ORIGINAL ARTICLE
The Almost-normal Liver Biopsy
Presentation, Clinical Associations, and Outcome
Thomas W. Czeczok, MD,* John S. Van Arnam, MD,* Laura D. Wood, MD, PhD,w
Michael S. Torbenson, MD,* and Taofic Mounajjed, MD*
Abstract: Liver biopsies obtained for abnormal liver enzymes or
unexplained ascites occasionally appear histologically almost
normal. The differential diagnosis for these cases is challenging
because literature addressing this topic is lacking. We aimed to
establish a differential diagnosis and determine clinical associa-
tions and outcomes for almost-normal liver biopsies. Ninety-
seven histologically almost-normal liver biopsies were collected
from 2 institutions. All cases lacked significant inflammation,
fatty change, biliary tract disease, vascular disease, nodular
regenerative hyperplasia, iron overload, inherited metabolic or
storage disorder, viral hepatitis, or fibrosis. Biopsies for follow-
up of known liver diseases were excluded. Transplant biopsies,
lesion-directed biopsies, biopsies obtained during bariatric sur-
gery, liver donor biopsies, and biopsies to evaluate methotrexate
toxicity were excluded. Clinical (including follow-up) and lab-
oratory data were collected. The frequency of almost-normal
liver biopsies was 0.6% and 3.7% at the 2 institutions. The most
common biopsy indications were elevated liver biochemistries or
clinical findings that suggested portal hypertension. In 70 pa-
tients (72%), an associated clinical abnormality was identified;
the most common were autoimmune systemic inflammatory
conditions (18%), vascular/ischemic events (13%), metabolic
syndrome (11%), drug effects (8%), and inflammatory con-
ditions of the gastrointestinal tract (7%). The median follow-up
period was 4.3 years (range = 0 to 10 y); detailed clinical follow-
up was available for 66 patients (68%). Liver biochemistries
normalized in 32 patients (48.5%) and remained elevated in 34
(51.5%). Seven patients (7.2%) eventually developed chronic
liver disease (autoimmune hepatitis [n = 3], primary biliary cir-
rhosis [n = 3], cryptogenic cirrhosis [n = 1]). This multicenter
study determines the differential diagnosis for almost-normal
liver biopsies; this will guide pathologists in subsequent workup
efforts in these challenging cases.
Key Words: normal liver, liver biopsy, normal histology
(Am J Surg Pathol 2017;00:000–000)
From the *Department of Laboratory Medicine and Pathology, Mayo
Clinic, Rochester, MN; and wDepartment of Pathology, Johns
Hopkins University School of Medicine, Baltimore, MD.
Conflicts of Interest and Source of Funding: The authors have disclosed
that they have no significant relationships with, or financial interest
in, any commercial companies pertaining to this article.
Correspondence: Taofic Mounajjed, MD, Department of Laboratory
Medicine and Pathology, Mayo Clinic, 200 First Street, SW,
Rochester, MN, 55905 (e-mail: mounajjed.taofic@mayo.edu).
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Am J Surg Pathol  Volume 00, Number 00, ’’ 2017
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espite the emergence of less-invasive techniques,1,2
D the liver biopsy has a central role in assessing liver
disease; it is an invaluable tool for diagnosis of disease,
assessment of disease activity, and determination of
degree of liver fibrosis.3–5 Liver biopsies are often
obtained during the investigation of abnormal liver bio-
chemistries, including elevated transaminases, alkaline
phosphatase, and/or bilirubin levels, or when evaluating
the liver in individuals with ascites of uncertain etiology.
Biopsies obtained in these settings can reveal a spectrum
of abnormalities, including a subset of cases that show
almost-normal histology.
These “almost-normal” liver biopsies are challeng-
ing because little is known about their differential diag-
nosis and natural history. The goal of this study is to
evaluate the frequency of liver biopsies with almost-
normal histology, identify the clinical entities that can be
associated with this finding, and examine patient out-
comes. These findings will enable the surgical pathologist
to generate a differential diagnosis when evaluating a liver
biopsy that shows almost-normal histology.
There is a separate set of liver specimens that show
subtle histologic changes, such as nodular regenerative
hyperplasia or hepatic stellate cell hyperplasia. Such
subtle histologic changes have specific histologic diag-
noses and known clinical associations6–8 and were
excluded in this study to focus on those cases without
abnormal histologic findings.
MATERIALS AND METHODS
The study was independently performed at 2 in-
stitutions (Johns Hopkins Hospital and Mayo Clinic) to
ensure the results are reproducible across institutions.
Both institutions are tertiary care centers. Cases from
Johns Hopkins Hospital were collected prospectively over
a 4-year period (2002 to 2006) by a specialized liver
pathologist (M.S.T.). For Mayo Clinic, the pathology
database was retrospectively searched for cases in which a
biopsy was performed for clinical suspicion of native liver
disease, but the histologic findings were essentially normal
and no specific histologic diagnosis could be made. Cases
at Mayo Clinic were collected between the years 2005 and
2009. Hematoxylin and eosin, Masson Trichrome, Peri-
odic Acid Schiff with diastase digestion (PAS-D), iron,
and reticulin stains were performed in all biopsies. All
biopsies had no significant inflammation, fatty change,
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Czeczok et al Am J Surg Pathol  Volume 00, Number 00, ’’ 2017

