepatitis is possible, but in patients with
a negative serologic workup for elevated transami-
nase, greater than two-thirds have NAFLD, with only
a small fraction having occult autoimmune hepatitis.
In NAFLD, improved glycemic control may decrease
transaminase levels.
4. B.
The patient, a middle-aged female with fatigue, pruri-
tus, and a markedly elevated alkaline phosphatase
with otherwise normal LFTs, likely has primary bil-
iary cirrhosis (PBC). AMA testing is positive in >90%
of cases, while the anti-smooth muscle antibody may
be weakly positive in a minority. Ultrasound testing is
normal in patients with PBC, as the large bile ducts are
spared. A bone scan is unnecessary, as the elevated
GGT confirms the liver origin of the elevated alkaline
phosphatase. Ursodiol is currently the recommended
therapy for PBC.
5. C.
An elevated alkaline phosphatase in a patient with
inflammatory bowel disease suggests primary scleros-
ing cholangitis. The negative ultrasound and negative
AMA help exclude other etiologies of cholestatic liver
disease. A p-ANCA level is elevated in up to 80% of
cases. The disease follows a progressive course
toward end stage liver disease, and cholangiocarci-
noma occurs in 7%-15% of cases. Liver biopsy shows
a characteristic lesion (“onion-skin fibrosis”) in only
15% of cases; ERCP is the diagnostic test of choice,
demonstrating the characteristic beading and strictur-
ing of the biliary tree.
6. D.
The patient most likely has hereditary hemochro-
matosis (HHC) with progression to cirrhosis. Autoim-
mune liver disease would not induce the abnormal
iron studies seen here. Genetic testing in Caucasian
patients with HHC is diagnostic in the majority of
cases. Identification of affected family members is
crucial, as phlebotomy clearly retards iron deposition
and prevents the complications of HHC. The risk of
hepatocellular carcinoma is significantly elevated in
patients with HHC and cirrhosis. Transplantation is
associated with lower survival rates than for other
conditions, thought to be due to the comorbid condi-
tions usually present in patients with cirrhosis from
HHC.
CHAPTER 8: NON-VIRAL LIVER DISEASE 289
7. E.
The patient in question has alpha-1 antitrypsin defi-
ciency that has progressed to cirrhosis. Liver biopsy
will demonstrate PAS(+), diastase resistant granules
composed of abnormally processed protein. Liver dis-
ease occurs in 12%-15% of cases, and is due to an
excess of abnormally processed alpha-1 antitrypsin in
hepatocytes, not a deficiency of enzyme. Thus,
enzyme replacement, which can be effective in ame-
liorating the lung injury seen in this condition, does
not improve the liver dysfunction. Liver transplanta-
tion is curative, as the genetic defect in production of
alpha-1 antitrypsin is localized to the liver; the donor
liver is able to produce enzyme at normal levels.

8. A.
This case describes a young person who develops ful-
minant hepatic failure with mild elevations of
AST/ALT, marked hyperbilirubinemia, and poor syn-
thetic function. The past history of psychiatric illness,
and the combination of a very low alkaline phos-
phatase and hemolytic anemia, suggest Wilson dis-
ease (WD) as the etiology of her presentation. The
hemolysis in WD is due to the toxic effect of serum
copper on erythrocytes, rather than an autoimmune
process. Ceruloplasmin levels may be normal in this
presentation, since ceruloplasmin is an acute phase
reactant that is released in times of physiologic stress.
Chelation therapy, though very successful in the
chronic setting, is not effective in fulminant Wilsonian
hepatitis; liver transplantation in these cases is the
only effective therapy.

9. C.
This patient presents with cholestatic liver enzymes,
peripheral and hilar adenopathy, vague constitutional
symptoms, and dyspnea on exertion. The normal
ultrasound rules out metastatic malignancy and duct
obstruction. She has no exposure history to suggest
drug-induced cholestasis. Her AMA is negative, and
although AMA-negative PBC is possible, the hilar
and peripheral adenopathy make sarcoidosis a more
likely diagnosis. Ova and parasite examination would
not be useful, and a liver biopsy will show the charac-
teristic noncaseating granulomas. Liver disease in sar-
coidosis generally follows a benign course, although a
minority of cases may develop severe hepatic disease
and portal hypertension.

290 EDUCATIONAL REVIEW MANUAL IN GASTROENTEROLOGY