Miscellaneous Conditions: Granulomatous Liver Disease Description and Causes

Chapter
12 MISCELLANEOUS
CONDITIONS
GRANULOMATOUS LIVER AUTOIMMUNE HEPATITIS 357 HYPERPYREXIA AND HEAT
DISEASE 353 AMYLOIDOSIS 361 STROKE 370
Description and Causes 353 CONDITIONS SEEN IN REYE SYNDROME 371
Sarcoidosis 353 PREGNANCY 364 OTHER MISCELLANEOUS
LIVER IN INFLAMMATORY BOWEL Acute Fatty Liver of Pregnancy 364 CONDITIONS ASSOCIATED
DISEASE 356 Toxemia of Pregnancy 366 WITH LIVER DISEASES 372
Nonspecific Reactive Changes 356 HYPERALIMENTATION (TOTAL
Biliary Tract Disorders 357 PARENTERAL NUTRITION) 367
Chronic Hepatitis 357 INFECTION-ASSOCIATED
Cirrhosis 357 (REACTIVE) HEMOPHAGOCYTIC
SYNDROME 368
GRANULOMATOUS LIVER DISEASE special stains can sometime be helpful (e.g., Ziehl-
Neelson or PAS stains for the microorganisms in Myco-
Description and Causes bacterium avium-intracellulare, phosphotungstic-acid
hematoxylin in demonstrating the fibrin ring in Q fever).
1. Granulomas are loosely defined as circumscribed collec- More times than not, however, the diagnosis and differ-
tions of inflammatory cells, predominantly lymphocytes, ential rest on clinical correlation.
histiocytes, plasma cells, activated macrophages, and 5. The incidence of the different causes is dependent in
rarely neutrophils. large part on geographic patterns. For instance, schisto-
2. There are two general morphologic classifications: somiasis is quite common in Africa but quite uncommon
a. Epithelioid type: The granulomas are well-demarcated, in the United States. A series from the Keck School of
with macrophages transformed into rather large cells Medicine at USC is outlined in Table 12-2.
having oval to elliptical clear nuclei and prominent 6. Tuberculosis and sarcoidosis are the two most common
eosinophilic cytoplasm (epithelioid cells), which are causes of hepatic granulomas in the United States in most
often multinucleated, these cells admixed and sur- series, with the incidence for tuberculosis ranging from
rounded by predominantly lymphocytes and plasma 11% to 53%, and sarcoidosis from 12% to 34%. Tubercu-
cells (e.g., tuberculosis, sarcoidosis). losis is discussed in detail in Chapter 7, and sarcoidosis is
b. Inflammatory type: These types of granulomas are addressed in this chapter.
poorly defined and composed of lymphocytes, plasma
cells, and occasionally eosinophils, neutrophils, and
histiocytes, without an epithelioid component (e.g., Sarcoidosis
brucellosis, drugs). The inflammatory response asso-
ciated with fat (lipogranulomas) is included in this (Figs. 12-1 through 12-4)
division.
Note that it is not infrequent that a combination of both epi- Major morphologic features
thelioid and inflammatory granulomas may be seen within 1. Multiple noncaseating epithelioid granulomas are present
the same biopsy specimen. consisting of transformed activated macrophages, occa-
3. Granulomas may occur in up to 10% of all liver biopsies sional multinucleated giant cells, scattered lymphocytes,
due to a variety of causes (see Table 12-1). and less commonly eosinophils.
4. In some instances, the histology of the granulomas may 2. The granulomas are seen usually within portal tracts or
be characteristic of a specific disease. For example, the the periportal zone, but are oftentimes found anywhere
central ovum seen in schistosomiasis is diagnostic. The within the lobules.
septate granulomas with perigranulomatous fibrosis are 3. The granulomas often exhibit segmentation into smaller
often seen in sarcoidosis but are extremely infrequent in units by fibrous septa, the collagen surrounding and with
the other diseases that cause granulomas. In addition, time eventually replacing the granulomas themselves.
353
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354 Part I / Liver and Hepatobiliary Pathology with Clinical Correlations
Table 12-1 Hepatic Granulomas

ETIOLOGY EXAMPLES
Nonviral infections • Actinomycosis
• Brucellosis
• Cat-scratch disease
• Coccidioidomycosis
• Cryptococcosis
• Histoplasmosis
• Leprosy
• Mycobacterium avium complex
• Nocardiasis
• Q fever
• Salmonellosis
• Schistosomiasis
• Tuberculosis
• V isceral larva migrans
Viral infections • Cytomegalovirus
• Epstein-Barr virus A
• V iral hepatitis due to HCV
Hypersensitivity Drugs:
reactions • Allopurinol
• Phenytoin
• Thiabendazole
• Sulfasalazine
Neoplasms • Fibrolamellar hepatocellular carcinoma
• Hodgkin’s lymphoma
• Liver cell adenoma
Foreign objects and • Barium
materials • Mineral oil
• Sutures
• Talc-like substances in IV drug users
• Thorotrast
Immunologic • Polyarteritis nodosa
disorders • Polymyalgia rheumatica
• Primary biliary cirrhosis
• Rheumatoid arthritis
• Systemic lupus erythematosis B
Miscellaneous • Chronic granulomatous disease of childhood Figure 12-1 Sarcoidosis. A and B, Multiple epithelioid granulomas
conditions • Sarcoidosis with perigranulomatous fibrosis are present in these two images.
• Status-post jejunoileal bypass surgery In addition, fibrous bands also frequently develop within the larger
• “Idiopathic” granulomas, forming septate division with the formation of multiple
smaller granuloma, as shown in these examples (trichrome).
Table 12-2 Hepatic Granulomas, USC Experience

(total 173 patients)
DISEASE NUMBER PERCENT OF TOTAL
Sarcoidosis 49 28.3
Tuberculosis 46 26.6
Leprosy 9 5.2
Brucellosis 9 5.2
Hodgkin’s disease 7 4.0
Q fever 6 3.5
Fungal infections 5 2.9
Syphilis 2 1.2
Miscellaneous (e.g., primary 15 8.7
biliary cirrhosis)
Unknown etiology 25 14.4
Figure 12-2 Sarcoidosis. The granulomas are well-circumscribed

and contain abundant epithelioid cells with scattered lymphocytes.
Septate division of these granulomas is also present.
Chapter 12 / Miscellaneous Conditions 355
A B
Figure 12-3 Sarcoidosis. The granulomas in sarcoidosis also at times coalesce and form masses that can be seen on imaging. A, This low-power
image on trichrome stain of a distinct hepatic mass shows extensive fibrosis. The numerous granulomas stain red on the trichrome counterstain
and are seen scattered throughout the specimen. B, The H&E stain on higher power shows three epithelioid granulomas with septate division.
A B
Figure 12-4 Sarcoidosis. Sarcoidosis can also show features of chronic hepatitis with duct damage. A, Marked periportal interface inflamma-
tory activity (“piecemeal” necrosis) is seen involving a fibrotic portal tract. B, The portal tract exhibits a moderate lymphocytic infiltrate with peri-
portal interface inflammatory activity; however, there is no interlobular bile duct, a feature that can occur in a minority of cases of sarcoidosis.
Other features 7. Nodular regenerative hyperplasia has been reported.