biliary tract disease, vascular disease, nodular re-
generative hyperplasia, iron overload, inherited metabolic
or storage disorders, or fibrosis (Fig. 1). None had viral
hepatitis.
Biopsies were considered acceptable for inclusion in
the study if they had minimal nonspecific changes in-
cluding <5% macrovesicular steatosis, focal minimal
portal inflammation without interface activity, or very
rare ceroid-laden macrophages (Fig. 2). Cases not meet-
ing these criteria were excluded (Fig. 3). Biopsies obtained
for follow-up of known liver disease were also excluded.
We also excluded all liver transplant biopsies, all lesion-
directed biopsies, all biopsies obtained during bariatric
surgeries, and all biopsies for other specific indications
such as pretransplant donor biopsies or biopsies obtained
before initiation of methotrexate treatment or to evaluate
for methotrexate toxicity. Clinical and laboratory data,
including clinical follow-up data when available, were
collected and analyzed for all patients. The diagnosis of
drug reaction was made by reviewing the clinical follow-
up notes. When the clinical follow-up notes attributed or
suspected the clinical/laboratory abnormality to be sec-
ondary to drugs, we felt this was sufficient to consider the
injury drug-associated. A minimum follow-up time of
1 year was regarded as sufficient. All biopsies were re-
viewed by a liver pathologist (M.S.T. and/or T.M.). The
study was approved by the Institutional Review Board at
both institutions. The w2 test was used to evaluate for
statistical association.
RESULTS
At Johns Hopkins Hospital, 94 cases with almost-
normal liver histology were identified out of a total of
2610, accounting for 3.7% of all liver biopsies. No suffi-
cient clinical information was available on 26 cases,
leaving 68 almost-normal liver biopsies that were included
in the study. At Mayo Clinic, a total of 29 cases (0.6% of
all liver biopsies) were identified. Thus, a total of 97 bi-
opsy specimens were included in the study. Each biopsy
was from a unique individual. The biopsies were more
common in women (64%) than men (36%). The patients

FIGURE 1. The normal liver biopsy. A and B, All biopsies included in the study showed no significant histologic abnormalities.
Notice the absence of significant inflammation, fatty change, biliary tract disease, and fibrosis (hematoxylin and eosin). C and D,
Trichrome stain confirms the absence of fibrosis.

