Liver Diseases in Autopsies from Forensic Medicine of
Rasoul Sotoudehmanesh MD•*,
Masoud Sotoudeh MD*, Ali Ali-Asgari MD*, Behnoush Abedi-Ardakani
MD*, Seyed-Mohammad Tavangar MD*, Ali Khakinejad MD*, Zohreh
Sadeghi MD*, Reza Malekzadeh MD*
*Digestive Disease Research Center, Shariati Hospital, Tehran
University of Medical Sciences, Tehran, Iran.
•Corresponding author and
Sotodehmanesh MD, Digestive Disease Research Center, Shariati
Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Telefax: +98-21-88012992, E-mail:
Accepted for publication: 5 July
Histology is the unique method for diagnosis of silent liver
diseases; so, we aimed to determine the prevalence of fatty
liver and other silent liver diseases among those who passed
away for causes other than liver diseases in Tehran.
two-year period (2002 – 2004) we enrolled autopsies performed at
the Forensic Medicine Center in Tehran. Demographic information,
history of known acute and chronic liver diseases, and causes of
death were determined. Samples from the right and left lobe and
one sample from deeper areas of the liver as well as specimens
from any grossly visible lesions were obtained in each case.
Tissue sections stained by hematoxylin and
evaluated. Reticulin and Masson’s trichrome stains were also
performed for evaluation of liver architecture and degree of
fibrosis when necessary.
tissue samples for histologic evaluation were available in 896
cases (777 males) with a mean age of 43.8 years. Normal
histology was found in 467 cases (52.1%). Important findings
included: steatosis in 283 (31.6%), steatohepatitis in 19
(2.1%), chronic hepatitis in 23 (2.6%), and cirrhosis in 7
(0.8%) cases. Causes of death were: trauma (35%), acute
myocardial infarction (30%), opiate overdose (13%),
cerebrovascular accidents (4%), infectious diseases (3%), and
diseases of the liver are not uncommon. Steatosis is the most
common finding but inflammatory disorders comprise a significant
of Iranian Medicine, Volume 9, Number 4, 2006: 324 – 328.
ost of the chronic liver
diseases, even in advanced stages, may cause no prominent
clinical signs or symptoms. They either go undiagnosed or are
found incidentally during general health check-ups,
investigations for other diseases, surgery, or autopsy. The
underlying causes of chronic liver diseases vary in different
geographic areas and are based on various factors such as
socioeconomic status, life style, diet, local or regional
infections, and other endemic diseases.
In the study of 4908 autopsy
cases from Russia, the most frequent hepatic lesions were
steatosis and inflammatory disorders.1 Berry in 1500
autopsies performed in the coronal system in South-East London
reported cirrhosis, adenoma, metastatic carcinoma, and
hammartoma as the most common findings. Space occupying lesions
were found in about 5% of livers in that study.2
Another study based on analysis of 1839 necropsies in Singapore
revealed that unanticipated liver lesions are common. The most
important ones were cholelithiasis, cirrhosis, and primary
carcinoma of the liver.3
Nonalcoholic fatty liver disease
(NAFLD) includes a spectrum of liver diseases, ranging from
simple steatosis to steatohepatitis, advanced fibrosis, and
cirrhosis. Nonalcoholic steatohepatitis (NASH) represents a
stage in the spectrum of NAFLD, characterized by presence of
inflammation leading to gradual fibrosis in some of the affected
patients. This disease is presently the most common chronic
liver problem in western societies.4, 5 The clinical
importance of NAFLD is related to its prevalence and natural
history. According to a recent study, the prevalence of NAFLD
and NASH in western general population is approximately 20% and
There is no published data on
the frequency of silent liver diseases, especially NAFLD and
NASH, in Iran. This study aimed to determine the prevalence of
these diseases in a series of forensic autopsies in Tehran.