1. Inclusions characteristic of sarcoidosis may be present 8. Endothelial inflammation by lymphocytes, with damage
within the granulomas, and include: of the terminal hepatic venules and veins, may occasion-
a. Schaumann bodies: Concentric basophilic laminated ally be seen but is relatively uncommon.
inclusions. 9. Lymphocytes can sometimes occur surrounding and
b. Asteroid bodies: Spindly radiating star-like structures invading into interlobular bile ducts (nonsuppurative
within the epithelioid cells. destructive duct damage), with eventual duct loss (duc-
2. Epithelioid granulomas may rarely show central fibrinoid topenia); biliary fibrosis and cirrhosis can be seen in a
necrosis with fragmentation of the inflammatory cells. minority of these cases.
3. The granulomas may coalesce, forming small mass 10. Variable degrees of portal fibrosis (21% of cases) can
lesions that can be visualized on imaging. occur with or without duct damage, with progression to
4. Portal tracts exhibit variable degrees of lymphocytic cirrhosis in up to 6% of cases.
infiltrates with mild bile duct proliferation.
5. Mononuclear predominantly lymphocytic inflamma-
tory infiltration within the parenchyma as well as portal Special stains
tracts can be quite variable but is often prominent in 1. Masson: Septate granulomas, perigranulomatous fibrosis,
the more active cases; in addition, periportal interface and sclerosis of the granulomas are best appreciated.
inflammatory activity can also occur. 2. Acid-fast, Gomori methenamine silver, periodic-acid Schiff:
6. Cholestasis may be seen but is uncommon unless con- These stains are useful in ruling out various infectious
comitant duct damage is also present. causes for the granulomas.
Differential diagnosis 6. In the early stages of the disease, multiple hepatic gran-
1. Granulomatous hepatitis from other causes: Segmenta- ulomas are present; in latter stages, however, fibrosis,
tion of hepatic granulomas is a characteristic feature of hyalinization, and occasionally total resolution of granu-
sarcoidosis and is rarely seen in granulomas from other lomas may occur.
etiologies. The epithelioid nature of the granulomas helps 7. Although hepatic granulomas are common, clinically
eliminate some causes where the granulomas are usually significant liver disease is unusual (6.7% of cases), mani-
“inflammatory” in type (e.g., brucellosis, drug-induced). fested by pre-sinusoidal portal hypertension, esophago-
In some instances, special stains will aid in identifying gastric varices, and rarely jaundice.
microorganisms (acid-fast bacilli and fungi). 8. Laboratory tests reveal moderate elevations in serum
2. Acute and chronic viral hepatitis, autoimmune hepatitis: alkaline phosphatase activity, mild to moderate increases
In some instances of sarcoidosis the portal and lobular in serum aminotransferases, and rarely hyperbilirubi-
inflammatory component can be striking, resembling nemia. The angiotensin-converting enzyme (ACE) is
that seen in acute viral hepatitis and the active stages of often elevated, and the Kviem skin test is positive in
chronic viral hepatitis and autoimmune hepatitis. Iden- 80% of patients in the early stages of the disease.
tification of granulomas may raise the possibility of viral 9. The rare case of portal hypertension is secondary to signif-
hepatitis superimposed on a granulomatous disorder. icant portal fibrosis and granuloma formation in the portal
These cases may be difficult to confidently evaluate on tracts, with consequent obstructive effects involving the
morphologic grounds alone, with serologic and clinical portal venous radicles (pre-sinusoidal portal hypertension).
correlations most often required. 10. The etiology is unknown, but felt to be related to a num-
3. Primary biliary cirrhosis: In the instances of sarcoidosis ber of different factors, including genetic (predisposition
with biliary fibrosis or cirrhosis, duct damage and loss, of members of the same family, increased incidence of
and granuloma formation, the possibility of primary bili- HLA-B8, B27) and autoimmune (decrease in periph-
ary cirrhosis must be entertained. Mitochondrial anti- eral T-lymphocytes, impairment of in vitro response of
body and high serum IgM levels, features characteristic lymphocytes to many antigens and mitogens). Helper
of primary biliary cirrhosis, are not present in sarcoidosis. T-lymphocytes, which are markedly increased in sarcoid-
In addition, perigranulomatous fibrosis, septate division, osis (normal helper/suppressor = 1.8/1, active sarcoidosis
and hyalinization of the granulomas are not seen in pri- = 5-20/1), release lymphokines (interferon, migration
mary biliary cirrhosis. Of note is that rarely the clinical inhibition factor, T-cell growth factor) which enhance
and histologic features of both primary biliary cirrhosis inflammatory responses and granuloma formation.
and sarcoidosis can occur in the same patient and biopsy,
and is felt to represent an overlap variant. Treatment and prognosis
1. Liver disease is seldom a clinical problem. When bleeding
Clinical and biologic behavior from esophageal varices develops in the rare case, manage-
1. Sarcoidosis is a multisystem granulomatous disease of ment is similar to methods employed in cirrhosis of other
unknown etiology, with the major clinical manifesta- etiologies. In the rare case of severe liver disease, liver
tions related to pulmonary involvement. transplantation is an option provided pulmonary disease
2. The prevalence is estimated at 1 to 40/100,000. Patients is not severe and pulmonary hypertension is not present.
present most commonly between the ages of 20 to 40 2. Prognosis is generally good when pulmonary interstitial
years, with a greater incidence in black women in the disease is absent or minimal, as seen in the majority of
US. The increase in lifetime risk of blacks is three-fold patients. With more systemic involvement, prognosis
compared to white individuals. becomes worse, mortality rising to as high as 40% when
3. A small percent present acutely with polyarthritis, iritis, significant pulmonary fibrosis is present.
and fever; however, the majority (74%) exhibit nonspe-
cific symptoms, with weakness, weight loss, anorexia,
and low-grade fever. Sixteen percent are entirely asymp- LIVER IN INFLAMMATORY BOWEL DISEASE
tomatic on diagnosis (abnormal chest radiograph on
routine physical). (Fig. 12-5)
4. Pulmonary manifestations are most common, present Up to 50% of patients with ulcerative colitis and Crohn’s
in 60% of patients at time of diagnosis, and are seen in disease have some degree of biochemical hepatic dysfunc-
90% as the disease progresses. The most common cause tion, with 5% to 30% of these patients exhibiting pathologic
of death is attributable to complications of pulmonary changes on liver biopsy. Most of the hepatic lesions associ-
fibrosis. ated with ulcerative colitis are also seen to variable degrees in
5. Other systems that are involved include the following: Crohn’s disease. A variety of hepatic changes may be present
a. Liver (55% to 90%). and are listed below.
b. Ocular (20% to 30%), possible blindness.
c. Neurologic (5%), encephalopathy, meningitis.
d. Myocardium, conduction defects. Nonspecific Reactive Changes (50% Frequency)
e. Cutaneous (3% to 25%), erythema nodosum.
f. Lacrimal, salivary glands (10%), bilateral lacrimal 1. Patients are clinically asymptomatic with regard to liver
swelling, sialadenitis, uveitis, fever (uveoparotid fever). disease, with only mild and fluctuating elevations of the
g. Bone, cysts (rare). serum aminotransferases and alkaline phosphatase activ-
h. Muscles and synovium, myositis, arthritis. ity. Hepatomegaly is uncommon.
Chronic Hepatitis (1% to 2% Frequency)
1. In a small percentage of cases, a portal fibrosis with portal

lymphocytic infiltrates and variable periportal interface
inflammatory activity can occur with no known cause
in patients with chronic ulcerative colitis, with little evi-
dence of an association with Crohn’s disease.
2. Various etiologies are suggested, including an autoim-
mune hepatitis variant.
3. There have also been case reports of primary biliary cir-
rhosis in patients with chronic ulcerative colitis.
Cirrhosis (2% to 5% Frequency)
1. The incidence of cirrhosis associated with chronic ulcer-

ative colitis is anywhere from 12 to 50 times more fre-
Figure 12-5 Inflammatory bowel disease. An epithelioid granuloma quent compared with controls. Cirrhosis is only rarely
surrounded and partially infiltrated by lymphocytes is seen in this
liver biopsy from a patient with Crohn’s disease. The parenchyma associated with Crohn’s disease.
shows a moderate degree of macrovesicular fatty change. 2. Although these cases most often show a biliary cirrhosis
secondary to primary sclerosing cholangitis, long-term
2. Morphologic features include the following: chronic hepatitis with progression to a macronodular or
a. Mild (1+ to 2+) macrovesicular fatty change, with no micronodular cirrhosis also can occur.
distinct zonal distribution, can be seen in up to 50% of
the cases.
b. Portal tracts exhibit mild bile duct proliferation and AUTOIMMUNE HEPATITIS
variable degrees of lymphocytic infiltration, without
periportal interface inflammatory activity. (Figs. 12-6 through 12-13)
c. Mild to moderate Kupffer cell hyperplasia with focal
but mild lobular necroinflammatory change is present. Major morphologic features
d. Infrequently, pylephlebitis and portal vein thrombosis 1. Portal tracts exhibit a moderate to marked inflammatory
may occur. Hepatic abscesses may rarely be seen associ- infiltrate consisting of lymphocytes and numerous plasma
ated with Crohn’s disease. cells, with periportal interface inflammatory activity com-
e. Granulomas and amyloidosis (AA-type) may also be seen mon and often striking.
but are more frequently associated with Crohn’s disease. 2. The lobules exhibit focal necrosis, apoptosis and necro-
inflammatory changes which can vary from mild to
marked, the latter oftentimes associated with perivenular
Biliary Tract Disorders (5% Frequency) accentuation.
3. Variable degrees of portal fibrosis are usually present. In
1. Primary sclerosing cholangitis (1% to 5%) nontreated cases or in those nonresponsive to corticoste-
a. Nonsuppurative fibrosing and obliterative lesions of the roid therapy, cirrhosis eventually occurs and is of a mac-
interlobular bile ducts are present and associated more ronodular or micronodular type.
often with ulcerative colitis (see a more detailed discus-
sion of Primary sclerosing cholangitis in Chapter 3). Other features
b. Portal fibrosis with progression to a biliary cirrhosis 1. In the active stage, perivenular confluent liver cell necro-
may eventually occur. sis and liver cell dropout may occur, accompanied by
2. Cholangiocarcinoma (0.4% to 1.4%) marked diffuse lobular necroinflammatory and balloon-
a. Cholangiocarcinoma is 10 to 30 times more frequent ing changes. Confluent necrosis with lobular collapse can
in patients with ulcerative colitis, but is quite infre- also be seen in the periportal zones as well, with bridging
quent when Crohn’s disease is present. necrosis between portal tracts as well as between portal
b. The tumor is a consequence of underlying primary tracts and perivenular zones also present.
sclerosing cholangitis. 2. The degree of portal and lobular inflammation can also
c. These tumors occur in patients approximately 20 years vary from one lobule to the next.
younger than in those with typical cholangiocarci- 3. The portal plasma cell infiltrates may be present through-
noma, and usually occur in patients with long-standing out the portal tract, but more often are accentuated at the
ulcerative colitis. periphery of the portal tracts and at the areas of interface
d. The neoplasms may in some instances be multicentric, activity. The plasma cells also tend to form clusters in the
with intra- and/or extrahepatic involvement of duct periportal zones and lobules.
structures. 4. Nonsuppurative destructive interlobular bile duct dam-
e. The morphologic features show an adenocarcinoma age may be present, with lymphocytes surrounding and
with variable and often prominent interstitial fibrosis attacking duct epithelium, accompanied by marked cyto-
that is typical of cholangiocarcinoma (see Chapter 10). logic duct atypia (autoimmune cholangitis, lymphocytic
Figure 12-6 Autoimmune hepatitis. Prominent periportal interface Figure 12-7 Autoimmune hepatitis. Numerous plasma cells are
inflammatory activity (“piecemeal” necrosis) is seen, the inflamma- seen involving the portal tract. The plasma cells are often grouped
tory cells consisting of lymphocytes and plasma cells. in variable sized clusters. In addition, portal plasma cells are often-
times more abundant at the border of the portal tracts and the paren-
chyma.
A B
Figure 12-8 Autoimmune hepatitis. A, Diffuse lobular necroinflammatory change is seen which at times is accentuated in the perivenular
zone. B, High-power shows a prominence of plasma cells within the parenchyma.
Figure 12-10 Autoimmune hepatitis. The perivenular zone shows

Figure 12-9 Autoimmune hepatitis. This perivenular zone shows marked inflammation by predominantly lymphocytes. Many lympho-
marked confluent necrosis with a striking infiltration by lymphocytes cytes are also seen attached to the vascular endothelium (endothe-
and numerous plasma cells. lialitis).
A B
Figure 12-11 Autoimmune hepatitis. A and B, These two images show interlobular bile ducts with considerable cytologic distortion, the ducts
focally infiltrated by lymphocytes (autoimmune cholangitis).
cholangitis). Duct loss (ductopenia) may eventually occur

in these cases, sometimes with progression to a biliary
cirrhosis.
5. Portal neutrophils can occasionally be seen, the neutro-
phils scattered within the portal tracts and not oriented
to duct structures.
6. Cholestasis and cholangiolar proliferation may occur and
are often prominent in association with active stages of
the disease.
7. Variable degrees of syncytial giant cell transformation of
hepatocytes can be seen and may be present anywhere
within the lobules, although there is a tendency for peri-
portal predominance.
8. The degree of portal and lobular inflammatory activity
markedly and rapidly diminishes in over 90% of cases
after steroid therapy is initiated.
Note: Although portal and lobular plasma cells are often-
Figure 12-12 Autoimmune hepatitis. At times autoimmune hepati- times striking, in up to one-third of the cases of autoimmune
tis can be associated with syncytial giant cell transformation of hepa-
tocytes, as evident in this example.
hepatitis the plasma cells can be relatively inconspicuous,
with lymphocytes the predominant inflammatory cell type.
Autoimmune hepatitis overlap variants