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Am J Surg Pathol  Volume 00, Number 00, ’’ 2017 The Almost-normal Liver Biopsy

FIGURE 2. Only very minimal changes were allowed in nearly normal liver biopsies. A and B, Only minimal (< 5%) steatosis was
allowed for inclusion in the study (hematoxylin and eosin). C, Only focal minimal portal inflammation is seen (hematoxylin and
eosin). D, Only very rare ceroid-laden macrophages (arrow) were considered acceptable in nearly normal liver biopsies (PAS-D).

ranged in age between 1 and 79 years (mean = 41.5 ±
16.9 y). The median clinical and laboratory follow-up
period was 4.3 years (range = 0 to 10 y).
The biopsy indications are summarized in Table 1. In
patients with elevated liver biochemistries, aspartate ami-
notransferase, alanine aminotransferase, and alkaline
phosphatase ranged from 53 to 228 U/L (mean = 121 U/L),
68 to 308 (mean = 127 U/L), and 241 to 502 U/L
(mean = 341 U/L), respectively. After review of the clinical
and laboratory data, including patient follow-up, a most
likely etiology for the clinical liver abnormalities were found
in most cases (70/97; 72%) patients). These etiologies could
be grouped into 9 broad categories (Table 2). The largest
category included systemic autoimmune inflammatory
conditions (n = 17), which included systemic lupus ery-
thematosus (n = 5), rheumatoid arthritis (n = 5), Wegener
granulomatosis (n = 1), dermatomyositis (n = 1), sarcoi-
dosis (n = 1), scleroderma (n = 1), polymyalgia rheumatic
(n = 1), polymyositis (n = 1), systemic IgG4 disease
(n = 1), Still disease (n = 1), and autoimmune systemic
inflammatory illness of uncertain nature (n = 1).
Vascular/ischemic events were the next biggest group
(n = 13) and included portal/splenic vein thrombosis or
damage (n = 5), coagulopathy with thrombosis (n = 3), hy-
povolemic/hypotensive status (n = 2), vascular malformation
(n = 2), or venous outflow impairment (n = 1). Despite the
minimal or absent steatosis in the liver biopsy specimens, the
metabolic syndrome was the only identifiable abnormality in
11 cases. Drug reactions were eventually diagnosed in 8 cases,
including azathioprine, methadone, cocaine, methotrexate,
chemotherapeutic agents, and analgesic agents. Inflammatory
conditions of the gastrointestinal tract were also not an un-
common association (n = 7) and included inflammatory
bowel disease (n = 4), celiac disease (n = 1), blind loop
bacterial overgrowth (n = 1), and strangulated volvulus
(n = 1). Other less-common categories included biliary out-
flow impairment (n = 3) that resulted from a pancreatic tu-
mor (n = 1) or gallstones (n = 2). Miscellaneous conditions
(n = 3) included Turner syndrome (n = 2) and familial
Mediterranean fever (n = 1). A clinical association was not
discovered in 27 patients (28%) despite complete clinical and
laboratory workup.