During a period of two years
(May 2002 - May 2004) random autopsies performed at the Forensic
Medicine Center in Tehran were studied. Demographic information,
causes of death, history of alcohol use, and previous hepatic
and nonhepatic chronic diseases such as diabetes mellitus were
asked from the first degree relatives of the cases. Gross
appearance of the liver was also recorded. Sampling was done by
Cases with a history of any
liver disease and those with autolyzed liver samples were
excluded. Wedge necropsies (2 × 2 × 2 cm) from the right and
left lobes and one biopsy of the same size from deeper areas of
the liver parenchyma were obtained in each case. Any grossly
abnormal area were also sampled.
All the liver specimens were
fixed in 10% neutral buffered formalin. The specimens were
processed, sectioned, and stained with hematoxylin and eosin
after standard procedures. Other sections were stained with
reticulin and Masson’s trichrome methods for evaluation of liver
architecture and fibrosis, when necessary.
Degree of steatosis was graded
When micro and
macrovesicular steatosis affected 5 – 25% of the liver
When 26 – 50% of the
parenchyma was affected;
When 51 – 75% was
When more than 75% of the
parenchyma was involved.
The three pathologists involved
in this study agreed on terms, definitions, and the histologic
criteria of the pathologic lesions. A second pathologist in the
group checked all positive findings again. In addition, one out
of each 10 samples was randomly selected and rechecked by
another pathologist. In case of any diagnostic discrepancy, the
result was reported according to the consensus of a joint slide
review session. Histologic findings were recorded in a standard
Categorical variables were
presented as percentages, and continuous variables were
presented as mean ± standard deviation. Chi-square test was used
for categorical and t test for continuous variables. Age,
sex, history of diabetes, alcohol use, and cause of death were
introduced in the stepwise backwards binary logistic regression
models to assess their role in steatosis. We used SPSS software,
version 11.5.0 for all statistical tests.
During the study period, 945
cases were assessed. Forty-nine cases were excluded because of
moderate to severe autolysis in liver tissue or history of known
chronic liver disease and 896 cases were enrolled in the study
including 777 males and 119 females with a mean age of
43.8 ± 19.7 years.
Causes of death were: trauma
(35%), ischemic heart disease (30%), opiate overdose (13%),
cerebrovascular accidents (4%), infectious diseases and sepsis
(3%), and others (15%). Completely normal liver histology was
found in 467 cases (52.1%). Major pathologic findings are shown
in Table 1. History of diabetes mellitus was found in 10 cases
with steatosis and one case with steatohepatitis. Pathologic
findings were not significantly different between patients with
and without history of diabetes. Thirteen cases with history of
diabetes did not show any evidence of steatosis or
steatohepatitis on biopsy. Table 2 shows grading of steatosis
with or without steatohepatitis in our patients.
Frequency of important lesions observed by
histologic evaluation of liver in autopsy series
Focal nodular hyperplasia
Grading of steatosis in cases with nonalcoholic
fatty liver disease in an autopsy series from
Age was the only significant
factor related to steatosis in the logistic regression analysis
(OR: 1.02, 95% CI: 1.01 – 1.03; P < 0.001). Other
variables including sex, history of diabetes, and causes of
death did not show significant correlation.
This study showed that steatosis
is the most common silent liver disease but inflammatory
disorders including NASH comprise a significant minority.
The true incidence and
prevalence of NAFLD and NASH are not well known in different
populations. This is partly because liver histology is required
as the gold standard for precise diagnosis of this condition and
the relatively invasive procedure of liver biopsy is still not
considered essential for management of NAFLD by many physicians.
Most of the reports about the
prevalence rates of this disease are based on ultrasonographic
studies and/or the presence of elevated serum levels of
aminotransferases in the absence of any other known liver
disease or significant alcohol consumption.5
The prevalence of NAFLD in
patients undergoing liver biopsy for any reason ranges between
15% and 39%.6 – 8 This wide range is naturally
related to the differences in the populations studied. In these
studies, the prevalence of NASH ranges between 1.4% and 4.8%.