1. Variants of autoimmune hepatitis are not infrequent.
Overlap syndromes of autoimmune hepatitis with other
known liver diseases have been well documented, where
the histology and clinical and serologic indicators imply
more than one liver disease.
2. The overlap variants include the following liver diseases:
a. Primary biliary cirrhosis: Non-suppurative granuloma-
tous duct damage, interface hepatitis, positive autoim-
mune antibodies (ANA and/or SMA), positive AMA.
b. Primary sclerosing cholangitis: Fibrous oblitera-
tive cholangitis, interface hepatitis, positive autoim-
mune antibodies (ANA and/or SMA), inflammatory
bowel disease, ERCP findings of primary sclerosing
cholangitis.
c. Chronic hepatitis C: HCV virus triggering autoim-
mune activation with positive autoimmune antibodies
Figure 12-13 Autoimmune hepatitis. After steroid therapy with clin- (ANA and/or SMA).
ical response, the inflammation can resolve quite rapidly (as early as
1 week), with the liver cells showing variable hydropic and regen- d. Sarcoidosis: Epithelioid granulomas with segmenta-
erative changes in this example. Note the absence of inflammatory tion, interface hepatitis, positive autoimmune antibod-
cells. ies (ANA and/or SMA) (very rare).
Note: In instances of the liver biopsy showing combined hepatitis may in some cases exhibit uniform parenchy-
features, the signout is generally worded to indicate the liver mal changes from one lobule to another, simulating acute
diseases involved (e.g., “primary biliary cirrhosis–autoim- viral hepatitis. A feature of marked increased numbers of
mune hepatitis overlap syndrome”). plasma cells is helpful in diagnosing autoimmune hepati-
tis; however, moderate numbers of plasma cells can occa-
Special stains sionally be seen in acute hepatitis A or chronic hepatitis
1. Reticulin: In cases of active disease, the perivenular necro- B. Immunoperoxidase staining for HBsAg, HBcAg, and
sis and lobular collapse of the reticulin framework can delta antigen (the latter strongly positive in acute delta
best be appreciated by noting condensation of the reticu- infection) as well as appropriate serum serologic mark-
lin fibers in the affected zones. ers for HAV, HBV and delta are very often necessary for
2. Orcein: In cases associated with duct damage, this granu- diagnosis.
lar black pigment representing copper-binding protein 3. Autoimmune diseases with associated duct damage and duct
may be seen in periportal or periseptal hepatocytes. loss: As listed in autoimmune overlap variants above, vari-
ous liver diseases associated with duct damage and even-
Histologic disease grading and staging tual duct loss such as primary biliary cirrhosis (PBC)
Using both morphologic features, liver tests, autoimmune and primary sclerosing cholangitis (PSC) can co-exist
markers and other parameters, an autoimmune hepati- with autoimmune hepatitis. Instances also occur, how-
tis scoring system was established in 1999 (International ever, where distinction between these biliary disorders
Autoimmune Hepatitis Group report), more as a research from autoimmune hepatitis is more easily apparent. For
tool, and revised in 2007. Its benefits relate to using mul- instance, nonsuppurative granulomatous duct injury or
tiple both clinical and laboratory factors in establishing a fibrous obliterative cholangitis without an accompanying
more confident diagnosis of autoimmune hepatitis, while its interface hepatitis or lobular inflammation and with neg-
drawbacks relate to its relative complexity and inadequate ative or only low titer autoimmune serologies are features
specificity in excluding a diagnosis of probable autoimmune aimed at PBC and PSC (respectively) alone rather than
disease in other disorders, particularly biliary tract diseases. the variant overlap diseases.
The recently revised system was found to have very good
specificity in excluding autoimmune hepatitis in patients Clinical and biologic behavior
with chronic liver diseases; however, it also lacked sensitiv- 1. Autoimmune chronic hepatitis, also termed “lupoid”
ity in detecting autoimmune hepatitis overlap syndromes or and “plasma cell” hepatitis in the past, is a liver disease
autoimmune hepatitis with coexisting other liver diseases. A first noted in the 1950’s which primarily affects young
detailed summary of the system devised in 1999 (Interna- women, often with hepatosplenomegaly, jaundice, and
tional Autoimmune Hepatitis Group report) is included in amenorrhea.
the Appendix (Table H). 2. Females are affected almost nine times more frequently
than males. The mean age is 47 years (range 8 to 92).
Differential diagnosis On physical examination stigmata of chronic liver disease
1. Chronic hepatitis of other etiologies (e.g., viral, drug-induced): may be seen.
Although the basic morphologic features of most forms 3. Associated immunologic disorders are present in 50% of
of chronic hepatitis are generally the same, the pres- the cases, including arthritis, vasculitis, ulcerative colitis,
ence of increased numbers of plasma cells and areas of Hashimoto’s thyroiditis, autoimmune hemolytic anemia,
confluent necrosis with parenchymal collapse hallmark and glomerulonephritis.
chronic hepatitis of the autoimmune type in untreated 4. Autoimmune hepatitis is subclassified into type 1 (clas-
patients. These features, however, are not always pres- sic type, also referred to as anti-actin hepatitis), type 2
ent, especially in patients receiving steroid therapy. The (anti-liver kidney microsomal [LKM-1]) and type 3
absence of certain morphologic features characteristic of (anti-soluble liver antigen [SLA]). These classifications
other etiologies (ground glass cells in chronic hepatitis are primarily based on the presence of auto-antibodies,
B; sinusoidal collagen, macrovesicular fat, portal lym- including those against LKM and SLA, and the clinical
phoid aggregates in chronic hepatitis C), the presence of course.
appropriate autoimmune serologic markers (anti-nuclear, a. In Type 1 disease, the mean age is 39, over 75% of
anti-smooth muscle antibodies), and the rapid return of patients affected are women, and 40% have other
aminotransferase activities to normal with low-dose ste- immune disorders. Seventy percent have smooth
roid therapy, are characteristic for autoimmune chronic muscle antibody, while 60% have antinuclear antibody.
liver disease. Approximately 75% are steroid responsive. About
2. Acute hepatitis alone or acute hepatitis superimposed on 40% progress to cirrhosis. Type 1 is associated with
underlying chronic liver disease: Severe acute hepatitis (viral HLA DR3 and DR4 haplotypes (84% in white North
or drug-induced) alone, acute delta infection in patients American and European patients). High resolution
with underlying chronic hepatitis B, and acute hepati- DNA based techniques have defined DRB1*0301 and
tis in a patient with fibrosis secondary to an unrelated DRB1*0401 as the principal susceptibility alleles for
cause (e.g., alcoholic fibrosis, or biliary fibrosis from bile Type 1 disease.
duct stricture) may in many ways resemble an extremely b. In Type 2, the mean age is 25 years, 89% of the patients
active autoimmune hepatitis with regard to marked are women, 40% have other immune disorders, and all
inflammatory change, perivenular liver cell dropout, and have antibodies to LKM-1. Although most respond
some degree of portal fibrosis. In addition, autoimmune to steroids, progression to cirrhosis occurs in the vast
majority of patients. The cytochrome P450 IID6 is the

major antigen for LKM antibodies.
c. In Type 3, the mean age is 37 years, over 90% of the
affected patients are women, and all have antibodies
to SLA. Although response to corticosteroids is seen,
progression to cirrhosis occurs in approximately 75%
patients. A specific associated HLA phenotype is not
certain.
5. In the typical case, serum globulins are elevated
(γ-globulins, predominantly immunoglobulin G),
sometimes up to 8 to 10 g/dL. Serum aminotrans-
ferases are moderately elevated (500 to 700 IU/L or
higher) with hyperbilirubinemia (sometimes marked),
decrease in serum albumin, and increase in prothrom-
bin time. The presence of autoantibodies in this disease
form the basis for a number of positive serologic tests
for antibodies that include anti-nuclear, anti-smooth Figure 12-14 Amyloidosis. Cut section of a liver involved by sys-
temic amyloidosis is light to dark red and has the characteristic waxy
muscle, liver-kidney microsomal, liver-specific lipopro- lardaceous appearance. The liver also has a rubbery texture and
tein (LSP) and liver membrane antigen (LMA). The tears easily on dissection.
M2 fractionation of antimitochondrial antibody, seen
in primary biliary cirrhosis, is not identified in autoim-
mune hepatitis.
6. The term “lupoid” hepatitis was initially used because
patients often have a positive LE cell test (due to positive
anti-nuclear antibodies); however, systemic lupus ery-
thematosus (SLE) is not an associated disorder. Patients
with SLE have livers that are normal or exhibit only mild
nonspecific changes.
7. The LSP and LMA autoantibodies are felt to be quite
sensitive for autoimmune hepatitis, but are not specific,
and can be seen in other liver diseases, including acute
viral hepatitis; however, linear fluorescent membrane
staining for LMA may be more specific for autoimmune
hepatitis.
8. Hepatocellular carcinoma is exceptionally rare in autoim-
mune hepatitis but has been documented in the cirrhotic
stage. Figure 12-15 Amyloidosis. Amyloid appears dark brown after stain-
9. Pathophysiology involves a defect in T-lymphocyte sup- ing with Lugol’s solution (iodine plus potassium iodine), highlighted
in the liver tissue (left) compared to the nonstaining of the Lugol’s
pressor cell function, with the formation of increased solution with a control liver (right).
levels of immunoglobulins and autoantibodies which
then attach to LSP and LMA resulting in cell damage. Major morphologic features
Genetic factors may be operative since autoantibod- 1. Amorphous eosinophilic extracellular deposits (amyloid)
ies may be seen in relatives of patients with autoim- are seen and are located within:
mune hepatitis (major histocompatibility complex on #6 a. Sinusoids beneath the space of Disse.
chromosome). b. Portal tract connective tissue.
c. Media of medium-sized hepatic arteries, and the walls
Treatment and prognosis of small hepatic arteries, arterioles, and portal and sub-
1. Although early cirrhosis is sometimes present at diagno- lobular veins.
sis, progression of the disease can be halted with steroid
therapy. Even in advanced disease a trial with steroids is Other features
worthwhile. Management of complications of cirrhosis is 1. Hepatocytes often exhibit atrophic changes adjacent
the same regardless of the etiology. to sinusoidal amyloid deposits, this change quite strik-
2. The treatment duration is indefinite, and prognosis for ing in instances where amyloid fills the entire sinusoid,
responsive cases is good. pushing Kupffer and endothelial cells towards the center
3. In advanced cases presenting with hepatic failure, or in of these sinusoids.
nonresponsive disease, hepatic transplantation should be 2. Variability in the degree of amyloid deposition may
offered. occur from one lobule to another.
3. Amyloid may also be seen beneath the lining epithelium
of large intrahepatic bile ducts and in peribiliary glands.
AMYLOIDOSIS 4. Amyloid can involve the sinusoids, portal tracts and
hepatic artery segments in the same biopsy; however at
(Figs. 12-14 through 12-21) times sinusoidal and artery involvement may occur alone.
A A
B B
Figure 12-16 Amyloidosis. The (A) medium- and (B) high-power Figure 12-18 Amyloidosis, globular type. Distinct extracellular
images demonstrate the acellular amorphous eosinophilic deposits round to oval eosinophilic deposits can be seen within portal macro-
within the hepatic sinusoids. The deposits are located within the phages (A) and within the sinusoidal space of Disse (B).
space of Disse, with the Kupffer cells present towards the center
of the sinusoids.
Figure 12-19 Amyloidosis, globular type (electron micrograph).