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Czeczok et al
FIGURE 3. Liver biopsies excluded from the study. A–C, Reactive
hepatitis. This biopsy showed too much inflammation to be included
in the study (A, hematoxylin and eosin). This biopsy showed too much
lobular inflammation to be included in the study (B, hematoxylin and
eosin, arrow). The lobules show too many ceroid-laden macrophages
to be included in the study (C, Periodic Acid Schiff stain).
Among the 97 biopsies, 41 (42%) were completely
normal. The frequencies of the 3 minimal findings (< 5%
macrovesicular steatosis, focal minimal portal inflammation
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Am J Surg Pathol  Volume 00, Number 00, ’’ 2017
TABLE 1. Indications of Liver Biopsies in Individuals Showing
Nearly-normal Histology
Biopsy Indication n (%)
Elevated liver biochemistries 77 (79.4)
Portal hypertension 6 (6.2)
Systemic illness/inflammatory disease 6 (6.2)
Elevated autoimmune antibodies 6 (6.2)
Ascites 5 (5.2)
Varices 4 (4.1)
Hepatosplenomegaly 4 (4.1)
Cirrhosis by imaging 2 (2.1)
without interface activity, or very rare ceroid-laden macro-
phages) and the completely normal biopsies were compared
between all the different categories. Neither the minimal
findings (P = 0.21, 0.32, and 0.11, respectively) nor the
completely normal histology (P = 0.18) showed significant
association with a specific category. Although ceroid-laden
macrophages were most commonly seen in association
with drug reactions (38%), this was not significantly more
frequent than other categories.
Follow-up information for at least 1 year was
available for 66 patients (68%). Among these, liver bio-
chemistries eventually normalized in 32 patients (48.5%)
and remained elevated in 34 (51.5%). In patients with
persistent elevation of liver biochemistries, most (28;
82%) had persistently elevated transaminases, and the
remaining 6 (8%) had elevated alkaline phosphatase. On
follow-up, 7 patients (7%) eventually developed estab-
lished chronic liver disease: autoimmune hepatitis (n = 3)
and primary biliary cirrhosis (n = 3), and cryptogenic
cirrhosis (n = 1) (Table 3).
DISCUSSION
Liver biopsies that show almost-normal histology
are not rare in clinical practice and can be particularly
challenging because the differential diagnosis is unclear.
These biopsies are also challenging because of the concern
of missing a subtle but diagnostic lesion. The most com-
monly encountered subtle but diagnosable lesions are
shown in Table 4. Once all causes of diagnosable liver
disease have been excluded, then the results of this study
become relevant, showing the most common clinical as-
sociations for the almost-normal liver biopsy.
The most common indications for the liver biopsies
in this study were elevated liver biochemistries or clinical
signs or symptoms that suggested portal hypertension.
One of the limitations of this study is that full clinical
follow-up was not available on all patients. However,
there was follow-up on sufficient numbers of patients
(68% of patients with a minimum of 1-year follow-up) to
generate clinically meaningful data. After complete clin-
ical and histologic evaluation, a diagnosis was achieved in
72% of cases, despite the almost-normal liver biopsy
findings. The top 5 most common final diagnoses for the
patients were a systemic autoimmune inflammatory condition
(18%), vascular disease (13%), metabolic syndrome (11%),
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Am J Surg Pathol  Volume 00, Number 00, ’’ 2017 The Almost-normal Liver Biopsy

TABLE 2. Associated Conditions and Their Clinical Characteristics in Patients With Liver Biopsies Showing Nearly-normal Histology
n (%)
Unknown Systemic Inflammation Vascular/Ischemic Metabolic Syndrome
(N = 27) (N = 17) (N = 13) (N = 11)
Age (SD) (y) 41.8 (16.2) 43.6 (14.2) 34.2 (20.3) 44.7 (11.7)
Median follow-up (range) 3.1 (0.2-7.4) 3.5 (0.1-9.0) 5.4 (0.6-7.4) 5.9 (0.04-10.0)
BMI (n) (SD) 26.0 (4) (3.1) 20.1 (3) (4.2) 22.7 (4) (3.4) 33.9 (4) (3.05)
Male 14 (52) 2 (12) 4 (31) 5 (46)
Female 13 (48) 15 (88) 9 (69) 6 (55)
Biopsy indication
Elevated LFTs 26 (96) 14 (82) 5 (38) 8 (73)
Portal hypertension 0 0 4 (31) 0
Systemic illness/inflammatory 0 5 (29) 0 0
disease
Elevated autoimmune antibodies 2 (7) 2 (12) 0 0
Ascites 0 1 (6) 2 (15) 0
Varices 2 (7) 0 2 (15) 0
Hepatosplenomegaly 1 (4) 0 1 (8) 1 (9)
Cirrhosis by imaging 0 0 0 1 (9)
LFTs at follow-up
Persistent elevated transaminases 14 (52) 1 (6) 1 (8) 5 (45)
Persistent elevated AP 1 (4) 2 (12) 1 (8) 0
Normalized 6 (22) 6 (35) 4 (31) 4 (36)
Unknown 6 (22) 8 (47) 7 (54) 2 (18)
AP indicates alkaline phosphatase; BMI, body mass index; GI, gastrointestinal; LFTs, liver function tests.