In clinical practice, diagnostic
liver biopsy is only performed for highly selected patients.
Therefore, the reported rates which are based on liver biopsies
cannot reflect the true prevalence of NAFLD in the general
population. Autopsies, performed for those who have passed away
for reasons other than liver diseases, are certainly better
sources for determination of a more reliable prevalence for
NAFLD and NASH.
The particular characteristics
of forensic autopsies are the relatively young age of subjects
and usually better general health condition before death. Among
our cases male gender was predominant, most of the subjects had
no history of chronic diseases, and in more than 70% of the
cases the cause of death was acute events like car accident,
trauma, and cardiovascular problems. Thus, this sample may not
be representative of the general population of Tehran.
The results of the present
investigation are similar to those reported from a random
pathology-based study looking at individuals who died from car
accidents. In that study, NAFLD and NASH had a rate of 24% and
2.4%, respectively.9 Our study showed that 34.9 % of
the cases undergoing autopsy for forensic reasons in Tehran had
evidence of NAFLD. More than 82.9% of these cases had grade I or
II fatty change in the hepatocytes and only 2.1% had NASH.
Although the prevalence of NAFLD was slightly more in females
(30.9% males, 37.0% females) and NASH was more prevalent in
males (2.3% males, 0.9% females), these differences were not
significant. The prevalence of NAFLD in this predominantly male
population was even higher than the rates reported from the
western countries.9 Malnutrition is very rare in the
adult population of Tehran and definitively can not be
considered as the cause of NAFLD. The reason for such a high
rate of NAFLD in our study is probably due to the life style and
the changes in the dietary habits.
Alcohol use was not reported in
any of our patients. In contrast to western countries, alcohol
trading is forbidden in Iran, though it is available in black
market. Thus, the alcohol use is rare but not nil. In the past
30 years, this habit have shown dramatic changes getting more
and more similar to industrialized countries.
We were not able to measure the
body mass index (BMI) in our cases, are recent studies more than
65% of people living in Tehran are overweight and 15% can be
considered obese.10 One of the most controversial
issues related to NAFLD and NASH is how often these conditions
lead to liver cirrhosis. Although there is substantial evidence
that NASH may lead to cirrhosis in about 20% of cases and is the
most common etiology for cryptogenic cirrhosis,11
well-designed prospective long-term studies for determination of
the patients' outcome with NAFLD are lacking.4, 5
A few studies describe a number
of patients with NASH and serial liver biopsies for
determination of histologic progression. Some cases developed
significant fibrosis, cirrhosis, and hepatocellular carcinoma on
follow-up.12, 13 We found NASH in 2.1% and cirrhosis
in 0.8% of our subjects; given the fact that viral hepatitis is
the most common cause of cirrhosis in Iran,14 this
may emphasize that only a minority of patients with NAFLD may
progress to NASH and cirrhosis.
Chronic hepatitis B (2% of the
general population are HBsAg carriers) is presently the most
common cause of cirrhosis and liver related mortality in Iran.
Hepatitis B is reported to be the etiology of at least 60% of
cirrhoses in this country.14, 15 Serologic studies
for viral markers were not performed in the present study, but
it is most likely that HBV (and probably HCV as the second
possibility) has been responsible for the 23 (2.5%) cases of
chronic hepatitis and the majority of seven cirrhotics (0.8%)
observed. Therefore, NASH can be considered to be as common as
HBV carrier state in Iran.15 In one study, about 25%
of cirrhotics were cryptogenic.15 Many of these cases
can be attributed to NASH. Shakoori reviewed the report of
histology of 4025 liver specimens during a 5-year period. He
found a 6.8% prevalence rate for chronic hepatitis.16
He did not separate steatohepatitis from chronic hepatitis and
this may be the reason for the difference between the prevalence
rates in these two studies.