Figure 12-17 Amyloidosis. This stain highlights the amorphous Amyloid is composed of nonbranching fibrillar material of indefinite
nature of the amyloid, and helps distinguish it from the intertwining length, the fibers measuring from 7.5 to 10 nm in diameter. In this
fibers characteristic of sinusoidal collagen (see Figs. 4 -14 and 4 -15, example the amyloid is forming a distinct globule.
Alcoholic hepatitis, for comparison) (trichrome).
Figure 12-20 Amyloidosis. This small hepatic artery branch shows Figure 12-21 Amyloidosis. Positive pink-red staining of the sinu-
prominent eosinophilic deposits within the vascular wall. soidal deposits is seen. Apple-green birefringence of the deposits
under polarized light is diagnostic for amyloid. (Congo red)
5. A variant of amyloid deposits may occur whereby globu- Fluorescence

lar deposits are identified and are characterized as round 1. Thioflavin-T: Amyloid stains intensely yellow-green.
to oval, 5 to 50 μm in diameter, having a laminated pat-
tern, often with intense central staining. Immunohistochemistry
6. The globular variant is present within the same locations 1. Light chains: These markers identify the amyloid com-
as the typical amyloid, although deposition within por- posed of immunoglobulin kappa and lambda light chains
tal macrophages is not uncommon. In addition, globular (plasma cell dyscrasias, primary amyloidosis).
amyloid may be seen in livers that also exhibit the more 2. Amyloid-associated (AA) protein: This marker identifies the
typical type of linear deposits (mixed type). Like typi- amyloid composed of AA (amyloid-associated) protein
cal amyloid, considerable variation of globular amyloid (chronic inflammatory disorders, secondary amyloidosis).
deposition may occur from one lobule to another.
7. Portal areas and bile ducts show no specific features Aspiration cytology
related to amyloidosis, although they may exhibit 1. The presence of an amorphous eosinophilic material and
changes such as portal lymphocytic infiltrates secondary adjacent atrophic liver cells is highly suggestive of amy-
to an underlying disease process that is contributing to loid, confirmed by positive Congo red staining.
amyloid deposition itself.
8. Cholestasis may be seen and is present in approximately Differential diagnosis
5% of cases. 1. Substances resembling sinusoidal amyloid:
9. Microcalcifications have been described. a. Collagen: Collagen under close inspection is fibrillar
10. Hepatic fibrosis is not a feature. and often loosely arranged.
b. Fibrin: These strands are deeply eosinophilic and
Special stains fibrillar, and are positive with PTAH stain.
1. Congo red: Positive pink-red staining of all types of 2. Substances resembling globular amyloid:
amyloid occur, with apple-green birefringence under a. Ground glass cells: In chronic HBV infection, these cells
polarized light (diagnostic). stain positively with orcein as well as immunoperoxi-
2. Congo red after trypsin digestion and potassium permanga- dase stains for HBsAg.
nate application: b. Pale bodies: Fibrolamellar hepatocellular carcinoma often
a. Resistant to digestion: Positive staining with apple-green shows these characteristic intracytoplasmic inclusions.
birefringence under polarized light occurs, indicative c. Periportal inclusions: Myoclonus epilepsy (La Fora bod-
of amyloid composed of immunoglobulin light chain ies) are seen within periportal hepatocytes.
moieties. d. Drug-induced inclusions: Phenytoin, phenobarbital,
b. Sensitive to digestion: Initial positive Congo red stain- chlorpromazine, and procainamide are drugs that
ing turning to negative staining after trypsin digestion may be associated with intracytoplasmic eosinophilic
is indicative of amyloid of nonimmunoglobulin (AA) inclusions.
type. e. Perivenular inclusions: In various forms of ischemia
3. Periodic-acid Schiff (PAS): Positive staining of various from hypotension, both sinusoidal and intracytoplas-
intensities is seen and is due to the “P” (pentagonal) com- mic eosinophilic hyaline globules may be seen predom-
ponent which occurs in all forms. inantly within the perivenular zone.
4. Masson trichrome: The amyloid stains light blue. Note: Collagen, fibrin, and the perivenular sinusoidal inclu-
5. Sirius Red: Variable positive red staining occurs. sions secondary to ischemia are extracellular but do not
stain with Congo red. The other substances listed above are stain with antibodies to pre-albumin, AA or AL, possi-
intracytoplasmic and are also Congo red negative. Of impor- bly a pattern peculiar to the liver and local environmen-
tance is that at times there may be false positive Congo red tal conditions.
staining. In these instances, the positively stained material is 11. Congo red and Sirius Red are direct cotton dyes that do
not birefringent under polarized light. not stain all types of amyloid with the same intensity. In
normal tissues, elastic fibers will bind the dyes, although
Clinical and biologic behavior birefringence does not occur. Certain organisms (Mucor,
1. Amyloidosis is a disorder of protein folding in which Aspergillus, Candida, Blastomyces) as well as materials
normally soluble proteins are deposited extracellularly such as cellulose and chitin can also bind the dyes and
as insoluble fibrils, impairing tissue structure and func- exhibit birefringence. It is necessary, therefore, to exam-
tion. Over 20 unrelated proteins form amyloid fibrils in ine the pattern of morphologic change for diagnosis.
vivo, with fibrils sharing a lamellar cross-β–pleated sheet 12. The fluorochrome thioflavin-T is useful in screening, as
structure composed of noncovalently associated protein amyloid is easily identified on low power. False-positives
or peptide subunits. (no false-negatives) do occur (elastic lamina, fibrin,
2. Amyloid is best defined in biophysical terms: mucus, keratin, skeletal muscle); hence, confirmation
a. Extracellular, homogeneously eosinophilic on hema- with Congo red is usually necessary.
toxylin-eosin stain, with apple-green birefringence on 13. Birefringence on polarized light after Congo red stain-
polarization after positive Congo red staining. ing is due to the fibrillar structure of amyloid and the
b. Characteristic rigid nonbranching linear fibers 7.5 to orderly molecular arrangement of the dye after bind-
10 nm in diameter of indefinite length on electron ing. Non-specific green birefringence is reported in
microscopy. liver tissue using Zenker’s or Carnoy’s fixation and not
c. Cross-β–pleated sheet appearance on x-ray formalin.
diffraction. 14. The diagnosis is confirmed by tissue biopsy, with rec-
3. Systemic amyloidosis is present 0.1% to 0.7% of the tal biopsy positive in 75% to 85% of the cases. Biop-
time in autopsy studies. Hepatic involvement is found sies of the liver, kidney, gingiva, skin, bone marrow, and
in approximately 50% of these cases. abdominal fat are also frequently positive. A rare com-
4. The clinical presentation is usually related to the spe- plication of liver biopsy is rupture with bleeding (frac-
cific associated disorders, and can be broken down into ture of a somewhat “brittle” parenchyma).
acquired systemic amyloidosis (e.g., multiple myeloma,
rheumatoid arthritis), organ-limited amyloidosis (e.g., Treatment and prognosis
cardiac), and localized amyloidosis (e.g., endocrine 1. Treatment and eradication of the underlying disease has
tumors such as medullary carcinoma of the thyroid). been shown to stop amyloid production, and possibly
5. Acquired systemic amyloidosis is associated with chronic even cause slow resolution.
inflammatory disorders 5% to 11% of the time, while 2. The most common causes of death from amyloid are
6% to 15% of patients with multiple myeloma develop renal failure and cardiac disease. Hepatic failure can occur
amyloidosis. but is quite rare. The mean survival varies and is depen-
6. In the acquired systemic type, the disease is slightly dent on the underlying disease.
more common in men and usually presents in the 5th to
7th decade.
7. Hepatic involvement results in hepatomegaly 47% to CONDITIONS SEEN IN PREGNANCY
57% of the time (weights ranging from 875 to 4880 g
in one series, with reports of up to 9000 g). The liver on Acute Fatty Liver of Pregnancy
cut section is waxy and lardaceous, and light to dark red.
The amyloid itself can be highlighted in gross specimens (Figs. 12-22 and 12-23)
by staining the tissue with Lugol’s iodine, the amyloid
then staining a rich brown color. Major morphologic features
8. Stigmata of chronic liver disease are not present, and 1. Marked microvesicular fatty change is seen in hepatocytes
jaundice occurs in less than 5% of cases, the serum bili- and is most prominent in the perivenular and midzonal
rubin usually below 5 mg/dL. Signs related to portal regions.
hypertension (ascites, esophageal varices) are rare, and
splenomegaly, which is present in only 9% of cases, is Other features
usually due to direct amyloid involvement of the spleen. 1. In severe cases the fatty change may be diffuse and involve
9. Laboratory tests relative to liver involvement are non- all zones.
specific. The serum albumin is occasionally slightly 2. Cholestasis is often present in the perivenular zone.
decreased, aminotranferases are normal or slightly ele- 3. Hepatocytes exhibiting microvesicular fat typically have
vated, and the bilirubin is usually normal. slightly small nuclei that are located towards the center of
10. Globular amyloidosis is seldom associated with plasma the cell.
cell dyscrasias, and most often involves the liver, spleen, 4. Variable degrees of macrovesicular fat are occasionally
kidneys and adrenal glands. Only the hepatic amyloid seen as well, especially in the recovery stage.
is globular, the other organs demonstrating deposition 5. Portal tracts are normal or may show only a minimal lym-
patterns of typical amyloid. Globular amyloid has been phocytic infiltrate with occasional eosinophils and plasma
shown to be resistant to trypsin digestion, and does not cells.
A B
Figure 12-22 Acute fatty liver of pregnancy. These (A) low- and (B) high-power images show the hepatocytes to be enlarged and appear
hydropic, with minimal lobular inflammation. The cytoplasm in the high power image shows small microvesicles, but in many areas appears
hydropic. Note that the nuclei often appear centrally located, a clue to the presence of microvesicular fat. A fat stain on frozen section from
fresh or formalin-fixed tissue at times is often necessary for diagnosis (see Fig. 12-23).
Differential diagnosis
Microvesicular fatty change seen in liver biopsies of preg-
nant women in the 3rd trimester is usually in itself diag-
nostic of acute fatty liver of pregnancy; however, instances
can occur when other predisposing factors that can cause a
microvesicular fatty change are also present in these women.
These other disorders are listed below.
1. Drugs: Various drugs such as tetracycline and valproic
acid (see Table 5-6) are associated with microvesicular fat.
a. Tetracycline: Although this drug is no longer admin-
istered intravenously in pregnant women, in the past
its use in these women for urinary tract infections
at first made recognition of acute fatty liver of preg-
nancy difficult, as tetracycline toxicity itself manifests
a microvesicular fatty change; however, acute fatty liver
of pregnancy does occur in the absence of tetracycline
Figure 12-23 Acute fatty liver of pregnancy. This stain for neutral usage. Tetracycline toxicity is usually associated with
triglycerides on a frozen section from formalin-fixed tissue confirms
the presence of microvesicular fat. (Oil Red O) moderate to marked degrees of nuclear anisocytosis
of hepatocytes that is not seen in acute fatty liver of
6. Minimal to absent lobular necroinflammatory change is pregnancy. In addition, tetracycline exhibits a strong
seen. characteristic golden-brown autofluorescence on fro-
7. Megamitochondria have been described in hepatocytes zen sections of fresh or formalin-fixed tissue.
upon recovery. b. Valproic acid: This anticonvulsant may elicit a microve-
8. Intrasinusoidal fibrin has been reported, occasionally sicular fatty change indistinguishable from that seen in
associated with acute hemorrhage, when concurrent dis- acute fatty liver of pregnancy. Discontinuation of the
seminated intravascular coagulation is present. drug results in resolution of these hepatic changes.
2. Reye syndrome: In acute fatty liver of pregnancy, the fatty
Special stains change usually tends to spare periportal hepatocytes,
1. Phosphotungstic-acid hematoxylin (PTAH): This stain while in Reye syndrome, panlobular microvesicular fatty
highlights the fibrin that can occur when disseminated change is typical. Importantly, Reye syndrome is a dis-
intravascular coagulation is also present. ease of infants and children and is rarely seen in pregnant
2. Periodic-acid Schiff (PAS): Sometimes the microvesicular women.
fat may be difficult to appreciate on hematoxylin-eosin 3. Alcoholic foamy degeneration: Microvesicular fat is present
stain, with the liver cells instead appearing “hydropic.” in perivenular hepatocytes in this form of acute alcoholic
The PAS stain for glycogen highlights the distinct liver disease; however, variable degrees of sinusoidal col-
microvesicles which appear as small empty spaces with lagen, portal arachnoid fibrosis, lobular necroinflamma-
routinely processed tissue where the rest of the cytoplasm tory change, and occasional Mallory bodies are features
intensely stains magenta due to the glycogen. of alcoholic liver injury sometimes seen associated with
3. Oil Red O: Performed on frozen sections, this stain easily alcoholic foamy degeneration, those features not present
demonstrates the cytoplasm as containing neutral fat. in acute fatty liver of pregnancy.
4. Non-alcoholic steatohepatitis: In some instances, non- Toxemia of Pregnancy