drug reactions (8%), and inflammatory conditions of the
gastrointestinal tract (7%). On follow-up, an additional
7 patients (7%) eventually developed more classic chronic
liver diseases, such as autoimmune hepatitis and primary
biliary cirrhosis.
The findings in this study overlap with what has
historically been called a nonspecific “reactive hepatitis”
pattern6 for which the differential was anecdotally ascribed
to primarily systemic inflammatory conditions, drugs, and
inflammatory conditions of the gastrointestinal tract. The

TABLE 3. Features of the 7 Cases that Developed Chronic Liver Disease

Patients With Chronic Sex, Age at Follow- Subsequent Biopsy Subsequent Biopsy
Liver Disease Dx (y) up (y) Interval (y) Findings Means of Diagnosis Diagnosis
Patient 1 F, 42 7 1 Panacinar hepatitis Biopsy AIH
Positive ANA
Elevated transaminases
Patient 2 M, 51 5 1.5 Chronic hepatitis, Biopsy AIH
stage 1 Positive ANA and ASMA
Elevated transaminases
Patient 3 F, 44 3 1 Chronic hepatitis, Biopsy AIH
stage 2 Positive ANA
Elevated transaminases
Patient 4 F, 61 3 1.5 Chronic biliary Biopsy PBC
disease, stage 1 Positive AMA
Elevated alkaline
phosphatase
Patient 5 F, 58 6 3 Chronic biliary Biopsy PBC
disease, stage 2 Positive AMA
Elevated alkaline
phosphatase
Patient 6 F, 53 6 2 Chronic biliary Biopsy PBC
disease, stage 1 Positive AMA
Elevated alkaline
phosphatase
Patient 7 M, 66 9 7 Cryptogenic cirrhosis Liver biopsy Cryptogenic
Clinical features of cirrhosis
cirrhosis (ascites)
Imaging studies
AIH indicates autoimmune hepatitis; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; Dx, diagnosis; F, female;
M, male; PBC, primary biliary cirrhosis.

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Czeczok et al Am J Surg Pathol  Volume 00, Number 00, ’’ 2017

TABLE 2. (continued)
n (%)
Drug (N = 8) GI Inflammation (N = 8) Chronic Liver Disease (N = 7) Biliary (N = 3) Miscellaneous (N = 3)
44.6 (8.7) 40.8 (22.6) 44.6 (20.5) 39.7 (15.8) 34.8 (38.8)
4.6 (1.3-9.7) 4.1 (0.01-9.4) 4.2 (1.2-5.8) 4.7 (1.2-8.3) 4.2 (1.2-7.2)
27.8 (5) (1.92) 24.1 (5) (3.7) 21 (1) (—) 27.4 (2) (1.6) 21.4 (2) (11.5)
4 (50) 3 (38) 1 (14) 1 (33) 2 (67)
4 (50) 5 (63) 6 (86) 2 (67) 1 (33)
Biopsy indication
6 (75) 7 (88) 5 (71) 3 (100) 3 (100)
1 (13) 0 1 (14) 0 0
0 1 (13) 0 0 0
0 1 (13) 1 (14) 0 0
1 (13) 0 0 0 1 (33)
0 0 0 0 0
0 0 1 (14) 0 0
0 1 (13) 0 0 0
LFTs at follow-up
2 (25) 0 3 (43) 1 (33) 1 (33)
1 (13) 1 (13) 0 0 0
3 (38) 5 (63) 2 (29) 1 (33) 1 (33)
2 (25) 2 (25) 2 (29) 1 (33) 1 (33)