Silent cirrhosis in our study is
less than 1%. Bethke and Schubert showed that in a fifty-year
autopsy series on 22000 cases, 0.4 – 7.2% of cases had
cirrhosis.17 Our result is lower than similar studies
and may indicate a lower prevalence of silent cirrhosis in Iran.
In addition, the most common cause of liver cirrhosis in this
country is post-necrotic (HBV-related) instead of alcoholic in
western countries,14 and this difference in etiology
of cirrhosis may explain the different natural course of being
silent or not.
In a study from Italy, the
prevalence of hepatocellular carcinoma in cirrhotic patients was
17.6% vs. 0.4% in noncirrhotics.18 The
etiology of hepatocellular carcinoma is different in different
geographic areas. Even among Asian countries, the proportion of
viral etiology is different. Hepatitis C virus plays a major
role in Japan, whereas hepatitis B predominates in other Asian
countries.19, 20 In our study, the prevalence of
silent hepatocellular carcinoma was low; one patient (0.1%)
without a background of cirrhosis.
Granulomas are frequently
encountered in liver biopsies and their existence will capture
the attention of clinicians and pathologists.21, 22
They have been detected in 2 – 10% of liver biopsies in large
series.23 Granulomas are found in virtually all
patients with disseminated tuberculosis.24 In one of
our two cases with granulomatous hepatitis (which were
compatible with tuberculosis), there were symptoms and signs of
tuberculosis and other clues in autopsy were in favor of
disseminated tuberculosis. In the other case there were no
complaints by history taken from the family of the patient and
the cause of death was myocardial infarction.
In our study, two cases had
nodular regenerative hyperplasia (0.2%). Both were males without
previous disease and their cause of death was trauma. In a study
from Japan performed on 577 cases, 2.1% had nodular regenerative
hyperplasia and their causes were organic cardiac disease,
pulmonary diseases with right-sided heart failure, and systemic
amyloidosis.25 In this study, all patients were
adults and there was no significant sex predominance. Wanless
proposed that uneven distribution of portal as well as arterial
blood flow related to portal venopathy and/or arterial disease
within the liver may be important for the occurrence of this
In summary, asymptomatic fatty
liver might be the most common silent liver disease among the
general population in Tehran. Since NAFLD and NASH are common
and may lead to serious clinical consequences, they should
seriously be considered as an important threat to the health of
the general population. Further studies to assess the etiology
and natural history of these lesions are certainly warranted.
This study was supported by a
grant from Digestive Disease Research Center of Tehran
University of Medical Sciences. We also wish to express our
gratitude towards the Forensic Medicine Center in Tehran;
Seyed-Bardia Hosseini, Hamid-Reza Khalatbari, Nasser Kordani,
and Afsaneh Mehrnami (medical students and physicians of Tehran
Azad University); and Dr. Zohreh Movahedi, for their
collaboration in this study.
Etiological and nosological structure of liver diseases (on
autopsy data of clinics of I.M. Sechenov Moscow Medical Academy
in 1988 – 1997). Arkh Patol. 2000; 62: 45 – 47.
Berry CL. Liver
lesions in an autopsy population. Hum Toxicol. 1987;
6: 209 – 214.
Lee YS. The pattern of
liver diseases in Singapore. An autopsy study. Trop Geogr Med.
1979; 31: 69 – 74.
Angulo P. Nonalcoholic
fatty liver disease. N Engl J Med. 2002; 346: 1221
Younossi ZM, Marchesini G, McCullough AJ. Clinical features and
natural history of nonalcoholic steatosis syndromes. Semin
Liver Dis. 2001; 21: 17 – 26.
Propst A, Propst T,
Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis.
Gastroenterology. 1995; 108: 1607.
Hultcrantz R, Glaumann
H, Lindberg G, Nilsson LH. Liver investigation in 149
asymptomatic patients with moderately elevated activities of
serum aminotransferases. Scand J Gastroenterol. 1986;
21: 109 – 113.