alcoholic steatohepatitis can be associated with microve-
sicular fatty change, although most often this type of fat (Fig. 12-24)
is admixed with macrovesicular fat as well. If the biopsy
is quite small, however, purely microvesicular fat alone Major morphologic features
may be seen. The presence of glycogenated nuclei and 1. Fibrin deposition is seen within the sinusoids in the peri-
Mallory bodies that can often occur in non-alcoholic portal zone, often associated with coagulative (ischemic)
steatohepatitis is not a feature of acute fatty liver of liver cell necrosis and acute hemorrhage.
pregnancy.
Other features
Clinical and biologic behavior 1. Fibrin thrombi may also be present in portal venules.
1. Acute fatty liver of pregnancy is a rare disorder, the inci- 2. Hepatic arteries and arterioles exhibit endothelial dam-
dence 1/13,328 deliveries, and occurs in young primigrav- age with fibrin deposition within the lumen.
ida women (mean age 26 years) during the 3rd trimester 3. In severe cases there may be multilobular confluent isch-
(usually around 35th week, although it may occur as early emic necrosis with large areas of infarction.
as 22 weeks). 4. W hen the areas of necrosis and hemorrhage are marked,
2. The initial symptoms are vague and nonspecific, with head- hepatic rupture can occur.
ache and nausea followed by jaundice (93% of patients), 5. The portal tracts show little mononuclear inflammatory
abdominal pain (58%) and encephalopathy (83%). infiltrates, with the bile ducts unremarkable.
3. Laboratory tests show leukocytosis (83%). The serum
bilirubin is approximately 5 to 6 mg/dL (93%). A mild Special stains
increase in alkaline phosphatase activity is seen, and 1. Phosphotungstic-acid hematoxylin (PTAH): Fibrin can eas-
aminotransferases are usually less than 500 IU/L (80%), ily be demonstrated within the sinusoidal spaces and vas-
though higher values have been reported. Hypoglycemia cular lumen.
is common. Disseminated intravascular coagulation and
renal failure may occur. Differential diagnosis
4. The etiology is unknown, with environmental and/or Other causes of fibrin thrombi within sinusoids and small
toxic factors possibly playing a role. Some cases occur vessels:
in mothers of fetuses homozygous for genetic defects in 1. Disseminated intravascular coagulation (DIC): DIC of any
mitochondrial β-oxidation of long chain fatty acids. This etiology may be responsible for occlusion of the portal
disorder is not familial nor infectious and subsequent venules, hepatic arterioles, and sinusoids.
pregnancies are uncomplicated. 2. Vasculitis: Vascular thrombosis with resultant lobular ische
mic necrosis may occur as a consequence of vasculitis.
Treatment and prognosis 3. Mass lesions: Secondary vascular thrombosis may occur in
1. Prompt resolution of signs and symptoms with termina- part due to the compressive effect on the adjacent liver
tion of pregnancy occurs. No progression to chronic liver due to mass (space-occupying) lesions. In addition, intra-
disease has been documented. vascular spread of tumor with resultant vascular occlusion
2. Early diagnosis (high index of suspicion in a pregnant may also cause secondary ischemia.
woman with abnormal liver tests) is associated with a bet- Note: In the above conditions, clinical correlation leads to the
ter prognosis. correct diagnosis.
A B
Figure 12-24 Toxemia of pregnancy. These (A) medium- and (B) high-power images show the presence of liver cell necrosis and dropout in
the periportal zone, with prominent fibrin deposition along the sinusoids.
A B
Figure 12-25 Hyperalimentation (neonate). A, Sinusoidal collagen deposition and macrovesicular fatty change is seen. B, Intracellular bile
pigment is also identified within the liver cell cytoplasm on higher magnification.
Clinical and biologic behavior

1. Toxemia of pregnancy (preeclampsia) is a systemic disease
manifested by hypertension, proteinuria, and peripheral
edema. The term eclampsia is used when the condition is
complicated by seizures.
2. The disease is responsible for approximately 5% of all
cases of jaundice in pregnancy, and occurs in both young
primiparous and older multiparous women during the
3rd trimester.
3. Laboratory values show variable elevations of serum
aminotransferases, but marked elevations may be seen in
severe cases. Jaundice is rare, but when present the biliru-
bin does not exceed 6 mg/dL.
4. Anywhere from 2% to 12% of patients also develop a
variant of toxemia manifested by hemolysis (H), elevated
liver enzymes (EL), and low platelet count (LP), also
denoted as the HELLP syndrome.
5. The pathogenesis of the liver lesion may be due to intra- Figure 12-26 Hyperalimentation (adult). Prominent intracellular and
vascular coagulation and/or segmental vasospasm of intracanalicular bile is seen, with the hepatocytes showing hydropic
small hepatic arterioles, with injury of endothelial cells change and mild macrovesicular fatty change.
in constricted regions. Prostaglandins are important in
controlling blood pressure during pregnancy; in toxemia
there may be a possible imbalance in synthesis of platelet-
aggregation (thromboxane) and anti-aggregation (pros- Other features
taglandin I2) factors responsible for the disseminated 1. Infants
intravascular coagulation. a. Rosettes of liver cells form around dilated canaliculi
containing bile plugs.
Treatment and prognosis b. Bile may be seen within cholangioles and rarely within
1. Supportive treatment, with termination of pregnancy, is interlobular bile ducts.
the rule. c. Fatty change is present but infrequent.
d. Syncytial giant cell transformation of hepatocytes may
be seen in the perivenular zone.
HYPERALIMENTATION (TOTAL PARENTERAL e. Sinusoidal collagen deposition is present to variable
NUTRITION) degrees, but can be prominent and diffuse in a minor-
ity of cases.
(Figs. 12-25 and 12-26) f. Portal tracts exhibit a mild inflammatory infiltrate
consisting of lymphocytes with occasional neutrophils,
Major morphologic features without orientation of the inflammatory cells to inter-
1. Infants and adults lobular ducts.
a. Intrahepatic and intracanalicular cholestasis is present, g. In prolonged hyperalimentation, cholangiolar prolif-
predominantly within the perivenular zone, with mild eration may be present. In addition, a biliary fibrosis
chronic lobular inflammatory infiltrates. can occur with time and lead to a biliary cirrhosis.
2. Adults 2. The disorder presents as jaundice 4 to 47 days after initia-