results from this study affirm this prior experience, provide
data to support this differential, and extend this differential
to include other less-common entities. This data allows
pathologists to provide a reasonable, data-driven differ-
ential for the almost-normal liver biopsy.
Eleven (11%) of the patients included in the study
had the metabolic syndrome. The association between the
metabolic syndrome and elevated liver enzymes is well
documented.9 The lack of steatosis on these biopsies could
reflect sampling effect, although even large-wedge biopsies
can be negative for steatosis in patients with the metabolic
syndrome, suggesting that some individuals with the meta-
bolic syndrome have elevated liver enzymes despite having
minimal or no histologic fatty liver disease.10 In the absence
of significant steatosis, different yet-to-be-identified mecha-
nisms that are not visible histologically (but perhaps seen
ultrastructurally such as mitochondrial injury)11,12 might be
responsible for the clinically perceived liver abnormality.
Interesting miscellaneous conditions associated with
biopsies showing nearly normal histology included Turner
syndrome and familial Mediterranean fever. Liver enzyme
abnormalities have been described in both conditions13–15;

TABLE 4. Subtle Diagnoses to Rule Out When Evaluating an Almost-normal Liver Biopsy
Diagnoses Major Findings
Alpha 1 anti-trypsin deficiency Zone 1 hepatocytes have eosinophilic cytoplasmic globules. Globules may not be evident in infants
Amyloid Acellular deposits in sinusoids or vessels
Cystic fibrosis Patchy areas of bile ductular proliferation and fibrosis. The parenchyma can show nodular regenerative
hyperplasia
Ferroportin disease Mild to moderate iron deposits, Kupffer cells, hepatocytes with elevated ferritin but low transferrin saturation
levels
Glycogenic hepatopathy Swollen, pale hepatocytes cells in an individual with poorly controlled diabetes
Glycogen pseudoground glass Hepatocytes with large amphophilic inclusions, associated with immunosuppression from various causes and
inclusions often with polypharmacy
Hemochromatosis Hepatocellular iron accumulation
Hepatoportal sclerosis Portal veins are absent, atrophic, or fibrotic; often associated with nodular regenerative hyperplasia
Hypervitaminosis A Stellate cell hyperplasia
Ischemia, low-grade or transient Scattered apoptotic hepatocytes; no inflammation
Leukocyte Chemotactic Factor 2 Amyloid deposited as round inclusions, most commonly in hepatocytes, can be subtle
amyloidosis
Light chain deposition disease Sinusoids lined with irregularly thickened deposits that mimic pericellular fibrosis
Mitochondrial injury Microvesicular steatosis
Nodular regenerative hyperplasia Distinct nodularity to the liver parenchyma but without fibrosis. These changes are best seen on low power
magnification
Thyroid disease Mild cholestasis with hyperthyroidism. Fatty change (may be minimal) with hypothyroidism
Urea cycle defects Children most common but can affect all ages; changes can range from essentially normal to mild fat and
glycogenosis
Wilson disease Mild fatty change with glycogenated nuclei

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Am J Surg Pathol  Volume 00, Number 00, ’’ 2017
while the mechanism of liver injury in the latter is akin to
that seen in other systemic inflammatory conditions, the
exact pathogenesis of liver injury in Turner syndrome is
unknown but may represent an autoimmune phenomenon
or be related to estrogen treatment or obesity, a common
finding in Turner syndrome patients.13,14
Of note, a clinical association was not discovered in 27
(28%) patients despite complete workup at the time of
biopsy and subsequent follow-up. Interestingly, about half
of these patients had normalization of liver enzymes without
intervention, while the other half had persistently elevated
liver enzymes. None developed any evidence of chronic liver
disease or fibrosis. In fact, of all patients, only 7 patients
(7.2%) eventually developed progressive liver disease; the
majority of cases showing nearly normal histology on biopsy
do not develop significant liver disease upon follow-up.
In summary, liver biopsies showing almost-normal
histology despite clinical suspicion for native liver disease
are uncommon (1% to 4% of all liver biopsies) but can be
a challenge for the pathologists and clinicians to in-
corporate into the patient management. This study shows
that the most common clinical associations are auto-
immune systemic inflammatory conditions, vascular/
ischemic events, the metabolic syndrome, inflammatory
conditions of the gastrointestinal tract, and drugs.
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