Nonomura A, Mizukami
Y, Unoura M, Kobayashi K, Takeda Y, Takeda R. Clinicopathologic
study of alcohol-like liver disease in nonalcoholics;
nonalcoholic steatohepatitis and fibrosis. Gastroenterol Jpn.
1992; 27: 521 – 528.
Christoffersen P, Juhl E, Dalgaard JB. Liver histology in a
'normal' population—examinations of 503 consecutive fatal
traffic casualties. Scand J Gastroenterol. 1977; 12:
593 – 597.
Nasseri-Moghaddam S, Sotoudeh M. Gastroesophageal reflux
disease: the new epidemic. Arch Iranian Med. 2003; 6:
127 – 140.
Caldwell SH, Oelsner
DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ.
Cryptogenic cirrhosis: clinical characterization and risk
factors for underlying disease. Hepatology. 1999; 29:
664 – 669.
Bonyhay L, Di Martino V, Charlotte F, Cavallaro L,
Sayegh-Tainturier MH, et al. Survival, liver failure,
and hepatocellular carcinoma in obesity-related cryptogenic
cirrhosis. Hepatology. 2002; 35: 1485 – 1493.
Kochar N, Lowes J,
Teague RH. Nonalcoholic fatty liver disease (NAFLD) in South
West England. Gastroenterology. 2002; 122: A-669.
Azimi K, Sarafi M,
Alavian SM, Alawi M, Mikaeli J, Malekzadeh R. Causes of
cirrhosis in cirrhotic patients in Shariati Hospital.
2002; 37: 19 – 26.
Malekzadeh R, Rezvan H, Khatibian M. Hepatitis B in Iran.
Arch Iranian Med. 2000; 3: 192 – 201.
Shakoori A. Silent
chronic hepatitis in forensic medicine [in Persian]. Pezeshki
Ghanooni. 1994; 1: 52 – 58.
Bethke BA, Schubert
GE. Primary hepatic cancer and liver cirrhosis.
Hepatogastroenterology. 1984; 31: 211 – 214.
Zotti S, Piccigallo E,
Rampinelli L, Romagnoli G, Tufano A, Dagnini G. Primary and
metastatic tumors of the liver associated with cirrhosis: a
study based on laparoscopy and autopsy. Gastrointest Endosc.
1986; 32: 91 – 95.
Shiratori Y, Shiina S,
Imamura M, Kato N, Kanai F, Okudaira T, et al. Characteristic
difference of hepatocellular carcinoma between hepatitis B- and
C-viral infection in Japan. Hepatology. 1995; 22:
1027 – 1033.
Sripattanawatb R, Theamboonlers A, Chongsrisawat V, Nuchprayoon
I. Hepatocellular carcinoma: significance of HBV vertical
transmission. Asian Pac J Allergy Immunol. 1998; 16:
93 – 103.
Zumla A, James DG.
Granulomatous infections: etiology and classification. Clin
Infect Dis. 1996; 23: 146 – 158.
Ishak KG. Granulomas
of the liver. Adv Pathol Lab Med. 1995; 8: 247 –
Cunnigham D, Mills PR,
Quigley EM, Patrick RS, Watkinson G, MacKenzie JF, et al.
Hepatic granulomas: experience over a 10-year period in the West
of Scotland. Q J Med. 1982; 51: 162 – 170.
Klatskin G. Hepatic
granulomata: problems in interpretation. Mt Sinai J Med.
1977; 44: 798 – 812.
Nakanuma Y. Nodular
regenerative hyperplasia of the liver: restrospective survey in
autopsy series. J Clin Gastroenterol. 1990; 12:
460 – 465.
Understanding noncirrhotic portal hypertension. Hepatology.
1988; 8: 192 – 193.
Wanless IR. The use of
morphometry in the study of nodular regenerative and vascular
lesions of the liver. Anal Quant Cytol Histol. 1987;
9: 39 – 41.