a. Macrovesicular fatty change is seen with or without tion of TPN. In the adult, serum aminotransferases are
lobular inflammation, and may be most apparent in the mildly to moderately elevated in 93% of patients about 8
periportal zone. days after commencing TPN. These abnormalities then
b. Mallory bodies have been described but are uncommon. decrease and peak again to slightly higher levels 20 days
c. Portal lymphocytic infiltrates are present but are usu- after the start of therapy in 26% of cases. Bilirubin rises
ally mild. to approximately 3 mg/dL.
d. Portal fibrosis may occur with eventual development of 3. In neonates, hyperbilirubinemia may be present in
a micronodular cirrhosis in a minority of cases. Sinu- approximately 23% of cases; however, when TPN is pro-
soidal collagen can occasionally be seen in these cases longed, lasting 60 to 90 days, elevations of serum biliru-
as well. bin will occur in 80% to 90% of patients.
e. Increase in copper and copper-binding protein is seen 4. With cessation of TPN, hyperbilirubinemia resolves and
in periportal hepatocytes in rare instances. the liver enzymes return to normal, sometimes rather
f. Hemosiderin may be noted within Kupffer cells and slowly. In rare cases, fibrosis or even cirrhosis may occur,
periportal hepatocytes. especially when TPN cannot be discontinued.
5. Gallstones and sludge are commonly present due to bile
Special stains stasis within the gallbladder.
1. Masson trichrome: Sinusoidal collagen deposition can best 6. Fatty change may be due to imbalance of fatty acid and
be appreciated. lipoprotein synthesis, with inability to properly secrete
2. Perl’s iron: The hemosiderin within occasional periportal lipids.
hepatocytes can be highlighted. 7. The pathogenesis in the neonate may be related to a
3. Orcein, rubeanic acid, rhodanine: The increase in peripor- number of factors, including:
tal copper (rubeanic acid, rhodanine) and copper-binding a. Immaturity of intracellular enzymes.
protein (orcein) can be seen. b. Associated sepsis.
c. Absence of oral feeding causing inadequate gastric-
Differential diagnosis duodenal stimulation of the gallbladder, decreased bile
1. In the infantile type: flow and decreased clearance of bacterial (and other)
a. Neonatal giant cell hepatitis: Both hyperalimentation toxins.
and acute hepatitis can elicit giant cell transformation, d. Abnormal carbohydrate:amino acid ratios.
sinusoidal collagen deposition, and cholestasis in the e. Breakdown of tryptophan into hepatotoxic metabolites
neonate. The cholestasis, however, is more prominent during storage of the intravenous solutions.
in TPN-induced injury, while the giant cells are more f. Relative amino acid and/or essential fatty acid
numerous in neonatal hepatitis. deficiency.
b. Extrahepatic biliary atresia, choledochal cyst: Giant cell g. Hypersensitivity (eosinophilia has been rarely
transformation, cholestasis, and biliary fibrosis may be documented).
seen in these two conditions as well as in hyperalimen-
tation-induced injury; however, bile duct proliferation, Treatment and prognosis
which is usually striking in extrahepatic biliary atre- 1. The frequency of significant TPN-related liver disease
sia and choledochal cysts, is much less pronounced in is decreasing presumably due to early recognition of the
hyperalimentation. abnormality and the availability of alternative feeding
2. In the adult type: measures. In the small group of infants with short bowel
a. Drug-induced (e.g., oral contraceptives; see Table syndrome where no alternative exists, significant liver dis-
5-9): The cholestasis seen in adults in early stages of ease is still encountered.
hyperalimentation-induced injury can be associated 2. Treatment with ursodeoxycholic acid has been tried but
with little portal and lobular inflammation and mimic the beneficial effects are not well established.
simple cholestasis seen with certain drugs. The clinical
history and time frame of drug usage and initiation of INFECTION-ASSOCIATED (REACTIVE)
hyperbilirubinemia are helpful clues. HEMOPHAGOCYTIC SYNDROME
b. Bile duct obstruction: The perivenular cholestasis
in bile duct obstruction can mimic hyperalimen- (Figs. 12-27 through 12-29)
tation-induced cholestasis in the early stage; how-
ever, hyperalimentation-induced cholestasis is not Major morphologic features
associated with bile duct dilatation and acute chol- 1. Kupffer cell hyperplasia and hypertrophy with prominent
angitis, features oftentimes present with bile duct erythrophagocytosis (hemophagocytosis) are present and
obstruction. often pronounced.
Clinical and biologic behavior Other features

1. Liver disease associated with hyperalimentation (total 1. Portal tracts exhibit a prominent mixed inflammatory
parenteral nutrition, TPN) may be seen in both the neo- infiltrate consisting of lymphocytes, histiocytes, and
nate and adult. The overall incidence is higher in chil- occasional plasma cells.
dren than in adults, the incidence ranging from 7.4% 2. Variable degrees of sinusoidal dilatation are usually
to 84%. apparent.
Figure 12-27 Infection-associated (reactive) hemophagocytic syn- Figure 12-28 Infection-associated (reactive) hemophagocytic syn-
drome (bone marrow aspirate). A macrophage shows phagocy- drome. The portal tract exhibits a mixed cellular infiltrate consisting
tosis of a number of red blood cells. (Courtesy Russell Brynes, Los of lymphocytes with occasional histiocytes.
Angeles, CA.)
A B
Figure 12-29 Infection-associated (reactive) hemophagocytic syndrome. A and B,Prominent erythrophagocytosis of red blood cells is seen
within the sinusoidal Kupffer cells.
3. Hemosiderin pigment is also present predominantly disorders for further discussion). Clinical correlation with
within the hypertrophic Kupffer cells identification of the specific activated macrophages
4. Morphologic changes of underlying inflammatory and within the bone marrow in infection-associated (reactive)
infectious processes (e.g., rheumatoid arthritis, Epstein- hemophagocytic syndrome is then necessary for appro-
Barr virus infection) can also occur. priate diagnosis.
Special stains Clinical and biologic behavior

1. Prussian blue: The hemosiderin within the Kupffer cells is 1. The hemophagocytic syndromes represent both an inher-
highlighted. ited as well as an acquired disorder associated with an
uncontrolled proliferation of activated histiocytes (bone
Differential diagnosis marrow, spleen, lymph nodes) that phagocytize red blood
1. Other causes of erythrophagocytosis: A variety of condi- cells.
tions are associated with phagocytosis of circulating red 2. Patients with the autosomal recessive inherited disorder
blood cells, and include parenteral overload from mul- (familial hemophagocytic lymphohistiocytosis, FLH) present
tiple blood transfusions, hemodialysis, various hemolytic with fever and fatigue, with hepatomegaly (80% of
anemias (e.g., hereditary spherocytosis, pyruvate kinase patients), splenomegaly (63%), and jaundice (60%) fre-
deficiency), anemias secondary to abnormal hemoglo- quently occurring. About 50% of patients have all of the
bins (e.g., sickle cell disease, β-thalassemia), anemias above manifestations. Ascites is noted in about 25%.
secondary to ineffective erythropoiesis (e.g., sideroblas- Serum ferritin and triglyceride levels are increased in all
tic and megaloblastic anemias), and anemias secondary patients. The AST values are approximately 5 times above
to chronic infections (see Chapter 9 under Iron storage normal, with slight elevations in the alkaline phosphatase
in most patients and sometimes hyperbilirubinemia. In

about 10% of patients, however, severe transaminitis can
occur. Factor V levels measured in about 30% of patients
show values less than 50% and very low levels are associ-
ated with disseminated intravascular coagulation. Hema-
tologic tests show anemia, leukopenia, thrombocytopenia,
and low fibrinogen levels. Underlying conditions such as
the acquired immunodeficiency syndrome, systemic lupus
erythematosus, lymphoma, or leukemia are often associ-
ated. The inherited disorder is associated with identifica-
tion of the FHL genes (1 and 2) located on the 9q21.3-22
and 10q21 genes respectively.
3. Patients with the acquired (reactive) disorder (infection-
associated hemophagocytic syndrome) also present with
abnormal liver tests similar to those seen with the inher-
ited disorder. This type of disease is felt to be primar-
ily related to Epstein-Barr virus infection, and is seen in
patients with various neoplasms and chronic inflamma- Figure 12-30 Hyperpyrexia. A portal tract exhibits a moderate
lymphocytic infiltrate. Most of the adjacent hepatocytes show coag-
tory disorders such as rheumatoid arthritis. ulative necrosis.
4. Liver biopsy findings with identification of the hemo-
phagocytic histiocytes is seen in all cases, and in conjunc-
tion with the clinical setting may be diagnostic.
5. The pathophysiologic mechanisms for the abnormality
are not clearly elucidated. Macrophages are stimulated
by proliferating T lymphocytes (polyclonal in viral and
bacterial infections, clonal in tumor cells). The activated
macrophages release cytokines (TNFα, IL-1, IL-2, inter-
feron γ) that increase phagocytic activity. These cytokines
may cause cholestasis and some of the inflammatory
responses seen in the histopathology of the liver.
Treatment and prognosis

1. Markedly elevated liver test abnormalities with jaundice
and low factor V levels are associated with a poor prog-
nosis. The mortality rate is also high (above 60%) in the
pediatric population, with many patients dying within a
few months of diagnosis.
2. Ganciclovir has been shown to have some helpful effect
in the EBV-induced disease. Figure 12-31 Hyperpyrexia. The parenchyma shows striking coagu-
lative ischemic necrosis of the hepatocytes.
HYPERPYREXIA AND HEAT STROKE
(Figs. 12-30 through 12-32)
Major morphologic features

1. Prominent perivenular and midzonal confluent coagula-
tive necrosis is seen involving virtually all of the hepatic
lobules.
2. Some degree of microvesicular fatty change usually occurs
and is more often seen in the early stages of the disease.
Other features
1. The viable hepatocytes show diffuse hydropic change and
cytoplasmic vacuolization.
2. Necroinflammatory changes in the lobule are minimal in
the early stages of the disease. Neutrophils can occur in
and amongst the dying hepatocytes in latter stages.
3. In severe disease, all of the zones (panacinar) can be
Figure 12-32 Hyperpyrexia. High-power image shows the liver cells
involved. undergoing coagulative ischemic necrosis. A few viable but dam-
4. Portal tracts show a mild mixed cellular infiltrate consist- aged hepatocytes show hydropic change and some degree of pre-
ing of lymphocytes with occasional neutrophils dominantly microvesicular fatty change.
5. Although interlobular bile duct injury does not usually

occur, variable degrees of ductular (cholangiolar) prolif-
eration with acute cholangitis, acute cholangiolitis, and
intralobular cholestasis may be seen at times.
Differential diagnosis
1. Coagulative necrosis from severe hypotension: The coag-
ulative-type necrosis seen in hyperpyrexia mimics that
present in severe hypotensive episodes. The portal
tracts show a mild mixed inflammatory infiltrate asso-
ciated with hyperpyrexia, that feature absent in severe
hypotension.
Clinical and biologic behavior

1. Hyperpyrexia and heat stroke occur when the heat-
regulating mechanisms in the body are overburdened.
The causes most frequently are related to overexertion for Figure 12-33 Reye syndrome. Cross-section of this liver taken at
long time periods and prolonged exposure to very hot and autopsy shows the parenchyma to be uniformly yellow and some-
humid weather. what greasy due to marked fatty change.
2. High risk patients are the elderly and sometimes the very
young, those with cardiac disease, those that take certain
medications (e.g., amphetamines), and those not used to
hot and dry weather.
3. Patients present initially with sweating, nausea, muscle
cramps, and dizziness, followed in the severe cases by
high-grade fever, shock, and coma, with high mor-
tality. Sepsis, coagulopathy, and renal failure are also
complications.
4. Hepatic dysfunction can occur in those severely affected,
and include marked elevation in the aminotransferases
(usually in the thousands) with marked elevation of
serum LDH levels, and sometimes jaundice.
Treatment and prognosis

1. Treating the causes of the hyperpyrexia (e.g., body cool-
ing, administration of adequate fluids) is the first step. A
2. In those patients with severe hepatic involvement, the
outcome is poor, with liver transplantation often the only
option.
REYE SYNDROME
(Figs. 12-33 and 12-34)
Major morphologic features

1. Microvesicular fatty change is seen uniformly involving
the entire lobule, the fat globules smaller than the size of
the liver cell nucleus.
2. Minimal to absent portal inflammation and lobular
necroinflammatory changes are present. B
Figure 12-34 Reye syndrome. A, The hepatocytes appear diffusely
Other features hydropic but in fact contain fine droplet fat, with no lobular inflam-
1. The liver cells may microscopically appear swollen and mation or Kupffer cell hyperplasia. B, Oil red O fat stain on frozen
vacuolated, whereby the fat may not be appreciated on section material confirms the presence of fat (neutral triglycerides)
hematoxylin-eosin stain, especially during the first 24 within all of the liver cells.
hours. These cells, however, are strongly positive for
neutral lipids on Oil Red O and Sudan black B stains 3. Irregular eosinophilic cytoplasmic inclusions may be present
(performed on frozen sections of fresh or formalin-fixed within hepatocytes, representing distorted mitochondria.
tissue). 4. Cholestasis may occur but is uncommon.
2. The fat droplets may be smaller in the perivenular zone 5. In exceptionally severe and fatal cases, focal lymphocytic
(zone 3 of Rappaport). infiltrates and liver cell necrosis may be present.
6. Periportal ballooning degeneration and necrosis of hepa- matrix and contain dense bodies. Glycogen depletion is
tocytes have been described, but are rare. common. These findings are found not only in hepa-
7. In the recovery phase, microvesicular and macrovesicular tocytes but also in neurons within the cerebral cortex,
fat are identified within hepatocytes, with fat deposition suggesting that Reye syndrome may be a generalized
sometimes apparent within portal macrophages. mitochondrial disorder.
9. The Centers for Disease Control (CDC) have estab-
Special stains lished criteria for the diagnosis of Reye syndrome:
1. Oil Red O, Sudan black: Frozen sections of fresh or for- a. Acute noninflammatory encephalopathy documented
malin fixed tissue demonstrate the fat within the liver cell by an alteration in consciousness and if available cere-
cytoplasm that stains red (ORO) or black (Sudan stain). brospinal fluid containing less than 8 leukcytes/mm3.
b. Hepatopathy documented by liver biopsy or autopsy
Differential diagnosis or a three fold or greater rise of AST, ALT, or serum
Various inherited, developmental, and acquired disorders ammonia.
associated with microvesicular fat deposition in the liver are c. No reasonable explanation for the cerebral and hepatic
known. Correlation with the clinical setting and appropriate abnormalities.
biochemical determinants distinguish these diseases from However, this is a descriptive definition covering a
Reye syndrome. Various diseases that cause microvesicular group of heterogeneous disorders caused by infectious,
fat are the following: metabolic, toxic, or drug-induced diseases.
1. In the pediatric age group: Cholesterol ester storage dis- 10. The etiology is most likely related to a viral illness; how-
ease, Wolman’s disease, carnitine deficiency, kwashiorkor ever, that cannot be the only factor, as the disease occurs
(early stage) only in children, and similar viral illnesses in other fam-
2. Drugs, toxins: Tetracycline, sodium valproate, hypoglycin ily members at the same time do not produce the dis-
( Jamaican vomiting sickness), margosa oil, aflatoxin, fialuri- ease. Concomitant environmental agents and toxins may
dine, ibuprofen, ketoprofen, pentenoic acid (see Table 5-6). also play a part, although the initial trigger may still be a
3. Miscellaneous conditions: Acute fatty liver of pregnancy, viral infection.
alcoholic foamy degeneration, non-alcoholic steatohepa- 11. Numerous investigations have implicated acetylsali-
titis, acute hepatitis HBV with acute delta infection, toxic cylate (aspirin) as a factor in the pathogenesis of Reye
shock syndrome, yellow fever, Lyme disease, hyperpyrexia. syndrome. Ninety-three percent to 97% of patients with
this disorder had taken aspirin compared to 23% to 59%
Clinical and biologic behavior in control groups. In addition, there has been a decrease
1. Reye syndrome is a rare disorder most often occurring in incidence since 1982 after warning labels concern-
in children before age 5 years, and almost exclusively ing Reye syndrome were placed on aspirin bottles. Some
before age 16, consisting of acute encephalopathy and recent evidence suggests that salicylate enhances and
diffuse microvesicular fatty change of the liver. Other prolongs the activity of key elements along the signaling
organ-systems also exhibit fatty change (kidney, heart, pathway through which γ-interferon generates inducible
pancreatic islets). Cerebral edema is present without nitric oxide (iNOS). Many feel that Reye syndrome and
inflammatory changes. aspirin toxicity are distinct entities presenting somewhat
2. The disease is seen worldwide, with an incidence of similar features.
approximately 3.1/100,000. The overall incidence in the
U.S. is 0.15 to 0.88 cases/100,000 children under age 18 Treatment and prognosis
years, with regional differences (2.8 to 4.7 in Ohio, the 1. The treatment is supportive, with monitoring of blood
latter associated with an influenza B epidemic). glucose levels and aggressive management of complica-
3. Both sexes are equally affected, with more frequent tions seen in acute hepatic failure.
involvement in those living in the suburban area. 2. Monitoring intracranial pressure is important to assure
4. The disease most often follows an upper respiratory that permanent neurologic damage does not occur in a
tract infection of viral etiology (90% of cases). The more liver transplant candidate.
common viruses are influenza B and varicella, but influ- 3. Exchange transfusions were previously tried and initially
enza A, reoviruses (1 and 2), echovirus, and coxsackie thought to show benefit; however, in severe disease and
viruses (A and B) have also been identified. hepatic failure, hepatic transplantation should be offered
5. Approximately 1 week after the viral illness, acute onset and is life saving.
of vomiting, delirium and coma occur. Seizures are pres- 4. Mortality, greater than 40% in the 1970s, has fallen con-
ent in 30% of cases. siderably in part due to careful monitoring after prompt
6. The liver is enlarged and grossly yellow. diagnosis, and possible recognition of the relationship to
7. On laboratory tests moderate elevations of serum ami- aspirin.
notransferases (not greater than 500 IU/L) are seen,
with the bilirubin and alkaline phosphatase activity
normal or only minimally elevated. Hypoglycemia, aci- OTHER MISCELLANEOUS CONDITIONS
dosis, elevated serum ammonia levels, and increase in ASSOCIATED WITH LIVER DISEASES
prothrombin time are often present.
8. Electron microscopy demonstrates enlarged and mark- (Table 12-3)
edly distorted mitochondria that have a decreased
Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases

Eosinophilic gastro- • Numerous eosinophils are present within portal tracts. • This rare disease may present with recurrent abdominal pain,
enteritis • Granulomas with giant cells and eosinophils have also sometimes with associated steatorrhea.
been described. • Intestinal perforation has been reported.
• In rare instances periductal fibrosis and sclerosis have • Hepatic involvement is unusual.
been reported.
Hemolysis, elevated • Periportal and/or focal lobular necrosis with fibrin • The HELLP syndrome is seen in patients with pregnancy-
liver enzymes, low deposition may occur (similar to that seen in toxemia). induced hypertension and is characterized by hemolysis, moder-
platelet (HELLP) • Intrahepatic and subcapsular hemorrhage with rup- ate elevations in serum transaminases, thrombocytopenia and
syndrome ture may also occur. preservation of hepatic synthetic function.
• Portal lymphocytic infiltration, mild lobular inflam- • Recovery is the rule following termination of pregnancy.
mation and macrovesicular fatty change are present. • The etiology is not clear, although a microangiopathic process
may be involved.
Hypereosinophilic • Prominent numbers of eosinophils are present within • This idiopathic disorder occurs predominantly in young to
syndrome portal tracts and sinusoids. middle aged males who have persistent eosinophilia of unknown
• Sinusoidal congestion may also be seen. cause; hypersensitivity reactions, parasitic infestation and other
• Portal lymphocytic infiltration is present, sometimes causes of eosinophilia must be ruled out.
associated with periportal interface inflammatory • Hepatomegaly with minimally abnormal liver tests occur in
activity. approximately 30% of these patients.
• Variable portal fibrosis may occur; although bridging • Complications include congestive heart failure, myocarditis, and
fibrosis has been reported, no true progression to a various neurologic abnormalities.
well-established cirrhosis has been described. • O verall the prognosis is poor, although chemotherapy may be
promising in some.
Hyperthyroidism • Mild portal lymphocytic infiltration, macrovesicular • Patients may present with clinical features of hyperthyroidism,
fatty change, and mild necroinflammatory changes including palpable thyroid gland, bruit, tremors, lid lag, and
may be seen. exophthalmos.
• Sinusoidal congestion with adjacent liver cell atrophy • Serum bilirubin is minimally elevated (3 mg/dL) and mild
may be present. increases in serum transaminases (ALT higher than AST) are
noted.
• In patients with associated cardiac disease, the liver test abnor-
malities may be markedly deranged.
Hypothyroidism • Concentric thickening of the terminal hepatic venules • Liver tests are usually normal.
may be seen, associated with perivenular fibrosis. • In some patients with severe hypothyroidism, ascites may be
present.
Idiopathic granulo- • Circumscribed collections of inflammatory cells • The initial report on this disorder included 12 patients who
matous hepatitis (“granulomas”) within portal tracts and lobules occur. presented with prolonged fever, elevated alkaline phosphatase
• The granulomas are usually of epithelioid type activity and no evidence of infection.
(transformed activated macrophages, lymphocytes and • None of these patients had lymphadenopathy, hypercalcemia or
multinucleated giant cells). pulmonary disease (features seen in sarcoidosis).
• Rarely the granulomas can also involve hepatic vein • In some patients, hepatomegaly is noted and therapy with corti-
segments, causing obliteration and inflammation costeroids is beneficial.
(granulomatous phlebitis). • Fever recurs when steroid therapy is withdrawn, and tempera-
ture returns to normal when steroids are reintroduced.
• The long term course is benign without progression to advanced
liver disease.
• It is postulated that some of these cases may represent sarcoid-
osis confined to the liver without pulmonary manifestations.
Intrahepatic cho- • Cholestasis is present within perivenular hepatocytes • This disorder occurs in 2% to 6% of uncomplicated pregnancies
lestasis of pregnancy and dilated canaliculi. and is manifested in the 3rd trimester with pruritus and only
• Portal tracts exhibit minimal to absent inflammatory slight bilirubin elevations (1–2 mg/dL), resolving within a few
infiltrates which, when present, are usually lympho- hours to days after delivery.
cytes. Portal fibrosis does not occur. • Although there are generally no obstetrical complications, there
• Interlobular bile ducts are normal to only minimally is a slight increase in incidence of stillborn and premature births.
increased in number, with occasional cholangioles • Scandinavian, Polish, and Chilean women appear most suscep-
(metaplastic ducts) seen. tible.
• Kupffer cell hyperplasia may be present but is mild. • There is an increased incidence of gallstone formation.
• Giant cell transformation of hepatocytes in the peri- • The etiology may be related to a genetic predisposition for
venular zone may at times be identified; however, no increased sensitivity to normally produced estrogens and proges-
lobular necroinflammatory changes are seen. terones, as high circulating levels of estrogens in certain patients
may lead to cholestasis by impairing sulfation and transport of
monohydroxy bile acids, resulting in the formation of glucuro-
nide conjugates.
Kwashiorkor • Marked fatty change is present, without accompany- • This distinct syndrome in children, similar to marasmus, is
ing lobular inflammation. primarily a deficiency of protein intake.
• The fat initially is microvesicular and is oriented in • Patients present with pallor, lethargy, edema and hepatomegaly.
the perivenular zone. • Marked hypoalbuminemia, mild to moderate increases in serum
• As the disease progresses, macrovesicular fat is seen transaminases, and normal prothrombin time are typical find-
involving all zones ings.
• With re-feeding, the perivenular fat disappears first. • Re-feeding and restitution of protein in the diet is carried out
• Mallory bodies have been described. slowly to prevent diarrhea and electrolyte abnormalities.
Continued
Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases—cont’d

Light chain disease • Acellular eosinophilic deposits (confirmed on • This plasma cell dyscrasia primarily involves the kidneys; how-
immunoperoxidase stains as light chains) are seen ever, the lungs, liver and vasculature may also be involved.
within the space of Disse and portal tracts, these • Hepatic involvement is uncommon; hepatomegaly may be pres-
deposits strongly PAS positive after diastase digestion ent with mildly abnormal serum transaminases, good hepatic
(DiPAS). function, and rarely hyperbilirubinemia.
• Sinusoidal dilatation and peliosis have been described. • Renal failure may occur.
• These deposits resemble but are not amyloid (negative
on Congo red staining).
• The deposits have been reported to also contain heavy
chains.
Marasmus • Fatty change is present but is mild and focal. • This distinct syndrome in children, related to kwashiorkor, is
• The fatty change is macrovesicular, without a zonal primarily protein calorie malnutrition.
distribution pattern. • There is marked cachexia with loss of muscle mass, lethargy,
• Variable sinusoidal dilatation occurs, with peliosis a distended abdomen from an enlarged liver, and increase in
hepatitis also described. susceptibility to infection.
• Liver tests are normal or mildly deranged; hypoalbuminemia is
striking
• Re-feeding and restitution of protein and calories in the diet is car-
ried out slowly to prevent diarrhea and electrolyte abnormalities.
Nonspecific reactive • Portal tracts exhibit variable lymphocytic infiltrates • This entity is a secondary response of the liver to numerous
hepatitis not uniformly involving all portal tracts, without extrahepatic and often systemic disorders.
periportal interface inflammatory activity • There are no distinct clinical features, with any symptoms
• Plasma cells and eosinophils can occasionally be seen related to the associated disorder.
within the portal structures but are not common. • Although serum transaminases may be mildly elevated, other
• The parenchyma shows generally mild focal necrosis liver tests are normal.
and hepatocytolysis, the inflammatory cells chiefly
lymphocytes, with macrophages also present in areas
of necrosis (positive on DiPAS stain).
• At times the lymphocytes may have a back-to-back
arrangement within the sinusoids.
• Small “microgranuloma” not exhibiting multinucle-
ated giant cells may occasionally be seen.
• Variable macrovesicular fatty change is usually
present.
Polymyalgia rheu- • Portal lymphocytic infiltration occurs and may be • This vasculitic disorder is seen in the elderly population who
matica prominent, with mild focal necrosis and predomi- develop pain and stiffness of the proximal upper limbs and
nantly macrovesicular fatty change present within the shoulders.
lobules. • A minority of patients may have increased alkaline phosphatase
• Granulomas and nodular regenerative hyperplasia activity.
have been reported. • Temporal arteritis and central retinol venous occlusion are
associated.
Rheumatoid arthritis • Portal lymphocytic infiltration is seen, with associated • Most patients with rheumatoid arthritis do not have hepatic
mild lobular mononuclear inflammatory infiltration; manifestations, although approximately 10% of patients may
in Felty’s syndrome, prominent sinusoidal lymphocy- have enlarged livers with abnormal alkaline phosphatase activity
tosis may also be seen. (biliary origin).
• Variable predominantly macrovesicular fatty change is • The serum transaminases are almost always normal; however,
present. when elevated, the usual cause relates to drugs used in therapy of
• Sinusoidal dilatation may also be seen. rheumatoid arthritis rather than the arthritis itself.
• Lipogranulomas have been described in association • In Felty’s syndrome, hepatomegaly is common, and patients may
with gold therapy (pigmented gold particles in granu- have some evidence of portal hypertension (ascites, esophageal
lomas). varices).
• Arteritis may occur, with secondary infarction and
hemorrhage within the lobules.
• Nodular regenerative hyperplasia has been reported
but is uncommon.
Spontaneous rupture • Focal and predominantly subcapsular acute hemor- • This rare but potentially fatal condition is seen in pregnancy-
in pregnancy rhage occurs with rupture. induced hypertension, may be associated with the HELLP
• Secondary ischemic coagulative necrosis of hepato- syndrome, or may be idiopathic.
cytes in hemorrhagic regions are often present. • Patients usually in the third trimester of pregnancy present
with an acute onset of severe right upper quadrant or epigastric
abdominal pain; anemia followed by hypotension, shock and
death will occur if untreated.
• Abdominal tenderness, guarding and distension related to blood
in the peritoneal cavity may be present.
• Ultrasound and computed tomography scans of the abdomen
confirm the presence of a large subcapsular hematoma of the
liver with free blood in the peritoneal cavity.
• Emergent cesarean section if presentation occurs prior to
delivery, and efforts to stem bleeding from the liver (including
hepatic lobectomy), may be necessary.
• Recovery occurs if managed expediently, with no apparent risk
of recurrence in subsequent pregnancies.
Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases—cont’d

Systemic lupus • Mild macrovesicular fatty change is usually seen, • Systemic lupus erythematosus (SLE) is associated with hepato-
erythematosus with mild focal necrosis and lymphocytic infiltration megaly and mildly abnormal liver tests in a minority of patients,
within the lobules. with hyperbilirubinemia uncommon.
• Sinusoidal congestion and cholestasis may also be • Although cirrhosis has in the past been described, further stud-
seen. ies have not supported this finding, as SLE in the clinical setting
• Granulomas have been reported, sometimes exhibit- may mimic autoimmune hepatitis (both disorders occurring in
ing a peripheral fibrin ring. young women with positive ANA), which is known to progress
• Arteritis has been described with secondary infarction to cirrhosis in untreated patients.
and hemorrhage within the lobules.
• Peliosis may also be present.
Systemic mastocy- • Increased numbers of mast cells are seen within the • Mastocytosis is a group of inherited disorders caused by
tosis portal tracts and occasionally within the hepatic increased numbers of mast cells and mast cell precursors in the
sinusoids. body.
• Mast cells are also present in vascular subendothelial • Cutaneous (urticaria pigmentosa) and systemic (liver, spleen,
regions. bone marrow) manifestations can occur.
• Cholestasis may occur. • Patients present with itching, various skin lesions, abdominal
• Non-cirrhotic portal fibrosis has also been reported, distension, nausea, vomiting, and diarrhea.
and cirrhosis has been reported in a small percentage • Slight abnormalities in serum transaminases and alkaline phos-
of patients. phatase can occur in systemic disease.
• Diagnosis rests on the identification of the characteristic mast
cells in biopsy material, in particular bone marrow.
Weber-Christian • Macrovesicular fatty change is present and may be • This uncommon disorder is characterized by the presence of
disease prominent, sometimes associated with a lymphocytic numerous subcutaneous nodules with associated inflammation
and neutrophilic infiltration within the lobules. (panniculitis).
• Mallory body formation may also be present. • Hepatomegaly may be striking.
REFERENCES
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Miscellaneous Conditions: Granulomatous Liver Disease Description and Causes

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Chapter

Table 12-1 Hepatic Granulomas

Table 12-2 Hepatic Granulomas, USC Experience

Figure 12-2 Sarcoidosis. The granulomas are well-circumscribed

Other features 7. Nodular regenerative hyperplasia has been reported.

Chronic Hepatitis (1% to 2% Frequency)

1. In a small percentage of cases, a portal fibrosis with portal

Cirrhosis (2% to 5% Frequency)

1. The incidence of cirrhosis associated with chronic ulcer-

Figure 12-10 Autoimmune hepatitis. The perivenular zone shows

cholangitis). Duct loss (ductopenia) may eventually occur

Autoimmune hepatitis overlap variants

majority of patients. The cytochrome P450 IID6 is the

Figure 12-19 Amyloidosis, globular type (electron micrograph).

5. A variant of amyloid deposits may occur whereby globu- Fluorescence

4. Non-alcoholic steatohepatitis: In some instances, non- Toxemia of Pregnancy

Clinical and biologic behavior

2. Adults 2. The disorder presents as jaundice 4 to 47 days after initia-

Clinical and biologic behavior Other features

Special stains Clinical and biologic behavior

in most patients and sometimes hyperbilirubinemia. In

Treatment and prognosis

HYPERPYREXIA AND HEAT STROKE

(Figs. 12-30 through 12-32)

Major morphologic features

5. Although interlobular bile duct injury does not usually

Clinical and biologic behavior

Treatment and prognosis

(Figs. 12-33 and 12-34)

Major morphologic features

Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases

Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases—cont’d

Table 12-3 Other Miscellaneous Conditions Associated with Liver Diseases—cont’d

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Table 12-2 Hepatic Granulomas, USC Experience

Other features 7. Nodular regenerative hyperplasia has been reported.

1. In a small percentage of cases, a portal fibrosis with portal

1. The incidence of cirrhosis associated with chronic ulcer-

5. A variant of amyloid deposits may occur whereby globu- Fluorescence

4. Non-alcoholic steatohepatitis: In some instances, non- Toxemia of Pregnancy

2. Adults 2. The disorder presents as jaundice 4 to 47 days after initia-

5. Although interlobular bile duct injury does not usually